Research Spotlight

Vanderver, A., C. Simons, G. Helman, J. Crawford, N. I. Wolf, G. Bernard, A. Pizzino, J. L. Schmidt, A. Takanohashi, D. Miller, A. Khouzam, V. Rajan, E. Ramos, S. Chowdhury, T. Hambuch, K. Ru, G. J. Baillie, S. M. Grimmond, L. Caldovic, J. Devaney, M. Bloom, S. H. Evans, J. L. Murphy, N. McNeill, B. L. Fogel, R. Schiffmann, M. S. van der Knaap and R. J. Taft (2016). “Whole exome sequencing in patients with white matter abnormalities.” Ann Neurol 79(6): 1031-1037.

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Here we report whole exome sequencing (WES) on a cohort of 71 patients with persistently unresolved white matter abnormalities with a suspected diagnosis of leukodystrophy or genetic leukoencephalopathy. WES analyses were performed on trio, or greater, family groups. Diagnostic pathogenic variants were identified in 35% (25 of 71) of patients. Potentially pathogenic variants were identified in clinically relevant genes in a further 7% (5 of 71) of cases, giving a total yield of clinical diagnoses in 42% of individuals. These findings provide evidence that WES can substantially decrease the number of unresolved white matter cases.

Smallwood, N. R., J. W. Fleshman, S. G. Leeds and J. S. Burdick (2016). “The use of endoluminal vacuum (e-vac) therapy in the management of upper gastrointestinal leaks and perforations.” Surg Endosc 30(6): 2473-2480.

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INTRODUCTION: Upper intestinal leaks and perforations are associated with high morbidity and mortality rates. Despite the growing experience using endoscopically placed stents, the treatment of these leaks and perforations remain a challenge. Endoluminal vacuum (E-Vac) therapy is a novel treatment that has been successfully used in Germany to treat upper gastrointestinal leaks and perforations. There currently are no reports on its use in the USA. METHODS: E-Vac therapy was used to treat 11 patients with upper gastrointestinal leaks and perforations from September 2013 to September 2014. Five patients with leaks following sleeve gastrectomy were excluded from this study. A total of six patients were treated with E-Vac therapy; these included: (n = 2) iatrogenic esophageal perforations, (n = 1) iatrogenic esophageal and gastric perforations, (n = 1) iatrogenic gastric perforation, (n = 1) gastric staple line leak following a surgical repair of a traumatic gastric perforation, and (n = 1) esophageal perforation due to an invasive fungal infection. Four patients had failed an initial surgical repair prior to starting E-Vac therapy. RESULTS: All six patients (100 %) had complete closure of their perforation or leak after an average of 35.8 days of E-Vac therapy requiring 7.2 different E-Vac changes. No deaths occurred in the 30 days following E-Vac therapy. One patient died following complete closure of his perforation and transfer to an acute care facility due to an unrelated complication. There were no complications directly related to the use of E-Vac therapy. Only one patient had any symptoms of dysphagia. This patient had severe dysphagia from an esophagogastric anastomotic stricture prior to her iatrogenic perforations. Following E-Vac therapy, her dysphagia had actually improved and she could now tolerate a soft diet. CONCLUSIONS: E-Vac therapy is a promising new method in the treatment of upper gastrointestinal leaks and perforations. Current successes need to be validated through future prospective controlled studies.

Packer, M. (2016). “Love of angiotensin-converting enzyme inhibitors in the time of cholera.” JACC Heart Fail: April 2016 [Epub ahead of print].

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The highly acclaimed novel Love in the Time of Cholera by the Nobel Prize-winning Colombian author Gabriel García Márquez is a brilliant exploration of the complexity of love, specifically the struggle between our attraction to the ideal and depraved dimensions of love and the importance of passion and societal expectations in defining the attributes and personal rewards of love (1). Lovesickness is viewed as an illness, just as cholera is defined (from an intriguing Spanish perspective) as a passion, separate from its conventional consideration as a disease. The flow of the story (which evolves over decades) can be viewed simplistically, but that would be a mistake. The author himself has warned readers “you have to be careful not to fall into my trap” (1).

Coveler, A. L., A. H. Ko, D. V. Catenacci, D. Von Hoff, C. Becerra, N. C. Whiting, J. Yang and B. Wolpin (2016). “A phase 1 clinical trial of asg-5me, a novel drug-antibody conjugate targeting slc44a4, in patients with advanced pancreatic and gastric cancers.” Invest New Drugs 34(3): 319-328.

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ASG-5ME is an antibody-drug conjugate (ADC) targeting SLC44A4, a novel cell surface target expressed on most pancreatic and gastric cancers. This first-in-human study of ASG-5ME evaluated safety, pharmacokinetics, and preliminary activity of ASG-5ME in advanced pancreatic and gastric cancer patients. Experimental Design This phase 1, dose-escalation, multicenter study determined the maximum tolerated dose (MTD) and assessed safety and antitumor activity. The dose-escalation portion enrolled metastatic pancreatic adenocarcinoma patients; gastric adenocarcinoma patients were included in the dose-expansion portion. Patients received ASG-5ME intravenously on Days 1, 8, and 15 of 28-day cycles. Results Thirty-five pancreatic cancer patients (median age 63 years; performance status 0 [40 %] or 1 [60 %]) were treated at doses of 0.3 to 1.5 mg/kg (median duration 8.1 weeks). The MTD was exceeded at 1.5 mg/kg (n = 7) with 1 dose-limiting toxicity (DLT) of Grade 4 gastrointestinal hemorrhage. Four patients experienced non-DLT Grade 3 or 4 neutropenia. Fifteen gastric cancer patients (median age 59 years; performance status 0 [33 %] or 1 [67 %]) were treated at the identified MTD of 1.2 mg/kg (median duration 8.7 weeks). Common drug-related adverse events included fatigue (29 %), nausea (23 %), and vomiting (23 %) for pancreatic cancer patients and fatigue (33 %) and decreased appetite (33 %) for gastric cancer patients. Best clinical response was 1 partial response in each cohort. Disease-control rates of 33 % (pancreatic) and 47 % (gastric) were observed at the MTD. All patient biopsies (23 pancreatic, 15 gastric) expressed the SLC44A4 antigen. Conclusions ASG-5ME treatment was generally well tolerated with limited evidence of antitumor activity.

Driver, S., L. Rachal, C. Swank and R. Dubiel (2016). “Objective assessment of activity in inpatients with traumatic brain injury: Initial findings.” Brain Impairment 17(1): 55-63.

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Purpose: Use accelerometers to examine the physical activity behaviours of individuals following TBI undergoing inpatient rehabilitation. Method: Twenty-one individuals with Traumatic brain injury (TBI) undergoing inpatient rehabilitation (9 females, 12 males; M age = 43.8 14.7 years; M GCS = 9.1 4.3; M time since injury = 40.8 +/- 22.1 days; M length of stay (LOS) = 30 +/- 14 days) wore accelerometers for an average of 8.4 +/- 2.0 consecutive days (1440 minutes/day). Activity counts (AC) were collected at 1 minute epochs and descriptive statistics were calculated to assess intensity of activity and time spent being active and sedentary. Results: During scheduled therapy, time individuals completed an average of 161.4 +/- 65.5 AC/minute, which decreased to 114.5 +/- 51.3 during non-therapy time and 22.2 +/- 10 when sleeping. Using population level cut points, individuals were on average considered inactive during therapy, inactive or sedentary during non-therapy time, and only one participant spent >1 minute in moderate intensity activity. The mean length of active and sedentary bouts was 9 minutes. Discussion: Findings indicate that the amount and intensity of activity completed is low amongst individuals completing inpatient rehabilitation after TBI, with the majority considered sedentary or inactive. While the sample is small, it is important to develop and implement safe and effective strategies to increase activity levels during rehabilitation.