Eric J. Grossman

Argatroban Anticoagulation in Patients with Heparin-Induced Thrombocytopenia Requiring Renal Replacement Therapy

BACKGROUND: Argatroban, a direct thrombin inhibitor, is used for prophylaxis or treatment of thrombosis in heparin-induced thrombocytopenia (HIT). The recommended initial dose is 2 μg/kg/min (0.5 μg/kg/min in hepatic impairment), adjusted to achieve activated partial thromboplastin time (aPTT) values 1.5–3.0 times baseline. However, few argatroban-treated patients with HIT and renal failure requiring renal replacement therapy (RRT) have been described. OBJECTIVE: To evaluate the safety and efficacy of argatroban anticoagulation during RRT in patients with HIT. METHODS: We retrospectively reviewed records from 47 patients with HIT and renal failure requiring RRT who underwent 50 treatment courses with argatroban. Patients with HIT had received argatroban during prospective, multicenter studies. Outcomes, safety, and dosing information were summarized. RESULTS: In the multicenter experience, no patient died due to thrombosis and 2 (4%) patients developed new thrombosis while on argatroban. No adverse outcomes occurred during argatroban reexposure. Starting doses were typically 2 μg/kg/min in patients without hepatic impairment and <1.5 μg/kg/min in those with hepatic impairment. Median (range) infusion doses were 1.7 (0.2–2.8) and 0.7 (0.1–1.7) μg/kg/min, respectively, with associated median (range) aPTT ratios, relative to baseline, of 2.2 (1.6–3.6) and 2.0 (1.4–4.1), respectively. Major bleeding occurred in 3 (6%) of 50 treatment courses. CONCLUSIONS: Argatroban provides effective anticoagulation upon initial and repeated administration in patients with HIT and renal impairment requiring RRT, with an acceptably low bleeding risk. Current dosing recommendations are adequate for these patients.

Liver transplantation for non–hepatocellular carcinoma malignancy: Indications, limitations, and analysis of the current literature

Orthotopic liver transplantation (OLT) is currently incorporated into the treatment regimens for specific nonhepatocellular malignancies. For patients suffering from early‐stage, unresectable hilar cholangiocarcinoma (CCA), OLT preceded by neoadjuvant radiotherapy has the potential to readily achieve a tumor‐free margin, accomplish a radical resection, and treat underlying primary sclerosing cholangitis when present. In highly selected stage I and II patients with CCA, the 5‐year survival rate is 80%. As additional data are accrued, OLT with neoadjuvant chemoradiation may become a viable alternative to resection for patients with localized, node‐negative hilar CCA. Hepatic involvement from neuroendocrine tumors can be treated with OLT when metastases are unresectable or for palliation of medically uncontrollable symptoms. Five‐year survival rates as high as 90% have been reported, and the Ki67 labeling index can be used to predict outcomes after OLT. Hepatic epithelioid hemangioendothelioma is a rare tumor of vascular origin. The data from single‐institution series are limited, but compiled reviews have reported 1‐ and 10‐year survival rates of 96% and 72%, respectively. Hepatoblastoma is the most common primary hepatic malignancy in children. There exist subtle differences in the timing of chemotherapy between US and European centers; however, the long‐term survival rate after transplantation ranges from 66% to 77%. Fibrolamellar hepatocellular carcinoma is a distinct liver malignancy best treated by surgical resection. However, there is an increasing amount of data supporting OLT when resection is contraindicated. In the treatment of either primary or metastatic hepatic sarcomas, unacceptable survival and recurrence rates currently prohibit the use of OLT. Liver Transpl 16:930‐942, 2010.

Bronchiolitis obliterans in lung transplantation: the good, the bad, and the future

Lung transplantation remains the hope for many incurable pulmonary diseases, such as cystic fibrosis, pulmonary fibrosis, and chronic obstructive pulmonary disease. Remarkable progress has been made in improving outcomes, although the incidence of acute rejection remains more than 50% in the 1st year, and the 5-year graft survival is still less than 50% primarily because of the development of chronic rejection and graft dysfunction. Chronic rejection is characterized by the development of obliterative bronchiolitis in allografts and manifests as bronchiolitis obliterans syndrome in humans with no effective treatment. Previous studies support a role for alloreactive T cells in the development of bronchiolitis obliterans syndrome, but the specific mechanisms are unknown. One major stumbling block to research in the field of lung transplantation has been the lack of physiologic models to study the disease in the laboratory. We will review the current understanding of the immunology of the pathogenesis of obliterative bronchiolitis and will discuss exciting new advances from the laboratory as well as the implications for future research in lung transplantation.

Glycemic Control Promotes Pancreatic Beta-Cell Regeneration in Streptozotocin-Induced Diabetic Mice

Background Pancreatic beta-cells proliferate following administration of the beta-cell toxin streptozotocin. Defining the conditions that promote beta-cell proliferation could benefit patients with diabetes. We have investigated the effect of insulin treatment on pancreatic beta-cell regeneration in streptozotocin-induced diabetic mice, and, in addition, report on a new approach to quantify beta-cell regeneration in vivo. Methodology/Principal Findings Streptozotocin-induced diabetic were treated with either syngeneic islets transplanted under the kidney capsule or subcutaneous insulin implants. After either 60 or 120 days of insulin treatment, the islet transplant or insulin implant were removed and blood glucose levels monitored for 30 days. The results showed that both islet transplants and insulin implants restored normoglycemia in the 60 and 120 day treated animals. However, only the 120-day islet and insulin implant groups maintained euglycemia (<200 mg/dl) following discontinuation of insulin treatment. The beta-cell was significantly increased in all the 120 day insulin-treated groups (insulin implant, 0.69±0.23 mg; and islet transplant, 0.91±0.23 mg) compared non-diabetic control mice (1.54±0.25 mg). We also show that we can use bioluminescent imaging to monitor beta-cell regeneration in living MIP-luc transgenic mice. Conclusions/Significance The results show that insulin treatment can promote beta-cell regeneration. Moreover, the extent of restoration of beta-cell function and mass depend on the length of treatment period and overall level of glycemic control with better control being associated with improved recovery. Finally, real-time bioluminescent imaging can be used to monitor beta-cell recovery in living MIP-luc transgenic mice.

Cellular therapies for type 1 diabetes.

Type 1 diabetes mellitus (T1DM) is a disease that results from the selective autoimmune destruction of insulin-producing beta-cells. This disease process lends itself to cellular therapy because of the single cell nature of insulin production. Murine models have provided opportunities for the study of cellular therapies for the treatment of diabetes, including the investigation of islet transplantation, and also the possibility of stem cell therapies and islet regeneration. Studies in islet transplantation have included both allo- and xeno-transplantation and have allowed for the study of new approaches for the reversal of autoimmunity and achieving immune tolerance. Stem cells from hematopoietic sources such as bone marrow and fetal cord blood, as well as from the pancreas, intestine, liver, and spleen promise either new sources of islets or may function as stimulators of islet regeneration. This review will summarize the various cellular interventions investigated as potential treatments of T1DM.

Ethics education in surgical residency: Past, present, and future

THE CONTEMPORARY PRACTICE OF MEDICINE is associated intimately with the field of bioethics. The principles of bioethics and moral reasoning are taught at all allopathic medical schools in the United States and Canada. Residency programs in several different specialties now include formal ethics education with specific emphasis on clinical decision making and resolving moral conflicts as a part of their core curriculum. Notably, both the American Boards of Pediatrics and Internal Medicine have required ethics education during residency and have tested for competency in their respective certifying examinations since the mid1980s. The breadth of ethics education has even expanded beyond traditional health care professions. The fields of psychopharmacology, bioengineering, computer science, engineering, dentistry, and even dental hygiene have all published formal plans for ethics education in their respective fields. In 1997, a survey of U.S. general surgery programs was conducted by Downing et al to evaluate the status of ethics teaching in general surgery. Of the respondents, 85% favored a formalized ethics curriculum; however, a lack of faculty expertise was cited as the major impediment to establishing such a program. One year later, a similar survey was conducted in the field of pediatric surgery with similar results; the majority of respondents supported the incorporation of bioethics teaching into the formal curriculum of pediatric surgery. As a result of these influential studies, surgery training programs have begun to adopt ethics education into residency training; however, the nature by which this education occurs, as well its effectiveness,

Futility: What Cool Hand Luke Can Teach the Surgical Community

When the iconic protagonist Luke Jackson, as played by Paul Newman in the 1967 classic movie Cool Hand Luke, defiantly mocked the warden in his last moments alive by uttering, ‘‘What we’ve got here is a failure to communicate,’’ the fields of medicine and cinema were forever married. No other phrase can so aptly encapsulate nearly every problem associated with the medical profession, and more specifically, the inherent difficulties with the term medical futility. In this brief editorial, we attempt to review the current medical futility policies; more importantly, however, we propose an innovative approach for surgeons caring for patient’s with complex problems. In today’s modern medical arena, there is nearly nothing that is truly impossible. Innumerable conditions that once proved to be uniformly fatal are now either completely reversible or at least manageable. As the fields of medicine and surgery improve, much of what was once inconceivable is now commonplace. However, simply because the technology exists to prolong life, does not imply that using such technology is always in our patients’ best interests.

Enhancing Pancreatic Beta-Cell Regeneration In Vivo with Pioglitazone and Alogliptin

Aims/Hypothesis Pancreatic beta-cells retain limited ability to regenerate and proliferate after various physiologic triggers. Identifying therapies that are able to enhance beta-cell regeneration may therefore be useful for the treatment of both type 1 and type 2 diabetes. Methods In this study we investigated endogenous and transplanted beta-cell regeneration by serially quantifying changes in bioluminescence from beta-cells from transgenic mice expressing firefly luciferase under the control of the mouse insulin I promoter. We tested the ability of pioglitazone and alogliptin, two drugs developed for the treatment of type 2 diabetes, to enhance beta-cell regeneration, and also defined the effect of the immunosuppression with rapamycin and tacrolimus on transplanted islet beta mass. Results Pioglitazone is a stimulator of nuclear receptor peroxisome proliferator-activated receptor gamma while alogliptin is a selective dipeptidyl peptidase IV inhibitor. Pioglitazone alone, or in combination with alogliptin, enhanced endogenous beta-cell regeneration in streptozotocin-treated mice, while alogliptin alone had modest effects. In a model of syngeneic islet transplantation, immunosuppression with rapamycin and tacrolimus induced an early loss of beta-cell mass, while treatment with insulin implants to maintain normoglycemia and pioglitazone plus alogliptin was able to partially promote beta-cell mass recovery. Conclusions/Interpretation These data highlight the utility of bioluminescence for serially quantifying functional beta-cell mass in living mice. They also demonstrate the ability of pioglitazone, used either alone or in combination with alogliptin, to enhance regeneration of endogenous islet beta-cells as well as transplanted islets into recipients treated with rapamycin and tacrolimus.

Surgical Management of Pancreaticobiliary Disease associated with Juxtapapillary Duodenal Diverticula: Case Series and Review of the Literature

IntroductionJuxtapapillary duodenal diverticula (DD), although usually asymptomatic, are occasionally associated with pancreaticobiliary conditions such as recurrent bile duct stones, cholangitis, and pancreatitis.Materials and methodsAn unusual case of DD associated with a dorsal duct stricture in a patient with recurrent pancreatitis and pancreas divisum is presented along with three additional instances of surgically treated DD and a review of the literature.ResultsThe role of surgical intervention depends upon the specific nature of the presentation and the anatomical relationship of the diverticulum to the ampullary and pancreaticobiliary ductal system.ConclusionOperations that divert bile and the food stream from DD are preferred over diverticulectomy.

Seeing is believing: how the MIP-luc mouse can advance the field of islet transplantation and β-cell regeneration.

In the last five years, bioluminescence has emerged as a vital tool in the non-invasive quantification of beta-cell mass following islet transplantation in murine models. The successes achieved in bioluminescence imaging in islet transplantation has prompted its use in the discipline of beta-cell regeneration. Employing bioluminescence permits quantifying changes in β-cell mass in an individual mouse over time, which can provide valuable insights into the kinetics of beta-cell regeneration.