Citations

In the INTRIGUE phase III trial (ClinicalTrials.gov identifier: NCT03673501 ), adult patients with advanced gastrointestinal stromal tumor previously treated with imatinib were randomly assigned 1:1 to ripretinib 150 mg once daily or sunitinib 50 mg once daily (4 weeks on/2 weeks off). In the primary analysis, overall survival (OS) was immature. In this study, we report the final planned analysis of OS (key secondary end point), progression-free survival (PFS) on third-line therapy (second PFS; prespecified exploratory end point), and long-term safety. Final OS analysis was prespecified to occur with approximately 200 and ≥145 events in the overall and KIT exon 11 intention-to-treat (ITT) populations, respectively. As of March 15, 2023, there were 211 and 151 OS events in the overall ITT and KIT exon 11 ITT populations, respectively. Median OS was similar between second-line ripretinib and sunitinib in both populations (overall, 35.5 v 31.5 months; KIT exon 11, 35.5 v 32.8 months). Median second PFS (on third-line therapy) for the overall ITT population was similar between the ripretinib and sunitinib arms (7.7 v 7.4 months). Safety was consistent with the primary analysis. OS from this analysis was similar between arms, and second PFS suggests that receiving ripretinib did not adversely affect the PFS of third-line therapy.

The gastrointestinal (GI) tract plays a crucial role in nutrient absorption, motility, and metabolism, while serving as a barrier against pathogens. The intestinal epithelial layer, particularly enteroendocrine cells (EEC), is pivotal in sensing luminal stimuli due to its strategic position. Although comprising only 1% of the GI epithelium, in total EEC comprises perhaps the largest endocrine organ that couples GI luminal stimuli with release of hormones and neurotransmitters such as serotonin, glucagon-like peptide-1 (GLP-1), and peptide–tyrosine–tyrosine (PYY), which regulate local and systemic physiology. In this review, we use EECs as a model to explore critical intracellular signaling pathways—centering around calcium (Ca²⁺) and cyclic adenosine monophosphate (cAMP). EECs utilize ionotropic and metabotropic receptors to detect luminal stimuli, leading to increased intracellular cytoplasmic Ca²⁺ and altered intracellular cAMP dynamics. Ca²⁺ influx is critical for the exocytosis of signaling molecules. The interplay between Ca²⁺ and cAMP signaling pathways enhances the release of these molecules, affecting both local and systemic responses. We make a point to discuss the conventional and emerging methodologies for measuring Ca²⁺ and cAMP dynamics in EECs, which is a rapidly expanding toolbox, containing genetically encoded indicators and resonance energy transfer techniques. Understanding these signaling cascades is essential for deciphering the complex roles of EECs in GI physiology and their impact on systemic health.

AbstractObstructive sleep apnea (OSA) is a widespread condition associated with an elevated risk of adverse outcomes. Continuous positive airway pressure (CPAP) is the gold standard treatment, particularly for moderate to severe OSA. However, in many instances, CPAP compliance falls short of expectations, necessitating physicians to consider additional interventions to alleviate patient symptoms. A comprehensive understanding of OSA endotypes and phenotypes can potentially enhance the confidence in selecting the appropriate combination or intervention to improve patient care. In this review, we will discuss various interventions and medications available to enhance the treatment of patients with OSA, following a precision medicine approach.

Abstract This study aimed to investigate the association between objective and subjective olfactory assessments in patients with recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection undergoing endoscopic endonasal skull base surgery (EESBS). Retrospective cohort study. Academic medical center. Adult patients with and without recent SARS-CoV-2 infection who underwent EESBS for sellar and parasellar lesion resection between 2020 and 2024 at the Mayo Clinic in Florida, Jacksonville, FL. Pre- and postoperative self-reported olfactory dysfunction and University of Pennsylvania Smell Identification Test (UPSIT) scores were collected. Patients with recent SARS-CoV-2 infection had a similar rate of discrepant preoperative objective olfactory assessments (38.2%, 26/68) compared with SARS-CoV-2-negative patients (39.9%, 127/318). SARS-CoV-2-positive patients were twice as likely to report postoperative subjective olfactory dysfunction (46.2%, 12/26) compared with SARS-CoV-2-negative patients (18.1%, 23/127, p = 0.002). There was no statistically significant difference in the mean preoperative (p = 0.162) or postoperative (p = 0.724) UPSIT scores between both groups. Patients with recent SARS-CoV-2 infection and discrepant preoperative objective olfactory assessments were twice as likely to self-report olfactory dysfunction following EESBS compared with SARS-CoV-2-negative controls. This increase in self-reported olfactory dysfunction was not accompanied by changes in objective psychophysical testing. These findings suggest that SARS-CoV-2 infection may impact subjective olfactory recovery following EESBS.

There is a context-dependent trade-off in body size of elite runners, such that smaller body sizes are observed among longer distance runners. However, it is unclear whether this trade-off in body size is observed in other Olympic sports, such as cycling and swimming. To understand the association between body size and athletic competition, we examined metrics of body size from male and female Olympic athletes competing in swimming, running, and cycling. We collected standard anthropometrics (height, mass, body mass index (BMI), and body surface area) of elite male and female athletes competing in the London 2012 Summer Olympics from a public repository. Anthropometric data were compared between sexes (male and female); between sports (swimming, running, and cycling); and between distances within sports (shorter and longer distance). Males were taller ( P < 0.001), heavier ( P < 0.001), and had a larger BMI ( P < 0.001) compared to females. Relative to athletes competing in longer distance events, athletes competing in shorter distance were generally taller (running: P < 0.001, swimming: P ≤ 0.014) and heavier (running: P < 0.001, swimming: P = 0.002 (males) and P = 0.148 (females), cycling: P < 0.001) for both males and females. Height was not different between shorter and longer distance cyclists. There was a trade-off between body size and distance for each of the three Olympics sports, such that smaller athletes were observed in longer distance events. Although there were large sex-based differences in body size, similar trade-offs in size and event were observed for both males and females. These data suggest that there is an optimal combination of skeletal muscle mass and body size to optimize movement economy that is generally preserved across different modes of human locomotion.

Background: How parental alcohol use disorder and liver disease-related mortality influence the risk and the outcomes of alcohol-associated hepatitis (AH) in the offspring is unknown. Methods: We analyzed data from 2 prospective observational studies of AH cases and heavy drinking controls (HDCs). Family history of parental alcohol use disorder and liver disease mortality was assessed at the study entry. Logistic regression and Cox proportional hazard models were used to assess the influences of family history on AH development and outcome. Results: Data from 1356 participants in two prospective cohorts (926 AH cases and 430 HDC) were combined and analyzed. Parental alcohol use disorder was found in 56.9% of AH cases and 61.1% of HDC; parental death due to liver disease was reported in 7.5% of AH cases and 5.7% of HDC. Multivariable logistic regression showed that parental liver disease-related mortality was associated with more than a doubled risk of AH development in the offspring after controlling for their demographic characteristics and drinking behavior (OR=2.26, 95% CI: [1.22, 4.20]). Moreover, among the AH cases, having a parent die of liver disease significantly increased the 90-day mortality of study participants after adjusting for the effects of other risk factors (HR=2.26, 95% CI: [1.05, 4.86]). Conclusions: The study highlights the influences of parental death due to liver disease on AH development and mortality. Identifying patients at risk of AH through family history might help facilitate discussions on reducing alcohol consumption.

Abstract The tumor landscape of pancreatic ductal adenocarcinoma (PDAC) is refractory to conventional photon radiotherapy (RT) due to a fibrotic tumor microenvironment (TME) that promotes chronic hypoxia and reduced immune surveillance. The radiobiological factors unique to carbon ion radiotherapy (CIRT), such as high linear energy transfer (LET) and less dependence on oxygen, make it well-suited to overcome the PDAC TME. Here, we utilized clonal syngeneic KPC pancreatic tumor cell lines and tumors to examine this postulate and to identify underlying factors that impact the response of PDAC to CIRT. While KPC cell lines exhibited radiobiologic effectiveness (RBE) greater than 3, subcutaneous tumors in the mouse hind leg showed lower RBEs – 1.3 based on quintupling time – at a LET of 75 keV/μm. Four days after CIRT, we observed widespread transcriptomic changes in the tumor immune microenvironment (TME), suggesting increased infiltration of anti-tumor immune cells, elevated expression of anti-tumor T cell cytokines, MHC class I molecules, and co-stimulatory signals. Fewer immunologic changes were observed following photon irradiation. By seven days after CIRT, tumor-supportive transcriptomic programs characterized by pro-tumor cytokines, M2 macrophages, and cancer-associated fibroblasts (CAFs) emerged, promoting resistance and limiting the durability of tumor growth delay. These findings suggest that CIRT may offer a favorable platform compared to conventional photon radiation therapy for combining with immunotherapies. Furthermore, these data highlight the risk of using in vitro survival data alone in treatment planning and indicate that underlying TME factors impact the response of PDAC in vivo .

Background: Periprosthetic tibial fractures around a total knee replacement (TKR) remain challenging to manage, with little published information for guidance. The purpose of this study was to review the types, management techniques, and outcomes of periprosthetic tibial fractures in the largest series to date. Methods: We identified 300 periprosthetic tibial fractures (285 patients) around a TKR (43% in primary TKRs and 57% in revision TKRs) sustained between 1996 and 2020. Fractures were classified according to Felix et al. as Type I (tibial plateau), Type II (adjacent to stem), Type III (distal to stem), or Type IV (tibial tubercle), with subtypes A (well-fixed component), B (loose component), and C (intraoperative fracture). Of the fractures in this study, 53% were Type I, 24% were Type II, 16% were Type III, and 8% were Type IV. A total of 46% of fractures occurred intraoperatively, and 54% of fractures occurred postoperatively (61% subtype A, 39% subtype B). The mean patient age at fracture was 67 years, and 64% of patients were female. The mean follow-up was 6 years. Results: The intraoperative fracture incidence was 1.40% in revision TKRs and 0.10% in primary TKRs. Among intraoperative fractures, the 2-year survivorship free from tibial component revision was highest in Type I (100%) and lowest in Type IV (67%) (p < 0.001). For postoperative fractures, the 2-year survivorship free from any reoperation was 29% and the 2-year survivorship free from tibial component revision was 51%. Type-I postoperative fractures had the lowest 2-year survivorship free from tibial component revision (10%), whereas Type-III fractures had the highest survivorship (88%) (p < 0.001). Conclusions: Intraoperative periprosthetic fracture of the tibia was fourteenfold more likely in revision TKRs compared with primary TKRs. Among all intraoperative fractures, Type-I fractures were well-tolerated, with 100% survivorship free from tibial component revision at 2 years. Conversely, Type-I postoperative fractures had only 10% survivorship at 2 years. Level of Evidence: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Introduction Infectious intracranial aneurysms (IIAs) are rare but serious complications of systemic infections, particularly infective endocarditis. These aneurysms are prone to rupture, leading to significant morbidity and mortality. Management strategies lack consensus due to the rarity of the condition and reliance on small case series. This study examines the clinical management of IIAs using data from a large multicenter cohort. Methods A retrospective registry-based cohort study was conducted across 11 tertiary care centers in the USA between 2018 and 2023. Patients with IIAs were identified based on clinical and radiographic criteria. The primary outcome was treatment failure defined as persistence, growth, or rupture of the aneurysm. Secondary outcomes were mortality and the modified Rankin Scale (mRS) score at 90 days and 1 year. Multivariate logistic regressions were used to identify outcome predictors. Results A total of 104 patients with 166 aneurysms were included, with a median age of 43 years. Medical management was successful in 56% of cases, with failure often within 18 days of initiation. Predictors of failure included younger age, larger aneurysm size, and rupture at presentation. Surgical and endovascular interventions achieved higher success rates with better outcomes. At 90 days, 57% of patients achieved functional independence (mRS 0–2), while the mortality rate was 24%. Conclusion This study highlights the limitations of medical management for IIAs and underscores the need for early surgical or endovascular intervention in high-risk patients. Outcome predictors aid clinical decision-making, optimizing patient management. Further research is needed to standardize management guidelines for IIAs.

Abstract Cues associated with food, such as fast-food advertising, can provoke food cravings and may lead to unhealthy overeating. Environmental enrichment (EE) that enhances cognitive and physical stimulation can reduce cue-evoked sucrose seeking in mice and recruitment of sucrose cue-reactive neurons or ‘neuronal ensembles’ in the prelimbic cortex (PL), which regulates appetitive behaviors. Hence, EE provides us with a behavioral model and neuronal targets to identify ‘anti-craving’ relevant mechanisms. Here, we investigated in the PL how EE modulated neuronal excitability and activity patterns in cue-reactive neuronal populations. Chemogenetic inhibition of cue-reactive neurons in PL blocked cue-evoked sucrose seeking, thereby confirming the function of these neurons in sucrose cue memory. EE boosted the baseline excitability of ‘originally’, or before EE exposure, cue-reactive, excitatory pyramidal cells in PL. Furthermore, their sucrose cue-specificity was lost – resulting in their persistent activation and non-cue selective activation or ‘excitatory overdrive’. Furthermore, EE reduced recruitment of cue-reactive, inhibitory interneurons reflecting ‘inhibitory underdrive’. Taken together, impaired neuronal food cue processing due to simultaneous prefrontal cortical excitatory ‘overdrive’ and inhibitory ‘underdrive’ likely underlies EE’s anti-craving action, thereby serving as potential neurophysiological targets to develop novel medications that help control food cravings.