Aravind Sekar

MSMP Expression and Macrophage Infiltration in Chronic Active and Chronic Antibody-Mediated Rejection

Membranous-like glomerulopathy with masked Ig ĸ deposits, which is characterised by a membranous pattern of glomerular injury, the absence of IgG staining on direct immunofluorescence of fresh tissue, and IgG positivity on DIF of proteinase-K-treated, formalin-fixed, paraffin-embedded tissue. Serum amyloid P deposition is a distinctive feature. We report a 51-year-old man with similar morphology but atypical features and plasma cell dyscrasia.

Background Gallbladder carcinoma (GBC) is an aggressive malignancy with poor prognosis, often diagnosed at advanced stages. While chemotherapy forms the cornerstone of treatment for locally advanced and metastatic disease, reliable predictors of response remain elusive. This exploratory pilot study aimed to develop a computed tomography (CT)-based prediction model incorporating clinical and biochemical parameters to identify patients likely to respond to chemotherapy. Methods This prospective study enrolled consecutive treatment-naïve patients with cytologically/histologically proven locally advanced or metastatic GBC scheduled for chemotherapy between July 2023 and March 2025. All patients underwent biphasic contrast-enhanced CT within 14 days prior to chemotherapy initiation. Demographic variables, biochemical parameters, and tumor markers (CA 19 − 9, CEA) were systematically recorded. CT-based response assessment was performed using RECIST 1.1 criteria after two cycles of chemotherapy. Three exploratory prediction models were developed using logistic regression with appropriate variable selection methods and penalized regression to address small sample size. Results Of 25 patients (18 females, mean age 50.0 ± 11.6), 11 (44%) achieved partial response while 14 (56%) were non-responders (stable or progressive disease). Univariate analysis identified calculus presence (p = 0.002), largest liver metastasis size (p = 0.001), ascites (p = 0.008), age (p = 0.128), ALT (p = 0.241), and CEA levels (p = 0.123) as potential predictors. After correction for optimism using bootstrap validation, the CT-only model achieved area under the receiver operating characteristic curve (AUC) of 0.82 (95% CI: 0.64–0.92) with 80.0% accuracy, 92.3% sensitivity, and 62.5% specificity (Nagelkerke R²=0.272). The clinical-only model yielded optimism-corrected AUC of 0.74 (95% CI: 0.51–0.88) with 68.0% accuracy, 71.4% sensitivity, and 63.6% specificity (Nagelkerke R²=0.424). The combined model showed better performance with optimism-corrected AUC of 0.85 (95% CI: 0.67–0.95), 84.0% accuracy, 85.7% sensitivity, 81.8% specificity, and highest explained variance (Nagelkerke R²=0.662). Gallstone presence emerged as a potential predictor associated with treatment response across models, while larger liver lesions and elevated CEA showed trends that may be associated with poor response. Conclusions This preliminary hypothesis-generating study suggests that integration of baseline CT imaging features with clinical parameters may potentially allow prediction of chemotherapy response in GBC patients. The identified factors require external validation in larger multi-institutional cohorts before clinical implementation can be considered.

Per-rectal endoscopic myotomy for ultrashort-segment Hirschsprung’s disease in adult patients

Background: Kidney transplantation significantly improves the quality of life and survival in ESKD. Despite advancements in immunosuppressive therapies reducing acute rejection rates, chronic graft outcomes remain suboptimal. Transplant glomerulopathy (TG), a hallmark of chronic allograft injury (CAI), majorly contributes to graft dysfunction. It arises from endothelial injury associated with antibody-mediated rejection (ABMR), T-cell-mediated rejection (TCMR), thrombotic microangiopathy, and infection, notably Hepatitis C infection. However, there is limited data on immune cell infiltrates and their role in TG pathogenesis. This study investigates the etiologies of TG and characterizes the types, distribution, and clinical relevance of immune cell infiltrates in renal allograft biopsies. Materials and Methods: We analyzed 80 renal allograft biopsies with histologically confirmed TG. Dual- and single-color immunohistochemistry was performed for CD3, CD20, CD4, CD8, CD68, CD163, and CD56. Results: Of the 80 cases, 49% were attributed to ABMR, 12.5% to TCMR, 15% had a prior documented hepatitis C infection, 10% showed immune complex deposits, 12.5% showed mixed ABMR and TCMR features, and 12.5% remained unclassified. M2 macrophages (CD163 ⁺ ) and CD8 ⁺ cytotoxic cells were predominant in glomeruli and the tubulointerstitial compartment, showing a macrophage and T- and B-lymphocytes admixture. Macrophage infiltration correlated with chronic injury markers, including interstitial fibrosis and tubular atrophy. Natural killer (NK) cells were minimally involved. Conclusion: TG is driven by multifactorial mechanisms, with M2 macrophages and CD8 ⁺ T-cells dominant in the glomeruli and tubulointerstitial compartments. Interventions targeting the depletion of specific immune cell subsets may mitigate CAI and enhance graft survival.

Amyloidosis refers to a heterogeneous group of disorders characterized by the extracellular deposition of insoluble fibrillar proteins, leading to tissue damage and functional impairment. Among these, serum amyloid A (SAA) amyloidosis, previously termed secondary amyloidosis, arises in the context of chronic inflammatory conditions. While common causes include autoimmune diseases and chronic infections, the underlying etiology remains unidentified in a subset of cases. We report a rare case of SAA-associated amyloidosis in a 29-year-old male with a history of childhood-onset cystic bronchiectasis. The patient presented with progressive renal dysfunction and was diagnosed with systemic amyloidosis based on histopathological evaluation. Common autoimmune and infectious etiologies were excluded during life. An autopsy revealed alpha-1 antitrypsin deficiency as the underlying cause of chronic pulmonary inflammation, manifesting as cystic bronchiectasis, which likely triggered sustained elevation of serum amyloid A and subsequent amyloid deposition.

Thiopurine S-methyltransferase (TPMT) and Nudix hydrolase (NUDT15) polymorphisms predispose to thiopurine-related leukopenia. Retrospective evaluation of inflammatory bowel disease (IBD) patients harboring NUDT15 polymorphisms and exposed to thiopurines. We report the frequency of NUDT15 polymorphism, frequency of leukopenia, the tolerated dose of azathioprine, and the clinical efficacy of thiopurines. Of 1440 patients, 118 (8.2%) had NUDT15 polymorphism. Among 51 with complete details, 46 were heterozygous (90.2%), and 5 homozygous (9.2%) for NUDT15. Twenty (43.5%) heterozygous and all homozygous patients developed leukopenia. Leukopenia was significantly more in NUDT15 heterozygous group compared to controls (43.45% vs 7.8%, Odds ratio: 9, 95% CI 3.57-22.9). The maximum tolerated dose of azathioprine was lower in NUDT15 heterozygous group (1.1 ± 0.4 mg per kg vs 1.7 ± 0.7 mg per kg, p = 0.002). The mean time to leukopenia was earlier in the heterozygous group vs controls (19 ± 56 weeks vs 70 ± 53 weeks, p-value 0.002). Seven (35%) of 20 heterozygous patients who developed leukopenia, could be maintained at a lower dose of thiopurine. Twenty-five maintained clinical remission while on thiopurines. Thiopurines should be avoided in NUDT15 homozygous but can be used cautiously at lower dosages with frequent monitoring among heterozygous patients.