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BACKGROUND: Recently, with the advancement of medical technology, the postoperative morbidity of pelvic exenteration (PE) has gradually decreased, and it has become a curative treatment option for some patients with recurrent gynecological malignancies. However, more evidence is still needed to support its efficacy. This study aimed to explore the safety and long-term survival outcome of PE and the feasibility of umbilical single-port laparoscopic PE for gynecologic malignancies in a single medical center in China. PATIENTS AND METHODS: PE for gynecological cancers except for ovarian cancer conducted by a single surgical team in Sun Yat-sen University Cancer Center between July 2014 and December 2019 were included and the data were retrospectively analyzed. RESULTS: Forty-one cases were included and median age at diagnosis was 53 years. Cervical cancer accounted for 87.8% of all cases, and most of them received prior treatment (95.1%). Sixteen procedures were performed in 2016 and before, and 25 after 2016. Three anterior PE were performed by umbilical single-site laparoscopy. The median operation time was 460 min, and the median estimated blood loss was 600 ml. There was no perioperative death. The years of the operations was significantly associated with the length of the operation time (P = 0.0018). The overall morbidity was 52.4%, while the severe complications rate was 19.0%. The most common complication was pelvic and abdominal infection. The years of surgery was also significantly associated with the occurrence of severe complication (P = 0.040). The median follow-up time was 55.8 months. The median disease-free survival (DFS) was 17.9 months, and the median overall survival (OS) was 25.3 months. The 5-year DFS was 28.5%, and the 5-year OS was 30.8%. CONCLUSION: PE is safe for patient who is selected by a multi-disciplinary treatment, and can be a curative treatment for some patients. PE demands a high level of experience from the surgical team. Umbilical single-port laparoscopy was a technically feasible approach for APE, meriting further investigation.
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Neoplasias de los Genitales Femeninos , Neoplasias Ováricas , Exenteración Pélvica , Neoplasias del Cuello Uterino , Humanos , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Exenteración Pélvica/efectos adversos , Exenteración Pélvica/métodos , Neoplasias del Cuello Uterino/cirugía , Neoplasias del Cuello Uterino/etiología , Neoplasias Ováricas/cirugía , Neoplasias Ováricas/etiología , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/cirugía , Recurrencia Local de Neoplasia/etiologíaRESUMEN
BACKGROUND: The aim of this study was to elucidate the value of putative cancer stem cell markers Musashi-1, ALDH1, Sox2, and CD49f in predicting the prognosis in cervical squamous cell carcinoma (CSCC). METHODS: Real-time PCR and immunohistochemistry staining was performed to examine Musashi-1, ALDH1, Sox2, and CD49f expression in archived specimens of CSCC patients with postoperative chemotherapy. Kaplan-Meier analysis and Cox proportional hazards model were used to assess the prognostic impact of CSC markers for overall survival (OS) and recurrent-free survival (RFS). RESULTS: The Real-time PCR data showed that the expression of all markers were increased in CSCC tissues compared with in paired normal cervical tissues (P < 0.05). The IHC result showed that high expression of Msi1, ALDH1, Sox2, and CD49f was found in 25.7%, 43.0%, 62.0% and 29.0% CSCC samples, respectively. Moreover, high expression of Msi1 (P = 0.033 and P = 0.003, respectively), ALDH1 (P = 0.015 and P = 0.002, respectively), and Sox2 (P = 0.005 and P = 0.003, respectively), and low expression of CD49f (P = 0.027 and P = 0.025, respectively) were correlated with poor OS and PFS in CSCC patients. Interestingly, tumors with Msi1(high)/CD49f(low) expression had the poorest prognosis according to Msi1/CD49f stratification. In multivariate Cox regression analysis, Sox2 expression (P = 0.047 and P = 0.018, respectively), ALDH1 expression (P = 0.013 and P = 0.003, respectively), and CD49f expression (P = 0.008 and P = 0.003, respectively) were independent prognostic markers for both OS and RFS. CONCLUSIONS: Our results suggest that cancer stem cell markers are linked with poor prognosis of CSCC patients.
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Biomarcadores de Tumor/biosíntesis , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/metabolismo , Células Madre Neoplásicas/metabolismo , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/metabolismo , Adulto , Familia de Aldehído Deshidrogenasa 1 , Carcinoma de Células Escamosas/mortalidad , Femenino , Humanos , Integrina alfa6/biosíntesis , Isoenzimas/biosíntesis , Persona de Mediana Edad , Células Madre Neoplásicas/patología , Proteínas del Tejido Nervioso/biosíntesis , Pronóstico , Proteínas de Unión al ARN/biosíntesis , Retinal-Deshidrogenasa/biosíntesis , Factores de Transcripción SOXB1/biosíntesis , Tasa de Supervivencia/tendencias , Resultado del Tratamiento , Neoplasias del Cuello Uterino/mortalidadRESUMEN
Loss of ferroptosis contributes to the development of human cancer, and restoration of ferroptosis has been demonstrated as a potential therapeutic strategy in cancer treatment. However, the mechanisms of how ferroptosis escape contributes to ovarian cancer (OV) development are not well elucidated. Here, we show that ferroptosis negative regulation signatures correlated with the tumorigenesis of OV and were associated with poor prognosis, suggesting that restoration of ferroptosis represents a potential therapeutic strategy in OV. High-throughput drug screening with a kinase inhibitor library identified MEK inhibitors as ferroptosis inducers in OV cells. We further demonstrated that MEK inhibitor-resistant OV cells were less vulnerable to trametinib-induced ferroptosis. Mechanistically, mTOR/eIF4E binding protein 1 (4EBP1) signaling promoted solute carrier family 7 member 11 (SLC7A11) protein synthesis, leading to ferroptosis inhibition in MEK inhibitor-resistant cells. Dual inhibition of MEK and mTOR/4EBP1 signaling restrained the protein synthesis of SLC7A11 via suppression of the mTOR/4EBP1 axis to reactivate ferroptosis in resistant cells. Together, these findings provide a promising therapeutic option for OV treatment through ferroptosis restoration by the combined inhibition of MEK and mTOR/4EBP1 pathways.
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Proteínas Adaptadoras Transductoras de Señales , Sistema de Transporte de Aminoácidos y+ , Ferroptosis , Neoplasias Ováricas , Inhibidores de Proteínas Quinasas , Serina-Treonina Quinasas TOR , Ferroptosis/efectos de los fármacos , Humanos , Femenino , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/genética , Línea Celular Tumoral , Sistema de Transporte de Aminoácidos y+/metabolismo , Sistema de Transporte de Aminoácidos y+/genética , Sistema de Transporte de Aminoácidos y+/antagonistas & inhibidores , Animales , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Ratones , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Serina-Treonina Quinasas TOR/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Transducción de Señal/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Piridonas/farmacología , Piridonas/uso terapéutico , Pirimidinonas/farmacología , Pirimidinonas/uso terapéuticoRESUMEN
PURPOSE: Checkpoint immunotherapy is a promising treatment option for advanced cervical cancer. To aid in selecting patients for this treatment, we identified potential predictors of the response to anti-PD-1 combination therapy. METHODS: We simultaneously characterized CD8+, FoxP3+, PD-L1+, CD68+, CD31+, PANCK+, and PANCK-PD-L1+ cells at the invasive margin (IM) of tumor by multispectral imaging of tissue sections from 37 patients with advanced cervical cancer in our previous trial cohort. The densities of each cell and cell-to-cell topography were compared between the responder and non-responder groups and evaluated for their predictive value in clinical response and survival. RESULTS: CD8+ T cells, PD-L1+ cells, and PANCK-PD-L1+ immune cells showed higher densities at the IM in the responders than in the non-responders (P = 0.022, 0.0094, and 0.049, respectively). A higher density of CD8+ T cells at the IM was related to prolonged progression-free survival (PFS; P = 0.031). A higher ratio of CD68+/CD8+ cells was found in the non-responder group (P = 0.003) and related to poor PFS (P = 0.016). A higher density of PANCK-PD-L1+ immune cells within 20, 30, and 45 µm of PANCK+ tumor cells was correlated with better clinical response (P = 0.017, 0.017, and 0.02, respectively). CONCLUSIONS: Multiparametric immune profiling of CD8+ T cells, PD-L1+ cells, CD68+ macrophages and PANCK-PD-L1+ immune cells at the invasive margin may help identify patients with cervical cancer who may benefit from anti-PD-1 combination therapy. CLINICAL TRIAL REGISTRATION: ClinicalTrials. gov identifier: NCT03816553, January 25, 2019.
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Linfocitos T CD8-positivos , Neoplasias del Cuello Uterino , Femenino , Humanos , Antígeno B7-H1 , Linfocitos Infiltrantes de Tumor , Supervivencia sin Progresión , Neoplasias del Cuello Uterino/tratamiento farmacológicoRESUMEN
OBJECTIVE: The role of lymphadenectomy in interval debulking surgery (IDS) performed after neoadjuvant chemotherapy (NACT) in advanced ovarian cancer remains unclear. We aimed to investigate the clinical significance of lymphadenectomy in IDS. METHODS: We retrospectively reviewed and analyzed the data of patients with advanced ovarian cancer who underwent NACT followed by IDS. RESULTS: In 303 patients receiving NACT-IDS, lymphadenectomy was performed in 127 (41.9%) patients. One hundred and sixty-three (53.8%) patients achieved no gross residual disease (NGRD), and 69 (22.8%) had residual disease < 1 cm, whereas 71 (23.4%) had residual disease ≥ 1cm. No significant difference in progression-free survival (PFS) and overall survival (OS) was observed between the lymphadenectomy group and the no lymphadenectomy group in patients with NGRD, residual disease < 1 cm, and residual disease ≥ 1 cm, respectively. The proportions of pelvic, para-aortic and distant lymph node recurrence were 7.9% (10/127), 4.7% (6/127) and 5.5% (7/127) in the lymphadenectomy group, compared with 5.7% (10/176, P = 0.448), 4.5% (8/176, P = 0.942) and 5.1% (9/176, P = 0.878), respectively, in no lymphadenectomy group. Multivariate analysis identified residual disease ≥ 1 cm [hazard ratios (HR), 4.094; P = 0.008] and elevated CA125 levels after 3 cycles of adjuvant chemotherapy (HR, 2.883; P = 0.004) were negative predictors for OS. CONCLUSION: Lymphadenectomy may have no therapeutic value in patients with advanced ovarian cancer underwent NACT-IDS. Our findings may help to better the therapeutic strategy for advanced ovarian cancer. More clinical trials are warranted to further clarify the real role of lymphadenectomy in IDS.
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BACKGROUND: The Camrelizumab Plus Apatinib in Patients with Advanced Cervical Cancer trial was a single-arm, phase II study that showed promising activity of the programmed death-1 (PD-1) inhibitor camrelizumab plus the vascular endothelial growth factor receptor-2 inhibitor apatinib in patients with advanced cervical cancer. However, the predictive biomarkers for treatment outcomes are unknown. In this study, we aimed to identify potential predictors of treatment response in PD-1 inhibitor combination therapy. METHODS: Genomic profiling was performed on patients with available biopsy or surgical samples by targeted next-generation sequencing of 425 cancer-related genes in this preplanned, secondary analysis. Somatic alterations, including all non-synonymous mutations, and tumor mutational burden (TMB) were assessed for their predictive values in objective response rate, progression-free survival (PFS), and overall survival (OS). RESULTS: A subset of 32 patients was included in this analysis. Top altered genes included PIK3CA (43.8%), STK11 (25%), FBXW7 (15.6%), and PTEN (15.6%). The PI3K/AKT pathway was among the most frequently dysregulated pathways, and its genetic alterations were identified in 68.8% of patients. PIK3CA (PFS HR 0.33, p=0.05; OS HR 0.23, p=0.04) and PTEN (PFS HR 3.71e-09, p=0.05; OS HR 3.64e-09, p=0.08) alterations were associated with improved outcomes. PI3K/AKT pathway genetic alterations showed improved predictive power compared with either PIK3CA or PTEN alterations alone (PFS HR 0.33, p=0.03; OS HR 0.25, p=0.02), while ERBB3 mutations (PFS HR 34.9, p<0.001; OS HR 19.8, p<0.001) correlated with poor survival. TMB-high (≥5 mut/Mb) was associated with prolonged PFS (HR 0.26, p<0.01) and OS (HR 0.31, p=0.05). Multivariate analysis showed ERBB3 mutations (PFS p=0.01, OS p<0.001), PD-L1 positive (PFS p=0.01, OS p=0.05), and high TMB (PFS p=0.01, OS p=0.05) remained significantly associated with survival. CONCLUSIONS: We uncovered that genetic alterations in PIK3CA, PTEN, ERBB3, and PI3K/AKT pathway, as well as TMB, could be novel predictive biomarkers in patients with cervical cancer treated with PD-1 inhibitor combination therapy. TRIAL REGISTRATION NUMBER: NCT03816553.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Perfilación de la Expresión Génica , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Transcriptoma , Neoplasias del Cuello Uterino/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunología , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridinas/uso terapéutico , Medición de Riesgo , Factores de Riesgo , Transducción de Señal/genética , Factores de Tiempo , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/inmunología , Neoplasias del Cuello Uterino/mortalidadRESUMEN
OBJECTIVE: To compare the long-term oncologic outcomes of minimally invasive surgery (MIS) vs laparotomy for patients with stage IB (2018 FIGO) cervical cancer. METHODS: A matched retrospective study of cervical cancer patients who underwent MIS or laparotomy at Sun Yat-sen University Cancer Center from January 2012 to December 2015 was carried out. Patients were restaged according to the 2018 FIGO staging system for cervical cancer, 700 cases with stage IB cervical cancer were enrolled. Propensity score matching (PSM) was performed by software SPSS version 22.0, and a total of 426 patients were enrolled and analyzed. Oncologic outcomes were compared between patients undergoing MIS vs laparotomy. RESULTS: After PSM, there were no statistical differences in other baseline characteristics between MIS and laparotomy, except for age (p = 0.008). In all stage IB patients, MIS group had significantly lower disease-free survival (DFS) rate and overall survival (OS) rate compared with laparotomy group (5-year DFS rate, 87.5% vs 94.1%, hazard ratio for disease recurrence, 2.403; 95% CI, 1.216-4.744; 5-year OS rate, 92.3% vs 98.1%, hazard ratio for death, 3.719; 95% CI, 1.370-10.093). In stage IB1 patients population, MIS was still associated with worse DFS and OS compared to laparotomy (5-year DFS rate: 89.5% vs 100%, p = 0.012; 5-year OS rate: 93.4% vs 100%, p = 0.043). Even in stage IB1 patients without lymph vascular space invasion, worse oncologic outcome could be observed in MIS group (DFS: p = 0.021; OS: p = 0.076). CONCLUSION: Our study suggested that laparotomy resulted in better OS and DFS compared with MIS among patients with stage IB cervical cancer. Even in stage IB1 patients without lymph vascular space invasion (2018 FIGO), laparotomy might be still an oncologically safer approach.
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Laparotomía/mortalidad , Procedimientos Quirúrgicos Mínimamente Invasivos/mortalidad , Recurrencia Local de Neoplasia/cirugía , Procedimientos Quirúrgicos Robotizados/mortalidad , Neoplasias del Cuello Uterino/cirugía , Femenino , Humanos , Laparotomía/métodos , Persona de Mediana Edad , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Puntaje de Propensión , Estudios Retrospectivos , Procedimientos Quirúrgicos Robotizados/métodos , Tasa de Supervivencia , Neoplasias del Cuello Uterino/patologíaRESUMEN
INTRODUCTION: Seventy-five percent of ovarian cancer would relapse within 18-28 months after platinum-base chemotherapy. Evidence suggests that maintenance chemotherapy is effective in prolonging remission. Recent target therapies such as poly(ADP-ribose) polymerase inhibitors (PARPis) and angiogenesis inhibitors (AIs) are known to ease burden and recurrence of ovarian cancer. There is limited data for head-to-head comparison of PARPis, AIs, and chemotherapeutic agents (CTAs) as maintenance treatment. This network meta-analysis thus assessed the effectiveness and toxicity of these three maintenance therapies in patients with ovarian cancer. METHODS: We searched relevant sources (PubMed, EMBASE) to identify randomized controlled trials assessing efficacy and safety of maintenance therapy in patients with ovarian cancer. Primary outcome was progression-free survival (PFS) as assessed by blinded review; safety and tolerability were secondary outcomes. A network meta-analysis to compare three drug classes was performed using statistical software R. RESULTS: We included 24 trials (11,366 patients) assessing efficacy and safety of PARPis (n = 4), AIs (n = 12), and CTAs (n = 8). PARPis [hazard ratio (HR) 0.64; 95% credible intervals (CrI) 0.55-0.73] and AIs (HR 0.87; 95% CrI 0.81-0.93) showed significant improvement in PFS compared to placebo but not CTA (HR 1.00; 95% CrI 0.86-1.15). PARPis showed significant improvement in PFS compared to AIs (HR 0.73; 95% CrI 0.63-0.86) and CTA (HR 0.64; 95% CrI 0.52-0.78). Adverse events (AEs) leading to treatment discontinuation and dose reduction were lower in PARPis [incidence rate ratio (IRR) 0.60; CrI 0.31-1.18 and IRR 0.73, 95% CrI 0.50-1.06, respectively] compared to AIs, but the differences were not significant. CONCLUSION: PARPi as maintenance treatment improved PFS in ovarian cancer and was relatively safer in terms of implications caused by AEs when compared to AIs. This network meta-analysis provides valuable evidence and significant insights into treatment of ovarian cancer.
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Inhibidores de la Angiogénesis/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Inhibidores de la Angiogénesis/administración & dosificación , Inhibidores de la Angiogénesis/efectos adversos , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Quimioterapia de Mantención , Recurrencia Local de Neoplasia , Metaanálisis en Red , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversosRESUMEN
COL6A1 has been shown to play an important role in tumor initiation and progression. The present study is to investigate the clinical significance of COL6A1 in cervical cancer. In this study, the COL6A1 expression levels in 10 paired cervical cancer tissues and the adjacent non-tumor tissues were examined by real-time PCR. The expression of COL6A1 protein was examined in 162 cervical cancer samples by immunohistochemistry, and the correlation of COL6A1 expression with clinicopathologic factors was analyzed. The overall and recurrent-free survival rates were estimated using Kaplan-Meier method and compared with the log-rank test. The prognostic analysis was carried out with multivariate Cox regressions model. The result showed that COL6A1 expression was up-regulated in cervical cancer tissues in compared with that in non-tumor tissues. High expression of COL6A1 was significantly correlated with FIGO stage (P<0.001), tumor size (P=0.025) and lymph node metastasis (P=0.028) of the disease. Moreover, survival analysis showed that high expression of COL6A1 was significantly associated with poorer overall (OS) and recurrent free (RFS) survival (p=0.004 and =0.001, respectively) of cervical cancer patients. Multivariate analysis suggested that COL6A1 expression was an independent prognostic marker of cervical cancer (P=0.029). Thus, COL6A1 may serve as an oncogene in the initiation and progression of cervical cancer, and as a predictor of poor prognosis in cervical cancer patients.
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AIMS: This study was conducted to analyze the clinical significance of ASAP1 in epithelial ovarian cancer (EOC). METHODS: A total of 95 patients with EOC were included in the study. The expression profile of ASAP1 in 10 pairs of ovarian cancer and normal ovary tissues were detected by Real-time PCR. The expression level of ASAP1 in 95 paraffin-embedded EOC specimens was measured by immunohistochemistry staining. Statistical analysis was performed to evaluate the clinicopathologic significance of ASAP1. RESULTS: Levels of ASAP1 mRNA were higher in EOC than in normal ovary tissues. Patients with higher ASAP1 expression had shorter overall (P=0.019) and recurrence-free (P=0.030) survival time, whereas those with lower ASAP1 expression survived longer. In addition, high expression of ASAP1 was correlated with poor overall (P=0.044) and recurrence-free (P=0.006) survival in patients with advanced carcinomas. Moreover, statistical analysis displayed a significant correlation in ASAP1 expression with pelvic metastasis (P=0.015). Multivariate analysis revealed that an elevated ASAP1 expression was a significant independent prognostic factor for the overall (P=0.039) and recurrence-free (P=0.028) survival of EOC patients. CONCLUSION: These results indicated that elevated expression of ASAP1 plays an important role in the progression and metastasis of ovarian cancer, and that ASAP1 may be used as a biomarker in predicting patient outcome in EOC patients.