RESUMO
Background: Ovarian cancer (OC) is a global malignancy characterized by metastatic invasiveness and recurrence. Long non-coding RNAs (lncRNAs) and Telomeres are closely connected with several cancers, but their potential as practical prognostic markers in OC is less well-defined. Methods: Relevant mRNA and clinical data for OC were sourced from The Cancer Genome Atlas (TCGA) database. The telomere-related lncRNAs (TRLs) prognostic model was established by univariate/LASSO/multivariate regression analyses. The effectiveness of the TRLs model was evaluated and measured via the nomogram. Additionally, immune infiltration, tumor mutational load (TMB), and drug sensitivity were evaluated. We validated the expression levels of prognostic genes. Subsequently, PTPRD-AS1 knockdown was utilized to perform the CCK8 assay, colony formation assay, transwell assay, and wound healing assay of CAOV3 cells. Results: A six-TRLs prognostic model (PTPRD-AS1, SPAG5-AS1, CHRM3-AS2, AC074286.1, FAM27E3, and AC018647.3) was established, which can effectively predict patient survival rates and was successfully validated using external datasets. According to the nomogram, the model could effectively predict prognosis. Furthermore, we detected the levels of regulatory T cells and M2 macrophages were comparatively higher in the high-risk TRLs group, but the levels of activated CD8 T cells and monocytes were the opposite. Finally, the low-risk group was more sensitive to anti-cancer drugs. The mRNA levels of PTPRD-AS1, SPAG5-AS1, FAM27E3, and AC018647.3 were significantly over-expressed in OC cell lines (SKOV3, A2780, CAOV3) in comparison to normal IOSE-80 cells. AC074286.1 were over-expressed in A2780 and CAOV3 cells and CHRM3-AS2 only in A2780 cells. PTPRD-AS1 knockdown decreased the proliferation, cloning, and migration of CAOV3 cells. Conclusion: Our study identified potential biomarkers for the six-TRLs model related to the prognosis of OC.
Assuntos
Biomarcadores Tumorais , Regulação Neoplásica da Expressão Gênica , Neoplasias Ovarianas , RNA Longo não Codificante , Telômero , Humanos , RNA Longo não Codificante/genética , Feminino , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/mortalidade , Prognóstico , Biomarcadores Tumorais/genética , Telômero/genética , Linhagem Celular Tumoral , Nomogramas , Pessoa de Meia-Idade , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismoRESUMO
INTRODUCTION: Epithelial ovarian cancer (EOC) is the fourth most common malignancy among Malaysian women. This study aims to evaluate the outcomes of EOC, fallopian tube cancer and primary peritoneal serous carcinoma (PPSC) between a centre managed by both clinical oncologists and gynaecologic oncologists, Institut Kanser Negara (IKN) and a centre managed solely by gynaecologic oncologists, Hospital Ampang (HA). MATERIALS AND METHODS: This retrospective cohort study involved data review of all the newly diagnosed patients with EOC, fallopian tube cancer and PPSC who received treatment in IKN and HA from January 2015 to December 2019, with follow-up continuing until December 2022. The primary outcome is overall survival (OS) and the secondary outcome is progression free survival (PFS) rates; estimated using the Kaplan-Meier method and compared using the logrank test. Another secondary outcome is to determine the prognostic factors affecting the OS of patients from these two cohorts using Cox regression analysis. RESULTS: A total of 256 patients from both centres were recruited (106 and 150 patients from IKN and HA respectively) and at the time of diagnosis, more than half of the patients were diagnosed with advanced stage disease (67.5% and 62% from IKN and HA respectively). The median OS for patients with EOC was significantly longer for HA compared to IKN (69 months vs 39 months, p < 0.042). There was no significant difference in the median PFS for both centres. Furthermore, when the comparison was made based on the disease staging, there was no difference in the median OS and median PFS. Multivariate analysis identified that patients aged between 41 and 60 years (Hazard ratio [HR]: 2.83; 95% CI: 1.11, 7.25, p = 0.030), patients with medical illness (HR 1.51; 95% CI: 1.04, 2.21, p = 0.033), patients with advanced-stage disease (HR: 3.63; 95% CI: 2.20, 6.00, p < 0.001) and patients with ECOG ≥ 1 (HR: 2.00; 95%CI: 1.38, 2.91, p < 0.001) as independent risk factors for adverse outcome. Meanwhile, optimal surgery is found to be a protective factor (HR 0.60; 95% CI: 0.41, 0.89, p = 0.011). Patients with optimal surgery had reduced the risk of adverse outcome. CONCLUSION: Our findings confirmed that the median OS was significantly longer for patients with EOC in HA compared to IKN. However, there was no significant difference in the median OS based on the disease staging; therefore, we could not establish the non-inferiority outcome between the two centres. Furthermore, there was no significant difference in median PFS for both centres. This could be due to small sample size to be able to detect any difference. In addition, it could also be contributed by the different treatment options available and unequal volume of patients treated in both centres. Thus, further study with larger sample size and longer time period is needed to provide better guidance and treatments for the patients.
Assuntos
Carcinoma Epitelial do Ovário , Neoplasias das Tubas Uterinas , Neoplasias Peritoneais , Humanos , Feminino , Neoplasias das Tubas Uterinas/mortalidade , Neoplasias das Tubas Uterinas/terapia , Neoplasias das Tubas Uterinas/patologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias Peritoneais/terapia , Neoplasias Peritoneais/mortalidade , Carcinoma Epitelial do Ovário/mortalidade , Carcinoma Epitelial do Ovário/terapia , Carcinoma Epitelial do Ovário/patologia , Idoso , Adulto , Malásia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/terapia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/diagnóstico , Cistadenocarcinoma Seroso/terapia , Cistadenocarcinoma Seroso/mortalidade , Cistadenocarcinoma Seroso/patologiaRESUMO
OBJECTIVE: This study presents the development and validation of a nomogram aimed at predicting platinum-sensitivity and survival outcomes in women with advanced epithelial ovarian cancer (EOC). MATERIALS AND METHODS: Data from a retrospective cohort of women diagnosed with stage III/IV EOC between Jan 2011 and Dec 2021 treated at our institute were collected. Clinical and pathological characteristics were analyzed using logistic regression analysis to identify independent predictors of platinum-sensitivity. Impact on progression-free (PFS) and overall survival (OS) was determined by Kaplan-Meier and Cox regression analysis. A nomogram was constructed based on the significant predictors, and its performance was evaluated using calibration, discrimination, and validation analyses. RESULTS: Of the 210 patients, 139 (66.19%) had platinum-sensitive and 71 (33.81%) were platinum-resistant disease. On multivariate analysis, platinum-resistance correlated with neoadjuvant chemotherapy (OR 2.15; 95% CI 1.10-4.21), clear cell/mucinous histology (OR 5.04; 95% CI 2.20-11.54), and sub-optimal debulking status (OR 3.37; 95% CI 1.44-7.91). Median PFS and OS were also significantly shorter for patients with neoadjuvant chemotherapy (23 vs. 10 months and 69 vs. 29 months, respectively), clear cell/mucinous histology (15 vs. 3 months and 63 vs. 11 months, respectively), and suboptimal debulking (26 vs. 5 months and 78 vs. 24 months, respectively). The nomogram demonstrated good predictive accuracy for platinum-sensitivity in the cohort as indicated by high concordance index of 0.745. Calibration plots showed excellent agreement and internal validation further confirmed the reliability of the nomogram's performance. CONCLUSION: A novel predictive nomogram based on type of initial treatment, histology, and debulking status was developed, which provides a friendly and reliable tool for predicting platinum-sensitivity and survival outcomes in women with advanced EOC. Its application may assist clinicians in individualizing treatment decisions.
Assuntos
Carcinoma Epitelial do Ovário , Resistencia a Medicamentos Antineoplásicos , Nomogramas , Neoplasias Ovarianas , Humanos , Feminino , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/mortalidade , Carcinoma Epitelial do Ovário/patologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Idoso , Adulto , Estadiamento de Neoplasias , Terapia Neoadjuvante/métodos , Procedimentos Cirúrgicos de Citorredução , Intervalo Livre de Progressão , Platina/uso terapêutico , Antineoplásicos/uso terapêutico , Estimativa de Kaplan-MeierRESUMO
OBJECTIVES: This is a protocol for a Cochrane Review (prognosis). The objectives are as follows: To evaluate the predictive value of the prognostic factor HRD status, as determined by various clinically validated HRD assays at the time of staging laparotomy, compared to BRCA1/2 mutation status for progression-free survival and overall survival in patients with tubo-ovarian high-grade serous carcinoma treated in the first-line setting with a combination of surgery and platinum-based chemotherapy and/or maintenance with PARP inhibitors.
Assuntos
Neoplasias Ovarianas , Humanos , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Feminino , Neoplasias das Tubas Uterinas/genética , Neoplasias das Tubas Uterinas/mortalidade , Neoplasias das Tubas Uterinas/patologia , Neoplasias das Tubas Uterinas/tratamento farmacológico , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/mortalidade , Prognóstico , Intervalo Livre de Progressão , Genes BRCA2 , Genes BRCA1 , MutaçãoRESUMO
Background: Ovarian surface epithelial cancer (OSEC) are an entity in which, according to genomics and pathology data accumulated in the last couple of decades, several different nosological entities with distinct etiologies are aggregated. In ovarian cancer, surgery is the pivot of treatment, to which medical oncological treatment is added by recommendation in most cases. Material and Methods: This is a single centre sample of 263 cases with OSEC operated from January 2014 until December 2021 with a 28-month period of follow-up, until 30th April 2024. OSEC surgical procedures in stages IIB to III and IV of the disease are complex interventions in order to have the R0/optimal cytoreduction achieved, so we summarised and coded them as follows: 1 = biopsy (of the tumour/peritoneum); 2 = bilateral/unilateral adnexectomy (BA/UA) total hysterectomy (TH) omentectomy +- peritoneal biopsies; 3 = (2) with total hysterectomy with bilateral adnexectomy (THBA) +- by extraperitoneal/subperitoneal route+peritonectomies (exclusively diaphragmatic) and electrocauterization of peritoneal carcinomatous lesions; 4 = (3) with visceral (multiple) resections +- stoma; 5 = (4) with diaphragmatic peritonectomies/stripping/partial resection of the diaphragm; 6 = palliative surgery. Results: Debulking surgery (DS) was carried out for n = 182 patients with no residual tissue = R0 being registered in n = 41. Results for patients with residual tissue (n = 141) after DS recorded the following findings: 1 cm (49% cases), 1.1-2 cm (29%) and 2 cm (22%). Recorded results for endometrial ovarian carcinoma (EC) n = 27 shown a tumour free survival probability estimate (%) at 60 months of 66% as both surgery and platinum based chemotherapy are efficient. For clear cell ovarian carcinoma (CCC) n = 7 recorded results shown a tumour free estimate (%) at 60 months of 14%, being known the controversy as to whether or not paclitaxel is an active drug for CCC. Major complications were recorded in 25 patients with a fatality ratio of 5/25. Conclusion: Considering OSEC is a relatively rare disease and the importance of collecting substantial numbers of samples by histotypes to further knowledge about ovarian cancer it comes crucial to establish collaborative endeavour of tertiary centers with standardised and quality control strategies.
Assuntos
Procedimentos Cirúrgicos de Citorredução , Histerectomia , Estadiamento de Neoplasias , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/cirurgia , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/mortalidade , Resultado do Tratamento , Histerectomia/métodos , Procedimentos Cirúrgicos de Citorredução/métodos , Carcinoma Epitelial do Ovário/cirurgia , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/mortalidade , Pessoa de Meia-Idade , Seguimentos , Idoso , Romênia/epidemiologia , Adulto , Estudos Retrospectivos , Omento/cirurgia , BiópsiaRESUMO
BACKGROUND: There is currently a lack of comprehensive evidence regarding the correlation between Alternate Mediterranean Diet (AMED) and the survival of patients with ovarian cancer (OC). This prospective cohort study first assessed the association of AMED, not only pre-diagnosis and post-diagnosis but also the change from pre-diagnosis to post-diagnosis with OC survival. METHODS: A total of 560 OC patients were included in the study, and their dietary intake was assessed using a reliable 111-item food frequency questionnaire. The overall survival (OS) of the patients was monitored through active follow-up and review of medical records until February 16th, 2023. Cox proportional hazard regression models were utilized to compute the hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs). RESULTS: Out of the total 560 patients with OC, 211 (37.68%) succumbed during a median follow-up period of 44.40 months (interquartile range: 26.97-61.37). Comparative analysis indicated a significant association between the highest tertiles of pre-diagnosis (HR = 0.59; 95% CI 0.38-0.90; Ptrend < 0.05) and post-diagnosis (HR = 0.61; 95% CI 0.41-0.91; Ptrend < 0.05) AMED intake and improved OS as opposed to the lowest tertile. Additionally, a significant linear trend was observed for AMED and OC survival. Notably, decreased intake (more than 5% change) and significantly increased intake (more than 15% change) of AMED from pre-diagnosis to post-diagnosis were linked to worse and better OS, respectively, when compared to the stable intake group (change within 5%). Furthermore, patients displaying consistently higher AMED intake both before and after diagnosis experienced enhanced OS in comparison to those with consistently low AMED intake (HRHigh-High vs. Low-Low = 0.47; 95% CI 0.31-0.70). CONCLUSION: High pre-diagnosis and post-diagnosis AMED was associated with an improved OS in patients with OC, suggesting that maintaining a consistently high intake of AMED could potentially benefit the prognosis of OC.
Assuntos
Dieta Mediterrânea , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/dietoterapia , Estudos Prospectivos , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Análise de Sobrevida , Adulto , Estimativa de Kaplan-Meier , IdosoRESUMO
BACKGROUND: The main challenge in treating ovarian cancer is chemotherapy resistance. Previous studies have shown that PAK2 is highly expressed in various cancers. This research investigates whether increased PAK2 expression contributes to chemo-resistance and poor prognosis in ovarian cancer. METHODS: Initially, bioinformatics analysis was used to assess the importance of PAK2 mRNA up-regulation in ovarian cancer. This was then validated using tissue microarray to confirm PAK2 protein expression and localization in clinical samples. Univariate and multivariate logistic regression analyses were carried out to identify potential risk factors for chemo-resistance in serous epithelial ovarian cancer (EOC), while multivariate Cox regression and Kaplan-Meier analysis were conducted to ascertain prognostic factors for overall survival (OS) and disease-free survival (DFS) in patients with serous EOC. In vitro experiments were conducted to verify if inhibiting PAK2 expression could increase A2780/Taxol cells' sensitivity to paclitaxel, as shown by evaluating cell proliferation, apoptosis, transwell, and clone formation. Additionally, the interaction between PAK2, lnc-SNHG1, and miR-216b-5p was verified using RIP and luciferase reporter assays. Rescue experiments were undertaken to examine the influence of the lnc-SNHG1/miR-216b-5p/PAK2 axis on the development of paclitaxel resistance in A2780/Taxol cells. RESULTS: The bioinformatics analysis indicated a notable increase in PAK2 expression in ovarian malignant tumors compared to adjacent tissues, particularly in patients with stage III-IV disease compared to those with stage I-II disease (P = 0.0056). Elevated levels of PAK2 were linked to reduced OS in ovarian cancer patients, although no significant association was observed with DFS. Immunohistochemistry findings further supported these results, showing positive PAK2 protein expression in chemo-resistant serous EOC tissues, predominantly localized in the cytoplasm, which correlated with poorer OS and DFS outcomes. In vitro experiments demonstrated that the downregulation of PAK2 in A2780/Taxol cells led to a reduction in colony formation, an increase in apoptosis, and a diminished capacity for cell invasion. Subsequent analysis confirmed that lnc-SNHG1 functions as a competitive endogenous RNA (ceRNA) by interacting with miR-216b-5p and regulating PAK2 expression. Rescue experiments demonstrated that lnc-SNHG1 induces resistance to paclitaxel in A2780/Taxol cells by modulating the miR-216b-5p/PAK2 axis. CONCLUSIONS: PAK2 shows promise as a predictor of chemotherapy resistance and poor outcomes in ovarian cancer, indicating its potential use as a treatment target to overcome this resistance.
Assuntos
Carcinoma Epitelial do Ovário , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , MicroRNAs , Neoplasias Ovarianas , Paclitaxel , Quinases Ativadas por p21 , Humanos , Quinases Ativadas por p21/metabolismo , Quinases Ativadas por p21/genética , Feminino , Resistencia a Medicamentos Antineoplásicos/genética , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/mortalidade , Prognóstico , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/mortalidade , MicroRNAs/genética , MicroRNAs/metabolismo , Linhagem Celular Tumoral , Pessoa de Meia-Idade , Proliferação de Células , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Apoptose/efeitos dos fármacos , Regulação para CimaRESUMO
BACKGROUND: Cytoreductive surgery is critical for optimal tumor clearance in advanced epithelial ovarian cancer (EOC). Despite best efforts, some patients may experience R2 (>1 cm) resection, while others may not undergo surgery at all. We aimed to compare outcomes between advanced EOC patients undergoing R2 resection and those who had no surgery. METHODS: Retrospective data from 51 patients with R2 resection were compared to 122 patients with no surgery between January 2015 and December 2019 at a UK tertiary referral centre. Progression-free survival (PFS) and overall survival (OS) were the study endpoints. Principal Component Analysis and Term Frequency - Inverse Document Frequency scores were utilized for data discrimination and prediction of R>2 cm from computed tomography pre-operative reports, respectively. RESULTS: No statistical significance was observed, except for age (73 vs 67 years in the no- surgery vs R2 group, P: .001). Principal Components explained 34% of data variances. Reasons for no surgery included age, co-morbidities, patient preference, refractory disease, patient deterioration or disease progression, and absence of measurable intra- abdominal disease). The median PFS and OS were 12 and 14 months for no-surgery, vs 14 and 26 months for R2 (P: .138 and P: .001, respectively). Serous histology and performance status independently predicted PFS in both no-surgery and R2 cohorts. In the no-surgery cohort, serous histology independently predicted OS, while in the R2 cohorts, both serous histology and adjuvant chemotherapy were independent prognostic features for OS. The bi-grams "abdominopelvic ascites" and "solid omental" were amongst those best discriminating between R>2 cm and R1-2 cm. CONCLUSIONS: R2 resection and no-surgery cohorts displayed unfavourable prognosis with a notable degree of uniformity. When cytoreduction results in suboptimal results, the survival benefit may still be higher compared to those who underwent no surgery.
The study examined outcomes in advanced epithelial ovarian cancer (EOC) patients who underwent either R2 (suboptimal) surgical resection or received no surgery at all at a UK tertiary referral center. Sophisticated machine learning methodolgies were used to analyze data patterns and predict the extent of resection (>2 cm) from pre-operative CT reports. Reasons for not undergoing surgery included older age, presence of other medical conditions, patient preference, progressive disease, patient decline, or lack of detectable intra-abdominal disease. Factors like serous histology and performance status iinfluenced the risk of recurrence in both groups, while serous histology and adjuvant chemotherapy predicted the risk of death in the R2 group. Word sequences like "omental disease" and "reduced bulk" helped differentiate between R>2 cm and less extensive resections (R1-2 cm). In summary, both R2 resection and no-surgery groups had poor outcomes, but patients who underwent R2 resection generally had better survival compared to those who received no surgery, even when complete tumor removal was not achieved.
Assuntos
Carcinoma Epitelial do Ovário , Procedimentos Cirúrgicos de Citorredução , Neoplasias Ovarianas , Humanos , Feminino , Idoso , Estudos Retrospectivos , Neoplasias Ovarianas/cirurgia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Procedimentos Cirúrgicos de Citorredução/métodos , Carcinoma Epitelial do Ovário/cirurgia , Carcinoma Epitelial do Ovário/mortalidade , Carcinoma Epitelial do Ovário/patologia , Pessoa de Meia-Idade , Intervalo Livre de Progressão , AdultoRESUMO
Protein lactylation has a poor prognosis in malignant tumors, but its impact on the prognosis of epithelial ovarian cancer (EOC) remains unknown. We analyzed 112 patients with EOC. Immunohistochemical staining was used to detect the level of pan lactylation (Pan Kla) and histone H3K18 lactylation (H3K18la) in the EOC tissues and normal ovarian tissues. The result showed that the protein lactylation level in EOC was higher than in normal tissues. Then, we analyzed the relationship between overall survival (OS), progression-free survival (PFS) of EOC, and lactylation. The result showed that patients with high histone H3K18la levels had poorer OS (p=0.028) and PFS (p<0.001). Multivariate Cox regression analysis of PFS showed histone H3K18la was an independent risk factor (p=0.001). In addition, we found that both histone H3K18la and Pan Kla in the cytoplasm were associated with platinum recurrence time (p=0.002/p=0.003). The results also indicated that the H3K18la level was related to a tumor stage (p=0.037). Furthermore, we explored the effects of lactylation on the metastasis of ovarian cancer. The results indicated a significant increase in migration in the promoter group compared to the negative control group and inhibitor group. In conclusion, high histone H3K18la level is associated with poor prognosis in EOC. Protein lactylation may have a significant impact on EOC and could potentially be used as a target for EOC therapy in the future.
Assuntos
Carcinoma Epitelial do Ovário , Histonas , Neoplasias Ovarianas , Humanos , Feminino , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/mortalidade , Histonas/metabolismo , Prognóstico , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/mortalidade , Pessoa de Meia-Idade , Idoso , Adulto , Biomarcadores Tumorais/metabolismoRESUMO
Ovarian cancer stands as the third most prevalent gynecological malignancy. The advent of PARP inhibitors, particularly rucaparib, has revolutionized the landscape of advanced ovarian cancer treatment, demonstrating notable efficacy with minimal toxicity, especially in patients not previously exposed to PARP inhibitors. Rucaparib's precision-driven approach, targeting specific genetic mutations, disrupts DNA repair mechanisms, resulting in cytotoxic effects on neoplastic cells. This comprehensive review delves into the clinical efficacy and safety profile of rucaparib in recurrent ovarian cancer, showcasing its promising therapeutic approach. A systematic search of studies reporting rucaparib efficacy and safety, up to September 2023, was conducted across various reputable databases and sources. The meta-analysis of seven articles revealed a pooled objective response rate (ORR) of 0.331 (95% CI, 0.221-0.449; I2 = 92.4%), underscoring rucaparib's efficacy, particularly evident in the BRCA-mutated cohort. Rucaparib consistently outperformed controls in progression-free survival (PFS) and overall survival (OS). Safety evaluations indicated that 98.7% of patients experienced treatment-emergent adverse events (TEAEs), with 61% being grade ≥3. Notable TEAEs included nausea (69.0%), fatigue (66.8%), vomiting (37.3%), and constipation (32.1%). Hematological concerns comprised anemia (47.9%), thrombocytopenia, elevated AST/ALT (37.3%), and serum creatinine levels (19.7%). Despite favourable outcomes, the rucaparib group recorded higher event rates across various metrics than controls. The findings underscore the need for meticulous monitoring and dose adjustments to optimize therapeutic outcomes and mitigate the increased risks associated with adverse events. International Prospective Register of Systematic Review Identifier: CRD42023459646.
Assuntos
Indóis , Recidiva Local de Neoplasia , Neoplasias Ovarianas , Inibidores de Poli(ADP-Ribose) Polimerases , Feminino , Humanos , Indóis/administração & dosagem , Indóis/efeitos adversos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/mortalidade , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Intervalo Livre de Progressão , Resultado do TratamentoRESUMO
BACKGROUND: Poly(ADP-ribose) polymerase inhibitors (PARPis) improved advanced ovarian cancer treatment. Most patients progress during or following PARPi exposure, however, with concerns about sensitivity of subsequent chemotherapy. PATIENTS AND METHODS: In this international cohort study, we evaluated the efficacy of a subsequent chemotherapy following PARPi exposure in high-grade ovarian carcinoma patients. Endpoints included progression-free survival (PFS), overall survival and a multivariable Cox model was built to identify factors influencing PFS. RESULTS: We included 291 patients from four international centers treated between January 2002 and December 2021. The median number of previous chemotherapy was 1 (1.0-7.0), the median duration of PARPi exposure was 6.5 months (0.2-54.3 months). PARPi was used in first line in 14.1% patients. Most progressions occurred under PARPi exposure (89.1%). A BRCA pathogenic variant was identified in 130 patients (44.7%), absent in 157 patients (54.0%), and undocumented in 4 patients (1.4%). Platinum-based CT (PBC) and non-PBC were administered as subsequent treatments in, respectively, 182 patients (62.5%) and 109 patients (37.5%). Multivariable analyses showed that platinum-free interval (PFI) >6 months [adjusted hazards ratio (HR), 0.52; 95% confidence interval (CI) 0.39-0.70] and type of initial surgery (adjusted HR, 1.41; 95% CI 1.07-1.87; interval or closing surgery versus primary surgery) were associated with PFS, independent of BRCA status or line of therapy (≥2 versus 1). In patients with a PFI >6 months, PBC was numerically associated with the best PFS (adjusted HR, 0.68; 95% CI 0.46-1.01). CONCLUSION: This is the largest real-world study assessing the efficacy of subsequent chemotherapy in patients progressing during PARPi exposure. The patients have poor outcomes. PBC is the best option in patients progressing on PARPi and eligible for PBC rechallenge (PFI >6 months).
Assuntos
Neoplasias Ovarianas , Inibidores de Poli(ADP-Ribose) Polimerases , Humanos , Feminino , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/genética , Pessoa de Meia-Idade , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Idoso , Progressão da Doença , Adulto , Intervalo Livre de Progressão , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Estudos de Coortes , Idoso de 80 Anos ou maisRESUMO
BACKGROUND: Personalized medicine remains an unmet need in ovarian cancer due to its heterogeneous nature and complex immune microenvironments, which has gained increasing attention in the era of immunotherapy. A key obstacle is the lack of reliable biomarkers to identify patients who would benefit significantly from the therapy. While conventional clinicopathological factors have exhibited limited efficacy as prognostic indicators in ovarian cancer, multi-omics profiling presents a promising avenue for comprehending the interplay between the tumor and immune components. Here we aimed to leverage the individual proteomic and transcriptomic profiles of ovarian cancer patients to develop an effective protein-based signature capable of prognostication and distinguishing responses to immunotherapy. METHODS: The workflow was demonstrated based on the Reverse Phase Protein Array (RPPA) and RNA-sequencing profiles of ovarian cancer patients from The Cancer Genome Atlas (TCGA). The algorithm began by clustering patients using immune-related gene sets, which allowed us to identify immune-related proteins of interest. Next, a multi-stage process involving LASSO and Cox regression was employed to distill a prognostic signature encompassing five immune-related proteins. Based on the signature, we subsequently calculated the risk score for each patient and evaluated its prognostic performance by comparing this model with conventional clinicopathological characteristics. RESULTS: We developed and validated a protein-based prognostic signature in a cohort of 377 ovarian cancer patients. The risk signature outperformed conventional clinicopathological factors, such as age, grade, stage, microsatellite instability (MSI), and homologous recombination deficiency (HRD) status, in terms of prognoses. Patients in the high-risk group had significantly unfavorable overall survival (p < 0.001). Moreover, our signature effectively stratified patients into subgroups with distinct immune landscapes. The high-risk group exhibited higher levels of CD8 T-cell infiltration and a potentially greater proportion of immunotherapy responders. The co-activation of the TGF-ß pathway and cancer-associated fibroblasts could impair the ability of cytotoxic T cells to eliminate cancer cells, leading to poor outcomes in the high-risk group. CONCLUSIONS: The protein-based signature not only aids in evaluating the prognosis but also provides valuable insights into the tumor immune microenvironments in ovarian cancer. Together our findings highlight the importance of a thorough understanding of the immunosuppressive tumor microenvironment in ovarian cancer to guide the development of more effective immunotherapies.
Assuntos
Imunoterapia , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/terapia , Neoplasias Ovarianas/mortalidade , Prognóstico , Imunoterapia/métodos , Biomarcadores Tumorais/genética , Pessoa de Meia-Idade , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , IdosoRESUMO
OBJECTIVES: This study aimed to investigate the changes in the incidence and mortality trends of ovarian cancer (OC), cervical cancer (CC) and uterine cancer (UC) in the Fujian Province, southeastern China. DESIGN: Provincial, population-based, retrospective observational study. SETTING: Fujian province, southeastern China between 2011-2020. PARTICIPANTS: From 2011 to 2020, 6178 new cases and 2037 deaths caused by 3 gynaecological cancers were eligible for analysis. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measures were the incidence and mortality rates, including the age-standardised incidence rate (ASIR) and age-standardised mortality rate (ASMR), of three gynaecological cancers. The secondary outcome measure was the prevalence (average annual per cent changes (AAPC)). RESULTS: The incidence of all three gynaecological cancers increased from 2011 to 2020. CC had the slowest upward trend, with an AAPC of 2.54% over the period. However, it had the highest ASIR among the 3 cancers in 2020 (10.41/100 000). UC showed a rapid increase, with an AAPC of 15.15% from 2016 to 2020. While the mortality rate of UC remained stable, both CC and OC also exhibited rising trends, with the CC having the highest ASMR (3.05/100 000) in 2020. The ASMR for CC increased rapidly, with the highest AAPC of 5.51%. Conversely, changes in the ASMR for UC were not statistically significant (p=0.601). Moreover, high incidence rates were more common among perimenopausal women and older participants in the respective cancer groups where the increased mortality was observed. CONCLUSIONS: Gynaecological cancer burden remains a public health issue in Fujian Province, with an increasing incidence. Improving the healthcare system and promoting a healthy lifestyle should be highlighted to reduce the cancer burden.
Assuntos
Sistema de Registros , Neoplasias do Colo do Útero , Humanos , Feminino , Estudos Retrospectivos , China/epidemiologia , Incidência , Pessoa de Meia-Idade , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/epidemiologia , Adulto , Idoso , Neoplasias Uterinas/mortalidade , Neoplasias Uterinas/epidemiologia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/epidemiologia , Neoplasias dos Genitais Femininos/mortalidade , Neoplasias dos Genitais Femininos/epidemiologia , Prevalência , Mortalidade/tendênciasRESUMO
OBJECTIVE: The TGF-ß superfamily member activin, a dimer of the gene products of INHBA and/or INHBB, has been implicated in immune cell maturation and recruitment, but its immune impact within epithelial ovarian cancer (EOC) is not well characterized. We sought to explore differences in activin (INHBA/ Inhibin-ßA and INHBB/ Inhibin-ßB) between malignant and ovarian tissues at the RNA and protein level and assess the relationship between activin and immune cells in EOC. METHODS: Publicly available RNA sequencing data were accessed from GEO (#GSE143897) with normalization and quantification performed via DESeq2. Immune gene expression profile was further explored within the TCGA-OV cohort derived from The Cancer Genome Atlas (TCGA). Immunohistochemical analysis was performed to evaluate activin A and T-cell markers CD8 and FoxP3 at the protein level. ELISA to activin-A was used to assess levels in the ascites of advanced EOC patients. Kaplan-Meier curves were generated to visualize survival outcomes. RESULTS: Gene expression levels of components of the activin signaling pathway were elevated within EOC when compared to a benign cohort, with differences in activin type I/II receptor gene profiles identified. Additionally, INHBA gene expression was linked to lymphocytic immune markers in EOC samples. Immunohistochemistry analysis revealed a positive correlation of CD8 and FOXP3 staining with activin A at the protein level in both primary and metastatic epithelial ovarian cancer samples. Furthermore, Activin-A (inhibin-ßA) is significantly elevated in EOC patient ascites. CONCLUSION: INHBA expression is elevated within EOC, correlating with worse survival, with activin protein levels correlating with specific immune infiltration. Our findings suggest that activin-A may play a role in suppressing anti-tumor immunity in EOC, highlighting its potential as a therapeutic target.
Assuntos
Ativinas , Carcinoma Epitelial do Ovário , Subunidades beta de Inibinas , Neoplasias Ovarianas , Humanos , Feminino , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/imunologia , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/mortalidade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/genética , Subunidades beta de Inibinas/genética , Subunidades beta de Inibinas/metabolismo , Ativinas/metabolismo , Ativinas/genética , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Pessoa de Meia-Idade , Regulação Neoplásica da Expressão Gênica , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Fatores de Transcrição Forkhead/metabolismo , Fatores de Transcrição Forkhead/genéticaRESUMO
Introduction: This research describes an eight-year case-series of ovarian carcinoma by surgical (pTNM) staging and surgical procedure, explores the characteristics of ovarian surface epithelial cell (OSEC) tumours by histopathological type in a single centre of reference. Material and Methods: survival analysis with overall survivor probabilities for n=263 patients for 12 months and 60-month tumour free survival status (TFS). Results by staging (pTNM stage classification), histotype and for poor surgical candidate (PSC) status are shown. Histotype high grade serous carcinoma (HGSC) was the most frequently diagnosed type (63%). Results: 12-month survivor probabilities according to histotype, rank as follows: clear cell carcinoma (CCC) - 14%; rare carcinoma (RC) - 15%; carcinosarcoma (CS) - 29%; HGSC - 46%; low grade serous carcinoma (LGSC) - 74%; endometrioid carcinoma (EC) - 79%; mucinous carcinoma (MC) - 80% and borderline tumours (BLT) - 94%. At 60 months results are: RC and MC - 0%; CCC - 14%; HGSC - 16%; CS - 29%; LGSC - 62%; EC - 66%; and BLT - 94%. Overall median survival time is 26 months (CI95% 15 to 37); and 20 months when BLT excluded (CI95% CI 15 to 25). Conclusions: These results may guide further research for the OSEC pathology and its histotypes.
Assuntos
Estadiamento de Neoplasias , Neoplasias Ovarianas , Humanos , Feminino , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Neoplasias Ovarianas/cirurgia , Pessoa de Meia-Idade , Idoso , Resultado do Tratamento , Carcinossarcoma/mortalidade , Carcinossarcoma/patologia , Carcinossarcoma/cirurgia , Gradação de Tumores , Adenocarcinoma Mucinoso/mortalidade , Adenocarcinoma Mucinoso/cirurgia , Adenocarcinoma Mucinoso/patologia , Adulto , Carcinoma Endometrioide/mortalidade , Carcinoma Endometrioide/patologia , Carcinoma Endometrioide/cirurgia , Análise de Sobrevida , Romênia/epidemiologia , Cistadenocarcinoma Seroso/mortalidade , Cistadenocarcinoma Seroso/patologia , Cistadenocarcinoma Seroso/cirurgia , Intervalo Livre de Doença , Carcinoma Epitelial do Ovário/mortalidade , Carcinoma Epitelial do Ovário/patologia , Carcinoma Epitelial do Ovário/cirurgia , Taxa de Sobrevida , Adenocarcinoma de Células Claras/mortalidade , Adenocarcinoma de Células Claras/patologia , Adenocarcinoma de Células Claras/cirurgia , Estudos Retrospectivos , Fatores de Risco , Prognóstico , Idoso de 80 Anos ou maisRESUMO
PURPOSE: This retrospective real-world study compared overall survival (OS) between patients with BRCA wild-type (BRCAwt) recurrent epithelial ovarian cancer (OC) who received niraparib second-line maintenance (2LM) versus active surveillance (AS) using target trial emulation, cloning, inverse probability of censoring weighting (IPCW) methodology to minimize immortal time bias. METHODS: Eligible patients from a United States-based, deidentified, electronic health record-derived database were diagnosed with epithelial OC (January 1, 2011-May 31, 2021), were BRCAwt, and completed second-line (2L) therapy (January 1, 2017-March 2, 2022). Patient data were cloned at index (2L last treatment date), assigned to niraparib 2LM and AS cohorts, and censored when treatment deviated from clone assignment. Follow-up was measured from index to earliest of study end (May 31, 2022), last activity, or death. Median OS (mOS) and hazard ratios were estimated from stabilized IPCW Kaplan-Meier curves and Cox regression models. RESULTS: Overall, 199 patients received niraparib 2LM, and 707 had their care managed with AS. Key characteristics were balanced across cohorts after cloning and stabilized IPCW. Median follow-up was 15.6- and 9.3-months pre-cloning. IPCW mOS was 24.1 months (95% CI: 20.9-29.5) and 18.4 months (95% CI: 15.1-22.8) in niraparib 2LM and AS cohorts, respectively (hazard ratio, 0.77; 95% CI: 0.66-0.89). CONCLUSIONS: This real-world study provides supportive evidence of an OS benefit for patients with BRCAwt recurrent OC who received 2LM niraparib monotherapy compared with those whose care was managed with AS. The analytic strategies implemented were useful in minimizing immortal time bias and measured confounding.
Assuntos
Indazóis , Recidiva Local de Neoplasia , Neoplasias Ovarianas , Piperidinas , Humanos , Feminino , Piperidinas/uso terapêutico , Piperidinas/administração & dosagem , Indazóis/uso terapêutico , Indazóis/administração & dosagem , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/mortalidade , Carcinoma Epitelial do Ovário/tratamento farmacológico , Carcinoma Epitelial do Ovário/mortalidade , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Adulto , Conduta Expectante , Estados Unidos/epidemiologia , Quimioterapia de Manutenção/métodos , Bases de Dados FactuaisRESUMO
Malignant ovarian sex cord-stromal tumors are rare neoplasms that account for approximately 5-7% of all ovarian malignancies, and they are primarily treated with surgery. The prognosis of patients with different surgical extents remains controversial. Therefore, the effects of different surgical extents on the prognosis of patients were explored in this retrospective cohort study. Patients with malignant ovarian sex cord-stromal tumors who underwent surgical treatment from January 2000 to December 2019 were selected. Disease-free survival and overall survival rates were calculated by the Kaplan-Meier method and compared by the log-rank test. Prognosis factors were identified by Cox regression analysis. P < 0.05 was considered a statistically significant difference. A total of 278 patients with an average age at onset of 42 (8-78) years old were enrolled. The median follow-up time was 73 months. There was no significant difference in disease-free survival and overall survival rates between patients who underwent fertility-sparing surgery and those who underwent Non-fertility-sparing surgery, and between patients underwent staging surgery and those underwent Non-staging surgery. Age < 40 years (P = 0.024), stage II-III (P = 0.038), a high CA125 level (P = 0.035) and WT-1 (+) (P = 0.016) were independent risk factors for recurrence. In conclusion, different surgical extents have no significant influence on recurrence and survival status of patients with malignant ovarian sex cord-stromal tumors.
Assuntos
Neoplasias Ovarianas , Tumores do Estroma Gonadal e dos Cordões Sexuais , Humanos , Feminino , Tumores do Estroma Gonadal e dos Cordões Sexuais/cirurgia , Tumores do Estroma Gonadal e dos Cordões Sexuais/patologia , Tumores do Estroma Gonadal e dos Cordões Sexuais/mortalidade , Adulto , Pessoa de Meia-Idade , Neoplasias Ovarianas/cirurgia , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Estudos Retrospectivos , Adolescente , Prognóstico , Adulto Jovem , Idoso , Criança , Intervalo Livre de Doença , Taxa de Sobrevida , Estadiamento de Neoplasias , Estimativa de Kaplan-Meier , Preservação da Fertilidade/métodosRESUMO
BACKGROUND: Ambient air pollution might serve as a prognostic factor for ovarian cancer (OC) survival, yet the relationships between plant-based diet indices (PDIs) and OC survival remain unclear. We aimed to investigate the associations of comprehensive air pollution and PDIs with OC survival and explored the effects of air pollution-diet interactions. METHODS: The present study encompassed 658 patients diagnosed with OC. The overall plant-based diet index (PDI), the healthful PDI (hPDI), and the unhealthful PDI (uPDI) were evaluated by a self-reported validated food frequency questionnaire. In addition, an air pollution score (APS) was formulated by summing the concentrations of particulate matter with a diameter of 2.5 microns or less, ozone, and nitrogen dioxide. Cox proportional hazard models were applied to calculate hazard ratios (HRs) and 95â¯% confidence intervals (CIs). The potential interactions of APS with PDIs in relation to overall survival (OS) were assessed on both multiplicative and additive scales. RESULTS: Throughout a median follow-up of 37.60 (interquartile: 24.77-50.70) months, 123 deaths were confirmed. Comparing to the lowest tertiles, highest uPDI was associated with lower OS of OC (HR = 2.06, 95â¯% CI = 1.30, 3.28; P-trend < 0.01), whereas no significant associations were found between either overall PDI or hPDI and OC survival. Higher APS (HR for per interquartile range = 1.27, 95â¯% CI = 1.01, 1.60) was significantly associated with worse OC survival, and the association was exacerbated by adherence to uPDI. Notably, an additive interaction was identified between combined air pollution and uPDI (P < 0.005 for high APS and high uPDI). We also found that adherence to overall PDI aggravated associations of air pollution with OC survival (P-interaction = 0.006). CONCLUSIONS: Joint exposure to various ambient air pollutants was significantly associated with lower survival among patients with OC, particularly for those who predominantly consumed unhealthy plant-based foods.
Assuntos
Poluentes Atmosféricos , Poluição do Ar , Neoplasias Ovarianas , Material Particulado , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Neoplasias Ovarianas/mortalidade , Poluição do Ar/efeitos adversos , Poluição do Ar/estatística & dados numéricos , Material Particulado/análise , Poluentes Atmosféricos/análise , Poluentes Atmosféricos/efeitos adversos , Adulto , Dieta Vegetariana , Modelos de Riscos Proporcionais , Ozônio/análise , Idoso , Dióxido de Nitrogênio/análise , Exposição Ambiental/estatística & dados numéricos , Exposição Ambiental/efeitos adversos , Estudos de Coortes , Dieta Baseada em PlantasRESUMO
BACKGROUND: Ovarian cancer (OC) is one of the cancers with a high incidence at present, which poses a severe threat to women's health. This study focused on identifying the heterogeneity among malignant epithelial cell OC and constructing an effective prognostic signature to predict prognosis and immunotherapy according to a multidisciplinary study. METHODS: The InterCNV algorithm was used to identify the heterogeneity of OC based on the scRNA-seq and bulk RNA-seq data. Six algorithms selected EMTscore. An effective prognostic signature was conducted using the COX and Least Absolute Shrinkage and Selection Operator (LASSO) regression algorithms. The texting datasets were used to assess the accuracy of the prognostic signature. We evaluated different immune characteristics and immunotherapy response differences among other risk groups. RESULTS: A prognostic signature including 14 genes was established. The patients in the high-risk group have poor survival outcomes. We also found that the patients in the low-risk group have higher immune cell infiltration, enrichment of immune checkpoints, and immunotherapy response, suggesting that the patients in the low-risk group may be more sensitive to immunotherapy. Finally, the laboratory test results showed that KREMEN2 was identified as a novel biomarker and therapeutic target for OC patients. CONCLUSIONS: Our study established a GRG signature consisting of 16 genes based on the scRNA-seq and bulk RNA-seq data, which provides a new perspective on the prediction of prognosis and treatment strategy for OC.
Assuntos
Biomarcadores Tumorais , Imunoterapia , Neoplasias Ovarianas , Análise de Célula Única , Humanos , Feminino , Prognóstico , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/terapia , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/mortalidade , Imunoterapia/métodos , Biomarcadores Tumorais/genética , Análise de Sequência de RNA , Regulação Neoplásica da Expressão Gênica , Algoritmos , Pessoa de Meia-IdadeRESUMO
We investigated whether developing an autoimmune disorder (AID) following a high-grade epithelial ovarian cancer diagnosis improves overall survival. This retrospective study included data from women treated for high-grade serous, endometrioid, or transitional cell ovarian, fallopian tube, or peritoneal cancer FIGO stage III or IV at a Swiss cantonal gynecological cancer center (2008-2023). We used Kaplan-Meier estimates and the Cox proportional hazards model using time-varying covariates for the survival function estimation. In all, 9 of 128 patients developed an AID following a cancer diagnosis. The median time from cancer diagnosis to AID was 2 years (IQR 2-5). These women survived for a median of 3031 days (IQR 1765-3963) versus 972 days (IQR 568-1819) for those who did not develop an AID (p = 0.001). The median overall survival of nine women with a pre-existing AID was 1093 days (IQR 716-1705), similar to those who never had an AID. The multivariate analyses showed older age (p = 0.003, HR 1.04, 95% CI 1.013-1.064) was associated with a poorer prognosis, and developing an AID after a cancer diagnosis was associated with longer survival (p = 0.033, HR 0.113, 95% CI 0.015-0.837). Clinical manifestations of autoimmune disorders following ovarian cancer diagnoses were associated with better overall survival (8 versus 2.7 years), indicating an overactive immune response may improve cancer control.