Faculty Bibliography

PURPOSE/OBJECTIVE:Outpatient specialist palliative care (SPC) referral improves patient outcomes; however, it is unclear whether additional remote monitoring (RM) would provide further benefit. This pilot, parallel-group, single-blind, randomized clinical trial examined the within-group effect of monthly SPC alone or with additional weekly RM on symptom burden in patients with advanced cancer undergoing phase I therapies. METHODS:Eligibility criteria included advanced solid tumor diagnosis and moderate-to-high symptom burden (ie, Edmonton Symptom Assessment System [ESAS] score ≥4/10 for ≥1 symptom and Global Distress Score [GDS] ≥20/90) before starting phase I therapies. Patients were randomly assigned 1:1 to either monthly outpatient SPC visits alone or with additional RM, consisting of weekly phone calls and concurrent electronic ESAS assessments between monthly SPC visits. The primary outcome was within-group change in symptom burden (ESAS-GDS) from baseline to 2 weeks; secondary outcomes included within-group change from baseline in ESAS-GDS and health-related quality of life (HRQOL; measured by Functional Assessment of Chronic Illness Therapy-Spiritual Well-Being [FACIT-Sp]) over 12 weeks. RESULTS:= .02). CONCLUSION/CONCLUSIONS:Incorporating RM into SPC may improve symptoms and HRQOL beyond SPC alone for patients with moderate-to-high symptom burden. Our findings are considered preliminary and larger confirmatory trials are needed.

BACKGROUND:Hypomethylating agents (HMAs) are a cornerstone of therapy for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Oral formulations offer an alternative to intravenous (IV) administration, but comparative real-world toxicity data remain limited. We evaluated hematologic toxicity and adverse events associated with oral versus IV HMAs. METHODS:We conducted a multicenter retrospective cohort study of 33 patients with MDS or AML treated with oral decitabine/cedazuridine or oral azacitidine between January 1, 2016 and June 1, 2023 across three academic cancer centers. Twenty patients who also received IV HMAs were included in an intrapatient paired analysis. Cytopenias were assessed by absolute values and percent change from baseline to nadir. Wilcoxon signed-rank tests were used for intrapatient comparisons, and clinically significant adverse events were recorded descriptively. RESULTS:Among the 20 patients included in the intrapatient analysis, median decreases in hemoglobin were 20.8% during oral HMA therapy and 20.5% during IV HMA therapy. Median decreases in absolute neutrophil count were 95.9% and 97.3%, respectively, while median decreases in platelet count were 81.9% and 88.6%, respectively. No statistically significant differences were observed between oral and IV HMA therapy for hemoglobin (p = 0.60), absolute neutrophil count (p = 0.63), or platelet count (p = 0.06). Hospitalization occurred in 60.6% of patients during oral HMA therapy and 70.0% during IV HMA therapy, while neutropenic fever occurred in 51.5% and 60.0%, respectively. CONCLUSIONS:Oral HMAs demonstrated cytopenia severity and adverse event rates comparable to IV HMAs, supporting oral formulations as a practical alternative in patients with MDS and AML. Although encouraging, these findings should be interpreted in the context of the retrospective design and modest sample size.

BACKGROUND & AIMS/OBJECTIVE:Adherence to guideline-based colonoscopy surveillance intervals remains suboptimal. Large language models show promise for automating interval assignment, but prior studies relied on proprietary models and have variably assessed generalizability. We developed and externally validated a clinical decision-support system that integrates locally deployable, open-source large language model-based variable extraction with a rules engine that encodes the 2020 United States Multi-Society Task Force guidelines. METHODS:We assembled development (n = 256), internal (n = 450), and external validation (n = 415) cohorts of colonoscopy-pathology dyads. We developed a 3-stage clinical decision-support system including: (1) large language model-based extraction of diagnosis-bearing sections from pathology reports; (2) large language model-based extraction of surveillance-relevant variables; and (3) deterministic assignment of surveillance intervals using United States Multi-Society Task Force logic. Seven open-source large language models (3.8-32B parameters) were benchmarked; the highest-performing model by macro-averaged F1 score was locked prior to validation. The primary outcome was guideline-concordant interval assignment (target, 90%); secondary outcomes included extraction performance and hallucination rate. RESULTS:The best-performing open-source model, Gemma-27B-Instruct (macro-averaged F1 score, 0.992), was locked. The clinical decision-support system achieved 94.0% guideline-concordant surveillance interval assignment in internal validation (95% confidence interval, 91.8%-96.0%; κ = 0.92; 95% confidence interval, 0.89-0.95) and 92.8% concordance in external validation (95% confidence interval, 90.1%-95.2%; κ = 0.88; 95% confidence interval, 0.84-0.91). Misclassifications were primarily due to adenoma miscounting and diagnostic biopsies misinterpreted as resections. Hallucination-related errors occurred in fewer than 1% of cases. CONCLUSIONS:We report an externally validated, hybrid large language model rules-based clinical decision-support system for colonoscopy surveillance that achieves >90% concordance while preserving transparency, auditability, and guideline traceability.

Coccidioidomycosis rarely presents as a lung mass, hypereosinophilia, and disseminated pericarditis with pericardial effusion. Even rarer is a case that presents with the constellation of all these findings. We present a case of coccidioidomycosis in an immunocompetent young Jamaican male with all these features, set against an interesting epidemiological context of a likely exposure to coccidioidomycosis spores during an on-foot crossing of the Mexican border into Texas. His treatment course was complicated by declining liver and kidney function due to triazole antifungal therapy, necessitating titration of these doses to tolerable levels. This case highlights the importance of a detailed travel history in unraveling infectious disease diagnoses and underscores the need for high clinical suspicion for coccidioidomycosis, even in patients outside of known endemic regions.

Medical treatment of Cushing syndrome (CS) with steroidogenesis inhibitors or ACTH-directed agents is typically given using a titration strategy to achieve "normal" exposure to cortisol, as determined by a 24-hour urine free cortisol (UFC) measurement. This approach generally achieves similar serum cortisol levels across the day and fails to provide a normal diurnal pattern of cortisol. Chronotherapy addresses this problem through weighted afternoon/evening dosing of cortisol-lowering drugs. Additionally, because of day-to-day variability of cortisol production, patients may be undertreated on days of higher cortisol production and overtreated on days of lower cortisol production. A "block and replace" strategy is an alternative approach in which consistent biochemical glucocorticoid deficiency is the goal, with added glucocorticoid replacement to provide physiologic diurnal exposure to cortisol. Recently, the term mild autonomous cortisol secretion (MACS) has been used to describe patients without clinical features of CS who fail to suppress cortisol after 1 mg dexamethasone. MACS includes individuals with an adrenal mass(es) who may have hypertension, type 2 diabetes mellitus, and/or osteoporosis. The role of medical vs surgical treatment of MACS is currently debated. We here review the advantages and disadvantages of each approach to medical treatment of CS and MACS, concluding that "block and replace" deserves wider consideration, especially in patients who have severe disease, and to avoid adrenal insufficiency in those with highly variable UFC, or are taking agents that may cause adrenal insufficiency. Conversely, in those with mild disease, chronotherapy normalizes nighttime cortisol exposure while reducing drug burden.

CONTEXT/UNASSIGNED:Although menstrual dysfunction occurs in Cushing syndrome (CS), drivers of its prevalence and prognosis are poorly documented. OBJECTIVE/UNASSIGNED:Assess the prevalence of menstrual dysfunction, time to resolution after restoration of eucortisolism, and predictive factors for development and resolution. DESIGN/UNASSIGNED:Retrospective evaluation. SETTING/UNASSIGNED:Tertiary referral center. PATIENTS/UNASSIGNED:93 women treated for CS from 1987 to 2024. INTERVENTIONS/UNASSIGNED:Surgery, medical therapy, and/or irradiation to restore eucortisolism. MAIN OUTCOME MEASURES/UNASSIGNED:Prevalence of affected menses; rate and time to return to baseline pattern after remission. Patient, hormonal, tumor, and treatment factors predicting resolution. RESULTS/UNASSIGNED:< .0001) predicted a delayed (>6 months) return to baseline. CONCLUSION/UNASSIGNED:Two-thirds of women with CS have menstrual dysfunction due to cortisol-induced suppression of gonadotropins. In most women with minimal pituitary damage, menses return to baseline after a median of 6 months of eucortisolism. Significant overweight can delay resolution.

OBJECTIVE:The desmopressin stimulation test (DesST) is used to identify Cushing disease (CD). Reportedly, most healthy people and patients with non-neoplastic hypercortisolism lack a significant response. We aimed to evaluate and improve DesST specificity (Sp). DESIGN/METHODS:Prospective evaluation of four DesST protocols in healthy volunteers. METHODS:Twenty healthy volunteers underwent four DesST protocols in a randomized order. Protocols involved fluid restriction with desmopressin 10 µg (10NPO; 'standard'), 4 µg (4NPO), and 10 µg preceded by dexamethasone 1 mg (10+DexNPO); and desmopressin 10 µg without fluid restriction (10H2O). We evaluated Sp for each protocol, using established response criteria. RESULTS:Previous criteria of relative increases of 35% and/or 20% for ACTH and cortisol, respectively, had low Sp: 50% (95% CI: 28-72%; 10NPO) to 85% (95% CI: 69-100%; 10+DexNPO). Using absolute ACTH increase >8.1 pmol/L (37 pg/mL) improved Sp to 100% across all protocols. Compared with 10NPO, median ACTH and cortisol were lower throughout during 10+DexNPO and also at +15 min during 4NPO (ACTH: 4.4 vs 4.9 pmol/L (19.9 vs 22.1 pg/mL), P = 0.06; cortisol: 248 vs 284 nmol/L (9.0 vs 10.3 µg/dL), P = 0.01). 10H2O and 10NPO results were similar. Adverse events were mild; hyponatremia occurred after 5/80 tests. CONCLUSION/CONCLUSIONS:After desmopressin, healthy volunteers have small absolute increases in ACTH and cortisol that equate to large relative changes from baseline. Optimized response criteria should likely incorporate absolute values. Fluid restriction did not impact Sp, but using a lower desmopressin dose and dexamethasone pre-treatment are promising ways to improve diagnostic accuracy, if sensitivity is maintained in CD. SIGNIFICANCE STATEMENT/CONCLUSIONS:Half of healthy volunteers had a response consistent with Cushing disease (CD) during a commonly used 10 µg desmopressin stimulation test, interpreted using relative ACTH and/or cortisol increases. This puts the test's reliability for excluding CD in question, particularly in settings of mild hypercortisolism. These situations include differentiating CD from non-neoplastic hypercortisolism, identifying cyclic ectopic ACTH-producing tumors during nadir phases, and establishing early CD recurrence. Optimized response criteria likely require absolute ACTH and/or cortisol cutoffs. Using a reduced 4 µg dose of desmopressin or pre-treatment with 1 mg dexamethasone improved test specificity, offering promising ways to improve test performance if sensitivity is maintained in CD. CLINICAL TRIAL REGISTRATION NUMBER/BACKGROUND:NCT06635629.

Background Stroke remains a leading cause of death and long-term disability. Although stem cell-based approaches are being investigated as possible regenerative strategies for stroke, public perceptions of their potential benefits, risks, mechanisms, and clinical use are not well-characterized. This exploratory survey described responses to an investigator-developed questionnaire about stem cell therapy for stroke. Methods A 10-item cross-sectional questionnaire was distributed electronically through Google Forms (Google, Inc., Mountain View, CA) to 36 individuals in a convenience sample; 26 completed questionnaires were received (response rate: 72.2%). The questionnaire was investigator-developed and was not validated as a measure of factual knowledge, clinical efficacy, or safety. Responses were categorized as "yes," "no," or "maybe"; one item used time-based response categories. Counts and percentages were calculated using the total number of completed questionnaires as the denominator. The survey was independently conducted as a student-led summer academic project and did not undergo review by an institutional review board, school ethics committee, or independent ethics authority. Results Twenty-six responses were analyzed. For the item asking whether embryonic stem cells are effective in stroke treatment, eight respondents (30.77%) selected "yes," 16 (61.54%) selected "maybe," and two (7.69%) selected "no." For the item asking whether stem cell treatment has advantages for stroke, 21 respondents (80.77%) selected "yes," four (15.38%) selected "maybe," and one (3.85%) selected "no." "Maybe" was the majority or joint-most-frequent response for six of 10 items, including items about animal testing, adverse effects, alternative regenerative treatments, and use during pregnancy. Conclusions In this small convenience sample, responses to an investigator-developed questionnaire suggested favorable perceptions of possible benefits of stem cell therapy for stroke, alongside frequent uncertainty about safety, mechanisms, the timing of improvement, and use in special populations. Because the questionnaire was not validated as a factual-knowledge instrument, findings should be interpreted strictly as descriptive perceptions rather than as evidence of respondents' medical knowledge, treatment confidence, or the clinical efficacy or safety of stem cell therapy. Larger studies using validated instruments and representative sampling are needed.

Excessive cyclin D1 accumulation is a frequent oncogenic event in head and neck squamous cell carcinoma (HNSCC) and esophageal squamous cell carcinoma (ESCC). Although classically associated with enhanced proliferation and genomic instability, we revealed that cyclin D1 dysregulation induces metabolic rewiring that leads to unexpected metabolic dependencies. Sustained nuclear retention of cyclin D1 drove metabolic reprogramming through activation of CDK4/6 and downregulation of mitochondrial isocitrate dehydrogenase 3 (IDH3), reducing α-ketoglutarate and NADH production. This metabolic alteration increased glutamine dependence and elevated autophagic flux, and co-targeting autophagy and glutamine metabolism suppressed the growth of squamous cell carcinoma models in vitro and in vivo. Together, these findings highlight a therapeutic strategy for HNSCC and ESCC that leverages metabolic reprogramming induced by dysregulated cyclin D1/CDK4 activity, with potential applicability to patients with tumors refractory to conventional therapies.

Autism affects male individuals four times more often than female individuals, yet the basis of this sex bias remains unclear. One hypothesis is that this sex bias is due to genetic variants in X chromosome genes where haploinsufficiency causes neurodevelopmental disorders (NDDs). In heterozygous XX female probands, a complete loss-of-function variant in one of these genes often causes syndromic NDD, but the same variant is too deleterious for survival in hemizygous XY males. A mild hypomorphic variant, however, may be tolerated in a female carrier but may produce milder neurological phenotypes in a male proband. We tested this by investigating cis-regulatory elements (CREs) of MECP2, a dosage-sensitive gene on the X chromosome where total loss-of-function variants cause Rett syndrome in female children and severe, usually fatal neonatal encephalopathies in male infants. Using a massively parallel reporter assay in human neurons, we mapped transcription factor binding sites within MECP2 CREs and tested autism-associated variants for functional impact. We identified two noncoding variants that change CRE activity and are associated with male-biased autism phenotypes in the proband pedigrees. One of these, a promoter variant, disrupts NFY binding and reduces MECP2 expression by ∼30%, a magnitude that produces social deficits, hyperactivity, and anxiety-like phenotypes in mice. These findings suggest noncoding MECP2 variants can cause idiopathic, male-biased autism and provide a framework for uncovering regulatory variants in other X chromosome neurodevelopmental genes that may contribute to autism's missing heritability.