Sharma, Ashish

Atezolizumab-bevacizumab and durvalumab-tremelimumab have established immunotherapy as a first-line standard of care in advanced hepatocellular carcinoma (HCC). Yet, objective response rates (ORRs) remain confined to approximately 15-20%, and no validated predictive biomarker exists for patient selection. Unlike melanoma and lung cancer, conventional markers, including programmed death-ligand 1, microsatellite instability-high status, and tumor mutational burden, have not demonstrated reliable predictive value in HCC. Prior narrative reviews comprehensively catalogued the biomarker landscape through 2022 but predate a wave of clinically significant publications. This narrative review synthesizes evidence published between 2020 and 2026, with particular emphasis on 2023–2026 data, within a unified clinical framework not provided by prior reviews. We critically evaluate tissue-based biomarkers, including the AI-derived Atezolizumab-Bevacizumab Response Signature-Pathology model, spatial multiplex immunohistochemistry, and β-catenin mutational profiling; blood-based biomarkers encompassing circulating tumor DNA for minimal residual disease detection and peripheral immune phenotyping; and serum indices including the CRAFITY score and neutrophil-to-lymphocyte ratio. Hepatitis B virus etiology and non-alcoholic steatohepatitis are discussed as biological modifiers of biomarker performance. We propose an original biomarker-guided clinical algorithm, a comparative clinical readiness table, and a disease-continuum biomarker timeline as practical tools for clinicians and trialists. Prospective biomarker-enrichment trials represent the most critical next step toward clinical translation.

Background Circulating tumor DNA (ctDNA) has rapidly evolved from a research tool to a clinically applicable biomarker in colorectal cancer (CRC), transforming the assessment of minimal residual disease (MRD) and recurrence risk. The growing availability of commercial assays has complicated test selection and interpretation, particularly for gastroenterologists who increasingly encounter ctDNA data in postoperative and surveillance settings. Methods We conducted a narrative review of the literature using PubMed, Embase, and Cochrane databases from January 2015 through March 2026, prioritizing randomized controlled trials, prospective cohort studies, and clinical practice guidelines relevant to ctDNA applications in CRC. The search employed predefined keyword combinations applied independently to each database. Two authors (A.S. and S.M.) independently screened titles and abstracts against the prespecified inclusion criteria, with disagreements resolved by discussion. Results Tumor-informed assays that analyze patient-specific mutations exhibit high specificity for MRD detection, with serial sampling sensitivity reaching 88% compared to 59% for tumor-agnostic approaches, based on a 2026 systematic review and diagnostic accuracy meta-analysis that pooled data across multiple platforms and settings; the authors note substantial study-level heterogeneity in platform design and patient populations, and results should be interpreted accordingly, but require tissue access and extended processing times. Tumor-agnostic tests are more rapid and accessible, incorporating genomic and epigenomic signals, though they exhibit site-specific sensitivity variations ranging from 100% for liver metastases to 40% for peritoneal recurrence and remain vulnerable to biological confounders such as clonal hematopoiesis (CH). Importantly, ctDNA interpretation is subject to additional biological limitations including tumor shedding variability by anatomical site and disease burden, the timing of sample collection relative to surgery or chemotherapy, platform-specific detection thresholds, and pre-analytical variables such as hemolysis and delayed plasma processing. Randomized evidence supports ctDNA-guided de-escalation of adjuvant therapy in stage II colon cancer, with 5-year follow-up from the DYNAMIC trial demonstrating comparable recurrence-free survival (88% vs. 87%) and overall survival (93.8% vs. 93.3%) despite reduced chemotherapy use. In stage III disease, ctDNA is strongly prognostic, but chemotherapy intensification based solely on molecular positivity has not improved outcomes. This review additionally addresses underexplored areas including ctDNA in rectal cancer and neoadjuvant therapy, the influence of microsatellite instability (MSI) status on assay performance, and disparities in ctDNA access across racial, socioeconomic, and geographic populations. Conclusions For gastroenterologists encountering ctDNA results in postoperative and surveillance settings, three principles should guide practice (i): match assay selection to clinical intent - tumor-informed platforms for MRD-directed adjuvant decisions, tumor-agnostic platforms when tissue is unavailable (ii); interpret results within biological and technical context, accounting for platform-specific sensitivity limitations, biological confounders, and quantitative VAF trajectory rather than binary thresholds; and (iii) integrate ctDNA findings into multidisciplinary pathways - de-escalation is supported by high-quality randomized evidence in stage II disease (Grade A; Level I), while chemotherapy escalation based solely on ctDNA positivity in stage III disease is not supported outside clinical trials (Grade C; Level I). Standardization of assay performance benchmarks and equitable access to testing remain critical unmet needs.

Background: Liver transplantation (LT) remains the definitive treatment for end-stage liver disease; however, post-LT outcomes may differ depending on underlying disease etiology. Our study aimed to compare post-LT outcomes between alcoholic and non-alcoholic steatohepatitis (NASH)-related liver transplant recipients in the United States. Methods: A retrospective cohort study was conducted using the TriNetX Research Network. Adult liver transplant recipients (≥18 years) were categorized into two mutually exclusive cohorts: alcoholic liver disease and NASH-related liver disease. Propensity score matching (1:1) was performed to balance baseline characteristics. Clinical outcomes were assessed. Comparative analyses included risk ratios, risk differences, odds ratios, Kaplan–Meier survival analysis, and hazard ratios with log-rank testing. Results: Compared with NASH recipients, alcoholic LT recipients had a significantly higher risk of rejection (14.5% vs. 12.1%; RR 1.195, 95% CI 1.076–1.327; p = 0.001) and hepatic encephalopathy (14.3% vs. 8.3%; RR 1.720, 95% CI 1.526–1.938; p < 0.001). Acute kidney injury was also more frequent in the alcoholic cohort (47.3% vs. 43.6%; RR 1.084, 95% CI 1.036–1.133; p < 0.001). In contrast, sepsis (15.6% vs. 18.0%; RR 0.869, 95% CI 0.794–0.952; p = 0.003) and CKD (46.1% vs. 51.1%; RR 0.901, 95% CI 0.863–0.939; p < 0.001) occurred less frequently in alcoholic LT patients. No significant differences were observed for liver transplant failure or ascites. Kaplan–Meier analyses demonstrated significantly lower rejection-free survival (HR 1.241, p < 0.001), higher hepatic encephalopathy (HR 1.808, p < 0.001), increased AKI risk (HR 1.150, p < 0.001) and higher all-cause mortality in the alcoholic cohort (HR 1.106, p = 0.031). Conclusions: In this large real-world matched cohort study, alcoholic LT recipients demonstrated higher risks of complications and all-cause mortality compared with NASH LT recipients.

Colorectal cancer (CRC) is responsible for a high cancer burden and a high number of deaths all over the world, although effective screening can make it preventable to a significant extent. Stool-based tests, such as the fecal immunochemical test (FIT) and multitarget stool DNA (mt-sDNA) testing, are gaining considerable popularity as non-invasive procedures that can be a replacement for colonoscopies for people at an average risk for colon cancer. Despite evidence from several randomized controlled trials supporting the use of these tests for colorectal cancer screening, their external validity in a real-world setting is influenced by many factors such as adherence, timely follow-up post testing, the healthcare cost burden, accessibility and the capacity of the health system. In this article, we have performed an extensive narrative literature review of research published between 2020 and 2025 comparing FIT and the mt-sDNA test with reference to diagnostic accuracy, cost-effectiveness, adherence and outcomes of implementation. We discuss the issues of sensitivity and specificity, look at post-test requirements for colonoscopy and check if there is any discrimination in healthcare. These findings suggest that FIT and mt-sDNA tests should not be considered competing technologies but rather complementary screening methods, with their overall effectiveness contingent upon appropriate patient selection and widespread system-level implementation. It is crucial to combine strategic test selection with a robust follow-up infrastructure to ensure that the entire population benefits from the CRC prevention program.

e24201 Background: Anthracyclines remain curative in many pediatric and adolescent/young adult (AYA) cancers but confer dose-dependent cardiotoxicity. Dexrazoxane reduces cardiac injury; however, concerns persist regarding potential impact on oncologic outcomes. Methods: We conducted a PRISMA-compliant systematic review and meta-analysis of studies comparing anthracycline therapy with versus without dexrazoxane in pediatric/AYA populations. Databases included MEDLINE, Embase, and CENTRAL. Outcomes included cardiac function (LVEF decline, clinical heart failure), event-free survival (EFS), overall survival (OS), relapse, and second malignant neoplasms (SMN). Random-effects meta-analysis pooled hazard ratios (HRs) for time-to-event outcomes and risk ratios (RRs) for binary endpoints. Results: Twelve studies with 1,384 patients were included. Dexrazoxane significantly reduced risk of clinical heart failure (RR 0.34, 95% CI 0.21–0.55) and preserved LVEF compared with controls. No significant differences were observed in EFS (HR 0.97, 95% CI 0.84–1.12), OS (HR 0.95, 95% CI 0.81–1.11), relapse (RR 1.02, 95% CI 0.87–1.19), or SMN incidence (RR 1.05, 95% CI 0.78–1.41). Benefits were consistent across cancer types, cumulative anthracycline doses, and follow-up durations. Conclusions: Dexrazoxane provides substantial cardio protection in pediatric and AYA patients receiving anthracyclines without compromising oncologic outcomes or increasing risk of SMNs. Clinical Takeaway: Routine incorporation of dexrazoxane in high-risk anthracycline regimens can prevent cardiotoxicity while maintaining curative potential.

e24198 Background: Even when radiotherapy is delivered outpatient, treatment-related nausea, vomiting, and dehydration can precipitate hospitalization, driving cost and morbidity. National estimates of this burden are limited. Methods: We analyzed the HCUP National Inpatient Sample (NIS) for 2016–2022 to identify hospitalizations with radiotherapy encounters (Z51.0) and concurrent diagnoses of nausea, vomiting, or dehydration using ICD-10 codes. Outcomes included length of stay (LOS), total charges, ICU use proxies, in-hospital mortality, and non-home discharge. Survey-weighted national estimates were calculated, and multivariable regression assessed predictors including cancer site proxies, age, comorbidity burden, insurance status, income quartile, and hospital characteristics. Results: Across 7,842 weighted admissions, mean LOS was 4.6 days (SD 2.1), mean total charges $23,400 (SD $8,700), and ICU-level care proxies were required in 12% of admissions. In-hospital mortality was 0.9%, and 21% of patients required non-home discharge. Older age, higher comorbidity burden, lower income quartile, and rural hospital location were independently associated with longer LOS, higher charges, and greater risk of non-home discharge (p < 0.01). Admissions for gastrointestinal or head/neck malignancies had the highest rates of RINV-related hospitalization. Temporal trends showed stable rates over the 7-year period. Conclusions: Hospitalizations for RINV and dehydration during radiotherapy represent a measurable national burden with disparities by socioeconomic status, tumor site, and hospital location. Clinical Takeaway: Targeted outpatient supportive interventions, particularly for high-risk patients, may reduce hospitalization, costs, and morbidity during radiotherapy.

e24087 Background: Radiotherapy-induced nausea and vomiting (RINV) negatively impacts adherence and quality of life. Multiple antiemetic strategies exist, but comparative effectiveness and ranking across regimens remain unclear, particularly regarding olanzapine-containing combinations. Methods: We conducted a systematic review and network meta-analysis of randomized and comparative studies evaluating antiemetic prophylaxis for RINV. Databases included MEDLINE, Embase, CENTRAL, and clinical trial registries. Interventions were categorized into clinically interpretable nodes (e.g., 5-HT3 antagonist ± dexamethasone, NK1-based combinations, olanzapine-containing regimens). The primary outcome was complete response (no emesis, no rescue therapy) during acute and delayed phases. Secondary outcomes included no nausea, severity, sedation, and discontinuation. Random-effects network meta-analysis was performed with treatment ranking using SUCRA probabilities. Results: Twenty-two studies encompassing 3,145 patients were included. Olanzapine-containing regimens ranked highest for complete response during both acute (SUCRA 92%) and delayed phases (SUCRA 89%), outperforming standard 5-HT3 + dexamethasone (SUCRA 64%). NK1-based triple therapy showed intermediate efficacy (SUCRA 78%). Olanzapine regimens had modest increases in sedation (RR 1.14, 95% CI 1.01–1.29) but no significant differences in discontinuation rates. Subgroup analyses indicated consistent benefits across radiation sites, fractionation schedules, and emetogenic risk. Conclusions: Olanzapine-based antiemetic regimens provide superior prevention of RINV compared with standard therapies, with acceptable tolerability across radiotherapy settings. Clinical Takeaway: Incorporating olanzapine into prophylactic antiemetic strategies can optimize symptom control, improve patient adherence, and enhance quality of life during radiotherapy.

e22007 Background: Long-term neurocognitive impairment is a major source of disability in survivors of pediatric CNS tumors. Proton radiotherapy may reduce dose to developing brain structures, potentially preserving cognition compared with conventional photon therapy. Methods: We performed a systematic review and meta-analysis of MEDLINE, Embase, PsycINFO, and CENTRAL. Eligible studies included pediatric CNS tumor patients treated with proton or photon radiotherapy reporting neurocognitive outcomes (full-scale IQ, attention, processing speed, executive function) over time. Standardized mean differences (SMD) were pooled using random-effects models, and slope analyses assessed longitudinal IQ change. Subgroups included age at radiotherapy, craniospinal vs focal fields, tumor type, chemotherapy exposure, and follow-up duration. Certainty of evidence was graded using GRADE. Results: Eleven studies encompassing 624 patients were included. Proton therapy was associated with significantly less decline in full-scale IQ compared with photon therapy (SMD 0.43, 95% CI 0.21–0.65, p < 0.001). Domain-specific analyses showed preservation of attention (SMD 0.36, 95% CI 0.10–0.61) and processing speed (SMD 0.41, 95% CI 0.18–0.64). Longitudinal slope analysis indicated an average IQ decline of 0.7 points/year after proton therapy versus 2.4 points/year after photon therapy. Benefits were greatest in younger children (<8 years) and those receiving craniospinal irradiation. Attrition and missing data were similar across groups. Conclusions: Proton radiotherapy in pediatric CNS tumors is associated with clinically meaningful preservation of neurocognitive function compared with photon therapy, particularly in younger patients and those receiving extensive fields. Clinical Takeaway: When available, proton therapy should be considered for children at high risk of cognitive decline to optimize long-term functional outcomes.

e19116 Background: PET/CT is the primary end-of-treatment (EOT) evaluation for diffuse large B-cell lymphoma (DLBCL); yet, false positives and insufficient prognostic clarity continue to be significant problems. Circulating tumor DNA (ctDNA)-based minimum residual disease (MRD) provides a tumor-informed, noninvasive way to assess recurrence risk. Methods: We used the MEDLINE, Embase, CENTRAL, and Web of Science databases to perform a systematic review and meta-analysis in accordance with PRISMA 2020 guidelines. DLBCL cohorts with end-of-treatment ctDNA-MRD status and survival outcomes were considered eligible research. The key outcome measures were progression-free survival (PFS) and overall survival (OS). Random-effects models calculated hazard ratios (HRs) and measured heterogeneity using I². Results: Eleven trials with 1,247 participants were included. Individuals with ctDNA-MRD had significantly worse progression-free survival (PFS) (pooled HR 5.48, 95% CI 3.96-7.58; I² = 42%) and overall survival (OS) (pooled HR 4.21, 95% CI 2.71-6.54; I² = 36%) compared to those without MRD. In MRD-positive patients, the 24-month recurrence rate was 68% compared to 14% in MRD-negative patients (absolute difference 54%, p < 0.001), with ctDNA indicating return 4.2 months before clinical advancement. In studies reporting combined PET/CT, ctDNA-MRD showed superior predictive performance, with a higher positive predictive value (79% vs 41%) and negative predictive value (92% vs 78%) compared to PET positivity. Conclusions: End-of-treatment ctDNA-MRD is a strong predictor of DLBCL recurrence and survival, outperforming PET/CT for risk classification. Integrating ctDNA-MRD into post-therapy assessments may allow for early intervention and reduce the number of unnecessary biopsies. Clinical Takeaway: ctDNA-MRD at EOT identifies high-risk DLBCL patients missed by imaging and supports precision-guided post-remission management.

e19092 Background: Advances in immunochemotherapy and cellular treatment have improved outcomes for diffuse large B-cell lymphoma (DLBCL), but the population-level effect and equity of benefit are unclear. Understanding mortality trends and inequality is critical to developing targeted medicines. Methods: We used ICD-10 codes to assess DLBCL mortality from the CDC WONDER Multiple Causes of Death data (1999-2023). The age-adjusted mortality rates (AAMR) per 100,000 were calculated using the 2000 US standard population. Trends were assessed using Joinpoint regression to calculate annual percent change (APC) and average annual percent change (AAPC). Mortality was broken out by gender, race/ethnicity, age group, US Census area, and urban-rural categorization. Results: From 1999 to 2023, the national AAMR for DLBCL decreased from 3.8 to 2.5 per 100,000 (AAPC -2.1%) (p < 0.001). Non-Hispanic White patients saw the greatest decline (AAPC -2.5%), followed by non-Hispanic Black patients (AAPC -1.2%), resulting in increasing racial inequalities (rate ratio Black:White 1.35 in 2023 vs. 1.18 in 1999). Urban areas had much larger mortality decreases than rural areas (AAPC −2.3% versus −1.1%). Regional disparities were clear, with rates typically higher in the Southeast and Midwest. Inflection points were identified in 2006 and 2012, coinciding with widespread use of rituximab-based therapy and better availability of second-line medications. Conclusions: Although DLBCL mortality has decreased throughout the US over the last two decades, progress has been patchy, with significant racial and regional differences. Clinical Takeaway: Targeted interventions addressing access to therapy and early detection in high-risk populations are needed to close persistent DLBCL outcome gaps.