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Temporal trends in incidence and mortality in biliary tract cancers in the United States, 2000–2023: A SEER-based analysis.
e16153 Background: Biliary tract cancers (BTCs) are aggressive malignancies with an increasing global burden. In the United States, recent changes in cholangiocarcinoma incidence and mortality, as well as demographic disparities, warrant clarification using contemporary national cancer data. Methods: We extracted incidence and mortality data from the SEER 21 registries (2000–2023). Biliary tract cancers were classified as intrahepatic cholangiocarcinoma (C22.1), extrahepatic cholangiocarcinoma (C24.0), or gallbladder cancer (C23.9). Histology was restricted to cholangiocarcinoma (8160/3) for bile duct sites, while all malignant histologies were included for gallbladder cancer. Age-adjusted rates were expressed per 100,000 person-years using the 2000 U.S. standard population. Temporal trends were evaluated by log-linear regression to estimate the Annual percent change (APC). Results: Intrahepatic cholangiocarcinoma increased by +5.14% annually (p<0.001), with a parallel rise in mortality by +3.32% (p<0.001). Extrahepatic cholangiocarcinoma showed smaller but still significant increases in incidence (+1.67%/year, p<0.001) and mortality (+1.30%/year, p<0.001). Conversely, gallbladder cancer incidence (−0.42%/year, p=0.20) and mortality (−0.39%/year, p=0.22) remained stable [Table 1]. Asian/Pacific Islanders exhibited the highest intrahepatic incidence rates, while Black individuals had disproportionately higher gallbladder mortality. Sex-specific analyses showed that males had higher cholangiocarcinoma incidence, whereas females had higher gallbladder cancer rates. Despite increased intrahepatic incidence, the mortality-to-incidence ratio remained high across all subtypes, demonstrating persistently poor outcomes. Conclusions: Intrahepatic and extrahepatic cholangiocarcinoma represent a rapidly growing cancer burden in the United States, while gallbladder cancer trends remain stable. Racial and sex disparities persist, underscoring a need for targeted prevention, earlier detection, and equitable access to care. These findings support BTC as an emerging public health priority. Incidence and mortality annual percent change with significance by cancer type. Category Anatomical Site Annual Percent Change (APC %) P-value Incidence Intrahepatic cholangiocarcinoma +5.14% <0.001 Extrahepatic cholangiocarcinoma +1.67% <0.001 Gallbladder cancer -0.42% 0.20 Mortality Intrahepatic cholangiocarcinoma +3.32% <0.001 Extrahepatic cholangiocarcinoma +1.3% <0.001 Gallbladder cancer -0.39% 0.22
Cancer screening in the transgender population: Examining the specificities of cancer risk from a health equity perspective—An analytical cross-sectional study.
e22545 Background: The transgender population faces significant structural and social barriers to healthcare access. In oncology, these disparities are intensified by the absence of adapted clinical protocols, lack of professional training, and scarcity of epidemiological data reflecting their biological and social specificities. We aimed to evaluate cancer screening adequacy and identify healthcare inequities in this population. Methods: This analytical cross-sectional study included 170 transgender and non-binary individuals over 18 years of age. Data were collected using a structured 32-item questionnaire addressing sociodemographic characteristics, personal and family history, habits, exposures, and healthcare experiences. Data collection occurred in-person and online at LGBTI+ reference centers, community clinics, and non-governmental organizations. Statistical analysis employed Chi-square, Fisher's exact, and Poisson regression tests using R software. Results: Non-binary individuals had higher income and education levels, while transgender women and travestis reported greater social vulnerability and less access to health insurance. Hormone therapy use varied from 93% among travestis to 68% among transgender men. Industrial silicone use ranged from 70% among travestis to 30% among transgender women. Smoking prevalence was 44% among transgender men and 26% among non-binary individuals. HIV prevalence was significant (26% travestis, 21% transgender women), with anal cancer screening adherence at 19%, exceeding literature benchmarks and strongly associated with regular healthcare access (PR 1.50; 95% CI 1.05–2.14; p = 0.02), reflecting the effectiveness of integrated HIV care through the Brazilian public health system. Cancer screening adherence varied by type: cervical 49%, colorectal 7%. Consistent use of one's social name was positively associated with screening adherence, particularly for gender-specific cancers (PR 1.28; 95% CI 1.02–1.61; p = 0.035). Conclusions: Significant inequities exist in cancer prevention and screening for the transgender population, with adherence varying by cancer type, gender identity, and healthcare access. Gender-specific clinical protocols addressing distinct biological exposures (hormone therapy, silicone, smoking), professional training, and targeted public policies are fundamental to reduce disparities. This study provides novel epidemiological data on barriers and facilitators to cancer screening among transgender people in Brazil, highlighting the urgent need for structural interventions and integrated care models that address biological specificities and social determinants.
Durvalumab and oleclumab in resectable pancreatic ductal adenocarcinoma: A window of opportunity trial (DORA).
TPS4268 Background: Resectable pancreatic ductal adenocarcinoma (PDAC) comprises < 20% of cases and remains associated with poor outcomes despite surgery and adjuvant chemotherapy. PDAC features a hypoxic, immunosuppressive and “cold” tumor microenvironment (TME). CD73 has emerged as a prognostic biomarker in PDAC, with high expression linked to poor survival. CD73 on tumor cells impairs antitumor T-cell responses and results in tumor immune escape. Inhibition of CD73 could reverse immune suppression by the TME. Preliminary data from the phase I combination trial of durvalumab (anti-PD-L1 antibody) and oleclumab (anti-CD73 antibody) has shown modest antitumor activity in patients in PDAC, colon cancer, and non-small cell lung cancer. A window-of-opportunity (WOO) study allows for rapid early identification of biological activity. We therefore designed a WOO trial to assess the impact of CD73 and PD-L1 blockade in resectable PDAC to test the hypothesis that this strategy would increase CD8+ T cell infiltration and reduce suppressive immune cells as assessed by digital spatial profiling and image mass cytometry. Methods: DORA (NCT06060405) is a prospective phase II multicentre WOO trial evaluating the immune activity of combined CD73 and PD-L1 blockade in upfront resectable PDAC. Eligible patients must have ECOG 0–1, histologically confirmed NCCN resectable PDAC, and be immunotherapy-naïve. Patients undergo an upfront EUS for histological diagnosis and for correlative studies, and then receive a single dose of durvalumab 1500 mg IV and oleclumab 3000 mg IV x 2 doses every two weeks prior to surgical resection. Patients receive standard-of-care adjuvant systemic therapy following surgery. The primary objective is to determine the increase in immune cell infiltration, specifically CD8+ T cells, between the paired pre-treatment and surgical resection specimens. Secondary objectives include the percent change in other immune cell populations (CD3/CD45RA/RO T cells, M1 vs. M2 macrophage), and the dynamic changes in immune cell populations as measured by flow cytometry/CyTOF. A total of 22 patients will be enrolled to ensure 20 evaluable subjects who undergo surgical resection. With 20 patients, this provides 80% power to detect an effect size of 0.66 using a two-sided alpha of 0.05. Planned correlatives include serial ctDNA analysis and whole genome and transcriptome sequencing of all surgical resections. This study was activated in January 2024. Clinical trial information: NCT06060405 .
Tumor-naïve multimodal cfDNA MRD assay to predict recurrence in a prospective cohort of patients undergoing curative-intent lung cancer resection.
8016 Background: Tumor-informed circulating tumor DNA (ctDNA) assays can achieve high sensitivity for minimal residual disease (MRD) detection after lung cancer resection but require tumor tissue and individualized assay design, limiting scalability and timeliness in routine practice. Tumor-naïve MRD approaches offer a practical alternative for postoperative surveillance; however, their sensitivity remains constrained. Integrating complementary cfDNA features beyond somatic mutations may enhance tumor-naïve MRD detection and postoperative risk stratification. Methods: A prospective cohort of 212 patients with resectable stage I–IV lung cancer, predominantly consisting of stage I disease (146 of 212), was enrolled. Postoperative plasma samples were collected at a landmark timepoint (~1 week after surgery) and longitudinally every 3–6 months for up to 3 years. MRD was assessed using ShieldingUltra, a tumor-naïve multimodal cfDNA assay integrating somatic mutations, copy number variations (CNVs), and fragmentomic features based on ultra-deep UMI-based sequencing of an integrated panel covering >2000 cancer-related genes. MRD positivity was determined from integrated multimodal cfDNA signals. Survival outcomes were evaluated using Kaplan–Meier analysis and Cox proportional hazards models, with subgroup analyses by disease stage, histology, and postoperative adjuvant therapy. Results: At the postsurgical landmark timepoint, MRD positivity was strongly associated with an increased risk of recurrence (hazard ratio [HR], 9.72; log-rank p=2.06×10⁻⁸). Longitudinal MRD monitoring further improved risk stratification, with MRD-positive patients exhibiting a markedly higher recurrence risk (HR, 16.64; log-rank p=1.66×10⁻⁹) while maintaining high specificity (~90%). Among the 27 patients who developed radiographically confirmed recurrence, MRD was detected prior to imaging in the majority of cases (21 of 27), providing a median lead time of 264 days. The prognostic value of MRD status was consistently observed across disease stages, histologic subtypes, and postoperative adjuvant treatment strategies, with particularly robust prognostic discrimination observed in patients with stage I disease. Multivariable analyses confirmed MRD positivity as an independent predictor of recurrence in both landmark and longitudinal settings. Conclusions: Tumor-naïve multimodal MRD assessment integrating mutation, CNV, and fragmentomic cfDNA features enables sensitive and clinically informative detection of residual disease after lung cancer surgery. Early and longitudinal MRD monitoring provides robust prognostic stratification and meaningful lead time over imaging, supporting its clinical utility for postoperative surveillance in resectable lung cancer.
Phase 1/2 study of YL201, an anti-B7H3 antibody–drug conjugate (ADC), in patients with previously treated advanced pancreatic ductal adenocarcinoma (PDAC).
4208 Background: The prognosis for patients with advanced PDAC after failure of first-line therapy remains dismal with limited effective treatment options. There is a critical unmet need for novel therapeutic agents in the second-line and beyond (2L+) setting. YL201 is a B7H3-targeting ADC with promising clinical activity in multiple advanced solid tumors. Here, we report the safety and preliminary efficacy of YL201 monotherapy in patients with 2L+ PDAC from a phase 1/2 dose expansion study. Methods: Patients with metastatic PDAC who had progressed on at least one prior line of systemic therapies without irinotecan were enrolled and treated with YL201 intravenously Q3W at 2.0 mg/kg or 2.4 mg/kg until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) per RECIST v1.1. Secondary endpoints included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Results: A total of 60 patients were enrolled, including 30 treated at 2.0 mg/kg and 30 at 2.4 mg/kg. The median age was 61.0 years, 63.3% were male, and 91.7% had an ECOG PS of 1. 48.3% of patients had ≥3 metastatic sites at baseline. Patients had received a median of 1 prior line of therapy (range: 1–3). 90.0% had received prior gemcitabine-based regimen and 46.7% had received prior fluoropyrimidine. As of 12 December 2025, the median follow-up was 9.2 months (95% CI: 8.2–9.8). Among the 60 patients enrolled, the confirmed ORR was 28.3% (95% CI: 17.5–41.4) with a median DoR of 7.6 months (95% CI: 4.9–NR), and the DCR was 85.0% (95% CI: 73.4–92.9). The median PFS was 7.7 months (95% CI: 5.5–9.7), and the median OS was 14.6 months (95% CI: 8.2–NR). Membrane B7H3 expression was detected by immunohistochemistry in most tumor samples with a median H-score of 65 (range: 0–275). However, no association was observed between tumor response and B7H3 expression level in PDAC patients. Treatment-related adverse events (TRAEs) of any grade and grade ≥3 occurred in 100.0% and 43.3% of patients, respectively. The most common grade ≥3 TRAEs included leukopenia (16.7%), neutropenia (15.0%), anemia (15.0%), and hypokalemia (6.7%). The rate of treatment discontinuation due to TRAEs was 5.0%, and no treatment-related deaths were reported. Conclusions: YL201 monotherapy showed promising antitumor activity and a manageable safety profile in pretreated patients with advanced PDAC. These compelling results warrant further investigation of YL201 in a randomized controlled trial for patients with advanced PDAC in the 2L+ setting. Clinical trial information: NCT06057922 .
Double‐Transition‐Metal MXenes: Multimetallic 2D Platforms for Next‐Generation Biomedicine
ABSTRACT MXenes, a rapidly expanding family of two‐dimensional transition metal carbides, nitrides, and carbonitrides, are versatile nanomaterials with broad applications in energy, catalysis, sensing, and biomedicine. While most studies have focused on mono–transition‐metal MXenes (e.g., Ti 3 C 2 T x ), recent advances have enabled the synthesis of double‐transition‐metal (DTM) MXenes, in which two distinct transition metals occupy ordered or disordered atomic arrangements. This added compositional and structural complexity broadens property range, enabling enhanced oxidative stability, programmable degradation behavior, tunable electromagnetic responses, and improved near‐infrared optical absorption. These attributes position DTM MXenes as a compelling biomedical materials platform. In this review, we summarize the discovery, synthesis strategies, and physicochemical characteristics of DTM MXenes, with systematic comparisons to classical mono–transition‐metal MXenes to elucidate multi‐metal structure–property relationships. We then critically examine emerging biomedical applications of DTM MXenes, including photothermal cancer therapy, multimodal imaging, drug delivery, antibacterial activity, and tissue engineering, highlighting insights from both in vitro and in vivo studies. Key challenges for clinical translation, including scalable synthesis, compositional and structural control, long‐term biocompatibility, biodegradation, and regulatory considerations, are discussed. By integrating perspectives from materials science, nanotechnology, and biomedical engineering, this review outlines opportunities, limitations, and future directions toward safe, effective multifunctional DTM MXene nanomedicine platforms.
Triply‐Twinned Metamaterials: Unraveling the Mechanics and Failure Pathways Through High‐Resolution XCT
ABSTRACT We designed and engineered a novel class of triply‐twinned Body‐Centred Cubic (BCCT) lattices that achieved up to three‐fold improvements in mechanical performance over conventional BCC lattice architecture. Inefficient strut deformation and defect‐sensitive failure limit the performance and reliability of architected metamaterials. Triply‐twinned meta‐crystal architectures transform the dominant strut‐scale deformation from bending to stretching in both polymeric (Rigid 4K) and metallic (Ti‐6Al‐4V) Additively Manufactured (AM) BCCT lattices, significantly enhancing their stiffness (+380%) and strength (+279%). Using high‐resolution synchrotron X‐ray computed tomography, image‐based finite element models, scanning electron microscopy, and pyrometry, we correlate fracture mechanisms to the architecture design and as‐built defects in these AM lattices. We further reduce defect‐driven fracture by 50% without altering the global failure mode by adjusting the build orientation of the lattices. This integrated, multi‐scale approach links fundamental deformation mechanics to manufacturability, providing a broadly applicable design strategy for next‐generation architected metamaterials with exceptional performance and reliability.
Real-world outcomes of biomarker-guided multidisciplinary management in localized and metastatic gastric cancer.
e16060 Background: Gastric cancer (GC) is a biologically heterogeneous disease with limited prognosis, particularly in advanced stages. In routine clinical practice, treatment decisions are commonly discussed within multidisciplinary teams (MDTs) integrating clinical, pathological, and molecular information. However, real-world data describing outcomes of patients managed through standard MDT discussions across different disease settings remain limited. Methods: We retrospectively evaluated 172 consecutive patients with gastric or gastroesophageal junction adenocarcinoma (96 localized/neoadjuvant, 76 metastatic) discussed within the institution’s standard weekly MDT for gastric cancer between January 2018 and December 2024. Data were collected retrospectively from institutional databases and medical records; MDT evaluation included tumor stage, ECOG performance status, comorbidities, and molecular profiling (HER2, PD-L1 combined positive score [CPS], microsatellite instability [MSI]). Neoadjuvant treatment consisted of platinum–fluoropyrimidine–based chemotherapy with or without docetaxel (FOLFOX or FLOT), followed by surgery when feasible. In metastatic disease, treatment selection included chemotherapy alone or combined with targeted therapy or immunotherapy according to molecular status. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), R0 resection rate, and treatment allocation. Results: Median age was 70 years (range 50–85); 59% were male. ECOG PS was 0–1 in 68% and PS 2 in 32% of patients. Molecular alterations included HER2 positivity in 18%, PD-L1 CPS ≥5 in 44%, and MSI-high status in 9%. In the localized/neoadjuvant cohort, MDT-guided management was associated with an R0 resection rate of 76%, median PFS of 14.5 months, and median OS not reached after a median follow-up of 32 months. In metastatic patients, MDT-guided treatment selection was associated with a median PFS of 7.2 months and median OS of 15.2 months, compared with 10.4 months in patients treated prior to routine MDT implementation. Objective response rate was 48% and disease control rate 68%. Grade ≥3 adverse events occurred in 24% of patients, mainly hematologic; no unexpected toxicities were observed. On multivariate analysis, MDT discussion was associated with improved OS (HR 0.66, 95% CI 0.50–0.87). Conclusions: In this real-world experience, systematic discussion within a standard weekly MDT integrating molecular profiling was associated with optimized treatment allocation and favorable clinical outcomes in both localized and metastatic GC. These findings support the role of a structured multidisciplinary discussion in routine clinical practice.
Olverembatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: Meta-analysis of efficacy and safety outcomes.
e18503 Background: Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is an aggressive B-cell malignancy with substantial relapse risk despite tyrosine kinase inhibitors (TKIs). Olverembatinib is a third-generation TKI with promising activity in CML and Ph+ ALL, particularly in T3151-mutated disease. We hereby report results of a meta-analysis evaluating the safety and efficacy of Olverembatinib. Methods: This is a meta-analysis aimed to systematically evaluate the efficacy outcomes (response rates) and safety profile of Olverembatinib in adolescent and adult patients with Ph+ ALL, integrating evidence from interventional trials and observational studies. A systematic literature search was conducted from database inception through October 2025 across PubMed, Scopus, Web of Science, and Cochrane Library to identify eligible studies (inclusion criteria: human subjects with Ph+ ALL; exclusion criteria: preclinical, single-case, non-English, and review studies). Proportions for objective response rate (ORR), complete response (CR), partial response (PR), minimal residual disease (MRD) negativity, and adverse events (AEs) were stabilized using Freeman-Tukey double arcsine transformation and pooled with inverse variance weighting. Between-study heterogeneity was estimated with DerSimonian-Laird method for τ 2 , with confidence intervals for τ 2 and τ derived via Jackson approach. Multiple meta-regression was utilized to assess moderator variables. Results: Fourteen studies were included; 7 clinical trials and 7 observational studies. Data from 253 patients were used for the efficacy analysis, and 320 were used for the safety analysis. Random-effects pooled estimates: ORR = 99.0% (95% CI: 94.0–100.0); CR = 96.0% (95% CI: 89.0–100.0); PR = 3.0% (95% CI: 0.0-15.0); MRD negativity at 1 month = 84.0% (95% CI: 59.0–99.0); complete molecular response (CMR) at 3 months = 84.0% (95% CI: 67.0–96.0). Meta-regression showed that median age significantly moderated ORR (p = 0.001), whereas study design and publication year did not (p > 0.05). Safety outcomes included any AE = 79.0% (95% CI: 64.0–91.0), severe AE = 34.0% (95% CI: 19.0–51.0), grade ≥3 neutropenia = 25.0% (95% CI: 6.0–49.0), and grade ≥3 infection = 14.0% (95% CI: 6.0–23.0), and discontinuation = 0.60% [95% CI: 0.00-2.90]. Conclusions: Olverembatinib achieved very high remission rates and molecular responses in Ph+ ALL, with MRD and CMR endpoints indicating rapid and durable disease control. Despite frequent hematologic and infectious toxicities, treatment discontinuation was rare, supporting a manageable safety profile.
Beyond translation: Leveraging interpreter expertise to enhance clinician training and language equity in pediatric oncology.
10025 Background: Medical interpreters play a critical role in pediatric oncology beyond translation by guiding conversations, interpreting cultural and emotional cues, and ensuring families with limited English proficiency (LEP) can access medical information. Yet few clinician training resources focus on interpreter-mediated communication. This study aimed to (1) identify communication best practices and challenges from the perspective of professional medical interpreters and (2) develop an educational toolkit for clinicians to promote equitable, patient-centered communication for families with LEP. Methods: We conducted semi-structured individual interviews and a focus group with Spanish medical interpreters from six freestanding children’s hospitals across the United States between 12/2024-10/2025. Verbatim transcripts were thematically analyzed in Dedoose, and resulting themes directly informed creation of an educational toolkit. Results: Sixteen interpreters (15 female, 1 male) who provide in-person interpretation participated. Benefits of in-person professional interpretation included perceiving non-verbal communication cues, serving as patient/family advocates, providing cultural and linguistic tailoring, explaining idiomatic or metaphorical clinical language, and continuity of interpreters across visits. Challenges included fragmented communication across medical teams, limited clinician understanding of cultural nuance, exclusion of parents from conversations, and remote interpreting. Based on these themes, we developed recommendations for clinicians focused on building collaborative relationships with interpreters, allowing time for interpretation, and actively checking patient and family understanding. We then designed a toolkit comprising three resources for clinicians working with interpreters: a badge reference card with a pre-, during-, and post-visit checklist; a decision-making learning module with case-based, first-person scenarios navigating interpreter-mediated encounters; and a self-paced modular course with structured lessons for in-depth learning. Conclusions: Interpreters identified concrete practices that enhance patient-centered care, with particular strengths evident during in-person interpretation, and challenges that undermine equitable communication. These insights informed a clinician-facing educational toolkit to improve interpreter-clinician encounters. Future studies will pilot the toolkit with ongoing, iterative refinement guided by interpreter input.
Efficacy and tolerability of duvelisib in relapsed/refractory peripheral T-cell lymphoma: A multicenter real-world analysis.
7067 Background: Relapsed/refractory (R/R) peripheral T-cell lymphomas (PTCL) are a rare group of non-Hodgkin lymphomas with median survival at relapse of 6-10 months and few treatment options. Duvelisib is a g/∆ phosphatidylinositol 3-kinase inhibitor approved in CLL and NCCN compendium listed in PTCL. In indolent lymphomas, concerns for cumulative duvelisib toxicity limit its use. In contrast, studies in R/R PTCL show duvelisib to be well-tolerated. Therefore, we sought to assess the efficacy and tolerability of duvelisib in a real world setting in R/R PTCL. Methods: We conducted a retrospective analysis of patients with R/R PTCL treated with duvelisib from 2012-2025 at 12 centers. Results: We identified 207 patients with PTCL: nodal PTCL with TFH phenotype (n=106, 51%), PTCL-NOS (n=78, 38%), ALCL (n=16, 8%), enteropathy associated T-cell lymphoma (n=4, 2%), NK/T-cell lymphoma (n=2, 1%), adult T-cell leukemia/lymphoma (n=1, 0.5%). 90 patients (43%) were female. Median age was 64; median International Prognostic Index score 3. Median prior lines of therapy was 2 (range 1-9). 26% received frontline transplant (23% auto, 3% allo). 118 patients received single agent duvelisib; 89 patients received duvelisib in combination with other agents (66 romidepsin, 12 bortezomib, 4 azacitadine, 3 ruxolitinib, 4 other). Of patients with response data, ORR was 51% (94/186; 31% CR, 17% PR) with median OS 12 months. ORR in patients with TFH-phenotype vs. non-TFH phenotype was 60% and 41% respectively. ORR in patients treated with single agent duvelisib and duvelisib combinations was 46% (46/99; 29% CR, 17% PR) and 55% (48/87; 39% CR, 16% PR), respectively with no difference in OS. Median duration of therapy was 84 days; the most common reason for discontinuation was progression (41%, 76/186). 13% (25/196) underwent allo-SCT after duvelisib therapy. Toxicity data is summarized in our table. In patients receiving single agent duvelisib therapy, rates of cytopenia were lower (7% vs. 34%, p<0.001) and rates of colitis were higher (17% vs. 7%, p= 0.03). Conclusions: In this real world, multicenter analysis of patients with R/R PTCL treated with duvelisib-based regimens, the ORR of 51% was consistent with published trials. Duvelisib therapy was well tolerated and a minority required hospitalization for toxicity. This suggests that duvelisib is safe in patients with R/R PTCL who have poor prognosis and limited treatment options. Adverse Event Full Cohortn (%)n=207 Single agent n (%)n=118 Combination therapyn (%)n=89 Single vs. Combination p value SteroidGivenn (% full cohort) Hospitalizationn (% full cohort) Rash 41 (20%) 24 (20%) 17 (19%) 0.83 23 (11%) 6 (3%) Colitis 26 (13%) 20 (17%) 6 (7%) 0.03 20 (10%) 16 (8%) Pneumonitis 7 (3%) 4 (3%) 3 (3%) 0.99 5 (2%) 3 (1%) Cytopenia 38(18%) 8 (7%) 30 (34%) <0.001 * * Transaminitis 33 (16%) 21 (18%) 12 (13%) 0.40 * * Infection 66 (32%) 36 (31%) 30 (34%) 0.63 N/A 42 (20%) *Not available.
Epstein-Barr virus reactivation and post-transplant lymphoproliferative disorder following letermovir prophylaxis in allogeneic hematopoietic stem cell transplant recipients: A systematic review and meta-analysis.
e18569 Background: Letermovir is a cytomegalovirus (CMV) terminase complex inhibitor that significantly reduces clinically significant CMV infection following allogeneic hematopoietic stem cell transplant (allo-HSCT). Recently, several studies have suggested that letermovir prophylaxis may delay immune reconstitution, potentially increasing the risk of Epstein-Barr virus (EBV) viremia and post-transplant lymphoproliferative disorder (PTLD), although consistency of this association remain unclear. We conducted a systematic review and meta-analysis to evaluate the incidence of EBV viremia, EBV-associated diseases, and PTLD in allo-HSCT recipients receiving letermovir prophylaxis. Methods: We systematically searched PubMed, Embase, and Cochrane Central Register of Controlled Trials from inception to December 2025 with the following eligibility criteria: (1) randomized or non-randomized trials; (2) adult patients with hematological malignancies treated with allo-HSCT; (3) comparing letermovir use versus no letermovir use; and (4) reporting at least one of the clinical outcomes of interest. The primary outcomes included: (1) incidence of EBV viremia; (2) EBV disease; and (3) PTLD. A random-effects model using restricted maximum likelihood estimation was applied, with effect sizes calculated using the Mantel-Haenszel method. This review adheres to the recommendations from the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement guidelines. Results: One randomized controlled trial and 12 retrospective cohort studies were included, comprising a total of 4,230 patients (1,903 receiving letermovir and 2,327 not receiving letermovir). In those receiving prophylactic letermovir, compared to those who did not, we found a significant association with higher incidence of PTLD (6.14% vs 2.31%; risk ratio [RR] 2.34; 95% CI 1.62 to 3.38; p <0.001). No statistically significant differences were observed in the incidence of EBV viremia (27.7% vs 24.3%; RR 1.29; 95% CI 0.98 to 1.70; p = 0.071) or EBV-associated diseases (8.6% vs 7.9%; RR 1.08; 95% CI 0.63 to 1.83; p = 0.783). Meta-regression analyses demonstrated a significant positive association between the proportion of umbilical cord blood transplantation and the risk of EBV viremia, whereas no significant associations were observed for the proportions of haploidentical donors or unrelated donors. Conclusions: Letermovir prophylaxis in allo-HSCT recipients is associated with higher incidence of PTLD, while no significant differences were observed in EBV viremia and EBV-associated diseases. Continued clinical vigilance is warranted in patients receiving letermovir prophylaxis, and prospective studies are needed to further clarify this association.
Tumor-informed molecular monitoring using patient-specific PCR assays and oncologist decision-support software.
e15082 Background: Tumor-informed molecular monitoring leveraging patient specific somatic mutations enables highly sensitive assessment of treatment response and detection of measurable residual disease. This approach has the potential to identify disease progression earlier than conventional clinical or radiographic methods. In this study, we evaluated an integrated workflow combining comprehensive genomic profiling with customized polymerase chain reaction (PCR) based assays to enable longitudinal detection of molecular progression across various cancers such as hematologic malignancies and diffuse glioma. Methods: Diagnostic tumor samples from 63 patients underwent targeted NGS profiling to identify patient specific somatic variants. Based on these results, custom digital and quantitative PCR assays were designed and developed in house to track selected variants, including MYD88 L265P in Waldenström macroglobulinemia; DNMT3A R882 and IDH2 R140Q in AML; and IDH1 R132 in diffuse glioma, in plasma samples. Molecular progression was defined as a sustained or increasing variant allele frequency above assay specific detection thresholds. Clinical progression was defined by radiographic, hematologic, or treatment triggering criteria. Lead time between molecular and clinical progression was calculated, and time to progression was assessed using Kaplan Meier and Cox proportional hazards models. Moreover, our decision support software was utilized to assist oncologists in guiding individualized treatment plans. Results: At least one trackable variant was identified in 58 of 63 patients (92%). During a median follow up of 20 to 24 months, molecular progression occurred in 26 patients (41%), with 18 (69% of those with molecular progression) detected prior to clinical relapse. Median molecular lead time was 9 weeks for AML, 13 weeks for diffuse glioma, and 17 weeks for Waldenström macroglobulinemia. Molecular positivity was associated with an increased risk of subsequent clinical progression (HR 3.8; 95% CI 1.9–7.3; p < 0.001). Conclusions: Our personalized PCR assays enable rapid, reliable, and highly sensitive detection of measurable residual disease across multiple malignancies. Molecular progression was identified weeks in advance of clinical relapse in a disease dependent manner, demonstrating the ability of liquid biopsy monitoring to anticipate overt progression. Compared with broad sequencing approaches, this targeted strategy offers advantages in turnaround time, cost efficiency, and analytical robustness, supporting its feasibility for scalable clinical implementation and its potential to inform earlier risk stratification and personalized therapeutic intervention.
Specialist referral patterns and relationship to outcomes in patients with hepatocellular carcinoma.
e16242 Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the third leading cause of cancer-related mortality, with a 5-year survival rate of approximately 20%. Management includes an interdisciplinary approach, involving medical oncologists, gastroenterologists, radiation oncologists, and surgeons. Early recognition and referral to a multi-disciplinary team is proven to improve survival rates. However, it is unclear if a first referral to and primary management by a particular subspecialist is associated with better or worse clinical outcomes. Methods: A retrospective study of patients aged > 18 years with HCC diagnosed at Sidney Kimmel Comprehensive Cancer Center (Greater Philadelphia Area) in 2021-2024 was conducted. Data on patient and tumor characteristics at the time of diagnosis, transplant and treatment eligibility were collected for analysis. Survival was monitored at annual intervals starting from one year to five years after diagnosis, or as time to first event from diagnosis. Patients were divided into subgroups depending on the first specialist seen. Results: Data from 433 patients (78% male, mean age at diagnosis: 65.5 years) were included. Thirty-eight percent had stage 3 or 4 disease. The majority had Class 0 (32.2%) or A (34.5%) disease per BCLC, while a smaller proportion had advanced disease of Class B (17.8%), C (10.9%), and D (4.6%). Most commonly seen first specialist was gastroenterologist (61%), followed by medical oncologist (15%), interventional radiologist (IR) (8.7%), surgeon (6.2%), and multidisciplinary teams (3.5%). Most common initial treatments were locoregional (58%), surgery (15.5%), systemic treatment (13%), transplant (4.5%), while 5.5% were not treatment eligible. The mean survival time for patients who followed up first with medical oncologist was 28.9 months (95% CI: 13-36 months), while for IR, surgeon, and gastroenterologist, it was 51.8 months (95% CI: 47-82 months), 48.1 months (95% CI: 46-56 months), and 46.0 months (95% CI: 44-54 months), respectively (p < 0.005). These differences disappeared after adjusting for BCLC staging. Importantly, medical oncologists saw patients with more advanced stages (32%) compared to other specialists (vs 8% surgery, vs 23% IR, vs 10% gastroenterologist). Conclusions: This analysis demonstrates differences in survival rates depending on the first specialist seen by patients with HCC. Patients seen first by a medical oncologist tended to have a more advanced stage of disease compared to individuals seen by gastroenterologists, interventional radiologists, or surgeons. This difference may, however, also reflect suboptimal utilization of multidisciplinary care and warrants further investigation.
Phase 1b/2 study of pembrolizumab plus lenvatinib or pembrolizumab coformulated with vibostolimab in participants (pts) with metastatic neuroendocrine prostate cancer (NEPC): KEYNOTE-365 cohorts F and H.
5055 Background: Effective therapy for NEPC is an unmet need due to poor prognosis and no established standard of care. The phase 1b/2 KEYNOTE-365 study (NCT02861573) evaluated the efficacy and safety of pembrolizumab (pembro) + lenvatinib (lenva; cohort F) or coformulated pembro/vibostolimab (vibo; cohort H) in pts with NEPC. Methods: Pts with pathologically confirmed treatment-emergent neuroendocrine (t-NE) or de novo metastatic NEPC (small cell carcinoma, large cell neuroendocrine carcinoma, or mixed morphology per central review), progression ≤6 mo before screening, and an ECOG PS of 0 or 1 were enrolled. Prior androgen deprivation therapy for metastatic disease was required for pts with t-NE. Prior chemotherapy regimens (≤2) for metastatic castration-resistant prostate cancer and second-generation hormonal agents (≤2) were permitted. Pts in cohort F received pembro 200 mg IV Q3W + lenva 20 mg PO QD. Pts in cohort H received pembro/vibo 200 mg/200 mg IV Q3W. Pembro or pembro/vibo were given for ≤35 cycles; lenva was given until discontinuation criteria were met. Primary end points were safety, ORR per RECIST v1.1 by blinded independent central review (BICR), and confirmed prostate-specific antigen (PSA) response rate (≥50% decrease from baseline measured twice ≥3 weeks apart). Secondary end points included ORR, time to PSA progression, radiographic PFS (rPFS) per Prostate Cancer Working Group 3 (PCWG3)–modified RECIST (mRECIST) v1.1 by BICR, DOR and DCR per RECIST v1.1 by BICR, and OS. Results: As of August 25, 2025, 14 and 20 pts received ≥1 dose of study treatment in cohort F or cohort H, respectively. Median follow-up was 25.6 mo (range, 22.9-35.1) and 31.4 mo (range, 23.2-45.9), respectively. Among pts with RECIST-measurable disease, confirmed ORR was 23.1% (3/13; 95% CI, 5.0-53.8) in cohort F and 12.5% (2/16; 95% CI, 1.6-38.3) in cohort H. Additional efficacy results are shown in the table. Treatment-related adverse events (TRAEs) occurred in 85.7% of pts in cohort F (64.3% grade 3 or 4) and 55.0% of pts in cohort H (25.0% grade 3 or 4). No grade 5 TRAEs occurred in either cohort. In cohorts F and H, TRAEs resulted in treatment discontinuation in 21.4% and 10.0% of pts, respectively, and immune-mediated AEs occurred in 35.7% and 15.0%. Conclusions: Pembro + lenva or pembro/vibo had a manageable safety profile and only modest antitumor activity in pts with NEPC. Clinical trial information: NCT02861573 . Cohort Fn = 14 Cohort Hn = 20 PSA response rate (95% CI), % 14.3 (1.8-42.8) 10.0 (1.2-31.7) Median time to PSA progression (95% CI), mo NR (NR-NR) NR (2.9-NR) ORR per mRECIST v1.1 (95% CI), % 15.4 (1.9-45.4) 12.5 (1.6-38.3) DCR per RECIST v1.1 (95% CI), % 23.1 (5.0-53.8) 12.5 (1.6-38.3) Median DOR per RECIST 1.1 (95% CI), mo NR (1.1-NR) NR (8.3-NR) Median rPFS per mRECIST v1.1 (95% CI), mo 3.9 (2.1-NR) 2.0 (1.6-4.3) Median OS (95% CI), mo 4.3 (2.8-NR) 7.0 (2.5-12.9)
Comparative efficacy and safety of novel agents versus standard chemotherapy in first-line (1L) locally advanced or metastatic triple-negative breast cancer (TNBC): A systematic review and network meta-analyses.
e13124 Background: Survival outcomes for patients with advanced TNBC remain poor. Several novel agents, including antibody–drug conjugates (ADC), immunotherapy, and targeted therapies, have demonstrated activity in 1L locally advanced or metastatic TNBC. We conducted a network meta-analysis to evaluate comparative efficacy and safety of novel agents against SC. Methods: MEDLINE, EMBASE, and SCOPUS were searched for phase II/III randomized trials comparing novel agents with SC in 1L locally advanced or metastatic TNBC through January 21, 2026. Outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and any-grade adverse events (AEs). Frequentist network meta-analysis was performed for time-to-event outcomes. Due to a star-shaped network, heterogeneity could not be reliably estimated. Pairwise random-effects meta-analyses were performed for ORR and safety. All analyses were performed using R (version 2026.01.0 ) employing netmeta and metabin packages. Results: Of 1,673 records identified, six trials comprising 2,409 patients met inclusion criteria.When compared with SC, Datopotamab deruxtecan (Dato-DXd) demonstrated largest relative effect size (P-score 0.80), followed by ipatasertib + SC (0.67), sacituzumab (0.64), atezolizumab + SC (0.54), and capivasertib + SC (0.35); hazard rations are summarised in table1. However, rankings should be interpreted as exploratory given star shaped network. None of the novel agents demonstrated a statistically significant OS benefit compared with SC (Table 01). No statistically significant difference was observed for ORR for novel agents compared to SC (OR 1.0; 95% CI 0.19-5.10). For safety outcomes, all novel agents were associated with higher odds of any-grade AE compared with SC (OR 2.49; 95% CI 1.93-3.21). Conclusions: For our analysis, Dato-DXd demonstrated the most consistent efficacy signal, particularly for PFS. However, no novel strategy showed a statistically significant OS benefit, and ORR effects were highly heterogeneous. While ADC-based and targeted approaches show promising activity, current evidence remains exploratory, and longer follow-up and direct comparative trials are needed to guide optimal treatment selection. Notably, most trials included in this analysis reported improved outcomes in specific biomarker-defined subpopulations, which may not be fully captured in overall population estimates. Treatment Arm (Ref: SC) HR for PFS (95% CI) HR for OS (95% CI) Dato-DXd 0.57 (0.47-0.69) 0.79 (0.49-1.28) Sacituzumab 0.64 (0.52-0.79) Not mature Capivasertib + SC 0.72 (0.62-0.84) 0.8 (0.44-1.17) Ipatasertib + SC 0.60 (0.37-0.98) 0.8 (0.42-1.52) Atezo + SC 0.66 (0.43-1.01) 0.60 (0.31-1.14)
Defining APOBEC-like signature in diffuse large B-cell lymphoma and demonstration of distinct transcriptomic profile.
7075 Background: APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) mutational signatures are uncommon in hematologic malignancies compared with solid tumors. This signature is characterized by C>T and C>G substitutions and clustered chromosomal abnormalities and is typically defined using whole-genome or whole-exome sequencing. Data on APOBEC signatures detected by targeted gene panels are limited. We interrogated a database of diffuse large B-cell lymphoma (DLBCL) cases sequenced between 2023 and 2025 using a targeted panel. Cases with >30 mutations were classified as “APOBEC-like,” and their molecular and expression features were analyzed. Methods: DNA and RNA were extracted from FFPE samples and sequenced by next-generation sequencing. DNA sequencing used a 302-gene panel and RNA sequencing a 1,600-gene panel. Hybrid-capture libraries were sequenced on an Illumina NovaSeq 6000. Results: Among 670 DLBCL cases, 39 (6%) demonstrated an APOBEC-like signature. A striking feature was the presence of multiple mutations within the same gene. One case harbored 20 distinct SOCS1 mutations, and 20 of 39 cases (51%) had at least one gene with ≥10 mutations. Cell of origin was germinal center B-cell in 21 cases (54%). All APOBEC-like cases showed numerous chromosomal abnormalities, most commonly 6q deletion/monosomy 6 (23 cases, 59%). Deletion of 17p was rare (2 cases). TP53 mutations were detected in 12 cases (31%), PIM1 in 23 (58%), and SOCS1 in 18 (46%). Gene expression profiling revealed significant differences between APOBEC-like and average DLBCL cases. TRAF3, TRAF5, and TRAF2 expression was significantly lower in APOBEC-like cases (log10 FDR < −12), while NAMPT, PRPF8, SF3A1, NFYC, LUC7L2-MCM3AP, and SMAD5 were significantly overexpressed (log10 FDR < −7). Despite the limited cohort size, random forest modeling demonstrated that expression profiling could distinguish APOBEC-like cases, with 20 genes achieving an AUC of 0.904 in a testing set. Conclusions: APOBEC-like mutational signatures can be identified in approximately 6% of DLBCL cases using targeted gene panels and are characterized by extreme intragenic hypermutation, recurrent chromosomal abnormalities, and a distinct expression profile that enables accurate classification by machine-learning approaches.
A phase 1b/2 study of mirdametinib in combination with sirolimus for patients with RAS-mutated relapsed/refractory multiple myeloma.
TPS7582 Background: Relapsed and refractory multiple myeloma (RRMM) remains a significant therapeutic challenge, particularly among patients with genomic alterations in the RAS pathway (KRAS/NRAS mutations). These mutations occur in 60-70% of RRMM and are associated with aggressive disease and poor outcomes. Preclinical evidence suggests that dual inhibition of MEK and mTOR is required to effectively suppress oncogenic signaling in RAS dependent MM. This study evaluates the combination of the MEK inhibitor mirdametinib and the mTOR inhibitor sirolimus in patients with RAS-mutated RRMM. Methods: This is an open-label, single center, Phase 1b/2 study in adults with RRMM who are penta-class exposed and have no remaining standard therapeutic options. Patients must have RAS dependent MM as evidenced by a KRAS or NRAS mutation. Patients will be screened for these mutations at the NIH clinical center if unknown prior to referral. The phase 1b portion uses a standard 3+3 dose-escalation design to determine the recommended phase 2 dose (RP2D) of mirdametinib in combination with sirolimus. Phase 2 is a dose-expansion cohort using a Simon two-stage design to evaluate preliminary efficacy at the RP2D by overall response rate per the IMWG. Key eligibility criteria include adults aged ≥18 years with relapsed or refractory multiple myeloma per IMWG criteria, documented KRAS or NRAS mutation, prior exposure to a proteasome inhibitor, immunomodulatory agent, and anti-CD38 monoclonal antibody, ECOG performance status 0–2, and adequate organ function. Correlative studies include serial assessment of MAPK and mTOR pathway inhibition and pharmacodynamic biomarkers in peripheral blood and bone marrow samples. The study is actively enrolling at the NIH Clinical Center (NCT06876142), with a planned total enrollment of 54 patients. Clinical trial information: NCT06876142 .
Cardiovascular toxicity across epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in <i>EGFR</i> -mutated non–small cell lung cancer: A population-based retrospective cohort study.
12155 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the therapeutic backbone for EGFR -mutated non-small cell lung cancer (NSCLC) and often requiring prolonged exposure. Adverse cardiovascular events limit a long-term treatment and remain a major concern for cancer survivors. Osimertinib, the 3 rd generation EGFR TKI, was associated with cardiac dysfunction. Although Osimertinib is a preferred first-line option, many countries still use first- or second-generation EGFR TKIs upfront; therefore, robust studies are needed to define cardiotoxicity across these earlier-generation EGFR TKIs. Methods: In this retrospective cohort study using a nationwide Health Insurance Claim Database in Korea, patients newly diagnosed with NSCLC between 2010 and 2023 were identified. Patients were classified into three groups: first-generation (1G) EGFR TKIs (gefitinib or erlotinib), second-generation (2G) TKIs (afatinib or dacomitinib), and third-generation (3G) TKI sequence (initial first- or second-generation TKI followed by a switched to osimertinib). The incidence of cardiovascular disease (CVD) during treatment period was compared between groups. CVD included ischemic heart disease, heart failure, atrial tachyarrhythmias, and stroke. For patients with pre-existing CVD, only new-onset CVD were counted as events. Follow-up was completed December 31, 2024. Results: Among the 51,218 patients (58,317 [51%] female; mean [SD] age, 65.5 [10.8] years), 36,335 (70.9%), 8173 (16.0%), 6710 (13.1%) were treated with 1G, 2G and 3G EGFR TKI respectively. Among all patients, 16.7% were receiving medication for diabetes, 52.7% for hypertension, and 19.8% for dyslipidemia. Before lung cancer diagnosis, 1.1% had coronary artery disease and 2.7% had heart failure. In patients treated with 1G EGFR TKIs, the cumulative incidence of CVD at 1, 2, 3, and 5 years was 4.8%, 8.1%, 11.2%, and 16.2%, respectively. In those treated with 2G EGFR TKIs, the corresponding cumulative incidence was 4.2%, 7.0%, 9.4%, and 12.3%. In the group of 3G TKI sequence, the cumulative incidence of CVD at 1, 2, 3, and 5 years was 2.9%, 6.1%, 8.9%, and 14.8%, respectively. There was no statistically significant long-term difference in CVD incidence between the 1G TKI and the 3G TKI group (p = .245). Conclusions: The long-term risk of CVD associated with sustained treatment with 1G EGFR TKIs appears comparable to the risk observed among patients who started with 1G or 2G and switched to 3G EGFR TKI sequence. As long-term survivors with EGFR mutant NSCLC increases in number, ongoing surveillance for cardiotoxicity and proactive risk mitigation are essential.
Racial and payer-based disparities in inpatient resource utilization and mortality among patients hospitalized with head and neck cancer in the United States, 2018 to 2022.
11099 Background: Inpatient hospitalizations for head and neck cancer (HNC) reflect advanced disease, treatment-related complications, and high healthcare utilization. National data on racial and payer-based disparities in inpatient length of stay (LOS), costs, and mortality remain limited. Methods: A survey-weighted cohort analysis of the Healthcare Cost and Utilization Project National Inpatient Sample (NIS), 2018 to 2022, was performed. Hospitalizations with a principal diagnosis of HNC were identified using ICD-10-CM codes C00 to C06, C07 to C08, C09 to C14, C30 to C32, and C76.0; thyroid cancer (C73) was excluded. Outcomes included in-hospital mortality, LOS, and hospitalization cost. Survey-weighted mean LOS and cost were estimated by race and primary payer. A survey-weighted multivariable logistic regression evaluated predictors of in-hospital mortality, adjusting for age, sex, year, anatomic subsite, race, payer, ZIP-code income quartile, elective admission status, and hospital teaching and location characteristics. Results: The weighted national estimate included 166,020 inpatient HNC hospitalizations (95% CI 158,702 to 173,338). Mean LOS ranged from 7.43 days among White patients (95% CI 7.29 to 7.56) to 10.21 days among Black patients (95% CI 9.81 to 10.60), with intermediate LOS among Hispanic (9.22 days), Asian or Pacific Islander (8.41 days), Native American (8.86 days), and Other race groups (8.25 days). Mean hospitalization costs were highest among Asian or Pacific Islander patients ($46,577, 95% CI $41,648 to $51,506) and Hispanic patients ($42,384, 95% CI $39,129 to $45,640), compared with White patients ($36,887, 95% CI $35,197 to $38,577). Medicaid hospitalizations had the longest LOS (10.58 days, 95% CI 10.16 to 10.99) and high costs ($42,217, 95% CI $40,126 to $44,308), whereas privately insured hospitalizations had the shortest LOS (6.54 days, 95% CI 6.37 to 6.72). In adjusted analyses, mortality increased with age (OR 1.02 per year, 95% CI 1.01 to 1.03). Asian or Pacific Islander (OR 1.51, 95% CI 1.07 to 2.13) and Other race patients (OR 1.59, 95% CI 1.09 to 2.32) had higher mortality than White patients. Non-Medicare other insurance was associated with higher mortality than Medicare (OR 2.56, 95% CI 1.89 to 3.46). Elective admissions (OR 0.21, 95% CI 0.16 to 0.27) and care at urban teaching hospitals (OR 0.34, 95% CI 0.25 to 0.47) were associated with lower mortality. Conclusions: Racial and payer-based disparities persist in inpatient LOS, costs, and mortality among patients hospitalized with HNC. Black and Medicaid-insured patients experience longer hospitalizations, while Asian or Pacific Islander and Hispanic patients incur higher costs. Persistent mortality differences after adjustment highlight structural and health-system contributors and support targeted equity-focused interventions.