Grupos Investigadores

Líneas de Investigación

  • Braquiterapia ó IPAM
  • Escalado / desescalado
  • Estudio de biomarcadores asociados a toxicidad (ej: cardiotoxicidad) y predicción de respuesta
  • IMT (vacunas celulares con células dendríticas, vacunas de mRNA, TILs, CAR-T, ICB)
  • Individualización terapeútica en función de RCB
  • Inhibición de célula madre tumoral
  • Neoadyuvancia en cáncer de mama triple negativo
  • Síndrome metabólico

Palabras Clave

  • Biomarcadores
  • Braquiterapia de alta tasa
  • Cardiotoxicidad
  • Células dendríticas
  • Esteatosis
  • Glucosa
  • IGFR
  • Insulina
  • Macrófagos
  • Neoadyuvancia
  • Obesidad
  • Quimiorresistencia
  • RCB
  • TILs
  • Vacunas

Publicaciones Científicas desde 2018

  • Autores: Aristei, C. (Autor de correspondencia); Tomatis, M.; Ponti, A.; et al.
    Revista: EUROPEAN JOURNAL OF CANCER
    ISSN: 0959-8049 Vol.196 2024 págs. 113438 - *
    Resumen
    Introduction: The present study was designed to describe tumour features and treatments for patients with breast cancer. It also aimed at assessing the risk of distant metastases in relation to biological profiles, disease stages and treatment.Methods: Data were analysed from 81,882 patients in the EUSOMA database (disease stages at diagnosis 0-IV; median age 61 years; range 20-100 years). All patients were treated between January 2016 and December 2021 in 53 Breast Centres within the EUSOMA certification process in 13 European countries. Cases were classified as HR+ /HER2-, HR+ /HER2 + , HR-/HER2 + or HR-/HER2- and data were analysed accordingly.Results: Univariable and multivariable analyses for distant metastases were conducted on a subset of 38,119 cases with information on whether or not they had developed them. Potential determinants included sub-group type, Ki67 value, disease stage, adjuvant systemic therapies and post-operative radiation therapy. In multivariable analysis, the HR-/HER2 + and HR-/HER2- sub-groups were associated with a higher risk of distant metastases than HR+ /HER2-. Ki67 > 20 % and advanced stage disease also carried a high risk. Radiation therapy emerged as a protective factor against distant metastases. Conclusions: Present results show a large patient database offers an information stream that can be applied to reduce uncertainties in clinical practice. Database parameters need to be updated dynamically for outcome monitoring. Molecular prognostic factors, gene-expression signatures, tumour-infiltrating lymphocytes and circulating tumoral DNA should be added.
  • Autores: Are, C. (Autor de correspondencia); Murthy, S. S.; Sullivan, R.; et al.
    Revista: LANCET ONCOLOGY
    ISSN: 1470-2045 Vol.24 N° 12 2023 págs. E472 - E518
    Resumen
    The first Lancet Oncology Commission on Global Cancer Surgery was published in 2015 and serves as a landmark paper in the field of cancer surgery. The Commission highlighted the burden of cancer and the importance of cancer surgery, while documenting the many inadequacies in the ability to deliver safe, timely, and affordable cancer surgical care. This Commission builds on the first Commission by focusing on solutions and actions to improve access to cancer surgery globally, developed by drawing upon the expertise from cancer surgery leaders across the world. We present solution frameworks in nine domains that can improve access to cancer surgery. These nine domains were refined to identify solutions specific to the six WHO regions. On the basis of these solutions, we developed eight actions to propel essential improvements in the global capacity for cancer surgery. Our initiatives are broad in scope, pragmatic, affordable, and contextually applicable, and aimed at cancer surgeons as well as leaders, administrators, elected officials, and health policy advocates. We envision that the solutions and actions contained within the Commission will address inequities and promote safe, timely, and affordable cancer surgery for every patient, regardless of their socioeconomic status or geographic location.
  • Autores: Banys-Paluchowski, M. (Autor de correspondencia); Kuehn, T.; Masannat, Y.; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.15 N° 4 2023 págs. 1173
    Resumen
    Simple Summary Most breast cancers are small and can be treated using breast-conserving surgery. Since these tumors are non-palpable, they require a localization step that helps the surgeon to decide which tissue needs to be removed. The oldest localization technique is a guidewire placed into the tumor before surgery, usually using ultrasound or mammography. Afterwards, the surgeon removes the tissue around the wire tip. However, this technique has several disadvantages: It can cause the patient discomfort, requires a radiologist or another professional specialized in breast diagnostics to perform the procedure shortly before surgery, and 15-20% of patients need a second surgery to completely remove the tumor. Therefore, new techniques have been developed but most of them have not yet been examined in large, prospective, multicenter studies. In this review, we discuss all available techniques and present the MELODY study that will investigate their safety, with a focus on patient, surgeon, and radiologist preference. Background: Surgical excision of a non-palpable breast lesion requires a localization step. Among available techniques, wire-guided localization (WGL) is most commonly used. Other techniques (radioactive, magnetic, radar or radiofrequency-based, and intraoperative ultrasound) have been developed in the last two decades with the aim of improving outcomes and logistics. Methods: We performed a systematic review on localization techniques for non-palpable breast cancer. Results: For most techniques, oncological outcomes such as lesion identification and clear margin rate seem either comparable with or better than for WGL, but evidence is limited to small cohort studies for some of the devices. Intraoperative ultrasound is associated with significantly higher negative margin rates in meta-analyses of randomized clinical trials (RCTs). Radioactive techniques were studied in several RCTs and are non-inferior to WGL. Smaller studies show higher patient preference towards wire-free localization, but little is known about surgeons' and radiologists' attitudes towards these techniques. Conclusions: Large studies with an additional focus on patient, surgeon, and radiologist preference are necessary. This review aims to present the rationale for the MELODY (NCT05559411) study and to enable standardization of outcome measures for future studies.
  • Autores: Schmidt, M. K. (Autor de correspondencia); Kelly, J. E.; Bredart, A.; et al.
    Revista: EUROPEAN JOURNAL OF CANCER
    ISSN: 0959-8049 Vol.181 2023 págs. 79 - 91
    Resumen
    After a diagnosis of unilateral breast cancer, increasing numbers of patients are requesting contralateral prophylactic mastectomy (CPM), the surgical removal of the healthy breast after diagnosis of unilateral breast cancer. It is important for the community of breast cancer specialists to provide meaningful guidance to women considering CPM. This manifesto discusses the issues and challenges of CPM and provides recommendations to improve onco-logical, surgical, physical and psychological outcomes for women presenting with unilateral breast cancer: (1) Communicate best available risks in manageable timeframes to prioritise ac-tions; better risk stratification and implementation of risk-assessment tools combining family history, genetic and genomic information, and treatment and prognosis of the first breast can-cer are required; (2) Reserve CPM for specific situations; in women not at high risk of contra -lateral breast cancer (CBC), ipsilateral breast-conserving surgery is the recommended option; (3) Encourage patients at low or intermediate risk of CBC to delay decisions on CPM until treatment for the primary cancer is complete, to focus on treating the existing disease first; (4) Provide patients with personalised information about the risk:benefit balance of CPM in manageable timeframes; (5) Ensure patients have an informed understanding of the competing risks for CBC and that there is a realistic plan for the patient; (6) Ensure patients understand the short-and long-term physical effects of CPM; (7) In patients considering CPM, offer psy-chological and surgical counselling before surgery; anxiety alone is not an indication for CPM; (8) Eliminate inequality between countries in reimbursement strategies; CPM should be reim-bursed if it is considered a reasonable option resulting from multidisciplinary tumour board assessment; (9) Treat breast cancer patients at specialist breast units providing the entire patient-centred pathway.
  • Autores: Pantiora, E.; Konstantinos-Tasoulis, M.; Valachis, A.; et al.
    Revista: BRITISH JOURNAL OF SURGERY
    ISSN: 0007-1323 Vol.110 N° 4 2023 págs. 410 - 419
    Resumen
    Background: Superparamagnetic iron oxide nanopArtículos (SPIO) have been used as a tracer for sentinel lymph node (SLN) localization in breast cancer, demonstrating comparable performance to the combination of radioisotope (RI) and blue dye (BD). Methods A systematic literature search and meta-analysis with subgroup and meta-regression analysis were undertaken to update the available evidence, assess technique evolution, and define knowledge gaps. Recommendations were made using the GRADE approach. Results In 20 comparative studies, the detection rate was 97.5 per cent for SPIO and 96.5 per cent for RI +/- BD (risk ratio 1.006, 95 per cent c.i. 0.992 to 1.019; P = 0.376, high-certainty evidence). Neoadjuvant therapy, injection site, injection volume or nodal metastasis burden did not affect the detection rate, but injection over 24 h before surgery increased the detection rate on meta-regression. Concordance was 99.0 per cent and reverse concordance 97.1 per cent (rate difference 0.003, 95 per cent c.i. -0.009 to 0.015; P = 0.656, high-certainty evidence). Use of SPIO led to retrieval of slightly more SLNs (pooled mean 1.96 versus 1.89) with a higher nodal detection rate (94.1 versus 83.5 per cent; RR 1.098, 1.058 to 1.140; P < 0.001; low-certainty evidence). In meta-regression, injection over 24 h before surgery increased the SPIO nodal yield over that of RI +/- BD. The skin-staining rate was 30.8 per cent (very low-certainty evidence), and possibly prevented with use of smaller doses and peritumoral injection. Conclusion: The performance of SPIO is comparable to that of RI +/- BD. Preoperative injection increases the detection rate and nodal yield, without affecting concordance. Whether skin staining and MRI artefacts are reduced by lower dose and peritumoral injection needs to be investigated. The magnetic technique for sentinel lymph node (SLN) biopsy has gained interest and popularity in recent years. In this comprehensive systematic review and meta-analysis, the performance of the magnetic technique was comparable to that of the isotope and blue dye combination for SLN detection (97.5 versus 96.5 per cent; risk ratio 1.006, 95 per cent c.i. 0.992 to 1.019; P = 0.376). The magnetic technique provides flexibility and facilitates logistics. Further research should focus on the existing knowledge gaps, namely expansion of novel techniques such as delayed SLN biopsy and reduction of the risk of skin staining and artefacts on postoperative MRI.
  • Autores: Monk, B. J. (Autor de correspondencia); González Martín, Antonio; Buckley, L.; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN: 1048-891X Vol.33 N° 6 2023 págs. 971 - 981
    Resumen
    Niraparib is a poly (ADP-ribose) polymerase inhibitor that has shown a significant improvement in progression-free survival irrespective of biomarker status in patients with advanced epithelial ovarian cancer. This review focuses on the adverse events associated with niraparib and their management to maintain efficacy of niraparib treatment and improve quality of life for patients. In five trials assessing efficacy of niraparib in patients with advanced epithelial ovarian cancer (PRIMA, NOVA, NORA, QUADRA, and PRIME), treatment-emergent adverse events of any grade were reported in nearly all patients (>= 99%) receiving niraparib; the events were grade >= 3 in 51-74% of patients. Across all lines of therapy, treatment-emergent adverse events led to dose interruptions in 62-80% of patients receiving niraparib and dose reductions in 47-71%. Hematologic events were most frequently reported, including thrombocytopenia, anemia, and neutropenia. Common non-hematologic events included gastrointestinal events, which were generally low grade (<5% were grade >= 3). Clinical strategies to manage these and other events, such as fatigue and insomnia, cognitive behavioral therapy and pharmacologic agents, are summarized. Once-daily niraparib dosing may be advantageous for some patients for many reasons, including night-time dosing which may help alleviate gastrointestinal symptoms. An individualized starting dose (determined by baseline body weight and platelet count) of niraparib demonstrated an improved safety profile while maintaining efficacy. Patients receiving the niraparib individualized starting dose had fewer grade >= 3 adverse events, dose interruptions, and dose reductions than patients receiving a fixed starting dose. The safety profile of niraparib across five pivotal studies in advanced epithelial ovarian cancer was consistent across multiple lines of treatment, including as maintenance therapy in first-line and recurrent settings and as treatment in heavily pre-treated patients. Long-term safety data from the NOVA trial confirmed that, with appropriate and early dose modifications, niraparib is well tolerated.
  • Autores: DiSilvestro, P. (Autor de correspondencia); Banerjee, S.; Colombo, N.; et al.
    Revista: OBSTETRICAL AND GYNECOLOGICAL SURVEY
    ISSN: 0029-7828 Vol.78 N° 1 2023 págs. 25 - 27
    Resumen
    Because of nonspecific symptoms at disease presentation and inadequate screening methods, ovarian cancer is often advanced at the time of diagnosis results in a 10-year survival of 17% in patients with advanced epithelial ovarian cancer. The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib is the new standard of care in patients with newly diagnosed advanced ovarian cancer and a BRCA1 and/or BRCA2 (BRCA) mutation. The SOLO1/GOG 3004 trial importantly found olaparib treatment resulted in a sustained progression-free survival (PFS) benefit in this patient population beyond the end of treatment and lasting up to 2 years, with a follow-up PFS analysis showing benefit up to 5 years. This analysis of the SOLO1/GOG 3004 cohort aimed to provide overall survival (OS) data up to 7 years following treatment of newly diagnosed advanced ovarian cancer with any PARP inhibitor. The SOLO1/GOG 3004 study included patients with newly diagnosed advanced high-grade serous or endometrioid ovarian, primary peritoneal, and/or fallopian tube cancer with a germline or somatic BRCA1 and/or BRCA2 mutation. Patients were randomized (2:1) to receive olaparib tablets or placebo within 8 weeks of their last dose of chemotherapy surgery and received treatment for up to 2 years. This analysis of OS was conducted using a log-rank test stratified by response to first-line platinum-based chemotherapy with hazard ratios (HRs) and 95% confidence intervals (CIs) estimated using a Cox proportional model. A total of 260 patients were randomly assigned to olaparib, and 130 of the 131 patients randomly assigned to placebo received study treatment. The median duration of follow-up for OS was 88.9 months (interquartile range, 85.7-93.6 months) in the olaparib group and 87.4 months (interquartile range, 84.3-91.7 months) in the placebo group. At the time of analysis, 149 of 391 patients had died. The median OS was not reached in the olaparib group compared with 75.2 months (95% CI, 65.4 months to not reached) in the placebo group, with an HR of 0.55 (95% CI, 0.40-0.76; P = 0.0004). This analysis was unadjusted for subsequent therapy, meaning the OS benefit was observed despite 44.3% of patients in the placebo group having received a PARP inhibitor in a subsequent line of therapy. On Kaplan-Meier estimate, 6.70% of olaparib patients versus 46.5% of placebo patients were alive 7 years after randomization. Of the patients randomized to olaparib, 45.3% of patients were alive and still yet to receive a first subsequent therapy after 7 years, compared with only 20.6% of patients randomized to placebo. Serious adverse events occurred in 21.2% of olaparib patients and 13.8% of placebo patients. The results of this follow-up survival analysis of the SOLO1/GOG 3004 study found that at a median follow-up time of 88 months, an HR for survival of 0.55 was observed with maintenance olaparib versus placebo. In addition, a considerable proportion of the olaparib patients were yet to receive a subsequent line of treatment compared with the placebo patients. De -spite these benefits, according to prespecified statistical criteria, improvement in OS with maintenance olaparib versus pla-cebo was not statistically significant.
  • Autores: Estiragués Cerdá, María; Hontanilla Calatayud, Bernardo Carlos (Autor de correspondencia)
    Revista: FACIAL PLASTIC SURGERY & AESTHETIC MEDICINE
    ISSN: 2689-3614 Vol.25 N° 6 2023 págs. 542 - 543
  • Autores: DiSilvestro, P.; Banerjee, S.; Colombo, N.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 1527-7755 Vol.41 2023 págs. 609 - 617
    Resumen
    PURPOSE: In SOLO1/GOG 3004 (ClinicalTrials.gov identifier: NCT01844986), maintenance therapy with the poly(ADP-ribose) polymerase inhibitor olaparib provided a sustained progression-free survival benefit in patients with newly diagnosed advanced ovarian cancer and a BRCA1 and/or BRCA2 (BRCA) mutation. We report overall survival (OS) after a 7-year follow-up, a clinically relevant time point and the longest follow-up for any poly(ADP-ribose) polymerase inhibitor in the first-line setting.METHODS: This double-blind phase III trial randomly assigned patients with newly diagnosed advanced ovarian cancer and a BRCA mutation in clinical response to platinum-based chemotherapy to maintenance olaparib (n = 260) or placebo (n = 131) for up to 2 years. A prespecified descriptive analysis of OS, a secondary end point, was conducted after a 7-year follow-up.RESULTS: The median duration of treatment was 24.6 months with olaparib and 13.9 months with placebo, and the median follow-up was 88.9 and 87.4 months, respectively. The hazard ratio for OS was 0.55 (95% CI, 0.40 to 0.76; P = .0004 [P < .0001 required to declare statistical significance]). At 7 years, 67.0% of olaparib patients versus 46.5% of placebo patients were alive, and 45.3% versus 20.6%, respectively, were alive and had not received a first subsequent treatment (Kaplan-Meier estimates). The incidence of myelodysplastic syndrome and acute myeloid leukemia remained low, and new primary malignancies remained balanced between treatment groups.CONCLUSION: Results indicate a clinically meaningful, albeit not statistically significant according to prespecified criteria, improvement in OS with maintenance olaparib in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation and support the use of maintenance olaparib to achieve long-term remission in this setting; the potential for cure may also be enhanced. No new safety signals were observed during long-term follow-up.
  • Autores: Redondo, A. (Autor de correspondencia); Barretina, P.; Pérez-Fidalgo, A.; et al.
    Revista: JOURNAL OF GYNECOLOGIC ONCOLOGY
    ISSN: 2005-0380 Vol.34 N° 5 2023 págs. e57
    Resumen
    Objective: Our aim was to reach a consensus on the management of the most controversial issues of advanced ovarian cancer.Methods: Nominal group and Delphi techniques were used. A steering committee of 5 experts analyzed current management of advanced ovarian cancer, identified controversies, critically analyzed the evidence, and formulated guiding statements for clinicians. Subsequently, a panel of 15 experts was selected to test agreement with the statements through two Delphi rounds. Items were scored on a 4-point Likert scale from 1 (totally disagree) to 4 (totally agree). In the first and second rounds, consensus was considered if & GE;70% of answers pertained to category 1 or category 4.Results: Overall, 112 statements were incorporated in the following areas: 1) biomarkers and hereditary ovarian cancer; 2) first-line treatment; 3) recurrent disease when platinum might be the best option; and 4) post-poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors setting. In the first Delphi round, 37 statements reached consensus and did thus not pass to the second round. After the second round, another 18 statements reached consensus. Forty-six of the consensus were with the agreement and 9 with the disagreement.Conclusion: Through the methodology used, a consensus was reached in approximately half of the statements. The results of this work may be useful in addressing the most controversial issues on the management of advanced ovarian cancer.
  • Autores: Morelló Vicente, Ana (Autor de correspondencia); Elizalde Pérez, Arlette María; España Alonso, Agustín
    Revista: ACTAS DERMO-SIFILIOGRAFICAS
    ISSN: 0001-7310 Vol.114 N° 6 2023 págs. 541 - 542
  • Autores: Igual Rouilleault, Alba Cristina (Autor de correspondencia); Soriano Aguadero, Ignacio; Quan Lopez, Paola Leonor; et al.
    Revista: EUROPEAN RADIOLOGY
    ISSN: 0938-7994 Vol.33 N° 10 2023 págs. 7178 - 7185
    Resumen
    Purpose: To study the association between ultrasound cortical thickness in reactive post-vaccination lymph nodes and the elicited humoral response and to evaluate the performance of cortical thickness as a predictor of vaccine effectiveness in patients with and without a previous history of COVID-19 infection. Methods: A total of 156 healthy volunteers were recruited and followed prospectively after receiving two COVID-19 vaccination doses using different protocols. Within a week after receiving the second dose, an axillary ultrasound of the ipsilateral vaccinated arm was performed, and serial post-vaccination serologic tests (PVST) were collected. Maximum cortical thickness was chosen as a nodal feature to analyze association with humoral immunity. Total antibodies quantified during consecutive PVST in previously-infected patients and in coronavirus-naïve volunteers were compared (Mann-Whitney U test). The association between hyperplastic-reactive lymph nodes and effective humoral response was studied (odds ratio). The performance of cortical thickness in detecting vaccination effectiveness was evaluated (area under the ROC curve). Results: Significantly higher values for total antibodies were observed in volunteers with a previous history of COVID-19 infection (p < 0.001). The odds ratio associating immunized coronavirus-naïve volunteers after 90 and 180 days of the second dose with a cortical thickness ¿ 3 mm was statistically significant (95% CI 1.52-6.97 and 95% CI 1.47-7.29, respectively). The best AUC result was obtained comparing antibody secretion of coronavirus-naïve volunteers at 180 days (0.738). Conclusions: Ultrasound cortical thickness of reactive lymph nodes in coronavirus-naïve patients may reflect antibody production and a long-term effective humoral response elicited by vaccination. Clinical relevance statement: In coronavirus-naïve patients, ultrasound cortical thickness of post-vaccination reactive lymphadenopathy shows a positive association with protective antibody titers against SARS-CoV-2, especially in the long term, providing new insights into previous publications. Key points: ¿ Hyperplastic lymphadenopathy was frequently observed after COVID-19 vaccination. ¿ Ultrasound cortical thickness of reactive post-vaccine lymph nodes may reflect a long-term effective humoral response in coronavirus-naïve patients.
  • Autores: Pérez-Fidalgo, J. A. (Autor de correspondencia); Guerra, E.; García, Y.; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN: 1048-891X Vol.33 N° 6 2023 págs. 929 - 936
    Resumen
    ObjectiveTo determine the potential prognostic value of clinical and molecular biomarkers in the survival of patients with platinum-resistant ovarian cancer treated with olaparib and pegylated liposomal doxorubicin. MethodsROLANDO was a single-arm phase II trial that included patients with high-grade serous or endometrioid tumors and at least one previous platinum-resistant recurrence regardless of BRCA status. Patients received 6 cycles of pegylated liposomal doxorubicin every 28 days plus olaparib 300 mg twice daily. followed by olaparib 300 mg twice daily; monotherapy until progression or unacceptable toxicity. Prognostic factors including previous lines (and platinum-containing ones), BRCA mutation status, previous bevacizumab, CA-125 levels, and the neutrophil/lymphocyte ratio, lymphocyte/monocyte ratio, and platelet/lymphocyte ratio calculated at inclusion were analyzed through a multivariate logistic regression and factor analysis of mixed data. ResultsThirty-one patients were included. Median age was 57 years (range 43-75), Eastern Cooperative Oncolgy Group performance status 0/1: 32.3%/67.7% and BRCA mutated: 16.1%. Prior treatment lines were >2 lines: 14 (45.2%) patients, >= 2 platinum lines: 21 patients (67.7%) and previous bevacizumab 19 (61.3%) patients. CA-125 was >2 upper limit normal in 24 (77.4%) patients. A high neutrophil/lymphocyte ratio was associated with worse overall survival by univariate/multivariate regression model (HR=11.18; 95% CI 1.1 to 114.5; p=0.042). No other factors were associated with overall survival in the multivariate model. A multifactorial signature based on clinical and molecular baseline characteristics was capable of defining six patient clusters. Three of these clusters had significantly better prognosis, with a median overall survival of 21.3 months (95% CI 12.2 to not reached). ConclusionsHigh neutrophil/lymphocyte ratio at platinum-resistant relapse indicated poor prognosis in patients treated with olaparib plus pegylated liposomal doxorubicin. A multifactorial clinical signature was more precise than single variables for implying the prognosis and may help in therapeutic assignment after further validation in large prospective cohorts.
  • Autores: Herzog, T. J. (Autor de correspondencia); Pignata, S.; Ghamande, S. A.; et al.
    Revista: GYNECOLOGIC ONCOLOGY
    ISSN: 0090-8258 Vol.170 2023 págs. 300 - 308
    Resumen
    Objective. The primary purpose of this study was to determine if farletuzumab, an antifolate receptor-alpha monoclonal antibody, improved progression-free survival (PFS) versus placebo when added to standard chemo-therapy regimens in patients with platinum-sensitive recurrent ovarian cancer (OC) in first relapse (platinum-free interval: 6-36 months) with low cancer antigen 125 (CA-125) levels. Gynecologic Oncology (2023) Methods. Eligibility included CA-125 <= 3 x upper limit of normal (ULN, 105 U/mL), high-grade serous, platinum-sensitive recurrent OC, previous treatment with debulking surgery, and first-line platinum-based che-motherapy with 1st recurrence between 6 and 36 months since frontline platinum-based treatment. Patients re-ceived investigator's choice of either carboplatin (CARBO)/paclitaxel (PTX) every 3 weeks or CARBO/pegylated liposomal doxorubicin (PLD) every 4 weeks x6 cycles in combination with either farletuzumab [5 mg/kg weekly] or placebo randomized in a 2:1 ratio. Maintenance treatment with farletuzumab (5 mg/kg weekly) or placebo was given until disease progression or intolerance. Results. 214 patients were randomly assigned to farletuzumab+chemotherapy (142 patients) versus placebo +chemotherapy (72 patients). The primary efficacy endpoint, PFS, was not significantly different between treat-ment groups (1-sided alpha = 0.10; p-value = 0.25; hazard ratio [HR] = 0.89, 80% confidence interval [CI]: 0.71, 1.11), a median of 11.7 months (95% CI: 10.2, 13.6) versus 10.8 months (95% CI: 9.5, 13.2) for farletuzumab+che-motherapy and placebo+chemotherapy, respectively. No new safety concerns were identified with the combi-nation of farletuzumab+chemotherapy. Conclusions. Adding farletuzumab to standard chemotherapy does not improve PFS in patients with OC who were platinum-sensitive in first relapse with low CA-125 levels. Folate receptor-alpha expression was not measured in this study. (Clinical Trial Registry NCT02289950) (c) 2023 Published by Elsevier Inc.
  • Autores: Riva, N. (Autor de correspondencia); Ibarra, M.; Parra Guillén, Zinnia Patricia; et al.
    Revista: BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
    ISSN: 0306-5251 Vol.89 N° 3 2023 págs. 1115 - 1126
    Resumen
    Aims Pharmacokinetics of tacrolimus after sublingual administration is not characterized in paediatric liver transplant patients. Therefore, we aimed to develop a population pharmacokinetic model of sublingually administered tacrolimus in patients who cannot swallow the capsules due to their age, sedation status and/or mechanical ventilation during the first weeks post-transplantation. Methods Demographic, clinical and pharmacological variables, including tacrolimus whole blood concentrations obtained from therapeutic drug monitoring and data from dense-sampling pharmacokinetic profiles, were recorded in 26 paediatric patients with biliary atresia who underwent liver transplantation between 2016 and 2021. Population pharmacokinetic analysis was performed with NONMEM v7.4. Results Disposition of tacrolimus was best characterized by a 2-compartment model with clearance achieving half of the maximum elimination capacity (CLMAX = 4.1 L/h) at 4.6 days post-transplantation (T-50). Compared to sedated patients, nonsedated status showed an increased first-order absorption rate constant (1.1 vs. 0.1 h(-1)) and a 24% reduction in bioavailability (F-NS) at 14 days post-transplant. The model was able to explain the oral absorption pattern in nonsedated patients as the result of gut bioavailability (0.9) and hepatic extraction ratio, with the latter being responsible for first-pass effects. Estimates of interindividual variability remained moderate (25.9% for the gut bioavailability) to high (79.8% for the apparent volume of distribution of the central compartment, and 101% for T-50). Conclusion A population pharmacokinetic model of sublingually administered tacrolimus in paediatric patients was developed to characterize different absorption mechanisms. Once the model is externally validated, the effect of post-transplant time on clearance and the sedation status may be considered in routine dosing management.
  • Autores: Mejías Sosa, Luis Daniel; López Janeiro, Álvaro; Cordoba Iturriagagoitia, A.; et al.
    Revista: BIOMEDICINES
    ISSN: 2227-9059 Vol.11 N° 2 2023 págs. 238
    Resumen
    Background: The addition of dendritic cell vaccines (DCV) to NAC could induce immune responses in those patients with residual disease (RD) by transforming the tumor microenvironment. Methods: Core diagnostic biopsies and surgical specimens from 80 patients (38 in the vaccinated group plus NAC (VG) and 42 in the control group (CG, treated only with NAC) were selected. We quantify TILs (CD8, CD4 and CD45RO) using immunohistochemistry and the automated cellular imaging system (ACIS III) in paired samples. Results: A CD8 rise in TNBC samples was observed after NAC plus DCV, changing from 4.48% in the biopsy to 6.70% in the surgical specimen, not reaching statistically significant differences (p = 0.11). This enrichment was seen in up to 67% of TNBC patients in the experimental arm as compared with the CG (20%). An association between CD8 TILs before NAC (4% cut-off point) and pathological complete response in the VG was found in the univariate and multivariate analysis (OR = 1.41, IC95% 1.05-1.90; p = 0.02, and OR = 2.0, IC95% 1.05-3.9; p = 0.03, respectively). Conclusion: Our findings suggest that patients with TNBC could benefit from the stimulation of the antitumor immune system by using DCV together with NAC.
  • Autores: Muñoz, P. (Autor de correspondencia); Corral, S.; Martínez Regueira, Fernando; et al.
    Revista: CLINICAL AND TRANSLATIONAL ONCOLOGY
    ISSN: 1699-048X Vol.25 N° 5 2023 págs. 1463 - 1471
    Resumen
    Introduction Given the high rate of complete nodal response, the role of axillary lymph node dissection on staging the axilla has been questioned. This survey, addressed to breast cancer surgeons in Spain, has the objective of assessing current clinical trends on axillary staging of cN + patients treated with NAC. Methods An online survey was conducted among breast surgeons from the Spanish Society of Surgery (AEC), Spanish Surgical Oncology Society (SEOQ), Spanish Breast Cancer Surgeons Society (AECIMA) and Spanish Gynecology and Obstetrics Society (SEGO). It was structured in 5 sections: general information and clinical practice, knowledge of clinical trials, diagnosis work-up and nodal marking, axillary staging, and axillary treatment. Results 150 breast cancer surgeons completed the full survey (96.7%). 81.8% of respondents performed SLNB or targeted axillary dissection in cN1 patients treated with NAC. Radiological axillary response was the preferred parameter guiding the surgical strategy. The excision of the clipped node (92.0%), use of dual tracer (73.2%), and axillary US (65.9%) after treatment were the most important variables considered by respondents, to increase the accuracy of SLNB in cN + patients. Conclusion This survey confirms a trend toward a less invasive approach for axillary staging in cN + patients treated with NAC among breast cancer surgeons in Spain. While there is widespread agreement in less invasive approaches to axillary staging, there is, however, a lack of consensus around treatment strategy. Further, it shows a wide heterogeneity in their clinical practice. This study highlights the need for clear evidence concerning less invasive staging procedures and their oncological safety, to ensure consistent recommendations in surgical practice.
  • Autores: Sancho Araiz, Aymara; Parra Guillén, Zinnia Patricia; Bragard Monier, Jean; et al.
    Revista: PLOS COMPUTATIONAL BIOLOGY
    ISSN: 1553-7358 Vol.19 N° 10 2023 págs. e1011507
    Resumen
    Mathematical modeling of unperturbed and perturbed tumor growth dynamics (TGD) in preclinical experiments provides an opportunity to establish translational frameworks. The most commonly used unperturbed tumor growth models (i.e. linear, exponential, Gompertz and Simeoni) describe a monotonic increase and although they capture the mean trend of the data reasonably well, systematic model misspecifications can be identified. This represents an opportunity to investigate possible underlying mechanisms controlling tumor growth dynamics through a mathematical framework. The overall goal of this work is to develop a data-driven semi-mechanistic model describing non-monotonic tumor growth in untreated mice. For this purpose, longitudinal tumor volume profiles from different tumor types and cell lines were pooled together and analyzed using the population approach. After characterizing the oscillatory patterns (oscillator half-periods between 8-11 days) and confirming that they were systematically observed across the different preclinical experiments available (p<10-9), a tumor growth model was built including the interplay between resources (i.e. oxygen or nutrients), angiogenesis and cancer cells. The new structure, in addition to improving the model diagnostic compared to the previously used tumor growth models (i.e. AIC reduction of 71.48 and absence of autocorrelation in the residuals (p>0.05)), allows the evaluation of the different oncologic treatments in a mechanistic way. Drug effects can potentially, be included in relevant processes taking place during tumor growth. In brief, the new model, in addition to describing non-monotonic tumor growth and the interaction between biological factors of the tumor microenvironment, can be used to explore different drug scenarios in monotherapy or combination during preclinical drug development.
  • Autores: Santin, A. D. (Autor de correspondencia); Vergote, I.; González Martín, Antonio; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN: 1048-891X Vol.33 N° 4 2023 págs. 1 - 9
    Resumen
    Objectives: Anetumab ravtansine is an antibody-drug conjugate consisting of a fully human anti-mesothelin monoclonal antibody conjugated to cytotoxic maytansinoid tubulin inhibitor DM4. Mesothelin is highly expressed in ovarian cancer. This phase Ib study determines the safety, pharmacokinetics, and anti-tumor activity of anetumab ravtansine and pegylated liposomal doxorubicin in mesothelin-expressing platinum-resistant ovarian cancer. Methods: Anetumab ravtansine (5.5 or 6.5 mg/kg) and pegylated liposomal doxorubicin (30 mg/m(2)) were administered intravenously every 3 weeks to 65 patients with platinum-resistant epithelial ovarian cancer. Mesothelin expression was assessed by central immunohistochemistry. Adverse events, tumor response (RECIST 1.1), and progression-free survival were determined. Biomarker samples were assessed by ELISA and next-generation sequencing. Results: In dose escalation, nine patients received anetumab ravtansine across two doses (5.5 or 6.5 mg/kg). The maximum tolerated dose of anetumab ravtansine was 6.5 mg/kg every 3 weeks and no dose-limiting toxicities were observed. In dose expansion, 56 patients were treated at the maximum tolerated dose. The most common treatment-emergent adverse events of any grade were nausea (47.7%), decreased appetite (43.1%), fatigue (38.5%), diarrhea (32.3%), and corneal disorder (29.2%). In all treated patients the objective response rate was 27.7% (95% CI 17.3% to 40.2%), including one complete (1.5%) and 17 partial responses (26.2%), with median duration of response of 7.6 (95% CI 3.3 to 10.2) months and median progression-free survival of 5.0 (95% CI 3.2 to 6.0) months. In an exploratory analysis of a sub-set of patients (n=19) with high mesothelin expression who received & LE;3 prior lines of systemic therapy, the objective response rate was 42.1% (95% CI 20.3% to 66.5%) with a median duration of response of 8.3 (95% CI 4.1 to 12.0) months and median progression-free survival of 8.5 (95% CI 4.0 to 11.4) months. Conclusions: Anetumab ravtansine and pegylated liposomal doxorubicin showed tolerability and promising clinical activity. These results established the dose schedule and the mesothelin-positive target population of this combination for a phase III study in platinum-resistant ovarian cancer.
  • Autores: Cueva, J. F.; Palacio, I.; Churruca, C.; et al.
    Revista: EUROPEAN JOURNAL OF CANCER
    ISSN: 0959-8049 Vol.182 2023 págs. 3-14
    Resumen
    Aim: To describe patient characteristics, effectiveness and safety in a real-world population treated with niraparib in the Spanish expanded-access programme. Patients and methods: This retrospective observational study included women with platinum-sensitive recurrent high-grade serous ovarian cancer who received maintenance niraparib within the Spanish niraparib expanded-access programme. Eligible patients had received ¿2 previous lines of platinum-containing therapy, remained platinum-sensitive after the penultimate line of platinum and had responded to the most recent platinum-containing therapy. Niraparib dosing was at the treating physician's discretion (300 mg/day fixed starting dose or individualised starting dose [ISD] according to baseline body weight and platelet count). Safety, impact of dose adjustments, patient characteristics and effectiveness were analysed using data extracted from medical records. Results: Among 316 eligible patients, 80% had BRCA wild-type tumours and 66% received an ISD. Median niraparib duration was 7.8 months. The most common adverse events typically occurred within 3 months of starting niraparib. Median progression-free survival was 8.6 (95% confidence interval [CI] 7.6-10.0) months. One- and 2-year overall survival rates were 86% (95% CI 81-89%) and 65% (95% CI 59-70%), respectively. Dose interruptions, dose reductions, haematological toxicities and asthenia/fatigue were less common with ISD than fixed starting dose niraparib, but progression-free survival was similar irrespective of dosing strategy. Subsequent therapy included platinum in 71% of patients who received further treatment.Conclusion: Outcomes in this large real-world dataset of niraparib-treated patients are consistent with phase III trials, providing reassuring evidence of the tolerability and activity of niraparib maintenance therapy for platinum-sensitive recurrent ovarian cancer.
  • Autores: Lawler, M. (Autor de correspondencia); Davies, L.; Oberst, S.; et al.
    Revista: LANCET ONCOLOGY
    ISSN: 1470-2045 Vol.24 N° 1 2023 págs. E11 - E56
    Resumen
    Cancer research is a crucial pillar for countries to deliver more affordable, higher quality, and more equitable cancer care. Patients treated in research-active hospitals have better outcomes than patients who are not treated in these settings. However, cancer in Europe is at a crossroads. Cancer was already a leading cause of premature death before the COVID-19 pandemic, and the disastrous effects of the pandemic on early diagnosis and treatment will probably set back cancer outcomes in Europe by almost a decade. Recognising the pivotal importance of research not just to mitigate the pandemic today, but to build better European cancer services and systems for patients tomorrow, the Lancet Oncology European Groundshot Commission on cancer research brings together a wide range of experts, together with detailed new data on cancer research activity across Europe during the past 12 years. We have deployed this knowledge to help inform Europe's Beating Cancer Plan and the EU Cancer Mission, and to set out an evidence-driven, patient-centred cancer research roadmap for Europe. The high-resolution cancer research data we have generated show current activities, captured through different metrics, including by region, disease burden, research domain, and effect on outcomes. We have also included granular data on research collaboration, gender of researchers, and research funding. The inclusion of granular data has facilitated the identification of areas that are perhaps overemphasised in current cancer research in Europe, while also highlighting domains that are underserved. Our detailed data emphasise the need for more information-driven and data-driven cancer research strategies and planning going forward. A particular focus must be on central and eastern Europe, because our findings emphasise the widening gap in cancer research activity, and capacity and outcomes, compared with the rest of Europe. Citizens and patients, no matter where they are, must benefit from advances in cancer research. This Commission also highlights that the narrow focus on discovery science and biopharmaceutical research in Europe needs to be widened to include such areas as prevention and early diagnosis; treatment modalities such as radiotherapy and surgery; and a larger concentration on developing a research and innovation strategy for the 20 million Europeans living beyond a cancer diagnosis. Our data highlight the important role of comprehensive cancer centres in driving the European cancer research agenda. Crucial to a functioning cancer research strategy and its translation into patient benefit is the need for a greater emphasis on health policy and systems research, including implementation science, so that the innovative techno-logical outputs from cancer research have a clear pathway to delivery. This European cancer research Commission has identified 12 key recommendations within a call to action to reimagine cancer research and its implementation in Europe. We hope this call to action will help to achieve our ambitious 70:35 target: 70% average 10-year survival for all European cancer patients by 2035.
  • Autores: Yubero, A. (Autor de correspondencia); Estevez, P.; Barquin, A.; et al.
    Revista: GYNECOLOGIC ONCOLOGY REPORTS
    ISSN: 2352-5789 Vol.48 2023 págs. 101211
    Resumen
    The poly(ADP-ribose) polymerase inhibitor (PARPi) rucaparib is approved as maintenance therapy for patients with platinum-sensitive recurrent high-grade ovarian cancer (HGOC). The efficacy and safety of rucaparib after PARPi therapy are largely unknown; therefore, we analyzed outcomes in the subgroup of PARPi-pretreated patients from Spanish hospitals participating in the Rucaparib Access Program. This post hoc subgroup analysis explored baseline characteristics, treatment exposure, safety, effectiveness, and subsequent therapy among women receiving rucaparib 600 mg twice daily after at least one prior PARPi for HGOC. Of 14 women eligible for the analysis, 11 (79%) had tumors harboring BRCA1/2 mutations. Patients had received a median of 5 (range 3-8) treatment lines before rucaparib. Twelve patients (86%) had previously received olaparib and two (14%) niraparib; 12 patients received rucaparib as treatment for platinum-resistant HGOC, one as treatment for platinum-sensitive HGOC, and one as maintenance therapy. Progression-free survival was 0.2-9.1 months. One of seven patients assessable for response by RECIST achieved stable disease. Adverse events occurred in 11 patients (79%; grade 3 in 29%), leading to treatment interruption in eight patients (57%), dose reduction in six (43%), but treatment discontinuation in only one (7%). No new safety signals were observed. This is one of the first reported series of real-world data on rucaparib after prior PARPi for HGOC. In this heavily pretreated population, rucaparib demonstrated meaningful activity in some patients and tolerability consistent with previous prospective trials. Future investigation should focus on identifying patients who may benefit from rucaparib after prior PARPi exposure.
  • Autores: Parra Guillén, Zinnia Patricia; Sancho Araiz, Aymara; Mayawala, K.; et al.
    Revista: CLINICAL PHARMACOLOGY AND THERAPEUTICS
    ISSN: 0009-9236 Vol.114 N° 3 2023 págs. 623 - 632
    Resumen
    Oncolytic viruses (OVs) represent a potential therapeutic strategy in cancer treatment. However, there is currently a lack of comprehensive quantitative models characterizing clinical OV kinetics and distribution to the tumor. In this work, we present a mechanistic modeling framework for V937 OV, after intratumoral (i.t.) or intravascular (i.v.) administration in patients with cancer. A minimal physiologically-based pharmacokinetic model was built to characterize biodistribution of OVs in humans. Viral dynamics was incorporated at the i.t. cellular level and linked to tumor response, enabling the characterization of a direct OV killing triggered by the death of infected tumor cells and an indirect killing induced by the immune response. The model provided an adequate description of changes in V937 mRNA levels and tumor size obtained from phase I/II clinical trials after V937 administration. The model showed prominent role of viral clearance from systemic circulation and infectivity in addition to known tumor aggressiveness on clinical response. After i.v. administration, i.t. exposure of V937 was predicted to be several orders of magnitude lower compared with i.t. administration. These differences could be overcome if there is high virus infectivity and/or replication. Unfortunately, the latter process could not be identified at the current clinical setting. This work provides insights on selecting optimal OV considering replication rate and infectivity.
  • Autores: Aldaz Pastor, Azucena (Autor de correspondencia); Schaiquevich, P.; Aramendía Beitia, José Manuel
    Revista: BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
    ISSN: 0306-5251 Vol.89 N° 2 2023 págs. 727 - 736
    Resumen
    Aims: We aimed to study the relation between pharmacokinetics (PK) and pharmacodynamics (PD) of docetaxel in early breast cancer and recommend a target exposure. Methods: A PK/PD study was performed in 27 early breast cancer patients treated with doxorubicin and cyclophosphamide for 4 cycles followed by 4 cycles of docetaxel 75-100 mg/m2 infused every 21 days. Individual Bayesian estimates of docetaxel PK parameters were obtained using a nonparametric population PK model developed with data from patients with metastatic breast cancer who received dose-intensified docetaxel (300-350 mg/m2 ). Docetaxel area under the curve (AUC) and maximum concentration (Cmax) in each cycle and total cumulative AUC (AUCcum) were calculated and related to the incidence of adverse effects and tumour recurrence. Results: Docetaxel clearance showed no change over the 4 treatment cycles, but a gradual increase in the volume of distribution was observed. One third of the patients had at least 1 dose reduction of docetaxel due to toxicity. The mean AUC, AUCcum and Cmax in patients showing docetaxel-associated adverse events were significantly higher than in patients free of toxicity (P < .05). Fatigue and decrease in haemoglobin and haematocrit levels were related to docetaxel AUC and Cmax and pain to AUC. AUC and Cmax >4.5 mg*h/L and 3.5 mg/L, respectively, were risk factors for docetaxel toxicity, while an AUC <4.5 mg*h/L was associated with tumour recurrence. Conclusion: We report for the first time a relation between docetaxel exposure and toxicity and recommend specific targets of drug exposure with implications for the clinical management of early breast cancer patients.
  • Autores: Bérniz Laborda, Carlos del Pilar; Carmona de la Torre, Francisco de Asís; Gómez Martínez de Lecea, Cristina; et al.
    Revista: AESTHETIC PLASTIC SURGERY
    ISSN: 0364-216X Vol.47 N° 5 2023 págs. 2093 - 2105
    Resumen
    Background Breast implant capsule development and behavior are mainly determined by implant surface combined with other external factors such as intraoperative contamination, radiation or concomitant pharmacologic treatment. Thus, there are several diseases: capsular contracture, breast implant illness or Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL), that have been correlated with the specific type of implant placed. This is the first study to compare all major implant and texture models available in the market on the development and behave of the capsules. Through a histopathological analysis, we compared the behavior of different implant surfaces and how different cellular and histological properties give rise to different susceptibilities to develop capsular contracture among these devices.Methods A total of 48 Wistar female rats were used to implant 6 different types of breast implants. Mentor (R), McGhan (R), Polytech polyurethane (R), Xtralane (R), Motiva (R) and Natrelle Smooth (R) implants were employed; 20 rats received Motiva (R), Xtralane (R) and Polytech polyurethane (R), and 28 rats received Mentor (R), McGhan (R) and Natrelle Smooth (R) implants. The capsules were removed five weeks after the implants placement. Further histological analysis compared capsule composition, collagen density and cellularity.Results High texturization implants showed the highest levels of collagen and cellularity along the capsule. However, polyurethane implants capsules behaved differently regarding capsule composition, with the thickest capsules but fewer collagen and myofibroblasts than expected, despite being generally considered as a macrotexturized implant. Nanotextured implants and microtextured implants histological findings showed similar characteristics and less susceptibility to develop a capsular contracture compared with smooth implants.Conclusions This study shows the relevance of the breast implant surface on the definitive capsules' development, since this is one of the most differentiated factors that determine the incidence of capsular contracture and probably other diseases like BIA-ALCL. A correlation of these findings with clinical cases will help to unify implant classification criteria based on their shell and their estimated incidence of capsule-associated pathologies. Up to this point, the establishment of additional groups is recommended as nanotexturized implants seem to behave differently to pure smooth surfaces and polyurethane implants present diverse features from macro- or microtextured implants.No Level Assigned This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.
  • Autores: Banys-Paluchowski, M.; Rubio, Isabel Teresa; Ditsch, N.; et al.
    Revista: BREAST
    ISSN: 0960-9776 Vol.69 2023 págs. 249 - 257
    Resumen
    The past two decades have seen an unprecedented trend towards de-escalation of surgical therapy in the setting of early BC, the most prominent examples being the reduction of re-excision rates for close surgical margins after breast-conserving surgery and replacing axillary lymph node dissection by less radical procedures such as sentinel lymph node biopsy (SLNB). Numerous studies confirmed that reducing the extent of surgery in the upfront surgery setting does not impact locoregional recurrences and overall outcome. In the setting of primary systemic treatment, there is an increased use of less invasive staging strategies reaching from SLNB and targeted lymph node biopsy (TLNB) to targeted axillary dissection (TAD). Omission of any axillary surgery in the presence of pathological complete response in the breast is currently being investigated in clinical trials. On the other hand, concerns have been raised that surgical de-escalation might induce an escalation of other treatment mo-dalities such as radiation therapy. Since most trials on surgical de-escalation did not include standardized pro-tocols for adjuvant radiotherapy, it remains unclear, whether the effect of surgical de-escalation was valid in itself or if radiotherapy compensated for the decreased surgical extent. Uncertainties in scientific evidence may therefore lead to escalation of radiotherapy in some settings of surgical de-escalation. Further, the increasing rate of mastectomies including contralateral procedures in patients without genetic risk is alarming. Future studies of locoregional treatment strategies need to include an interdisciplinary approach to integrate de-escalation approaches combining surgery and radiotherapy in a way that promotes optimal quality of life and shared decision-making.
  • Autores: Esgueva Colmenarejo, Antonio Jesús; Sobrido Sampedro, Carolina; Díaz Botero, Sebastián Dario; et al.
    Revista: EJSO
    ISSN: 0748-7983 Vol.49 N° 11 2023 págs. 107049
    Resumen
    Background Intraoperative ultrasound (IOUS) guided conservative surgery has been shown to reduce rates of positive margins in breast cancer. The aim of the study is to evaluate the feasibility of using IOUS to assess superficial/anterior margins in nipple and skin sparing mastectomy (NSM/SSM) and its impact on reducing rates of positive margins. Methods This prospective study includes all breast cancer patients who had an indication for NSM/SSM at our Institution. Superficial margin width was measured by IOUS before surgery and the area marked on the skin. Same measurement was performed afterwards in the mastectomy specimen. Any superficial margin < 5 mm was re-excised intraoperatively following the mark on the skin. Results Fifty-nine patients were included, 47 patients (79.7%) underwent NSM, and 12 patients (20.3%) a SSM. Of the 59 patients, 23 (38.98%) had margins ¿5 mm and 36 patients (61.02%) had margins of ¿5 mm. Of the 36 patients with superficial margins ¿5 mm, 20 had margins <2 mm, and 6 of them had intraoperative involved superficial margins in final pathology. However, after IOUS-guided re-excision, final pathology showed no involved margins. A 2 mm margin was set as the cut-off point for performing an intraoperative re-excision. IOUS guided re-excisions for intraoperative margins ¿2 mm significantly reduced the risk of close/positive margins in final pathology, p < 0.0001. Conclusion The results showed that IOUS margin evaluation significantly reduced the rate of superficial positive margins in NSM/SSM. It is feasible and effective and may avoid challenging reoperations and/or additional radiation therapy for positive margins.
  • Autores: Cardoso, F.; McCartney, A.; Ponti, A.; et al.
    Revista: EUROPEAN JOURNAL OF CANCER
    ISSN: 0959-8049 Vol.187 2023 págs. 105 - 113
    Resumen
    Aims: Improvement in the care of patients with metastatic breast cancer (MBC) can only occur if the adequate quality of care is implemented and verified, including access to multidisciplinary, specialised care given in accordance with high-quality guidelines. To this purpose, European Society of Breast Cancer Specialists and the Advanced Breast Cancer Global Alliance joined efforts to develop the first set of quality indicators (QI) specifically for MBC that should be routinely measured and evaluated to ensure that breast cancer centres meet the required standards. Methods: A working group of multidisciplinary European experts in breast cancer met to discuss each identified QI, reporting the definition, the minimum and target standard for breast cancer centres to achieve, and the motivation for selection. The level of evidence was determined according to the short version of the United States Agency for Healthcare Results: QI to measure access to and involvement in multidisciplinary and supportive care, appropriate pathological characterisation of disease, systemic therapies and radiotherapy were developed with the consensus of the working group. Conclusions: This is the first effort of a multistep project that aims to have QI for MBC routinely measured and evaluated to ensure that breast cancer centres achieve mandated standards in the care of patients with metastatic disease. (c) 2023 Elsevier Ltd. All rights reserved.
  • Autores: Schiavo, A.; Maldonado, C.; Vázquez, M.; et al.
    Revista: EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
    ISSN: 0928-0987 Vol.183 2023 págs. 106399
    Resumen
    Valproic acid (VPA) is a short-chain fatty acid widely prescribed in the treatment of seizure disorders and epi-lepsy syndromes, although its therapeutic value may be undermined by its toxicity. VPA serious adverse effects are reported to have a significant and dose-dependent incidence, many associated with VPA-induced hyper-ammonemia. This effect has been linked with reduced levels of carnitine; an endogenous compound involved in fatty acid's mitochondrial beta-oxidation by facilitation of its entrance via the carnitine shuttle. High exposure to VPA can lead to carnitine depletion causing a misbalance between the intra-mitochondrial beta-oxidation and the microsomal co-oxidation, a pathway that produces toxic metabolites such as 4-en-VPA which inhibits ammonia elimination. Moreover, a reduction in carnitine levels might be also related to VPA-induced obesity and lipids disorder. In turn, L-carnitine supplementation (CS) has been recommended and empirically used to reduce VPA's hepatotoxicity. The aim of this work was to develop a Quantitative Systems Pharmacology (QSP) model to characterize VPA-induced hyperammonemia and evaluate the benefits of CS in preventing hyperammonemia under both chronic treatment and after VPA overdosing. The QSP model included a VPA population pharma-cokinetics model that allowed the prediction of total and unbound concentrations after single and multiple oral doses considering its saturable binding to plasma proteins. Predictions of time courses for 2-en-VPA, 4-en-DPA, VPA-glucuronide, carnitine, ammonia and urea levels, and for the relative change in fatty acids, Acetyl-CoA, and glutamate reflected the VPA induced changes and the efficacy of the treatment with L-carnitine. The QSP model was implemented to give a rational basis for the L-carnitine dose selection to optimize CS depending on VPA dosage regime and to assess the currently recommended L-carnitine rescue therapy after VPA overdosing. Results show that a L-carnitine dose equal to the double of the VPA dose using the same interdose interval would maintain the ammonia levels at baseline. The QSP model may be expanded in the future to describe other adverse events linked to VPA-induced changes in endogenous compounds.
  • Autores: González Martín, Antonio (Autor de correspondencia); Pothuri, B.; Vergote, I.; et al.
    Revista: EUROPEAN JOURNAL OF CANCER
    ISSN: 0959-8049 Vol.189 2023 págs. 112908 - *
    Resumen
    Purpose: To report updated long-term efficacy and safety from the double-blind, placebo-controlled, phase 3 PRIMA/ENGOT-OV26/GOG-3012 study (NCT02655016).Methods: Patients with newly diagnosed advanced ovarian cancer with complete or partial response (CR or PR) to first-line platinum-based chemotherapy received niraparib or placebo once daily (2:1 ratio). Stratification factors were best response to first-line chemotherapy re-gimen (CR/PR), receipt of neoadjuvant chemotherapy (yes/no), and homologous re-combination deficiency (HRD) status (deficient [HRd]/proficient [HRp] or not determined). Updated (ad hoc) progression-free survival (PFS) data (as of November 17, 2021) by in-vestigator assessment (INV) are reported. Results: In 733 randomised patients (niraparib, 487; placebo, 246), median PFS follow-up was 3.5 years. Median INV-PFS was 24.5 versus 11.2 months (hazard ratio, 0.52; 95% confidence interval [CI], 0.40-0.68) in the HRd population and 13.8 versus 8.2 months (ha-zard ratio, 0.66; 95% CI, 0.56-0.79) in the overall population for niraparib and placebo, respectively. In the HRp population, median INV-PFS was 8.4 versus 5.4 months (hazard ratio, 0.65; 95% CI, 0.49-0.87), respectively.Results were concordant with the primary analysis. Niraparib-treated patients were more likely to be free of progression or death at 4 years than placebo-treated patients (HRd, 38% versus 17%; overall, 24% versus 14%). The most common grade & GE; 3 treatment-emergent adverse events in niraparib patients were thrombocytopenia (39.7%), anaemia (31.6%), and neutropenia (21.3%). Myelodysplastic syndromes/acute myeloid leukaemia incidence rate (1.2%) was the same for niraparib-and placebo-treated patients. Overall survival remained immature.Conclusions: Niraparib maintained clinically significant improvements in PFS with 3.5 years of follow-up in patients with newly diagnosed advanced ovarian cancer at high risk of pro-gression irrespective of HRD status. No new safety signals were identified.& COPY; 2023 Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
  • Autores: Leman, R. (Autor de correspondencia); Muller, E.; Legros, A.; et al.
    Revista: CLINICAL CANCER RESEARCH
    ISSN: 1078-0432 Vol.29 N° 21 2023 págs. 4419 - 4429
    Resumen
    Purpose: The optimal application of maintenance PARP inhibitor therapy for ovarian cancer requires accessible, robust, and rapid testing of homologous recombination deficiency (HRD). However, in many countries, access to HRD testing is problematic and the failure rate is high. We developed an academic HRD test to support treatment decision-making.Experimental Design: Genomic Instability Scar (GIScar) was developed through targeted sequencing of a 127-gene panel to determine HRD status. GIScar was trained from a noninterventional study with 250 prospectively collected ovarian tumor samples. GIScar was validated on 469 DNA tumor samples from the PAOLA-1 trial evaluating maintenance olaparib for newly diagnosed ovarian cancer, and its predictive value was compared with Myriad Genetics MyChoice (MGMC).Results: GIScar showed significant correlation with MGMC HRD classification (kappa statistics: 0.780). From PAOLA-1 samples, more HRD-positive tumors were identified by GIScar (258) than MGMC (242), with a lower proportion of inconclusive results (1% vs. 9%, respectively). The HRs for progression-free survival (PFS) with olaparib versus placebo were 0.45 [95% confidence interval (CI), 0.33-0.62] in GIScar-identified HRD-positive BRCA-mutated tumors, 0.50 (95% CI, 0.31-0.80) in HRD-positive BRCA-wild-type tumors, and 1.02 (95% CI, 0.74-1.40) in HRD-negative tumors. Tumors identified as HRD positive by GIScar but HRD negative by MGMC had better PFS with olaparib (HR, 0.23; 95% CI, 0.07-0.72).Conclusions: GIScar is a valuable diagnostic tool, reliably detecting HRD and predicting sensitivity to olaparib for ovarian cancer. GIScar showed high analytic concordance with MGMC test and fewer inconclusive results. GIScar is easily implemented into diagnostic laboratories with a rapid turnaround.
  • Autores: Arjona-Sanchez, A. (Autor de correspondencia); Aziz, O.; Passot, G.; et al.
    Revista: EJSO
    ISSN: 0748-7983 Vol.49 N° 10 2023 págs. 107001
    Resumen
    The laparoscopic approach for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (L-CRS + HIPEC) in highly selected patients was previously reported from the PSOGI registry with a demonstrable reduction in length of stay and post-operative morbidity. This study aims to update this international PSOGI registry with a larger cohort of patients and a longer follow-up period. Methods: An international registry was designed through a networking database (REDCAP & REG;). All centers performing L-CRS + HIPEC were invited through PSOGI to submit data on their cases. Variables such as demographics, clinical outcomes, and survival were analyzed. Results: A total of 315 L-CRS + HIPEC cases were provided by 14 worldwide centers. A total of 215 patients were included in the L-CRS + HIPEC group. The median peritoneal cancer index (PCI) was 3 (3-5). The median length of stay was 7 days (5-10) and the major morbidity (Clavien-Dindo & GE;3) was 6.1% after 30 days. The 5 year disease-free survival (DFS) per tumor origin was: 94% for PMP-LG, 85% for PMP-HG, 100% for benign multicyst peritoneal mesothelioma (MPM), 37.4% for colonic origin, and 54%(at 3 years) for ovarian origin. The 5 years overall survival (OS) per tumor origin was: 100% for PMP-LG, PMP-HG and MPM; 61% for colonic origin, and 74% (at 3 years) for ovarian origin. In addition, a total of 85 patients were analyzed in the laparoscopic risk-reducing HIPEC (L-RR + HIPEC). The median length of stay was 5 days (4-6) and the major morbidity was 6% after 30 days. The 5-year DFS per tumor origin was: 96% for perforated low grade appendiceal mucinous neoplasm (LAMN II) and 68.1% for colon origin. The 5 years OS per tumor origin was: 98% for LAMN II and 83.5% for colonic origin. Conclusions: Minimally invasive CRS + HIPEC is a safe procedure for selected patients with peritoneal carcinomatosis in specialized centers. It improves perioperative results while providing satisfactory oncologic outcomes. L-RR + HIPEC represents a promising strategy that could be evaluated in patients with high risk of developing peritoneal carcinomatosis into prospective randomized trials.
  • Autores: Willing, E. M. (Autor de correspondencia); Vollbrecht, C.; Voessing, C.; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.15 N° 13 2023 págs. 3445
    Resumen
    Simple Summary: Genomic instability (GI) caused by homologous repair deficiency (HRD) is a novel highly clinically relevant biomarker that cannot only identify patients suffering from high-grade serous ovarian cancer that may benefit from poly-ADP ribose polymerase (PARP) inhibitors but also helps in functionally annotating mutations found within genes of the homologous repair pathway. Tumors in which GI plays a role in therapeutic considerations currently include ovarian, breast, prostate, and pancreatic cancer. Therefore, we developed, implemented, and clinically validated a comprehensive custom Agilent XT HS2 hybrid capture next-generation sequencing (NGS) assay that allows in addition to the analysis of homologous recombination repair (HRR) pathway and relevant cancer genes, complex BRCA1 and BRCA2 alterations including large deletions and the evaluation of the GI-Score (GIS) status on one single tumor sample. The NOGGO (Northeastern German Society for Gynecologic Oncology) GIS v1 assay was validated as part of the European Network for Gynaecological Oncological Trial groups (ENGOT) HRD European Initiative on a subset of the ENGOT PAOLA-1 clinical trial samples. Patients identified as HRD-positive using the NOGGO GIS v1 assay showed a benefit of progression-free survival (PFS) and overall survival (OS) with comparable hazard ratios to the Myriad MyChoice assay. The worldwide approval of the combination maintenance therapy of olaparib and bevacizumab in advanced high-grade serous ovarian cancer requires complex molecular diagnostic assays that are sufficiently robust for the routine detection of driver mutations in homologous recombination repair (HRR) genes and genomic instability (GI), employing formalin-fixed (FFPE) paraffin-embedded tumor samples without matched normal tissue. We therefore established a DNA-based hybrid capture NGS assay and an associated bioinformatic pipeline that fulfils our institution's specific needs. The assays target regions cover the full exonic territory of relevant cancer-related genes and HRR genes and more than 20,000 evenly distributed single nucleotide polymorphism (SNP) loci to allow for the detection of genome-wide allele specific copy number alterations (CNA). To determine GI status, we implemented an %CNA score that is robust across a broad range of tumor cell content (25-85%) often found in routine FFPE samples. The assay was established using high-grade serous ovarian cancer samples for which BRCA1 and BRCA2 mutation status as well as Myriad MyChoice homologous repair deficiency (HRD) status was known. The NOGGO (Northeastern German Society for Gynecologic Oncology) GIS (GI-Score) v1 assay was clinically validated on more than 400 samples of the ENGOT PAOLA-1 clinical trial as part of the European Network for Gynaecological Oncological Trial groups (ENGOT) HRD European Initiative. The NOGGO GIS v1 assay performed using highly robust hazard ratios for progression-free survival (PFS) and overall survival (OS), as well a significantly lower dropout rate than the Myriad MyChoice clinical trial assay supporting the clinical utility of the assay. We also provide proof of a modular and scalable routine diagnostic method, that can be flexibly adapted and adjusted to meet future clinical needs, emerging biomarkers, and further tumor entities.
  • Autores: Bronte Viedma, Angela (Autor de correspondencia); Bastidas Tamayo, Juan Fernando; Rosales Castillo, Juan Jose; et al.
    Revista: CLINICAL NUCLEAR MEDICINE
    ISSN: 0363-9762 Vol.48 N° 10 2023 págs. e494 - e495
    Resumen
    A 53-year-old man with persisting increased serum prostate-specific antigen level (9.53 ng/mL) and repeated negative prostate biopsies was referred for a PET/CT with 68 Ga-PSMA-11. The PET/CT revealed focal uptake in the prostate suggestive of localized prostate cancer. Incidentally, it also showed a diffuse uptake in the tracheobronchial tree suspicious for a benign etiology. Because of the clinical history of asthma exacerbation in the previous week, further supplementary studies were performed showing a pathological fractional exhaled nitric oxide level (92 ppb; reference values, <25 ppb) and mild airway obstruction in the spirometry. These findings confirmed asthma as an inflammatory etiology of the tracheobronchial PSMA uptake.
  • Autores: Peribáñez Domínguez, Sara; Parra Guillén, Zinnia Patricia (Autor de correspondencia); Freshwater, T.; et al.
    Revista: FRONTIERS IN PHARMACOLOGY
    ISSN: 1663-9812 Vol.14 2023 págs. 1211452
    Resumen
    Introduction: Oncolytic viruses (OVs) represent a novel therapeutic strategy in oncology due to their capability to selectively infect and replicate in cancer cells, triggering a direct and/or immune-induced tumor lysis. However, the mechanisms governing OV pharmacokinetics are still poorly understood. This work aims to develop a physiologically based pharmacokinetic model of the novel OV, V937, in non-tumor-bearing mice to get a quantitative understanding of its elimination and tissue uptake processes.Materials and methods: Model development was performed using data obtained from 60 mice. Viral levels were quantified from eight tissues after a single intravenous V937 dose. An external dataset was used for model validation. This test set included multiple-dose experiments with different routes of administration. V937 distribution in each organ was described using a physiological structure based on mouse-specific organ blood flows and volumes. Analyses were performed using the non-linear mixed-effects approach with NONMEM 7.4.Results: Viral levels showed a drop from 108 to 105 copies/mu g RNA at day 1 in blood, reflected in a high estimate of total clearance (18.2 mL/h). A well-stirred model provided an adequate description for all organs except the muscle and heart, where a saturable uptake process improved data description. The highest numbers of viral copies were observed in the brain, lymph node, kidney, liver, lung, and spleen on the first day after injection. On the other hand, the maximum amount of viral copies in the heart, muscle, and pancreas occurred 3 days after administration.Conclusion: To the best of our knowledge, this is the first physiologically based pharmacokinetic model developed to characterize OV biodistribution, representing a relevant source of quantitative knowledge regarding the in vivo behavior of OVs. This model can be further expanded by adding a tumor compartment, where OVs could replicate.
  • Autores: Mirza, M. R. (Autor de correspondencia); González Martín, Antonio; Graybill, W. S.; et al.
    Revista: CANCER
    ISSN: 0008-543X Vol.129 N° 12 2023 págs. 1846 - 1855
    Resumen
    Background: The PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) trial was amended to prospectively evaluate the safety and efficacy of an individualized starting dose (ISD) regimen of niraparib for first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer. Methods: In the phase 3 PRIMA trial, patients with newly diagnosed advanced ovarian cancer with a complete/partial response to first-line platinum-based chemotherapy (N = 733) were initially treated with a fixed starting dose (FSD) regimen of 300 mg every day. Subsequently, the protocol was amended so newly enrolled patients received an ISD: 200 mg every day in patients with baseline body weight < 77 kg or baseline platelet count < 150,000/mu L, and 300 mg every day in all other patients. Efficacy and safety outcomes were assessed by starting dose. Results: Overall, 475 (64.8%) patients were assigned to an FSD (niraparib, n = 317; placebo, n = 158) and 258 (35.2%) were assigned to an ISD (niraparib, n = 170; placebo, n = 88). Efficacy in patients who received FSD or ISD was similar for the overall (FSD hazard ratio [HR], 0.59 [95% CI, 0.46-0.76] vs. ISD HR, 0.69 [95% CI, 0.48-0.98]) and the homologous recombination-deficient (FSD HR, 0.44 [95% CI, 0.30-0.64] vs. ISD HR, 0.39 [95% CI, 0.22-0.72]) populations. In patients with low body weight/platelet count, rates of grades =3 and 4 hematologic treatment-emergent adverse events, dose interruptions, and dose reductions were lower for those who received ISD than for those who received FSD. Conclusions: In PRIMA, similar dose intensity, similar efficacy, and improved safety were observed with the ISD compared with the FSD regimen.
  • Autores: Mao, R. M.; WIlliams, T.; Snyder, C.; et al.
    Revista: ANNALS OF SURGICAL ONCOLOGY
    ISSN: 1068-9265 Vol.30 N° Supl 2 2023 págs. S512 - S513
  • Autores: Garcia Porrero, Guillermo; López Janeiro, Álvaro; Argueta Morales, Allan; et al.
    Revista: LABORATORY INVESTIGATION
    ISSN: 0023-6837 Vol.103 N° 3 2023 págs. S300 - S301
  • Autores: Konstantinopoulos, P. A. (Autor de correspondencia); González Martín, Antonio; Melo-Cruz, F.; et al.
    Revista: FUTURE ONCOLOGY
    ISSN: 1479-6694 Vol.18 N° 31 2022 págs. 3481 - 3492
    Resumen
    Patients with platinum-resistant or -refractory high-grade serous ovarian cancer (HGSOC) have a poor prognosis, and their management represents a substantial unmet medical need. Preclinical data and results from a phase lb trial demonstrated the efficacy and tolerability of the combination of the specific phosphatidylinositol-3-kinase (P13K) inhibitor alpelisib plus the poly (adenosine diphosphateribose) polymerase (PARP) inhibitor olaparib in platinum-resistant, non-BRCA-mutated ovarian cancer. Here, we describe the study design and rationale for the phase III, multicenter, open-label, randomized, active-controlled EPIK-O/ENGOT-OV61 trial investigating alpelisib in combination with olaparib compared with standard-of-care chemotherapy in patients with platinum-resistant or -refractory HGSOC with no germline BRCA mutation. Progression-free survival (blinded independent review committee) is the primary end point. Overall survival is a key secondary end point.
  • Autores: González Martín, Antonio; Matulonis, U. A.; Korach, J.; et al.
    Revista: FUTURE ONCOLOGY
    ISSN: 1479-6694 Vol.18 N° 23 2022 págs. 2505 - 2536
    Resumen
    We reviewed clinical data for niraparib monotherapy in BRCA-mutated (BRCAm) epithelial ovarian cancer (OC), contextualizing results with data from other poly(ADP-ribose) polymerase inhibitors (PARPis). Niraparib reduced the likelihood of progression or death by 60% as first-line maintenance therapy and by 73-78% in recurrent disease. In heavily pretreated OC, efficacy was greater in the BRCAm versus non-BRCAm cohort. Quality-of-life (QoL) was maintained throughout treatment. Adverse events were consistent with the known niraparib safety profile. Cumulative efficacy, safety and QoL evidence demonstrate niraparib maintenance monotherapy has a positive benefit:risk ratio in BRCAm OC. Niraparib significantly improved progression-free survival as first-line maintenance therapy in all patients with OC (i.e., of any biomarker status). Plain language summary: This article reviewed niraparib monotherapy in patients with ovarian cancer (OC) who have mutations in a specific gene (BRCA). Across multiple clinical trials, niraparib maintenance treatment was able to delay further progression of disease or death compared with patients who had received placebo; the tumors of patients who had received extensive prior treatment for OC were also more likely to respond to niraparib treatment. Patients were able to have the same quality-of-life with niraparib as they would if they had not received treatment. Side effects were predictable from previous clinical trial experience. Together, these data show that niraparib, like other inhibitors of poly(ADP-ribose) polymerase, is beneficial in patients with OC who have a deleterious BRCA mutation. A plain language version of this article is available and is published alongside the paper online: www.futuremedicine.com/doi/suppl/10.2217/fon-2022-0206
  • Autores: Sánchez Lorenzo, María Luisa; Salas Benito, Diego; Villamayor Sánchez, Julia; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.14 N° 5 2022 págs. 1235
    Resumen
    Epithelial ovarian cancer (EOC) is still the most lethal gynecological cancer. Germline alterations in breast cancer 1 (gBRCA1) and breast cancer 2 (gBRCA2) genes have been identified in up to 18% of women diagnosed with EOC, and somatic mutations are found in an additional 7%. Testing of BRCA at the primary diagnosis of patients with EOC is recommended due to the implications in the genomic counseling of the patients and their families, as well as for the therapeutic implications. Indeed, the introduction of poly-(ADP ribose) polymerase inhibitors (PARPis) has changed the natural history of patients harboring a mutation in BRCA, and has resulted in a new era in the treatment of patients with ovarian cancer harboring a BRCA mutation.
  • Autores: van Niel, J.; Bloms-Funke, P.; Caspani, O.; et al.
    Revista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
    ISSN: 1422-0067 Vol.23 N° 15 2022 págs. 8295
    Resumen
    There is an urgent need for analgesics with improved efficacy, especially in neuropathic and other chronic pain conditions. Unfortunately, in recent decades, many candidate analgesics have failed in clinical phase II or III trials despite promising preclinical results. Translational assessment tools to verify engagement of pharmacological targets and actions on compartments of the nociceptive system are missing in both rodents and humans. Through the Innovative Medicines Initiative of the European Union and EFPIA, a consortium of researchers from academia and the pharmaceutical industry was established to identify and validate a set of functional biomarkers to assess drug-induced effects on nociceptive processing at peripheral, spinal and supraspinal levels using electrophysiological and functional neuroimaging techniques. Here, we report the results of a systematic literature search for pharmacological probes that allow for validation of these biomarkers. Of 26 candidate substances, only 7 met the inclusion criteria: evidence for nociceptive system modulation, tolerability, availability in oral form for human use and absence of active metabolites. Based on pharmacokinetic characteristics, three were selected for a set of crossover studies in rodents and healthy humans. All currently available probes act on more than one compartment of the nociceptive system. Once validated, biomarkers of nociceptive signal processing, combined with a pharmacometric modelling, will enable a more rational approach to selecting dose ranges and verifying target engagement. Combined with advances in classification of chronic pain conditions, these biomarkers are expected to accelerate analgesic drug development.
  • Autores: Monk, B. J. (Autor de correspondencia); Enomoto, T.; Kast, W. M.; et al.
    Revista: CANCER TREATMENT REVIEWS
    ISSN: 0305-7372 Vol.106 2022 págs. 102385
    Resumen
    Cervical cancer constitutes a significant health burden for women globally. While most patients with early-stage disease can be cured with radical surgery or chemoradiotherapy, patients with high-risk locally advanced disease or with recurrent/metastatic disease have a poor prognosis with standard treatments. Immunotherapies are a rational treatment for this HPV-driven cancer that commonly expresses programmed cell death ligand-1. Before 2021, pembrolizumab was the only United States Food and Drug Administration-approved immunotherapy in cervical cancer, specifically for the second-line recurrent or metastatic (r/m) setting. In late 2021, the antibody-drug conjugate tisotumab vedotin was approved for second-line r/m cervical cancer and pembrolizumab com-bined with chemotherapy +/- bevacizumab was approved for first-line r/m disease based on results from KEYNOTE-826. Moreover, with at least 2 dozen additional immunotherapy clinical trials in the second-line and first-line r/m setting, as well as in locally advanced disease, the treatment landscape for cervical cancer may eventually encounter a potential paradigm shift. Pivotal trials of immunotherapies for cervical cancer that were recently approved or with the potential for regulatory consideration through 2024 are reviewed. As immuno-therapy has the opportunity to establish new standards of care in the treatment of cervical cancers, new bio-markers to identify the ideal patient populations for these therapies may also become important. However, issues with access, affordability, and compliance in low-and middle-income countries are anticipated.
  • Autores: Banys-Paluchowski, M. (Autor de correspondencia); Rubio, Isabel Teresa; Cakmak, G. K.; et al.
    Revista: ULTRASCHALL IN DER MEDIZIN
    ISSN: 0172-4614 Vol.43 N° 4 2022 págs. 367 - 379
    Resumen
    Wire-guided localization (WGL) is the most frequently used localization technique in non-palpable breast cancer (BC). However, low negative margin rates, patient discomfort, and the possibility of wire dislocation have been discussed as potential disadvantages, and re-operation due to positive margins may increase relapse risk. Intraoperative ultrasound (IOUS)-guided excision allows direct visualization of the lesion and the resection volume and reduces positive margins in palpable and non-palpable tumors. We performed a systematic review on IOUS in breast cancer and 2 meta-analyses of randomized clinical trials (RCTs). In non-palpable BC, 3 RCTs have shown higher negative margin rates in the IOUS arm compared to WGL. Meta-analysis confirmed a significant difference between IOUS and WGL in terms of positive margins favoring IOUS (risk ratio 4.34, p < 0.0001, I2 = 0%). 41 cohort studies including 3291 patients were identified, of which most reported higher negative margin and lower re-operation rates if IOUS was used. In palpable BC, IOUS was compared to palpation-guided excision in 3 RCTs. Meta-analysis showed significantly higher rates of positive margins in the palpation arm (risk ratio 2.84, p = 0.0047, I2 = 0%). In 13 cohort studies including 942 patients with palpable BC, negative margin rates were higher if IOUS was used, and tissue volumes were higher in palpation-guided cohorts in most studies. IOUS is a safe noninvasive technique for the localization of sonographically visible tumors that significantly improves margin rates in palpable and non-palpable BC. Surgeons should be encouraged to acquire ultrasound skills and participate in breast ultrasound training.
  • Autores: Esgueva Colmenarejo, Antonio Jesús; Noordhoek, I.; Kranenbarg, E. M. K.; et al.
    Revista: ANNALS OF SURGICAL ONCOLOGY
    ISSN: 1068-9265 Vol.29 N° 9 2022 págs. 5828 - 5828
  • Autores: Esgueva Colmenarejo, Antonio Jesús; Noordhoek, I.; Kranenbarg, E. M. K.; et al.
    Revista: ANNALS OF SURGICAL ONCOLOGY
    ISSN: 1068-9265 Vol.29 N° 3 2022 págs. 1735 - 1736
  • Autores: Kühn, T. (Autor de correspondencia); Rubio, Isabel Teresa; Gentilini, O. D.; et al.
    Revista: BREAST CARE
    ISSN: 1661-3791 Vol.17 N° 6 2022 págs. 588 - 589
  • Autores: Hontanilla Calatayud, Bernardo Carlos (Autor de correspondencia)
    Revista: SCIENTIA ET FIDES
    ISSN: 2300-7648 Vol.10 N° 1 2022 págs. 91 - 114
    Resumen
    It has been assumed that the person represented on the Shroud of Turin is dead and the image corresponds to a person dead from crucifixion. We have conducted an analysis of the cadaveric data of a body and the presence of face life signs and we could think that the image could correspond to a living person. Therefore, it might correspond to a man starting a getting up gesture. If we examine the Gospels, a remarkable symmetry is found between the data obtained from the image and the events described in the Gospels, regarding the death and resurrection of Jesus.
  • Autores: González Martín, Antonio (Autor de correspondencia); Desauw, C.; Heitz, F.; et al.
    Revista: EUROPEAN JOURNAL OF CANCER
    ISSN: 0959-8049 Vol.174 2022 págs. 221 - 231
    Resumen
    Background: PAOLA-1/ENGOT-ov25 (NCT02477644) demonstrated a significant progression-free survival (PFS) benefit with maintenance olaparib plus bevacizumab versus placebo plus bevacizumab in newly diagnosed, advanced ovarian cancer. We report the pre -specified main second progression-free survival (PFS2) analysis for PAOLA-1.Methods: This randomised, double-blind, phase III trial was conducted in 11 countries. Eligible patients had newly diagnosed, advanced, high-grade ovarian cancer and were in response after first-line platinum-based chemotherapy plus bevacizumab. Patients were rando-mised 2:1 to olaparib (300 mg twice daily) or placebo for up to 24 months; all patients received bevacizumab (15 mg/kg every 3 weeks) for up to 15 months. Primary PFS end-point was re-ported previously. Time from randomisation to second disease progression or death was a key secondary end-point included in the hierarchical-testing procedure.Results: After a median follow-up of 35.5 months and 36.5 months, respectively, median PFS2 was 36.5 months (olaparib plus bevacizumab) and 32.6 months (placebo plus bevacizumab), hazard ratio 0.78; 95% confidence interval (CI) 0.64-0.95; P = 0.0125. Median time to second subsequent therapy or death was 38.2 months (olaparib plus bevacizumab) and 31.5 months (placebo plus bevacizumab), hazard ratio 0.78; 95% CI 0.64-0.95; P = 0.0115. Seventy-two (27%) patients in the placebo plus bevacizumab group received a poly(ADP-ribose) polymer-ase inhibitor as first subsequent therapy. No new safety signals were observed for olaparib plus bevacizumab.Conclusion: In newly diagnosed, advanced ovarian cancer, maintenance olaparib plus bevaci-zumab provided continued benefit beyond first progression, with a significant PFS2 improve-ment and a time to second subsequent therapy or death delay versus placebo plus bevacizumab.
  • Autores: Poveda, A. (Autor de correspondencia); Lheureux, S.; Colombo, N.; et al.
    Revista: GYNECOLOGIC ONCOLOGY
    ISSN: 0090-8258 Vol.164 N° 3 2022 págs. 498 - 504
    Resumen
    Objective. The phase IIIb OPINION trial (NCT03402841) investigated olaparib maintenance monotherapy in patients without a deleterious or suspected deleterious germline BRCA1/BRCA2 mutation (gBRCAm) who had platinum-sensitive relapsed ovarian cancer (PSROC) and had received >= 2 previous lines of platinum-based chemotherapy. Methods. In this single-arm, open-label, international study, patients who had responded to platinum-based chemotherapy received maintenance olaparib tablets (300 mg twice daily) until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS) (modified RECIST version 1.1). A key secondary endpoint was PFS by homologous recombination deficiency (HRD) and somatic BRCAm (sBRCAm) status. The primary analysis of PFS was planned for 18 months after the last patient received their first dose. Results. Two hundred and seventy-nine patients were enrolled and received olaparib. At data cutoff (October 2, 2020), 210 PFS events had occurred (75.3% maturity) and median PFS was 92 months (95% confidence interval [0], 7.6-10.9) in the overall population. At 12 and 18 months, 38.5% and 243% of patients were progression-free, respectively. In the predefined biomarker subgroups, median PFS was 16.4, 11.1, 9.7, and 73 months in sBRCAm, HRD-positive including sBRCAm, HRD-positive excluding sBRCAm, and HRD-negative patients, respectively. The most common treatment-emergent adverse events (TEAEs) were nausea (48.4%) and fatigue/asthenia (44.1%). TEAEs led to dose interruption, dose reduction, and treatment discontinuation in 47.0%, 22.6%, and 7.5% of patients, respectively. Conclusion. Maintenance olaparib demonstrated clinical benefit in patients without a gBRCAm, and across all subgroups, compared with historical placebo controls. There were no new safety signals.
  • Autores: Yubero, A. (Autor de correspondencia); Barquin, A.; Estevez, P.; et al.
    Revista: BMC CANCER
    ISSN: 1471-2407 Vol.22 N° 1 2022 págs. 1150
    Resumen
    Background: Rucaparib is a poly(ADP-ribose) polymerase inhibitor approved in Europe as maintenance therapy for recurrent platinum-sensitive (Pt-S) ovarian cancer (OC). The Rucaparib Access Programme (RAP) was designed to provide early access to rucaparib for the above-mentioned indication, as well as for patients with BRCA-mutated Pt-S or platinum-resistant (Pt-R) OC and no therapeutic alternatives. Methods: In this observational, retrospective study we analysed the efficacy and safety of rucaparib within the RAP in Spain. Hospitals associated with the Spanish Ovarian Cancer Research Group (GEICO) recruited patients with high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer treated with rucaparib 600 mg twice daily as maintenance or treatment (Pt-S/Pt-R) in the RAP. Baseline characteristics, efficacy, and safety data were collected. Results: Between July 2020 and February 2021, 51 patients treated in 22 hospitals in the RAP were included in the study. Eighteen patients with a median of 3 (range, 1-6) prior treatment lines received rucaparib as maintenance; median progression-free survival (PFS) for this group was 9.1 months (95% confidence interval [CI], 4.2-11.6 months). Among 33 patients (median 5 [range, 1-9] prior treatment lines) who received rucaparib as treatment, 7 and 26 patients had Pt-S and Pt-R disease, respectively. Median PFS was 10.6 months (95% CI, 2.5 months-not reached) in the Pt-S group and 2.2 months (95% CI, 1.1-3.2 months) in the Pt-R group. Grade >= 3 treatment-emergent adverse events were reported in 39% of all patients, the most common being anaemia (12% and 15% in the maintenance and treatment groups, respectively). At data cut-off, 5 patients remained on treatment. Conclusion Efficacy results in these heavily pre-treated patients were similar to those from previous trials. The safety profile of rucaparib in real life was predictable and manageable.
  • Autores: Esgueva Colmenarejo, Antonio Jesús; Noordhoek, I.; Kranenbarg, E. M. K.; et al.
    Revista: ANNALS OF SURGICAL ONCOLOGY
    ISSN: 1068-9265 Vol.29 N° 3 2022 págs. 1722 - 1734
    Resumen
    Introduction Nipple-sparing mastectomy (NSM) with immediate breast reconstruction (IBR) is increasingly used for both breast cancer (TNSM) and risk reduction (RRNSM). The aim of the study is to report the results of the INSPIRE registry assessing health-related quality of life (HRQoL) comparing baseline and 1-year follow-up, regarding surgical indications and chemotherapy (CT) received. Methods INSPIRE is a prospective database including women undergoing NSM and IBR from 18 countries. HRQoL was measured using EORTC QLQC30 and QLQ-BR23 before surgery and after 1 year. Results A total of 677 women were included, of whom 537 (79.3%) underwent TNSM and 140 (21.6%) RRNSM: in total, 806 NSM (556 TNSM and 250 RRNSM). Nipple involvement was present in 7.73% of TNSM and incidental carcinoma in 1.2% of the RRNSM group. Out of the overall 537 patients with systemic treatment, 177 (32.96%) received neoadjuvant chemotherapy (NCT) and 118 (21.92%) adjuvant chemotherapy (CT). A total of 227 patients (28.16%) developed at least one complication postoperatively, 164 (29.5%) in the TNSM group and 63 (25.2%) in the RRNSM group. The TNSM group improved in global health status and emotional functioning after 1 year. No differences were found when comparing HRQoL at 1 year between patients who received NCT and those who received adjuvant CT. The RRNSM group showed improvement in HRQoL, with better emotional functioning and fatigue after 1 year. Conclusions This registry reports HRQoL findings after NSM. The impact of CT on worse HRQoL is independent from its timing. Patients with RRNSM showed an improved HRQoL at 1-year follow-up. Discussion of HRQoL outcomes with patients will facilitate the informed decision-making when considering NSM.
  • Autores: O'Cearbhaill, R. E. (Autor de correspondencia); Pérez-Fidalgo, J. A.; Monk, B. J.; et al.
    Revista: GYNECOLOGIC ONCOLOGY
    ISSN: 0090-8258 Vol.166 N° 1 2022 págs. 36 - 43
    Resumen
    Objective. To evaluate the association between surgical timing and postoperative residual disease status on the efficacy of niraparib first-line maintenance therapy in patients with newly diagnosed advanced ovarian can-cer at high risk of recurrence.Methods. Post hoc analysis of the phase 3 PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) study of niraparib in patients with newly diagnosed primary advanced ovarian, primary peritoneal, or fallopian tube cancer with a complete/partial response to first-line platinum-based chemotherapy. Progression-free survival (PFS) was assessed by surgical status (primary debulking surgery [PDS] vs neoadjuvant chemotherapy/interval debulking surgery [NACT/IDS]) and postoperative residual disease status (no visible residual disease [NVRD] vs visible re-sidual disease [VRD]) in the intent-to-treat population.Results. In PRIMA (N = 733), 236 (32.2%) patients underwent PDS, and 481 (65.6%) received NACT/IDS before enrollment. Median PFS (niraparib vs placebo) and hazard ratios (95% CI) for progression were similar in PDS (13.7 vs 8.2 months; HR, 0.67 [0.47-0.96]) and NACT/IDS (14.2 vs 8.2 months; HR, 0.57 [0.44-0.73]) subgroups. In patients who received NACT/IDS and had NVRD (n = 304), the hazard ratio (95% CI) for progression was 0.65 (0.46-0.91). In patients with VRD following PDS (n = 183) or NACT/IDS (n = 149), the hazard ratios (95% CI) for progression were 0.58 (0.39-0.86) and 0.41 (0.27-0.62), respectively. PFS was not evaluable for patients with PDS and NVRD because of sample size (n = 37).Conclusions. In this post hoc analysis, niraparib efficacy was similar across PDS and NACT/IDS subgroups. Pa-tients who had NACT/IDS and VRD had the highest reduction in the risk of progression with niraparib mainte-nance.
  • Autores: Mirza, M. R.; Lindahl, G.; Mahner, S.; et al.
    Revista: CANCER RESEARCH COMMUNICATIONS
    ISSN: 2767-9764 Vol.2 N° 11 2022 págs. 1436 - 1444
  • Autores: Harter, P. (Autor de correspondencia); Mouret-Reynier, M. A.; Pignata, S.; et al.
    Revista: GYNECOLOGIC ONCOLOGY
    ISSN: 0090-8258 Vol.164 N° 2 2022 págs. 254 - 264
    Resumen
    Objectives. Adding maintenance olaparib to bevacizumab provided a significant progression-free survival (PFS) benefit in patients with newly diagnosed, advanced ovarian cancer in the randomized, double-blind PAOLA-1/ENGOT-ov25 trial (NCT02477644). We analyzed PFS by clinical risk and biomarker status. Methods. Patients received olaparib 300 mg twice daily for up to 24 months plus bevacizumab 15 mg/kg every 3 weeks for up to 15 months in total, or placebo plus bevacizumab. This post hoc exploratory analysis evaluated PFS in patients classified as higher risk (stage III with upfront surgery and residual disease or neoadjuvant chemotherapy; stage IV) or lower risk (stage III with upfront surgery and no residual disease), and by biomarker status. Results. Of 806 randomized patients, 74% were higher risk and 26% were lower risk. After a median 22.9 months of follow-up, PFS favored olaparib plus bevacizumab versus placebo plus bevacizumab in higher risk patients (hazard ratio [HR] 0.60; 95% confidence interval [CI] 0.49-0.74) and lower-risk patients (0.46; 0.30-0.72). Olaparib plus bevacizumab provided a substantial PFS benefit versus bevacizumab alone in the homologous recombination deficiency (HRD)-positive subgroup (higher risk: HR 0.39; 95% CI 0.28-0.54 and lower risk: 0.15; 0.07-0.30), with 24-month PFS rates in lower-risk patients of 90% versus 43%, respectively (Kaplan-Meier estimates). Conclusions. In PAOLA-1, maintenance olaparib plus bevacizumab provided a substantial PFS benefit in HRDpositive patients with a reduction of risk of progression or death of 61% in the higher-risk group and of 85% in the lower-risk group compared with bevacizumab alone.
  • Autores: Simonelli, M. (Autor de correspondencia); Garralda, E.; Eskens, F.; et al.
    Revista: ESMO OPEN
    ISSN: 2059-7029 Vol.7 N° 5 2022
    Resumen
    Background: The anti-CD38 antibody isatuximab is approved for the treatment of relapsed/refractory multiple myeloma, but there are no data on its efficacy in solid tumors. This phase I/II study (NCT03637764) assessed the safety and activity of isatuximab plus atezolizumab (Isa + Atezo), an anti-programmed death-ligand 1 (PD-L1) antibody, in patients with immunotherapy-naive solid tumors: epithelial ovarian cancer (EOC), glioblastoma (GBM), hepatocellular carcinoma (HCC), and squamous cell carcinoma of the head and neck (SCCHN). Patients and methods: Phase I assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and the recommended phase II dose (RP2D) of isatuximab 10 mg/kg intravenously (i.v.) every week for 3 weeks followed by once every 3 weeks + atezolizumab 1200 mg i.v. every 3 weeks. Phase II used a Simon's two-stage design to assess the overall response rate or progression-free survival rate at 6 months (GBM cohort). Interim analysis was carried out at 6 months following first dose of the last enrolled patient in each cohort. Pharmacodynamic biomarkers were tested for CD38, PD-L1, tumor-infiltrating immune cells, and FOXP3+ regulatory T cells (Tregs) in the tumor microenvironment (TME). Results: Overall, 107 patients were treated (EOC, n = 18; GBM, n = 33; HCC, n = 27; SCCHN, n = 29). In phase I, Isa + Atezo showed an acceptable safety profile, no dose-limiting toxicities were observed, and RP2D was confirmed. Most patients experienced >= 1 treatment-emergent adverse event (TEAE), with <= 48.5% being grade >= 3. The most frequent TEAE was infusion reactions. The study did not continue to stage 2 based on prespecified targets. Tumor-infiltrating CD38+ immune cells were reduced and almost cleared after treatment. Isa + Atezo did not significantly modulate Tregs or PD-L1 expression in the TME. Conclusions: Isa + Atezo had acceptable safety and tolerability. Clinical pharmacodynamic evaluation revealed efficient target engagement of isatuximab via treatment-mediated reduction of CD38+ immune cells in the TME. Based on clinical data, CD38 inhibition does not improve responsiveness to PD-L1 blockade in these patients.
  • Autores: van Dam, P. (Autor de correspondencia); Tomatis, M.; Ponti, A.; et al.
    Revista: EUROPEAN JOURNAL OF CANCER
    ISSN: 0959-8049 Vol.177 2022 págs. 72 - 79
    Resumen
    Aims: We analysed the impact of the SARS-CoV-2 pandemic (COVID-19) on the quality of breast cancer care in certified EUSOMA (European Society of Breast Cancer Spe-cialists) breast centres.Materials and methods: The results of the EUSOMA quality indicators were compared, based on pseudonymised individual records, for the periods 1 March 2020 till 30 June 2020 (first COVID-19 peak in most countries in Europe) and 1 March 2019 till 30 June 2019. In addition, a questionnaire was sent to the participating Centres for investigating the impact of the COVID-19 pandemic on the organisation and the quality of breast cancer care.Results: Forty-five centres provided data and 31 (67%) responded to the questionnaire. The total number of new cases dropped by 19% and there was a small significant higher tumour (p = 0.003) and lymph node (p = 0.011) stage at presentation. Comparing quality indicators (12,736 patients) by multivariable analysis showed mostly non-significant differences. Surgery could be performed in a COVID-free zone in 94% of the centres, COVID testing was per-formed before surgery in 96% of the centres, and surgical case load was reduced in 55% of the centres. Modifications of the indications for neoadjuvant endocrine therapy, chemo-therapy, and targeted therapy were necessary in 23%, 23%, and 10% of the centres; changes in indications for adjuvant endocrine, chemo-, targeted, immune, and radiotherapy in 3%, 19%, 3%, 6%, and 10%, respectively.Conclusion: Quality of breast cancer care was well maintained in EUSOMA breast centres during the first wave of the COVID-19 pandemic. A small but significantly higher tumour and lymph node stage at presentation was observed. 2022 Elsevier Ltd. All rights reserved.
  • Autores: Carmona de la Torre, Francisco de Asís; Fernández Ciriza, Leire; Bérniz Laborda, Carlos del Pilar; et al.
    Revista: MICROORGANISMS
    ISSN: 2076-2607 Vol.10 N° 10 2022 págs. 2004
    Resumen
    Capsular contracture is the most frequently associated complication following breast implant placement. Biofilm formation on the surface of such implants could significantly influence the pathogenesis of this complication. The objective of this study was to design an experimental model of breast implant infection that allowed us to compare the in vivo S. epidermidis ability to form and perpetuate biofilms on commonly used types of breast implants (i.e., macrotexturized, microtexturized, and smooth). A biofilm forming S. epidermidis strain (ATCC 35984) was used for all experiments. Three different implant surface types were tested: McGhan BIOCELL (R) (i.e., macrotexturized); Mentor Siltex (R) (i.e., microtexturized); and Allergan Natrelle Smooth (R) (i.e., smooth). Two different infection scenarios were simulated. The ability to form biofilm on capsules and implants over time was evaluated by quantitative post-sonication culture of implants and capsules biopsies. This experimental model allows the generation of a subclinical staphylococcal infection associated with a breast implant placed in the subcutaneous tissue of Wistar rats. The probability of generating an infection was different according to the type of implant studied and to the time from implantation to implant removal. Infection was achieved in 88.9% of macrotextured implants (i.e., McGhan), 37.0% of microtexturized implants (i.e., Mentor), and 18.5% of smooth implants (i.e., Allergan Smooth) in the short-term (p < 0.001). Infection was achieved in 47.2% of macrotextured implants, 2.8% of microtexturized implants, and 2.8% of smooth implants (i.e., Allergan Smooth) in the longterm (p < 0.001). There was a clear positive correlation between biofilm formation on any type of implant and capsule colonization/infection. Uniformly, the capsules formed around the macro- or microtexturized implants were consistently macroscopically thicker than those formed around the smooth implants regardless of the time at which they were removed (i.e., 1-2 weeks or 3-5 weeks). We have shown that there is a difference in the ability of S epidermidis to develop in vivo biofilms on macrotextured, microtextured, and smooth implants. Smooth implants clearly thwart bacterial adherence and, consequently, biofilm formation and persistence are hindered.
  • Autores: Vergote, I. (Autor de correspondencia); González Martín, Antonio; Ray-Coquard, I.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.33 N° 3 2022 págs. 276 - 287
    Resumen
    Background: Homologous recombination repair (HRR) enables fault-free repair of double-stranded DNA breaks. HRR deficiency is predicted to occur in around half of high-grade serous ovarian carcinomas. Ovarian cancers harbouring HRR deficiency typically exhibit sensitivity to poly-ADP ribose polymerase inhibitors (PARPi). Current guidelines recommend a range of approaches for genetic testing to identify predictors of sensitivity to PARPi in ovarian cancer and to identify genetic predisposition. Design: To establish a European-wide consensus for genetic testing (including the genetic care pathway), decision making and clinical management of patients with recently diagnosed advanced ovarian cancer, and the validity of biomarkers to predict the effectiveness of PARPi in the first-line setting. The collaborative European experts' consensus group consisted of a steering committee (n = 14) and contributors (n = 84). A (modified) Delphi process was used to establish consensus statements based on a systematic literature search, conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Results: A consensus was reached on 34 statements amongst 98 caregivers (including oncologists, pathologists, clinical geneticists, genetic researchers, and patient advocates). The statements concentrated on (i) the value of testing for BRCA1/2 mutations and HRR deficiency testing, including when and whom to test; (ii) the importance of developing new and better HRR deficiency tests; (iii) the importance of germline non-BRCA HRR and mismatch repair gene mutations for predicting familial risk, but not for predicting sensitivity to PARPi, in the first-line setting; (iv) who should be able to inform patients about genetic testing, and what training and education should these caregivers receive. Conclusion: These consensus recommendations, from a multidisciplinary panel of experts from across Europe, provide clear guidance on the use of BRCA and HRR deficiency testing for recently diagnosed patients with advanced ovarian cancer.
  • Autores: Barretina-Ginesta, M. P. (Autor de correspondencia); Monk, B. J.; Han, S.; et al.
    Revista: THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY
    ISSN: 1758-8340 Vol.14 2022
    Resumen
    Background: The PRIMA phase 3 trial showed niraparib significantly prolongs median progression-free survival (PFS) versus placebo in patients with advanced ovarian cancer (OC) responsive to first-line platinum-based chemotherapy, including those who had tumors with homologous recombination deficiency (HRd). This analysis of PRIMA examined the quality-adjusted PFS (QA-PFS) and quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) of patients on maintenance niraparib versus placebo. Methods: Patients were randomized 2:1 to receive once-daily maintenance niraparib (n = 487) or placebo (n = 246). QA-PFS was defined as the PFS of patients adjusted for their health-related quality of life (HRQoL) prior to disease progression, measured using European Quality of Life Five-Dimension (EQ-5D) questionnaire index scores from the PRIMA trial. Q-TWiST was calculated by combining data on PFS, duration of symptomatic grade >= 2 adverse events (fatigue or asthenia, nausea, vomiting, abdominal pain, and abdominal bloating) prior to disease progression, and EQ-5D index scores. Analyses used data collected up to the last date of PFS assessment (May 17, 2019). Results: The restricted mean QA-PFS was significantly longer with niraparib versus placebo in the HRd (n = 373) and overall intention-to-treat (ITT; n = 733) populations (mean gains of 6.5 [95% confidence interval; CI, 3.9-8.9] and 4.1 [95% CI, 2.2-5.8] months, respectively). There were also significant improvements in restricted mean Q-TWiST for niraparib versus placebo (mean gains of 5.9 [95% CI, 3.5-8.6] and 3.5 [95% CI, 1.7-5.6] months, respectively) in the HRd and ITT populations. Conclusions: In patients with advanced OC, first-line niraparib maintenance was associated with significant gains in QA-PFS and Q-TWiST versus placebo. These findings demonstrate that niraparib maintenance treatment is associated with a PFS improvement and that treatment benefit is maintained even when HRQoL and/or toxicity data are combined with PFS in a single measure.
  • Autores: Vergote, I. (Autor de correspondencia); González Martín, Antonio; Lorusso, D.; et al.
    Revista: LANCET ONCOLOGY
    ISSN: 1470-2045 Vol.23 N° 8 2022 págs. E374 - E384
    Resumen
    The Gynecologic Cancer InterGroup (GCIG) sixth Ovarian Cancer Conference on Clinical Research was held virtually in October, 2021, following published consensus guidelines. The goal of the consensus meeting was to achieve harmonisation on the design elements of upcoming trials in ovarian cancer, to select important questions for future study, and to identify unmet needs. All 33 GCIG member groups participated in the development, refinement, and adoption of 20 statements within four topic groups on clinical research in ovarian cancer including first line treatment, recurrent disease, disease subgroups, and future trials. Unanimous consensus was obtained for 14 of 20 statements, with greater than 90% concordance in the remaining six statements. The high acceptance rate following active deliberation among the GCIG groups confirmed that a consensus process could be applied in a virtual setting. Together with detailed categorisation of unmet needs, these consensus statements will promote the harmonisation of international clinical research in ovarian cancer.
  • Autores: Sánchez Bayona, Rodrigo; García del Barrio, María Ángeles; Alegre Martínez, Estíbaliz; et al.
    Revista: JOURNAL OF CANCER RESEARCH AND THERAPEUTICS
    ISSN: 0973-1482 Vol.18 N° 4 2022 págs. 1183 - 1185
    Resumen
    The incidence of autoimmune thyroid disorders is higher among women with breast cancer (BC) than in other solid malignancies, while it has not a prognostic impact. Trastuzumab (T) is a humanized monoclonal antibody approved for human epidermal growth factor receptor 2 (HER2)-positive BC in the neoadjuvant, adjuvant, and metastatic scenarios. Since 2014, subcutaneous (SC) T has been employed with the same efficacy as the intravenous formulation together with an easier way of administration. To date, autoimmune thyroiditis has been linked rarely to the use of intravenous T, and no cases have been related to the SC presentation. We report two cases of HER2-positive early BC patients who developed hypothyroidism during maintenance therapy with SC T that required levothyroxine supplementation. SC T includes recombinant human hyaluronidase to facilitate tissue penetration of the drug. This enzyme may alter the thyroid gland stroma and facilitate the development of thyroid disorders. Thyroid function tests are recommended in patients on SC T.
  • Autores: Igual Rouilleault, Alba Cristina (Autor de correspondencia); Soriano Aguadero, Ignacio; Quan Lopez, Paola Leonor; et al.
    Revista: EUROPEAN RADIOLOGY
    ISSN: 0938-7994 Vol.32 N° 5 2022 págs. 3199 - 3206
    Resumen
    Objectives This study was conducted in order to investigate COVID-19 vaccine influence on unilateral axillary lymph nodes, comparing nodal basal features with their characteristics after the first and second vaccination dose. Methods Ninety-one volunteer employees from our center who participated in the BNT162b2 (Pfizer-BioNTech) vaccination campaign were prospectively recruited. A total of three axillary ultrasound evaluations of the ipsilateral vaccinated arm were performed: before vaccination, the week after the first dose and the week after the second dose. The following findings were recorded: the total number of visible nodes, the maximum measurements of the diameter and cortex, Bedi's classification, and color Doppler evaluation. The collected data were compared using paired-sample Student's t-test for quantitative continuous variables and Wilcoxon rank-sum test for ordinal variables. Additional analyses were performed after classifying patients according to the previous history of COVID-19 disease. Differences among both groups were evaluated with the Mann-Whitney U test. Variables with a p value < 0.05 were considered statistically significant. Results Comparative analyses between the three US examinations showed a statistically significant augmentation of total visible nodes, maximum diameter, cortical thickness, grade of Bedi's classification, and Doppler signal (p < 0.001). Analyses between patients with and without previous COVID-19 infection showed a higher lymph node response in naive patients compared to those who were previously infected. Conclusions According to our results, both doses of COVID-19 vaccine induced an increase of all axillary lymph node parameters with statistically significant differences, especially in coronavirus-naive patients.
  • Autores: Couto, M. (Autor de correspondencia); Vide, S.; Marco-Ariño, N.; et al.
    Revista: BRITISH JOURNAL OF ANAESTHESIA
    ISSN: 0007-0912 Vol.128 N° 3 2022 págs. 473 - 481
    Resumen
    Background: Profound neuromuscular block (NMB) is important in surgeries where complete immobility is considered essential to improve tracheal intubation and surgical conditions. Rocuronium bromide is a commonly used NMB agent. This work describes a noninvasive approach for estimation of post-tetanic count (PTC) based on two pharmacokinetic (PK) models, the Saldien and the De Haes models. The aim was to investigate the rocuronium bromide PK-pharmacodynamic (PD) relationship in estimating the PTC effect during profound NMB. Methods: In this prospective, non-randomised, observational study, an induction bolus of rocuronium bromide was administered followed by continuous infusion for maintenance of a PTC of 1-2. measured every 3 min. Measurements were analysed as discrete categorical data and by applying the nonlinear mixed-effect modelling approach. Performance of the selected models was evaluated through simulation model-based diagnostics, further assessing the precision of the parameter estimates and the performance of the models at the individual level. Results: Data from 30 adult patients undergoing elective abdominal or neurosurgical procedures were included. Post-tetanic count response profiles during rocuronium bromide infusion were successfully characterised using the population PD analysis. The models showed a good performance for all PTC categories, albeit with a moderate over-prediction of PTC >6. Conclusions: Our findings indicate that using plasma concentrations of rocuronium bromide estimated with either of the two models, combined with a PD model, provides equal model performance when predicting PTC. These promising results may provide an important advance in guiding rocuronium bromide administration when profound NMB in routine clinical practice is desired.
  • Autores: Hontanilla Calatayud, Bernardo Carlos (Autor de correspondencia); Bérniz Laborda, Carlos del Pilar
    Revista: JOURNAL OF PLASTIC RECONSTRUCTIVE AND AESTHETIC SURGERY
    ISSN: 1748-6815 Vol.75 N° 2 2022 págs. 767 - 772
    Resumen
    Masseteric nerve transposition has shown to be an effective technique for the treatment of facial paralysis. Due to its low morbidity at the donor site, its consistent anatomy, and one-stage operation, it constitutes a reliable option for both complete and incomplete facial paralysis. Masseteric nerve transference has proven to achieve good commissural excursion and dynamic symmetry. However, some patients with heavy faces and complete facial paralysis recover incompletely after surgery characterized by an asymmetrical smile with asymmetry at rest, affecting the cosmetic appearance. For these patients, we propose a novel combination of masseteric nerve transposition for the dynamic rehabilitation of the smile with a tendon sling suspension to create symmetry at rest. A detailed description of the surgical technique is given and results after using it with eight patients show good functional and aesthetic satisfaction. A combination of both dynamic and static techniques for complete facial paralysis rehabilitation may provide adequate symmetry with the contralateral healthy side both at rest and when smiling.
  • Autores: Marco-Ariño, N.; Vide, S.; Agusti, M.; et al.
    Revista: CPT: PHARMACOMETRICS & SYSTEMS PHARMACOLOGY
    ISSN: 2163-8306 Vol.11 N° 5 2022 págs. 581 - 593
    Resumen
    Intraoperative targeting of the analgesic effect still lacks an optimal solution. Opioids are currently the main drug used to achieve antinociception, and although underdosing can lead to an increased stress response, overdose can also lead to undesirable adverse effects. To better understand how to achieve the optimal analgesic effect of opioids, we studied the influence of remifentanil on the pupillary reflex dilation (PRD) and its relationship with the reflex movement response to a standardized noxious stimulus. The main objective was to generate population pharmacodynamic models relating remifentanil predicted concentrations to movement and to pupillary dilation during general anesthesia. A total of 78 patients undergoing gynecological surgery under general anesthesia were recruited for the study. PRD and movement response to a tetanic stimulus were measured multiple times before and after surgery. We used nonlinear mixed effects modeling to generate a population pharmacodynamic model to describe both the time profiles of PRD and movement responses to noxious stimulation. Our model demonstrated that movement and PRD are equally depressed by remifentanil. Using the developed model, we changed the intensity of stimulation and simulated remifentanil predicted concentrations maximizing the probability of absence of movement response. An estimated effect site concentration of 2 ng/ml of remifentanil was found to inhibit movement to a tetanic stimulation with a probability of 81%.
  • Autores: Vera Yunca, Diego; Parra Guillén, Zinnia Patricia; Girard, P.; et al.
    Revista: BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
    ISSN: 0306-5251 Vol.88 N° 1 2022 págs. 166 - 177
    Resumen
    Aims The aims of this work were to build a semi-mechanistic tumour growth inhibition (TGI) model for metastatic colorectal cancer (mCRC) patients receiving either cetuximab + chemotherapy or chemotherapy alone and to identify early predictors of overall survival (OS). Methods A total of 1716 patients from 4 mCRC clinical studies were included in the analysis. The TGI model was built with 8973 tumour size measurements where the probability of drop-out was also included and modelled as a time-to-event variable using parametric survival models, as it was the case in the OS analysis. The effects of patient- and tumour-related covariates on model parameters were explored. Results Chemotherapy and cetuximab effects were included in an additive form in the TGI model. Development of resistance was found to be faster for chemotherapy (drug effect halved at wk 8) compared to cetuximab (drug effect halved at wk 12). KRAS wild-type status and presenting a right-sided primary lesion were related to a 3.5-fold increase in cetuximab drug effect and a 4.7x larger cetuximab resistance, respectively. The early appearance of a new lesion (HR = 4.14), a large tumour size at baseline (HR = 1.62) and tumour heterogeneity (HR = 1.36) were the main predictors of OS. Conclusions Semi-mechanistic TGI and OS models have been developed in a large population of mCRC patients receiving chemotherapy in combination or not with cetuximab. Tumour-related predictors, including a machine learning derived-index of tumour heterogeneity, were linked to changes in drug effect, resistance to treatment or OS, contributing to the understanding of the variability in clinical response.
  • Autores: Gasparri, M. L. (Autor de correspondencia); de Boniface, J.; Poortmans, P.; et al.
    Revista: BRITISH JOURNAL OF SURGERY
    ISSN: 0007-1323 Vol.109 N° 9 2022 págs. 857 - 863
    Resumen
    Background There is no consensus on axillary management after neoadjuvant therapy (NAT) in patients with clinically node-positive (cN+) breast cancer. To investigate current clinical practice, an international survey was conducted among breast surgeons and radiation oncologists. The aim of the first part of the survey was to provide a snapshot of international discrepancies regarding axillary surgery in this context. Methods The European Breast Cancer Research Association of Surgical Trialists (EUBREAST) developed a web-based survey containing 39 questions describing clinical scenarios in the setting of axillary management in patients with cN1 disease converting to ycN0 after NAT. The survey was then distributed to breast surgeons and radiation oncologists via 14 breast cancer societies between April and October 2021. Results Responses from 349 physicians in 45 countries were recorded. The most common post-NAT axillary surgery in patients with cN1 disease converting to ycN0 was targeted axillary dissection (54.2 per cent), followed by sentinel lymph node biopsy (SLNB) alone (20.9 per cent), level 1-2 axillary lymph node dissection (ALND) (18.4 per cent), level 1-3 ALND (4 per cent), and targeted lymph node biopsy (2.5 per cent). For SLNB alone, dual tracers were most commonly used (62.3 per cent). Management varied widely in patients with ambiguous axillary status before initiation of treatment or a residual metastatic burden in the axilla after NAT. In patients with ycN+ tumours, ALND was the preferred surgical approach for 66.8 per cent of respondents. Conclusion These results highlight the wide heterogeneity in surgical approaches to the axilla after NAT. To standardize the guidelines, further data from clinical research are urgently needed, which underlines the importance of the ongoing AXSANA (EUBREAST-3) study. Several discrepancies in the surgical approach to the axilla in patients with cN+ disease converting to ycN0 exist. The most common axillary surgical approaches in patients with cN1 tumours converting to ycN0 are targeted axillary dissection (TAD) and sentinel lymph node biopsy. In targeted lymph node biopsy/TAD, there was a wide heterogeneity with regard to localization techniques.
  • Autores: Weber, W. P. (Autor de correspondencia); Shaw, J.; Pusic, A.; et al.
    Revista: BREAST
    ISSN: 0960-9776 Vol.63 2022 págs. 123 - 139
    Resumen
    Aim: Demand for nipple-and skin-sparing mastectomy (NSM/SSM) with immediate breast reconstruction (BR) has increased at the same time as indications for post-mastectomy radiation therapy (PMRT) have broadened. The aim of the Oncoplastic Breast Consortium initiative was to address relevant questions arising with this clinically challenging scenario. Methods: A large global panel of oncologic, oncoplastic and reconstructive breast surgeons, patient advocates and radiation oncologists developed recommendations for clinical practice in an iterative process based on the principles of Delphi methodology. Results: The panel agreed that surgical technique for NSM/SSM should not be formally modified when PMRT is planned with preference for autologous over implant-based BR due to lower risk of long-term complications and support for immediate and delayed-immediate reconstructive approaches. Nevertheless, it was strongly believed that PMRT is not an absolute contraindication for implant-based or other types of BR, but no specific recom-mendations regarding implant positioning, use of mesh or timing were made due to absence of high-quality evidence. The panel endorsed use of patient-reported outcomes in clinical practice. It was acknowledged that the shape and size of reconstructed breasts can hinder radiotherapy planning and attention to details of PMRT techniques is important in determining aesthetic outcomes after immediate BR. Conclusions: The panel endorsed the need for prospective, ideally randomised phase III studies and for surgical and radiation oncology teams to work together for determination of optimal sequencing and techniques for PMRT for each patient in the context of BR
  • Autores: Leone, C. (Autor de correspondencia); Di Stefano, G.; Di Pietro, G.; et al.
    Revista: TRIALS
    ISSN: 1745-6215 Vol.23 N° 1 2022 págs. 739
    Resumen
    Background: IMI2-PainCare-BioPain-RCT2 is one of four similarly designed clinical studies aiming at profiling a set of functional biomarkers of drug effects on specific compartments of the nociceptive system that could serve to accelerate the future development of analgesics. IMI2-PainCare-BioPain-RCT2 will focus on human spinal cord and brainstem activity using biomarkers derived from non-invasive neurophysiological measurements. Methods: This is a multisite, single-dose, double-blind, randomized, placebo-controlled, 4-period, 4-way crossover, pharmacodynamic (PD) and pharmacokinetic (PK) study in healthy subjects. Neurophysiological biomarkers of spinal and brainstem activity (the RIII flexion reflex, the N13 component of somatosensory evoked potentials (SEP) and the R2 component of the blink reflex) will be recorded before and at three distinct time points after administration of three medications known to act on the nociceptive system (lacosamide, pregabalin, tapentadol), and placebo, given as a single oral dose in separate study periods. Medication effects on neurophysiological measures will be assessed in a clinically relevant hyperalgesic condition (high-frequency electrical stimulation of the skin), and in a non-sensitized normal condition. Patient-reported outcome measures (pain ratings and predictive psychological traits) will also be collected; and blood samples will be taken for pharmacokinetic modelling. A sequentially rejective multiple testing approach will be used with overall alpha error of the primary analysis split between the two primary endpoints, namely the percentage amplitude changes of the RIII area and N13 amplitude under tapentadol. Remaining treatment arm effects on RIII, N13 and R2 recovery cycle are key secondary confirmatory analyses. Complex statistical analyses and PK-PD modelling are exploratory. Discussion: The RIII component of the flexion reflex is a pure nociceptive spinal reflex widely used for investigating pain processing at the spinal level. It is sensitive to different experimental pain models and to the antinociceptive activity of drugs. The N13 is mediated by large myelinated non-nociceptive fibers and reflects segmental postsynaptic response of wide dynamic range dorsal horn neurons at the level of cervical spinal cord, and it could be therefore sensitive to the action of drugs specifically targeting the dorsal horn. The R2 reflex is mediated by large myelinated non-nociceptive fibers, its circuit consists of a polysynaptic chain lying in the reticular formation of the pons and medulla. The recovery cycle of R2 is widely used for assessing brainstem excitability. For these reasons, IMI2-PainCare-BioPain-RCT2 hypothesizes that spinal and brainstem neurophysiological measures can serve as biomarkers of target engagement of analgesic drugs for future Phase 1 clinical trials. Phase 2 and 3 clinical trials could also benefit from these tools for patient stratification.
  • Autores: Butragueno-Laiseca, L.; Marco-Ariño, N.; Fernández de Trocóniz Fernández, José Ignacio; et al.
    Revista: CLINICAL MICROBIOLOGY AND INFECTION
    ISSN: 1198-743X Vol.28 N° 9 2022
    Resumen
    Objectives: Despite that piperacillin-tazobactam combination is commonly used in critically ill children, increasing evidence suggests that the current dosing schedules are not optimal for these patients. The aim of this work is to develop a population pharmacokinetic model for piperacillin to evaluate the efficacy of standard dosing in children with and without continuous kidney replacement therapy (CKRT) and to propose alternative dosing schemes maximizing target attainment. Methods: Four hundred twenty-nine piperacillin concentrations measured in different matrices, obtained from 32 critically ill children (19 without CKRT, 13 with CKRT) receiving 100 mg/kg of piperacillin/tazobactam every 8 hours (increased to 12 hours after the fourth dose) were modelled simultaneously using the population approach with NONMEM 7.4. The percentage of patients with 90% fT > MIC and target attainment (percentage of dosing interval above MIC) were estimated for different intermittent and continuous infusions in the studied population. Results: Piperacillin pharmacokinetic was best described with a two-compartment model. Renal, nonrenal, and hemofilter clearances were found to be influenced by the glomerular filtration rate, height (renal clearance), weight (nonrenal clearance), and filter surface (hemofilter clearance). Only seven (37%) children without CKRT and seven (54%) with CKRT achieved 90% fT > MIC with the current dosing schedule. Of the alternative regimens evaluated, a 24-hour continuous infusion of 200 mg/kg (CKRT) and 300 mg/kg (no CKRT) provided 100% fT > MIC (percent of time free drug remains above the minimum inhibitory concentration) (<= 16 mg/L) and target attainments >= 90% across all evaluated MICs. Discussion: In children with and without CKRT, standard dosing failed to provide an adequate systemic exposure, while prolonged and continuous infusions showed an improved efficacy. (C) 2022 The Author(s). Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases.
  • Autores: Chase, D. M. (Autor de correspondencia); Marín, M. R.; Backes, F.; et al.
    Revista: GYNECOLOGIC ONCOLOGY
    ISSN: 0090-8258 Vol.166 N° 3 2022 págs. 494 - 502
    Resumen
    Objective. Progression-free survival (PFS) is an important early efficacy endpoint in ovarian cancer (OC) and its relevance to patients should be assessed. PRIMA, a phase III trial, assessed niraparib in patients with OC; this post hoc analysis examined the relationship between disease progression in OC and health-related quality of life (HRQoL).Methods. The PRIMA trial randomized patients with advanced OC responsive to first-line platinum-based chemotherapy to once daily maintenance oral niraparib or placebo. This post hoc analysis evaluated the impact of dis-ease progression on HRQoL by comparing HRQoL at the last visit pre-progression to end of treatment (EoT), and after 4, 8, 12, and 24 weeks. Assessments included the Functional Assessment of Cancer Therapy-Ovarian Symptom Index (FOSI), the European Quality of Life Five Dimension Five Level questionnaire (EQ-5D-5L) and EQ Visual Analogue Scale (EQ-VAS), the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Question-naire (EORTC-QLQ-C30), and the EORTC Quality of Life Questionnaire Ovarian Cancer module (EORTC-QLQ-OV28).Results. This post hoc analysis included 733 patients. Mean FOSI, EQ-5D-5L, and EQ-VAS scores deteriorated from last visit pre-progression to EoT and remained low up to 24-week follow-up. Least squares mean changes from last visit pre-progression to EoT were -2.1 (95% confidence interval -2.4, -1.7) for FOSI, -4.6 (-5.6, -3.5) for the EQ-5D-5L index, and -7.9 (-9.6, -6.3) for EQ-VAS.Conclusions. Disease progression negatively impacted HRQoL in patients with OC. PFS is clinically relevant, and prolonging PFS may preserve HRQoL.
  • Autores: Nochi, Z.; Pia, H.; Bloms-Funke, P.; et al.
    Revista: TRIALS
    ISSN: 1745-6215 Vol.23 N° 1 2022 págs. 163
    Resumen
    Background Few new drugs have been developed for chronic pain. Drug development is challenged by uncertainty about whether the drug engages the human target sufficiently to have a meaningful pharmacodynamic effect. IMI2-PainCare-BioPain-RCT1 is one of four similarly designed studies that aim to link different functional biomarkers of drug effects on the nociceptive system that could serve to accelerate the future development of analgesics. This study focusses on biomarkers derived from nerve excitability testing (NET) using threshold tracking of the peripheral nervous system. Methods This is a multisite single-dose, subject and assessor-blind, randomized, placebo-controlled, 4-period, 4-way crossover, pharmacodynamic (PD), and pharmacokinetic (PK) study in healthy subjects. Biomarkers derived from NET of large sensory and motor fibers and small sensory fibers using perception threshold tracking will be obtained before and three times after administration of three medications known to act on the nociceptive system (lacosamide, pregabalin, tapentadol) and placebo, given as a single oral dose with at least 1 week apart. Motor and sensory NET will be assessed on the right wrist in a non-sensitized normal condition while perception threshold tracking will be performed bilaterally on both non-sensitized and sensitized forearm skin. Cutaneous high-frequency electrical stimulation is used to induce hyperalgesia. Blood samples will be taken for pharmacokinetic purposes and pain ratings as well as predictive psychological traits will be collected. A sequentially rejective multiple testing approach will be used with overall alpha error of the primary analysis split across the two primary outcomes: strength-duration time constant (SDTC; a measure of passive membrane properties and nodal persistent Na+ conductance) of large sensory fibers and SDTC of large motor fibers comparing lacosamide and placebo. The key secondary endpoint is the SDTC measured in small sensory fibers. Remaining treatment arm effects on key NET outcomes and PK modelling are other prespecified secondary or exploratory analyses. Discussion Measurements of NET using threshold tracking protocols are sensitive to membrane potential at the site of stimulation. Sets of useful indices of axonal excitability collectively may provide insights into the mechanisms responsible for membrane polarization, ion channel function, and activity of ionic pumps during the process of impulse conduction. IMI2-PainCare-BioPain-RCT1 hypothesizes that NET can serve as biomarkers of target engagement of analgesic drugs in this compartment of the nociceptive system for future Phase 1 clinical trials. Phase 2 and 3 clinical trials could also benefit from these tools for patient stratification.
  • Autores: López-Guerrero, J. A. (Autor de correspondencia); Mendiola, M.; Pérez-Fidalgo, J. A.; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.14 N° 8 2022 págs. 1965
    Resumen
    Patient registries linked to biorepositories constitute a valuable asset for clinical and translational research in oncology. The Spanish Group of Ovarian Cancer Research (GEICO), in collaboration with the Spanish Biobank Network (RNBB), has developed a multicentre, multistakeholder, prospective virtual clinical registry (VCR) associated with biobanks for the collection of real-world data and biological samples of gynaecological cancer patients. This collaborative project aims to promote research by providing broad access to high-quality clinical data and biospecimens for future research according to the needs of investigators and to increase diagnostic and therapeutic opportunities for gynaecological cancer patients in Spain. The VCR will include the participation of more than 60 Spanish hospitals entering relevant clinical information in harmonised electronic case report forms (eCRFs) in four different cohorts: ovarian, endometrial, cervical, and rare gynaecological cancers (gestational trophoblastic disease). Initial data for the cases included till December 2021 are presented. The model described herein establishes a real-world win-win collaboration between multicentre structures, promoted and supported by GEICO, that will contribute to the success of translational research in gynaecological cancer
  • Autores: Rubio, Isabel Teresa (Autor de correspondencia); Sobrido Sampedro, Carolina
    Revista: BREAST
    ISSN: 0960-9776 Vol.62 2022 págs. S17 - S24
    Resumen
    Neoadjuvant treatment (NAT) has become an option in early stage (stage I-II) breast cancer (EBC). New advances in systemic and targeted therapies have increased rates of pathologic complete response increasing the number of patients undergoing NAT. Clear benefits of NAT are downstaging the tumor and the axillary nodes to de-escalate surgery and to evaluate response to treatment. Selection of patients for NAT in EBC rely in several factors that are related to patient characteristics (i.e, age and comorbidities), to tumor histology, to stage at diagnosis and to the potential changes in surgical or adjuvant treatments when NAT is administered. Imaging and histologic confirmation is performed to assess extent of disease y to confirm diagnosis. Besides mammogram and ultrasound, functional breast imaging MRI has been incorporated to better predict treatment response and residual disease. Contrast enhanced mammogram (CEM), shear wave elastography (SWE), or Dynamic Optical Breast Imaging (DOBI) are emerging techniques under investigation for assessment of response to neoadjuvant therapy as well as for predicting response. Surgical plan should be delineated after NAT taking into account baseline characteristics, tumor response and patient desire. In the COVID era, we have witnessed also the increasing use of NAT in patients who may be directed to surgery, unable to have it performed as surgery has been reserved for emergency cases only.
  • Autores: Igual Rouilleault, Alba Cristina (Autor de correspondencia); Soriano Aguadero, Ignacio; Elizalde Pérez, Arlette María; et al.
    Revista: EUROPEAN RADIOLOGY
    ISSN: 0938-7994 Vol.32 N° 10 2022 págs. 6598 - 6607
    Resumen
    Objectives To assess ultrasound characteristics of ipsilateral axillary lymph nodes after two doses of four different COVID-19 vaccination protocols, to determine whether these parameters differed with age, and to describe how they changed on follow-up imaging. Methods A total of 247 volunteer employees from our center who had received two doses of COVID-19 vaccination were recruited and followed prospectively. Axillary ultrasound of the ipsilateral vaccinated arm was performed the week after receiving the second dose to analyze lymph node features (number, long-axis, cortical thickness, morphology, and vascular imaging). Axillary lymphadenopathy resulting from four vaccination protocols-mRNA (BNT162b2, mRNA-1273), ChAdOx1-S, and mix-and-match-was compared. Analysis was conducted using the Kruskal-Wallis test and post hoc analysis with Bonferroni corrections. Nodal reactogenicity was evaluated for two age groups: young (< 45 years old) and middle-aged ( >= 45 years old). All parameters were compared between both groups using an unpaired-sample Student t test. A p value < 0.05 was considered statistically significant. Results Significantly higher values for total number of visible nodes, cortical thickness, Bedi's classification (p < 0.001), and vascularity (p < 0.05) were observed in mRNA vaccine recipients compared to full ChAdOx1-S protocol recipients. Moreover, mix-and-match protocol recipients showed greater nodal cortical thickness and higher Bedi's classification than full ChAdOx1-S recipients (p < 0.001). Analyses between age groups revealed greater cortical thickness, Bedi's classification, and color Doppler signal in younger patients (p < 0.05). Conclusions Nodal parameters of Bedi's classification and cortical thickness were more often increased in mRNA and mix-and-match vaccine recipients when compared to ChAdOx1-S vaccine alone, especially in younger patients.
  • Autores: Razumova, Z. (Autor de correspondencia); Bizzarri, N.; Pletnev, A.; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN: 1048-891X Vol.32 N° 11 2022 págs. 1363-1369
    Resumen
    This is a report from the 22nd Meeting of the European Society of Gynaecological Oncology, held October 23-25, 2021. The 3-day event offered an educational experience covering the major scientific and clinical advances in gynecological oncology. The Congress program included different session formats, including guidelines updates and state-of-the-art lectures. This article provides an overview of the main Congress activities as well as of the most important studies that were presented at the event for the first time.
  • Autores: de la Cruz-Merino, L. (Autor de correspondencia); Gion, M.; Cruz, J.; et al.
    Revista: BMC CANCER
    ISSN: 1471-2407 Vol.22 N° 1 2022 págs. 1258
    Resumen
    BackgroundWe evaluated a new chemoimmunotherapy combination based on the anti-PD1 monoclonal antibody pembrolizumab and the pyrimidine antimetabolite gemcitabine in HER2- advanced breast cancer (ABC) patients previously treated in the advanced setting, in order to explore a potential synergism that could eventually obtain long term benefit in these patients. MethodsHER2-negative ABC patients received 21-day cycles of pembrolizumab 200 mg (day 1) and gemcitabine (days 1 and 8). A run-in-phase (6 + 6 design) was planned with two dose levels (DL) of gemcitabine (1,250 mg/m(2) [DL0]; 1,000 mg/m(2) [DL1]) to determine the recommended phase II dose (RP2D). The primary objective was objective response rate (ORR). Tumor infiltrating lymphocytes (TILs) density and PD-L1 expression in tumors and myeloid-derived suppressor cells (MDSCs) levels in peripheral blood were analyzed. ResultsFourteen patients were treated with DL0, resulting in RP2D. Thirty-six patients were evaluated during the first stage of Simon's design. Recruitment was stopped as statistical assumptions were not met. The median age was 52; 21 (58%) patients had triple-negative disease, 28 (78%) visceral involvement, and 27 (75%) & GE; 2 metastatic locations. Progression disease was observed in 29 patients. ORR was 15% (95% CI, 5-32). Eight patients were treated & GE; 6 months before progression. Fourteen patients reported grade & GE; 3 treatment-related adverse events. Due to the small sample size, we did not find any clear association between immune tumor biomarkers and treatment efficacy that could identify a subgroup with higher probability of response or better survival. However, patients that experienced a clinical benefit showed decreased MDSCs levels in peripheral blood along the treatment. ConclusionPembrolizumab 200 mg and gemcitabine 1,250 mg/m(2) were considered as RP2D. The objective of ORR was not met; however, 22% patients were on treatment for & GE; 6 months. ABC patients that could benefit of chemoimmunotherapy strategies must be carefully selected by robust and validated biomarkers. In our heavily pretreated population, TILs, PD-L1 expression and MDSCs levels could not identify a subgroup of patients for whom the combination of gemcitabine and pembrolizumab would induce long term benefit.
  • Autores: Buisson, A.; Saintigny, P.; Pujade-Lauraine, E.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.40 N° 16 2022 págs. E17599
    Resumen
    Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) induce synthetic lethality in cells with homologous recombination deficiency (HRD). PARPi treatment revolutionized management of patients with cancer, particularly in types where HRD is common, such as ovarian and breast cancer. However, challenges in the implementation of available methods currently limit adoption of HRD testing in the clinics. Here we present the analytical performance evaluation of the Genomic Integrity Index (GII) (SOPHiA GENETICs SA). Methods: GII is a deep-learning based solution for identification of HRD positive tumors from low-pass whole genome sequencing (lpWGS) data (X1 fold coverage). The analytical performance of the GII was evaluated as positive (PPA), negative (NPA) and overall (OPA) percentage of agreement with the HRD status determined by Myriad myChoice CDx (Myriad Genetic Laboratories, Inc.; US FDA-approved). We generated whole genome sequencing libraries for DNA extracted from 139 ovarian cancer Formalin-Fixed Paraffin- Embedded samples, in 4 independent clinical laboratories. We sequenced to the equivalent of 1X coverage (¿10 million reads, 150 base paired end reads, Illumina) and performed HRD classification data using GII using manufacturer¿s recommended thresholds. Results: The GII demonstrated high analytical concordance with Myriad myChoice CDx with 91.7% PPA, 95.5% NPA and 94.5% OPA (Table). The HRD status obtained by GII from a subset of positive and negative samples was 100% reproducible (n = 4) between runs. Conclusions: The HRD status obtained by GII is highly concordant with that obtained from standard method, supporting that GII allows accurate and reproducible detection of HRD from lpWGS data. LpWGS is amongst the most cost-effective and easy to implement genome profiling methods, making it uniquely suited for clinical applications.
  • Autores: Yubero-Esteban, A.; Reche-Molina, P.; Salvador-Coloma, C.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.40 N° 16 2022 págs. E17598
    Resumen
    Background: Rucaparib is a PARP inhibitor (PARPi) approved as maintenance therapy for platinum (Pt)-sensitive recurrent high-grade ovarian cancer (HGOC), and as treatment for BRCA-mutant HGOC patients. To date, there is little evidence about the efficacy and safety of rucaparib after prior exposure to PARPi. This subanalysis aims to describe the patients¿ characteristics and treatment outcomes with rucaparib in women who were included in the rucaparib early access program (RAP) in Spain and had received a prior PARPi. Methods: A retrospective study was conducted by GEICO at 22 hospitals in Spain to analyze data of 51 women treated within the RAP (600 mg BID). Adult women with HGOC, fallopian tube, or primary peritoneal cancer, who had received at least one prior PARPi before rucaparib were analyzed. Patients¿ characteristics, medical history, safety, efficacy, and dosing data were collected. Results: A total of 14 women, with a median age of 63 years old (42-78) were included in this subanalysis. Of them, 92.9% were diagnosed of epithelial ovarian cancer and 78.6% had mutations in BRCA1/2 genes. The median number of lines before rucaparib was 5 (3-8), while the number of lines before the first PARPi was 3 (2-5). Except for one woman who had received 2 prior PARPis before rucaparib, the others had received just 1. Most patients were given olaparib as the first PARPi (n = 12, 85.8%), while niraparib was the initial PARPi in the remaining cases (n = 2, 14.3%). The outcomes of the treatment with rucaparib in these patients are outlined in table 1. Rucaparib was given as maintenance therapy in 1 patient and as treatment in 13 patients, 12 of them being Pt-resistant. The progression-free survival (PFS) ranged from 0.23 to 9.12 months. Adverse events (AE) of any grade were detected in 78.6% of patients, whereas AE of grade ¿3 affected 28.6% of women. Rucaparib dose was interrupted in 57.1% and reduced in 42.9% of patients. Only 1 patient discontinued rucaparib due to toxicity. No new safety signals were detected. Conclusions: This is one of the first real-word studies reporting the use of rucaparib after treatment with another PARPi. Even in these heavily pre-treated patients who had received prior PARPi, rucaparib efficacy has been notable in some cases, and its safety profile is consistent with that reported in previous clinical trials. Future studies should focus on the selection of patients who could benefit from rucaparib after prior PARPi exposure.
  • Autores: Nagao, S.; Harter, P.; Leary, A.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.33 N° SUPPL 9 2022 págs. S1503 - S1504
    Resumen
    Background In the PAOLA-1/ENGOT-ov25 (NCT02477644) primary analysis, adding ola to maintenance bev after first-line (1L) platinum-based chemotherapy (PBC) + bev led to a significant progression-free survival (PFS) benefit in AOC (HR 0.59, 95% CI 0.49¿0.72; P<0.001), particularly in pts with homologous recombination deficiency (HRD+; BRCA1/2 mutation [BRCAm] and/or genomic instability; Ray-Coquard et al NEJM 2019). Here, we report the prespecified final OS analysis. Methods Pts with high-grade AOC, in response after PBC + bev, were randomized 2:1 to ola tablets (300 mg bid; up to 24 months [mo]) + bev (15 mg/kg q3w; 15 mo total) or placebo [pbo] + bev. OS (intent-to-treat [ITT] population) was a key secondary endpoint, with analysis planned for 3 years after the primary analysis as part of hierarchical testing. Results 537 pts were randomized to ola + bev and 269 to pbo + bev (median follow-up 61.7 and 61.9 mo, respectively; OS data maturity: 55.3%). Median OS in the ITT population was 56.5 mo with ola + bev vs 51.6 mo with pbo + bev (HR 0.92, 95% CI 0.76¿1.12; P=0.4118; OS at 5 y, 47.3 vs 41.5%). In HRD+ pts, OS was prolonged with ola + bev (HR 0.62, 95% CI 0.45¿0.85; OS at 5 y, 65.5 vs 48.4%), with benefit in HRD+ pts with or without a tumour BRCAm (tBRCAm; Table). No benefit was seen in HRD- pts (HR 1.19, 95% CI 0.88¿1.63). Subsequent PARP inhibitor therapy was received by 105 (19.6%) ola + bev pts vs 123 (45.7%) pbo + bev pts. Myelodysplastic syndrome, acute myeloid leukaemia and aplastic anaemia incidence, and new primary malignancy incidence, was respectively: ola + bev, 9 pts [1.6%] and 22 pts [4.1%]; pbo + bev, 6 pts [2.2%]) and 8 pts [2.9%]). Table: 176O. Conclusions Despite a high proportion of pts in the control arm receiving a PARP inhibitor post-progression, ola + bev provided a clinically meaningful improvement in OS for 1L HRD+ pts with and without a tBRCAm, confirming ola + bev as standard of care in this setting. Clinical trial identification NCT02477644.
  • Autores: Herzog, T.; Wahab, S. A.; Mirza, M.; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN: 1048-891X Vol.32 N° SUPPL 3 2022 págs. A140 - A141
    Resumen
    Objectives Progression-free survival (PFS) is a rational surrogate primary endpoint in ovarian cancer (OC) trials. However, PFS is subject to biases, with validity dependent upon proper methodologic assessment. Therefore, blinded independent centralized radiologic review (BICR) is often recommended. We evaluated BICR and investigator-assessed evaluation of progressive disease (PD) in the PRIMA/ENGOT-ov26/GOG-3012 trial examining niraparib monotherapy in intent-to-treat (ITT) and homologous recombination deficient (HRd) populations. Methods In the randomized, double-blind, placebo-controlled phase 3 PRIMA/ENGOT-ov26/GOG-3012 trial, patients with newly diagnosed stage III/IV OC were assigned to receive either niraparib or placebo. The primary endpoint was PFS (per RECIST v.1.1) by BICR. Discordance between BICR and investigator assessments of PD ([#BICR reviews with unconfirmed PD assessment]/[total# investigator-triggered reviews]) was monitored throughout the study. A training intervention was developed for BICR reviewers based on PD determination in OC. Results In an initial patient subset (n=80), a 39% discordance rate was identified between BICR and investigator-assessed PD by the sponsor, most commonly due to peritoneal carcinomatosis or fluid collections arising from new non-target lesions. After reviewer intervention, final discordance rate between BICR and investigator improved to 12% and 13% for ITT (N=733) and HRd (n=373) populations, respectively (figure 1). Across the entire study population, median PFS and hazard ratios for the ITT and HRd populations were comparable between BICR and investigator (table 1). Conclusions PRIMA/ENGOT-ov26/GOG-3012 highlights the need to optimize BICR and investigator concordance using early, specialized OC-specific training to maximize trial validity.
  • Autores: Ray-Coquard, I. L.; Leary, A.; Pignata, S.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.33 N° SUPPL 7 2022 págs. S1396 - S1397
    Resumen
    Background In the PAOLA-1/ENGOT-ov25 (NCT02477644) primary analysis, adding ola to maintenance bev after first-line (1L) platinum-based chemotherapy (PBC) + bev led to a significant progression-free survival (PFS) benefit in AOC (HR 0.59, 95% CI 0.49¿0.72; P<0.001), particularly in pts with homologous recombination deficiency (HRD+; BRCA1/2 mutation [BRCAm] and/or genomic instability; Ray-Coquard et al NEJM 2019). Here, we report the prespecified final OS analysis. Methods Pts with high-grade AOC, in response after PBC + bev, were randomized 2:1 to ola tablets (300 mg bid; up to 24 months [mo]) + bev (15 mg/kg q3w; 15 mo total) or placebo [pbo] + bev. OS (intent-to-treat [ITT] population) was a key secondary endpoint, with analysis planned for 3 years (y) after the primary analysis as part of hierarchical testing. Results 537 pts were randomized to ola + bev and 269 to pbo + bev (median follow-up 61.7 and 61.9 mo, respectively; OS data maturity: 55.3%). Median OS in the ITT population was 56.5 mo with ola + bev vs 51.6 mo with pbo + bev (HR 0.92, 95% CI 0.76¿1.12; P=0.4118; OS at 5 y, 47.3 vs 41.5%). In HRD+ pts, OS was prolonged with ola + bev (HR 0.62, 95% CI 0.45¿0.85; OS at 5 y, 65.5 vs 48.4%), with benefit in HRD+ pts with or without a tumour BRCAm (tBRCAm; Table). No benefit was seen in HRD- pts (HR 1.19, 95% CI 0.88¿1.63). Subsequent PARP inhibitor therapy was received by 105 (19.6%) ola + bev pts vs 123 (45.7%) pbo + bev pts. Myelodysplastic syndrome, acute myeloid leukaemia and aplastic anaemia incidence, and new primary malignancy incidence, was respectively: ola + bev, 9 pts [1.6%] and 22 pts [4.1%]; pbo + bev, 6 pts [2.2%]) and 8 pts [2.9%]). Table: LBA29. Conclusions Despite a high proportion of pts in the control arm receiving a PARP inhibitor post-progression, ola + bev provided a clinically meaningful improvement in OS for 1L HRD+ pts with and without a tBRCAm, confirming ola + bev as standard of care in this setting. Clinical trial identification NCT02477644.
  • Autores: Moore, K.; O'Malley, D.; Vergote, I.; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN: 1048-891X Vol.32 N° SUPPL 3 2022 págs. A33 - A34
    Resumen
    Objectives Mirvetuximab soravtansine (MIRV) is a first-in-class ADC comprising a folate receptor-¿ (FR¿)-binding antibody, cleavable linker, and maytansinoid DM4 payload. As part of the phase 1b/2 trial (NCT02606305), efficacy and safety of MIRV and carboplatin (carbo) were evaluated in patients with recurrent FR¿-positive platinum sensitive ovarian cancer (PSOC) measured by immunohistochemistry (PS2+ ¿25%; table 1). Methods Eighteen patients received MIRV and carbo intravenously on Day 1 of a 3-week cycle using a standard 3 + 3 design, with a starting dose of MIRV 5 mg/kg adjusted ideal body weight (AIBW) and carbo AUC4. FR¿ positivity by immunohistochemistry (PS2+ ¿25%) was required. Primary endpoint was confirmed ORR by RECIST v1.1. Results Ten patients received MIRV 6 mg/kg AIBW and carbo AUC5. Anti-tumor activity was observed in all dose escalation cohorts with varying levels of FR¿ expression. Patients receiving MIRV 6 mg/kg AIBW and carbo AUC5 had an ORR of 89%, mDOR of 12.1, and mPFS of 16.5 months. Patients with medium/high FR¿-expressing tumors had an ORR of 80%, mDOR of 24.2, and mPFS of 15.0 months across all escalation cohorts (table 2). The most frequent treatment-emergent adverse events (all, grade 3+) included nausea (72%, 0%), diarrhea (67%, 6%), blurred vision (67%, 0%), thrombocytopenia (61%, 17%), fatigue (61%, 11%), and neutropenia (56%, 28%). Conclusions MIRV and carbo demonstrated anti-tumor activity in patients with recurrent FR¿-positive PSOC. MIRV 6 mg/kg AIBW and carbo AUC5 was selected as the phase 2 dose. This combination is being evaluated in one planned and two ongoing (NCT04606914 and NCT04274426) studies.
  • Autores: Di Cosimo, S.; Pizzamiglio, S.; Sotiriou, C.; et al.
    Revista: EUROPEAN JOURNAL OF CANCER
    ISSN: 0959-8049 Vol.175 N° SUPPL 1 2022 págs. S78
    Resumen
    Background: NeoALTTO showed increased pathological complete response (pCR) with paclitaxel combined with dual over single anti-HER2 blockade. The trial included six initial weeks of treatment with lapatinib (L), trastuzumab (T) or their combination (L+T) followed by chemotherapy (CHT). A tumor biopsy was planned during the CHT-free window at day14 ± 2. Herein, we tested the hypothesis that prognostication of clinical outcome is feasible through assessment of gene expression profile (GEP) following two weeks of anti-HER2 therapy. Patients and methods: RNA from matched baseline and day14 ± 2 biopsies were profiled using Clariom S microarray (ThermoFisher). The levels of the molecular classifier TRAR, which proved to identify HER2-addicted (HER2 high/ESR1 low, TRAR-low) and non HER2-addicted (TRAR high, Estrogen Receptor [ER]-dependent) primary tumors, and five immune-related metagenes, namely, the T-cell surrogate lymphocyte-specific kinase (LCK), the monocyte/myeloid lineage hemopoietic cell kinase (HCK), interferon (IFN), major histocompatibility complex II (MHCII), and signal transducer and activator of transcription 1 (STAT1) were computed. Logistic and Cox regression models were applied to evaluate the association between TRAR and immune-related metagenes with pCR and event free survival (EFS), at baseline and after two weeks of treatment with anti-HER 2 therapy. Results: Overall, 180 matched baseline and day14 ± 2 GEP samples were analyzed from patients treated with L (n = 65), T (n = 66), and L+T (n = 49). No significant differences in patient characteristics or outcomes were observed between the cohort included in our study and the whole NeoALTTO patient population. At baseline, none of the immune-related metagenes tested were informative of patient outcomes. After 2 weeks of treatment with anti-HER2, the expression levels of LCK (OR: 3.92, 95%CI: 1.96; 7.85), HCK (OR: 3.22, 95%CI: 1.55; 6.68), and MHCII (OR: 2.68, 95%CI: 1.37; 5.26) were significantly positively associated with pCR, independently from ER status and treatment arm. When considering changes from baseline, increased levels of LCK were also predictive (2.90, 95% CI:1.48;5.71), and those of HCK were associated with EFS regardless of pCR and nodal status (HR: 0.57, 95%CI: 0.34; 0.96). TRAR assessment at day 14 ± 2 was not predictive of response. However, both pre-treatment TRAR (Odds Ratio [OR]: 0.19, 95% CI: 0.08;0.47), and its increase during treatment (OR:3.99 95%CI1.90; 8.39) were independently associated with pCR. Conclusions: Biomarkers of early T-cell and monocyte-macrophage activation, as well as HER2 downregulation hold the potential to reliably identify patients likely to achieve a pCR and a favorable prognosis. New effective treatments need to be explored for cases lacking an early GEP response.
  • Autores: Esgueva Colmenarejo, Antonio Jesús; Regueira, F.; Rodríguez-Spiteri Sagredo, Natalia; et al.
    Revista: EUROPEAN JOURNAL OF CANCER
    ISSN: 0959-8049 Vol.175 N° Suppl. 1 2022 págs. S4 - S5
  • Autores: Garcia Porrero, Guillermo; Argueta Morales, Allan; Villalba Esparza, María; et al.
    Revista: LABORATORY INVESTIGATION
    ISSN: 0023-6837 Vol.102 N° Supl. 1 2022 págs. 258
  • Autores: González Martín, Antonio; Pothuri, B.; Vergote, I. B.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.33 N° SUPPL 7 2022 págs. S789
    Resumen
    Background Niraparib (nir) has shown PFS benefit as a first-line (1L) maintenance therapy (MT) in the PRIMA primary analysis (data cut 17 May 2019) in all subgroups regardless of biomarker status. These results were the basis for approval of nir as MT after response to 1L platinum-based chemo (CT). Here we report updated long-term efficacy and safety in the PRIMA study. Methods This double-blind, placebo (PBO)-controlled phase 3 trial evaluated nir in pts with newly diagnosed advanced high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube cancer (OC) with a complete or partial response (CR or PR) to 1L platinum-based CT. Stratification factors were best response to 1L CT regimen (CR/PR), receipt of neoadjuvant CT (NACT; yes/no), and homologous recombination deficiency (HRD) status (HRd/HRp/HRnd) per Myriad myChoice HRD test. Pts received nir or PBO QD (2:1 ratio). The primary endpoint of PFS by blinded independent central review was concordant with investigator assessment (INV). Updated (ad hoc) data are by INV, as of 17 Nov 2021. Results Of 733 randomized pts (nir, 487; PBO, 246), 373 (51%) were HRd (nir, 247; PBO, 126), and 249 (34%) were HRp (nir, 169; PBO, 80). Overall, 35% had stage IV disease, 67% received NACT, and 33% had a PR to 1L CT. As of 17 Nov 2021, median PFS follow-up time was 3.5 y. Nir-treated pts (HRd/HRp/overall) received continued PFS benefit vs PBO (Table). All subgroups showed a sustained and durable treatment effect. The most common grade ¿3 adverse events in the nir arm were thrombocytopenia (40%), anemia (32%), and neutropenia (21%). No related on-treatment deaths occurred. MDS/AML were reported at the same incidence in nir 6/484 (1.2%) and PBO 3/244 (1.2%) arms. OS remains immature at 41% for the overall population; 33% of PBO vs 9% of nir pts received subsequent PARPi (Table: 530P). Conclusions Nir maintained clinically significant improvement in PFS with 3.5 y of follow-up in pts with newly diagnosed advanced OC at high risk of progression irrespective of HRD status. No new safety signals were identified. Clinical trial identification NCT02655016
  • Autores: Vergote, I.; Kim, S.; Ursell, P.; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN: 1048-891X Vol.32 N° SUPPL 3 2022 págs. A74 - A75
    Resumen
    Objectives Tisotumab vedotin (TV), a tissue factor (TF)-directed antibody-drug conjugate (ADC) with a monomethyl auristatin E payload, received accelerated FDA approval for treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. TV-associated ocular adverse events (OAEs) present as symptomatic ocular surface inflammations, dissimilar to microcystic keratopathies reported for other ADCs. We hypothesize TF expression in the eye may be linked to TV-associated OAEs. Methods In vitro human tissue cross-reactivity (TCR) and repeat-dose cynomolgus monkey toxicity studies were conducted. TV was evaluated for efficacy and safety in the pivotal innovaTV 204/GOG-3023/ENGOT-cx6 trial; patients performed mandatory eye care to mitigate OAE risk. Results TCR results indicate TV binds to cryosections of human ocular tissues, including conjunctival epithelium (n=3 donors per tissue). Ocular findings from cynomolgus monkeys receiving TV Q3W for 5 doses (n=5M/5F per dose level) included partially closed eyes and reddened eyes and/or conjunctiva. Binding or inhibiting TF with unconjugated anti-TF antibody in cynomolgus monkeys did not lead to similar ocular findings. In innovaTV 204, 54% of patients exhibited OAEs (1.4-month median onset, IQR 0.7¿2.0), mostly Grade 1¿2 in severity. Common events included conjunctivitis, dry eye, and keratitis. Four patients experienced visual acuity changes; 3 resolved at last follow-up. Conclusions Preclinical data suggest an ocular surface-expressed TF-dependent phenomenon and provide potential mechanistic rationale which may partly contribute to the inflammatory and symptomatic nature of clinically observed TV-associated OAEs. Clinical trial experience suggests adherence to required eye care and appropriate dose modifications reduce risk and severity of OAEs.
  • Autores: Heitz, F.; Oaknin, A.; Backes, F. J.; et al.
    Revista: GEBURTSHILFE UND FRAUENHEILKUNDE
    ISSN: 0016-5751 Vol.82 N° 10 2022 págs. E87 - E88
    Resumen
    Zielsetzung¿In dieser Phase II Studie kommt der antiangiogenische Multikinase-Inhibitor Lucitanib in Kombination mit dem PD-1 Inhibitor Nivolumab in 4 Patientinnenkohorten zur Anwendung (Zervix-, Endometrium-, Ovarialkarzinom, gepoolte Klarzellkohorte Endometrium-/Ovarialkarzinom). Wir präsentieren hier die Interim-Daten der Zervixkarzinomkohorte. Material und Methoden¿Patientinnen mit persistierendem/rezidiviertem Zervixkarzinom nach ¿1 Platin-haltiger Chemotherapielinie +/- Bevacizumab wurden mit einer Startdosis von 6mg Lucitanib oral 1x täglich + 480mg Nivolumab iv alle 28 Tage behandelt. Die erste Dosis Lucitanib wurde für Patientinnen, die bestimmte Sicherheits-Titrationskriterien erfüllten, von 6 zu 8zu 10mg täglich gesteigert. Eine vorhergehende Behandlung mit einem PD-1/PDL-1 Inhibitor war nicht erlaubt. Daten cut-off war der 1. September 2021. Ergebnisse¿Zwanzig Patientinnen wurden/werden behandelt (mediane Behandlungsdauer 85 Tage, Spannweite 1¿343+). Elf (55%) Patientinnen haben ¿2 vorherige Therapielinien erhalten; 9 (45%) hatten bereits Bevacizumab. Aktuell haben 17 (85%) ¿1 Zyklus komplettiert. Die häufigsten treatment-emergent adverse events (TEAEs) jeden Grades waren Hypertension (n=13 [65%]), Appetitlosigkeit (n=11 [55%]), Fatigue (n=10 [50%]), und Übelkeit (n=10 [50%]); das häufigste ¿ Grad 3 TEAE war Hypertension (n=4 [20%]). Vier (20%) Patientinnen haben Lucitanib auf Grund eines TEAE beendet, 3 davon wurden mit Lucitanib in Verbindung gebracht (Hypertension, Proteinurie, Kolonfistel). Bisher zeigte sich bei 4 Patientinnen ein bestätigtes partielles Ansprechen per RECIST v1.1, mit einer Ansprechdauer von 1.8+ bis 9.3+ Monaten; 3/4 ansprechenden Patientinnen hatte vorheriges Bevacizumab. Zusammenfassung¿Die preliminären Daten zeigen eine vielversprechende Aktivität. Die Toxizität war gut behandelbar und konsistent mit dem zuvor berichteten Profil. Aktualisierte Daten der vollständigen Zervixkarzinomkohorte (n=46) inklusive Biomarkeranalysen werden beim Kongress gezeigt werden.
  • Autores: Freyer, G.; González Martín, Antonio; Raspagliesi, F.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.33 N° SUPPL 7 2022 págs. S826
    Resumen
    Background A standard therapy for advanced high grade ovarian carcinoma (AHGOC) is an upfront complete surgery followed by adjuvant platinum-taxane chemotherapy adding maintenance targeted therapies. The most common maintenance strategies include bevacizumab and PARP inhibitors. Following the results of the PRIMA (Gonzales Martin, et al NEJM 2019) and PAOLA-1 (Ray-Coquard, et al NEJM 2019) studies, the question of the most efficient maintenance therapy for FIGO stage III patients remains uncertain considering PARPi alone or in combination with bev. Trial design NIRVANA-1 is an international randomized, open-label, phase II trial. 390 FIGO stage III patients with completely resected AHGOC, receive a first CP cycle and are randomized (1:1) to receive either 5 additional CP cycles followed by maintenance with nira or 5 cycles of CP + bev followed by maintenance with nira + bev. The total treatment duration will be 24 months for nira in both arms and 15 months for bev. Stratification factors include tumour BRCA status, FIGO stage (IIIA versus IIIB/IIIC) and use of hyperthermic intraperitoneal chemotherapy during surgery. The primary endpoint will be progression-free survival rate at 24 months. Secondary endpoints include safety, median PFS, PFS2, Time to First Subsequent Therapy (TFST), Time to Second Subsequent Therapy (TSST), OS, KELIM (K CA-125 ELIMination rate constant). The study is calibrated to detect a treatment effect corresponding to a 24-months PFS rate of 75% in the nira + bev arm and a 24-months PFS rate of 65% in the nira arm, translating in a HR of 0.67. The sample size is calculated to provide an 80% power to show a statistically significant PFS difference, accepting a 1-sided alpha risk of 10%, considering a minimal follow-up of 24 months, and dropout rate of 5%. The NIRVANA-1/GINECO-OV129b/ENGOT-ov63 trial is sponsored by the GINECO and currently recruiting in France, Spain, Italy, Belgium, Japan and Korea. The first patient was randomized in March 2022. Clinical trial identification NCT 05183984.
  • Autores: Ruf, F.; Kuehn, T.; Hartmann, S.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.33 N° Suppl. 3 2022 págs. S178 - S179
  • Autores: Richardson, D.; Harter, P.; O'Malley, D.; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN: 1048-891X Vol.32 N° SUPPL 3 2022 págs. A241
    Resumen
    Objectives UpRi is a first-in-class NaPi2b-targeting ADC with a novel scaffold-linker-payload that enables high drug-to-antibody ratio and controlled bystander effect. NaPi2b is a sodium-dependent phosphate transporter protein broadly expressed in high-grade serous ovarian cancer (HGSOC) with limited expression in healthy tissues. It¿s estimated that about two-thirds of HGSOC patients are NaPi2b-high. Studies are being conducted to evaluate UpRi safety and efficacy in platinum-resistant ovarian cancer (PROC), but there remains an unmet need in in the maintenance setting for patients with platinum-sensitive, recurrent ovarian cancer (PSOC), particularly patients who received standard-of-care treatment and are at high-risk of early relapse. Methods UP-NEXT is a Ph3 study evaluating UpRi monotherapy as post-platinum maintenance therapy in recurrent PSOC, enrolling patients with NaPi2b-high tumors (defined as TPS ¿75). Patients must have received 2¿4 prior lines of platinum containing chemotherapy, achieved a partial or complete response in their penultimate platinum regimen, and progressed >6mo after completion of the last dose of platinum. Patients may be enrolled if their best response to the last line of treatment is no evidence of disease, complete or partial response, or stable disease. If patients have a known BRCA mutation, prior PARPi treatment is required. Patients who received bevacizumab in combination with their last platinum containing regimen are excluded. Patients are randomized 2:1 to UpRi or placebo, given IV Q4W. The primary endpoint is PFS assessed by BICR, with key secondary endpoint of OS. UP-NEXT is conducted in collaboration with GOG(3049) and ENGOT(Ov71-NSGO-CTU) . ~350 patients will be enrolled globally. NCT05329545. Results TrialinProgress. Conclusions TrialinProgress.
  • Autores: Moore, K.; Mirza, M.; Gourley, C.; et al.
    Revista: GYNECOLOGIC ONCOLOGY
    ISSN: 0090-8258 Vol.166 N° SUPPL 1 2022 págs. S20 - S21
    Resumen
    Objectives: The ovarian cancer (OC) treatment (tx) landscape has evolved with recent approvals from the FDA and EMA for several novel tx regimens, including first-line maintenance (1Lm) therapies. The antiangiogenic agent (VEGF inhibitor [VEGFi]) bevacizumab (bev) was the first 1Lm tx to be approved for advanced OC (Dec 2011 EMA; June 2018 FDA), followed by the PARPi olaparib (Dec 2018 FDA; June 2019 EMA), PARPi niraparib (Apr 2020 FDA; Oct 2020 EMA), and olaparib + bev (May 2020 FDA; Nov 2020 EMA). There is currently a lack of real-world data evaluating the impact of these approvals on the OC tx paradigm. This analysis describes patient (pt) characteristics, biomarker testing rates, and tx patterns for pts diagnosed with advanced OC in Europe and the US, with a focus on 1Lm. Methods: A retrospective chart review study of electronic medical records (EMRs) in Italy (IT), France (FR), Germany (DE), Spain, the UK, and the US was conducted for pts diagnosed with OC between Jun 1, 2017, and May 31, 2020. The study was conducted in line with Healthcare Market Research guidelines. Data were extracted by oncologists from EMRs to pt record forms (PRFs) and descriptively summarized. Pts with advanced (stage III/IV) disease were stratified by country and diagnosis date to provide information on tx patterns at different tx lines (Cohort 1: Jun 1, 2017-May 31, 2018; Cohort 2: Jun 1, 2018-May 31, 2019; and Cohort 3: Jun 1, 2019-May 31, 2020). Results: Overall, 416 oncologists completed PRFs for 7072 pts; 5386 pts had stage III/IV disease (Table). In total, 79.3%, 83.3%, and 84.7% of pts were tested for BRCA mutations or homologous recombination deficiency in Cohorts 1, 2, and 3, respectively. Of pts who received primary tx, 53.0%, 60.5%, and 65.8% received 1Lm in Cohorts 1, 2, and 3, respectively; the remainder received active surveillance. Use of 1Lm was highest in FR (71.5%; 710/993) and lowest in the UK (47.8%; 339/709). The number of pts receiving 1Lm increased (Cohort 1 vs 3) in all countries except DE. In Cohorts 1, 2, and 3, 81.6%, 73.2%, and 57.1% of pts received VEGFi monotherapy (mono), respectively; 11.9%, 20.9%, and 35.0% received PARPi mono; 2.3%, 3.5%, and 4.5% received PARPi + VEGFi tx; and 4.2%, 2.4%, and 3.4% received chemotherapy or other agents. For all cohorts combined, use of 1Lm PARPi mono was numerically highest in the US (40.0%; 174/435) and lowest in FR (12.0%; 85/710); VEGFi mono use was highest in FR (84.8%; 602/710) and lowest in the US (42.8%; 186/435). Conclusions: This real-world study showed that many pts with advanced OC do not receive 1Lm tx and tx patterns vary by country. There was increased use of 1Lm PARPi mono over time, with a decrease in 1Lm VEGFi mono. Around 15% of pts in Cohort 3 did not receive biomarker testing, highlighting an unmet need in testing access. Data on second-line maintenance tx patterns will also be presented at the meeting.
  • Autores: Buisson, A.; Saintigny, P.; Harle, A.; et al.
    Revista: JOURNAL OF MOLECULAR DIAGNOSTICS
    ISSN: 1525-1578 Vol.24 N° 10 2022 págs. S93 - S93
  • Autores: Buisson, A.; Saintigny, P.; Pujade-Lauraine, E.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.33 N° SUPPL 7 2022 págs. S811 - S812
    Resumen
    Background Poly (ADP-ribose) polymerase inhibitors (PARPi) induce synthetic lethality in homologous recombination deficient (HRD) tumors and have revolutionized ovarian cancer treatment. Patient stratification methods currently used are based on genome-wide enumeration of known HRD biomarkers and require deep sequence profiles (> 30x), in some cases from tumor-normal pairs. The cost and challenges introduced by implementing the current solutions hinder the clinical adoption of HRD testing. Here we present a multicenter performance evaluation study of an alternative deep learning-based decentralized solution for HRD detection, the SOPHiA DDM Dx HRD Solution (SOPHiA GENETICS SA), which leverages the impact of HRD on the coverage profiles obtained from low-pass whole-genome sequencing (lpWGS) data (X1 fold coverage). Methods We generated and sequenced, in 5 independent clinical laboratories, 153 low pass WGS libraries (X1, ~10 million reads, Illumina) for 150 Formalin-Fixed Paraffin-Embedded ovarian cancer samples. HRD classification was performed according to the manufacturer¿s recommendations. The analytical performance was evaluated as overall (OPA), positive (PPA), and negative (NPA) percentage of agreement with Myriad myChoice CDx status (Myriad Genetic Laboratories, Inc.; US FDA-approved). Results The Quality Control criteria for SOPHiA DDM Dx HRD Solution analysis were met for 97,3% of the libraries (n=149). We found a high overall percentage agreement, 93.7% (97.1% NPA and 90.4% PPA) between SOPHiA DDM Dx HRD Solution and Myriad myChoice CDx classification (Table). Additionally, SOPHiA DDM Dx HRD Solution results for samples analyzed in duplicate were 100% reproducible. Table: 579P. Confusion matrix of comparison between Myriad myChoice CDx and SOPHiA DDM Dx HRD Solution results (149 unique samples) Conclusions We conclude that SOPHiA DDM Dx HRD Solution supports accurate HRD detection from low pass whole genome sequencing data, which is amongst the most cost-effective and easy to implement genome profiling methods.
  • Autores: Rief, A.; Kuhn, T.; Peintinger, F.; et al.
    Revista: GEBURTSHILFE UND FRAUENHEILKUNDE
    ISSN: 0016-5751 Vol.82 N° 6 2022 págs. S47 - S48
    Resumen
    Einleitung Die systematische axilläre Lymphknotendissektion (ALND) stellte über sehr lange Zeit den Standard in der operativen Therapie des Mammakarzinoms dar. In den letzten zwei Jahrzehnten hat eine stufenweise Deeskalation der Axillachirurgie stattgefunden mit dem Ziel einer Morbiditätsreduktion ohne eine Kompromittierung der onkologischen Sicherheit zu riskieren. Bei Patientinnen, die nach der neoadjuvanten Chemotherapie vom cN+ zum cN0 Stadium konvertieren, wird die Methode der Wahl im axillären Staging allerdings noch kontroversiell diskutiert. In den Empfehlungen internationaler Leitlinien sind derzeit neben der ALND die Sentinel-Lymphknoten-Biopsie (SLNB), die gezielte Axilladissektion (targeted axillary dissection = TAD) und unter Studienbedingungen die Target-Lymphknoten-Biopsie (TLNB) vertreten. Material und Methodik AXSANA ist eine prospektive, multizentrische Kohortenstudie zur Evaluierung des axillären Staging bei PatientInnen mit initial positivem Nodalstatus und geplanter neoadjuvanter Chemotherapie. Das Operationsverfahren in der Axilla wird dabei von dem behandelnden Zentrum festgelegt. Zu den primären Endpunkten der Studie gehören die Erfassung des krankheitsfreien Überlebens, der axillären Rezidivrate und der erkrankungsbezogenen Lebensqualität. PatientInnen werden derzeit auf internationaler Ebene von insgesamt 217 angemeldeten Studienzentren aus 19 Ländern rekrutiert. In Österreich nehmen 6 Zentren an der AXSANA Studie teil, nämlich das Univ. Klinikum Graz, das LKH Leoben, das LKH Villach, die Privatklinik Villach und die Klinik Hietzing. Ergebnisse Mit Stand Februar 2022 wurden in einer Studienlaufzeit von 21 Monaten bereits 1704 PatientInnen (1680 Frauen und 24 Männer), d.h. mehr als die Hälfte der geplanten Anzahl von 3000 PatientInnen rekrutiert. Das mediane Alter der Patientinnen beträgt 52 Jahre. Bei 55% der PatientInnen wurde vor Beginn der neoadjuvanten Chemotherapie zumindest ein klinisch suspekter Lymphknoten markiert. Die dabei am häufigsten verwendete Methode ist mit 82,5% die Lymphknotenmarkierung mittels eines Clips oder Coils. 65% der rekrutierten PatientInnen konvertierten unter der neoadjuvanten Chemotherapie vom cN+ zum cN0 Status. Bei 43% der PatientInnen wurde eine TAD geplant, bei 39% eine axilläre Dissektion und bei 13% eine SLNB. Zusammenfassung AXSANA soll die aktuelle operative Behandlungsrealität auf internationaler Ebene bei PatientInnen nach neoadjuvanter Chemotherapie mit initialem Nodalbefall darstellen. Erste Daten zeigen deutliche Unterschiede in der Axillachirurgie in diesem PatientInnenkollektiv zwischen den teilnehmenden Zentren. Durch die Studie wird sich feststellen lassen, welche der angewandten Methoden mit einer höheren onkologischen Sicherheit und einer höheren Lebensqualität assoziiert ist.
  • Autores: Poveda-Velasco, A. M.; Lheureux, S.; Colombo, N.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.33 N° SUPPL 7 2022 págs. S790
    Resumen
    Background The Phase IIIb, single-arm OPINION study reported a median progression-free survival (PFS) of 9.2 months (mo) with maintenance olaparib in pts with non-gBRCAm PSR OC (Poveda et al. Gynecol Oncol 2022). Here, we report final OS and updated safety data. Methods Pts with non-gBRCAm PSR OC and ¿2 prior lines of platinum-based chemotherapy (PBC) in complete or partial response to their last PBC received maintenance olaparib (300 mg bid) until progression/unacceptable toxicity. OS was a secondary endpoint. Ad hoc subgroup analyses included OS by homologous recombination deficiency (HRD) and somatic BRCA mutation (sBRCAm) status according to central Myriad tumor and germline testing. Results In total, 279 pts were enrolled and received olaparib (median [range] age: 65 [40¿85] years); 253 (90.7%) pts were retrospectively confirmed as non-gBRCAm. At data cutoff (Sep 17, 2021), 46 (16.5%) pts remained on therapy; discontinuation was mainly due to disease progression (n=196; 70.3%). Overall, there were 146 deaths (52.3% maturity); median follow-up in censored pts was 33.1 mo. Median OS was 32.7 (95% confidence interval [CI], 29.5¿35.3) mo; 24- and 30-mo Kaplan¿Meier OS rates were 65.8% and 54.9%, respectively. OS by HRD status and platinum sensitivity is in the Table. With a median total duration of therapy of 9.6 mo, grade ¿3 treatment-emergent adverse events (TEAEs) occurred in 82 (29.4%) pts, and serious TEAEs in 58 (20.8%). TEAEs led to dose interruption and reduction in 139 (49.8%) and 65 (23.3%) pts, respectively; TEAEs led to olaparib discontinuation in 23 (8.2%) pts. In total, two cases of myelodysplastic syndrome were reported, with no new cases since the primary analysis. There were no new safety findings (Table: 531P). Conclusions OS and updated safety data from OPINION further support the use of maintenance olaparib in pts with non-gBRCAm PSR OC. Clinical trial identification NCT03402841.
  • Autores: Fuh, K.; Moore, K.; Baert, T.; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN: 1048-891X Vol.32 N° SUPPL 3 2022 págs. A234 - A235
    Resumen
    Objectives Introduction: The AXL receptor and its sole activating ligand, GAS6, are important drivers of metastasis and therapeutic resistance in human cancers. This signaling axis represents an attractive target for therapeutic intervention. The strong picomolar binding affinity between endogenous GAS6 and AXL and the promiscuity of small molecule AXL inhibitors have presented a barrier to specific and potent inhibition of AXL. Batiraxcept (AVB-S6¿500) is a recombinant fusion protein with ~200-fold higher affinity for GAS6 than wild-type (WT) AXL. Batiraxcept binds GAS6, inhibiting its interaction with AXL thereby dramatically reducing AXL signaled invasion and migration of highly metastatic cells in vitro and inhibiting metastatic disease in nonclinical models of aggressive human cancers. The Phase 1b study showed no DLTs and established a RP2D of 15 mg/kg IV every 2 weeks with PAC/PLD. Longer PFS and OS times were observed in patients who had not been previously treated with bevacizumab (bev-naïve). Methods High-grade serous PROC, who received 1¿4 prior lines randomized (1:1) batiraxcept/PAC or placebo/PAC; stratified by last platinum regimen, prior lines, and prior bevacizumab. The primary endpoint is PFS by RECIST v1.1 assessed by the investigator with OS a secondary endpoint. The primary PFS analysis will be triggered when 130 PFS events occur in the bev-naïve; with an interim analysis of OS. Recruitment began April 2021; 252 of ~350 patients have been randomized globally (132 sites) (NCT04729608). Results Trial in progress: there are no available results at the time of submission. Conclusions Trial in progress: there are no available conclusions at the time of submission.
  • Autores: van Walle, L.; Verhoeven, D. M. E. C.; Marotti, L.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.33 N° SUPPL 7 2022 págs. S620
    Resumen
    Background Quality indicators (QI) are a specific tool to measure the quality of provided care. QI must be reliable, relevant, interpretable, actionable, and measurable. Contrarily to invasive breast cancer (IBC), the management of in situ breast cancer (BCIS) with adjuvant endocrine treatment (ET) remains controversial. The study aims to investigate the use of adjuvant ET in breast cancer in European (EU) countries, employing the European Society of Breast Cancer Specialists (EUSOMA) database that contains data collected by EU breast centers, that in the relevant time period were part of the EUSOMA Network. Methods We identified all females with a new breast cancer diagnosed in the period 2010 to 2019 in the EUSOMA database. The analysis was conducted on anonymous and cumulative data. The data were registered by 58 EU breast centers, all of which entered at least 500 new diagnoses in the database in the ten-year period. Geographically, the contributing centers are located in Northern (Belgium, the Netherlands, Sweden), Central (Austria, France, Germany, Switzerland) and Southern (Italy, Portugal) EU. The use of ET by tumor behavior was studied in operated endocrine sensitive breast cancer. Trends were evaluated by age group (<50y, 50-69y, ¿70y) and geographical region (North, Central, South). Results A total of 77,835 operated patients with endocrine sensitive breast cancer was included, 72,749 IBC and 5,086 BCIS. In IBC, adjuvant ET was systematically given (94%) and in all age groups at least in 90%. Geographically, proportions were slightly higher in Southern EU breast centers (97%) compared to both Northern and Central EU (91%). In BCIS, 46% of endocrine sensitive patients received adjuvant ET. In patients older than 70 less adjuvant ET was used (38%) compared with the younger patients. Geographically, the same gradient as for IBC was observed: higher proportions in Southern EU breast centers (52%) compared to both Northern and Central EU (40%). Conclusions The study of the real-world use of adjuvant ET in BCIS revealed a remarkably high percentage. Geographical study between EU centers and regions demonstrated different practices. QI making use of real-world EU data can help to monitor, evaluate, and eventually guide and align good clinical practice in the management of BC.
  • Autores: Yubero-Esteban, A.; Barquín, A.; Gaba, L.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.40 N° 16 2022 págs. E17562
    Resumen
    Background: Rucaparib is a PARP inhibitor approved for the treatment of high-grade ovarian cancer (HGOC). Clinical trials have demonstrated its benefit both as maintenance therapy (MTN) for platinum (Pt)-sensitive recurrent HGOC, and as treatment (Tx) in BRCA-mutated relapsed or recurrent HGOC patients. Here we analyze real-world data from the rucaparib early access program (RAP) in Spain with focus in the long-term responder patients (LTR). Methods: A retrospective observational study was performed by GEICO at 22 hospitals in Spain that had treated patients within the RAP. Adult women with HGOC, fallopian tube, or primary peritoneal cancer were included and received rucaparib (600 mg BID) in the MTN, Tx Pt-sensitive or Tx Pt-resistant setting. Patients¿ characteristics, medical history, safety, efficacy, and dosing data were collected. In this analysis, long-term response was defined as progression-free survival (PFS) ¿12 months for the MTN group and ¿6 months for the Tx group. LTR were stratified based on the rucaparib indication (MTN/Tx). Results: Between July 2020 and February 2021, 51 patients were recruited: 18 received rucaparib as MTN and 33 as Tx. In the MTN group, 6 patients (33.3%) were LTR, with a median age of 65 years (54-79). Of them, 2 patients (33.2%) harbored BRCA or RAD51C mutations. The median number of prior lines was 3 (2-6), being ¿5 in 33.2%, and 50.0% received prior bevacizumab. ECOG PS was ¿1 in all these patients, 66.6% had measurable disease and 50.0% achieved a partial response to prior Pt-based chemotherapy. In the Tx group, 10 patients (30.3%) were LTR, with a median age of 71 years (47-86). All of them harbored BRCA and/or RAD51C mutations. The median number of prior lines was 6 (2-9), with 60.0% receiving ¿5 prior lines, and 50.0% received prior bevacizumab. Regarding Pt-status, 40.0% of patients were Pt-sensitive and 60.0% were Pt-resistant. The ECOG PS was ¿1 in 30.0% of patients and 60.0% had measurable disease. The median PFS of LTR was not achieved in the MTN group and was 10.9 months (95% CI: 7.0-16.7) in the Tx group. Adverse events (AE) of any grade were reported in 66.6% of LTR within the MTN group and in 100.0% within the Tx group, while AE of grade ¿3 occurred in 16.6% and 50.0%, respectively. Rucaparib dose was reduced in 50.0% of LTR in the MTN group and 80.0% in the Tx group. Discontinuation rate due to rucaparib toxicity was 20.0% in the Tx group and there were no discontinuations due to toxicity in the MTN group. No new safety signals were detected. At present, 3 and 1 patients are still receiving rucaparib as MTN and Tx, respectively. Conclusions: A durable response was achieved in a notable proportion of patients, even despite their unfavorable conditions at treatment initiation (heavily pre-treated patients, partial response or resistance to Pt, or high volume of disease). The safety profile of rucaparib in this real-world setting is consistent with that reported in clinical trials.
  • Autores: DiSilvestro, P.; Banerjee, S.; Colombo, N.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.33 N° SUPPL 7 2022 págs. S779
    Resumen
    Background In the Phase III SOLO1/GOG-3004 trial (NCT01844986), maintenance olaparib provided sustained benefit beyond the end of treatment in pts with newly diagnosed advanced OC and a BRCAm. At 5-y f/u, median progression-free survival was 56.0 months [m] with olaparib vs 13.8m with placebo (pbo) (HR 0.33; 95% CI 0.25¿0.43); 48% vs 21% of pts, respectively, were progression-free (KM estimates) (Banerjee et al. Lancet Oncol 2021). Given that most OC deaths occur 5¿10y after diagnosis, we report OS in SOLO1 at 7-y f/u, a clinically relevant timepoint. Methods Pts who were in response to first-line platinum-based chemotherapy received maintenance olaparib tablets 300 mg bid or pbo for up to 2y or until progression. A descriptive analysis of OS, a secondary endpoint, was performed 7y after the last pt was randomized; prespecified final analysis of OS is planned at 60% data maturity. Results 260 pts were randomized to olaparib and 131 to pbo (median treatment duration 24.6 vs 13.9m, respectively). At OS data maturity of 38.1% (data cut-off 7 Mar 2022), median OS was not reached in olaparib pts vs 75.2m in pbo pts, with an OS HR of 0.55 (95% CI 0.40¿0.76; unadjusted for crossover; 44.3% of pbo pts received a PARP inhibitor in a subsequent line of therapy) (Table). At 7y, 45.3% of olaparib pts vs 20.6% of pbo pts were alive and had still not received a first subsequent treatment (KM estimates). The incidence of MDS/AML remained low and new primary malignancies remained balanced between arms (Table: 517O). Conclusions 2y of maintenance olaparib provided a clinically meaningful improvement in OS over pbo in pts with newly diagnosed advanced OC and a BRCAm. At 7y, 67.0% of olaparib pts vs 46.5% of pbo pts were alive; no new safety signals were detected. These data provide the longest f/u for any PARP inhibitor in this setting and support use of maintenance olaparib to achieve long-term remission and enhance the potential for cure. Clinical trial identification NCT01844986.
  • Autores: Patel, M. R.; Makker, V.; Oaknin, A.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.40 N° 16 2022 págs. 5517
    Resumen
    Background: LIO-1 is assessing the oral antiangiogenic, multikinase inhibitor lucitanib in combination with the programmed cell death receptor 1 (PD-1) inhibitor nivolumab. Individualized lucitanib dose titration is being explored to maximize lucitanib exposure and potential clinical benefit of the combination. Here, we present data from stage 1 of a Simon 2-stage design across 4 different types of advanced gynecologic cancers from the phase 2 part of LIO-1. Methods: Patients (pts) with advanced, recurrent, or metastatic endometrial cancer (EC, who received ¿1 prior platinum-based chemotherapy); cervical cancer (CC, who received ¿1 prior platinum-based chemotherapy ± bevacizumab); high-grade ovarian cancer (OC, who received ¿2 prior chemotherapies); or EC/OC with clear-cell histology (EOCC, who received ¿1 prior platinum-based chemotherapy + taxane) were enrolled. Prior PD-1 or programmed cell death ligand 1 (PD-L1) inhibitor treatment was excluded, except for up to 10 pts in the EC cohort. Pts received lucitanib at a starting dose of 6 mg once daily (QD), escalating to 8 mg QD and then 10 mg QD if safety-based titration criteria were met, plus intravenous nivolumab 480 mg every 28 days. The data cutoff was Jan 10, 2022. Results: Across cohorts, 100 pts were enrolled to stage 1; 27 (27%) remain on treatment. To date, 28 (28%) have escalated to lucitanib 8 mg, and 17 (17%) have escalated to the maximum dose of 10 mg. Confirmed responses per RECIST v1.1 have been reported in 5/22 (22.7%; 5 partial responses [PRs]) EC pts, 7/22 (31.8%; 2 complete responses [CRs], 5 PRs) CC pts, 4/33 (12.1%; 4 PRs) OC pts, and 5/23 (21.7%; 1 CR, 4 PRs) EOCC pts. Response duration ranges from 1.9+ to 13.1+ months. Of 5 pts with EC who received prior PD-1 inhibitor, there were 2 PRs, and 1 pt with ongoing stable disease of 7+ months. Grade ¿3 treatment-emergent adverse events (TEAEs) considered related to study treatment were reported in 43 (43%) pts, with hypertension the most frequent (n = 25 [25%]). Forty-six (46%) pts had a lucitanib-related TEAE that led to lucitanib interruption and 12 (12%) had one that led to lucitanib dose reduction. Eleven (11%) and 8 (8%) pts discontinued lucitanib and nivolumab, respectively, due to a treatment-related TEAE. Safety results were generally consistent across tumor cohorts. Conclusions: The combination of lucitanib + nivolumab is active in the treatment of advanced gynecological malignancies and has a manageable safety profile through effective dose titration. Stage 2 enrollment has continued in the CC cohort. Biomarker analysis is ongoing, and more mature efficacy and safety data will be presented at the meeting.
  • Autores: Konstantinopoulos, P.; González Martín, Antonio; Cruz, F.; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN: 1048-891X Vol.32 N° SUPPL 3 2022 págs. A238 - A238
    Resumen
    Objectives High-grade serous ovarian cancer (HGSOC) represents most epithelial ovarian cancers. Whilst initially responding to platinum-based therapy, ~75\% of patients develop resistance, conferring poor prognosis. Homologous recombination repair proficiency is associated with platinum resistance and limited response to PARP inhibitors. PI3K pathway inhibition downregulates BRCA expression, abrogating homologous recombination repair proficiency, and may lead to (re)sensitization to PARP inhibitors. As alpelisib (PI3Ka inhibitor) + olaparib (PARP inhibitor) demonstrated preliminary evidence of synergism in platinum-resistant/refractory, BRCA-wild-type, recurrent HGSOC in a phase 1b study, the EPIK-O study is further evaluating this combination.Methods EPIK-O/ENGOT-OV61 (NCT04729387) is a phase 3, randomized (1:1), open-label, active-controlled trial evaluating the efficacy and safety of alpelisib + olaparib versus single-agent chemotherapy in patients (N¿358) with no germline BRCA mutation and platinum-resistant/refractory HGSOC. Adult patients with platinum-resistant/refractory, histologically confirmed HGSOC, high-grade endometrioid ovarian, fallopian tube, or primary peritoneal cancer, with no germline BRCA1/2 mutation, are included; patients must have received 1{\textendash}3 prior systemic therapies. In Arm 1, patients receive alpelisib 200 mg orally OD + olaparib 200 mg orally BID; in Arm 2, patients receive paclitaxel 80 mg/m2 IV weekly or pegylated liposomal doxorubicin 40{\textendash}50 mg/m2 IV Q28D (investigator{\textquoteright}s choice). The primary endpoint is progression-free survival per RECIST 1.1 assessment by a blinded independent review committee. Key secondary endpoint is overall survival. Other secondary endpoints include overall response rate, clinical benefit rate, safety, and quality of life. Enrollment is planned in 26 countries; completion of data collection for the primary endpoint is anticipated in 2023.Results No resultsConclusions Trial in Progress
  • Autores: Kamavra, M.; González Martín, Antonio; Pothuri, B.; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN: 1048-891X Vol.32 N° SUPPL 3 2022 págs. A144
    Resumen
    Objectives Patterns of recurrence on PARP inhibitor maintenance therapy are unclear and may affect treatment choices for subsequent therapy, including secondary cytoreductive surgery (SCS). This analysis of PRIMA/ENGOT-OV26/GOG-3012 evaluated patterns of recurrence on niraparib maintenance therapy. Methods This post hoc subgroup analysis included 314 patients treated with niraparib maintenance monotherapy following first-line chemotherapy and who had no lesions identified by CT/MRI (or by investigator assessment) at baseline. Number and site(s) of initial recurrent lesions at the time of investigator-assessed RECIST-defined progressive disease (PD) were evaluated. Results As of the primary data cut, May 17, 2019, with a median follow-up of 13.8 months (range <1¿28), 141/314 (45%) patients developed investigator-assessed PD, with an average 1.9 (standard deviation 0.9) lesions at PD. At the time of recurrence, 62 patients (44%) had 1 lesion, 46 (33%) had 2 lesions, 24 (17%) had 3 lesions, and 9 (6%) had 4¿5 lesions. The five most common sites with ¿1 lesion at PD were the peritoneum (n=45), lymph nodes (n=36), liver (n=34), other (n=26), and pelvis (n=20). Conclusions For patients who received niraparib maintenance monotherapy after first-line chemotherapy and had no lesions at baseline, <50% had recurrent disease after a median 13.8 months of follow-up and >75% of patients with recurrence progressed in 1¿2 sites. Prospective evaluation is required to determine whether patients with oligoprogressive disease have improved outcomes with local therapies, like SCS, in addition to systemic therapy.
  • Autores: Richardson, D.; Pérez Fidalgo, J. A.; González Martín, Antonio; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN: 1048-891X Vol.32 N° SUPPL 3 2022 págs. A241
    Resumen
    Objectives UpRi is a first-in-class NaPi2b ADC with a novel scaffold-linker-payload that enables high drug-to-antibody ratio and controlled bystander effect. NaPi2b is a sodium-dependent phosphate transporter protein broadly expressed in high-grade serous ovarian cancer (HGSOC), with limited expression in healthy tissues. Interim data from the Phase 1b expansion cohort of heavily pretreated patients with recurrent HGSOC has been reported. These data demonstrated clinically meaningful activity, notably in patients with NaPi2b-high tumors (TPS¿75). Effective and well-tolerated treatments for PROC remains an unmet medical need. The standard of care, single-agent chemotherapy, has limited efficacy, significant toxicities, and short duration of response. UPLIFT was designed as a single-arm Ph2 registrational trial for UpRi monotherapy in PROC. Methods UPLIFT is enrolling patients with PROC with up to 4 prior LoT. Prior bevacizumab is required for patients with 1¿2 prior LoT only; it¿s not required for patients with 3¿4 prior LoT. Patients may enroll regardless of NaPi2b expression; ¿ Grade 2 peripheral neuropathy is permitted. Primary platinum refractory patients are excluded. UPLIFT will enroll ~180 patients globally, including ~100 patients with high NaPi2b expression. UpRi is dosed IV at 36 mg/m2 up to ~80 mg dose maximum Q4W. Baseline tumor samples (fresh or archived) will be collected for central analysis of NaPi2b expression. The primary endpoint is ORR in NaPi2b-high expressing patients. The cut-off for high NaPi2b expression is TPS¿75. Secondary endpoints include ORR in the overall population, duration of response, and safety. UPLIFT is conducted in collaboration with ENGOT (ENGOT-ov67) and GOG (GOG-3048). NCT03319628. Results trialinprogress. Conclusions trialinprogress.
  • Autores: Lorusso, D.; Monk, B.; Sehouli, J.; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN: 1048-891X Vol.32 N° SUPPL 3 2022 págs. A157 - A158
    Resumen
    Objectives Ovarian cancer (OC) treatment options include VEGF inhibitors (VEGFi) and PARP inhibitors (PARPi) as first-line maintenance (1Lm) treatments. There is interest in understanding patient contribution in treatment selection. We describe physician-reported patient involvement in treatment decisions in the 1L setting. Methods Retrospective chart review study of electronic medical records (EMRs) in Italy/France/Germany/Spain/UK/US, conducted for patients diagnosed with OC (June 1, 2017¿May 31, 2020) in line with Healthcare Market Research guidelines. Eligible oncologists extracted data from EMRs by completing standardized patient record forms (PRFs), including questions on patient involvement in treatment decisions. Data were descriptively summarized. Results PRFs for 7072 patients with OC were completed by 416 oncologists; 4986 patients received 1L adjuvant treatment. Higher rates of patient involvement were seen in Germany/UK/US; treatments selected differed when patient input was considered for 1L adjuvant (n=754) or 1Lm treatment (n=521; table 1). Timing of patient involvement in 1L treatment decisions varied (table 2). For 1Lm treatment, most patients (44%) discussed options with their physician at treatment initiation (36%¿49% across countries), 16% after surgery, 24% at chemotherapy initiation, and 16% when chemotherapy response was evaluated. Conclusions Rates of physician-reported patient involvement in treatment decisions were consistent between 1L (15%) and 1Lm (16%); <50% of patients discussed 1Lm with their physician at treatment initiation, highlighting a need for early discussion with patients. Funding: GSK study OneCDP#214555. Editorial support provided by Fishawack Health, funded by GSK.
  • Autores: Baert, T. (Autor de correspondencia); Ferrero, A.; Sehouli, J.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.32 N° 6 2021 págs. 710 - 725
    Resumen
    Treatment approaches for relapsed ovarian cancer have evolved over the past decade from a calendar-based decision tree to a patient-oriented biologically driven algorithm. Nowadays, platinum-based chemotherapy should be offered to all patients with a reasonable chance of responding to this therapy. The treatment-free interval for platinum is only one of many factors affecting patients' eligibility for platinum re-treatment. Bevacizumab increases the response to chemotherapy irrespective of the cytotoxic regimen and can be valuable in patients with an urgent need for symptom relief (e.g. pleural effusion, ascites). For patients with recurrent high-grade ovarian cancer, which responds to platinum-based treatment, maintenance therapy with a poly(ADP-ribose) polymerase inhibitor can be offered, regardless of the BRCA mutation status. Here we review contemporary decision-making processes in the systemic treatment of relapsed ovarian cancer.
  • Autores: Zugasti, A.; Hontanilla Calatayud, Bernardo Carlos (Autor de correspondencia)
    Revista: PLASTIC AND RECONSTRUCTIVE SURGERY. GLOBAL OPEN
    ISSN: 2169-7574 Vol.9 N° 11 2021 págs. e3910
    Resumen
    Background: Adjuvant radiotherapy could be a necessary step in the oncological treatment for breast cancer. However, radiotherapy may have negative effects on implant-based immediate breast reconstruction. The aim of this study was to determine the impact of adjuvant radiation therapy on surgical results and patient-reported satisfaction outcomes in women undergoing immediate implant-based breast reconstruction. Methods: A systematic search in PubMed was conducted on September 2019 and updated on April 2021. The risk of bias of the included studies was assessed using the Newcastle-Ottawa Quality Assessment Form for Observational Studies. RevMan 5 was used for statistical analysis. We obtained relative risks to determine the complication incidence and mean differences for 2-year BREAST-Q scores. Results: Fourteen studies were included. A total of 11,958 implant-based immediate reconstructions were performed, 2311 received postmastectomy radiation therapy, and 9647 were considered as control group. Surgical complications, reoperation rates, and reconstruction failure were significantly higher among irradiated breasts. Significantly lower BREAST-Q scores were reported by irradiated women receiving radiotherapy. Conclusions: This systematic review and meta-analysis combines reconstruction complication rates with aesthetic and patient-reported satisfaction outcomes. Adjuvant radiotherapy is consistently associated with greater complication rates and poorer aesthetic and satisfaction outcomes. The magnitude of association is significantly lower when the reconstruction is based on autologous tissues.
  • Autores: Dubsky, P. (Autor de correspondencia); Pinker, K.; Cardoso, F.; et al.
    Revista: LANCET ONCOLOGY
    ISSN: 1470-2045 Vol.22 N° 1 2021 págs. E18 - E28
    Resumen
    Primary systemic therapy is increasingly used in the treatment of patients with early-stage breast cancer but few guidelines specifically address optimal locoregional therapies. Therefore, we established an international consortium to discuss clinical evidence and to provide expert advice on technical management of patients with early-stage breast cancer. The steering committee prepared six working packages to address all major clinical questions from diagnosis to surgery. During a consensus meeting that included members from European scientific oncology societies, clinical trial groups, and patient advocates, statements were discussed and voted on. A consensus was reached in 42% of statements, a majority in 38%, and no decision in 21%. Based on these findings, the panel developed clinical guidance recommendations and a toolbox to overcome many clinical and technical requirements associated with the diagnosis, response assessment, surgical planning, and surgery of patients with early-stage breast cancer. This guidance could convince clinicians and patients of the major clinical advancements purported by primary systemic therapy, the use of less extensive and more targeted surgery to improve the lives of patients with breast cancer.
  • Autores: DiSilvestro, P. (Autor de correspondencia); Colombo, N.; Harter, P.; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.13 N° 22 2021 págs. 5756
    Resumen
    Simple SummaryAdvanced epithelial ovarian cancer has a poor prognosis, but targeted therapies have been developed and are providing new hope. We reviewed recent results with PARP inhibitors as treatment and/or maintenance therapy following chemotherapy in newly diagnosed advanced ovarian cancer. Data confirm the benefit of PARP inhibitors in this setting, especially in subgroups with genomic instability. We describe the implications of these trial results for clinical practice, focusing on the need for a personalized treatment approach based on biomarker profile and other factors, including tolerability, cost considerations, and physician and patient preference. We have developed a systemic treatment algorithm for newly diagnosed advanced ovarian cancer, intended as a tool for clinicians to aid decision making in their daily practice. We also consider areas of future research, such as exploring further options for patients whose disease relapses following PARP inhibitor treatment.Recent data have demonstrated substantial efficacy with poly (ADP-ribose) polymerase (PARP) inhibitors as treatment and/or maintenance therapy in patients with newly diagnosed advanced epithelial ovarian cancer (EOC). Here, we review efficacy and safety results from four recent Phase III trials in newly diagnosed EOC: SOLO1 (olaparib), PAOLA-1 (olaparib in combination with bevacizumab), PRIMA (niraparib), and VELIA (veliparib). The implications of these data for current clinical practice and areas for future research are discussed, including ongoing studies of targeted agents in the newly diagnosed setting. Data from SOLO1, PAOLA-1, PRIMA, and VELIA confirm the benefit of PARP inhibitors (olaparib, niraparib, veliparib) for women with newly diagnosed EOC. The greatest benefit was seen in patients with a BRCA1 and/or BRCA2 mutation or in the homologous recombination deficiency (HRD)-test positive subgroup. These four well-conducted studies have generated practice-changing data. However, deciding how to apply these results in clinical practice is challenging, and substantial differences in trial design impede cross-trial comparisons. Recent PARP inhibitor approvals (olaparib, niraparib) in the newly diagnosed EOC setting have provided new maintenance treatment options for a broader patient population. The results of these studies call for personalized medicine based on biomarker profile and other factors, including tolerability, cost considerations, and physician and patient preference. Important areas for future research include appropriate use of both BRCA mutation and HRD testing to inform magnitude of PARP inhibitor benefit as well as exploring further options for patients who are HRD-test negative and for those who become PARP inhibitor resistant.
  • Autores: Machiels, M.; Kaidar Person, O.; Rubio, Isabel Teresa; et al.
    Revista: CANCER JOURNAL
    ISSN: 1528-9117 Vol.27 N° 1 2021 págs. 32 - 40
    Resumen
    Triple-negative breast cancer, compared with other molecular subtypes, poses particular challenges for optimizing the timing and the extent of locoregional treatments. In the past, the combination of increased rates of both locoregional and distant recurrences led to a preference of radical surgery and extensive radiation therapy; however, since the introduction of more effective chemotherapy, a sharp de-escalation in the extent of locoregional treatments followed. Current evidence confirms that less aggressive surgery in combination with tailored radiation therapy offers improved oncological outcomes combined with better quality of life. However, further research is required to optimize locoregional treatments, considering the significant heterogeneity in biological behavior and tumor response to systemic treatments.
  • Autores: Lorusso, D.; González Martín, Antonio; Ray Coquard, I. (Autor de correspondencia)
    Revista: FUTURE ONCOLOGY
    ISSN: 1479-6694 Vol.17 N° 3S 2021 págs. 9 - 19
    Resumen
    Following failure of first-line platinum-based chemotherapy in ovarian cancer, options for further therapy in potentially platinum-responsive patients are: carboplatin doublets with pegylated liposomal doxorubicin, gemcitabine or paclitaxel in association with bevacizumab, followed by maintenance with bevacizumab (for nonpretreated patients); or maintenance monotherapy with a poly(ADP-ribose) polymerase inhibitor after a response. The choice of biological therapy depends on a patient's previous treatments and priority for a symptomatic response. In cases of a rapidly growing tumor or need for symptomatic relief, the addition of bevacizumab should be considered. Patients with limited potential sensitivity to platinum, such as those with a platinum treatment-free interval of 6-12 months, may benefit from intercalation with trabectedin and pegylated liposomal doxorubicin to possibly restore platinum sensitivity.
  • Autores: Banys-Paluchowski, M.; Gasparri, M. L.; de-Boniface, J.; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.13 N° 7 2021 págs. 1565
    Resumen
    Simple Summary Currently, it is unclear which kind of axillary staging surgery breast cancer patients with lymph node metastasis should receive after neoadjuvant chemotherapy. For decades, these patients have been treated with a full axillary lymph node dissection, even if they converted to clinical node negativity. However, the removal of a large number of lymph nodes during the procedure can increase arm morbidity and impact quality of life. Therefore, several studies investigated less radical surgical strategies in this setting, such as sentinel lymph node biopsy or targeted axillary dissection, i.e., removal of a previously marked node combined with sentinel node removal. In this review, we summarize current evidence on the different surgical techniques and compare national and international recommendations. We show that many questions regarding oncological safety of different surgery types and the optimal marking technique remain unanswered and present the multinational prospective cohort study AXSANA that will address these open issues. In the last two decades, surgical methods for axillary staging in breast cancer patients have become less extensive, and full axillary lymph node dissection (ALND) is confined to selected patients. In initially node-positive patients undergoing neoadjuvant chemotherapy, however, the optimal management remains unclear. Current guidelines vary widely, endorsing different strategies. We performed a literature review on axillary staging strategies and their place in international recommendations. This overview defines knowledge gaps associated with specific procedures, summarizes currently ongoing clinical trials that address these unsolved issues, and provides the rationale for further research. While some guidelines have already implemented surgical de-escalation, replacing ALND with, e.g., sentinel lymph node biopsy (SLNB) or targeted axillary dissection (TAD) in cN+ patients converting to clinical node negativity, others recommend ALND. Numerous techniques are in use for tagging lymph node metastasis, but many questions regarding the marking technique, i.e., the optimal time for marker placement and the number of marked nodes, remain unanswered. The optimal number of SLNs to be excised also remains a matter of debate. Data on oncological safety and quality of life following different staging procedures are lacking. These results provide the rationale for the multinational prospective cohort study AXSANA initiated by EUBREAST, which started enrollment in June 2020 and aims at recruiting 3000 patients in 20 countries (NCT04373655; Funded by AGO-B, Claudia von Schilling Foundation for Breast Cancer Research, AWOgyn, EndoMag, Mammotome, and MeritMedical).
  • Autores: Mirza, M. R. (Autor de correspondencia); Coleman, R. L.; González Martín, Antonio; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.32 N° 8 2021 págs. 1066 - 1067
  • Autores: Cardoso, F. (Autor de correspondencia); Kyriakides, S.; Ohno, S.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.32 N° 2 2021 págs. 284 - 284
  • Autores: González Martín, Antonio (Autor de correspondencia)
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN: 1048-891X Vol.31 N° 7 2021 págs. 959 - 960
  • Autores: Sancho Araiz, Aymara; Zalba Oteiza, Sara; Garrido Cid, María Jesús; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.13 N° 20 2021 págs. 5049
    Resumen
    Simple Summary: The clinical efficacy of immunotherapies when treating cold tumors is still low, and different treatment combinations are needed when dealing with this challenging scenario. In this work, a middle-out strategy was followed to develop a model describing the antitumor efficacy of different immune-modulator combinations, including an antigen, a toll-like receptor-3 agonist, and an immune checkpoint inhibitor in mice treated with non-inflamed tumor cells. Our results support that clinical response requires antigen-presenting cell activation and also relies on the amount of CD8 T cells and tumor resistance mechanisms present. This mathematical model is a very useful platform to evaluate different immuno-oncology combinations in both preclinical and clinical settings. Immune checkpoint inhibitors, administered as single agents, have demonstrated clinical efficacy. However, when treating cold tumors, different combination strategies are needed. This work aims to develop a semi-mechanistic model describing the antitumor efficacy of immunotherapy combinations in cold tumors. Tumor size of mice treated with TC-1/A9 non-inflamed tumors and the drug effects of an antigen, a toll-like receptor-3 agonist (PIC), and an immune checkpoint inhibitor (anti-programmed cell death 1 antibody) were modeled using Monolix and following a middle-out strategy. Tumor growth was best characterized by an exponential model with an estimated initial tumor size of 19.5 mm(3) and a doubling time of 3.6 days. In the treatment groups, contrary to the lack of response observed in monotherapy, combinations including the antigen were able to induce an antitumor response. The final model successfully captured the 23% increase in the probability of cure from bi-therapy to triple-therapy. Moreover, our work supports that CD8(+) T lymphocytes and resistance mechanisms are strongly related to the clinical outcome. The activation of antigen-presenting cells might be needed to achieve an antitumor response in reduced immunogenic tumors when combined with other immunotherapies. These models can be used as a platform to evaluate different immuno-oncology combinations in preclinical and clinical scenarios.
  • Autores: Friedlander, M. (Autor de correspondencia); Moore, K. N.; Colombo, N.; et al.
    Revista: LANCET ONCOLOGY
    ISSN: 1470-2045 Vol.22 N° 5 2021 págs. 632 - 642
    Resumen
    Background In the phase 3 SOLO1 trial, maintenance olaparib provided a significant progression-free survival benefit versus placebo in patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation in response after platinum-based chemotherapy. We analysed health-related quality of life (HRQOL) and patient-centred outcomes in SOLO1, and the effect of radiological disease progression on health status. Methods SOLO1 is a randomised, double-blind, international trial done in 118 centres and 15 countries. Eligible patients were aged 18 years or older; had an Eastern Cooperative Oncology Group performance status score of 0-1; had newly diagnosed, advanced, high-grade serous or endometrioid ovarian cancer, primary peritoneal cancer, or fallopian tube cancer with a BRCA mutation; and were in clinical complete or partial response to platinum-based chemotherapy. Patients were randomly assigned (2:1) to either 300 mg olaparib tablets or placebo twice per day using an interactive voice and web response system and were treated for up to 2 years. Treatment assignment was masked for patients and for clinicians giving the interventions, and those collecting and analysing the data. Randomisation was stratified by response to platinum-based chemotherapy (clinical complete or partial response). HRQOL was a secondary endpoint and the prespecified primary HRQOL endpoint was the change from baseline in the Functional Assessment of Cancer Therapy-Ovarian Cancer Trial Outcome Index (TOI) score for the first 24 months. TOI scores range from 0 to 100 (higher scores indicated better HRQOL), with a clinically meaningful difference defined as a difference of at least 10 points. Prespecified exploratory endpoints were quality-adjusted progression-free survival and time without significant symptoms of toxicity (TWiST). HRQOL endpoints were analysed in all randomly assigned patients. The trial is ongoing but closed to new participants. This trial is registered with ClinicalTrials.gov, NCT01844986. Findings Between Sept 3, 2013, and March 6, 2015, 1084 patients were enrolled. 693 patients were ineligible, leaving 391 eligible patients who were randomly assigned to olaparib (n=260) or placebo (n=131; one placebo patient withdrew before receiving any study treatment), with a median duration of follow-up of 40.7 months (IQR 34.9-42.9) for olaparib and 41.2 months (32.2-41.6) for placebo. There was no clinically meaningful change in TOI score at 24 months within or between the olaparib and placebo groups (adjusted mean change in score from baseline over 24 months was 0.30 points [95% CI -0.72 to 1.32] in the olaparib group vs 3.30 points [1.84 to 4.76] in the placebo group; between-group difference of -3.00, 95% CI -4.78 to -1.22; p=0.0010). Mean quality-adjusted progression-free survival (olaparib 29.75 months [95% CI 28.20-31.63] vs placebo 17.58 [15.05-20.18]; difference 12.17 months [95% CI 9.07-15.11], p<0.0001) and the mean duration of TWiST (olaparib 33.15 months [95% CI 30.82-35.49] vs placebo 20.24 months [17.36-23.11]; difference 12.92 months [95% CI 9.30-16.54]; p<0.0001) were significantly longer with olaparib than with placebo. Interpretation The substantial progression-free survival benefit provided by maintenance olaparib in the newly diagnosed setting was achieved with no detrimental effect on patients' HRQOL and was supported by clinically meaningful quality-adjusted progression-free survival and TWiST benefits with maintenance olaparib versus placebo. Copyright (C) 2021 Elsevier Ltd. All rights reserved.
  • Autores: González Martín, Antonio (Autor de correspondencia); Sánchez Lorenzo, María Luisa; Colombo, N.; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN: 1048-891X Vol.31 N° 4 2021 págs. 617 - 622
    Resumen
    Background Platinum based chemotherapy is the treatment of choice for ovarian cancer patients with a platinum treatment free interval of >6 months. Niraparib is an oral poly (ADP-ribose) polymerase inhibitor approved as maintenance therapy after a response to platinum rechallenge, regardless of BRCA status. Atezolizumab is a humanized monoclonal antibody targeting programmed death-ligand 1 (PD-L1). A combination of poly (ADP-ribose) polymerase inhibitor and anti-PD-L1/programmed cell death protein 1 (PD-1) has shown synergy in preclinical models and promising clinical activity. Primary objective To determine whether the addition of atezolizumab to carboplatin based chemotherapy and to subsequent maintenance with niraparib improves progression free survival compared with placebo in patients with recurrent disease and a platinum treatment free interval of >6 months. Trial design The Atezolizumab and NIraparib Treatment Association (ANITA) trial is a GEICO (Grupo Espanol de Investigacion en Cancer de Ovario) led phase III, randomized, double-blinded, multicenter European Network for Gynecological Oncological Trials (ENGOT) study. Patients will be randomized to arm A (control arm) consisting of platinum based chemotherapy (investigator's choice) plus a placebo of atezolizumab followed by maintenance niraparib plus a placebo of atezolizumab, or to arm B (experimental arm) consisting of platinum based chemotherapy (investigator's choice) plus atezolizumab followed by maintenance niraparib plus atezolizumab. Major inclusion/exclusion criteria Inclusion criteria are women aged over 18 years, diagnosed with relapsed high grade serous, endometrioid, or undifferentiated ovarian, fallopian tube, or primary peritoneal carcinoma. Patients are eligible if they received no more than two previous lines of chemotherapy, relapsed >= 6 months after the last platinum containing regimen, and have at least one measurable lesion according to the response evaluation criteria in solid tumors, version 1.1. Primary endpoint The primary endpoint for this study is progression free survival. Sample size Approximately 414 patients will be recruited and randomized in a 1:1 ratio, with the aim of demonstrating a benefit in progression free survival for the experimental arm with a hazard ratio of 0.7, using a two sided alpha of 0.05 and a power of 80%. Estimated dates for completing accrual and presenting results The trial was launched in the fourth quarter of 2018 and is estimated to close in the second quarter of 2021. Mature results for progression free survival are expected to be presented by 2023.
  • Autores: Mouraux, A. (Autor de correspondencia); Bloms-Funke, P.; Boesl, I.; et al.
    Revista: TRIALS
    ISSN: 1745-6215 Vol.22 N° 1 2021 págs. 404
    Resumen
    Background: IMI2-PainCare-BioPain-RCT3 is one of four similarly designed clinical studies aiming at profiling a set of functional biomarkers of drug effects on the nociceptive system that could serve to accelerate the future development of analgesics, by providing a quantitative understanding between drug exposure and effects of the drug on nociceptive signal processing in human volunteers. IMI2-PainCare-BioPain-RCT3 will focus on biomarkers derived from non-invasive electroencephalographic (EEG) measures of brain activity. Methods: This is a multisite single-dose, double-blind, randomized, placebo-controlled, 4-period, 4-way crossover, pharmacodynamic (PD) and pharmacokinetic (PK) study in healthy subjects. Biomarkers derived from scalp EEG measurements (laser-evoked brain potentials [LEPs], pinprick-evoked brain potentials [PEPs], resting EEG) will be obtained before and three times after administration of three medications known to act on the nociceptive system (lacosamide, pregabalin, tapentadol) and placebo, given as a single oral dose in separate study periods. Medication effects will be assessed concurrently in a non-sensitized normal condition and a clinically relevant hyperalgesic condition (high-frequency electrical stimulation of the skin). Patient-reported outcomes will also be collected. A sequentially rejective multiple testing approach will be used with overall alpha error of the primary analysis split between LEP and PEP under tapentadol. Remaining treatment arm effects on LEP or PEP or effects on EEG are key secondary confirmatory analyses. Complex statistical analyses and PK-PD modeling are exploratory. Discussion: LEPs and PEPs are brain responses related to the selective activation of thermonociceptors and mechanonociceptors. Their amplitudes are dependent on the responsiveness of these nociceptors and the state of the pathways relaying nociceptive input at the level of the spinal cord and brain. The magnitude of resting EEG oscillations is sensitive to changes in brain network function, and some modulations of oscillation magnitude can relate to perceived pain intensity, variations in vigilance, and attentional states. These oscillations can also be affected by analgesic drugs acting on the central nervous system. For these reasons, IMI2-PainCare-BioPain-RCT3 hypothesizes that EEG-derived measures can serve as biomarkers of target engagement of analgesic drugs for future Phase 1 clinical trials. Phase 2 and 3 clinical trials could also benefit from these tools for patient stratification.
  • Autores: Hontanilla Calatayud, Bernardo Carlos (Autor de correspondencia); Olivas Menayo, Jesus; Marré Medina, Diego Antonio; et al.
    Revista: FACIAL PLASTIC SURGERY
    ISSN: 0736-6825 Vol.37 N° 3 2021 págs. 360 - 369
    Resumen
    Over the last two decades, the senior author (B.H.) has had an extensive experience with facial paralysis reconstruction. During this period, the techniques have evolved substantially based on the experience and after observing and analyzing the surgical outcomes. The purpose of this article is to relay the lessons learned from the 20 years' experience and suggest an algorithm. In this retrospective study, we have included 343 cases of facial paralysis cases. Complete facial paralysis cases were 285 and 58 were incomplete facial paralyses, both requiring surgical procedures. Complete facial paralyses were divided in to short term ( n =83) and long term ( n =202). In total, 58% of the patients were women and 42% were men. The age range was 6 to 82 years. The techniques employed were direct suture, nerve grafts, cross-facial nerve grafts (CFNGs), masseteric-to-facial nerve transference, hypoglossal-to-facial nerve transference, free muscle transplants, and lengthening temporal myoplasty to achieve the best symmetry after reanimation of unilateral, bilateral, complete, and incomplete facial paralysis. The type of paralysis, objective measurements, the personal patient's smile, and the gender are key concepts to be considered before scheduling a dynamic facial paralysis reconstruction. For unilateral facial paralysis, the time of onset, the type of paralysis, the patient's comorbidities, and the healthy side status are some of the determining factors when selecting the correct technique. The preferred techniques for unilateral facial paralysis are direct repair, CFNG, masseteric-to-facial transposition, and free gracilis transfer. For incomplete facial paralysis, the masseteric-to-facial nerve transference is preferred. In bilateral facial paralysis, bilateral free gracilis transfer is performed in two stages using the nerve of the masseter muscle as the source of innervation. The authors provide an algorithm which simplifies facial paralysis reconstruction to achieve the greatest facial symmetry while thinking about the potential comorbidities and developing spontaneity smile according to the gender of the patient.
  • Autores: Coleman, R. L. (Autor de correspondencia); Lorusso, D.; Gennigens, C.; et al.
    Revista: LANCET ONCOLOGY
    ISSN: 1470-2045 Vol.22 N° 5 2021 págs. 609 - 619
    Resumen
    Background Few effective second-line treatments exist for women with recurrent or metastatic cervical cancer. Accordingly, we aimed to evaluate the efficacy and safety of tisotumab vedotin, a tissue factor-directed antibody-drug conjugate, in this patient population. Methods This multicentre, open-label, single-arm, phase 2 study was done across 35 academic centres, hospitals, and community practices in Europe and the USA. The study included patients aged 18 years or older who had recurrent or metastatic squamous cell, adenocarcinoma, or adenosquamous cervical cancer; disease progression on or after doublet chemotherapy with bevacizumab (if eligible by local standards); who had received two or fewer previous systemic regimens for recurrent or metastatic disease; had measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1); and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received 2.0 mg/kg (up to a maximum of 200 mg) tisotumab vedotin intravenously once every 3 weeks until disease progression (determined by the independent review committee) or unacceptable toxicity. The primary endpoint was confirmed objective response rate based on RECIST (version 1.1), as assessed by the independent review committee. Activity and safety analyses were done in patients who received at least one dose of the drug. This study is ongoing with recruitment completed and is registered with ClinicalTrials.gov, NCT03438396. Findings 102 patients were enrolled between June 12, 2018, and April 11, 2019; 101 patients received at least one dose of tisotumab vedotin. Median follow-up at the time of analysis was 10.0 months (IQR 6.1-13.0). The confirmed objective response rate was 24% (95% CI 16-33), with seven (7%) complete responses and 17 (17%) partial responses. The most common treatment-related adverse events included alopecia (38 [38%] of 101 patients), epistaxis (30 [30%]), nausea (27 [27%]), conjunctivitis (26 [26%]), fatigue (26 [26%]), and dry eye (23 [23%]). Grade 3 or worse treatmentrelated adverse events were reported in 28 (28%) patients and included neutropenia (three [3%] patients), fatigue (two [2%]), ulcerative keratitis (two [2%]), and peripheral neuropathies (two [2%] each with sensory, motor, sensorimotor, and neuropathy peripheral). Serious treatment-related adverse events occurred in 13 (13%) patients, the most common of which included peripheral sensorimotor neuropathy (two [2%] patients) and pyrexia (two [2%]). One death due to septic shock was considered by the investigator to be related to therapy. Three deaths unrelated to treatment were reported, including one case of ileus and two unknown causes. Interpretation Tisotumab vedotin showed clinically meaningful and durable antitumour activity with a manageable and tolerable safety profile in women with previously treated recurrent or metastatic cervical cancer. Given the poor prognosis for this patient population and the low activity of current therapies in this setting, tisotumab vedotin, if approved, would represent a new treatment for women with recurrent or metastatic cervical cancer. Copyright (C) 2021 Elsevier Ltd. All rights reserved.
  • Autores: Redondo, A. (Autor de correspondencia); Oaknin, A.; Rubio, M. J.; et al.
    Revista: JOURNAL OF OVARIAN RESEARCH
    ISSN: 1757-2215 Vol.14 N° 1 2021 págs. 72
    Resumen
    Background To determine the state of current practice and to reach a consensus on recommendations for the management of advanced ovarian cancer using a Delphi survey with a group of Spanish gynecologists and medical oncologists specially dedicated to gynecological tumors. Methods The questionnaire was developed by the byline authors. All questions but one were answered using a 9-item Likert-like scale with three types of answers: frequency, relevance and agreement. We performed two rounds between December 2018 and July 2019. A consensus was considered reached when at least 75% of the answers were located within three consecutive points of the Likert scale. Results In the first round, 32 oncologists and gynecologists were invited to participate, and 31 (96.9%) completed the online questionnaire. In the second round, 27 (87.1%) completed the online questionnaire. The results for the questions on first-line management of advanced disease, treatment of patients with recurrent disease for whom platinum might be the best option, and treatment of patients with recurrent disease for whom platinum might not be the best option are presented. Conclusions This survey shows a snapshot of current recommendations by this selected group of physicians. Although the majority of the agreements and recommendations are aligned with the recently published ESMO-ESGO consensus, there are some discrepancies that can be explained by differences in the interpretation of certain clinical trials, reimbursement or accessibility issues.
  • Autores: Banerjee, S. (Autor de correspondencia); Moore, K. N.; Colombo, N.; et al.
    Revista: LANCET ONCOLOGY
    ISSN: 1470-2045 Vol.22 N° 12 2021 págs. 1721 - 1731
    Resumen
    Background There is a high unmet need for treatment regimens that increase the chance of long-term remission and possibly cure for women with newly diagnosed advanced ovarian cancer. In the primary analysis of SOLO1/GOG 3004, the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib significantly improved progression-free survival versus placebo in patients with a BRCA mutation; median progression-free survival was not reached. Here, we report an updated, post-hoc analysis of progression-free survival from SOLO1, after 5 years of follow-up. Methods SOLO1 was a randomised, double-blind, placebo-controlled, phase 3 trial, done across 118 centres in 15 countries, that enrolled patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1 and with BRCA-mutated, newly diagnosed, advanced, high-grade serous or endometrioid ovarian cancer with a complete or partial clinical response after platinum-based chemotherapy. Patients were randomly assigned (2:1) via a web-based or interactive voice-response system to receive olaparib (300 mg twice daily) or placebo tablets orally as maintenance monotherapy for up to 2 years; randomisation was by blocks and was stratified according to clinical response after platinum-based chemotherapy. Patients, treatment providers, and data assessors were masked to group assignment. The primary endpoint was investigator-assessed progression-free survival. Efficacy is reported in the intention-to-treat population and safety in patients who received at least one dose of treatment. The data cutoff for this updated, post-hoc analysis was March 5, 2020. This trial is registered with ClinicalTrials.gov (NCT01844986) and is ongoing but closed to new participants. Findings Between Sept 3,2013, and March 6,2015,260 patients were randomly assigned to olaparib and 131 to placebo. The median treatment duration was 24.6 months (IQR 11. 2-24 9) in the olaparib group and 13.9 months (8.0-24.8) in the placebo group; median follow-up was 4.8 years (2.8-5.3) in the olaparib group and 5.0 years (2.6-5.3) in the placebo group. In this post-hoc analysis, median progression-free survival was 56.0 months (95% CI 41.9-not reached) with olaparib versus 13.8 months (11.1-18.2) with placebo (hazard ratio 0.33 [95% CI 0.25-0.43]). The most common grade 3-4 adverse events were anaemia (57 122%] of 260 patients receiving olaparib vs two 12.degrees 4] of 130 receiving placebo) and neutropenia (22 [8%] vs six [5%]), and serious adverse events occurred in 55 (21%) of 260 patients in the olaparib group and 17 (13%) of 130 in the placebo group. No treatment-related adverse events that occurred during study treatment or up to 30 days after discontinuation were reported as leading to death. No additional cases of myelodysplastic syndrome or acute myeloid leukaemia were reported since the primary data cutoff, including after the 30-day safety follow-up period. Interpretation For patients with newly diagnosed advanced ovarian cancer and a BRCA mutation, after, to our knowledge, the longest follow-up for any randomised controlled trial of a PARP inhibitor in this setting, the benefit derived from 2 years' maintenance therapy with olaparib was sustained beyond the end of treatment, extending median progression-free survival past 4.5 years. These results support the use of maintenance olaparib as a standard of care in this setting. Copyright (C) 2021 Elsevier Ltd. All rights reserved.
  • Autores: Concin, N. (Autor de correspondencia); Matias-Guiu, X.; Vergote, I.; et al.
    Revista: RADIOTHERAPY AND ONCOLOGY
    ISSN: 0167-8140 Vol.154 2021 págs. 327 - 353
    Resumen
    A European consensus conference on endometrial carcinoma was held in 2014 to produce multidisciplinary evidence-based guidelines on selected questions. Given the large body of literature on the management of endometrial carcinoma published since 2014, the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy & Oncology (ESTRO) and the European Society of Pathology (ESP) jointly decided to update these evidence-based guidelines and to cover new topics in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide. ESGO/ESTRO/ESP nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of endometrial carcinoma (27 experts across Europe). To ensure that the guidelines are evidence-based, the literature published since 2014, identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 191 independent international practitioners in cancer care delivery and patient representatives. The guidelines comprehensively cover endometrial carcinoma staging, definition of prognostic risk groups integrating molecular markers, pre- and intra-operative work-up, fertility preservation, management for early, advanced, metastatic, and recurrent disease and palliative treatment. Principles of radiotherapy and pathological evaluation are also defined. (C) 2021, Elsevier B.V.; International Gynecologic Cancer Society and European Society of Gynecological Oncology; Springer Verlag GmbH Berlin Heidelberg, part of Springer Nature. All rights reserved. Radiotherapy and Oncology
  • Autores: Ibarra, M. (Autor de correspondencia); Fernández de Trocóniz Fernández, José Ignacio; Fagiolino, P.
    Revista: SCIENTIFIC REPORTS
    ISSN: 2045-2322 Vol.11 N° 1 2021 págs. 5794
    Resumen
    Enteric reabsorption occurs when a drug is secreted into the intestinal lumen and reabsorbed into the systemic circulation. This distribution process is evidenced by multiple peaks in pharmacokinetic profiles. Commonly, hepatobiliary drug secretion is assumed to be the underlying mechanism (enterohepatic reabsorption, EHR), neglecting other possible mechanisms such as gastric secretion (enterogastric reabsorption, EGR). In addition, the impact of drug reabsorption on systemic clearance, volume of distribution and bioavailability has been a subject of long-standing discussions. In this work, we propose semi-mechanistic pharmacokinetic models to reflect EHR and EGR and compare their respective impact on primary pharmacokinetic parameters. A simulation-based analysis was carried out considering three drug types with the potential for reabsorption, classified according to their primary route of elimination and their hepatic extraction: (A) hepatic metabolism-low extraction; (B) hepatic metabolism-intermediate/high extraction; (C) renal excretion. Results show that an increase in EHR can significantly reduce the clearance of drugs A and B, increase bioavailability of B drugs, and increase the volume of distribution for all drugs. Conversely, EGR had negligible impact in all pharmacokinetic parameters. Findings provide background to explain and forecast the role that this process can play in pharmacokinetic variability, including drug-drug interactions and disease states.
  • Autores: Morice, P. M. ; Leary, A.; Dolladille, C.; et al.
    Revista: THE LANCET. HAEMATOLOGY
    ISSN: 2352-3026 Vol.8 N° 2 2021 págs. e122 - e134
    Resumen
    Background Poly(ADP-ribose) polymerase (PARP) inhibitors have shown efficacy and acceptable safety in a range of neoplasms, particularly in ovarian cancers. However, some concerns have emerged regarding rare and delayed adverse events including cases of myelodysplastic syndrome and acute myeloid leukaemia, for which data are scarce. The aim of this study was to estimate the risk of myelodysplastic syndrome and acute myeloid leukaemia related to PARP inhibitors, via a systematic review and safety meta-analysis, and to describe clinical features of PARP inhibitor related myelodysplastic syndrome and acute myeloid leukaemia cases reported in WHO's pharmacovigilance database (VigiBase). Methods We systematically reviewed randomised controlled trials (RCTs) comparing PARP inhibitor therapy versus control treatments (placebo and non-placebo) in adults (age >= 18 years) treated for cancer in MEDLINE, the Cochrane Central Register of Controlled Trials, and the ClinicalTrials.gov registry with ongoing surveillance up to May 31, 2020. The date range for included studies was not restricted. By a stepwise method to capture all available adverse events, we first extracted data on myelodysplastic syndrome and acute myeloid leukaemia cases from ClinicalTrials.gov. If cases were not available, we extracted them from published manuscripts, or subsequently contacted corresponding authors or sponsors to provide data. RCTs without available data from ClinicalTrials.gov, publications, or corresponding authors or sponsors were excluded. The primary outcome was the summary risk of myelodysplastic syndrome and acute myeloid leukaemia related to PARP inhibition versus placebo treatment in RCTs. We used a fixed-effects meta-analysis to obtain Peto odds ratios (ORs) with 95% CIs. In a separate observational, retrospective, cross-sectional pharmacovigilance study of VigiBase, cases of myelodysplastic syndrome and acute myeloid leukaemia related to PARP inhibitor therapy were extracted on May 3, 2020, and clinical features summarised with a focus on median duration of PARP inhibitor exposure, median latency period between first drug exposure and diagnosis, and proportion of cases resulting in death. Our systematic review and safety meta-analysis were registered with PROSPERO, CRD42020175050. Our retrospective pharmacovigilance study was registered on ClinicalTrials.gov, NCT04326023. Findings For our safety meta-analysis, initial searches identified 1617 citations, and 31 RCTs were systematically reviewed for eligibility. 28 RCTs with available adverse events were analysed (18 placebo and ten non-placebo RCTs), with 5693 patients in PARP inhibitor groups and 3406 patients in control groups. Based on the 18 placebo RCTs (n=7307 patients), PARP inhibitors significantly increased the risk of myelodysplastic syndrome and acute myeloid leukaemia compared with placebo treatment (Peto OR 2.63 [95% CI 1.13-6.14], p=0.026) with no between-study heterogeneity ((I)2=0%, chi(2) p=0.91). The incidence of myelodysplastic syndrome and acute myeloid leukaemia across PARP inhibitor groups was 0.73% (95% CI 0.50-1.07; I-2=0%, chi(2) p=0.87; 21 events out of 4533 patients) and across placebo groups was 0.47% (0.26-0.85; I-2=0%, chi(2) p=1.00; three events out of 2774 patients). All 28 RCTs were rated as having unclear risk of bias. In VigiBase, 178 cases of myelodysplastic syndrome (n=99) and acute myeloid leukaemia (n=79) related to PARP inhibitor therapy were extracted. In cases with available data, median treatment duration was 9.8 months (IQR 3.6-17.4; n=96) and median latency period since first exposure to a PARP inhibitor was 17.8 months (8.4-29.2; n=58). Of 104 cases that reported outcomes, 47 (45%) resulted in death. Interpretation PARP inhibitors increased the risk of myelodysplastic syndrome and acute myeloid leukaemia versus placebo treatment. These delayed and often lethal adverse events should be studied further to improve clinical understanding, particularly in the front-line maintenance setting. Copyright (c) 2020 Elsevier Ltd. All rights reserved.
  • Autores: Concin, N. (Autor de correspondencia); Matias Guiu, X.; Vergote, I.; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN: 1048-891X Vol.31 N° 1 2021 págs. 12 - 39
    Resumen
    A European consensus conference on endometrial carcinoma was held in 2014 to produce multi-disciplinary evidence-based guidelines on selected questions. Given the large body of literature on the management of endometrial carcinoma published since 2014, the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy and Oncology (ESTRO), and the European Society of Pathology (ESP) jointly decided to update these evidence-based guidelines and to cover new topics in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide.
  • Autores: Esgueva Colmenarejo, Antonio Jesús; Siso, C.; Espinosa-Bravo, M. ; et al.
    Revista: JOURNAL OF SURGICAL ONCOLOGY
    ISSN: 0022-4790 Vol.123 N° 1 2021 págs. 71 - 79
    Resumen
    Introduction Breast conservative surgery (BCS) and sentinel lymph node biopsy (SLNB) after neoadjuvant treatment (NAT) is safe and effective for selected patients. This aim of this study is to evaluate the impact of anatomic site of response on outcomes and to assess the real population who may benefit from nonsurgical approaches after NAT. Material and Methods From a prospectively maintained database, patients with T1-4 N0-2 breast cancer undergoing NAT were identified. Clinicopathological and survival rates were compared in relation to response and anatomic site of response. Results Six hundred and forty-six patients were included in the study. Pathologic complete response (pCR) was an independent factor for BCS and SLN. HER2 positive and TN tumors with cN0 achieving a breast pCR remain ypN0 (p = .002). Residual axillary disease was associated with breast residual tumor (p = .05) and subtype (p = .001). With a median follow up of 35.25 months, patients with any pCR had improved survival when compared with partial response, but not significant differences between pCR, axillary pCR, or breast pCR. Conclusion Achieving a pCR increases BCS and SLN. In selected subgroups, sparing any axillary surgery after NAT maybe feasible. In cN+ patients, any pCR was associated with survival, but not the anatomic site of response.
  • Autores: Rocco, N. (Autor de correspondencia); Montagna, G.; Di Micco, R.; et al.
    Revista: ONCOLOGIST
    ISSN: 1083-7159 Vol.26 N° 1 2021 págs. E66 - E77
    Resumen
    Introduction The rapid spread of COVID-19 across the globe is forcing surgical oncologists to change their daily practice. We sought to evaluate how breast surgeons are adapting their surgical activity to limit viral spread and spare hospital resources. Methods A panel of 12 breast surgeons from the most affected regions of the world convened a virtual meeting on April 7, 2020, to discuss the changes in their local surgical practice during the COVID-19 pandemic. Similarly, a Web-based poll based was created to evaluate changes in surgical practice among breast surgeons from several countries. Results The virtual meeting showed that distinct countries and regions were experiencing different phases of the pandemic. Surgical priority was given to patients with aggressive disease not candidate for primary systemic therapy, those with progressive disease under neoadjuvant systemic therapy, and patients who have finished neoadjuvant therapy. One hundred breast surgeons filled out the poll. The trend showed reductions in operating room schedules, indications for surgery, and consultations, with an increasingly restrictive approach to elective surgery with worsening of the pandemic. Conclusion The COVID-19 emergency should not compromise treatment of a potentially lethal disease such as breast cancer. Our results reveal that physicians are instinctively reluctant to abandon conventional standards of care when possible. However, as the situation deteriorates, alternative strategies of de-escalation are being adopted. Implications for Practice This study aimed to characterize how the COVID-19 pandemic is affecting breast cancer surgery and which strategies are being adopted to cope with the situation.
  • Autores: López-Vega, J. M.; Álvarez, I.; Antón, A.; et al.
    Revista: CANCERS
    ISSN: 2072-6694 Vol.13 N° 14 2021 págs. 3511
    Resumen
    Simple Summary New blood vessel formation (angiogenesis) has a crucial role in tumour growth and spread. Bevacizumab is an anticancer therapy that targets angiogenesis by inhibiting the vascular endothelial growth factor (VEGF) and is approved for the treatment of metastatic breast cancer. However, there are no validated methods for predicting which patients will respond to bevacizumab, although some have investigated whether a response can be predicted by using scanning (imaging) techniques that study tumour blood vessels or by using the levels of VEGF markers before treatment. In this study, we used a combination of imaging techniques and VEGF marker levels to show that bevacizumab caused structural and functional changes in the blood vessels of breast tumours and substantially slowed tumour growth. The increasing availability and refinement of imaging technology can help to identify biomarkers that will be able to predict which patients with breast cancer are most likely to respond to bevacizumab. This prospective, phase II study evaluated novel biomarkers as predictors of response to bevacizumab in patients with breast cancer (BC), using serial imaging methods and gene expression analysis. Patients with primary stage II/III BC received bevacizumab 15 mg/kg (cycle 1; C1), then four cycles of neoadjuvant docetaxel doxorubicin, and bevacizumab every 3 weeks (C2-C5). Tumour proliferation and hypoxic status were evaluated using F-18-fluoro-3 '-deoxy-3 '-L-fluorothymidine (FLT)- and F-18-fluoromisonidazole (FMISO)-positron emission tomography (PET) at baseline, and during C1 and C5. Pre- and post-bevacizumab vascular changes were evaluated using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Molecular biomarkers were assessed using microarray analysis. A total of 70 patients were assessed for treatment efficacy. Significant decreases from baseline in tumour proliferation (FLT-PET), vascularity, and perfusion (DCE-MRI) were observed during C1 (p <= 0.001), independent of tumour subtype. Bevacizumab treatment did not affect hypoxic tumour status (FMISO-PET). Significant changes in the expression of 28 genes were observed after C1. Changes in vascular endothelial growth factor receptor (VEGFR)-2p levels were observed in 65 patients, with a > 20% decrease in VEGFR-2p observed in 13/65. Serial imaging techniques and molecular gene profiling identified several potentially predictive biomarkers that may predict response to neoadjuvant bevacizumab therapy in BC patients.
  • Autores: Redondo, A. (Autor de correspondencia); Girones, R.; Ruiz, N.; et al.
    Revista: EUROPEAN JOURNAL OF GYNAECOLOGICAL ONCOLOGY
    ISSN: 0392-2936 Vol.42 N° 6 2021 págs. 1116 - 1123
    Resumen
    Objective: To assess epidemiological, pathological and clinical characteristics, therapeutic management patterns and outcomes in the management of advanced ovarian cancer (AOC) in clinical practice. Methods: Multicenter, retrospective, epidemiological, observational real-world study reviewing clinical records from 277 patients diagnosed with AOC between January 2008 and December 2010 who were treated and followed in 31 Spanish hospitals belonging to the Spanish Ovarian Cancer Research Group (GEICO). Survival curves were estimated by Kaplan-Meier and differences analyzed by the log-rank test. Results: Median age at diagnosis was 62 years (range 26-96), 62% of patients had a high-grade serous carcinoma, and 64% and 21% of patients had stage IIIC and stage IV disease, respectively. Overall, 46% of patients underwent primary debulking surgery (PDS), with complete cytoreduction in 63% of procedures, and 34% underwent interval debulking surgery, with complete cytoreduction in 71% of them. Overall, 96% of patients received at least one cycle of front-line chemotherapy. Recurrence occurred in 77% of patients, and 90% of them (69% of total) received a second line chemotherapy. Median progression-free survival (PFS) was 14 months (95% CI: 13-17) and median overall survival (OS) was 41 months (95% CI: 34-49). PDS and complete cytoreduction had a statistically significant correlation with PFS and OS. Conclusions: This retrospective study provides real-world data of clinical characteristics, therapeutic management, and outcomes in Spanish AOC patients. Primary debulking surgery and complete cytoreduction were favorable prognostic factors in this series.
  • Autores: Callens, C.; Vaur, D.; Soubeyran, I.; et al.
    Revista: JOURNAL OF THE NATIONAL CANCER INSTITUTE
    ISSN: 0027-8874 Vol.113 N° 7 2021 págs. 917 - 923
    Resumen
    Background: PAOLA1 is a phase III study assessing olaparib maintenance therapy in advanced high-grade ovarian carcinoma patients responding to first-line platinum-taxane-based chemotherapy plus bevacizumab as standard of care. Randomization was stratified by treatment outcome and tumor BRCA1/2 status (tBRCA) at screening. Methods: tBRCA was tested on formalin-fixed, paraffin-embedded tumor blocks on 5 French platforms using 2 next-generation sequencing methods based either on hybrid capture or amplicon technology. One of the exploratory objectives was to assess the concordance between germline (gBRCA) and tBRCA testing in French patients. gBRCA testing was performed on blood samples on the same platforms. Results: From May 2015 to July 2017, tBRCA tests were performed for 1176 screened patients. Only 52 (4.4%) tumor samples were noncontributive. The median interval between reception of the tumor sample and availability of the tBRCA status result was 37 days (range = 8-260). A pathogenic variant was reported in 27.1% tumor samples (319 of 1176 screened patients). tBRCA and gBRCA testing were performed for 451 French patients with negative results for both tests in 306 patients (67.8%) and positive results for both tests in 85 patients (18.8%). Only 1 large genomic rearrangement of BRCA1 was detected, exclusively in the blood sample. Interestingly, tBRCA testing revealed 6.4% of pathogenic variant (29 of 451) not detected by gBRCA testing. Conclusions: tBRCA testing is an appropriate tool with an acceptable turnaround time for clinical practice and a low failure rate, ensuring reliable identification of patients likely to benefit from poly(ADP-ribose) polymerase inhibitor therapy.
  • Autores: Redondo, A. (Autor de correspondencia); Guerra, E.; Manso, L.; et al.
    Revista: CLINICAL AND TRANSLATIONAL ONCOLOGY
    ISSN: 1699-048X Vol.23 N° 5 2021 págs. 961 - 968
    Resumen
    Despite remarkable advances in the knowledge of molecular biology and treatment, ovarian cancer remains the leading cause of death from gynecologic cancer. In the last decade, there have been important advances both in systemic and surgical treatment. However, there is no doubt that the incorporation of PARP inhibitors as maintenance after the response to platinum-based chemotherapy, first in recurrent disease and recently also in first line, will change the natural history of the disease. The objective of this guide is to summarize the current evidence for the diagnosis, treatment, and follow-up of ovarian cancer, and to provide evidence-based recommendations for clinical practice.
  • Autores: Colombo, N. (Autor de correspondencia); Moore, K.; Scambia, G.; et al.
    Revista: GYNECOLOGIC ONCOLOGY
    ISSN: 0090-8258 Vol.163 N° 1 2021 págs. 41 - 49
    Resumen
    Objectives. In the phase III SOLO1 trial (NCT01844986), maintenance olaparib provided a substantial progression-free survival benefit in patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation who were in response after platinum-based chemotherapy. We analyzed the timing, duration and grade of the most common hematologic and non-hematologic adverse events in SOLO1. Methods. Eligible patients were randomized to olaparib tablets 300 mg twice daily (N = 260) or placebo (N = 131), with a 2-year treatment cap in most patients. Safety outcomes were analyzed in detail in randomized patients who received at least one dose of study drug (olaparib, n = 260; placebo, n = 130). Results. Median time to first onset of the most common hematologic (anemia, neutropenia, thrombocytopenia) and non-hematologic (nausea, fatigue/asthenia, vomiting) adverse events was <3 months in olaparibtreated patients. The first event of anemia, neutropenia, thrombocytopenia, nausea and vomiting lasted a median of <2 months and the first event of fatigue/asthenia lasted a median of 3.48 months in the olaparib group. These adverse events were manageable with supportive treatment and/or olaparib dose modification in most patients, with few patients requiring discontinuation of olaparib. Of 162 patients still receiving olaparib at month 24, 64.2% were receiving the recommended starting dose of olaparib 300 mg twice daily. Conclusions. Maintenance olaparib had a predictable and manageable adverse event profile in the newly diagnosed setting with no new safety signals identified. Adverse events usually occurred early, were largely manageable and led to discontinuation in a minority of patients. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).
  • Autores: Vicente Ruiz, Miriam (Autor de correspondencia); Hontanilla Calatayud, Bernardo Carlos
    Revista: CIRUGIA PLASTICA IBERO-LATINOAMERICANA
    ISSN: 0376-7892 Vol.47 N° 3 2021 págs. 305 - 308
    Resumen
    Aunque existe abundante literatura sobre las distintas complicaciones de los colgajos libres, la descripción de necrosis superficial completa en colgajos libres es escasa. Presentamos un caso de reconstrucción postraumática de pie con colgajo libre de músculo gracilis, que en el postoperatorio desarrolló una escara oscura y seca que cubría toda su superficie y semejaba una pérdida total del colgajo. Sin embargo, el pedículo del colgajo mantuvo en todo momento un tono activo en ecografía doppler, por lo que se decidió un manejo expectante. De manera diferida, se realizó cirugía de revisión con desbridamiento de la escara y del tejido necrótico superficial a los 21 días, descubriendo tejido sano del colgajo subyacente, que fue injertado. Posteriormente, el colgajo mostró una evolución favorable con una buena integración del injerto. Aunque en nuestro paciente no se identificó la causa exacta de esta complicación, se discuten las posibles etiologías con especial hincapié en el tabaco como factor de riesgo.
  • Autores: Concin, N. (Autor de correspondencia); Creutzberg, C. L. ; Cibula, D.; et al.
    Revista: VIRCHOWS ARCHIV
    ISSN: 0945-6317 Vol.478 N° 2 2021 págs. 153 - 190
    Resumen
    A European consensus conference on endometrial carcinoma was held in 2014 to produce multidisciplinary evidence-based guidelines on selected questions. Given the large body of literature on the management of endometrial carcinoma published since 2014, the European Society of Gynaecological Oncology (ESGO), the European SocieTy for Radiotherapy & Oncology (ESTRO) and the European Society of Pathology (ESP) jointly decided to update these evidence-based guidelines and to cover new topics in order to improve the quality of care for women with endometrial carcinoma across Europe and worldwide. ESGO/ESTRO/ESP nominated an international multidisciplinary development group consisting of practicing clinicians and researchers who have demonstrated leadership and expertise in the care and research of endometrial carcinoma (27 experts across Europe). To ensure that the guidelines are evidence-based, the literature published since 2014, identified from a systematic search was reviewed and critically appraised. In the absence of any clear scientific evidence, judgment was based on the professional experience and consensus of the development group. The guidelines are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines were reviewed by 191 independent international practitioners in cancer care delivery and patient representatives. The guidelines comprehensively cover endometrial carcinoma staging, definition of prognostic risk groups integrating molecular markers, pre- and intra-operative work-up, fertility preservation, management for early, advanced, metastatic, and recurrent disease and palliative treatment. Principles of radiotherapy and pathological evaluation are also defined.
  • Autores: Parra Guillén, Zinnia Patricia; Freshwater, T.; Cao, Y.; et al.
    Revista: FRONTIERS IN PHARMACOLOGY
    ISSN: 1663-9812 Vol.12 2021 págs. 705443
    Resumen
    V937 is an investigational novel oncolytic non-genetically modified Kuykendall strain of Coxsackievirus A21 which is in clinical development for the treatment of advanced solid tumor malignancies. V937 infects and lyses tumor cells expressing the intercellular adhesion molecule I (ICAM-I) receptor. We integrated in vitro and in vivo data from six different preclinical studies to build a mechanistic model that allowed a quantitative analysis of the biological processes of V937 viral kinetics and dynamics, viral distribution to tumor, and anti-tumor response elicited by V937 in human xenograft models in immunodeficient mice following intratumoral and intravenous administration. Estimates of viral infection and replication which were calculated from in vitro experiments were successfully used to describe the tumor response in vivo under various experimental conditions. Despite the predicted high clearance rate of V937 in systemic circulation (t(1/2) = 4.3 min), high viral replication was observed in immunodeficient mice which resulted in tumor shrinkage with both intratumoral and intravenous administration. The described framework represents a step towards the quantitative characterization of viral distribution, replication, and oncolytic effect of a novel oncolytic virus following intratumoral and intravenous administrations in the absence of an immune response. This model may further be expanded to integrate the role of the immune system on viral and tumor dynamics to support the clinical development of oncolytic viruses.
  • Autores: Piccart, M.; 't-Veer, L. J. V.; Poncet, C.; et al.
    Revista: LANCET ONCOLOGY
    ISSN: 1470-2045 Vol.22 N° 4 2021 págs. 476 - 488
    Resumen
    Background The MINDACT trial showed excellent 5-year distant metastasis-free survival of 94.7% (95% CI 92.5-96.2) in patients with breast cancer of high clinical and low genomic risk who did not receive chemotherapy. We present long-term follow-up results together with an exploratory analysis by age. Methods MINDACT was a multicentre, randomised, phase 3 trial done in 112 academic and community hospitals in nine European countries. Patients aged 18-70 years, with histologically confirmed primary invasive breast cancer (stage T1, T2, or operable T3) with up to three positive lymph nodes, no distant metastases, and a WHO performance status of 0-1 were enrolled and their genomic risk (using the MammaPrint 70-gene signature) and clinical risk (using a modified version of Adjuvant! Online) were determined. Patients with low clinical and low genomic risk results did not receive chemotherapy, and patients with high clinical and high genomic risk did receive chemotherapy (mostly anthracycline-based or taxane-based, or a combination thereof). Patients with discordant risk results (ie, patients with high clinical risk but low genomic risk, and those with low clinical risk but high genomic risk) were randomly assigned (1:1) to receive chemotherapy or not based on either the clinical risk or the genomic risk. Randomisation was done centrally and used a minimisation technique that was stratified by institution, risk group, and clinical-pathological characteristics. Treatment allocation was not masked. The primary endpoint was to test whether the distant metastasis-free survival rate at 5 years in patients with high clinical risk and low genomic risk not receiving chemotherapy had a lower boundary of the 95% CI above the predefined non-inferiority boundary of 92%. In the primary test population of patients with high clinical risk and low genomic risk who adhered to the treatment allocation of no chemotherapy and had no change in risk post-enrolment. Here, we present updated follow-up as well as an exploratory analysis of a potential age effect (<= 50 years vs >50 years) and an analysis by nodal status for patients with hormone receptor-positive and HER2-negative disease. These analyses were done in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT00433589, and the European Clinical Trials database, EudraCT2005-002625-31. Recruitment is complete and further long-term follow-up is ongoing. Findings Between Feb 8, 2007, and July 11, 2011, 6693 patients were enrolled. On Feb 26, 2020, median follow-up was 8.7 years (IQR 7.8-9.7). The updated 5-year distant metastasis-free survival rate for patients with high clinical risk and low genomic risk receiving no chemotherapy (primary test population, n=644) was 95.1% (95% CI 93.1-96.6), which is above the predefined non-inferiority boundary of 92%, supporting the previous analysis and proving MINDACT as a positive de-escalation trial. Patients with high clinical risk and low genomic risk were randomly assigned to receive chemotherapy (n=749) or not (n=748); this was the intention-to-treat population. The 8-year estimates for distant metastasis-free survival in the intention-to-treat population were 92.0% (95% CI 89.6-93.8) for chemotherapy versus 89.4% (86.8-91.5) for no chemotherapy (hazard ratio 0.66; 95% CI 0.48-0.92). An exploratory analysis confined to the subset of patients with hormone receptor-positive, HER2-negative disease (1358 [90.7%] of 1497 randomly assigned patients, of whom 676 received chemotherapy and 682 did not) shows different effects of chemotherapy administration on 8-year distant metastasis-free survival according to age: 93.6% (95% CI 89.3-96.3) with chemotherapy versus 88.6% (83.5-92.3) without chemotherapy in 464 women aged 50 years or younger (absolute difference 5.0 percentage points [SE 2.8, 95% CI -0.5 to 10.4]) and 90.2% (86.8-92.7) versus 90.0% (86.6-92.6) in 894 women older than 50 years (absolute difference 0.2 percentage points [2.1, -4.0 to 4.4]). The 8-year distant metastasis-free survival in the exploratory analysis by nodal status in these patients was 91.7% (95% CI 88.1-94.3) with chemotherapy and 89.2% (85.2-92.2) without chemotherapy in 699 node-negative patients (absolute difference 2.5 percentage points [SE 2.3, 95% CI -2.1 to 7.2]) and 91.2% (87.2-94.0) versus 89.9% (85.8-92.8) for 658 patients with one to three positive nodes (absolute difference 1.3 percentage points [2.4, -3.5 to 6.1]). Interpretation With a more mature follow-up approaching 9 years, the 70-gene signature shows an intact ability of identifying among women with high clinical risk, a subgroup, namely patients with a low genomic risk, with an excellent distant metastasis-free survival when treated with endocrine therapy alone. For these women the magnitude of the benefit from adding chemotherapy to endocrine therapy remains small (2.6 percentage points) and is not enhanced by nodal positivity. However, in an underpowered exploratory analysis this benefit appears to be age-dependent, as it is only seen in women younger than 50 years where it reaches a clinically relevant threshold of 5 percentage points. Although, possibly due to chemotherapy-induced ovarian function suppression, it should be part of informed, shared decision making. Further study is needed in younger women, who might need reinforced endocrine therapy to forego chemotherapy. Copyright (C) 2021 Esevier Ltd. All rights reserved.
  • Autores: Asín Prieto, Eduardo; Parra Guillén, Zinnia Patricia; Gómez Mantilla, José David; et al.
    Revista: COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
    ISSN: 2001-0370 Vol.19 2021 págs. 4997 - 5007
    Resumen
    Hepatitis B liver infection is caused by hepatitis B virus (HBV) and represents a major global disease problem when it becomes chronic, as is the case for 80-90% of vertical or early life infections. However, in the vast majority (>95%) of adult exposures, the infected individuals are capable of mounting an effective immune response leading to infection resolution. A good understanding of HBV dynamics and the interaction between the virus and immune system during acute infection represents an essential step to characterize and understand the key biological processes involved in disease resolution, which may help to identify potential interventions to prevent chronic hepatitis B. In this work, a quantitative systems pharmacology model for acute hepatitis B characterizing viral dynamics and the main components of the innate, adaptive, and tolerant immune response has been successfully developed. To do so, information from multiple sources and across different organization levels has been integrated in a common mechanistic framework. The final model adequately describes the chronology and plausibility of an HBV-triggered immune response, as well as clinical data from acute patients reported in the literature. Given the holistic nature of the framework, the model can be used to illustrate the relevance of the different immune pathways and biological processes to ultimate response, observing the negligible contribution of the innate response and the key contribution of the cellular response on viral clearance. More specifically, moderate reductions of the proliferation of activated cytotoxic CD8+ lymphocytes or increased immunoregulatory effects can drive the system towards chronicity. (c) 2021 The Author(s). Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.
  • Autores: Santisteban Eslava, Marta (Autor de correspondencia); Pérez Solans, Belén; Hato Alvaro, Laura; et al.
    Revista: THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY
    ISSN: 1758-8340 Vol.13 2021 págs. 1 - 14
    Resumen
    Background: Primary breast cancer (BC) has shown a higher immune infiltration than the metastatic disease, justifying the optimal scenario for immunotherapy. Recently, neoadjuvant chemotherapy (NAC) combined with immune checkpoint inhibitors has demonstrated a gain in pathological complete responses (tpCR) in patients with BC. The aim of our study is to evaluate the safety, feasibility, and efficacy of the addition of dendritic cell vaccines (DCV) to NAC in HER2-negative BC patients. Methods: Thirty-nine patients with early BC received DCV together with NAC conforming the vaccinated group (VG) and compared with 44 patients as the control group (CG). All patients received anthracyclines and taxanes-based NAC (ddECx4 -> Dx4) followed by surgery +/- radiotherapy +/- hormonotherapy. Results: The tpCR rate was 28.9% in the VG and 9.09% in the CG (p = 0.03). Pathological CR in the triple negative (TN) BC were 50.0% versus 30.7% (p = 0.25), 16.6% versus 0% in luminal B (p = 0.15), and none among luminal A patients in VG versus CG, respectively. Impact of DCV was significantly higher in the programmed cell death ligand 1 (PD-L1) negative population (p < 0.001). PD-L1 expression was increased in patients with residual disease in the VG as compared with the CG (p < 0.01). No grade > 3 vaccine-related adverse events occurred. With a median follow-up of 8 years, no changes were seen in event-free survival or overall survival. Phenotypic changes post DCV in peripheral blood were observed in myeloid-derived suppressor cells (MDSC), NK, and T cells. Increase in blood cell proliferation and interferon (IFN)-gamma production was detected in 69% and 74% in the VG, respectively. Humoral response was also found. Clonality changes in TCR-beta repertoire were detected in 67% of the patients with a drop in diversity index after treatment. Conclusion: The combination of DCV plus NAC is safe and increases tpCR, with a significant benefit among PD-L1-negative tumors. DCV modify tumor milieu and perform cellular and humoral responses in peripheral blood with no impact in outcome.
  • Autores: Hontanilla Calatayud, Bernardo Carlos (Autor de correspondencia); Vicente Ruiz, Miriam
    Revista: FACIAL PLASTIC SURGERY & AESTHETIC MEDICINE
    ISSN: 2689-3614 Vol.23 N° 6 2021 págs. 449 - 454
    Resumen
    Background: In facial palsy reconstruction, static techniques with the use of slings can improve the appearance and functionality of the paralyzed face and may be used in patients who cannot undergo complex surgeries or as an ancillary procedure to a dynamic reconstruction. The objective of this study was to assess the improvement in facial symmetry and quality of life among older patients with flaccid facial palsy with the use of a plantaris tendon sling. Methods: A total of 46 patients who had undergone a static reconstruction with the plantaris tendon sling were studied. The surgical technique is detailed emphasizing the tips and pearls. Results: The displacement of the oral commissure was assessed with the FACIAL CLIMA demonstrating a mean elevation of 1.5 +/- 0.4 cm and an improvement of 97 +/- 7% in the recovery of oral commissure symmetry 2 years after the surgery, whereas the Sunnybrook Facial Grading System showed an improvement of symmetry at rest (-15 +/- 5) at 2 years. The Facial Disability Score indicated an improvement of the physical disability (+73.5 +/- 14) as well as the social impairment (+21 +/- 7) at 1 year postoperatively. Patients were followed for a median of 2 years (range 2-6 years). Conclusions: The use of tendon slings for static facial paralysis reconstruction is a reliable technique with no functional sequelae and good long-term results.
  • Autores: Ameijeiras Rodríguez , C. (Autor de correspondencia); Henriques, S. C. ; Sancho-Arauz, A.; et al.
    Revista: PHARMACEUTICAL RESEARCH
    ISSN: 0724-8741 Vol.38 N° 12 2021 págs. 2047 - 2063
    Resumen
    Purpose Both inter-individual (IIV) and inter-occasion (IOV) variabilities are observed in bioequivalence studies. High IOV may be a cause of problems on the demonstration of bioequivalence, despite strict measures are taken to control it. The objective of this study is to investigate further means of controlling IIV by optimizing study design of crossover studies. Methods Data from 18 bioequivalence studies were used to develop population pharmacokinetics (popPK) models to characterize the absorption and disposition processes of 14 drugs, to estimate IOV for each drug substance and to evaluate possible correlations with biopharmaceutical properties of drug substances, classified in accordance to the Biopharmaceutics Drug Disposition Classification System (BDDCS). Results Plasma-pharmacokinetics profiles for the 14 drugs analyzed were successfully described using popPK. The pharmacokinetic parameters that showed greater variability were first-order rate constant of absorption, duration of the zero-order absorption process, relative bioavailability and time of latency. ISCV% estimated for C-max seems to correlate with the log-DoseNumber for Class 1, 2 and 3, despite no direct correlation was observed between popPK model residual variability (RUV) and ISCV%. Nevertheless, higher RUV estimates were observed for Class 2 drugs in comparison to Class 1 and 3. Conclusion Pharmacokinetic parameters related to drug absorption showed greater variability. Ingestion of the IMP along with 240 mL of water showed to standardize gastric emptying. Given the dependency between C-max variability and dose-solubility ratio, for classes 2 and 4, ad libitum water intake may increase C(max )and AUC ISCV%. A water ingestion standardization until the expected T-max of the drug is suggested.
  • Autores: Razumova, Z. (Autor de correspondencia); Bizzarri, N.; Kacperczyk-Bartnik, J.; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN: 1048-891X Vol.31 N° 5 2021 págs. 658 - 669
    Resumen
    This is a report from the European Society of Gynaecological Oncology State-of-the-Art Virtual Meeting held December 14-16, 2020. The unique 3-day conference offered comprehensive state-of-the-art summaries on the major advances in the treatment of different types of gynecological cancers. Sessions opened with a case presentation followed by a keynote lecture and interactive debates with opinion leaders in the field. The speakers also presented scientific reviews on the clinical trial landscape in collaboration with the European Network of Gynecological Oncological Trial (ENGOT) groups. In addition, the new ESGO-ESRTO-ESP endometrial cancer guidelines were officially presented in public. This paper describes the key information and latest studies that were presented for the first time at the conference.
  • Autores: Pérez Fidalgo, J. A.; Cortes, A.; García, Y.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.32 N° Supl. 5 2021 págs. S735 - S735
  • Autores: Konstantinopoulos, P.; González Martín, Antonio; Cruz, F.; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN: 1048-891X Vol.31 N° Suppl. 4 2021 págs. A139 - A140
  • Autores: Pérez-Fidalgo, J. A.; Cortes Salgado, A.; García, Y.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.39 N° 15 (supl) 2021
  • Autores: O'Cearbhaill, R.; Pérez-Fidalgo, J. A.; Monk, B.; et al.
    Revista: GYNECOLOGIC ONCOLOGY
    ISSN: 0090-8258 Vol.162 N° S1 2021 págs. S65
  • Autores: Hamilton, E. P.; Jackson, C. C.; Eskander, R. N.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.39 N° 15 (Supplement) 2021
  • Autores: Esgueva Colmenarejo, Antonio Jesús; Noordhoek, I.; Kranenbarg, E. M. K.; et al.
    Revista: BREAST
    ISSN: 0960-9776 Vol.56 N° Suppl.1 2021 págs. S81 - S82
  • Autores: Vergote, I.; Randall, L. M.; Kalbacher, E.; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN: 1048-891X Vol.31 N° Suppl. 4 2021 págs. A129 - A130
  • Autores: van 't Veer, L. J.; Cardoso, F.; Poncet, C.; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.81 N° 4 Supl. 2021 págs. GS4-11
  • Autores: van't Veer, L. J.; Cardoso, F.; Poncet, C.; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.81 N° 4 Supl. 2021 págs. PS6-01
  • Autores: Ortego Zabalza, Ignacio; Vizcay Atienza, Ángel; de la Cruz Sánchez, Susana; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.39 N° 15 2021
  • Autores: Bradley, W.; Moore, K.; Colombo, N.; et al.
    Revista: GYNECOLOGIC ONCOLOGY
    ISSN: 0090-8258 Vol.162 N° Supplement 1 2021 págs. S25 - S26
  • Autores: González Martín, Antonio; Matulonis, U. A.; Korach, J.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.39 N° 15 (Supplement) 2021
  • Autores: Banerjee, A.; González Martín, Antonio; Matulonis, U.; et al.
    Revista: ASIA-PACIFIC JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 1743-7555 Vol.17 N° S9 2021 págs. 116 - 117
  • Autores: Poveda, A.; Lheureux, S.; Colombo, N.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.39 N° 15 2021
  • Autores: Pautier, P.; Harter, P.; Pisano, C.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.39 N° 15 (Supplement) 2021
  • Autores: Gasparri, M. L. ; Kuehn, T.; Rubio, Isabel Teresa; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.81 N° 4 Suppl. 2021
  • Autores: Lindemann, K.; Skof, E.; Colombo, N.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.32 N° Supl. 5 2021 págs. S738 - S739
  • Autores: Barretina-Ginesta, M. P.; Monk, B. J.; Han, S.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.32 N° Supl. 5 2021 págs. S736 - S737
  • Autores: Rubio, Isabel Teresa
    Revista: BREAST
    ISSN: 0960-9776 Vol.56 2021 págs. S12 - S13
  • Autores: Farinas-Madrid, L.; Rubio, M. J.; Redondo, A.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.32 N° Supl. 5 2021 págs. S761 - S762
  • Autores: Vergote, I.; Monk, B. J.; Coleman, R. L.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN: 0732-183X Vol.39 N° 15 (Supplement) 2021
  • Autores: Chase, D.; Perhanidis, J.; Gupta, D.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN: 0923-7534 Vol.32 N° Supl. 5 2021 págs. S739 - S740
  • Autores: Vieito Villar, M.; Simonelli, M.; Eskens, F. A. L. M; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.81 N° 13 Supplement 2021
  • Autores: Esgueva Colmenarejo, Antonio Jesús; Noordhoek, I.; Kranenbarg, E. M. K. ; et al.
    Revista: ANNALS OF SURGICAL ONCOLOGY
    ISSN: 1068-9265 Vol.28 N° SUPPL 1 2021 págs. S52 - S52
  • Autores: De la Cruz, L.; Gion, M.; Cruz, J.; et al.
    Revista: CANCER RESEARCH
    ISSN: 0008-5472 Vol.81 N° 4 Supl. S 2021
  • Autores: Matulonis, U.; Herrstedt, J.; Oza, A.; et al.
    Revista: GYNECOLOGIC ONCOLOGY
    ISSN: 0090-8258 Vol.162 N° Supplement 1 2021 págs. S24 - S25
  • Autores: Banerjee, S.; González Martín, Antonio; Harter, P.; et al.
    Revista: ESMO OPEN
    ISSN: 2059-7029 Vol.5 N° 6 2020 págs. e001110.
    Resumen
    Poly(ADP-ribose) polymerase (PARP) inhibitor maintenance therapy is the latest breakthrough in the management of newly diagnosed advanced ovarian cancer. The results of the SOLO-1 trial in 2018 led to European Medicines Agency and Food and Drug Administration approval of olaparib as first-line maintenance therapy in patients with BRCA1/2 mutation, establishing a new standard of care. Subsequently, the results of three phase III trials (PRIMA, PAOLA-1, VELIA) evaluating the use of first-line PARP inhibitors beyond patients with BRCA1/2 mutations and as combination strategies were presented in 2019, leading to the recent approval of maintenance niraparib irrespective of biomarker status and olaparib in combination with bevacizumab in homologous recombination deficiency-positive-associated advanced ovarian cancer. An ESMO Open - Cancer Horizons round-table expert panel discussed the four phase III trials of first-line PARP inhibitor therapy and how they are changing the clinical management of advanced ovarian cancer.
  • Autores: Navarro-Barrios, A.; Gil-Martinez, J.; Ramos-Bernardo, I.; et al.
    Revista: SURGICAL ONCOLOGY-OXFORD
    ISSN: 0960-7404 Vol.33 2020 págs. 19 - 23
    Resumen
    Background: Endometrial cancer is the most common malignancy of the female genital tract. For cancers detected at an advanced stage or intraperitoneal relapse, the prognosis is poor. Optimal cytoreductive surgery (CRS) is the most accepted treatment; however, patients with advanced intraperitoneal disease might benefit from hyperthermic intraoperative peritoneal chemotherapy (HIPEC). The aim of this study was to analyze recurrence-free survival (RFS) after CRS and HIPEC in a large series of patients with peritoneal metastases from endometrial cancer. Methods: Patients with a diagnosis of endometrial cancer with primary or recurrent peritoneal dissemination were included. All patients underwent CRS plus HIPEC. Data were prospectively collected in the Spanish Group of Peritoneal Oncological Surgery (GECOP) database. Results: Forty-three patients with endometrial cancer and peritoneal metastasis were included. Fifteen patients (35%) were diagnosed with G3 endometrioid carcinomas and 28 (65%) with other non-endometroid histologies. A completeness of cytoreduction score of CC-0 was achieved in 41 patients (95%). RFS at 5 years was 23%, being factors related to worse RFS: treatment with preoperative chemotherapy (p = 0.027), resection of more than three peritoneal areas (p = 0.010), cytoreduction of the upper abdominal space (p = 0.023), HIPEC treatment with paclitaxel = 0.013), and the presence of metastatic lymph nodes (p = 0.029). Conclusions: Better RFS rates after CRS and HIPEC were observed for patients with the following characteristics: cytoreductive surgery without preoperative chemotherapy, complete surgery performed with limited surgical maneuvers, treated with cisplatin, and no lymph node metastases. Synopsis: Endometrial cancer has a poor prognosis when diagnosed at advance stage. Patients with intraperitoneal metastases from endometrial cancer may benefit from CRS plus HIPEC with improvement in the recurrence-free survival results.
  • Autores: Irurzun Arana, Itziar (Autor de correspondencia); Rackauckas, C. ; McDonald, T. O.; et al.
    Revista: TRENDS IN PHARMACOLOGICAL SCIENCES
    ISSN: 0165-6147 Vol.41 N° 11 2020 págs. 882 - 895
    Resumen
    The model-informed drug discovery and development paradigm is now well established among the pharmaceutical industry and regulatory agencies. This success has been mainly due to the ability of pharmacometrics to bring together different modeling strategies, such as population pharmacokinetics/pharmacodynamics (PK/PD) and systems biology/pharmacology. However, there are promising quantitative approaches that are still seldom used by pharmacometricians and that deserve consideration. One such case is the stochastic modeling approach, which can be important when modeling small populations because random events can have a huge impact on these systems. In this review, we aim to raise awareness of stochastic models and how to combine themwith existingmodeling techniques, with the ultimate goal ofmaking future drug-disease models more versatile and realistic.
  • Autores: Ditsch, N.; Rubio, Isabel Teresa; Gasparri, M. L.; et al.
    Revista: CURRENT OPINION IN OBSTETRICS AND GYNECOLOGY
    ISSN: 1040-872X Vol.32 N° 1 2020 págs. 91 - 99
    Resumen
    Purpose of review There have been fundamental changes in the surgical approach to breast cancer management over the last decades. The primary objective of achieving locoregional control, however, remains unchanged. Recent findings In addition to strategies optimizing systemic treatment and radiotherapy, current discussions focus on improving the surgical approach to breast cancer. Especially in view of the increasingly pivotal role of neoadjuvant chemotherapy NAT/NAC (NACT), gauging the extent of tissue removal in the breast and the width of resection margins in breast-conserving surgery is highly important, as is the extent of axillary surgery. Although sentinel lymph node (SLN)-positive patients always underwent axillary lymph node dissection in the past, this paradigm has been challenged in recent years. Targeted axillary dissection (TAD) has emerged as a new staging option in biopsy-proven node-positive patients who convert to clinical node negativity (cN0) after NACT. TAD combines the removal of the SLN and of the target lymph node marked prior to NACT. The accuracy of axillary staging both before and after NACT plays an important role for prognostication and multidisciplinary treatment plans, while its extent has significant effects on patients' arm morbidity and quality of life. The current review focuses on recent evidence regarding surgical management of the breast and axilla in patients with primary breast cancer based on a PubMed and EMBASE literature search for publication years 2018 and 2019.
  • Autores: Pérez Solans, Belén (Autor de correspondencia); Garrido Cid, María Jesús; Fernández de Trocóniz Fernández, José Ignacio (Autor de correspondencia)
    Revista: CLINICAL PHARMACOKINETICS
    ISSN: 0312-5963 Vol.59 N° 2 2020 págs. 123 - 135
    Resumen
    In the oncology field, understanding the relationship between the dose administered and the exerted effect is particularly important because of the narrow therapeutic index associated with anti-cancer drugs and the high interpatient variability. Therefore, in this review, we provide a critical perspective of the different methods of characterising treatment exposure in the oncology setting. The increasing number of modelling applications in oncology reflects the applicability and the impact of pharmacometrics on all phases of the drug development process and patient management as well. Pharmacometric modelling is a worthy component within the current paradigm of model-based drug development, but pharmacometric modelling techniques are also accessible for the clinician in the optimisation of current oncology therapies. Consequently, the application of population models in a hospital setting by generating close collaborations between physicians and pharmacometricians is highly recommended, providing a systematic means of developing and assessing model-based metrics as 'drivers' for various responses to treatments, which can then be evaluated as predictors for treatment success. Characterising the key determinants of variability in exposure is of particular importance for anticancer agents, as efficacy and toxicity are associated with exposure. We present the different strategies to describe and predict drug exposure that can be applied depending on the data available, with the objective of obtaining the most useful information in the patients' favour throughout the full drug cycle. Therefore, the objective of the present article is to review the different approaches used to characterise a patient's exposure to oncology drugs, which will result in a better understanding of the time course of the response and the magnitude of interpatient variability.
  • Autores: González Martín, Antonio (Autor de correspondencia); Monk, B. J.
    Revista: NEW ENGLAND JOURNAL OF MEDICINE
    ISSN: 0028-4793 Vol.382 N° 16 2020 págs. 1574 - 1574
  • Autores: Balbás Martínez, Violeta (Autor de correspondencia); Michelet, R.; Edginton, A. N.; et al.
    Revista: EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
    ISSN: 0928-0987 Vol.143 2020
  • Autores: Rubio, Isabel Teresa (Autor de correspondencia); Kontos, M. (Autor de correspondencia); Vrancken-Peeters, M. T. F. D. ; et al.
    Revista: EJSO
    ISSN: 0748-7983 Vol.46 N° 4 2020 págs. 501 - 503
  • Autores: González Martín, Antonio; Pothuri, B.; Vergote, I.; et al.
    Revista: OBSTETRICAL AND GYNECOLOGICAL SURVEY
    ISSN: 0029-7828 Vol.75 N° 1 2020 págs. 29 - 31
    Resumen
    The standard treatment for newly diagnosed advanced epithelial ovarian cancer involves cytoreductive surgery and platinum- taxane combination chemotherapy. Unfortunately, recurrence occurs in up to 85% of patients after completing this chemotherapy regimen. Approximately 15% to 20% of ovarian cancer cases involve a mutation in a BRCA gene. Inhibitors of poly(adenosine-diphosphate-ribose) (PARP) have shown significant increases in progression-free survival (PFS) among patients with BRCA mutations after response to first-line platinum-based chemotherapy. Niraparib, a selective PARP1 and PARP2 inhibitor, has demonstrated an increase in PFS among patients with and without BRCA mutated ovarian cancer, leading to its approval in patients with recurrent ovarian cancer who experienced a response to platinum-based chemotherapy. This randomized, double-blind, placebo-controlled, phase 3 trial (PRIMAtrial) aimed to examine the safety and efficacy of niraparib maintenance therapy in patients with newly diagnosed, platinum-sensitive, advanced ovarian cancer at high risk of relapse. This trial was conducted in 2 countries at 181 clinical sites. Patients were randomized in a 2:1 ratio to receive niraparib or placebo once daily for 3 years or until disease progression as demonstrated on computed tomography or magnetic resonance imaging performed every 12 weeks. Eligible subjects had newly diagnosed ovarian cancer classified as stage III or IV with previous partial or complete response to at least 6 cycles of first-line platinum-based chemotherapy. Tumor samples underwent homologous-recombinant deficiency (HRD) testing, where a deficiency was defined as either presence of a BRCA deleterious mutation or a score greater than 42 on the my-Choice test. The primary endpoint evaluated was PFS defined as time from randomization after completion of platinum-based chemotherapy to date of objective disease progression or death. A total of 733 subjects underwent randomization between July 2016 and June 2018. Of the cohort, 373 (50.9%) tested positive for HRD on my-Choice; of these 373, 223 had tumors with BRCA mutations, and 150 had no BRCA mutation. The median duration of PFS in the HRD group was 21.9 and 10.4 months for the niraparib and placebo groups, respectively (hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.31-0.59; P < 0.001). In the total cohort, the median duration of PFS was 13.8 and 8.2 months for the niraparib and placebo groups, respectively (HR, 0.62; 95% CI, 0.50-0.76; P < 0.001). Secondary endpoint analysis found the probability of survival at 24 months in the total cohort to be 84% in the niraparib group and 77% in the placebo group (HR, 0.70; 95% CI, 0.44-1.11). When restricted to the HRD group, survival was estimated at 91% in the niraparib group and 85% in the placebo group (HR, 0.61; 95% CI, 0.27-1.39). The most common grade 3 or higher adverse events in the niraparib group were anemia (31.0%), thrombocytopenia (28.7%), and neutropenia (12.8%). Dose reduction occurred in 70.9% of patients in the niraparib group. The results of the PRIMA trial show a significantly increased period of PFS in patients with newly diagnosed platinum-sensitive advanced ovarian cancer receiving niraparib compared with placebo especially in patients with BRCA mutations and HRD.
  • Autores: Montagna, G. (Autor de correspondencia); Morgan, J. ; Wandschneider, W. ; et al.
    Revista: EJSO
    ISSN: 0748-7983 Vol.46 N° 4 2020 págs. 715 - 716
  • Autores: Ramirez, P. T. (Autor de correspondencia); Chiva de Agustín, Luis; Eriksson, A. G. Z. ; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN: 1048-891X Vol.30 N° 5 2020 págs. 561 - 563
  • Autores: Vidya, R. (Autor de correspondencia); Rubio, Isabel Teresa; Paulinelli, R. R.; et al.
    Revista: ECANCERMEDICALSCIENCE
    ISSN: 1754-6605 Vol.14 N° 1041 2020
    Resumen
    The onset of the COVID-19 pandemic has changed the face of the treatment of breast cancer and breast reconstruction globally. Mastectomy with immediate implant-based breast reconstruction was on the rise due to advances in meshes and implants. However, due to the prioritisation of the critically ill and diversion of the work force, breast cancer treatment has drastically changed. This is an opinion paper written by the authors with experience and importance in the scenario of breast reconstructive surgery. The authors are from different countries with the COVID-19 pandemic in different stages.
  • Autores: Hontanilla Calatayud, Bernardo Carlos (Autor de correspondencia)
    Revista: SCIENTIA ET FIDES
    ISSN: 2300-7648 Vol.8 N° 1 2020 págs. 9 - 31
    Resumen
    In this article it is exposed several signs present in the Shroud of Turin. Following the development of rigor mortis the image position impressed in the Shroud is analyzed. Furthermore, the presence of specific facial folds indicates that the person is alive. Then, the Shroud of Turin shows death signs together with live signs and the image was impressed when he was alive. If it is a case of fraud, it should be considered as an artwork performed by a genious with medical, forensic and image processing from at least the XX century. If we follow the Gospels there is a perfect simmetry between tha data showed in the image and those described in the Gospels, during the death as well as the resurrection.
  • Autores: Biganzoli, L.; Cardoso, F.; Beishon, M.; et al.
    Revista: BREAST
    ISSN: 0960-9776 Vol.51 2020 págs. 65 - 84
    Resumen
    This article is an update of the requirements of a specialist breast centre, produced by EUSOMA and endorsed by ECCO as part of Essential Requirements for Quality Cancer Care (ERQCC) programme, and ESMO. To meet aspirations for comprehensive cancer control, healthcare organisations must consider the requirements in this article, paying particular attention to multidisciplinarity and patient-centred pathways from diagnosis, to treatment, to survivorship. The centrepiece of this article is the requirements section, comprising definitions; multidisciplinary structure; minimum case, procedure and staffing volumes; and detailed descriptions of the skills of, and resources needed by, members and specialisms in the multidisciplinary team in a breast centre. These requirements are positioned within narrative on European breast cancer epidemiology, the standard of care, challenges to delivering this standard, and supporting evidence, to enable a broad audience to appreciate the importance of establishing these requirements in specialist breast centres. (C) 2020 The Authors. Published by Elsevier Ltd.
  • Autores: Gimeno Morales, Marta; Martínez Regueira, Fernando; Rodríguez-Spiteri Sagredo, Natalia; et al.
    Revista: JOURNAL OF CONTEMPORARY BRACHYTHERAPY
    ISSN: 1689-832X Vol.12 N° 6 2020 págs. 521 - 532
    Resumen
    Purpose: To evaluate our institutional experience of minimally invasive tumor bed implantation (MITBI) during breast-conserving surgery (BCS) for ductal carcinoma in situ (DCIS) to deliver peri-operative high-dose-rate brachytherapy (PHDRBT) as accelerated minimal breast irradiation (AMBI) or anticipated boost (A-PHDRBT-boost). Material and methods: Patients older than 40, with clinical and radiological unifocal DCIS < 3 cm were considered potential candidates for accelerated partial breast irradiation (APBI) and were implanted during BCS using MITBI-technique. Patients who in final pathology reports showed free margins and no other microscopic tumor foci, received AMBI with PHDRBT (3.4 Gy BID in 5 days). Patients with adverse features received A-PHDRBT-boost with post-operative external beam radiotherapy (EBRT). Results: Forty-one patients were implanted, and 36 were treated and analyzed. According to final pathology, 24 (67%) patients were suitable for AMBI and 12 (33%) were qualified for A-PHDRBT-boost. Reoperation rate for those with clear margins was 16.6% (6/36); this rate increased to 33% (4/12) for G3 histology, and 66% (4/6) were rescued using AMBI. Early complications were documented in 5 patients (14%). With a median follow-up of 97 (range, 42-138) months, 5-year rates of local, elsewhere, locoregional, and distant control were all 97.2%. 5-year ipsilateral breast tumor recurrence rates (IBTR) were 5.6% (2/36), 8.3% (2/24) for AMBI, and 0% (0/12) for A-PHDRBT-boost patients. Both instances of IBTR were confirmed G3 tumors in pre-operative biopsies; no IBTR was documented in G1-2 tumors. Cosmetic outcomes were excellent/good in 96% of AMBI vs. 67% in A-PHDRBT-boost (p = 0.034). Conclusions: The MITBI-PHDRBT program allows selection of patients with excellent prognoses (G1-2 DCIS with negative margins and no multifocality), for whom AMBI could be a good alternative with low recurrence rate, decrease of unnecessary radiation, treatment logistics improvement, and over-treatment reduction. Patients whose pre-operative biopsy showed G3 tumor, presents with inferior local control and more risk of reoperation due to positive margins.
  • Autores: Feliciano, A. ; Gonzalez, L. ; Garcia-Mayea, Y. ; et al.
    Revista: FRONTIERS IN ONCOLOGY
    ISSN: 2234-943X Vol.10 2020
    Resumen
    Breast cancer is the cancer with the most incidence and mortality in women. microRNAs are emerging as novel prognosis/diagnostic tools. Our aim was to identify a serum microRNA signature useful to predict cancer development. We focused on studying the expression levels of 30 microRNAs in the serum of 96 breast cancer patients vs. 92 control individuals. Bioinformatic studies provide a microRNA signature, designated as a predictor, based on the expression levels of five microRNAs. Then, we tested the predictor in a group of 60 randomly chosen women. Lastly, a proteomic study unveiled the overexpression and downregulation of proteins differently expressed in the serum of breast cancer patients vs. that of control individuals. Twenty-six microRNAs differentiate cancer tissue from healthy tissue, and 16 microRNAs differentiate the serum of cancer patients from that of the control group. The tissue expression of miR-99a, miR-497, miR-362, and miR-1274, and the serum levels of miR-141 correlated with patient survival. Moreover, the predictor consisting of miR-125b, miR-29c, miR-16, miR-1260, and miR-451 was able to differentiate breast cancer patients from controls. The predictor was validated in 20 new cases of breast cancer patients and tested in 60 volunteer women, assigning 11 out of 60 women to the cancer group. An association of low levels of miR-16 with a high content of CD44 protein in serum was found. Circulating microRNAs in serum can represent biomarkers for cancer prediction. Their clinical relevance and the potential use of the predictor here described are discussed.
  • Autores: Rubio, Isabel Teresa (Autor de correspondencia); Rodriguez-Revuelto, R.; Espinosa-Bravo, M.; et al.
    Revista: EJSO
    ISSN: 0748-7983 Vol.46 N° 12 2020 págs. 2195 - 2201
    Resumen
    Introduction: The non-radioactive method that uses the magnetic tracer (SPIO/Sienna) has shown to be a feasible technique for the SLN detection in breast cancer patients. The aim of this study is to assess the efficacy of different doses of a new magnetic tracer Sienna XP (Magtrace) compared to Tc-99 m and to evaluate its non-inferiority. Methods: Patients diagnosed with early-stage breast cancer cT1-3 N0, from October 2016 to August 2018 were eligible and consecutively randomized to three different doses of new SPIO used: group 1 (1 mL), group 2 (1.5 mL) and group 3 (2 mL). Results: A total of 135 patients were included in the study, 45 in each group. Detection of SLNs with the three doses of Sienna XP (1 mL, 1.5 mL and 2 mL) showed non-inferior rates compared to the conventional technique with radiotracer (p = 0.654). Concordance by patients with SLN positive was 100% for all groups. 83 (70.3%) patients reported skin staining at one month postoperatively, significantly lower in group 1 (p = 0.042). At 6 months follow up, group 1 remains with significantly lower skin discoloration (p = 0,01). In multivariate analysis, dose of 2 mL showed statistically significant for the skin staining. The majority of patients (70%) felt that skin discoloration does not represent a problem. Conclusion: The use of the Sienna XP magnetic tracer at 1 mL is not inferior to higher doses of magnetic tracer neither is inferior to radiotracer. 1 mL of magnetic tracer resulted in significantly less skin discoloration compared to higher doses. (C) 2020 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.
  • Autores: Parra Guillén, Zinnia Patricia; Schmid, U.; Janda Galán, Álvaro; et al.
    Revista: CLINICAL PHARMACOLOGY AND THERAPEUTICS
    ISSN: 0009-9236 Vol.107 N° 3 2020 págs. 597 - 606
    Resumen
    Over the past decade, the insulin-like growth factor (IGF)-signaling pathway has gained substantial interest as potential therapeutic target in oncology. Xentuzumab, a humanized IgG1 monoclonal antibody, binds to IGF-I and IGF-II thereby inhibiting the downstream signaling essential for survival and tumor growth. This pathway is further regulated by circulating IGF binding proteins (IGFBPs). In this work, a mechanistic model characterizing the dynamics and interactions of IGFs, IGFBPs, and Xentuzumab has been developed to guide dose selection. Therefore, in vitro and in vivo literature information was combined with temporal IGF-I, IGF-II, and IGFBP-3 total plasma concentrations from two phase I studies. Based on the established quantitative framework, the time-course of free IGFs as ultimate drug targets not measured in clinics was predicted. Finally, a dose of 1000 mg/week-predicted to reduce free IGF-I and free IGF-II at steady-state by at least 90% and 64%, respectively-was suggested for phase II.
  • Autores: Redondo, A. (Autor de correspondencia); Colombo, N.; McCormack, M.; et al.
    Revista: GYNECOLOGIC ONCOLOGY
    ISSN: 0090-8258 Vol.159 N° 1 2020 págs. 142 - 149
    Resumen
    Objective. Adding bevacizumab to cisplatin-paclitaxel for advanced cervical cancer significantly improves overall and progression-free survival. We evaluated bevacizumab with a widely used carboplatin-paclitaxel backbone. Methods. Patients with metastatic/recurrent/persistent cervical cancer not amenable to curative surgery and/ or radiotherapy received 3-weekly bevacizumab 15 mg/kg, paditaxel 175 mg/m(2), and carboplatin AUC 5 until progression or unacceptable toxicity. Maintenance bevacizumab was allowed. Patients with ongoing bladder/rectal involvement, prior cobalt radiotherapy, a history of fistula/gastrointestinal perforation, or recent bowel resection/chemoradiation were excluded. The primary objective was to determine incidences of gastrointestinal perforation/fistula, gastrointestinal-vaginal fistula, and genitourinary fistula. Results. Among 150 treated patients, disease at study entry was persistent in 21%, recurrent in 56%, and newly diagnosed metastatic in 23%. After 27.8 months median follow-up, median bevadzumab duration was 6.7 months; 57% received maintenance bevacizumab. Seventeen patients (11.3%; 95% CI: 6.7-17.5%) experienced >= 1 perforation/fistula event: gastrointestinal perforation/fistula in 4.7% (1.9-9.4%), gastrointestinal-vaginal fistula in 4.0% (1.5-8.5%), and genitourinary fistula in 4.7% (1.9-9.4%). Of these, 16 were previously irradiated, several with ongoing radiation effects. The most common grade 3/4 adverse events were neutropenia (25%), anemia (19%), and hypertension (14%). Five patients (3%) had fatal adverse events. Objective response rate was 61% (95% CI: 52-69%), median progression-free survival was 10.9 (10.1-13.7) months, and median overall survival was 25.0 (20.9-30.4) months. Conclusions. Bevadzumab can be combined with carboplatin-paclitaxel in the CECILIA study population. The fistula/gastrointestinal perforation incidence is in line with GOG-0240: efficacy results are encouraging. (C) 2020 Elsevier Inc. All rights reserved.
  • Autores: DiSilvestro, P.; Colombo, N.; Scambia, G.; et al.