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A patient with gastrointestinal stroma tumor (GIST) and KIT p.V559D and BRAF p.G469A alterations was referred to our institutional molecular tumor board (MTB) to discuss therapeutic implications. The patient had been diagnosed with B-cell chronic lymphocytic leukemia (CLL) years prior to the MTB presentation. GIST had been diagnosed 1 month earlier. After structured clinical annotation of the molecular alterations and interdisciplinary discussion, we considered BRAF/KIT co-mutation unlikely in a treatment-naïve GIST. Discordant variant allele frequencies furthermore suggested a second malignancy. NGS of a CLL sample revealed the identical class 2 BRAF alteration, thus supporting admixture of CLL cells in the paragastric mass, leading to the detection of 2 alterations. Following the MTB recommendation, the patient received imatinib and had a radiographic response. Structured annotation and interdisciplinary discussion in specialized tumor boards facilitate the clinical management of complex molecular findings. Coexisting malignancies and clonal hematopoiesis warrant consideration in case of complex and uncommon molecular findings., (© The Author(s) 2024. Published by Oxford University Press.)

Importance: Clinical interpretation of complex biomarkers for precision oncology currently requires manual investigations of previous studies and databases. Conversational large language models (LLMs) might be beneficial as automated tools for assisting clinical decision-making., Objective: To assess performance and define their role using 4 recent LLMs as support tools for precision oncology., Design, Setting, and Participants: This diagnostic study examined 10 fictional cases of patients with advanced cancer with genetic alterations. Each case was submitted to 4 different LLMs (ChatGPT, Galactica, Perplexity, and BioMedLM) and 1 expert physician to identify personalized treatment options in 2023. Treatment options were masked and presented to a molecular tumor board (MTB), whose members rated the likelihood of a treatment option coming from an LLM on a scale from 0 to 10 (0, extremely unlikely; 10, extremely likely) and decided whether the treatment option was clinically useful., Main Outcomes and Measures: Number of treatment options, precision, recall, F1 score of LLMs compared with human experts, recognizability, and usefulness of recommendations., Results: For 10 fictional cancer patients (4 with lung cancer, 6 with other; median [IQR] 3.5 [3.0-4.8] molecular alterations per patient), a median (IQR) number of 4.0 (4.0-4.0) compared with 3.0 (3.0-5.0), 7.5 (4.3-9.8), 11.5 (7.8-13.0), and 13.0 (11.3-21.5) treatment options each was identified by the human expert and 4 LLMs, respectively. When considering the expert as a criterion standard, LLM-proposed treatment options reached F1 scores of 0.04, 0.17, 0.14, and 0.19 across all patients combined. Combining treatment options from different LLMs allowed a precision of 0.29 and a recall of 0.29 for an F1 score of 0.29. LLM-generated treatment options were recognized as AI-generated with a median (IQR) 7.5 (5.3-9.0) points in contrast to 2.0 (1.0-3.0) points for manually annotated cases. A crucial reason for identifying AI-generated treatment options was insufficient accompanying evidence. For each patient, at least 1 LLM generated a treatment option that was considered helpful by MTB members. Two unique useful treatment options (including 1 unique treatment strategy) were identified only by LLM., Conclusions and Relevance: In this diagnostic study, treatment options of LLMs in precision oncology did not reach the quality and credibility of human experts; however, they generated helpful ideas that might have complemented established procedures. Considering technological progress, LLMs could play an increasingly important role in assisting with screening and selecting relevant biomedical literature to support evidence-based, personalized treatment decisions.

Adoptive T cell-receptor therapy (ACT) could represent a promising approach in the targeted treatment of epithelial ovarian cancer (EOC). However, the identification of suitable tumor-associated antigens (TAAs) as targets is challenging. We identified and prioritized TAAs for ACT and other immunotherapeutic interventions in EOC. A comprehensive list of pre-described TAAs was created and candidates were prioritized, using predefined weighted criteria. Highly ranked TAAs were immunohistochemically stained in a tissue microarray of 58 EOC samples to identify associations of TAA expression with grade, stage, response to platinum, and prognosis. Preselection based on expression data resulted in 38 TAAs, which were prioritized. Along with already published Cyclin A1, the TAAs KIF20A, CT45, and LY6K emerged as most promising targets, with high expression in EOC samples and several identified peptides in ligandome analysis. Expression of these TAAs showed prognostic relevance independent of molecular subtypes. By using a systematic vetting algorithm, we identified KIF20A, CT45, and LY6K to be promising candidates for immunotherapy in EOC. Results are supported by IHC and HLA-ligandome data. The described method might be helpful for the prioritization of TAAs in other tumor entities.

Background: Burnout and anxiety compromise physical and mental well-being of nurses and jeopardize patient safety. Personal, professional, and workplace characteristics have been associated with burnout and anxiety across diverse practice settings, yet none in rural, community trauma centers. We sought to identify the severity and predictors of burnout and anxiety in the trauma nursing staff of a rural Level I trauma center., Methods: A convenience sample of trauma nurses from the emergency department (ED), intensive care unit (ICU), and trauma ward was voluntarily surveyed using a demographic questionnaire, the Maslach Burnout Inventory (MBI) subscales: depersonalization (DP), emotional exhaustion (EE), and reduced personal accomplishment, as well as the Generalized Anxiety Disorder seven-item (GAD-7) scale. Multivariable linear regression identified the significant predictors of burnout and anxiety., Results: Ninety-six nurses completed surveys (response rate: 83.5%). Married or divorced status, and ICU or trauma ward job assignments were associated with significantly lower adjusted DP scores. Thus, the model-predicted score for a single ED nurse was 15 versus a predicted score of 7 for a divorced ICU or trauma ward nurse, p < .001 for each group. The GAD-7 model demonstrated that race/ethnicity (Asian compared with White, coefficient: -5.06, p = .03), number of children (2 compared with 0, coefficient: -2.54, p = .02), and job tenure (5-10 years vs. <2, coefficient: -3.18, p = .01) were each associated with fewer GAD-7 points., Conclusion: Depersonalization and anxiety vary across the trauma nursing workforce based on identifiable personal and work-related risk factors. Group-specific, targeted interventions are needed to effectively reduce burnout and anxiety in trauma nursing staff., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Society of Trauma Nurses.)

Background: Cigarette smoking is the leading preventable cause of death and is responsible for more than 480,000 deaths per year in the United States. Smoking cessation is challenging for many patients. Regardless of available treatment options, most quit attempts are unaided, and it takes multiple attempts before a patient is successful. With the ever-increasing use of smartphones, mobile apps hold promise in supporting cessation efforts. This study evaluates the ease of use and user satisfaction with the Pfizer Meds app to support smoking cessation among patients prescribed varenicline (Chantix)., Objective: Study participants included varenicline users who downloaded and used the app on their personal smartphone. The main objectives were to report mobile app download frequency and usage details and to describe the participant-reported satisfaction with and usefulness of the app over the 14-week follow-up study period., Methods: Adults aged 18 years or older who had been prescribed varenicline were identified from the Express Scripts Incorporated pharmacy claims database. After meeting privacy restrictions, subjects were sent an invitation letter and second reminder letter with instructions on how to download the Pfizer Meds mobile app. Participants received a push notification to complete a smartphone-enabled survey regarding the utility of the app 12 weeks after downloading the app. Descriptive statistics summarized sociodemographics, use of varenicline, and details of use and satisfaction with the mobile app., Results: Of the 38,129 varenicline users who were sent invitation letters, 1281 participants (3.35%) downloaded the Pfizer Meds app. Of the 1032 users with demographic and other data, 585 (56.68%) were females, and 446 (43.22%) were males; mean age was 46.4 years (SD 10.8). The mean number of app sessions per participant was 4.0 (SD 6.8). The end-of-study survey was completed by 131 survey respondents (10.23%, 131/1281); a large number of participants (117/131, 89.3%) reported being extremely, very, or moderately satisfied with the app. A total of 97 survey respondents (97/131, 74.0%) reported setting up a quit date in the app. Of those, 74 (74/97, 76%) reported quitting on their quit date., Conclusions: Positive patient engagement was observed in this study based on app download and usage. This study quantified how the Pfizer Meds app performed in an observational real-world data setting. The findings demonstrate the willingness of participants to set a quit date and use the app for support in medication adherence, refill reminders, and information regarding how to take the medication. This study provides real-world evidence of the contribution apps can make to the continued encouragement of smokers to improve their health by smoking cessation., (©Marianna Bruno, Marcia Wright, Christine L Baker, Birol Emir, Eric Carda, Michelle Clausen, Catherine Sigler, Aanal Patel. Originally published in JMIR Mhealth and Uhealth (http://mhealth.jmir.org), 17.04.2018.)

Our understanding of oncogenic signaling pathways has strongly fostered current concepts for targeted therapies in metastatic colorectal cancer. The RALA pathway is novel candidate due to its independent role in controlling expression of genes downstream of RAS.We compared RALA GTPase activities in three colorectal cancer cell lines by GTPase pull-down assay and analyzed the transcriptional and phenotypic effects of transient RALA silencing. Knocking-down RALA expression strongly diminished the active GTP-bound form of the protein. Proliferation of KRAS mutated cell lines was significantly reduced, while BRAF mutated cells were mostly unaffected. By microarray analysis we identified common genes showing altered expression upon RALA silencing in all cell lines. None of these genes were affected when the RAF/MAPK or PI3K pathways were blocked.To investigate the potential clinical relevance of the RALA pathway and its associated transcriptome, we performed a meta-analysis interrogating progression-free survival of colorectal cancer patients of five independent data sets using Cox regression. In each dataset, the RALA-responsive signature correlated with worse outcome.In summary, we uncovered the impact of the RAL signal transduction on genetic program and growth control in KRAS- and BRAF-mutated colorectal cells and demonstrated prognostic potential of the pathway-responsive gene signature in cancer patients.

Epidemiological studies increasingly inform Alzheimer's disease (AD) public health impact, prevention strategies, drug targets, therapeutic interventions, and clinical trial design. For this reason, the Alzheimer's Association Research Roundtable convened an international group of AD experts with experience in conducting both observational and clinical trials for a meeting on October 19 and 20, 2010, in Washington, DC, to discuss the role of epidemiologic studies in AD research and therapeutic advances. Topics included wellness markers and risk factors, with a focus on special populations such as those at elevated risk, super agers, and underserved populations. Discussions also highlighted lessons learned from observational studies of aging, cardiovascular disease, and other disease areas, as well as how new technologies have enabled the gathering of data relevant to drug development and clinical trial conduct., (Copyright © 2012 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Objective: To assess the economic efficiency of adding troglitazone to sulfonylurea therapy to improve glycemic control., Background: Despite the high prevalence of type 2 diabetes, existing treatment strategies often fail. New oral agents give a wider segment of the population with type 2 diabetes hope of achieving near-normal blood-glucose levels. Troglitazone, a novel chemical entity, is one promising new agent., Methods: We conducted an economic analysis based on glycemic-control data from a randomized clinical trial comparing troglitazone with placebo, each added to glyburide. A patient simulation model was used to translate these data to long-term outcomes associated with diabetes. Patients had poorly controlled type 2 diabetes mellitus despite glyburide therapy. Risk functions of developing and progressing through nephropathy, retinopathy, neuropathy, hypoglycemia, and macrovascular disease were developed from the Diabetes Control and Complications Trial and large epidemiologic studies. Cost estimates were based on data from 5 states, all payor databases, surveys, and literature. The main outcomes of the model were cost-consequences, number of patients developing each type of complication, mean time to development of the complication, cost per life-year gained (LYG), and cost per quality-adjusted life-year., Results: The model predicts that for every 1000 patients treated with troglitazone, the improved glycemic control could mean that 95 to 140 fewer patients would experience one of the most severe diabetic complications (eg, blindness, end-stage renal disease, amputation), which may increase life expectancy by 2.0 years. These benefits are obtained at an additional $2100 per LYG (undiscounted). The ratio remains <$50,000 per LYG for most variations in input., Conclusions: The clinical trial demonstrated that troglitazone + glyburide improves glycemic control compared with glyburide alone. Based on these results, the model estimates fewer diabetic complications at a cost well below accepted cost-effective thresholds.

High density lipoprotein (HDL) cholesterol levels can be used to predict cardiovascular disease risk in women. To better understand variability in HDL cholesterol levels, the authors examined the relation with three domains (body size and type, sex hormone status, and carbohydrate metabolism) in a cross-sectional population-based 1993-1994 study of 402 premenopausal women from Tecumseh, Michigan. They found that these domains explained 27% of the total variation in HDL cholesterol levels; waist-to-hip ratio was the term that explained the highest proportion of variability (6% after fat mass, sex hormone binding globulin, and insulin levels were added to the model). In analyses restricted to women whose body mass index was > or = 32 kg/m2, which constituted 19% of this population, neither body mass index nor fat mass was a significant predictor of variability in HDL cholesterol levels. Significant variables were insulin levels, waist-to-hip ratio, and smoking. This finding suggests that there is a saturation of the relation between increasing fat mass and lower HDL cholesterol levels, as evidenced by the lack of a relation between the two among the heaviest women. Meanwhile, among the heaviest women, increasing insulin levels and a higher waist-to-hip ratio remained predictors of low levels of HDL cholesterol.

Objective: To determine if mean levels of complement components and carboxypeptidase N differed when comparing patients who exhibited angioedema following angiotensin-converting enzyme inhibitor therapy to those who received angiotensin-converting enzyme inhibitor therapy but did not have angioedema., Design: Case-control study nested within an 8-week, open-label study of the use of quinapril hydrochloride for hypertension in 12275 patients., Setting: Multicenter, with sites throughout the United States., Patients: Of the 36 patients with angioedema described, 22 participated in the study. They were matched to 48 controls by age, sex, race, length of follow-up, and geographical region., Intervention: All patients received quinapril therapy prior to participation in this case-control study., Main Outcome Measures: Levels of carboxypeptidase N, total hemolytic complement, C1 esterase inhibitor, and C4, along with questionnaire data, including a history of angioedema-like episodes and family history of angioedema., Results: The 22 patients had significantly lower mean levels of carboxypeptidase N (kininase I) (P = .03) and C1 esterase inhibitor (P = .04) compared with the 48 matched controls, but all mean values were within normal laboratory ranges. A history of prior angioedema-like episodes was associated with an approximate 6-fold increase in the subsequent risk of angioedema following angiotensin-converting enzyme inhibitor therapy., Conclusions: Small differences in levels of carboxypeptidase N or C1 esterase inhibitor may contribute to an increased risk of angioedema with angiotensin-converting enzyme inhibitor therapy. Given the large overlap in the distributions of carboxypeptidase N and C1 esterase inhibitor levels, prior testing could not be used to evaluate angioedema risk for an individual patient considering angiotensin-converting enzyme inhibitor therapy. A history of prior angioedema-like episodes was associated with increased risk, but this result should be interpreted with caution because of possible recall bias.

Cause of death among 917 of the 959 subjects in a population-based incidence cohort with Alzheimer's disease (AD) during the years 1960 to 1984 was compared to that of an age- and gender-matched control group (n = 703). In general, a summary of the diagnostic codes entered anywhere on a death certificate suggests that control subjects had more cardiovascular disease and neoplasms than did patients, while patients more often had a diagnostic code of bronchitis/pneumonia (P < 0.01). By logistic regression, this difference remained statistically significant after adjusting for age and gender.

The development of cyclophosphamide-induced pulmonary lesions over a 1-year period was studied in mice. Male BALB/c mice received a single intraperitoneal injection of 100 mg/kg of cyclophosphamide. Within 3 weeks there were scattered foci of intraalveolar foamy macrophages. With time, these foci increased in size and, 1 year later, occupied large areas in all lung lobes. There was also diffuse interstitial fibrosis. Chemical determination done 3, 12, 24, and 52 weeks after cyclophosphamide showed that lungs of animals treated with cyclophosphamide had significantly more hydroxyproline per lung than controls. One year after cyclophosphamide pressure-volume curves measured in vivo were shifted down and to the right and total lung volumes were decreased. A single injection of cyclophosphamide produced an irreversible and progressive pulmonary lesion.