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BRCA1/BRCA2 genes play a central role in DNA repair and their mutations increase sensitivity to DNA-damaging agents. There are conflicting data regarding the prognostic value of BRCA germline mutations in breast cancer (BC) patients. We collected clinical, pathological and genetic data of a cohort 925 BC patients preselected for genetic screening and treated with neoadjuvant or adjuvant chemotherapy, of whom 266 were BRCA carriers. Overall, 171 women carried a BRCA1 mutation, 95 carried a BRCA2 mutation, and 659 were non-carriers. In the entire cohort, there was a prolonged disease-free survival (DFS) for BRCA carriers (hazard ratio (HR) = 0.63; 95% confidence interval (CI), 0.44–0.90 for BRCA1; HR = 0.72; 95%CI, 0.47–1.1 for BRCA2 ; p  = 0.020) and a trend toward prolonged disease-specific survival (DSS; HR = 0.65; 95%CI, 0.40–1.1 for BRCA1 ; HR = 0.78; 95%CI, 0.44–1.38 for BRCA2 ; p  = 0.19) though not statistically significant. In the TNBC group, BRCA carriers had prolonged DFS (adjusted HR = 0.50; 95%CI, 0.28–0.89 for BRCA1; adjusted HR = 0.37; 95%CI, 0.11–1.25, for BRCA2; p  = 0.034) and DSS (adjusted HR = 0.42; 95%CI, 0.21–0.82 for BRCA1; adjusted HR = 0.45; 95%CI, 0.11–1.9 for BRCA2; p  = 0.023). In the non-TNBC group, the BRCA1 or BRCA2 mutations did not have any impact on survival. These results suggest that BRCA1/BRCA2 germline mutations are associated with prolonged survival only if women were diagnosed with TNBC.

High-grade serous ovarian carcinoma (HGSOC) is the most frequent type of ovarian cancer and has a poor outcome. It has been proposed that fallopian tube cancers may be precursors of HGSOC but evolutionary evidence for this hypothesis has been limited. Here, we perform whole-exome sequence and copy number analyses of laser capture microdissected fallopian tube lesions (p53 signatures, serous tubal intraepithelial carcinomas (STICs), and fallopian tube carcinomas), ovarian cancers, and metastases from nine patients. The majority of tumor-specific alterations in ovarian cancers were present in STICs, including those affecting TP53, BRCA1 , BRCA2 or PTEN . Evolutionary analyses reveal that p53 signatures and STICs are precursors of ovarian carcinoma and identify a window of 7 years between development of a STIC and initiation of ovarian carcinoma, with metastases following rapidly thereafter. Our results provide insights into the etiology of ovarian cancer and have implications for prevention, early detection and therapeutic intervention of this disease. It has previously been proposed that high-grade serous ovarian carcinoma (HGSOC) may originate from the fallopian tube. Here, the authors analyze genetic aberrances in fallopian tube lesions, ovarian cancers, and metastases from HGSOC patients and establish the evolutionary origins of HGSOC in the fallopian tube.

Histone H2AX plays a key role in DNA damage signalling in the surrounding regions of DNA double-strand breaks (DSBs). In response to DNA damage, H2AX becomes phosphorylated on serine residue 139 (known as γH2AX), resulting in the recruitment of the DNA repair effectors 53BP1 and BRCA1. Here, by studying resistance to poly(ADP-ribose) polymerase (PARP) inhibitors in BRCA1/2-deficient mammary tumours, we identify a function for γH2AX in orchestrating drug-induced replication fork degradation. Mechanistically, γH2AX-driven replication fork degradation is elicited by suppressing CtIP-mediated fork protection. As a result, H2AX loss restores replication fork stability and increases chemoresistance in BRCA1/2-deficient tumour cells without restoring homology-directed DNA repair, as highlighted by the lack of DNA damage-induced RAD51 foci. Furthermore, in the attempt to discover acquired genetic vulnerabilities, we find that ATM but not ATR inhibition overcomes PARP inhibitor (PARPi) resistance in H2AX-deficient tumours by interfering with CtIP-mediated fork protection. In summary, our results demonstrate a role for H2AX in replication fork biology in BRCA-deficient tumours and establish a function of H2AX separable from its classical role in DNA damage signalling and DSB repair. Histone H2AX has a known role in DNA damage repair but interestingly, its loss is associated with resistance to poly(ADP-ribose) polymerase (PARP) inhibition in BRCA-deficient tumours. Here, the authors identify a role of γH2AX in the degradation of replication forks and demonstrate that H2AX loss drives PARP inhibitor resistance via increased stressed fork stability in BRCA-deficient tumours.

Endometriosis is an oestrogen‐dependent, inflammation‐driven gynaecologic disorder causing severe disability. Endometriosis implants are characterized by unbalanced local oestrogen metabolism leading to hyperoestrogenism and aromatase up‐regulation is one of main mechanism involved. Aromatase inhibitors such as letrozole or anastrozole use in young women are associated with severely side effects limiting their long‐term clinical use. An endometriosis‐targeted inhibition of local aromatase could be a viable alternative, although the role of the local inhibition of this enzyme is still unclear. Using a new chick embryo allantoic membrane (CAM) model incorporating xenografted human endometriosis cyst, we showed that topical treatment with anastrozole reduced lesion size, although oestrogens produced by CAM female embryo blunted this effect. Xenografted human endometriosis CAM is a new efficient model for the screening of new drugs targeting endometriosis tissue.

The prognostic impact of tumor-infiltrating lymphocytes (TILs) within invasive lobular carcinoma (ILC) remains to be better characterized. In estrogen receptor (ER)-negative invasive ductal carcinomas of no special type (IDC-NST), TILs are associated with good prognosis. The aim of this study was to examine TILs in ILC, with particular focus on prognostic and clinicopathologic features. A cohort comprising 459 consecutive ILCs diagnosed in a single institution from 2005 to 2008 met the eligibility criteria for this study. The percentage of tumor area occupied by TILs was quantified by two breast pathologists and categorized into three groups: no TILs, ≤5%, >5%. Clinicopathologic features were tested by Fisher's exact tests or Chi2 tests. Overall survival (OS) and invasive disease-free survival (iDFS) were estimated by Kaplan–Meier and Cox proportional hazard statistics. There were 239 TIL-negative cases, 185 cases with ≤5% TILs, and 35 cases with >5% TILs. TILs were associated with younger age, larger tumors, lymph node involvement, poor Nottingham prognostic index, HER2 amplification, multinucleation, and prominent nucleoli (p < 0.05). Poor OS was significantly associated with increasing TILs in the univariate Cox proportional hazards model (p < 0.001) and Kaplan–Meier estimator (p < 0.05, log-rank test). Similar results were observed for iDFS (p = 0.004 for Cox univariate and p = 0.005 for log-rank test). Notably, TILs can identify a subset of ILC patients with poor OS independently of molecular subtype and lymph node metastases (multivariate Cox, p < 0.001, OS hazard ratio (HR) = 4.38 and HR = 6.15, for ≤5% and >5% TILs, respectively, vs. absence of TILs). Prominent nucleoli was the only nuclear feature associated with poor OS (p = 0.05) and iDFS (p = 0.05) in univariate Cox survival analysis. TILs represent a promising new morphologic biomarker associated with poor outcome of ILC, in contrast with that observed in ER-negative IDC-NST.

Background/Objectives: Despite recent therapeutic advances, the clinical management of renal cell carcinoma (RCC) remains suboptimal. Current treatments are hindered by limited efficacy, the emergence of acquired drug resistance, suboptimal tolerability, and a lack of tumor-specific targeting. While development of novel agents remains an important avenue, it is often constrained by high costs, long development time, and low success rates. As an alternative approach, drug combinations of approved agents offer a promising strategy. Methods: Using our proprietary drug combination methodology, we identified multidrug combinations in RCC cells representing the clear cell (786O) and sarcomatoid chromophobe (UOK276) histological subtypes of RCC. Results: From an initial panel of 10 drugs, either approved or undergoing clinical trial, the optimized drug combinations (ODCs) contained crizotinib, telaglenastat, U-104, and vismodegib at clinical and subtherapeutic doses. The ODCs were non-toxic in advanced hepatic, renal, and cardiac cellular models. Importantly, their anti-tumor activity, already notable in normoxic (21% O2) conditions (approx. 50%) was markedly enhanced in tumor-relevant hypoxia (1.5% O2), reaching up to 77% in 2D and 62% in 3D spheroid 786O models. Moreover, chronic exposure of 786O and UOK276 cells led to durable responses, suggesting a prolonged effect in responders. Conclusions: Our findings demonstrate the potential of optimized, non-toxic drug combinations as a highly selective and effective strategy for accelerating the development of precision RCC treatment.

Inflammation plays a pivotal role in cancer development, with chronic inflammation promoting tumor progression and treatment resistance, whereas acute inflammatory responses contribute to protective anti-tumor immunity. Gasdermin D (GSDMD) mediates the release of pro-inflammatory cytokines such as IL-1β. While the release of IL-1β is directly linked to the progression of several types of cancers, the role of GSDMD in cancer is less clear. In this study, we show that GSDMD expression is upregulated in human breast, kidney, liver, and prostate cancer. Higher GSDMD expression correlated with increased survival in primary breast invasive carcinoma (BRCA), but not in liver hepatocellular carcinoma (LIHC). In BRCA, but not in LIHC, high GSDMD expression correlated with a myeloid cell signature associated with improved prognosis. To further investigate the role of GSDMD in anticancer immunity, we induced breast cancer and hepatoma tumors in GSDMD-deficient mice. Contrary to our expectations, GSDMD deficiency had no effect on tumor growth, immune cell infiltration, or cytokine expression in the tumor microenvironment, except for Cxcl10 upregulation in hepatoma tumors. In vitro and in vivo innate immune activation with TLR ligands, that prime inflammatory responses, revealed no significant difference between GSDMD-deficient and wild-type mice. These results suggest that the impact of GSDMD on anticancer immunity is dependent on the tumor type. They underscore the complex role of inflammatory pathways in cancer, emphasizing the need for further exploration into the multifaceted effects of GSDMD in various tumor microenvironments. As several pharmacological modulators of GSDMD are available, this may lead to novel strategies for combination therapy in cancer.

Background We explored, within the EORTC10994 study, the outcomes for patients with molecular apocrine (MA) breast cancer, and defined immunohistochemistry (IHC) as androgen-receptor (AR) positive, oestrogen (ER) and progesterone (PR) negative. We also assessed the concordance between IHC and gene expression arrays (GEA) in the identification of MA cancers. Methods Centrally assessed biopsies for AR, ER, PR, HER2 and Ki67 by IHC were classified into six subtypes: MA, triple-negative (TN) basal-like, luminal A, luminal B HER2 negative, luminal B HER2 positive and “other”. The two main objectives were the pCR rates and survival outcomes in the overall MA subtype (and further divided by HER2 status) and the remaining five subtypes. Results IHC subtyping was obtained in 846 eligible patients. Ninety-three (11%) tumours were classified as the MA subtype. Both IHC and GEA data were available for 64 patients. In this subset, IHC concordance was 88.3% in identifying MA tumours compared with GEA. Within the MA subtype, pCR was observed in 33.3% of the patients (95% CI: 29.4–43.9) and the 5-year recurrence-free interval was 59.2% (95% CI: 48.2–68.6). Patients with MA and TN basal-like tumours have lower survival outcomes. Conclusions Irrespective of their HER2 status, the prognosis for MA tumours remains poor and adjuvant trials evaluating anti-androgens should be considered.

ObjectivesA simple system for visual inspection with acetic acid assessment, named ABCD criteria, has been developed to increase accuracy for triaging of high-risk human papillomavirus (HPV)-positive women. This study aimed to determine the accuracy of ABCD criteria for the detection of histologically confirmed cervical intraepithelial neoplasia grade two or worse (CIN2+) in HPV-positive women living in a low-resource setting.DesignProspective study of diagnostic accuracy.SettingCervical cancer screening programme based on a 3T-Approach (test, triage and treat) in the Health District of Dschang, West Cameroon.ParticipantsAsymptomatic non-pregnant women aged 30–49 years were eligible to participate. Exclusion criteria included history of CIN treatment, anogenital cancer or hysterectomy. A total of 1980 women were recruited (median age, 40 years; IQR 35–45 years), of whom 361 (18.4%) were HPV-positive and 340 (94.2%) completed the trial.InterventionsHPV-positive women underwent a pelvic examination for visual assessment of the cervix according to ABCD criteria. The criteria comprised A for acetowhiteness, B for bleeding, C for colouring and D for diameter. The ABCD criteria results were codified as positive or negative and compared with histological analysis findings (reference standards).Primary outcome measureDiagnostic performance of ABCD criteria for CIN2+, defined as sensitivity, specificity, negative and positive predictive values.ResultsABCD criteria had a sensitivity of 77.5% (95% CI 61.3% to 88.2%), specificity of 42.0% (95% CI 36.5% to 47.7%), positive predictive value of 15.1% (95% CI 10.8% to 20.8%), and negative predictive value of 93.3% (95% CI 87.6% to 96.5%) for detection of CIN2 +lesions. Most (86.7%) of the ABCD-positive women were treated on the same day.ConclusionsABCD criteria can be used in the context of a single-visit approach and may be the preferred triage method for management of HPV-positive women in a low-income context.Trial registration numberNCT03757299.

Objective To determine whether knowledge of cytology affects the colposcopist’s diagnostic accuracy in the identification of cervical intraepithelial neoplasia grade 2 and worse (≥ CIN2). Method In this cross-over study, healthcare professionals interpreted colposcopy images from 80 patient cases with known histological diagnoses. For each case, 2 images taken with a colposcope were provided (native and after acetic acid application). Inclusion criteria consisted of women with a transformation zone type 1 or 2, who had both a cytological and histological diagnosis. Cases were distributed across two online surveys, one including and one omitting the cytology. A wash-out period of six weeks between surveys was implemented. Colposcopists were asked to give their diagnosis for each case as < CIN2 or ≥ CIN2 on both assessments. Statistical analysis was conducted to compare the two interpretations. Results Knowledge of cytology significantly improved the sensitivity when interpreting colposcopic images, from 51.1% [95%CI: 39.3 to 62.8] to 63.7% [95%CI: 52.1 to 73.9] and improved the specificity from 63.5% [95%CI: 52.3 to 73.5] to 76.6% [95%CI: 67.2 to 84.0]. Sensitivity was higher by 38.6% when a high-grade cytology (ASC-H, HSIL, AGC) was communicated compared to a low-grade cytology (inflammation, ASC-US, LSIL). Specificity was higher by 31% when a low-grade cytology was communicated compared to a high-grade. Conclusions Our data suggests that knowledge of cytology increases sensitivity and specificity for diagnosis of ≥ CIN2 lesions at colposcopy. Association between cytology and histology may have contributed to the findings.