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Infiltrative gliomas (IG), including astrocytomas, oligodendrogliomas, and glioblastomas, are the most common primary brain tumors in humans.1 IG display a poor prognosis, especially glioblastomas, which represent the most aggressive subtype.1 The tumors of this group are characterized by a pattern of infiltrative growth into the surrounding normal brain,2 making complete surgical excision very difficult. Recurrence or progression after surgery almost always occurs despite adjuvant treatment with radiotherapy and/or chemotherapy.1 Morphological patterns of IG are often heterogeneous, and the diagnosis may be challenging for pathologists.2 Glial tumor cells may also be difficult to distinguish from reactive cells on the basis of morphology alone. Reactive astrocytes may become very large and may even display pleomorphic nuclei resembling neoplastic tumor cells.3 The differential diagnosis between IG and gliosis can thus be difficult, especially in small biopsy samples.4 IG can also be difficult to differentiate from benign and/or curable noninfiltrative glial tumors, including pilocytic astrocytomas, gangliogliomas, and dysembryoplastic neuroepithelial tumors,1,2 and from demyelinating disease.5 It is therefore very important for pathologists to develop histological markers to identify infiltrating glioma cells. To date, no ideal marker has been identified for this purpose. In practice, the most useful markers are MIB1/Ki676,7 and p53,8,9 but these lack sensitivity and specificity.10 More recently, the mutated R132H form of isocitrate dehydrogenase 1 (IDH1), which can be specifically detected by immunohistochemistry,11,12 has been shown to be a good marker of grade II and grade III gliomas and of secondary glioblastomas.13–15 However IDH1 (R132H) is rare in primary glioblastomas16 and is not useful for the diagnosis of this subtype, which represents the most common IG. A marker specific for infiltrating cells, which are characteristic of IG regardless of grade or histological subtype, would be of value. Recently, we showed that the EGFR immunolabelling pattern can discriminate low-grade glioma from gliosis.17 The criterion that characterized low-grade gliomas was strong EGFR immunostaining in cells with a high nuclear to cytoplasmic ratio. EGFR overexpression is frequent in gliomas. In 40% of glioblastomas, EGFR overexpression is secondary to gene amplification and is often associated with expression of EGFRvIII, a constitutively activated mutated variant.18 Conversely, EGFR amplification is rare in low-grade gliomas,18–21 although protein overexpression has been detected with a frequency ranging from 11.5% to 100% of cases in the literature.19,20,22–24 The mechanism of this overexpression in low-grade IG remains unknown. Several ligands, including EGF and TGFα, may activate EGFR. The activation of EGFR is involved in several processes, including cell survival, differentiation, proliferation, and migration.25 Because EGFR has been shown to influence cell migration during the development of the central nervous system26–28 and in gliomas,29–31 we postulated that EGFR could be a marker of migrating cells, specific for IG. The aim of the present study was to assess whether elevated EGFR expression in cells with a high nuclear to cytoplasmic ratio, as we previously observed in low-grade glioma,17 may be a valuable criterion to discriminate infiltrative gliomas of any grade or histological subtype from noninfiltrative glial lesions. We also sought to further characterize these strongly EGFR-positive cells.

Caloric restriction (CR) is proposed to decrease tumorigenesis through a variety of mechanisms including effects on glycolysis. However, the understanding of how CR affects the response to cancer therapy is still rudimentary. Here, using the Eµ-Myc transgenic mouse model of B-cell lymphoma, we report that by reducing protein translation, CR can reduce expression of the prosurvival Bcl-2 family member Mcl-1 and sensitize lymphomas to ABT-737-induced death in vivo. By using Eµ-Myc lymphoma cells lacking p53, we showed that CR mimetics such as 2-deoxyglucose led to a decrease in Mcl-1 expression and sensitized lymphoma cells to ABT-737-induced death independently of p53. In keeping with this, Eµ-Myc lymphoma cells lacking the BH3-only proapoptotic members Noxa, Puma, or Bim were also sensitized by CR mimetics to ABT-737-induced death. Remarkably, neither the loss of both Puma and Noxa, the loss of both Puma and Bim, nor the loss of all three BH3-only proteins prevented sensitization to ABT-737 induced by CR mimetics. Thus, CR can influence Mcl-1 expression and sensitize cells to BH3 mimetic-induced apoptosis, independently of the main BH3-only proteins and of p53. Exploiting this may improve the efficiency of, or prevent resistance to, cancer therapy.

Objet L’enjeu actuel est de pouvoir depister le cancer de la prostate (CaP) a un stade precoce et d’evaluer leur potentiel agressif. Notre objectif etait d’evaluer les niveaux d’expression plasmatique et tissulaire de microARNs (miARNs) chez des patients ayant un CaP traite par prostatectomie radicale. Methodes Le sang provient de patients sains ( n = 25) et atteints d’un CaP localise ( n = 48). L’analyse tissulaire sur bloc de paraffine ( n = 19 des patients de la cohorte) a permis d’extraire les miARNs du tissu prostatique tumoral et non tumoral adjacent chez chaque patient. L’expression relative des miARNs a ete analysee par RT-qPCR (Taqman) rapportee a un miARN endogene (U6) pour le tissu et un miARN exogene (cel-miR-39) pour le plasma. Six miARNs ont ete selectionnes, miR-375, 141, 101, 34a, 182, 195. Resultats Nous observons une surexpression significative des miRNA-375 ( p = 0,0047), miRNA-141 ( p = 0,0293) et du miR-195 ( p p = 0,003411) pour le miR-375, de 69,2 %, 82,6 % et 73 % ( p = 0,02886) pour le miR-141 et de 79,4 %, 83,3 % et 80 % ( p Conclusion Cette approche par analyse combinee tissulaire et plasmatique de microARNs a permis d’identifier les miR-375 et 141 comme nouvel outil prometteur (associes aux indicateurs actuels) pour le diagnostic du cancer de la prostate. L’analyse sur une plus grande cohorte est necessaire pour confirmer ces donnees.

Dnmt2/Trdmt1 is a methyltransferase, which has been shown to methylate tRNAs. Deficient mutants were reported to exhibit various, seemingly unrelated, defects in development and RNA-mediated epigenetic heredity. Here we report a role in a distinct developmental regulation effected by a noncoding RNA. We show that Dnmt2-deficiency in mice results in cardiac hypertrophy. Echocardiographic measurements revealed that cardiac function is preserved notwithstanding the increased dimensions of the organ due to cardiomyocyte enlargement. Mechanistically, activation of the P-TEFb complex, a critical step for cardiac growth, results from increased dissociation of the negatively regulating Rn7sk non-coding RNA component in Dnmt2-deficient cells. Our data suggest that Dnmt2 plays an unexpected role for regulation of cardiac growth by modulating activity of the P-TEFb complex.

Cutaneous lesions in Mediterranean visceral leishmaniasis (VL) are very unusual, except for the presence of Leishmania organisms in cutaneous Kaposi's sarcoma in patients with acquired immunodeficiency syndrome (AIDS). We have identified two unusual cutaneous histological features of VL in three patients with AIDS not described previously; two had "silent leishmaniasis," and in the third, Leishmania organisms were present in sweat ducts, suggesting transepithelial elimination through eccrine sweat glands and/or eccrine epithelial tropism.

International audience; Epithelial cell contribution to the natural history of childhood allergic respiratory disease remains poorly understood. Our aims were to identify epithelial pathways that are dysregulated in different phenotypes of respiratory allergy. We established gene expression signatures of nasal brushings from children with dust mite-allergic rhinitis, associated or not associated with controlled or uncontrolled asthma. Supervised learning and unsupervised clustering were used to predict the different subgroups of patients and define altered signalling pathways. These profiles were compared with those of primary cultures of human nasal epithelial cells stimulated with either interleukin (IL)-4, IL-13, interferon (IFN)-α, IFN-β or IFN-γ, or during in vitro differentiation. A supervised method discriminated children with allergic rhinitis from healthy controls (prediction accuracy 91%), based on 61 transcripts, including 21 T-helper cell (Th) type 2-responsive genes. This method was then applied to predict children with controlled or uncontrolled asthma (prediction accuracy 75%), based on 41 transcripts: nine of them, which were down-regulated in uncontrolled asthma, are directly linked to IFN. This group also included GSDML, which is genetically associated with asthma. Our data revealed a Th2-driven epithelial phenotype common to all children with dust mite allergic rhinitis. It highlights the influence of epithelially expressed molecules on the control of asthma, in association with atopy and impaired viral response.

Subungual malignant epithelial tumors with tricholemmal keratinization have rarely been described as "malignant proliferating onycholemmal cyst" and "onycholemmal carcinoma (OC)." We report an additional case of a slow growing OC occurring on the middle finger of a 58-year-old man, which was unusual as it showed sebaceous-apocrine differentiation, in addition to a nail bed carcinoma with tricholemmal microcysts. We therefore consider the descriptive term of microcystic nail bed carcinoma more appropriate than OC. It is recognized that none of the rare cases of OC meet the classical additional criteria proposed by Headington for tricholemmal carcinoma, that is, lobular arrangement, peripheral palisading, thickened basement membrane, and glycogen-positive tumors cells. On the other hand, we suggest that the term follicular microcysts of the nail bed should be retained to describe the true nature of subungual epidermoid inclusions, which show usually a limited differentiation toward the follicular isthmus. Therefore, the previous cases of OC without sebaceous-apocrine differentiation could be best classified as a microcystic nail bed carcinoma arising from the follicular microcysts of the nail bed, with a limited differentiation toward the keratinization of the follicular isthmus.

MutS homologs play a central role in maintaining genetic stability. We show that MSH5 (MutSHomolog 5) is localized into the mitochondria of germ and somatic cells. This protein binds to mtDNA and interacts with the Twinkle helicase and the DNA polymerase gamma. hMSH5 stimulates mtDNA repair in response to DNA damage induced by oxidative stress. Furthermore, we observed a subsarcolemmal accumulation of hMSH5 in COX negative muscle fibers of patients presenting a mitochondrial myopathy. We report a novel localization for hMSH5 suggesting that this protein may have functions other than those known in meiotic recombination.

Summary A 30-year-old black female, from Burkina Faso, bad AIDS in 1990. She died in March 1993 following a cachexia secondary to a chronic intestinal isosporiasis. The autopsy revealed a massive parasitic infection by I. belli of the small intestine mesenteric and mediastinal lymph nodes and liver and spleen. The parasite stage observed in extra intestinal sites corresponded to unizoite tissue cysts. This is the first report of I. belli infection in liver and spleen.

International audience; Bone marrow stromal cells (BMSCs) have been demonstrated to induce bone formation when associated to osteoconductive biomaterials and implanted in vivo. Nevertheless, their role in bone reconstruction is not fully understood and rare studies have been conducted to follow their destiny after implantation in syngenic models. The aim of the present work was to use sensitive and quantitative methods to track donor and recipient cells after implantation of BMSCs in a syngenic model of ectopic bone formation. Using polymerase chain reaction (PCR) amplification of the Sex determining Region Y (Sry) gene and in situ hybridization of the Y chromosome in parallel to histological analysis, we have quantified within the implants the survival of the donor cells and the colonization by the recipient cells. The putative migration of the BMSCs in peripheral organs was also analyzed. We show here that grafted cells do not survive more than 3 weeks after implantation and might migrate in peripheral lymphoid organs. These cells are responsible for the attraction of host cells within the implants, leading to the centripetal colonization of the biomaterial by new bone.

A strong tendency is currently emerging to remove not only serum but also any product of animal origin from animal cell culture media during production of biopharmaceuticals. The cell line CHO-320 producing human γ-interferon was cultivated in a serum- and protein-free medium supplemented with a soy peptone (Hy-Soy®, Kerry). Although the addition of this plant peptone to the culture medium resulted in a decreased cell growth, an increase of recombinant protein production was observed. Experiments were conducted to elucidate how the peptone contributes to an increased protein production. Results related to transcription activation, protein glycosylation, apoptotic cell death and protein stability suggested that none of these mechanisms could explain the peptone effect. That soy peptone increases protein translation or improves protein secretion is suggested.

Juvenile ossifying fibroma is a rare benign tumour of childhood. It is hardly distinguishable from others fibro-osseous lesions because of their overlapping microscopic features. Juvenile variant of ossifying fibroma may be mistaken for malignancy, particularly osteosarcoma. Radiology is central to their diagnosis because of the very limited nature of the tumour. Microscopically, the lack of cytologic atypia or abnormal mitosis, and the presence of bone maturation or cementum deposits are consistent with an ossifying fibroma. This entity should be kept in mind regarding any bone lesion jaws in children.

Issu des actes du Carrefour pathologie 2011, symposium organisé par la Société française de pathologie, 21-25 novembre 2011, Maison de la Chimie, Paris.; International audience

Ante-mortem diagnosis of vesical toxoplasmosis in a patient with acquired immunodeficiency syndrome (AIDS), was made by cystoscopic examination and biopsy of the bladder. Vesical biopsies can be helpful in determining appropriate therapy for AIDS patients with urinary tract involvement/disease.

We present a case of pityriasis rubra pilaris (PRP)-like eruption, in association with human immunodeficiency virus (HIV) infection, clinically characterized by follicular papules with some elongated spines and comedo-like lesions. The lesions were located on the back, flanks, and proximal extremities. Orthokeratotic follicular plugs and perifollicular mucinous degeneration were consistently observed on three biopsies. The most characteristic histological features of PRP were absent. To our knowledge, this is the first reported case of this kind. Such a case could suggest an atypical PRP modified by HIV infection. It is also possible that it represents a new entity associated with advanced HIV infection (horny perifollicular mucinosis).

Summary Enterocytozoon bieneusi is a microsporidian parasite found only in the enterocytes of the small bowel of HIV positive patients, producing chronic diarrhea and malabsorption. Since January 1990, we have seen the 13 first Mediterranean cases, diagnosed on duodenal pinch biopsy samples. Diarrhea was the major symptom in all instances, and E. bieneusi was the sole identified pathogen in 6 cases. The diagnosis was made on HES or Giemsa-stained paraffin sections and on Giemsa-stained smears (9 cases). In 3 cases, the parasite was also found on ileal biopsies, but was never encountered in the colonic mucosa. In all patients, transmission electron microscopy of the duodenal mucosa was used, and it confirmed the diagnosis of intestinal microsporidiosis. No instance with negative optic examination had evidence of an infection by E. bieneusi with electron microscopy. Due to the small size of the spores, routine fecal parasitological diagnosis is still a difficult procedure, but it is possible that greater experience may avoid many of today's invasive investigations. Cytologic and histologic routine examination of paraffin sections of the distal duodenal or ileal mucosae is a reliable method to diagnose intestinal microsporidiosis in HIV-positive patients with diarrhea.

International audience; Renal cell carcinoma (RCC) with translocation involving Xp11.2 (Xp11.2-RCC) is a rare neoplasm that usually occurs in children and young adults. This incidence is underestimated in adults because its morphological similarities with clear-cell RCC or papillary RCC2,3, as well as immunohistochemical and cytogenetic analyses are not carried out systematically in adults. We present a novel case of Xp11.2-RCC in a 57-year-old woman. The histologic features were those of a clear-cell RCC. Molecular cytogenetic analysis showed an uncommon t(X;1)(p11.2;p34) with TFE3 rearrangement and no alteration of chromosome 3. The immunohistochemical analysis showed expression of the TFE3 protein. Only nine cases of (X;1)(p11.2;p34) have been published, most of them occurring in children or young adults. To our knowledge, this is the second report of such a translocation in a patient older than 55 years. After a follow-up period of 13 months, the patient showed no evidence of disease. The clinical outcome was favorable, indicating that this particular translocation might be associated with a good prognosis. This observation confirms that Xp11.2-RCC are very likely to be underestimated in adults older than 40 years, and it highlights the importance of performing immunohistochemical and cytogenetic analyses in RCC for accurate diagnosis.

Issu des actes du Carrefour Pathologie 2010, symposium de l'Association française d'assurance qualité en anatomie pathologique (AFAQAP), 22-26 novembre 2010, Maison de la Chimie, Paris.; International audience

A case of multicentric reticulohistiocytosis is presented with extensive immunohistochemical study of the infiltrate in both paraffin and cryostat sections. Factor XIIIa dermal dendrocyte marker was demonstrated in the cytoplasm of histiocytes, which has not been reported previously in this disease. In addition, the S100 protein stained positive. This immunophenotyping study suggests a dermal dendrocyte lineage with an unusual expression of S100 protein.

Adenomatoid tumors (AT) are benign mesothelial tumors that usually affect both male and female genital tracts. They characteristically arise in the epididymis, testicular tunica, spermatic cord, fallopian tube, and in the uterus. Extragenital AT are uncommon. They have been reported in the omentum, skin, mesentery, pancreas, mediastinum, pleura, and heart. AT of the adrenal gland are very uncommon. Only 27 cases of AT of the adrenal gland have been reported (Evans et al. 1988; Travis et al. 1990; Raaf et al. 1996; Angeles-Angeles et al. 1997; Rodrigo Gasque et al. 1999; Glatz and Wegmann 2000; Chung-Park et al. 2003; Isotalo et al. 2003; Kim and Ro 2003; Schadde et al. 2003; Denicol et al. 2004; Burel-Vandenbos et al. 2005; Fan et al. 2005; Garg et al. 2005; Hamamatsu et al. 2005; Koren and Cunderlik 2005; Varkarakis et al., 2005; Furedi et al. 2007). In extragenital locations, such as the adrenal gland, AT may pose a diagnostic challenge, with a wide range of differential diagnoses, especially malignant tumors. The challenge is due to the lack of radiological and clinical characteristics and to the histological heterogeneity of AT. In this chapter, we emphasize that immunohistochemistry plays an important role in reaching the diagnosis. The proper identification of this benign tumor in the adrenal gland and the knowledge of its differential diagnosis deserve attention to avoid invasive treatment.

To assess the reliability of systematic and exhaustive cancer Adicap code registration by French pathology laboratories within the Crisap of Paca East network.The Adicap code includes tumour site, histology and pathology technique. A quality control programme was applied to malignant and in situ tumours with an Adicap code to assess data quality, correct errors and supply missing data, based on IARC recommendations.In 2005 and 2006, 45,980 pathology examinations were entered in the Crisap of Paca East database. There was at least one Adicap code per examination, patients, surgeons and pathologists were identified and date of diagnosis was completed, as recommended by the HAS-Afaqap 2005 French pathologist professional quality control. Discrepancies between histopathology tissue and tumour site were found in 0.32% of cases (n=147), between age and histopathology in 0.04% of cases (n=19), and between genital tumour and sex in 0.01% of cases (n=3). In 2006, within 9535 subjects, dates of birth and postcodes of residence were missing, respectively, in 0.39% (n=37) and 22.46% (n=2142) of cases.Data quality for the Adicap code database may be considered satisfactory. Extended to Paca in 2007, Crisap Paca database can now be exploited for Paca regional cancer control strategy.

Introduction: Investigations on primary osteocytes, which compose over 90-95% of bone cells, embedded throughout the mineralized matrix, is a major challenge due to their difficult accessibility and the very rare models available in vitro. We engineered a three-dimensional (3D) culture method of primary human osteoblast differentiation into osteocytes. These 3D-differentiated osteocytes were compared with 2D-cultured cells and with human microdissected cortical osteocytes obtained from bone cryosections. Materials and Methods: Human primary osteoblasts were seeded either within the interspace of calibrated biphasic calcium phosphate particles or on plastic culture dishes and cultured for four weeks in the absence of differentiation factors. Osteocyte differentiation was assessed by histological and immunohistological analysis after paraffin embedding of culture after various times as well as by quantitative RT-PCR analysis of a panel of osteoblast and osteocyte markers after nucleic acid extraction. Results: Histological analysis revealed, after only one week, the presence of an osteoid matrix including many lacunae in which the cells were individually embedded, exhibiting characteristics of osteocyte-like cells. Real time PCR expression of a set of bone-related genes confirmed their osteocyte phenotype. Comparison with plastic-cultured cells and mature osteocytes microdissected from human cortical bone allowed to assess their maturation stage as osteoid-osteocytes. Conclusions: This model of primary osteocyte differentiation is a new tool to gain insights into the biology of osteocytes. It should be a suitable method to study the osteoblast-osteocyte differentiation pathway, the osteocyte interaction with the other bone cells and orchestration of bone remodeling transmitted by mechanical loading and shear stress. It should be used in important cancer research areas such as the crosstalk of osteocytes with tumor cells in bone metastasis since it has been recently shown that gene expression in osteocytes is strongly affected by cancer cells of different origin. It could be also a very efficient tool for drug testing and bone tissue engineering applications.

Plasmodium falciparum infection is an emergency because of the risk of cerebral malaria, that is the most severe complication. Malaria diagnosis is usually made on blood samples of feverish patients coming from endemic area. The pathologist is rarely confronted with malaria lesions. If the occasion arises, the diagnosis of malaria is often already known or suspected and the pathologist has to confirm it. Rarely, malaria is unknown before histological examination and the diagnosis is based on the identification of specific histological features. We report a case of sudden death due to cerebral malaria diagnosed on autopsy findings.

Prostate cancer with 60,000 new cases a year is a public health problem which requires adapted and effective responses. The era of PSA screening dramatically increased the number of prostate biopsies that pathologists have to screen and consequently the number of difficult cases requiring analysis. Immunohistochemistry with anti-AMACR/p504s is useful for detecting prostate cancer in the full range of prostate specimens encountered in needle biopsies. In particular, studies to date with AMACR/p504s clearly demonstrate the ability of this marker to support a diagnosis of malignancy in prostate needle biopsies, combined with negative staining for a basal cell marker, such as p63. This study conducted by the Prostate Committee of the French Association of quality assurance in pathological anatomy and cytology (AFAQAP), reports the evaluation of the current practices with available anti-p63 and -p504s antibodies. The results of this investigation show a correct evaluation of the immunostaining procedure. Overall, from the 39/56 structures tested, the value of the test was positive in 85%. The best results were obtained after antigenic restoration with TRIS-EDTA pH 9, p504s (13H4, 1/200) and p63 (A4A, 1/100).

Dysembryoplastic neuro-epithelial tumors (DNET) are glioneuronal tumors with a common astrocytic or oligodendroglial differentiation. We report a case of DNET with an ependymal differentiation. A 13 years-old girl had refractory focal seizures for 3 years. Successive MRI showed a stable cortical lesion of the right temporal lobe with DNET characteristics. The lesion was resected. Histological examination revealed a pure ependymal differentiation characterized by perivascular pseudorosettes containing EMA immunoreactive cells. Mib1 positive cells were absent. In spite of histologic features of ependymoma, this tumor showed clinical, radiological and behaviour characteristics of DNET. We are not aware of any other case of DNET with ependymal differentiation in the literature. Our observation suggests that the glial component of DNET may show an ependymal differentiation.

The Wilms’ tumor suppressor gene WT1 is an important regulator of development. Mutations in this gene have been associated with Wilms’ tumor, Frasier syndrome, and Denys–Drash syndrome, as well as isolated glomerular disease. Here we report the case of a 4-month-old girl, who presented with end-stage renal disease, thrombopenia, anemia, and cardiac hypertrophy accompanied by severe hypertension. Histological analysis of kidney biopsies revealed a massive and diffuse nephroblastomatosis with a dramatic reduction in the number of glomeruli. Although no normal cortical nephrons could be detected, medullary organization was nearly normal. Sequence analysis demonstrated a heterozygous nonsense mutation in exon 9 of WT1, which leads to a truncation of the WT1 protein at the beginning of zinc finger 3. Given the requirement of WT1 for normal development of the kidney and heart, these data raise the hypothesis that the mutation identified was responsible for the severe phenotype observed in our patient.

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.

Overexpression of epidermal growth factor receptor (EGFR) is common in gliomas. Gliomas are infiltrating tumors in which neoplastic glial cells can be intermingled with reactive glial cells, particularly in diffuse low-grade gliomas. As overexpression of EGFR has also been described in gliosis, it can be difficult to evaluate EGFR immunolabeling in diffuse low-grade gliomas because of this cell mix. We compared EGFR immunolabeling between gliosis and low-grade gliomas in order to identify distinctive criteria. We studied EGFR expression in 28 cases of gliosis and 39 diffuse low-grade gliomas (23 astrocytomas and 16 oligodendrogliomas). EGFR immunohistochemistry staining was performed on paraffin-embedded sections with a mouse monoclonal antibody (clone 2-18C9; Dako). Co-expression of EGFR with Olig2, Mib-1, and p53 was assessed in seven cases of low-grade gliomas using double immunolabeling. Then, EGFR immunostaining was blindly tested on 22 small specimens of indeterminate glial lesions provided by a reference neuropathological center. Two pathologists of our local center were asked to classify the lesions into diffuse low-grade glioma or gliosis according to the pattern of EGFR expression. Weak expression of EGFR was commonly detected in gliosis (23/28 cases). Strongly-stained cells were absent. Positive cells had reactive glial cell morphology. EGFR expression in gliomas was characterized by constant strongly-stained cells (39/39 cases). All strongly-stained cells had a high nucleus-to-cytoplasm ratio, with minimal to moderate nuclear atypia. Most of the strongly EGFR-positive cells were Olig2-positive. All the cases displayed cells co-expressing EGFR and Mib-1. In three p53-positive tumors, many p53-positive cells were strongly EGFR-positive. On the basis of EGFR expression, 14 out of the 22 indeterminate cases were classified as gliomas and eight as gliosis by both pathologists. Concordance with the initial diagnosis established by the reference center and concordance between the pathologists were 100%. Our results confirm that weak EGFR expression can be detected by immunohistochemistry in gliosis. They show that strong EGFR expression may be specific for neoplastic glial cells. As all low-grade gliomas contained strongly-stained cells in our study, we believe that EGFR immunohistochemistry could be a useful tool for detection of neoplastic glial cells in case of indeterminate glial lesions.

International audience; Cell-based therapies are used to treat bone defects. We recently described that human multipotent adipose-derived stem (hMADS) cells, which exhibit a normal karyotype, self renewal, and the maintenance of their differentiation properties, are able to differentiate into different lineages. Herein, we show that hMADS cells can differentiate into osteocyte-like cells. In the presence of a low amount of serum and EGF, hMADS cells express specific molecular markers, among which alkaline phosphatase, CBFA-1, osteocalcin, DMP1, PHEX, and podoplanin and develop functional gap-junctions. When loaded on a hardening injectable bone substitute (HIBS) biomaterial and injected subcutaneously into nude mice, hMADS cells develop mineralized woven bone 4 weeks after implantation. Thus hMADS cells represent a valuable tool for pharmacological and biological studies of osteoblast differentiation in vitro and bone development in vivo.

We recently showed that telomeric repeat-binding factor 2 (TRF2) regulates gene expression to promote angiogenesis. We found that TRF2 is highly expressed in tumor vessels and transcriptionally activates platelet-derived growth factor receptor β to promote endothelial cell angiogenic properties independently of its function in telomere protection. This work identifies TRF2 as a promising dual target for cancer therapy.

Pilocytic astrocytoma is histologically characterized by a biphasic pattern. We report a myxoid form of frontocallosal pilocytic astrocytoma in a 13-year-old girl. MRI showed a relatively well-defined tumor with necrosis and ring-like zone of contrast enhancement. Histological examination showed a monophasic tumor composed of piloid cells on a myxoid background corresponding to a pilomyxoid astrocytoma. This unusual form of pilocytic astrocytoma can be mistaken for a high grade infiltrating glioma. Pilomyxoid astrocytoma is more aggressive than classic pilocytic astrocytoma and has to be distinguished from it.

Primary malignant melanoma of the bile duct is very rare. We report a case of a malignant melanoma involving the common bile duct in a 41-year-old man. The patient presented to the hospital with an isolated jaundice and underwent pancreaticoduodenectomy. Absolute exclusion of a metastatic tumor is not entirely possible.

Adenomatoid tumors are benign mesothelial tumors that usually affect the genital tract. We report the case of a 65-year-old man with an adenomatoid tumor of the adrenal gland. This uncommon location and its histological heterogeneity can lead to a mistaken diagnosis of malignant tumor. Positive cells with mesothelial markers in immunohistochemistry improve diagnosis. The proper identification of this benign tumor in the adrenal gland and the knowledge of its differential diagnosis deserve attention to avoid invasive treatment.

International audience; We have used a new synthetic injectable composite constituted of hydroxyapatite/tricalcium phosphate (HA/TCP) particles in suspension in a self-hardening Si-hydroxypropylmethylcellulose (HPMC) hydrogel. The aim of this study was to evaluate in vivo the biocompatibility and the new bone formation efficacy of this scaffold loaded with undifferentiated bone marrow stromal cells (BMSCs). This biomaterial was mixed extemporaneously with BMSCs prepared from C57BL/6 mice, injected in subcutaneous and intramuscular sites and retrieved 4 and 8 weeks after implantation. Dissection of the implants revealed a hard consistency and the absence of a fibrous capsule reflecting a good integration into the host tissues. Histological analysis showed mineralized woven bone in the granule inter-space with numerous active osteoclasts attached to the particles as assessed by the presence of multinucleated cells positively stained for TRAP activity and for the a3 subunit of the V-ATPase. Small vessels were homogenously distributed in the whole implants. Similar results were obtained in SC and IM sites and no bone formation was observed in the control groups when cell-free and particle-free transplants were injected. These results indicate that this injectable biphasic calcium phosphate-hydrogel composite mixed with undifferentiated BMSCs is a new promising osteoinductive bone substitute. It also provides with an original in vivo model of osteoclast differentiation and function.

The present work evaluates a newly developed silated hydroxypropylmethylcellulose (Si-HPMC)-based hydrogel as a scaffold for 3D culture of osteogenic cells. The pH variation at room temperature catalyzes the reticulation and self-hardening of the viscous polymer solution into a gelatine state. We designed reticulation time, final consistency and pH in order to obtain an easy handling matrice, suitable for in vitro culture and in vivo injection. Three human osteogenic cell lines and normal human osteogenic (HOST) cells were cultured in 3D inside this Si-HPMC hydrogel. We show here that osteosarcoma cells proliferate as clonogenic spheroids and that HOST colonies survive for at least 3 weeks. Mineralization assay and gene expression analysis of osteoblastic markers and cytokines, indicate that all the cells cultured in 3D into this hydrogel, exhibited a more mature differentiation status than cells cultured in monolayer on plastic. This study demonstrates that this Si-HPMC hydrogel is well suited to support osteoblastic survival, proliferation and differentiation when used as a new scaffold for 3D culture and represents also a potential basis for an innovative bone repair material.

One hundred and forty-nine women received a suburethral woven polypropylene mesh insertion for urodynamic stress incontinence. Eleven patients (7.5%) presented between 4 and 17 months after surgery (mean 10 months) with symptoms of retropubic infection. Ten patients required surgical exploration, drainage of the collection and removal of the tape either unilaterally (six) or bilaterally (four). Bacterial cultures were negative in nine women. Following removal of the tape, eight patients reported residual incontinence, either stress leakage (five) or de novo urge incontinence (three). Multifilament polypropylene meshes appear to be more at risk of infection, usually requiring sling removal, which may be related to pore size of the mesh. Our data reinforce the importance of proper evaluation of new surgical procedures by rigorously designed randomised trials with adequate follow up to identify rare but potentially serious complications.

Hereditary predisposition to neuroblastoma accounts for less than 5% of neuroblastomas and is probably heterogeneous. Recently, a predisposition gene has been mapped to 16p12-p13, but has not yet been identified. Occurrence of neuroblastoma in association with congenital central hypoventilation and Hirschsprung's disease suggests that genes, involved in the development of neural-crest-derived cells, may be altered in these conditions. The recent identification of PHOX2B as the major disease-causing gene in congenital central hypoventilation prompted us to test it as a candidate gene in familial neuroblastoma. We report a family with three first-degree relatives with neuroblastic tumours (namely two ganglioneuromas and one neuroblastoma) in one branch and two siblings with Hirschsprung's disease in another branch. A constitutional R100L PHOX2B mutation was identified in all three patients affected with tumours. We also report a germline PHOX2B mutation in one patient treated for Hirschsprung's disease who subsequently developed a multifocal neuroblastoma in infancy. Both mutations disrupt the homeodomain of the PHOX2B protein. No loss of heterozygosity at the PHOX2B locus was observed in the tumour, suggesting that haplo-insufficiency, gain of function or dominant negative effects may account for the oncogenic effects of these mutations. These observations identify PHOX2B as the first predisposing gene to hereditary neuroblastic tumours.

Background: The impact of immune reconstitution on liver fibrosis in HIV/hepatitis C virus (HCV) patients is unknown. In this case-control study, we investigated the impact of HIV infection on the severity of liver fibrosis and identified related factors. Methods: We studied 116 HIV/HCV patients and 235 HCV only patients all untreated for HCV. Each co-infected patient was matched with two singly-infected patients according to gender, age at contamination and duration of infection. Liver biopsy was analysed using the METAVIR score. Results: Alcohol consumption and route of contamination differed between HCV-infected and HCV/HIV co-infected patients. Among co-infected patients, a F3-F4 Metavir score was significantly more frequent than in mono-infected patients. Co-infected patients with severe fibrosis (F3-F4) had higher transaminase, ferritin levels and lower CD4 T-cell count than patients with none to moderate fibrosis (F0-F2). Although median duration of treatment with nucleoside analogues, non-nucleoside analogues and protease inhibitors were comparable in both groups, the delay between the presumed date of contamination and treatment initiation with highly active antiretroviral therapy (HAART) was significantly longer for patients with severe fibrosis than those with none to moderate fibrosis. Finally, the mean rate of fibrosis progression was significantly slower among patients exposed to HAART. Conclusion: Early antiretroviral therapy in co-infected HIV-HCV patients may slow liver fibrosis progression.

Primary rhabdomyosarcoma (RMS) of the kidney in an adult is a very rare and unusual tumor in this site. The clinical signs associated with the flank tumoral syndrome, the histologic appearance of cytoplasmic double striation in rhabdomyoblasts and the immunohistochemical expression of skeletal muscle differentiation (desmin, myoglobin, myogenin) are described in the context of a rapidly evolving renal RMS in a 77-year old man. The differential diagnosis are mainly represented by sarcomatoid renal cell carcinoma. According to the neoplastic extent, the treatment includes radical nephrectomy, chemotherapy and surgery. The prognosis of primary renal RMS is extremely poor, with lymph node, hepatic, bone marrow and pulmonary metastasis and a short survival rate.

We report the case of a 76-year-old woman who presented with abdominal pain caused by a gastric tumor. The stomach was resected and found to have developed an elastofibroma. The lesion was yellowish, unencapsulated, and characterized histologically by abundant collagen fibers mixed with numerous elastic serrated fibers. Elastofibromatous change of the gastrointestinal tract is a rare event.