Revistas
Revista:
BIOMEDICINES
ISSN:
2227-9059
Año:
2023
Vol.:
11
N°:
2
Págs.:
238
Background: The addition of dendritic cell vaccines (DCV) to NAC could induce immune responses in those patients with residual disease (RD) by transforming the tumor microenvironment. Methods: Core diagnostic biopsies and surgical specimens from 80 patients (38 in the vaccinated group plus NAC (VG) and 42 in the control group (CG, treated only with NAC) were selected. We quantify TILs (CD8, CD4 and CD45RO) using immunohistochemistry and the automated cellular imaging system (ACIS III) in paired samples. Results: A CD8 rise in TNBC samples was observed after NAC plus DCV, changing from 4.48% in the biopsy to 6.70% in the surgical specimen, not reaching statistically significant differences (p = 0.11). This enrichment was seen in up to 67% of TNBC patients in the experimental arm as compared with the CG (20%). An association between CD8 TILs before NAC (4% cut-off point) and pathological complete response in the VG was found in the univariate and multivariate analysis (OR = 1.41, IC95% 1.05-1.90; p = 0.02, and OR = 2.0, IC95% 1.05-3.9; p = 0.03, respectively). Conclusion: Our findings suggest that patients with TNBC could benefit from the stimulation of the antitumor immune system by using DCV together with NAC.
Revista:
SCIENTIFIC REPORTS
ISSN:
2045-2322
Año:
2022
Vol.:
12
N°:
1
Págs.:
1777
Lobar selective internal radiation therapy (SIRT) is widely used to treat liver tumors inducing atrophy of the treated lobe and contralateral hypertrophy. The lack of animal model has precluded further investigations to improve this treatment. We developed an animal model of liver damage and atrophy-hypertrophy complex after SIRT. Three groups of 5-8 rabbits received transportal SIRT with Yttrium 90 resin microspheres of the cranial lobes with different activities (0.3, 0.6 and 1.2 GBq), corresponding to predicted absorbed radiation dose of 200, 400 and 800 Gy, respectively. Another group received non-loaded microspheres (sham group). Cranial and caudal lobes volumes were assessed using CT volumetry before, 15 and 30 days after SIRT. Liver biochemistry, histopathology and gene expression were evaluated. Four untreated rabbits were used as controls for gene expression studies. All animals receiving 1.2 GBq were euthanized due to clinical deterioration. Cranial SIRT with 0.6 GBq induced caudal lobe hypertrophy after 15 days (median increase 34% -ns-) but produced significant toxicity. Cranial SIRT with 0.3 GBq induced caudal lobe hypertrophy after 30 days (median increase 82%, p = 0.04). No volumetric changes were detected in sham group. Transient increase in serum transaminases was detected in all treated groups returning to normal values at 15 days. There was dose-dependent liver dysfunction with bilirubin elevation and albumin decrease. Histologically, 1.2 GBq group developed permanent severe liver damage with massive necrosis, 0.6 and 0.3 GBq groups developed moderate damage with inflammation and portal fibrosis at 15 days, partially recovering at 30 days. There was no difference in the expression of hepatocyte function and differentiation genes between 0.3 GBq and control groups. Cranial SIRT with 0.3 GBq of Y-90 resin microspheres in rabbits is a reliable animal model to analyse the atrophy-hypertrophy complex and liver damage without toxicity.
Revista:
BIOMEDICINES
ISSN:
2227-9059
Año:
2022
Vol.:
10
N°:
7
Págs.:
1753
Objectives: Immunostimulatory therapies using immune checkpoint blockers show clinical activity in a subset of glioblastoma (GBM) patients. Several inhibitory mechanisms play a relevant role in the immune response to GBM. With the objective of analyzing the tumor immune microenvironment and its clinical significance, we quantified several relevant immune biomarkers. Design: We studied 76 primary (non-recurrent) GBMs with sufficient clinical follow-up, including a subgroup of patients treated with a dendritic cell vaccine. The IDH-mutation, EGFR-amplification, and MGMT methylation statuses were determined. Several relevant immune biomarkers, including CD163, CD8, PD1, and PDL1, were quantified in representative selected areas by digital image analysis and semiquantitative evaluation. The percentage of each immune expression was calculated with respect to the total number of tumor cells. Results: All GBMs were wild-type IDH, with a subgroup of classical GBMs according to the EGFR amplification (44%). Morphologically, CD163 immunostained microglia and intratumor clusters of macrophages were observed. A significant direct correlation was found between the expression of CD8 and the mechanisms of lymphocyte immunosuppression, in such a way that higher values of CD8 were directly associated with higher values of CD163 (p < 0.001), PDL1 (0.026), and PD1 (0.007). In a multivariate analysis, high expressions of CD8+ (HR = 2.05, 95%CI (1.02-4.13), p = 0.034) and CD163+ cells (HR 2.50, 95%CI (1.29-4.85), p = 0.007), were associated with shorter survival durations. The expression of immune biomarkers was higher in the non-classical (non-EGFR amplified tumors) GBMs. Other relevant prognostic factors were age, receipt of the dendritic cell vaccine, and MGMT methylation status. Conclusions: In accordance with the inverse correlation between CD8 and survival and the direct correlation between effector cells and CD163 macrophages and immune-checkpoint expression, we postulate that CD8 infiltration could be placed in a state of anergy or lymphocytic inefficient activity. Furthermore, the significant inverse correlation between CD163 tissue concentration and survival explains the relevance of this type of immune cell when creating a strong immunosuppressive environment. This information may potentially be used to support the selection of patients for immunotherapy.
Revista:
DIAGNOSTICS
ISSN:
2075-4418
Año:
2022
Vol.:
12
N°:
2
Págs.:
450
Osteosarcoma is a primary malignant bone tumor usually arising at the metaphysis of long bones, particularly around the knee. The physis has been regarded as a barrier capable of blocking tumor extension, thus allowing it to preserve their epiphysis and therefore improve functional results. With the objective of clarifying how effective the physis is as a barrier to tumor spread, a large series of skeletally immature patients with osteosarcoma were reviewed. From 452 metaphyseal osteosarcomas a selection of 282 cases in which the tumor was close or crossing the physis were carried out. This sub-sample was split into two groups according to the surgical treatment (epiphyseal preservation or not). The specimens obtained by resection were studied, and the physeal and metaphyseal areas were studied by multiple sections. Immunostaining against VEGF of physis was obtained in selected cases. In about half of the patients affected by metaphyseal malignant bone tumors, the growth plate and epiphysis were not compromised by the tumor. Three sequential invasive growth patterns of an osteosarcoma in its relationship with the physis could be distinguished. An intense angiogenesis and osteoclastic reaction could be observed in the growth plate in the free zone between the tumor and the physis. The local recurrence incidence was lower in the epiphyseal preservation treated patients than it was in the conventional treatment (8% vs. 12%). Most local recurrences appeared in the first 2 years. The overall survival of patients treated with epiphyseal preservation was better than that of the patients treated without preserving the epiphysis (73% vs. 59%; p = 0.03) at a mean follow-up of 18 years. We have described an angiogenic and osteoclastic reaction in the base of the growth plate in the proximity of the advance front of the tumor, which could facilitate the osteosarcoma invasion. It is also shown that the preoperative imaging method for examination is a valid approach for the decision to carry out epiphyseal preservation. Finally, we concluded that epiphyseal preservation combined with protective chemotherapy is an excellent clinical approach for selected patients with metaphyseal osteosarcoma.
Revista:
JOURNAL OF ULTRASOUND
ISSN:
1971-3495
Año:
2022
Vol.:
25
N°:
2
Págs.:
289 - 295
Purpose Diagnosis of granuloma annulare (GA) is based on the clinical and histopathological findings. However, only sporadic case reports of subcutaneous GA sonography have been published to date. The objective of this study was to evaluate the ultrasonographic patterns of the different clinical variants of GA: localized, generalized, subcutaneous, and perforating. Methods In this retrospective observational study, we analyzed and correlated the clinical, histopathological, and sonographic features of 15 patients diagnosed with GA. Results We included 8 women and 7 men with a mean age of 48.4 years (8-77 years). We found three different sonographic patterns depending on the clinical variant of GA: poorly defined hypoechoic band including the dermis (dermal pattern), irregularly shaped hypoechoic hypodermal lumps (hypodermal pattern), and ill-defined hypoechoic dermal and subcutaneous lesions (mixed pattern). Five cases showed increased blood flow signal on Doppler interrogation. Conclusion Although our findings are broadly consistent with the previous reports of subcutaneous GA, the sonographic features in localized, generalized, and perforating GA have not been previously reported.
Revista:
REVISTA ESPAÑOLA DE PATOLOGIA
ISSN:
1988-561X
Año:
2022
Vol.:
55
N°:
3
Págs.:
192 - 196
A 54-year-old female patient presented with a left nasal obstruction. On physical examination a pink delimited mass in the left nostril was observed. A cranial computed tomography scan revealed an expansive mass in the upper anterior third of the left nasal fossa, partially obstructing it. Endoscopic resection of the mass was performed. Histopathology revealed an atypical mesenchymal proliferation formed by cells disposed in disorganized and interconnected long bundles. Tumor cells had abundant eosinophilic cytoplasm and an oval, vesicular and hyperchromatic nucleus. Frequent mitotic figures were observed, many of them atypical. Necrosis was not observed. Immunohistochemistry showed tumor cells to be positive for calponin, muscle specific actin, caldesmon and smooth muscle specific myosin. Ki-67 index proliferation was 30%. A diagnosis of leiomyosarcoma of the nasal fossa was established.
Revista:
NEW ENGLAND JOURNAL OF MEDICINE
ISSN:
0028-4793
Año:
2022
Vol.:
386
N°:
26
Págs.:
2471 - 2481
Background: Pediatric patients with diffuse intrinsic pontine glioma (DIPG) have a poor prognosis, with a median survival of less than 1 year. Oncolytic viral therapy has been evaluated in patients with pediatric gliomas elsewhere in the brain, but data regarding oncolytic viral therapy in patients with DIPG are lacking.
Methods: We conducted a single-center, dose-escalation study of DNX-2401, an oncolytic adenovirus that selectively replicates in tumor cells, in patients with newly diagnosed DIPG. The patients received a single virus infusion through a catheter placed in the cerebellar peduncle, followed by radiotherapy. The primary objective was to assess the safety and adverse-event profile of DNX-2401. The secondary objectives were to evaluate the effect of DNX-2401 on overall survival and quality of life, to determine the percentage of patients who have an objective response, and to collect tumor-biopsy and peripheral-blood samples for correlative studies of the molecular features of DIPG and antitumor immune responses.
Results: A total of 12 patients, 3 to 18 years of age, with newly diagnosed DIPG received 1×1010 (the first 4 patients) or 5×1010 (the subsequent 8 patients) viral particles of DNX-2401, and 11 received subsequent radiotherapy. Adverse events among the patients included headache, nausea, vomiting, and fatigue. Hemiparesis and tetraparesis developed in 1 patient each. Over a median follow-up of 17.8 months (range, 5.9 to 33.5), a reduction in tumor size, as assessed on magnetic resonance imaging, was reported in 9 patients, a partial response in 3 patients, and stable disease in 8 patients. The median survival was 17.8 months. Two patients were alive at the time of preparation of the current report, 1 of whom was free of tumor progression at 38 months. Examination of a tumor sample obtained during autopsy from 1 patient and peripheral-blood studies revealed alteration of the tumor microenvironment and T-cell repertoire.
Conclusions: Intratumoral infusion of oncolytic virus DNX-2401 followed by radiotherapy in pediatric patients with DIPG resulted in changes in T-cell activity and a reduction in or stabilization of tumor size in some patients but was associated with adverse events. (Funded by the European Research Council under the European Union's Horizon 2020 Research and Innovation Program and others; EudraCT number, 2016-001577-33; ClinicalTrials.gov number, NCT03178032.).
Revista:
INTERNATIONAL JOURNAL OF ONCOLOGY
ISSN:
1019-6439
Año:
2021
Vol.:
58
N°:
3
Págs.:
312 - 330
Glioblastoma is the most malignant brain tumor and presents high resistance to chemotherapy and radiotherapy. Surgery, radiotherapy and chemotherapy with temozolomide are the only treatments against this tumor. New targeted therapies, including epigenetic modulators such as 3-deazane-planocin A (DZ-Nep; an EZH2 inhibitor) and panobinostat (a histone deacetylase inhibitor) are being tested in vitro, together with temozolomide. The present study combined APR-246 with DZ-Nep, panobinostat and teomozolomide in order to explore the possibility of restoring p53 function in mutated cases of glioblastoma. Following the Chou-Talalay method it was demonstrated that APR-246 acts in an additive manner together with the other compounds, reducing clonogenicity and inducing apoptosis in glioblastoma cells independently of p53 status.
Revista:
THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY
ISSN:
1758-8340
Año:
2021
Vol.:
13
Págs.:
1 - 14
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.
Revista:
GLIOMA
ISSN:
2589-6113
Año:
2021
Vol.:
4
N°:
2
Págs.:
27 - 33
Background and Aim: Glioblastoma is the most lethal brain tumor. No effective curative treatment is available yet, and it is treated by surgery,
temozolomide (TMZ), and radiotherapy, with an average overall survival of around 15 months. Inhibitors of histone deacetylases (HDACs)
are being explored against a variety of tumors, including glioblastoma. Specific inhibitors of HDAC6, such as tubastatin A (Tub A), may
potentially be beneficial as HDAC6 has been demonstrated to be the most expressed HDACs in glioblastoma. Our aim was to test whether
Tub A could reverse the malignant phenotype of U87MG cells via the inhibition of HDAC6. Materials and Methods: U87MG cells were
treated with cyclopamine (Cyp), TMZ, and Tub A. Two double treatments were performed as well (Cyp + Tub A and TMZ + Tub A). Colony
formation, wound healing, Caspase¿Glo 3/7, quantitative reverse transcription¿polymerase chain reaction, luciferase assay, and Western blot
assays were conducted to determine clonogenic and migration capacity, apoptosis, activation of the Sonic Hedgehog pathway, acetylation of
¿¿tubulin and epithelial-to-mesenchymal transition, and autophagic flux of U87MG glioblastoma cells, respectively. Results: Tub A treatment
caused a reversal of the U87MG malignant phenotype by reducing its clonogenic and migratory cellular potential, and inducing apoptosis.
Revista:
JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY
ISSN:
0926-9959
Año:
2021
Vol.:
35
N°:
4
Págs.:
988 - 994
Background Confusion exists regarding interstitial granulomatous dermatitis (IGD) and palisaded neutrophilic and granulomatous dermatitis (PNGD). Objective To determine whether IGD and PNGD are two different entities, or whether they must be considered as two subtypes of the same reactive pattern, and thus whether the unification of the nomenclature is necessary. Methods Observational retrospective multicentre study of patients with IGD and PNGD evaluated between 1999 and 2019 and review of their clinical and histological features. Results We identified 52 patients (38 women and 14 men). Clinical and histological findings of IGD were observed in 88.4% of cases. The most common cutaneous lesions were plaques/macules (IGD) or annular plaques and papules/nodules (PNGD), located mostly on the limbs and trunk. The rope sign was developed in two patients with IGD that associated autoimmune disorders. Similar associated comorbidities (75%) were found in both entities, mainly autoimmune diseases (53.8%). In IGD, the infiltrate was predominantly lympho-histiocytic. Neutrophilic infiltrates, karyorrhexis and skin lesions with limited clinical course were mainly associated with PNGD biopsies. In biopsies with a limited recurrent course, a predominant lymphocytic inflammatory infiltrate was found. Collagen degeneration was present in 75.9% of cases. The floating sign was observed only in IGD type patients (63%). Overlapping histological findings were found in one fourth of cases, especia
Revista:
BIOLOGY
ISSN:
2079-7737
Año:
2021
Vol.:
10
N°:
6
Págs.:
467
Simple Summary Glioblastoma multiforme (GBM) is the most common as well as the most aggressive malignant brain tumor, with an overall survival of almost 15 months. Histone deacetylase 6 (HDAC6), an enzyme related to the deacetylation of alpha-tubulin, is overexpressed in GBM. The aim of our research was to study the effects of HDAC6 silencing in GBM cells. We first confirmed the overexpression of HDAC6 in GBM tissue (n = 40) against control brain (n = 10). Treatment with siHDAC6 diminished viability, clonogenic potential, and migration ability in GBM-derived cell lines. HDAC6 inhibition also reverted the mesenchymal phenotype, inhibited the Sonic Hedgehog pathway, restored primary cilium structure, and decreased autophagy. Thus, we confirm that HDAC6 is a good therapeutic target for GBM treatment. Glioblastoma multiforme, the most common type of malignant brain tumor as well as the most aggressive one, lacks an effective therapy. Glioblastoma presents overexpression of mesenchymal markers Snail, Slug, and N-Cadherin and of the autophagic marker p62. Glioblastoma cell lines also present increased autophagy, overexpression of mesenchymal markers, Shh pathway activation, and lack of primary cilia. In this study, we aimed to evaluate the role of HDAC6 in the pathogenesis of glioblastoma, as HDAC6 is the most overexpressed of all HDACs isoforms in this tumor.
Revista:
PEDIATRIC DERMATOLOGY
ISSN:
0736-8046
Año:
2020
Vol.:
37
Págs.:
750 - 751
Revista:
JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT
ISSN:
1610-0379
Año:
2020
Vol.:
18
N°:
10
Págs.:
1192 - 1196
Revista:
MODERN PATHOLOGY
ISSN:
0893-3952
Año:
2020
Vol.:
33
N°:
12
Págs.:
2507 - 2519
The precise nature of the local immune responses in lung tuberculosis (TB) granulomas requires a comprehensive understanding of their environmental complexities. At its most basic level, a granuloma is a compact, organized immune aggregate of macrophages surrounded by myeloid, B and T cells. We established two complementary multiplex immunolabeling panels to simultaneously evaluate the myeloid and lymphocytic contexture of 14 human lung TB granulomas in formalin-fixed paraffin-embedded tissue samples. We observed diverse CD3+ and CD8+ T-cell and CD20+ B lymphocyte compositions of the granuloma immune environment and a relatively homogeneous distribution of all myeloid cells. We also found significant associations between CD8+ T-cell densities and the myeloid marker CD11b and phagocytic cell marker CD68. In addition, significantly more CD68+ macrophages and CD8+ T cells were found inMycobacterium tuberculosis-infected granulomas, as detected by Ziehl-Neelsen staining. FOXP3 expression was predominately found in a small subset of CD4+ T cells in different granulomas. As the success or failure of each granuloma is determined by the immune response within that granuloma at a local and not a systemic level, we attempted to identify the presence of reactive T cells based on expression of the T-cell activation marker CD137 (4-1BB) and programmed cell death-1 (PD-1). Only a small fraction of the CD4+ and CD8+ T cells expressed PD-1. CD137 expression was found only in a very small fra
Revista:
JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT
ISSN:
1610-0379
Año:
2020
Vol.:
18
N°:
9
Págs.:
1028 - 1030
Revista:
JOURNAL OF CONTEMPORARY BRACHYTHERAPY
ISSN:
1689-832X
Año:
2020
Vol.:
12
N°:
6
Págs.:
521 - 532
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.
Revista:
NEUROMUSCULAR DISORDERS
ISSN:
0960-8966
Año:
2020
Vol.:
30
N°:
1
Págs.:
67 - 69
The rapidly growing field of cancer immunotherapy has led to the development of new treatments such as immune checkpoint inhibitors. These agents are monoclonal antibodies that enable tumor-reactive T cells to overcome regulatory mechanisms and produce effective antitumor responses. The use of immune checkpoint inhibitors is expected to progressively increase because they have shown promising therapeutic outcomes in multiple types of cancer and clinicians should be aware of their possible side-effects. We report a case of a man diagnosed with a non-microcytic lung carcinoma who started treatment with a combination of immune checkpoint inhibitors (Nivolumab and Ipilimumab). He subsequently developed binocular diplopia, fatigue, mild dyspnea and upper back pain resembling a myasthenia gravis presentation. Finally, a diagnosis of immune checkpoint inhibitor-related myositis and myocarditis was made. The detection of GFAP antibodies in CSF has unclear clinical and pathogenic significance and they may rather represent an epiphenomenon of the immune inflammation process.
Revista:
INTERNATIONAL JOURNAL OF ONCOLOGY
ISSN:
1019-6439
Año:
2020
Vol.:
56
N°:
1
Págs.:
283 - 300
Current treatment against glioblastoma consists of surgical resection followed by temozolomide, with or without combined radiotherapy. Glioblastoma frequently acquires resistance to chemotherapy and/or radiotherapy. Novel therapeutic approaches are thus required. The inhibition of enhancer of zeste homolog 2 (EZH2; a histone methylase) and histone deacetylases (HDACs) are possible epigenetic treatments. Temozolomide, 3-deazaneplanocin A (DZ-Nep; an EZH2 inhibitor) and panobinostat (an HDAC inhibitor) were tested in regular and temozolomide-resistant glioblastoma cells to confirm whether the compounds could behave in a synergistic, additive or antagonistic manner. A total of six commercial cell lines, two temozolomide-induced resistant cell lines and two primary cultures derived from glioblastoma samples were used. Cell lines were exposed to single treatments of the drugs in addition to all possible two-and three-drug combinations. Colony formation assays, synergistic assays and reverse transcription-quantitative PCR analysis of apoptosis-associated genes were performed. The highest synergistic combination was DZ-Nep + panobinostat. Triple treatment was also synergistic. Reduced clonogenicity and increased apoptosis were both induced. It was concluded that the therapeutic potential of the combination of these three drugs in glioblastoma was evident and should be further explored.
Revista:
THORAX
ISSN:
0040-6376
Año:
2019
Vol.:
74
N°:
4
Págs.:
371 - 379
Introduction Prognostic biomarkers have been very elusive in the lung squamous cell carcinoma (SCC) and none is currently being used in the clinical setting. We aimed to identify and validate the clinical utility of a protein-based prognostic signature to stratify patients with early lung SCC according to their risk of recurrence or death. Methods Patients were staged following the new International Association for the Study of Lung Cancer (IASLC) staging criteria (eighth edition, 2018). Three independent retrospective cohorts of 117, 96 and 105 patients with lung SCC were analysed to develop and validate a prognostic signature based on immunohistochemistry for five proteins. Results We identified a five protein-based signature whose prognostic index (PI) was an independent and significant predictor of disease-free survival (DFS) (p<0.001; HR=4.06, 95% CI 2.18 to 7.56) and overall survival (OS) (p=0.004; HR=2.38, 95% CI 1.32 to 4.31). The prognostic capability of PI was confirmed in an external multi-institutional cohort for DFS (p=0.042; HR=2.01, 95% CI 1.03 to 3.94) and for OS (p=0.031; HR=2.29, 95% CI 1.08 to 4.86). Moreover, PI added complementary information to the newly established IASLC TNM 8th edition staging system. A combined prognostic model including both molecular and anatomical (TNM) criteria improved the risk stratification in both cohorts (p<0.05). Conclusion We have identified and validated a clinically feasible protein-based prognostic model that complements the updated TNM system allowing more accurate risk stratification. This signature may be used as an advantageous tool to improve the clinical management of the patients, allowing the reduction of lung SCC mortality through a more accurate knowledge of the patient's potential outcome.
Revista:
PLOS ONE
ISSN:
1932-6203
Año:
2019
Vol.:
14
N°:
6
Págs.:
e0217881
Background Hypofractionated radiation therapy is a feasible and safe treatment option in elderly and frail patients with glioblastoma. The aim of this study was to evaluate the effectiveness of hypofractionated radiation therapy with concurrent temozolomide in terms of feasibility and disease control in primary glioblastoma patients with poor prognostic factors other than advanced age, such as post-surgical neurological complications, high tumor burden, unresectable or multifocal lesions, and potential low treatment compliance due to social factors or rapidly progressive disease. Material and methods GTV included the surgical cavity plus disease visible in T1WI-MRI, FLAIR-MRI and in the MET-uptake. The CTV was defined as the GTV plus 1.5-2 cm margin; the PTV was the CTV+0.3 cm margin. Forty, fourty-five, and fifty grays in 15 fractions were prescribed to 95% of PTV, CTV, and GTV, respectively. Treatment was delivered using IMRT or the VMAT technique. Simultaneously, 75 mg/m(2)/day of temozolomide were administered. Results Between January 2010 and November 2017, we treated a total of 17 patients. The median age at diagnosis was 68-years; median KPS was 50-70%. MGMT-methylation status was negative in 5 patients, and 8 patients were IDH-wildtype. Eight of 18 patients were younger than 65-years. Median tumor volume was 26.95cc; median PTV volume was 322cc. Four lesions were unresectable; 6 patients underwent complete surgical resection. Median residual volume was 1.14cc. Progression-free survival was 60% at 6 months, 33% at 1-year and 13% at 2-years (median OS = 7 months). No acute grade 3-5 toxicities were documented. Symptomatic grade 3 radiation necrosis was observed in one patient. Conclusions Patients with poor clinical factors other than advanced age can be selected for hypofractionated radiotherapy. The OS and PFS rates obtained in our series are similar to those in patients treated with standard fractionation, assuring good treatment adherence, low rates of toxicity and probable improved cost-effectiveness.
Revista:
NATURE MEDICINE
ISSN:
1078-8956
Año:
2019
Vol.:
25
N°:
3
Págs.:
470 - 476
Glioblastoma is the most common primary central nervous system malignancy and has a poor prognosis. Standard first-line treatment, which includes surgery followed by adjuvant radio-chemotherapy, produces only modest benefits to survival1,2. Here, to explore the feasibility, safety and immunobiological effects of PD-1 blockade in patients undergoing surgery for glioblastoma, we conducted a single-arm phase II clinical trial (NCT02550249) in which we tested a presurgical dose of nivolumab followed by postsurgical nivolumab until disease progression or unacceptable toxicity in 30 patients (27 salvage surgeries for recurrent cases and 3¿cases of primary surgery for newly diagnosed patients). Availability of tumor tissue pre- and post-nivolumab dosing and from additional patients who did not receive nivolumab allowed the evaluation of changes in the tumor immune microenvironment using multiple molecular and cellular analyses. Neoadjuvant nivolumab resulted in enhanced expression of chemokine transcripts, higher immune cell infiltration and augmented TCR clonal diversity among tumor-infiltrating T lymphocytes, supporting a local immunomodulatory effect of treatment. Although no obvious clinical benefit was substantiated following salvage surgery, two of the three patients treated with nivolumab before and after primary surgery remain alive 33 and 28 months later.
Revista:
PEDIATRIC DERMATOLOGY
ISSN:
0736-8046
Revista:
INTERNATIONAL JOURNAL OF ONCOLOGY
ISSN:
1019-6439
Año:
2019
Vol.:
54
N°:
5
Págs.:
1797 - 1808
Glioblastoma or grade IV astrocytoma is the most common and lethal form of glioma. Current glioblastoma treatment strategies use surgery followed by chemotherapy with temozolomide. Despite this, numerous glioblastoma cases develop resistance to temozolomide treatments, resulting in a poor prognosis for the patients. Novel approaches are being investigated, including the inhibition of histone deacetylase 6 (HDAC6), an enzyme that deacetylates a-tubulin, and whose overexpression in glioblastoma is associated with the loss of primary cilia. The aim of the present study was to treat glioblastoma cells with a selective HDAC6 inhibitor, tubastatin A, to determine if the malignant phenotype may be reverted. The results demonstrated a notable increase in acetylated a-tubulin levels in treated cells, which associated with downregulation of the sonic hedgehog pathway, and may hypothetically promote ciliogenesis in those cells. Treatment with tubastatin A also reduced glioblastoma clonogenicity and migration capacities, and accelerated temozolomide-induced apoptosis. Finally, HDAC6 inhibition decreased the expression of mesenchymal markers, contributing to reverse epithelial-mesenchymal transition in glioblastoma cells.
Revista:
HAEMATOLOGICA
ISSN:
0390-6078
Año:
2018
Vol.:
103
N°:
7
Págs.:
E318 - E321
Autores:
Sievers, P.; Stichel, D.; Hielscher, T.; et al.
Revista:
ACTA NEUROPATHOLOGICA
ISSN:
0001-6322
Año:
2018
Vol.:
136
N°:
6
Págs.:
975 - 978
Revista:
ONCOLOGY LETTERS
ISSN:
1792-1074
Año:
2018
Vol.:
16
N°:
3
Págs.:
4043 - 4048
Pazopanib is the first multitargeted tyrosine¿kinase inhibitor approved for the treatment of patients with advanced non¿adipocytic soft tissue sarcoma (STS). It has been demonstrated to improve progression¿free survival without impairing health¿associated quality of life. However, Pazopanib is associated with several adverse side effects associated with inhibition of the vascular endothelial growth factor receptor. These include hepatotoxicity, as manifested by abnormal liver function tests. To the best of our knowledge, the current study presents the first case of a patient with recurrent STS who developed biopsy proven Pazopanib¿induced chronic active hepatitis and whose previous computed tomography examination demonstrated multiple hypervascular liver lesions. These lesions were indistinguishable from metastases and to the best of our knowledge, have not been described previously. These lesions therefore appear to be a novel finding of Pazopanib¿induced chronic active hepatitis. It is crucial to be aware of this unusual finding within a clinical setting, to avoid overstaging and early discontinuation of effective treatment.
Revista:
JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT
ISSN:
1610-0379
Año:
2018
Vol.:
16
N°:
6
Págs.:
763 - 768
Revista:
ARCHIVES OF PATHOLOGY AND LABORATORY MEDICINE
ISSN:
0003-9985
Año:
2018
Vol.:
142
N°:
3
Págs.:
291 - 298
CONTEXT:
- The rapid advances in targeted therapies in non-small cell lung cancer (NSCLC) make the optimization and implementation of cytology specimens for molecular testing a priority. Up to 70% of patients with NSCLC are diagnosed at advanced stages and tissue biopsies often cannot be taken. Although cytology samples provide high-quality material for molecular testing, molecular cytopathology is not yet well known or widely used.
OBJECTIVE:
- To report the many advances in molecular cytopathology and the suitability and utility of cytology samples in molecular and genetic testing of NSCLC.
DATA SOURCES:
- Data sources comprised published peer-reviewed literature and personal experience of the authors.
CONCLUSIONS:
- Molecular testing can be performed on cytologic specimens, especially on direct smears. Rapid on-site evaluation by cytopathologists has improved the adequacy and the management of cytology samples for molecular testing. Mutational profiling of NSCLC using next-generation sequencing can be performed on cytology samples from very small amounts of DNA. Fluorescence in situ hybridization assays on cytology specimens, including stained direct smear, offer some distinct advantages over their histologic counterpart, and are used to detect ALK and ROS1 rearrangements in NSCLC. Cytology specimens allow assessment of the entire tumor cell nucleus, avoiding signal loss from truncation artifacts. The use of cytology samples for assessing programmed death ligand-1 protein expression is currently being developed. Protocols for bisulfite conversion and DNA droplet digital polymerase chain reaction assays have been optimized for cytology smear to investigate aberrant DNA methylation of several NSCLC-related genes
Revista:
FRONTIERS IN ONCOLOGY
ISSN:
2234-943X
Año:
2018
Vol.:
12
N°:
8
Págs.:
61
Diffuse intrinsic pontine gliomas (DIPGs) are aggressive glial brain tumors that primarily affect children, for which there is no curative treatment. Median overall survival is only one year. Currently, the scientific focus is on expanding the knowledge base of the molecular biology of DIPG, and identifying effective therapies. Oncolytic adenovirus DNX-2401 is a replication-competent, genetically modified virus capable of infecting and killing glioma cells, and stimulating an anti-tumor immune response. Clinical trials evaluating intratumoral DNX-2401 in adults with recurrent glioblastoma have demonstrated that the virus has a favorable safety profile and can prolong survival. Subsequently, these results have encouraged the transition of this biologically active therapy from adults into the pediatric population. To this aim, we have designed a clinical Phase I trial for newly diagnosed pediatric DIPG to investigate the feasibility, safety, and preliminary efficacy of delivering DNX-2401 into tumors within the pons following biopsy. This case report presents a pediatric patient enrolled in this ongoing Phase I trial for children and adolescents with newly diagnosed DIPG. The case involves an 8-year-old female patient with radiologically diagnosed DIPG who underwent stereotactic tumor biopsy immediately followed by intratumoral DNX-2401 in the same biopsy track. Because there were no safety concerns or new neurological deficits, the patient was discharged 3¿days after the procedures. To our knowledge, this is the first report of intratumoral DNX-2401 for a patient with DIPG in a clinical trial. We plan to demonstrate that intratumoral delivery of an oncolytic virus following tumor biopsy for pediatric patients with DIPG is a novel and feasible approach and that DNX-2401 represents an innovative treatment for the disease.
Revista:
GLIOMA
ISSN:
2589-6113
Año:
2018
Vol.:
1
N°:
1
Págs.:
22 - 26
Background: Glioblastoma multiforme (GBM) is the most malignant primary brain tumor. Current treatment against this tumor consists of maximal surgical resection without threatening the patient's life, followed by a treatment with temozolomide, with or without combined radiotherapy. GBM is resistant to the conventional antitumor therapies, so in this research, we tried to inhibit tumor growth with the combination of three drugs: (1) panobinostat, an inhibitor of histone deacetylases, (2) 3-Dezaneplanocin-A (DZNep), an inhibitor of EZH2, a protein which belongs to the polycomb repressor complex 2, acting as a histone methylase, and (3) temozolomide, an alkylating agent. Methods: The T98G GBM commercial cell line was used. Cells were exposed to single treatments of the drugs and to the three possible combinations among them. Soon after, two-dimensional (2D) and 3D clonogenic assays were assessed for in vitro tumorigenicity testing. Real-time quantitative polymerase chain reaction of 2 proapoptotic genes (BAX and NOXA) and 2 antiapoptotic genes (BCL2 and BCL-XL) was also assessed. Results: The panobinostat and temozolomide combination produced a positive effect against T98G glioblastoma cells by reducing soft agar colony formation, by inducing high expression levels of NOXA, and by reducing BCL-XL expression.
Revista:
CANCER TRANSLATIONAL MEDICINE
ISSN:
2395-3012
Año:
2018
Vol.:
4
N°:
5
Págs.:
39 - 47
Revista:
EPIGENOMES
ISSN:
2075-4655
Glioblastoma is the most common form of glioma, as well as the most aggressive. Patients suffering from this disease have a very poor prognosis. Surgery, radiotherapy, and temozolomide are the only approved treatments nowadays. Panobinostat is a pan-inhibitor of histone deacetylases (HDACs) that has been shown to break some pathways which play an important role in cancer development. A global intention of using panobinostat as a therapeutic agent against glioblastoma is beginning to be a reality. We have treated the LN405 glioblastoma cell line with temozolomide, panobinostat, and combined treatment, in order to test apoptosis, colony formation, and a possible molecular reversion of the mesenchymal phenotype of the cells to an epithelial one. Our results show that panobinostat decreased N-cadherin levels in the LN405 glioblastoma cell line while it increased the expression of E-cadherin, which might be associated with a mesenchymal-epithelial transition in glioblastoma cells. Colony formation was reduced, and apoptosis was increased with treatments. Our research highlights the importance of panobinostat as a potential adjuvant therapy to be used with temozolomide to treat glioblastoma and the advantages of the combined treatment versus temozolomide alone, which is currently the first-line treatment used to treat this tumor.
Revista:
ANNALS OF HEMATOLOGY
ISSN:
0939-5555
Año:
2018
Vol.:
97
N°:
3
Págs.:
543 - 544
Revista:
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
ISSN:
1542-3565
Año:
2018
Vol.:
16
N°:
2
Págs.:
A29 - A30
Revista:
JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT
ISSN:
1610-0379
Año:
2018
Vol.:
16
N°:
8
Págs.:
1036 - 1038
Revista:
JOURNAL DER DEUTSCHEN DERMATOLOGISCHEN GESELLSCHAFT
ISSN:
1610-0379
Año:
2018
Vol.:
16
N°:
8
Págs.:
1036-1038
Revista:
JOURNAL OF TRANSLATIONAL MEDICINE
ISSN:
1479-5876
Año:
2017
Vol.:
15
N°:
1
Págs.:
Article number 104
Background: Prognosis of patients with glioblastoma multiforme (GBM) remains dismal, with median overall survival (OS) of about 15 months. It is therefore crucial to search alternative strategies that improve these results obtained with conventional treatments. In this context, immunotherapy seems to be a promising therapeutic option. We hypothesized that the addition of tumor lysate-pulsed autologous dendritic cells (DCs) vaccination to maximal safe resection followed by radiotherapy and concomitant and adjuvant temozolomide could improve patients' survival.
Methods: We conducted a phase-II clinical trial of autologous DCs vaccination in patients with newly diagnosed patients GBM who were candidates to complete or near complete resection. Candidates were finally included if residual tumor volume was lower than 1 cc on postoperative radiological examination. Autologous DCs were generated from peripheral blood monocytes and pulsed with autologous whole tumor lysate. The vaccination calendar started before radiotherapy and was continued during adjuvant chemotherapy. Progression free survival (PFS) and OS were analyzed with the Kaplan-Meier method. Immune response were assessed in blood samples obtained before each vaccines.
Results: Thirty-two consecutive patients were screened, one of which was a screening failure due to insufficient resection. Median age was 61 years (range 42-70). Karnofsky performance score (KPS) was 90-100 in 29%, 80 in 35.5% and 60-70 in 35.5% of cases. MGMT (O6-methylguanine-DNA-methyltransferase) promoter was methylated in 45.2% of patients. No severe adverse effects related to immunotherapy were registered. Median PFS was 12.7 months (CI 95% 7-16) and median OS was 23.4 months (95% CI 16-33.1). Increase in post-vaccination tumor specific immune response after vaccines (proliferation or cytokine production) was detected in 11/27 evaluated patients. No correlation between immune response and survival was found.
Conclusions: Our results suggest that the addition of tumor lysate-pulsed autologous DCs vaccination to tumor resection and combined radio-chemotherapy is feasible and safe. A multicenter randomized clinical trial is warranted to evaluate the potential survival benefit of this therapeutic approach. Trial registration This phase-II trial was registered as EudraCT: 2009-009879-35 and ClinicalTrials.gov Identifier: NCT01006044 retrospectively registered.
Revista:
PLOS ONE
ISSN:
1932-6203
Año:
2017
Vol.:
12
N°:
1
Págs.:
e0170501
Objective In this work we set to develop and to validate a new in vivo frameless orthotopic Diffuse Intrinsic Pontine Glioma (DIPG) model based in the implantation of a guide-screw system. Methods It consisted of a guide-screw also called bolt, a Hamilton syringe with a 26-gauge needle and an insulin-like 15-gauge needle. The guide screw is 2.6 mm in length and harbors a 0.5 mm central hole which accepts the needle of the Hamilton syringe avoiding a theoretical displacement during insertion. The guide-screw is fixed on the mouse skull according to the coordinates: 1 mm right to and 0.8 mm posterior to lambda. To reach the pons the Hamilton syringe is adjusted to a 6.5 mm depth using a cuff that serves as a stopper. This system allows delivering not only cells but also any kind of intratumoral chemotherapy, antibodies or gene/viral therapies. Results The guide-screw was successfully implanted in 10 immunodeficient mice and the animals were inoculated with DIPG human cell lines during the same anesthetic period. All the mice developed severe neurologic symptoms and had a median overall survival of 95 days ranging the time of death from 81 to 116 days. Histopathological analysis confirmed tumor into the pons in all animals confirming the validity of this model. Conclusion Here we presented a reproducible and frameless DIPG model that allows for rapid evaluation of tumorigenicity and efficacy of chemotherapeutic or gene therapy products delivered intratumorally to the pons.
Revista:
JOURNAL OF MEDICAL CASE REPORTS
ISSN:
1752-1947
Año:
2017
Vol.:
11
N°:
1
Págs.:
115
BACKGROUND:
Chemotherapy is considered the most appropriate treatment for metastatic uterine sarcoma, despite its limited efficacy. No other treatment has been conclusively proved to be a real alternative, but some reports suggest that anti-hormonal therapy could be active in a small subset of patients. We report the case of a patient with metastatic uterine carcinosarcoma with positive hormonal receptors and a complete pathological response.
CASE PRESENTATION:
A 54-year-old white woman presented to our emergency room with hypovolemic shock and serious vaginal bleeding. After stabilization, she was diagnosed as having a locally advanced uterine carcinosarcoma with lymph nodes and bone metastatic disease. In order to control the bleeding, palliative radiotherapy was administered. Based on the fact that positive hormone receptors were found in the biopsy, non-steroidal aromatase inhibitor therapy with letrozole was started. In the following weeks, her general status improved and restaging imaging tests demonstrated a partial response of the primary tumor. Ten months after initiating aromatase inhibitor therapy, she underwent a radical hysterectomy and the pathological report showed a complete response. After completing 5 years of treatment, aromatase inhibitor therapy was stopped. She currently continues free of disease, without further therapy, and maintains a normal and active life.
CONCLUSIONS:
This case shows that patients with uterine carcinosarcoma and positive hormone receptors may benefit from aromatase inhibitor therapy. A multidisciplinary strategy that includes local therapies such as radiation and/or surgery should be considered the mainstay of treatment. Systemic therapies such as hormone inhibitors should be taken into consideration and deserve further clinical research in the era of precision medicine.
Revista:
JOURNAL OF TUMOUR AND RESEARCH & REPORTS
ISSN:
2684-1614
Año:
2017
Vol.:
2
N°:
2
Págs.:
113
Medulloblastoma is the malignant brain tumor that most affects children and young people. Its treatment is very aggressive and can leave important neurocognitive sequelae in patients. Medulloblastoma can be classified histologically and molecularly in different subtypes. Our work focuses on the specific subtype in which the sonic hedgehog pathway is altered. DAOY cells, which correspond to desmoplastic Shh medulloblastoma, were independently treated with two pharmacological inhibitors: cyclopamine and DZNep. Cyclopamine directly inhibits Smo, thus inhibiting the sonic hedgehog pathway; while DZNep acts at the epigenetic level by inhibiting EZH2 function, a histone-lysine N-methyltransferase. The two inhibitions were compared cellularly and molecularly, demonstrating that both drugs reduced cell viability, colony formation, cell migration and the expression of cancer stem cells related genes, like CD133. In addition, the expression of different genes of the sonic hedgehog, EZH2, and other genes regulated by EZH2 and GLI1 were evaluated. The initial hypothesis, according to which the expression of EZH2 would regulate the sonic hedgehog pathway was not demonstrated. Quite the opposite, we observed that the sonic hedgehog pathway could positively regulate EZH2 expression.
Revista:
REVISTA ESPAÑOLA DE CIRUGIA ORTOPEDICA Y TRAUMATOLOGIA
ISSN:
1888-4415
Año:
2017
Vol.:
61
N°:
2
Págs.:
82 - 87
OBJECTIVE:
To evaluate the clinical, radiological and histological factors that can predict local recurrence of fibromatosis.
METHODS:
A retrospective study was conducted on 51 patients diagnosed with fibromatosis in this hospital from 1983 to 2014. The mean follow-up was 83 months. A study was made of the clinical parameters, location, depth, size, surgical margins, and proliferation index (Ki-67). An evaluation was also made of the risk of recurrence depending on the adjuvant treatment and the relationship between treatment and patient functionality.
RESULTS:
Tumour location and depth were identified as risk factors for local recurrence, showing statistically significant differences (P<.001 and P=.003, respectively). There were no statistically significant differences in age, gender, size, surgical margins, or adjuvant treatments, or in the Musculoskeletal Tumour Society Score according to the treatment received. The mean Ki-67 was 1.9% (range 1-4), and its value was not associated with the risk of recurrence.
DISCUSSION:
Deep fibromatosis fascia tumours, and those located in extremities are more aggressive than superficial tumours and those located in trunk. The Ki-67 has no predictive value in local recurrence of fibromatosis. Radiotherapy, chemotherapy, or other adjuvant treatments such as tamoxifen have not been effective in local control of the disease. Given the high recurrence rate, even with adequate margins, a wait and see attitude should be considered in asymptomatic patients and/or stable disease.
Revista:
ACTA SCIENTIFIC CANCER BIOLOGY
ISSN:
2582-4473
Año:
2017
Vol.:
1
N°:
1
Págs.:
29 - 34
We present a study on neuroblastoma cells, treated with up to six cycles of cyclopamine, an SMO inhibitor of the sonic hedgehog
pathway. Several genes involved in apoptosis, cancer stem cell phenotype, and sonic hedgehog pathway regulation were tested for expression before and after treatments. Also, cell proliferation and colony formation in 2D and 3D assay systems were used. The genes
related to cancer stem cell phenotypes (CD133 and CD15) seemed to increase their expression after exposition to several treatment
cycles, coincident with the idea of neuroblastoma resistance to cyclopamine. MYCN, SMO and BCL-2 equally showed higher expression levels after several cycles of treatment. Cyclopamine treatment of neuroblastoma cells reduced cell proliferation and in vitro
tumorigenesis determined by 3D colony formation assays in soft agar. The treatments also induced apoptosis and increased MYCN
expression. As a whole, we may consider cyclopamine a good inhibitor against neuroblastoma along the first stages of the treatment, while
resistance to this compound can occur later on. More studies on cyclopamine resistance are needed to better approach to neuroblastoma treatment.
Revista:
JOURNAL OF TUMOR
ISSN:
1819-6187
Año:
2017
Vol.:
5
N°:
5 - 6
Págs.:
498 - 503
Current treatment against medulloblastoma, one of the most frequent tumors in childhood and early adolescence, is not effective enough,
presenting long time relapses in addition to side effects in growth and intellectual outcome of patients. Among the different types of medulloblastoma, we focused on the sonic hedgehog (Shh) type of this disease. Cyclopamine inhibits the Shh pathway. Medulloblastoma very often presents chemotherapy resistance. We tried, in this work to understand the mechanism of cyclopamine resistance in Shh meduloblastoma. In our study we induced cyclopamine resistance to Daoy desmoplastic Shh type medulloblastoma cells by treating them with this drug for a long period of time. Cellular assays (proliferation, clonogenicity, and migration), together with qRT-PCR molecular experiments allowed us to verify the different behaviour of the cells after each cyclopamine exposure. The results highlight the evidence that cells became resistant because they were able to grow in soft agar without attachment, to migrate and to overexpress genes related to cancer stem-like cell phenotypes. The resistance induced seems to have a cyclic behaviour, as according with the results Daoy cells might sustain a subgroup of cancer stem-like cells in the tumor that never disappear despite cyclopamine treatments. Induction of cyclopamine resistance in desmoplastic Shh medulloblastoma cells increases their cancer stem-like cell compartment and their in vitro tumorigenic potential.
Revista:
EUROPEAN RADIOLOGY
ISSN:
0938-7994
Año:
2017
Vol.:
27
N°:
8
Págs.:
3190-3198
Our aim was to evaluate the diagnostic accuracy of magnetic resonance imaging (MRI) fused with prone 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) in primary tumour staging of patients with breast cancer. METHODS: This retrospective study evaluated 45 women with 49 pathologically proven breast carcinomas. MRI and prone PET-CT scans with time-of-flight and point-spread-function reconstruction were performed with the same dedicated breast coil. The studies were assessed by a radiologist and a nuclear medicine physician, and evaluation of fused images was made by consensus. The final diagnosis was based on pathology (90 lesions) or follow-up¿¿¿24 months (17 lesions).
RESULTS:
The study assessed 72 malignant and 35 benign lesions with a median size of 1.8 cm (range 0.3-8.4 cm): 31 focal, nine multifocal and nine multicentric cases. In lesion-by-lesion analysis, sensitivity, specificity, positive and negative predictive values were 97%, 80%, 91% and 93% for MRI, 96%, 71%, 87%, and 89% for prone PET, and 97%. 94%, 97% and 94% for MRI fused with PET. Areas under the curve (AUC) were 0.953, 0.850, and 0.983, respectively (p¿<¿0.01). CONCLUSIONS: MRI fused with FDG-PET is more accurate than FDG-PET in primary tumour staging of breast cancer patients and increases the specificity of MRI.
Revista:
JOURNAL OF THE AMERICAN ACADEMY OF ORTHOPAEDIC SURGEONS
ISSN:
1067-151X
Año:
2017
Vol.:
25
N°:
11
Págs.:
e272 - e274
Revista:
ULTRASOUND IN OBSTETRICS AND GYNECOLOGY
ISSN:
0960-7692
Año:
2016
Vol.:
47
N°:
3
Págs.:
369 - 373
OBJECTIVE:
To compare diagnostic performance of preoperative transvaginal ultrasound (TVS) and intraoperative macroscopic examination for determining myometrial infiltration in women with low-risk endometrial cancer, and to estimate the agreement between the two methods.
METHODS:
This was a single-center observational study comprising women with preoperative diagnosis of well- or moderately differentiated endometrioid carcinoma of the endometrium. All women underwent preoperative TVS by a single examiner. According to the examiner's subjective impression, myometrial infiltration was stated as¿¿¿50% or¿<¿50%. Surgical staging was performed in all cases. Intraoperative macroscopic examination of the removed uterus was performed by pathologists who were unaware of the ultrasound findings, and myometrial infiltration was stated as¿¿¿50% or¿<¿50%. Definitive histological diagnosis of myometrial infiltration was made by frozen section analysis and was used as the gold standard. Sensitivity and specificity with 95% CIs were calculated for TVS and intraoperative macroscopic inspection and compared using McNemar's test. Agreement between TVS and intraoperative macroscopic inspection was estimated using Cohen's kappa index (¿) and percentage of agreement.
RESULTS:
Of 209 eligible women, 152 were ultimately included. Mean (±¿SD) age was 60.9¿±¿10.2¿years, with a range of 32-91¿years. Definitive histological diagnosis revealed that myometrial infiltration was <¿50% in 114 women and ¿¿50% in 38 women. Sensitivity and specificity of TVS for detecting deep myometrial infiltration were 81.6% and 89.5%, respectively, whereas the respective values for intraoperative macroscopic examination were 78.9% and 90.4% (McNemar's test, P¿>¿0.05 when comparing TVS and intraoperative macroscopic examination). Agreement between methods was moderate with ¿¿=¿0.54 (95%¿CI, 0.39-0.69) and percentage of agreement of 82%.
CONCLUSIONS:
Although the agreement between preoperative TVS and intraoperative macroscopic examination for detecting deep myometrial infiltration was only moderate, both methods had similar accuracy when compared with frozen section histology. Preoperative TVS might reasonably be proposed as a method for assessing myometrial infiltration as an alternative to intraoperative macroscopic examination, especially when performed by an experienced examiner and image quality is not poor.
Revista:
CLINICAL NEUROPATHOLOGY
ISSN:
0722-5091
Año:
2016
Vol.:
35
N°:
2
Págs.:
53 - 57
Digital technology is progressively changing our vision of the practice of neuropathology. There are a number of facts that support the introduction of digital neuropathology. With the development of wholeslide imaging (WSI) systems the difficulties involved in implementing a neuropathology network have been solved. A relevant difficulty has been image standardization, but an open digital image communication protocol defined by the Digital Imaging and Communications in Medicine (DICOM) standard is already a reality. The neuropathology network should be established in Europe because it is the expected geographic context for relationships among European neuropathologists. There are several limitations in the implementation of a digital neuropathology consultancy network such as financial support, operational costs, legal issues, and technical assistance of clients. All of these items have been considered and should be solved before implementing the proposal. Finally, the authors conclude that a European digital neuropathology network should be created for patients' benefit.
Revista:
JOURNAL OF CARCINOGENESIS & MUTAGENESIS
ISSN:
2157-2518
Año:
2016
Vol.:
7
N°:
6
Págs.:
1000278
Glioblastoma is the most common malignant brain tumor in adults and it is currently treated with a combination of surgery, radiotherapy and chemotherapy with temozolomide (TMZ). Many patients show resistance to TMZ, which is a challenge in the treatment of this type of brain cancer. New strategies are being tested, like the inhibition of EZH2, a histone methyltransferase which is overexpressed in cancer cells, leading to angiogenesis and metastasis. In this work, the EZH2 inhibitor DZNeP was tested in A172 glioblastoma cells and in A172-TMZ-resistant glioblastoma cells. Inhibition of cell proliferation, adhesion, colony formation, and migration was noted in control and TMZresistant glioblastoma cells after DZNeP treatment. At the level of EZH2 target gene expression, DZNeP decreased EZH2 expression, and increased the expression of its target genes (E-cadherin and TIMP3), which might probably contribute to inhibiting the development of a cancer metastatic phenotype. Finally, DZNeP negatively regulated the TGFß pathway. In conclusion, we propose that inhibition of EZH2 might be considered as a therapeutic strategy against glioblastoma.
Revista:
NEURO-ONCOLOGY
ISSN:
1522-8517
Año:
2016
Vol.:
18
N°:
8
Págs.:
1109-1119
These findings provide a strong rationale for combining temozolomide with ER stress-inducing drugs as an alternative therapeutic strategy for glioblastoma.
Revista:
ENDOCRINE PATHOLOGY
ISSN:
1046-3976
Año:
2016
Vol.:
27
N°:
1
Págs.:
50 - 54
The most common cause of organic fasting hypoglycemia in adults is the presence of an insulin-producing pancreatic adenoma, but when high insulin levels are not found, the differential diagnosis is challenging. Misdiagnosis can lead to an unnecessary pancreatectomy. Insulin concentrations may be low in some cases despite a clinical history suggestive of insulinoma. In these cases, a proinsulinoma should be suspected, although the rarity of this condition requires an extensive workup before reaching a final diagnosis. We describe an unusual case of a 38-year-old man with a severe hypoglycemic syndrome due to a proinsulin-secreting pancreatic adenoma. Insulin was measured by the specific assay and suppressed under the lower detection limit during fasting hypoglycemia. Serum proinsulin and C-peptide levels were abnormally elevated, and further tests revealed an islet cell tumor. The tumor was surgically removed, relieving the fasting hypoglycemia. Histopathological study showed a conventional well-differentiated neuroendocrine tumor with high immunoreactivity against proinsulin and with lesser intensity against insulin. Interestingly, GS-9A8 antibody clone used for immunostaining proinsulin did not cross-react with human insulin or C-peptide, providing an unbiased picture of proinsulin secretion. The resolution of symptoms, the fall of proinsulin concentrations after tumor removal and the histopathology study confirmed the diagnosis of proinsulinoma
Revista:
BRACHYTHERAPY
ISSN:
1538-4721
Año:
2016
Vol.:
15
N°:
4
Págs.:
485 - 494
Purpose: To assess the safety, feasibility, and efficacy of free-hand intraoperative multicatheter breast implant (FHIOMBI) and perioperative high-dose-rate brachytherapy (PHDRBT) in early breast cancer. Methods and Materials: Patients with early breast cancer candidates for breast conservative surgery (BCS) were prospectively enrolled. Patients suitable for accelerated partial breast irradiation (APBI) (low or intermediate risk according GEC-ESTRO criteria) received PHDRBT (3.4 Gy BID × 10 in 5 days). Patients not suitable for APBI (high risk patients according GEC-ESTRO criteria) received PHDRBT boost (3.4 Gy BID × 4 in 2 days) followed by whole breast irradiation. Results: From June 2007 to November 2014, 119 patients were treated and 122 FHIOMBI procedures were performed. Median duration of FHIOMBI was 25 minutes. A median of eight catheters (range, 4-14) were used. No severe intraoperative complications were observed. Severe early postoperative complications (bleeding) were documented in 2 patients (1.6%), wound healing complications in 3 (2.4%), and infection (mastitis or abscess) in 2 (1.6%). PHDRBT was delivered as APBI in 88 cases (72.1%) and as a boost in 34 (27.8%). The median clinical target volume T was 40.8 cc (range, 12.3-160.5); median D90 was 3.32 Gy (range, 3.11-3.85); median dose homogeneity index was 0.72 (range, 0.48-0.82). With a median followup of 38.4 months (range, 8.7-98.7) no local, elsewhere, or regional relapses were observed; there was only one distant failure in PHDRBT boost. No major (acute or late) RTOG grade 3 or higher were documented in any of the 119 patients treated with PHDRBT. Cosmetic outcome in APBI patients was excellent or good in (87.0%) and fair or poor in (11.9%) while in boost patients was excellent or good in (76.4%) and fair in (23.5%). Conclusion: The FHIOMBI-PHDRBT program does not add complications to conservative surgery. It allows precise selection of APBI patients and offers excellent results in disease control and cosmetics. It also offers logistic advantages because it dramatically shortens the time of local treatment and avoids further invasive procedures.
Revista:
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN:
0021-9258
Año:
2015
Vol.:
290
N°:
7
Págs.:
4272 - 4281
Bethlem myopathy and Ullrich congenital muscular dystrophy (UCMD) sit at opposite ends of a clinical spectrum caused by mutations in the extracellular matrix protein collagen VI. Bethlem myopathy is relatively mild, and patients remain ambulant in adulthood while many UCMD patients lose ambulation by their teenage years and require respiratory interventions. Dominant and recessive mutations are found across the entire clinical spectrum; however, recessive Bethlem myopathy is rare, and our understanding of the molecular pathology is limited. We studied a patient with Bethlem myopathy. Electron microscopy of his muscle biopsy revealed abnormal mitochondria. We identified a homozygous COL6A2 p. D871N amino acid substitution in the C-terminal C2 A-domain. Mutant alpha 2(VI) chains are unable to associate with alpha 1(VI) and alpha 3(VI) and are degraded by the proteasomal pathway. Some collagen VI is assembled, albeit more slowly than normal, and is secreted. These molecules contain the minor alpha 2(VI) C2a splice form that has an alternative C terminus that does include the mutation. Collagen VI tetramers containing the alpha 2(VI) C2a chain do not assemble efficiently into microfibrils and there is a severe collagen VI deficiency in the extracellular matrix. We expressed wildtype and mutant alpha 2(VI) C2 domains in mammalian cells and showed that while wild-type C2 domains are efficiently secreted, the mutant p.D871N domain is retained in the cell. These studies shed new light on the protein domains important for intracellular and extracellular collagen VI assembly and emphasize the importance of molecular investigations for families with collagen VI disorders to ensure accurate diagnosis and genetic counseling.
Revista:
BRITISH JOURNAL OF DERMATOLOGY
ISSN:
0007-0963
Año:
2015
Vol.:
172
N°:
1
Págs.:
296 - 298
Revista:
JOURNAL OF CANCER
ISSN:
1837-9664
Año:
2015
Vol.:
6
N°:
2
Págs.:
139 - 143
Methods: GLUT12 expression was determined by immunohistochemistry in a selection of cancer cell lines and a tumour spheroid model.
Results: GLUT12 expression was high in A549 and RH-36; low in HT29; and absent in NB-EB cancer cell lines. GLUT12 expression was located in the necrotic centre of HT29 spheroids, which is characterised by anaerobic metabolism.
Conclusion: The data supports the involvement of GLUT12 in the glycolytic metabolism of cancer cells and therefore, its potential as a novel therapeutic target for cancer treatment
Revista:
JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY
ISSN:
0190-9622
Año:
2015
Vol.:
72
N°:
Supl. 1
Págs.:
S73 - S75
Revista:
PLOS ONE
ISSN:
1932-6203
Año:
2015
Vol.:
10
N°:
4
Págs.:
e0124670
Sirtuin 1 (SIRT1) and sirtuin 2 (SIRT2) are NAD+-dependent protein deacetylases involved in the regulation of key cancer-associated genes. In this study we evaluated the relevance of these deacetylases in lung cancer biology.
Material and Methods
Protein levels of SIRT1 and SIRT2 were determined in non-small cell lung cancer (NSCLC) cell lines and primary tumors from 105 patients. Changes in proliferation were assessed after SIRT1 and SIRT2 downregulation in lung cancer cell lines using siRNA-mediated technology or tenovin-1, a SIRT1 and SIRT2 inhibitor.
Results
High SIRT1 and SIRT2 protein levels were found in NSCLC cell lines compared with nontumor lung epithelial cells. The expression of SIRT1 and SIRT2 proteins was also significantly higher in lung primary tumors than in normal tissue (P<0.001 for both sirtuins). Stronger nuclear SIRT1 staining was observed in adenocarcinomas than in squamous cell carcinomas (P=0.033). Interestingly, in NSCLC patients, high SIRT1 and SIRT2 expression levels were associated with shorter recurrence-free survival (P=0.04 and P=0.007, respectively). Moreover, the combination of high SIRT1 and SIRT2 expression was an independent prognostic factor for shorter recurrence-free survival (P=0.002) and overall survival (P=0.022). In vitro studies showed that SIRT1 and/or SIRT2 downregulation significantly decreased proliferation of NSCLC.
Conclusions
Our results support the hypothesis that SIRT1 and SIRT2 have a protumorigenic role in lu
Revista:
CLINICAL AND EXPERIMENTAL DERMATOLOGY
ISSN:
0307-6938
Año:
2015
Vol.:
40
N°:
6
Págs.:
640 - 643
Eccrine naevus (EN) is a rare skin hamartoma included in the organoid group of epidermal naevi, histologically defined as focal hyperplasia and/or hypertrophy of eccrine glands. Clinically, EN usually presents as hyperhidrotic patches with no visible skin changes, frequently located on the forearms. The decision to treat EN or not usually depends on the grade of hyperhidrosis, but there is no therapeutic consensus because of the rarity of this condition. We present a case diagnosed as EN in an adult patient with severe localized hyperhidrosis, which was successfully treated with botulinum toxin.
Revista:
ONCOIMMUNOLOGY
ISSN:
2162-4011
Año:
2015
Vol.:
4
N°:
12
Págs.:
e1054597
CD137 (4-1BB) is a surface marker discovered on activated T lymphocytes. However, its expression pattern is broader and has also been described on activated NK cells, B-cells and myeloid cells including mature dendritic cells. In this study, we have immunostained for CD137 on paraffin-embedded lymphoid tissues including tonsils, lymph nodes, ectopic tertiary lymphoid tissue in Hashimoto thyroiditis and cancer. Surprisingly, immunostaining mainly decorates intrafollicular lymphocytes in the tissues analyzed, with only scattered staining in interfollicular areas. Moreover, pathologic lymphoid follicles in follicular lymphoma and tertiary lymphoid tissue associated to non-small cell lung cancer showed a similar pattern of immunostaining. Multicolor flow cytometry demonstrated that CD137 expression was restricted to CD4+ CXCR5+ follicular T helper lymphocytes in tonsils and lymph nodes. Short term culture of lymph node cell suspensions in the presence of an agonist anti-CD137 mAb or CD137-ligand results in the functional upregulation of TFH cells, including CD40L surface expression and cytokine production, in three out of six cases. As a consequence, immunostimulatory monoclonal antibodies, anti-CD137 mAb such as urelumab and PF-05082566 should be expected to primarily act on this lymphocyte subset, thus modifying ongoing humoral immune responses.
Revista:
EUROPEAN JOURNAL OF CANCER
ISSN:
0959-8049
Año:
2015
Vol.:
51
N°:
14
Págs.:
1897 - 1903
Background: Mortality in early stage, resectable lung cancer is sufficiently high to warrant consideration of post-surgical treatment. Novel markers to stratify resectable lung cancer patients may help with the selection of treatment to improve outcome.
Methods: Primary tumour tissue from 485 patients, surgically treated for stage I-II lung adenocarcinoma, was analysed for the RNA expression of 31 cell cycle progression (CCP) genes by quantitative polymerase chain reaction (PCR). The expression average, the CCP score, was combined with pathological stage into a prognostic score (PS). Cox proportional hazards regression assessed prediction of 5-year lung cancer mortality above clinical variables. The PS threshold was tested for risk discrimination by the Mantel-Cox log-rank test.
Results: The CCP score added significant information above clinical markers (all patients, P = 0.0029; stage I patients, P = 0.013). The prognostic score was a superior predictor of outcome compared to pathological stage alone (PS, P = 0.00084; stage, P = 0.24). Five-year lung cancer mortality was significantly different between the low-risk (90%, 95% confidence interval (CI) 81-95%), and high-risk groups (65%, 95% CI 57-72%), P = 4.2 x 10(-6)).
Conclusions: The CCP score is an independent prognostic marker in early stage lung adenocarcinoma. The prognostic score provides superior risk estimates than stage alone. The threefold higher risk in the high-risk group defines a subset of patients that should consider therapeutic choices to improve outcome.
Revista:
JAMA DERMATOLOGY
ISSN:
2168-6068
Año:
2014
Vol.:
150
N°:
6
Págs.:
664 - 666
Revista:
NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY
ISSN:
0305-1846
Año:
2014
Vol.:
40
N°:
6
Págs.:
736 - 746
AIMS:
Glioblastomas display marked phenotypic and molecular heterogeneity. The expression of the PTEN protein in glioblastomas also shows great intratumour heterogeneity, but the significance of this heterogeneity has so far received little attention.
METHODS:
We conducted a comparative study on paraffin and frozen samples from 60 glioblastomas. Based on PTEN immunostaining, paraffin glioblastomas were divided into positive (homogeneous staining) and both positive and negative (heterogeneous staining) tumours. DNA was extracted from manually microdissected samples from representative areas, and from frozen samples taken randomly from the same tumours. Loss of heterozygosity (LOH) of 10q23 and hypermethylation status of the PTEN promoter were studied, and the molecular findings were correlated with overall survival.
RESULTS:
PTEN protein was present heterogeneously in 42 cases and homogeneously in 18 cases. In homogeneous glioblastomas, no correlation was found between PTEN protein expression and the LOH of the gene. Surprisingly, in the heterogeneous glioblastomas, LOH was found significantly more frequently (P < 0.001) in PTEN-positive areas (81%) than in PTEN-negative ones (35.7%). In general, molecular results of frozen tissue were representative of the tumour. Only two cases of methylation of the PTEN promoter were identified. A significant difference was found for overall survival for LOH10q23 status (P = 0.005) and for homogeneous vs. heterogeneous tumours (P = 0.014).
CONCLUSION:
The expression of PTEN protein does not correlate with the abnormalities of the LOH of the gene. Interestingly, patients with glioblastomas presenting either LOH of 10q23 or heterogeneous PTEN expression have a poorer prognosis.
Revista:
JOURNAL OF COSMETIC AND LASER THERAPY
ISSN:
1476-4172
Año:
2014
Vol.:
16
N°:
3
Págs.:
141-143
Fox Fordyce disease (FFD) has been recently described as an adverse effect of laser hair removal. It is an apocrine gland disorder characterized by pruritus and a folliculocentric papular eruption in apocrine sweat gland areas. Different etiologies have been proposed to be the cause of this entity. It has been suggested that a fisical factor could contribute to FFD phatogenesis. We report a new case of FFD after laser hair removal.
Autores:
Cariaga-Martínez, A. E.; Cortés, I.; García, E.; et al.
Revista:
BIOLOGY OPEN
ISSN:
2046-6390
Año:
2014
Vol.:
3
N°:
10
Págs.:
924 - 936
The acquisition of invasiveness is characteristic of tumor progression. Numerous genetic changes are associated with metastasis, but the mechanism by which a cell becomes invasive remains unclear. Expression of p85ß, a regulatory subunit of phosphoinositide-3-kinase, markedly increases in advanced carcinoma, but its mode of action is unknown. We postulated that p85ß might facilitate cell invasion. We show that p85ß localized at cell adhesions in complex with focal adhesion kinase and enhanced stability and maturation of cell adhesions. In addition, p85ß induced development at cell adhesions of an F-actin core that extended several microns into the cell z-axis resembling the skeleton of invadopodia. p85ß lead to F-actin polymerization at cell adhesions by recruiting active Cdc42/Rac at these structures. In accordance with p85ß function in invadopodium-like formation, p85ß levels increased in metastatic melanoma and p85ß depletion reduced invadopodium formation and invasion. These results show that p85ß enhances invasion by inducing cell adhesion development into invadopodia-like structures explaining the metastatic potential of tumors with increased p85ß levels.
Revista:
JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY
ISSN:
0190-9622
Año:
2014
Vol.:
71
N°:
4
Págs.:
e121 - e122
Revista:
HEADACHE
ISSN:
0017-8748
Año:
2013
Vol.:
53
N°:
6
Págs.:
994 - 997
Cephalalgia alopecia is a rare and recently described headache syndrome in which recurrent, burning head and neck pain is associated with hair loss from areas of scalp affected by the pain. We here report the case of a 33-year-old woman with continuous unilateral occipital pain and colocalized alopecia, only responsive to onabotulinumtoxin A injections. We hypothesize whether this clinical phenotype may correspond to either cephalalgia alopecia or nummular headache with trophic changes, conditions that might represent 2 manifestations of the same spectrum of disorders.
Revista:
JOURNAL OF INVESTIGATIONAL ALLERGOLOGY AND CLINICAL IMMUNOLOGY
ISSN:
1018-9068
Año:
2013
Vol.:
23
N°:
6
Págs.:
392 - 397
Background: 2D7 and BB1 are thought to be basophil-specific markers. In this study, we tested both antibodies in different skin and mast cell disorders with the aim of determining whether it was possible to differentiate between benign and aggressive presentations of mastocytosis.
Methods: Using the antibodies 2D7, BB 1, and c-Kit, we performed an immunohistochemical study of skin biopsy specimens from patients with cutaneous mastocytosis (15 urticaria pigmentosa and telangiectatic macularis eruptive perstans) and liver or bone marrow biopsy specimens from patients with systemic mastocytosis. A basophil leukemia cell line was used as a reference. Peripheral blood basophils from healthy donors were used as controls.
Results: We observed intense expression of 2D7 and BB1 in all skin biopsy specimens from patients with cutaneous mastocytosis. Immunostaining of liver and bone marrow specimens from patients with systemic mastocytosis with 2D7 and BB1 antibodies was negative. Specimens from patients with either type of mastocytosis showed similarly strong expression of c-Kit. The basophil cell line showed a 2D7 and a BB1 profile, with intense expression of c-Kit. Peripheral blood basophils exhibited notable immunostaining for 2D7, BB1, and c-Kit.
Conclusions: 2D7 and BB1 are expressed in cutaneous mastocytosis, although this expression is lost when mast cell proliferation is systemic, thus reflecting either a different cellular differentiation stage or the presence of basophils in these skin diseases.
Revista:
NEUROCIRUGIA
ISSN:
1130-1473
Año:
2013
Vol.:
24
N°:
2
Págs.:
78-81
Single metastasis from a prostate adenocarcinoma in the brainstem without systemic disease is exceptional. Due to the different diagnostic possibilities, biopsy should be performed in order to obtain a diagnosis, especially in the context of Muir-Torre syndrome.
Revista:
NEUROSURGERY
ISSN:
0148-396X
Año:
2013
Vol.:
72
N°:
6
Págs.:
915 - 921
There is evidence that fluorescent tissue signal extends farther than tissue highlighted in Gad T1 sequence MRI.
To study whether the presence of residual fluorescent tissue after surgery carries a different prognosis for glioblastoma (GBM) with complete resection confirmed by MRI.
A retrospective review in our center found 118 consecutive patients with high-grade GBMs operated on with 5-aminolevulinic acid. The 52 patients with newly diagnosed GBM and complete resection of enhancing tumor (CRET) in early MRI were selected for analysis. We studied the influence of residual fluorescence in the surgical field on overall survival (OS) and neurological complication rate. Multivariate analysis included potential relevant factors: age, Karnofsky Performance Scale, O-methylguanine methyltransferase methylation promoter status, tumor eloquent location, preoperative tumor volume, and adjuvant therapy.
The median OS was 27.0 months in patients with nonresidual fluorescence (n = 25) and 17.5 months for the group with residual fluorescence (n = 27) (P = .015). The influence of residual fluorescence was maintained in multivariate analysis with all covariables, hazard ratio = 2.5 (P = .041). The neurological complication rate was 18.5% in patients with nonresidual fluorescence and 8% for the group with residual fluorescence (P = .267).
GBM patients with CRET in early MRI and no fluorescent residual tissue had longer overall survival than patients with CRET and residual fluorescent tissue.
Revista:
ANNALS OF PHARMACOTHERAPY
ISSN:
1060-0280
Año:
2013
Vol.:
47
N°:
3
Págs.:
e16
This appears to be the first report of a case of TEN that occurred in a patient being treated with oral tranexamic acid. Clinicians should be made aware of this potential severe cutaneous adverse reaction that may be caused by tranexamic acid administration.
Revista:
WORLD JOURNAL OF CLINICAL ONCOLOGY
ISSN:
2218-4333
Año:
2012
Vol.:
3
N°:
11
Págs.:
142-149
Active immunotherapy with tumor lysate-pulsed, autologous dendritic cells is feasible, safe, well tolerated and biologically efficacious. A phase-II study is ongoing to possibly improve further on our very encouraging clinical results.
Revista:
GYNECOLOGIC AND OBSTETRIC INVESTIGATION
ISSN:
0378-7346
Año:
2012
Vol.:
73
N°:
4
Págs.:
265 - 271
The diagnosis rate of deep pelvic endometriosis is increasing. Endometrial stromal sarcoma (ESS) is a rare neoplasm. Extragenital ESS is an extremely uncommon event. Very few cases of extragenital ESS have been reported to date. The diagnosis of this entity is very difficult in some instances. Knowledge about its management is also limited. In this paper, we review the current literature on the clinical management, histology, immunohistochemistry, treatment and outcome of ESS arising in pelvic endometriosis.
Revista:
MODERN PATHOLOGY
ISSN:
0893-3952
Año:
2012
Vol.:
25
N°:
9
Págs.:
1275 - 1283
The distinction between benign and malignant cartilaginous tumors located peripherally in the bone may be a challenging task in surgical pathology. The aim of this study was to investigate interobserver reliability in histological diagnosis of cartilaginous tumors in the setting of multiple osteochondromas and to evaluate possible histological parameters that could differentiate among osteochondroma, low- and high-grade secondary peripheral chondrosarcoma. Interobserver reliability was assessed by 12 specialized bone-tumor pathologists in a set of 38 cases. Substantial agreement on diagnosis among all the reviewers was observed (intraclass correlation coefficient=0.78). Our study confirmed that mitotic figures and nuclear pleomorphism are hallmarks of high-grade secondary peripheral chondrosarcoma. However, despite the substantial agreement, we demonstrated that histology alone cannot distinguish osteochondroma from low-grade secondary peripheral chondrosarcoma in the setting of multiple osteochondromas, as nodularity, the presence of binucleated cells, irregular calcification, cystic/mucoid changes and necrosis were not helpful to indicate malignant transformation of an osteochondroma. On the other hand, among the concordant cases, the cartilage cap in osteochondroma was significantly less thicker than in low- and high-grade secondary peripheral chondrosarcoma. Therefore, our study showed that a multidisciplinary approach integrating clinical and radiographical features and the size of the cartilaginous cap in combination with a histological assessment are crucial to the diagnosis of cartilaginous tumors.
Revista:
JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY
ISSN:
0190-9622
Año:
2012
Vol.:
67
N°:
4
Págs.:
e152 - e154
Case report of uncommon presentation of calciphylaxis
Revista:
EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
ISSN:
1619-7070
Año:
2012
Vol.:
39
N°:
5
Págs.:
771 - 781
PURPOSE:
The aim of the study was to evaluate the volumetric integration patterns of standard MRI and (11)C-methionine positron emission tomography (PET) images in the surgery planning of gliomas and their relationship to the histological grade.
METHODS:
We studied 23 patients with suspected or previously treated glioma who underwent preoperative (11)C-methionine PET because MRI was imprecise in defining the surgical target contour. Images were transferred to the treatment planning system, coregistered and fused (BrainLAB). Tumour delineation was performed by (11)C-methionine PET thresholding (vPET) and manual segmentation over MRI (vMRI). A 3-D volumetric study was conducted to evaluate the contribution of each modality to tumour target volume. All cases were surgically treated and histological classification was performed according to WHO grades. Additionally, several biopsy samples were taken according to the results derived either from PET or from MRI and analysed separately.
RESULTS:
Fifteen patients had high-grade tumours [ten glioblastoma multiforme (GBM) and five anaplastic), whereas eight patients had low-grade tumours. Biopsies from areas with high (11)C-methionine uptake without correspondence in MRI showed tumour proliferation, including infiltrative zones, distinguishing them from dysplasia and radionecrosis. Two main PET/MRI integration patterns emerged after analysis of volumetric data: pattern vMRI-in-vPET (11/23) and pattern vPET-in-vMRI (9/23). Besides, a possible third pattern with differences in both directions (vMRI-diff-vPET) could also be observed (3/23). There was a statistically significant association between the tumour classification and integration patterns described above (p¿<¿0.001, ¿¿=¿0.72). GBM was associated with pattern vMRI-in-vPET (9/10), low-grade with pattern vPET-in-vMRI (7/8) and anaplastic with pattern vMRI-diff-vPET (3/5).
CONCLUSION:
The metabolically active tumour volume observed in (11)C-methionine PET differs from the volume of MRI by showing areas of infiltrative tumour and distinguishing from non-tumour lesions. Differences in (11)C-methionine PET/MRI integration patterns can be assigned to tumour grades according to the WHO classification. This finding may improve tumour delineation and therapy planning for gliomas.
Revista:
ONCOLOGIST
ISSN:
1083-7159
Año:
2011
Vol.:
16
N°:
6
Págs.:
877 - 885
The mutation status was identical in patients who had both biopsies and cytological samples analyzed. Conclusion. Assessment of EGFR and K-ras mutations in cytological samples is feasible and comparable with biopsy results, making individualized treatment
Revista:
ONCOLOGIST
ISSN:
1083-7159
Año:
2011
Vol.:
16
N°:
6
Págs.:
877 - 885
Objective. Epidermal growth factor receptor (EGFR) and K-ras mutations guide treatment selection in non-small cell lung cancer (NSCLC) patients. Although mutation status is routinely assessed in biopsies, cytological specimens are frequently the only samples available. We determined EGFR and K-ras mutations in cytological samples. Methods. DNA was extracted from 150 consecutive samples, including 120 Papanicolau smears (80%), 10 cell blocks (7%), nine fresh samples (6%), six ThinPrep(R) tests (4%), and five body cavity fluids (3.3%). Papanicolau smears were analyzed when they had > 50% malignant cells. Polymerase chain reaction and direct sequencing of exons 18-21 of EGFR and exon 2 of K-ras were performed. EGFR mutations were simultaneously determined in biopsies and cytological samples from 20 patients. Activity of EGFR tyrosine kinase inhibitors (TKIs) was assessed. Results. The cytological diagnosis was adenocarcinoma in 110 samples (73%) and nonadenocarcinoma in 40 (27%) samples. EGFR mutations were identified in 26 samples (17%) and K-ras mutations were identified in 18 (12%) samples. EGFR and K-ras mutations were mutually exclusive. In EGFR-mutated cases, DNA was obtained from stained smears in 24 cases (92%), pleural fluid in one case (4%), and cell block in one case (4%). The response rate to EGFR TKIs in patients harboring mutations was 75%. The mutation status was identical in patients who had both biopsies and cytological samples analyzed. Conclusion. Assessment of EGFR and K-ras mutations in cytological samples is feasible and comparable with biopsy results, making individualized treatment selection possible for NSCLC patients from whom tumor biopsies are not available.
Revista:
CANCER CYTOPATHOLOGY
ISSN:
1934-662X
Año:
2011
Vol.:
119
N°:
3
Págs.:
209 - 2014
Cystic lesions of the pancreas are being detected with increasing frequency. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is one of the most precise methods of diagnosis but still has limited accuracy. A new, through-the-needle cytologic brush system (EchoBrush; Cook Medical, Bloomington, Ind) has been approved for use during EUS evaluation of cystic pancreatic lesions.
METHODS:
Data from 127 EUS-FNAs of pancreatic cystic lesions were analyzed to compare the cytologic yield of EchoBrush with conventional EUS-FNA. An attending cytopathologist was present on site to assess specimen adequacy in all the cases. Diagnostic yields of both procedures, as well as related adverse events, were recorded. Statistical analysis was performed with the SPSS 15.0 version software (SPSS, Chicago, Ill).
RESULTS:
A total of 127 cystic lesions of the pancreas from 120 patients (42 men and 78 women, mean age of 62.17 ± 12.17 years) were included in the study. Mean size of lesions was 23.58 ± 21.69 mm. Adequacy of the samples and diagnostic yield were higher using EchoBrush. In 80 (63 %) cases, conventional EUS-FNA was performed, whereas in 47 (37%), we used EchoBrush. Diagnostic material was obtained in 85.1% (40 of 47) of cases using EchoBrush and in 66.3% (53 of 80) with conventional EUS-FNA. (P < .05). There were very few clinically relevant complications related to EUS-FNA and EUS-EchoBrush techniques.
CONCLUSIONS:
This study suggests that cytological specimens from pancreatic cystic lesions obtained using EchoBrush at the time of EUS are superior to conventional EUS-FNA mainly because of the higher yield of epithelial cells. Larger studies are needed to compare both methods.
Revista:
PLoS One
ISSN:
1932-6203
Año:
2011
Vol.:
6
N°:
11
Págs.:
-
We undertook this study to understand how the transcription factor Sox2 contributes to the malignant phenotype of glioblastoma multiforme (GBM), the most aggressive primary brain tumor. We initially looked for unbalanced genomic rearrangements in the Sox2 locus in 42 GBM samples and found that Sox2 was amplified in 11.5% and overexpressed in all the samples. These results prompted us to further investigate the mechanisms involved in Sox2 overexpression in GBM. We analyzed the methylation status of the Sox2 promoter because high CpG density promoters are associated with key developmental genes. The Sox2 promoter presented a CpG island that was hypomethylated in all the patient samples when compared to normal cell lines. Treatment of Sox2-negative glioma cell lines with 5-azacitidine resulted in the re-expression of Sox2 and in a change in the methylation status of the Sox2 promoter. We further confirmed these results by analyzing data from GBM cases generated by The Cancer Genome Atlas project. We observed Sox2 overexpression (86%; N¿=¿414), Sox2 gene amplification (8.5%; N¿=¿492), and Sox 2 promoter hypomethylation (100%; N¿=¿258), suggesting the relevance of this factor in the malignant phenotype of GBMs. To further explore the role of Sox2, we performed in vitro analysis with brain tumor stem cells (BTSCs) and established glioma cell lines. Downmodulation of Sox2 in BTSCs resulted in the loss of their self-renewal properties. Surprisingly, ectopic expression of Sox2 in esta
Revista:
JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY
ISSN:
0190-9622
Año:
2011
Vol.:
64
N°:
6
Págs.:
e121-1
Revista:
NEUROPATHOLOGY
ISSN:
0919-6544
Año:
2011
Vol.:
31
N°:
6
Págs.:
575 - 582
Thirty consecutive surgical patients with glioblastoma, were operated upon using fluorescence induced by 5-aminolevulinic acid as guidance. The fluorescent quality of the tissue was used to take biopsies from the tumor center, from the invasive area around it and from adjacent normal-looking tissue. These samples were analyzed with HE, Ki-67 and nestin. Nestin expression in tissue surrounding glioblastoma cases was compared to tissue surrounding vascular lesions, metastasis and hippocampal sclerosis. The rate of gross total resection assessed by volumetric MRI was 83%. Using HE examination as the gold standard, fluorescence identified solid tumor with 100% positive predictive value, invasive areas with 97%, and normal tissue with 67% negative predictive value. Ki67 stained some cells in 69% of the non-fluorescent samples around the tumor. There was always strong nestin expression around the tumor but it was similar to control cases in non-glioma lesions with subacute expansion. 5-aminolevulinic acid fluorescence guidance is very reliable and can help to study the tumor-brain interface. Nestin expression is strong and constant in the tissue around the tumor, but is mostly an acute glial reaction, not specific of the neoplasm. Nestin staining is not recommended as a tumor stem cell marker.
Revista:
JOURNAL OF NEURO-ONCOLOGY
ISSN:
0167-594X
Año:
2010
Vol.:
102
N°:
1
Págs.:
105 - 113
We analyzed the efficacy and applicability of surgery guided by 5-aminolevulinic acid (ALA) fluorescence in consecutive patients with glioblastoma multiforme (GBM). Thirty-six patients with GBM were operated on using ALA fluorescence. Resections were performed using the fluorescent light to assess the right plane of dissection. In each case, biopsies with different fluorescent quality were taken from the tumor center, from the edges, and from the surrounding tissue. These samples were analyzed separately with hematoxylin¿eosin examination and immunostaining against Ki67. Tumor volume was quantified with pre- and postoperative volumetric magnetic resonance imaging. Strong fluorescence identified solid tumor with 100% positive predictive value. Invaded tissue beyond the solid tumor mass was identified by vague fluorescence with 97% positive predictive value and 66% negative predictive value, measured against hematoxylin¿eosin examination. All the contrast-enhancing volume was resected in 83.3% of the patients, all patients had resection over 98% of the volume and mean volume resected was 99.8%. One month after surgery there was no mortality, and new or increased neurological morbidity was 8.2%. The fluorescence induced by 5-aminolevulinic can help to achieve near total resection of enhancing tumor volume in most surgical cases of GBM. It is possible during surgery to obtain separate samples of the infiltrating cells from the tumor border.