Citations

The treatment landscape for soft tissue sarcomas (STS) is evolving constantly. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for STS specific to surgical management and systemic therapy recommendations for various subtypes.

Cellular senescence is defined as a state of permanent cell cycle arrest, providing a natural barrier against cancer. However, senescent cells are very metabolically active and secrete a complex mixture of bioactive molecules collectively known as the senescence-associated secretory phenotype (SASP), which play a dual role in cancer biology. While the SASP can suppress tumors by facilitating immunosurveillance, it can also promote tumor progression by fostering a pro-inflammatory milieu, stimulating angiogenesis, enhancing invasiveness, and enabling immune evasion. In Head and Neck Cancers (HNCs), a highly heterogeneous group of malignancies, SASP has emerged as a critical player in disease progression and treatment resistance. Persistent DNA damage response (DDR) signaling drives SASP and thereby contributes to the progression of head and neck cancer by modulating the tumour microenvironment. It influences the tumor microenvironment (TME) by facilitating epithelial-to-mesenchymal transition (EMT), promoting cancer stem cell-like properties, and impairing the efficacy of radiotherapy, chemotherapy, and immune checkpoint inhibitors. These effects underscore the need for targeted interventions to regulate SASP activity. This review presents a comprehensive overview of the molecular mechanisms underlying SASP generation and its effects on HNCs. We discuss the dual roles of SASP in tumor suppression and progression, its contribution to therapy resistance, and emerging therapeutic strategies, including novel senolytic and senomorphic drugs. Finally, we highlight key challenges and future directions for translating SASP-targeted therapies into clinical practice, emphasizing the need for biomarker discovery, and a deeper understanding of SASP heterogeneity. By targeting the SASP, there is potential to enhance therapeutic outcomes and improve the management of HNCs.

Abstract Objective Clinical neuropsychology is an evidence-based discipline that draws heavily from the field’s peer-reviewed journal articles. However, our scientific understanding of the methods and content that comprise the articles published in clinical neuropsychology journals is quite limited. Method A mixed methods approach was used to describe the aims, methods, and content of clinical neuropsychology’s major lifespan journals. Six-hundred articles were randomly sampled from the 2020–2024 volumes of six lifespan clinical neuropsychology journals. All articles were coded across 42 dimensions, including article type, population, design, methods, ability domains, and miscellaneous topics (e.g., brain health). The aims/scope sections of the journals were subjected to qualitative analyses, to identify relevant themes. Results The most common article content was observed in the areas of empirical/data-driven studies, cross-sectional and observational designs, older and neurological participants, cognitive testing of higher-order abilities, and psychometrics/methods. Results showed significant between-journal differences for some of these content areas at broadly medium effect sizes (e.g., experimental design, brain health topics). Qualitative analyses yielded five shared themes, suggesting that the lifespan clinical neuropsychology journals are interested in submissions on brain-behavior relationships, clinical applications, both clinical and healthy/typical populations, professional/guild matters, and multidisciplinary investigations. Conclusions The scientific content published within clinical neuropsychology’s six primary lifespan journals varies in some dimensions, but largely focuses on cross-sectional, observational studies of psychometrics and higher-order cognition. The implications of these findings for future research in clinical neuropsychology are contextualized for authors, reviewers, and readers.

Importance The choice of induction agent during rapid sequence intubation (RSI) of critically ill adults may affect clinical outcomes. Although ketamine and etomidate are frequently used for RSI, their comparative effectiveness remains controversial. Objective To compare the safety of etomidate vs ketamine for emergency RSI in critically ill adults. Design, Setting, and Participants This cohort study used a target trial emulation with observational data collected between March 1, 2022, and April 30, 2024, from 18 emergency departments across Brazil, with data from the Brazilian Airway Registry Cooperation. Adults who underwent RSI and received either etomidate or ketamine as a sole hypnotic agent were included; those with preintubation cardiac arrest or immediate postintubation transfer were excluded. Exposure Administration of etomidate or ketamine as the induction agent for RSI. Main Outcomes and Measures The primary outcome was 28-day in-hospital mortality. Secondary outcomes included 7-day in-hospital mortality, first-attempt intubation success, and major adverse events (new hemodynamic instability, severe hypoxemia, and cardiac arrest) within 30 minutes after intubation. Inverse probability of treatment weighting was used to adjust for confounding. Risk ratios (RRs) and risk differences (RDs) with 95% CIs were used to compare outcomes between groups. Results Among 1810 patients (median age, 64 years [IQR, 50-74 years]; 1048 men [57.9%]), 514 received ketamine and 1296 received etomidate. The median shock index was higher in the ketamine group than the etomidate group (0.81 [IQR, 0.65-1.01] vs 0.76 [IQR, 0.59-0.99]), and preintubation vasopressor use was more common in the ketamine group than the etomidate group (191 of 514 [37.2%] vs 391 of 1296 [30.2%]). Weighted 28-day mortality was higher with etomidate than ketamine (60.5% [95% CI, 57.2%-63.8%] vs 54.4% [95% CI, 45.0%-63.9%]; RR, 1.14 [95% CI, 1.03-1.27]; RD, 7.6% [95% CI, 2.0%-13.3%]). Seven-day mortality was also higher with etomidate than ketamine (35.2% [95% CI, 32.0%-38.3%] vs 30.1% [95% CI, 23.5%-36.7%]; RR, 1.19 [95% CI, 1.04-1.35]). New hemodynamic instability within 30 minutes after intubation was more frequent with ketamine (24.2% [95% CI, 20.4%-28.0%] vs 18.9% [95% CI, 16.7%-21.0%]; RR, 0.78 [0.64-0.95]). There were no statistically significant differences in the other secondary outcomes. Conclusions and Relevance In this cohort study of critically ill adults undergoing RSI, etomidate use was associated with higher in-hospital mortality at 7 and 28 days compared with ketamine. These findings highlight the need for definitive randomized clinical trials to compare both agents.

Background ‘Exception from informed consent’ research requires community consultation to ensure that the views of the local population have been considered. Using market research companies to distribute surveys across local populations is attractive because it ensures adequate response rates. It is not known whether individuals who respond to surveys are typical of the targeted communities. The purpose of this study is to compare the demographics of the survey respondents with that of the general population in the same area. Methods This is an analysis of data collected as part of the ‘Trauma Resuscitation with Group O Whole Blood or Products’ (TROOP) trial. The surveys used a commercial market research service to reach the communities of interest and consisted of 18 questions designed to evaluate respondents’ willingness to be enrolled in the TROOP trial and the demographics of survey respondents. Results Catchment populations varied from 0.5 to 9.4 million residents, with a total of 33.5 million. The racial and ethnic composition of the population (and the survey respondents, in brackets) was 44.8% (57.0%) white, 25.7% (13.4%) Hispanic, 12.7% (19.4%) black, 8.0% (2.5%) multiracial, 7.9% (4.4%) Asian, 0.7% (0.9%) Native American, and 0.2% (0.5%) Islanders. Of the male population (and survey respondents, in brackets), 12.2% (15.3%) were aged 18years to 24 years, 20.5% (22.3%) aged 25 years to 34 years, 18.1% (24.9%) aged 35 years to 44 years, 16.3% (18.5%) aged 45 years to 54 years, 15.5% (14.8%) aged 55 years to 64 years, and 17.4% (4.3%) aged 65 years and over. Of the female population (and survey respondents, in brackets), 11.0% (18.5%) were aged 18 years to 24 years, 18.4% (22.6%) aged 25 years to 34 years, 16.4% (23.5%) aged 35 years to 44 years, 15.0% (17.3%) aged 45 years to 54 years, 18.5% (14.1%) aged 55 years to 64 years, and 20.6% (3.9%) aged 65 years and over. Conclusions For this trial, using a market research company to distribute community surveys resulted in respondents that are broadly representative of the geographic areas where the trial will be conducted, except for individuals over the age of 65 years and older. This finding provides reassurance to investigators and institutional review boards that the views expressed by respondents are representative of the population where the trial will be conducted. Level of evidence III

Abstract Background Topical steroid withdrawal syndrome (TSW) is an adverse event following discontinuation of topical corticosteroids (TCS) and is of growing interest among patients and dermatologists. The absence of well-defined diagnostic criteria and limited insights into the pathomechanisms make diagnosis and future research challenging. Objectives To propose preliminary diagnostic criteria for TSW with the erythemato-oedematous subtype applicable for adult and paediatric populations using a Delphi consensus approach informed by a thorough literature review that summarizes the signs, symptoms and histology of TSW. Methods Eleven clinicians experienced in diagnosing and treating suspected TSW in both children and adults participated in a three-round modified Delphi process. Two rounds of surveys were conducted, with items ranked using a 5-point Likert scale. A predefined consensus threshold of ≥ 75% was established for any one feature to be deemed important. The third round involved a live video conference where the panel reached a consensus on essential diagnostic criteria. Results The panel identified 18 critical diagnostic items, encompassing elements from the patient’s clinical history, signs and symptoms. This includes history of escalating TCS requirement, morphology and distribution differing from primary condition, regional or generalized spontaneous neuropathic pain and severe burning sensation of the skin. Conclusions Differentiating TSW from conditions such as severe atopic dermatitis remains challenging. By emphasizing the common signs and symptoms of TSW, we aim to encourage discussions among healthcare professionals and progress towards the development of a reliable diagnostic tool. An author video to accompany this article is available online.

PURPOSE The HER2CLIMB-05 study (ClinicalTrials.gov identifier: NCT05132582 ) is investigating the efficacy and safety of adding tucatinib to trastuzumab and pertuzumab as first-line (1L) maintenance therapy in patients with human epidermal growth factor receptor 2–positive (HER2+) metastatic breast cancer (MBC). METHODS Patients with centrally confirmed HER2+ MBC without evidence of progression post induction therapy and no or asymptomatic brain metastases (BM) were enrolled. Patients were randomly assigned 1:1 to tucatinib (300 mg) or placebo twice a day combined with trastuzumab/pertuzumab. The primary end point is investigator-assessed progression-free survival (PFS); secondary end points include overall survival (OS), PFS per blinded independent central review, CNS-PFS, and safety. RESULTS Between March 2022 and July 2024, 654 patients were randomly assigned to tucatinib (n = 326) and placebo (n = 328) arms. All patients were female (median age, 54 years), 69.3% had de novo MBC, 52.6% were hormone receptor–positive, and 12.4% had presence/history of baseline BM. In this primary analysis, PFS was statistically significantly improved with addition of tucatinib versus placebo (hazard ratio, 0.641 [95% CI, 0.514 to 0.799]; P < .0001; median PFS: 24.9 v 16.3 months); a PFS benefit was seen regardless of the presence/absence of BM or hormone receptor status. OS data remain immature. The most common treatment-emergent adverse events (TEAEs) in the tucatinib arm were diarrhea (72.7%), nausea (33.1%), and elevated liver enzymes (ALT: 28.2%; AST: 25.8%), of which 6.1%, 0.9%, 13.5%, and 7.1%, respectively, were grade ≥3. In the tucatinib arm, 13.5% discontinued tucatinib because of TEAEs. CONCLUSION Tucatinib addition to trastuzumab and pertuzumab demonstrated improvement in PFS with no new safety signals identified and may be an option for 1L maintenance therapy in patients with HER2+ MBC.

Abstract Immune checkpoint inhibitor–associated immune thrombocytopenia (ICI-ITP) has been described in case reports and small case series, but comprehensive data on its incidence, risk factors, clinical features, treatment, and outcomes are lacking. We reviewed medical records of all adults initiating ICI therapy between 2016 and 2023 at 29 US hospitals across 7 major cancer centers to identify patients with ICI-ITP. Multivariable logistic regression was used to identify risk factors, and Cox modeling was performed to assess the association between ICI-ITP, its severity, and mortality. Among 86 467 patients, ICI-ITP occurred in 214 (0.25%). Independent risk factors included lower baseline platelet count, combination ICI therapy, stage IV cancer, and additional immune-related adverse events. ICI-ITP occurred at a median of 8 weeks (interquartile range [IQR], 4-18) after ICI initiation, with a median nadir platelet count of 41 × 109/L (IQR, 17 × 109/L to 64 × 109/L). Patients were treated with glucocorticoids (n = 106 [49.5%]), immune globulin (n = 39 [18.2%]), and thrombopoietin receptor agonists (n = 29 [13.6%]). Recovery occurred in 161 patients (75.2%) at a median of 2.3 weeks (IQR, 1.0-5.3). Of 76 patients rechallenged with ICIs, 23 (30.3%) developed recurrent ICI-ITP. ICI-ITP and its severity were associated with higher all-cause mortality, with a nearly threefold increase in risk among patients with severe ICI-ITP than those without ICI-ITP (adjusted hazard ratio, 2.96 [95% confidence interval, 2.14-4.08]). These findings establish ICI-ITP as a rare but clinically significant complication of ICI therapy, provide, to our knowledge, the first large-scale description of its risk factors and clinical course, and underscore the importance of timely recognition and management.

Introduction: Mass casualty incident (MCI) simulation scenarios are developed based on detailed review and planning by multidisciplinary trauma teams. This study aimed to assess the feasibility of using generative artificial intelligence (AI) in developing mass casualty trauma simulation scenarios. The study evaluated a range of mass casualty trauma simulation scenarios generated from a public generative artificial intelligence platform based on publicly available data with a validated objective simulation scoring tool. Methods: Using a large language model (LLM) platform (ChatGPT4, OpenAI, San Francisco, CA, USA), 10 complex MCI trauma simulation scenarios were generated based on publicly available US reported trauma data. Each scenario was evaluated by two Advanced Trauma Life Support (ATLS) certified raters based on the Simulation Scenario Evaluation Tool (SSET), a validated scoring tool out of 100 points. The tool scoring is based on learning objectives, tasks for performance, clinical progression, debriefing criteria, and resources. Two publicly available mass casualty trauma scenarios were similarly evaluated as controls. Revision and recommended feedback was provided for the scenarios, with review time recorded. Post-revision scenarios were evaluated. Interrater reliability was calculated based on Intraclass Correlation Coefficients (2, k) (ICCs). For the scenarios, scores and review times were reported as medians with interquartile range (IQR) as 25th and 75th percentiles. Results: Ten mass casualty trauma simulation scenarios were generated by an LLM, producing a total of 62 simulated patients. The initial LLM-generated scenarios demonstrated a median SSET score of 78.5 (IQR 74–82), substantially lower than the median score of 94 (IQR 93–95) observed in publicly available scenarios. The interrater reliability ICC for the LLM-generated scenarios was 0.965 and 1.00 for publicly available scenarios. Following secondary human revision and iterative refinement, the LLM-generated scenarios improved, achieving a median SSET score of 94 (IQR 93–96) with an interrater reliability ICC of 0.7425. Conclusions: The feasibility study suggests that a structured, collaborative workflow combining LLM-based generation with expert human review may enable a new approach to mass casualty trauma simulation scenario creation. LLMs hold promise as a scalable tool for the development of MCI training materials. However, consistent human oversight, quality assurance processes, and governance frameworks remain essential to ensure clinical accuracy, safety, and educational value.