Research Spotlight

Kathania, M., P. Khare, M. Zeng, B. Cantarel, H. Zhang, H. Ueno and K. Venuprasad (2016). “Itch inhibits il-17-mediated colon inflammation and tumorigenesis by ror-gammat ubiquitination.” Nat Immunol 17(8): 997-1004.

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Dysregulated expression of interleukin 17 (IL-17) in the colonic mucosa is associated with colonic inflammation and cancer. However, the cell-intrinsic molecular mechanisms by which IL-17 expression is regulated remain unclear. We found that deficiency in the ubiquitin ligase Itch led to spontaneous colitis and increased susceptibility to colon cancer. Itch deficiency in the TH17 subset of helper T cells, innate lymphoid cells and gammadelta T cells resulted in the production of elevated amounts of IL-17 in the colonic mucosa. Mechanistically, Itch bound to the transcription factor ROR-gammat and targeted ROR-gammat for ubiquitination. Inhibition or genetic inactivation of ROR-gammat attenuated IL-17 expression and reduced spontaneous colonic inflammation in Itch(-/-) mice. Thus, we have identified a previously unknown role for Itch in regulating IL-17-mediated colonic inflammation and carcinogenesis.

Klein, J. A., S. A. Gonzalez, B. V. Fischbach, A. F. Yango, A. Rajagopal, K. M. Rice, M. Saim, Y. M. Barri, L. B. Melton, G. B. Klintmalm and A. Chandrakantan (2016). “Routine ultrasonography surveillance of native kidneys for renal cell carcinoma in kidney transplant candidates.” Clin Transplant 30(8): 946-953.

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Renal cell carcinoma (RCC) has a high incidence in the kidney transplant population and annual surveillance detects these tumors early in their natural history. Minimal guidelines exist regarding RCC surveillance in ESRD patients awaiting transplant. A retrospective review of our kidney transplant database examined the outcomes of annual ultrasonographic surveillance during initial kidney transplant evaluation and upon annual reassessment. Of 2642 patients listed for transplant, 145 patients were found to have masses during initial kidney transplant evaluation or annual imaging consistent with new complex cystic disease or RCC. A total of 71 patients had RCC identified, with 52 found on initial kidney transplant evaluation and 19 identified on annual surveillance. Male gender and African-American race were independently associated with RCC (P<.05). RCC was detected a median of 2.0 years after listing (two annual ultrasonography studies). Patients with complex cysts were more likely to undergo transplantation (48.7%) compared to patients with RCC (21.1%; P<.001). There was no significant difference in survival between RCC patients and those found to have complex cystic disease, suggesting incidental RCC can be diagnosed early in the natural history and at a curable stage through implementation of a biennial surveillance program.

Klein, J. A., S. A. Gonzalez, B. V. Fischbach, A. F. Yango, A. Rajagopal, K. M. Rice, M. Saim, Y. M. Barri, L. B. Melton, G. B. Klintmalm and A. Chandrakantan (2016). “Routine ultrasonography surveillance of native kidneys for renal cell carcinoma in kidney transplant candidates.” Clin Transplant 30(8): 946-953.

Full text of this article.

Renal cell carcinoma (RCC) has a high incidence in the kidney transplant population and annual surveillance detects these tumors early in their natural history. Minimal guidelines exist regarding RCC surveillance in ESRD patients awaiting transplant. A retrospective review of our kidney transplant database examined the outcomes of annual ultrasonographic surveillance during initial kidney transplant evaluation and upon annual reassessment. Of 2642 patients listed for transplant, 145 patients were found to have masses during initial kidney transplant evaluation or annual imaging consistent with new complex cystic disease or RCC. A total of 71 patients had RCC identified, with 52 found on initial kidney transplant evaluation and 19 identified on annual surveillance. Male gender and African-American race were independently associated with RCC (P<.05). RCC was detected a median of 2.0 years after listing (two annual ultrasonography studies). Patients with complex cysts were more likely to undergo transplantation (48.7%) compared to patients with RCC (21.1%; P<.001). There was no significant difference in survival between RCC patients and those found to have complex cystic disease, suggesting incidental RCC can be diagnosed early in the natural history and at a curable stage through implementation of a biennial surveillance program.

Lee, S. D., D. T. Rubin, W. J. Sandborn, C. Randall, Z. Younes, S. Schreiber, D. A. Schwartz, R. Burakoff, D. Binion, T. Dassopoulos, R. Arsenescu, A. Gutierrez, E. Scherl, C. Kayhan, I. Hasan, G. Kosutic, M. Spearman, D. Sen, J. Coarse and S. Hanauer (2016). “Reinduction with certolizumab pegol in patients with crohn’s disease experiencing disease exacerbation: 7-year data from the precise 4 study.” Inflamm Bowel Dis 22(8): 1870-1880.

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BACKGROUND: Patients with Crohn’s disease in whom tumor necrosis factor antagonist therapy fails have limited treatment options, and the benefit of reintroducing the same therapy remains unclear. Here, we report results from PRECiSE 4 (NCT00160706), an open-label extension study of certolizumab pegol in patients who withdrew from the placebo-controlled studies PRECiSE 1 or 2. METHODS: Patients eligible for PRECiSE 4 had Crohn’s disease exacerbation on placebo or primary or secondary failure to certolizumab pegol in PRECiSE 1 or 2, and received 400 mg certolizumab pegol subcutaneously at weeks 0, 2, and 4 and every 4 weeks thereafter up to 360 weeks. We assessed safety (adverse events) and efficacy (clinical remission) of extended certolizumab pegol therapy. RESULTS: Patients enrolled in PRECiSE 4 (N = 310; mean age, 37 yr; 58% female; 95% white) had a mean Crohn’s disease duration of 8.5 years before entering the qualifying studies. At weeks 52, 104, and 156, remission rates were 28.5%, 17.5%, and 12.6% by nonremitter imputation, and 63.8%, 60.0%, and 63.5% by observed cases, with 47.4%, 31.9%, and 23.2% of patients, respectively, remaining on therapy. By study end (7.5 yr), 92.3% of patients discontinued therapy, 49% on account of adverse events. No new safety signals emerged. Incidence rate (new cases)/100 patient-years was 6.11 for serious infections and 1.29 for malignancies. CONCLUSIONS: Certolizumab pegol was effective in many patients who previously discontinued certolizumab pegol for lack or loss of response. Thus, discontinuation of therapy may not always be necessary. Safety was consistent with previous findings.

Mack, M. J. and E. M. Holper (2016). “Tavr risk assessment: Does the eyeball test have 20/20 vision, or can we do better?” J Am Coll Cardiol 68(4): 353-355.

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The Society of Thoracic Surgeons (STS) analyzed the outcomes of thousands of cardiac operations to develop a risk algorithm. The STS Predicted Risk of Mortality (PROM) predicts 30-day mortality and major morbidity rates after the most common cardiac operations; subsequent studies also showed a correlation with 1-year mortality rates (1). The STS PROM and other risk algorithms, including the European System for Cardiac Operative Risk Evaluation (EuroSCORE), logistic EuroSCORE, and EuroSCORE II, which have been developed and validated in surgical populations, have been used to assess risk in patients considered for transcatheter aortic valve replacement (TAVR). Despite the obvious invalidity of using risk algorithms to assess candidacy for a procedure for which these algorithms were not developed or validated, no alternatives have been available until recently.