Cixutumumab reveals a critical role for IGF-1 in adipose and hepatic tissue remodelling during the development of diet-induced obesity.

High fat diet (HFD)-induced obesity leads to perturbation in the storage function of white adipose tissue (WAT) resulting in deposition of lipids in tissues ill-equipped to deal with this challenge. The role of insulin like growth factor-1 (IGF-1) in the systemic and organ-specific responses to HFD is unclear. Using cixutumumab, a monoclonal antibody that internalizes and degrades cell surface IGF-1 receptors (IGF-1 R), leaving insulin receptor expression unchanged we aimed to establish the role of IGF-1 R in the response to a HFD. Mice treated with cixutumumab fed standard chow developed mild hyperinsulinemia with no change in WAT. When challenged by HFD mice treated with cixutumumab had reduced weight gain, reduced WAT expansion, and reduced hepatic lipid vacuole formation. In HFD-fed mice, cixutumumab led to reduced levels of genes encoding proteins important in fatty acid metabolism in WAT and liver. Cixutumumab protected against blunting of insulin-stimulated phosphorylation of Akt in liver of HFD fed mice. These data reveal an important role for IGF-1 R in the WAT and hepatic response to short-term nutrient excess. IGF-1 R inhibition during HFD leads to a lipodystrophic phenotype with a failure of WAT lipid storage and protection from HFD-induced hepatic insulin resistance.

Characterisation of dysplastic liver nodules using low-pass DNA sequencing and detection of chromosome arm-level abnormalities in blood-derived cell-free DNA.

High-grade dysplasia carries significant risk of transformation to hepatocellular carcinoma (HCC). Despite this, at the current standard of care, all non-malignant hepatic nodules including high-grade dysplastic nodules are managed similarly. This is partly related to difficulties in distinguishing high-risk pathology in the liver. We aimed to identify chromosome arm-level somatic copy number alterations (SCNAs) that characterise the transition of liver nodules along the cirrhosis-dysplasia-carcinoma axis. We validated our findings on an independent cohort using blood-derived cell-free DNA. A repository of non-cancer DNA sequences obtained from patients with HCC (n = 389) was analysed to generate cut-off thresholds aiming to minimise false-positive SCNAs. Tissue samples representing stages from the multistep process of hepatocarcinogenesis (n = 184) were subjected to low-pass whole genome sequencing. Chromosome arm-level SCNAs were identified in liver cirrhosis, dysplastic nodules, and HCC to assess their discriminative capacity. Samples positive for 1q+ or 8q+ arm-level duplications were likely to be either HCC or high-grade dysplastic nodules as opposed to low-grade dysplastic nodules or cirrhotic tissue with an odds ratio (OR) of 35.5 (95% CI 11.5-110) and 16 (95% CI 6.4-40.2), respectively (p < 0.0001). In an independent cohort of patients recruited from Nottingham, UK, at least two out of four alterations (1q+, 4q-, 8p-, and 8q+) were detectable in blood-derived cell-free DNA of patients with HCC (n = 22) but none of the control patients with liver cirrhosis (n = 9). Arm-level SCNAs on 1q+ or 8q+ are associated with high-risk liver pathology. These can be detected using low-pass sequencing of cell-free DNA isolated from blood, which may be a future early cancer screening tool for patients with liver cirrhosis. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Does the extent of lymphadenectomy, number of lymph nodes, positive lymph node ratio and neutrophil-lymphocyte ratio impact surgical outcome of perihilar cholangiocarcinoma?

BACKGROUND: Lymph node (LN) status is an important predictor of survival following resection of perihilar cholangiocarcinoma (PHCCA). Controversies still exist with regard to the prognostic value of optimum extent of lymphadenectomy, total number of nodes removed, LN ratio (LNR) and neutrophil-lymphocyte ratio (NLR) on overall survival (OS) and disease-free survival (DFS) following PHCCA resection. METHODS: From 1994 to 2010, 84 PHCCAs were resected; 78 are included in this analysis. Kaplan-Meier survival curves were studied using log-rank statistics to assess which variables affected OS and DFS. The variables that showed statistical significance (P<0.05) on Kaplan-Meier univariate analysis were subjected to multivariate analysis using Cox proportional hazards model. RESULTS: Five-year OS for node-positive status (n=45) was 10%, whereas node-negative (n=33) OS was 41% (P<0.001). Similarly, 5-year DFS was worse in the node-positive group (8%) than in the node-negative group (36%, P=0.001). There was no difference in 5-year OS (31 vs. 12%, P=0.135) and DFS (22 vs. 16%, P=0.518) between those with regional lymphadenectomy and those who underwent regional plus para-aortic lymphadenectomy, respectively. On univariate analysis, patients with 20 or more LNs removed had worse 5-year OS (0%) when compared with those with less than 20 LNs removed (29%, P=0.047). Moderate/poor tumour differentiation, distant metastasis and LN involvement were independent predictors of OS. Positive LNR had no effect on OS. Vascular invasion and an LNR of at least 0.37 were independent predictors of DFS. NLR had no effect on OS and DFS. CONCLUSION: Extended lymphadenectomy patients (≥20 LNs) had worse OS when compared with those with more limited (<20 LNs) resection. An LNR of at least 0.37 is an independent predictor of DFS.

Detection of colorectal metastases in patients being treated with chemotherapy utilising SPIO-MRI: a radiological-pathological study.

OBJECTIVE: Chemotherapy commonly causes liver injury through sinusoidal obstructive syndrome and steatosis. Chemotherapy-induced liver injury may make it more difficult to detect metastases secondary to reduced contrast between the injured liver and metastases. The aim of this study was to determine the sensitivity of superparamagnetic iron oxide (SPIO) contrast-enhanced imaging in patients who have undergone chemotherapy prior to liver surgery. METHODS: Local ethics committee approval was obtained. Thirty-one patients with hepatic metastases completing preoperative chemotherapy were prospectively recruited. Images were reviewed independently by two blinded observers who identified and localized lesions with a four-point confidence scale. The alternative free-response receiver operator characteristic method was used to analyze the results. RESULTS: The sensitivity in detecting colorectal metastases following chemotherapy was 78% and 76%, respectively, for observers 1 and 2 (95% confidence interval: 71%-85% and 68%-82%). The areas under the alternative free-response receiver operator curves were 0.73 and 0.80 for observers 1 and 2, respectively. CONCLUSION: Compared to previously published work on chemotherapy-naïve patients, it is clear that the sensitivity of SPIO-enhanced magnetic resonance imaging (MRI) in detecting colorectal metastases following chemotherapy is reduced. It is therefore critical that all imaging--pre-, during and postchemotherapy--is reviewed when reporting liver MRI prior to surgery.

Liver transplant pathology - messages for the non-specialist.

This review, based on a presentation at the BDIAP meeting in London 2008, aims to guide histopathologists working outside transplant centres in the differential diagnosis of late post transplant liver biopsies. It focuses on the histological patterns of the late post transplant complications - autoimmune hepatitis, acute and chronic rejection, recurrent viral hepatitis, and biliary disease. Analysis of the character and distribution of inflammatory infiltrate, bile duct changes, and fibrosis by the histopathologist must then be set within the clinical context to arrive at the most appropriate diagnosis. For this reason, review of the biopsy at the transplant centre is recommended. In a broader context, the tabulation of diagnostic features in chronic inflammatory liver diseases produced by the Banff Working Group can, with the exception of rejection, usefully be applied outside the transplant setting.

Sinusoidal obstructive syndrome diagnosed with superparamagnetic iron oxide-enhanced magnetic resonance imaging in patients with chemotherapy-treated colorectal liver metastases.

PURPOSE: To assess the predictive value of superparamagnetic iron oxide (SPIO) -enhanced T2-weighted gradient echo (GRE) imaging to determine the presence and severity of sinusoidal obstructive syndrome (SOS). PATIENTS AND METHODS: Sixty hepatic resection patients with colorectal metastases treated with chemotherapy underwent unenhanced magnetic resonance imaging (MRI) followed by T2-weighted GRE sequences obtained after SPIO. The images were reviewed in consensus by two experienced observers who determined the presence and severity of linear and reticular hyperintensities, indicating SOS-type liver injury, using a 4-point ordinal scale. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) with 95% CIs for the detection of SOS were calculated. RESULTS: Twenty-four of 60 patients had moderate to severe SOS on MRI. MRI achieved a sensitivity of 87% (95% CI, 66% to 97%), specificity of 89% (95% CI, 75% to 97%), PPV of 83% (95% CI, 63% to 95%), and NPV of 92% (95% CI, 77% to 98%). SOS was never found at surgery or histology in patients whose background liver parenchyma was normal on SPIO-enhanced MRI. CONCLUSION: SOS is present in a significant proportion of patients with treated colorectal metastases and is effectively detected on SPIO-enhanced T2-weighted GRE images.

Solitary liver cysts in children: not always so simple.

AIM: Liver cysts in children are uncommon. Many are simple and solitary and do not require intervention. However, this series demonstrates a broad range of potential pathologies, some of which are life-threatening. METHODS: All children referred to our unit during an 8-year period (1998-2005) and found to have a solitary liver cyst were prospectively recorded. Clinical, radiologic, and pathologic features were analyzed. Children with an isolated extrahepatic choledochal cyst and polycystic disease were excluded. RESULTS: Twenty-one children with a liver cyst were identified. Two had undergone unsuccessful surgical intervention before referral. There were 11 prenatally detected cysts. Median gestational age at detection was 22 weeks (19-35 weeks); only 1 was specifically characterized as a liver cyst prenatally. Six of these required surgery: 2 large simple cysts, 2 intrahepatic choledochal cysts, 1 giant complex biliary cyst causing respiratory distress, and 1 ciliated hepatic foregut cyst. Of the 5 cysts remaining under ultrasound surveillance, 4 decreased in size or resolved. In 10 children presenting between birth and 15.8 years, a liver cyst was diagnosed postnatally: 3 huge cystic mesenchymal hamartomas, 1 type V choledochal cyst, 1 hydatid cyst, and 5 simple cysts. Four of these required surgical resection. Simple cysts tended to be small and could be distinguished from other pathologies using a combination of imaging techniques (ultrasound, magnetic resonance imaging/magnetic resonance cholangiopancreatography [MRCP], radionuclide scan). Only 2 of 12 children with "simple" cysts required surgery for symptoms. However, a wide range of other cyst pathologies were found in 9 children, and although none was malignant, some were life-threatening and 7 required resection. CONCLUSIONS: Simple solitary nonparasitic liver cysts rarely cause symptoms or require surgery, but the pediatric surgeon should be aware of the wide range of other types of liver cyst in children to ensure appropriate treatment.

Diagnostic variation and outcome for high-grade gastric epithelial dysplasia.

HYPOTHESIS: High-grade dysplasia (HGD) of the gastric epithelium is associated with high prevalence of invasive carcinoma, and distinction by endoscopic biopsy is difficult. DESIGN: Cohort study, 1996 to 2003. SETTING: Tertiary care center. PATIENTS: Consecutive sample of 22 patients with initial diagnosis of gastric HGD by endoscopic biopsy. Biopsy specimens were separately reviewed by 3 experienced pathologists. Clinical management was individually decided. MAIN OUTCOME MEASURES: Strength of interpathologist agreement (kappa) and final pathological diagnosis. RESULTS: The diagnosis was revised to intramucosal carcinoma in 14% to 32% of patients or suspicious for invasive carcinoma in 23% to 41%. The strength of agreement between any 2 pathologists for distinguishing between dysplasia and invasive carcinoma was fair (kappa = 0.35-0.36). A diagnosis of intramucosal carcinoma or suspicious for invasive carcinoma by 2 pathologists correlated strongly with subsequent detection of invasive carcinoma. Three patients underwent gastrectomy for HGD, and invasive carcinoma was detected in all (2 patients, T1 N0; 1 patient, T2 N0). Six patients had invasive carcinoma on endoscopic surveillance at a median of 15 months (range, 3-34 months) after diagnosis of HGD and underwent endoscopic mucosal resection (2 patients, T1 NX), gastrectomy (2 patients, T1 N0), or no resection (2 patients). Another patient had metastatic gastric adenocarcinoma despite having a diagnosis of only HGD by endoscopy. Seven patients (32%) died of unrelated causes, without invasive carcinoma, at a median of 19 months (range, 1-38 months). Three patients were alive with persistent HGD at 26 to 61 months. Two patients had no dysplasia on follow-up. CONCLUSIONS: Experienced pathologists often disagreed in distinguishing invasive carcinoma from HGD in gastric biopsy specimens. One third of patients with gastric HGD died of causes unrelated to cancer. Invasive carcinoma was detected in 67% of the remainder.

Gallbladder polyps in children--classification and management.

Polypoid lesions of the gallbladder (PLG) are rare in childhood. The authors describe 2 additional cases. A 12 year-old-girl was found to have a 5-mm gallbladder polyp during an ultrasound examination for nonspecific abdominal pain. Investigation showed no other biliary tract abnormality. During the next 5 years, she was reviewed periodically with ultrasound scans and underwent cholecystectomy when the diameter of the polyp increased to 1 cm. Histology results showed a benign cholesterol polyp. A 12-year-old-boy was found to have an incidental gallbladder polyp, which 2 years later remained static in size for 10 months. The polyp had disappeared spontaneously. The authors suggest that PLGs in children may be either primary or secondary. Only 11 primary PLGs have been reported, and their histology is variable (adenoma, gastric heterotopia, and epithelial hyperplasia). Secondary PLGs may be found in association with metachromatic leukodystrophy, Peutz-Jeghers syndrome, or pancreato-biliary malunion. The pathologic spectrum of PLGs in children appears to be different from that in adults. For primary PLGs, cholecystectomy is advisable if there are biliary symptoms or if the polyp is > or =1 cm in size. Asymptomatic cases should be maintained under ultrasound surveillance.

Heterotopic gastric mucosa in a duplicate gallbladder.

A 7-year-old girl presented with recurrent acute pancreatitis. Detailed investigations, including endoscopic retrograde cholangiography, suggested a poorly defined biliary tract abnormality. At laparotomy, this was discovered to be a duplicate gallbladder each with a separate cystic duct but contained within a single serosal envelope. Both gallbladders were removed, and histologic examination found the inferior organ to be lined by heterotopic fundic-type gastric mucosa. Despite the absence of any remaining structural biliary abnormality and no evidence of residual ectopic gastric mucosa, the patient experienced a few further episodes of self-limiting mild acute pancreatitis during the following 3 years. The presence of heterotopic gastric mucosa in a duplicate gallbladder has not been described previously.