Search Results (1,272)

During the 2024 growing season, black carrot (Daucus carota subsp. sativus) plants showing symptoms consistent with phytoplasma infection, including leaf chlorosis, reduced leaf size, witches’ broom, excessive fibrous root formation, multiple lateral taproots, and floral phyllody, were observed in production fields in Hatay Province, Türkiye. To identify the associated phytoplasma, 23 symptomatic plants and two asymptomatic control plants were analysed using PCR-based molecular detection, sequencing, BLASTn comparison, and phylogenetic analyses of the 16S rRNA, secA, tuf, and imp gene regions. The SAP11 gene was also screened as an additional virulence-associated molecular marker, but no functional characterization was performed. All symptomatic samples yielded amplicons of the expected sizes for the targeted loci, whereas no amplification was obtained from asymptomatic controls. Sequence comparisons revealed >99% nucleotide identity with members of the peanut witches’ broom group, and multilocus phylogenetic analyses consistently placed the black carrot phytoplasma isolate within the 16SrII-D subgroup. To our knowledge, this study provides the first documented evidence of a 16SrII-D phytoplasma associated with black carrot in Türkiye. The finding is relevant for plant pathology and plant protection because it indicates the occurrence of a phytoplasma lineage with potential epidemiological importance in an economically important vegetable production area. These results provide a basis for future studies on disease distribution, insect vectors, alternative host plants, epidemiology, and management strategies in black carrot production systems. Full article

In this study, an exploratory transcriptomic investigation was conducted to evaluate the feasibility of using feather transcriptomics to detect sex differences and gene responses to physiological changes in chickens. Feathers represent a promising non-invasive biological source of RNA, as the feather pulp of growing feathers contains living cells capable of active transcription. Growing feathers were collected from 150-day-old male and female chickens (Bionda Piemontese, a slow-growing breed) raised under a free-range system and fed two finisher diets differing in lipid content: low-lipid (LL, ether extract 3.6%) and high-lipid (HL, ether extract 9.3%) diets. RNA was extracted from feather pulp, and 12 pools were subjected to whole RNA-Seq analysis. The study was designed as 2 × 2 factorial experiments investigating the effects of diet and sex on gene expression. A total of 17,360 transcripts were detected and used for downstream analyses. Differential gene expression and functional enrichment analyses were performed. The main effects of diet and sex were estimated with an additive design using the DEseq2 package, while for the sex-specific diet analyses, subgroup comparisons were conducted on the RaNA-Seq platform. The analysis of the main effect of diet reveals that three genes associated with ether lipid metabolism (PLA2G10, PLA2G4F, and ENPP6) were upregulated in chickens fed the HL diet. In roosters, HL feeding significantly altered the expression of APOA1 and SLC27A4, suggesting an effect on lipid transport and metabolic regulation within the PPAR signaling pathway. In contrast, hens showed differential expression primarily in pathways related to apelin signaling, extracellular matrix remodeling, and cardiovascular function, rather than classical lipid metabolism pathways; additionally, gene set enrichment analysis indicated a limited enrichment of linoleic acid metabolism, suggesting secondary involvement of lipid metabolic processes. These findings are consistent with those in the literature reporting sex-related differences between males and females. The results further suggest that transcriptomic responses to dietary lipid supplementation can be investigated through the expression of selected candidate genes in feather pulp. Among the genes identified, PLA2G10, PLA2G4F, ENPP6, APOA1, and SLC27A4 emerged as potential molecular markers associated with dietary treatment, and the importance of sex-dependent transcriptional responses was highlighted. In conclusion, this study demonstrates the potential of feather pulp as a viable source of RNA for transcriptomic analyses in live chickens, providing a minimally invasive alternative to conventional tissue sampling. These preliminary results also support the hypothesis that feathers represent a practical and ethically favorable tissue for future nutrigenomic and genetic improvement studies, ultimately supporting more sustainable poultry production. Full article

Sea Island cotton (Gossypium barbadense L.) is a premium raw material for high-end textiles due to its excellent fiber quality. The AP2/ERF transcription factor family plays critical roles in plant growth and hormone signaling. Here, 161 GbERF family members were identified in Sea Island cotton and classified into nine subgroups, with GbERF13 belonging to Group V. Expression analysis revealed that GbERF13 was specifically and highly expressed in fibers, with transcript abundance peaking at 15–30 days post-anthesis (DPA), coinciding with the transition from fiber elongation to secondary wall thickening. Exogenous abscisic acid (ABA) treatment significantly induced GbERF13 expression and inhibited fiber elongation. Heterologous overexpression of GbERF13 in Arabidopsis increased trichome and root hair numbers while suppressing primary root growth, confirming its role in cell elongation and development. A nonsynonymous SNP (A/C) at the 117th base pair of the GbERF13 coding region (GbERF13-117SNP) was identified in 213 Sea Island cotton accessions. Association analysis showed the C allele was significantly and positively associated with fiber length, strength, and uniformity. An allele-specific PCR marker was further developed for molecular breeding. Collectively, GbERF13 acts as a key ABA-responsive transcription factor regulating fiber development, and its functional SNP marker provides a valuable tool for improving Sea Island cotton fiber quality. Full article

Background/Objectives: Myelodysplastic syndromes (MDS) carry a highly variable prognosis, stratified by the Revised International Prognostic Scoring System (IPSS-R) and the Molecular IPSS (IPSS-M). CEBPA mutations define a favorable-risk subgroup in acute myeloid leukemia (AML), yet their prognostic significance in MDS has not been characterized. Methods: We analyzed 2442 patients from the International Working Group (IWG) 2022 multi-center MDS registry after pre-specified exclusions. Overall survival (OS) and leukemia-free survival (LFS) were compared between CEBPA-mutated (n = 66; 2.7%) and wild-type patients using Kaplan–Meier estimation and Cox proportional hazards regression, adjusting for age, sex, and IPSS-R score; pre-specified subgroup, sensitivity, competing-risk, and mutation subtype analyses were performed. Results:CEBPA-mutated patients had markedly inferior OS (median 17.2 versus 42.2 months; HR 2.05, 95% CI 1.50–2.79; p < 0.001). After IPSS-R adjustment, the hazard ratio remained adverse (HR 1.39, 95% CI 1.00–1.94; p = 0.053), with uniform directionality across all 13 evaluable subgroups and no significant interaction. Co-mutation adjustment for ASXL1 and STAG2 further attenuated the hazard ratio to HR 1.11 (95% CI 0.79–1.57; p = 0.54), suggesting part of the observed signal reflects co-mutation burden rather than an independent CEBPA effect. Competing-risk analysis suggested that the excess mortality is mediated through AML transformation (CEBPA-mutated versus wild-type subdistribution hazard ratio of 1.89, 95% CI 1.20–2.99; p = 0.006) rather than non-transformative MDS mortality (cause-specific HR 0.97; p = 0.890). Truncating mutations drove the adverse signal (HR 2.21; p = 0.023), while basic leucine zipper (bZIP) domain mutations showed no significant effect (HR 1.25; p = 0.470). Conclusions:CEBPA mutations identify a rare MDS subgroup with markedly inferior survival, driven by truncating loss-of-function mutations and associated with leukemic transformation; the AML-derived bZIP-favorable paradigm does not translate to MDS, and CEBPA mutation status merits a prospective study to assess clinical utility for risk stratification. Full article

Diffuse large B-cell lymphoma (DLBCL) is a biologically heterogeneous mature B-cell neoplasm whose classification, prognosis, and therapy have been reshaped by advances in genomic, transcriptomic, epigenomic, single-cell, and spatial profiling technologies. This review focuses on how these approaches have refined the molecular landscape of DLBCL, including recurrent chromosomal translocations, tumor-suppressor alterations, oncogenic signaling pathways, and tumor-microenvironment programs. Cell-of-origin (COO) frameworks remain clinically useful. However, contemporary models extend beyond conventional germinal center categories by incorporating probabilistic genetic subtypes, expression-defined high-risk states, and spatially resolved lymphoma-cell and immune-cell ecosystems. These high-resolution methods clarify intratumoral heterogeneity, identify biologically distinct subgroups, and inform prognosis and therapeutic selection. The review also summarizes how tumor-intrinsic biology and the tumor-microenvironment (TME) shape responses to frontline therapy, targeted agents, antibody-drug conjugates, bispecific antibodies, and CD19-directed CAR T-cell therapy. Particular emphasis is placed on product-specific evidence in relapsed/refractory disease, rational sequencing of immunotherapies, and emerging biomarkers such as circulating tumor DNA-based measurable residual disease (ctDNA-MRD). Together, these developments support a shift from COO-centric classification toward dynamic, biology-driven models that incorporate tumor-intrinsic and microenvironmental determinants to guide personalized therapy in DLBCL. Full article

Uridine diphosphate glucuronosyltransferase 2B (UGT2B) enzymes constitute a critical subgroup of phase II metabolizing enzymes that modulate the clearance of steroid hormones, carcinogens, and numerous anticancer agents, thereby influencing cancer susceptibility, progression, and therapeutic outcomes. This review provides a comprehensive synthesis of the genetic, regulatory, and functional roles of UGT2B family members, particularly UGT2B4, UGT2B7, UGT2B10, UGT2B15, UGT2B17, and UGT2B28, in oncogenesis and cancer treatment. We summarize evidence from molecular, epidemiological, pharmacogenetic, and clinical studies demonstrating how UGT2B expression patterns, polymorphisms, copy number variations, epigenetic regulation, and microRNA-mediated control shape intratumoral hormone homeostasis, carcinogen detoxification, and drug resistance across multiple malignancies, including prostate, breast, lung, colorectal, hematological, and hormone-dependent cancers. UGT2B enzymes metabolize several widely used anticancer drugs and active metabolites, thereby affecting pharmacokinetics, efficacy, and toxicity. Understanding the context-specific roles of UGT2B family members offers a compelling opportunity for therapeutic exploitation. In particular, rational combination strategies incorporating UGT2B inhibitors or modulators alongside standard anticancer agents may enhance drug effectiveness without increasing dosage, while simultaneously enabling the dose reduction of the partner agent to mitigate dose-dependent toxicities. Such approaches are especially relevant for therapies with narrow therapeutic indices. Overall, this review highlights UGT2B enzymes as multifunctional determinants of cancer risk and treatment response and underscores their promise as biomarkers and actionable targets for precision oncology and optimized combination regimens. Full article

Background: This review aims to provide a comprehensive and practical overview of the evolving role of autologous transplantation in leukaemias, a strategy that was once largely abandoned but has recently regained interest in selected clinical settings. Methods: We reviewed the historical development of autologous transplantation in acute leukaemias, including the early period during which autologous transplantation was considered inferior to allogeneic approaches because of limited graft purification techniques and the inability to induce effective graft-versus-leukaemia (GVL)-like immune responses. We further summarise more recent experimental strategies aimed at improving stem cell purification and enhancing anti-leukaemic immune activity in autologous settings. In addition, we discuss how advances in measurable residual disease (MRD) assessment and molecular risk stratification have contributed to the renewed interest in autologous transplantation in selected subgroups of leukaemia patients. Results: This review identifies clinical situations in which autologous transplantation remains an important therapeutic option, including plasma cell leukaemia, where it continues to represent a standard first-line approach. We also discuss well-defined patient subgroups, particularly selected AML subtypes with intermediate-risk molecular profiles and acute promyelocytic leukaemia (APL) in second remission, in which outcomes following autologous transplantation may be comparable to, or occasionally superior to, those achieved with allogeneic transplantation. In contrast, autologous transplantation currently plays only a limited role in diseases such as chronic lymphocytic leukaemia (CLL) and chronic myeloid leukaemia (CML). Although attempts to induce potent anti-leukaemic immune effects in autologous settings have so far shown limited clinical efficacy, several emerging strategies appear promising and may further expand the role of autologous transplantation, particularly in elderly or frail patients. Discussion: Overall, current molecular and MRD-based risk stratification strategies, together with emerging immunological and graft-manipulation approaches, may redefine the role of autologous transplantation as a personalised therapeutic option in selected subgroups of leukaemia patients. Full article

Pediatric acute myeloid leukemia (AML) is biologically heterogeneous, and genomic profiling increasingly informs risk stratification and treatment. We evaluated the relationship between induction response, genomic risk, transplant allocation, and survival in pediatric AML. We retrospectively analyzed 38 pediatric patients with newly diagnosed AML, treated between 2020 and 2025. Clinical, cytogenetic, molecular, treatment, and outcome data were collected. Genomic alterations were assessed using cytogenetics, fluorescence in situ hybridization (FISH), molecular testing, and next-generation sequencing (NGS). Survival was estimated by Kaplan–Meier analysis, and prognostic factors for event-free survival (EFS) were assessed using univariable Cox regression. This study is exploratory given the limited sample size and should be interpreted accordingly. Complete remission (CR) after the first course of induction was achieved in 25/38 patients (65.8%), partial remission (PR) in 3/38 (7.9%), and refractory disease in 10/38 (26.3%). Twenty-four patients underwent allogeneic hematopoietic stem cell transplantation; 17/24 (70.8%) were alive at last follow-up, with a 2-year overall survival rate of 72.9%. Both induction response and genomic risk stratification showed suggestive associations with outcome; descriptively, induction response showed the strongest prognostic discrimination, with achievement of CR associated with markedly improved survival. High cytogenetic risk and FLT3-ITD were significantly associated with inferior EFS. Post-induction measurable residual disease (MRD) positivity was detected in 16 of 38 patients (42.1%) and was associated with suboptimal induction response; MRD negativity did not uniformly preclude adverse outcomes, particularly in the high-risk genomic subgroup. Genomic profiling refined biological risk and post-remission treatment allocation. Integrated assessment of genomic risk, induction response, and MRD status may improve therapeutic stratification in pediatric AML. Full article

Background: Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality worldwide. While established molecular biomarkers such as microsatellite instability (MSI), KRAS, and BRAF are routinely used in clinical practice, the prognostic relevance of tumor suppressor proteins p53 and PTEN remains incompletely defined, particularly when assessed using immunohistochemistry. Objective: The primary aim of this study was to evaluate the prognostic significance of p53 expression and PTEN deficiency in colorectal adenocarcinoma. Secondary aims included assessment of their association with clinicopathological characteristics. Methods: This retrospective cohort study included 103 consecutive patients who underwent surgical resection for colorectal adenocarcinoma. Immunohistochemical analysis of formalin-fixed paraffin-embedded (FFPE) tumor samples was performed to assess aberrant p53 expression and PTEN deficiency. Associations with clinicopathological variables were evaluated, and overall survival was analyzed using Kaplan–Meier curves and Cox proportional hazards regression models. Results: Aberrant p53 expression and PTEN deficiency were both associated with shorter overall survival in univariate analyses. Patients with concurrent aberrant p53 expression and PTEN deficiency demonstrated the poorest survival outcomes. However, in multivariate Cox regression analysis, only nodal status and age remained independent predictors of overall survival, while p53 and PTEN did not retain independent prognostic significance after adjustment for clinicopathological variables. Conclusions: Aberrant p53 expression and PTEN deficiency are associated with reduced overall survival in colorectal cancer; however, their prognostic impact appears secondary to established clinicopathological factors. The combined presence of these alterations may identify a biologically aggressive subgroup of patients with particularly unfavorable outcomes, although this observation should be considered exploratory. Further validation in larger, independent cohorts is required. Full article

Background: Metastasis and poor chemotherapy response have stagnated therapeutic progress in osteosarcoma (OS) for the past three decades. Defining the transition from localized to metastatic OS before overt dissemination is fundamental for improving survival. However, effective early diagnostic tools remain scarce, largely due to limited exploitation of the metastasis-associated tumor microenvironment’s own record of prior environmental and stress exposures encoded in cell-intrinsic transcriptional states. Here, we employed a supervised machine learning framework with iterative resampling and multi-stage model selection to identify molecular markers associated with metastasis in osteosarcoma and to develop a computational signature, Auto-RS. Methods: Transcriptomic and clinical data from 139 OS patients with ≥5 years of follow-up were analyzed. A LASSO–Cox framework was applied to derive a gene expression-based risk score, Auto-RS, from which a nomogram integrating age and sex was generated for individualized prognosis. Model interpretability was assessed across six independent single-cell OS patient datasets, and drug sensitivity predictions were inferred by integrating Auto-RS with the Precily algorithm to uncover actionable therapeutic vulnerabilities. Results: Auto-RS, constructed from the expression of four autophagy genes (BNIP3, MYC, PEA15, and SAR1A), served as an independent prognostic factor for overall survival (HR = 1.091; 95% CI, 1.047–1.136; p < 0.001). Time-dependent ROC analysis showed that Auto-RS was the most accurate single predictor (AUC = 0.88), exceeding metastasis (0.83), sex (0.45), and age (0.39). A basic prognostic model (BpM) incorporating metastasis status yielded a C-index of 0.741 (95% CI, 0.679–0.803). The addition of Auto-RS (CpM) improved discrimination (C-index = 0.788; 95% CI, 0.731–0.845), whereas a model without metastasis information (ApM) retained predictive ability (C-index = 0.709; 95% CI, 0.640–0.778). Single-cell analysis confirmed that Auto-RS features aligned with known metastatic trajectories, reflecting the transition from proliferative to invasive tumor states and highlighting coordinated programs among cancer-associated fibroblasts and immune cells. Drug sensitivity integration through Precily identified gemcitabine and cytarabine as FDA-approved agents predicted in silico to show greater sensitivity in the high-risk subgroup. Conclusions: We identified autophagy-mediated transcriptional ‘stress fingerprints’ that are tightly associated with OS metastasis. The Auto-RS signature, composed of BNIP3, MYC, PEA15, and SAR1A, enables early therapeutic stratification of patients independent of overt metastatic status. Moreover, Auto-RS delineates key molecular underpinnings of OS metastasis at single-cell resolution. As a practical laboratory tool, Auto-RS may represent a step toward improved risk stratification, where advances in metastasis prediction and therapeutic guidance converge to improve outcomes in OS. Full article

Background/Objectives: Brain metastases (BMs) are a major cause of morbidity and mortality in non-small-cell lung cancer (NSCLC). In this setting, EGFR-mutant and ALK-rearranged tumors represent clinically actionable, CNS-relevant oncogenic subgroups for which matched TKIs are essential to management, yet lesion-level molecular profiling is not always feasible or immediately available. We aimed to develop and externally validate DriverNet, a clinical and MRI-based framework for noninvasive pre-treatment molecular triage of EGFR/ALK status in NSCLC-BM. Methods: In this multicenter study, we analyzed pretreatment clinical, T1CE and T2-FLAIR MRI data to develop unimodal radiomics, 2D/2.5D deep learning (DL), and multimodal fusion models. The final model used ImageNet-pretrained CNNs for feature extraction and a Transformer-based architecture for fusion. The primary cohort was split strictly at the patient level before slice extraction and model development, and two independent external cohorts were used for testing. Clinical-only, imaging-only, and clinical-imaging models were compared using discrimination, calibration, Brier score, and decision-curve analyses. Model interpretability and exploratory prognostic stratification were also assessed. Results: A total of 374 patients from three centers were included. Center 1 comprised 224 patients (Chinese) and was divided into training (n = 179, EGFR/ALK+ 55.3%) and internal validation (n = 45, EGFR/ALK+ 57.8%) sets. External cohorts included 54 patients from Center 2 (Chinese, test 1, EGFR/ALK+ 42.6%) and 96 from Center 3 (Western, test 2, EGFR/ALK+ 12.5%). Among all evaluated models, DriverNet achieved the best overall performance, with AUCs of 0.967, 0.947, 0.962, and 0.952 in the training, internal validation, and two external cohorts, respectively, outperforming the clinical-only and imaging-only models. Model-derived labels were also associated with overall survival in exploratory analyses. Conclusions: DriverNet is a clinical and MRI-based framework for noninvasive pre-treatment molecular triage in NSCLC-BM. It may provide complementary information for future molecular triage studies when lesion-level profiling is unavailable or delayed. Prospective validation in larger and more molecularly balanced cohorts remains necessary before any clinical implementation can be considered. Full article

Objective: To evaluate the clinical benefit of platinum rechallenge in patients with platinum-resistant ovarian cancer (PROC) and to explore the predictive role of BRCA mutation status. Methods: We retrospectively evaluated platinum rechallenge in PROC at Vall d’Hebron University Hospital between 2010 and 2023. Eligibility required ≥1 prior non-platinum regimen and ≥12 months since the last platinum dose. Objective response rate (ORR) per RECIST 1.1 and survival outcomes were analyzed by BRCA status and prior treatment lines. Results: ORR was 57% (95%CI, 42.1–73.0%) in the overall cohort (n = 63), 77% in BRCA-mutated patients (n = 13), and 50% in BRCA wild-type patients (n = 46). Median progression-free survival (PFS) was 7.3 months overall, which was longer in BRCA-mutated versus BRCA wild-type patients (8.4 vs. 7.4 months; HR 0.47, 95%CI 0.23–0.94; p = 0.033). An exploratory subgroup analysis suggested longer PFS among BRCA-mutated patients with ≤4 prior lines; however, this small subgroup finding should be considered hypothesis-generating. A platinum-free interval >6 months after rechallenging was observed in 38.5% of BRCA-mutated versus 13% of BRCA wild-type patients. Conclusions: Platinum rechallenge showed clinically meaningful activity in selected patients with PROC after an extended interval of intervening non-platinum therapy. These findings support the concept that platinum sensitivity may be dynamic and suggest that BRCA status and clinical selection factors may help inform individualized treatment sequencing in the post-PARP inhibitor era. Prospective validation with broader molecular characterization is warranted. Full article

Despite advances in precision medicine, therapeutic options for pancreatic adenocarcinomas are limited, alongside a significant increase in incidence and mortality in recent years. We present the case of an exceptional response to immunotherapy in a heavily pre-treated pancreatic adenocarcinoma. The patient is a 73-year-old man that was diagnosed in 2017 with locally advanced pancreatic adenocarcinoma. He underwent different lines of chemotherapy and after exhausting standard treatment options, he practiced the FoundationOne^® CDx analysis (Foundation Medicine, Inc., Cambridge, MA, USA), that pointed out a High Tumor mutational burden that permitted our Oncology Center to request Pembrolizumab 200mg flat dose q 21 as an off-label therapy. The patient started the treatment in July 2021 and is still ongoing, having achieved a complete radiological response of hepatic metastases. Although immunotherapy is not part of the standard treatment paradigm for advanced pancreatic cancer, our case suggests that it may provide substantial and durable clinical benefit in a small molecularly selected subgroup of patients who have exhausted conventional therapeutic options, highlighting the critical role of comprehensive molecular profiling in identifying actionable treatment opportunities. Full article

Background/Objectives: Immune surveillance is increasingly recognized as a modifier of myeloproliferative neoplasm (MPN) initiation and evolution, yet the contribution of the NKG2D receptor and its ligands MICA/MICB to CALR-mutated disease remains unclear. Methods: We performed high-resolution next-generation sequencing genotyping of MICA and MICB in 43 patients with CALR-mutated MPN (WHO 2022 criteria) and compared the allele and haplotype distributions with those of 156 healthy Bulgarian controls and 85 patients with JAK2 V617F-positive MPN. Associations were tested using age- and sex-adjusted additive generalized linear models; bi-locus haplotypes were evaluated using haplotype score methods. In a genotyped subgroup (35 CALR-mutated MPN patients and 105 controls), functional KLRK1 (NKG2D) polymorphisms were analyzed for haplotype-level associations. We also performed 700 ns molecular dynamics simulations of selected MICA variants in complex with NKG2D and reanalyzed publicly available single-cell RNA-sequencing data (GSE117826) and RNA-sequencing data from CRISPR/Cas9-edited CALR-mutant iPSC-derived megakaryocytes to evaluate MICA/MICB expression. Results: MICA*004:001 was significantly associated with CALR-mutated MPN versus controls (p = 0.004; Bonferroni-adjusted p = 0.047), while MICB*008:001 showed only nominal association. Exploratory haplotype analyses identified a MICA*009:01-MICB*004:001 haplotype associated with CALR-mutated status (p = 0.008) and a KLRK1 G-A-G-T haplotype (rs1049174-rs2617160-rs2246809-rs2617170) associated with increased CALR-mutated MPN risk (OR = 3.61; p = 0.029). Transcriptomic reanalysis indicated a higher fraction of CALR-mutant stem and progenitor cells expressing detectable MICA/MICB transcripts, and heterozygous CALR-mutant megakaryocytes exhibited higher MICA expression than the wild type. Conclusions: Together, these data support an exploratory immunogenetic and transcriptomic link between the NKG2D-MICA/MICB axis and CALR-mutated MPN, but direct protein-level and functional studies are required before mechanistic or therapeutic conclusions can be drawn. Full article

Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a near-universal presence of KRAS mutations and limited responsiveness to immunotherapy. Biologic heterogeneity among KRAS subtypes may shape tumor immunobiology and treatment resistance. Methods: We evaluated 109 patients with advanced PDAC treated in early-phase trials between August 2014 and August 2023. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan–Meier method, and Cox proportional hazard models were used to assess the clinical and molecular predictors of survival. Results: Among the 109 patients, 64% harbored KRAS mutations, 18% were KRAS wild type, and 17% had an unknown KRAS status. The median age was 65 years, and 83% had liver metastases. Among the KRAS-mutant tumors, subtype distribution was G12D (46%), G12V (31%), G12R (13%), and other variants (10%). Immunomodulatory agents were administered to 39% of the patients, most commonly in the first-line setting (49%). The median OS and PFS for the entire cohort were 5.65 and 2.73 months, respectively. The restricted mean OS (7.54 vs. 8.65, p = 0.53) and PFS (3.82 vs. 4.24, p = 0.70) did not differ between patients with KRAS mutants and wild-type KRAS. Among patients with KRAS mutations, receipt of immunomodulatory therapy was associated with shorter OS compared with those who did not receive immunomodulatory therapy, with the strongest association observed in the KRAS G12D subgroup. This pattern was not observed in KRAS wild-type tumors. On univariate analysis, immunomodulatory therapy exposure, number of prior treatment lines, and presence of liver metastases were each associated with inferior OS. On multivariable analysis, immunotherapy exposure demonstrated a non-significant trend toward inferior OS (hazard ratio [HR] 1.61, 95% Cl 0.98–2.66; p = 0.06), while the other variables remained independently associated with worse OS, suggesting confounding in the unadjusted association between immunomodulatory therapy and survival. Conclusions: Among patients with KRAS-mutant PDAC—particularly those with G12D—receipt of immunomodulatory therapy in early-phase trials was associated with shorter OS in this exploratory analysis. These findings should be considered hypothesis-generating and require validation in prospective, KRAS-subtype-informed studies. Full article