Progressive Ulnar Neuropathy Following a Presumed Catfish Sting.

Catfish are a highly diverse group of fish comprising more than 3500 species found in both freshwater and marine ecosystems. Upon handling, they can inflict a sting, with certain species capable of inducing significant pain and injury to the affected extremity. The prevalence of aquatic activities, such as fishing by line or manual capture ("noodling"), increases the likelihood of catfish stings, making prompt identification and treatment an important aspect of managing such encounters. A case of a presumed catfish spine injury during noodling in Tallahassee, Florida, is presented. The pectoral fin penetrated the volar aspect of the patient's right hand resulting in immediate pain and numbness. Over the course of 2 weeks, the patient developed distal ulnar neuropathy with conduction block at the wrist level. Surgical exploration revealed the ulnar nerve to be grossly intact, but the area surrounding the terminal division point of the ulnar nerve in the hand displayed infiltration by fibrous tissue that entrapped the nerve and its branches. Following surgical release of the ulnar nerve and its terminal branches from the fibrous tissue, complete resolution of distal ulnar neuropathy was achieved. In this patient's case, the absence of foreign bodies and the lack of visible nerve damage suggest that the injury to the patient's hand was largely attributable to toxin-mediated proinflammatory response and fibrosis.

A Comprehensive Analysis of Metastatic Disease following Surgery for Clinically Localized Cutaneous Melanoma.

INTRODUCTION: The NCCN considers "baseline staging" (whole body CT or PET scan +/- brain MRI) for all asymptomatic melanoma patients with a positive sentinel lymph node biopsy. The true yield of these workups is unknown. METHODS: We created cohorts of adult malignant melanoma patients, using the National Cancer Database (2012-2020) to mimic three common scenarios: (1) clinically node negative, with positive sentinel lymph node(s) (SLNB[+]); (2) clinically node negative, with negative sentinel lymph node(s) (SLNB[-]); (3) clinically node positive with confirmed lymph node metastases (cN[+] and pN[+]). Multivariable regression, supervised decision trees, and nomograms were constructed to assess the risk of metastases based on key features. RESULTS: 10,371 patients were SLNB[+], 55,172 were SLNB[-], and 4,012 were cN[+] and pN[+]. The proportion of patients with any metastatic disease (brain metastases) were as follows: SLNB[+]: 1.4% (0.3%); SLNB[-] 0.3% (<0.1%); cN[+] and pN[+] 11.6% (1.6%). On multivariable regression, Breslow depth > 4, ulceration, and lymphovascular invasion were associated with greater risk of metastatic disease. A supervised decision tree for SLNB[+] and SLNB[-] patients found the only groups with >2% risk of metastases were T4 tumors or T2/T3 tumors with ulceration and LVI. Most groups had a negligible risk (<0.1%) of brain metastases. CONCLUSION: This is the first large analysis to guide the use of imaging for cutaneous melanoma. Among clinically node negative patients, metastatic disease is uncommon and brain metastases are exceedingly rare. Further investigation could promote a tailored approach to metastatic workups guided by individual risk factors.

Hurricanes and Health: A Scoping Review of Recent Developments in Physical Injuries, Mental Health, and Emergency Interventions.

Hurricanes, as one of the most devastating natural disasters, significantly impact the public's health, causing both physical injuries and long-lasting mental health issues. Although substantial research has focused on hurricane-related injuries, this study aims to synthesize findings from recent literature, specifically evaluating the 10 most recent hurricanes, to identify research gaps and inform future studies. This scoping review, conducted in accordance with PRISMA-Scr guidelines, assessed studies from PubMed, CINAHL, Cochrane databases, and Medline as of February 2024. Eligibility criteria focused on studies examining physical and mental health impacts, COVID-19 effects, and emergency medical services (EMS) interventions related to Hurricanes Ian, Nicholas, Ida, Zeta, Delta, Sally, Laura, Isaias, Hanna, and Dorian. Twenty articles met the inclusion criteria. The studies were categorized into four themes: physical injuries and fatalities, mental health impacts, hurricane-COVID-19 interplay, and EMS interventions. Findings revealed varied mechanisms of injuries and deaths, significant mental health challenges, compounded crises due to COVID-19, and diverse EMS strategies, including AI utilization and strategic planning for medical care delivery. Addressing the social determinants of health and evaluating hurricane readiness initiatives were two gaps in the literature identified. Future research should focus on the mental health impacts and concurrent crisis challenges to develop comprehensive disaster management practices that enhance community resilience against future hurricanes and public health crises.

Patient-specific mutation of Dync1h1 in mice causes brain and behavioral deficits.

AIMS: Cytoplasmic dynein heavy chain (DYNC1H1) is a multi-subunit protein complex that provides motor force for movement of cargo on microtubules and traffics them back to the soma. In humans, mutations along the DYNC1H1 gene result in intellectual disabilities, cognitive delays, and neurologic and motor deficits. The aim of the study was to generate a mouse model to a newly identified de novo heterozygous DYNC1H1 mutation, within a functional ATPase domain (c9052C > T(P3018S)), identified in a child with motor deficits, and intellectual disabilities. RESULTS: P3018S heterozygous (HET) knockin mice are viable; homozygotes are lethal. Metabolic and EchoMRI™ testing show that HET mice have a higher metabolic rate, are more active, and have less body fat compared to wildtype mice. Neurobehavioral studies show that HET mice perform worse when traversing elevated balance beams, and on the negative geotaxis test. Immunofluorescent staining shows neuronal migration abnormalities in the dorsal and lateral neocortex with heterotopia in layer I. Neuron-subtype specific transcription factors CUX1 and CTGF identified neurons from layers II/III and VI respectively in cortical layer I, and abnormal pyramidal neurons with MAP2+ dendrites projecting downward from the pial surface. CONCLUSION: The HET mice are a good model for the motor deficits seen in the child, and highlights the importance of cytoplasmic dynein in the maintenance of cortical function and dendritic orientation relative to the pial surface. Our results are discussed in the context of other dynein mutant mice and in relation to clinical presentation in humans with DYNC1H1 mutations.

Single-cell profiling of sarcomas from archival tissue reveals programs associated with resistance to immune checkpoint blockade.

PURPOSE: Sarcoma encompasses a diverse group of cancers that are typically resistant to current therapies, including immune checkpoint blockade (ICB), and underlying mechanisms are poorly understood. The contexture of sarcomas limits generation of high-quality data using cutting-edge molecular profiling methods, such as single-cell RNA-seq, thus hampering progress in understanding these understudied cancers. EXPERIMENTAL DESIGN: Here, we demonstrate feasibility of producing multi-modal single-cell genomics and whole-genome sequencing data from frozen tissues, profiling 75,716 cell transcriptomes of five undifferentiated pleomorphic (UPS) and three intimal sarcomas (INS) samples, including paired specimens from two patients treated with ICB. RESULTS: We find that genomic diversity decreases in patients with response to ICB, and, in unbiased analyses, identify cancer cell programs associated with therapy resistance. Although interactions of tumor-infiltrating T lymphocytes within the tumor ecosystem increase in ICB responders, clonal expansion of CD8+ T cells alone was insufficient to predict drug responses. CONCLUSION: This study provides a framework for studying rare tumors and identifies salient and treatment-associated cancer cell intrinsic and tumor-microenvironmental features in sarcomas.

Real-world assessment of longitudinal opioid use and healthcare resource utilization in patients undergoing colorectal resection.

Liposomal bupivacaine (LB) has been used in multimodal pain management regimens to improve postsurgical analgesia. This retrospective cohort analysis assessed clinical and economic outcomes of LB vs non-LB analgesia in minimally invasive colorectal resection surgery using real-world patient data from the IQVIA linkage claims databases. Patients who received LB were 1:1 matched to patients who did not receive LB (non-LB) via propensity scores. Outcomes included opioid use during the perioperative (2 weeks before surgery to 2 weeks after discharge), continued (>2 weeks to 3 months after discharge), and persistent (>3 months to 6 months after discharge) periods and healthcare resource utilization (HRU) during the first 3 months after discharge. Mean opioid consumption was lower in the LB (n = 4397) versus non-LB (n = 4397) cohort perioperatively (483 vs 538 morphine milligram equivalents [MMEs]; P = 0.001) and after discharge within ∼3 months (222 vs 328 MMEs; P < 0.0001) and 3-6 months (245 vs 384 MMEs; P < 0.0001). The LB cohort had shorter mean length of stay (5.2 vs 5.7 days; P < 0.0001) and fewer inpatient readmissions (odds ratio [OR], 0.71; P < 0.0001), emergency department visits (OR, 0.78; P < 0.0001), and outpatient/office visits (OR, 0.91; P = 0.028) than the non-LB cohort 3 months after discharge. These data suggest use of LB in minimally invasive colorectal resection surgery may reduce perioperative and postdischarge opioid use as well as HRU. Although additional studies are needed to confirm these findings, this analysis provides valuable real-world data from large claims databases to evaluate clinical and economic outcomes that complement other types of retrospective and prospective studies.

Insulin and leptin oscillations license food-entrained browning and metabolic flexibility.

Timed feeding drives adipose browning, although the integrative mechanisms for the same remain unclear. Here, we show that twice-a-night (TAN) feeding generates biphasic oscillations of circulating insulin and leptin, representing their entrainment by timed feeding. Insulin and leptin surges lead to marked cellular, functional, and metabolic remodeling of subcutaneous white adipose tissue (sWAT), resulting in increased energy expenditure. Single-cell RNA-sequencing (scRNA-seq) analyses and flow cytometry demonstrate a role for insulin and leptin surges in innate lymphoid type 2 (ILC2) cell recruitment and sWAT browning, since sWAT depot denervation or loss of leptin or insulin receptor signaling or ILC2 recruitment each dampens TAN feeding-induced sWAT remodeling and energy expenditure. Consistently, recreating insulin and leptin oscillations via once-a-day timed co-injections is sufficient to favorably remodel innervated sWAT. Innervation is necessary for sWAT remodeling, since denervation of sWAT, but not brown adipose tissue (BAT), blocks TAN-induced sWAT remodeling and resolution of inflammation. In sum, reorganization of nutrient-sensitive pathways remodels sWAT and drives the metabolic benefits of timed feeding.

Botensilimab plus balstilimab in relapsed/refractory microsatellite stable metastatic colorectal cancer: a phase 1 trial.

Microsatellite stable metastatic colorectal cancer (MSS mCRC; mismatch repair proficient) has previously responded poorly to immune checkpoint blockade. Botensilimab (BOT) is an Fc-enhanced multifunctional anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody designed to expand therapy to cold/poorly immunogenic solid tumors, such as MSS mCRC. BOT with or without balstilimab (BAL; anti-PD-1 antibody) is being evaluated in an ongoing expanded phase 1 study. The primary endpoint is safety and tolerability, which was evaluated separately in the dose-escalation portion of the study and in patients with MSS mCRC (using combined dose-escalation/dose-expansion data). Secondary endpoints include investigator-assessed RECIST version 1.1-confirmed objective response rate (ORR), disease control rate (DCR), duration of response (DOR) and progression-free survival (PFS). Here we present outcomes in 148 heavily pre-treated patients with MSS mCRC (six from the dose-escalation cohort; 142 from the dose-expansion cohort) treated with BOT and BAL, 101 of whom were considered response evaluable with at least 6 months of follow-up. Treatment-related adverse events (TRAEs) occurred in 89% of patients with MSS mCRC (131/148), most commonly fatigue (35%, 52/148), diarrhea (32%, 47/148) and pyrexia (24%, 36/148), with no grade 5 TRAEs reported and a 12% discontinuation rate due to a TRAE (18/148; data fully mature). In the response-evaluable population (n = 101), ORR was 17% (17/101; 95% confidence interval (CI), 10-26%), and DCR was 61% (62/101; 95% CI, 51-71%). Median DOR was not reached (NR; 95% CI, 5.7 months-NR), and median PFS was 3.5 months (95% CI, 2.7-4.1 months), at a median follow-up of 10.3 months (range, 0.5-42.6 months; data continuing to mature). The combination of BOT plus BAL demonstrated a manageable safety profile with no new immune-mediated safety signals and encouraging clinical activity with durable responses. ClinicalTrials.gov identifier: NCT03860272 .

Development of Novel Tools for Dissection of Central Versus Peripheral Dopamine D2-Like Receptor Signaling in Dysglycemia.

Dopamine (DA) D2-like receptors in both the central nervous system (CNS) and the periphery are key modulators of metabolism. Moreover, disruption of D2-like receptor signaling is implicated in dysglycemia. Yet, the respective metabolic contributions of CNS versus peripheral D2-like receptors, including D2 (D2R) and D3 (D3R) receptors, remain poorly understood. To address this, we developed new pharmacological tools, D2-like receptor agonists with diminished and delayed blood-brain barrier capability, to selectively manipulate D2R/D3R signaling in the periphery. We designated bromocriptine methiodide (BrMeI), a quaternary methiodide analog of D2R/D3R agonist and diabetes drug bromocriptine, as our lead compound based on preservation of D2R/D3R binding and functional efficacy. We then used BrMeI and unmodified bromocriptine to dissect relative contributions of CNS versus peripheral D2R/D3R signaling in treating dysglycemia. Systemic administration of bromocriptine, with unrestricted access to CNS and peripheral targets, significantly improved both insulin sensitivity and glucose tolerance in obese, dysglycemic mice in vivo. In contrast, metabolic improvements were attenuated when access to bromocriptine was restricted either to the CNS through intracerebroventricular administration or delayed access to the CNS via BrMeI. Our findings demonstrate that the coordinated actions of both CNS and peripheral D2-like receptors are required for correcting dysglycemia. Ultimately, the development of a first-generation of drugs designed to selectively target the periphery provides a blueprint for dissecting mechanisms of central versus peripheral DA signaling and paves the way for novel strategies to treat dysglycemia.

Nontuberculous Mycobacterial Flexor Tenosynovitis of the Wrist and Hand.

Nontuberculous mycobacteria (NTM) are uncommon causes of cutaneous and musculoskeletal infections. Here, we present an immunocompromised patient with persistent swelling in the left hand, wrist, and distal forearm. MRI findings revealed flexor tenosynovitis with synovial hypertrophy of the left hand and wrist and loculated fluid containing rice bodies along the distal flexor digitorum muscles in the volar aspect of the left wrist. The patient underwent flexor tenosynovectomy, and histological examination of the excised tenosynovium and mass revealed noncaseating granulomas. Mycobacterium intracellulare was identified in microbiological cultures. Antimycobacterial therapy was administered postoperatively to manage the infection. This report underscores the significance of maintaining a high index of suspicion for NTM infection when assessing chronic hand swelling, particularly in individuals with compromised immune systems.

The histone methyltransferase SUV420H2 regulates brown and beige adipocyte thermogenesis.

Activation of brown adipose tissue (BAT) thermogenesis increases energy expenditure and alleviates obesity. Here we discover that histone methyltransferase suppressor of variegation 4-20 homolog 2 (Suv420h2) expression parallels that of Ucp1 in brown and beige adipocytes and that Suv420h2 knockdown significantly reduces - whereas Suv420h2 overexpression significantly increases - Ucp1 levels in brown adipocytes. Suv420h2 knockout (H2KO) mice exhibit impaired cold-induced thermogenesis and are prone to diet-induced obesity. In contrast, mice with specific overexpression of Suv420h2 in adipocytes display enhanced cold-induced thermogenesis and are resistant to diet-induced obesity. Further study shows that Suv420h2 catalyzes H4K20 trimethylation at eukaryotic translation initiation factor 4E-binding protein 1 (4e-bp1) promoter, leading to downregulated expression of 4e-bp1, a negative regulator of the translation initiation complex. This in turn upregulates PGC1α protein levels, and this upregulation is associated with increased expression of thermogenic program. We conclude that Suv420h2 is a key regulator of brown/beige adipocyte development and thermogenesis.

Short Communication: Radon testing via a state tobacco quitline.

Objective: Exposure to radon gas at home is the second largest cause of lung cancer after smoking and dramatically increases smokers' risk of lung cancer. State tobacco quitlines are uniquely positioned to inform smokers about radon, yet, to our knowledge, none does so. We explored the feasibility of introducing free radon tests via the tobacco quitline in North Dakota, a state with one of the highest radon levels in the U.S. Methods: Five hundred consecutive callers to the ND Quits Tobacco quitline from February 2021 to February 2023 were invited to complete a brief radon questionnaire and receive a free radon test kit. Radon tests were bar-coded so that the return rate of the tests and the radon levels could be determined. Results: Two hundred fifty-one (51 %) callers completed the questionnaire and seventy-five radon tests were successfully returned to the laboratory. More than one third of the test results were ≥ 4.0 pCi/L, the action level recommended by the EPA. Only 1 in 5 participants reported knowing that radon caused lung cancer. Conclusion: Radon knowledge among ND smokers is poor. Radon test distribution via quitlines is feasible and may be a valuable addition to quitline services, particularly in states with high radon levels.

A Phase I Trial Evaluating the Addition of Lenalidomide to Patients with Relapsed/Refractory Multiple Myeloma Progressing on Ruxolitinib and Methylprednisolone.

BACKGROUND: Ruxolitinib (RUX), an orally administered selective Janus kinase 1/2 inhibitor, has received approval for the treatment of myelofibrosis, polycythemia vera, and graft-versus-host disease. We have previously demonstrated the anti-multiple myeloma effects of RUX alone and in combination with the immunomodulatory agent lenalidomide (LEN) and glucocorticosteroids both pre-clinically and clinically. OBJECTIVE: This study aims to evaluate whether LEN can achieve clinical activity among patients with multiple myeloma progressing on the combination of RUX and methylprednisolone (MP). METHODS: In this part of a phase I, multicenter, open-label study, we evaluated the safety and efficacy of RUX and MP for patients with multiple myeloma with progressive disease who had previously received a proteasome inhibitor, LEN, glucocorticosteroids, and at least three prior regimens; we also determined the safety and efficacy of adding LEN at the time of disease progression from the initial doublet treatment. Initially, all subjects received oral RUX 15 mg twice daily and oral MP 40 mg every other day. Those patients who developed progressive disease according to the International Myeloma Working Group criteria then received LEN 10 mg once daily on days 1-21 within a 28-day cycle in addition to RUX and MP, which were administered at the same doses these patients were receiving at the time progressive disease developed. RESULTS: Twenty-nine subjects (median age 64 years; 18 [62%] male) were enrolled in this part of the study and initially received the two-drug combination of RUX and MP. The median number of prior therapies was six (range 3-12). The overall response rate from this two-drug combination was 31% and the clinical benefit rate was 34%. The best responses were 1 very good partial response, 8 partial responses, 1 minor response, 12 stable disease, and 7 progressive disease. The median progression-free survival was 3.5 months (range  0.5-36.2 months). The median time to response was 3.0 months. The median duration of response was 12.5 months (range 2.8-36.2 months). Twenty (69%) patients who showed progressive disease had LEN added to RUX and MP; all patients had prior exposure to LEN and all but one patient was refractory to their last LEN-containing regimen. After the addition of LEN, the overall response rate was 30% and the clinical benefit rate was 40%. The best responses of patients following the addition of LEN were 2 very good partial responses, 4 partial responses, 2 minor responses, 8 stable disease, and 4 progressive disease. The median time to response was 2.6 months (range 0.7-15.0 months). The median duration of response was not reached. The median progression-free survival following the addition of LEN was 3.5 months (range 0.3-25.9 months). CONCLUSIONS: For patients with multiple myeloma, treatment with RUX and MP is effective and well tolerated, and LEN can be used to extend the benefit of this RUX-based treatment. CLINICAL TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov, NCT03110822, and is ongoing.

Phase Ib Study of Unesbulin (PTC596) Plus Dacarbazine for the Treatment of Locally Recurrent, Unresectable or Metastatic, Relapsed or Refractory Leiomyosarcoma.

PURPOSE: This multicenter, single-arm, open-label, phase Ib study was designed to determine the recommended phase II dose (RP2D) and to evaluate the safety and preliminary efficacy of unesbulin plus dacarbazine (DTIC) in patients with advanced leiomyosarcoma (LMS). PATIENTS AND METHODS: Adult subjects with locally advanced, unresectable or metastatic, relapsed or refractory LMS were treated with escalating doses of unesbulin orally twice per week in combination with DTIC 1,000 mg/m2 intravenously (IV) once every 21 days. The time-to-event continual reassessment method was used to determine the RP2D on the basis of dose-limiting toxicities (DLTs) assessed during the first two 21-day treatment cycles. All explored doses of unesbulin (200 mg up to 400 mg) were in combination with DTIC. An expansion cohort was enrolled to evaluate the safety and efficacy of unesbulin at the RP2D. RESULTS: Unesbulin 300 mg administered orally twice per week in combination with DTIC 1,000 mg/m2 IV once every 21 days was identified as the RP2D. On the basis of data from 27 subjects who were deemed DLT-evaluable, toxicity was higher in the unesbulin 400 mg group, with three of four subjects (75%) experiencing DLTs versus one of four subjects (25%) in the 200 mg group and three of 19 subjects (15.8%) in the 300 mg group. The most commonly reported DLTs and treatment-related grade 3 and 4 adverse events were thrombocytopenia and neutropenia. At the RP2D, seven subjects who were efficacy evaluable achieved partial response for an objective response rate of 24.1%. CONCLUSION: Unesbulin 300 mg twice per week plus DTIC 1,000 mg/m2 once every 21 days was identified as the RP2D, demonstrating a favorable benefit-risk profile in a heavily pretreated population of adults with advanced LMS.

Liver-innervating vagal sensory neurons play an indispensable role in the development of hepatic steatosis and anxiety-like behavior in mice fed a high-fat diet.

Background and Aims: The visceral organ-brain axis, mediated by vagal sensory neurons in the vagal nerve ganglion, is essential for maintaining various physiological functions. In this study, we investigated the impact of liver-projecting vagal sensory neurons on energy balance, hepatic steatosis, and anxiety-like behavior in mice under obesogenic conditions. Methods: We performed single-nucleus RNA sequencing of vagal sensory neurons innervating the liver. Based on our snRNA-Seq results, we used the Avil CreERT2 strain to identify vagal sensory neurons that innervate the liver. Results: A small subset of polymodal sensory neurons innervating the liver was located in the left and right ganglia, projecting centrally to the nucleus of the tractus solitarius, area postrema, and dorsal motor nucleus of the vagus, and peripherally to the periportal areas in the liver. Male and female control mice developed diet-induced obesity (DIO) during high-fat diet feeding. Deleting liver-projecting advillin-positive vagal sensory neurons prevented DIO in male and female mice, and these outcomes are associated with increased energy expenditure. Although males and females exhibited improved glucose homeostasis following disruption of liver-projecting vagal sensory neurons, only male mice displayed increased insulin sensitivity. The loss of liver-projecting vagal sensory neurons limited the progression of hepatic steatosis in male and female mice fed a steatogenic diet. Finally, mice lacking liver-innervating vagal sensory neurons exhibited less anxiety-like behavior compared to the control mice. Conclusions: The liver-brain axis contributes to the regulation of energy balance, glucose tolerance, hepatic steatosis, and anxiety-like behavior depending on the nutrient status in healthy and obesogenic conditions.

Development of novel tools for dissection of central versus peripheral dopamine D2-like receptor signaling in dysglycemia.

Dopamine (DA) D2-like receptors in both the central nervous system (CNS) and the periphery are key modulators of metabolism. Moreover, disruption of D2-like receptor signaling is implicated in dysglycemia. Yet, the respective metabolic contributions of CNS versus peripheral D2-like receptors including D2 (D2R) and D3 (D3R) receptors remain poorly understood. To address this, we developed new pharmacological tools, D2-like receptor agonists with diminished and delayed blood-brain barrier capability, to selectively manipulate D2R/D3R signaling in the periphery. We designated bromocriptine methiodide (BrMeI), a quaternary methiodide analogue of D2/3R agonist and diabetes drug bromocriptine, as our lead compound based on preservation of D2R/D3R binding and functional efficacy. We then used BrMeI and unmodified bromocriptine to dissect relative contributions of CNS versus peripheral D2R/D3R signaling in treating dysglycemia. Systemic administration of bromocriptine, with unrestricted access to CNS and peripheral targets, significantly improved both insulin sensitivity and glucose tolerance in obese, dysglycemic mice in vivo. In contrast, metabolic improvements were attenuated when access to bromocriptine was restricted either to the CNS through intracerebroventricular administration or delayed access to the CNS via BrMeI. Our findings demonstrate that the coordinated actions of both CNS and peripheral D2-like receptors are required for correcting dysglycemia. Ultimately, the development of a first-generation of drugs designed to selectively target the periphery provides a blueprint for dissecting mechanisms of central versus peripheral DA signaling and paves the way for novel strategies to treat dysglycemia.

A Single Arm Phase 2 Trial of Trametinib in Patients With Locally Advanced or Metastatic Epithelioid Hemangioendothelioma.

PURPOSE: Epithelioid hemangioendothelioma (EHE) is a rare vascular cancer with pathogenic TAZ-CAMTA1 operating as an oncogenic driver through activation of MAPK pathway. Trametinib is an inhibitor of MEK, a critical kinase in the MAPK pathway. We sought to evaluate the effect of trametinib in patients with EHE. PATIENTS AND METHODS: A phase 2 trial of trametinib was conducted in patients with locally advanced or metastatic EHE. Eligibility requirements included evidence of tumor progression or presence of EHE-related pain requiring opiates for management prior to enrollment. The primary endpoint was objective response rate (ORR) per RECIST1.1 in cases with TAZ-CAMTA1 confirmed by fusion-FISH. Secondary objectives were to estimate ORR for all patients, median PFS, 2-year OS rate, patient safety, and change in patient-reported global health and pain scores per PROMIS questionnaires. RESULTS: 44 patients enrolled and 42 started trametinib. TAZ-CAMTA1 was detected in 27 tumor samples. The ORR was 3.7% (95% CI: 0.094, 19.0), median PFS was 10.4 months (95% CI: 7.1, NA), and 2-year OS rate was 33.3% (95% CI: 19.1, 58.2) in the target population. Median pain intensity and interference scores improved significantly after 4 weeks of trametinib in patients using opiates. Common AEs related to trametinib were rash, fatigue, nausea/vomiting, diarrhea/constipation, alopecia and edema; one Grade 5 ARDS/pneumonitis was related to trametinib. CONCLUSIONS: Trametinib was associated with reduction in EHE-related pain and median PFS of more than 6 months providing palliative benefit in patients with advanced EHE, but the trial did not meet the ORR goal.

Radon Exposure and Incident Stroke Risk in the Women's Health Initiative.

BACKGROUND AND OBJECTIVES: Little is known about the role of radon in the epidemiology of stroke among women. We therefore examined the association between home radon exposure and risk of stroke among middle-aged and older women in the United States. METHODS: We conducted a prospective cohort study of postmenopausal women aged 50-79 years at baseline (1993-1998) in the Women's Health Initiative. We measured exposures as 2-day, indoor, lowest living-level average radon concentrations in picocuries per liter (pCi/L) as estimated in 1993 by the US Geological Survey and reviewed by the Association of American State Geologists under the Indoor Radon Abatement Act. We used Cox proportional hazards models to estimate risk of incident, neurologist-adjudicated stroke during follow-up through 2020 as a hazard ratio and 95% CI, adjusting for study design and participant demographic, social, behavioral, and clinical characteristics. RESULTS: Among 158,910 women without stroke at baseline (mean age 63.2 years; 83% white), 6,979 incident strokes were identified over follow-up (mean 13.4 years). Incidence rates were 333, 343, and 349 strokes per 100,000 woman-years at radon concentrations of <2, 2-4, and >4 pCi/L, respectively. Compared with women living at concentrations <2 pCi/L, those at 2-4 and >4 pCi/L had higher covariate-adjusted risks of incident stroke: hazard ratio (95% CI) 1.06 (0.99-1.13) and 1.14 (1.05-1.22). Using nonlinear spline functions to model radon, stroke risk was significantly elevated at concentrations ranging from 2 to 4 pCi/L (p = 0.0004), that is, below the United States Environmental Protection Agency Radon Action Level for mitigation (4 pCi/L). Associations were slightly stronger for ischemic (especially cardioembolic, small vessel occlusive, and large artery atherosclerotic) than hemorrhagic stroke, but otherwise robust in sensitivity analyses. DISCUSSION: Radon exposure is associated with moderately increased stroke risk among middle-aged and older women in the United States, suggesting that promulgation of a lower Radon Action Level may help reduce the domestic impact of cerebrovascular disease on public health.

Deep Vein Thrombosis Prophylaxis in Orthopedic Surgery.

Deep vein thrombosis (DVT) is a complex and multifactorial process arising from a variety of factors, including recent surgical procedures, traumatic events, and periods of prolonged immobility. The extended period of stasis post-orthopedic surgery places patients at a notably high risk of developing DVT, and DVT-related pulmonary embolism (PE) ranks as the third most common cause of death in orthopedic surgery patients. This review examines the multifaceted risk factors contributing to the development of DVT in orthopedic patients. Additionally, it addresses the importance of DVT prophylaxis in orthopedic settings, the efficacy and safety of various prophylactic methods encompassing both mechanical and pharmacological approaches, and the economic dimensions of DVT prophylaxis, including scrutiny of cost-effectiveness and the exploration of strategies for optimization.