Istanbul Memorial Hospital

Background: Microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) colorectal cancer (CRC) accounts for approximately 5% of metastatic CRC cases. Immune checkpoint inhibitors (ICIs) are the standard of care based on pivotal clinical trials; however, real-world data, particularly from low-resource countries, remain scarce, and prognostic factors are not yet fully defined. Therefore, we evaluated the efficacy and the safety of ICIs in a multi-center cohort. Methods: This multi-center retrospective study included 45 patients treated with ICIs across six oncology centers in Türkiye between June 2017 and December 2024. Patients received either anti-PD-1/PD-L1 monotherapy or anti-CTLA-4-based combination therapy. Key clinical variables and 1-, 2-, and 3-year OS and PFS outcomes were systematically collected. Results: The median age was 61 years, and most patients (75.6%) received ICIs in later treatment lines. After a median follow-up of 24.1 months, median OS and PFS were not reached. The estimated 1-, 2-, and 3-year OS rates were 82%, 76.1%, and 76.1%; PFS rates were 75.6%, 67.5%, and 67.5%, respectively. In multivariate analysis, an ECOG < 1 (HR: 0.072; 95% CI: 0.012-0.453; p = 0.005), a metastatic burden of fewer than two sites (HR: 0.211; 95% CI: 0.052-0.860; p = 0.030), and absence of antibiotic exposure within one month prior to immunotherapy initiation (HR: 0.145; 95% CI: 0.034-0.614; p = 0.009) were independently associated with improved overall survival. For PFS, ECOG < 1 (HR: 0.172; 95% CI: 0.052-0.573; p = 0.004), a metastatic burden of fewer than two sites (HR: 0.248; 95% CI: 0.078-0.788; p = 0.018), and no recent antibiotic exposure (HR: 0.209; 95% CI: 0.064-0.687; p = 0.010) remained independent predictors of prolonged survival. Conclusions: We observed overall survival outcomes similar to those reported in phase III clinical trials of immunotherapy in MSI-H/dMMR colorectal cancer, despite a substantial proportion of patients receiving immunotherapy in later lines of treatment. These findings support immune checkpoint inhibitors as the standard of care for MSI-H/dMMR metastatic colorectal cancer and emphasize the importance of improving access to immunotherapy, particularly in low-resource settings.

Background/Objectives: Non-invasive fibrosis scores are widely used for risk stratification in metabolic dysfunction-associated steatotic liver disease (MASLD); however, their performance in obese individuals remains controversial. The Fibrosis-4 (FIB-4) index is commonly recommended as a first-line tool, yet it may underestimate fibrosis risk in severe obesity. The BAST score, which incorporates metabolic and anthropometric parameters, has been proposed as an alternative. This study aimed to characterize both the degree and direction of discordance between FIB-4 and BAST in obese patients with MASLD. Methods: This predefined secondary analysis included 2950 adults with obesity (BMI ≥ 30 kg/m2) and MASLD from the multicenter OBREDI-TR cohort. Fibrosis risk categories were assigned using standard cut-offs for FIB-4 and BAST, and agreement was assessed using weighted Cohen's kappa. Associations among discordance patterns, obesity class, and the visceral adiposity index (VAI) were evaluated using chi-square tests and general linear models. Results: Overall agreement between FIB-4 and BAST was very poor (κ = 0.041, p < 0.001). Discordance was observed in 22.3% of patients and increased markedly with obesity severity. In class III obesity, discordance was predominantly driven by low-risk classification according to FIB-4 despite high-risk classification according to BAST. Patients with this discordant pattern exhibited significantly higher VAI values than concordant cases (p < 0.001), independently of the study center. Conclusions: In obese patients with MASLD, particularly those with morbid obesity, FIB-4 frequently classifies patients as low risk, while BAST identifies elevated fibrosis risk. This systematic discordance suggests that FIB-4 may underestimate fibrosis burden in the context of severe obesity and visceral adiposity, supporting the need for a phenotype-oriented, multimodal approach to fibrosis risk assessment.

Serrated adenocarcinoma (SAC) represents a molecularly heterogeneous subtype of colorectal carcinoma (CRC) linked to the serrated pathway. It is aimed to clarify the molecular mechanisms underlying SAC development. Digital slides from The Cancer Genome Atlas (TCGA) colorectal adenocarcinoma Firehose Legacy dataset (632 cases) were reviewed, and cases were classified as SAC, partial-SAC, or classical CRC. Genomic alterations, mRNA expression, and DNA hypermethylation were compared using cBioPortal. Enrichment analyses were performed via WebGestalt, and protein-protein interaction (PPI) networks with hub genes were identified using STRING and Cytoscape. Statistical significance was defined as p < 0.05 and q < 0.05. The results revealed that the groups showed significant differences in the expression of 327 genomic alterations, 20 mRNAs, and 21 methylated genes (p < 0.0001, q < 0.0001). Hub genes were PSMC1, FLT3LG, SNW1, H3C2, H1-2, H2BC14, H1-5, RPS16, SUPT5H, and MYOD1. The pathways associated with differently expressed genes were the following: cell structure and morphology (phagocytic vesicle, microvillus, endocytosis, and immobile cilium), protein kinase activity (particularly MAPK), and immunological mechanisms. The hub genes act as molecular bridges connecting the observed genomic and epigenetic variations, particularly driving chromatin-related regulation and MAPK signaling pathways. In particular, PSMC1, SNW1, H3C2, H1-2, and H2BC14 genes offer promising molecular targets for future therapeutic approaches in SACs.

Accurate determination of tumour size is critical for pT staging in pancreatic ductal adenocarcinoma (PDAC), yet gross measurement alone often underestimates the true tumour extent because of the tumour's ill-defined and infiltrative nature. This study aimed to evaluate the diagnostic and prognostic value of incorporating microscopic rectification into tumour size assessment in PDAC. A total of 342 therapy-naïve pancreatoduodenectomies were analysed using a grossing protocol that includes separate sampling of anterior and posterior soft tissues via the 'orange-peeling' technique to retrieve lymph nodes and document soft tissue involvement. Peripancreatic soft tissue involvement was present in 91% of cases, and isolated microscopic foci distant from the main mass in 48%. Of the 266 tumours grossly classified as pT1/T2 (≤4 cm), 39 (14%) showed carcinoma in both anterior and posterior soft tissues, and were reclassified as pT3. This subset showed significantly worse survival (P = 0.04) and higher nodal positivity (87% versus 69%, P = 0.02) than the remaining pT2 cases, comparable to conventional pT3 tumours (86%, P = 0.77). Multivariable Cox regression adjusted for age, sex, nodal status, margin, and lymphovascular/perineural invasion confirmed the survival disadvantage of this subgroup. Reclassification yielded a more balanced distribution of T categories (pT2 66% → 52%, pT3 22% → 34%) and modestly improved prognostic discrimination (C-index: 0.592 versus 0.574). This study elucidates that PDAC frequently extends beyond the visible mass ('horses out of the barn' phenomenon); peripancreatic soft tissue involvement is common, and gross size often underestimates the true tumour extent, making microscopic correction crucial. Approximately one in six pT1/T2 tumours (≤4 cm) shows carcinoma in both anterior and posterior soft tissues and behave like pT3 in outcomes and nodal status. Therefore, gross-micro rectification is essential to avoid understaging, particularly for T2 tumours. The orange-peeling protocol should classify tumours with foci in both anterior and posterior soft tissues as pT3, while other approaches may employ mapping techniques to enable microscopic reconstruction and biologically accurate staging.

The objective was to compare the outcomes of dorsal and ventral onlay urethroplasties using buccal mucosal grafts for the treatment of urethral strictures in women, focusing on patency, complications, de novo incontinence, and impact on sexual function. A retrospective analysis was conducted on 65 patients who underwent dorsal (n = 38) and ventral (n = 27) onlay female urethroplasty using a buccal mucosal graft between July 2017 and January 2024 across three centers. Patency was determined by the successful passage of a 16-French cystoscope or by a maximum flow rate exceeding 15ml/s. Median age, etiology, and stenosis characteristics of the two groups were comparable. At the final follow-up, the patency rates for dorsal and ventral onlay female urethroplasty were 92.1% and 92.6% respectively (p = 1.0). There was no significant difference in postoperative maximum flow rates, postvoid residual urine, Female Sexual Function Index scores, Patient Global Impressions of Change scores, and de novo incontinence rates between the groups. The median blood loss was significantly lower in the ventral onlay group than in the dorsal onlay group (10 vs 20ml, p = 0.001). Dorsal and ventral onlay urethroplasties with buccal mucosal graft are safe and effective techniques for managing female urethral stricture, with similar patency, complications, de novo incontinence rates, and improvements in sexual function. Ventral onlay female urethroplasty has been associated with reduced intraoperative bleeding. To the best of our knowledge, this study represents the largest individual comparative cohort in the literature that directly evaluates dorsal and ventral onlay female urethroplasty.

Solitary fibrous tumor (SFT) is a fibroblastic neoplasm characterized by prominent, staghorn, or delicate "hemangiopericytoma (HPC)-like vasculature", NAB2::STAT6 gene fusion, and its surrogate STAT6 expression. SFT may exhibit an unpredictable clinical course, necessitating risk assessment based on tumor characteristics. Renal SFTs are rare and have not been well characterized. Forty-three primary kidney SFT cases are reviewed for clinical, morphological, and immunohistochemical (STAT6, BCL2, CD34, and PAX8) features. A four-variable risk stratification by Demicco was applied based on patient age, tumor size, mitotic activity, and tumor necrosis. The mean age was 49years (range 11-83years) with a slight female predominance (male:female = 20:23). The mean tumor size was 7.8cm (1.6-32cm). Tumors were mainly located at the hilus (22/32, 68%) and had well-demarcated borders (31/42, 74%). Morphologically, tumors were categorized as 1) Fibrous ("SFT-like", 19/43, 44%), characterized by hypocellularity and prominent fine-reticular or keloidal collagen; 2) Cellular ("HPC-like", 8/43, 19%), with hypercellularity, short spindle to small cell-like proliferation, and lacking a collagenous background; 3) mixed fibrous/cellular (16/43, 37%) displaying both components. Four cases featured a lipomatous component. BCL2 was positive in all tested cases (28/28), CD34 in all but 3 cases (93%), and STAT6 in all but one case (39/40, 97.5%). PAX8 was positive in 6/34 (18%) cases. Most cases (29/43, 68%) were classified as low-risk, followed by intermediate (12/43, 27%) and high-risk (2/43, 5%) groups. Five of 29 (18%) patients had metastatic disease, and two patients with high-risk and one with intermediate-risk tumors died from the disease, while 25 patients with low- or intermediate-risk tumors were alive for an average of about 36months. We emphasize the usefulness of the risk stratification system in predicting prognosis. PAX8 expression in a subset of renal SFT represents a potential diagnostic pitfall.