Research Spotlight

Roberts, W. C., S. P. McCullough and A. Vasudevan (2018). “Characteristics of Adults Having Aortic Valve Replacement for Pure Aortic Regurgitation Involving a Congenitally Bicuspid Aortic Valve Unaffected by Infective Endocarditis or Aortic Dissection.” Am J Cardiol 122(12): 2104-2111.

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Few reports have appeared describing patients with a purely regurgitant congenitally bicuspid aortic valve (BAV) unassociated with active or healed infective endocarditis or with acute or healed aortic dissection. This report describes a large group of such patients who had replacement of the purely regurgitant BAV with or without concomitant resection of the ascending aorta. Operatively excised purely regurgitant BAVs were examined and then their clinical records were examined to confirm that the valves indeed were purely regurgitant. The patients were aged 21 to 86 years (median 50). Of the 133 patients, 114 (86%) were men. The degree of aortic regurgitation (AR) ranged from 1+ to 4+/4+. Of the 133 patients, 52 (39%) had simultaneous resection of the ascending aorta, its frequency varying inversely with the degree of AR. Histologic study of sections of the operatively excised aortas disclosed that 28 (54%) had a normal or nearly normal aorta (0-1+ loss of medial elastic fibers) and that 24 (46%) had an abnormal loss (grade 2+ -4+/4+). In conclusion, the congenitally BAV, unassociated with either infective endocarditis or aortic dissection, is a common cause of pure AR in adults in the Western World undergoing AVR for AR. About half the patients had a dilated ascending aorta and those resected were histologically abnormal half the time. Why one BAV becomes stenotic, another purely regurgitant, another the site of infective endocarditis, and another functions normally for an entire lifetime remains unclear.

Raymond, G. V. and R. Schiffmann (2018). “Cerebrotendinous xanthomatosis: The rare “treatable” disease you never consider.” Neurology Dec 7. [Epub ahead of print].

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Cerebrotendinous xanthomatosis (CTX; Online Mendelian Inheritance in Man No. 213700) is an autosomal recessive disorder due to pathogenic variant in the CYP27A1 gene resulting in a defect in the mitochondrial enzyme sterol 27-hydroxylase. The enzyme catalyzes multiple hydroxylation reactions involved in cholesterol metabolism and bile acid synthesis. When affected, it results in decreased synthesis of bile acids, with the resultant production of cholestanol and cholesterol affecting all tissues.

Ramlawi, B., K. Bedeir and J. R. Edgerton (2019). “Totally Thoracoscopic Closure of the Left Atrial Appendage.” Ann Thorac Surg 107(1): e71-e73.

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The left atrial appendage (LAA) is a major site of clot formation in atrial fibrillation. Stand-alone thoracoscopic LAA complete closure can decrease stroke risk and may be an alternative to life-long oral anticoagulation. This report describes a technique for totally thoracoscopic LAA exclusion with an epicardial clip device. This approach provides a safe and likely more effective alternative to LAA management than other endocardial devices.

Quist, J., H. Mirza, M. C. U. Cheang, M. L. Telli, J. A. O’Shaughnessy, C. J. Lord, A. N. J. Tutt and A. Grigoriadis (2019). “A Four-gene Decision Tree Signature Classification of Triple-negative Breast Cancer: Implications for Targeted Therapeutics.” Mol Cancer Ther 18(1): 204-212.

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The molecular complexity of triple-negative breast cancers (TNBCs) provides a challenge for patient management. We set out to characterize this heterogeneous disease by combining transcriptomics and genomics data, with the aim of revealing convergent pathway dependencies with the potential for treatment intervention. A Bayesian algorithm was used to integrate molecular profiles in two TNBC cohorts, followed by validation using five independent cohorts (n = 1,168), including three clinical trials. A four-gene decision tree signature was identified, which robustly classified TNBCs into six subtypes. All four genes in the signature (EXO1, TP53BP2, FOXM1, and RSU1) are associated with either genomic instability, malignant growth, or treatment response. One of the six subtypes, MC6, encompassed the largest proportion of tumors ( approximately 50%) in early diagnosed TNBCs. In TNBC patients with metastatic disease, the MC6 proportion was reduced to 25%, and was independently associated with a higher response rate to platinum-based chemotherapy. In TNBC cell line data, platinum sensitivity was recapitulated, and a sensitivity to the inhibition of the phosphatase PPM1D was revealed. Molecularly, MC6-TNBCs displayed high levels of telomeric allelic imbalances, enrichment of CD4(+) and CD8(+) immune signatures, and reduced expression of genes negatively regulating the MAPK signaling pathway. These observations suggest that our integrative classification approach may identify TNBC patients with discernible and theoretically pharmacologically tractable features that merit further studies in prospective trials.

Puri, V., H. A. Gaissert, D. W. Wormuth, E. L. Grogan, W. R. Burfeind, A. C. Chang, C. W. Seder, F. G. Fernandez, L. Brown, M. J. Magee, A. S. Kosinski, D. P. Raymond, S. R. Broderick, R. J. Welsh, M. M. DeCamp, F. Farjah, M. A. Edwards and B. D. Kozower (2019). “Defining Proficiency for The Society of Thoracic Surgeons Participants Performing Thoracoscopic Lobectomy.” Ann Thorac Surg 107(1): 202-208.

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BACKGROUND: Parameters defining attainment and maintenance of proficiency in thoracoscopic video-assisted thoracic surgery (VATS) lobectomy remain unknown. To address this knowledge gap, this study investigated the institutional performance curve for VATS lobectomy by using risk-adjusted cumulative sum (Cusum) analysis. METHODS: Using The Society of Thoracic Surgeons General Thoracic Surgery Database, the study investigators identified centers that had performed a total of 30 or more VATS lobectomies. Major morbidity, mortality, and blood transfusion were deemed primary outcomes, with expected incidence derived from risk-adjusted regression models. Acceptable and unacceptable failure rates for outcomes were set a priori according to clinical relevance and informed by regression model output. RESULTS: Between 2001 and 2016, 24,196 patients underwent VATS lobectomy at 159 centers with a median volume of 103 (range, 30 to 760). Overall rates of operative mortality, major morbidity, and transfusion were 1% (244 of 24,189), 17.1% (4,145 of 24,196), and 4% (975 of 24,196), respectively. Of the highest-volume centers (>/=100 cases), 84% (65 of 77) and 82 % (63 of 77) (p = 0.48) were proficient by major morbidity standards by their 50th and 100th cases, respectively. Similarly, 92% (71 of 77) and 90% (69 of 77) (p = 0.41) of centers showed proficiency by transfusion standards by their 50th and 100th cases, respectively. Three performance patterns were observed: (1) initial and sustained proficiency, (2) crossing unacceptability thresholds with subsequent improved performance; and (3) crossing unacceptability thresholds without subsequent improved performance. CONCLUSIONS: VATS lobectomy outcomes have improved with lower mortality and transfusion rates. The majority of high-volume centers demonstrated proficiency after 50 cases; however, maintenance of proficiency is not ensured. Cusum provides a simple yet powerful tool that can trigger internal audits and performance improvement initiatives.