Research Spotlight

Myers, R. M., B. T. Hill, B. E. Shaw, S. Kim, H. R. Millard, M. Battiwalla, N. S. Majhail, D. Buchbinder, H. M. Lazarus, B. N. Savani, M. E. D. Flowers, A. D’Souza, M. J. Ehrhardt, A. Langston, J. A. Yared, R. J. Hayashi, A. Daly, R. F. Olsson, Y. Inamoto, A. K. Malone, Z. DeFilipp, S. P. Margossian, A. B. Warwick, S. Jaglowski, A. Beitinjaneh, H. Fung, K. A. Kasow, D. I. Marks, J. Reynolds, K. Stockerl-Goldstein, B. Wirk, W. A. Wood, M. Hamadani and P. Satwani (2018). “Long-term outcomes among 2-year survivors of autologous hematopoietic cell transplantation for Hodgkin and diffuse large b-cell lymphoma.” Cancer 124(4): 816-825.

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BACKGROUND: Autologous hematopoietic cell transplantation (auto-HCT) is a standard therapy for relapsed classic Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL); however, long-term outcomes are not well described. METHODS: This study analyzed survival, nonrelapse mortality, late effects, and subsequent malignant neoplasms (SMNs) in 1617 patients who survived progression-free for >/=2 years after auto-HCT for cHL or DLBCL between 1990 and 2008. The median age at auto-HCT was 40 years; the median follow-up was 10.6 years. RESULTS: The 5-year overall survival rate was 90% (95% confidence interval [CI], 87%-92%) for patients with cHL and 89% (95% CI, 87%-91%) for patients with DLBCL. The risk of late mortality in comparison with the general population was 9.6-fold higher for patients with cHL (standardized mortality ratio [SMR], 9.6) and 3.4-fold higher for patients with DLBCL (SMR, 3.4). Relapse accounted for 44% of late deaths. At least 1 late effect was reported for 9% of the patients. A total of 105 SMNs were confirmed: 44 in the cHL group and 61 in the DLBCL group. According to a multivariate analysis, older age, male sex, a Karnofsky score < 90, total body irradiation (TBI) exposure, and a higher number of lines of chemotherapy before auto-HCT were risk factors for overall mortality in cHL. Risk factors in DLBCL were older age and TBI exposure. A subanalysis of 798 adolescent and young adult patients mirrored the outcomes of the overall study population. CONCLUSIONS: Despite generally favorable outcomes, 2-year survivors of auto-HCT for cHL or DLBCL have an excess late-mortality risk in comparison with the general population and experience an assortment of late complications. Cancer 2018;124:816-25. (c) 2017 American Cancer Society.

Mogensen, U. M., J. Gong, P. S. Jhund, L. Shen, L. Kober, A. S. Desai, M. P. Lefkowitz, M. Packer, J. L. Rouleau, S. D. Solomon, B. L. Claggett, K. Swedberg, M. R. Zile, G. Mueller-Velten and J. J. V. McMurray (2018). “Effect of sacubitril/valsartan on recurrent events in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF).” Eur J Heart Fail. Feb 12. [Epub ahead of print].

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AIMS: Recurrent hospitalizations are a major part of the disease burden in heart failure (HF), but conventional analyses consider only the first event. We compared the effect of sacubitril/valsartan vs. enalapril on recurrent events, incorporating all HF hospitalizations and cardiovascular (CV) deaths in PARADIGM-HF, using a variety of statistical approaches advocated for this type of analysis. METHODS AND RESULTS: In PARADIGM-HF, a total of 8399 patients were randomized and followed for a median of 27 months. We applied various recurrent event analyses, including a negative binomial model, the Wei, Lin and Weissfeld (WLW), and Lin, Wei, Ying and Yang (LWYY) methods, and a joint frailty model, all adjusted for treatment and region. Among a total of 3181 primary endpoint events (including 1251 CV deaths) during the trial, only 2031 (63.8%) were first events (836 CV deaths). Among a total of 1195 patients with at least one HF hospitalization, 410 (34%) had at least one further HF hospitalization. Sacubitril/valsartan compared with enalapril reduced the risk of recurrent HF hospitalization using the negative binomial model [rate ratio (RR) 0.77, 95% confidence interval (CI) 0.67-0.89], the WLW method [hazard ratio (HR) 0.79, 95% CI 0.71-0.89], the LWYY method (RR 0.78, 95% CI 0.68-0.90), and the joint frailty model (HR 0.75, 95% CI 0.66-0.86) (all P < 0.001). The effect of sacubitril/valsartan vs. enalapril on recurrent HF hospitalizations/CV death was similar. CONCLUSIONS: In PARADIGM-HF, approximately one third of patients with a primary endpoint (time-to-first) experienced a further event. Compared with enalapril, sacubitril/valsartan reduced both first and recurrent events. The treatment effect size was similar, regardless of the statistical approach applied.E

Michel, P., A. Menter and J. Griffin (2018). “A congenital naevus in a blaschkoid distribution.” Clin Exp Dermatol 43(2): 216-218.

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A 70-year-old man presented with a lesion on his lip of undetermined duration, which was considered to be nonmalignant. Total body skin examination revealed extensive areas of dilated follicular openings with hyperpigmented keratinous plugs within the follicles, extending from the lateral aspect of the patient’s right hip (Fig. 1) to the medial side of his ipsilateral thigh. Two areas with similar findings were found adjacent to the right gluteal cleft and the lateral aspect of the right shin. Discrete areas of atrophic scars were interspersed between the main lesions following the lines of Blaschko. On closer questioning, the patient stated that he was born with these lesions, which had remained relatively unchanged throughout his life. There was no associated family history. (Excerpt from text, p. 216; no abstract available.)

Meng, X. L., E. Arning, M. Wight-Carter, T. S. Day, S. Jabbarzadeh-Tabrizi, S. Chen, R. J. Ziegler, T. Bottiglieri, J. W. Schneider, S. H. Cheng, R. Schiffmann and J. S. Shen (2018). “Priapism in a Fabry disease mouse model is associated with upregulated penile nNOS and eNOS expression.” J Inherit Metab Dis 41(2): 231-238.

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Fabry disease is a glycosphingolipidosis caused by deficient activity of alpha-galactosidase A; it is one of a few diseases that are associated with priapism, an abnormal prolonged erection of the penis. The goal of this study was to investigate the pathogenesis of Fabry disease-associated priapism in a mouse model of the disease. We found that Fabry mice develop late-onset priapism. Neuronal nitric oxide synthase (nNOS), which was predominantly present as the 120-kDa N-terminus-truncated form, was significantly upregulated in the penis of 18-month-old Fabry mice compared to wild type controls (~fivefold). Endothelial NOS (eNOS) was also upregulated (~twofold). NO level in penile tissues of Fabry mice was significantly higher than wild type controls at 18 months. Gene transfer-mediated enzyme replacement therapy reversed abnormal nNOS expression in the Fabry mouse penis. The penile nNOS level was restored by antiandrogen treatment, suggesting that hyperactive androgen receptor signaling in Fabry mice may contribute to nNOS upregulation. However, the phosphodiesterase-5A expression level and the adenosine content in the penis, which are known to play roles in the development of priapism in other etiologies, were unchanged in Fabry mice. In conclusion, these data suggested that increased nNOS (and probably eNOS) content and the consequential elevated NO production and high arterial blood flow in the penis may be the underlying mechanism of priapism in Fabry mice. Furthermore, in combination with previous findings, this study suggested that regulation of NOS expression is susceptible to alpha-galactosidase A deficiency, and this may represent a general pathogenic mechanism of Fabry vasculopathy.

McLaughlin, C. M., N. Channabasappa, J. Pace, H. Nguyen and H. G. Piper (2018). “Growth Trajectory in Children With Short Bowel Syndrome During the First 2 Years of Life.” J Pediatr Gastroenterol Nutr 66(3): 484-488.

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OBJECTIVES: Infants with short bowel syndrome (SBS) require diligent nutritional support for adequate growth. Enteral independence is a primary goal, but must be balanced with ensuring sufficient nutrition. We aimed to describe growth trajectory in infants with SBS as function of nutritional intake during first 2 years of life. METHODS: Infants with SBS were reviewed (2008-2016). z Scores for weight, height, and head circumference (HC) were recorded at birth, 3, 6, 12, 18, and 24 months. Nutritional intake, serum liver enzyme, and bilirubin levels were assessed at all time points. Pearson correlation coefficients were used to measure association with P < 0.05 considered significant. RESULTS: Forty-one infants were included, with median gestational age of 34 weeks (interquartile range [IQR] 29-36 weeks). Median small bowel length was 36 cm (IQR 26-52 cm) and median % expected small bowel length was 28% (IQR 20%-42%). Mean z scores for weight and length were >0 at birth, but <0 from 3 months to 2 years. HC remained <0 throughout the study. Mean z scores at 2 years for weight, length, HC, and weight-for-length were -0.90 (SD 1.1), -1.33 (SD 1.4), -0.67 (SD 1.2), and -0.12 (SD 1.2), respectively. Percentage calories from PN was positively correlated with weight in the first 3 months of life (P = 0.01). CONCLUSIONS: Babies with SBS are high risk for poor growth during the first 2 years of life. Although weaning PN is important for these patients, doing so too quickly in infancy may contribute to compromised growth. The long-term impact on overall development is not known.