The introduction of antibody-drug conjugates (ADCs) such as trastuzumab deruxtecan (T-DXd) has challenged the traditional binary classification of HER2 in breast cancer. Evidence from the DESTINY-Breast04/06 and DAISY trials demonstrates clinically meaningful antitumour activity across a continuum of HER2 expression, including HER2-low and HER2-ultralow categories, while efficacy in HER2-null tumours remains uncertain. Despite this graded biological response, regulatory criteria remain categorical, requiring detectable membrane staining for treatment eligibility and excluding IHC 0 tumours. Pathologists face diagnostic challenges at the null-ultralow boundary, where conventional immunohistochemistry (IHC) assays operate near their analytical limits, reproducibility is constrained, and inter-observer variability is high. Pathologists should exercise caution when assigning IHC 0, and practical measures such as reflexive re-evaluation, re-staining of alternative blocks, and referral to high-sensitivity laboratories are recommended. Transparent communication of analytical uncertainty is essential to optimise patient access to ADC therapy.
INTRODUCTION:Microplastic (MP) exposure has increasingly been associated with tissue-level impact in toxicology studies, including inflammatory changes and histopathological injury in aquatic and mammalian models. However, there is currently no consistently developed histological scoring approach for assessing the structural damage across different tissue types induced by MPs following acute exposure. This study aimed to develop and apply a semi-quantitative histological scoring framework to investigate the histological alterations of polyethylene terephthalate (PET) MPs in Sprague-Dawley rat aorta, trachea, and bladder ex vivo. MATERIALS AND METHODS:Rat tissues were excised and incubated for 22 to 24 hours at 4°C with different concentrations of PET particles (0.3 - 5.0 mg/mL). Trachea and bladder tissues were processed for haematoxylin and eosin staining, whereas aorta sections were stained using CD31 immunohistochemistry to assess the endothelial integrity. Images were randomised and scored independently by three blinded observers using tissue-specific grading criteria for aorta endothelium, tracheal epithelium, and bladder urothelium. RESULTS:Across the three tissues, the scoring system suggests organ-specific differences in terms of sensitivity to acute exposure, with bladder urothelium appearing as the most structurally vulnerable under the tested conditions. CONCLUSION:This method provides a structured framework for screening MPs-induced tissue damage and may improve reproducibility in histological evaluation of tissue structural integrity.
Autophagy is a highly conserved intracellular degradation pathway that plays a central role in maintaining testicular homeostasis and male reproductive function. This review summarises recent advances in the understanding of autophagy in the testis, with particular emphasis on its roles in Sertoli cells, Leydig cells, and germ cells, as well as its regulatory mechanisms and implications for male infertility. Autophagy contributes to key processes, including spermatogenesis, spermiogenesis, blood-testis barrier integrity, and steroidogenesis, through coordinated organelle turnover and cellular remodelling. Core regulatory pathways such as mTOR, AMPK, PI3K/Akt, and oxidative stress-responsive signalling dynamically controls autophagic flux in response to metabolic and environmental cues. Emerging evidence highlights extensive molecular crosstalk between autophagy, apoptosis, ferroptosis, and ubiquitin-mediated proteostasis, with oxidative stress serving as a central upstream regulator. Dysregulation of autophagy, whether through impaired flux or excessive activation, is strongly associated with male infertility phenotypes, including azoospermia, oligozoospermia, and asthenozoospermia. These effects are driven by defects in germ cell development, mitochondrial function, and hormonal balance, and are further exacerbated by environmental toxicants, lifestyle factors, and ageing. Although autophagy-related proteins such as microtubule-associated protein 1 light-chain 3, p62, and Beclin-1 show promise as biomarkers, their clinical application remains limited by challenges in accurately measuring autophagic flux and context-dependent interpretation. Therapeutic modulation of autophagy using pharmacological agents and antioxidants represents a promising but complex strategy that requires precise, context-specific application. Overall, this review underscores the dual role of autophagy in male fertility and highlights the need for improved biomarkers and translational approaches.
Age-related macular degeneration (AMD) is one of the leading causes of irreversible central vision loss among elderly individuals in developed countries. The neovascular form of AMD is currently treated with intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents, particularly ranibizumab, aflibercept, and bevacizumab. Although these therapies significantly improve visual outcomes, repeated intravitreal administration requires continuous monitoring of ocular and systemic adverse events. This review compares the safety profiles of the three principal anti-VEGF agents used for AMD treatment through analysis of pharmacovigilance data, regulatory reports, and major clinical trials. Particular attention is dedicated to ocular complications, systemic thromboembolic events, and the implications of off-label bevacizumab use. Current evidence suggests an overall comparable efficacy and safety profile among the three agents, although Bevacizumab requires stricter preparation and monitoring protocols because of its off-label use. Pharmacovigilance remains essential for identifying safety signals, supporting regulatory decisions, and optimising therapeutic strategies in ophthalmology.
This is a diagnostically challenging case that concerns a 29-year-old man with an eight-year history of right-sided neck swelling. The magnetic resonance imaging (MRI) of the neck revealed multiple well-encapsulated, lobulated, matted right cervical lymphadenopathy. He reported significant weight loss, but denied shortness of breath, altered bowel habits, or bone pain. His initial investigations revealed a normocytic hypochromic anaemia, mild leukocytosis, and thrombocytosis. The initial histological findings showed many IgG4-positive plasma cells, but lacked stromal fibrosis, granuloma, obliterative phlebitis, or malignant cells. In addition, the IgG4+/IgG plasma cell ratio was only about 20%. The serum IgG4 subclass was raised at 258 mg/dl, along with a raised serum IgG1 subclass at 3630 mg/dl. His bone marrow aspirate findings showed reactive plasmacytosis without marrow infiltration or acute leukaemia. Multiple myeloma was excluded by the absence of paraproteins in the serum and urine electrophoresis. A working diagnosis of probable IgG4-RD was made, and he was treated with glucocorticoids and azathioprine. However, the neck mass did not resolve, and the serum globulin was persistently high, ranging from 75 g/l to 95 g/l. A repeat biopsy of the neck swelling demonstrated Hodgkin lymphoma (HL) with mixed cellularity, and the Epstein-Barr virus (EBV) RNA-in-situ hybridisation was negative. He was started on chemotherapy and achieved complete remission, with an episode of relapse 9 months later. Salvage chemotherapy was initiated and is currently awaiting haematopoietic stem cell transplantation. This case highlights the need for repeated histopathological evaluation and reflects the complexity and overlap between HL and IgG4-RD.
