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Showing 80 of 2662 matching items (19450 indexed).

CochraneSystematic review

The Cochrane database of systematic reviews · Cochrane

Long-term hormone therapy for perimenopausal and postmenopausal women.

BACKGROUND: Hormone therapy is widely provided to control menopausal symptoms and has been used for the management and prevention of cardiovascular disease, osteoporosis and dementia in older women. This is an updated version of a Cochrane review first published in 2005. OBJECTIVES: To assess the long-term effects of prolonged use (at least one year) of hormone therapy on mortality, cardiovascular outcomes, cancer, gallbladder disease, fractures and cognition in perimenopausal and postmenopausal women. SEARCH METHODS: We used the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, three other databases and two trial registers, together with reference checking, citation searching and contact with study authors to identify the studies included in the review. The latest search date was 26 September 2024. SELECTION CRITERIA: We included randomised, double-blind trials in which peri- or postmenopausal women took hormone therapy or placebo for at least one year. We included various oestrogen formulations, with or without progestogens. We focused on studies assessing hormone therapy's effects on long-term clinical outcomes, including death, coronary events and cancer. Hormone therapy's efficacy in managing menopausal symptoms was beyond the scope of this review, and is assessed in other Cochrane reviews. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risk of bias and extracted data. We calculated risk ratios (RRs) for dichotomous data and mean differences (MDs) for continuous data, along with 95% confidence intervals (CIs). We assessed the certainty of the evidence using GRADE. MAIN RESULTS: We included 24 studies - with two newly added in this update - involving 45,660 participants. We derived nearly 70% of the data from two well-conducted studies: the Heart and Estrogen/progestin Replacement Study (HERS 1998) and the large, multi-component Women's Health Initiative research programme, which included two hormone therapy arms (WHI 1998). Across all the studies, most participants were postmenopausal American women with one or more comorbidities. The mean participant age in most studies was over 60 years. Only one included study focused on perimenopausal women. We present full results for all included studies with available data in the main review. The results presented below are drawn from WHI 1998, in which the combined hormone therapy arm and the oestrogen-only arm were run concurrently, with women assigned to the appropriate trial based on their uterus status. One study with 16,608 postmenopausal women with an intact uterus compared combined continuous hormone therapy (conjugated equine oestrogen and medroxyprogesterone acetate) to placebo, and measured outcomes at an average of 5.6 years of follow-up. Based on this study, combined continuous hormone therapy probably makes little to no difference to the risk of a coronary event (RR 1.17, 95% CI 0.95 to 1.44; moderate-certainty evidence). It may increase the risk of stroke (RR 1.39, 95% CI 1.09 to 2.09; low-certainty evidence) and venous thromboembolism (RR 2.03, 95% CI 1.55 to 6.64; low-certainty evidence). Compared to placebo, combined continuous hormone therapy probably increases the risk of breast cancer (RR 1.27, 95% CI 1.03 to 1.56; moderate-certainty evidence) and probably makes little to no difference to the risk of lung cancer (RR 1.06, 95% CI 0.77 to 1.46; moderate-certainty evidence). It may increase gallbladder disease requiring surgery (RR 1.64, 95% CI 1.30 to 2.06; 14,203 participants; low-certainty evidence), and probably reduces the risk of all clinical fractures (RR 0.78, 95% CI 0.71 to 0.86; moderate-certainty evidence). One study including 10,739 postmenopausal women who had undergone a hysterectomy compared oestrogen-only (conjugated equine oestrogen) hormone therapy to placebo, and measured outcomes at an average of seven years' follow-up. Based on this study, oestrogen-only hormone therapy probably makes little to no difference to the risk of coronary events (RR 0.94, 95% CI 0.78 to 1.13), venous thromboembolism (RR 1.32, 95% CI 1.00 to 1.74) and breast cancer (RR 0.79, 95% CI 0.61 to 1.01), all with moderate-certainty evidence. It may make little to no difference to the risk of lung cancer (RR 1.04, 95% CI 0.73 to 1.48; low-certainty evidence). Oestrogen-only hormone therapy probably increases the risk of stroke (RR 1.33, 95% CI 1.06 to 1.67) and gallbladder disease requiring surgery (RR 1.78, 95% CI 1.42 to 2.24), and probably reduces the risk of all clinical fractures (RR 0.73, 95% CI 0.65 to 0.80), all with moderate-certainty evidence. We judged most included studies to have a low risk of bias for most domains. The overall certainty of evidence for the main comparisons was moderate. The main limitation was that only about 30% of women were 50 to 59 years old at baseline, the age group most likely to consider hormone therapy for vasomotor symptoms. AUTHORS' CONCLUSIONS: Long-term follow-up of women using hormone therapy suggests that the risk profiles vary between combined hormone therapy and oestrogen-only therapy. Oestrogen-only hormone therapy probably makes little to no difference to coronary events, and probably increases the risk of stroke and gallbladder disease. It probably makes little to no difference in the risk of breast cancer, and probably reduces the risk of all fractures. Combined hormone therapy may increase the risk of thromboembolism and probably increases the risk of breast cancer. These results should be interpreted with caution as they are based on one study using oral hormone therapy, which may not represent the risks of the hormone therapy currently used in clinical practice.

NEJMRCT

The New England journal of medicine

Azacitidine-Venetoclax or Induction Chemotherapy for Acute Myeloid Leukemia.

BACKGROUND: Induction chemotherapy has long been a key component of curative therapy for fit patients with acute myeloid leukemia (AML), despite its frequently severe side effects and substantial health care utilization. For patients who are ineligible for induction chemotherapy, hypomethylating therapy plus venetoclax is the standard treatment owing to its efficacy and side-effect profile. METHODS: In this multicenter, phase 2 trial, we randomly assigned, in a 1:1 ratio, previously untreated adults with AML who were eligible for induction chemotherapy to receive either azacitidine plus venetoclax or induction chemotherapy. Patients with core binding factor fusions, mutations in the gene encoding FMS-like tyrosine kinase 3 (), or mutations in the gene encoding nucleophosmin-1 (; unless the patient was ≥60 years of age) were excluded. The primary end point was event-free survival. RESULTS: A total of 172 patients underwent randomization, with 86 patients assigned to each group. The median age of the patients was 64 years. A total of 72% of the patients had adverse-risk disease according to the European LeukemiaNet 2022 classification. At a median follow-up of 21.9 months, the median event-free survival was 14.5 months (95% confidence interval [CI], 10.4 to 24.4) in the azacitidine-venetoclax group, as compared with 6.2 months (95% CI, 4.1 to 10.1) in the induction chemotherapy group, corresponding to a hazard ratio for event or death of 0.57 (95% CI, 0.39 to 0.84; P = 0.002 by the stratified log-rank test). Infection of grade 3 or higher occurred in 28% of the patients (95% CI, 19 to 39) receiving azacitidine-venetoclax and in 41% of those (95% CI, 30 to 52) receiving induction chemotherapy; hemorrhage of grade 3 or higher occurred in 2% (95% CI, 0.3 to 8) and 12% (95% CI, 6 to 20), respectively. CONCLUSIONS: In this phase 2, randomized trial, azacitidine-venetoclax therapy led to significantly longer event-free survival than induction chemotherapy among induction-eligible patients with AML. (Funded by AbbVie and others; PARADIGM ClinicalTrials.gov number, NCT04801797.).

JNCCNArticle

Journal of the National Comprehensive Cancer Network : JNCCN · NCCN

Comparative Cost-Effectiveness Analysis of First-Line Immunotherapy for Advanced Melanoma Based on 10-Year Clinical Outcomes.

BACKGROUND: Recently, the CheckMate 067, KEYNOTE-006, and RELATIVITY-047 trials demonstrated the long-term efficacy and safety of 5 first-line therapies for advanced melanoma, including nivolumab + relatlimab, with >10 years of follow-up. However, the long-term economic outcomes are still unclear. This study aimed to assess the comparative cost-effectiveness of these strategies from a US health care perspective using more than a decade of clinical trial data. METHODS: Based on the data from clinical trial reports, we simulated a cohort of 1,662 patients with advanced melanoma across 5 treatment groups in which patients received ipilimumab, nivolumab, pembrolizumab, nivolumab + ipilimumab, or nivolumab + relatlimab as first-line therapy. A flexible parametric survival model was used, combined with background mortality rates, to estimate patients' lifetime overall survival and progression-free survival. A partitioned survival model was constructed to assess the total cost, quality-adjusted life-years (QALYs), total life-years, and incremental cost-effectiveness ratios (ICERs) for the 5 treatment strategies. Sensitivity analyses, including univariate, probabilistic, scenario, and subgroup analyses, were conducted to evaluate the robustness of the model and population differences. RESULTS: Nivolumab + ipilimumab provided the highest QALYs (7.30), followed by nivolumab + relatlimab (6.67 QALYs). Ipilimumab and nivolumab + relatlimab were associated with the lowest ($239,168) and highest ($471,610) costs, respectively. Compared with nivolumab, only nivolumab + ipilimumab resulted in ICERs below the willingness-to-pay threshold of $150,000/QALY. Drug costs and body weight were the most influential factors affecting ICERs. Nivolumab + ipilimumab demonstrated the highest probability of being the most cost-effective strategy. CONCLUSIONS: Among first-line immunotherapy strategies for advanced melanoma, nivolumab + ipilimumab and nivolumab + relatlimab provided the greatest survival benefits. After integrating treatment costs, safety, and health-related quality of life, nivolumab + ipilimumab was the most cost-effective strategy under base-case assumptions, followed by nivolumab monotherapy.

NEJMArticle

The New England journal of medicine

Daraxonrasib for Previously Treated-Mutant Non-Small-Cell Lung Cancer.

BACKGROUND: mutations, as a group, are the most common oncogenic drivers of non-small-cell lung cancer (NSCLC), and they occur in approximately 30% of patients. Whether daraxonrasib (RMC-6236) - an oral RAS(ON) multiselective, tri-complex inhibitor of guanosine triphosphate-bound mutant and wild-type RAS protein isoforms - is safe and effective in patients with-mutant NSCLC is unknown. METHODS: In this phase 1-2, multicenter, dose-escalation and dose-expansion study of daraxonrasib, we enrolled patients with previously treated advanced-mutant NSCLC and administered daraxonrasib in doses of 10 to 400 mg orally once daily in 21-day cycles. The primary end point was safety. Secondary end points included investigator-assessed objective response (complete or partial response) and the duration of response, with response assessed according to Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS: As of the data-cutoff date of July 21, 2025, a total of 136 patients with NSCLC who had been enrolled and treated with daraxonrasib at doses of 300 mg or less had been evaluated for safety and efficacy. Adverse events of any grade occurring with a dose of 300 mg or less, regardless of attribution, were reported in 99% of the patients, with rash, diarrhea, nausea, vomiting, and mucositis or stomatitis occurring in at least 30% of patients. Adverse events of grade 3 or higher were reported in 54% of the patients, with pneumonia (in 10%), diarrhea (in 9%), rash (in 8%), and anemia (in 5%) occurring in at least 5% of patients; four grade 5 adverse events occurred. The percentage of patients who had an objective response was 31% with daraxonrasib at a dose of 120 mg or less, 34% at doses of 160 to 220 mg, and 37% at a dose of 300 mg. CONCLUSIONS: Among patients with previously treated metastatic-mutant NSCLC receiving daraxonrasib at a dose of 300 mg or less daily, 54% had adverse events of grade 3 or higher, and antitumor activity was reported in more than 30%. (Funded by Revolution Medicines; RMC-6236-001 ClinicalTrials.gov number, NCT05379985.).

Nature MedicineArticle

Nature Medicine

Induced proximity comes of age

Nature Medicine, Published online: 03 September 2026; doi:10.1038/d41591-026-00045-z The first approved PROTAC for breast cancer validated the idea that medicines can work by bringing proteins together rather than by simply blocking them. Now, a new generation of proximity-based therapies is pushing that principle further.

NEJMArticle

The New England journal of medicine

Pulmonary Nodules.

Pulmonary nodules are classified as solid or subsolid, with subsolid nodules further classified as part-solid or pure ground-glass. Management strategies differ according to the type of nodule. A comparison of current and previous imaging studies, when available, is essential to assess the risk of the nodule being malignant. Solid nodules that have been stable for 2 years are considered to be benign, whereas subsolid nodules require a longer period of stability to be considered benign. Prediction models to stratify the risk of the nodule being malignant can be used to guide the management of solid nodules. Computed tomographic (CT) surveillance is indicated for low-risk nodules; positron-emission tomography-CT, biopsy, or both for intermediate-risk nodules; and surgical resection for selected high-risk nodules. Subsolid nodules are often slower growing than solid nodules but are associated with a higher risk of being malignant, especially if a solid component develops or progressively enlarges. Biopsy methods include transthoracic needle biopsy and navigational bronchoscopy. Optimal overall management balances timely diagnosis in persons who have cancer with the avoidance of unnecessary invasive procedures in persons who have benign disease.

NatureArticle

Nature

Biomarkers that predict improved outcomes after perioperative immune-based therapy for lung cancer.

Nature, Published online: 02 September 2026; doi:10.1038/d41586-026-02486-5 Comprehensive exploratory analyses of biomarkers were done in the phase III CheckMate 77T study of pre- and post-surgical treatment with the immunotherapy nivolumab in individuals with surgically resectable non-small-cell lung cancer. The analyses indicate that pre-surgical clearance of circulating tumour DNA, among other

NatureArticle

Nature

Current therapeutic landscape and future treatment perspectives of MASH.

Metabolic dysfunction-associated steatohepatitis (MASH), the progressive form of metabolic dysfunction-associated steatotic liver disease (MASLD), is a heterogeneous and systemic disease that confers risk not only for cirrhosis and hepatocellular carcinoma (HCC) but also for extrahepatic complications including cardiovascular disease and chronic kidney disease. Over the past decade, numerous late-stage clinical trials have advanced the therapeutic landscape of MASH, culminating in a pivotal inflection point with accelerated approval of the thyroid hormone receptor-β (THRβ) agonist resmetirom and the glucagon-like peptide-1 receptor (GLP-1R) agonist semaglutide, establishing pharmacological options for patients with non-cirrhotic MASH and fibrosis. Concurrently, growing evidence indicates that MASH comprises distinct, partially overlapping disease subsets, ranging from liver-centric phenotypes with accelerated fibrogenesis and liver-related outcomes to cardiometabolic phenotypes characterized by insulin resistance and increased cardiovascular risk. This suggests that optimal treatment efficacy will require stratified and potentially combinatorial approaches. In addition to lifestyle interventions, a cornerstone of MASLD management, pharmacotherapies targeting metabolic dysfunction (including PPAR agonists, FGF21 analogues or incretin-based and glucagon-based therapies), fibrogenesis, inflammation and/or the gut-liver axis are emerging. In this Review, we summarize the therapeutic landscape for MASH and discuss how recent advances in disease phenotyping and biomarkers may enable a transition towards personalized therapy.

NatureArticle

Nature

Molecular mechanisms and pathogenesis of MASH.

Metabolic dysfunction-associated steatotic liver disease (MASLD), including its progressive form metabolic dysfunction-associated steatohepatitis (MASH), represents the hepatic manifestation of metabolic syndrome and is increasingly recognized as a multi-organ disease. MASLD is now the most prevalent chronic liver disease worldwide and a rising indication for liver transplantation. MASLD incidence continues to increase, driven by sedentary lifestyles, the obesity epidemic and associated pathologies such as type 2 diabetes. MASH is a significant risk factor for fibrosis, cirrhosis and hepatocellular carcinoma (HCC)-a leading cause of cancer-related death. Over the past decade, substantial progress has been made in elucidating the molecular and cellular mechanisms driving MASLD initiation and progression. Key pathogenic processes include insulin resistance, genetic drivers, dysregulated hepatic lipid metabolism, lipotoxicity, adipose tissue dysfunction, immune-mediated inflammation, fibrogenesis and perturbations of the gut-liver axis. Increasingly, these mechanistic insights are informing clinical translation. Genetic risk variants and polygenic risk scores are beginning to enable improved risk stratification for disease progression and HCC. Furthermore, therapeutic strategies targeting defined metabolic pathways are emerging, including approaches that reduce hepatic lipogenesis or modulate mitochondrial metabolism. Here we highlight the state of the art of molecular and cellular mechanisms underlying MASH pathogenesis and its transition to HCC.

Nature MedicineArticle

Nature medicine

Atezolizumab in early triple-negative breast cancer: the randomized phase 3 NSABP B-59/GeparDouze trial.

Triple-negative breast cancer (TNBC) is an aggressive subtype with an activated tumor immune microenvironment. The multicenter, multinational, double-blinded NSABP B-59/GeparDouze trial evaluated the addition of atezolizumab (atezo) (773 patients randomized) or placebo (777 patients) to sequential taxane-carboplatin-anthracycline-based neoadjuvant chemotherapy in stage II-III TNBC. The addition of atezo did not significantly improve the primary endpoint of event-free survival (EFS) (HR, 0.80 (95% CI, 0.062-1.03); stratified log-rank P = 0.083, 4-year EFS rates difference 3.3%). The HR for overall survival was 0.86 (95% CI, 0.62-1.19), with a 4-year benefit of 0.7%. Prespecified subgroup analyses suggested heterogeneity in EFS, with benefit of atezo in patients presenting with clinical lymph node involvement (P = 0.039). Treatment-emergent adverse events with grades ≥3 were reported in 75.3% (atezo) versus 73.4% (placebo), and immune-related adverse events were reported in 27.6% (atezo) versus 11.4% (placebo). A total of 196 (25.5%) patients discontinued atezo and 143 (18.8%) patients discontinued placebo in the neoadjuvant phase. In an exploratory mRNA-based subset analysis, patients with basal-like immune-activated tumors may have benefited from atezo. TNBC subtyping to identify basal-like immune-activated tumors and quantification of tumor-infiltrating lymphocytes to identify tumors with high tumor-infiltrating lymphocyte counts could be a promising strategy to identify patients who benefit from the addition of immune checkpoint inhibitors to neoadjuvant chemotherapy. ClinicalTrials.gov registration: NCT03281954 .

JAMA Network OpenArticle

JAMA network open

Dietary Fat Intake and Mortality Among Patients With Nonmetastatic Prostate Cancer.

IMPORTANCE: There are 3.5 million prostate cancer survivors in the US, with a need for evidence-based lifestyle recommendations that improve survivorship. OBJECTIVE: To assess whether consumption of specific dietary fats after diagnosis is associated with long-term survival among patients with nonmetastatic prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: This study, nested in the Health Professionals Follow-Up Study, a cohort of male health professionals from across 50 US states ongoing since 1986, included participants with confirmed nonmetastatic prostate cancer between 1986 and January 2019, followed up through December 2022. Statistical analysis was conducted from July 2024 to May 2026. EXPOSURES: Dietary data were collected every 4 years from validated food frequency questionnaires and used to estimate intake of saturated, polyunsaturated, monounsaturated, trans, plant, and animal fat after cancer diagnosis. MAIN OUTCOMES AND MEASURES: Main outcomes were all-cause mortality and death from prostate cancer, other cancers, cardiovascular disease, and other causes during a median 12.8 years (IQR, 8.1-16.8 years) of follow-up through 2022. Hazard ratios (HRs) and 95% CIs from multivariable Cox proportional hazards regression and multivariate nutrient-density models examined associations with mortality, adjusting for demographic, epidemiologic, and clinical factors. RESULTS: Among 4884 patients with nonmetastatic prostate cancer, the mean (SD) age at diagnosis was 69.5 (6.9) years. During follow-up, 3040 deaths from any cause were confirmed. When comparing patients in the highest quintile of saturated fat consumption with those in the lowest quintile, higher postdiagnostic saturated fat intake was associated with greater all-cause (HR, 1.24 [95% CI, 1.05-1.47), cardiovascular (HR, 1.42 [95% CI, 1.02-1.98]), and other cancer mortality (HR, 1.42 [95% CI, 0.93-2.17]). Animal fat, a major source of saturated fats, was also positively associated with all-cause mortality (HR, 1.14 [95% CI, 0.97-1.33]), as well as deaths from other cancers (HR, 1.49 [95% CI, 1.00-2.21]). Replacing 10% of calories from animal fats with plant-based fats (HR, 0.84 [95% CI, 0.76-0.93]) and replacing 5% of calories from saturated fats with monounsaturated fats (HR, 0.80 [95% CI, 0.70-0.91]) was associated with a decrease in all-cause mortality. There were no associations between dietary fats and prostate cancer mortality. CONCLUSIONS AND RELEVANCE: In this cohort study of patients with nonmetastatic prostate cancer, saturated fats, including animal fats, were associated with greater all-cause mortality owing to deaths from cardiovascular disease and other cancers. Diets rich in monounsaturated and polyunsaturated fats and plant-based fats after prostate cancer diagnosis were associated with improved survival outcomes for patients. These findings support evidence-based recommendations for patients and clinicians around dietary fat consumption to improve survivorship outcomes in the clinical setting of nonmetastatic prostate cancer.

JAMA Network OpenArticle

JAMA network open

Historical Redlining and Spatiotemporal Patterns in Breast Cancer Screening.

IMPORTANCE: Geographic variation in breast cancer screening may reflect persistent structural inequities in access to preventive care. Understanding whether historical redlining remains associated with screening, independent of contemporary social vulnerability, neighborhood conditions, and geographic access, is critical for targeting interventions within cancer center catchment areas. OBJECTIVES: To examine the association between historical redlining and breast cancer screening prevalence, accounting for social vulnerability, neighborhood characteristics, and geographic access, and to characterize spatiotemporal screening patterns. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used Census tract-level data from 2016 to 2024 across the University of Kansas Cancer Center catchment area, including communities in Kansas and adjacent Missouri counties. The analytic sample included Census tracts with available Homeowners' Loan Corporation (HOLC) grades A (indicating the least redlining) to D (indicating the most redlining). Statistical analysis was performed from July to December 2025. EXPOSURES: HOLC grades; Social Vulnerability Index quintiles (with the first quintile indicating the lowest vulnerability and the fifth quintile indicating the highest); Census tract-level socioeconomic, housing, and transportation indicators; and distance to the nearest mammography facility. MAIN OUTCOMES AND MEASURES: Census tract-level breast cancer screening prevalence from the Centers for Disease Control and Prevention's PLACES database, reported as odds ratios (ORs) with 95% credible intervals (CrIs). RESULTS: A total of 1152 historically redlined Census tracts were analyzed. Tracts were categorized by HOLC grades A (n = 27), B (n = 99), C (n = 423), and D (n = 603). The median (IQR) screening prevalence was highest in grade A tracts (79.6% [79.0%-80.0%]) and lowest in grade D tracts (75.2% [71.7%-79.2%]). Models demonstrated substantial spatial and temporal dependence with geographic clustering and localized variability. Compared with grade A tracts, grade C (OR, 0.94; 95% CrI, 0.90-0.99) and grade D tracts (OR, 0.94; 95% CrI, 0.89-0.99) had lower screening prevalence after adjustment. The highest Social Vulnerability Index quintile was associated with increased screening odds (OR, 1.08; 95% CrI, 1.01-1.14). Lower educational attainment (OR, 0.94; 95% CrI, 0.92-0.96) and higher mobile home prevalence (OR, 0.98; 95% CrI, 0.97-1.00) were associated with lower screening odds. Residual spatial heterogeneity persisted (711 of 1152 tracts [61.7%] excluding the null). Screening peaked in 2018 to 2019, stabilized through 2023, and declined in 2024, with most areas remaining below the Healthy People 2030 target of 80.3%. CONCLUSIONS AND RELEVANCE: This study found that historical redlining was associated with lower breast cancer screening prevalence independent of contemporary social vulnerability, neighborhood conditions, and geographic access. These findings support sustained, place-based strategies addressing structural and socioeconomic barriers to improve screening uptake and progress toward national screening targets.

JAMA Network OpenArticle

JAMA network open

Laterality of Breast Radiotherapy and Ischemic Heart Disease by Cardiovascular Risk Burden.

IMPORTANCE: Although modern radiotherapy (RT) techniques have reduced cardiac exposure, concerns regarding RT-induced heart disease persist. Identifying which patients are most vulnerable to cardiac toxic effects is crucial for personalized survivorship care. OBJECTIVE: To evaluate whether the association between tumor laterality and ischemic heart disease (IHD) risk varies by cumulative baseline cardiovascular risk burden. DESIGN, SETTING, AND PARTICIPANTS: This retrospective nationwide cohort study used data on 23 305 women in the Korean National Health Insurance Service database who underwent postoperative RT for breast cancer without prior IHD from January 1, 2002, to December 31, 2018. The median follow-up was 4.3 years (IQR, 2.5-6.5 years); data analysis was completed in March 2023. EXPOSURES: Treatment laterality (left-sided vs right-sided RT) and baseline cardiovascular risk burden (defined as a count of 6 factors: age ≥55 years, obesity, smoking, hypertension, diabetes, and dyslipidemia). MAIN OUTCOMES AND MEASURES: The cumulative incidence of IHD was estimated using competing-risk analysis. Subdistribution hazard ratios (sHRs) were calculated using Fine-Gray models. RESULTS: Of 23 305 patients (mean [SD] age, 51.7 [9.2] years), 11 723 (50.3%) received left-sided RT and 11 582 (49.7%) received right-sided RT. Left-sided RT was associated with a statistically significant increase in IHD risk (sHR, 1.11; 95% CI, 1.01-1.22; P = .04). No statistically significant difference in IHD risk between left- and right-sided RT was observed among patients with 0 to 2 cardiovascular risk factors, whereas left-sided RT was associated with significantly higher IHD risk among patients with 3 risk factors (adjusted sHR, 1.37; 95% CI, 1.10-1.71; Gray test P = .004). CONCLUSIONS AND RELEVANCE: In this cohort study of 23 305 women with breast cancer, excess cardiac risk associated with left-sided RT was concentrated among patients with 3 cardiovascular risk factors. These findings suggest that among patients with low baseline risk profiles, the difference in IHD risk between left- and right-sided treatment may be small, whereas those with high cardiovascular burden warrant prioritized access to advanced heart-sparing modalities and aggressive risk factor management.

JNCCNArticle

Journal of the National Comprehensive Cancer Network : JNCCN · NCCN

New Paradigms in the Management of Castleman Disease.

Castleman disease (CD) comprises a heterogeneous group of rare lymphoproliferative disorders unified by characteristic lymph node histopathology but with substantial clinical, biologic, and therapeutic diversity. Over the past decade, major advances in disease classification, pathophysiologic understanding, and targeted therapy have reshaped the management of CD, particularly idiopathic multicentric CD (iMCD). The introduction of IL-6-directed therapy has transformed the management of iMCD by shifting treatment from empirical immunosuppression or cytotoxic chemotherapy toward a biologic-based approach, achieving durable disease control in most patients. Progress has also been made over the past several years in the anatomic, etiologic, and clinical classification of CD, enabling more individualized, severity-adapted treatment approaches across the disease spectrum. Emerging paradigms in CD management include the recognition of oligocentric CD (OligoCD) as an intermediate anatomic entity with distinct therapeutic implications, as well as the validation of idiopathic plasmacytic lymphadenopathy (IPL) as a clinically distinct subtype of iMCD. These developments underscore the importance of integrating disease distribution, subtype, and severity into therapeutic decision-making. In addition, the recent paradigm of CD management emphasizes early identification of refractory disease and timely escalation beyond biologic therapy. This review provides an updated overview of CD management, drawing on recent advances to discuss practical considerations in treatment selection across disease subtypes, as well as ongoing challenges and future directions.

JAMA Network OpenArticle

JAMA network open

Regional Variation in Bladder Cancer Clinical Trial Availability in the US.

IMPORTANCE: Geographic disparities in cancer clinical trial access are well described in the US, but patterns in bladder cancer remain poorly defined. OBJECTIVE: To evaluate bladder cancer trial availability across US counties and its associations with epidemiologic and socioeconomic factors. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study of completed, open, or active bladder cancer clinical trials from June 1, 2019, to June 1, 2025, on ClinicalTrials.gov used data on county-level incidence, mortality, and Social Vulnerability Index (SVI) obtained from the Centers for Disease Control and Prevention, the National Cancer Institute, and the Agency for Toxic Substances and Disease Registry and included interventional bladder cancer clinical trials of adults at 1 or more US sites. Data were analyzed from July 1, 2025, to October 20, 2025. EXPOSURES: Epidemiologic and socioeconomic characteristics of bladder cancer clinical trials. MAIN OUTCOME AND MEASURES: Trial availability was defined as 1 or more bladder cancer trial sites per county. Trial volume (number of unique trials per county) was modeled using a multivariable zero-inflated negative binomial regression and reported as incidence rate ratios. Associations between trial characteristics and location in highest vs lowest bladder cancer mortality quintile counties were assessed using a generalized linear mixed-effects logistic regression model. RESULTS: The study identified 436 bladder cancer trials across 713 US counties. Of 3145 counties, 713 (22.7%) had 1 or more trial sites, and 2432 (77.3%) had none. Most trials were sponsored by pharmaceutical companies (211 [48.4%]) or academic institutions (170 [39%]). Most trials were drug focused (350 [80.2%]) and early phase (phase 1 or phase 2; 314 [72%]). Higher bladder cancer incidence was associated with higher trial rates (incidence rate ratio [IRR], 1.03; 95% CI, 1.003-1.06). A higher bladder cancer mortality rate was associated with lower trial rates (IRR, 0.80; 95% CI, 0.73-0.88). Compared with counties with a high SVI, trial rates were higher in counties with a lower-middle (IRR, 1.57; 95% CI, 1.18-2.08), middle-high (IRR, 1.60; 95% CI, 1.22-2.11), and low SVI (IRR, 2.53; 95% CI, 1.89-3.38). Of 7091 trial sites, 225 (3.2%) were located in counties in the highest quintile for bladder cancer mortality. Pharmaceutical company-sponsored trials were less likely than academic trials to be in counties with the highest mortality rate (odds ratio, 0.11; 95% CI, 0.04-0.29; P < .001), as were trials enrolling fewer than 100 participants compared with more than 100 participants (odds ratio, 0.20; 95% CI, 0.09-0.46; P < .001). CONCLUSIONS AND RELEVANCE: In this cross-sectional study of 436 bladder cancer clinical trials across US counties, most counties lacked trials, with geographic availability concentrated in counties with a high bladder cancer incidence and low social vulnerability. Expanding trial sites to counties with a high mortality rate or a high SVI may improve the geographic availability of bladder cancer clinical trials.

JNCCNArticle

Journal of the National Comprehensive Cancer Network : JNCCN · NCCN

Fostering Improvements in Equitable Care Delivery: Insights From the Health Equity Report Card (HERC) Pilot in Academic Cancer Centers.

BACKGROUND: The Health Equity Report Card (HERC) was developed to support institutions in measuring equitable care practices and implementing improvement efforts. An objective of this study was to determine whether academic cancer centers can use their baseline HERC scores to identify institution-specific strategies to improve equitable care delivery. METHODS: This quality improvement study collected quantitative and qualitative data from 5 NCCN Member Institutions about their quality improvement efforts in response to their HERC baseline scores. This project took place over 18 months, between April 2022 and October 2024. RESULTS: The secondary objective of utilizing HERC baseline scores to identify improvement efforts was met, with 4 sites identifying and implementing improvement efforts in at least one domain. Sites reported barriers and facilitators for their improvement projects. Utilization of the HERC to develop strategies to improve equitable care delivery in response to baseline scores was feasible in academic cancer centers. Four sites used the HERC findings to support and prioritize strategies that had been previously identified and discussed but not fully implemented. Two sites identified new improvement efforts that had not been previously considered by their institution. The complexity of the health system, collaboration across departments, resource allocation, competing priorities, and leadership support were discussed as both challenges and facilitators in identifying and implementing improvement strategies. CONCLUSIONS: The HERC may offer a useful framework for prioritizing and assessing improvement efforts for academic cancer centers seeking to improve equitable care delivery.

NatureArticle

Nature

A binding-to-release strategy for targeted anticancer drug delivery.

Drug conjugates, such as antibody-drug conjugates (ADCs) and small molecule-drug conjugates (SMDCs), are often dependent on efficient receptor-mediated endocytosis for payload release-supported by about 10% of targets. For poorly internalizing targets, drug conjugates dissociate and clear rapidly, limiting efficacy. To overcome the limitation in the internalization-to-release (ITR) pattern, we introduce a binding-to-release (BTR) strategy that decouples drug release from endocytosis by positioning an electrophile for direct cleavage by a proximal nucleophilic residue within the binding pocket. To realize this, we developed phosphorus(V)-phenol exchange (PhoPEx), a sulfur(VI) fluoride exchange-inspired chemistry enabling release of various payloads. This platform demonstrated high specificity from in vitro to clinical specimens, achieving precise detection of fibroblast activation protein (FAP) expression in patient-derived lymph nodes. In therapeutic settings, the FAP-BTR-SMDC achieved 5.9-fold higher monomethyl auristatin E exposure (AUC) in tumours than internalization-dependent FAP-ITR-SMDC, matching FAP-ITR-ADC levels while minimizing off-target release. This led to improved ratios: the tumour-to-blood ratio was 14.7- and 3.6-fold higher than that of FAP-ITR-SMDC and FAP-ITR-ADC, respectively, and the tumour-to-liver ratio was 55.1- and 58.7-fold higher, respectively. This biodistribution increased the maximum tolerated dose and led to near-complete tumour regression in various tumour models. We further extended BTR to programmed cell death ligand 1 (PD-L1) and an mRNA-display-derived FAP peptide, suggesting potential broad applicability. This work establishes a framework that overcomes the internalization barrier, broadening the target scope for therapeutic and diagnostic conjugates.

CochraneSystematic review

The Cochrane database of systematic reviews · Cochrane

Electronic cigarettes for smoking cessation.

RATIONALE: Electronic cigarettes (EC) are handheld electronic vaping devices that produce an aerosol by heating a liquid. People who smoke, healthcare providers, and regulators want to know if EC can help people quit smoking, and if they are safe to use for this purpose. This update was conducted as part of a living systematic review. OBJECTIVES: To examine the safety, tolerability, and effectiveness of EC for helping people who smoke tobacco achieve long-term smoking abstinence, in comparison to non-nicotine EC, other smoking cessation treatments, and no treatment. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and PsycINFO to 1 January 2026, reference-checked, and contacted study authors. ELIGIBILITY CRITERIA: We included randomised controlled trials (RCTs) randomising people who smoked to an EC or control condition. Studies had to measure an eligible outcome. OUTCOMES: Critical outcomes were abstinence from smoking after at least six months, adverse events (AEs), and serious adverse events (SAEs). Important outcomes were biomarkers, toxicants/carcinogens, long-term study product use and long-term patterns of EC and combustible cigarette use. RISK OF BIAS: We used the RoB 1 tool to assess risk of bias for each study and GRADE to assess evidence certainty. SYNTHESIS METHODS: We followed standard Cochrane methods for screening and data extraction. Where appropriate, we pooled data using random-effects models to calculate risk ratios (RRs) with 95% confidence intervals (CI) for dichotomous outcomes apart from SAEs. For SAEs, we calculated risk differences (RD) and 95% CI. For continuous outcomes, we calculated mean differences (MD) or standardised mean differences (SMD) with 95% CIs. INCLUDED STUDIES: We included 80 completed RCTs, representing 29,861 participants. Nine of these RCTs were new to this update. We rated 12 included studies as being at low risk of bias, 41 at high risk, and the remainder at unclear risk overall. SYNTHESIS OF RESULTS: Nicotine EC result in increased quit rates compared to nicotine replacement therapy (NRT) (high-certainty evidence) (RR 1.61, 95% CI 1.23 to 2.12; I² = 55%; 11 studies, 4114 participants). In absolute terms, this might translate to an additional four quitters per 100 (95% CI 1 to 7 more). The proportion of participants experiencing AEs may be similar between groups (low-certainty evidence, limited by imprecision and inconsistency) (RR 0.95, 95% CI 0.72 to 1.24; I² = 72%; 8 studies, 3107 participants) and the proportion of participants experiencing SAEs is probably similar between groups (moderate-certainty evidence, limited by imprecision) (RD 0.01, 95% CI -0.01 to 0.02; I² = 0%; 10 studies, 4045 participants). Nicotine EC probably result in increased quit rates compared to non-nicotine EC (moderate-certainty evidence, limited by imprecision) (RR 1.34, 95% CI 1.05 to 1.69; I² = 0%; 7 studies, 1918 participants). In absolute terms, this might lead to an additional two quitters per 100 (95% CI 0 to 4 more). There is probably little to no difference in the proportion of participants experiencing AEs between these groups (moderate-certainty evidence, limited by imprecision) (RR 1.01, 95% CI 0.95 to 1.08; I² = 0%; 6 studies, 909 participants) and there may be similar proportions of SAEs (RD 0.00, 95% CI -0.01 to 0.01; I² = 0%; 11 studies, 1786 participants; low-certainty evidence downgraded due to very serious imprecision). Compared to behavioural support only or no support, quit rates may be higher for participants randomised to nicotine EC (low-certainty evidence due to risk of bias) (RR 1.75, 95% CI 1.39 to 2.20; I² = 13%; 11 studies, 7214 participants). In absolute terms, this represents an additional two quitters per 100 (95% CI 2 to 6 more). There was some evidence that people randomised to nicotine EC may be more likely to experience (non-serious) AEs (RR 1.22, 95% CI 1.00 to 1.49; I² = 58%; 11 studies, 2801 participants; very low-certainty evidence due to imprecision and risk of bias), but the evidence is uncertain. There was insufficient evidence to determine whether rates of SAEs differed between groups (RD 0.00, 95% CI -0.00 to 0.01; I² = 0%; 18 studies, 5032 participants; very low-certainty evidence downgraded due to imprecision and risk of bias). AUTHORS' CONCLUSIONS: There is high-certainty evidence that nicotine EC increase quit rates compared to NRT, and moderate-certainty evidence that they probably increase quit rates compared to EC without nicotine. Evidence comparing nicotine EC with behavioural support or no support also suggests benefit, but is less certain due to risk of bias inherent in the study designs. Overall incidence of SAEs was low across all study arms and there is now moderate-certainty evidence that SAE rates are similar when comparing nicotine EC with NRT. There was also no evidence of a difference in AEs between nicotine and non-nicotine EC nor between nicotine EC and NRT, but low-certainty evidence for increased AEs compared with behavioural support/no support. We did not detect evidence of serious short-term harm from nicotine EC, but longer, larger trials are needed to fully evaluate safety. The included studies tested regulated nicotine-containing EC; illicit products and/or products containing other active substances (e.g. tetrahydrocannabinol (THC)) may have different harm profiles. The main limitation of the evidence base remains imprecision for some comparisons. Further RCTs are underway. To ensure the review continues to provide up-to-date information, this is a living systematic review. We run and screen searches monthly, with the review updated when relevant new evidence becomes available. Please refer to the Cochrane Database of Systematic Reviews for the most recent version of this review. FUNDING: Cancer Research UK (PICCTR-2024/100012). The addition of new outcomes relating to vaping and smoking at six months or more was supported by the National Cancer Institute of the National Institutes of Health (NIH) and FDA Center for Tobacco Products (CTP) under Award Number 2U54CA229974. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the Food and Drug Administration. The funders were not involved in the decision to submit for publication. REGISTRATION: Protocol (2012) available via DOI: 10.1002/14651858.CD010216 (updates to 2012 protocol available via https://osf.io/upgjc/overview.

NatureArticle

Nature

Insights into longevity and virus-driven adaptation from Myotis bat genomes.

The genus Myotis is one of the largest clades of bats, and it exhibits some of the most extreme variation in lifespans among mammals, alongside unique adaptations to viral tolerance and immune defence. Here, to study the evolution of these phenotypes, we generated cell lines and near-complete genome assemblies for eight closely related Myotis species. Using genome-wide screens of positive selection, analyses of structural variation and functional experiments in primary cells, we identify patterns of adaptation contributing to longevity, cancer resistance and viral interactions. We demonstrate distinct modes of adaptation to DNA and RNA viruses compared with all other mammals, with bats exhibiting genome-wide over-representation of positive selection for DNA-virus-interacting proteins and elevated rates of copy-number variation for RNA-virus-interacting proteins. Characterization of Myotis-specific duplications of the key immune factor EIF2AK2 (also known as PKR) reveals multiple ancient segregating trans-species copy-number polymorphisms. We show that the recurrent evolution of longevity seen in Myotis is associated with positive selection in cancer pathways, and demonstrate a unique response to DNA damage in primary cells of the long-lived Myotis lucifugus. Together, our results suggest that bats' remarkable longevity and immunity are linked through pleiotropic adaptations to viruses and ageing-related disease.

Oto-HNSArticle

Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery · AAO-HNS

Preoperative Visualization of the Intraparotid Facial Nerve-Tumor Relationship in Parotidectomy.

Preoperative visualization of the intraparotid facial nerve remains challenging with conventional imaging. This retrospective case series evaluated the feasibility of three-dimensional double-echo steady-state with water excitation magnetic resonance imaging for identifying the intraparotid facial nerve and its relationship to parotid tumors. Fifteen lesions in 14 patients who underwent parotidectomy with preoperative imaging using this sequence were analyzed. The main trunk and major divisions were identified in 14 of 15 lesions (93%). Three-dimensional reconstructions demonstrated the tumor-main trunk relationship, and findings were concordant with intraoperative observations in all evaluable cases, including in the setting of distorted anatomy. Visualization of distal branches was limited. These findings suggest that this imaging technique enables preoperative assessment of the intraparotid facial nerve and may support surgical planning in anatomically complex cases.

NatureArticle

Nature

Functional role of skull lymphoid structures in CNS immunosurveillance.

Accumulating evidence demonstrates that the central nervous system (CNS) is not disconnected from the peripheral immune system; however, precisely how the adaptive immune system surveils the CNS remains a critical question. Recent findings reveal that channels between the skull and the dura mater facilitate the exchange of cerebrospinal fluid and immune cells between the CNS and skull bone marrow of mice under both homeostatic and disease conditions. Skull bone marrow functions as a source of immune cells for the CNS, yet its role in CNS antigen-specific adaptive immune responses remains unclear. Here we identify lymphoid structures within the skull bone marrow, featuring germinal-centre-like formations and containing a distinct population of follicular-helper-like T cells that promote B cell activation and humoral immunity through CD40L, IL-21 and IFNγ signalling. Adaptive immune cells within these skull bone marrow lymphoid structures surveil and respond to CNS-derived antigens and contribute to anti-tumour immune responses in mouse brain cancer models. Together, our findings show that the skull bone marrow is a site of CNS immunosurveillance that may influence immune responses across diverse neurological diseases.

NEJMArticle

The New England journal of medicine

Myeloproliferative Neoplasms.

Classic myeloproliferative neoplasms, including essential thrombocythemia, polycythemia vera, and primary myelofibrosis, are chronic, clonal hematopoietic stem-cell disorders. These disorders are driven by gain-of-function mutations in the genes Janus kinase 2 (), calreticulin (), or the thrombopoietin receptor () that activate cytokine signaling. These mutations arise decades before clinical disease develops and confer a clonal advantage that is further shaped by comutations in epigenetic, splicing, or signaling genes. Inflammation enhances clonal dominance, favoring the development of myelofibrosis and thrombotic complications. Disease evolution may culminate in secondary acute myeloid leukemia, which has a poor prognosis. Current therapies primarily aim to control symptoms, thrombosis, and splenomegaly, but they have limited disease-modifying effects, except for pegylated interferon alfa and JAK2 inhibitors in some patients. Emerging therapies that selectively target mutant CALR and JAK2 V617F using immunotherapy and selective inhibitors could be a breakthrough in the treatment of persons with myeloproliferative neoplasms, with the expectation of achieving durable disease modification and potentially clonal eradication.

JNCCNArticle

Journal of the National Comprehensive Cancer Network : JNCCN · NCCN

County-Level Medical Debt and Its Associations With Cancer Stage and Survival in the United States.

BACKGROUND: Medical debt is recognized as a social determinant of health. This study examines associations of county-level medical debt in collections with diagnosis stage and survival among individuals newly diagnosed with cancer in the United States. PATIENTS AND METHODS: A cohort of individuals aged ≥18 years newly diagnosed with cancer in 2011-2019 was identified from the National Cancer Database and followed through December 31, 2019. The county-level share of adults with medical debt in collections was combined with patient-level data. Hierarchical multivariable logistic and Cox proportional hazard models estimated associations of county-level medical debt with cancer diagnosis stage and overall survival, respectively, for all patients and by cancer type, clinical, and socioeconomic subgroups. RESULTS: A total of 7,558,658 individuals with cancer were identified, with median county-level medical debt of 18%, ranging from 0% to 56%. Patients in the highest medical debt quartile had the highest proportion with stage IV disease and lowest 5-year survival rate. After adjusting for other patient- and county-level characteristics, patients living in counties in the highest quartile of medical debt were more likely to be diagnosed with stage IV disease (odds ratio, 1.079; 95% CI, 1.064-1.094) and had poorer survival (hazard ratio, 1.072; 95% CI, 1.061-1.082) than those living in counties in the lowest quartile of medical debt, with a statistically significant dose-response relationship (P for trend <.001). Patterns were observed across major cancer types and were consistent across socioeconomic and clinical subgroups. CONCLUSIONS: County-level medical debt was associated with advanced-stage diagnosis and worse survival among individuals newly diagnosed with cancer. Future research is warranted to evaluate the recent and ongoing US policy changes on medical debt prevalence and their effects on cancer care and outcomes.

CochraneSystematic review

The Cochrane database of systematic reviews · Cochrane

Multimodal prehabilitation versus no prehabilitation to improve functional capacity, reduce postoperative complications and improve quality of life in colorectal cancer surgery.

This is a protocol for a Cochrane review (intervention). The objectives are as follows: To evaluate the benefits and harms of a multimodal prehabilitation programme versus no prehabilitation with respect to functional capacity, postoperative outcomes, and health-related quality of life for people with colorectal cancer undergoing elective resection.

AFPArticle

American family physician · AAFP

Amenorrhea: A Practical Approach to Diagnosis and Management.

Menstrual patterns can indicate overall health and reflect changes in endocrine, metabolic, or other systemic functions. Primary amenorrhea, defined as the lifelong absence of menses, warrants evaluation by age 15 years or 3 years postthelarche. Secondary amenorrhea is defined as the cessation of previously regular menses for 3 months or irregular menses for 6 months. Evaluation begins with a focused medical history, including prior menstrual patterns; eating and exercise habits; psychosocial stressors; medication use; chronic illness; and neurologic, vasomotor, or hyperandrogenic symptoms. Physical examination should assess anthropometric trends and pubertal development. Routine laboratory testing includes pregnancy testing and serum estradiol, follicle-stimulating hormone, luteinizing hormone, prolactin, and thyroid-stimulating hormone (thyrotropin) levels. Additional testing, including karyotyping, serum androgen evaluation, and pelvic or brain imaging, is individualized. Functional hypothalamic amenorrhea may indicate treatment for underlying disordered eating or low bone density. Patients with premature ovarian insufficiency benefit from hormone therapy until the average age of natural menopause. Addressing lifetime metabolic disease and endometrial cancer risk is necessary for patients with polyendocrine metabolic ovarian syndrome (formerly polycystic ovary syndrome).

AFPArticle

American family physician · AAFP

Atypical Moles.

Atypical moles are melanocytic lesions that clinically present with asymmetry, border irregularity, color variegation, or diameter 6 mm or greater. They are more common in patients with fair skin and high cumulative sun exposure. High mole density (more than 100) and presence of atypical moles are associated with increased risk of melanoma and should prompt periodic, systematic skin examinations. The US Preventive Services Task Force recommends patient or parent counseling for individuals with fair skin who are 6 months to 24 years of age on sun protection to reduce skin cancer risk and selective counseling for adults older than 24 years with fair skin and certain risk factors. To distinguish benign moles from melanoma, clinicians should use the ugly duckling assessment and ABCDE (asymmetry, border irregularity, color unevenness, diameter 6 mm or greater, evolution) mnemonic during clinical examination, incorporating dermoscopy if appropriately trained. Biopsy is sometimes necessary to exclude melanoma. Excisional biopsy should include 1- to 3-mm circumferential margins and sufficient depth. Postbiopsy management is guided by the degree of histopathologic atypia determined by the dermatopathologist, margin involvement, and patient risk factors.

Oto-HNSArticle

Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery · AAO-HNS

Awake Blue Laser Excision and Balloon Dilation of Oropharyngeal Stenosis in High-Risk Patients.

Oropharyngeal stenosis is a rare condition that can develop following head and neck cancer treatment, leading to progressive dyspnea, dysphagia, and dysphonia. Patients with symptomatic dyspnea may benefit from endoscopic surgery. However, head and neck cancer survivors can have severe trismus, limited neck extension, and altered laryngeal landmarks, which make rigid endoscopic surgery under general anesthesia high-risk or potentially not feasible without a tracheostomy tube. We describe an awake approach for the management of oropharyngeal stenosis for 2 head and neck cancer survivors with high-risk airways. Briefly, under monitored anesthesia care in the operating room, a flexible channeled nasolaryngoscope was utilized to perform awake blue light laser excision of stenosis followed by balloon dilation. Postoperatively, both patients reported symptomatic improvement, and objective increases in airway patency were noted at clinic follow-up. This operative technique represents a feasible, well-tolerated approach for high-risk airway patients with oropharyngeal stenosis.

JNCCNArticle

Journal of the National Comprehensive Cancer Network : JNCCN · NCCN

Current Surgical Perspectives for Pleural Mesothelioma.

This review summarizes the current NCCN recommendations for the surgical management of pleural mesothelioma, highlighting the clinical trials and retrospective analyses that have shaped current practice and informed guideline recommendations. Advances in systemic therapy, surgical technique, and radiation therapy have shifted management toward multidisciplinary care. Contemporary treatment paradigms emphasize the importance of histology, stage, performance status, and institutional expertise when considering surgical intervention. Surgery can still be considered part of the multimodality treatment strategy in carefully selected patients, despite recent evidence suggesting its possible lack of benefit. Further investigation is required to improve patient stratification, refine multimodal regimens, and develop novel therapeutic approaches. This review aims to provide a contemporary framework for understanding the current role of surgery within the broader management of pleural mesothelioma.

CochraneSystematic review

The Cochrane database of systematic reviews · Cochrane

Gemcitabine-based chemotherapy for advanced biliary tract carcinomas.

This is a protocol for a Cochrane review (intervention). The objectives are as follows: To assess the benefits and harms of intravenous administration of gemcitabine monotherapy or gemcitabine-based combination chemotherapy versus placebo or non-gemcitabine-based chemotherapy in people with advanced biliary tract carcinomas.

Oto-HNSArticle

Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery · AAO-HNS

Hospitalization Utilization Metric After Major Oncologic Head and Neck Surgery With Microvascular Free Flap.

OBJECTIVE: The primary length of stay (PLOS) metric fails to capture added time, costs, and reduced patient quality of life (QOL) associated with readmissions. To address these limitations, we propose a novel metric, the hospitalization utilization metric (HUM), which integrates PLOS and readmission LOS (RLOS). STUDY DESIGN: Retrospective review of 626 head and neck microvascular free flap (MVFF) cases from August 2019 to May 2024. SETTING: University of Pittsburgh Medical Center. METHODS: Main outcome measure was HUM, calculated as total length of stay (TLOS) (TLOS = [PLOS + RLOS]/60 days). High HUM, determined by median split, was >0.18. RESULTS: Our 626-patient cohort averaged 62.7 ± 11.9 years old. The majority of patients were male (68.2%), white (92.0%), with advanced tumors (III/IV: 74.1%), and public insurance (63.1%). The median (interquartile range [IQR]) PLOS was 9 (7-14), median (IQR) HUM was 0.18 (0.13-0.28), and the rate of 60-day re-presentation/readmission was 34.3%. Multivariable logistic regression identified postoperative complications (β: .08, P < .001; β: 4.44, P < .001, respectively) and private insurance (β: -.04, P < .02; -2.71, P < .01) as predictive factors associated with both higher HUM and PLOS (>9 days), respectively. Return to intensive care unit (ICU) (β: .08, P < .003) and duration of surgery (β: .005, P < .048) were independently associated with higher HUM, although both effect sizes are relatively small. Kaplan-Meier survival curves revealed that higher HUM (P = .030) but not PLOS (P = .098) was associated with worse survival 1 year postoperatively. CONCLUSION: HUM provides a comprehensive assessment of healthcare utilization compared to PLOS and re-presentation alone and may be a practical surrogate for patient QOL and healthcare costs.

Oto-HNSArticle

Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery · AAO-HNS

Management of Malignant Salivary Gland Tumors: A 20-Year SEER Database Analysis.

OBJECTIVE: Malignant salivary gland tumors represent a heterogeneous group of neoplasms with variable management. This study evaluated trends in therapeutic approaches to these cancers to inform evidence-based, personalized care and optimize patient outcomes. STUDY DESIGN: Retrospective cohort study. SETTING: Population-based analysis using the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: Cases of malignant salivary gland tumors diagnosed between 2000 and 2021 were categorized by treatment modality and stage at diagnosis. Trends over time were assessed using JoinPoint segmented log-linear regression. RESULTS: A total of 24,029 patients were included. Surgery alone (36.3%) and surgery with adjuvant radiation (36.5%) comprised the majority of treatments. Chemotherapy alone increased significantly over time (annual percent change [APC] +5.81%; 95% CI, 3.46-9.24; P < .05), though it remained infrequently used. Combined modalities including surgery, chemotherapy, and radiation also showed modest growth over the study period. Stage analysis revealed increasing proportions of localized and regional tumors and a decline in distant disease. CONCLUSION: Surgery remains the cornerstone of malignant salivary gland tumor management, but use of combined treatment approaches is rising, likely reflecting advances in systemic therapies and radiation techniques. Awareness of these trends is critical for guiding multidisciplinary, personalized care. Future studies integrating clinical outcomes and histologic subtype are warranted to clarify the role of expanding systemic and combined modalities.

Oto-HNSArticle

Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery · AAO-HNS

Management Patterns and Outcomes of Vestibular Schwannoma in Older Adults: Assessment of the SEER Database.

OBJECTIVE: Vestibular schwannoma (VS) is a benign intracranial tumor that is increasingly diagnosed in older adults. The relative contributions of tumor burden and surgical management to overall survival in elderly and very elderly patients remain incompletely characterized at a population level in VS patients. STUDY DESIGN: Retrospective Cohort. SETTING: SEER Database study between the years 2000 and 2022 to identify patients aged 70 to 89 years diagnosed with VS. METHODS: Patients were stratified into very elderly (80-89 years) and elderly (70-79 years) cohorts. Overall survival was assessed using Kaplan-Meier methods and multivariable Cox proportional hazards models. RESULTS: A total of 4156 patients were included (950 aged 80-89 years; 3206 aged 70-79 years). Overall survival was shorter in patients aged 80 to 89 years (median 46 months) compared with those aged 70 to 79 years (median 61 months) (P < .001). In the 80 to 89-year cohort, tumor size was independently associated with mortality when modeled continuously (HR 1.07 per 10-mm increase; 95% CI 1.03-1.12; P < .001). In a subanalysis of surgical patients aged 80 to 89 years, tumors ≤32 mm were associated with better overall survival compared with tumors >32 mm (HR 0.23; 95% CI 0.10-0.57; P = .001). In patients aged 70 to 79 years, survival differed by resection group, and gross total resection was associated with overall survival in adjusted analyses (HR 1.48; 95% CI 1.13-1.93; P = .005). CONCLUSION: In this dataset, surgical resection status was not associated with overall survival in patients aged 80 to 89 years, whereas associations between resection status and overall survival were observed in patients aged 70 to 79 years. These findings should be interpreted cautiously because this study cannot account for treatment-selection factors such as frailty, comorbidity burden, symptom severity, or treatment intent.

JNCCNGuideline

Journal of the National Comprehensive Cancer Network : JNCCN · NCCN

Mesothelioma: Pleural, Version 3.2026, NCCN Clinical Practice Guidelines In Oncology.

Mesothelioma is a rare cancer that originates from the mesothelial surfaces of certain sites within the body. Pleural mesothelioma is the most common type and represents approximately 85% of mesotheliomas. The NCCN Guidelines for Mesothelioma: Pleural provide recommendations for evaluation and treatment in patients with pleural mesothelioma. The NCCN Guidelines will continue to be updated annually based on available clinical evidence and panel consensus.

JNCCNGuideline

Journal of the National Comprehensive Cancer Network : JNCCN · NCCN

NCCN Guidelines® Insights: Survivorship, Version 3.2026.

The NCCN Guidelines for Survivorship offer guidance for health care providers who care for survivors of adult-onset cancer. These guidelines include screening, evaluation, and treatment recommendations for common physical and psychosocial problems resulting from cancer and its treatment and provide a framework for care coordination. They also present guidance for helping cancer survivors to enhance their wellness and maintain a healthy lifestyle. This article summarizes the panel's current recommendations and recent updates regarding anxiety, depression, distress, and trauma in cancer survivors.

Oto-HNSArticle

Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery · AAO-HNS

Safety and Efficacy of the Versius Surgical System in Transoral Robotic Surgery: A Prospective Study.

OBJECTIVE: To evaluate the safety and feasibility of the Versius surgical robotic system for transoral robotic surgery in benign and malignant head and neck indications. STUDY DESIGN: Open-label, prospective, single-arm, phase II clinical trial. SETTING: Liverpool Head and Neck Centre, United Kingdom. METHODS: Between December 2023 and March 2025, 62 patients were enrolled, with 60 undergoing transoral robotic surgery on the Versius system. Eligible adults had either confirmed oropharyngeal or unknown primary squamous cell carcinoma, or benign indications (recurrent tonsillitis or peritonsillar abscess). The primary endpoint was successful procedure completion without conversion, and safety was assessed by 30-day complication incidence. Secondary endpoints included operative and setup times, blood loss, length of stay, nasogastric tube use, readmissions, reoperations and margin status in malignant resections. RESULTS: All 60 procedures were completed successfully without conversion. Median setup time was 10 minutes and operative time 46 minutes. Estimated blood loss was <100 mL in 98% of cases, with no transfusions required. Median hospital stay was 1 day, with a 35% same day discharge rate. No patient required nasogastric tube feeding. Eleven postoperative complications occurred (18.3%), none device-related, and a secondary hemorrhage rate of 6.7%. Among 28 oncological resections, 25 (89.3%) achieved negative margins, including 21 of 22 (95.7%) cases with T1-T2 disease. CONCLUSION: The Versius surgical robotic system demonstrated high procedural success, low morbidity and oncological outcomes comparable to established robotic platforms. It represents a safe and feasible robotic platform for integration into a contemporary head and neck transoral surgery practice.

Oto-HNSArticle

Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery · AAO-HNS

Structural Racism and Head and Neck Cancer Risks and Outcomes: A Scoping Review.

OBJECTIVE: Persistent health inequities exist in Head and Neck Cancer (HNC) outcomes among racial and ethnic minority populations. Structural racism creates inequitable population-level risk for health conditions, including cancer. This study is the first to review the effects of structural racism on HNC risk factors and outcomes. DATA SOURCES: PubMed, Embase, Scopus, ProQuest, PapersFirst, MedNar, and Open Access Theses and Dissertations. REVIEW METHODS: PRISMA guidelines were utilized to search 7 databases from inception to May 6, 2024. 6734 deduplicated titles and abstracts were screened, of which 45 underwent full-text review. Thirty-one studies met the inclusion criteria of reporting a domain of structural racism impacting head and neck cancer risk factors or outcomes. RESULTS: Survival outcomes of HNC in racial and ethnic minority populations were associated with and compounded by neighborhood factors and socioeconomic status. Insurance status affected survival disproportionately in Black compared to White participants. Black participants demonstrated stronger estimates of association for higher intensity and duration of cigarette smoking. Perceived barriers to access to care among Black males contributed to delays in seeking treatment. Native Hawaiian and other Pacific Islanders were more likely to present with advanced-stage disease and had worse disease-specific survival compared to White populations. CONCLUSION: Structural racism significantly contributes to disparities in HNC risk factors and treatment outcomes experienced by racial and ethnic minorities in the United States. Further research is needed to evaluate structural racism domains to inform multi-level interventions to eliminate inequities in HNC among racial and ethnic minority populations.

Oto-HNSArticle

Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery · AAO-HNS

The Audiologic and Otolaryngologic Phenotype in WHIM Syndrome.

OBJECTIVE: WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis syndrome) is an ultra-rare primary immunodeficiency disease caused by autosomal dominant hyperfunctional mutations in the chemokine receptor CXCR4. Otolaryngologists are frequently consulted to evaluate WHIM patients because of recurrent acute ear and sinus infections, particularly in early childhood; however, a systematic assessment of otolaryngologic and audiometric phenotypes is lacking. This study comprehensively describes the auditory and otolaryngology phenotype of WHIM syndrome. STUDY DESIGN: Prospective observational case-series. SETTING: Quaternary Care Research Facility. METHODS: We report qualitative and quantitative otolaryngologic and audiometric assessments for 44 WHIM patients followed at the National Institutes of Health Clinical Center (NIH CC) for up to 17 years. RESULTS: Thirty-five patients gave a history of recurrent otitis media and 29 had a history of chronic or recurrent sinusitis. Hearing loss, usually bilateral and ranging from mild to profound, was identified in 43% (n = 18) of patients. Two previously unreported otolaryngologic phenotypes were also identified: maxillary sinus hypoplasia (n = 19, 51%) and defective olfaction (n = 22, 73%), including 6 patients (27%) with anosmia. Neither impaired olfaction nor maxillary sinus hypoplasia was associated with upper respiratory infection frequency or severity. Two patients were diagnosed with human papillomavirus head and neck squamous cell carcinoma (HNSCC). CONCLUSION: The results reveal a possible noninfectious direct effect of hyperfunctional CXCR4 on paranasal sinus development and odorant sensing and demonstrate a high risk of hearing loss. Further, the results emphasize the importance of baseline assessment and careful follow-up of WHIM patients by otolaryngologists and audiologists. CLINICALTRIALS: gov NCT02231879 and NCT00128973.

JNCCNArticle

Journal of the National Comprehensive Cancer Network : JNCCN · NCCN

Metabolic Tumor Volume as a Predictor of Benefit From Prophylactic Cranial Irradiation in Limited-Stage Small Cell Lung Cancer.

BACKGROUND: Prophylactic cranial irradiation (PCI) reduces the incidence of brain metastases (BMs) in patients with limited-stage small cell lung cancer (LS-SCLC). However, predictive biomarkers that identify patients most likely to benefit from PCI have not been established. This study investigates the potential of 18F-fluoro-2-deoxyglucose (18F-FDG) PET as a predictor of PCI benefit in patients with LS-SCLC. PATIENTS AND METHODS: This multicenter study analyzed patients with LS-SCLC who underwent brain MRI and 18F-FDG PET/CT at baseline, followed by treatment with concurrent chemoradiotherapy. To evaluate whether the benefit of PCI varies according to BM risk, we compared outcomes between PCI-treated and untreated patients stratified by risk group. RESULTS: Of 261 patients overall, 171 received PCI and 90 did not. In patients not receiving PCI, high metabolic tumor volume (MTV; >45.201 cm3) was associated with inferior intracranial time to progression (iTTP; hazard ratio [HR], 5.62; 95% CI, 1.69-18.77; P=.005), progression-free survival (PFS; HR, 2.35; 95% CI, 1.38-4.02; P=.002), and overall survival (OS; HR, 2.23; 95% CI, 1.27-3.91; P=.005). Conversely, MTV demonstrated no significant association with survival outcomes among PCI recipients. Subgroup analysis revealed that PCI conferred no survival advantage in the low-MTV group, whereas in the high-MTV group, PCI was associated with improved iTTP (HR, 0.27; 95% CI, 0.15-0.51; P<.001), PFS (HR, 0.49; 95% CI, 0.35-0.69; P<.001), and OS (HR, 0.56; 95% CI, 0.40-0.80; P=.001). Interaction analysis confirmed a significant effect modification between MTV status and PCI benefit for iTTP, PFS, and OS, supporting MTV as an independent predictive biomarker for PCI benefit. CONCLUSIONS: Baseline PET-derived MTV serves as a clinically relevant predictor of PCI benefit in LS-SCLC, supporting a risk-adapted PCI strategy guided by metabolic imaging biomarkers. This approach may reduce unnecessary neurotoxicity and optimize treatment outcomes and should be prospectively validated.

JAMAArticle

JAMA

Stereotactic Body Radiotherapy vs Moderately Hypofractionated IMRT for Localized Intermediate-Risk Prostate Cancer: A Randomized Clinical Trial.

IMPORTANCE: The treatment of prostate cancer with radiotherapy is evolving. How quickly radiotherapy can be delivered, and the relative risks and benefits of such a treatment, is of significant public interest. OBJECTIVE: To determine whether stereotactic body radiotherapy (SBRT) was superior to moderately hypofractionated intensity-modulated radiation therapy (MH-IMRT) in terms of patient-reported urinary irritative/obstructive and bowel quality of life and disease-free survival (DFS). DESIGN, SETTING, AND PARTICIPANTS: NRG-GU005 was a phase-3, international, open-label, randomized clinical trial. The study was activated on November 16, 2017, and closed to accrual on June 8, 2022. Date of last follow-up was October 13, 2024. There were 136 centers in Asia, Canada, Europe, and the United States that accrued patients to the study. Patients with localized prostate cancer, clinical stage T1-T2b with Gleason 3 + 4 (grade group 2) and prostate-specific antigen (PSA) level less than 20 ng/mL or Gleason 3 + 3 (grade group 1) and PSA level 10 to 20 ng/mL were eligible. Intended accrual of 692 patients provided reductions of 8% and 10% in minimal clinically important decline (MCID) frequency for urinary-irritative/obstructive and bowel domains of the Expanded Prostate Cancer Index Composite-26 Item (EPIC-26) instrument at 2 years and greater than 80% power to detect a hazard ratio of 0.62 in DFS. INTERVENTIONS: Patients were randomized 1:1 to receive SBRT (36.25 Gy in 5 fractions; n = 353) or MH-IMRT (70 Gy in 28 fractions or 60 Gy in 20 fractions; n  =345). MAIN OUTCOMES AND MEASURES: Primary outcomes were the frequency of an MCID in the urinary irritative/obstructive and bowel domains of the EPIC-26 at 2 years and DFS at 3 years. RESULTS: A total of 698 patients were randomized. Median age was 68 years; 3% were Asian, 13% Black, and 80% White. Median follow-up was 3.2 years (range, 0-6.5). At 2 years, there was no significant difference in the urinary-irritative domain (35.4% vs 33.7%, P = .68). Urinary incontinence at 1 and 2 years after treatment and sexual function at 1 year after treatment favored SBRT. Fewer grade 3 + 4 genitourinary adverse events occurred in the SBRT vs MH-IMRT group (0.6% vs 2.5%, P = .04). There were significantly fewer MCIDs with SBRT vs MH-IMRT in the bowel domain (34.9% vs 43.8%, P = .03). At 3 years, DFS for MH-IMRT was 92.1% (95% CI, 88.9%-95.2%) vs 88.6% for SBRT (95% CI, 85.2%-92.1%) (1-sided log-rank P < .001). CONCLUSIONS AND RELEVANCE: Stereotactic body radiotherapy using a modest dose prescription improved multiple quality-of-life domains but was not superior to MH-IMRT in terms of DFS. The rate of PSA failure was not significantly improved in the SBRT vs MH-IMRT group. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03367702.

NatureArticle

Nature

Biomarkers of nivolumab benefit in resectable non-small cell lung cancer.

Perioperative nivolumab significantly improved event-free survival (EFS) compared with placebo in patients with resectable non-small cell lung cancer (NSCLC) in the CheckMate 77T study (ClinicalTrials.gov NCT04025879 ). Here, after randomization, 98 out of 229 patients who received nivolumab and 92 out of 232 patients who received placebo had evaluable biomarkers (41% of randomized patients). Of the 98 patients receiving nivolumab, 83 (85%) had detectable circulating tumour DNA (ctDNA) before initiating neoadjuvant treatment and 90 (92%) at neoadjuvant treatment completion. Of the 92 placebo-treated patients, 75 (82%) had detectable ctDNA at the treatment start and 78 (85%) at completion. Among the 98 nivolumab-treated patients, 76 (78%) had detectable and evaluable ctDNA before and after neoadjuvant treatment, and 50 of them (66%) had pre-surgical ctDNA clearance, and 25 out of 50 (50%) had pathologic complete response (pCR). For the placebo-treated group, these values were 64 out 92 (70%) for detectable and evaluable ctDNA before and after neoadjuvant treatment, and 24 out of 64 (38%) had pre-surgical ctDNA clearance, and 3 out of 24 (12%) had pCR. Furthermore, 4 out of 48 (8%) patients in the nivolumab group and 9 out of 44 (20%) in the placebo group who were negative for molecular residual disease (MRD) after surgery and before adjuvant treatment initiation became positive during the adjuvant treatment period; all had disease recurrence. EFS seemed to be prolonged with nivolumab (n = 60) versus placebo (n = 45) in patients with single or co-alterations in any of the KEAP1, STK11, CDKN2A and/or SMARCA4 driver genes (hazard ratio, 0.48; 95% confidence interval, 0.28-0.83). In a machine-learning model trained using biomarker-evaluable patients, top predictors of prolonged EFS included pre-surgical ctDNA clearance, non-N2 NSCLC, pCR, squamous tumour histology and nivolumab treatment. These findings provide insights into predictive markers for outcomes with perioperative nivolumab in resectable NSCLC.

Nature MedicineArticle

Nature medicine

First-line PD-1/VEGF bispecific antibody plus chemotherapy in triple-negative breast cancer: a phase 2 trial.

Triple-negative breast cancer is an aggressive subtype comprising 10-20% of all breast cancer cases and has a worse prognosis than other subtypes. This open-label, multicenter, single-arm, phase 2 clinical trial evaluates the safety and efficacy of ivonescimab combined with chemotherapy as first-line treatment in female patients with locally advanced unresectable or metastatic triple-negative breast cancer who have not received previous systemic therapy. Eligible patients received ivonescimab 20 mg kgintravenously every 2 weeks and paclitaxel 90 mg mor nab-paclitaxel 100 mg mintravenously on days 1, 8 and 15 of each 4-week treatment cycle. The primary endpoints were safety and the investigator-assessed objective response rate per RECIST v.1.1. A total of 36 patients were enrolled. As of July 15, 2025, the median follow-up duration was 22.1 months. The primary endpoints were met. Treatment-related adverse events occurred in 36 (100.0%) patients. Grade ≥3 treatment-related adverse events were reported in 21 (58.3%) patients. No treatment-related deaths occurred. Immune-related adverse events occurred in 15 (41.7%) patients, with grade ≥3 events in 4 (11.1%) patients. Of the 35 patients evaluable for treatment efficacy, the objective response rate was 80.0% (95% confidence interval: 63.1-91.6), including 2 (5.7%) complete responses and 26 (74.3%) partial responses. Ivonescimab plus chemotherapy demonstrated encouraging antitumor activity as first-line therapy for patients with previously untreated advanced triple-negative breast cancer and merits further investigation. ClinicalTrials.gov identifier: NCT05227664 .

NatureArticle

Nature

In vivo genome-wide CRISPR screens of human T cells in solid tumours.

Large-scale CRISPR screening in human T cells holds significant promise for identifying genetic modifications that enhance cellular immunotherapy. Yet, many regulators of T cell performance in solid tumours are not revealed in vitro. In vivo screening in tumour-bearing mice is more physiological but has been limited by low intratumoural T cell recovery. Here we developed an in vivo model that efficiently recovers human T cells from solid tumours, permitting genome-wide CRISPR screens with few mice. Tumour-infiltrating T cells from this model exhibit hallmarks of dysfunction compared with splenic T cells, creating an ideal screening context. We performed two genome-wide CRISPR knockout screens to identify regulators of intratumoural T cell abundance and effector function. The abundance screen revealed the P2RY8-Gα13 GPCR signalling axis as a negative regulator of T cell tumour infiltration. The effector function screen identified GNAS as a key driver of T cell dysfunction in tumours, whose product, Gαs, acts as a convergent node downstream of multiple GPCRs sensing distinct suppressive ligands. Knockout of GNAS rendered T cells resistant to multiple suppressive cues and significantly improved efficacy across diverse solid tumour models in chimeric antigen receptor (CAR) and T cell receptor (TCR) systems. Combinatorial knockout of P2RY8-GNAS further enhanced tumour control, demonstrating that complementary in vivo screens can identify orthogonal targets whose combined editing improves therapeutic potency. This flexible, scalable platform can be adapted for systematic discovery of genetic strategies to improve solid tumour T cell therapies.

NatureArticle

Nature

Rb-driven transcription limits its tumour-suppressive effects in breast cancer.

The retinoblastoma protein (Rb) is a tumour suppressor best known for repressing E2F transcription factors and halting cell cycle progression. In hormone receptor-positive (HR) breast cancer, CDK4/6 inhibitors activate Rb by preventing its phosphorylation, forming a key component of current endocrine therapy regimens. How pharmacologically activated Rb remodels chromatin and influences transcription beyond cell cycle arrest remains poorly understood. Here we show that CDK4/6 inhibition induces redistribution of hypophosphorylated Rb to promoters and enhancers. Although Rb predictably binds to cell cycle gene promoters to repress transcription, at other sites, it unexpectedly promotes expression of oestrogen-responsive genes by integrating into oestrogen receptor (ER)-rich transcriptional hubs. CDK4/6 inhibition enhances ER target gene expression in breast cancer cells, patient-derived xenografts and clinical HRbreast cancer samples in an Rb-dependent manner. This reprogramming is mediated in part by KDM5A, whose interaction with Rb contributes to gene regulation at these loci. Critically, components of this Rb-driven ER transcriptional program are pro-proliferative. In endocrine-sensitive tumours, this effect can be neutralized with anti-oestrogen therapy, explaining therapeutic synergy. In endocrine-resistant settings such as ESR1-mutant breast cancer, the program persists, limiting the therapeutic efficacy of CDK4/6 inhibition. These findings reframe Rb as a dual-function transcriptional regulator that, although enforcing cell cycle arrest, can also activate programs that counteract its tumour suppressor function.

Nature MedicineArticle

Nature medicine

Acquired resistance to the RAS(ON) multi-selective inhibitor daraxonrasib guides rational combination therapy strategies in pancreatic cancer.

Daraxonrasib is an orally bioavailable RAS(ON) multi-selective tri-complex inhibitor of the oncogenic mutant and wild-type variants of N, H and KRAS. We previously reported encouraging efficacy in a phase 1/2 clinical trial evaluating daraxonrasib monotherapy at clinically active dose levels in patients with previously treated, RAS mutant metastatic pancreatic adenocarcinoma (PDAC), providing the basis for confirmatory evaluation in the randomized phase 3 RASolute 302 clinical trial. Here we report mechanisms of acquired resistance to daraxonrasib monotherapy observed through targeted sequencing of over 800 genes in paired pretreatment and end of treatment circulating tumor DNA samples from 44 patients in the phase 1/2 clinical trial. Treatment-emergent genomic alterations in the RAS signaling pathway were observed in more than half (26 of 44; 59%) of these patients, including, most notably, mutant KRAS amplifications in one-third (16 of 44; 36%), as well as alterations in receptor tyrosine kinase (RTK) (4 of 44; 9%), MAPK (11 of 44; 25%) and PI3K (4 of 44; 9%) pathways. Notably, no acquired secondary KRAS mutations were observed, distinct from resistance profiles of mutant-selective KRAS G12C(OFF) inhibitors. To corroborate these clinical findings, we found, or mechanistically established, concordant mechanisms of daraxonrasib resistance in human and murine preclinical models of PDAC, including mutant KRAS and MYC amplification and RTK upregulation, with these alterations guiding various combination therapy concepts. Notably, daraxonrasib combined with agents targeting DNA damage response, RTKs or the mutant-selective RAS(ON) G12D inhibitor zoldonrasib averted resistance in preclinical models. Collectively, these results show that most daraxonrasib genomic resistance mechanisms drive reactivation of RAS pathway signaling and guide potential combination strategies in PDAC for further investigation.

CochraneSystematic review

The Cochrane database of systematic reviews · Cochrane

First-line systemic treatment for people with extensive-stage small cell lung cancer: a network meta-analysis.

RATIONALE: Extensive-stage small cell lung cancer (SCLC) carries a poor prognosis and has limited therapeutic options. The addition of immune-checkpoint inhibitors (ICIs) to platinum-etoposide (PE) chemotherapy has become an important first-line treatment strategy. However, the comparative benefits and harms of different first-line chemotherapy-based regimens, including ICI-containing combinations, remain unclear. OBJECTIVES: To evaluate the comparative benefits and harms of immunotherapy (anti-PD-1, anti-PD-L1, or anti-CTLA-4), plus chemotherapy and other relevant first-line systemic chemotherapy-based regimens, for the first-line systemic treatment of extensive-stage SCLC with a network meta-analysis; to rank the interventions according to their benefits and harms; and to explore the potential role of biomarkers or clinical factors, where data are available. SEARCH METHODS: We used CENTRAL, MEDLINE, and Embase, together with clinical trial registries, to identify studies that were included in the review. The latest search date was 12 December 2025. ELIGIBILITY CRITERIA: We included randomised controlled trials (RCTs) comparing first-line systemic chemotherapy-based regimens, including chemotherapy alone, chemotherapy combined with ICIs, and other relevant combination strategies, in adults (≥ 18 years) with previously untreated extensive-stage SCLC. OUTCOMES: Critical outcomes were overall survival (OS) and adverse events (AEs). These include any grade AEs, serious AEs, and grade ≥ 3 AEs. Important outcomes were progression-free survival (PFS), objective response rate (ORR), and health-related quality of life (HRQoL). RISK OF BIAS: We assessed the risk of bias using the Cochrane RoB 2 tool. We judged most studies to have low risk of bias or some concerns across key domains. Some concerns mainly related to measurement of the outcome in open-label trials and selection of the reported result where protocols or registry entries were unavailable or incomplete. The extent to which these limitations may have influenced the critical outcomes of OS and AEs remains uncertain. SYNTHESIS METHODS: We synthesised results for each outcome using meta-analysis where possible, using a contrast-based random-effects network meta-analysis with a common heterogeneity parameter. For network meta-analysis, we assessed the certainty of the evidence using the GRADE approach, informed by the CINeMA framework. INCLUDED STUDIES: Fourteen RCTs were included, with 7541 participants contributing to the critical outcome of OS. The evidence network comprised a total of 17 treatment regimens. Most studies compared PE chemotherapy combined with ICIs targeting programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1). Some trials evaluated additional immune-checkpoint pathways, including cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and T-cell immunoreceptor with Ig and ITIM domains (TIGIT), or incorporated anti-angiogenic agents. SYNTHESIS OF RESULTS: For OS, based on a network meta-analysis of 14 studies (7541 participants), PE + benmelstobart + anlotinib reduced the hazard of death most compared with PE (hazard ratio (HR) 0.61, 95% confidence interval (CI) 0.47 to 0.79; high-certainty evidence), followed by PE + serplulimab (HR 0.63, 95% CI 0.49 to 0.82), PE + durvalumab (HR 0.71, 95% CI 0.59 to 0.85), and PE + adebrelimab (HR 0.72, 95% CI 0.58 to 0.90). Several other regimens, including PE + tislelizumab, PE + atezolizumab, PE + pembrolizumab, PE + toripalimab, and PE + durvalumab + tremelimumab, also reduced the hazard of death compared with PE. For PFS, based on 14 studies (7541 participants), the largest reductions in the hazard of progression were with PE + benmelstobart + anlotinib (HR 0.32, 95% CI 0.25 to 0.40) and PE + anlotinib (HR 0.44, 95% CI 0.36 to 0.54; high-certainty evidence). Several other regimens, including PE + tislelizumab, PE + serplulimab, PE + toripalimab, PE + adebrelimab, PE + pembrolizumab, PE + atezolizumab, and PE + durvalumab, also reduced the hazard of progression compared with PE. For ORR, based on 14 studies (7385 participants), PE + benmelstobart + anlotinib (RR 1.22, 95% CI 1.09 to 1.35), PE + anlotinib (RR 1.22, 95% CI 1.09 to 1.35), PE + pembrolizumab (RR 1.14, 95% CI 1.00 to 1.31), and PE + serplulimab (RR 1.14, 95% CI 1.03 to 1.26) increased the ORR compared with PE (high-certainty evidence), whereas most other regimens showed little or no difference compared with PE. Safety profiles varied across regimens. For any AEs, based on 11 studies (6249 participants), the risk was higher with PE + serplulimab (RR 1.25, 95% CI 1.08 to 1.43; high-certainty evidence) and was also increased with PE + ipilimumab and PE + atezolizumab-based combinations. For serious AEs, based on 10 studies (4264 participants), several regimens showed higher risks compared with PE. The largest increases were with PE + tislelizumab (RR 1.75, 95% CI 1.25 to 2.45) and PE + durvalumab + tremelimumab (RR 1.42, 95% CI 1.14 to 1.77). Higher risks were also seen with PE + adebrelimab, PE + benmelstobart + anlotinib, PE + toripalimab, and PE + socazolimab. For grade ≥ 3 AEs, based on 12 studies (6446 participants), differences between most regimens and PE were small, with increases for PE + atezolizumab + tiragolumab, PE + durvalumab + tremelimumab, PE + anlotinib, and PE + benmelstobart + anlotinib. HRQoL data were insufficient for quantitative synthesis because measurement instruments and reporting formats differed across studies; therefore, we summarised the findings narratively. AUTHORS' CONCLUSIONS: In people with extensive-stage SCLC, several ICI-based combinations with PE chemotherapy improve OS compared with PE alone (high-certainty evidence), although the magnitude of benefit varies across regimens. Some combinations probably or may have little to no effect on OS. Effects on PFS and ORR vary across treatments, and some combinations increase the risk of AEs whereas others result in little to no difference. HRQoL data were insufficient for quantitative synthesis, and so we are unable to draw conclusions about this outcome. The certainty of the evidence varies across outcomes and comparisons, reflecting differences in study design, variability in safety reporting, and limited direct head-to-head comparisons. Further RCTs directly comparing commonly used first-line regimens, with consistent reporting of AEs and patient-reported outcomes including HRQoL, are needed to reduce uncertainty and inform treatment decisions. FUNDING: Takeshi Hasegawa and Hisashi Noma were supported by the Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (Grant numbers: 22H03554, 19K03092, 24K06239). REGISTRATION: Protocol available via doi.org/10.1002/14651858.CD015738.

Trials

Showing 12 of 1709 matching trials (5527 indexed).

TrialRECRUITINGNA

NCT05621291

A Multicenter Study to Evaluate Next-Generation Sequencing (NGS) Testing and Monitoring of B-Cell Recovery to Guide Management Following Chimeric Antigen Receptor T-cell (CART) Induced Remission in Children and Young Adults With B Lineage Acute Lymph...

Background: Chimeric antigen receptor T-cell (CART) therapy is a form of immunotherapy which can be used to treat people with relapsed B-ALL. For those who achieve remission after CART alone, it may cure up to 50% of people who receive this therapy. However, for people who relapse after CART, it can be hard to achieve remission again. In patients where CART fails, stem cell transplant (HCT) can be used to prevent relapse and achieve cure. But HCT can cause serious side effects. Better testing is needed to distinguish people who can be cured with CART alone from people who may also need to have HCT. Objective: To see if the use of a series of blood and bone marrow tests at regular intervals can help monitor for B-ALL relapse after CART therapy. Eligibility: People aged 1 to 25 years with B-ALL who have had CART therapy within the past 42 days. They must never have had a blood stem cell transplant; they must also have no measurable blood cancer cells. Design: Participants will visit the clinic every 2 weeks starting 42 days after they receive CART therapy. Each visit will be about the same amount of time as a regular clinic visit. about 8 hours. Participants will have blood drawn for testing on each visit. Bone marrow biopsy/aspirate will be done during 4 of the visits at routine timepoints after CART. A needle will be inserted to draw a sample of tissue from inside the bone in the hip. A small amount of blood and tissue will be tested with ClonoSEQ and to evaluate for normal B-cells side by side with the standard tests. The combined testing may help determine whether participants are eligible for HCT and/or at risk of relapse after CART. Participants will be in the study for 2 years.

B-All · Acute Lymphoblastic Leukemia

TrialRECRUITINGPHASE1

NCT07578571

A Phase 1 Study of IM-1617 in Participants With Advanced Cancer

This study will test the safety and effectiveness of a drug called IM-1617 in participants with solid tumors. Participants will have solid tumor cancer that has spread through the body (metastatic) or cannot be removed with surgery (unresectable). This study will have two parts. Part A will test increasing doses of IM-1617 to find out the safe dose and schedule of IM-1617 for participants. Part B will use the dose and schedule found in Part A to further study the safety of IM-1617 and if it works to treat solid tumor cancers.

Colorectal Cancer · Non-Small Cell Lung Cancer · Breast Cancer · Esophageal Cancer

TrialRECRUITINGPHASE1

NCT06641609

A Phase I Study of CFT8919 in Patients With Advanced NSCLC

The goal of this clinical trial is to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of CFT8919 capsules in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) carrying EGFR mutations. The main questions it aims to answer are: * What is the maximum tolerated dose (MTD) of CFT8919? * Does CFT8919 demonstrate antitumor activity in these patients? Participants will: * Take CFT8919 capsules at different doses. * Undergo regular assessments for safety, pharmacokinetics, and tumor response. Researchers will compare different dose levels to determine the best balance between safety and efficacy.

Non-Small Cell Lung Cancer With EGFR Mutation

TrialRECRUITINGNA

NCT07298096

A Prospective Single Center, Single Arm, Single-institution Registry That Aims to Assess the Safety and Quality of Life Benefits of Computer-assisted Vacuum Thrombectomy (CAVT) in the Treatment of Cancer Patients With Intermediate Risk Pulmonary Embolism (PE)

The goal of this clinical research study is to gather information about the quality of life benefits of cancer patients with intermediate risk PE who underwent thrombectomy. The safety of thrombectomy in this patient population will also be studied.

Cancer

TrialRECRUITINGPHASE1, PHASE2

NCT07567846

A Study Evaluating the Safety, Pharmacokinetics, and Preliminary Activity of GDC-1261 in Participants With Advanced or Metastatic Prostate Cancer

The purpose of this study is to evaluate the safety, pharmacokinetics (PK), and preliminary activity of GDC-1261 in participants with advanced or metastatic prostate cancer. It's also to identify a recommended dose(s) and regimen for GDC-1261 for subsequent studies.

Advanced Prostate Cancer · Metastatic Prostate Cancer

TrialRECRUITINGPHASE1

NCT07661641

A Study of [177Lu]Lu-A9-0631 and [225Ac]Ac-A9-0642 With [68Ga]Ga-A9-6217 or [177Lu]Lu-A9-0631 Imaging in GRPR+ Solid Tumors

This is a Phase 1-1b multicenter clinical study to evaluate the safety, efficacy, and dosimetry of \[177Lu\]Lu-A9-0631 and \[225Ac\]Ac-0642 in participants with Gastrin-Releasing Peptide Receptor (GRPR) expressing locally advanced, unresectable or metastatic solid tumors.

Breast Cancer · Prostate Cancer · Colorectal Cancer · GRPR-positive Solid Tumors

TrialRECRUITINGPHASE1

NCT07361562

A Study of a Selective ERBB2 Inhibitor (CGT4255), in Patients With Advanced Solid Tumors

This is an open-label, phase 1/1b study evaluating the safety, tolerability, pharmacokinetic (what the body does to the drug), pharmacodynamic (what the drug does to the body), and antitumor activity of CGT4255 in adult participants with advanced solid tumors with ERBB2 alterations or HER2 overexpression.

Advanced Solid Tumor, Adult · ERBB2 Altered Breast Cancer · ERBB2 Gene Amplification · HER2 Overexpression

TrialRECRUITINGPHASE1

NCT06393738

A Study of ARV-393 in Relapsed/Refractory Non-Hodgkin Lymphoma.

This clinical trial is studying the safety and potential anti-tumor activity of an investigational drug called ARV-393 in patients diagnosed with advanced Relapsed/Refractory non-Hodgkin's lymphoma (R/R NHL) to determine if ARV-393 may be a possible treatment option. ARV-393 is thought to work by breaking down a protein present in many types of non-Hodgkins lymphomas, which may prevent, slow or stop tumor growth. This is the first time ARV-393 will be used by people. The investigational drug will be given as an oral tablet.

Relapsed/Refractory (R/R) Mature B Cell Non Hodgkin Lymphoma (NHL) · Relapsed/Refractory (R/R) Angioimmunoblastic T-cell Lymphoma (AITL)

TrialRECRUITINGPHASE1, PHASE2

NCT07805551

A Study of HDM2017 Combination Therapy in Advanced Colorectal Cancer

This is a multicenter, open-label, dose-escalation/dose-expansion, Phase Ib/II study to evaluate the safety, tolerability, PK characteristics, and preliminary anti-tumor efficacy of HDM2017 combination therapy in participants with advanced CRC. The study is divided into two periods: dose escalation (Phase Ib) and dose expansion (Phase II). Phase Ib of this study is a dose-finding study of different HDM2017 combination therapies. The Phase II study will be conducted at a dose determined to be safe and potentially effective in Phase Ib.

CRC, Colorectal Cancer

TrialRECRUITINGPHASE2

NCT07287098

A Study of Imlunestrant (LY3484356) in Premenopausal Women With Estrogen Receptor-Positive (ER+) Human Epidermal Growth Factor Receptor 2 Negative (HER2-) Early Breast Cancer

This study will include two groups of patients: Cohort 1 and Cohort 2. Cohort 1: will help researchers learn how a medicine called imlunestrant (LY3484356) affects a specific type of breast cancer. Some patients will take both imlunestrant and another treatment to suppress their ovarian function. Some will take it without ovarian suppression. Researchers will compare the effects in breast cancer cells to those of another medicine called tamoxifen. All patients in this group will be premenopausal women who have a type of early breast cancer called estrogen receptor-positive, HER2-negative. The treatment in this group will last for up to 29 days. Cohort 2: will help researchers understand how imlunestrant affects the ovaries when it is taken without ovarian suppression. Researchers will compare the effects to those of another medicine called tamoxifen. This group will also include premenopausal women with the same type of breast cancer. The treatment in this group will last for up to 6 months.

Breast Neoplasms

Clinical Evidence