Astodrimer sodium nasal spray forms a barrier to SARS-CoV-2 in vitro and preserves normal mucociliary function in human nasal epithelium.

COVID-19 remains a severe condition for many including immunocompromised individuals. There remains a need for effective measures against this and other respiratory infections, which transmit via virus-laden droplets that reach the nasal or oral mucosae. Nasal sprays offer potential protection against viruses. Such formulations should preserve normal nasal mucociliary function. The antiviral barrier efficacy and effects on mucociliary function of astodrimer sodium nasal spray (AS-NS) were evaluated and compared with other available nasal sprays-low pH hydroxypropyl methylcellulose (HPMC-NS), iota-carrageenan (Carr-NS), nitric oxide (NO-NS), and povidone iodine (PI-NS). Assays simulated clinical conditions. Antiviral barrier function and cell viability were assessed in airway cell monolayers, while a model of fully differentiated human nasal epithelium (MucilAir™) was utilized to evaluate tissue integrity, cytotoxicity, cilia beating frequency, and mucociliary clearance. AS-NS reduced infectious virus in cell monolayers and demonstrated a benign cytotoxicity profile. In human nasal epithelium ex vivo, AS-NS had no impact on mucociliary function (cilia beating nor mucociliary clearance). Carr-NS, HPMC-NS, NO-NS and PI-NS demonstrated limited antiviral effects, while HPMC-NS caused inhibition of mucociliary function. Astodrimer sodium nasal spray demonstrates an acceptable nonclinical efficacy and safety profile as a barrier nasal spray against respiratory viral infection in the nasal cavity.

Using an in-office passive leg raise to identify older adults with suboptimal blood pressure control.

INTRODUCTION: Passive leg raise (PLR) is a simple, dynamic maneuver that has been used to increase preload to the heart. We hypothesize that PLR may offer a new and efficient office-based tool for assessing blood pressure (BP) control in older adults. METHODS: One hundred and three veterans (≥60 years old) without known cardiovascular disease and varying degrees of blood pressure control were included in this cross-sectional cohort study. Twenty-four hour ambulatory BP monitoring identified Veterans with optimal and suboptimal BP control (≥125/75 mmHg). Bioimpedance electrodes (Baxter Medical, Deerfield, Illinois, USA) and brachial BP were used to calculate hemodynamic parameter changes across PLR states [pre-PLR, active PLR (3 min), and post-PLR]. Multiple linear regression was used to assess associations between BP control status with changes in hemodynamic parameters between PLR states. RESULTS: The 24-h ambulatory BP monitoring identified 43 (42%) older Veterans with optimal BP control (mean age of 70.5 ±â€Š7.0 years) and 55 (54%) with suboptimal BP (mean age of 71.3 ±â€Š8.7 years). Veterans with suboptimal BP control had significantly reduced change in total peripheral resistance (ΔTPR) (7.0 ±â€Š156.0 vs. 127.3 ±â€Š145.6 dynes s/cm5; P = 0.002) following PLR compared with Veterans with optimal BP control. Suboptimal BP control (ß = -0.35, P = 0.004) had a significant association with reduced ΔTPR, even after adjusting for demographic variables. CONCLUSION: Measuring PLR-induced hemodynamic changes in the office setting may represent an alternative way to identify older adults with suboptimal BP control when 24-h ambulatory BP monitoring is not available.

A Review of Force Health Protection Aspects of Lyme Disease in the U.S. Military.

INTRODUCTION: Lyme disease (LD) is an underrated threat to the military that negatively impacts mission readiness. Lyme disease has traditionally been thought to only be a risk in an operational context, where training or deployments are frequently conducted in heavily wooded environments. However, this view diminishes risks posed by many off-duty outdoor recreational activities. Furthermore, although the Army introduced a permethrin factory-treated Army Combat Uniform in 2012, permethrin retention and subsequent protection have been shown to decrease significantly after 3 months of wear. Thus, although LD is a known health risk that threatens unit readiness, beyond using treated uniforms there has been little progress at the unit level to address this threat. MATERIALS AND METHODS: Focusing on a narrative review of LD and its impact on U.S. military force health protection, sources included DoD websites and policies, government press releases and information papers from sources like the CDC and FDA, and scholarly peer-reviewed journals with full-text access from the online databases EBSCOhost, MEDLINE, SCOUT, and Google Scholar. Searches included the following key words: LD and military, Army, etiology, epidemiology, incidence, treatments, post-treatment LD, and chronic LD. Articles were selected for review based on the relevance of their abstracts and titles. RESULTS: Although the incidence of LD appears to be increasing among service members, it is difficult to attribute this increase to military-related duties. Also, despite ongoing LD research specifically conducted and funded by the DoD, there are limited data on the mitigating effects of force education and permethrin-treated uniforms on the LD threat. Therefore, it is reasonable to conclude that LD negatively impacts military readiness and monetary costs diverted from other priorities. CONCLUSION: Lyme disease poses a genuine threat to the health and careers of service members and is an often-overlooked disruptor to military operations. Simple, feasible prevention strategies that are tailored to high-risk geographic regions can be emphasized by military units to reduce the incidence of on-duty and off-duty cases. Additionally, there remains a critical need for new preventative and diagnostic measures for LD.

Rational Phase Control in the Synthesis of Cobalt Sulfides.

A library of substituted thioureas was used as sulfur reagents in the synthesis of cobalt sulfides. The substitution pattern of the thioureas controls the decomposition rate of precursors into sulfur monomers and thereby aids in the exploration of decomposition kinetics on cobalt sulfide-phase formation, including phase-pure jaipurite (CoS), cobalt pentlandite (Co8S9), linnaeite (Co3S4), and cattierite (CoS2). We hypothesize that the available transformation pathways between phases during synthesis are dictated by the approximate ccp or hcp stacking of the sulfur lattice. Through gaining a complex understanding of the cobalt sulfide crystal system, phase-pure syntheses of all four naturally occurring crystalline structures in the cobalt sulfide system were achieved.

Transcriptome profiling of pediatric extracranial solid tumors and lymphomas enables rapid low-cost diagnostic classification.

Approximately 80% of pediatric tumors occur in low- and middle-income countries (LMIC), where diagnostic tools essential for treatment decisions are often unavailable or incomplete. Development of cost-effective molecular diagnostics will help bridge the cancer diagnostic gap and ultimately improve pediatric cancer outcomes in LMIC settings. We investigated the feasibility of using nanopore whole transcriptome sequencing on formalin-fixed paraffin embedded (FFPE)-derived RNA and a composite machine learning model for pediatric solid tumor diagnosis. Transcriptome cDNA sequencing was performed on a heterogenous set of 221 FFPE and 32 fresh frozen pediatric solid tumor and lymphoma specimens on Oxford Nanopore Technologies' sequencing platforms. A composite machine learning model was then used to classify transcriptional profiles into clinically actionable tumor types and subtypes. In total, 95.6% and 89.7% of pediatric solid tumors and lymphoma specimens were correctly classified, respectively. 71.5% of pediatric solid tumors had prediction probabilities > 0.8 and were classified with 100% accuracy. Similarly, for lymphomas, 72.4% of samples that had prediction probabilities > 0.6 were classified with 97.6% accuracy. Additionally, FOXO1 fusion status was predicted accurately for 97.4% of rhabdomyosarcomas and MYCN amplification was predicted with 88% accuracy in neuroblastoma. Whole transcriptome sequencing from FFPE-derived pediatric solid tumor and lymphoma samples has the potential to provide clinical classification of both tissue lineage and core genomic classification. Further expansion, refinement, and validation of this approach is necessary to explore whether this technology could be part of the solution of addressing the diagnostic limitations in LMIC.

The development of pGALSplus: evaluating feasibility and acceptability of an assessment to facilitate the identification and triage of children with musculoskeletal presentations.

Objectives: Healthcare professionals (HCPs) need to identify potentially serious musculoskeletal (MSK) presentations in children and refer them to specialists appropriately. Our aim was to develop 'pGALSplus' (paediatric gait, arms, legs and spine plus) to support clinical assessment, aid decision-making and assess feasibility and acceptability in exemplar MSK pathologies. Methods: We used a three-phase mixed methods approach: phase 1, preliminary stakeholder engagement and scoping review to propose pGALSplus; phase 2, iterative development of pGALSplus involving an expert working group; and phase 3, testing the feasibility of pGALSplus in exemplar MSK conditions [JIA, mucopolysaccharidoses (MPS), muscular dystrophy (MD), developmental coordination disorder (DCD) and healthy controls (HCs)]. The final pGALSplus was derived from analysis of phase 3 data and feedback from HCPs, families and expert consensus input from an international e-survey (n = 22) and virtual event (n = 13). Results: Feasibility was tested in 45 children (JIA, n = 10; MPS, n = 6; MD, n = 9; DCD, n = 10; HCs, n = 10). Overall the assessment was achievable in the target age range (2-10 years) and quick to complete [median 12 min (range 8-20)], with high acceptability from families. Expert feedback deemed pGALSplus to be very useful and of particular use to non-specialists in MSK paediatrics. The final pGALSplus comprises 26 clinical observations/skills with a colour-coding approach to aid decision-making and identification of more serious MSK presentations and additional resources to support its use in clinical practice. Conclusions: pGALSplus is a novel evidence- and consensus-based assessment building on pGALS, with high acceptability and feasibility. As community-based MSK assessment in children becomes more established, we propose that pGALSplus will facilitate and inform decision-making to promote access to specialist care.

Genomic Determinants of Outcome in Acute Lymphoblastic Leukemia.

PURPOSE: Although cure rates for childhood acute lymphoblastic leukemia (ALL) exceed 90%, ALL remains a leading cause of cancer death in children. Half of relapses arise in children initially classified with standard-risk (SR) disease. MATERIALS AND METHODS: To identify genomic determinants of relapse in children with SR ALL, we performed genome and transcriptome sequencing of diagnostic and remission samples of children with SR (n = 1,381) or high-risk B-ALL with favorable cytogenetic features (n = 115) enrolled on Children's Oncology Group trials. We used a case-control study design analyzing 439 patients who relapsed and 1,057 who remained in complete remission for at least 5 years. RESULTS: Genomic subtype was associated with relapse, which occurred in approximately 50% of cases of PAX5-altered ALL (odds ratio [OR], 3.31 [95% CI, 2.17 to 5.03]; P = 3.18 × 10-8). Within high-hyperdiploid ALL, gain of chromosome 10 with disomy of chromosome 7 was associated with favorable outcome (OR, 0.27 [95% CI, 0.17 to 0.42]; P = 8.02 × 10-10; St Jude Children's Research Hospital validation cohort: OR, 0.22 [95% CI, 0.05 to 0.80]; P = .009), and disomy of chromosomes 10 and 17 with gain of chromosome 6 was associated with relapse (OR, 7.16 [95% CI, 2.63 to 21.51]; P = 2.19 × 10-5; validation cohort: OR, 21.32 [95% CI, 3.62 to 119.30]; P = .0004). Genomic alterations were associated with relapse in a subtype-dependent manner, including alterations of INO80 in ETV6::RUNX1 ALL, IKZF1, and CREBBP in high-hyperdiploid ALL and FHIT in BCR::ABL1-like ALL. Genomic alterations were also associated with the presence of minimal residual disease, including NRAS and CREBBP in high-hyperdiploid ALL. CONCLUSION: Genetic subtype, patterns of aneuploidy, and secondary genomic alterations determine risk of relapse in childhood ALL. Comprehensive genomic analysis is required for optimal risk stratification.

The unique allosteric property of crocodilian haemoglobin elucidated by cryo-EM.

The principal effect controlling the oxygen affinity of vertebrate haemoglobins (Hbs) is the allosteric switch between R and T forms with relatively high and low oxygen affinity respectively. Uniquely among jawed vertebrates, crocodilians possess Hb that shows a profound drop in oxygen affinity in the presence of bicarbonate ions. This allows them to stay underwater for extended periods by consuming almost all the oxygen present in the blood-stream, as metabolism releases carbon dioxide, whose conversion to bicarbonate and hydrogen ions is catalysed by carbonic anhydrase. Despite the apparent universal utility of bicarbonate as an allosteric regulator of Hb, this property evolved only in crocodilians. We report here the molecular structures of both human and a crocodilian Hb in the deoxy and liganded states, solved by cryo-electron microscopy. We reveal the precise interactions between two bicarbonate ions and the crocodilian protein at symmetry-related sites found only in the T state. No other known effector of vertebrate Hbs binds anywhere near these sites.

Professional perspectives on facilitators and barriers for high quality provision of health, education and social care services to disabled children in England during the COVID-19 pandemic: a qualitative study.

OBJECTIVES: To understand how health, education and social care services for disabled children changed during the COVID-19 pandemic, what did or did not work well and what the impacts of service changes were on both professionals and families. DESIGN: Qualitative study using semistructured interviews. SETTING: Telephone and video call interviews and focus groups with professionals working in one of five local authority areas in England. PARTICIPANTS: 78 health, education and social care professionals working with children in one of five local authority areas in England. RESULTS: There was a significant disruption to services and reduced contact with families during the early stages of the pandemic; nevertheless, professionals were able to reflect on innovative ways they interacted with and sought to support and maintain health, education and social care provision to disabled children and their families. As waitlists have substantially increased, this and the longevity of the pandemic were perceived to have had negative consequences for staff health and well-being, the health and psychosocial outcomes of children and young people, and their parent carers. CONCLUSIONS: Key learning from this study for service recovery and planning for future emergencies is the need to be able to identify disabled children, classify their level of need and risk, assess the impact of loss of services and maintain clear communication across services to meet the needs of disabled children. Finally, services need to work collaboratively with families to develop child-centred care to strengthen resilience during service disruption.

High-level cognition is supported by information-rich but compressible brain activity patterns.

To efficiently yet reliably represent and process information, our brains need to produce information-rich signals that differentiate between moments or cognitive states, while also being robust to noise or corruption. For many, though not all, natural systems, these two properties are often inversely related: More information-rich signals are less robust, and vice versa. Here, we examined how these properties change with ongoing cognitive demands. To this end, we applied dimensionality reduction algorithms and pattern classifiers to functional neuroimaging data collected as participants listened to a story, temporally scrambled versions of the story, or underwent a resting state scanning session. We considered two primary aspects of the neural data recorded in these different experimental conditions. First, we treated the maximum achievable decoding accuracy across participants as an indicator of the "informativeness" of the recorded patterns. Second, we treated the number of features (components) required to achieve a threshold decoding accuracy as a proxy for the "compressibility" of the neural patterns (where fewer components indicate greater compression). Overall, we found that the peak decoding accuracy (achievable without restricting the numbers of features) was highest in the intact (unscrambled) story listening condition. However, the number of features required to achieve comparable classification accuracy was also lowest in the intact story listening condition. Taken together, our work suggests that our brain networks flexibly reconfigure according to ongoing task demands and that the activity patterns associated with higher-order cognition and high engagement are both more informative and more compressible than the activity patterns associated with lower-order tasks and lower engagement.

junctionCounts: comprehensive alternative splicing analysis and prediction of isoform-level impacts to the coding sequence.

Alternative splicing (AS) is emerging as an important regulatory process for complex biological processes. Transcriptomic studies therefore commonly involve the identification and quantification of alternative processing events, but the need for predicting the functional consequences of changes to the relative inclusion of alternative events remains largely unaddressed. Many tools exist for the former task, albeit each constrained to its own event type definitions. Few tools exist for the latter task; each with significant limitations. To address these issues we developed junctionCounts, which captures both simple and complex pairwise AS events and quantifies them with straightforward exon-exon and exon-intron junction reads in RNA-seq data, performing competitively among similar tools in terms of sensitivity, false discovery rate and quantification accuracy. Its partner utility, cdsInsertion, identifies transcript coding sequence (CDS) information via in silico translation from annotated start codons, including the presence of premature termination codons. Finally, findSwitchEvents connects AS events with CDS information to predict the impact of individual events to the isoform-level CDS. We used junctionCounts to characterize splicing dynamics and NMD regulation during neuronal differentiation across four primates, demonstrating junctionCounts' capacity to robustly characterize AS in a variety of organisms and to predict its effect on mRNA isoform fate.

Elevated serum neurologic biomarker profiles after cardiac arrest in a porcine model.

Introduction: Swine exhibit cerebral cortex mitochondrial dysfunction and neuropathologic injury after hypoxic cardiac arrest treated with hemodynamic-directed CPR (HD-CPR) despite normal Cerebral Performance Category scores. We analyzed the temporal evolution of plasma protein biomarkers of brain injury and inflammatory cytokines, as well as cerebral cortical mitochondrial injury and neuropathology for five days following pediatric asphyxia-associated cardiac arrest treated with HD-CPR. Methods: One-month-old swine underwent asphyxia associated cardiac arrest, 10-20 min of HD-CPR (goal SBP 90 mmHg, coronary perfusion pressure 20 mmHg), and randomization to post-ROSC survival duration (24, 48, 72, 96, 120 h; n = 3 per group) with standardized post-resuscitation care. Plasma neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and cytokine levels were collected pre-injury and 1, 6, 24, 48, 72, 96, and 120 h post-ROSC. Cerebral cortical tissue was assessed for: mitochondrial respirometry, mass, and dynamic proteins; oxidative injury; and neuropathology. Results: Relative to pre-arrest baseline (9.4 pg/ml [6.7-12.6]), plasma NfL was increased at all post-ROSC time points. Each sequential NfL measurement through 48 h was greater than the previous value {1 h (12.7 pg/ml [8.4-14.6], p = 0.01), 6 h (30.9 pg/ml [17.7-44.0], p = 0.0004), 24 h (59.4 pg/ml [50.8-96.1], p = 0.0003) and 48 h (85.7 pg/ml [61.9-118.7], p = 0.046)}. Plasma GFAP, inflammatory cytokines or cerebral cortical tissue measurements were not demonstrably different between time points. Conclusions: In a swine model of pediatric cardiac arrest, plasma NfL had an upward trajectory until 48 h post-ROSC after which it remained elevated through five days, suggesting it may be a sensitive marker of neurologic injury following pediatric cardiac arrest.

A pharmacist's guide to mitigating sleep dysfunction and promoting good sleep in the intensive care unit.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: To review causes, risk factors, and consequences of sleep disruption in critically ill patients; evaluate the role of nonpharmacological and pharmacological therapies for management of sleep in the intensive care unit (ICU); and discuss the role of pharmacists in implementation of sleep bundles. SUMMARY: Critically ill patients often have disrupted sleep and circadian rhythm alterations that cause anxiety, stress, and traumatic memories. This can be caused by factors such as critical illness, environmental factors, mechanical ventilation, and medications. Methods to evaluate sleep, including polysomnography and questionnaires, have limitations that should be considered. Multicomponent sleep bundles with a focus on nonpharmacological therapy aiming to reduce nocturnal noise, light, and unnecessary patient care may improve sleep disorders in critically ill patients. While pharmacological agents are often used to facilitate sleep in critically ill patients, evidence supporting their use is often of low quality, which limits use to patients who have sleep disruption refractory to nonpharmacological therapy. Dedicated interprofessional teams are needed for implementation of sleep bundles in the ICU. Extensive pharmacotherapeutic training and participation in daily patient care rounds make pharmacists vital members of the team who can help with all components of the bundle. This narrative review discusses evidence for elements of the multicomponent sleep bundle and provides guidance on how pharmacists can help with implementation of nonpharmacological therapies and management of neuroactive medications to facilitate sleep. CONCLUSION: Sleep bundles are necessary for patients in the ICU, and dedicated interprofessional teams that include pharmacists are vital for their successful creation and implementation.

A long section of serpentinized depleted mantle peridotite.

The upper mantle is critical for our understanding of terrestrial magmatism, crust formation, and element cycling between Earth's solid interior, hydrosphere, atmosphere, and biosphere. Mantle composition and evolution have been primarily inferred by surface sampling and indirect methods. We recovered a long (1268-meter) section of serpentinized abyssal mantle peridotite interleaved with thin gabbroic intrusions. We find depleted compositions with notable variations in mantle mineralogy controlled by melt flow. Dunite zones have predominantly intermediate dips, in contrast to the originally steep mantle fabrics, indicative of oblique melt transport. Extensive hydrothermal fluid-rock interaction is recorded across the full depth of the core and is overprinted by oxidation in the upper 200 meters. Alteration patterns are consistent with vent fluid composition in the nearby Lost City hydrothermal field.

CASCADE: Dataset of extant coccolithophore size, carbon content and global distribution.

Coccolithophores are marine calcifying phytoplankton important to the carbon cycle and a model organism for studying diversity. Here, we present CASCADE (Coccolithophore Abundance, Size, Carbon And Distribution Estimates), a new global dataset for 139 extant coccolithophore taxonomic units. CASCADE includes a trait database (size and cellular organic and inorganic carbon contents) and taxonomic-unit-specific global spatiotemporal distributions (Latitude/Longitude/Depth/Month/Year) of coccolithophore abundance and organic and inorganic carbon stocks. CASCADE covers all ocean basins over the upper 275 meters, spans the years 1964-2019 and includes 33,119 gridded taxonomic-unit-specific abundance observations. Within CASCADE, we characterise the underlying uncertainties due to measurement errors by propagating error estimates between the different studies. This error propagation pipeline is statistically robust and could be applied to other plankton groups. CASCADE can contribute to (observational or modelling) studies that focus on coccolithophore distribution and diversity and the impacts of anthropogenic pressures on historical populations. Additionally, our new taxonomic-unit-specific cellular carbon content estimates provide essential conversions to quantify the role of coccolithophores on ecosystem functioning and global biogeochemistry.

Volatile anesthetics for lung- and diaphragm-protective sedation.

This review explores the complex interactions between sedation and invasive ventilation and examines the potential of volatile anesthetics for lung- and diaphragm-protective sedation. In the early stages of invasive ventilation, many critically ill patients experience insufficient respiratory drive and effort, leading to compromised diaphragm function. Compared with common intravenous agents, inhaled sedation with volatile anesthetics better preserves respiratory drive, potentially helping to maintain diaphragm function during prolonged periods of invasive ventilation. In turn, higher concentrations of volatile anesthetics reduce the size of spontaneously generated tidal volumes, potentially reducing lung stress and strain and with that the risk of self-inflicted lung injury. Taken together, inhaled sedation may allow titration of respiratory drive to maintain inspiratory efforts within lung- and diaphragm-protective ranges. Particularly in patients who are expected to require prolonged invasive ventilation, in whom the restoration of adequate but safe inspiratory effort is crucial for successful weaning, inhaled sedation represents an attractive option for lung- and diaphragm-protective sedation. A technical limitation is ventilatory dead space introduced by volatile anesthetic reflectors, although this impact is minimal and comparable to ventilation with heat and moisture exchangers. Further studies are imperative for a comprehensive understanding of the specific effects of inhaled sedation on respiratory drive and effort and, ultimately, how this translates into patient-centered outcomes in critically ill patients.

Novel therapeutic regimens in previously untreated metastatic urothelial carcinoma: A systematic review and bayesian network meta-analysis.

Metastatic urothelial carcinoma (muC) has historically had few effective therapeutic options. Recently, immune checkpoint inhibitors (ICIs), were introduced as therapeutic options for cisplatin-ineligible patients, however, direct head-to-head trials comparing these treatments are lacking. To address this gap, this study employs a Bayesian framework to indirectly compare the performance of ICIs as first-line agents for muC. A systematic review was performed to identify randomized controlled trials evaluating different ICI for mUC. Data was inputted into Review Manager 5.4 for pairwise meta-analysis. Data was then used to build a network in R Studio. These networks were used to model 200,000 Markov Chains via MonteCarlo sampling. The results are expressed as hazard ratios (HR) with 95% credible intervals (CrI). Six studies with 5,449 patients were included, 3,255 received ICI monotherapy or combination. Moreover, a total of 3,006 had PD-L1 positive tumors and 2,362 were PD-L1 negative. Median overall survival (OS) ranged from 12.1 to 31.5 months across the studies, with the combination of enfortumab vedotin and pembrolizumab demonstrating the most substantial reduction in the risk of death (HR 0.47 [95% CrI: 0.38, 0.58]), followed by avelumab monotherapy (HR 0.69 [95% CrI: 0.56, 0.86]). The limitations of this network meta-analysis include variability in study follow-up duration, lack of standardized methods for assessing PD-L1 positivity, and potential bias introduced by control arms with poorer survival outcomes across included trials. The enfortumab vedotin/pembrolizumab combination significantly improved survival and response rates. Avelumab showed notable single-agent activity. These findings provide a valuable framework to guide clinical decision-making and highlight priority areas for future research, including biomarker refinement and novel combination strategies to enhance antitumor immunity in this challenging malignancy.