Sedat Biter

Background and Objectives: This study aimed to compare the real-world outcomes of first-line pembrolizumab monotherapy (Mono-IO) versus pembrolizumab plus platinum-based chemotherapy (IO + ChT) in patients with metastatic non-small cell lung cancer (mNSCLC) and a PD-L1 tumor proportion score (TPS) ≥ 50%. Materials and Methods: This retrospective, multicenter, real-world study evaluated 148 patients with mNSCLC and PD-L1 expression ≥ 50% who received either first-line Mono-IO or IO + ChT. Overall survival (OS), progression-free survival (PFS), and clinical benefit rate were compared between the two treatment strategies. Additionally, clinical prognostic factors, patterns of progression, and post-progression treatments were analyzed. Survival outcomes were assessed using Kaplan–Meier estimates, multivariable Cox regression, and restricted mean survival time (RMST) analysis. Results: Patients in the Mono-IO group were significantly older (median 69 vs. 63 years; p < 0.001) and had a higher proportion of ECOG PS 2 (35.3% vs. 5.2%; p < 0.001). No significant differences were observed between Mono-IO and IO + ChT in median OS (32.0 vs. 26.0 months; p = 0.559) or PFS (19.6 vs. 19.4 months; p = 0.572). In an exploratory multivariable analysis adjusting for organ-specific metastases and antibiotic exposure, ECOG PS ≥ 1 (aHR: 1.86, 95% CI: 1.16–2.97; p = 0.009), antibiotic use (aHR: 1.85, 95% CI: 1.16–2.95; p = 0.010), and liver metastasis (aHR: 2.58, 95% CI: 1.16–5.74; p = 0.020) were independent predictors of worse OS. Conversely, PD-L1 TPS ≥ 90% (aHR: 0.56, 95% CI: 0.35–0.91; p = 0.018) was independently associated with superior OS. In exploratory subgroup analysis, a numerical survival trend favoring Mono-IO was observed in patients with PD-L1 TPS ≥ 90%, although this finding remains hypothesis-generating. Following disease progression, 64.7% of patients received no further systemic therapy. Conclusions: In this real-world cohort, no statistically significant differences in OS or PFS were detected between Mono-IO and IO + ChT; however, the wide confidence intervals do not exclude clinically meaningful differences, and equivalence cannot be inferred from these data. PD-L1 TPS ≥ 90% may potentially serve as a biomarker to identify patients who derive benefit from monotherapy, although this exploratory finding requires validation in larger cohorts. Given that the majority of patients did not transition to subsequent therapy in routine practice, likely reflecting multifactorial host frailty and rapid disease evolution, first-line therapeutic optimization warrants careful individualized consideration.

CD44, a stem cell-associated adhesion molecule, and CD47, an anti-phagocytic checkpoint, have been implicated in breast cancer chemoresistance, but their relationship to neoadjuvant response is poorly defined. We assessed both markers by immunohistochemistry in pre-treatment core biopsies from 43 women treated with neoadjuvant therapy at a single center. Total pathological complete response (pCR; ypT0/is ypN0), designated the primary endpoint during peer review, occurred in 12 patients (27.9%), and breast pCR (ypT0/is) in 14 (32.6%). Total pCR rates were 18.2% in CD44-positive and 38.1% in CD44-negative tumors (odds ratio, 0.36; 95% CI, 0.09–1.46; Fisher exact p = 0.185). CD44 positivity was concentrated in rarely responding hormone receptor-positive/HER2-negative tumors, and stratification by subtype moved the odds ratio toward the null (0.62; exact 95% CI, 0.07–5.25). For CD47, the odds ratio per one-point increase in immunoreactivity score was 0.80 (95% CI, 0.54–1.19; p = 0.264), but immunoreactivity was low (only two tumors reached the prespecified high-expression threshold) and possibly technically compromised, so these findings are inconclusive. No statistically detectable association was observed between either marker and total or breast pCR; treatment could not be adjusted for, and only very large effects were detectable. These exploratory data do not provide sufficient evidence to support CD44 or CD47 as response markers.

Aim: Leptomeningeal metastasis (LM) from breast cancer carries a poor prognosis, and most published cohorts originate from high-volume referral centers. We aimed to identify factors associated with overall survival (OS) after an LM diagnosis in routine practice and to describe diagnostic and treatment patterns.Methods: We retrospectively reviewed consecutive women treated for breast cancer–related LM at a single tertiary center between February 2018 and December 2023. LM was classified according to the European Association of Neuro-Oncology–European Society for Medical Oncology criteria. OS was measured from the LM diagnosis and estimated by the Kaplan–Meier method. Candidate variables were examined by Cox regression. Landmark analyses at 4 weeks were used to limit immortal time bias.Results: Thirty-eight women were included; median age at LM diagnosis was 57.0 years. The diagnosis was cytologically or histologically confirmed (type I) in 12 patients (31.6%). After the LM diagnosis, 32 patients (84.2%) received systemic therapy, 22 (57.9%) radiotherapy, and 5 (13.2%) intrathecal methotrexate. Thirty-five patients (92.1%) had died. Median OS was 2.8 months (95% confidence interval [CI], 1.4–8.8); 6- and 24-month survival were 39.5% and 12.3%, respectively. No variable reached P < 0.10 in univariable analysis; radiotherapy had the lowest P value (hazard ratio 0.57; 95% CI, 0.28–1.15; P = 0.11). An exploratory multivariable model, specified before fitting, showed no independent association.Conclusions: Median survival was 2.8 months, and no independent prognostic factor was identified. The low rate of cytological confirmation limits comparison with referral-center series.

Purpose: Enhancer of zeste homolog 2 (EZH2) is an epigenetic regulator implicated in the pathogenesis of diffuse large B-cell lymphoma, but the prognostic value of its protein expression is uncertain. We evaluated EZH2 expression and its associations with clinicopathological features and survival.Materials and Methods: We retrospectively studied 50 patients with diffuse large B-cell lymphoma treated with rituximab-based immunochemotherapy. EZH2 expression was assessed by immunohistochemistry using an H-score and classified as high (≥150) or low (

Background/Objectives: Immune checkpoint inhibitors have become a standard treatment option for advanced/metastatic non-small cell lung cancer (NSCLC); however, considerable heterogeneity exists among patients regarding treatment response and survival. This study aimed to determine whether the pretreatment modified Glasgow Prognostic Score (mGPS), a marker of systemic inflammation and nutritional status, is prognostically associated with progression-free survival (PFS) and overall survival (OS) in patients with advanced/metastatic NSCLC treated with nivolumab at a single tertiary oncology center. Methods: This retrospective, single-center cohort study included 130 adult patients with histologically confirmed advanced/metastatic NSCLC who received nivolumab at the Department of Medical Oncology, Çukurova University Faculty of Medicine. The pretreatment mGPS (0, 1, or 2), derived from baseline serum C-reactive protein (CRP) and albumin levels, was analyzed in relation to PFS and OS using the Kaplan–Meier method, log-rank test, and Cox proportional hazards regression. The prognostic value of mGPS was tested in multivariable Cox models adjusted for age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, histology, brain metastasis, liver metastasis, and neutrophil-to-lymphocyte ratio (NLR); the proportional hazards assumption was formally tested, and the incremental discriminative contribution of mGPS was assessed using bootstrap resampling. Results: Among 130 patients, 83.8% received nivolumab as second-line therapy. Pretreatment mGPS was 0, 1, and 2 in 40 (30.8%), 55 (42.3%), and 35 (26.9%) patients, respectively. Median OS was not reached, 9.7 months, and 3.0 months across mGPS 0, 1, and 2, respectively; corresponding median PFS values were 10.2, 4.8, and 3.0 months (log-rank p < 0.001 for both endpoints). After adjustment for age, sex, ECOG performance status, histology, brain metastasis, liver metastasis, and NLR, each one-point increase in mGPS remained associated with worse OS (adjusted HR 2.38; 95% CI 1.64–3.46; p < 0.001) and PFS (adjusted HR 1.81; 95% CI 1.32–2.48; p < 0.001), independent of the covariates included in the model. The proportional hazards assumption held for mGPS in both models. Addition of mGPS to the clinical-variables-only model was associated with higher model discrimination (Harrell’s C-index: 0.676 to 0.737 for OS and 0.620 to 0.666 for PFS), a difference confirmed as statistically significant by bootstrap resampling (2000 iterations; 95% CI for the difference excluding zero, p < 0.001 for both endpoints). Conclusions: Pretreatment mGPS is a simple, readily available marker that shows a robust prognostic—rather than treatment-predictive—association with both OS and PFS in patients with advanced/metastatic NSCLC treated predominantly as second-line nivolumab monotherapy. Its addition to established clinical variables was associated with a statistically significant, though modest, improvement in prognostic discrimination. These findings require prospective, multicenter validation, including in first-line immunotherapy settings, before mGPS can be recommended for routine clinical risk stratification.

Background/Objectives: In diffuse large B-cell lymphoma (DLBCL), the prognostic value of programmed death-ligand 1 (PD-L1) depends on the immunohistochemical threshold applied. We asked whether tumor-cell PD-L1 adds prognostic information beyond the International Prognostic Index (IPI). Methods: Tumor-cell PD-L1, quantified by the 22C3 tumor proportion score (TPS), was assessed retrospectively in 95 patients with large B-cell lymphoma (87 DLBCL-NOS) given frontline chemoimmunotherapy. TPS was analyzed at the prespecified ≥1% threshold, post hoc at ≥10%, ≥25%, ≥50% and ≥70%, continuously, and with restricted cubic splines. Results: PD-L1 positivity (TPS ≥ 1%) was present in 73 patients (77%). After a median follow-up of 89.8 months, PD-L1 was not independently associated with overall survival (OS; adjusted hazard ratio [HR], 0.73; 95% CI, 0.35–1.53) or progression-free survival (adjusted HR, 0.91; 95% CI, 0.44–1.86); no threshold survived correction for multiplicity. An unadjusted association with OS emerged at TPS ≥ 70% (HR, 2.02; 95% CI, 1.02–4.02), but these patients more often had an IPI ≥ 3 (72% versus 36%) and it was attenuated after adjustment (1.53; 0.74–3.18). No definition improved model fit or discrimination beyond the IPI; the null result held in DLBCL-NOS and R-CHOP subgroups. Conclusions: Tumor-cell PD-L1 did not add prognostic information beyond the IPI for overall survival.

PURPOSE: Primary bone sarcomas, including osteosarcoma, chondrosarcoma, and Ewing sarcoma, have poor prognoses, with 5-year overall survival (OS) rates of < 20%-30% in metastatic or recurrent disease. Although tyrosine kinase inhibitors (TKIs) targeting angiogenic and oncogenic pathways have shown efficacy in phase II trials, there is a lack of supporting real-world data. This study aimed to evaluate the efficacy and safety of TKI use in patients with advanced bone sarcomas in a real-world setting. MATERIALS AND METHODS: This multicenter, retrospective study included 72 patients with advanced or metastatic osteosarcoma, chondrosarcoma, or Ewing sarcoma who received at least one TKI (regorafenib, pazopanib, sorafenib, or cabozantinib) at multiple centers in Türkiye. Progression-free survival (PFS) and OS were estimated using the Kaplan-Meier method. Adverse events were recorded and graded according to standard criteria. RESULTS: The median age was 28.5 years (range, 17-72 years), and 62.5% (n = 45) of the patients were male. The most frequently used TKIs were regorafenib (n = 31, 43.1%) and pazopanib (n = 22, 30.6%); in the majority of patients (n = 68, 94.4%), TKIs were used as second-line or subsequent treatment. The median PFS for the entire cohort was 4.8 months (95% CI, 3.05 to 6.48), and the median OS was 9.9 months (95% CI, 6.48 to 13.25). In histologic subgroup analyses, the median PFS was 4.4 months for osteosarcoma, 4.8 months for chondrosarcoma, and 5.4 months for Ewing sarcoma. Adverse events were observed in 50% (n = 36) of patients, and 89.2% (n = 58) of these were grade 1-2. Dose reduction was required in 27.8% (n = 20) of patients, and permanent treatment discontinuation due to toxicity was necessary in 6.9% (n = 5) of patients. CONCLUSION: In this real-world cohort, although TKIs were associated with limited survival outcomes, they had an acceptable safety profile in patients with advanced bone sarcomas. These findings are consistent with the results of phase II studies and suggest that TKIs may be a treatment option for patients who have disease progression after standard therapies.

Background and Objectives: The modified Glasgow Prognostic Score (mGPS)—a composite of serum C-reactive protein (CRP) and albumin—simultaneously reflects systemic inflammatory activity and nutritional reserve. Its specific prognostic role in patients with metastatic renal cell carcinoma (mRCC) treated with nivolumab in the second-line setting has not previously been examined in a large multicentre cohort. The aims of this study are to determine whether baseline mGPS independently predicts overall survival (OS) and progression-free survival (PFS) in this population and whether its discriminatory capacity compares favourably with the International Metastatic RCC Database Consortium (IMDC) risk score. Methods: This multicentre retrospective cohort study included 174 consecutive patients with histopathologically confirmed mRCC who progressed on first-line VEGF-targeted tyrosine kinase inhibitor (TKI) therapy and subsequently received nivolumab monotherapy at six oncology centres in Türkiye between January 2015 and December 2023. Baseline mGPS was calculated from serum albumin and CRP measured within four weeks before treatment initiation. Kaplan–Meier analysis with log-rank testing and Cox proportional-hazards regression were used for survival analyses; discriminatory capacity was quantified using Uno’s concordance (C) statistic. Results: The median follow-up was 24.2 months. The median OS was 44.5, 15.3, and 10.0 months for the mGPS 0, 1, and 2 groups, respectively (log-rank p < 0.0001); the median PFS was 6.7, 4.2, and 2.6 months (p = 0.022). On multivariable analysis, mGPS 2 independently predicted inferior OS (hazard ratio [HR] 3.61, 95% confidence interval [CI] 1.78–7.31; p < 0.001) and PFS (HR 1.87, 95% CI 1.17–2.97; p = 0.008). Uno’s C-statistic for OS was numerically higher for the combined mGPS + IMDC model (0.70) than for either the mGPS (0.66) or IMDC (0.63) alone; these differences were not formally tested and are presented descriptively. Conclusions: Baseline mGPS is a simple, inexpensive, and independent prognostic biomarker in mRCC patients treated with second-line nivolumab, providing discriminatory information that may be complementary alongside IMDC risk stratification. Prospective validation in randomised trials is warranted.

Background: Recent transcriptomic studies classify small-cell lung cancer (SCLC) into molecular subtypes driven by ASCL1, NEUROD1, POU2F3, and YAP1. This study evaluated an immunohistochemistry (IHC)-based subtyping framework using real-world data and assessed its ability to predict chemoimmunotherapy outcomes. Methods: Proteomic expression profiles were quantified by IHC in 100 patients with SCLC. Clinicopathological trajectories and overall survival (OS) were analyzed using a parsimonious multivariate Cox model designed to mitigate overfitting. Results: Significant subclonal heterogeneity was captured by co-dominant hybrid phenotypes, including SCLC-AN (9%) and SCLC-AP (5%). In the treatment-adjusted, parsimonious multivariate analysis, individual continuous biomarker expressions showed an independent association with ASCL1 percentage (HR = 1.011, p = 0.017). Traditional extensive-stage disease (HR = 3.801, 95% CI: 1.669–8.657, p = 0.001) and synchronous bone metastases (HR = 1.968, 95% CI: 1.074–3.604, p = 0.028) remained the only robust clinical predictors of poor OS. When adjusted for therapeutic interventions, first-line chemoimmunotherapy showed a strong protective numerical trend, reducing mortality risk by 49% (HR = 0.512, p = 0.060). Within the immunotherapy subgroup (n = 19), the NE-low group had a 100% response rate and a numerically longer median overall survival than the NE-high group (49.4 vs. 21.4 months; log-rank p = 0.080). Conclusions: Our pilot evaluation provides a clinically feasible routine IHC framework for characterizing subclonal mosaicism in SCLC.

Background: Sorafenib remains an important treatment option for patients with radioiodine-refractory differentiated thyroid cancer (RAI-R DTC). This study evaluated real-world outcomes and prognostic factors in patients treated with sorafenib. Materials and Methods: This retrospective multicenter study included 176 patients with RAI-R DTC treated with sorafenib between 2000 and 2024 across sixteen centers. Clinical, pathological and treatment-related variables, including metastatic sites, radiotherapy, dose reduction, inflammatory markers (neutrophil-to-lymphocyte ratio [NLR] and platelet-to-lymphocyte ratio [PLR]) and pretreatment thyroglobulin (Tg), were analyzed. Progression-free survival (PFS) was evaluated using Kaplan–Meier analysis. Prognostic factors were assessed using univariate and multivariate Cox regression analyses. Results: The median follow-up duration was 24 months and the median PFS was 21 months (95% CI: 15.5–26.5). Partial response was observed in 82 patients (46.6%), stable disease in 55 (31.3%) and progressive disease in 35 (19.9%). Patients who underwent dose reduction had longer PFS than those without dose reduction (42 vs. 19 months, p = 0.030), and absence of dose reduction remained independently associated with progression risk. Patients who received radiotherapy had shorter PFS than those who did not receive radiotherapy (16 vs. 37 months, p = 0.002), and radiotherapy-related variables remained independent predictors of progression. Patients with PLR values >138.2 had shorter PFS than those with PLR values ≤ 138.2 (19 vs. 34 months, p = 0.047), although this association was not maintained in Cox regression analysis. Similarly, associations between NLR and Tg values and PFS did not reach statistical significance (p = 0.112 and p = 0.072, respectively). Hand–foot syndrome was the most common toxicity, occurring in 59 patients (33.5%), while Grade 3 hand–foot syndrome was observed in 7 patients (4.0%). Conclusions: Sorafenib provided meaningful disease control with a median PFS of 21 months in this real-world cohort. Dose reduction was associated with longer PFS, whereas radiotherapy requirement appeared to reflect a higher-risk subgroup. Toxicities were generally manageable.