Citations

Abstract Rationale Non-cystic fibrosis bronchiectasis (hereafter bronchiectasis) is a chronic and progressive respiratory disease. Neutrophilic inflammation plays a key role in the pathophysiology of bronchiectasis. Neutrophil serine proteases (NSPs), especially neutrophil elastase, have been associated with disease progression and poorer clinical outcomes. Brensocatib, an oral, selective, competitive, and reversible inhibitor of dipeptidyl peptidase 1, prevents activation of NSPs. In the phase 3, randomized, double-blind ASPEN trial (NCT04594369), treatment with once-daily brensocatib 10- or 25-mg significantly reduced the annualized rate of adjudicated pulmonary exacerbations over 52 weeks vs placebo; brensocatib 25-mg also significantly reduced lung function decline and improved patient-reported symptoms. Here, we further evaluate the impact of brensocatib on lung function in patients with bronchiectasis. Methods ASPEN enrolled patients with bronchiectasis and a history of pulmonary exacerbations in the 12 months prior to screening (adults [18-85 years], ≥2; adolescents [12-<18 years], ≥1). Patients were randomized to receive once-daily brensocatib (10- or 25-mg) or matching placebo for 52 weeks (adults, 1:1:1; adolescents, 2:2:1). Post-hoc analyses were conducted to evaluate the extent of lung function response to treatment, as measured by change from baseline in post-bronchodilator (BD) forced expiratory volume in 1 second (FEV1) over the 52-week treatment period in patients who did vs did not have ≥1 on-study pulmonary exacerbation, and the level of change in post-BD FEV1 and forced vital capacity (FVC) at week 52. Results A total of 583 patients received brensocatib 10-mg, 575 received brensocatib 25-mg, and 563 received placebo. Overall, a greater decline in FEV1 was observed among patients with ≥1 on-study pulmonary exacerbation vs those without. Treatment with brensocatib 10-mg or 25-mg led to less FEV1 decline at week 52 vs placebo for patients regardless of on-study exacerbation (no exacerbation: -42mL, -8mL, vs -48mL; ≥1 exacerbation: -59mL, -41mL, vs -70mL, for 10-mg, 25-mg brensocatib and placebo, respectively [Figure]). In the overall population, no change or an improvement (≥0 mL difference vs baseline) in post-BD FEV1 at week 52 was observed in 38.7%, 45.4%, and 31.2% of patients in the brensocatib 10-mg, 25-mg, and placebo groups, respectively. Similar impacts of brensocatib were observed in FVC (no change or improvement, 10-mg: 41.3%; 25-mg: 48.9%; placebo: 31.8%). Conclusions Overall, greater lung function decline was observed in patients who had on-study pulmonary exacerbations vs those who did not. Brensocatib 25-mg reduced lung function decline vs placebo regardless of whether patients had on-study exacerbations, consistent with overall ASPEN results.

Gastric cancer is the fifth leading cause of cancer-related deaths worldwide. Over 95% of gastric cancers are adenocarcinomas, which are typically classified based on anatomic location and histologic type. Gastric cancer generally carries a poor prognosis because it is often diagnosed at an advanced stage. Systemic therapy can provide palliation, improve survival, and enhance the quality of life in patients with locally advanced or metastatic disease. The implementation of biomarker testing has had a significant impact on clinical practice and patient care. Targeted therapies have demonstrated encouraging results in clinical trials for the treatment of patients with locally advanced or metastatic disease. This selection from the NCCN Clinical Practice Guidelines in Oncology for Gastric Cancer highlights recommendations for biomarker testing and discusses updates for the treatment of advanced disease, including peritoneal carcinoma as only disease and unresectable locally advanced, recurrent, or metastatic disease.

OBJECTIVE Despite the use of multiple glucose-lowering medications, glycemic targets are not met in a significant fraction of people with type 2 diabetes. In this prospective, observational study we assessed the prevalence of hypercortisolism, a potential contributing factor to inadequate glucose control. RESEARCH DESIGN AND METHODS Individuals with type 2 diabetes and HbA1c 7.5%–11.5% (58–102 mmol/mol) on two or more glucose-lowering medications with or without micro-/macrovascular complications or taking multiple blood pressure–lowering medications were screened with a 1-mg dexamethasone suppression test. Common causes of false-positive DSTs were excluded. The primary end point was the prevalence of hypercortisolism, defined as post-DST cortisol >1.8 μg/dL (50 nmol/L). Characteristics associated with hypercortisolism were assessed with multiple logistic regression. The percentage and characteristics of participants with hypercortisolism and adrenal imaging abnormalities were also assessed. RESULTS Post-DST cortisol was unsuppressed in 252 of 1,057 participants (prevalence 23.8%; 95% CI 21.3, 26.5). Hypercortisolism prevalence was 33.3% among participants with cardiac disorders and 36.6% among those taking three or more blood pressure–lowering medications. Adrenal imaging abnormalities were reported in 34.7% of participants with hypercortisolism. Use of sodium–glucose cotransporter 2 inhibitors (odds ratio 1.558), maximum-dose glucagon-like peptide 1 receptor agonists (1.544), tirzepatide (1.981), or a higher number of blood pressure–lowering medications (1.390); older age (1.316); BMI <30 kg/m2 (1.639); non-Latino/Hispanic ethnicity (3.718); and use of fibrates (2.676) or analgesics (1.457) were associated with higher prevalence (all P < 0.03). CONCLUSIONS Hypercortisolism was associated with hyperglycemia in approximately one-quarter of individuals with inadequately controlled type 2 diabetes despite multiple medications.

Inadequate light penetration in tissues restricts photodynamic therapy to treating only superficial tumors. To enable x-ray–excited photodynamic therapy (XPDT) that targets deep-seated tumors, we synthesized a nanoscintillator-photosensitizer complex containing 5% Eu-doped Y 2 O 3 fluorescing at 611 nanometers and decorated with SiO 2 containing the scintillation-coupled photosensitizer methylene blue and a polyethylene glycol coating [PEGylated Y 2 O 3 :Eu@SiO 2 -methylene blue (pYSM)]. When irradiated, pYSMs generate singlet oxygen species in vitro, causing cytotoxicity with hallmarks of immunogenic cell death (calreticulin translocation to the cell membrane). Intravenously administered pYSMs home passively to pancreatic tumor xenografts and, upon 10 gray irradiation, cause significant tumor regression ( P < 0.01). On combining XPDT with anti-PD1 immunotherapy, a distant nonirradiated tumor also regresses via an increase in intratumoral activated CD8 + cytotoxic T cells. Collectively, we advance a systemically delivered XPDT strategy that mediates an antitumor effect in both irradiated and nonirradiated (abscopal) tumors when coupled with immunotherapy, converting an immunologically “cold” tumor to an immunologically “hot” tumor.

ABSTRACTPatients with vascular anomalies (VAs) require expert multidisciplinary care. No prior studies have characterized the sociodemographic characteristics across multiple VA centers. We collected data on 5783 patients receiving care at 20 VA centers between July 1, 2020 through December 31, 2022. Male patients were underrepresented compared to the state‐level census data at 17/20 centers. Black and Asian patients were underrepresented at 14/20 and 12/20 centers, respectively. The median distance to the hospital was 48 miles, and median age was 12.0 years. These data suggest that race, sex, age, and distance from the hospital could impede the ability to access expert VA care.

OBJECTIVE Cervical spondylotic myelopathy (CSM) can be associated with urinary dysfunction, leading to an inability or marked difficulty with micturition. This study aimed to evaluate the urinary dysfunction, long-term prognosis, and recovery in patients with CSM following surgical intervention. METHODS The CSM cases of the Quality Outcomes Database SpineCORe study group were analyzed. Urinary control was assessed using the modified Japanese Orthopaedic Association (mJOA) urinary function subscore. Improvement was defined as a minimum improvement of 1 point in the mJOA urinary function subscore at the 2-year follow-up. Univariate and multivariable analyses were conducted as appropriate. RESULTS Of 1141 patients, 772 (67.7%) patients were identified with a minimum 2-year follow-up mJOA score, and 249 (32.3%) of these patients reported baseline urinary dysfunction. Of those 249 patients with baseline urinary control problems, 193 (77.5%) had improvement in urinary function postoperatively, and more women than men had improved urinary control after CSM surgery (54.9% vs 45.1%, p = 0.03). Apart from sex, demographic characteristics of patients who experienced urinary function improvement versus those who did not were similar. Patients who experienced urinary function improvement had lower overall baseline mJOA scores (10.2 vs 13, p < 0.01). Both cohorts reported similar rates of postoperative satisfaction (North American Spine Society scores of 1 and 2) (89.1% vs 85.9%, p = 0.26). CONCLUSIONS Among the one-third of patients with CSM experiencing urinary dysfunction, nearly 78% achieve improved urinary function at the 2-year postoperative follow-up. Women are more likely to experience improvement in this function. Patients with and without improvements in urinary function are equally satisfied with their surgery and report similar outcomes on long-term follow-up.

ABSTRACT Genes involved in the regulation of chromatin structure are frequently disrupted in cancer, contributing to an aberrant transcriptome and phenotypic plasticity. Yet, therapeutics targeting mutant forms of chromatin-modifying enzymes have yielded only modest clinical utility, underscoring the difficulty of targeting the epigenomic underpinnings of aberrant gene regulatory networks. Here, we sought to identify novel epigenetic vulnerabilities in diffuse large B-cell lymphoma (DLBCL). Through phenotypic screens and biochemical analysis, we demonstrated that inhibition of the H3K9 demethylases KDM4A and KDM4C elicits potent, subtype-agnostic cytotoxicity by antagonizing transcriptional networks associated with B-cell identity and epigenetically rewiring heterochromatin. KDM4 demethylases associated with the KRAB zinc finger ZNF587, and their enzymatic inhibition led to DNA replication stress and DNA damage-induced cGAS-STING activation. Broad surveys of transcriptional data from patients also revealed KDM4 family dysregulation in several other cancer types. To explore this potential therapeutic avenue, we performed high-throughput small molecule screens with H3K9me3 nucleosome substrates and identified novel KDM4 demethylase inhibitors. AI-guided protein-ligand binding predictions suggested diverse modes of action for various small molecule hits. Our findings underscore the relevance of targeting fundamental transcriptional and epigenetic mechanisms for anti-cancer therapy. HIGHLIGHTS Phenotypic screens identified JIB-04 as a potent anti-cancer agent for multiple subtypes of diffuse large B-cell lymphoma JIB-04 binds and inhibits KDM4 demethylases resulting in epigenomic rewiring of heterochromatin KDM4 demethylases cooperate with KRAB zinc fingers to limit DNA replication stress, and KDM4 inhibition instigates DNA-damage and cGAS-STING activation in several human cancers High-throughput small molecule screens with semi-synthetic nucleosome substrates and AI-guided molecular docking simulations identify novel KDM4 inhibitors

ABSTRACTAccurate staging of nodal involvement in pediatric sarcoma patients is important to determine correct systemic and local therapy, with the goal to reduce subsequent recurrences. However, differences in lymph node staging strategies, definitions, and treatment protocols between the Children's Oncology Group (COG), European paediatric Soft tissue sarcoma Study Group (EpSSG), and the Cooperative Weichteilsarkom Studiengruppe (CWS) complicate comparisons. In this article, we aim to establish internationally recognized recommendations for lymph node assessment and treatment of children and adolescents diagnosed with rhabdomyosarcoma (RMS) and non‐rhabdomyosarcoma soft tissue sarcoma (NRSTS) according to the Consensus Conference Standard Operating Procedure methodology.