Research Spotlight

Peterson, D. E., J. A. O’Shaughnessy, H. S. Rugo, S. Elad, M. M. Schubert, C. T. Viet, C. Campbell-Baird, J. Hronek, V. Seery, J. Divers, J. Glaspy, B. L. Schmidt and T. F. Meiller (2016). “Oral mucosal injury caused by mammalian target of rapamycin inhibitors: Emerging perspectives on pathobiology and impact on clinical practice.” Cancer Med. 2016 June [Epub ahead of print].

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In recent years oral mucosal injury has been increasingly recognized as an important toxicity associated with mammalian target of rapamycin (mTOR) inhibitors, including in patients with breast cancer who are receiving everolimus. This review addresses the state-of-the-science regarding mTOR inhibitor-associated stomatitis (mIAS), and delineates its clinical characteristics and management. Given the clinically impactful pain associated with mIAS, this review also specifically highlights new research focusing on the study of the molecular basis of pain. The incidence of mIAS varies widely (2-78%). As reported across multiple mTOR inhibitor clinical trials, grade 3/4 toxicity occurs in up to 9% of patients. Managing mTOR-associated oral lesions with topical oral, intralesional, and/or systemic steroids can be beneficial, in contrast to the lack of evidence supporting steroid treatment of oral mucositis caused by high-dose chemotherapy or radiation. However, steroid management is not uniformly efficacious in all patients receiving mTOR inhibitors. Furthermore, technology does not presently exist to permit clinicians to predict a priori which of their patients will develop these lesions. There thus remains a strategic need to define the pathobiology of mIAS, the molecular basis of pain, and risk prediction relative to development of the clinical lesion. This knowledge could lead to novel future interventions designed to more effectively prevent mIAS and improve pain management if clinically significant mIAS lesions develop.

Sherwood, M. and P. A. McCullough (2016). “Chronic kidney disease from screening, detection, and awareness, to prevention.” Lancet Glob Health 4(5): e288-289.

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A critical link exists between awareness of risk, the presence of disease, and steps taken by the patient and clinician to change the natural history of disease. Chronic illnesses such as diabetes mellitus, dyslipidaemia, anaemia and a multitude of endocrinological and rheumatological diseases are relatively silent and rely on the clinical laboratory for diagnosis, particularly in their early stages. Probably no such illness permits such a large loss of organ function before symptoms become present as chronic kidney disease (CKD). 1 Thus, the considerable dependence on the laboratory to establish the diagnosis of CKD is an issue for low-income and middle-income countries (LMIC), where access to in-vitro diagnostics on a screening basis might not be universally available. Even in high-income countries where routine laboratory tests are performed, CKD seems to lag considerably behind diabetes mellitus, hypertension, and cardiovascular disease in terms of patient and clinician awareness. 2 This difference is partly due to the two-dimensional nature of CKD defined as a reduction in estimated glomerular filtration rate (eGFR) and the presence of markers of chronic kidney damage (albuminuria or imaging evidence) over 3 months time. Thus, to have the eGFR and albumin:creatinine ratio at the same time and clearly inform the patient of the potential presence of CKD is complex.

Klintmalm, G. B., F. Vincenti and A. Kirk (2016). “Steroid responsive acute rejection should not be the endpoint for immunosuppressive trials.” Am J Transplant: May 2016 [Epub ahead of print].

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In 1979 calcineurin Inhibitors (CNI) were introduced clinically as an immunosuppressive option (1). The transplant community finally had a drug powerful enough to control allograft rejection, enabling routine long-term survival. Thirty-five years ago, acute rejection caused graft loss, and thus could appropriately be equated with outcome. Although the nephrotoxicity of cyclosporine was recognized, the benefit of CNI in controlling rejection far out-weighted the nephrotoxicity.

Leon, M. B., C. R. Smith, M. J. Mack, R. R. Makkar, L. G. Svensson, S. K. Kodali, V. H. Thourani, E. M. Tuzcu, D. C. Miller, H. C. Herrmann, D. Doshi, D. J. Cohen, A. D. Pichard, S. Kapadia, T. Dewey, V. Babaliaros, W. Y. Szeto, M. R. Williams, D. Kereiakes, A. Zajarias, K. L. Greason, B. K. Whisenant, R. W. Hodson, J. W. Moses, A. Trento, D. L. Brown, W. F. Fearon, P. Pibarot, R. T. Hahn, W. A. Jaber, W. N. Anderson, M. C. Alu and J. G. Webb (2016). “Transcatheter or surgical aortic-valve replacement in intermediate-risk patients.” N Engl J Med 374(17): 1609-1620.

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BACKGROUND: Previous trials have shown that among high-risk patients with aortic stenosis, survival rates are similar with transcatheter aortic-valve replacement (TAVR) and surgical aortic-valve replacement. We evaluated the two procedures in a randomized trial involving intermediate-risk patients. METHODS: We randomly assigned 2032 intermediate-risk patients with severe aortic stenosis, at 57 centers, to undergo either TAVR or surgical replacement. The primary end point was death from any cause or disabling stroke at 2 years. The primary hypothesis was that TAVR would not be inferior to surgical replacement. Before randomization, patients were entered into one of two cohorts on the basis of clinical and imaging findings; 76.3% of the patients were included in the transfemoral-access cohort and 23.7% in the transthoracic-access cohort. RESULTS: The rate of death from any cause or disabling stroke was similar in the TAVR group and the surgery group (P=0.001 for noninferiority). At 2 years, the Kaplan-Meier event rates were 19.3% in the TAVR group and 21.1% in the surgery group (hazard ratio in the TAVR group, 0.89; 95% confidence interval [CI], 0.73 to 1.09; P=0.25). In the transfemoral-access cohort, TAVR resulted in a lower rate of death or disabling stroke than surgery (hazard ratio, 0.79; 95% CI, 0.62 to 1.00; P=0.05), whereas in the transthoracic-access cohort, outcomes were similar in the two groups. TAVR resulted in larger aortic-valve areas than did surgery and also resulted in lower rates of acute kidney injury, severe bleeding, and new-onset atrial fibrillation; surgery resulted in fewer major vascular complications and less paravalvular aortic regurgitation. CONCLUSIONS: In intermediate-risk patients, TAVR was similar to surgical aortic-valve replacement with respect to the primary end point of death or disabling stroke.

Shalowitz, D. I., M. A. Spillman and M. A. Morgan (2016). “Interactions with industry under the sunshine act: An example from gynecologic oncology.” Am J Obstet Gynecol 214(6): 703-707.

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THE PROBLEM: Clinicians may be unaware that industry payments to physicians are now publicly searchable under the Physician Payments Sunshine Act. Furthermore, the extent of industry’s financial involvement in subspecialty practice has not been previously accessible. As an example, 6948 direct, research-unrelated payments totaling $1,957,004 were made to 765 gynecologic oncologists in 2014, the first full year of data available. A total of 153 companies reported at least 1 payment; however, the 10 manufacturers reporting the highest total payment amount accounted for 82% of all payments to physicians. In all, 48 gynecologic oncologists received >$10,000 from manufacturers, accounting for $1,202,228, or 61%, of total payments. A SOLUTION: Obstetrician-gynecologists, including gynecologic oncologists, should be aware of their publicly reported payments from industry and ensure reports’ accuracy. Professional organizations, including the Society of Gynecologic Oncology (SGO), should strongly consider proactively developing guidelines regarding interactions with industry for their general memberships.