Person:

Weng, Qing Yu

The SWI/SNF complex is a multiunit chromatin remodeling complex required for normal cell development. Mutations within SWI/SNF are associated with rapid tumor formation and aggressive progression of melanoma and other cancers. SWI/SNF dysregulation can alter gene expression globally across multiple oncogenic pathways. By bypassing signaling molecules targeted by current drugs, aberrant SWI/SNF complexes create unique challenges for cancer therapy.

Given these challenges, we aim to define the molecular alterations in melanoma upon loss of SWI/SNF and determine whether its dysregulation produces characteristic dependencies on alternative epigenetic pathways. Identification of these synthetically lethal vulnerabilities may uncover novel epigenetic mechanisms in oncogenesis.

We generated stable melanoma cell lines with precise knockdown efficiencies of SWI/SNF subunits using short hairpin RNAs and single cell cloning. Using this pool of SWI/SNF mutant cells, we assayed 100 compounds targeting epigenetic regulators. We identified multiple independent dependencies in SWI/SNF-deficient tumor cells vulnerable to synthetic inhibition. These targets also provide opportunities for synergistic combination with other treatment modalities. In addition, we show crosstalk between the SWI/SNF complex and MITF pathway that alters cancer cell phenotype. These findings offer insight into the poorly understood mechanisms by which SWI/SNF dysregulation contributes to melanomagenesis and uncover targetable vulnerabilities in these tumors.

Importance Spironolactone has been shown to be an effective treatment option for hormonally mediated acne but can cause hyperkalemia. The prevalence of hyperkalemia among healthy young women taking spironolactone for acne is unclear.

Objective To measure the rate of hyperkalemia in healthy young women taking spironolactone for acne or for an endocrine disorder with associated acne.

Design, Setting, and Participants Retrospective study of healthy young women taking spironolactone for acne. Data from December 1, 2000, through March 31, 2014, were obtained from a clinical data repository. Outpatient data were collected from 2 tertiary care centers in the United States. We analyzed rates of hyperkalemia in 974 healthy young women taking spironolactone for acne. We also analyzed 1165 healthy young women taking and not taking spironolactone to obtain a profile for the baseline rate of hyperkalemia in this population. Exclusion criteria were cardiovascular disease, renal failure, and the use of medications that affect the renin-angiotensin-aldosterone system.

Main Outcomes and Measures The rate of hyperkalemia in healthy young women taking spironolactone for acne was calculated. Secondary measures included spironolactone prescriber profiles and potassium monitoring practices.

Results There were 13 abnormal serum potassium measurements in 1802 measurements obtained among young women receiving spironolactone therapy, yielding a hyperkalemia rate of 0.72%, equivalent to the 0.76% baseline rate of hyperkalemia in this population. Repeat testing in 6 of 13 patients demonstrated normal values, suggesting that these measurements may have been erroneous. In the remaining 7 patients, no action was taken.

Conclusions and Relevance The rate of hyperkalemia in healthy young women taking spironolactone for acne is equivalent to the baseline rate of hyperkalemia in this population. Routine potassium monitoring is unnecessary for healthy women taking spironolactone for acne.

Patient nonattendance occurs when patients miss appointments without notifying their health care professionals in advance. In dermatology, nonattendance rates range from 7.8% to 31.0% of scheduled appointments. The consequences of nonattendance range from compromised care to wasted appointment slots, decreased efficiency, and diluted residency training. We seek to define the effect of nonattendance on subsequent use of health care resources and health care spending in dermatology.

Question What is the national health care burden of misdiagnosed lower extremity cellulitis in patients admitted to the hospital from the emergency department?

Findings In this cross-sectional study that included 259 patients, 30% were misdiagnosed with cellulitis, of which 85% did not require hospitalization and 92% received unnecessary antibiotics. Combining these findings with previously published data, cost estimates, and and projections indicate that cellulitis misdiagnosis leads to 50 000 to 130 000 unnecessary hospitalizations in the United States and $195 million to $515 million in avoidable health care spending annually.

Meaning Misdiagnosis of lower extremity cellulitis is common and may lead to unnecessary patient morbidity and considerable health care spending.

Background Cellulitis has many clinical mimickers (pseudocellulitis), which leads to frequent misdiagnosis.

Objective To create a model for predicting the likelihood of lower extremity cellulitis.

Methods A cross-sectional review was performed of all patients admitted with a diagnosis of lower extremity cellulitis through the emergency department at a large hospital between 2010 and 2012. Patients discharged with diagnosis of cellulitis were categorized as having cellulitis, while those given an alternative diagnosis were considered to have pseudocellulitis. Bivariate associations between predictor variables and final diagnosis were assessed to develop a 4-variable model.

Results In total, 79 (30.5%) of 259 patients were misdiagnosed with lower extremity cellulitis. Of the variables associated with true cellulitis, the 4 in the final model were asymmetry (unilateral involvement), leukocytosis (white blood cell count ≥10,000/uL), tachycardia (heart rate ≥90 bpm), and age ≥70 years. We converted these variables into a points system to create the ALT-70 cellulitis score as follows: Asymmetry (3 points), Leukocytosis (1 point), Tachycardia (1 point), and age ≥70 (2 points). With this score, 0-2 points indicate ≥83.3% likelihood of pseudocellulitis, and ≥5 points indicate ≥82.2% likelihood of true cellulitis.

Limitations Prospective validation of this model is needed before widespread clinical use.

Conclusion Asymmetry, leukocytosis, tachycardia, and age ≥70 are predictive of lower extremity cellulitis. This model might facilitate more accurate diagnosis and improve patient care.