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

Evolution histologique précoce des lésions de stéatohépatite alcoolique sévère sous traitement de stéroïdes en association avec un anti-TNFα versus un placebo

La stéatohépatite alcoolique, complication sévère de l'abus d'alcool, bénéficie d'un traitement de corticostéroïdes. Cette étude pilote a pour but d'établir la validité de l'adjonction d'anti-TNFα à ce traitement de référence. Un collectif de 20 patients, avec stéatohépatite alcoolique sévère confirmée histologiquement, a été considéré avec un bilan d'évolution pratiqué 7 à 10 jours après introduction de corticostéroïdes combinés à un anti-TNFα ou à un placebo. Cette étude suggère que l'infliximab serait bien toléré par des patients avec insuffisance hépatique sévère. Une diminution statistiquement significative du score de Maddrey - indicateur fiable de la sévérité de l'atteinte hépatique - a pu être observée, de même qu'une diminution de la bilirubine sérique. Une tendance à l'amélioration des lésions histologiques hépatocellulaires se dessinait et l'absence de modification significative de l'atteinte inflammatoire est à pondérer avec le décalage temporel existant entre réponse clinique au traitement et évolution histologique des lésions

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

Role of HNF1β in the differential diagnosis from other germ cell tumors

Identification of the yolk sac tumor (YST) component in germ cell tumors (GCT) may prove challenging, and highly sensitive and specific immunohistochemical markers are still lacking. Preliminary data from the literature suggest that HNF1β may represent a sensitive marker of YST. The specificity of HNF1β has not been addressed in GCT. A cohort of 49 YST specimens from 45 patients was designed, occurring either as pure tumors, or as a component of a mixed GCT. Immunohistochemistry was conducted on whole tumor sections using HNF1β. SALL4, OCT4, CD30, CDX2, Cytokeratin 19, Glypican 3, and GATA3 were used for classification of the GCT components. Patients were mostly male (39/45), aged 14 months to 49 years, with primary testicular tumors (37/39), or primary mediastinal pure YSTs (2/39). All 6 primary tumors occurring in females (6/45) were pure ovarian YSTs; age range was 4 to 72 years. HNF1β nuclear reactivity was seen in the YST component in all 49 tumors, with a moderate to strong nuclear pattern of staining. Embryonal carcinoma (EC, 0/32) and seminoma (0/6) were negative. Choriocarcinoma (6/6) showed faint focal cytoplasmic reactivity to HNF1β but no nuclear staining. In teratomas, only enteric-type glands showed nuclear reactivity to HNF1β (11/16). Therefore, HNF1β sensitivity in YST component identification was 100% and specificity was 80%. Thus, in our experience, HNF1β is a sensitive and reliable marker of the YST component in GCT, and allows distinction of YST from intricately admixed EC, especially in the diffuse embryoma pattern

Duplication of the gallbladder with heterotopic mucosa: A case report and proposal for a classification for gastrointestinal duplications

Gastrointestinal duplications are rare congenital malformations that can occur anywhere between the mouth and the anus, including the digestive annexes. Numerous classifications of these malformations exist, varying from one author to another. This study describes a rare case of gallbladder duplication and suggests a unified classification of gastrointestinal duplications in order to merge epidemiological and clinical considerations

Pigmented villonodular synovitis of the hip

Pigmented villonodular synovitis (PVNS) is a rare disease that can affect any joint, bursa or tendon sheath.The hip is less frequently affected than the knee, and hence is less discussed in scientific journals.PVNS of the hip mainly occurs in young adults, requiring early diagnosis and adequate treatment to obtain good results.There is no consensus on the management of PVNS of the hip in current literature.We will discuss the options for surgical intervention in hip PVNS using a literature review of clinical, biological, etiological, histological and radiographic aspects of the disease. Cite this article: Steinmetz S, Rougemont A-L, Peter R. Pigmented villonodular synovitis of the hip. EFORT Open Rev 2016;1:260-266. DOI: 10.1302/2058-5241.1.000021