Hepatic Stem-like Phenotype and Interplay of Wnt/β-Catenin and Myc Signaling in Aggressive Childhood Liver Cancer

SummaryHepatoblastoma, the most common pediatric liver cancer, is tightly linked to excessive Wnt/β-catenin signaling. Here, we used microarray analysis to identify two tumor subclasses resembling distinct phases of liver development and a discriminating 16-gene signature. β-catenin activated different transcriptional programs in the two tumor types, with distinctive expression of hepatic stem/progenitor markers in immature tumors. This highly proliferating subclass was typified by gains of chromosomes 8q and 2p and upregulated Myc signaling. Myc-induced hepatoblastoma-like tumors in mice strikingly resembled the human immature subtype, and Myc downregulation in hepatoblastoma cells impaired tumorigenesis in vivo. Remarkably, the 16-gene signature discriminated invasive and metastatic hepatoblastomas and predicted prognosis with high accuracy

The uterosacral complex: ligament or neurovascular pathway? Anatomical and histological study of fetuses and adults.

International audienceThe aim of this study was to define the anatomical relationships of the uterosacral ligament complex (USLC) and to analyze histologically its content. Three fetal and four adult cadavers were used. Anatomical dissections were carried out. Eight fresh biopsies (four fetal and four adult) of the USLC were analyzed histologically and immunohistochemically. Specimens were stained with hematoxylin eosin safran coloration, with anti-nervous cell antibodies (PS 100) and with anti-smooth muscle antibodies (to visualize vessel walls). By removing the visceral pelvic fascia, nervous fibers were found within the USLC forming the hypogastric plexus. Histologically, the USLC contained connective tissue, nervous fibers, sympathetic nodes, vessels, and fatty tissue. No structured ligamentous organization was identified. The uterosacral "ligament" is a "complex" integrating connective tissue as well as nervous and vascular elements. Radical excisions and USLC suspension during pelvic floor reconstructive surgery should be performed with caution in order to preserve pelvic innervation

Echinococcus ortleppi infections in humans and cattle, France.

International audienceIn 2011 and 2012, liver infections caused by Echinococcus ortleppi tapeworms were diagnosed in 2 humans in France. In 2012, a nationwide slaughterhouse survey identified 7 E. ortleppi infections in cattle. The foci for these infections were spatially distinct. The prevalence of E. ortleppi infections in France may be underestimated

Prognostic value of phosphorylated STAT3 in advanced rectal cancer: a study from 104 French patients included in the EORTC 22921 trial.

International audienceBACKGROUND: Signal transducer and activator of transcription 3 (STAT3) has been implicated as an oncogene in several neoplastic diseases. However, the biological effects of STAT3 have not been extensively studied in rectal carcinogenesis. AIMS: To evaluate STAT3 activation in advanced rectal cancers and its association with clinicopathological variables and prognosis. METHODS: Nuclear immunohistochemical expression of phosphorylated STAT3 (p-STAT3) was studied in 104 advanced rectal cancers (T3-T4). All patients were participating in the EORTC 22921 trial to assess whether preoperative chemoradiotherapy followed by postoperative chemotherapy improved overall and progression-free survival. RESULTS: Nuclear p-STAT3 expression was detected in 37.5% of rectal cancer patients. No correlation was observed between p-STAT3 and any clinicopathological variables tested. However, patients with tumours positive for p-STAT3 had significantly improved overall survival. CONCLUSION: These results highlight an unexpected role for nuclear p-STAT3 expression in advanced rectal cancers and need further investigation to clarify this finding

Severe sex differentiation disorder in a boy with a 3.8 Mb 10q25.3-q26.12 microdeletion encompassing EMX2

International audienceThe molecular basis of male disorders of sex development (DSD) remains unexplained in a large number of cases. EMX2 has been proposed to play a role in the masculinization process for the past two decades, but formal evidence for this causal role is scarce. The aim of this study is to yield additional support to this hypothesis by reporting on a male patient who presented with 46,XY DSD, a single kidney, intellectual disability, and the smallest microdeletion including EMX2 reported to date. EMX2 haploinsufficiency is likely to explain the masculinization defect observed in our patient, similar to what has been described in the mouse. In the case of cytogenetically diagnosed cases, deletions of EMX2 have been associated with a wide range of DSD, ranging from hypospadias to complete sex reversal

Autopsy findings of ectodermal dysplasia and sex development disorder in a fetus with 19q12q13 microdeletion

International audienceA 5,6 Mb de novo 19q12-q13.12 interstitial deletion was diagnosed prenatally by array-comparative genomic hybridization in a 26 weeks male fetus presenting with intra-uterine growth retardation, left clubfoot, atypical genitalia and dysmorphic features. Autopsic examination following termination of pregnancy identified a severe disorder of sex development (DSD) including hypospadias, micropenis, bifid scrotum and right cryptorchidism associated with signs of ectodermal dysplasia: scalp hypopigmentation, thick and frizzy hair, absence of eyelashes, poorly developed nails and a thin skin with prominent superficial veins. Other findings were abnormal lung lobation and facial dysmorphism.This new case of DSD with a 19q12q13 deletion expands the phenotypic spectrum associated with this chromosomal rearrangment and suggests that WTIP is a strong candidate gene involved in male sex differentiation

Signature patterns of human papillomavirus type 16 in invasive anal carcinoma.

International audienceMany studies have reported that most invasive anal carcinomas contain high-risk human papillomaviruses (HPVs), HPV16 being the most prevalent type. This study aimed to investigate HPV status and cellular biomarkers in invasive anal cancers. HPV genotype distribution was determined in 76 anal cancers by the INNO-LiPA assay (Innogenetics, Gent, Belgium). HPV16-positive samples were then tested for viral load and physical state with type-specific real-time polymerase chain reaction targeting E6, E2, and albumin genes. Samples were also subjected to immunohistochemical analysis of p16, Ki-67, p53, and p21. Of the analyzable tumors, 98.6% were positive for α-HPV DNA. HPV16 was the most prevalent genotype (89.0%), followed by HPV39 (4.1%) and HPV33 (2.7%). HPV16 viral load was high, ranging from 2.1 × 10(3) to 1.5 × 10(7) copies/10(3) cells. Integration of HPV16 estimated by the E2/E6 ratio was detected in 77.8% of cases, among which 70.4% were mixed integrated and episomal DNA cases and 7.4% were fully integrated DNA cases. The latter cases were associated with a low HPV16 load compared with cases containing either episomes or mixed integrated and episomal DNA. As expected, most HPV16-positive tumors expressed p16 (92.6%) with a high proliferative index, whereas a minority of them overexpressed p53 (10.3%). p21 expression did not appear to correlate with p53 expression. Although HPV16 was almost exclusively detected, high viral load and differences in DNA integration have been identified in the present series of anal cancers. HPV features assessed in conjunction with expression of cell-cycle regulators could be helpful, as joint biomarkers, in predicting clinical outcome

Etude LYMPHOREC. Réponse immunitaire intra-tumorale à la radiothérapie préopératoire pour des cancers du rectum de stades II-III: nouveau paramètre pronostic de la survie des patients

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Tumoral lymphocyte immune response to preoperative radiotherapy in locally advanced rectal cancer as a prognostic factor for survival: the LYMPHOREC study

Présentation PosterInternational audienceBackground: Short-course preoperative radiotherapy (sc-preopRT) and long-course preoperative radiotherapy (lc-preopRT) followed by total mesorectal excision (TME) are worldwide standards of care in locally advanced T3–4 N0 or N1 rectal adenocarcinoma. It is now well established that the host immune system participates in the elimination of tumor cells and that significant tumor infiltration by T-cells (LT), such as CD8+, is associated with a better prognosis. In colorectal tumors, the infiltration of Treg FoxP3+ is also described as a prognostic factor associated with better survival. We aimed to investigate the impact of the immune response to preoperative RT on progression-free survival (PFS) and overall survival (OS) in rectal cancer managed with TME.Material and Methods: We analyzed data for 237 patients with rectal cancer who underwent TME between 1995 and 2007 after neo-adjuvant treatment with preoperative RT with or without CT in 3 French centers. The LYMPHOREC study was approved by the French national review boards and independent ethics committee (CPP, CCTIRS and the CNIL). Our primary objective was to assess the impact of the immune infiltration of the tumor or tumor site (in cases with complete response) by CD8+ and FoxP3+ lymphocytes after sc-preopRT or lc-preopRT with or without CT on progression-free survival (PFS) and overall survival (OS). Our secondary objectives were to assess changes in the quantities of these lymphocyte infiltrations with respect to the type of preoperative RT (with vs without chemotherapy) or the dose fractionation scheme (≤2Gy vs >2Gy/fraction). These second analyses were performed with 133 patients from whom one biopsy sample was collected. A biopsy-based pretherapeutic lymphocyte infiltration was thus evaluated.Results: In univariate analysis, TNM stage, the delay between surgery and RT, CD8+, FoxP3+ and the ratio CD8+/FoxP3+ were significantly correlated with survival outcomes while chemotherapy as a component of preoperative radiotherapy was not. In multivariate analysis, when adjusted for clinical and treatment-related variables, tumor infiltration by FoxP3 lymphocytes after treatment significantly correlated with PFS (p=0.007). Variations in the CD8/FoxP3 ratio inside the epithelial tissue from before to after preoperative RT correlated with PFS and OS (p=0.049 and p=0.024, respectively). Interestingly, the dose per fraction (<2Gy vs. ≥2Gy) significantly influenced the CD8/FoxP3 ratio after treatment (p=0.027) with a lower ratio with hypofractionated RT.Conclusions: Patients with rectal cancer who had a significant decrease in the CD8/FoxP3 ratio after preoperative radiotherapy had better survival outcomes. The CD8/FoxP3 ratio needs to be validated prospectively. The immune response to preoperative RT may guide physicians in the decision to give adjuvant treatment to patients with rectal cancer