Faculty Bibliography

Treatment of NSCLC KRAS G12C mutant tumors with the allele-selective sotorasib and adagrasib inhibitors is invariably associated with acquired resistance. The MUC1-encoded oncogenic M1C protein is necessary for self-renewal of NSCLC KRAS mutant cells. We report that treatment of NSCLC KRAS G12C cells with sotorasib induces M1C expression by a STAT1-dependent pathway. In turn, M1C drives the sotorasib resistant phenotype by NF-κB-mediated induction of the epithelial-mesenchymal transition (EMT) and a mucinous gene program. Targeting M1C→NF-κB signaling (i) suppresses EMT and mucin genes, and (ii) reverses sotorasib resistance. Of translational relevance, treatment with a M1C antibody-drug conjugate (ADC) is effective against two sotorasib-resistant NSCLC KRAS G12C cell lines and two patient-derived tumor xenograft models. Analysis of patients with NSCLC KRAS G12C tumors treated with sotorasib/adagrasib and overexpressing MUC1 associates with decreases in overall survival. These findings identify M1C as a key effector of sotorasib resistance and as a target for treatment of patients with refractory NSCLC KRAS G12C mutant tumors.

BACKGROUND:Coronary microvascular dysfunction (CMD) is a mechanism of ischemia with nonobstructive coronary arteries (INOCA) diagnosed by invasive coronary function testing (CFT). It is unknown whether CMD reflects a systemic microcirculatory disorder. Sidestream darkfield (SDF) microscopy permits noninvasive imaging of red blood cells (RBCs) in the sublingual microcirculation. OBJECTIVES/OBJECTIVE:We sought to evaluate whether SDF microscopy identifies sublingual microvascular abnormalities in patients with INOCA due to CMD. METHODS:Adults with INOCA underwent CFT for CMD, defined by abnormal coronary flow reserve <2.5 or index of microcirculatory resistance ≥25. Sublingual SDF microscopy was performed to determine the endothelial glycocalyx perfused boundary region (PBR), RBC filling percentage (%RBC), and perfused microvascular density (PMVD). RESULTS:A total of 135 participants with INOCA (mean age 59.3 ± 12.1 years, 80% female) underwent CFT and sublingual SDF microscopy. CMD was present in 63 participants (46.7%). The median PBR was 1.96 (IQR: 0.4), median %RBC was 72.6 (IQR: 8.0), and median PMVD was 406 (IQR: 141). No differences in sublingual PBR, %RBC, and PMVD were observed by CMD status. No correlations between sublingual parameters and continuous measures of coronary flow reserve or index of microcirculatory resistance were observed. CONCLUSIONS:Noninvasive SDF microscopy did not identify sublingual microvascular abnormalities in INOCA patients with CMD.

OBJECTIVES/OBJECTIVE:The COVID-19 pandemic highlighted an urgent need to more efficiently identify patients at highest risk for developing respiratory failure. We investigated whether plasma levels of lung injury biomarkers are associated with progression to respiratory failure among adults hospitalized with COVID-19 pneumonia without respiratory failure at admission. DESIGN/METHODS:This was a nested case-control study of COVID-19 patients enrolled in the Accelerating COVID-19 Therapeutic Interventions and Vaccines-3 (ACTIV-3)/Therapeutics for Inpatients with COVID-19 (TICO) platform trial who were on less than 20 L/min supplemental oxygen at enrollment. We compared baseline measurements of lung injury biomarkers between participants who progressed to respiratory failure or died by study day 10 (cases) and matched controls who did not progress to respiratory failure or death. Cases and controls were matched 1:1 on age, baseline oxygen requirement, immunomodulator use, and study arm. SETTING/METHODS:Hospitals enrolling in the ACTIV-3/TICO trials. PATIENTS/METHODS:Four hundred five cases and 405 matched controls. INTERVENTIONS/METHODS:None. MEASUREMENTS AND MAIN RESULTS/RESULTS:Baseline levels of plasma interleukin (IL)-6, IL-8, IL-18, tumor necrosis factor receptor, angiopoietin-2, soluble receptor for advanced glycation end-products (sRAGE), C-reactive protein (CRP), and surfactant protein D (SPD) were compared between cases and controls using matched logistic regression. Forward variable selection was used to identify biomarkers that were independently associated with progression to respiratory failure or death in a multivariate model. All lung injury biomarkers with the exception of SPD were significantly associated with progression to respiratory failure or death, with sRAGE demonstrating the highest odds ratio (OR) for each doubling of biomarker level (OR, 1.85; 95% CI, 1.61-2.12). In multivariate regression analysis, sRAGE, IL-6, and CRP were independently associated with progression, with sRAGE as the biomarker with the strongest association. CONCLUSIONS:Baseline levels of plasma lung injury biomarkers are significantly associated with progression to respiratory failure or death among hospitalized COVID-19 patients without respiratory failure at admission. These findings support the potential utility of measuring lung injury biomarkers in patients hospitalized without respiratory failure and should be tested in more heterogeneous patient groups including non-COVID-19 cohorts.

BACKGROUND:Immunotherapies have improved survival in patients with metastatic non-small cell lung cancer (mNSCLC), yet a substantial fraction of eligible patients remain untreated with immunotherapy in routine clinical practice. This study examined treatment patterns and factors associated with receipt of non-immunotherapy-containing first-line (1L) regimens among patients with mNSCLC not eligible for targeted therapies. METHODS:This retrospective, observational study used the Flatiron Health Research Database and included patients diagnosed with mNSCLC not eligible for targeted therapy who initiated 1L treatment on or after July 1, 2019 (data cutoff: September 30, 2023). Treatment patterns, classified by inclusion of an FDA-approved immunotherapy, and patient and disease characteristics were summarized. Logistic regression was used to identify factors that were associated with receipt of a non-immunotherapy-containing 1L regimen. RESULTS:In total, 13,223 patients were included in the study. Overall, 25% received a non-immunotherapy-containing 1L regimen, which was similar across study years. Platinum-based chemotherapy was the most common non-immunotherapy-containing 1L regimen. In a multivariable model, a wide range of factors were associated with use of non-immunotherapy-containing 1L regimens, including age, ethnicity, year of diagnosis, programmed death-ligand 1 (PD-L1) expression status, prior treatment with immunotherapy, practice type, geographical region, smoking status, and stage at initial diagnosis. CONCLUSIONS:A sizeable proportion of patients with mNSCLC continue to receive non-immunotherapy-containing 1L regimens, despite widespread availability and guideline recommendations as the preferred 1L therapy. These findings suggest that non-use of immunotherapy is influenced by clinical and structural factors, highlighting persistent gaps in equitable access to 1L immunotherapy.

[This corrects the article DOI: 10.7759/cureus.113024.].

PURPOSE/UNASSIGNED:To examine the correlation between hydroxychloroquine levels with real body weight and ideal body weight dose and identify patient characteristics at risk for subtherapeutic or supratherapeutic dosing. METHODS/UNASSIGNED:A retrospective chart review of 181 patients with lupus (429 unique hydroxychloroquine whole blood levels) was performed. Hydroxychloroquine levels <100 (indicating medication noncompliance) were excluded (n = 26). Summary statistics, linear regression of hydroxychloroquine level and real body weight/ideal body weight, and odds ratios (ORs) for factors associated with supratherapeutic (>2000 ng/mL) or subtherapeutic (<750 ng/mL) hydroxychloroquine levels were calculated. RESULTS/UNASSIGNED:, respectively. CONCLUSIONS/UNASSIGNED:All dosing schedules show variability in hydroxychloroquine levels. Ideal body weight may correlate more strongly with hydroxychloroquine level than real body weight. Under real body weight-based guidelines, obesity may increase the risk for supratherapeutic hydroxychloroquine levels, and low weight may increase the risk for subtherapeutic levels.

BACKGROUND/UNASSIGNED:Lifestyle interventions are effective in reducing cardiovascular disease (CVD) risk, but few target mothers of toddlers and preschool-aged children. Cardiovascular risk factors may emerge or worsen during this life stage due to high child-rearing demands, with the potential to persist long-term. We scoped the literature to synthesize findings and highlight future research opportunities regarding CVD prevention interventions among mothers of young children. METHODS/UNASSIGNED:We searched PubMed, Scopus, Web of Science, CINAHL, Embase, and APA PsycINFO for 2010-2024 peer-reviewed, English-language articles about CVD risk reduction lifestyle interventions for mothers with young children aged 1-5 years. Due to limited initial results, we broadened this demographic criterion to include mothers with children either <1-5 years (infants to young children) or 1-12 years (young to school-age children). RESULTS/UNASSIGNED:= 2). None addressed nicotine exposure nor sleep. Five studies reported statistically significant results for at least one of their outcomes. CONCLUSION/UNASSIGNED:Very few studies discuss lifestyle interventions for CVD prevention among mothers of young children, highlighting a salient gap and opportunities for additional research in this population.

BACKGROUND:Despite the important role of Geriatricians in our society, there is a shortage of Geriatric Medicine specialists. This study surveyed fellows enrolled in ACGME approved Geriatric Medicine fellowships in the United States for insight into why they joined a Geriatric Medicine fellowship. METHODS:Survey links were sent to all Geriatric Medicine Program Directors from July-Sept in 2019 and 2020 and we asked them to share the surveys with their fellows. Survey responses were summarized using descriptive statistics. The Likert-scaled dataset was analyzed with percentage of responses for each item related to "influence" and "barrier" domains. We examined the associations between variables using the Chi-Square test. The free-text fields were analyzed using inductive thematic analysis. RESULTS:There were 149 respondents (80% female) and approximately half of the respondents were from foreign medical schools (52%). Geriatric Medicine was the first fellowship choice for 75% of respondents. Among respondents who were US medical graduates, 89% chose Geriatric Medicine as first-choice specialty for fellowship, in contrast to 61.5% among the Foreign Medical Graduates (FMGs) (p < 0.001). Major reasons why fellows chose Geriatric Medicine were unique career opportunities and care of complex patients. The largest barrier/concern for pursuing Geriatric Medicine fellowship was the low salary associated with the field. CONCLUSIONS:As the first national survey of Geriatric Medicine fellows evaluating their reasons for pursuing a Geriatric Medicine fellowship, these results can be used by Geriatric Medicine fellowship programs and health care systems to improve recruitment into Geriatric Medicine fellowships.

Acute cholecystitis affects ∼200,000 individuals annually in the United States, with laparoscopic cholecystectomy as the gold standard treatment. However, in high-risk surgical candidates, alternative drainage methods are necessary. Percutaneous transhepatic gallbladder drainage (PT-GBD) has traditionally served as the primary alternative intervention, offering rapid decompression, but is limited by a negative impact on the patient's quality of life, the risk of long-term or even permanent tube placement, adverse events, and high recurrence rates. Endoscopic approaches, such as endoscopic transpapillary gallbladder drainage (ET-GBD) and, more recently, endoscopic ultrasound-guided gallbladder drainage (EUS-GBD), have emerged as viable alternatives to PT-GBD. EUS-GBD, first introduced in 2007, offers technical and clinical outcomes comparable to PT-GBD with fewer adverse events, shorter hospital stays, and lower rates of recurrence. The introduction of lumen-apposing metal stents (LAMS) has revolutionized EUS-GBD, simplifying deployment and enabling subsequent internal gallbladder access, which allows additional interventions such as cholecystoscopy and stone removal. EUS-GBD is now supported by international guidelines, and 1 device has achieved FDA approval for the management of acute cholecystitis in nonsurgical candidates. Proper patient selection is essential, guided by multidisciplinary evaluation, with EUS-GBD contraindicated in specific scenarios such as gallbladder perforation, coagulopathy, and large-volume ascites. Technical considerations include choice of access site (transgastric versus transduodenal), stent type, and procedural route [direct (freehand) or wire-guided]. Postprocedural care and stent management remain variable and nonstandardized. Emerging data suggest that interval cholecystectomy can still be performed safely after EUS-GBD. As adoption of EUS-GBD with LAMS expands, structured training and standardization of practice are crucial to optimizing outcomes.