Chemoresistance is a major obstacle in triple negative breast cancer (TNBC), the most aggressive breast cancer subtype. Here we identify hypoxia-induced ECM re-modeler, lysyl oxidase (LOX) as a key inducer of chemoresistance by developing chemoresistant TNBC tumors in vivo and characterizing their transcriptomes by RNA-sequencing. Inhibiting LOX reduces collagen cross-linking and fibronectin assembly, increases drug penetration, and downregulates ITGA5/FN1 expression, resulting in inhibition of FAK/Src signaling, induction of apoptosis and re-sensitization to chemotherapy. Similarly, inhibiting FAK/Src results in chemosensitization. These effects are observed in 3D-cultured cell lines, tumor organoids, chemoresistant xenografts, syngeneic tumors and PDX models. Re-expressing the hypoxia-repressed miR-142-3p, which targets HIF1A, LOX and ITGA5, causes further suppression of the HIF-1α/LOX/ITGA5/FN1 axis. Notably, higher LOX, ITGA5, or FN1, or lower miR-142-3p levels are associated with shorter survival in chemotherapy-treated TNBC patients. These results provide strong pre-clinical rationale for developing and testing LOX inhibitors to overcome chemoresistance in TNBC patients.

Background: Prognostic scores derived from the blood count have garnered significant interest as an indirect measure of the inflammatory pressure in cancer. The recently developed pan-immune-inflammation value (PIV), an equation including the neutrophil, platelet, monocyte, and lymphocyte levels, has been evaluated in several cohorts, although with variations in the tumor types, disease stages, cut-offs, and treatments. Therefore, we evaluated the association between survival and PIV in cancer, performing a systematic review and meta-analysis. Methods: We conducted a systematic review from the Pubmed, Medline, and Embase databases to filter the published studies until 17 May 2022. The meta-analyses were performed with the generic inverse-variance method with a random-effects model. Results: Fifteen studies encompassing 4942 patients were included. In the pooled analysis of fifteen studies, the patients with higher PIV levels had significantly increased risk of death than those with lower PIV levels (HR: 2.00, 95% CI: 1.51–2.64, p < 0.001) and increased risk of progression or death (HR: 1.80, 95% CI: 1.39–2.32, p < 0.001). Analyses were consistent across several clinical scenarios, including non-metastatic or metastatic disease, different cut-offs (500, 400, and 300), and treatment with targeted therapy or immunotherapy (p < 0.001 for each). Conclusion: The available evidence demonstrates that PIV could be a prognostic biomarker in cancer. However, further research is needed to explore the promise of PIV as a prognostic biomarker in patients with non-metastatic disease or patients treated without immunotherapy or targeted therapy.

Recently, a human/mouse chimeric monoclonal antibody, rituximab, has been successfully used to treat cases of B-cell non-Hodgkin's lymphoma and some autoimmune diseases. However, several viral infections related to rituximab have been reported in the literature, but were not well characterized. To further investigate this topic, relevant English language studies were identified through Medline. There were 64 previously reported cases of serious viral infection after rituximab treatment. The median age of the cases was 61 years (range: 21 - 79). The median time period from the start of rituximab treatment to viral infection diagnosis was 5.0 months (range: 1 - 20). The most frequently experienced viral infections were hepatitis B virus (HBV) (39.1%, n = 25), cytomegalovirus infection (CMV) (23.4%, n = 15), varicella-zoster virus (VZV) (9.4%, n = 6), and others (28.1%, n = 18). Of the patients with HBV infections, 13 (52.0%) died due to hepatic failure. Among the 39 cases that had viral infections other than HBV, 13 died due to these specific infections. In this study, about 50% of the rituximab-related HBV infections resulted in death, whereas this was the case in only 33% of the cases with other infections. Close monitoring for viral infection, particularly HBV and CMV, in patients treated with rituximab should be recommended.

Background: Cancer remains a leading cause of death globally, necessitating the identification of prognostic biomarkers to guide treatment decisions. The Royal Marsden Hospital (RMH) score, based on readily available blood tests and clinical features, has emerged as a prognostic tool, although its performance across variable clinical scenarios is not thoroughly delineated. Therefore, we aimed to systematically assess the association between RMH score and survival in cancer patients. Methods: We conducted a systematic literature search across Pubmed, Scopus, and Web of Science databases for studies published up to 15 February 2024. We performed a meta-analysis with the generic inverse variance method with a random-effects model and reported hazard ratios (HR) with 95% confidence intervals (CI). Results: Nineteen studies encompassing 127,230 patients were included. A higher RMH score was significantly associated with worse overall survival (OS) (HR: 2.09, 95% CI: 1.87–2.33, p < 0.001) and progression-free survival (PFS) (HR: 1.80, 95% CI: 1.48–2.18, p < 0.001). This association was consistent across various subgroups, including study population (clinical trial vs. real-world cohort), geographic region, and tumor type. Conclusion: This meta-analysis, including over a hundred thousand patients, demonstrates a negative association between a higher RMH score and survival in cancer patients. The RMH score holds promise as a readily available prognostic tool across diverse cancer types and clinical settings. Future research should focus on validating and refining this score to aid clinical decision-making.

Background:: The level of serum cardiac troponin-T (cTnT) increases with myocardial damage. We sought to assess whether cTnT level could be a useful marker for the early detection of anthracycline cardiotoxicity. Patients and methods:: Forty-one patients who had been scheduled to receive anthracycline-containing combination chemotherapy were included in the study. Serum cTnT levels were measured before (baseline) and after the first cycle of chemotherapy, and again, after the last cycle of chemotherapy. In all patients, the left ventricular ejection fraction (LVEF), fractional shortening (FS), early peak flow/atrial flow velocity (E/A) ratio, and the isovolemic relaxation time (IRT) were measured echocardiographically, both before and after the completion of chemotherapy. Results:: LVEF and FS did not change in any patients. In 21 patients (49%), the E/A ratio decreased after therapy as compared to the pre-treatment values. The decrease in E/A ratio was more prominent in patients who were older than the mean age of our study group, which was 44 years. The post-treatment IRT was prolonged compared with the pretreatment IRT (94.0 ± 2.0 versus 85.6 ± 10.5 ms, respectively). cTnT levels after completion of therapy were elevated in 14 (34%) patients, and exceeded the upper limit of the normal range (>0.1 ng/ml) in only one patient. cTnT levels measured after completion of therapy were significantly higher, compared with those measured at baseline and after the first cycle of therapy. In the younger age group (≤44 years old), there was a two-fold decrease in the E/A ratio in those patients whose cTnT levels increased during the therapy, when compared with those whose cTnT levels did not change (21% versus 43%, respectively). Conclusion:: Increased serum cTnT level can be detected in the early stages of anthracycline therapy and it is associated with diastolic dysfunction of the left ventricle. Therefore, serum cTnT level could be a useful measure for early detection of anthracycline-induced cardiotoxicity.