This correspondence provides a methodological commentary on the recent study by Nishio et al, which used single-cell RNA sequencing (CITE-seq) to identify circulating immune biomarkers for combination immunotherapies in advanced hepatocellular carcinoma (HCC). While the original study offers high-resolution insights into systemic immunity, we identify three critical areas that warrant further consideration to ensure the clinical validity of the proposed biomarkers. First, we discuss how etiological heterogeneity (viral vs non-viral HCC) may confound regimen-specific immune signatures. Second, we highlight the potential for "selection bias" and statistical inflation of effect sizes resulting from the balanced 1:1 responder to non-responder study design, as well as the inherent mathematical artifacts in compositional single-cell data analysis. Third, we question the biological applicability of modeling stable ligand-receptor interactions (CellChat) within the high-flow environment of peripheral circulation. We conclude that future validation in unselected, prospective cohorts is essential to confirm whether these circulating immune subsets can serve as robust clinical predictors in real-world settings.

Immune checkpoint inhibitor-based combinations represent the standard of care for advanced renal cell carcinoma. The OMNIVORE trial investigated a response-adaptive strategy, including treatment discontinuation in early nivolumab responders (Arm A) and salvage ipilimumab addition in non-responders (Arm B). Here we report outcomes with extended follow-up.

OMNIVORE was a phase II response-adaptive trial in which patients received induction nivolumab monotherapy. Patients achieving a confirmed complete or partial response discontinued nivolumab and entered observation (Arm A), while patients with stable disease or progressive disease received two doses of ipilimumab added to ongoing nivolumab (Arm B). This analysis characterizes long-term overall survival across the full study cohort and durability of response among patients who discontinued nivolumab following an early objective response.

Of 83 patients who initiated treatment, 12 (14%) were allocated to Arm A and 57 (69%) to Arm B, with a median follow-up among living patients of 59.4 months (range 29.1-85.4 months) in Arm A and 31.4 months (range 4.6-62.6 months) in Arm B. The 3-year overall survival rate from nivolumab initiation was 64% (95% CI 51% to 74%) in the overall cohort, 83% (95% CI 48% to 96%) in Arm A, and 63% (95% CI 47% to 76%) in Arm B. Of the 12 Arm A patients, 6 (50%) remained off nivolumab at 1 year following treatment discontinuation, of whom 5 maintained responses beyond 43 months off therapy, with all remaining alive at last known follow-up, with overall survival ranging from 48.8 to 85.4 months from nivolumab initiation. Of the six patients who resumed treatment, only one achieved a durable complete response remaining on treatment at 83.2 months from nivolumab initiation. All 57 Arm B patients discontinued treatment with a median treatment duration of 3.7 months (range 1-24.8 months) and a median progression-free survival from nivolumab plus ipilimumab initiation of 4.6 months (95% CI 2.7 to 6.5 months).

With extended follow-up, a meaningful subset of patients achieving an early objective response to nivolumab maintained prolonged treatment-free survival following a short course of treatment. Salvage ipilimumab in nivolumab non-responders demonstrated limited benefit, reinforcing that upfront concurrent dual checkpoint blockade remains the preferred approach.

NCT03203473.

The aim of this quality improvement initiative was to increase colorectal cancer (CRC) screening rates from 17.75% and 28.45% to 40% in patients aged 45-49 years and 50-75 years, respectively, at a resource-limited primary care clinic within 1 year. We identified a major gap in CRC screening in both age groups (45-49 and 50-75 years).

We implemented multifaceted, patient-centred interventions in a community clinic serving a diverse population. The intervention incorporated the use of stool-based testing (faecal immunochemical test and multi-targeted stool DNA test), colonoscopy referrals, patient navigation, multilingual education, electronic health record alerts and a real-time tracking dashboard. The primary outcome measure was CRC screening completion rates. Colonoscopy and stool test completion rates were the process measures.

In 45-49 years, we observed a sustainable, steady increase in CRC screening rates from 17.75% (n=400) to 41.25% during the study period and 59.50% 6 months poststudy, with a median rate of 52.38% in a run chart and a mean of 37.00% in the statistical process control (SPC) chart. In 50-75 years, we observed a sustainable increase in CRC screening rate from 28.45% (n=2879) to 46.16% during the study period and to 61.06% 6 months poststudy, with a median rate of 55.47% in a run chart and mean of 43.00% in a SPC chart. In 45-49 years, colonoscopy completion rates increased from the baseline rate of 25.93% (n=108) to 37.04% during the study period and to 43.52% 6 months poststudy. In 50-75 years, colonoscopy completion rates increased from the baseline rate of 74.01% (n=654) to 92.05% during the study period and to 97.55% 6 months poststudy.

We exceeded our goals to increase CRC screening in both age groups. Patient-centred care and system-integrated interventions may substantially increase CRC screening among underserved individuals.

To determine whether robotic pancreatoduodenectomy (RPD) is non-inferior to open pancreatoduodenectomy (OPD) in terms of postoperative functional recovery, without compromising safety or oncological quality.

Multicentre, single masked, phase 3, non-inferiority randomised controlled trial.

Seven tertiary high volume pancreatic centres in China, 15 June 2020 to 28 November 2024.

268 adults with resectable pancreatic or periampullary disease.

Participants were randomised to receive standardised RPD (n=142) or OPD (n=126), with enhanced recovery pathways.

The primary outcome was time from surgery to postoperative functional recovery, defined as adequate pain control without parenteral analgesia, ≥50% oral intake without intravenous fluids, independent mobilisation, and absence of active intra-abdominal infection. The restricted mean event time (RMET) within 40 days was a summary for time from surgery to postoperative functional recovery. Secondary outcomes included operative metrics, disease related outcomes, length of stay, postoperative morbidity, including complications of Clavien-Dindo grade II or higher (defined as complications requiring drug treatment or more intensive intervention), and hospital admission costs.

Overall, 254 of 268 randomly assigned participants (mean age 62 years; 172 (64.2%) men) underwent surgery, completed follow-up, and were included in the modified intention-to-treat population; 14 did not undergo surgery. In the modified intention-to-treat population, the RMET was 12.1 days (95% confidence interval (CI) 11.2 to 13.1) in the RPD group and 16.0 days (14.5 to 17.5) in the OPD group (difference -3.9 days, 95% CI -5.6 to -2.2; P<0.001). Operative time was longer in the RPD group (300 minutes (interquartile range (IQR) 240-360 minutes) versus 270 (210-300) minutes in the OPD group, P<0.001) but postoperative length of stay was shorter in the RPD group (13 (IQR 11-16) days v 16 (13-20) days, P<0.001). Overall postoperative morbidity was 31.1% (41/132) in the RPD group versus 36.1% (44/122) in the OPD group and incidence of any complications of Clavien-Dindo grade II or higher was 23.5% (31/132) versus 34.4% (42/122), respectively. 90 day mortality was 0.8% (1) in the RPD group and 2.5% (3) in the OPD group. Median total costs of hospital admission (including readmission cost) were higher in the RPD group than in the OPD group (¥130 905 (£14 369; $19 351; €16 628) (IQR ¥114 853-¥152 547) v ¥108 071 (¥92 134-¥128 035), difference ¥22 834 (95% CI ¥16 744 to ¥30 522); P<0.001).

In high volume centres with credentialled surgeons, RPD met the non-inferiority margin for time from surgery to postoperative functional recovery, with comparable disease related outcomes and overall burden from postoperative complications. To generate wider system level efficiency gains, the implementation of RPD should take account of institutional expertise, procedural volume, acquisition of robotic surgical platforms and maintenance costs, and the potential for shorter hospital stay.

ClinicalTrials.gov NCT04400357.

Cancer-related anemia (CRA) adversely affects quality of life and clinical outcomes. Despite extensive research, uncertainty remains regarding the optimal use of erythropoiesis-stimulating agents (ESAs), iron, and transfusions. This scoping review synthesizes efficacy and safety evidence and compares international management guidelines.

A systematic search of PubMed and Embase identified English-language studies on CRA published from 2000 up to November 30, 2024. Randomized controlled trials were reviewed to assess treatment efficacy and safety, and international guidelines were analyzed to compare management recommendations.

Fifty-six randomized controlled trials and 10 international guidelines were included. ESAs and iron supplementation were effective in improving hemoglobin concentration and reducing transfusion requirements, particularly in context-dependent settings. Combination therapy with ESAs and iron consistently demonstrated superior hematologic responses compared with ESA monotherapy without additional safety concerns. Both conventional and newer intravenous (IV) and oral iron formulations showed benefit across different clinical contexts, with faster responses generally favoring IV iron in some settings, while emerging evidence supports oral iron as a viable alternative in absolute iron deficiency. Emerging therapies, including sotatercept and selected adjunctive approaches, showed preliminary signals of efficacy in limited studies, warranting further investigation. Guidelines generally restrict ESAs to chemotherapy-induced anemia or high-risk patients. For iron therapy, discrepancies exist regarding indications and administration route; most guidelines prioritize IV over oral iron for both functional iron deficiency and absolute iron deficiency. Significant regional gaps in guideline availability were identified, particularly in Africa, South America, Asia-Pacific, and the Middle East.

CRA management relies on ESAs, iron supplementation, and transfusions, but guideline heterogeneity and regional discrepancies necessitate harmonization and individualized approaches. Updated, globally representative recommendations and further research in under-studied populations are essential.

There is an unmet need to predict immune-related adverse events (irAEs) in patients receiving immune checkpoint inhibitors. This study aimed to examine whether eosinophils can predict irAEs in metastatic urothelial carcinoma (mUC). In this multicenter cohort study, we retrospectively examined eosinophil before (baseline sample) and 3 weeks after treatment (3-week sample) in 124 patients with mUC treated with pembrolizumab between January 2018 and October 2024. We divided the patients into two groups depending on whether they had experienced an irAE (irAE group) or not (non-irAE group). The variation in eosinophil proportion from baseline to 3 weeks was significantly higher in the irAE group than in the non-irAE group (non-irAE, 2.4%-3.1%; irAE, 2.2%-4.3%; p < 0.05). Notably, the variation in eosinophils from baseline to 3 weeks in patients with bladder cancer was significantly higher in the irAE group than in the non-irAE group (non-irAE, 2.5%-2.8%; irAE, 1.9%-4.1%; p < 0.05), but not in upper urinary tract urothelial cancer (non-irAE, 2.2%-3.7%; irAE, 2.8%-4.4%; p = 0.97). The optimal cutoff value for eosinophils in patients with bladder cancer against the occurrence of any-grade irAEs was 5.0% (area under the curve = 0.655). Multivariable analyses showed that eosinophil levels ≥ 5.0% increased the risk of any-grade irAEs in patients with bladder cancer (odds ratio 3.61, 95% confidence interval, 1.00-13.0). An eosinophil proportion ≥ 5.0% may be an effective biomarker for evaluating pembrolizumab-induced irAEs in patients with mUC, particularly those with bladder cancer.

Combination therapies incorporating immune checkpoint inhibitors (ICIs) are widely used as first-line treatment for metastatic renal cell carcinoma (mRCC). However, the optimal sequence of subsequent therapies remains unclear. In this study, we investigated the real-world outcomes of nivolumab rechallenge after first-line ICI-based combination therapy.

Twenty-eight consecutive patients with mRCC who received nivolumab monotherapy as third- or later-line treatment after first-line ICI-based combination therapy were identified from a multicenter database. The best overall response (BOR), progression-free survival (PFS), overall survival (OS), immune-related adverse events (irAEs), and prognostic factors associated with PFS were retrospectively analyzed.

The median age was 68 years. Twenty-two patients (78.6%) had clear cell RCC. Nivolumab was administered as third-, fourth-, and fifth-line therapy in 19 (67.9%), 7 (25.0%), and 2 (7.1%) patients, respectively. The median follow-up period was 6.4 months. The BORs were complete response, partial response, stable disease, and progressive disease in 0, 2 (7.1%), 7 (25.0%), and 19 (67.9%) patients, respectively. The median PFS and OS were 2.2 and 8.8 months, respectively. irAEs occurred in 7 patients (25.0%), including 5 patients (17.9%) with grade 3 irAEs. No grade 4 or higher events were observed. In multivariable analysis, good performance status and a shorter duration of first-line ICI-based combination therapy were associated with improved PFS.

Nivolumab rechallenge demonstrated modest efficacy in patients with mRCC after first-line ICI-based combination therapy, although a limited subset of patients may derive clinical benefit from this approach. irAEs during nivolumab rechallenge were generally manageable.

Gemcitabine, oxaliplatin, and paclitaxel (GOP) therapy has shown antitumor activity as a conventional-dose salvage regimen for relapsed or refractory germ cell tumors (GCTs) in European studies; however, data on Japanese patients remain limited. Therefore, we aimed to evaluate the real-world efficacy and safety of GOP therapy in a multicenter Japanese cohort and explore outcomes according to platinum sensitivity.

This retrospective multicenter study included 25 patients with relapsed or refractory GCTs treated with GOP between January 2012 and May 2025 at two institutions in Japan. Treatment response was assessed using the Response Evaluation Criteria in Solid Tumors version 1.1, along with tumor marker evaluations. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method.

Of the 25 patients, 15 (60%) and 10 (40%) had platinum-refractory disease and platinum-non-refractory disease, respectively. The median follow-up was 14.4 months. The overall response rate was 56%, with a complete response rate of 28%. The median PFS and OS were 6.9 and 23.1 months, respectively. The estimated 2-year OS and PFS rates were 48.7% and 36.0%, respectively. Survival outcomes were comparable between patients with platinum-non-refractory and platinum-refractory diseases. Overall, 40% of patients survived for more than 2 years after initiation of GOP therapy. Grades 3-4 hematologic toxicities were common but manageable, with no unexpected safety signals.

GOP therapy demonstrated clinically meaningful activity and acceptable tolerability in Japanese patients with relapsed or refractory GCTs, supporting GOP as a practical, conventional-dose salvage option for platinum-refractory diseases.

The current bedrock of precision prevention is selecting high-risk individuals for screening or other prevention services under the assumption that those at highest risk would have the highest benefit from prevention services. However, this may not hold when disease risk and competing mortality are highly correlated. In such cases, risk-based prevention may preferentially select older individuals with multiple comorbidities who would have substantially reduced life-years gainable from the service and increased risks of harm from any resulting surgical procedures. For such prevention services, we propose a benefit-based selection strategy in which individuals are selected according to their expected gain in life-years (i.e., difference in mean survival time with and without the prevention service). We estimate the expected gain in life-years for individuals in a target screening population by combining data from a randomized trial, which may not be population-representative, and data from a population-representative survey that has larger sample size, more covariates, and longer follow-up time to evaluate mortality than the trial. We derive the Taylor-linearized variances for the estimated expected gain in life-years that take into account the randomness due to both trial and survey sample. We show that benefit-based selection of ever-smokers for lung-cancer screening can identify individuals with more favorable benefit-harm trade-offs compared to risk-based selection. Using simulation studies, we examine the conditions in which one strategy may be preferable over the other.

Anatomical changes during radiotherapy for nasopharyngeal carcinoma (NPC) frequently compromise target volume coverage while escalating dose delivery to organs at risk (OARs). In adaptive radiotherapy (ART), optimizing workflow efficiency to minimize clinical workload while maximizing patient benefit remains a fundamental challenge. Previous investigations inadequately tackled the critical aspects of identifying robust triggers and optimal timing for ART initiation. To bridge this gap, we quantified weekly sCT-derived volumetric and dosimetric changes on a C-arm linac workflow to determine robust, literature-based thresholds and optimal replanning time points for NPC ART.

This study analyzed 52 NPC patients undergoing VMAT. Weekly cone-beam CT (CBCT) scans (n = 312) were processed through ArcherQA using a CycleGAN-based sCT generation pipeline, which enabled automated segmentation and GPU-accelerated Monte Carlo dose recalculation. Longitudinal volumetric/dosimetric changes in targets and organs at risk (OARs) were tracked, with Spearman correlation analyzing variable relationships. Binary logistic regression and Receiver Operating Characteristic (ROC) curve analysis identified evidence-based triggers and optimal timing for adaptive replanning, enabling quantitative criteria for ART initiation while balancing precision and workflow efficiency.

Anatomical changes drove dosimetric deviations: PGTVn (nodal targets) showed ≥8% volume reduction by week 2 (OR = 2.03, p = 0.006, AUC = 0.83), while PGTVp/PTV1 (primary targets) required ≥10% reduction by week 4 (AUC = 0.76). OAR correlations included left submandibular gland volume inversely linking to mean dose (peak r = -0.575 at week 3, p < 0.001) and delayed ipsilateral parotid atrophy (week 4). Triggers were defined: ≥15% contralateral parotid reduction at week 2 (AUC = 0.89) and ≥19% left submandibular gland loss at week 3 (AUC = 0.97). Pharyngeal constrictor analysis revealed that week 2 ≥4% volume loss predicted ≥0.9 Gy week 3 dose rise (AUC = 0.93).

Weekly sCT monitoring clarified the optimal timing for offline ART, revealing that structure-specific dosimetric changes necessitate distinct intervention windows, notably week 2 for nodal/contralateral parotid and week 4 for primary/ipsilateral parotid, providing a practical framework for prospective validation.