Methadone maintenance treatment, criminality and overdose‐related deaths: An ecological study, 1983-1999

Background: Methadone maintenance treatments (MMTs) are the commonest substitution treatments offered to opiate addiction in Switzerland, in order to reduce criminal behaviour, infectious disease transmission and overdose death. Method: To investigate the relationship between the increase in the number of methadone maintenance treatments, criminal activity of addicts and overdose‐related deaths, an ecological study was undertaken in the Canton of Geneva, from 1983 to 1999. Results: The regular and extensive increase in the number of MMTs is not significantly associated, during the 1983-1999 period, with a fall either in drug addict incarcerations or in overdose‐related deaths. However, a slight decrease is observed in the number of imprisoned opiate addicts since 1994, and a marked decrease is seen in overdose deaths from 1997 on. An important and stable number of these deaths is due to methadone itself. Conclusion: Public health objectives to diminish delinquency and overdose deaths cannot solely be fulfilled by extensive use of MMTs. A positive result could appear when access to MMT is highly favoured. This hypothesis must be proved correct by observational studies conducted on a general populatio

Extensive biliary intraepithelial neoplasia (BilIN) and multifocal early intrahepatic cholangiocarcinoma in non-biliary cirrhosis

Biliary intraepithelial neoplasia (BilIN), a preneoplastic condition that may precede invasive intrahepatic cholangiocarcinoma (ICC), has been compared to pancreatic intraepithelial neoplasia (PanIN), a precursor lesion of pancreatic carcinoma. Biliary tract carcinoma development and progression is associated with several gene alterations, but BilIN lesions have yet to be studied in detail by molecular techniques. We describe a case of extensive intrahepatic biliary dysplasia, with lesions ranging from BilIN-1 to BilIN-3 lesions, and multifocal microscopic ICC in hepatitis C virus (HCV)- and alcohol-related cirrhosis. The small ICC foci had remained undetected prior to transplantation. Fluorescence in situ hybridization (FISH) analysis was performed on three foci of BilIN-3 lesions and on three microinvasive ICC foci with a combination of three FISH probes directed against genes frequently altered in pancreatic and biliary tract carcinomas. FISH analysis revealed a CDKNA2 heterozygous deletion in one BilIN-3 focus, and in one non-contiguous ICC focus, although the deletion was just above the chosen threshold. No deletions were detected in the genomic regions encoding TP53 and SMAD4. This report documents for the first time the development of multifocal ICC in the setting of extensive biliary dysplasia in a patient with three risk factors, HCV infection, alcohol abuse, and cirrhosis, and suggests heterogeneous carcinogenesis in ICC and possible involvement of the CDKNA2 gen

Acoustic radiation force impulse (ARFI) elastography for the noninvasive diagnosis of liver fibrosis in children

Background: Acoustic radiation force impulse (ARFI) imaging) is correlated with histopathological findings using METAVIR and semiquantitative scoring system (SSS) criteria for liver fibrosis. Objective: To compare acoustic radiation force impulse imaging with biopsy results in the evaluation of liver fibrosis in children. Materials and methods: Children with chronic liver disease and healthy children underwent acoustic radiation force impulse imaging liver measurements. ARFI gives a shear-wave velocity corresponding to tissue elasticity. In 39 children with liver disease, the values obtained were correlated with biopsy results. Receiver-operating characteristic (ROC) curves were used to determine the reliability of ARFI in estimating liver fibrosis in children. Results: ARFI mean value was 1.12 in the healthy group and 1.99 in children with chronic liver disease. ROC curves show that an ARFI cutoff of 1.34m/s is predictive of both METAVIR and SSS scores with a sensitivity of SSS > 2:0.85; METAVIR > F0:0.82. A cutoff of 2m/s yielded a sensitivity of 100% to detect SSS > 4 or METAVIR > F2. Conclusion: Acoustic radiation force impulse imaging is a reliable, noninvasive and rapid method to estimate moderate to severe liver fibrosis in children. It might prove useful to clinicians for fibrosis monitoring in children with liver disease and postpone the time of liver biops

Human Hepatocyte-Derived Induced Pluripotent Stem Cells: MYC Expression, Similarities to Human Germ Cell Tumors, and Safety Issues

Induced pluripotent stem cells (iPSC) are a most promising approach to the development of a hepatocyte transplantable mass sufficient to induce long-term correction of inherited liver metabolic diseases, thus avoiding liver transplantation. Their intrinsic self-renewal ability and potential to differentiate into any of the three germ layers identify iPSC as the most promising cell-based therapeutics, but also as drivers of tumor development. Teratoma development currently represents the gold standard to assess iPSC pluripotency. We analyzed the tumorigenic potential of iPSC generated from human hepatocytes (HEP-iPSC) and compared their immunohistochemical profiles to that of tumors developed from fibroblast and hematopoietic stem cell-derived iPSC. HEP-iPSC generated tumors significantly presented more malignant morphological features than reprogrammed fibroblasts or CD34+ iPSC. Moreover, the protooncogene myc showed the strongest expression in HEP-iPSC, compared to only faint expression in the other cell subsets. Random integration of transgenes and the use of potent protooncogenes such as myc might be a risk factor for malignant tumor development if hepatocytes are used for reprogramming. Nonviral vector delivery systems or reprogramming of cells obtained from less invasive harvesting methods would represent interesting options for future developments in stem cell-based approaches for liver metabolic diseases

Mutant <i>CTNNB1</i> and histological heterogeneity define metabolic subtypes of hepatoblastoma.

Hepatoblastoma is the most common malignant pediatric liver cancer. Histological evaluation of tumor biopsies is used to distinguish among the different subtypes of hepatoblastoma, with fetal and embryonal representing the two main epithelial components. With frequent &lt;i&gt;CTNNB1&lt;/i&gt; mutations, hepatoblastoma is a Wnt/β-catenin-driven malignancy. Considering that Wnt activation has been associated with tumor metabolic reprogramming, we characterized the metabolic profile of cells from hepatoblastoma and compared it to cells from hepatocellular carcinoma. First, we demonstrated that glucose transporter &lt;i&gt;GLUT3&lt;/i&gt; is a direct TCF4/β-catenin target gene. RNA sequencing enabled to identify molecular and metabolic features specific to hepatoblastoma and revealed that several glycolytic enzymes are overexpressed in embryonal-like compared to fetal-like tumor cells. This led us to implement successfully three biomarkers to distinguish embryonal from fetal components by immunohistochemistry from a large panel of human hepatoblastoma samples. Functional analyses demonstrated that embryonal-like hepatoblastoma cells are highly glycolytic and sensitive to hexokinase-1 silencing. Altogether, our findings reveal a new, metabolic classification of human hepatoblastoma, with potential future implications for patients' diagnosis and treatment

Caroli disease, bilateral diffuse cystic renal dysplasia, situs inversus, postaxial polydactyly, and preauricular fistulas: a ciliopathy caused by a homozygous NPHP3 mutation

We report the rare association of Caroli disease (intrahepatic bile duct ectasia associated with congenital hepatic fibrosis), bilateral cystic renal dysplasia, situs inversus, postaxial polydactyly, and preauricular fistulas in a female child. She presented with end-stage renal disease at the age of 1month, followed by a rapidly progressing hepatic fibrosis and dilatation of the intrahepatic bile ducts, leading to secondary biliary cirrhosis and portal hypertension. Combined liver-kidney transplantation was performed at the age of 4years, with excellent outcome. DNA analysis showed a NPHP3 (coding nephrocystin-3) homozygote mutation, confirming that this malformation complex is a ciliopathy. Conclusion: This rare association required an exceptional therapeutic approach: combined simultaneous orthotopic liver and kidney transplantation in a situs inversus recipient. The long-term follow-up was excellent with a very good evolution of the renal and hepatic grafts and normalization of growth and weight. This malformation complex has an autosomal recessive inheritance with a 25% recurrence risk in each pregnanc

Human Hepatocyte-Derived Induced Pluripotent Stem Cells: MYC Expression, Similarities to Human Germ Cell Tumors, and Safety Issues

Induced pluripotent stem cells (iPSC) are a most promising approach to the development of a hepatocyte transplantable mass sufficient to induce long-term correction of inherited liver metabolic diseases, thus avoiding liver transplantation. Their intrinsic self-renewal ability and potential to differentiate into any of the three germ layers identify iPSC as the most promising cell-based therapeutics, but also as drivers of tumor development. Teratoma development currently represents the gold standard to assess iPSC pluripotency. We analyzed the tumorigenic potential of iPSC generated from human hepatocytes (HEP-iPSC) and compared their immunohistochemical profiles to that of tumors developed from fibroblast and hematopoietic stem cell-derived iPSC. HEP-iPSC generated tumors significantly presented more malignant morphological features than reprogrammed fibroblasts or CD34+ iPSC. Moreover, the protooncogene myc showed the strongest expression in HEP-iPSC, compared to only faint expression in the other cell subsets. Random integration of transgenes and the use of potent protooncogenes such as myc might be a risk factor for malignant tumor development if hepatocytes are used for reprogramming. Nonviral vector delivery systems or reprogramming of cells obtained from less invasive harvesting methods would represent interesting options for future developments in stemcell-based approaches for liver metabolic diseases

Pediatric Pathology: At the crossroads between development & tumorigenesis

Tumors and developmental anomalies arising in the pediatric population are rare, or even considered as orphan diseases, and childhood solid tumors may rarely be encountered in the adult population. Increasing evidence essentially based on adult-type tumors occurring in children, or in adolescents and young adults, however points towards differences in terms of biological behavior, prognosis, and response to treatment according to the age groups, thereby suggesting the existence of distinct age-related categories of diseases. Therefore, not only better characterization, but also comparison between different age groups will allow better understanding of these tumors, and of their similarities or differences. A unique feature of pediatric embryonal or blastemal tumors is their striking resemblance to developing tissue or organs, albeit at various embryonal or fetal stages. Blastemal tumors may show heterologous differentiation, in accordance with an early pluripotent phenotype: for instance osteoid/bone formation may be seen in hepatoblastoma. Developmental pathways as well as developmental anomalies therefore provide insights into pediatric tumorigenesis. Conversely, the genetic landscapes of pediatric tumors may help delineate the various contributions of deviation from normal development pathways, or lineage specification. Molecular characterization of these rare pediatric tumors is underway. Despite similar morphological findings, pediatric tumors may show divergent biological behavior according to their molecular signature and to the patient age group. Therefore, molecular analyses should be strictly correlated to morphology, and to the multiple lines of differentiation displayed. Our group is involved in the study of both developmental anomalies and tumorigenesis, with a special focus on liver pathology. In particular, we studied the anomalies of the biliary tree development in the setting of Alagille syndrome, the generation of hepatocyte-like cells to replenish the liver in inborn errors of metabolism, and hepatoblastoma, a rare embryonal primary liver tumor. By the study of the molecular mechanisms and pathways underlying normal and abnormal development and further comparison with their counterparts in tumor development, we provided insights into developmental pathways, and opened perspectives into personalized patient treatment