The classification of breast cancer has undergone a paradigm shift with the identification of HER2-low and HER2-ultra-low subtypes, representing a continuum of HER2 protein expression. These categories challenge the traditional binary system of HER2-positive and HER2-negative cancers, offering new insights into tumor biology and therapeutic opportunities. This review was done to look into the emerging concepts of HER2-low and ultra-low breast cancers, their molecular characteristics, diagnostic challenges, and evolving therapeutic landscape. A comprehensive review of recent literature was conducted, focusing on definitions, diagnostic criteria, and clinical implications of HER2-low (immunohistochemistry (IHC) 1 + or 2+, FISH-negative) and HER2-ultra-low (IHC 0 with faint staining) breast cancers. Emphasis was placed on assay standardisation, emerging diagnostic modalities, and ongoing clinical trials evaluating targeted therapies. HER2-low and ultra-low tumors demonstrate distinct molecular signatures and clinical behaviours compared with both HER2-positive and completely HER2-negative counterparts. Conventional immunohistochemistry often fails to accurately distinguish these subgroups due to limited sensitivity. Novel, standardised, and more sensitive assays are essential to reliably identify these categories. Several ongoing trials are exploring the efficacy of novel anti-HER2 agents and antibody-drug conjugates in these subtypes, indicating promising therapeutic potential. Recognition of HER2-low and HER2-ultra-low breast cancers marks a critical evolution in breast cancer pathology and precision oncology. Improved diagnostic tools and targeted therapies may enable more personalised treatment approaches, refining prognostic assessment and improving patient outcomes.
Gallbladder cancer (GBC) is a rare yet highly aggressive malignancy and remains the most prevalent cancer of the biliary tract. The pathogenesis is multifactorial, involving chronic inflammation, gallstone disease, genetic predisposition, and environmental and lifestyle determinants. Notably, GBC exhibits pronounced disparities across multiple dimensions, including sex, geography, ethnicity, and others which altogether shape disease incidence and outcomes. Using protein–protein interaction and gene ontology analyses, we identify candidate molecular pathways and genes implicated in GBC pathogenesis that may differentially operate across biological contexts, some of which are supported by prior experimental findings. This review examines the varied disparities in GBC, emphasising variations in incidence, pathophysiology, risk profiles, and therapeutic responses.
Staphylococcus aureus is now the leading cause of infective endocarditis (IE) worldwide and is associated with high mortality and frequent complications. Combination antimicrobial therapy has long been proposed to enhance bactericidal activity, improve biofilm penetration, and limit resistance; however, its true clinical value remains uncertain. This narrative review examines the experimental and clinical evidence for combination regimens in Staphylococcus aureus infective endocarditis (S. aureus IE). We searched PubMed, Embase, Scopus, Web of Science, and the Cochrane Library through September 2025 for randomised trials, comparative observational studies, major guidelines, and key experimental reports. Evidence is synthesised across methicillin-susceptible and methicillin-resistant strains, and across native and prosthetic valve disease. We summarise the biological rationale, potential benefits, and stewardship impact of combination therapy. We also highlight the practical implications for when to consider, avoid, or de-escalate combination therapy, and outline priorities for future research. We find that evidence for combination therapy in S. aureus endocarditis remains limited and largely observational. Adjunctive rifampin and aminoglycosides have not shown consistent clinical benefit and are associated with increased toxicity. Beta-lactam combinations with vancomycin or daptomycin may reduce the bacteremia duration, but this has not translated into improved survival. Emerging regimens, particularly daptomycin combined with ceftaroline show promise in persistent bacteremia, although evidence remains observational. Overall, current data do not support routine use of combination therapy and favour a selective, case-based approach. High-quality multicentre studies integrating microbiological, pharmacodynamic, and clinical endpoints are urgently needed to define optimal combination strategies.
