There is a dearth of head-to-head studies comparing covalent Bruton tyrosine kinase(cBTK) inhibitors in adults with chronic lymphocytic leukemia (CLL). Real-world evidence may complement clinical trial data by assessing relative effectiveness in routine practice. This retrospective observational study used a de-identified Medicare Fee-For-Service database to compare real-world outcomes associated with first-line cBTKi monotherapies in older adults with CLL. Patients aged ≥ 65years with CLL initiating first-line ibrutinib, acalabrutinib, or zanubrutinib monotherapy between January 1, 2020 and September 30, 2025 were included. Real-world time to treatment discontinuation (rwTTD), time to next treatment (rwTTNT), and overall survival (rwOS) were evaluated using Kaplan-Meier analyses and Cox proportional hazards models. Subgroup analyses were performed by age group. Among 10,523 patients included, 3006 (28.6%) received zanubrutinib (median follow-up 15.8months), 4309 (40.9%) received acalabrutinib (20.7months), and 3208 (30.5%) received ibrutinib (34.9months). Median rwTTD was not reached (NR) for zanubrutinib, compared with 24months for acalabrutinib and 14months for ibrutinib. Median rwTTNT was NR for zanubrutinib, 40months for acalabrutinib, and 20months for ibrutinib. After adjustments for age, sex, race, CCI, and year of index, zanubrutinib had significantly longer rwTTD (hazard ratio [HR] 0.57 [95%CI 0.51-0.61]), rwTTNT (HR 0.63 [0.55-0.71]), and rwOS (HR 0.64 [0.54-0.77]) compared to ibrutinib. Zanubrutinib also had significantly improved rwTTD (HR 0.86 [0.78-0.94]), rwTTNT (HR 0.87 [0.78-0.96]), and rwOS (HR 0.77 [0.66-0.88]) compared to acalabrutinib. Similar patterns were observed when stratified by age group over 65. These findings demonstrate that zanubrutinib is associated with improved real-world outcomes compared with other cBTKinhibitors.

Comprehensive genomic profiling (CGP) enables identification of patients eligible for targeted treatments, making it essential in the management of advanced cancer. This retrospective real-world study compared actionable mutations in CGP-tested patients with advanced/metastatic solid tumors to those who received single-gene/small-panel (SP) tests. Patients aged > 18years with advanced/metastatic solid tumors (including non-small cell lung cancer (NSCLC), colorectal cancer, prostate cancer, breast cancer, or melanoma) with a CGP or SP test reported between 1 January 2018, and 31 December 2022, were included. OncoKB-derived actionability was compared between the two cohorts. Inverse probability of treatment weighting (IPTW) was used to adjust for baseline characteristics. A weighted generalized linear model with log link was used to report actionability ratio (AR) and 95% confidence intervals (CI). Among 406 patients (CGP-tested cohort: 202, SP-tested cohort: 204), approximately half were diagnosed with NSCLC. After adjusting for baseline characteristics, CGP testing detected more actionable alterations than SP: OncoKB level 1 (50.0% versus 31.4%; AR 1.76 [95% CI: 1.24, 2.51]; p = 0.002), OncoKB level 2 (22.8% versus 10.3%; AR 2.53 [95% CI: 1.17, 5.48]; p = 0.018), and OncoKB level 1 or level 2 or level R1 (55.9% versus 41.2%; AR 1.5 [95% CI: 1.11, 2.01]; p = 0.008). CGP testing identified more actionable genetic alterations compared with SP testing methods for patients with advanced/metastatic NSCLC, colorectal cancer, prostate cancer, breast cancer, or melanoma. Expanding reimbursement and coverage for CGP testing as well as expanding CGP use can facilitate equitable treatment access for patients with advanced/metastatic cancer.

Bladder cancer (BC) is the most common malignancy of the urinary tract, with more than 75% of cases diagnosed as non-muscle-invasive bladder cancer (NMIBC). Intravesical Bacillus Calmette-Guérin (BCG) remains the gold standard adjuvant treatment for high-risk NMIBC owing to its ability to induce a robust local immune response within the bladder tumor microenvironment. Nevertheless, a substantial proportion of patients experience disease recurrence or progression, highlighting the need for improved therapeutic strategies. This narrative review examines the biological rationale and available clinical evidence supporting the combination of intravesical BCG with immune checkpoint inhibitors (ICIs) in high-risk NMIBC. A literature review was conducted to analyze the immunological mechanisms underlying BCG-induced antitumor activity, adaptive immune resistance, and the potential role of ICIs in modulating the tumor microenvironment. Clinical trials were evaluated with particular attention to patient populations, study design, safety profiles, and efficacy end points. From a biological perspective, BCG acts as an immunological primer by recruiting and activating innate and adaptive immune cells, while immune checkpoint inhibitors may counteract functional exhaustion of BCG-induced antitumor responses. However, translation of this rationale into consistent clinical benefit remains challenging. Early-phase studies have reported variable response rates in selected patient populations, particularly in BCG-unresponsive disease. In contrast, recent phase III data have shown that upfront combination strategies do not necessarily translate into improved oncological outcomes. Overall, while the combination of BCG and immune checkpoint inhibition is supported by a strong immunological rationale, current clinical evidence remains heterogeneous and largely derived from early-phase or ongoing trials, precluding definitive conclusions regarding long-term oncological benefit and durable bladder preservation. Despite a strong immunological rationale, the combination of BCG with immune checkpoint inhibitors remains investigational. Its adoption into routine clinical practice will require mature phase III evidence, validated predictive biomarkers, and a clear demonstration of superiority over established bladder-preserving treatment strategies.

Evidence guiding the optimal sequencing of later-line systemic therapy in advanced soft tissue sarcoma (STS) remains limited. The aim of this study was to identify prognostic factors for overall survival (OS) beyond second-line treatment and to explore therapy sequencing in routine clinical practice. A total of 90 patients with advanced STS receiving third-line or later systemic therapy were retrospectively analyzed. Extreme gradient boosting (XGBoost) was used to identify clinical predictors of 1-year OS. The most influential variables were subsequently evaluated in multivariable Cox models for OS from the start of third- and fourth-line therapy. Sequencing analyses compared OS according to the line of administration of commonly used later-line agents. In the third-line cohort (n = 88), inferior OS was independently associated with progression on second-line therapy (hazard ratio [HR] 2.31, p = 0.005). In contrast, lipo-/leiomyosarcoma histology was associated with improved survival (HR 0.37, p = 0.002), as was a time to progression ≥ 12months on first-line therapy (HR 0.43, p = 0.007). Findings were largely consistent in the fourth-line cohort (n = 57). Sequencing analyses suggested sustained activity of trabectedin in later lines (p = 0.023), greater benefit of earlier pazopanib use (p = 0.022), and no significant impact of treatment line for gemcitabine + docetaxel combination therapy (p = 0.12). Machine learning-guided variable selection identified clinically relevant predictors of survival in later-line STS. Prior treatment response and histology strongly influence outcomes, and exploratory sequencing analyses suggest differential timing effects across systemic therapy agents.

Interindividual variability in the efficacy and toxicity of 6-mercaptopurine (6-MP) and methotrexate (MTX) drugs remains a major challenge in the treatment of pediatric acute lymphoblastic leukemia (ALL). Germline variation in pharmacogenes involved in drug metabolism, transport, and folate pathways may contribute to this variability. In this retrospective cohort study, 43 pediatric patients with ALL treated at a tertiary referral center in Croatia according to ALL IC-BFM 2002 or 2009 protocols were genotyped for eleven variants in TPMT, ITPA, NUDT15, PACSIN2, MTHFR, TYMS, SLC19A1, and SLCO1B1 genes. Associations with average 6-MP dose during maintenance therapy, MTX pharmacokinetics during consolidation and MTX-related toxicity were analyzed. A polygenic risk score (PRS) was constructed to assess cumulative genetic risk of developing toxicity when administering these two drugs. Carriers of the ITPA rs1127354 variant required significantly lower average 6-MP doses compared with wild-type carriers. The NUDT15 rs61973267 variant was associated with higher tolerated 6-MP doses after exclusion of outliers. No significant associations were observed between individual variants and MTX clearance. A trend toward reduced risk of oral mucositis was observed in carriers of the SLCO1B1 rs4149056 variant. PRS analyses that included carriers of the TPMT rs1142345 and ITPA rs1127354 variants showed a borderline association with the requirement for 6-MP dose reduction. Our findings support a role for ITPA and NUDT15 variants in modulating 6-MP dose requirements, while single-variant associations with MTX pharmacokinetics and toxicity were limited and not supported. These results underscore the complexity of antimetabolite pharmacogenetics and suggest that integrative polygenic approaches may better capture clinically relevant pharmacogenetic risk.

Teclistamab is an established standard of care for the treatment of relapsed/refractory multiple myeloma (RRMM) based on MajesTEC-1 study results. United States (US)-based real-world studies of teclistamab treatment have had limited follow-up, were conducted in academic settings and/or had small sample sizes. This real-world study was conducted in a primarily US community-based oncology provider network to assess the real-world effectiveness and safety profile of teclistamab. This retrospective, observational, cohort study used Cardinal Health's Oncology Provider Extended Network. Adult patients with RRMM who received teclistamab on or after 25 October 2022, were identified through medical chart review. Patient characteristics, treatment patterns, and treatment history were described. Clinical outcomes included adverse events, response and survival rates, and duration of response. Data are presented for all patients and US Prescribing Information (USPI)-aligned and unaligned subgroups. The overall population included 101 patients, of which 30 and 71 were USPI-aligned and USPI-unaligned, respectively. Median age was 65.4years, 86.1% had an Eastern Cooperative Oncology Group Performance Status score of 1 and 37.6% had a high-risk cytogenetic profile. Most patients were triple-class exposed (93.1%) and/or refractory (65.3%). Median follow-up was 13.8months and overall response rates were 80.2%, 90.0%, and 76.1% in the overall, USPI-aligned, and USPI-unaligned subgroups, respectively. During step-up dosing, 32.7% and 8.9% of all patients had cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, respectively; 26.7% of all patients developed infections while receiving teclistamab. This real-world study demonstrated numerically higher response rates and broadly similar rates of adverse events in this population compared with the MajesTEC-1 trial, despite many patients having higher disease burden and worse performance status. These findings from primarily community oncology settings suggest that teclistamab is an effective treatment option for patients with RRMM in the real world.

Laryngeal cancer (LC) constitutes almost one third of the head and neck cancers, and its main risk factors, alcohol use and smoking, are well established. Our aim was to explore the variation in the incidence of LC between different occupations. This study was based on data from the Nordic Occupational Cancer Study (NOCCA), involving 14.9 million individuals from Denmark, Finland, Iceland, Norway, and Sweden. Occupational data from censuses were linked to cancer registry data from a period of up to 45years (21,166 LC diagnoses) using personal identity codes. Standardized incidence ratios (SIRs) were calculated for different occupations, using the respective national populations as a reference. Of the 21,166 patients with LC, 18,488 (87%) were men. The highest SIRs in men were noted among waiters (3.31, 95% confidence interval [CI] 2.69-4.02), beverage workers (2.51, 95% CI 1.91-3.24), and cooks and stewards (2.25, 95% CI 1.82-2.74). Among women, the highest SIRs were observed among building hands (7.37, 95% CI 3.53-13.55) and public safety workers (3.60, 95% CI 1.17-8.40). Farming and teaching occupations showed reduced SIRs in both sexes. The SIRs among male farmers, teachers, gardeners, and technical workers were reduced in all countries. The SIRs remained elevated and stable among cooks and stewards, waiters, packers, seamen, sales agents, and economically inactive males across the three 15-year periods from 1961 to 2005. The study confirms a major variation in the incidence of LC between occupations. The findings underscore the importance of considering lifestyle factors typical of each occupation in cancer risk assessments and the potential benefits of targeted prevention efforts.

Metabolic disorders are risk factors for hepatocellular carcinoma (HCC) through complex proinflammatory, molecular, and cellular processes within a systemic dysmetabolic milieu. Despite significant advancements in the last two decades, HCC remains a challenging condition to treat. Resmetirom is a liver‑directed, selective THR‑β agonist that enhances mitochondrial β-oxidation, reduces de novo lipogenesis, improves lipid and cholesterol homeostasis, and, in preclinical HCC associated with metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH-HCC) models, attenuates midkine/lipoprotein receptor-related protein 1 (MDK/LRP1)-mediated immunosuppressive crosstalk. In this article, we discuss the possibility and rationale for repurposing Resmetirom, which has recently been approved for the treatment of MASH, to potentially suppress MASLD/MASH-HCC. This discussion considers the evolving epidemiology of HCC, the ongoing challenges in HCC treatment, and the intricate connection between thyroid hormone signaling, MASLD, and HCC.

Understanding performance status (PS) is an essential aspect of oncologic care. PS is traditionally evaluated using the Karnofsky Performance Status (KPS) or Eastern Cooperative Oncology Group (ECOG) performance scales. Despite their ubiquity, these tools rely on subjective clinician interpretation and broad clinical categories, which contribute to poor inter-rater reliability and imprecise patient characterization. This study explores digital approaches to PS by leveraging three-dimensional video recordings and kinematic movement data to provide more objective, granular evaluations. In this single-center observational study, 34 oncology patients performed a standardized chair-to-table (CTT) movement. Of these participants, 52.9% were male and 47.1% were female. Patient movement was recorded using the Microsoft Kinect v2 sensor, which captures both color video (RGB) and depth-based skeletal tracking (Skeleton). Four oncologists independently reviewed the recordings and assigned KPS scores. Inter-rater reliability was assessed using the intraclass correlation coefficient (ICC). Pelvic acceleration metrics extracted from the Kinect data were correlated with summed KPS scores using Spearman's rank correlation. The ICC for KPS scoring was 0.844 for RGB and 0.790 for Skeleton recordings, indicating good inter-rater reliability despite notable inter-observer variability. Vertical pelvic acceleration (mean and median) strongly correlated with summed KPS scores in both RGB (ρ ≈ 0.73-0.75, p < 0.0001) and Skeleton recordings (ρ ≈ 0.69-0.72, p < 0.0001). Horizontal and maximum acceleration showed weaker or nonsignificant associations. Kinect-derived motion capture offers an objective and reproducible approach to characterizing a patient's PS. Strong correlations between vertical pelvic acceleration and clinician-assigned KPS scores support its potential to augment both the accuracy and granularity of PS evaluation. ClinicalTrials.gov ID: NCT07082257.