RESUMEN
Introduction and objective: The approach to patients with advanced or metastatic high-grade epithelial ovarian cancer (EOC) has evolved over time with the advent of new therapies and multimodal strategies. The objective of this consensus of experts is to generate national recommendations for the profiling and management of advanced or metastatic high-grade OEC, defined as stages III and IV of the "The International Federation of Gynecology and Obstetrics (FIGO) classification at the time of diagnosis to base on the literature review that included international evidence-based clinical practice guidelines (CPG). Material and methods: Eleven panelists (oncologists and gynecological oncologists) answered 8 questions about the profiling and management of advanced or metastatic ovarian epithelial carcinoma. The panelists were chosen for their academic profile and influence in national health institutions. Guidelines from the "ESMO Standardized Operating Procedures Consensus Conference" were used to develop the consensus. It was agreed that the level of agreement to accept a recommendation should be ≥ 80%. The document was peer reviewed. Results: Eight general recommendations are made, which are presented into five domains. Some of these recommendations are subdivided into specific recommendations. Initial treatment Recommendation 1.1 Complete primary cytoreduction (PCS) surgery is suggested as the initial therapy of choice for patients with high-grade or metastatic EOC, which should ideally be carried out in centers with experience, followed by adjuvant therapy. 1.2 Neoadjuvant chemotherapy followed by interval cytoreduction surgery (ICS) is suggested in those who are unlikely to achieve a complete cytoreduction in PCS either due to unresectable metastatic disease or who present unresectability criteria (imaging, laparoscopic and/or by laparotomy) and that have been defined by a gynecological oncologist and patients with poor functional status and comorbidities according to the criteria of the multidisciplinary team (clinical oncology, gynecological oncology, radiology, etc.). Recommendation 2. In patients with high-grade epithelial ovarian cancer (EOC), in stage III locally advanced or metastatic, who received neoadjuvant chemotherapy and achieved a complete or partial response (cytoreduction with tumor residue < 2.5 mm), the use of Hyperthermic IntraPeritoneal Chemotherapy (HIPEC) could be considered as an alternative to standard platinum-based adjuvant intravenous chemotherapy during interval cytoreductive surgery, after discussion in a multidisciplinary tumor board, at a center experienced in treating this type of patients. Use of genetic testing. Recommendation 3. It is suggested at the time of diagnosis to offer molecular genetic testing to all patients with high-grade advanced or metastatic EOC regardless of family history. Recommendation 4. It is suggested to offer genetic counseling, by qualified personnel, to all patients with high-grade advanced or metastatic EOC who are ordered genetic testing. Recommendation 5. It is suggested that all patients with advanced or metastatic high-grade EOC undergo a germ panel that includes the Breast Cancer Susceptibility Genes 1/2 genes (BRCA 1/2) and the other susceptibility genes according to with institutional protocols and the availability of genetic testing panels; If it is negative, then somatic testing should be performed that includes the homologous recombination deficiency (HRD) status, regardless of family history. Adjuvant Therapy Recommendation 6. 6.1. It is suggested that all patients with advanced stage III/IV EOC, with PSC of (0-2), got adjuvant intravenous chemotherapy as standard treatment within six weeks after Prc. It is suggested paclitaxel/carboplatin. Recommendation 6.2. It is suggested to use standard chemotherapy base on platinum plus Bevacizumab as adjuvant chemotherapy to patients with high-risk disease (EOC stage IV or stage III with suboptimal tumor cytoreduction), following by bevacizumab as maintenance. The use of bevacizumab as maintenance therapy is not recommended if bevacizumab was not included in the first line of treatment. We suggested the dose used in GOG-0218 and ICON7 trials. Recommendation 6.3 It is suggested combined intravenous/intraperitoneal chemotherapy only for selected patients, with optimal cytoreduction (residual lesions < 1 cm), especially those without residual disease (R0) and who are evaluated in a multidisciplinary meeting. It is not considered standard treatment. Recommendation 6.4. 6.4.1 It is suggested to use Poly ADP ribose polymerase (PARP) inhibitors such as olaparib or niraparib as maintenance after receiving first-line chemotherapy in patients with stage III/IV BRCA1/2 positive EOC who received platinumbased chemotherapy and obtained complete response/partial response (CR/PR), 6.4.2 It is suggested to use olaparib alone or in combination with bevacizumab or niraparib in patients with stage III/IV BRCA1/2 positive EOC who received platinum-based chemotherapy plus bevacizumab and achieved CR/PR. 6.4.3 It is suggested to use niraparibin patients with stage III/IV BRCA1/2 negative or unknown EOC who received platinum-based chemotherapy and achieved CR/PR. 6.4.4 It is suggested to use bevacizumab or olaparib plus bevacizumab in patients with EOC stage III/IV BRCA1/2 negative or unknown (HRD positive) who received platinum-based chemotherapy plus bevacizumab and obtained CR/PR. Treatment of disease relapse Recommendation 7. Secondary cytoreductive surgery followed by chemotherapy is suggested for selected patients with high-grade advanced EOC in first relapse, platinum-sensitive (platinum-free interval ≥ 6 months), positive "Arbeitsgemeinschaft Gynäkologische Onkologie AGO" score or "I-model" positive (< 4.7) with a potential resection to R0 in centers with access to optimal surgical and postoperative support. Note: Platinum-free interval and AGO score have only been developed as positive predictors of complete resection and not to exclude patients from surgery. Recommendation 8. 8.1 For patients with relapse advanced high-grade EOC platinum-sensitive, the following is suggested: Platinum-based combination chemotherapy: carboplatin/liposomal doxorubicin or carboplatin/paclitaxel or carboplatin/nab-paclitaxel or carboplatin/docetaxel or carboplatin/gemcitabine) for six cycles. If combination therapy is not tolerated, give carboplatin or cisplatin alone. Combination chemotherapy (carboplatin/gemcitabine or carboplatin/paclitaxel or carboplatin/doxorubicin liposomal) plus bevacizumab followed by bevacizumab as maintenance (until progression or toxicity). Recommendation 8.2 For patients with relapsed advanced high-grade EOC platinum-resistant, it is suggested: Sequential treatment with chemotherapy, preferably with a non-platinum single agent (weekly paclitaxel or pegylated liposomal doxorubicin or docetaxel or oral etoposide or gemcitabine or trabectidine or, topotecan). Weekly paclitaxel or pegylated liposomal doxorubicin or topotecan could be administrate with or without bevacizumab. Other agents are considered potentially active (capecitabine, cyclophosphamide, ifosfamide, irinotecan, oxaliplatin, pemetrexed, vinorelbine, cyclophosphamide) could be recommended for later lines. Hormone receptor-positive patients who do not tolerate or have no response to cytotoxic regimens may receive hormone therapy with tamoxifen or other agents, including aromatase inhibitors (anastrozole and letrozole) or leuprolide acetate, or megestrol acetate. Patients with a performance score ≥ 3 should be considered only for best supportive care. Recommendation 8.3 Maintenance therapy with PARP inhibitors: It is suggested in patients with relapse advanced high-grade EOC stage III/IV BRCA1/2 (positive, negative or unknown) who have received two or more lines of platinum-based chemotherapy and have achieved CR/PR, use olaparib, niraparib or rucaparib. Niraparib could be useful in BRCA 1/2 +/-/unknown patients, as rucaparib, however, the latter does not yet have approval from the regulatory office in Colombia. Conclusions: It is expected that the recommendations issued in this consensus will contribute to improving clinical care, oncological impact, and quality of life of these women.
Introducción y objetivo: el abordaje de pacientes con cáncer epitelial de ovario (CEO) de alto grado avanzado o metastásico ha ido evolucionando a través del tiempo con el advenimiento de nuevas terapias y estrategias multimodales. El objetivo de este consenso de expertos es generar recomendaciones nacionales para el perfilamiento y manejo del CEO de alto grado avanzado o metastásico, definido como estadios III y IV de la clasificación de la Federación Internacional de Ginecología y Obstetricia (FIGO) al momento del diagnóstico, a partir de la revisión de la literatura que incluyó guías de práctica clínica (GPC) internacionales basadas en la evidencia. Materiales y métodos: once panelistas (oncólogos y ginecólogos oncólogos) respondieron ocho preguntas sobre el perfilamiento y manejo del carcinoma epitelial de ovario avanzado o metastásico. Los panelistas fueron escogidos por su perfil académico e influencia en instituciones de salud nacionales. Para el desarrollo del consenso se utilizaron los lineamientos de la "Conferencia de consenso de procedimientos operativos estandarizados de ESMO". Se definió que el nivel de acuerdo para aceptar una recomendación debía ser ≥ 80%. El documento fue revisado por pares. Resultados: Se hacen 8 recomendaciones generales, presentadas en cinco dominios; algunas de ellas se subdividen en recomendaciones específicas. Tratamiento inicial Recomendación 1 1.1. Como terapia inicial de elección para pacientes con CEO de alto grado o metastásico se sugiere la cirugía de citorreducción primaria (Cpr) completa que, idealmente, debe realizarse en centros con experiencia, seguida de terapia adyuvante. 1.2. Se sugiere quimioterapia neoadyuvante seguida de cirugía de citorreducción de intervalo (Cint) en quienes sea improbable alcanzar una citorreducción completa en la Cpr, bien sea por enfermedad metastásica no resecable o que presenten criterios de irresecabilidad (imagenológicos, laparoscópicos o por laparotomía) que hayan sido definidos por un ginecólogo oncólogo. También en pacientes con un pobre estado funcional y comorbilidades de acuerdo con el criterio del equipo multidisciplinario (oncología clínica, ginecología oncológica, radiología, etc.). Recomendación 2. En pacientes con CEO de alto grado, en estadio III localmente avanzado o metastásico, que recibieron quimioterapia neoadyuvante y alcanzaron respuesta completa o parcial (citorreducción con residuo tumoral < 2,5 mm), se podría evaluar el uso de la quimioterapia intraperitoneal hipertérmica (Hyperthermic IntraPeritoneal Chemotherapy - HIPEC) como alternativa a la quimioterapia IV adyuvante estándar basada en platinos durante la Cint, previa discusión en junta multidisciplinaria, en un centro de experiencia en este tipo de pacientes. Uso de pruebas genéticas Recomendación 3. Al momento del diagnóstico, se sugiere ofrecer testeo molecular genético a toda paciente con CEO de alto grado avanzado o metastásico, independientemente de la historia familiar. Recomendación 4. Se sugiere ofrecer asesoramiento genético, por parte de personal calificado, a toda paciente con CEO de alto grado avanzado o metastásico a quien se le ordene un testeo genético. Recomendación 5. Se sugiere que a toda paciente con CEO de alto grado avanzado o metastásico se le realice panel germinal que incluya los genes de susceptibilidad al cáncer de mama 1/2 (BRCA 1/2) y los otros genes de susceptibilidad de acuerdo con los protocolos institucionales y la disponibilidad de paneles de testeo genético; si es negativo entonces se debería realizar testeo somático que incluya el estatus de deficiencia de la recombinación homóloga (homologous recombination deficiency - HRD), independientemente de la historia familiar. Terapia adyuvante Recomendación 6 6.1. Se sugiere que a toda paciente con CEO estadios III/IV avanzado o metastásico, con estatus de desempeño (performance score care - PSC) de 0-2 se le administre como tratamiento estándar quimioterapia intravenosa (IV) adyuvante dentro de las seis semanas posteriores a la Cpr. Se sugiere administrar paclitaxel/carboplatino. 6.2. Se sugiere utilizar quimioterapia estándar basada en platino más bevacizumab como adyuvancia en pacientes con enfermedad de alto riesgo (CEO estadios IV o III con citorreducción tumoral subóptima), continuando con bevacizumab como mantenimiento. No se recomienda el uso de bevacizumab como terapia de mantenimiento si no se incluyó en la primera línea de tratamiento. Se sugiere seguir los esquemas de los estudios Gynecologic Oncology Group Study (GOG-0218) e International Collaborative Ovarian Neoplasm (ICON7). 6.3. Se sugiere la quimioterapia combinada IV/intraperitoneal (IP) solo para pacientes seleccionadas, con una citorreducción óptima (lesiones residuales < 1 cm), en especial aquellas sin enfermedad residual (R0) y que sean evaluadas en junta multidisciplinaria. La quimioterapia combinada IV/IP no se considera como tratamiento estándar. 6.4. 6.4.1. Se sugiere utilizar inhibidores de poli(ADP-ribosa) polimerasa (PARP) tales como olaparib o niraparib como mantenimiento después de recibir una primera línea de quimioterapia en pacientes con CEO estadios III/IV BRCA1/2 positivo que recibieron quimioterapia basada en platino y obtuvieron respuesta completa/respuesta parcial (RC/RP). 6.4.2. Se sugiere utilizar olaparib solo o en combinación con bevacizumab o niraparib en pacientes con CEO estadios III/IV BRCA1/2 positivo que recibieron quimioterapia basada en platino más bevacizumab y obtuvieron RC/RP. 6.4.3. Se sugiere utilizar niraparib en pacientes con CEO estadio III/IV BRCA1/2 negativo o desconocido que recibieron quimioterapia basada en platino y obtuvieron RC/RP. 6.4.4. Se sugiere utilizar bevacizumab u olaparib más bevacizumab en pacientes con CEO estadios III/IV BRCA1/2 negativo o desconocido (HRD positivo) que recibieron quimioterapia basada en platino más bevacizumab y obtuvieron RC/RP. Tratamiento de la recaída de la enfermedad Recomendación 7. Se sugiere la realización de la cirugía de citorreducción secundaria (Csec), seguida de quimioterapia, a pacientes seleccionadas con CEO de alto grado avanzado o metastásico en primera recaída, platino-sensibles (intervalo libre de platinos ≥ 6 meses), puntuación Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) positiva o Integrate model (I-Model) positivo (< 4,7), y con una potencial resección a R0, en centros con acceso a soporte quirúrgico y posoperatorio óptimo. Nota: el intervalo libre de tratamiento con platinos y la puntuación AGO solo se han desarrollado como predictores positivos de resección completa y no para excluir a las pacientes de la cirugía. Recomendación 8 8.1. Para pacientes con CEO de alto grado avanzado o metastásico en recaída platino-sensibles se sugiere: Quimioterapia combinada basada en platino: carboplatino/doxorrubicina liposomal o carboplatino/paclitaxel o carboplatino/ nab-paclitaxel o carboplatino/docetaxel o carboplatino/gemcitabina, por seis ciclos. Si no se tolera la terapia combinada, dar carboplatino o cisplatino solo. Quimioterapia combinada: carboplatino/gemcitabina o carboplatino/paclitaxel o carboplatino/doxorubicina liposomal, más bevacizumab, seguida de bevacizumab como mantenimiento (hasta progresión o toxicidad). 8.2. Para pacientes con CEO de alto grado avanzado o metastásico en recaída, platino-resistentes, se sugiere: Tratamiento secuencial con quimioterapia, preferiblemente con un agente único que no sea un platino (paclitaxel semanal o doxorrubicina liposomal pegilada o docetaxel o etopósido oral o gemcitabina o trabectidina o topotecan). El paclitaxel semanal o la doxorrubicina liposomal pegilada o el topotecan pueden ser administrados con o sin bevacizumab. Existen otros agentes que se consideran potencialmente act ivos (capecitabina, ciclofosfamida, ifosfamida, irinotecán, oxaliplatino, pemetrexed, vinorelbina, ciclofosfamida), que se podrían recomendar para líneas posteriores. Las pacientes con receptores hormonales positivos que no toleran o no tienen respuesta a los regímenes citotóxicos pueden recibir terapia hormonal con tamoxifeno u otros agentes, incluidos los inhibidores de la aromatasa (anastrozol y letrozol) o acetato de leuprolide o acetato de megestrol. Pacientes con PSC ≥ 3 deberían ser consideradas solo para el mejor cuidado de soporte. 8.3. Terapia de mantenimiento con inhibidores PARP. Para pacientes con CEO de alto grado avanzado o metastásico en recaída estadios III/IV BRCA1/2 (positivo, negativo o desconocido), que hayan recibido dos o más líneas de quimioterapia basada en platino y hayan alcanzado RC/RP, se sugiere utilizar olaparib, niraparib o rucaparib. El niraparib podría ser útil en pacientes BRCA 1/2 +/-/desconocido, al igual que el rucaparib, sin embargo, este último no tiene aún aprobación del ente regulador en Colombia. Conclusiones: se espera que las recomendaciones emitidas en este consenso contribuyan a mejorar la atención clínica, el impacto oncológico y la calidad de vida de estas mujeres.
Asunto(s)
Carcinoma Epitelial de Ovario , Medicina Basada en la Evidencia , Neoplasias Ováricas , Humanos , Femenino , Neoplasias Ováricas/terapia , Neoplasias Ováricas/patología , Neoplasias Ováricas/diagnóstico , Carcinoma Epitelial de Ovario/terapia , Carcinoma Epitelial de Ovario/patología , Carcinoma Epitelial de Ovario/diagnóstico , Clasificación del Tumor , Estadificación de Neoplasias , Procedimientos Quirúrgicos de Citorreducción/métodos , Neoplasias Glandulares y Epiteliales/terapia , Neoplasias Glandulares y Epiteliales/patología , Neoplasias Glandulares y Epiteliales/diagnóstico , Consenso , Terapia CombinadaRESUMEN
Objectives: To determine if there is an association between the neutrophil to lymphocyte ratio (NLR) and prognosis in patients with epithelial ovarian cancer (EOC) diagnosed and treated in a Spanish population. Material and methods: Retrospective cohort of patients with epithelial ovarian cancer who had neutrophil and lymphocyte values in complete blood count before the histopathological diagnosis and survival of at least three months, in an intermediate complexity hospital. Convenience sampling. Measured variables included age, menopausal stage, parity, International Federation of Gynecology and Obstetrics (FIGO) stage, treatment type, residual tumor, lymph node involvement, presence of ascites, cytology, histologic type, differentiation grade, and CA-125 values. Additionally, outcomes, overall survival, disease/progression-free survival were also measured. Bivariate inferential and Cox regression analyses were performed. Results: Out of 78 candidates, 60 women with EOC were included. Of them, 24 (40%) had a low NLR (≤ 2,9) while 36 (60%) had a high NLR (> 2,9). An association was found between high NLR levels and suboptimal cytoreductive surgery. High NLR ratios were associated with lower overall survival (Hazard ratio (HR): 4.1; 95% CI: 1.4-11.8) and lower 5-year disease-free survival (HR: 2.6; 95% CI: 1.2-5.7). Conclusions: A plasma neutrophil to lymphocyte ratio of more than 2.9 was associated with poor prognosis in patients with epithelial ovarian cancer in our setting. There is a need to establish the optimal cut-off point and conduct prospective studies with larger patient numbers in order to support this information.
Objetivos: evaluar si hay asociación entre los valores del cociente plasmático neutrófilos/ linfocitos (NLR) y el pronóstico en pacientes con cáncer epitelial de ovario (CEO) diagnosticadas y tratadas en una población española. Materiales y métodos: cohorte retrospectiva de pacientes con cáncer epitelial de ovario que tuvieran un recuento de neutrófilos y linfocitos en hemograma previo al diagnóstico histopatológico en un hospital de nivel medio de complejidad y posterior sobrevida de, al menos, 3 meses. Muestreo por conveniencia. Se midieron: edad, estado menopáusico, paridad, estadio Federación International de Ginecología y Obstetricia (FIGO), tipo de tratamiento, tumor residual, afectación ganglionar, presencia de ascitis, citología, tipo histológico, grado de diferenciación y cifras de CA-125; como desenlaces, sobrevida global y sobrevida libre de enfermedad o progresión. Análisis inferencial bivariado y por regresión de Cox. Resultados: de 78 candidatas, ingresaron 60 mujeres con CEO. De ellas, 24 (40%) presentaron un NLR bajo (≤ 2,9) y 36 (60 %) elevado (> 2,9). Se encontró asociación entre los niveles altos de NLR y cirugía citoreductora subóptima. Los niveles altos de NLR se asociaron a menor sobrevida global (Hazard ratio (HR): 4,1; IC 95%: 1,4-11,8) y menor sobrevida libre de enfermedad a los 5 años (HR:2,6; IC 95 %: 1,2-5,7). Conclusiones: un cociente plasmático neutrófilos/linfocitos mayor de 2,9 se asoció a un mal pronóstico en pacientes con cáncer epitelial de ovario en nuestro medio. Se necesita determinar el punto de corte óptimo y realizar estudios prospectivos con mayor número de pacientes que avalen esta información.
Asunto(s)
Carcinoma Epitelial de Ovario , Linfocitos , Neutrófilos , Neoplasias Ováricas , Humanos , Femenino , Estudios Retrospectivos , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/sangre , Neoplasias Ováricas/patología , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/cirugía , Carcinoma Epitelial de Ovario/sangre , Carcinoma Epitelial de Ovario/mortalidad , Carcinoma Epitelial de Ovario/patología , Carcinoma Epitelial de Ovario/cirugía , Pronóstico , Persona de Mediana Edad , Linfocitos/patología , Anciano , Adulto , Estudios de Cohortes , Procedimientos Quirúrgicos de Citorreducción , España/epidemiología , Supervivencia sin Enfermedad , Recuento de Linfocitos , Tasa de Supervivencia , Periodo Preoperatorio , Recuento de LeucocitosRESUMEN
In recent years, the incorporation of new strategies to the therapeutic armamentarium has completely changed the outcomes of epithelial ovarian cancer (EOC). The identification of new predictive and prognostic biomarkers has also enabled the selection of those patients more likely to respond to targeted agents. Nevertheless, EOC is still a highly lethal disease and resistance to many of these new agents is common. The objective of this guideline is to summarize the most relevant strategies to manage EOC, to help the clinician throughout the challenging diagnostic and therapeutic processes and to provide evidence-based recommendations.
Asunto(s)
Carcinoma Epitelial de Ovario , Neoplasias Ováricas , Humanos , Carcinoma Epitelial de Ovario/terapia , Carcinoma Epitelial de Ovario/patología , Femenino , Neoplasias Ováricas/terapia , Neoplasias Ováricas/patología , Neoplasias Ováricas/diagnóstico , Pronóstico , Oncología Médica/normas , Oncología Médica/métodosRESUMEN
OBJECTIVE: Our objective was to analyze the prevalence of lymph node metastasis in early-stage ovarian carcinoma after systematic lymph node dissection and its impact on indication of adjuvant chemotherapy. STUDY DESIGN: We evaluated a series of 765 patients diagnosed with ovarian carcinoma who underwent surgical treatment from February 2007 to December 2019. Patients with peritoneal disease and incomplete surgical staging were excluded. All cases underwent systematic pelvic and para-aortic lymphadenectomy up to the renal vessels. RESULTS: A total of 142 cases were analyzed. Median pelvic and para-aortic lymph node dissected were 30 (range, 6-81) and 21 (range, 3-86), respectively. Twelve (8.4%) patients had metastatic lymph nodes - high-grade serous, 10.4% (5/48); clear cell, 17.2% (5/29) and endometrioid, 5.7% (2/35). Any other histology (low grade serous, mucinous, carcinosarcoma or mixed) had lymph node metastasis. Notably, 50% of patients with positive lymph nodes had preoperative suspicious lymph nodes in imaging. The median hospital stay length was 6 days (range, 2-33) and 4.2% cases had grade ≥ 3 complications. A total of 110 (77.6%) patients underwent adjuvant chemotherapy and all cases had indication of adjuvant chemotherapy after histological type, despite the lymph node status. After a median follow-up of 52.5 months, we noted 24 (16.9%) recurrences. The 5-year recurrence-free survival and overall survival were 86.4% and 98.1%, respectively. High grade histology was the only variable that negatively impacted disease-free survival in univariate analysis [HR 4.70 (95%CI: 1.09-20); p = 0.037]. CONCLUSIONS: We found a positive lymph node rate of less than 10% after lymphadenectomy in presumed early-stage ovarian carcinoma. Lymph node status was not determinant for adjuvant chemotherapy.
Asunto(s)
Carcinoma , Neoplasias Ováricas , Femenino , Humanos , Metástasis Linfática/patología , Estadificación de Neoplasias , Carcinoma Epitelial de Ovario/patología , Ganglios Linfáticos/cirugía , Ganglios Linfáticos/patología , Neoplasias Ováricas/patología , Escisión del Ganglio Linfático/métodos , Carcinoma/cirugía , Carcinoma/patología , Estudios RetrospectivosRESUMEN
Nerve growth factor (NGF) and its high-affinity receptor TRKA are overexpressed in epithelial ovarian cancer (EOC) displaying a crucial role in the disease progression. Otherwise, NGF interacts with its low-affinity receptor P75, activating pro-apoptotic pathways. In neurons, P75 could be cleaved by metalloproteinases (α and γ-secretases), leading to a decrease in P75 signaling. Therefore, this study aimed to evaluate whether the shedding of P75 occurs in EOC cells and whether NGF/TRKA could promote the cleavage of the P75 receptor. The immunodetection of the α-secretase, ADAM17, TRKA, P75, and P75 fragments was assessed by immunohisto/cytochemistry and Western blot in biopsies and ovarian cell lines. The TRKA and secretases' inhibition was performed using specific inhibitors. The results show that P75 immunodetection decreased during EOC progression and was negatively correlated with the presence of TRKA in EOC biopsies. NGF/TRKA increases ADAM17 levels and the fragments of P75 in ovarian cells. This effect is abolished when cells are previously treated with ADAM17, γ-secretase, and TRKA inhibitors. These results indicate that NGF/TRKA promotes the shedding of P75, involving the activation of secretases such as ADAM17. Since ADAM17 has been proposed as a screening marker for early detection of EOC, our results contribute to understanding better the role of ADAM17 and NGF/TRKA in EOC pathogenesis, which includes the NGF/TRKA-mediated cleavage of P75.
Asunto(s)
Proteína ADAM17/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Factor de Crecimiento Nervioso/metabolismo , Neoplasias Ováricas/metabolismo , Ovario/metabolismo , Receptor trkA/metabolismo , Factores de Transcripción/metabolismo , Carcinoma Epitelial de Ovario/metabolismo , Carcinoma Epitelial de Ovario/patología , Línea Celular , Línea Celular Tumoral , Femenino , Humanos , Persona de Mediana Edad , Neuronas/metabolismo , Neoplasias Ováricas/patología , Ovario/patología , Transducción de Señal/fisiologíaRESUMEN
The main goal of this study is to evaluate the efficacy of the paclitaxel (PTX) drug formulated with a liposomal nanosystem (L-PTX) in a peritoneal carcinomatosis derived from ovarian cancer. In vitro cell viability studies with the human ovarian cancer line A2780 showed a 50% decrease in the inhibitory concentration for L-PTX compared to free PTX. A2780 cells treated with the L-PTX formulation demonstrated a reduced capacity to form colonies in comparison to those treated with PTX. Cell death following L-PTX administration hinted at apoptosis, with most cells undergoing initial apoptosis. A2780 cells exhibited an inhibitory migration profile when analyzed by Wound Healing and real-time cell analysis (xCELLigence) methods after L-PTX administration. This inhibition was related to decreased expression of the zinc finger E-box-binding homeobox 1 (ZEB1) and transforming growth factor 2 (TGF-ß2) genes. In vivoL-PTX administration strongly inhibited tumor cell proliferation in ovarian peritoneal carcinomatosis derived from ovarian cancer, indicating higher antitumor activity than PTX. L-PTX formulation did not show toxicity in the mice model. This study demonstrated that liposomal paclitaxel formulations are less toxic to normal tissues than free paclitaxel and are more effective in inhibiting tumor cell proliferation/migration and inducing ZEB1/TGF-ß2 gene expression.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Paclitaxel/farmacología , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Apoptosis/efectos de los fármacos , Carcinoma Epitelial de Ovario/genética , Carcinoma Epitelial de Ovario/patología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Liposomas , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Paclitaxel/administración & dosificación , Neoplasias Peritoneales/tratamiento farmacológicoRESUMEN
Ovarian cancer represents the third gynecological cancer in frequency in Argentina. There is a lack of information on this pathology in our country regarding the treatment and evolution of patients who suffer it. The aim of this study was to evaluate the perioperative and oncological results in patients with advanced epithelial ovarian tumor. We present a retrospective cohort in which we evaluated disease-free survival and overall survival in patients with epithelial ovarian tumor treated at the Hospital Italiano de Buenos Aires between June 2009 and June 2017. Of 170 patients included in the study, 72 (42.4%) received primary debulking surgery (CCP), while 98 (57.6%) received neoadjuvant therapy and interval surgery (CI). The optimal cyto-reduction rate was 75% and 79% respectively. No differences were found in perioperative outcomes, or in severe complications between the two groups. The median disease-free survival in the CCP group was 2.5 years (95% CI 1.6-3.1) while in the CI group it was 1.4 (95% CI 1.2-1.7) p < 0.001. The median overall survival was 5.8 years in CPP, and 3.5 years in CI. Faced with a meticulous selection by a group of experts, patients with advanced ovarian cancer treated with CCP present better oncological results than those who received neoadjuvant therapy and CI.
El cáncer de ovario ocupa el tercer lugar en frecuencia entre los cánceres ginecológicos en Argentina. Existe un déficit de información de esta enfermedad en nuestro país respecto al tratamiento y evolución oncológica de las pacientes. El objetivo de nuestro trabajo fue evaluar los resultados perioperatorios y oncológicos, en pacientes con tumor epitelial de ovario con estadios avanzados. Presentamos una cohorte retrospectiva en la que se evaluó la supervivencia libre de enfermedad y la supervivencia global en pacientes con tumores epiteliales de ovario tratadas en el Hospital Italiano de Buenos Aires entre junio del 2009 a junio del 2017. De 170 pacientes incluidas en el estudio, 72 (42.4%) fueron tratadas con una cirugía de citorreducción primaria (CCP), mientras que 98 (57.6%) recibieron neoadyuvancia y luego cirugía del intervalo (CI). La tasa de citorreducción óptima fue de 75% y de 79% respectivamente. No se encontraron diferencias en los resultados perioperatorios, ni en las complicaciones graves entre ambos grupos. La mediana de SLE en el grupo de CCP fue de 2.5 años (IC 95% 1.6-3.1) mientras que en el grupo de CI fue de 1.4 (IC 95% 1.2-1.7) p < 0.001. La mediana de supervivencia global fue de 5.8 años en CCP, y de 3.5 años en CI. En pacientes adecuadamente seleccionadas la CCP presenta mejores resultados oncológicos a la neoadyuvancia y CI. La selección correcta de las pacientes para tratamiento primario es fundamental para definir la conducta terapéutica.
Asunto(s)
Neoplasias Ováricas , Carcinoma Epitelial de Ovario/patología , Carcinoma Epitelial de Ovario/terapia , Femenino , Hospitales , Humanos , Terapia Neoadyuvante , Estadificación de Neoplasias , Neoplasias Ováricas/patología , Neoplasias Ováricas/terapia , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Resumen El cáncer de ovario ocupa el tercer lugar en frecuencia entre los cánceres ginecológicos en Argentina. Existe un déficit de información de esta enfermedad en nuestro país respecto al tratamiento y evolución oncológica de las pacientes. El objetivo de nuestro trabajo fue evaluar los resultados perioperatorios y oncológicos, en pacientes con tumor epitelial de ovario con estadios avanzados. Presentamos una cohorte retrospectiva en la que se evaluó la supervivencia libre de enfermedad y la supervivencia global en pacientes con tumores epiteliales de ovario tratadas en el Hospital Italiano de Buenos Aires entre junio del 2009 a junio del 2017. De 170 pacientes incluidas en el estudio, 72 (42.4%) fueron tratadas con una cirugía de citorreducción primaria (CCP), mientras que 98 (57.6%) recibieron neoadyuvancia y luego cirugía del intervalo (CI). La tasa de citorreducción óptima fue de 75% y de 79% respectivamente. No se encontraron diferencias en los resultados perioperatorios, ni en las complicaciones graves entre ambos grupos. La mediana de SLE en el grupo de CCP fue de 2.5 años (IC 95% 1.6-3.1) mientras que en el grupo de CI fue de 1.4 (IC 95% 1.2-1.7) p < 0.001. La mediana de supervivencia global fue de 5.8 años en CCP, y de 3.5 años en CI. En pacientes adecuadamente seleccionadas la CCP presenta mejores resultados oncológicos a la neoadyuvancia y CI. La selección correcta de las pacientes para tratamiento primario es fundamental para definir la conducta terapéutica.
Abstract Ovarian cancer represents the third gynecological cancer in frequency in Argentina. There is a lack of information on this pathology in our country regarding the treatment and evolution of patients who suffer it. The aim of this study was to evaluate the perioperative and oncological results in patients with advanced epithelial ovarian tumor. We present a retrospective cohort in which we evaluated disease-free survival and overall survival in patients with epithelial ovarian tumor treated at the Hospital Italiano de Buenos Aires between June 2009 and June 2017. Of 170 patients included in the study, 72 (42.4%) received primary debulking surgery (CCP), while 98 (57.6%) received neoadjuvant therapy and interval surgery (CI). The optimal cyto-reduction rate was 75% and 79% respectively. No differences were found in perioperative outcomes, or in severe complications between the two groups. The median disease-free survival in the CCP group was 2.5 years (95% CI 1.6-3.1) while in the CI group it was 1.4 (95% CI 1.2-1.7) p < 0.001. The median overall survival was 5.8 years in CPP, and 3.5 years in CI. Faced with a meticulous selection by a group of experts, patients with advanced ovarian cancer treated with CCP present better oncological results than those who received neoadjuvant therapy and CI.
Asunto(s)
Humanos , Femenino , Neoplasias Ováricas/patología , Neoplasias Ováricas/terapia , Estudios Retrospectivos , Resultado del Tratamiento , Terapia Neoadyuvante , Carcinoma Epitelial de Ovario/patología , Carcinoma Epitelial de Ovario/terapia , Hospitales , Estadificación de NeoplasiasRESUMEN
Early diagnosis of ovarian carcinoma is bound to boost the long-term endurance rate of the patients. Most ovarian tumors happen post menopause when the ovaries have no vital operation and therefore irregular ovarian role causes no signs. According to Muinao T. et al. (Heliyon. 5(12):e02826, 2019), if we consider the frequency of ovarian carcinoma to be moderate, a screening technique must accomplish a base specificity of 99.6% and sensitivity of over 75%. The classification and approval of early diagnostic biomarkers explicit to ovarian carcinoma are essentially required. Prevailing methods for early diagnosis of ovarian carcinoma incorporate TVS, biological marker examination, or a blend of the two or other. In recent years, it has been revealed that a combination of at least two biomarkers has beaten single biomarkers in measures for early diagnosis of the illness. In the present document, we survey the ongoing exploration of innovative characteristic methodologies and possible panels of carcinoma biological markers for the early diagnosis of ovarian carcinoma and discuss biomarkers as the plausible apparatus for model improvement and other progressed approaches as an effective alternative to the prevailing methods for early diagnosis of this dreadful disease to evade bogus analysis and inordinate expense.
Asunto(s)
Biomarcadores de Tumor/sangre , Detección Precoz del Cáncer/métodos , Neoplasias Ováricas/diagnóstico , Área Bajo la Curva , Autoanticuerpos/sangre , Teorema de Bayes , Antígeno Ca-125/sangre , Carcinoma Epitelial de Ovario/sangre , Carcinoma Epitelial de Ovario/diagnóstico , Carcinoma Epitelial de Ovario/patología , Metilación de ADN , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Proteínas de la Membrana/sangre , MicroARNs/sangre , Persona de Mediana Edad , Método de Montecarlo , Neoplasias Ováricas/sangre , Neoplasias Ováricas/diagnóstico por imagen , Neoplasias Ováricas/patología , Sensibilidad y Especificidad , Espectrometría Raman , Ultrasonografía , Proteína 2 de Dominio del Núcleo de Cuatro Disulfuros WAP/análisisRESUMEN
Despite remarkable advances in the knowledge of molecular biology and treatment, ovarian cancer remains the leading cause of death from gynecologic cancer. In the last decade, there have been important advances both in systemic and surgical treatment. However, there is no doubt that the incorporation of PARP inhibitors as maintenance after the response to platinum-based chemotherapy, first in recurrent disease and recently also in first line, will change the natural history of the disease.The objective of this guide is to summarize the current evidence for the diagnosis, treatment, and follow-up of ovarian cancer, and to provide evidence-based recommendations for clinical practice.
Asunto(s)
Carcinoma Epitelial de Ovario/diagnóstico , Carcinoma Epitelial de Ovario/terapia , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/terapia , Antineoplásicos Inmunológicos/uso terapéutico , Bevacizumab/uso terapéutico , Carcinoma Epitelial de Ovario/patología , Quimioterapia Adyuvante/métodos , Ensayos Clínicos Fase III como Asunto , Procedimientos Quirúrgicos de Citorreducción/métodos , Femenino , Humanos , Quimioterapia de Mantención/métodos , Oncología Médica , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/cirugía , Estadificación de Neoplasias/métodos , Neoplasias Ováricas/patología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Sociedades Médicas , EspañaRESUMEN
BACKGROUND: The current study evaluated the metalloproteinases MMP-2 and MMP-9 expression in epithelial cells and the surrounding stroma in ovarian tumors and the association of MMPs with the histological subtypes, the clinical stage and the presence of steroid hormone receptors. Tumor samples were obtained from 88 patients undergoing surgical cytoreduction of primary ovarian tumors in Instituto Nacional de Cancerología, from México City. The formalin fixed and paraffin embedded samples were processed in order to demonstrate the presence of androgen receptor,estrogen receptor alpha, progesterone receptor, MMP-2,MMP-9 and collagen IV by immunohistochemistry and/or immunofluorescence. RESULTS: MMP-2 and MMP-9 were differentially expressed in the epithelium and the stroma of ovarian tumors associated to histological subtype, clinical stage and sexual steroid hormone receptor expression. Based on Cox proportional hazard regression model we demonstrated that MMP-2 located in the epithelium and the stroma are independent prognostic biomarkers for overall survival in epithelial ovarian tumors. Kaplan Meir analysis of the combination of AR (+) with MMP-2 (+) in epithelium and AR (+) with MMP-2 (-) in stroma displayed a significant reduction of survival. CONCLUSIONS: The presence of MMP-2 in the stroma of the tumor was a protective factor while the presence of MMP-2 in the epithelium indicated an adverse prognosis. The presence of AR associated with MMP-2 in the tumor cells was a risk factor for overall survival in epithelial ovarian cancer.
Asunto(s)
Carcinoma Epitelial de Ovario/patología , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Neoplasias Ováricas/patología , Receptores Androgénicos/metabolismo , Adulto , Carcinoma Epitelial de Ovario/metabolismo , Epitelio/metabolismo , Epitelio/patología , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Ováricas/metabolismo , Pronóstico , Estudios Retrospectivos , Células del Estroma/metabolismo , Células del Estroma/patología , Análisis de SupervivenciaRESUMEN
Epithelial ovarian cancer (EOC) is a heterogeneous disease that can be categorized into four major histological subtypes. Its etiology remains poorly understood due mainly to this heterogeneity. Follicle-stimulating hormone (FSH) has been implicated as a risk factor in EOC and has been suggested that may influence the development of specific subtypes. In addition, FSH regulates different aspects of ovarian cancer tumorigenesis. FSH downstream target genes in EOC have not been fully identified. Progranulin (PGRN) overexpression is associated with cell proliferation, invasion, chemoresistance, and shortened overall survival in ovarian cancer. Recently, we demonstrated that PGRN expression is regulated through the PI3K signaling pathway in clear cell ovarian carcinoma (CCOC) cells. In contrast, we also demonstrated that PGRN synthesis in serous ovarian cancer (SOC) cells is regulated via PKC but not by the PI3K signaling pathway. Several studies have demonstrated that FSH induces PKC and PI3K activation. Thus, this study was to investigate the effect of FSH on PGRN production in the CCOC cell line TOV-21G as compared to the SOC cell lines SKOV3 and OVCAR3. Cultured TOV-21G, SKOV3, and OVCAR3 cells were incubated with different concentrations of FSH for 48 h. PGRN mRNA and protein expression were assessed by RT-PCR and Western blotting, while PGRN secretion was measured by ELISA. PGRN mRNA and protein expression, as well as PGRN secretion, significantly increased after FSH stimulation in TOV-21G but not in SKOV3 and OVCAR3 cells. These data indicate that FSH induces PGRN expression and secretion only in CCOC cells. Establishing specific features for CCOC could reveal potential diagnostic and therapeutic targets.
Asunto(s)
Carcinoma Epitelial de Ovario/metabolismo , Hormona Folículo Estimulante/farmacología , Neoplasias Ováricas/metabolismo , Progranulinas/biosíntesis , Apoptosis/efectos de los fármacos , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/genética , Carcinoma Epitelial de Ovario/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Fosfatidilinositol 3-Quinasas/metabolismo , Progranulinas/genética , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Proteínas Recombinantes/farmacologíaRESUMEN
In the last 40 years ovarian cancer mortality rates have slightly declined and, consequently, it continues to be the fifth cause of cancer death in women. In the present study, we showed that ß-catenin signaling is involved in the functions of ovarian cancer cells and interacts with the Notch system. Wnt and Notch systems showed to be prosurvival for ovarian cancer cells and their inhibition impaired cell proliferation and migration. We also demonstrated that the inhibition of ß-catenin by means of two molecules, XAV939 and ICG-001, decreased the proliferation of the IGROV1 and SKOV3 ovarian cancer cell lines and that ICG-001 increased the percentage of IGROV1 cells undergoing apoptosis. The simultaneous inhibition of ß-catenin and Notch signaling, by using the DAPT inhibitor, decreased ovarian cancer cell proliferation to the same extent as targeting only the Wnt/ß-catenin pathway. A similar effect was observed in IGROV1 cell migration with ICG-001 and DAPT. ICG-001 increased the Notch target genes Hes-1 and Hey-1 and increased Jagged1 expression. However, no changes were observed in Dll4 or Notch 1 and 4 expressions. Our results suggest that Notch and ß-catenin signaling co-operate in ovarian cancer to ensure the proliferation and migration of cells and that this could be achieved, at least partly, by the upregulation of Notch Jagged1 ligand in the absence of Wnt signaling. We showed that the Wnt pathway crosstalks with Notch in ovarian cancer cell functions, which may have implications in ovarian cancer therapeutics.
Asunto(s)
Carcinoma Epitelial de Ovario/patología , Neoplasias Ováricas/patología , Receptores Notch/metabolismo , Transducción de Señal/fisiología , Vía de Señalización Wnt/fisiología , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Carcinoma Epitelial de Ovario/metabolismo , Movimiento Celular/efectos de los fármacos , Movimiento Celular/fisiología , Proliferación Celular/efectos de los fármacos , Proliferación Celular/fisiología , Supervivencia Celular , Diaminas/farmacología , Femenino , Humanos , Ratones , Ratones Desnudos , Neoplasias Ováricas/metabolismo , Pirimidinonas/farmacología , Tiazoles/farmacología , Vía de Señalización Wnt/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
PURPOSE: Our main aim is to analyze the survival results in women operated on for advanced ovarian cancer with two different HIPEC regimens (cisplatin plus doxorubicin versus paclitaxel). PATIENTS AND METHODS: A prospective cohort of patients with stage IIIC or IV epithelial ovarian cancer operated on with cytoreductive surgery and HIPEC, from October-2008 to February-2016, was retrospectively analyzed. The two drugs used, cisplatin/doxorubicin (Group A) and paclitaxel (Group B), were compared. RESULTS: Forty-one patients were treated with cytoreductive surgery and HIPEC; 19 patients (46%) were in Group A and 22 (54%) were in Group B. The extent of peritoneal disease was comparable between groups (Peritoneal Cancer Index of 10 in Group A versus PCI of 12.5 in Group B). There were no differences in morbidity between groups, with a severe morbidity (Dindo-Clavien III or IV) of 36.8% versus 27.3%, respectively. There was no postoperative mortality. Median follow-up was 39 months. Median overall survival was 79 months. Overall survival at 3 years in Group A was 66% versus 82.9% in Group B (p = 0.248). Incomplete cytoreduction (macroscopic residual tumour after surgery) was identified as the only independent factor that influenced overall survival (HR 12.30, 95% CI 1.28-118.33, p = 0.03). The cytostatic used in HIPEC had no influence in overall survival. CONCLUSION: The cytostatic used in HIPEC did not have a negative effect in the prognosis of patients with advanced ovarian cancer.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma Epitelial de Ovario/terapia , Hipertermia Inducida , Neoplasias Ováricas/terapia , Neoplasias Peritoneales/terapia , Adulto , Anciano , Carcinoma Epitelial de Ovario/mortalidad , Carcinoma Epitelial de Ovario/patología , Cisplatino/administración & dosificación , Terapia Combinada/efectos adversos , Terapia Combinada/métodos , Procedimientos Quirúrgicos de Citorreducción/efectos adversos , Procedimientos Quirúrgicos de Citorreducción/estadística & datos numéricos , Doxorrubicina/administración & dosificación , Femenino , Humanos , Hipertermia Inducida/efectos adversos , Hipertermia Inducida/estadística & datos numéricos , Persona de Mediana Edad , Neoplasia Residual , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Paclitaxel/administración & dosificación , Neoplasias Peritoneales/mortalidad , Neoplasias Peritoneales/patología , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
BACKGROUND: Ovarian cancer is the most lethal of all gynecologic malignancies. The relationship between sexual steroids receptors and ovarian cancer progression has been largely evaluated. The presence of progesterone receptors has been associated with an increase of a disease-free period and overall survival in patients with ovarian carcinoma. In the present study, primary cultures of ovarian carcinoma obtained from 35 patients diagnosed with epithelial ovarian cancer were evaluated for cell survival after treatment with 10- 8 M of 17ß-estradiol, progesterone, testosterone and dihydrotestosterone. RESULTS: The results were analyzed considering histological subtypes: low grade serous, high grade serous, endometrioid and mucinous carcinoma; clear cell carcinoma was not included due to failure in obtaining successful cultures of this subtype. A significant reduction of cell survival was observed after progesterone treatment in endometrioid ovarian carcinoma. Changes were not observed in low grade serous, high grade serous and mucinous carcinoma. The effect of progesterone was related to the presence of progesterone receptor (PR), a 43% reduction in the cell number was observed in PR (+) endometrioid ovarian carcinoma. CONCLUSIONS: This study supports the importance of progesterone and the presence of progesterone receptor in the reduction of ovarian cancer progression in the endometrioid ovarian carcinoma.
Asunto(s)
Antineoplásicos Hormonales/farmacología , Carcinoma Endometrioide/patología , Supervivencia Celular/efectos de los fármacos , Neoplasias Ováricas/patología , Progesterona/farmacología , Adulto , Carcinoma Endometrioide/metabolismo , Carcinoma Epitelial de Ovario/metabolismo , Carcinoma Epitelial de Ovario/patología , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/metabolismo , Estudios Prospectivos , Receptores de Progesterona/metabolismo , Receptores de Esteroides/metabolismo , Células Tumorales Cultivadas/efectos de los fármacosRESUMEN
About 132 thousand cases of melanoma (more severe type of skin cancer) were registered in 2014 according to the World Health Organization. This type of cancer significantly affects the quality of life of individuals. Caffeine has shown potential inhibitory effect against epithelial cancer. In this study, it was proposed to obtain new caffeine-based molecules with potential epithelial anticancer activity. For this, a training set of 21 molecules was used for pharmacophore perception procedures. Multiple linear regression analyses were used to propose mono-, bi-, tri-, and tetra-parametric models applied in the prediction of the activity. The generated pharmacophore was used to select 350 molecules available at the ZINCpharmer server, followed by reduction to 24 molecules, after selection using the Tanimoto index, yielding 10 molecules after final selection by predicted activity values > 1.5229. These ten molecules had better pharmacokinetic properties than the other ones used as reference and within the clinically significant limits. Only two molecules show minor hits of toxicity and were submitted to molecular docking procedures, showing BFE (binding free energy) values lower than the reference values. Statistical analyses indicated strong negative correlations between BFE and pharmacophoric properties (high influence on BFE lowering) and practically null correlation between BFE and BBB. The two most promising molecules can be indicated as candidates for further in vitro and in vivo analyzes.
Asunto(s)
Antineoplásicos/farmacología , Cafeína/farmacología , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Diseño de Fármacos , Neoplasias Ováricas/tratamiento farmacológico , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Cafeína/análogos & derivados , Cafeína/química , Carcinoma Epitelial de Ovario/patología , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Simulación del Acoplamiento Molecular , Neoplasias Ováricas/patología , Ratas , Estadística como AsuntoRESUMEN
Cáncer epitelial de ovario es una enfermedad altamente letal. Constituye la quinta causa de muerte por cáncer en mujeres a nivel mundial. El subtipo histológico más frecuente es el carcinoma seroso de alto grado. Este es el responsable de la alta letalidad de la enfermedad. Se presenta evidencia que respalda el origen tubario de este tipo histológico desde lesiones precursoras. A partir de estos datos se ha establecido que el cáncer tradicionalmente conocido como cáncer ovárico seroso de alto grado, el cáncer de trompa de Falopio y el carcinoma peritoneal primario, corresponden a una misma entidad nosológica: cáncer seroso pélvico de alto grado. Se revisa además la evidencia disponible para establecer que la salpingectomía podría constituir una medida de prevención para este tipo de cáncer.
Epithelial ovarian cancer is a highly lethal disease. It is the 5th cause of cancer death in women worldwide. The most common histologic subtype is the high-grade serous carcinoma. This is the responsible for the high lethality of the disease. Evidence supporting the tubal origin of this histological type from precursor lesions is presented. From these data it has been established that cancer traditionally known as serous high-grade ovarian cancer, cancer of the fallopian tube and primary peritoneal carcinoma, correspond to a single disease entity: pelvic serous high-grade cancer. We also check the available evidence to establish that the salpingectomy could be a preventive measure for this type of cancer.