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.
INTRODUCTION:Recent clinical trials have shown the usefulness of anti-HER2 (Human epidermal growth factor receptor 2) treatment in the newly described "HER2-low" subset of breast carcinoma, offering added treatment option to the once considered non-responders. This study aimed to identify this important new subset's demographic and pathological features in a Malaysian cohort. MATERIALS AND METHODS:All newly and recurrent histopathologically-diagnosed invasive breast carcinomas encountered at the University of Malaya Medical Centre (UMMC) between January 2018 to December 2023 that satisfied inclusion criteria were enrolled. Patient demographics were retrieved from the histopathological requests. All haematoxylin and eosin (H&E) stained, immunohistochemically (IHC) stained HER2, oestrogen receptor (ER) and progesterone receptor (PR) together with HER2 amplification assayed by dual-colour dual-hapten in situ hybridisation (DDISH) sections for all cases were reviewed for histological type, histological grade, pathological stage, hormone receptors (HR encompassing ER and PR) and HER2 status. RESULTS:710 invasive breast carcinomas were finally included. HER2-low was noted in 48.2% (n = 342) of the carcinomas, while 191 (26.9%) were in the conventional HER2 positive category. HER2-low carcinomas demonstrated significantly lower (Grade 1 and 2) histological grade and were more commonly hormone status positive compared with both HER2 positive and negative groups. CONCLUSION:HER2-low constituted a significant number of breast carcinomas and appears to have its own unique features. The recognition of this category has expanded anti-HER2 treatment options to an additional 48% of breast carcinomas.
INTRODUCTION:Myxopapillary ependymomas are a subset of spinal ependymomas that arise almost exclusively in the conus medullaris and filum terminale, and most commonly affect young adults. However, multifocality has been described, originating in the cervicothoracic spinal cord, the lateral ventricle, the fourth ventricle, and the brain. Spinal myxopapillary ependymomas are associated with a favourable prognosis in children and adults, with 10-year overall survival rates > 90%. Many patients, however, live with persistent disease and require repeated operations and adjuvant therapy, because myxopapillary ependymomas often resist complete removal owing to locally advanced growth and/or cerebrospinal fluid-borne seeding of the thecal sac or more rostral neuraxis. CASE REPORT:We present a case of a 27-year-old woman who underwent gross-total resection and adjuvant radiotherapy for an L2-L3 spinal tumour, which was diagnosed histologically as ependymoma, but developed a recurrent tumour of myxopapillary ependymoma after a long-term symptom-free period. The recurrent tumour is larger, multifocal, heterogeneously enhancing and extending from the lumbar into the sacrum, resulting in local effects on the bones. Previously, the diagnosis of ependymoma was based solely on histomorphology, with no molecular confirmation of DNA methylation profiling. DISCUSSION:This case highlights the importance of diagnostic accuracy when molecular testing is limited, emphasising the crucial role of clinical and histopathological correlation. Hence, a histo-molecular classification is vital for risk stratification and tailored surveillance.
Penicillium is a diverse genus of fungus that widely exists in the environment and is often non-pathogenic. Only a handful of literature have reported its association as a cause of infection in humans. Here, we report a case of a Penicillium maxillary sinus fungal ball in an elderly man complaining of chronic headache, progressive unilateral nasal blockage and post-nasal drip. The role of Penicillium in a fungal ball and management are further discussed.
Hormonal and immune system changes during pregnancy may disrupt the resident oral microbiota causing dysbiosis that may render these women prone to gum health disease, such as gingivitis and periodontitis. This may in turn lead to systemic disorders, such as maternal gestational diabetes mellitus and hypertension, preterm birth, and low birth weight infants. Emerging evidence has associated dysbiosis of the oral microbiota during pregnancy with an imbalance and a preponderance of pathogenic bacteria such as Porphyromonas gingivalis and Fusobacterium nucleatum that may cause both placental and systemic inflammation. To mitigate the consequential adverse effects originating from poor oral health, some strategies have been proposed which include the use of probiotics, antimicrobial agents, laser therapy, and nanotechnology aimed at regulating a healthier oral microbiota to promote better overall health and pregnancy outcomes. This paper also highlights the importance of routine maternal oral health examination and management as a crucial inclusive component of antenatal care, which could positively impact on both the maternal and neonatal health outcomes. Advances and further research in this area will unravel the molecular mechanisms underlying the oral dysbiosis, systemic interactions and the fundamental basis for newer therapies to curb oral health related disorders in pregnancy.
The lung's granular cell tumour (GCT) is a rare neoplasm originating from Schwann cells. GCT often grows in various sites and can be benign or malignant. Only 2-6% of GCTs occur in a tracheobronchial tree. We aim to present two cases of tracheobronchial GCT. A 68-year-old man had multiple endobronchial GCTs, while a 54-year-old woman had one endotracheal nodule of GCT. GCTs consist of submucosal infiltrates, round to oval cells, with abundant granular cytoplasm positive for S100 (2/2), NSE (2/2), and CD68 (2/2). One of the patients had a GCT on the right, treated by bronchoscopic extirpation and associated with acinic adenocarcinoma on the opposite side, which was diagnosed after the lobectomy on the right. Other patients had a tracheal GCT with fatal outcomes on the tenth day after the surgery due to the development of acute pulmonary oedema, which was confirmed at autopsy. Tracheobronchial GCT has a broad spectrum of clinicopathological symptoms and signs with different outcomes.
The transition from traditional microscopy-based diagnostic workflows to digital pathology for primary diagnosis necessitates a robust understanding of the applicable legal and regulatory frameworks. This review synthesises the multi-layered regulatory landscape governing digital pathology adoption in Malaysia. Key statutory and professional requirements are examined, including the Medical Device Act 2012 for system registration; MS ISO 15189 and STR 2.2 for laboratory accreditation and clinical validation; and the Malaysian Medical Council's 2024 Telemedicine Guideline for its implications on telepathology practice. In addition, the integration of digitised slides into formal medical records is considered under the Private Healthcare Facilities and Services Regulations 2006, alongside data privacy obligations under the Personal Data Protection Act 2010 and evidentiary admissibility requirements under the Evidence Act 1950 Malaysia. This review underscores that safe and legally compliant implementation of digital pathology requires rigorous system validation, strict data security protocols, appropriate institutional credentialing, and comprehensive audit trail maintenance.
Placental pathology provides critical diagnostic, prognostic and clinicopathological insights into maternal-foetal outcomes. While frequently discarded post-delivery, macroscopic and histopathological evaluation can clarify adverse outcomes, including stillbirth, neonatal death, prematurity, foetal growth restriction, hydrops, infection and complicated multiple gestations. This paper outlines a standardized framework for placental examination by covering rationale, indications, specimen handling, sampling and reporting designed for universal implementation across all public, private and academic healthcare facilities. To optimise institutional resources, a phased, indication-based approach is recommended initially, prioritising cases most likely to influence clinical management, parental counselling and future pregnancy care. Pre-analytical optimisation, which includes proper specimen handling, adequate fixation, representative sampling and complete clinical history, is essential to maximize diagnostic yield nationwide. We propose a structured reporting proforma aligned with the current Amsterdam Consensus Classification, including a dedicated section for multiple gestations. This standardises reporting across key pathophysiological domains: maternal vascular malperfusion (MVM), foetal vascular malperfusion (FVM), infections, inflammatory/immune lesions and villous developmental abnormalities. Finally, contextual ancillary investigations are discussed. Ultimately, establishing a unified, cross-sector national placental pathology service holds the potential to significantly improve the audit of adverse perinatal outcomes and elevate maternal-foetal care.
INTRODUCTION:Breast cancer continues to be a substantial global health concern, constituting a substantial proportion of new cancers diagnosed. Breast Imaging Reporting and Data System (BI-RADS) is a standardised instrument that facilitates the appraisal of lesions in mammographic reporting. A hook wire localisation biopsy (HWLB) is frequently employed to diagnose suspicious microcalcifications or non-palpable lesions. The study aims to ascertain the probability of detecting malignancies in non-palpable breast lesions by examining the malignancy rate detected by BI-RADS classification and HWLB results. MATERIALS AND METHODS:This retrospective study utilised data from patients who underwent HWLB at a tertiary hospital from January 2016 to December 2021. RESULTS:Among the 65 patients analysed, 21.5% exhibited malignant lesions, predominantly detected through routine mammogram screening. There was a statistically significant association (p=0.007) between BI-RADS classification and the malignancy status. Using BI-RADS 4A as the threshold ensures 100% sensitivity but leads to a low specificity of 13.73%, Positive Predictive Value (PPV) of 24.1% and Positive Likelihood Ratio (LR+) of 1.2. While increasing the threshold to BI-RADS 4B improves specificity to 80.4%, reducing false positives. This suggests that many BI-RADS 4A cases are actually mostly benign. CONCLUSION:BI-RADS 4A notably exhibited a high false-positive rate, possibly due to benign lesions mimicking cancer radiologically and the operator-dependent nature of radiology. Despite these constraints, findings affirm the crucial role of hook wire localisation biopsy and BI-RADS classification in evaluating non-palpable breast lesions.
INTRODUCTION:Peripheral T-cell lymphomas are rare, aggressive malignancies with significant diagnostic challenges due to their heterogeneity. MATERIALS AND METHODS:This retrospective study analysed 43 nodal Peripheral T-cell lymphomas cases diagnosed between 2019 and 2024 at the Blood Transfusion Hematology Hospital in Southern Vietnam and reclassified them using the World Health Organization 2022 classification. RESULTS:Nodal T-follicular helper cell lymphoma, angioimmunoblastic type, emerged as the most prevalent subtype (51.2%), markedly exceeding rates reported in Western (32.5%) and East Asian studies (36.2%). Despite the higher prevalence of Epstein-Barr Virus in Vietnam, the proportion of Epstein-Barr Virus positive in Peripheral T-cell lymphomas was not elevated (20%), suggesting additional genetic or environmental factors influencing lymphoma pathogenesis. CONCLUSION:These findings underscore the critical role of updated diagnostic standards and the utility of advanced markers in improving Peripheral T-cell lymphomas classification. This study provides rare insights into Peripheral T-cell lymphomas pathology in Vietnam, contributing valuable data to the global understanding of these rare lymphomas.
INTRODUCTION:Legionella pneumophila, a microorganism that thrives in both natural freshwater and man-made water systems, is a significant pathogen that causes Legionnaires' disease, a potentially fatal form of pneumonia. This study aimed to investigate the distribution of L. pneumophila sequence types (ST) within the water supply system of the Klang Valley Integrated Transit System (KVITS) in Malaysia. MATERIALS AND METHODS:Sequence-Based Typing (SBT) was used to determine the sequence type of the L. pneumophila isolates by amplifying seven different loci (flaA, pilE, asd, mip, mompS, proA, and neuA), as per the European Working Group for Legionella Infections (protocol version 5.0). RESULTS:L. pneumophila was isolated from five out of 80 samples (6.3%). These isolates comprised five distinct sequence types: ST1, ST22, ST2210, ST3017, and ST3029. Three isolates typed as ST1, ST22 and ST2210 belong to serogroup 1. Phylogenetic analysis suggested multiple sources of contamination. CONCLUSION:This study suggests the need for a comprehensive water management plan for KVITS, including routine testing and risk assessments, to reduce the risk of Legionnaires' disease outbreaks.
INTRODUCTION:The haemoglobin glycation index (HGI) reflects individual variations in glycation tendency and may offer additional value beyond HbA1c in predicting diabetes-related complications. This study aimed to evaluate the association and predictive value of HGI for diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS:A total of 400 T2DM patients were enrolled. Predicted HbA1c was calculated using a linear regression equation (R2=0.454) derived from fasting plasma glucose (FPG) and HGI was defined as the difference between measured and predicted HbA1c. Paired t-tests and Pearson correlation assessed the relationship between measured and predicted HbA1c. Multivariate logistic regression and receiver operating characteristic (ROC) analysis used to evaluate HGI as a predictor of DKD. RESULTS:A strong positive correlation observed (r=0.674, p<0.001) between measured and predicted HbA1c and no significant difference observed (p=0.964) among the T2DM population. DKD was identified in 192 participants, who demonstrated significantly higher HGI compared to non-DKD patients (p=0.002). Multivariate analysis showed HGI (OR: 1.249, 95% CI: 1.053-1.482, p=0.011) and eGFR (OR: 0.964, 95% CI: 0.952-0.976, p<0.001) were independent risk factors for DKD. ROC analysis showed HGI as a moderate predictor of DKD (AUC=0.722, p<0.001), with an optimal cutoff of 0.53 carries 56.3% sensitivity and 81.2% specificity. CONCLUSION:HGI is independently associated with DKD in T2DM and may serve as a useful adjunct marker, complimenting HbA1c and urinary albumin-to-creatinine ratio (UACR) for early identification of those at increased risk of kidney complications.
INTRODUCTION:The COVID-19 pandemic has caused a rise in secondary infections, including invasive fungal diseases (IFDs), which have greatly increased morbidity and mortality. This study aimed to explore the demographics, risk factors and outcomes of IFDs in COVID-19 patients admitted to our centre. MATERIALS AND METHODS:We retrospectively reviewed data from PCR-confirmed category 4 or 5 COVID-19 patients between 2020 and 2023 who also had positive mycology cultures or serology. Patients with positive fungal tests more than 90 days after their initial COVID-19 diagnosis were excluded. RESULTS:Among 5,075 PCR-positive COVID-19 patients, 23 (0.45%) met the criteria. Of these, 15 (65.2%) had candidiasis, seven (30.4%) aspergillosis, and one (4.3%) Exophiala fungaemia. No mucormycosis cases were identified. The male-to-female ratio of IFDs was 2.8:1, with ages ranging from 26 to 77 years (mean 59.6). The interval between COVID-19 diagnosis and positive fungal test ranged from 3 to 38 days, averaging 12.6 days for candidiasis and 16 days for aspergillosis (difference not statistically significant). Only acute kidney injury was significantly linked to candidiasis. Common factors across all cases included indwelling vascular catheters (95.7%), ICU admission (91.3%), mechanical ventilation (87%), lung diseases (65.2%), kidney impairment (60.9%), poorly controlled diabetes (34.8%), and liver impairment (26.1%). Overall mortality was 91.3% (100% for aspergillosis and Exophiala fungaemia, 86.7% for candidiasis). CONCLUSION:Although IFD prevalence in COVID-19 patients is low, its high morbidity and mortality make it a critical concern. Early identification of risk factors may help reduce its occurrence and improve outcomes.
INTRODUCTION:Acute monocytic leukaemia (AML-M5) disease models are scarce. To address this, we reprogrammed THP-1 cells from a patient into AML-M5-specific induced pluripotent stem cells (AML-M5-iPSCs) and differentiated them into monocytic-like cells. Unexpectedly, reprogramming transgenes Oct3/4, Sox2 and c-Myc were reactivated in the AML-M5-iPSC genome. This study examined how transgene reactivation influences responses to doxorubicin in differentiated monocytic-like cells; MATERIALS AND METHODS: AML-M5-iPSCs were differentiated into monocytic-like cells using hM-CSF and IL-3. Cell morphology, phagocytotic activity and surface markers expression of monocytic-like and THP-1 cells were assessed and compared. Cytotoxicity and apoptotic effects of doxorubicin were investigated with CCK-SK assay and flow cytometry; RESULTS: Monocytic-like cells showed morphology, size, and phagocytosis comparable to THP-1 cells. However, they expressed lower surface markers CD4, CD117, CD33, CD64 and HLA-DR than THP-1 cells. Following 24h doxorubicin exposure, THP-1 cells exhibited an IC 50 of 0.59 μM, while the IC 50 for monocytic-like cells could not be determined. Upon similar treatment conditions, 92.47±3.90% of THP-1 cells underwent late apoptosis. In contrast, only 0.26±0.21% of monocytic-like cells entered late apoptosis, 37.23±1.52% underwent necrosis and 62.47±1.63% remained viable; CONCLUSION: Reactivation of Oct3/4, Sox2 and c-Myc in AML-M5-iPSCs induced lower surface marker expression and doxorubicin resistance in monocytic-like cells. Moreover, the apoptotic effect of doxorubicin had been switched to necrotic effect. Surprisingly, morphology and phagocytic function were unaffected. We postulate that transgene reactivation disrupts epigenetic stability and downstream apoptotic pathways. Further investigations are warranted to clarify mechanisms underlying transgene-mediated drug resistance in iPSC-derived disease models.
INTRODUCTION:Haemophilus influenzae (HI) is a significant pathogen responsible for respiratory and invasive infections globally. Following the introduction of the Haemophilus influenzae serotype B (Hib) vaccine in Malaysia in 2002, cases of Hib-related diseases declined sharply. Still, the prevalence of nontypeable Haemophilus influenzae (NTHi) emerged as a public health concern. This study investigates epidemiological and demographic patterns of HI infections in Malaysia's southern region. MATERIALS AND METHODS:Clinical isolates of HI were recovered during routine diagnostic testing and analysed from June 2023 to December 2024. All isolates were identified using conventional laboratory methods, biochemical assays, and Matrix-Assisted Laser Desorption/Ionisation Time-of-Flight Mass Spectrometry (MALDI-TOF MS). Confirmatory serotyping was outsourced to the National Public Health Laboratory in Sungai Buloh, Selangor. Epidemiological trends were assessed based on demographics, sample types, and seasonal variations. RESULTS:A total of 281 samples were analysed. NTHi accounted for 96.5% of isolates, with sputum as the dominant sample type (56.4%). Infants and elderly individuals constitute the most vulnerable groups. Peaks in sample submissions correlated with monsoon seasons. Foreign nationals had disproportionately higher mortality rates, reflecting challenges in vaccination access. CONCLUSION:The study underscores the dominance of NTHi infections in post-Hib vaccination settings in Malaysia. Seasonal trends and demographic disparities emphasise the need for tailored public health interventions and infrastructure strengthening to reduce the burden of HI infections.
