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Background: We designed a prospective feasibility study to assess the 5x-multiplier (5x) calculation (eg, 3 pills in last 24 hours × 5 = 15) to standardize discharge opioid prescriptions compared to usual care. Methods: Faculty-based surgical teams volunteered for either 5x or usual care arms. Patients undergoing inpatient (≥48 hours) surgery and discharged by surgical teams were included. The primary end point was discharge oral morphine equivalents. Secondary end points were opioid-free discharges and 30-day refill rates. Results: Median last 24-hour oral morphine equivalents was similar between arms (7.5 mg 5x vs 10 mg usual care, P = .830). Median discharge oral morphine equivalents were less in the 5x arm (50 mg 5x vs 75 mg usual care, P

Purpose: Given the relative radioresistance of sarcomas and their often large size, conventional palliative radiation therapy (RT) often offers limited tumor control and symptom relief. We report on our use of hypofractionated RT (HFRT) as a strategy to promote durable local disease control and optimize palliation. Methods and Materials: We retrospectively reviewed 73 consecutive patients with sarcoma who received >10 fractions of HFRT from 2017 to 2020. Clinical scenarios included: (1) palliative or symptomatic intent (34%), (2) an unresectable primary (27%), (3) oligometastatic disease (16%), and (4) oligoprogressive disease (23%). Results: The HFRT target was a primary tumor in 64% of patients with a median dose of 45 Gy in 15 fractions (59% ≥45 Gy). The 1-year disease-specific survival was 59%, which was more favorable for patients receiving HFRT for oligometastatic (1-year 100%) or oligoprogressive (1-year 73%) disease (P = .001). The 1-year local control (LC) of targeted lesions was 73%. A metastatic target (1-year 95% vs 60% primary; P = .02; hazard ratio, 0.27; P = .04) and soft tissue origin (1-year 78% vs 61% bone; P = .01; hazard ratio, 0.33; P = .02) were associated with better LC. The rate of distant failure was high with a 6-month distant metastasis-free survival of only 43%. For patients not planned for adjuvant systemic therapy (n = 53), the median systemic therapy break was 9 months and notably longer in oligometastatic (13 months), oligoprogressive (12 months) or unresectable (13 months) disease. HFRT provided palliative relief in 95% of cases with symptoms. Overall, 49% of patients developed acute grade 1 to 2 RT toxicities (no grade 3-5). No late grade 2 to 5 toxicities were observed. Conclusions: HFRT is an effective treatment strategy for patients with unresectable or metastatic sarcoma to provide durable LC, symptom relief, and systemic therapy breaks with limited toxic effects.

Summary: Histone methyltransferase KMT2D harbors frequent loss-of-function somatic point mutations in several tumor types, including melanoma. Here, we identify KMT2D as a potent tumor suppressor in melanoma through an in vivo epigenome-focused pooled RNAi screen and confirm the finding by using a genetically engineered mouse model (GEMM) based on conditional and melanocyte-specific deletion of KMT2D. KMT2D-deficient tumors show substantial reprogramming of key metabolic pathways, including glycolysis. KMT2D deficiency aberrantly upregulates glycolysis enzymes, intermediate metabolites, and glucose consumption rates. Mechanistically, KMT2D loss causes genome-wide reduction of H3K4me1-marked active enhancer chromatin states. Enhancer loss and subsequent repression of IGFBP5 activates IGF1R-AKT to increase glycolysis in KMT2D-deficient cells. Pharmacological inhibition of glycolysis and insulin growth factor (IGF) signaling reduce proliferation and tumorigenesis preferentially in KMT2D-deficient cells. We conclude that KMT2D loss promotes tumorigenesis by facilitating an increased use of the glycolysis pathway for enhanced biomass needs via enhancer reprogramming, thus presenting an opportunity for therapeutic intervention through glycolysis or IGF pathway inhibitors.

The extent and nature of epigenomic changes associated with melanoma progression is poorly understood. Through systematic epigenomic profiling of 35 epigenetic modifications and transcriptomic analysis, we define chromatin state changes associated with melanomagenesis by using a cell phenotypic model of non-tumorigenic and tumorigenic states. Computation of specific chromatin state transitions showed loss of histone acetylations and H3K4me2/3 on regulatory regions proximal to specific cancer-regulatory genes in important melanoma-driving cell signaling pathways. Importantly, such acetylation changes were also observed between benign nevi and malignant melanoma human tissues. Intriguingly, only a small fraction of chromatin state transitions correlated with expected changes in gene expression patterns. Restoration of acetylation levels on deacetylated loci by histone deacetylase (HDAC) inhibitors selectively blocked excessive proliferation in tumorigenic cells and human melanoma cells, suggesting functional roles of observed chromatin state transitions in driving hyperproliferative phenotype. Through these results, we define functionally relevant chromatin states associated with melanoma progression.