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The tumor suppressor miR-34 family is transcriptionally induced by p53. Clinical significance of the various miR-34 family members has not been studied in ovarian cancer. In 228 ovarian cancers and in 19 non-neoplastic fallopian tube samples we analysed miR-34 a/b/c expression in relation to clinicopathological characteristics and clinical outcome. We found significantly lower levels of miR-34 a/b/c in ovarian cancers as compared to control-tissues ( =0.002, <0.001, <0.001, respectively). Expression of miR-34 b/c revealed an inverse correlation with mRNA-expression (BRCA1: miR34 b/c =0.002 each; BRCA2: miR-34 b/c P<0.001 each), the same was true for miR-34a and mRNA-expression ( <0.001). The miR-34 family expression was found to be significantly lower in type 2 in comparison to type 1 cancers (P<0.001) and in -mutated compared with -wild-type ovarian cancers ( <0.001, =0.002, =0.004, respectively). When low grade serous ovarian cancers were compared with high grade serous cancers the respective miR-34 a/b/c expression was 2.6-, 40.8- and 32.3-fold higher. The expression of each of the miR-34 family members was revealed to be of independent prognostic relevance regarding progression free survival (PFS); miR-34a: HR 0.6, =0.033; miR-34b: HR 0.2, =0.001 and miR-34c: HR 0.3, =0.002, respectively). For overall survival (OS) independency of the prognostic value was confined to miR-34b (HR 0.4, =0.016) and miR-34c (HR 0.6, =0.049). The independency of the prognostic value of our identified thresholds was confirmed for PFS for miR-34c in a publicly available dataset (NCBI Gene Expression Omnibus GSE73582). Our findings suggest that downregulation of miR-34 family is a crucial part in ovarian cancer development. Low miR-34 levels are linked to a worse overall survival and progression free survival and may indicate a more aggressive disease.

SMARCA4 and EZH2 are two functional key players of their respective antagonizing chromatin remodeling complexes SWI/SNF and PRC2. EZH2 inhibitory drugs may abrogate pro-oncogenic features of PRC2 and turn the balance to cell differentiation via SWI/SNF activity in cancers. SMARCA4 and EZH2 expression was assessed by RT-PCR in 238 epithelial ovarian cancers (OCs) and put in relation to clinico-pathological parameters and patients’ outcome. Optimal thresholds for high and low expression of both variables were calculated by the Youden’s index based on receiver operating characteristic (ROC) curves. High SMARCA4 mRNA expression was independently associated with favorable progression-free survival (PFS) ( P  = 0.03) and overall survival (OS) ( P  = 0.018). As Youden’s threshold determination for EZH2 yielded a S-shaped ROC-curve, two cut-off points (29th and 94th percentile) predicting opposite features were defined. Whereas EZH2 mRNA levels beyond the 29th percentile independently predicted poor PFS ( P  = 0.034), Cox-regression in EZH2 transcripts above the 94th percentile revealed a conversion from unfavorable to favorable PFS and OS ( P  = 0.009 and P  = 0.032, respectively). High SMARCA4 expression associates with improved survival, whereas moderate/high EZH2 expression predicts poor outcome, which converts to favorable survival in ultra-high expressing OCs. This small OC subgroup could be characterized by REV7-abrogated platinum hypersensitivity but concomitant PARP-inhibitor resistance.

Background In high-grade ovarian cancer (HGOC), determination of homologous recombination deficiency (HRD) status is commonly used in routine practice to predict response to platinum-based therapy or poly (ADP-ribose) polymerase inhibitors (PARPi). Here we tested the hypothesis that BRCA loss of function (LOF) due to epigenetic or genetic aberrations is a better predictor for the clinical outcome than HRD. One hundred thirty-one HGOC tissues were tested for BRCA DNA-methylation, BRCA mutations, HRD and BRCA1 mRNA expression, followed by a comprehensive survival analysis. Results BRCA1 -methylation was detected in 11% of the tumors, exclusively in BRCA1- wild-type (wt) HGOCs. BRCA1- methylated tumors ( BRCA1 -meth) had HRD-scores similar to those of BRCA -mutated (mut) tumors, and higher compared to unmethylated- BRCA -wt tumors ( BRCA -wt-unmeth; P  < 0.001). Platinum-refractory or -resistant HGOCs at first recurrence were all BRCA -unmeth cancers. Only one of the BRCA- mut cancers had a platinum-resistant recurrence. Thus, 99% of relapses in cancers with epigenetic or genetic BRCA -alterations were platinum-sensitive. Multivariate analysis confirmed BRCA-LOF as an independent predictor of progression-free survival (PFS) and overall survival (OS), whereas HRD-status had no predictive value for PFS and OS. Patients with BRCA -wt-unmeth cancers had the worst outcome compared to patients with cancers harboring epigenetic or genetic BRCA -alterations (PFS: P  = 0.007; OS: P  = 0.022). Most importantly, the BRCA -wt-unmeth subfraction of HRD-positive HGOCs exhibited the same poor survival as the entire HRD-negative cohort. Conclusion In HGOC BRCA mutational status together with BRCA1 -methylation exhibit the best predictive power for favorable clinical outcome and thus high sensitivity to platinum-based therapy, whereas BRCA -unrelated HRD positivity was not associated with improved platinum sensitivity.

Inflammation plays a crucial role in the pathogenesis of cancer with tumor necrosis factor‐α (TNF‐α) as a key mediator. Recently, spermatogenesis‐associated protein 2 (SPATA2) was identified as a TNF receptor modulator which is required for TNF‐induced inflammation and apoptosis. The available data on TNF‐α in ovarian cancer (OC) are inconsistent, and SPATA2 is completely uncharacterized in tumorigenesis. We analyzed expression of SPATA2 and TNFA by quantitative real‐time polymerase chain reaction in tissues of 171 patients with low‐grade serous (LGSOC), high‐grade serous (HGSOC), endometrioid and clear cell OC compared with 28 non‐malignant control tissues. We stimulated OC cells (OVCAR3) with pro‐inflammatory (TNF‐α, interleukin [IL]‐1β) and mitogenic stimuli (IL‐6, lysophosphatidic acid) to establish a direct effect between inflammatory signaling and SPATA2. Pro‐inflammatory, but not mitogenic stimuli, potently induced SPATA2 expression in OC cells. Expression of TNFA and SPATA2 was higher in OC compared with control tissues (P = 0.010 and P = 0.001, respectively) and correlated with each other (P = 0.034, rs = 0.198). When compared with grade 1 cancers, SPATA2 was expressed higher in grade 2 and 3 tumors (P = 0.011) as well as in HGSOC compared with LGSOC (P = 0.024). Multivariate survival analyses revealed that OC with high SPATA2 expression were associated with reduced progression‐free survival (P = 0.048) and overall survival (P < 0.001). In conclusion, SPATA2 expression is regulated by TNF‐α and IL‐1β and is found to independently affect clinical outcome in OC patients. These data implicate a role of SPATA2 in tumorigenesis which warrants further investigation in gynecological malignancies. TNFA and the TNF receptor modulator SPATA2 are high in ovarian cancer supporting the inflammatory character of this disease. High SPATA2, which was markedly induced by inflammatory stimuli in vitro, independently reflected poor clinical outcome of ovarian cancer patients.

Polybromo-1 ( PBRM1 ) loss of function mutations are present in a fraction of biliary tract cancers (BTCs). PBRM1 , a subunit of the PBAF chromatin-remodeling complex, is involved in DNA damage repair. Herein, we aimed to decipher the molecular landscape of PBRM1 mutated (mut) BTCs and to define potential translational aspects. Totally, 1848 BTC samples were analyzed using next-generation DNA-sequencing and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). siRNA-mediated knockdown of PBRM1 was performed in the BTC cell line EGI1 to assess the therapeutic vulnerabilities of ATR and PARP inhibitors in vitro. PBRM1 mutations were identified in 8.1% ( n  = 150) of BTCs and were more prevalent in intrahepatic BTCs (9.9%) compared to gallbladder cancers (6.0%) or extrahepatic BTCs (4.5%). Higher rates of co-mutations in chromatin-remodeling genes (e.g., ARID1A 31% vs. 16%) and DNA damage repair genes (e.g., ATRX 4.4% vs. 0.3%) were detected in PBRM1 -mutated (mut) vs. PBRM1 -wildtype (wt) BTCs. No difference in real-world overall survival was observed between PBRM1 -mut and PBRM1 -wt patients (HR 1.043, 95% CI 0.821–1.325, p  = 0.731). In vitro, experiments suggested that PARP ± ATR inhibitors induce synthetic lethality in the PBRM1 knockdown BTC model. Our findings served as the scientific rationale for PARP inhibition in a heavily pretreated PBRM1- mut BTC patient, which induced disease control. This study represents the largest and most extensive molecular profiling study of PBRM1- mut BTCs, which in vitro sensitizes to DNA damage repair inhibiting compounds. Our findings might serve as a rationale for future testing of PARP/ATR inhibitors in PBRM1- mut BTCs.

Germ cell tumors (GCTs) represent about 5% of urological cancers affecting mostly younger males with increasing incidence in the last decades. GCTs are very sensitive to cisplatin-based therapy and are highly curable regardless of metastatic stage, likely based on having inherited unique mechanisms of sensitivity to DNA damage and other stressors to prevent germline mutations. Here, we present the first case of a 60-year Caucasian male with a heavily pretreated, cisplatin-refractory extragonadal non-seminomatous GCT (choriocarcinoma) treated with pembrolizumab and olaparib based on high programmed death-ligand 1 expression (tumor proportion score 50% and a combined positive score 55%) high tumor mutational burden, borderline genomic loss of heterozygosity, and a heterozygous variant of uncertain significance in the DNA repair gene ATM, as confirmed by next-generation sequencing (NGS) analysis. Despite a notable decrease in b-hCG within 4 weeks after starting pembrolizumab and olaparib, b-hCG increased steadily again afterward. In addition, the patient developed an immune-related pneumonitis with a fatal outcome 3 months later. NGS with subsequent targeted treatment possibilities might present a helpful step toward precision medicine in GCT patients who have exhausted all other conventional treatment options, and genetic testing should therefore be offered to patients prior to progression.

Deep learning is expected to aid pathologists in tasks such as tumour segmentation. We developed a general tumour segmentation model for histopathological images and examined its performance in different cancer types. The model was developed using over 20,000 whole-slide images from over 4000 patients with colorectal, endometrial, lung, or prostate carcinoma. Performance was validated in pre-planned analyses on external cohorts with over 3000 patients across six cancer types. Exploratory analyses included over 1500 additional patients from The Cancer Genome Atlas. Average Dice coefficient was over 80% in all validation cohorts with en bloc resection specimens and in The Cancer Genome Atlas cohorts. No performance loss was observed when comparing the general model with single-cancer models specialised in cancer types from the development set. In conclusion, extensive and rigorous evaluations demonstrate that generic tumour segmentation by a single model is possible across cancer types, patient populations, sample preparations and slide scanners.

Background Diagnosis and treatment of ovarian cancer (OC) entail severe symptom burden and a significant loss of quality of life (QOL). Somatic and psychological impairments may persist well beyond active therapy. Although essential for optimal symptom management as well as for the interpretation of treatment outcomes, knowledge on the course of QOL-related issues is scarce. This study aimed at assessing the course of depressive symptoms, anxiety, fatigue and QOL in patients with OC over the course of chemotherapy until early after-care. Methods 23 patients were assessed longitudinally (eight time points) with regard to symptom burden (depression, anxiety, fatigue, and QOL) by means of patient-reported outcome instruments (HADS, MFI-20, EORTC QLQ-C30/-OV28) and clinician ratings (HAMA/D) at each chemotherapy cycle and at the first two aftercare visits. Results Statistically significant decrease over time was found for depressive symptoms and anxiety as well as for all fatigue scales. With regard to QOL, results indicated significant increase for 11 of 15 QOL scales, best for Social (effect size = 1.95; p < 0.001), Emotional (e.s. = 1.62; p < 0.001) and Physical Functioning (e.s. = 1.47; p < 0.001). Abdominal Symptoms (e.s. = 1.01; p = 0.009) decreased, Attitudes towards Disease and Treatment (e.s. = 1.80; p < 0.001) improved significantly over time. Analysis of Sexual Functioning was not possible due to a high percentage of missing responses (61.9%). Conclusions The present study underlines the importance of longitudinal assessment of QOL in order to facilitate the identification of symptom burden in OC patients. We found that patients show high levels of fatigue, anxiety and depressive symptoms and severely impaired QOL post-surgery (i.e. at start of chemotherapy) but condition improves considerably throughout chemotherapy reaching nearly general population symptoms levels until aftercare.

Following publication of the original article [1], we have been alerted to errors in Figs. 2 and 8. In Fig. 2B, the GAPDH loading control for Hec1A cells is shown twice in error (in Fig. 2B and Fig. 2C). In Fig. 8, in testis case 1 (first column) the MAGE-A4 staining panel was repeated and also appears as the NY-ESO-1 staining panel in error. The corrected versions of Fig. 2 and Fig. 8 are shown below. We apologize for this inconvenience.

Cancer immunotherapy has emerged as one of the most promising approaches in oncology, and comprises the activation of the immune system to induce tumor immune surveillance or to reverse the tumor immune escape. Different therapeutic strategies for ovarian carcinoma have evolved over the years. Already 30 years ago, the first clinical studies focused on modulating the tumor cytokine network with special attention to interferon-mediated immune responses. With the exploration of specific tumor antigens such as NY-ESO-1, which is expressed in ovarian carcinoma and other malignancies, the development of therapeutic cancer vaccines has been pursued initiating the era of personalized anti-cancer medicine. Almost at the same time, the adoptive transfer of genetically modified autologous tumor-reactive T-cells occurred, but response rates in ovarian carcinoma were disappointing. Today, probably the most promising therapeutic approach in this context is the blockade of immune checkpoints, such as programed cell death protein 1 (PD-1) and one of its ligands (PD-L1) or cytotoxic T-cell lymphocyte-associated antigen 4 (CTLA-4), which has demonstrated impressive response rates in malignant melanoma and non-small cell lung cancer. Despite increasing availability of treatment approaches that target tumor immune surveillance in ovarian carcinoma, selecting patient groups that particularly benefit from these treatment modalities is clinically challenging as predictive biomarkers are lacking. Here, we summarize different immunotherapy approaches in ovarian cancer and discuss why immunotherapy in ovarian cancer is still in its infancy.