Out-of-hospital PIP-AAD can be an effective for highly selected patients; however, the rates of treatment failure and adverse events are clinically relevant, which limits the widespread application of a PIP-AAD approach.

Conventional cytotoxic therapies for synovial sarcoma provide limited benefit, and no drugs specifically targeting its driving SS18-SSX fusion oncoprotein are currently available. Patients remain at high risk for early and late metastasis. A high-throughput drug screen consisting of over 900 tool compounds and epigenetic modifiers, representing over 100 drug classes, was undertaken in a panel of synovial sarcoma cell lines to uncover novel sensitizing agents and targetable pathways. Top scoring drug categories were found to be HDAC inhibitors and proteasomal targeting agents. We find that the HDAC inhibitor quisinostat disrupts the SS18-SSX driving protein complex, thereby reestablishing expression of EGR1 and CDKN2A tumor suppressors. In combination with proteasome inhibition, HDAC inhibitors synergize to decrease cell viability and elicit apoptosis. Quisinostat inhibits aggresome formation in response to proteasome inhibition, and combination treatment leads to elevated endoplasmic reticulum stress, activation of pro-apoptotic effector proteins BIM and BIK, phosphorylation of BCL-2, increased levels of reactive oxygen species, and suppression of tumor growth in a murine model of synovial sarcoma. This study identifies and provides mechanistic support for a particular susceptibility of synovial sarcoma to the combination of quisinostat and proteasome inhibition.

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Introduction: Atrial fibrillation (AF) is the commonest arrhythmia and a major cause of stroke and health care utilization. Researchers and administrators use electronic health data to assess disease burden, quality and variance in care, value of interventions and prognosis. We performed a systematic review and meta-analysis to assess the validity of AF case definitions in administrative databases. Methods: Medline was searched from 2000 to 2018. Extracted information included sensitivity, specificity, positive and negative predictive values (PPV and NPV) for various AF case definitions. Estimates were pooled using random-effects models due to significant heterogeneity between studies. Results: We identified 24 studies, including 21 from North America or Scandinavia. Hospital, ambulatory and mixed data sources were assessed in 10, 4 and 10 studies, respectively. Nine different AF case definitions were evaluated, most based on ICD-9 or 10 codes. Twenty-two studies assessed case definitions in patients diagnosed with AF and thus could generate PPV alone. Half the studies sampled unrestricted populations including a mix of those with and without AF to assess sensitivity. Only 13 studies included ECG confirmation as a gold standard. The pooled random effects estimates were: sensitivity 80% (95% CI 72-86%); specificity 98% (96-99%); PPV 88% (82-94%); NPV 97% (94-99%). Only 3 studies reported all accuracy parameters and included rhythm monitoring in the gold standard definition. Conclusion: Relatively few studies examined sensitivity, and fewer still included rhythm monitoring in the gold standard comparison. Administrative data may fail to identify a significant proportion of patients with AF. This, in turn, may bias estimates of quality of care and prognosis.