Rashmi Agni

Resection of hilar cholangiocarcinoma: concomitant liver resection decreases hepatic recurrence.

Background:Hilar cholangiocarcinoma is an uncommon tumor with a poor prognosis. We sought to evaluate recurrence patterns and prognostic factors for disease-specific and disease-free survival in patients with surgically resected hilar cholangiocarcinoma in a single institution over the last 21 years. Methods:From 1985 to 2006, all patients with hilar cholangiocarcinoma referred to a tertiary surgical clinic were evaluated. Demographic data, tumor characteristics, and outcome were analyzed retrospectively. Outcome was compared in patients treated in a recent era (1995–2006) compared with an earlier era (1985–1994). Results:Of 91 patients evaluated, 22 patients (24%) had unresectable disease at presentation. Of the 69 patients submitted to laparotomy, resection was possible in 55% and the curative (R0) resection rate was 63%. In patients submitted to exploration, the operative (60 day) morbidity and mortality rates were 26% and 3%. Median disease-specific (DSS) and disease-free survival (DFS) were 29 and 20 months, respectively (median FU, 29 months.). In patients undergoing R0 resection, the median survival was prolonged (65 months). In the more recent era, resectability rates improved (69% vs. 17%; P = 0.0002), and this was associated with an improvement in median survival (30 vs. 4 months; P < 0.001). Factors predictive of improved disease-specific and disease-free survival included negative histologic margins, concomitant hepatic lobectomy, lack of nodal disease, well-differentiated histology, and an earlier tumor stage (P < 0.05). Concomitant liver resection was associated with a higher R0 resection rate (P = 0.006) and improved DSS and DFS (P = 0.005). In addition, concomitant liver resection was associated with a decreased incidence of initial recurrence in liver (P = 0.031). Conclusions:In patients with hilar cholangiocarcinoma, concomitant hepatic resection is associated with improved DFS, DSS, and decreased hepatic recurrence. Therefore, hepatectomy combined with bile duct resection should be considered standard treatment.

NAFLD recurrence in liver transplant recipients.

Background and Aims. Nonalcoholic fatty liver disease (NAFLD) is a common indication for liver transplantation and can recur in the graft. To describe this recurrence, we performed a cohort study of individuals undergoing liver transplantation for NAFLD-related cirrhosis between 1993 and 2007. Predictors of NAFLD recurrence and outcomes in this cohort were also studied. Methods. Eighty-eight liver transplant recipients were included in this study. NAFLD recurrence was described by performing a blinded reevaluation of posttransplant liver biopsies and classified according to histologic activity (NAFLD activity score) and fibrosis. Results. Recurrent NAFLD was seen in 34 (39%) recipients with isolated steatosis in 9 and steatohepatitis in 25 recipients. Severe recurrence was seen in 3 of 34 recipients (NAFLD activity score ≥5) and advanced fibrosis in 3 recipients. NAFLD recurrence correlated with higher pretransplant (P=0.001) and posttransplant body mass index (P<0.0001) and increased triglyceride levels posttransplantation. Serum triglyceride levels at 6 and 12 months were 280±129 and 324±265 mg/dL, respectively, in those with NAFLD recurrence versus 206±96 mg/dL at 6 months and 190±103 mg/dL in those without NAFLD recurrence (P=0.007 at 6 months and P=0.005 at 12 months). Average steroid dose at 6 months posttransplant was also higher in those with NALFD recurrence than those without (11±8.5 and 7.2±5.7 mg/day, P=0.04). Posttransplant survival did not differ between those with and without NAFLD recurrence during the entire follow-up period (P=0.78). Posttransplant cardiovascular disease was significantly and adversely correlated with posttransplant survival. Conclusions. NAFLD recurrence is common in the first 5 years postliver transplantation and is associated with features of the metabolic syndrome. Although NAFLD recurrence was not associated with higher mortality in our cohort, cardiovascular mortality and morbidity were common, suggesting that the metabolic syndrome is an important link to NAFLD recurrence and cardiovascular deaths posttransplantation.

The impact of acute alcoholic hepatitis in the explanted recipient liver on outcome after liver transplantation

Patients with clinical acute alcoholic hepatitis (AAH) are not considered suitable candidates for orthotopic liver transplantation (OLT). The histological correlates of AAH are often seen in the explanted liver at the time of transplantation. The importance of these findings remains inconclusive regarding their role as a prognostic marker for patient or allograft health. Our aim was to examine the explanted liver of patients with purely alcoholic liver disease (ALD) for findings of histologic AAH and to correlate these to patient and graft outcomes. We compared patients with and without histological AAH with patients transplanted for non‐ALD. Of 1,097 liver transplant recipients, 148 had ALD and 125 were non‐ALD control patients with similar demographics. Thirty‐two of 148 ALD patients had histologic AAH, and 116 had bland alcoholic cirrhosis (BAC). Twenty‐eight percent of the ALD patients reported <6 months abstinence, and 54% reported <12 months abstinence. There was a statistically significant relationship between the presence of histologic AAH and abstinence durations <12 months (P = 0.009), but not <6 months. Overall, posttransplantation patient and graft survival between the ALD and non‐ALD groups was not significantly different (P = 0.53). Furthermore, patient and graft survival between ALD patients with histologic AAH and BAC were similar (P = 0.13 and P = 0.11, respectively). The rate of posttransplantation relapse among ALD patients was 16%; however, there was no increase in graft loss, nor was there decreased survival compared with controls. The patients with histologic AAH and those with BAC had no differences in posttransplantation relapse (P = 0.13). In multivariate analysis, patient and graft survival was not influenced by pretransplantation abstinence or posttransplantation relapse. In conclusion, histological alcoholic hepatitis in the explant did not predict worse outcome regarding relapse, and allograft or patient survival for liver transplant recipients. Caution should be exercised when liver histology is used to discriminate among suitable candidates for OLT concerning alcoholic patients. Liver Transpl 13: 1728–1735, 2007.

Abusive drinking after liver transplantation is associated with allograft loss and advanced allograft fibrosis

In patients who undergo liver transplantation for alcoholic liver disease (ALD), alcohol relapse is common. A return to abusive or excessive drinking likely decreases overall survival; however, the effects of alcohol use on allograft outcomes and histopathology are less well defined. We reviewed all cases of liver transplantation with ALD as an indication between January 1, 1995 and December 31, 2007. Allograft outcomes and histopathological results were compared for patients who relapsed into alcohol use and patients who maintained abstinence. Three hundred patients who underwent transplantation for ALD during this period survived at least 1 year, and 48 (16.0%) relapsed into alcohol use that came to clinical attention. The pattern of relapse was a single event for 10 patients (20.8%), intermittent relapses for 22 patients (45.8%), and continuous heavy drinking for 16 patients (33.3%). Continuous heavy drinking was associated with allograft loss in a univariate Cox proportional hazards analysis [hazard ratio (HR) = 2.43, 95% confidence interval (CI) = 1.26‐4.68, P = 0.008] and in a multivariate Cox proportional hazards regression (HR = 2.57, 95% CI = 1.32‐5.00, P = 0.006). A matched‐pair analysis that controlled for the hepatitis C virus status and the time to biopsy compared the results of allograft histopathology for patients who relapsed into alcohol use and patients who maintained abstinence. Significant steatosis [odds ratio (OR) = 3.46, 95% CI = 1.29‐9.31, P = 0.01], steatohepatitis (OR = 6.2, 95% CI = 1.70‐22.71, P = 0.006), and advanced (stage 3 or higher) fibrosis (OR = 23.18, 95% CI = 3.01‐177.30, P = 0.003) were associated with alcohol relapse. In conclusion, alcohol relapse after liver transplantation (particularly heavy drinking) is associated with decreased graft survival and advanced allograft fibrosis. Liver Transpl 19:1377‐1386, 2013.

Quantification of Hepatic Steatosis With Dual-Energy Computed Tomography: Comparison With Tissue Reference Standards and Quantitative Magnetic Resonance Imaging in the ob/ob Mouse

ObjectiveThe aim of this study was to compare dual-energy computed tomography (DECT) and magnetic resonance imaging (MRI) for fat quantification using tissue triglyceride concentration and histology as references in an animal model of hepatic steatosis. Materials and MethodsThis animal study was approved by our institution’s Research Animal Resource Center. After validation of DECT and MRI using a phantom consisting of different triglyceride concentrations, a leptin-deficient obese mouse model (ob/ob) was used for this study. Twenty mice were divided into 3 groups based on expected levels of hepatic steatosis: low (n = 6), medium (n = 7), and high (n = 7) fat. After MRI at 3 T, a DECT scan was immediately performed. The caudate lobe of the liver was harvested and analyzed for triglyceride concentration using a colorimetric assay. The left lateral lobe was also extracted for histology. Magnetic resonance imaging fat-fraction (FF) and DECT measurements (attenuation, fat density, and effective atomic number) were compared with triglycerides and histology. ResultsPhantom results demonstrated excellent correlation between triglyceride content and each of the MRI and DECT measurements (r2 ≥ 0.96, P ⩽ 0.003). In vivo, however, excellent triglyceride correlation was observed only with attenuation (r2 = 0.89, P < 0.001) and MRI-FF (r2 = 0.92, P < 0.001). Strong correlation existed between attenuation and MRI-FF (r2 = 0.86, P < 0.001). Nonlinear correlation with histology was also excellent for attenuation and MRI-FF. ConclusionsDual-energy computed tomography (CT) data generated by the current Gemstone Spectral Imaging analysis tool do not improve the accuracy of fat quantification in the liver beyond what CT attenuation can already provide. Furthermore, MRI may provide an excellent reference standard for liver fat quantification when validating new CT or DECT methods in human subjects.

Validation of MRI biomarkers of hepatic steatosis in the presence of iron overload in the ob/ob mouse.

To validate the utility and performance of a T  2* correction method for hepatic fat quantification in an animal model of both steatosis and iron overload.

Quantitative magnetic resonance imaging of hepatic steatosis: Validation in ex vivo human livers.

Emerging magnetic resonance imaging (MRI) biomarkers of hepatic steatosis have demonstrated tremendous promise for accurate quantification of hepatic triglyceride concentration. These methods quantify the proton density fat‐fraction (PDFF), which reflects the concentration of triglycerides in tissue. Previous in vivo studies have compared MRI‐PDFF with histologic steatosis grading for assessment of hepatic steatosis. However, the correlation of MRI‐PDFF with the underlying hepatic triglyceride content remained unknown. The aim of this ex vivo study was to validate the accuracy of MRI‐PDFF as an imaging biomarker of hepatic steatosis. Using ex vivo human livers, we compared MRI‐PDFF with magnetic resonance spectroscopy‐PDFF (MRS‐PDFF), biochemical triglyceride extraction, and histology as three independent reference standards. A secondary aim was to compare the precision of MRI‐PDFF relative to biopsy for the quantification of hepatic steatosis. MRI‐PDFF was prospectively performed at 1.5 Tesla in 13 explanted human livers. We performed colocalized paired evaluation of liver fat content in all nine Couinaud segments using single‐voxel MRS‐PDFF (n = 117) and tissue wedges for biochemical triglyceride extraction (n = 117), and five core biopsies performed in each segment for histologic grading (n = 585). Accuracy of MRI‐PDFF was assessed through linear regression with MRS‐PDFF, triglyceride extraction, and histology. Intraobserver agreement, interobserver agreement, and repeatability of MRI‐PDFF and histologic grading were assessed through Bland‐Altman analyses. MRI‐PDFF showed an excellent correlation with MRS‐PDFF (r = 0.984, confidence interval 0.978‐0.989) and strong correlation with histology (r = 0.850, confidence interval 0.791‐0.894) and triglyceride extraction (r = 0.871, confidence interval 0.818‐0.909). Intraobserver agreement, interobserver agreement, and repeatability showed a significantly smaller variance for MRI‐PDFF than for histologic steatosis grading (all P < 0.001). Conclusion: MRI‐PDFF is an accurate, precise, and reader‐independent noninvasive imaging biomarker of liver triglyceride content, capable of steatosis quantification over the entire liver. (Hepatology 2015;62:1444–1455)

Pretransplant donor‐specific anti‐HLA antibodies as predictors of early allograft rejection in ABO‐compatible liver transplantation

The significance of preexisting donor‐specific HLA antibodies (HLA‐DSAs) for liver allograft function is unclear. Our previous studies have shown that humoral alloreactivity frequently accompanies acute cellular rejection (ACR). In the present study, we set out to determine whether pretransplant HLA‐DSAs correlate with clinically significant ACR in the first 90 days after transplantation and, if so, to determine their predictive values. Class I HLA‐DSAs and class II HLA‐DSAs were determined by single‐antigen bead flow cytometry for 113 consecutive adult transplants. A statistical analysis was performed for data from 109 consecutive patients with graft survival greater than or equal to 90 days. All patients who developed biochemical graft dysfunction underwent liver biopsy for hematoxylin‐eosin and complement component 4d staining. Cox proportional hazards models and associated hazard ratios revealed a significant association of pretransplant HLA‐DSAs with clinically significant ACR: this association started with a mean fluorescence intensity (MFI) as low as 300 for both class I (hazard ratio = 2.7, P  < 0.01) and class II (hazard ratio = 6.0, P  < 0.01). Pretransplant HLA‐DSAs were associated with an increased risk of ACR: P  < 0.01 for class I (42% versus 18%), P  < 0.001 for class II (37% versus 7%), and P  < 0.001 for either class I or II (36% versus 3%). Class I or II HLA‐DSAs with an MFI ≥ 1000 had the best positive predictive value for clinically significant ACR at 46%, whereas class I or II HLA‐DSAs with an MFI ≥ 300 had the best negative predictive value at 97.1%. Although our study was based on consecutive patients, it was limited by the relatively low number of single‐center subjects. In conclusion, the present study indicates that pretransplant HLA‐DSAs, even at low levels of allosensitization, correlate with the risk of clinically significant ACR. Our findings suggest that anti–human leukocyte antigen antibodies could serve as donor‐specific markers of immunoreactivity to the liver graft. Liver Transpl 19:1132‐1141, 2013.

Characterizing the compression-dependent viscoelastic properties of human hepatic pathologies using dynamic compression testing

Recent advances in elastography have provided several imaging modalities capable of quantifying the elasticity of tissue, an intrinsic tissue property. This information is useful for determining tumour margins and may also be useful for diagnosing specific tumour types. In this study, we used dynamic compression testing to quantify the viscoelastic properties of 16 human hepatic primary and secondary malignancies and their corresponding background tissue obtained following surgical resection. Two additional backgrounds were also tested. An analysis of the background tissue showed that F4-graded fibrotic liver tissue was significantly stiffer than F0-graded tissue, with a modulus contrast of 4:1. Steatotic liver tissue was slightly stiffer than normal liver tissue, but not significantly so. The tumour-to-background storage modulus contrast of hepatocellular carcinomas, a primary tumour, was approximately 1:1, and the contrast decreased with increasing fibrosis grade of the background tissue. Ramp testing showed that the background stiffness increased faster than the malignant tissue. Conversely, secondary tumours were typically much stiffer than the surrounding background, with a tumour-to-background contrast of 10:1 for colon metastases and 10:1 for cholangiocarcinomas. Ramp testing showed that colon metastases stiffened faster than their corresponding backgrounds. These data have provided insights into the mechanical properties of specific tumour types, which may prove beneficial as the use of quantitative stiffness imaging increases.

Use of i-scan Endoscopic Image Enhancement Technology in Clinical Practice to Assist in Diagnostic and Therapeutic Endoscopy: A Case Series and Review of the Literature

Background. i-scan is a software-driven technology that allows modifications of sharpness, hue, and contrast to enhance mucosal imaging. It uses postimage acquisition software with real-time mapping technology embedded in the endoscopic processor. Aims. To review applications of i-scan technology in clinical endoscopic practice. Methods. This is a case series of 20 consecutive patients who underwent endoscopic procedures where i-scan image enhancement algorithms were applied. The main outcome measures were to compare mucosal lesions with high-definition white light endoscopy (HD-WLE) and i-scan image enhancement for the application of diagnostic sampling and therapy. Results. 13 cases involving the upper GI tract and 7 cases of the lower GI tract are included. For upper GI tract pathology i-scan assisted in diagnosis or therapy of Barretts esophagus with dysplasia, esophageal adenocarcinoma, HSV esophagitis, gastric MALT lymphoma, gastric antral intestinal metaplasia with dysplasia, duodenal follicular lymphoma, and a flat duodenal adenoma. For lower GI tract pathology i-scan assisted in diagnosis or therapy of right-sided serrated adenomas, flat tubular adenoma, rectal adenocarcinoma, anal squamous cell cancer, solitary rectal ulcer, and radiation proctitis. Conclusions. i-scan imaging provides detailed topography of mucosal surfaces and delineates lesion edges, which can directly impact endoscopic management.