Research Spotlight

Campa, M., C. Ryan and A. Menter (2016). “Developing more open and equitable relationships with industry to improve advancements in clinical research in dermatology.” Br J Dermatol 174(6): 1365-1369.

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Relationships between physicians, scientists, and the pharmaceutical industry can be complicated by conflicts of interest. Honest and equitable relationships, however, are essential to the advancement of dermatologic clinical research. Several factors can increase transparency in clinical trials including preregistration of clinical trials, reporting of all data produced from clinical trials, non-industry ownership of clinical trial data, clarity of statistical methods and publication of both positive and negative results. Through collaborative, scientifically rigorous studies, physicians and industry can achieve significant advances in dermatologic care.

Bunnell, A. E., C. A. Garby, E. J. Pearson, S. A. Walker, L. E. Panos and J. L. Blum (2016). “The clinical utility of next generation sequencing results in a community-based hereditary cancer risk program.” J Genet Couns. 2016 Jun 9. [Epub ahead of print]

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Since the 2013 Supreme Court ruling on BRCA1/BRCA2 patenting, hereditary cancer gene panels now include BRCA1 and BRCA2, making these panels an option for first-tier testing. However, questions remain about the clinical utility and implications of these panels for medical management with inclusion of genes of unknown to moderate penetrance. To better understand how use of these panels affected our practice, we reviewed patients who underwent testing in our clinic from July 1, 2013 through May 23, 2014. Indications for testing included personal and/or family history of breast and/or ovarian cancer. A total of 136 patients underwent panel testing via a single commercial laboratory; 12 (8.8 %) patients were positive for a pathogenic or likely pathogenic mutation (four BRCA2 mutations, two TP53 mutations, one CDH1 mutation, two ATM mutations, and one patient each with a CHEK2, NBN, or PALB2 mutation). Of these positive patients, 100 % met the National Comprehensive Cancer Network (NCCN) guidelines for Hereditary Breast and Ovarian Cancer genetic testing (2.2014). Mutations in seven of twelve (58 %) patients led to changes in medical management; three of seven (43 %) had a non-BRCA1 or BRCA2 gene mutation. Our findings suggest that there is clinical utility of panels that include genes of unknown to moderate penetrance.

Bentebibel, S. E., S. Khurana, N. Schmitt, P. Kurup, C. Mueller, G. Obermoser, A. K. Palucka, R. A. Albrecht, A. Garcia-Sastre, H. Golding and H. Ueno (2016). “Icos(+)pd-1(+)cxcr3(+) t follicular helper cells contribute to the generation of high-avidity antibodies following influenza vaccination.” Sci Rep 6: 26494.

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The immune mechanism leading to the generation of protective antibody responses following influenza trivalent inactivated vaccine (TIV) vaccinations remains largely uncharacterized. We recently reported that TIV vaccination induced a transient increase of circulating ICOS(+)PD-1(+)CXCR3(+) T follicular helper (cTfh) cells in blood, which positively correlated with the induction of protective antibody responses measured at day 28. However, whether and how these T cells directly contribute to antibody response remains unclear. In this study, we analyzed the changes after TIV vaccination in the amount and the avidity of the polyclonal antibodies specific for the HA1 subunit of the pandemic H1N1 virus, and analyzed the correlation with the increase of ICOS(+)PD-1(+)CXCR3(+) cTfh cells. We found that both the amount and the avidity of specific antibodies rapidly increased during the first 7 days after TIV. Importantly, the increase of ICOS(+)PD-1(+)CXCR3(+) cTfh cells strongly correlated with the increase in the avidity of antibodies, particularly in subjects who did not have high affinity antibodies at baseline. We propose that ICOS(+)PD-1(+)CXCR3(+) Tfh cells directly contribute to the generation of high-avidity antibodies after TIV vaccinations by selectively interacting with high affinity B cells at extrafollicular sites.

Amar, E., Y. Warschawski, Z. T. Sharfman, H. D. Martin, M. R. Safran and E. Rath (2016). “Pathological findings in patients with low anterior inferior iliac spine impingement.” Surg Radiol Anat 38(5): 569-575.

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PURPOSE: Femoroacetabular impingement (FAI) has been well described in recent years as one of the major causes of hip pain potentially leading to acetabular labral tears and cartilage damage, which may in turn lead to the development of early degenerative changes. More recently, extra-articular patterns of impingement such as the anterior inferior iliac spine (AIIS)/subspine hip impingement have gained focus as a cause of hip pain and limitation in terminal hip flexion and internal rotation. The purpose of this study was to evaluate the prevalence of low AIIS in patients undergoing hip arthroscopy and to characterize the concomitant intra-articular lesions. METHODS: Between November 2011 and April 2013, 100 consecutive patients underwent hip arthroscopy for various diagnoses by a single surgeon. After intra-operative diagnosis of low AIIS was made, a comprehensive review of the patients’ records, preoperative radiographs, and intra-operative findings was conducted to document the existence and location of labral and chondral lesions. RESULTS: Twenty-one (21 %) patients had low AIIS. There were 13 males (mean age 38.4 years) and eight females (mean age 35.5 years). Eight patients had pre-operative radiographic evidence of low AIIS. All patients had a labral tear anteriorly, at the level of the AIIS; 17 had chondrolabral disruption and 17 had chondral lesions in zone two (antero-superior); and four patients had lesion in zones two and three. CONCLUSIONS: Low AIIS is a common intra-operative finding in hip arthroscopy patients. Characteristic labral and chondral lesions are routinely found in a predictable location that effaces the low AIIS.

Desai, A. S., S. Solomon, B. Claggett, J. J. McMurray, J. Rouleau, K. Swedberg, M. Zile, M. Lefkowitz, V. Shi and M. Packer (2016). “Factors associated with noncompletion during the run-in period before randomization and influence on the estimated benefit of lcz696 in the paradigm-hf trial.” Circ Heart Fail 9(6).

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BACKGROUND: The 8442 patients randomized in the Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With an Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, in which sacubitril/valsartan (LCZ696) reduced both death and HF hospitalization more than enalapril, were a subset of 10 521 patients entering sequential, single-blind run-in periods (enalapril 10 mg twice daily for 2 weeks followed by LCZ696 200 mg twice daily for 4 to 6 weeks) to ensure short-term tolerability of the 2 study medications. We identified the predictors of run-in noncompletion and estimated the implications of noncompletion for the overall study result. METHODS AND RESULTS: Patient factors associated with run-in noncompletion were defined in multivariable logistic regression models. The effectiveness of LCZ696 in a broader cohort approximating the full run-in population was estimated by weighting randomized patients according to the inverse probability of run-in completion; 2079 (19.8%) subjects discontinued the study during the run-in period, including 1102 (10.5%) during the enalapril phase and 977 (9.3%) during the LCZ696 phase. In multivariable models, lower systolic blood pressure, lower estimated glomerular filtration rate, higher N-terminal pro-B-type natriuretic peptide, and ischemic cause of heart failure were associated with higher risk for run-in noncompletion. Repeat analysis of the effect of randomized treatment giving greater weight to randomized patients resembling those who did not complete the run-in did not alter the hazard ratio favoring LCZ696 over enalapril for the primary end point of cardiovascular death or heart failure hospitalization, or the additional key end points of cardiovascular death and all-cause mortality. CONCLUSIONS: Patients with lower blood pressure, lower glomerular filtration rate, and more severe heart failure were at higher risk for noncompletion during the run-in period of PARADIGM-HF. Weighted analysis of key study outcomes accounting for the effect of run-in noncompletion did not alter the benefit of LCZ696 over enalapril.