Evaluación de los resultados terapéuticos en el cáncer avanzado de ovario

Consultable des del TDXTítol obtingut de la portada digitalitzadaEl tratamiento estándar del cáncer avanzado de ovario es la cirugía citoreductora y la quimioterapia combinada con taxol y platino. Se han evaluado a un total de 167 pacientes diagnosticadas en estadios avanzados de cáncer epitelial de ovario (estadio IIB-IV según la clasificación de la FIGO), durante el periodo de 1995-2003, tratadas en el Hospital U. Materno-Infantil Valle Hebron de Barcelona. El periodo de seguimiento fue de 20,2 meses (rango= 0,3-109 meses). El VPP de las pruebas complementarias para el estudio preoperatorio fueron del 89,9% para el CA 125, del 94% para la ecografía vaginal y del 98,1% para la TAC abdomino-pélvica. Un 77,9% de las pacientes se les realizó una cirugía de citoreducción primaria. Un 70,1% se practicó una cirugía de citoreducción óptima (tamaño tumor residual postquirúrgico <2cm) y un 7,9% una cirugía subóptima (tamaño tumor residual de ?2cm). Un 11,3% se realizó tratamiento con quimioterapia neoadyuvante y cirugía citoreductora de intervalo. La tasa de mortalidad operatoria en el grupo de pacientes con citoreducción primaria fue del 4,2% y del 0% en las pacientes que se les realizó la cirugía de intervalo. Se realizaron estudios multivariados con las variables de edad, ascitis, CA 125, histología, grado histológico, estadio clínico de la FIGO) para conocer los factores de mal pronóstico para no poder efectuar la cirugía de citoreducción primaria óptima y la linfadenectomía. Las pacientes de ?70 años [OR 4,4 (IC 95%=1,8-10,7)], CA 125 ?500 [OR 2,1 (IC 95%=1,0-4,4)], estadio IIIC [OR 4,7 (IC 95%=1,6-14,0)] y estadio IV [OR 11,9 (IC 95%=3,2-44,5)] presentaron valores estadísticamente significativos para la imposibilidad de conseguir la cirugía óptima con tamaño del tumor residual de 0cm. Los factores de mal pronóstico con una p<0,05 para conseguir la realización de una linfadenectomía sistemática fueron la edad ?70 años [OR 2,8 (IC 95%=1,1-7,0)], la ascitis [OR 2,7 (IC 95%=1,2-6,1)] y el estadio IV [OR 9,0 (IC 95%=2,1-39,0)]. A un 74,4% de las pacientes del estudio se les efectuó una linfadenectomía sistemática. La supervivencia (SPV) de las 120 pacientes con una linfadenectomía sistemática comparadas con las pacientes a quienes no se les efectuó fue del 55,8% y del 40,0% respectivamente (p<0,05). No se encontraron diferencias estadísticamente significativas en el estudio del periodo libre de enfermedad (PLE). De igual modo, se encontraron diferencias en la supervivencia de las pacientes que obtuvieron una cirugía óptima (TR=0cm) comparadas con las demás pacientes a quienes se les realizó una cirugía citoreductora (óptima con TR<2cm y subóptima). Se efectuó un análisis de las pacientes del estadio más frecuente, el estadio IIIIC con un total de 101 pacientes, para poder determinar diferencias según el tipo de cirugía citoreductora primaria o de intervalo y el grado de afectación tumoral de la cavidad abdominal y retroperitoneal ganglionar, sin encontrar diferencias estadísticamente significativas. Los factores de buen pronóstico para la SPV y PLE de las pacientes con cáncer avanzado de ovario fueron la edad ?60 años y el tipo histológico endometriode (p<0,05). La mediana de SPV global fue de 3,5 años (p25-p75= NC-1,3) y la mediana del PLE global de 1,7 años (p25-p75= 5,3-0,7). El 51,7% de las pacientes presentaron una recidiva con una mediana de SPV de 3,2 años (p25-p75= 5,7-1,5).The standard treatment of the advanced cancer of ovary is the citoreductive surgery and the chemotherapy combined with taxol and platinum. There has been evaluated a whole of 167 patients diagnosed in advanced stages of cancer epithelial of ovary (stage IIB-IV as the classification of FIGO), during the period of 1995-2003, treated in the Materno-Infantil University Hospital of the Valle of Hebron of Barcelona (Spain). The period of pursuit was 20.2 months (range= 0.3-109 months). The VPP of the complementary tests for the preoperative study they were 89.9% for the CA 125, 94% for the vaginal ultrasound scan and 98.1% for the abdomino-pelvic CT. 77.9% of the patients one realized them a primary debulking surgery (DS). 70.1% practised on himself a surgery of ideal DS (size residual postsurgical tumor <2cm) and 7.9% a suboptimal surgery (size residual tumor ?2cm). 11.3% realized treatment with neoadjuvant chemotherapy and DS of interval. The valuation of operative mortality in the group of patients with primary DS was 4.2% and 0% in the patients that one realized them the surgery of interval. There were realized multivariated studies with the variables of age, ascites, CA 125, histology, histological grade, clinical stage of FIGO) to know the factors of bad prognosis not to be able to carry out the surgery of primary optimal DS and the limphadenectomy. The patients of ?70 years [OR 4.4 (95 %CI = 1.8-10.7)], CA 125 ?500 U/ml [OR 2.1 (95 CI % = 1.0-4.4)], stage IIIC [OR 4.7 (95 CI % = 1.6-14.0)] and stage IV [OR 11.9 (95 % CI = 3.2-44.5)] presented values statistically for the inability to obtain the ideal surgery with size of the residual tumor of 0cm. The factors of bad prognosis with one p<0.05 to obtain the achievement of a systematical limphadenectomy were the age ?70 years [OR 2.8 (95 CI % = 1.1-7.0)], the dropsy [OR 2.7 (95 CI % = 1.2-6.1)] and the stage IV [OR 9.0 (95 CI % = 2.1-39.0)]. To 74.4% of the patients of the study a systematical limphadenectomy was carried them out. The survival (SV) of 120 patients with a systematical limphadenectomy compared with the patients those who were not carried out was 55.8% and 40.0% respectively (p<0.05). Statistically significant differences were not in the study of the progression-free survival (PFS). Of equal way, differences were in the survival of the patients who obtained an ideal surgery (RT=0cm) compared with other patients to whom a surgery was realized them DS (optimal with RT <2cm and suboptimal). There was carried out an analysis of the patients of the most frequent stage, the stage IIIIC with a whole of 101 patients, to be able to determine differences according to the type of primary DS or of interval and the grade of tumor affectation of the abdominal cavity and retroperitoneal nodes, without finding statistically significant differences. The factors of good prognosis for the SV and PFS of the patients with advanced cancer of ovary were the age ?60 years and the histological type endometriode (p<0.05). The median of global SV was 3.5 years (p25-p75 = NC-1.3) and the median of the global PFS of 1.7 years (p25-p75 = 5.3-0.7). 51.7% of the patients presented a relapse with a median of SV of 3.2 years (p25-p75 = 5.7-1.5)

Ovarian Fibrosarcoma: Clinicopathologic Considerations about the Intraoperative and Post-Surgical Procedures

Primary ovarian fibrosarcomas are very uncommon neoplasms. Since the diagnostic criteria were established in 1981, less than one hundred cases have been reported. This diagnosis can be difficult to establish and other similar appearing mesenchymal processes must be ruled out. In every case this diagnosis is under consideration. Multiple sections of the specimen and immunohistochemical stains will be necessary to support this diagnosis. The difficulty of recognition in frozen section in the majority of the situations implies that the diagnosis should be deferred to the definitive study of the permanent sections with immunohistochemical studies. There exists a histological resemblance between a primary ovarian fibrosarcoma and actively mitotic fibroma. In some cases, it can be impossible to separate exactly these two entities. We report a well-differentiated ovarian fibrosarcoma, with less than 1-2 mitosis ×10 HPF and low-grade cytological atypia, similar to active mitotic fibromas, developing liver metastasis one year later. Despite having distant metastasis, some cases with long survival rates have been reported in patients who received chemotherapy after surgery; so that the adjuvant chemotherapy should be considered, especially in young females

A combination of molecular and clinical parameters provides a new strategy for high-grade serous ovarian cancer patient management

High-grade serous carcinoma (HGSC) is the most common and deadly subtype of ovarian cancer. Although most patients will initially respond to first-line treatment with a combination of surgery and platinum-based chemotherapy, up to a quarter will be resistant to treatment. We aimed to identify a new strategy to improve HGSC patient management at the time of cancer diagnosis (HGSC-1LTR). A total of 109 ready-available formalin-fixed paraffin-embedded HGSC tissues obtained at the time of HGSC diagnosis were selected for proteomic analysis. Clinical data, treatment approach and outcomes were collected for all patients. An initial discovery cohort (n = 21) were divided into chemoresistant and chemosensitive groups and evaluated using discovery mass-spectrometry (MS)-based proteomics. Proteins showing differential abundance between groups were verified in a verification cohort (n = 88) using targeted MS-based proteomics. A logistic regression model was used to select those proteins able to correctly classify patients into chemoresistant and chemosensitive. The classification performance of the protein and clinical data combinations were assessed through the generation of receiver operating characteristic (ROC) curves. Using the HGSC-1LTR strategy we have identified a molecular signature (TKT, LAMC1 and FUCO) that combined with ready available clinical data (patients' age, menopausal status, serum CA125 levels, and treatment approach) is able to predict patient response to first-line treatment with an AUC: 0.82 (95% CI 0.72-0.92). We have established a new strategy that combines molecular and clinical parameters to predict the response to first-line treatment in HGSC patients (HGSC-1LTR). This strategy can allow the identification of chemoresistance at the time of diagnosis providing the optimization of therapeutic decision making and the evaluation of alternative treatment strategies. Thus, advancing towards the improvement of patient outcome and the individualization of HGSC patients' care. The online version contains supplementary material available at 10.1186/s12967-022-03816-7

Exosome-like vesicles in uterine aspirates : a comparison of ultracentrifugation-based isolation protocols

Altres ajuts: This work was supported by the "Fondo Europeo de Desarrollo Regional" FEDER (RTC-2014-3110-1), the AECC (Grupos Estables de Investigacion 2011 - AECC- GCB 110333 REVE), the Fundació La Marató TV3 (2/C/2013).Altres ajuts: MSCBS/RD12-0036-0035Uterine aspirates are used in the diagnostic process of endometrial disorders, yet further applications could emerge if its complex milieu was simplified. Exosome-like vesicles isolated from uterine aspirates could become an attractive source of biomarkers, but there is a need to standardize isolation protocols. The objective of the study was to determine whether exosome-like vesicles exist in the fluid fraction of uterine aspirates and to compare protocols for their isolation, characterization, and analysis. We collected uterine aspirates from 39 pre-menopausal women suffering from benign gynecological diseases. The fluid fraction of 27 of those aspirates were pooled and split into equal volumes to evaluate three differential centrifugation-based procedures: (1) a standard protocol, (2) a filtration protocol, and (3) a sucrose cushion protocol. Characterization of isolated vesicles was assessed by electron microscopy, nanoparticle tracking analysis and immunoblot. Specifically for RNA material, we evaluate the effect of sonication and RNase A treatment at different steps of the protocol. We finally confirmed the efficiency of the selected methods in non-pooled samples. All protocols were useful to isolate exosome-like vesicles. However, the Standard procedure was the best performing protocol to isolate exosome-like vesicles from uterine aspirates: nanoparticle tracking analysis revealed a higher concentration of vesicles with a mode of 135 ± 5 nm, and immunoblot showed a higher expression of exosome-related markers (CD9, CD63, and CD81) thus verifying an enrichment in this type of vesicles. RNA contained in exosome-like vesicles was successfully extracted with no sonication treatment and exogenous nucleic acids digestion with RNaseA, allowing the analysis of the specific inner cargo by Real-Time qPCR. We confirmed the existence of exosome-like vesicles in the fluid fraction of uterine aspirates. They were successfully isolated by differential centrifugation giving sufficient proteomic and transcriptomic material for further analyses. The Standard protocol was the best performing procedure since the other two tested protocols did not ameliorate neither yield nor purity of exosome-like vesicles. This study contributes to establishing the basis for future comparative studies to foster the field of biomarker research in gynecology. The online version of this article (doi:10.1186/s12967-016-0935-4) contains supplementary material, which is available to authorized users

Nerve-sparing versus non-nerve-sparing radical hysterectomy : surgical and long-term oncological outcomes

There are controversies regarding the long-term oncological safety of preservation of pelvic innervation during radical hysterectomy (RH). This study aimed to analyze the feasibility and safety of nerve-sparing radical hysterectomy (NSRH) for cervical cancer compared with non-NSRH following 17 years of experience in a tertiary cancer referral center. Between May 1999 and June 2016, all patients who underwent RH for cervical cancer were followed-up prospectively. Comparison analyses regarding surgical outcomes, complications, overall survival (OS), disease-free survival (DFS), and cancer-specific survival (CSS) were performed between patients treated with NSRH and non-NSRH. A total of 188 patients were included (113 non-NSRH and 75 NSRH). The median follow-up was 112 months. Estimated blood loss and hospital stay were all significantly lower in the NSRH group. Overall intraoperative complication rate (p = 0.02) and need for transfusion (p = 0.016) were lower in the NSRH group. There were no differences in the median operation time, OS, DFS, CSS, or recurrence rates between the NSRH and non-NSRH group. Our study provides a wide perspective on the developments of nerve-sparing procedures for the management of women with early-stage cervical cancer. Our results suggest that NSRH is a feasible and safe procedure, with reduced morbidity outcomes

Proteomic studies on the management of high-grade serous ovarian cancer patients: a mini-review

High-grade serous ovarian cancer (HGSC) remains the most common and deadly subtype of ovarian cancer. It is characterized by its late diagnosis and frequent relapse despite standardized treatment with cytoreductive surgery and platinum-based chemotherapy. The past decade has seen significant advances in the clinical management and molecular understanding of HGSC following the publication of the Cancer Genome Atlas (TCGA) researchers and the introduction of targeted therapies with anti-angiogenic drugs and poly(ADP-ribose) polymerase inhibitors in specific subgroups of patients. We provide a comprehensive review of HGSC, focusing on the most important molecular advances aimed at providing a better understanding of the disease and its response to treatment. We emphasize the role that proteomic technologies are now playing in these two aspects of the disease, through the identification of proteins and their post-translational modifications in ovarian cancer tumors. Finally, we highlight how the integration of proteomics with genomics, exemplified by the work performed by the Clinical Proteomic Tumor Analysis Consortium (CPTAC), can guide the development of new biomarkers and therapeutic targets.This work was supported by the PhD4MD collaborative research program between the Vall d’Hebron Research Institute (VHIR) and the Centre for Genomic Regulation (CRG). The CRG/UPF Proteomics Unit is part of the Spanish Infrastructure for Omics Technologies (ICTS OmicsTech) and it is a member of the ProteoRed PRB3 consortium which is supported by grant PT17/0019 of the PE I + D + i 2013–2016 from the Instituto de Salud Carlos III (ISCIII) and ERDF. We acknowledge support from the Spanish Ministry of Science and Innovation (CTQ2016-80364-P) and “Centro de Excelencia Severo Ochoa 2013–2017”, SEV-2012-0208; the “Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya” (2017SGR595 and 2017SGR1661), from the Instituto de Salud Carlos III (PI15/02238, PI18/01017, CPII18/00027) and from the Ministerio de Economia y Competitividad y Fondos FEDER (RTC-2015-3821). We also acknowledge the support of the Spanish Ministry of Science and Innovation to the EMBL partnership, the Centro de Excelencia Severo Ochoa and the CERCA Programme/Generalitat de Cataluny

Proteomic Studies on the Management of High-Grade Serous Ovarian Cancer Patients : A Mini-Review

In this manuscript, we review the management strategies available for high-grade serous ovarian cancer patients and the molecular advances that are helping improve our understanding of the tumor and its response to treatment. We emphasize the role that proteomics is now playing in the study of ovarian cancer tumors and how its integration with genomics can guide the development of new biomarkers and therapeutic targets. High-grade serous ovarian cancer (HGSC) remains the most common and deadly subtype of ovarian cancer. It is characterized by its late diagnosis and frequent relapse despite standardized treatment with cytoreductive surgery and platinum-based chemotherapy. The past decade has seen significant advances in the clinical management and molecular understanding of HGSC following the publication of the Cancer Genome Atlas (TCGA) researchers and the introduction of targeted therapies with anti-angiogenic drugs and poly(ADP-ribose) polymerase inhibitors in specific subgroups of patients. We provide a comprehensive review of HGSC, focusing on the most important molecular advances aimed at providing a better understanding of the disease and its response to treatment. We emphasize the role that proteomic technologies are now playing in these two aspects of the disease, through the identification of proteins and their post-translational modifications in ovarian cancer tumors. Finally, we highlight how the integration of proteomics with genomics, exemplified by the work performed by the Clinical Proteomic Tumor Analysis Consortium (CPTAC), can guide the development of new biomarkers and therapeutic target

BRCA1 mutations in high-grade serous ovarian cancer are associated with proteomic changes in DNA repair, splicing, transcription regulation and signaling

Despite recent advances in the management of BRCA1 mutated high-grade serous ovarian cancer (HGSC), the physiology of these tumors remains poorly understood. Here we provide a comprehensive molecular understanding of the signaling processes that drive HGSC pathogenesis with the addition of valuable ubiquitination profiling, and their dependency on BRCA1 mutation-state directly in patient-derived tissues. Using a multilayered proteomic approach, we show the tight coordination between the ubiquitination and phosphorylation regulatory layers and their role in key cellular processes related to BRCA1-dependent HGSC pathogenesis. In addition, we identify key bridging proteins, kinase activity, and post-translational modifications responsible for molding distinct cancer phenotypes, thus providing new opportunities for therapeutic intervention, and ultimately advance towards a more personalized patient care.This work was supported by the PhD4MD collaborative research program between the Vall d’Hebron Research Institute (VHIR) and the Centre for Genomic Regulation (CRG). The CRG/UPF Proteomics Unit is part of the Spanish Infrastructure for Omics Technologies (ICTS OmicsTech) and it is a member of the ProteoRed PRB3 consortium which is supported by grant PT17/0019 of the PE I+D+i 2013-2016 from the Instituto de Salud Carlos III (ISCIII) and ERDF. We acknowledge support from the Spanish Ministry of Science, Innovation and Universities, (CTQ2016-80364-P and “Centro de Excelencia Severo Ochoa 2013-2017”, SEV-2012-0208), and “Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement de la Generalitat de Catalunya” (2017SGR595 and 2017SGR1661). This project has also received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No 823839 (EPIC-XS). It has also been supported by grants from the Instituto Carlos III (PI15/00238, PI18/01017, PI21/00977), the Miguel Servet Program (CP13/00158 and CPII18/00027) and the Ministerio de Economía y Competitividad y Fondos FEDER (RTC-2015-3821-1