Grupos Investigadores

Líneas de Investigación

  • Terapia con vismodegib (inhibidor vía Hedgehog) añadido a la quimioterapia neoadyuvante en paciente con cáncer de mama triple negativo.
  • Terapia celular activa con células dentríticas con quimioterapia neoadyuvante y en posterior mantenimiento en pacientes con cáncer de mama triple negativo.
  • Irradiación parcial acelerada de la mama en pacientes con cáncer de mama localizado.
  • Estudio del efecto de las vacunas en el estroma y en el tumor residual para desarrollar nuevas estrategias de inmunoterapia combinada con inhibidores de checkpoints.
  • Aplicación de modelos matemáticos para detectar factores predicitivos y pronósticos en las nuevas estrategias sistémicas neoadyuvantes en cáncer de mama triple negativo.

Palabras Clave

  • Vía Sonic Hedgehog
  • Vacunas con células dentríticas
  • Quimioterapia neoadyuvante
  • Irradiación parcial acelerada
  • Célula madre tumoral
  • Cáncer de mama triple negativo
  • Braquiterapia de alta tasa

Publicaciones Científicas desde 2018

  • 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: 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: 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: Vera Yunca, Diego; Parra-Guillen, Z. P.; 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: 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: Ameijeiras Rodríguez , C. (Autor de correspondencia); Henriques, S. C. ; Sancho-Arauz, A.; et al.
    Revista: PHARMACEUTICAL RESEARCH
    ISSN 0724-8741 Vol.38 N° 12 2022 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: Rubio, Isabel Teresa
    Revista: BREAST
    ISSN 0960-9776 Vol.56 2021 págs. S12 - S13
  • 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: 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: De la Cruz, L.; Gion, M.; Cruz, J.; et al.
    Revista: CANCER RESEARCH
    ISSN 0008-5472 Vol.81 N° 4 Supl. S 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: 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: 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: 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: 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: Gasparri, M. L. ; Kuehn, T.; Rubio, Isabel Teresa; et al.
    Revista: CANCER RESEARCH
    ISSN 0008-5472 Vol.81 N° 4 Suppl. 2021
  • 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: 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: 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: 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: 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: 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: 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: 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: 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: 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: Pérez Solans, Belén; Chiesa, R.; Doncheva, B.; et al.
    Revista: BRITISH JOURNAL OF CLINICAL PHARMACOLOGY
    ISSN 0306-5251 Vol.86 N° 8 2020 págs. 1537 - 1549
    Resumen
    Aims Busulfan and treosulfan are cytotoxic agents used in the conditioning regime prior to paediatric haematopoietic stem cell transplantation (HSCT). These agents cause suppression of myeloid cells leaving patients severely immunocompromised in the early post-HSCT period. The main objectives were: (i) to establish a mechanistic pharmacokinetic-pharmacodynamic (PKPD) model for the treatment and engraftment effects on neutrophil counts comparing busulfan and treosulfan-based conditioning, and (ii) to explore current dosing schedules with respect to time to HSCT. Methods Data on 126 patients, 72 receiving busulfan (7 months-18 years, 5.1-47.0 kg) and 54 treosulfan (4 months-17 years, 3.8-35.8 kg), were collected. In total, 8935 neutrophil count observations were recorded during the study period in addition to drug concentrations to develop a mechanistic PKPD model. Absolute neutrophil count profiles were modelled semimechanistically, accounting for transplant effects and differing set points pre- and post-transplant. Results PK were best described by 2-compartment models for both drugs. The Friberg semimechanistic neutropenia model was applied with a linear model for busulfan and a maximum efficacy model for treosulfan describing drug effects at various stages of neutrophil maturation. System parameters were consistent across both drugs. The HSCT was represented by an amount of progenitor cells enhancing the neutrophils' proliferation and maturation compartments. Alemtuzumab was found to enhance the proliferative rate under which the absolute neutrophil count begin to grow after HSCT. Conclusion A semimechanistic PKPD model linking exposure to either busulfan or treosulfan to the neutrophil reconstitution dynamics was successfully built. Alemtuzumab coadministration enhanced the neutrophil proliferative rate after HSCT. Treosulfan administration was suggested to be delayed with respect to time to HSCT, leaving less time between the end of the administration and stem cell infusion.
  • Autores: García-Cremades Mira, María; Melillo, N. ; Fernández de Trocóniz Fernández, José Ignacio; et al.
    Revista: CTS-CLINICAL AND TRANSLATIONAL SCIENCE
    ISSN 1752-8054 Vol.13 N° 3 2020 págs. 608 - 617
    Resumen
    The aim of this work is to build a mechanistic multiscale pharmacokinetic model for the anticancer drug 2',2'-difluorodeoxycytidine (gemcitabine, dFdC), able to describe the concentrations of dFdC metabolites in the pancreatic tumor tissue in dependence of physiological and genetic patient characteristics, and, more in general, to explore the capabilities and limitations of this kind of modeling strategy. A mechanistic model characterizing dFdC metabolic pathway (metabolic network) was developed using in vitro literature data from two pancreatic cancer cell lines. The network was able to describe the time course of extracellular and intracellular dFdC metabolites concentrations. Moreover, a physiologically-based pharmacokinetic model was developed to describe clinical dFdC profiles by using enzymatic and physiological information available in the literature. This model was then coupled with the metabolic network to describe the dFdC active metabolite profile in the pancreatic tumor tissue. Finally, global sensitivity analysis was performed to identify the parameters that mainly drive the interindividual variability for the area under the curve (AUC) of dFdC in plasma and of its active metabolite (dFdCTP) in tumor tissue. From this analysis, cytidine deaminase (CDA) concentration was identified as the main driver of plasma dFdC AUC interindividual variability, whereas CDA and deoxycytidine kinase concentration mainly explained the tumor dFdCTP AUC variability. However, the lack of in vitro and in vivo information needed to characterize key model parameters hampers the development of this kind of mechanistic approach. Further studies to better characterize pancreatic cell lines and patient enzymes polymorphisms are encouraged to refine and validate the current model.
  • Autores: Balbás Martínez, Violeta; Asín Prieto, Eduardo; Parra Guillén, Zinnia Patricia; et al.
    Revista: JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
    ISSN 0022-3565 Vol.372 N° 3 2020 págs. 299 - 307
    Resumen
    Crohn's disease (CD) is a complex inflammatory bowel disease whose pathogenesis appears to involve several immunologic defects causing functional impairment of the gut. Its complexity and the reported loss of effectiveness over time of standard of care together with the increase in its worldwide incidence require the application of techniques aiming to find new therapeutic strategies. Currently, systems pharmacology modeling has been gaining importance as it integrates the available knowledge of the system into a single computational model. In this work, the following workflow for robust application of systems pharmacology modeling was followed: 1) scope definition; 2) species selection and circulating plasma levels based on a search in the literature; 3) representation of model topology and parametrization of the interactions, after literature data extraction and curation, and the implementation of ordinary differential equations in SimBiology (MATLAB version R2018b); and 4) model curation and evaluation by visual comparison of simulated interleukin (IL) concentrations with the reported levels in plasma, and sensitivity analysis performed to confirm model robustness and identify the most influential parameters. Finally, 5) exposure to two dose levels of recombinant human IL10 was evaluated by simulation and comparison with reported clinical study results. In summary, we present a quantitative systems pharmacology model for the main ILs involved in CD developed using a standardized methodology and supported by a comprehensive repository summarizing the most relevant literature in the field. However, it has to be taken into account that external validation is still pending as available clinical data were primarily used for model training. SIGNIFICANCE STATEMENT Crohn's disease (CD) is a complex heterogeneous inflammatory bowel disorder. Systems pharmacology modeling offers a great opportunity for integration of the available knowledge on the disease using a computational framework. As a result of this work, a comprehensive repository along with a quantitative systems pharmacology model for the main interleukins involved in CD is provided. This model is useful for the in silico evaluation of biomarkers and potential therapeutic targets and can be adapted to address research gaps regarding CD.
  • Autores: Gavila, J.; De La Haba, J. ; Bermejo, B.; et al.
    Revista: CLINICAL AND TRANSLATIONAL ONCOLOGY
    ISSN 1699-048X Vol.22 N° 3 2020 págs. 420 - 428
    Resumen
    Purpose To evaluate the efficacy and safety of lapatinib (L) and trastuzumab (T) combination in HER2-positive metastatic breast cancer (MBC) patients previously treated with T and/or L. Materials and methods We conducted a retrospective, post-authorized, multicenter study including patients with HER2-positive MBC or locally advanced breast cancer (ABC) treated with the combination of L-T. Concomitant endocrine therapy, as well as brain metastasis and/or prior exposure to L, were allowed. Results One hundred and fifteen patients from 14 institutions were included. The median age was 59.8 years. The median number of prior T regimens in the advanced setting was 3 and 73 patients had received a prior L regimen. The clinical benefit rate (CBR) was 34.8% (95% CI 26.1-43.5). Among other efficacy endpoints, the overall response rate was 21.7%, and median progression-free survival (PFS) and overall survival were 3.9 and 21.6 months, respectively. Heavily pretreated and >= 3 metastatic organ patients showed lower CBR and PFS than patients with a low number of previous regimens and < 3 metastatic organs. Moreover, CBR did not significantly change in L-pretreated compared with L-naive patients (31.5% versus 40.5% for L-pretreated versus L-naive). Grade 3/4 adverse events were reported in 19 patients (16.5%). Conclusion The combination of L-T is an effective and well-tolerated regimen in heavily pretreated patients and remains active among patients progressing on prior L-based therapy. Our study suggests that the L-T regimen is a safe and active chemotherapy-free option for MBC patients previously treated with T and/or L.
  • Autores: DiSilvestro, P.; Colombo, N.; Scambia, G.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN 0732-183X Vol.38 N° 30 2020 págs. 3528 - 3537
    Resumen
    PURPOSEIn SOLO1, maintenance olaparib (300 mg twice daily) significantly improved progression-free survival (PFS) for patients with newly diagnosed BRCA1- and/or BRCA2-mutated advanced ovarian cancer compared with placebo (hazard ratio [HR], 0.30; 95% CI, 0.23 to 0.41; median not reached v 13.8 months). We investigated PFS in SOLO1 for subgroups of patients based on preselected baseline factors.PATIENTS AND METHODSInvestigator-assessed PFS subgroup analyses of SOLO1 included clinical response after platinum-based chemotherapy (complete [CR] or partial response [PR]), surgery type (upfront or interval surgery), disease status after surgery (residual or no gross residual disease), and BRCA mutation status (BRCA1 or BRCA2). Additionally, we evaluated PFS in patients with stage III disease who underwent upfront surgery and had no gross residual disease. We also report objective response rate.RESULTSThe risk of disease progression or death was reduced with olaparib compared with placebo by 69% (HR, 0.31; 95% CI, 0.21 to 0.46) and 63% (HR, 0.37; 95% CI, 0.24 to 0.58) in patients undergoing upfront or interval surgery; 56% (HR, 0.44; 95% CI, 0.25 to 0.77) and 67% (HR, 0.33; 95% CI, 0.23 to 0.46) in patients with residual or no residual disease after surgery; 66% (HR, 0.34; 95% CI, 0.24 to 0.47) and 69% in women with clinical CR or PR at baseline (HR, 0.31; 95% CI, 0.18 to 0.52); and 59% (HR, 0.41; 95% CI, 0.30 to 0.56) and 80% (HR 0.20; 95% CI, 0.10 to 0.37) in patients with a BRCA1 or BRCA2 mutation, respectively.CONCLUSIONPatients with newly diagnosed advanced ovarian cancer achieve substantial benefit from maintenance olaparib treatment regardless of baseline surgery outcome, response to chemotherapy, or BRCA mutation type.
  • Autores: Álvarez-Cienfuegos Suárez, Francisco Javier; Rodríguez Rodríguez, Javier; Baixauli Fons, Jorge; et al.
    Revista: REVISTA ESPAÑOLA DE ENFERMEDADES DIGESTIVAS
    ISSN 1130-0108 Vol.112 N° 1 2020 págs. 16 - 22
    Resumen
    Background: the standard treatment for locally advanced rectal cancer is neoadjuvant chemo-radiotherapy, surgery and adjuvant chemotherapy. Only 50% of patients receive the adjuvant treatment due to the surgical complications and toxicity of radiotherapy. Recently, neoadjuvant chemotherapy has been investigated in the locally advanced rectal cancer setting, with the aim of guaranteeing an uninterrupted systemic treatment. The objective of the present study was to assess the safety and efficacy of neoadjuvant chemotherapy in locally advanced rectal cancer. Methods and patients: patients treated with neoadjuvant chemotherapy and surgery were identified from a prospective database of patients with rectal cancer (cII-III). The primary outcomes were the assessment of the number of R0 resections, the degree of pathologic response, patterns of recurrence and overall and disease-free survival. Treatment schedule: patients received 6-8 cycles of oxaliplatin and fluoropyrimides based chemotherapy. Results: twenty-seven patients who received neoadjuvant chemotherapy were identified. Twenty-six anterior resections and one Hartmann intervention were performed. An R0 resection was performed in 27 (100%) patients and no involvement of the circumferential margin was observed. Complete pathologic response (ypT0N0) was confirmed in four (14.8%) patients.The median follow-up was 35 months (range: 10-81) and four distant recurrences were recorded. Overall and disease-free survival at five years was 85% and 84.7%, respectively. Twenty-seven (100%) patients received all the cycles of chemotherapy, with a mean of six cycles (range 5-8) per patient. Conclusions: neoadjuvant chemotherapy is a promising alternative in the locally advanced rectal cancer setting and further phase III clinical trials are clearly warranted.
  • 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: 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: Gónzalez-Santiago, S. (Autor de correspondencia); Saura, C.; Ciruelos, E.; et al.
    Revista: BREAST CANCER RESEARCH AND TREATMENT
    ISSN 0167-6806 Vol.184 N° 2 2020 págs. 469 - 479
  • 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: Concin, N. (Autor de correspondencia); Ray-Coquard, I.; Glasspool, R. M.; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN 1048-891X Vol.30 N° 6 2020 págs. 730 - 734
  • 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: Ortega, S.; Mínguez Milio, José Ángel; Aramendía Beitia, José Manuel; et al.
    Revista: EUROPEAN JOURNAL OF GYNAECOLOGICAL ONCOLOGY
    ISSN 0392-2936 Vol.41 N° 4 2020 págs. 523 - 530
    Resumen
    Objective: Analyze the effect on survival of secondary cytoreduction surgery (SCS) in treatment of first recurrence platinum-sensitive epithelial ovarian cancer (REOC). Methods: Retrospective analysis of patients with first REOC who had platinum time-free interval (TFIp) > 6 months and were treated either with SCS followed by chemotherapy or chemotherapy only (CT). Clinical data such as patient's performance status and number of sites with metastases were specifically assessed. The primary endpoint was overall survival (OS). Results: Seventy-one patients were treated either by SCS (n = 37) or CT (n = 34). Complete resection after SCS was achieved in 89% of patients. After a median follow-up of 51.2 months, median OS, and progression-free survival (PFS) were 68.2 and 21.6 months, respectively, for the whole series of the SCS patients had better survival and disease progression survival than the CT only patients (HR: 0.33, 95% CI: 0.17-0.6; p= 0.001) and (HR: 0.28, 95% CI: 0.15-0.5; p= 0.001), respectively. TFIp < 12 months and multiple metastases were most important prognostic factors for risk of death (HR: 7.7 and 6.2, respectively) and recurrence (HR: 5.8 and 3.8, respectively). Probability to undergo successful SCS is related to oligometastatic disease and no residual disease after first surgery (OR: 30.0 and 5.9, respectively). Conclusions: In women with REOC oligometastatic disease and no residual disease at first surgery are associated with successful SCS. In these patients oligometastatic disease and long platinum TFI are associated with improved probability of survival.
  • Autores: Martin, M. (Autor de correspondencia); Guerrero-Zotano, A. ; Montero, A. ; et al.
    Revista: ONCOLOGIST
    ISSN 1083-7159 Vol.25 N° 9 2020 págs. e1339 - e1345
    Resumen
    Breast cancer (BC) is the most common cancer in women in Spain. During the COVID-19 pandemic caused by the SARS-CoV-2 virus, patients with BC still require timely treatment and follow-up; however, hospitals are overwhelmed with infected patients and, if exposed, patients with BC are at higher risk for infection and serious complications if infected. Thus, health care providers need to evaluate each BC treatment and in-hospital visit to minimize pandemic-associated risks while maintaining adequate treatment efficacy. Here we present a set of guidelines regarding available options for BC patient management and treatment by BC subtype in the context of the COVID-19 pandemic. Owing to the lack of evidence about COVID-19 infection, these recommendations are mainly based on expert opinion, medical organizations' and societies' recommendations, and some published evidence. We consider this a useful tool to facilitate medical decision making in this health crisis situation we are facing. Implications for Practice This work presents a set of guidelines regarding available options for breast cancer (BC) patient management and treatment by BC subtype in the context of the COVID-19 pandemic. Owing to the suddenness of this health crisis, specialists have to make decisions with little evidence at hand. Thus, these expert guidelines may be a useful tool to facilitate medical decision making in the context of a worldwide pandemic with no resources to spare.
  • 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: Parra Guillén, Zinnia Patricia; Fontanellas Roma, Antonio; Jiang, L.; et al.
    Revista: BRITISH JOURNAL OF PHARMACOLOGY
    ISSN 0007-1188 Vol.177 N° 14 2020 págs. 3168 - 3182
    Resumen
    Background and Purpose Acute intermittent porphyria (AIP) results from haplo-insufficiency of the porphobilinogen deaminase (PBGD) gene encoding the third enzyme in the haem biosynthesis pathway. As liver is the main organ of pathology for AIP, emerging therapies that restore enzyme hepatic levels are appealing. The objective of this work was to develop a mechanistic-based computational framework to describe the effects of novel PBGD mRNA therapy on the accumulation of neurotoxic haem precursors in small and large animal models. Experimental Approach Liver PBGD activity data and/or 24-hr urinary haem precursors were obtained from genetic AIP mice and wild-type mice, rats, rabbits, and macaques. To mimic acute attacks, porphyrogenic drugs were administered over one or multiple challenges, and animals were used as controls or treated with different PBGD mRNA products. Available experimental data were sequentially used to build and validate a semi-mechanistic mathematical model using non-linear mixed-effects approach. Key Results The developed framework accounts for the different biological processes involved (i.e., mRNA sequence, release from lipid nanoparticle and degradation, mRNA translation, increased PBGD activity in liver, and haem precursor metabolism) in a simplified mechanistic fashion. The model, validated using external data, shows robustness in the extrapolation of PBGD activity data in rat, rabbit, and non-human primate species. Conclusion and Implications This quantitative framework provides a valuable tool to compare PBGD mRNA drug products during early preclinical stages, optimize the amount of experimental data required, and project results to humans, thus supporting drug development and clinical dose and dosing regimen selection.
  • Autores: Rubio, M. J.; Lecumberri, M. J.; Varela, S.; et al.
    Revista: GYNECOLOGIC ONCOLOGY REPORTS
    ISSN 2352-5789 Vol.33 2020 págs. 100594
    Resumen
    Objective: We assessed trabectedin in patients with advanced uterine leiomyosarcoma (uLMS) in real-life clinical practice given according to the marketing authorization. Methods: Thirty-six women from 11 tertiary hospitals across Spain who received trabectedin after anthracycline-containing regimen/s were retrospectively analyzed. The primary endpoint was progression-free survival (PFS). Results: Median PFS and overall survival (OS) since starting trabectedin treatment were 5.4 (95%CI: 3.5-7.3) and 18.5 months (95%CI: 11.5-25.6), respectively. Median OS was significantly higher (P = 0.028) in patients receiving trabectedin in <= 2nd line (25.3 months) than in >= 3rd (15.1 months) and with ECOG performance status <= 1 at trabectedin start (19.8 months) than ECOG 2-3 (6.0 months, P = 0.013). When calculating OS since diagnosis, patients had longer OS with localized disease at diagnosis (87.4 months) vs. locally advanced (30.0 months) or metastatic (44.0 months, P = 0.041); and patients who received adjuvant therapy (87.4 months) compared with those who did not (30.0 months, P = 0.003), especially when receiving radio-chemotherapy (106.7 months, P = 0.027). One patient (2.8%) had a complete response (CR) and nine patients (25.0%) achieved a partial response (PR) for an objective response rate of 27.8% with median response duration of 11 months (range: 4-93). Eighteen patients (50.0%) had disease stabilization for a disease control rate (DCR) of 77.8%. More patients receiving trabectedin in 1st-line of advanced disease achieved CR (16.7%) and PR (50.0%) than those in >= 2nd line/s (0.0% and 20.0%), whereas the DCR was similar across treatment lines. Reversible neutropenia was the most common grade 3/4 laboratory abnormality (19.4%). Conclusions: Trabectedin confers clinical benefit in patients with recurrent/metastatic uLMS, given after failure to an anthracycline-based regimen being comparable to those reported in clinical trials and with a manageable safety profile.
  • Autores: Greggi, S. (Autor de correspondencia); Falcone, F. ; Scaffa, C.; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN 1048-891X Vol.30 N° 6 2020 págs. 819 - 824
    Resumen
    Objective Laparoscopy is one of the diagnostic tools available for the complex clinical decision-making process in advanced ovarian, fallopian tube, and peritoneal carcinoma. This article presents the results of a survey conducted within the European Network of Gynaecological Oncology Trial (ENGOT) group aimed at reviewing the current patterns of practice at gynecologic oncology centers with regard to the evaluation of resection in advanced ovarian, fallopian tube, and peritoneal carcinoma. Methods A 24-item questionnaire was sent to the chair of the 20 cooperative groups that are currently part of the ENGOT group, and forwarded to the members within each group. Results A total of 142 questionnaires were returned. Only 39 respondents (27.5%) reported using some form of clinical (not operative) score for the evaluation of resection. The frequency of use of diagnostic laparoscopy to assess disease status and feasibility of resection was as follows: never, 21 centers (15%); only in select cases, 83 centers (58.5%); and routinely, 36 centers (25.4%). When laparoscopy was performed, 64% of users declared they made the decision to proceed with maximal effort cytoreductive surgery based on their personal/staff opinion, and 36% based on a laparoscopic score. To the question of whether laparoscopy should be considered the gold standard in the evaluation of resection, 71 respondents (50%) answered no, 66 respondents (46.5%) answered yes, whereas 5 respondents (3.5%) did not provide an answer. Conclusions This study found that laparoscopy was routinely performed to assess feasibility of cytoreduction in only 25.4% of centers in Europe. However, it was commonly used to select patients and in a minority of centers it was never used . When laparoscopy was adopted, the treatment strategy was based on laparoscopic scores only in a minority of centers.
  • 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: 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: Sansano, I.; Vieites, B.; de Salas, M. S.; et al.
    Revista: PATHOLOGY RESEARCH AND PRACTICE
    ISSN 0344-0338 Vol.216 N° 11 2020
    Resumen
    Introduction: Axillary staging (pN) is a strong predictor of outcome in early stage breast cancer yet following the publication of the Z0011 trial there has been an increasing tendency to spare lymph node dissection. Automated molecular detection of cytokeratin 19mRNA by one-step nucleic acid amplification (OSNA) has been demon-strated to be an accurate method to assess sentinel lymph node (SLN) metastasis. In this study we compare histological and molecular methods following complete axillary lymph node dissection (cALND), determine whether molecular axillary staging affects survival, and evaluate the predictive and prognostic value of total tumor load in ALND (AD-TTL) and in all positive nodes (G-TTL). Material and methods: Axillary lymph nodes were collected from 102 patients with primary breast cancer with histological confirmation of axillary involvement (cN+) or positive SLN. The central 1-mm portion of each nonSLN was processed for hematoxylin-eosin staining and the remaining tissue was analyzed by OSNA. Results: Non-SLNs were diagnosed as positive in 72 out of 102 patients (70.6 %) on OSNA compared with only 53 (52 %) on histology (p < 0.01). Thirteen patients would have changed staging if the diagnoses provided had been by molecular methods (p < 0.01), but without a change in prognosis. AD-TTL and G-TTL were predictive of recurrence and mortality. Conclusions: Compared to molecular detection, histological examination significantly underestimates the frequency of axillary node metastases. However, the increase in pN did not show a clinical effect on survival in those patients.
  • Autores: Mirza, M. R. (Autor de correspondencia); Coleman, R. L. ; González Martín, Antonio; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.31 N° 9 2020 págs. 1148 - 1159
    Resumen
    Background: In recurrent ovarian cancer, poly(ADP-ribose) polymerase (PARP)-inhibiting agents have transformed the treatment of platinum-sensitive disease. New data support use of PARP inhibitors earlier in the treatment algorithm. Design: We review results from recent phase III trials evaluating PARP inhibitors as treatment and/or maintenance therapy for patients with newly diagnosed ovarian cancer. We discuss the efficacy and safety of these agents in the all-corner and biomarker-selected populations studied in clinical trials, and compare the strengths and limitations of the various trial designs. We also consider priorities for future research, with a particular focus on patient selection and future regimens for populations with high unmet need. Result: Four phase III trials (SOLO-1, PAOLA-1/ENGOT-OV25, PRIMA/ENGOT-OV26 and VELIA/GOG-3005) demonstrated remarkable improvements in progression-free survival with PARP inhibitor therapy (olaparib, niraparib or veliparib) for newly diagnosed ovarian cancer. Differences in trial design (treatment and/or maintenance setting; single agent or combination; bevacizumab or no bevacizumab), patient selection (surgical outcome, biomarker eligibility, prognosis) and primary analysis population (intention-to-treat, BRCA mutated or homologous recombination deficiency positive) affect the conclusions that can be drawn from these trials. Overall survival data are pending and there is limited experience regarding long-term safety. Conclusion: PARP inhibitors play a pivotal role in the management of newly diagnosed ovarian cancer, which will affect subsequent treatment choices. Refinement of testing for patient selection and identification of regimens to treat populations that appear to benefit less from PARP inhibitors are a priority.
  • Autores: Armbrust, R.; Alavi, S. ; Pirmorady, A.; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN 1048-891X Vol.30 N° 10 2020 págs. 1603 - 1607
    Resumen
    Background Patients' reported outcomes and their perspectives around their therapeutic management is a field of continuously increasing relevance in gynecological oncology. We report the results of the Berlin dialog on seven patient-reported parameters and outcomes concerning chemotherapy and maintenance treatment in patients with gynecological cancer. Methods Key opinion leaders in gynecological oncology from different European counties and representatives of leading patients' advocate groups in Berlin held a consensus meeting in Berlin on April 6, 2019. Seven topics of interest were identified in advance around quality of life, iatrogenic toxicity, treatment decision-making processes, sexuality, participation in clinical trials, second opinion, and long-term survivors with the the following standard operating procedure for processing and discussion: (1) agreement on its relevance; (2) literature review, and (3) discussion and consensus statements. Results All main topics reached a consensus approval. The defined statements emphasized the importance of patients' role in incorporating and establishing quality of life as an outcome parameter in clinical trials. Furthermore, discussants raised the importance of identifying new tools for reflecting patient-reported iatrogenic toxicity as well as emphasizing patients' rights in providing personal information, access to second opinion in the decision-making process, and their participation in clinical trials. Conclusion The results of this round table meeting could help redefine perspectives on the discussed topics and the importance for therapeutic management as well as for trial designs.
  • 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: Rischin, D.; Gil-Martín, M.; González Martín, Antonio; et al.
    Revista: GYNECOLOGIC ONCOLOGY
    ISSN 0090-8258 Vol.159 N° 2 2020 págs. 322 - 328
    Resumen
    Objectives. To characterize the safety, tolerability, and anti-tumor activity of cemiplimab asmonotherapy or in combination with hypofractionated radiation therapy (hfRT) in patients with recurrent or metastatic cervical cancer. To determine the association between histology and programmed death-ligand 1 (PD-L1) expression. Methods. In non-randomized phase I expansion cohorts, patients (squamous or non-squamous histology) received cemiplimab 3 mg/kg intravenously every 2 weeks for 48 weeks, either alone (monotherapy cohort) or with hfRT during week 2 (combination cohort). Due to insufficient tissue material, PD-L1 protein expression was evaluated in commercially purchased samples and mRNA expression levelswere analyzed fromThe Cancer Genome Atlas (TCGA). Results. Twenty patients enrolled in both cohorts in total; 10 had squamous histology. Themost common adverse events of any grade were diarrhea, fatigue, and hypokalemia, occurring in 35%, 25%, and 25%, respectively. Objective response rate was 10% in each cohort; responders had squamous histology. Duration of response was 11.2 months and 6.4 months for the responder in the monotherapy and combination cohort, respectively. Irradiated lesionswere not included in the response assessments. In separate archived specimens (N= 155), PD-L1 protein expression in tumor and immune cells was negative (<1%) more commonly in adenocarcinoma than in squamous tumors. PD-L1 mRNA levels were lower in adenocarcinoma than squamous cell tumors (1.2 vs 5.0 mean transcripts per million, respectively) in TCGA. Conclusions. Cemiplimab has activity in cervical squamous cell carcinoma. The phase I results, combinedwith results fromother anti-PD-1 trials in cervical cancer and our biomarker analyses have informed the design of the ongoing phase III trial, with the primary overall survival hierarchical analyses being done first in patients with squamous histology. (C) 2020 The Authors. Published by Elsevier Inc.
  • Autores: O'Malley, D. M. (Autor de correspondencia); Matulonis, U. A.; Birrer, M. J.; et al.
    Revista: GYNECOLOGIC ONCOLOGY
    ISSN 0090-8258 Vol.157 N° 2 2020 págs. 379 - 385
    Resumen
    Purpose. To evaluate the safety and clinical activity of mirvetuximab soravtansine, an antibody-drug conjugate comprising a humanized anti-folate receptor alpha (FR alpha) monoclonal antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent, in combination with bevacizumab in patients with FR alpha-positive, platinum-resistant ovarian cancer. Methods. Patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer were administered mirvetuximab soravtansine (6 mg/kg. adjusted ideal body weight) and bevacizumab (15 mg/kg) once every 3 weeks. Eligibility included FR alpha positivity by immunochemistry and prior bevacizumab exposure was permitted. Adverse events, tumor response, and progression-free survival (PFS) were determined. Results. Sixty-six patients, with a median of 3 prior lines of therapy (range, 1-8), received the combination of mirvetuximab soravtansine and bevacizumab at full dosing during the escalation and expansion stages of the study. Adverse events were generally mild-to-moderate (<= grade 2) with diarrhea, blurred vision, nausea, and fatigue being the most common treatment-related toxici ties. Six cases of pneumonitis (9%: all grade 1 or 2), an adverse event of special interest, were observed. The confirmed objective response rate (ORR) was 39%, including 5 complete responses and 21 partial responses, and the median PFS was 6.9 months. The combination was particularly active in the subset of patients (n = 16) who were bevacizumab-naive, less heavily pretreated (1-2 prior lines), and whose tumors exhibited medium/high FR alpha expression (ORR, 56% with a median duration of response of 12 months; PFS, 9.9 months). Conclusion. The combination of mirvetuximab soravtansine with bevacizumab is well tolerated in patients with platinum-resistant. recurrent ovarian cancer. The encouraging efficacy measures compare favorably to reported outcomes for bevacizumab combined with standard chemotherapy in similar patient populations. (C) 2020 Elsevier Inc. All rights reserved.
  • Autores: Perez-Echaguen, S. (Autor de correspondencia); Sanz-Freire, C. J. ; Guinot-Rodriguez, J. L.; et al.
    Revista: REPORTS ON PRACTICAL ONCOLOGY AND RADIOTHERAPY
    ISSN 1507-1367 Vol.25 N° 5 2020 págs. 832 - 839
    Resumen
    Aim: To establish consensus guidelines for a safe clinical practice of accelerated partial breast irradiation (APBI) interstitial multicatheter brachytherapy (BT). Background: APBI with interstitial multicatheter BT has proved to be effective in the treatment of early stage breast cancer. This paradigm shift in the approach to early breast cancer conservative treatment, along with the existing controversies on the clinical practice of APBI, prompted the Spanish Brachytherapy Group (GEB) of the Spanish Societies of Radiation Oncology (SEOR) and Medical Physics (SEFM) to address BT APBI in a consensus meeting. Materials and methods: Prior to the meeting, a survey with 27 questions on indication, inclusion criteria, BT modality, implant technique, image guidance and simulation, CTV and OAR definition, dose prescription and fractionation, dose calculation, implant quality metrics and OAR dose constrains was distributed. Items not reaching a level of agreement of 70% were discussed and voted during the meeting. Results: 26 Institutions completed the survey, 60% of them perform APBI procedures. The analysis of the survey showed consensus reached on approximately half the questions. An expert panel discussed the remaining items; thereafter, a voting established the definite consensus. Conclusions: This document summarizes the consensus guidelines agreed during the meeting of the Spanish Brachytherapy Group SEOR-SEFM. Institutions with BT facilities available should offer interstitial BT APBI as a treatment option to patients fulfilling the inclusion criteria. Institutions willing to implement interstitial BT APBI are encouraged to follow the consensus guidelines established herein. (C) 2020 Published by Elsevier B.V. on behalf of Greater Poland Cancer Centre.
  • Autores: Vera Yunca, Diego; Girard, P.; Parra Guillén, Zinnia Patricia; et al.
    Revista: AAPS JOURNAL
    ISSN 1550-7416 Vol.22 N° 3 2020 págs. 58
    Resumen
    Total tumor size (TS) metrics used in TS models in oncology do not consider tumor heterogeneity, which could help to better predict drug efficacy. We analyzed individual target lesions (iTLs) of patients with metastatic colorectal carcinoma (mCRC) to determine differences in TS dynamics by using the ClassIfication Clustering of Individual Lesions (CICIL) methodology. Results from subgroup analyses comparing genetic mutations and TS metrics were assessed and applied to survival analyses. Data from four mCRC clinical studies were analyzed (1781 patients, 6369 iTLs). CICIL was used to assess differences in lesion TS dynamics within a tissue (intra-class) or across different tissues (inter-class). First, lesions were automatically classified based on their location. Cross-correlation coefficients (CCs) determined if each pair of lesions followed similar or opposite dynamics. Finally, CCs were grouped by using the K-means clustering method. Heterogeneity in tumor dynamics was lower in the intra-class analysis than in the inter-class analysis for patients receiving cetuximab. More tumor heterogeneity was found in KRAS mutated patients compared to KRAS wild-type (KRASwt) patients and when using sum of longest diameters versus sum of products of diameters. Tumor heterogeneity quantified as the median patient's CC was found to be a predictor of overall survival (OS) (HR = 1.44, 95% CI 1.08-1.92), especially in KRASwt patients. Intra- and inter-tumor tissue heterogeneities were assessed with CICIL. Derived metrics of heterogeneity were found to be a predictor of OS time. Considering differences between lesions' TS dynamics could improve oncology models in favor of a better prediction of OS.
  • Autores: Irurzun Arana, Itziar; McDonald, T. O.; Fernández de Trocóniz Fernández, José Ignacio; et al.
    Revista: CANCER RESEARCH
    ISSN 0008-5472 Vol.80 N° 16 2020 págs. 3372 - 3382
    Resumen
    Identification of optimal schedules for combination drug administration relies on accurately estimating the correct pharmacokinetics, pharmacodynamics, and drug interaction effects. Misspecification of pharmacokinetics can lead to wrongly predicted timing or order of treatments, leading to schedules recommended on the basis of incorrect assumptions about absorption and elimination of a drug and its effect on tumor growth. Here, we developed a computational modeling platform and software package for combination treatment strategies with flexible pharmacokinetic profiles and multidrug interaction curves that are estimated from data. The software can be used to compare prespecified schedules on the basis of the number of resistant cells where drug interactions and pharmacokinetic curves can be estimated from user-provided data or models. We applied our approach to publicly available in vitro data of treatment with different tyrosine kinase inhibitors of BT-20 triple-negative breast cancer cells and of treatment with erlotinib of PC-9 non-small cell lung cancer cells. Our approach is publicly available in the form of an R package called ACESO ( https://github.com/Michorlab/aceso) and can be used to investigate optimum dosing for any combination treatment. Significance: These findings introduce a computational modeling platform and software package for combination treatment strategies with flexible pharmacokinetic profiles and multidrug interaction curves that are estimated from data.
  • Autores: Manso, L.; Hernando, C.; Galan, M.; et al.
    Revista: BREAST
    ISSN 0960-9776 Vol.54 2020 págs. 286 - 292
    Resumen
    Background: This study evaluated efficacy and safety of palbociclib, a CDK4/6 inhibitor, in heavilypretreated hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/ HER2(-)) metastatic breast cancer (mBC) patients during the compassionate use program in Spain from February 2015 to November 2017. Patients and methods: Patient data were collected retrospectively from 35 hospitals in Spain. Patients with HR+/HER2(-) mBC who had progressed on >= 4 treatments for advanced disease were eligible. Results: A total of 219 patients received palbociclib in combination with aromatase inhibitors (110; 50.2%), fulvestrant (87; 39.7%), tamoxifen (8; 3.6%) or as single agent (10; 4.6%). Mean age of the patients was 58 years; 31 patients (16.1%) were premenopausal and 162 (83.9%) were postmenopausal at the beginning of treatment with palbociclib. Patients had received a median of 3 previous lines of endocrine therapy (ET) for advanced disease. Real-world tumor response (rwTR) and clinical benefit rate were 5.9% (n = 13) and 46.2% (n = 101), respectively. The median real world progression-free survival (rwPFS) was 6.0 months (95% CI 5.7-7.0) and the median overall survival was 19.0 months (95% CI 16.4-21.7). Subgroup analysis revealed a significant difference in median rwPFS in patients treated with palbociclib plus fulvestrant depending on the duration of prior treatment with fulvestrant monotherapy (>6 versus <= 6 months; HR 1.93, 95% CI 1.37-2.73, p < 0.001). The most frequently reported toxicities were neutropenia, asthenia, thrombopenia and anemia. Conclusions: Palbociclib can be an effective and safe treatment option in patients with heavily pretreated endocrine-sensitive mBC, especially in those with longer PFS to previous ET. (C) 2020 The Author(s). Published by Elsevier Ltd.
  • Autores: González de la Huebra Rodríguez, Ignacio Javier (Autor de correspondencia); Malmierca Ordoqui, Patricia; Elizalde Pérez, Arlette María; et al.
    Revista: ACTA RADIOLOGICA
    ISSN 0284-1851 Vol.61 N° 10 2020 págs. 1335 - 1342
    Resumen
    Background Recently, a new mammography system to perform contrast-enhanced mammography has become available in the market. For the high-energy acquisition, it uses a titanium filter instead of a copper one, reducing the tube load while maintaining image quality. Purpose To retrospectively evaluate the accuracy of contrast-enhanced mammography with a titanium filter (TiCEM) in three readers with different grades of experience. Material and Methods IRB-approved retrospective multicentric lesion by lesion study with 200 lesions, all of them initially classified as BI-RADS categories 0/3/4/5 on mammography and/or ultrasound and with pathological confirmation, in 135 patients. Three readers with different levels of experience (expert, resident, intermediate) blinded to the final diagnosis, retrospectively evaluated the low-energy (LE) images and the combination of LE and recombined (subtracted) images and classified the lesions according to the BI-RADS categories. Reader 1 also categorized the breast density. ROC curves were performed for each reader. Results Out of the 200 lesions, 82 were benign and 118 malignant (20 DCIS, 10 ILC, 88 IDC). The AUCs of LE versus TiCEM for were: Reader 1: 0.7 vs. 0.88, P < 0.001; Reader 2: 0.63 vs. 0.83, P < 0.001; and Reader 3: 0.63 vs. 0.84, P < 0.001. For the three readers, the AUCs of LE versus TiCEM were significantly superior in both dense and non-dense breasts (P < 0.001). Comparing the AUC of LE for Reader 1 (expert) versus the AUC of TiCEM for Reader 2 (resident) there were significant differences (0.7 vs. 0.83, P < 0.001). Conclusion The accuracy of TiCEM was significantly better for all the readers, in both dense and non-dense breasts. The accuracy of a resident reading a TiCEM study was better than the accuracy of an expert radiologist reading LE images.
  • Autores: Siso, C.; Esgueva Colmenarejo, Antonio Jesús; Miranda, I.; et al.
    Revista: ANNALS OF SURGICAL ONCOLOGY
    ISSN 1068-9265 Vol.27 N° SUPPL 1 2020 págs. S67 - S67
  • Autores: Concin, N. ; González Martín, Antonio; Vergote, I. ; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.31 N° Suppl.4 2020 págs. S648 - S648
  • Autores: Guerrero, J. A. L.; Mendiola, M.; Perez-Fidalgo, J. A.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.31 N° S4 2020 págs. S635 - S636
  • Autores: Esgueva Colmenarejo, Antonio Jesús; Siso, C. ; Miranda, I. ; et al.
    Revista: EUROPEAN JOURNAL OF CANCER
    ISSN 0959-8049 Vol.138 N° S1 2020 págs. S91 - S92
  • Autores: Dahlstrand, H.; Pothuri, B.; Graybill, W.; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN 1048-891X Vol.30 2020 págs. A69 - A70
  • Autores: Mirza, M. R. ; González Martín, Antonio; Graybill, W.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN 0732-183X Vol.38 N° 15 2020
  • Autores: Urrizola Martínez, Amaia; Pérez Solans, Belén; Sánchez Bayona, Rodrigo; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.31 2020 págs. S710 - S710
  • Autores: Heitz, F.; Pothuri, B.; Han, S.; et al.
    Revista: GEBURTSHILFE UND FRAUENHEILKUNDE
    ISSN 0016-5751 Vol.80 N° 10 2020 págs. E221 - E222
  • Autores: Imizcoz Fabra, Teresa; Cañada Higueras, Eva María; de-Vicuna-Bilbao, N. G.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN 0732-183X Vol.38 N° 15 2020 págs. e13678
  • Autores: Pothuri, B. ; Han, S.; Chase, D.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.31 N° Suppl.4 2020 págs. S612 - S613
  • Autores: Graybill, W.; Mirza, M.; González Martín, Antonio; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN 1048-891X Vol.30 2020 págs. A10 - A10
  • Autores: Lozano Escario, María Dolores; Abengozar Muela, Marta; Alvarez, M.; et al.
    Revista: LABORATORY INVESTIGATION
    ISSN 0023-6837 Vol.100 N° Supl. 1 2020 págs. 391 - 392
  • Autores: González Martín, Antonio; Chung, H. C. ; Saada-Bouzid, E.; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN 1048-891X Vol.30 2020 págs. A64 - A65
  • Autores: Matulonis, U. A.; Shapira, R.; Santin, A.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN 0732-183X Vol.38 N° 15 2020
  • Autores: Chase, D. ; Perhanidis, J. ; Gupta, D. ; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN 1048-891X Vol.30 2020 págs. A74 - A75
  • Autores: Freyer, G.; Pothuri, B.; Han, S.; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN 1048-891X Vol.30 N° Suppl. 3 2020 págs. A12 - A13
  • Autores: Karakatsanis, A.; Foukakis, T. ; Karlsson, P.; et al.
    Revista: ANNALS OF SURGICAL ONCOLOGY
    ISSN 1068-9265 Vol.27 N° SUPPL 2 2020 págs. S337 - S338
  • Autores: Marme, F. ; Mirza, M. R. ; González Martín, Antonio; et al.
    Revista: GEBURTSHILFE UND FRAUENHEILKUNDE
    ISSN 0016-5751 Vol.80 N° 10 2020 págs. E219 - E220
  • Autores: Oaknin, A.; Iglesias, M. ; Alarcon, J. D. ; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.31 N° Suppl.4 2020 págs. S645 - S645
  • Autores: Siso, C. ; Esgueva Colmenarejo, Antonio Jesús; Salazar, J. P. ; et al.
    Revista: EUROPEAN JOURNAL OF CANCER
    ISSN 0959-8049 Vol.138 2020 págs. S47 - S48
  • Autores: Fidalgo, J. A. P.; Cortes, A.; Garcia, Y. ; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.31 N° Suppl.4 2020 págs. S626 - S626
  • Autores: González Martín, Antonio; Chung, H.; Saada Bouzid, E.; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN 1048-891X Vol.30 N° Suppl. 3 2020 págs. A1 - A2
  • Autores: Ledermann, J. A.; Shapira-Frommer, R. ; Santin, A. D.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.31 N° Suppl.4 2020 págs. S631 - S632
  • Autores: Coleman, R. L. ; Lorusso, D. ; Gennigens, C. ; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.31 N° Suppl.4 2020 págs. S1162 - S1163
  • Autores: Banerjee, S.; Moore, K. N. ; Colombo, N. ; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.31 N° Suppl.4 2020 págs. S613 - S613
  • Autores: Peen, U.; Graybill, W.; González Martín, Antonio; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN 1048-891X Vol.30 2020 págs. A90 - A91
  • Autores: González Martín, Antonio; Tazi, Y. ; Heitz, F. ; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.31 N° Suppl.4 2020 págs. S1163 - S1164
  • Autores: Cardoso, F.; Van't Veer, L.; Poncet, C.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN 0732-183X Vol.38 N° 15 2020
  • Autores: Han, S. N.; Monk, B. J. ; González Martín, Antonio
    Revista: GYNECOLOGIC ONCOLOGY
    ISSN 0090-8258 Vol.159 N° Suppl.1 2020 págs. 18 - 19
  • Autores: Halla, K.; Mirza, M. R. ; Li, Y.; et al.
    Revista: ONCOLOGY NURSING FORUM
    ISSN 0190-535X Vol.47 N° 2 2020 págs. 13 - 14
  • Autores: Lozano Escario, María Dolores; García Tobar, Laura; Abengozar Muela, Marta; et al.
    Revista: LABORATORY INVESTIGATION
    ISSN 0023-6837 Vol.100 N° Supl. 1 2020 págs. 392
  • Autores: Valabrega, G. ; Pothuri, B. ; Oaknin, A. ; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.31 N° Suppl.4 2020 págs. S619 - S619
  • Autores: Vergote, I; Salutari, V. ; Cibula, D. ; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN 1048-891X Vol.30 2020 págs. A147 - A148
  • Autores: Gimeno Morales, Marta; Martínez Monge, Rafael; Martínez Regueira, Fernando; et al.
    Revista: RADIOTHERAPY AND ONCOLOGY
    ISSN 0167-8140 Vol.152 N° Suppl.1 2020 págs. S1103 - S1104
  • Autores: Korach, J.; Graybill, W.; Redondo, A.; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN 1048-891X Vol.30 2020 págs. A125 - A126
  • Autores: Monk, B. J.; Romero, I.; Graybill, W. ; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN 0732-183X Vol.38 N° 15 2020
  • Autores: Colombo, N. ; Bradley, W. ; Moore, K.; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN 1048-891X Vol.30 2020 págs. A76 - A77
  • Autores: Monk, B. J.; González Martín, Antonio
    Revista: GYNECOLOGIC ONCOLOGY
    ISSN 0090-8258 Vol.159 2020 págs. 18 - 18
  • Autores: Biganzoli, L. (Autor de correspondencia); Marotti, L.; Cardoso, M. J.; et al.
    Revista: BREAST CARE
    ISSN 1661-3791 Vol.14 N° 6 2019 págs. 359-364
    Resumen
    Background: EUSOMA undertook the commitment of defining the requirements for a specialist breast centre, which has become the reference document for the implementation of breast centres. Summary: The EUSOMA requirements for a specialist breast centre give clear indications regarding the requisite caseload, dedicated team composition (core and non-core team), organisation, availability of services and equipment throughout the patient pathway, quality control, and application of a multidisciplinary approach. The minimum number of cases is 150 newly diagnosed breast cancer cases per year. Based on the EUSOMA requirements, a voluntary and accredited certification scheme has been developed. In Europe, other voluntary certification schemes are available, such as those developed by the German Cancer Society and German Society for Breast Disease, the National Cancer Peer Review Programme in the UK, and the "label de qualite" established by the Swiss Anticancer League and the Swiss Senology Society. The European Commission Initiative on Breast Cancer (ECIBC) has overseen the development of a European Quality Assurance Scheme. Key Messages: Nearly 20 years after the initial publication of the EUSOMA requirements, ensuring that all breast cancer patients in Europe are treated only in certified breast centres should be considered a high priority and eventually achieved through collaborative efforts.
  • Autores: Salvo, G. (Autor de correspondencia); Martin, A. G.; González Martín, Antonio; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN 1048-891X Vol.29 N° 6 2019 págs. 986 - 995
    Resumen
    Neuroendocrine carcinomas of the cervix account for less than 2% of all invasive cervical cancers and are classified as low-grade (carcinoid, atypical carcinoid tumor) or high-grade (known as small- and large-cell) neuroendocrine carcinomas. There are increasing data showing that cervical neuroendocrine carcinomas may be associated with the human papillomavirus (HPV), especially HPV18, and most will stain positive for p16. Immunohistochemistry markers such as synaptophysin and CD56 are the most sensitive markers. Although there are no commonly associated mutations, PIK3CA, KRAS, and TP53 are the most frequently found mutations in neuroendocrine tumors. Neuroendocrine cervical carcinomas are exceedingly aggressive tumors with a high tendency for nodal involvement and distant metastases. Age, lymph node metastases, smoking, pure small-cell histology, and tumor size are independent prognostic factors. Overall, the 5-year survival rate is 36% and the median overall survival ranges between 22 and 25 months. Treatment options are often extrapolated from small-cell lung cancer and limited retrospective studies. The preferred treatment is a multimodal approach of surgery, chemoradiation, and systemic chemotherapy. The most common chemotherapy regimen used as initial therapy is a combination of cisplatin and etoposide. In the setting of recurrent disease, a combination of topotecan, paclitaxel, and bevacizumab has demonstrated favorable outcomes. Multicenter tumor registries, such as the Neuroendocrine Cervical Tumor Registry (NeCTuR), are an opportunity to evaluate patterns of disease treatment and oncologic outcomes.
  • Autores: Centanni, M.; Moes, D. J. A. R. ; Fernández de Trocóniz Fernández, José Ignacio; et al.
    Revista: CLINICAL PHARMACOKINETICS
    ISSN 0312-5963 Vol.58 N° 7 2019 págs. 835 - 857
    Resumen
    Immune checkpoint inhibitors (ICIs) have demonstrated significant clinical impact in improving overall survival of several malignancies associated with poor outcomes; however, only 20-40% of patients will show long-lasting survival. Further clarification of factors related to treatment response can support improvements in clinical outcome and guide the development of novel immune checkpoint therapies. In this article, we have provided an overview of the pharmacokinetic (PK) aspects related to current ICIs, which include target-mediated drug disposition and time-varying drug clearance. In response to the variation in treatment exposure of ICIs and the significant healthcare costs associated with these agents, arguments for both dose individualization and generalization are provided. We address important issues related to the efficacy and safety, the pharmacodynamics (PD), of ICIs, including exposure-response relationships related to clinical outcome. The unique PK and PD aspects of ICIs give rise to issues of confounding and suboptimal surrogate endpoints that complicate interpretation of exposure-response analysis. Biomarkers to identify patients benefiting from treatment with ICIs have been brought forward. However, validated biomarkers to monitor treatment response are currently lacking.
  • Autores: Wyld, L. (Autor de correspondencia); Rubio, Isabel Teresa; Kovacs, T.
    Revista: BREAST CARE
    ISSN 1661-3791 Vol.14 N° 6 2019 págs. 366 - 372
    Resumen
    Background: The substantial increase in the complexity of breast cancer care in the last few decades has resulted in significant improvements in survival rates and also in the quality of life of breast cancer survivors. However, across Europe there are variations in outcomes and access to the latest techniques. Whilst much of this variance is due to differences in health economies between European member states, training variation may also play a part. Training in breast cancer surgery varies greatly across Europe, not only in its basal discipline (general surgery, gynaecology or plastic surgery) but also in the length of training and whether there is any requirement for specialist training. Several countries have been leading the way in training breast specialist surgeons (the USA, the UK, Australia and New Zealand) with dedicated 1- or 2-year fellowships either within or in addition to standard training. Access to such training is limited and consequently many women in Europe are still treated by generalists, potentially denying them access to the best care. This paper reviews the issues surrounding training provision in breast surgery and some of the challenges which need to be addressed to improve the current situation. Summary: Breast surgery training in Europe is of variable quality and duration, which may result in variations in the quality of care received by patients with breast cancer. Specialist training standards are urgently required which should be adopted by all European member states. Excellent models are available in the USA, the UK and Australia and New Zealand on which to base this training. Key Messages: The quality of training in breast surgery needs to be upgraded and harmonised across Europe.
  • Autores: Cardoso, M. J. (Autor de correspondencia); Biganzoli, L. ; Rubio, Isabel Teresa; et al.
    Revista: BREAST
    ISSN 0960-9776 Vol.46 2019 págs. 95 - 96
  • Autores: Santisteban Eslava, Marta (Autor de correspondencia)
    Revista: ANALES DEL SISTEMA SANITARIO DE NAVARRA
    ISSN 1137-6627 Vol.42 N° 2 2019 págs. 245 - 248
  • Autores: Gentilini, O. D. (Autor de correspondencia); De Boniface, J. ; Classe, J. M. ; et al.
    Revista: LANCET ONCOLOGY
    ISSN 1470-2045 Vol.20 N° 1 2019 págs. E521- E533
  • Autores: Cardoso, M. J.; Wyld, L.; Rubio, Isabel Teresa; et al.
    Revista: BREAST
    ISSN 0960-9776 Vol.48 2019 págs. 102-102
  • Autores: Vergote, I. (Autor de correspondencia); Coleman, R. L.; Pignata, S.; et al.
    Revista: GYNECOLOGIC ONCOLOGY
    ISSN 0090-8258 Vol.154 N° 2 2019 págs. 255 - 258
  • Autores: Lorusso, D. (Autor de correspondencia); Pignata, S. ; González Martín, Antonio
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.30 N° 4 2019 págs. 497 - 498
  • Autores: Cardoso, F.; Busoi, C. S.; Cattaneo, I.; et al.
    Revista: BREAST
    ISSN 0960-9776 Vol.48 2019 págs. 54-57
    Resumen
    With the European Parliament elections having taken place in May 2019 and a new European Commission (EC) taking office in November 2019, this year is critical for European policymakers, as goals and priorities of the European Union (EU) for the next five years will be discussed and agreed upon. This Manifesto issued by the Transforming Breast Cancer Together initiative calls upon policymakers to improve services for patients in an area still of high unmet need and reduce the societal impact of breast cancer by elevating it as a health policy priority to improve breast cancer prevention, diagnosis and care across Europe. (C) 2019 Elsevier Ltd. All rights reserved.
  • Autores: García-Cremades Mira, María; Pitou, C.; Iversen, P. W.; et al.
    Revista: AAPS JOURNAL
    ISSN 1550-7416 Vol.21 N° 2 2019
    Resumen
    The aim of this evaluation was to predict tumour response to gemcitabine in patients with advanced pancreas or ovarian cancer using pre-clinical data obtained from xenograft tumour-bearing mice. The approach consisted of building a translational model combining pre-clinical pharmacokinetic-pharmacodynamic (PKPD) models and parameters, with dosing paradigms used in the clinics along with clinical PK models to derive tumour profiles in humans driving overall survival. Tumour growth inhibition simulations were performed using drug effect parameters obtained from mice, system parameters obtained from mice after appropriate scaling, patient PK models for gemcitabine and carboplatin, and the standard dosing schedules given in the clinical scenario for both types of cancers. Tumour profiles in mice were scaled by body weight to their equivalent values in humans. As models for survival in humans showed that tumour size was the main driver of the hazard rate, it was possible to describe overall survival in pancreatic and ovarian cancer patients. Simulated tumour dynamics in pancreatic and ovarian cancer patients were evaluated using available data from clinical trials. Furthermore, calculated metrics showed values (maximal tumour regression [0-17%] and tumour size ratio at week 12 with respect to baseline [-9, -4.5]) in the range of those predicted with the clinical PKPD models. The model-informed Drug Discovery and Development paradigm has been successfully applied retrospectively to gemcitabine data, through a semi-mechanistic translational approach, describing the time course of the tumour response in patients from pre-clinical studies.
  • Autores: Perez-Fidalgo, J. A. (Autor de correspondencia); Iglesias, M. ; Bohn, U.; et al.
    Revista: FUTURE SCIENCE OA
    ISSN 2056-5623 Vol.5 N° 2 2019
    Resumen
    Response to polyadenosine diphosphate ribose polymerase (PARP)inhibitors in platinum-resistant ovarian cancer and in the absence of BRCA mutations is very low. Combining PARP inhibitors with other agents might overcome this lack of activity. Here we describe the rationale and design of GEICO1601-ROLANDO (resistant ovarian cancer treated with olaparib and pegylated liposomal doxorubin; NCT03161132). ROLANDO is a Phase II single-arm multicenter trial in which patients are treated with a combination of olaparib and pegylated liposomal doxorubicin (PLD) in platinum-resistant epithelial ovarian, primary peritoneal, or Fallopian tube cancer regardless of the BRCA mutation status. The primary end point is progression-free survival at 6 months. Other secondary end points are response rate, disease control rate, quality of life and overall survival. Lay abstract: PARP inhibitors as a single agent have shown very modest activity in platinum-resistant ovarian cancer in a BRCA nonselected population. The GEICO1601-ROLANDO trial is a protocol designed with the aim of assessing efficacy and safety of the combination of olaparib and pegylated liposomal doxorubin followed by olaparib maintenance in this setting.
  • Autores: Cattrall, J. W. S.; Asín Prieto, Eduardo; Freeman, J. ; et al.
    Revista: EUROPEAN JOURNAL OF CLINICAL MICROBIOLOGY AND INFECTIOUS DISEASES
    ISSN 0934-9723 Vol.38 N° 12 2019 págs. 2311 - 2321
    Resumen
    Antibiotic resistance to oral antibiotics recommended for pyelonephritis is increasing. The objective was to determine if there is a pharmacological basis to consider alternative treatments/novel dosing regimens for the oral treatment of pyelonephritis. A systematic review identified pharmacokinetic models of suitable quality for a selection of antibiotics with activity against Escherichia coli. MIC data was obtained for a population of E. coli isolates derived from patients with pyelonephritis. Pharmacokinetic/pharmacodynamic (PK/PD) simulations determined probability of target attainment (PTA) and cumulative fraction response (CFR) values for sub-populations of the E. coli population at varying doses. There are limited high-quality models available for the agents investigated. Pharmacokinetic models of sufficient quality for simulation were identified for amoxicillin, amoxicillin-clavulanic acid, cephalexin, ciprofloxacin, and fosfomycin trometamol. These antibiotics were predicted to have PTAs >= 0.85 at or below standard doses for the tested E. coli population including cephalexin 1500 mg 8 hourly for 22% of the population (MIC <= 4 mg/L) and ciprofloxacin 100 mg 12 hourly for 71% of the population (MIC <= 0.06 mg/L). For EUCAST-susceptible E. coli isolates, doses achieving CFRs >= 0.9 included amoxicillin 2500 mg 8 hourly, cephalexin 4000 mg 6 hourly, ciprofloxacin 200 mg 12 hourly, and 3000 mg of fosfomycin 24 hourly. Limitations in the PK data support carrying out additional PK studies in populations of interest. Oral antibiotics including amoxicillin, amoxicillin-clavulanic acid, and cephalexin have potential to be effective for a proportion of patients with pyelonephritis. Ciprofloxacin may be effective at lower doses than currently prescribed.
  • Autores: González Martín, Antonio (Autor de correspondencia); Sánchez Lorenzo, María Luisa
    Revista: CANCER
    ISSN 0008-543X Vol.125 N° Suppl. 24 2019 págs. 4616 - 4622
    Resumen
    Despite advances in surgery and chemotherapy and the integration of antivascular endothelial growth factor therapy as well as poly(adenosine diphosphate-ribose) polymerase inhibitors into daily clinical practice, epithelial ovarian cancer remains the leading cause of death from gynecological cancer. The incorporation of new therapies with the potential to achieve long-term disease remission is a clear need for patients with ovarian cancer. Immunotherapy with checkpoint inhibitors (CPIs) (antiprogrammed cell death protein 1 [anti-PD-1] or antiprogrammed death-ligand 1 [anti-PD-L1]) has been adopted in several malignancies based on improvements shown with regard to progression-free survival and in particular overall survival. Although there is a solid rationale for the use of CPIs in patients with ovarian cancer, to our knowledge the clinical data presented to date are not very convincing. This article reviews the current data regarding CPIs in patients with ovarian cancer along with the future directions and designs of clinical trials aiming to overcome the low efficacy of CPIs in these individuals.
  • Autores: Lee, C. K. (Autor de correspondencia); Asher, R.; Friedlander, M. ; et al.
    Revista: EUROPEAN JOURNAL OF CANCER
    ISSN 0959-8049 Vol.117 2019 págs. 99 - 106
    Resumen
    Background: Platinum-resistant ovarian cancer (PROC) is associated with a variable prognosis and unpredictable survival times. We have developed and validated a prognostic nomogram with the objective of improving the prediction of overall survival (OS) in patients treated with chemotherapy. Methods: The nomogram was developed using data from a training cohort of patients from two trials, including the chemotherapy-only arm in AURELIA and all randomised patients in CARTAXHY. Multivariable proportional hazards models were generated based on pretreatment characteristics to develop a nomogram that classifies patients based on OS. We subsequently assessed the performance of the nomogram in terms of discrimination and calibration in independent validation patient cohorts: PENELOPE and the bevacizumab-chemotherapy arm of AURELIA. Results: The nomogram included six significant OS predictors, in order of importance: performance status, ascites, size of the largest tumour, CA-125, platinum-free interval and primary platinum resistance (C-statistic 0.69). In the training cohort, the median OS in the good, intermediate and poor prognosis groups was 25.3, 15.2 and 7.4 months, respectively. In the PENELOPE validation cohort (C-statistic 0.59), the median OS in the good, intermediate and poor prognosis groups was 18.5, 10.3 and 5.8 months, respectively. In the AURELIA bevacizumab-chemotherapy validation cohort (C-statistic 0.67), the median OS in good, intermediate and poor prognosis groups was 26.7, 13.8 and 10.0 months, respectively. Conclusions: This nomogram with six pretreatment characteristics allows prediction of OS in PROC and could be used for stratification of patients in clinical trials as well as for counselling patients about prognosis. (C) 2019 Published by Elsevier Ltd.
  • Autores: Colombo, N. (Autor de correspondencia); Sessa, C.; du Bois, A.; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN 1048-891X Vol.29 N° 4 2019 págs. 728 - 760
    Resumen
    The development of guidelines recommendations is one of the core activities of the European Society for Medical Oncology (ESMO) and European Society of Gynaecologial Oncology (ESGO), as part of the mission of both societies to improve the quality of care for patients with cancer across Europe. ESMO and ESGO jointly developed clinically relevant and evidence-based recommendations in several selected areas in order to improve the quality of care for women with ovarian cancer. The ESMO-ESGO consensus conference on ovarian cancer was held on April 12-14, 2018 in Milan, Italy, and comprised a multidisciplinary panel of 40 leading experts in the management of ovarian cancer. Before the conference, the expert panel worked on five clinically relevant questions regarding ovarian cancer relating to each of the following four areas: pathology and molecular biology, early-stage and borderline tumours, advanced stage disease and recurrent disease. Relevant scientific literature, as identified using a systematic search, was reviewed in advance. During the consensus conference, the panel developed recommendations for each specific question and a consensus was reached. The recommendations presented here are thus based on the best available evidence and expert agreement. This article presents the recommendations of this ESMO-ESGO consensus conference, together with a summary of evidence supporting each recommendation.
  • Autores: Moya-Alarcon, C.; Gonzalez-Dominguez, A. (Autor de correspondencia); Simon, S. ; et al.
    Revista: CLINICAL AND TRANSLATIONAL ONCOLOGY
    ISSN 1699-048X Vol.21 N° 8 2019 págs. 1076 - 1084
    Resumen
    PurposeGermline mutations in BRCA1 and/or BRCA2 genes (gBRCA1/2m) are associated with an increased risk of breast cancer (BC) and ovarian cancer (OC). The aim of this study was to estimate the efficiency of providing germline BRCA1/2 testing to high-grade epithelial ovarian cancer (HGEOC) patients without family history of OC or BC and the subsequent testing and management of their relatives with gBRCA1/2m in Spain.Methods/patientsIncident HGEOC patients without family history of OC or BC who were gBRCA1/2m carriers and their relatives were simulated in a 50-year time horizon. The study compared two scenarios: BRCA1/2 testing vs no testing, using the perspective of the Spanish National Health Service. Cancer risk among gBRCA1/2m carriers was estimated based on their age and whether they had undergone risk-reducing surgeries. Direct healthcare costs and utilities of patients who developed EOC and BC were also included. A probabilistic sensitivity analysis (PSA) with 5 thousand simulations was developed considering25% of the base-case value.ResultsThe BRCA1/2-testing scenario amounted to Euro13,437,897.43 while the no-testing scenario amounted to Euro12,053,291.17. It was estimated that the screening test improved the quality of life among the patients' relatives by 43.8 quality-adjusted life years (QALYs). The incremental cost-utility ratio (ICUR) was Euro31,621.33/QALY in the base case. The PSA showed that 89.12% of the simulations were below the Euro50,000/QALY threshold.Conclusion Providing this screening test to HGEOC patients and their relatives is cost-effective and it allows one to identify a target population with high risk of cancer to provide effective prevention strategies.
  • Autores: Martín Romano, Patricia (Autor de correspondencia); Pérez Solans, Belén; Cano Rafart, David; et al.
    Revista: PLOS ONE
    ISSN 1932-6203 Vol.14 N° 5 2019 págs. e0215970
    Resumen
    Background Perioperative chemotherapy (CT) or neoadjuvant chemoradiotherapy (CRT) in patients with locally advanced gastric (GC) or gastroesophageal junction cancer (GEJC) has been shown to improve survival compared to an exclusive surgical approach. However, most patients retain a poor prognosis due to important relapse rates. Population pharmacokinetic-pharma-codynamic (PK/PD) modeling may allow identifying at risk-patients. We aimed to develop a mechanistic PK/PD model to characterize the relationship between the type of neoadjuvant therapy, histopathologic response and survival times in locally advanced GC and GEJC patients. Methods Patients with locally advanced GC and GEJC treated with neoadjuvant CT with or without preoperative CRT were analyzed. Clinical response was assessed by CT-scan and EUS. Pathologic response was defined as a reduction on pTNM stage compared to baseline cTNM. Metastasis development risk and overall survival (OS) were described using the population approach with NONMEM 7.3. Model evaluation was performed through predictive checks. Results A low correlation was observed between clinical and pathologic TNM stage for both T (R = 0.32) and N (R = 0.19) categories. A low correlation between clinical and pathologic response was noticed (R = -0.29). The OS model adequately described the observed survival rates. Disease recurrence, cTNM stage >= 3 and linitis plastica absence, were correlated to a higher risk of death. Conclusion Our model adequately described clinical response profiles, though pathologic response could not be predicted. Although the risk of disease recurrence and survival were linked, the identification of alternative approaches aimed to tailor therapeutic strategies to the individual patient risk warrants further research.
  • Autores: Garcia, Y. G. (Autor de correspondencia); Ferre, A. D.; Mendiola, C.; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN 1048-891X Vol.29 N° 6 2019 págs. 1050 - 1056
    Resumen
    Background Bevacizumab is an approved treatment after primary debulking surgery for ovarian cancer. However, there is limited information on bevacizumab added to neoadjuvant chemotherapy before interval debulking surgery. Objective To evaluate neoadjuvant bevacizumab in a randomized phase II trial. Methods Patients with newly diagnosed stage III/IV high-grade serous/endometrioid ovarian cancer were randomized to receive four cycles of neoadjuvant chemotherapy with or without >= 3 cycles of bevacizumab 15 mg/kg every 3 weeks. After interval debulking surgery, all patients received post-operative chemotherapy (three cycles) and bevacizumab for 15 months. The primary end point was complete macroscopic response rate at interval debulking surgery. Results Of 68 patients randomized, 64 completed four neoadjuvant cycles; 22 of 33 (67%) in the chemotherapy-alone arm and 31 of 35 (89%) in the bevacizumab arm (p=0.029) underwent surgery. The complete macroscopic response rate did not differ between treatment arms in either the intention-to-treat population of 68 patients (6.1% vs 5.7%, respectively; p=0.25) or the 55 patients who underwent surgery (8.3% vs 6.5%; p=1.00). There was no difference in complete cytoreduction rate or progression-free survival between the treatment arms. During neoadjuvant therapy, grade >= 3 adverse events were more common with chemotherapy alone than with bevacizumab (61% vs 29%, respectively; p=0.008). Intestinal (sub)occlusion, fatigue/asthenia, abdominal infection, and thrombocytopenia were less frequent with bevacizumab. The incidence of grade >= 3 adverse events was 9% in the control arm versus 16% in the experimental arm in the month after surgery. Conclusions Adding three to four pre-operative cycles of bevacizumab to neoadjuvant chemotherapy for unresectable disease did not improve the complete macroscopic response rate or surgical outcome, but improved surgical operability without increasing toxicity. These results support the early integration of bevacizumab in carefully selected high-risk patients requiring neoadjuvant chemotherapy for initially unresectable ovarian cancer.
  • Autores: Asín Prieto, Eduardo; Parra Guillén, Zinnia Patricia; Gómez Mantilla, José David; et al.
    Revista: EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
    ISSN 0928-0987 Vol.136 2019
    Resumen
    The liver is a well-known immunotolerogenic environment, which provides the adequate setting for liver infectious pathogens persistence such as the hepatitis B virus (HBV). Consequently, HBV infection can derive in the development of chronic disease in a proportion of the patients. If this situation persists in time, chronic hepatitis B (CHB) would end in cirrhosis, hepatocellular carcinoma and eventually, the death of the patient. It is thought that this immunotolerogenic environment is the result of complex interactions between different elements of the immune system and the viral biology. Therefore, the purpose of this work is to unravel the mechanisms implied in the development of CHB and to design a tool able to help in the study of adequate therapies. Firstly, a conceptual framework with the main components of the immune system and viral dynamics was constructed providing an overall insight on the pathways and interactions implied in this disease. Secondly, a review of the literature was performed in a modular fashion: (i) viral dynamics, (ii) innate immune response, (iii) humoral and (iv) cellular adaptive immune responses and (v) tolerogenic aspects. Finally, the information collected was integrated into a single topological representation that could serve as the plan for the systems pharmacology model architecture. This representation can be considered as the previous unavoidable step to the construction of a quantitative model that could assist in biomarker and target identification, drug design and development, dosing optimization and disease progression analysis.
  • Autores: Balbas-Martinez, V. (Autor de correspondencia); Michelet, R. ; Edginton, A. N.; et al.
    Revista: EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
    ISSN 0928-0987 Vol.128 2019 págs. 171 - 179
    Resumen
    In a recent multicenter population pharmacokinetic study of ciprofloxacin administered to children suffering from complicated urinary tract infection (cUTI), the apparent volume of distribution (V) and total plasma clearance (CL) were decreased by 83.6% and 41.5% respectively, compared to healthy children. To understand these differences, a physiologically-based pharmacokinetic model (PBPK) for ciprofloxacin was developed for cUTI children. First, a PBPK model in adults was developed, modified incorporating age-dependent functions and evaluated with paediatric data generated from a published model in healthy children. Then, the model was then adapted to a cUTI paediatric population according to the degree of renal impairment (KF) affecting renal clearance (CLRenal,) and CYP1A2 clearance (CLCYP1A2). Serum and urine samples obtained from 22 cUTI children were used for model evaluation. Lastly, a parameter sensitivity analysis identified the most influential parameters on V and CL. The PBPK model predicted the ciprofloxacin exposure in adults and children, capturing age-related pharmacokinetic changes. Plasma concentrations and fraction excreted unchanged in urine (f(e)) predictions improved in paediatric cUTI patients once CLrenal and CLCYP1A2 were corrected by KF. The presented PBPK model for ciprofloxacin demonstrates its adequacy to simulate different dosing scenarios to obtain PK predictions in a healthy population from 3 months old onwards. Model adaptation of CLRenal and CLCYP1A2 according to KF explained partially the differences seen in the plasma drug concentrations and f(e) vs time profiles between healthy and cUTI children. Nevertheless, it is necessary to further investigate the disease-related changes in cUTI to improve model predictions.
  • Autores: González Martín, Antonio (Autor de correspondencia); Pothuri, B.; Vergote, I.; et al.
    Revista: NEW ENGLAND JOURNAL OF MEDICINE
    ISSN 0028-4793 Vol.381 N° 25 2019 págs. 2391 - 2402
    Resumen
    BACKGROUND Niraparib, an inhibitor of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP), has been associated with significantly increased progression-free survival among patients with recurrent ovarian cancer after platinum-based chemotherapy, regardless of the presence or absence of BRCA mutations. The efficacy of niraparib in patients with newly diagnosed advanced ovarian cancer after a response to first-line platinum-based chemotherapy is unknown. METHODS In this randomized, double-blind, phase 3 trial, we randomly assigned patients with newly diagnosed advanced ovarian cancer in a 2:1 ratio to receive niraparib or placebo once daily after a response to platinum-based chemotherapy. The primary end point was progression-free survival in patients who had tumors with homologous-recombination deficiency and in those in the overall population, as determined on hierarchical testing. A prespecified interim analysis for overall survival was conducted at the time of the primary analysis of progression-free survival. RESULTS Of the 733 patients who underwent randomization, 373 (50.9%) had tumors with homologous-recombination deficiency. Among the patients in this category, the median progression-free survival was significantly longer in the niraparib group than in the placebo group (21.9 months vs. 10.4 months; hazard ratio for disease progression or death, 0.43; 95% confidence interval [CI], 0.31 to 0.59; P<0.001). In the overall population, the corresponding progression-free survival was 13.8 months and 8.2 months (hazard ratio, 0.62; 95% CI, 0.50 to 0.76; P<0.001). At the 24-month interim analysis, the rate of overall survival was 84% in the niraparib group and 77% in the placebo group (hazard ratio, 0.70; 95% CI, 0.44 to 1.11). The most common adverse events of grade 3 or higher were anemia (in 31.0% of the patients), thrombocytopenia (in 28.7%), and neutropenia (in 12.8%). No treatment-related deaths occurred. CONCLUSIONS Among patients with newly diagnosed advanced ovarian cancer who had a response to platinum-based chemotherapy, those who received niraparib had significantly longer progression-free survival than those who received placebo, regardless of the presence or absence of homologous-recombination deficiency.
  • Autores: Kirby, Andrew (Autor de correspondencia); Asín Prieto, Eduardo; Burns, Flora Agnes; et al.
    Revista: EUROPEAN JOURNAL OF CLINICAL MICROBIOLOGY & INFECTIOUS DISEASES
    ISSN 1435-4373 Vol.38 N° 2 2019 págs. 357 - 363
    Resumen
    Standard bolus-dosed antibiotic prophylaxis may not inhibit growth of antibiotic resistant colonic bacteria, a cause of SSIs after colorectal surgery. An alternative strategy is continuous administration of antibiotic throughout surgery, maintaining concentrations of antibiotics that inhibit growth of resistant bacteria. This study is a pilot comparing bolus-continuous infusion with bolus-dosed cefuroxime prophylaxis in colorectal surgery. This is a pilot randomised controlled trial in which participants received cefuroxime bolus-infusion (intervention arm) targeting free serum cefuroxime concentrations of 64mg/L, or 1.5g cefuroxime as a bolus dose four-hourly (standard arm). Patients in both arms received metronidazole (500mg intravenously). Eligible participants were adults undergoing colorectal surgery expected to last for over 2h. Results were analysed on an intention-to-treat basis. The study was successfully piloted, with 46% (90/196) of eligible patients recruited and 89% (80/90) of participants completing all components of the protocol. A trialled bolus-continuous dosing regimen was successful in maintaining free serum cefuroxime concentrations of 64mg/L. No serious adverse reactions were identified. Rates of SSIs (superficial and deep SSIs) were lower in the intervention arm than the standard treatment arm (24% (10/42) vs. 30% (13/43)), as were infection within 30days of operation (41% (17/43) vs 51% (22/43)) and urinary tract infections (2% (1/42) vs. 9% (4/43)). Th
  • Autores: Pardo, R.; Quintana, R.; Piñero, A.; et al.
    Revista: REVISTA DE SENOLOGIA Y PATOLOGIA MAMARIA
    ISSN 0214-1582 Vol.32 N° 2 2019 págs. 67 - 74
  • Autores: Martinez-Cuadron, D. ; Gil, C.; Serrano, J.; et al.
    Revista: LEUKEMIA RESEARCH
    ISSN 0145-2126 Vol.76 2019 págs. 1 - 10
    Resumen
    Complete remission (CR) after induction therapy is the first treatment goal in acute myeloid leukemia (AML) patients and has prognostic impact. Our purpose is to determine the correlation between the observed CR/CRi rate after idarubicin (IDA) and cytarabine (CYT) 3+ 7 induction and the leukemic chemosensitivity measured by an ex vivo test of drug activity. Bone marrow samples from adult patients with newly diagnosed AML were included in this study. Whole bone marrow samples were incubated for 48 h in well plates containing IDA, CYT, or their combination. Pharmacological response parameters were estimated using population pharmacodynamic models. Patients attaining a CR/CRi with up to two induction cycles of 3+ 7 were classified as responders and the remaining as resistant. A total of 123 patients fulfilled the inclusion criteria and were evaluable for correlation analyses. The strongest clinical predictors were the area under the curve of the concentration response curves of CYT and IDA. The overall accuracy achieved using MaxSpSe criteria to define positivity was 81%, predicting better responder (93%) than non-responder patients (60%). The ex vivo test provides better yet similar information than cytogenetics, but can be provided before treatment representing a valuable in-time addition. After validation in an external cohort, this novel ex vivo test could be useful to select AML patients for 3+ 7 regimen vs. alternative schedules.
  • Autores: Matulonis, U. A. (Autor de correspondencia); Shapira-Frommer, R.; Santin, A. D.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.30 N° 7 2019 págs. 1080 - 1087
    Resumen
    Background Advanced recurrent ovarian cancer (ROC) is the leading cause of gynecologic cancer-related death in developed countries and new treatments are needed. Previous studies of immune checkpoint blockade showed low objective response rates (ORR) in ROC with no identified predictive biomarker. Patients and methods This phase II study of pembrolizumab (NCT02674061) examined two patient cohorts with ROC: cohort A received one to three prior lines of treatment with a platinum-free interval (PFI) or treatment-free interval (TFI) between 3 and 12months and cohort B received four to six prior lines with a PFI/TFI of >= 3months. Pembrolizumab 200mg was administered intravenously every 3weeks until cancer progression, toxicity, or completion of 2years. Primary end points were ORR by Response Evaluation Criteria in Solid Tumors version 1.1 per blinded independent central review by cohort and by PD-L1 expression measured as combined positive score (CPS). Secondary end points included duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. Results Cohort A enrolled 285 patients; the first 100 served as the training set for PD-L1 biomarker analysis. Cohort B enrolled 91 patients. ORR was 7.4% for cohort A and 9.9% for cohort B. Median DOR was 8.2months for cohort A and not reached for cohort B. DCR was 37.2% and 37.4%, respectively, in cohorts A and B. Based on the training set analysis, CPS 1 and 10 were selected for evaluation in the confirmation set. In the confirmation set, ORR was 4.1% for CPS<1, 5.7% CPS >= 1, and 10.0% for CPS >= 10. PFS was 2.1months for both cohorts. Median OS was not reached for cohort A and was 17.6months for cohort B. Toxicities were consistent with other single-agent pembrolizumab trials. Conclusions Single-agent pembrolizumab showed modest activity in patients with ROC. Higher PD-L1 expression was correlated with higher response. Clinical Trial Number Clinicaltrials.gov, NCT02674061
  • Autores: Manzanedo, I. (Autor de correspondencia); Pereira, F. ; Caro, C. R.; et al.
    Revista: ANNALS OF SURGICAL ONCOLOGY
    ISSN 1068-9265 Vol.26 N° 8 2019 págs. 2615 - 2621
    Resumen
    BackgroundGastric cancer (GC) with peritoneal carcinomatosis (PC) is traditionally considered a terminal stage of the disease. The use of a multimodal treatment, including cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), can benefit these patients. Our goal was to evaluate the morbidity and survival outcomes of these patients.MethodsThis is a retrospective, multicenter study from a prospective national database of patients diagnosed with PC secondary to GC treated with CRS and HIPEC from June 2006 to October 2017.ResultsEighty-eight patients from seven specialized Spanish institutions were treated with CRS and HIPEC, with median age of 53years; 51% were women. Median Peritoneal Cancer Index (PCI) was 6, and complete cytoreduction was achieved in 80 patients (90.9%). HIPEC was administered in 85 cases with 4 different regimens (Cisplatin+Doxorubicin, Mitomycin-C+Cisplatin, Mitomycin-C and Oxaliplatin). Twenty-seven cases (31%) had severe morbidity (grade III-IV) and 3 patients died in the postoperative period (3.4%). Median follow-up was 32months. Median overall survival (OS) was 21.2months, with 1-year OS of 79.9% and 3-year OS of 30.9%. Median disease-free survival (DFS) was 11.6months, with 1-year DFS of 46.1% and 3-year DFS of 21.7%. After multivariate analysis, the extent of peritoneal disease (PCI >= 7) was identified as the only independent factor that influenced OS (hazard ratio [HR] 2.37, 95% confidence interval [CI] 1.26-4.46, p=0.007).ConclusionsThe multimodal treatment, including CRS and HIPEC, for GC with PC can improve the survival results in selected patients (PCI<7) and in referral centers.
  • Autores: Evrard, S. (Autor de correspondencia); van de Velde, C.; Noordhoek, I.; et al.
    Revista: EJSO
    ISSN 0748-7983 Vol.45 N° 9 2019 págs. 1515 - 1519
    Resumen
    As part of its mission to promote the best surgical care for cancer patients, the European Society of Surgical Oncology (ESSO) has been developing multiple programmes for clinical research along with its educational portfolio. This position paper describes the different research activities of the Society over the past decade and an action plan for the upcoming five years to lead innovative and high quality surgical oncology research. ESSO proposes to consider pragmatic research methodologies as a complement to randomised clinical trials (RCT), advocates for increased funding and operational support in conducting research and aims to enable young surgeons to be active in research and establish partnerships for translational research activities. (C) 2019 Published by Elsevier Ltd.
  • Autores: González de la Huebra Rodríguez, Ignacio Javier (Autor de correspondencia); Elizalde Pérez, Arlette María; García Baizán, Alejandra; et al.
    Revista: MAGNETIC RESONANCE IMAGING
    ISSN 0730-725X Vol.57 2019 págs. 317 - 322
    Resumen
    Background: The use of preoperative breast MRI remains controversial despite being the most sensitive technique for the detection of breast malignancies. Purpose: To evaluate the benefit of preoperative breast MRI after performing the three conventional techniques (DM, US, DBT). To analyze the influence of breast density in the sensitivity of the different imaging techniques. Material and methods: Retrospective review of 280 histologically confirmed breast cancers in 192 women. We reviewed the medical records and evaluated the change of treatment induced by MRI. Also, we assessed the reports of DM and the combination of the different imaging techniques, and categorized them according to ACR density (a-d) and as negative (BI-RADS 1-3) or positive (BIRADS 4 or 5). The gold standard was the pathologic assessment of the surgical specimen. The sensitivity of the different techniques was compared using McNemar test. Results: Among these 192 women the use of MRI did not significantly increase the mastectomy rate (from 16.6% to 17.6%; p = 0.5). The addition of any technique demonstrated a higher sensitivity than DM alone. The sensitivity of DM alone was 52.5% while using all the techniques, including MRI, was 94.3% (p < 0.001). Regardless of breast density pattern, the addition of any technique significantly increased the sensitivity of DM (p < 0.001). Conclusions: The addition of MRI to the three conventional techniques increased the sensitivity but did not significantly modify the rate of mastectomies. Additional techniques increased the sensitivity of DM in both dense and non-dense breasts.
  • Autores: Vergote, I. (Autor de correspondencia); Coleman, R. L. ; Pignata, S.; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN 1048-891X Vol.29 N° 7 2019 págs. 1094 - 1097
  • Autores: Esgueva Colmenarejo, Antonio Jesús; Rodriguez-Revuelto, R.; Espinosa-Bravo, M.; et al.
    Revista: EJSO
    ISSN 0748-7983 Vol.45 N° 4 2019 págs. 578 - 583
    Resumen
    Background: Intraoperative ultrasound guided surgery (IOUS) is an effective surgical technique for breast cancer with advantages over wire localization guided surgery (WL), enabling smaller lumpectomies without compromising margins. Nevertheless, it has had a slow implementation, maybe due to lacking a learning curve. Also differences in costs are not clearly reported. The aim of the study is to assess differences in volume of healthy breast tissue excised, to establish a learning curve and to prove it is cost saving. Patients and methods: From February 2009 to April 2013, women diagnosed with invasive breast cancer eligible for IOUS or WL breast conserving surgery were recorded into a prospectively maintained database. Both groups were compared for differences in margin status, second surgeries and excess of healthy tissue resected, defined by the calculated resection ratio (CRR). A raw cost study was assessed. IOUS learning curve was analyzed using Cumulative sum control chart (CUSUM). Results: The study included 214 patients, 148 (69.16%) in the IOUS group and 66 (30.84%) in the WL group. IOUS showed significantly smaller surgical volumes (p = 0.02), smaller CRR (p = 0.006), higher rate of negative margins (p = 0.017) and less surgical time (p = 0.006) than WL. Learning curves based on complete tumor excision and no need for second surgeries showed that 11 cases were enough to master the technique. Around 900(sic) per surgery was saved using IOUS vs. WL. Conclusion: IOUS decreases excision of healthy breast tissue while increasing negative margin rates compared to WL. IOUS can be easily implemented; 11 cases are enough to acquire skills for performing the technique. Savings can be up to 900(sic) per surgery. (C) 2019 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.
  • Autores: Rubio, I. T. (Autor de correspondencia); Wyld, L.; Esgueva Colmenarejo, Antonio Jesús; et al.
    Revista: EJSO
    ISSN 0748-7983 Vol.45 N° 4 2019 págs. 567 - 572
    Resumen
    Background: At present there is a lack of standardization of training in breast cancer surgery across Europe. The aim of this survey was to assess current practice in Europe regarding training in breast cancer (BC) surgery. Material and methods: General surgeons, surgical oncologists, gynecologist, and plastic surgeons in Europe were invited to participate in this bespoke survey including 19 questions. Results: The survey was sent to 3.000 surgical oncologists across Europe. A total of 671 physicians (387 general surgeons, 152 gynecologists, 126 surgical oncologist, 31 plastic surgeons) answered the survey (23% response rate). Four hundred and sixty-eight physicians devoted between 50%-100% of their job to treating breast cancer. 45% worked in a community/University hospital within a dedicated Breast Unit. Specific additional breast surgery training was not universal: 20% had undertaken an accredited breast fellowship, 30% in a Breast Unit as a trainee, 21% had done additional courses, masters or diploma and 8% had not done any additional training. The majority (61%) of respondents worked in Units treating >150 BC cases per year, while 26% of the responders treat >120 new primary cases per year, and 23% less than 50 new cases a year. Multivariate analysis showed that breast surgeons working in a Breast Unit and treating more than 50 cases/year significantly performed oncoplastic procedures. Conclusion: There is a great variability in breast cancer surgery training in Europe. It is imperative to develop quality standards for breast cancer surgery training to ensure that patients get standardized and certified surgical management regardless of the country in which they are treated. (C) 2019 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.
  • Autores: González Martín, Antonio (Autor de correspondencia); Oza, A. M. ; Embleton, A. C.; et al.
    Revista: GYNECOLOGIC ONCOLOGY
    ISSN 0090-8258 Vol.152 N° 1 2019 págs. 53 - 60
    Resumen
    Objective. In the randomized phase 3 ICON7 trial (ISRCTN91273375), adding bevacizumab to chemotherapy for newly diagnosed ovarian cancer significantly improved progression-free survival (PFS; primary endpoint) but not overall survival (OS; secondary endpoint) in the intent-to-treat (FIT) population. We explored treatment effect according to stage and extent of residual disease. Methods. Patients with stage IIB-IV or high-risk (grade 3/clear-cell) stage 1-IIA ovarian cancer were randomized to receive six cycles of carboplatin and paclitaxel either alone or with bevacizumab 7.5 mg/kg every 3 weeks followed by single-agent bevacizumab for 12 further cycles (total duration 12 months). Post hoc exploratory analyses of subgroups defined by stage and extent of residual disease at diagnosis within the stage IIIB-IV population (European indication) was performed. Results. The PFS benefit from bevacizumab was seen consistently in all subgroups explored. The PFS hazard ratio was 0.77 (95% confidence interval [CI], 0.59-0.99) in 411 patients with stage IIIB-IV ovarian cancer with no visible residuum and 0.81 (95% CI, 0.69-0.95) in 749 patients with stage IIIB-IV disease and visible residuum. As in the ITT population, no OS difference was detected in any subgroup except the previously described 'high-risk' subgroup. Safety results in analyzed subgroups were consistent with the overall population. Conclusions. Adding bevacizumab to front-line chemotherapy improves PFS irrespective of stage/residual disease. In patients with stage III with >1 cm residuum, stage IV or inoperable disease, this translates into an OS benefit. No OS benefit or detriment was seen in other subgroups explored. (C) 2018 The Authors. Published by Elsevier Inc.
  • Autores: Salazar, J. P.; Miranda, I. ; De Torres, J.; et al.
    Revista: BRITISH JOURNAL OF RADIOLOGY
    ISSN 0007-1285 Vol.92 N° 1094 2019
    Resumen
    Objective: To evaluate the efficacy and learning curve of ultrasoundguided vacuum-assisted excision (US-VAE) of benign breast lesions, and to assess characteristics associated with residual lesion. Methods: This was a retrospective study with institutional review board-approval. Sonographic and clinical follow-up were performed 6 months after intervention. Effectiveness and safety of the technique were analyzed. The cumulative summation (CUSUM) graphs were used to evaluate learning curves concerning complete excision and hematoma. Results: 152 ultrasound-VAEs in 143 patients were included. Initial complete resection was achieved in 90.8 % (138 of 152). 6-month follow-up was completed for 143 (94%) of cases and complete resection was observed in 72 % (100 of 143). Mean maximum size without residual tumor was 16.9 mm, while with residual lesion it was 21.9 mm (p = < 0.001), with a volume of 1.53 and 3.39 cm(3), respectively (p = < 0.001). Increase in lesion size and volume was associated with less effectiveness (p = 0.05), clinical control (p = 0.05), and higher risk of clinically significant hematoma (p = 0.05). Receiver operating characteristic analysis demonstrate a volume threshold of 2.6 cm(3) (r = 0.71, specificity 84.5%) for leaving no residual lesion. Cumulative summation graphs demonstrate that, on average, 11 excisions were required to acquire skills to perform complete excision in more than 80% at the end of the ultrasound-VAE and 18 excisions at 6 months. Conclusion: Ultrasound-VAE is an effective treatment for benign breast lesions. Breast lesion volume should be considered when assessing for percutaneous treatment. Advances in knowledge: A follow-up of the learning process of ultrasound-VAE will be a valuable tool to assess the efectiveness and safety of the technique i
  • Autores: Fernandez-Teruel, C. (Autor de correspondencia); Gonzalez, I. ; Fernández de Trocóniz Fernández, José Ignacio; et al.
    Revista: CLINICAL PHARMACOKINETICS
    ISSN 0312-5963 Vol.58 N° 3 2019 págs. 363 - 374
    Resumen
    Background and Objectives Lurbinectedin is an inhibitor of RNA polymerase II currently under clinical development for intravenous administration as a single agent and in combination with other anti-tumor agents for the treatment of several tumor types. The objective of this work was to develop a population-pharmacokinetic model in this patient setting and to elucidate the main predictors to guide the late stages of development. Methods Data from 443 patients with solid and hematologic malignancies treated in six phase I and three phase II trials with lurbinectedin as a single agent or combined with other agents were included in the analysis. The potential influence of demographic, co-treatment, and laboratory characteristics on lurbinectedin pharmacokinetics was evaluated. Results The final population-pharmacokinetic model was an open three-compartment model with linear distribution and linear elimination from the central compartment. Population estimates for total plasma clearance, and apparent volume at steady state were 11.2 L/h and 438 L, respectively. Inter-individual variability was moderate for all parameters, ranging from 20.9 to 51.2%. High alpha-1-acid glycoprotein and C-reactive protein, and low albumin reduced clearance by 28, 20, and 20%, respectively. Co-administration of cytochrome P450 3A inhibitors reduced clearance by 30%. Combinations with other anti-tumor agents did not modify the pharmacokinetics of lurbinectedin significantly. Conclusion The population-pharmacokinetic model indicated neither a dose nor time dependency, and no clinically meaningful pharmacokinetic differences were found when co-administered with other anticancer agents. A chronic inflammation pattern characterized by decreased albumin and increased C-reactive protein and alpha-1-acid glycoprotein levels led to high lurbinectedin exposure. Co-administration of cytochrome P450 3A inhibitors increased lurbinectedin exposure.
  • Autores: Moore, K. ; Colombo, N. ; Scambia, G.; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN 1048-891X Vol.29 2019 págs. A14 - A15
  • Autores: Vergote, I.; Sehouli, J.; Salutari, V.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN 0732-183X Vol.37 N° 15 2019
  • Autores: Colombo, N.; Dreosti, L.; McCormack, M. ; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN 1048-891X Vol.29 2019 págs. A22 - A23
  • Autores: Friedlander, M. L.; Moore, K.; Colombo, N.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.30 N° Suppl.5 2019 págs. V405-V406
  • Autores: Oaknin, A. ; Perez, M. J. R.; Madrid, L. F. ; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.30 N° Suppl.5 2019
  • Autores: González Martín, Antonio; Pothuri, B.; Vergote, I. B. ; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.30 2019 págs. 893 - 893
  • Autores: Chacon Cruz, Enrique Maria; Alcázar Zambrano, Juan Luis; Mínguez Milio, José Ángel; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN 1048-891X Vol.29 N° Supl. 4 2019 págs. A450 - A451
  • Autores: Rubio, I. T.; Esgueva Colmenarejo, Antonio Jesús; Espinosa-Bravo, M.; et al.
    Revista: CANCER RESEARCH
    ISSN 0008-5472 Vol.79 N° 4 2019
  • Autores: Salas Benito, Diego; De Andrea, Carlos Eduardo; Aramendía Beitia, José Manuel; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.30 N° Supl. 5 2019 págs. 419
  • Autores: Redondo, A. ; Colombo, N.; Dreosti, L. M.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.30 N° Suppl.5 2019 págs. 429 - 429
  • Autores: Vergote, I.; Copeland, L.; Monk, B.; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN 1048-891X Vol.29 N° Suppl. 4 2019 págs. A151 - A152
  • Autores: Vergote, I. B. ; Copeland, L. ; Monk, B. J.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.30 N° Suppl.5 2019 págs. v431
  • Autores: Piccart-Gebhart, M. J.; Aftimos, P. G. ; Duhoux, F. P.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN 0732-183X Vol.37 N° 15 2019
  • Autores: Palazon-Carrion, N.; Jimenez-Cortegana, C.; Holgado, E.; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN 0732-183X Vol.37 N° 15 2019
  • Autores: Cattrall, J. W. S.; Asín Prieto, Eduardo; Freeman, J. ; et al.
    Revista: JOURNAL OF PATHOLOGY
    ISSN 0022-3417 Vol.249 N° Supl. 1 2019 págs. S22 - S22
  • Autores: González Martín, Antonio; Pothuri, B. ; Vergote, I.; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN 1048-891X Vol.29 2019 págs. A9 - A10
  • Autores: Chacon, J. I. ; Saura, C.; Ciruelos, E. ; et al.
    Revista: CANCER RESEARCH
    ISSN 0008-5472 Vol.79 N° 4 2019
  • Autores: Spoerke, J. M.; Daemen, A.; Chang, C. W.; et al.
    Revista: CANCER RESEARCH
    ISSN 0008-5472 Vol.79 N° 4, Suppl. 2019 págs. P5-11-01
  • Autores: Oaknin, A.; Gladieff, L. ; Colombo, N. ; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN 0732-183X Vol.37 N° 15 2019
  • Autores: González Martín, Antonio; Colombo, N. ; Heitz, F. ; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN 0732-183X Vol.37 N° 15 2019 págs. TPS5599-TPS5599
  • Autores: O'Malley, D. M.; Matulonis, U. A.; Birrer, M. J. ; et al.
    Revista: JOURNAL OF CLINICAL ONCOLOGY
    ISSN 0732-183X Vol.37 N° 15, Suppl. S 2019 págs. 5520
  • Autores: Chiva de Agustín, Luis; Chacon Cruz, Enrique Maria; Carriles Rivero, Isabel María; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN 1048-891X Vol.29 N° Supl. 4 2019 págs. A20 - A21
  • Autores: Sánchez Lorenzo, María Luisa; Espinosa Mariscal, Íñigo; Chacon Cruz, Enrique Maria; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN 1048-891X Vol.29 N° Supl. 4 2019 págs. A515 - A516
  • Autores: Oaknin, A. ; Moore, K. ; Colombo, N.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.30 N° Suppl.5 2019 págs. 405 - 405
  • Autores: Fujiwara, K. ; Harter, P.; Leary, A.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.30 N° Suppl.9 2019 págs. IX191-IX192
  • Autores: Weber, W. P. (Autor de correspondencia); Haug, M.; Kurzeder, C.; et al.
    Revista: BREAST CANCER RESEARCH AND TREATMENT
    ISSN 0167-6806 Vol.172 N° 3 2018 págs. 523 - 537
    Resumen
    PurposeIndications for nipple-sparing mastectomy(NSM) have broadened to include the risk reducing setting and locally advanced tumors, which resulted in a dramatic increase in the use of NSM. The Oncoplastic Breast Consortium consensus conference on NSM and immediate reconstruction was held to address a variety of questions in clinical practice and research based on published evidence and expert panel opinion.MethodsThe panel consisted of 44 breast surgeons from 14 countries across four continents with a background in gynecology, general or reconstructive surgery and a practice dedicated to breast cancer, as well as a patient advocate. Panelists presented evidence summaries relating to each topic for debate during the in-person consensus conference. The iterative process in question development, voting, and wording of the recommendations followed the modified Delphi methodology.ResultsConsensus recommendations were reached in 35, majority recommendations in 24, and no recommendations in the remaining 12 questions. The panel acknowledged the need for standardization of various aspects of NSM and immediate reconstruction. It endorsed several oncological contraindications to the preservation of the skin and nipple. Furthermore, it recommended inclusion of patients in prospective registries and routine assessment of patient-reported outcomes. Considerable heterogeneity in breast reconstruction practice became obvious during the conference.ConclusionsIn case of conflicting or missing evidence to guide treatment, the consensus conference revealed substantial disagreement in expert panel opinion, which, among others, supports the need for a randomized trial to evaluate the safest and most efficacious reconstruction techniques.
  • Autores: Rubio, Isabel Teresa (Autor de correspondencia)
    Revista: ANNALS OF SURGICAL ONCOLOGY
    ISSN 1068-9265 Vol.25 2018 págs. 638 - 639
  • Autores: Ruiz Cerdá, María Leire; Asín Prieto, Eduardo; Parra Guillén, Zinnia Patricia; et al.
    Revista: CLINICAL CANCER RESEARCH
    ISSN 1078-0432 Vol.24 N° 14 2018 págs. 3236 - 3238
    Resumen
    Pharmacokinetic modeling, traditionally using drug exposure, is widely used to support decision-making in translational medicine and patient care. The development of mechanistic computational models that integrate drug concentrations at the site of action making use of existing knowledge opens a new paradigm in optimal dosing. (C) 2018 AACR.
  • Autores: Rubio, Isabel Teresa (Autor de correspondencia); Wyld, L.; Cardoso, E.; et al.
    Revista: BREAST
    ISSN 0960-9776 Vol.41 2018 págs. 133 - 135
    Resumen
    Preoperative systemic therapy (PST) has become an accepted treatment not only for locally advanced but also for early stage breast cancer patients. Clinical trials have demonstrated that the use of PST is equally to adjuvant treatments in terms of overall survival, and has the advantage of increasing rates of breast conservative surgery and rates of pathologic complete response, a surrogate endpoint for the effectiveness of systemic therapy. Initial studies have suggested higher rates of locoregional recurrence with this approach. However, the optimization of systemic and targeted therapy and the multidisciplinary care is key to achieving optimal outcomes in this setting. (C) 2018 Published by Elsevier Ltd.
  • Autores: Pérez Solans, Belén; Fleury, A.; Freiwald, M.; et al.
    Revista: CLINICAL PHARMACOKINETICS
    ISSN 0312-5963 Vol.57 N° 3 2018 págs. 379 - 392
    Resumen
    Background Volasertib, a potent and selective polo-like kinase inhibitor, has shown to increase response rates and improve survival with a clinically manageable safety profile, administered alone and in combination with cytarabine in patients with acute myeloid leukaemia. Objectives The objectives of this analysis were to describe the pharmacokinetics of volasertib and cytarabine, administered as single agents or in combination. Methods Three thousand, six hundred and six plasma volasertib concentrations from 501 patients receiving either volasertib alone, or in combination with cytarabine, and 826 plasma cytarabine concentrations from 650 patients receiving cytarabine as multiple subcutaneous injections per cycle either alone, or in combination with volasertib, were analysed using NONMEM Version 7.3. Covariates evaluated included demographic and disease-related parameters. Results The pharmacokinetics of volasertib were found to be dose independent from 150 to 550 mg. Body surface area and ethnicity showed significant effects in all the patients. This is reflected as an increase in drug exposure for Japanese patients, although this finding has to be interpreted with caution because only 7% of patients were part of that population group. Volasertib showed low-to-mild inter-individual variability in total clearance. For the case of cytarabine, its pharmacokinetics was affected by body surface area. Finally, volasertib and cytarabine did not influence the pharmacokinetic characteristics of each other. Conclusions The pharmacokinetics of volasertib in patients with acute myeloid leukaemia alone or in combination with cytarabine is predictable and associated with low-to-mild patient variability with the exception of the high variability associated with the volume of distribution of the central compartment, having no effect on the area under the plasma concentration-time curve.
  • Autores: Reynaldo-Fernandez, G. ; Solozabal, J.; Amaro, D.; et al.
    Revista: EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
    ISSN 0928-0987 Vol.120 2018 págs. 123 - 132
    Resumen
    Marketed formulations of erythropoietin (EPO) ior (R) EPOCIM, MIRCERA (R) and two newly developed pegylated-EPO analogues (PEG-EPO 32 and 40 kDa) formulations were intravenously administered to New Zealand rabbits. A semi-mechanistic Pharmacokinetic/Pharmacodynamic (PK/PD) model describing in a simultaneous and integrated form the time course of reticulocytes, red blood cells and hemoglobin was built to account for the time course of hematopoiesis stimulation after erythropoietin administration. Data analysis was performed based on the population approach with the software NONMEM version 7.3. Erythropoietin disposition of each of the administered formulations was best described with a two compartment model and linear elimination. Different formulations show different clearance and apparent volume of distribution of the central compartment but share estimates of inter-compartmental clearance and apparent peripheral volume of distribution. A semi-mechanistic model including cell proliferation, maturation, and homeostatic regulation provided a good description of the data regardless the type of erythropoietin formulation administered. The system-, and drug-related parameters showed consistency and differed across formulations, respectively. A single IV administration of PEG-EPO 32 and 40 kDa formulations in New Zealand rabbits achieves a median change of 27% and 22% on RET levels, and of 47% and 63% on RBC and HGB levels, respectively compared to MIRCERA (R). The administration of new branched PEG-chains formulations improves PK and PD properties of EPO, in terms of increasing elimination halflives and pharmacological activity on RET, RBC and HGB compared to commercially available formulations (ior (R) EPOCIM and MIRCERA (R)).
  • Autores: Álvarez-Cienfuegos Suárez, Francisco Javier; Baixauli Fons, Jorge; Martínez Ortega, Patricia; et al.
    Revista: REVISTA ESPAÑOLA DE ENFERMEDADES DIGESTIVAS
    ISSN 1130-0108 Vol.110 N° 11 2018 págs. 684 - 690
    Resumen
    Purpose: the aim of this study was to compare overall and disease-free survival among patients with colorectal cancer detected via a screening program as compared to those with symptomatic cancer. Material and methods: patients diagnosed via colonoscopy (screening group) and those with clinical symptoms (non-screening) were identified from 1995 to 2014. Demographic, clinical, surgical and pathologic variables were recorded. Stage I, II and III cancers were included. Overall and disease-free survival were calculated at five and ten years after tumor resection and survival was calculated by matching both groups for cancers at stage I, II and III. Results: two hundred and fifty patients were identified as a result of screening procedures and 1,330 patients presented with symptomatic cancers.There were no significant differences in the baseline characteristics between the two groups. Pathologic stage, degree of differentiation, perineural invasion and lymphovascular invasion were lower in the screening group (p < 0.01). Overall and disease-free survival at five and ten years were higher in the screening group (p < 0.01). However, when the subjects were matched for pathologic stage, significant differences were found between the two groups with regard to stage I and III tumors. Disease-free survival in stage III at five years (79.1 vs 61.7%; p < 0.001) and ten years (79.1% vs 58.5%; p < 0.001) were significantly higher in the screening group. Conclusions: patients with stage I and III tumors that were diagnosed via a screening program have a higher overall and disease-free survival at five and ten years.
  • Autores: Hontanilla Calatayud, Bernardo Carlos (Autor de correspondencia); Olivas Menayo, Jesus; Cabello Pérez, Alvaro; et al.
    Revista: PLASTIC AND RECONSTRUCTIVE SURGERY
    ISSN 0032-1052 Vol.142 N° 2 2018 págs. 179E - 191E
    Resumen
    Background: Incomplete facial paralysis is still a challenge because we must restore what is missing without causing damage to what has recovered. The current literature is insufficient, with a small number of cases. The use of nerve transfers has gained recent popularity for reanimating facial palsy. The authors present a comparative study between cross-face nerve grafting and masseteric-to-facial nerve transposition for incomplete facial paralysis. Methods: Twenty-eight patients with incomplete unilateral facial paralysis were reanimated with either cross-face nerve grafting (group I, n = 10) or masseteric nerve transfer (group II, n = 18). Commissural displacement and commissural contraction velocity were measured using the FACIAL CLIMA dystem. Spontaneity of the movement and satisfaction were also assessed. Results: When comparing the reconstructed and the healthy sides, statistical differences were found in group I but not in group II, suggesting that the resulting movement was symmetrical in group II but not in group I. Intergroup comparison showed that both commissural displacement and commissural contraction velocity were higher in group II. Spontaneity in group I was higher than in group II, but patients in group II showed more satisfaction, both without being statistically significant. Conclusions: Reanimation of incomplete facial paralysis can be satisfactorily achieved with both cross-face nerve grafting and direct masseteric-to-facial nerve transposition. However, with the masseteric nerve, better symmetry, a higher degree of recovery, and an increased level of satisfaction are achieved in a one-stage operation. Furthermore, both nerve sources are able to restore spontaneity in more than 50 percent of the patient's daily life, with no significant differences between them.
  • Autores: García-Cremades Mira, María; Pitou, C.; Iversen, P. W.; et al.
    Revista: EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
    ISSN 0928-0987 Vol.115 2018 págs. 296 - 303
    Resumen
    The aim of this evaluation was to characterize the impact of the tumour size (TS) effects driven by the anticancer drug gemcitabine on overall survival (OS) in patients with advanced pancreatic cancer by building and validating a predictive semi-mechanistic joint TS-OS model. TS and OS data were obtained from one phase II and one phase III study where gemcitabine was administered (1000-1250 mg/kg over 30-60 min i.v infusion) as single agent to patients (n=285) with advanced pancreatic cancer. Drug exposure, TS and OS were linked using the population approach with NONMEM 7.3. Pancreatic tumour progression was characterized by exponential growth (doubling time = 67 weeks), and tumour response to treatment was described as a function of the weekly area under the gemcitabine triphosphate concentration vs time curve (AUC), including treatment-related resistance development. The typical predicted percentage of tumour growth inhibition with respect to no treatment was 22.3% at the end of 6 chemotherapy cycles. Emerging resistance elicited a 57% decrease in drug effects during the 6th chemotherapy cycle. Predicted TS profile was identified as main prognostic factor of OS, with tumours responders' profiles improving median OS by 30 weeks compared to stable-disease TS profiles. Results of NCT00574275 trial were predicted using this modelling framework, thereby validating the approach as a prediction tool in clinical development. Our analyses show that despite the advanced stage of the disease in this patient population, the modelling framework herein can be used to predict the likelihood of treatment success using early clinical data.
  • Autores: Provencher, DM.; Gallagher, CJ.; Parulekar, WR.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.29 N° 2 2018 págs. 431-438
    Resumen
    BACKGROUND: The purpose of this multistage, adaptively, designed randomized phase II study was to evaluate the role of intraperitoneal (i.p.) chemotherapy following neoadjuvant chemotherapy (NACT) and optimal debulking surgery in women with epithelial ovarian cancer (EOC). PATIENTS AND METHODS: We carried out a multicenter, two-stage, phase II trial. Eligible patients with stage IIB-IVA EOC treated with platinum-based intravenous (i.v.) NACT followed by optimal (<1¿cm) debulking surgery were randomized to one of the three treatment arms: (i) i.v. carboplatin/paclitaxel, (ii) i.p. cisplatin plus i.v./i.p. paclitaxel, or (iii) i.p. carboplatin plus i.v./i.p. paclitaxel. The primary end point was 9-month progressive disease rate (PD9). Secondary end points included progression-free survival (PFS), overall survival (OS), toxicity, and quality of life (QOL). RESULTS: Between 2009 and 2015, 275 patients were randomized; i.p. cisplatin containing arm did not progress beyond the first stage of the study after failing to meet the pre-set superiority rule. The final analysis compared i.v. carboplatin/paclitaxel (n¿=¿101) with i.p. carboplatin, i.v./i.p. paclitaxel (n¿=¿102). The intention to treat PD9 was lower in the i.p. carboplatin arm compared with the i.v. carboplatin arm: 24.5% (95% CI 16.2% to 32.9%) versus 38.6% (95% CI 29.1% to 48.1%) P¿=¿0.065. The study was underpowered to detect differences in PFS: HR PFS 0.82 (95% CI 0.57-1.17); P¿=¿0.27 and OS HR 0.80 (95% CI 0.47-1.35)
  • Autores: Parra Guillén, Zinnia Patricia; Mangas Sanjuan, Víctor; García-Cremades Mira, María; et al.
    Revista: JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
    ISSN 0022-3565 Vol.366 N° 1 2018 págs. 96 - 104
    Resumen
    Xenograft mice are largely used to evaluate the efficacy of oncological drugs during preclinical phases of drug discovery and development. Mathematical models provide a useful tool to quantitatively characterize tumor growth dynamics and also optimize upcoming experiments. To the best of our knowledge, this is the first report where unperturbed growth of a large set of tumor cell lines (n=28) has been systematically analyzed using a previously proposed model of nonlinear mixed effects (NLME). Exponential growth was identified as the governing mechanism in the majority of the cell lines, with constant rate values ranging from 0.0204 to 0.203 day(-1). No common patterns could be observed across tumor types, highlighting the importance of combining information from different cell lines when evaluating drug activity. Overall, typical model parameters were precisely estimated using designs in which tumor size measurements were taken every 2 days. Moreover, reducing the number of measurements to twice per week, or even once per week for cell lines with low growth rates, showed little impact on parameter precision. However, a sample size of at least 50 mice is needed to accurately characterize parameter variability (i.e., relative S.E. values below 50%). This work illustrates the feasibility of systematically applying NLME models to characterize tumor growth in drug discovery and development, and constitutes a valuable source of data to optimize experimental designs by providing an a priori sampling window and minimizing the number of samples required.
  • Autores: Mangas Sanjuan, Víctor; Navarro-Fontestad, C.; Garcia-Arieta, A.; et al.
    Revista: EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
    ISSN 0928-0987 Vol.117 2018 págs. 193 - 203
    Resumen
    A semi-physiological two compartment pharmacokinetic model with two active metabolites (primary (PM) and secondary metabolites (SM)) with saturable and non-saturable pre-systemic efflux transporter, intestinal and hepatic metabolism has been developed. The aim of this work is to explore in several scenarios which analyte (parent drug or any of the metabolites) is the most sensitive to changes in drug product performance (i.e. differences in in vivo dissolution) and to make recommendations based on the simulations outcome. A total of 128 scenarios (2 Biopharmaceutics Classification System (BCS) drug types, 2 levels of K-M Pgp, in 4 metabolic scenarios at 2 dose levels in 4 quality levels of the drug product) were simulated for BCS class II and IV drugs. Monte Carlo simulations of all bioequivalence studies were performed in NONMEM 7.3. Results showed the parent drug (PD) was the most sensitive analyte for bioequivalence trials in all the studied scenarios. PM and SM revealed less or the same sensitivity to detect differences in pharmaceutical quality as the PD. Another relevant result is that mean point estimate of C-max and AUC methodology from Monte Carlo simulations allows to select more accurately the most sensitive analyte compared to the criterion on the percentage of failed or successful BE studies, even for metabolites which frequently show greater variability than PD.
  • Autores: Oaknin, A.; Guarch, R.; Barretina, P.; et al.
    Revista: REVISTA ESPAÑOLA DE PATOLOGIA
    ISSN 1699-8855 Vol.51 N° 2 2018 págs. 84-96
    Resumen
    Advances in the understanding of the histological and molecular characteristics of ovarian cancer now allow 5subtypes to be identified, leading to a more refined therapeutic approach and improved clinical trials. Each of the subtypes has specific histological features and a particular biomarker expression, as well as mutations in different genes, some of which have prognostic and predictive value. CA125 and HE4 are examples of ovarian cancer biomarkers used in diagnosis and follow-up. Currently, somatic or germinal mutations on BRCA1 and BRCA2 genes are the most important biomarkers in epithelial ovarian cancer, having prognostic and predictive value. In this article, a group of experts from the Spanish Society of Medical Oncology and the Spanish Society of Pathology review the histological and molecular characteristics of the 5subtypes of ovarian cancer and describe the most useful biomarkers and mutations for diagnosis, screening and tailored treatment strategy.
  • Autores: Santaballa, A. (Autor de correspondencia); Matias-Guiu, X.; Redondo, A.; et al.
    Revista: CLINICAL AND TRANSLATIONAL ONCOLOGY
    ISSN 1699-048X Vol.20 N° 1 2018 págs. 29 - 37
    Resumen
    Endometrial cancer (EC) is the most common gynecological cancer in developed countries. Most patients are diagnosed at an early stage with a low risk of relapse. However, there is a group of patients with a high risk of relapse and poor prognosis. Despite the recent publication of randomized trials, the adjuvant treatment of high-risk EC is still to be defined and there are many open questions about the best approach and the right timing. Unfortunately, the survival of metastatic or recurrent EC is short, due to the poor results of chemotherapy and the lack of a second line of treatment. Advances in the knowledge of the molecular abnormalities in EC have permitted the development of promising targeted therapies.
  • Autores: Martínez Monge, Rafael (Autor de correspondencia); Valtueña Peydro, Germán; Cambeiro Vázquez, Felix Mauricio; et al.
    Revista: BRACHYTHERAPY
    ISSN 1538-4721 Vol.17 N° 5 2018 págs. 734 - 741
    Resumen
    PURPOSE: To determine the long-term results of a Phase II trial of perioperative high-dose-rate brachytherapy (PHDRB) in primary advanced or recurrent gynecological cancer. METHODS AND MATERIALS: Fifty patients with locally advanced and recurrent gynecological cancer suitable for salvage surgery were included. Unirradiated patients (n = 25) received preoperative chemoradiation followed by surgery and PHDRB (16-24 Gy). Previously irradiated patients (n = 25) received surgery and PHDRB alone (32-40 Gy). RESULTS: Median followup was 11.5 years. Eight unirradiated patients (32%) developed Grade >= 3 toxic events including two fatal events. Local and locoregional control rates at 16 years were 87.3% and 78.9%, respectively. Sixteen-year disease-free and overall survival rates were 42.9% and 46.4%, respectively. Ten previously irradiated patients (40.0%) developed Grade >= 3 adverse events, including four fatal events. Local and locoregional control rates at 14 years were 59.6% and 42.6%, respectively. Fourteen-year disease-free and overall survival rates were 16.0% and 19.2%, respectively. CONCLUSIONS: PHDRB allows effective salvage of a subset of unfavorable gynecological tumors with high-risk surgical margins. Toxicity was unacceptable at the initial dose levels but deescalation resulted in the absence of severe toxicity without a negative impact on locoregional control. A substantial percentage of patients remain alive and controlled at >10 years including a few previously irradiated cases with positive margins. (C) 2018 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
  • Autores: Balbas-Martinez, V.; Ruiz Cerdá, María Leire; Irurzun Arana, Itziar; et al.
    Revista: PLOS ONE
    ISSN 1932-6203 Vol.13 N° 3 2018 págs. e0192949
    Resumen
    Motivation The literature on complex diseases is abundant but not always quantitative. This is particularly so for Inflammatory Bowel Disease (IBD), where many molecular pathways are qualitatively well described but this information cannot be used in traditional quantitative mathematical models employed in drug development. We propose the elaboration and validation of a logic network for IBD able to capture the information available in the literature that will facilitate the identification/validation of therapeutic targets. Results In this article, we propose a logic model for Inflammatory Bowel Disease (IBD) which consists of 43 nodes and 298 qualitative interactions. The model presented is able to describe the pathogenic mechanisms of the disorder and qualitatively describes the characteristic chronic inflammation. A perturbation analysis performed on the IBD network indicates that the model is robust. Also, as described in clinical trials, a simulation of anti-TNF alpha, anti-IL2 and Granulocyte and Monocyte Apheresis showed a decrease in the Metalloproteinases node (MMPs), which means a decrease in tissue damage. In contrast, as clinical trials have demonstrated, a simulation of anti-IL17 and anti-IFN gamma or IL10 overexpression therapy did not show any major change in MMPs expression, as corresponds to a failed therapy. The model proved to be a promising in silico tool for the evaluation of potential therapeutic targets, the identification of new IBD biomarkers, the integration of IBD polymorphisms to anticipate responders and non-responders and can be reduced and transformed in quantitative model/s.
  • Autores: Oaknin, A.; Guarch, R.; Barretina, P.; et al.
    Revista: CLINICAL AND TRANSLATIONAL ONCOLOGY
    ISSN 1699-048X Vol.20 N° 3 2018 págs. 424
    Resumen
    Because of advances in the understanding of histological and molecular characteristics in ovarian cancer, it is now possible to recognize the existence of five subtypes, which in turn has allowed a more refined therapeutic approach and better design of clinical trials. Each of these five subtypes has specific histological features and a particular biomarker expression, as well as mutations in different genes, some of which have prognostic and predictive value. CA125 and HE4 are examples of ovarian cancer biomarkers used in the diagnosis and follow-up of these malignancies. Currently, somatic or germinal mutations on BRCA1 and BRCA2 genes are the most important biomarkers in epithelial ovarian cancer having prognostic and predictive value. This article will review the histological and molecular characteristics of the five subtypes of ovarian cancer, describing the most important biomarkers and mutations that can guide in diagnosis, screening and tailored treatment strategy.
  • Autores: Farago-Magrini, S. ; Auba Guedea, Cristina; Camargo, C.; et al.
    Revista: AESTHETIC PLASTIC SURGERY
    ISSN 0364-216X Vol.42 N° 3 2018 págs. 702 - 707
    Resumen
    Background Breast reconstruction after mastectomy is a part of breast cancer treatment. There is a lack of data regarding the impact of reconstruction over psychological traits and quality of life. The aim of this study is to evaluate personality changes in patients who underwent recon-tructive surgery. Methods Thirty-seven women underwent breast reconstruction. These women took the Crown-Crisp Experiential Index before and after the different procedures. The questionnaire analyzes: (a) the satisfaction level with personal relationships before and after surgery, and the level of satisfaction with surgical results and (b) personality index. Comparisons of preoperative and postoperative personality traits were made by using the Crown-Crisp test and analyzed by Chi-square test. Correlations between preoperative concerns and CCEI traits and correlations between physical aspects and Crown-Crisp, both preoperatively and postoperatively, were performed using the Spearman test. Results We found statistically significant differences in the following traits: anxiety anticipating possible technique failures (p = 0.01); cancer recurrence (p = 0.04); dissatisfaction with results (p = 0.02); phobic anxiety for possible technique failure (p = 0.03); obsessionality with possible technique failure (p = 0.01); preoccupations around cancer recurrence (p = 0.01) and dissatisfaction with results (p = 0.03); somatic of technique failure (p = 0.05); and finally, depression and hysteria traits in response to surgical procedures except anesthesia. Conclusion This prospective study suggests that personality traits define perceptions of body image, which has an influence over quality of life and satisfaction with results.
  • Autores: Irurzun Arana, Itziar; Janda Galán, Álvaro; Ardanza-Trevijano Moras, Sergio; et al.
    Revista: PLOS COMPUTATIONAL BIOLOGY
    ISSN 1553-7358 Vol.14 N° 4 2018 págs. e1006087
    Resumen
    Numerous problems encountered in computational biology can be formulated as optimization problems. In this context, optimization of drug release characteristics or dosing schedules for anticancer agents has become a prominent area not only for the development of new drugs, but also for established drugs. However, in complex systems, optimization of drug exposure is not a trivial task and cannot be efficiently addressed through trial-error simulation exercises. Finding a solution to those problems is a challenging task which requires more advanced strategies like optimal control theory. In this work, we perform an optimal control analysis on a previously developed computational model for the testosterone effects of triptorelin in prostate cancer patients with the goal of finding optimal drug-release characteristics. We demonstrate how numerical control optimization of non-linear models can be used to find better therapeutic approaches in order to improve the final outcome of the patients.
  • Autores: Fernandez, L.; Arean, C.; Panizo, A.; et al.
    Revista: NEPHROLOGY DIALYSIS TRANSPLANTATION
    ISSN 0931-0509 Vol.33 N° Supl.1 2018 págs. 399 - 400
  • Autores: Pérez Solans, Belén; Chiesa, R. ; Fernández de Trocóniz Fernández, José Ignacio; et al.
    Revista: JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS
    ISSN 1567-567X Vol.45 N° Supl. 1 2018 págs. S60
  • Autores: Ledermann, J. A.; Shapira-Frommer, R. ; Santin, A.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.29 N° Suppl.8 2018 págs. 728 - 728
  • Autores: Ballesteros, J.; Martinez-Cuadron, D. ; Lopez, J. M.; et al.
    Revista: BLOOD
    ISSN 0006-4971 Vol.132 N° Supl. 1 2018
  • Autores: Moore, K. N.; Colombo, N.; Scambia, G. ; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.29 N° Suppl. 9 2018 págs. 727 - 727
  • Autores: Lozano Escario, María Dolores; Abengozar Muela, Marta; Labiano Miravalles, Tania; et al.
    Revista: MODERN PATHOLOGY
    ISSN 0893-3952 Vol.31 N° Supl. 2 2018 págs. 158
  • Autores: Rischin, D.; Gil-Martin, M.; González Martín, Antonio; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.29 N° Suppl. 10 2018
  • Autores: Rubio, M. J.; Lecumberri, M. J.; Varela, S. ; et al.
    Revista: INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER
    ISSN 1048-891X Vol.28 N° Suppl.2 2018 págs. 1173 - 1173
  • Autores: Idoate Gastearena, Miguel Ángel; Mejías Sosa, Luis Daniel; Abengozar Muela, Marta; et al.
    Revista: MODERN PATHOLOGY
    ISSN 0893-3952 Vol.31 N° Supl. 2 2018 págs. 74 - 74
  • Autores: De Andrea, Carlos Eduardo; Abengozar Muela, Marta; Mejías Sosa, Luis Daniel; et al.
    Revista: MODERN PATHOLOGY
    ISSN 0893-3952 Vol.31 N° Supl. 2 2018 págs. 158 - 158
  • Autores: Sánchez Bayona, Rodrigo; Chang-Azancot, L.; Álvarez de Mon González, Miguel; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.29 N° Supl. 8 2018 págs. 711
    Resumen
    Background: In the era of big data, the presence of cancer in social media is undeniable. Twitter is one of the biggest networks worldwide, therefore, it establishes an enormous real-world data field of interest when studying health issues. As far as we know, there are no exploratory studies about the content or the authorship of tweets related to breast cancer. Methods: Tweets (original and re-tweets) with the hashtag #BreastCancer posted on Twitter during a 7-day period were collected. For the analysis, tweets were categorised based on their content (medical vs non medical and if medical, appropriate vs inappropriate), user information (private account vs institution or public account), the aim of the tweet (patients¿ experience, relatives¿ experience, advertising, scientific content, fund-raising and patient advocacy) and also on the extent to which they indicated a stigmatising attitude towards cancer. Tweets were further grouped into subthemes: diagnosis, treatment, prognosis and prevention (life-style and other risk factors). Results: A total of 6341 tweets were collected (3703 original and 2638 re-tweets). When analysing original tweets, only 31% had medical content and in these, 90% were considered to have appropriate content. A stigmatising attitude towards cancer was identified in 14.8% of the tweets classified as non-medical content. 60% of the tweets came from private accounts and 40% from institutions or public accounts. Most of the tweets came from patients¿ experiences (30.7%), followed by patient advocacy (25.3%). When considering subthemes, the most common topic was cancer prevention (44.5%). Description of tweets (%) containing #BreastCancer in a 7-day period.
  • Autores: Gonzalez-Dominguez, A.; Moya, C.; Simon, S.; et al.
    Revista: VALUE IN HEALTH
    ISSN 1098-3015 Vol.21 N° Suppl. 3 2018 págs. S47 - S47
  • Autores: González Martín, Antonio; Mirza, M. R.; Vergote, I.; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.29 N° Supl. 8 2018
  • Autores: Irurzun Arana, Itziar; Janda Galán, Álvaro; Ardanza-Trevijano Moras, Sergio; et al.
    Revista: JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS
    ISSN 1567-567X Vol.45 2018 págs. S47 - S48
  • Autores: Dickler, M. N.; Villanueva, R. ; Fidalgo, J. A. P. ; et al.
    Revista: CANCER RESEARCH
    ISSN 0008-5472 Vol.78 N° 4 Supl. 2018 págs. 1
  • Autores: Irurzun Arana, Itziar; McDonald, T. O.; Fernández de Trocóniz Fernández, José Ignacio; et al.
    Revista: JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS
    ISSN 1567-567X Vol.45 2018 págs. S47 - S47
  • Autores: Owonikoko, T. K.; Papadopoulos, K. P.; Gil-Martin, M. ; et al.
    Revista: ANNALS OF ONCOLOGY
    ISSN 0923-7534 Vol.29 N° Suppl.8 2018

Proyectos desde 2018

  • Título: Aplicaciones del estudio multi-ómico de la microbiota al desarrollo de soluciones biotecnológicas innovadoras en el área de la salud (microBiomics)
    Código de expediente: 0011-1411-2021-000106
    Investigador principal: MARIA TERESA HERRAIZ BAYOD.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2021 GN PROYECTOS ESTRATEGICOS DE I+D 2021-2024
    Fecha de inicio: 15-04-2021
    Fecha fin: 30-11-2023
    Importe concedido: 366.577,17 €
    Fondos FEDER: NO
  • Título: Utilización de datos genómicos para generar una vacuna contra el cáncer (BLANCA: Breast Long non coding ANti-Cancer Antigens)
    Código de expediente: 0011-1411-2021-000103
    Investigador principal: MARTA SANTISTEBAN ESLAVA.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2021 GN PROYECTOS ESTRATEGICOS DE I+D 2021-2024
    Fecha de inicio: 15-04-2021
    Fecha fin: 31-12-2023
    Importe concedido: 85.358,50 €
    Fondos FEDER: NO
  • Título: Registro prospectivo de hipofraccionamiento con fotonterapia y protonterapia con sobreimpresion en zona GaPSMA positiva en el rescate tras prostatectomia
    Código de expediente: pi20/01598
    Investigador principal: FELIX MAURICIO CAMBEIRO VAZQUEZ.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2020 AES Proyectos de investigación
    Fecha de inicio: 01-01-2021
    Fecha fin: 31-12-2023
    Importe concedido: 68.970,00 €
    Fondos FEDER: SI
  • Título: Estudio de marcadores predictivos de respuesta y resistencia a la combinación de inmnunoterapia (anti-PD-L1) e inhibidores de PARP en cáncer de ovario recurrente.
    Código de expediente: PI20/00959
    Investigador principal: ANTONIO JOSE GONZALEZ MARTIN.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2020 AES Proyectos de investigación
    Fecha de inicio: 01-01-2021
    Fecha fin: 31-12-2023
    Importe concedido: 220.220,00 €
    Fondos FEDER: SI
  • Título: Nueva Plataforma para el tratamiento personalizado del cáncer de colon ONCO-CEBRA-GEN
    Código de expediente: 0011-1365-2020-000282
    Investigador principal: JOSE IGNACIO FERNANDEZ DE TROCONIZ FERNANDEZ.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2020 GN I+D Transferencia del conocimiento (empresas)
    Fecha de inicio: 01-04-2020
    Fecha fin: 30-07-2022
    Importe concedido: 145.126,12 €
    Fondos FEDER: SI
  • Título: Evaluación de YES1 como nueva diana terapéutica y biomarcador de respuesta a dasanitib en cáncer de pulmón.
    Código de expediente: PI19/00230
    Investigador principal: ALFONSO CALVO GONZALEZ.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2019 AES Proyectos de investigación
    Fecha de inicio: 01-01-2020
    Fecha fin: 31-12-2022
    Importe concedido: 127.050,00 €
    Fondos FEDER: SI
  • Título: Modelando inmnunoterapia del cáncer de riñón en ratones humanizados
    Código de expediente: PI19/00668
    Investigador principal: MIGUEL FERNANDEZ DE SANMAMED GUTIERREZ.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2019 AES Proyectos de investigación
    Fecha de inicio: 01-01-2020
    Fecha fin: 31-12-2022
    Importe concedido: 111.320,00 €
    Fondos FEDER: SI
  • Título: Disección de los mecanismos de las recidivas locales post-resección y post braquiterapia.
    Código de expediente: PI19/01884
    Investigador principal: RAFAEL MARTINEZ MONGE.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2019 AES Proyectos de investigación
    Fecha de inicio: 01-01-2020
    Fecha fin: 31-12-2022
    Importe concedido: 93.170,00 €
    Fondos FEDER: SI
  • Título: Creación de una plataforma para el desarrollo de vectores de terapia génica con tropismo renal (DRONES GÉNICOS)
    Código de expediente: 0011-1411-2019-000048
    Investigador principal: NURIA GARCIA FERNANDEZ.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2019 GN PROYECTOS ESTRATEGICOS DE I+D 2019-2021
    Fecha de inicio: 01-04-2019
    Fecha fin: 30-11-2021
    Importe concedido: 64.625,00 €
    Fondos FEDER: NO
  • Título: Optimización de la radiembolización hepática mediante un modelo de simulación computacional
    Código de expediente: PI18/00692
    Investigador principal: JOSE IGNACIO BILBAO JAUREGUIZAR, MARIA MACARENA RODRIGUEZ FRAILE.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: AES2018 PI
    Fecha de inicio: 01-01-2019
    Fecha fin: 31-12-2022
    Importe concedido: 59.290,00 €
    Fondos FEDER: SI
  • Título: Estilos de vida y cáncer de mama - Ensayo LifeBreast
    Código de expediente: PI18/00631
    Investigador principal: ESTEFANIA AINHOA TOLEDO ATUCHA.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: AES2018 PI
    Fecha de inicio: 01-01-2019
    Fecha fin: 30-06-2023
    Importe concedido: 140.360,00 €
    Fondos FEDER: SI
  • Título: Descifrando el papel clínico-funcional del entramado transcripcional de FOSL1-FRA1 en el colangiocarcinoma hepático (DesciFRA)
    Código de expediente: 58/2018
    Investigador principal: SILVESTRE VICENT CAMBRA.
    Financiador: GOBIERNO DE NAVARRA. DEPARTAMENTO DE SALUD
    Convocatoria: 2018 PROYECTOS DE I+D EN SALUD
    Fecha de inicio: 31-12-2018
    Fecha fin: 30-12-2021
    Importe concedido: 79.563,90 €
    Fondos FEDER: SI
  • Título: Estudio de la fibrosis intersticial miocárdica en la toxicidad cardíaca asociada al tratamiento del cáncer de mama. Implicaciones diagnósticas y terapéuticas
    Código de expediente: PI17/01999
    Investigador principal: SUSANA RAVASSA ALBENIZ, DOMINGO FRANCISCO JAVIER DIEZ MARTINEZ.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2017 - PROYECTOS DE I+D EN SALUD
    Fecha de inicio: 01-01-2018
    Fecha fin: 30-06-2022
    Importe concedido: 111.320,00 €
    Fondos FEDER: SI
  • Título: Investigación hacia europa: plan de acción para la preparación y presentación de un proyecto de I+D+I en horizonte 2020.
    Código de expediente: EUIN2017-88682
    Investigador principal: JOSE IGNACIO FERNANDEZ DE TROCONIZ FERNANDEZ.
    Financiador: MINISTERIO DE CIENCIA E INNOVACIÓN
    Convocatoria: 2017 MINECO EUIN
    Fecha de inicio: 01-01-2018
    Fecha fin: 31-01-2020
    Importe concedido: 17.145,00 €
    Fondos FEDER: NO
  • Título: Efecto del tratamiento antibiótico en la progresión de la contractura capsular de un implante de mama en un modelo murino.
    Código de expediente: PI17/00974
    Investigador principal: JOSE LUIS DEL POZO LEON, BERNARDO CARLOS HONTANILLA CALATAYUD.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: AES2017 PROYECTOS DE INVESTIGACIÓN
    Fecha de inicio: 01-01-2018
    Fecha fin: 27-02-2022
    Importe concedido: 111.320,00 €
    Fondos FEDER: SI
  • Título: Papel de la resonancia magnética y de los marcadores séricos CA-125 y HE-4 en la evaluación de las masas anexiales "indeterminadas" según ecografía convencional
    Código de expediente: PI17/01326
    Investigador principal: JUAN LUIS ALCAZAR ZAMBRANO.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: AES2017 PROYECTOS DE INVESTIGACIÓN
    Fecha de inicio: 01-01-2018
    Fecha fin: 31-12-2021
    Importe concedido: 62.920,00 €
    Fondos FEDER: SI
  • Título: Normalización de la vasculatura tumoral como herramienta para mejorar la eficacia de la inmunoterapia del cáncer
    Código de expediente: PI17/00816
    Investigador principal: ANA ROUZAUT SUBIRA.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: AES2017 PROYECTOS DE INVESTIGACIÓN
    Fecha de inicio: 01-01-2018
    Fecha fin: 30-06-2021
    Importe concedido: 87.120,00 €
    Fondos FEDER: SI
  • Título: Humanised-mouse models to implement immunotherapy of cancer
    Código de expediente: CP17/00196
    Investigador principal: MIGUEL FERNANDEZ DE SANMAMED GUTIERREZ.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: AES 2017 MIGUEL SERVET TIPO I
    Fecha de inicio: 01-01-2018
    Fecha fin: 30-06-2022
    Importe concedido: 100.000,00 €
    Fondos FEDER: SI
  • Título: Tecnología de secuenciación de nueva generación (NGS) para optimizar la eficacia del diagnóstico y tratamiento en pacientes con tumores de alta mortalidad (DIANA: Diagnostico biomédico e Innovación Abierta en Navarra)
    Código de expediente: 0011-1411-2017-000030
    Investigador principal: FELIPE LUIS PROSPER CARDOSO.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2017 GN ESTRATEGICOS
    Fecha de inicio: 01-04-2017
    Fecha fin: 30-11-2019
    Importe concedido: 37.315,72 €
    Fondos FEDER: NO
  • Título: Estudio de la respuesta inmune inducida por vacunas de células dendríticas autólogas en pacientes con cáncer de mama para el desarrollo de nuevas estrategias terapéuticas.
    Código de expediente: PI16/01245
    Investigador principal: MARTA SANTISTEBAN ESLAVA, SUSANA INMACULADA INOGES SANCHO.
    Financiador: INSTITUTO DE SALUD CARLOS III
    Convocatoria: 2016 AES PROYECTOS DE INVESTIGACIÓN
    Fecha de inicio: 01-01-2017
    Fecha fin: 31-12-2019
    Importe concedido: 96.800,00 €
    Fondos FEDER: SI
  • Título: Determinantes nutricionales del Cáncer de mama
    Código de expediente: 41/2016
    Investigador principal: ESTEFANIA AINHOA TOLEDO ATUCHA.
    Financiador: GOBIERNO DE NAVARRA
    Convocatoria: 2016 GN SALUD
    Fecha de inicio: 08-12-2016
    Fecha fin: 08-12-2020
    Importe concedido: 47.004,31 €
    Fondos FEDER: NO
  • Título: Improving the care of patients suffering from acute or chronic pain
    Código de expediente: 777500
    Investigador principal: JOSE IGNACIO FERNANDEZ DE TROCONIZ FERNANDEZ
    Financiador: COMISIÓN EUROPEA
    Convocatoria: H2020-JTI-IMI2-2015-06
    Fecha de inicio: 01-04-2018
    Fecha fin: 31-03-2023
    Importe concedido: 123.500,00 €
    Fondos FEDER: NO