Purpose:Fecal immunochemical tests (FIT) are widely used for colorectal cancer (CRC) screening. This systematic review and meta-analysis evaluated the diagnostic accuracy of quantitative FIT for CRC and advanced neoplasm (AN), and examined variations in performance by sex, geographic region, study design, FIT platform, and positivity threshold. Materials and Methods:A comprehensive search of MEDLINE, Embase, Cochrane Library, and KoreaMed was conducted. Studies evaluating the accuracy of quantitative FIT for CRC or AN using colonoscopy as a reference standard were included. The pooled sensitivity and specificity were estimated using a bivariate random-effects model. Meta-regression analysis was performed to analyze the diagnostic differences between sexes. Results:Thirty-three studies were included. FIT showed higher sensitivity for CRC than for AN (78.6% vs. 32.3%), with high specificity for both outcomes (93.7% and 95.2%, respectively). Case-control studies yielded a significantly higher AN sensitivity than cohort studies (50.7% vs. 29.7%; p<0.05). Western studies showed significantly higher AN sensitivity and lower specificity than Eastern studies (31.6% vs. 24.2%, p<0.05; and 95.0% vs. 96.5%, p<0.05, respectively). In the sex-stratified analyses, males showed higher AN sensitivity than females (34.1% vs. 30.8%) and significantly lower CRC specificity (90.1% vs. 93.1%; p<0.05); however, the meta-regression showed no significant sex effect on the overall diagnostic accuracy for CRC or AN. Conclusion:Quantitative FIT demonstrated strong performance for CRC detection but limited sensitivity for AN. Variations in the study design, FIT platform, threshold, region, and sex should be considered when interpreting FIT accuracy.
Purpose:Chemoimmunotherapy has improved outcomes in extensive-stage small-cell lung cancer (ES-SCLC), but its benefit in older adults remains uncertain because this population is underrepresented in clinical trials. We evaluated the real-world efficacy of first-line atezolizumab plus etoposide-carboplatin according to age in patients with ES-SCLC. Materials and Methods:We conducted a multicenter retrospective study across seven Korean institutions and identified patients with ES-SCLC treated between 2016 and 2022 with atezolizumab plus etoposide-carboplatin or etoposide-platinum chemotherapy alone. Patients with recurrence after prior limited-stage disease or incomplete records were excluded. End points were overall response rate (ORR), progression-free survival (PFS), and overall survival (OS), assessed using Kaplan-Meier methods and Cox regression models. Results:Among 550 identified patients, 538 were included: 247 received atezolizumab plus chemotherapy and 291 received chemotherapy alone. Overall, 111 patients (20.2%) were aged 75-80 and 57 (10.4%) were older than 80years. In the overall population, atezolizumab was associated with improved PFS (hazard ratio [HR], 0.78; 95% CI, 0.65 to 0.93; p=0.006) and OS (HR, 0.76; 95% CI, 0.63 to 0.93; p=0.006). Age-stratified analyses showed significant PFS benefit only in patients aged 70-75 (HR, 0.67; p=0.049) and significant OS benefit only in patients aged 65-70 (HR, 0.65; p=0.044). Beyond 75 years, neither PFS nor OS was significantly improved. Patients aged ≥75years also had lower ORR and more progressive or non-evaluable disease compared with <75years. Conclusion:The clinical benefit of adding atezolizumab appears attenuated in ES-SCLC patients age 75 years or older, supporting careful selection and age-adapted treatment strategies.
Purpose:The role of autologous stem cell transplantation (ASCT) in transplant-eligible patients with dialysis-dependent multiple myeloma (DDMM) remains unclear. We compared outcomes between ASCT and non-ASCT approaches in newly diagnosed DDMM. Materials and Methods:In this multicenter retrospective study, 117 patients with newly diagnosed DDMM who remained dialysis-dependent throughout induction therapy were included. Patients who achieved dialysis independence during induction were excluded. In the ASCT group, patients also remained dialysis-dependent at transplantation. Results:Post-induction overall response and ≥VGPR rates were comparable between groups. In the ASCT group, responses deepened significantly after transplantation. Among 53 paired-evaluable patients, ≥CR increased from 18.9% before ASCT to 60.4% after ASCT, while ≥VGPR from 52.8% to 83.0%; 67.9% experienced response deepening. In diagnosis-anchored analyses, ASCT was associated with significantly longer progression-free survival (PFS) (median, 39.4 vs. 12.1 months; p<0.001) and overall survival (OS) (median, 71.4 vs. 40.3 months; p=0.020); however, when ASCT was modeled as a time-dependent covariate and adjusted for baseline covariates, neither PFS (HR, 0.63; p=0.122) nor OS (HR, 0.78; p=0.463) remained statistically significant, indicating that the apparent survival advantage should be regarded as hypothesis-generating. Early post-transplant mortality was 5.5%, and non-relapse mortality was 3.6%. Durable dialysis discontinuation occurred in 16.4% and 12.9% of the ASCT and non-ASCT groups, respectively (p=0.611). Conclusion:In transplant-eligible patients with DDMM, ASCT was feasible and was associated with substantial deepening of response. After accounting for immortal time bias, the apparent survival advantage was attenuated and should be regarded as hypothesis-generating, warranting confirmation in prospective studies.
Purpose:To describe perioperative imatinib continuation patterns and explore associations with long-term outcomes in patients with locally advanced gastrointestinal stromal tumors (GIST) undergoing curative-intent surgery after neoadjuvant therapy. Materials and Methods:We retrospectively screened 395 patients receiving preoperative imatinib at two centers from 2012 to 2024. The analytic cohort comprised 171 patients with primary locally advanced GIST who underwent curative-intent surgery after neoadjuvant imatinib. Total perioperative exposure combined neoadjuvant and adjuvant treatment durations. Kaplan-Meier, Cox regression, and a 36-month landmark analysis were performed. Recurrence patterns and post-recurrence management were reviewed in 39 recurrent cases. Results:Median follow-up was 46 months; 39 patients (22.8%) recurred and 20 (11.7%) died. Five-year overall survival was 76.1%, 91.7%, and 96.7% for total exposure ≤36, >36 to ≤48, and >48 months, respectively, whereas recurrence-free survival did not differ significantly. In the landmark cohort (n=97), exposure >36 months was not significantly associated with post-landmark recurrence-free survival (HR, 0.881; 95% CI, 0.319 to 2.431; P=0.807) or overall survival (HR, 0.238; 95% CI, 0.043 to 1.303; P=0.098). Liver metastasis (53.8%) and peritoneal/abdominal dissemination (48.7%) were the most frequently documented first recurrence sites; 38.5% had multisite recurrence and 15.4% received local treatment. Conclusion:Longer perioperative imatinib exposure showed favorable survival patterns in fixed-exposure analyses, but the association was attenuated in landmark analysis. These surgery-conditioned findings are exploratory and do not establish an optimal treatment duration.
Purpose:We assessed whether baseline and early on-treatment measurements of host fitness using the Prognostic Nutritional Index (PNI) provide complementary prognostic information in advanced non-small cell lung cancer (NSCLC). Materials and Methods:Within the prospective, multicenter OPTIMUS trial, 497 patients with advanced NSCLC receiving first-line pembrolizumab-based therapy were analyzed. PNI was calculated from serum albumin and lymphocyte count at baseline and before cycle 2 (early on-treatment). Using a cutoff of 50.5, 441 patients with paired measurements were classified by baseline/early on-treatment PNI status as high/high, high/low, low/high, or low/low. Results:Low baseline PNI was associated with lower objective response and higher treatment-related mortality. Among responders, low early on-treatment PNI was associated with lower odds of 6-month response maintenance (adjusted OR, 0.40; 95% CI, 0.17-0.97). Response-maintenance rates were lowest in the low/low group at both 6 and 12 months. In multivariable analyses including both PNI time points, low early on-treatment PNI was associated with shorter PFS (HR, 1.50; 95% CI, 1.11-2.04), whereas low baseline PNI was not (HR, 1.27; 95% CI, 0.94-1.71). Both low baseline PNI (HR, 1.53; 95% CI, 1.07-2.19) and low early on-treatment PNI (HR, 1.47; 95% CI, 1.02-2.12) were associated with shorter OS. The higher mortality risk in the low/low group was generally consistent across PD-L1 expression and treatment regimen subgroups. Conclusion:PNI assessment at baseline and before cycle 2 provides complementary prognostic information, with early on-treatment PNI particularly related to PFS and response durability (ClinicalTrials.gov Identifier: NCT04909164).
Purpose:The clinical outcome of urothelial carcinoma presents significant variability, reflecting its molecular composition, epidemiologic attributes, and primary site of origin. Despite histological similarities, upper tract urothelial carcinoma (UTUC) and bladder urothelial carcinoma (BLCA) represent two distinct disease entities with disparate treatment responses and mutational patterns. Materials and Methods:To assess the impact of molecular heterogeneity on treatment outcomes, we conducted a comprehensive genomic analysis of 231 metastatic urothelial carcinoma patients, including 175 patients with BLCA and 56 patients with UTUC, in the K-MASTER program. Results:Our investigation unveiled dynamic molecular properties and mutational patterns in key molecules, including TP53, FGFR3, CREBBP, and SPEN. BLCA patients demonstrated enrichment of APOBEC mutational signature activities, whereas UTUC patients were characterized by activation of the cell cycle pathway. Transcriptome analysis uncovered unique biological signatures, highlighting increased cell migration and WNT signaling in BLCA, while FGFR3 and stem-cell-like pathways predominated in UTUC. Moreover, our study highlighted increased resistance to platinum-based chemotherapy and immunotherapy among UTUC patients. Importantly, tumor mutational burden (TMB) emerged as a robust independent predictor of immunotherapy response in BLCA. Additionally, a machine learning-based multivariable model identified FGFR3 mutation as a molecular determinant associated with favorable clinical outcomes, in contrast to FGFR2 mutations, which were linked to increased resistance to chemotherapy. The study also has limitations, including a limited sample size of UTUC patients and a lack of functional validation of the identified molecular mechanism. Conclusion:Our findings provide unprecedented insights into the significance of molecular and clinical disparities in urothelial carcinoma, facilitating disease-specific treatment interventions.
Purpose:To determine the association between metabolic syndrome (MetS) and lung cancer risk in a large population-based cohort of never-smokers in Korea. Materials and Methods:Using the Korean National Health Insurance Service database, we identified adults who underwent national health screening in 2009 and consistently reported their never-smoker status at baseline and subsequent examinations. Cox proportional hazards models were used to estimate hazard ratios (HRs) for lung cancer incidence, adjusting for age, sex, body mass index (BMI), physical activity, residential area, income, and alcohol consumption. Analyses were further stratified according to sex and BMI. Results:Overall, 2,721,804 never-smokers were followed up for a mean of 14.0 years. The incidence of lung cancer was higher among participants with MetS than those without (adjusted HR: 1.04, 95% CI: 1.01-1.07). MetS was significantly associated with lung cancer risk in men (HR: 1.18, 95% CI 1.11-1.25) but not in women (HR: 1.03, 95% CI 0.99-1.07), with the risk evident in normal-weight and pre-obese men but, in women, mainly in those with obesity (HR: 1.10, 95% CI 1.03-1.16). Conclusion:MetS was associated with a modest increase in the risk of lung cancer among Korean never-smokers, showing a significant association among men but not women. MetS risk was evident even among normal-weight men, whereas among women, it was more pronounced in those with obesity. These findings suggest that metabolic abnormalities, relatively underrecognized as cancer-related risk factors, could contribute to the risk of lung cancer, even in the absence of tobacco exposure.
Purpose:This study aimed to identify germline pathogenic/likely pathogenic variants in DNA damage repair genes associated with increased cancer risk in Korean patients with biliary tract cancer and characterize their population-specific patterns. Materials and Methods:In this retrospective multicenter cohort study, we performed germline whole-exome sequencing in 172 Korean patients diagnosed with intrahepatic cholangiocarcinoma (n = 83) or gallbladder cancer (n = 89) between June 2001 and February 2022. Germline variants were analyzed in 210 hereditary cancer genes, and the germline landscape of this cohort was compared with that of global cohorts. Results:Pathogenic/likely pathogenic variants were identified in 24 of 172 (14.0%) patients, predominantly in DNA damage repair genes (18 of 24 [75.0%]). BRCA2 was among the most frequently altered genes, harboring two distinct pathogenic variants (2 of 24 [8.3%]; both cases of intrahepatic cholangiocarcinoma). Of the 24 carriers, five (20.8%) harbored Tier 1-2 variants of potential, tumor-confirmation-dependent therapeutic relevance. Notably, 15 of 24 (62.5%) carriers reported no family cancer history. In population-stratified comparisons across nine biliary tract cancer cohorts (n = 4,018), PMS2 showed a Korean-enriched signal after accounting for heterogeneous gene coverage, whereas TP53 showed only a directional, non-significant increase after multiple-testing correction. Conclusion:The study findings provide reference data for genetic counseling in East Asian patients with biliary tract cancer and suggest that germline testing may warrant consideration regardless of family history.
Purpose:Outcomes of children and adolescents with acute lymphoblastic leukemia (ALL) treated using an institutional risk-adapted strategy were assessed, and survival was compared among risk groups. Materials and Methods:This retrospective study included patients newly diagnosed with ALL during 2006-2020. Patients were stratified as standard-risk (SR), high-risk (HR), or very-high-risk (VHR). The SR group received a POG 9605-based protocol in 2006-2011 and a modified regimen with an additional delayed intensification phase in 2012-2020. The HR group received the ALL 0601 regimen, and the VHR group received institutional hematopoietic stem cell transplantation-oriented treatment. Results:Ninety-two patients were included (SR, 34; HR, 45; and VHR, 13). The 10-year overall survival (OS) and event-free survival (EFS) were 85.2% and 70.9%, with cumulative incidences of relapse and treatment-related mortality of 22.6% and 3.3%, respectively. The 10-year OS was 92.8%, 88.7%, and 60.9% in the SR, HR, and VHR groups, and the corresponding 10-year EFS was 78.5%, 77.2%, and 34.2%, respectively. In SR, 10-year OS/EFS were 85.1%/71.4% in 2006-2011 and 100%/84.4% in 2012-2020. In the HR group, rapid early responders exhibited significantly better outcomes than did slow early responders, with 10-year OS of 97.0% vs. 63.6% (p = 0.001) and 10-year EFS of 87.9% vs. 43.6% (p < 0.001). Most relapses occurred during therapy or within 3 years of treatment completion. Conclusion:VHR patients and HR patients with slow early response demonstrated the poorest outcomes. This supports refining risk-directed treatment strategies, including prospective evaluation of intensified and novel therapeutic approaches.
Purpose:Diffuse large B-cell lymphoma (DLBCL) is genetically heterogeneous. We aimed to define a compartment-aware driver mutation landscape of DLBCL by integrating tumor tissue and circulating cell-free DNA (cfDNA) sequencing, and to assess its biological and prognostic relevance. Materials and Methods:Somatic mutations were analyzed from targeted sequencing of tumor tissue or bone marrow and cfDNA from peripheral blood or cerebrospinal fluid, including paired tissue-liquid samples, together with whole-genome sequencing data from TCGA. Driver genes were identified using four complementary algorithms. Functional enrichment and protein-protein interaction analyses were performed. Prognostic relevance was evaluated using multigene expression-based modeling with Cox and LASSO regression in independent cohorts. Results:Recurrent driver alterations converged on core pathogenic pathways, including B-cell receptor signaling, NF-κB activation, epigenetic regulation, and immune escape. Twenty-two high-confidence driver genes, including PIM1, KMT2D, CD79B, B2M, TP53, MYC, and EZH2, were consistently identified across clinical cohorts and supported by TCGA data. cfDNA profiling showed substantial concordance with tissue-derived drivers while revealing gene-specific differences in mutation burden and co-mutation patterns, indicating complementary capture of clinically relevant heterogeneity. Network analysis highlighted TP53, MYC, EP300, and CREBBP as central hubs. A four-gene expression-based model (MYC, PLCL1, IRF8, LNPEP) stratified patients by overall survival and modestly improved prognostic discrimination beyond the International Prognostic Index. Conclusion:Integrated analysis of tumor tissue and cfDNA sequencing defines a clinically relevant driver framework for DLBCL. cfDNA preserves core oncogenic signals while complementing tissue profiling, supporting refined genomic risk stratification.
Purpose:Identifying nonresponders to atezolizumab plus bevacizumab (AB) remains challenging in unresectable hepatocellular carcinoma (uHCC). We aimed to develop and externally validate a simple risk scoring system using baseline neutrophil-to-lymphocyte ratio (NLR) and extrahepatic spread (EHS) to predict treatment outcomes. Materials and Methods:We included 304 patients with uHCC receiving first-line AB from multiple Korean centers (discovery, n = 220; validation, n = 84). Study outcomes included objective response rate (ORR) assessed by modified Response Evaluation Criteria in Solid Tumors, overall survival (OS), and progression-free survival (PFS). Multivariable analysis identified high NLR (>4.575) and EHS as independent predictors of nonresponse. The NLR-EHS score assigned 2 points for high NLR and 1 point for EHS (range, 0-3). Results:In the discovery cohort, the score predicted nonresponse with an area under the receiver operating characteristic curve (AUC) of 0.749 (95% CI, 0.688-0.810); ORR fell across low- (0), moderate- (1-2), and high-risk (3) groups (67.3%, 47.7%, and 8.2%; p < 0.001). Validation confirmed comparable discrimination (AUC, 0.705; 95% CI, 0.603-0.806) and a consistent ORR gradient (77.8%, 54.2%, and 22.2%; p < 0.001). The score was prognostic for OS in discovery (HR, 1.28; p = 0.003) and validation cohorts (HR, 1.45; p = 0.007), remaining significant after adjustment (adjusted HR, 1.25 and 1.61, respectively). High-risk patients had inferior median OS (6.9 vs. 17.1 months in validation). Conclusion:The NLR-EHS score is a practical tool for stratifying nonresponse risk and survival in uHCC patients receiving AB, facilitating early identification of high-risk patients who may benefit from alternative strategies.
Purpose:Resilience is an important psychosocial resource for adolescents and young adults (AYAs) with cancer; however, family-related factors influencing resilience among Korean AYAs remain understudied. This study examined the associations between family environment variables (family strength, parent-adolescent communication, and family support) and resilience among Korean AYAs with childhood cancer. Materials and Methods:In this cross-sectional study, 141 Korean AYAs (ages 11-26 years) completed self-report questionnaires between June 2019 and January 2021. Guided by the Resilience in Illness Model, parent-AYA communication, family strengths, and family support were assessed. Data were analyzed using descriptive statistics, correlations, and hierarchical regression models. Results:Resilience was positively correlated with all family-related variables. After adjusting for demographic and clinical characteristics, family strengths (β=0.290, p=0.044) and family support (β=0.447, p<0.001) significantly predicted resilience, explaining 34.7% of the variance. Moderation analysis using Hayes' PROCESS macro showed that that the association between family strength and resilience was stronger among AYAs receiving active treatment (b=1.2416, p<0.001). In addition, the association between family support and resilience was stronger influence among male AYAs and those under treatment (b=0.530, p<0.001). Conclusion:Family strength and perceived family support are important correlates of resilience among Korean AYAs with childhood cancer, particularly among male AYAs and those undergoing active cancer treatment. These findings highlight the importance of understanding family dynamics and implementing family-centered approaches to support resilience among AYAs throughout the cancer treatment trajectory.
Purpose:Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis characterized by heterogeneous multisystem manifestations and frequent MAPK-ERK pathway alterations. Data on the clinico-pathologic features and real-world outcomes of adult ECD in South Korea are limited. Materials and Methods:We conducted a retrospective multicenter cohort study of adult patients (≥18 years) with ECD at seven Korean Cancer Study Group (KCSG)-affiliated institutions between October 2008 and June 2024. Clinical and pathologic features, BRAF V600E mutation status, treatment patterns, and overall survival (OS) were analyzed using the Kaplan-Meier method. Results:Twenty-two patients were included (median age 57 years [IQR 45-64]; 50% male). Organ involvement was heterogeneous: bone (54.5%), retroperitoneal/renal (31.8%), central nervous system (27.3%), cardiovascular (27.3%), hypothalamic-pituitary axis (27.3%), pulmonary (18.2%), and skin (13.6%); multisystem disease (≥2 organs) was present in 40.9%. BRAF V600E was positive in 11 of 19 tested patients (57.9%). Systemic treatment was initiated in 18 patients (81.8%); interferon-α-based regimens were the most common first-line approach (50.0%). Among 16 evaluable patients, the disease control rate (CR/PR/SD) was 87.5%. With a median follow-up of 4.6 years (IQR 1.3-6.5), 2- and 5-year OS rates were 90.0% and 74.3%, respectively. Conclusion:Korean adult patients with ECD demonstrate heterogeneous organ involvement and frequent BRAF V600E positivity. Real-world treatment remains dominated by interferon-α-based approaches, underscoring the need for standardized molecular testing and improved access to targeted therapy.
Purpose:East Asia has the highest gastric cancer incidence globally [1]. Real-world (rw) treatment patterns and outcomes for HER2-positive (HER2+) advanced gastric or gastroesophageal junction cancer (aGC/GEJC) remain poorly understood. Materials and Methods:This study enrolled adults with HER2+ aGC/GEJC diagnosed since January 2016 who received ≥2 lines of therapies (LOTs) with ≥6 months of follow-up across 31 centers in South Korea (KR), China (CN), Taiwan (TW), and Hong Kong (HK). Data were collected through November 2023. Treatment patterns, rw-efficacy outcomes, and adverse events of interest were analyzed descriptively. Results:Of 356 eligible patients (KR: 119, CN: 137, TW: 75, HK: 25), chemotherapy plus HER2-targeted monoclonal antibody was the most common 1st LOT regimen (61.0%), although utilization varied across countries/regions. Cross-country/region heterogeneity in treatment patterns emerged from the 2nd LOT onward. Median rw-overall survival varied across countries/regions (KR: 37.1; TW: 13.7; HK: 18.1 months); reliable survival estimation was precluded in CN due to ~50% loss to follow-up. Exploratory analyses suggested no survival benefit with trastuzumab use across multiple versus single LOT(s) (nominal p=0.96); however, sequential use of ≥2 HER2-targeted therapy types with distinct mechanisms of action (MoAs) may be associated with longer survival compared to a single type (nominal p=0.009). Conclusion:Cross-country/region heterogeneity in HER2+ aGC/GEJC treatment exists, likely driven by differential drug accessibility. Exploratory analyses suggested possible associations between HER2-targeted therapy and improved outcomes; however, inherent biases preclude causal inference. The sequential use of HER2-targeted therapies with distinct MoAs may be associated with clinical benefit, requiring prospective validation (NCT05606094).
Purpose:Preclinical studies suggest that sodium-glucose cotransporter-2 inhibitors (SGLT-2is) may have cancer-preventive effects; however, clinical evidence remains inconclusive. Therefore, this study aimed to evaluate the association between the use of SGLT-2is (empagliflozin or dapagliflozin) and the incidence of new-onset cancer in patients with type 2 diabetes. Materials and Methods:This nationwide retrospective cohort study used Korean national health claims data. Patients with type 2 diabetes who started empagliflozin, dapagliflozin, or other glucose-lowering drugs (oGLDs) between 2016 and 2019 were included, and propensity score matching between the SGLT-2is users and oGLDs users was applied. The primary outcome was overall cancer incidence, and the secondary outcomes were the incidence of 11 site-specific cancers. Hazard ratios (HRs) and confidence intervals (CIs) for cancer incidence adjusted for covariates were estimated using a Cox proportional hazards model. Results:After propensity score matching, each group comprised 20,456 patients. There was no significant difference in the overall incidence of new-onset cancer in either the empagliflozin or dapagliflozin groups when compared to the oGLDs user group (adjusted HR 0.85, 95% CI 0.65-1.12; adjusted HR 0.87, 95% CI 0.66-1.14, respectively). Similar results were observed in site-specific cancer incidence. Furthermore, there were no significant differences in overall or site-specific cancer incidence between the empagliflozin and dapagliflozin user groups. The results were consistent across subgroup analyses and various sensitivity analyses. Conclusion:In this large-scale national cohort study, the use of empagliflozin or dapagliflozin did not show a significant difference in the incidence of new-onset cancer in patients with type 2 diabetes. These results provide evidence supporting the association between SGLT-2i use and cancer risk in this population, based on real-world clinical data. Longer-term follow-up studies would be helpful in strengthening the validity of these findings.
Purpose:This study evaluated the comparative clinical effectiveness and cost-effectiveness of robot-assisted minimally invasive esophagectomy (RAMIE) versus open esophagectomy (OE) and conventional minimally invasive esophagectomy (MIE) in a nationwide real-world setting. Materials and Methods:A target trial emulation was conducted using the Korean National Health Insurance Service database, including patients who underwent first-time esophagectomy for esophageal cancer between 2010 and 2023, with survival followed through June 2024. Propensity score-matched cohorts were created for RAMIE versus OE (n=1,713 per group) and RAMIE versus MIE (n=1,162 per group). Clinical outcomes were compared, and a 5-year semi-Markov model was used to estimate quality-adjusted life-years (QALYs) and costs from a healthcare sector perspective with a 4.5% annual discount rate. Incremental cost-effectiveness ratios (ICERs), incremental net benefits (INBs), and probabilistic sensitivity analyses were calculated. Results:RAMIE showed comparable or better short-term outcomes, including lower incidence of transfusion-requiring bleeding risk than OE (23.6% vs. 32.5%; relative risk [RR], 0.73; 95% CI, 0.65-0.81) and MIE (27.9% vs. 33.6%; RR, 0.88; 95% CI, 0.77-0.99). Long-term survival was superior to OE (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.72-0.88) and similar to MIE (HR, 0.93; 95% CI, 0.82-1.06). RAMIE yielded higher QALYs (Δ0.311 vs. OE; Δ0.126 vs MIE) and lower 5-year costs ($12,372-$19,765 vs. OE; $1,703-$9,097 vs. MIE), resulting in negative ICERs, positive INBs, and high probabilities of cost-effectiveness in sensitivity analyses. Conclusion:RAMIE showed a favorable clinical and cost-effectiveness profile compared with OE and MIE, adding to the evidence base for its broader adoption.
Purpose:Bulk transcriptomic biomarkers for immune checkpoint inhibitor (ICI) response in hepatocellular carcinoma (HCC) often lack reproducibility because bulk RNA sequencing captures composite signals from malignant, immune, and stromal compartments. Variability in tumor purity and malignant cell composition can confound immune-based interpretations. We developed an integrative framework combining single-cell-derived digital cytometry with inference of tumor-intrinsic genomic states to better interpret transcriptomic variation associated with ICI response. Materials and Methods:Single-cell RNA sequencing data from HCC tumors (GSE206325) were used to construct a nine-cell-type signature matrix for CIBERSORTx deconvolution and to infer chromosome arm-level copy number variation in malignant hepatocytes using inferCNV. Signature stability was evaluated through pseudobulk reconstruction and gradient simulations. Digital cytometry was applied to three bulk RNA-seq ICI cohorts (GSE202069, GSE215011, and GSE279750). Arm-level alterations were projected onto bulk transcriptomes by mapping arm-associated genes, standardizing expression within samples, and aggregating direction-adjusted Q90 statistics into a composite arm-axis score. Results:Digital cytometry revealed cohort-dependent variability in malignant hepatocyte dominance and limited reproducibility of immune fraction differences. Differential expression analysis also showed poor cross-cohort concordance. InferCNV identified recurrent arm-level alterations (1q/8q gain, 12p/13q loss), defining a continuous genomic axis. In pooled analysis (n=36), integrating the arm-axis score with PD-L1 improved discrimination (AUC 0.775; 95% CI, 0.602-0.920). In TCGA-LIHC (n=361), arm-level burden was inversely associated with cytolytic activity and positively associated with proliferation. Conclusion:Tumor-intrinsic hepatocyte genomic states provide complementary predictive information beyond immune activation alone and may help explain heterogeneity in ICI response across HCC cohorts.
