Atypical Reactivation of Varicella Zoster Virus Associated with Pancreatitis in a Heart Transplant Patient.

BACKGROUND Acute pancreatitis is rare following solid organ transplantation but is associated with high mortality. It has been most commonly reported following renal transplant but can occur with other solid organ transplantations. CASE REPORT A 46-year-old male who had an orthotopic heart transplant 6 months ago presented with a 3-week history of abdominal pain. The patient described it as intermittent, sharp, and stabbing, originating in the periumbilical area and radiating to the back. His lipase was elevated at 232 U/L. Given that the patient\u27s symptoms and lipase were elevated to greater than three times the upper limit of normal, he patient was diagnosed with acute pancreatitis. The patient also mentioned a diffuse itchy rash that started a few days prior to admission. Dermatology was consulted, and given the man\u27s clinical presentation, there was concern for atypical reactivation of varicella zoster virus (VZV). VZV polymerase chain reaction of the vesicles returned positive. The patient was started on acyclovir and his symptoms improved. CONCLUSIONS This is the first reported case of VZV-associated pancreatitis in a heart transplant patient. Our patient presented with acute pancreatitis and was treated supportively. However, he did not receive antiviral treatment until his rash was discovered. Timely treatment of VZV resulted in resolution of both the rash and pancreatitis. Timely diagnosis of pancreatitis and VZV is important to prevent development of multiorgan failure and death

Timely diagnosis and staging of non-alcoholic fatty liver disease using transient elastography and clinical parameters.

Background and Aim: There is no standardized guideline to screen, image, or refer patients with non-alcoholic fatty liver disease (NAFLD) to a specialist. In this study, we used transient elastography (TE) to examine the fibrosis stages at which patients are first diagnosed with NAFLD. Subsequently, we analyzed metabolic markers to establish cut-offs beyond which noninvasive imaging should be considered to confirm NAFLD/non-alcoholic steatohepatitis fibrosis in patients. Methods: Charts spanning July 2015-April 2018 for 116 NAFLD patients who had TE performed were reviewed. Univariate and multivariate analysis of metabolic markers was conducted. Results: At the first hepatology visit, TE showed 73% F0-F2 and 27% F3-F4. Univariate analysis showed that high-density lipoproteins (HDL), hemoglobin A1c (A1c), aspartate transaminase (AST), and alanine transaminase (ALT) were significantly different between the F0-F2 and F3-F4 groups. Multivariate analysis showed that AST (P = 0.01) and A1c (P = 0.05) were significantly different. Optimal cut-offs for these markers to detect liver fibrosis on TE were AST \u3e43 U/L and A1c \u3e6.6%. The logistic regression function combining these two variables to reflect the probability (P) of the patient having advanced fibrosis (F3-F4) on TE yielded the formula: P = e R /(1 + e R ), where R = -8.56 + 0.052 * AST + 0.89 * A1c. Conclusions: Our study suggested that \u3e25% of patients presenting to a specialist for NAFLD may have advanced fibrosis (F3-F4). Diabetes (A1c \u3e6.6%) and AST \u3e43 U/L were the most predictive in identifying NAFLD patients with advanced fibrosis on imaging. We proposed a formula that may be used to prioritize NAFLD patients at higher risk of having advanced fibrosis for specialist referral and imaging follow-up

Corneal perforation in ocular graft-versus-host disease

PURPOSE: Corneal perforation is a rare, vision-threatening complication of ocular graft-versus-host disease (GVHD) and is not well understood. Our objective was to examine the clinical disease course and histopathologic correlation in patients who progressed to this outcome. METHODS: This study is a retrospective case series from four academic centers in the United States. All patients received a hematopoietic stem cell transplant (HSCT) prior to developing ocular GVHD. Variables of interest included patient demographics, time interval between HSCT and ocular events, visual acuity throughout clinical course, corticosteroid and infection prophylaxis regimens at time of corneal perforation, medical/surgical interventions, and histopathology. RESULTS: Fourteen eyes from 14 patients were analyzed. Most patients were male (86%) and Caucasian (86%), and average age at time of hematopoietic stem cell transplant was 47 years. The mean interval between hematopoietic stem cell transplant and diagnosis of ocular graft-versus-host disease was 9.5 months, and between hematopoietic stem cell transplant and corneal perforation was 37 months. Initial best-corrected visual acuity was 20/40 or better in 9 eyes, and all eyes had moderate or poor visual outcomes despite aggressive management, including corneal gluing in all patients followed by keratoplasty in 8 patients. The mean follow-up after perforation was 34 months (range 2-140 months). Oral prednisone was used prior to perforation in 11 patients (79%). On histopathology, representative specimens in the acute phase demonstrated ulcerative keratitis with perforation but minimal inflammatory cells and no microorganisms, consistent with sterile corneal melt in the setting of immunosuppression; and in the healed phase, filling in of the perforation site with fibrous scar. CONCLUSIONS: In these patients, an extended time interval was identified between the diagnosis of ocular graft-versus-host disease and corneal perforation. This represents a critical window to potentially prevent this devastating outcome. Further study is required to identify those patients at greatest risk as well as to optimize prevention strategies

Activation of HER3 Interferes with Antitumor Effects of Axl Receptor Tyrosine Kinase Inhibitors: Suggestion of Combination Therapy.

The Axl receptor tyrosine kinase (RTK) has been established as a strong candidate for targeted therapy of cancer. However, the benefits of targeted therapies are limited due to acquired resistance and activation of alternative RTKs. Therefore, we asked if cancer cells are able to overcome targeted Axl therapies. Here, we demonstrate that inhibition of Axl by short interfering RNA or the tyrosine kinase inhibitor (TKI) BMS777607 induces the expression of human epidermal growth factor receptor 3 (HER3) and the neuregulin 1(NRG1)-dependent phosphorylation of HER3 in MDA-MB231 and Ovcar8 cells. Moreover, analysis of 20 Axl-expressing cancer cell lines of different tissue origin indicates a low basal phosphorylation of RAC-alpha serine/threonine-protein kinase (AKT) as a general requirement for HER3 activation on Axl inhibition. Consequently, phosphorylation of AKT arises as an independent biomarker for Axl treatment. Additionally, we introduce phosphorylation of HER3 as an independent pharmacodynamic biomarker for monitoring of anti-Axl therapy response. Inhibition of cell viability by BMS777607 could be rescued by NRG1-dependent activation of HER3, suggesting an escape mechanism by tumor microenvironment. The Axl-TKI MPCD84111 simultaneously blocked Axl and HER2/3 signaling and thereby prohibited HER3 feedback activation. Furthermore, dual inhibition of Axl and HER2/3 using BMS777607 and lapatinib led to a significant inhibition of cell viability in Axl-expressing MDA-MB231 and Ovcar8 cells. Therefore, we conclude that, in patient cohorts with expression of Axl and low basal activity of AKT, a combined inhibition of Axl and HER2/3 kinase would be beneficial to overcome acquired resistance to Axl-targeted therapies

Dose Frequency Ranging Pharmacokinetic Study of Tenofovir-Emtricitabine After Directly Observed Dosing in Healthy Volunteers to Establish Adherence Benchmarks (HPTN 066)

Oral preexposure prophylaxis (PrEP) trials report disparate efficacy attributed to variable adherence. HPTN 066 was conducted to establish objective, quantitative benchmarks for discrete, regular levels of adherence using directly observed dosing of tenofovir (TFV) disoproxil fumarate (TDF)/emtricitabine (FTC). Healthy, HIV-uninfected men and women were randomized to one of four oral regimens of fixed-dose TDF 300 mg/FTC 200 mg tablet for 5 weeks with all doses observed: one tablet weekly (one/week), one tablet twice weekly (two/week), two tablets twice weekly (four/week), or one tablet daily (seven/week). Trough serum TFV and FTC, peripheral blood mononuclear cell (PBMC), and CD4+ TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP) concentrations were determined throughout dosing and 2 weeks after the last dose. Rectosigmoidal, semen, and cervicovaginal samples were collected for drug assessment at end of dosing and 2 weeks later in a subset of participants. The 49 enrolled participants tolerated the regimens well. All regimens achieved steady-state concentrations by the second dose for serum TFV/FTC and by 7 days for PBMC TFV-DP/FTC-TP. Steady-state median TFV-DP predose concentrations demonstrated dose proportionality: one/week 1.6 fmol/106 PBMCs, two/week 9.1, four/week 18.8, seven/week, 36.3. Further, TFV-DP was consistently quantifiable 2 weeks after the last dose for the ≥4/week regimens. Adherence benchmarks were identified using receiver operating characteristic curves, which had areas under the curve ≥0.93 for all analytes in serum and PBMCs. Intersubject and intrasubject coefficients of variation (%CV) ranged from 33% to 63% and 14% to 34%, respectively, for all analytes in serum and PBMCs. Steady-state PBMC TFV-DP was established earlier and at lower concentrations than predicted and was the only analyte demonstrating predose concentration dose proportionality. Steady-state daily dosing serum TFV and PBMC TFV-DP was consistent with highly effective PrEP clinical trials. HPTN 066 provides adherence benchmarks for oral TFV/FTC regimens to assist interpreting study outcomes

SJS/TEN 2019: From science to translation.

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are potentially life-threatening, immune-mediated adverse reactions characterized by widespread erythema, epidermal necrosis, and detachment of skin and mucosa. Efforts to grow and develop functional international collaborations and a multidisciplinary interactive network focusing on SJS/TEN as an uncommon but high burden disease will be necessary to improve efforts in prevention, early diagnosis and improved acute and long-term management. SJS/TEN 2019: From Science to Translation was a 1.5-day scientific program held April 26-27, 2019, in Vancouver, Canada. The meeting successfully engaged clinicians, researchers, and patients and conducted many productive discussions on research and patient care needs

Eicosapentaenoic Acid Enriched Enteral Nutrition Improves Lean Body Mass in Esophageal, Head and Neck Cancer Patients

OBJECTIVE: Cachexia is a nutrient deficient condition affecting millions of cancer patients. Cancers of the upper gastrointestinal tract, head and neck are often the most severely affected. Currently, there is no established therapy for cachexia, although several potential anti-cachectic agents are being explored. A meta-analysis was conducted to review the effect of eicosapentaenoic acid (EPA) enriched enteral nutrition on lean body mass (LBM) in esophageal, head and neck cancer patients at risk for progression of cachexia. METHODS: An evidence based review was conducted beginning with a Pubmed database literature search using the terms ‘EPA esophageal cancer’, ‘Eicosapentaenoic acid esophageal cachexia’, ‘Eicosapentaenoic acid esophageal’, ‘Eicosapentaenoic acid cachexia head and neck cancer’, and ‘EPA cachexia head and neck cancer’ for human clinical trials. The results were reviewed for relevance and the data from original research was abstracted for amount of EPA enriched formula supplemented, EPA intake, method of intake, LBM measurements, study design, intervention duration, and population characteristics.RESULTS: Three trials were identified that met the criteria and were reviewed.  EPA supplementation in enteral nutrition was provided at concentrations ranging between 1.6 g/day and 2.2 g/day for a time span ranging between 3 weeks and 14 weeks. Two randomized clinical trials showed maintenance of > 1.5 kg LBM relative to the control group while a single arm trial showed a gain of 3.2 kg LBM in patients. Differences in results could be attributed to variability in the degree of cachexia, the contents of each enteral nutrition formula, duration of supplementation, and cancer treatments that subjects in each trial were undergoing.CONCLUSIONS: All three trials showed a trend in EPA enriched enteral nutrition improving the loss of LBM in esophageal, head and neck cancer patients at risk for cachexia progression. This type of formula should therefore be considered in treatment of these types of cancers and possibly, in the treatment of other seriously ill patients with cachexia