Research Spotlight

Posted May 15th 2019

Common laboratory parameters as indicators of multi-organ dysfunction in acute heart failure.

Peter McCullough M.D.

Peter McCullough M.D.

Sudhakaran, S. and P. A. McCullough (2019). “Common laboratory parameters as indicators of multi-organ dysfunction in acute heart failure.” Eur J Heart Fail Apr 11. [Epub ahead of print].

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Understanding of diagnosis, classification, pathophysiology, prognosis, and treatment of heart failure remains of major interest in clinical cardiology. There are approximately 23 million people with heart failure worldwide, and that estimate is expected to increase by roughly 772 000 by the year 2040. Patients on average have a 5‐year mortality of 50% after the diagnosis is established, most commonly in the setting of hospitalization for acute heart failure (AHF), and clinically, prognostication when admitted to the inpatient setting is challenging. In this issue of the Journal, the retrospective analysis by Zymliński et al.demonstrates how multi‐organ dysfunction as reflected by commonly measured laboratory parameters impacts AHF outcomes. The authors evaluated worsening heart failure and 1‐year mortality in AHF stratified by laboratory evidence of concomitant multi‐organ failure (namely cardiac, kidney, and liver injury/dysfunction) . . . The data presented by Zymliński et al. incites numerous areas of future direction that warrant further investigation. The sample size was small at 284 for multiple comparisons, and thus, it would be beneficial to validate these findings in a larger, prospective cohort. Finally, utilizing these data to delineate a scoring system for prognostication and to assess disease acuity, similar to Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) or Sequential Organ Failure Assessment (SOFA), but tailored specifically for AHF, would be a practical tool for those involved in the care of patients with AHF. (Excerpts from text, p. 1, 2; no abstract available; commenting on a study in the same issue, Zymliński R, et al., Multi‐organ dysfunction/injury on admission identifies acute heart failure patients at high risk of poor outcome; no abstract available.)


Posted May 15th 2019

Genome-wide Discovery of a Novel Gene-expression Signature for the Identification of Lymph Node Metastasis in Esophageal Squamous Cell Carcinoma.

Ajay Goel Ph.D.

Ajay Goel Ph.D.

Sonohara, F., F. Gao, N. Iwata, M. Kanda, M. Koike, N. Takahashi, Y. Yamada, Y. Kodera, X. Wang and A. Goel (2019). “Genome-wide Discovery of a Novel Gene-expression Signature for the Identification of Lymph Node Metastasis in Esophageal Squamous Cell Carcinoma.” Ann Surg 269(5): 879-886.

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OBJECTIVE: This study aimed to develop a gene-expression signature for identification of lymph node (LN) metastasis in esophageal squamous cell carcinoma (ESCC) patients. SUMMARY OF BACKGROUND DATA: LN metastasis is recognized as the most important independent risk factor for therapeutic decision-making of ESCC patients. METHODS: A bioinformatic approach was used to analyze RNA sequencing profiles of ESCC patients, and to develop a gene-expression signature for identifying LN metastasis. The robustness of this panel was assessed in 2 independent patient cohorts (n = 56 and 224). RESULTS: We initially prioritized a 16-gene signature out of the total 20,531 mRNAs. The model estimated by these 16 genes discriminated LN status with an area under the curve (AUC) of 0.77 [95% confidence interval (95% CI), 0.68-0.87, 5-fold cross-validation]. Subsequently, a reduced and optimized 5-gene panel was trained in a clinical cohort, which effectively distinguished ESCC patients with LN metastasis (cohort-1: AUC, 0.74; 95% CI, 0.58-0.89; cohort-2, T1-T2: AUC, 0.74; 95% CI, 0.63-0.86), and was significantly superior to preoperative computed tomography (AUC, 0.61; 95% CI, 0.50-0.72). Furthermore, a combination signature comprising of the 5-gene panel together with the lymphatic vessel invasion (LVI) and venous invasion (VI) demonstrated a significantly improved diagnostic performance compared with individual clinical variables, in both cohorts (cohort-1: AUC, 0.87; 95% CI, 0.78-0.96; cohort-2: AUC, 0.76; 95% CI, 0.65-0.88). CONCLUSION: Our novel 5-gene panel is a robust diagnostic tool for LN metastasis, especially in early-T stage ESCC patients, with a promising clinical potential.


Posted May 15th 2019

Volumetric laser endomicroscopy and its application to Barrett’s esophagus: results from a 1,000 patient registry.

Vani J.A. Konda M.D.

Vani J.A. Konda M.D.

Smith, M. S., B. Cash, V. Konda, A. J. Trindade, S. Gordon, S. DeMeester, V. Joshi, D. Diehl, E. Ganguly, H. Mashimo, S. Singh, B. Jobe, M. McKinley, M. Wallace, Y. Komatsu, S. Thakkar, F. Schnoll-Sussman, R. Sharaiha, M. Kahaleh, P. Tarnasky, H. Wolfsen, R. Hawes, J. Lipham, H. Khara, D. Pleskow, U. Navaneethan, P. Kedia, M. Hasan, A. Sethi, J. Samarasena, U. D. Siddiqui, F. Gress, R. Rodriguez, C. Lee, T. Gonda, I. Waxman, S. Hyder, J. Poneros, K. Sharzehi, J. A. Di Palma, D. V. Sejpal, D. Oh, J. Hagen, R. Rothstein, M. Sawhney, T. Berzin, Z. Malik and K. Chang (2019). “Volumetric laser endomicroscopy and its application to Barrett’s esophagus: results from a 1,000 patient registry.” Dis Esophagus Apr 30. [Epub ahead of print].

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Volumetric laser endomicroscopy (VLE) uses optical coherence tomography (OCT) for real-time, microscopic cross-sectional imaging. A US-based multi-center registry was constructed to prospectively collect data on patients undergoing upper endoscopy during which a VLE scan was performed. The objective of this registry was to determine usage patterns of VLE in clinical practice and to estimate quantitative and qualitative performance metrics as they are applied to Barrett’s esophagus (BE) management. All procedures utilized the NvisionVLE Imaging System (NinePoint Medical, Bedford, MA) which was used by investigators to identify the tissue types present, along with focal areas of concern. Following the VLE procedure, investigators were asked to answer six key questions regarding how VLE impacted each case. Statistical analyses including neoplasia diagnostic yield improvement using VLE was performed. One thousand patients were enrolled across 18 US trial sites from August 2014 through April 2016. In patients with previously diagnosed or suspected BE (894/1000), investigators used VLE and identified areas of concern not seen on white light endoscopy (WLE) in 59% of the procedures. VLE imaging also guided tissue acquisition and treatment in 71% and 54% of procedures, respectively. VLE as an adjunct modality improved the neoplasia diagnostic yield by 55% beyond the standard of care practice. In patients with no prior history of therapy, and without visual findings from other technologies, VLE-guided tissue acquisition increased neoplasia detection over random biopsies by 700%. Registry investigators reported that VLE improved the BE management process when used as an adjunct tissue acquisition and treatment guidance tool. The ability of VLE to image large segments of the esophagus with microscopic cross-sectional detail may provide additional benefits including higher yield biopsies and more efficient tissue acquisition. Clinicaltrials.gov NCT02215291.


Posted May 15th 2019

Outcomes of immunosuppression minimization and withdrawal early after liver transplantation.

Göran Klintmalm M.D.

Göran Klintmalm M.D.

Shaked, A., M. R. DesMarais, H. Kopetskie, S. Feng, J. D. Punch, J. Levitsky, J. Reyes, G. B. Klintmalm, A. J. Demetris, B. E. Burrell, A. Priore, N. D. Bridges and P. H. Sayre (2019). “Outcomes of immunosuppression minimization and withdrawal early after liver transplantation.” Am J Transplant 19(5): 1397-1409.

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The Immune Tolerance Network ITN030ST A-WISH assessed immunosuppression withdrawal in liver transplant recipients with hepatitis C or nonimmune nonviral liver disease. Of 275 recipients enrolled before transplantation, 95 were randomly assigned 4:1 to withdrawal (n = 77) or maintenance (n = 18) 1- to 2-years posttransplant. Randomization eligibility criteria included stable immunosuppression monotherapy; adequate liver and kidney function; /=8 weeks per level. Fifty-two of 77 subjects (67.5%) reduced to /=1 year. Acute rejection and/or abnormal liver tests were treated with increased immunosuppression; 5 of 32 rejection episodes required a methylprednisolone bolus. The composite end point (death or graft loss; grade 4 secondary malignancy or opportunistic infection; Ishak stage >/=3; or >25% decrease in glomerular filtration rate within 24 months of randomization) occurred in 12 of 66 (18%) and 4 of 13 (31%) subjects in the withdrawal and maintenance groups. Early immunosuppression minimization is feasible in selected liver recipients, while complete withdrawal is successful in only a small proportion. The composite end point comparison was inconclusive for noninferiority of the withdrawal to the maintenance group.


Posted May 15th 2019

The impact of surgical complications on the outcome of total pancreatectomy with islet autotransplantation.

Nicholas Onaca M.D.

Nicholas Onaca M.D.

Shahbazov, R., B. Naziruddin, O. Salam, G. Saracino, M. F. Levy, E. Beecherl and N. Onaca (2019). “The impact of surgical complications on the outcome of total pancreatectomy with islet autotransplantation.” Am J Surg Apr 15. [Epub ahead of print].

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Total pancreatectomy with islet autotransplantation is a promising treatment for refractory chronic pancreatitis. We analyzed postoperative complications in 83 TPIAT patients and their impact on islet graft function. We examined patient demographics, preoperative risk factors, intraoperative variables, and 30- and 90-day postoperative morbidity and mortality. Daily insulin requirement, HbA1c, C-peptide levels, and narcotic requirements were analyzed before and after surgery. Adverse events were recorded, with postoperative complications graded according to the Clavien-Dindo classification. There was no mortality in this patient group. Postoperative complications occurred in 38 patients (45.7%). Patients with postoperative complications were readmitted significantly more often within 30 days (p=0.01) and 90 days posttransplant (p<0.0003) and had a significantly longer hospital stay (p=0.004) and intensive care unit stay (p=0.001). Insulin dependence and graft function assessed by HbA1c, C-Peptide and insulin requirements did not differ significantly by these complications. Postoperative complications after TPIAT are associated with longer hospital and intensive care unit stay and with readmission; however, the surgical complications do not affect islet graft function.