Arpan Mohanty

MRI Steatosis Grading: Development and Initial Validation of a Color Mapping System

OBJECTIVE The purpose of this article is to develop and validate a chemical-shift imaging-derived color mapping system for evaluation of liver steatosis. MATERIALS AND METHODS Opposed phase MRI was evaluated for 85 subjects (51 with presumed nonalcoholic fatty liver disease and 34 healthy volunteers). Liver signal intensity loss was compared with histologic analysis for 52 subjects, assuming grade 0 steatosis for healthy volunteers, to determine signal-intensity-loss threshold points differentiating steatosis grades and subsequent Spearman correlation. Color scale grading was then applied for 78 subjects. Interpretation of color maps for steatosis severity and heterogeneity was performed by three readers. Analyses of agreement among readers and of color map steatosis grade with biopsy were performed using weighted kappa values. RESULTS The numbers of subjects with steatosis grades 0, 1, 2, and 3 were 41, 12, 13, and 19, respectively. A correlation of 0.90 was obtained using selected threshold values of 5.9% or less, 6-26.1%, 26.2-36.8%, and greater than 36.8% for steatosis grades 0, 1, 2, and 3, respectively. Interobserver agreement for color map grading of steatosis was excellent (κ = 0.93-0.94). Color map interpretation for all readers also showed excellent agreement with histologic findings for whole liver (κ = 0.82-0.86) and estimated biopsy site location (κ = 0.81-0.86; anterior region of right lobe). Heterogeneous steatosis on color maps was identified in 56-60% of subjects with nonalcoholic fatty liver disease and in 7% of healthy volunteers and was associated with greater disagreement between color map and histology grading (61-74%) compared with the whole group (37-40%). CONCLUSION MRI-derived color map estimation of liver steatosis grade appears to be reproducible and accurate.

Therapy for Hepatitis C Virus Infection Increases Survival of Patients With Pretreatment Anemia

BACKGROUND & AIMS Individuals with chronic hepatitis C virus (HCV) infection and pretreatment anemia are less likely to begin and complete a full course of treatment for HCV. However, among those who are treated for HCV infection, the effect of treatment on mortality is not clear. METHODS We performed a retrospective analysis of 200,139 HCV-infected veterans using data from the Electronically Retrieved Cohort of Hepatitis C-Infected veterans (2001-2008). The effects of treatment and treatment duration on survival were compared based on data from 1820 treated and 27,690 untreated anemic HCV-infected veterans. The association between HCV treatment and mortality was estimated using the Cox proportional hazard models, with adjustments for potential confounders. The main outcome was all-cause mortality. RESULTS In multivariable analysis, pretreatment anemia was associated significantly with African American race (odds ratio [OR], 2.03; 95% confidence interval [CI], 1.95-2.11), chronic kidney disease (OR, 3.36; 95% CI, 3.23-3.51), and decompensated liver disease (OR, 3.69; 95% CI, 3.53-3.86). All-cause mortality for treated, anemic, HCV-infected veterans was lower (54.2 per 1000 person-years; 95% CI, 49.2-59.7 per 1000 person years) than for untreated, anemic HCV-infected veterans (146.8 per 1000 person-years; 95% CI, 144.2-149.4 per 1000 person-years). The adjusted hazard ratio for treatment of HCV in anemic veterans was 0.45 (95% CI, 0.39-0.51), which was reduced after exclusion of comorbidities (hazard ratio, 0.28; 95% CI, 0.22-0.37). CONCLUSIONS Based on a retrospective analysis of a veterans database, HCV therapy increases survival rates of individuals with pretreatment anemia. Additional studies are needed to determine strategies to increase rates of HCV therapy for this group.

Predictors of Mortality among United States Veterans with Human Immunodeficiency Virus and Hepatitis C Virus Coinfection

Background. Understanding the predictors of mortality in individuals with human immunodeficiency virus and hepatitis C virus (HIV/HCV) coinfection can be useful in management of these patients. Methods. We used the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES) for these analyses. Multivariate Cox-regression models were used to determine predictors of mortality. Results. Among 8,039 HIV infected veterans, 5251 (65.3%) had HCV coinfection. The all-cause mortality rate was 74.1 (70.4–77.9) per 1000 person-years (PY) among veterans with HIV/HCV coinfection and 39.8 (36.3–43.6) per 1000 PY for veterans with HIV monoinfection. The multivariable adjusted hazard ratio (95% confidence interval) of all-cause mortality for HCV infection was 1.58 (1.36–1.84). Positive predictors of mortality included decompensated liver disease (2.33 (1.98–2.74)), coronary artery disease (1.74 (1.32–2.28)), chronic kidney disease (1.62 (1.36–1.92)), and anemia (1.58 (1.31–1.89)). Factors associated with reduced mortality included HCV treatment (0.41 (0.27–0.63)) and higher CD4 count (0.90 (0.87–0.93) per 100 cells/μL higher count). Data were insufficient to make informative analyses of the role of HCV virologic response. Conclusion. HCV coinfection was associated with substantial increased risk of mortality among HIV infected veterans. HCV treatment was associated with significantly lower risk of mortality.

New Perspectives on Bone Marrow Contrast Agents and Molecular Imaging

Magnetic resonance (MR) imaging of bone marrow provides a noninvasive diagnosis of the vascularity, cell quantity, and composition of the normal and pathological bone marrow. This article reviews new and evolving techniques for bone marrow MR imaging with a special focus on translational and clinical applications. Evaluations of bone marrow perfusion with standard small molecular contrast agents and, more recently, with macromolecular contrast agents are currently being applied for therapy monitoring. Cell-specific contrast agents are expected to improve the sensitivity and specificity of bone marrow MR imaging. Novel cellular and molecular imaging techniques for the depiction of cell metabolism and specific biochemical pathways are discussed. Cell tracking techniques may allow specific diagnoses of inflammatory processes as well as monitoring of novel therapies based on stem cells. Future developments of fusion imaging techniques and bifunctional contrast agents are directed to combine comprehensive information about bone marrow structure and function with targeted and image-guided therapies.

Hepatitis C virus treatment and survival in patients with hepatitis C and human immunodeficiency virus co-infection and baseline anaemia

The impact of pretreatment anaemia on survival in individuals with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) co‐infection is not known. Moreover, HCV treatment is offered less frequently to individuals with anaemia, due to haematological side effects of the treatment regimen. This study aimed to determine the effect of HCV treatment on survival among HCV/HIV co‐infected individuals with pretreatment anaemia using the Electronically Retrieved Cohort of HCV‐Infected Veterans (ERCHIVES). Individuals with HCV/HIV co‐infection were included in current analyses. Participants were considered treated if they were prescribed ≥4 weeks of HCV treatment. All‐cause mortality data were obtained using record linkage. Survival analyses were performed using Cox proportional hazard models. Among 5000 HCV/HIV co‐infected individuals, 1671 (33.4%) had pretreatment anaemia. In a follow‐up period of up to 7 years (19 500 person‐years), individuals with anaemia had significantly higher mortality rate compared with those without anaemia [144.2 (95% CI: 134.5–154.7) vs 47.5 (44.0–51.2) per 1000 person‐years, respectively]. Among individuals with anaemia, HCV treatment was associated with significantly lower mortality rate [66.6 (44.3–100.2) vs 149.6 (139.2–160.5) per 1000 person‐years, for treated vs untreated, respectively]. Treatment remained associated with substantial survival benefit after taking into account the effect of multiple comorbidities (hazards ratio: 0.34, 95% CI: 0.21–0.62). These data suggest that HCV/HIV co‐infected individuals with pretreatment anaemia have significantly higher mortality compared with those without anaemia. HCV treatment is associated with substantial survival benefit in this group. Additional studies are needed to determine strategies to improve HCV treatment rates among this group.

Aortic dissection and renal failure in a patient with severe hypothyroidism.

Acute aortic dissection (AAD) is a life-threatening condition associated with high morbidity and mortality. The most important recognized acquired cause that leads to dissection is chronic arterial hypertension. With respect to the anuria and renal failure, aortic dissection is not something that is always considered and is still not a very common presentation unless both renal arteries come off the false lumen of the dissection. However, when present, preoperative renal failure in patients with acute type B dissection has been noted to be an independent predictor of mortality. Early recognition and diagnosis is the key and as noted by previous studies as well, almost a third of these patients are initially worked up for other causes until later when they are diagnosed with aortic dissection. Here we present a case of a patient presenting with severe hypothyroidism, long-standing hypertension, and anuria. Through the case, we highlight the importance of having aortic dissection as an important differential in patients presenting with anuria who have a long standing history of uncontrolled hypertension. Pathophysiology relating to severe hypothyroidism-induced renal dysfunction is also discussed.

Systemic Mastocytosis Complicated by Non-Cirrhotic Portal Hypertension and Variceal Bleeding

Systemic mastocytosis is a myeloproliferative disorder characterized by extracutaneous involvement of at least one organ. Although rare, infiltration of inflammatory mast cells within the portal vein may lead to obstruction of the sinusoids resulting in non-cirrhotic portal hypertension. We present a patient with known history of systemic mastocytosis with bone marrow involvement presenting with new-onset esophageal variceal bleeding. Although systemic mastocytosis is uncommon, the subsequent development of hepatic involvement and non-cirrhotic portal hypertension are discussed. Further highlighted is a lack of organization guidelines and the potential for gastrointestinal and hepatic screening of mastocytosis patients with known extracutaneous involvement.

Why Pursue a Fourth Year in Advanced/Transplant Hepatology?

The traditional pathway for advanced/transplant hepatology training consists of a 1-year fellowship program, accredited by the Accreditation Council for Graduate Medical Education (ACGME), and is usually completed after finishing a 3-year gastroenterology fellowship—thus referred to as a ‘‘fourth year.’’ However, in hopes to increase the number of trained transplant hepatologists given the growing job demand, the American Board of Internal Medicine (ABIM) and American Association for the Study of Liver Diseases (AASLD) have developed a collaborative pilot program, which combines training in gastroenterology and advanced/transplant hepatology within a 3-year timeline at selected institutions [1]. So far, 31 fellows (14 fellows for the current academic year 2015–2016) have enrolled in the program. Interval data evaluating the early metrics of the pilot program are not yet available. This article will focus on the potential strengths in pursuing a fourth year of training in advanced/transplant hepatology as well as the potential pitfalls of the combined pilot program. In the last few decades, immense strides have been made in the discovery, diagnosis, prevention, and management of liver diseases. The incipient field of hepatology continues to evolve with the discovery of novel pathophysiologic mechanisms, drugs, therapeutic modalities, and diagnostic approaches. In spite of this brisk progress, mortality rates from chronic liver disease and liver cancer have increased substantially over the past three decades [2]. Liver cancer is the seventh largest contributor of cancer mortality in the USA [3]. Even with the availability of highly effective hepatitis C virus (HCV) therapies, it is estimated that 300,000 persons will die of HCV in the next three decades [4]. Nonalcoholic fatty liver disease (NAFLD) is estimated to affect 10–46 % of the American population, and the morbidity and mortality associated with NAFLD continue to rise [5, 6]. Although nearly six thousand people underwent liver transplantation in 2015, nearly 15,000 remain actively listed for liver transplantation today [7]. In the foreseeable future, the practice of hepatology will evolve and become more complex with increased applications of personalized medicine as seen with the use of genomics in management of hepatocellular carcinoma. Thus, with rapid expansion of medical knowledge in the field of hepatology and due to the substantial disease burden from liver diseases, there remains great demand for dedicated professional expertise in hepatology. Yet, there is a shortage of providers to fulfill this need and groups have attempted to create pathways in hope to increase the number of such providers. A search on a popular employment search website, www.indeed.com, shows at least twenty current listings for hepatologists across the country (date of search: February 5, 2016). The three-year ABIM pilot training program in gastroenterology and advanced/transplant hepatology was instituted to address the shortage of trained clinical hepatologists in the coming years. However, the ‘‘fourth year’’ still remains relevant, especially for the training of future physician–scientists, whether in basic or clinical research, as this next generation will be instrumental in the continued advancement in the field of hepatology. The traditional training pathway in advanced/transplant hepatology provides opportunity for meaningful research and career development with the provision of dedicated research time during the first 3 years of gastroenterology & Brett E. Fortune brett.fortune@yale.edu

Current Management of Hepatitis B in 2016

Chronic hepatitis B infection represents a global public health burden, infecting over 240 million persons worldwide. It is associated with significant morbidity and mortality and represents a leading cause for cirrhosis, liver failure, liver cancer, and liver-related death. Current treatment of hepatitis B is focused on identification of patients with active hepatitis within the immune clearance or reactivation phases of chronic infection, for whom antiviral therapy with peg-interferon or nucleos(t)ide analogs are recommended. Seven antiviral agents are currently approved by the US FDA for treatment of chronic hepatitis B, of which three are recommended as first-line agents by major liver societies. As none are associated with virologic cure, the primary objective of antiviral therapy in 2016 is long-term virologic suppression, which is associated with a decreased risk for cirrhosis and hepatocellular carcinoma, and may reverse liver fibrosis or cirrhosis in some patients. Although biochemical improvement in liver enzymes is common, HBeAg seroconversion occurs in only a minority of patients, and HBsAg seroconversion is rare. Due to ongoing deficits along multiple steps of the care cascade, including screening, diagnosis, linkage to care, and antiviral therapy, many patients with chronic hepatitis B remain undiagnosed, lack access to care by specialists with expertise in the management of CHB, or have not been treated with antiviral agents. Future therapies are currently in development with the aim of functional viral cure, which may transform the treatment of CHB and improve liver outcomes.

Tu1874 Earlier Age of Presentation of Pancreatic Adenocarcinoma in Individuals With Chronic Pancreatitis

Systemic therapies for cancer, including pancreatic cancer, have provided only limited efficacy for patients to date. Adenovirus (Ad) has frequently been used as a backbone of oncolytic viral agents. However, unlike loco-regional therapy, systemic application of cancer gene therapy mandates different level of selectivity of gene delivery. So far, insufficient cancer selectivity at the stage of infection has greatly hampered efficacy of Ad-based therapy upon systemic administration. The controlled distribution and selective transduction of the vector would overcome the obstacles for systemic delivery and enable efficient systemic treatment of cancer. We have recently developed transductionally-targeted Ads by high-throughput screening of high-diversity (10^9-level) Ad-library. Mesothelin (MSLN) is highly overexpressed in pancreatic cancers. Ad with redesigned AB-loop targeted to MSLN (AdMLVTIN)was successfully isolated from the high throughput screening of Ad library by infectivity for MSLN-expressing 293 cells (293-MSLN). The in vitro binding of AdML-VTIN corresponded to MSLN-expression of each cell line, and the suppression of MSLN-expression with siRNA or antibody blocked the binding to MSLN-expressing cells, which indicates the vector is targeted to mesothelin. In MSLN-positive cells (Panc-1), this virus exhibited higher binding ability than that of Ad with 5/3 modified fiber which is known to exhibit highest infectivity in pancreatic cancer cells. The in vivo antitumor effect was compared in Panc-1 (MSLN-positive) and MiaPaCa-2 (MSLN-negative) subcutaneous xenografts. The injection of the MSLN-retargeted oncolytic Ad showed significant antitumor effect against Panc-1 tumors, and disappearance of tumors was observed in 4 out of 8 mice. Contrarily, the same virus showed no antitumor effect in MiaPaCa-2. Viral DNA amount in the tumors correlated to the anti-tumor effect. Upon systemic administration in the nude mice with Panc-1 subcutaneous xenografts, AdML-VTIN showed significantly lower liver sequestration compared to the wild-type Ad5, and the copy number of this retargeted virus was significantly (1000-fold) higher in the tumor. These data indicates that this vector enables efficient systemic delivery and treatment of MSLN-expressing pancreatic cancer xenografts. In this study, our MSLN-targeted Ad vector exhibited selective infectivity to MSLN-positive pancreatic cancer cells in vitro and in vivo. Moreover, this virus showed dramatically augmented delivery to the tumors and significantly reduced liver sequestration upon systemic administration. This new genetically modified Ad, which is transductionally retargeted to pancreatic cancer, may embody a next generation systemic therapy for this devastating disease.