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BACKGROUND Myeloperoxidase (MPO) is a member of the peroxidase-cyclooxygenase superfamily, which is secreted from stimulated leucocytes at inflammatory sites. It is well known that MPO catalyses oxidation reactions via the release of reactive halogenating and nitrating species and thus induces tissue damage. Several studies have already implicated MPO in the development of neoplasia. Chronic or recurrent prostatic inflammation has long been recognized as having the potential to initiate and promote the development of prostate cancer. The objective was to investigate whether MPO is present in the prostate. METHODS Human prostate material was obtained from biopsies, transurethral resections of the prostate (TURP), prostatic adenomectomies, and retropubic radical prostatectomies. Twenty-nine slides of normal prostate tissue, benign prostatic hyperplasia (BPH), and prostate cancer were reviewed by a pathologist. Immunohistochemical analysis using MPO-specific human antibody was performed to detect MPO in the prostate tissue. RESULTS Immunocytohistochemistry showed cellular colocalization of MPO in the secretory epithelial cells of the prostate with staining varying from light to strong intensity. Staining in the glandular apical snouts was often reinforced although staining of basal as well as of luminal glandular cells was also present. CONCLUSIONS We identified, for the first time, the presence of MPO at the surface of prostatic epithelial cells. In view of the pro-oxidant properties of this enzyme, further research is needed to define whether MPO contributes to the development of prostatic lesions. Prostate 72:507–513, 2012. © 2011 Wiley Periodicals, Inc.

Background and Objectives: To evaluate the long-term prognostic value of the combination of the EORTC risk calculator and proapoptotic, antiapoptotic, proliferation, and invasiveness molecular markers in predicting the outcome of intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC) treated with intravesical Bacille Calmette-Guérin (BCG) therapy. Materials and Methods: This study included 42 patients accrued prospectively presenting with intermediate- to high-risk NMIBC (high-grade T1 tumors or multiple rapidly recurrent tumors refractory to intravesical chemotherapy) treated with transurethral resection (TUR) and BCG. TUR samples were analyzed for the molecular markers p53, p21 waf1/cip, Bcl-2, CyclinD1, and metallothionein 9 (MMP9) using immunohistochemistry. Frequency of positivity, measured as a percentage, was assessed alone or in combination with EORTC risk calculator, for interaction with outcome in terms of recurrence and progression using univariate analysis and Kaplan-Meier survival curves. Results: Median follow-up was 88 months (mean, 99; range, 14-212 months). The overall recurrence rate was 61.9% and progression rate was 21.4%. In univariate analysis, CyclinD1 and EORTC risk groups were significantly associated with recurrence (P value 0.03 and 0.02, respectively), although none of the markers showed a correlation to progression. In combining EORTC risk groups to markers expression status, high-risk group associated with positive MMP9, Bcl-2, CyclinD1, or p21 was significantly correlated to tumor recurrence (log rank P values

Based on the molecular profiling of astrocytomas, we previously identified a series of genes involved in astrocytoma invasion. Of these, tissue inhibitor of metalloproteinase-4 (TIMP-4) was found to be overexpressed in pilocytic astrocytomas relative to diffuse astrocytomas of any histological grade. Although some data suggest that TIMP-4 may be an anti-tumoral actor in astrocytomas, recent findings challenge this concept. The present study aims to investigate the diagnostic and prognostic values of TIMP-4 and its putative partner CD63 in human astrocytomas. Tissue microarray and image analysis were first carried out to quantitatively analyze the immunohistochemical expression of these proteins in 471 gliomas including 354 astrocytomas. Pathological semi-quantitative scores of both markers' expression were then established and correlated to astrocytoma diagnosis and patient prognosis. TIMP-4 and CD63 expressions were both overexpressed in astrocytomas compared with oligodendrogliomas (P

ObjectiveTo evaluate the diagnostic value of fine-needle aspiration (FNA) cytology and the additive contribution brought by clinical and ultrasound (US) features.MethodCytological and histological diagnoses were compared in a series of 924 patients who underwent US-guided FNA before surgery. We additionally developed a grading system for follicular proliferation (FP) FNA diagnosis, and investigated its impact on the malignancy risk as well as the additive contribution of clinical and US features by means of decision tree analysis.ResultsExcluding FP cases (n=395), our data demonstrated that strictly benign or malignant FNA diagnoses exhibit great concordance with benign or malignant histological diagnoses (97.8% accuracy). Our grading system that was applied to the 395 FP cases revealed that grades 1, 2 and 3 were associated with a 7.7, 17.7 and 45.7% incidence of malignancy respectively. Decision tree analysis resulted in a classification model which involved FP grade, patient's age, serum thyroglobulin level, nodule size and nodule uniqueness. This model identified a subgroup of patients with grade 1 FP nodules who were older than 50 years, and who had a higher risk of malignancy (17.9%). In addition, high serum thyroglobulin levels were associated with a very high malignancy risk (75.0%) for patients with grade 3 FP nodules. Finally, among grade 2 FP patients, unique and large nodules were associated with a high malignancy risk of 36.1%.ConclusionsThe integration of FP grade, clinical and US features allows the stratification of patients with FP cytology according to their risk of malignancy.

Breast cancer is the most frequent cancer in women and consists of heterogeneous types of tumours that are classified into different histological and molecular subtypes. PIK3CA and P53 (also known as TP53) are the two most frequently mutated genes and are associated with different types of human breast cancers. The cellular origin and the mechanisms leading to PIK3CA-induced tumour heterogeneity remain unknown. Here we used a genetic approach in mice to define the cellular origin of Pik3ca-derived tumours and the impact of mutations in this gene on tumour heterogeneity. Surprisingly, oncogenic Pik3ca(H1047R) mutant expression at physiological levels in basal cells using keratin (K)5-CreER(T2) mice induced the formation of luminal oestrogen receptor (ER)-positive/progesterone receptor (PR)-positive tumours, while its expression in luminal cells using K8-CReER(T2) mice gave rise to luminal ER(+)PR(+) tumours or basal-like ER(-)PR(-) tumours. Concomitant deletion of p53 and expression of Pik3ca(H1047R) accelerated tumour development and induced more aggressive mammary tumours. Interestingly, expression of Pik3ca(H1047R) in unipotent basal cells gave rise to luminal-like cells, while its expression in unipotent luminal cells gave rise to basal-like cells before progressing into invasive tumours. Transcriptional profiling of cells that underwent cell fate transition upon Pik3ca(H1047R) expression in unipotent progenitors demonstrated a profound oncogene-induced reprogramming of these newly formed cells and identified gene signatures characteristic of the different cell fate switches that occur upon Pik3ca(H1047R) expression in basal and luminal cells, which correlated with the cell of origin, tumour type and different clinical outcomes. Altogether our study identifies the cellular origin of Pik3ca-induced tumours and reveals that oncogenic Pik3ca(H1047R) activates a multipotent genetic program in normally lineage-restricted populations at the early stage of tumour initiation, setting the stage for future intratumoural heterogeneity. These results have important implications for our understanding of the mechanisms controlling tumour heterogeneity and the development of new strategies to block PIK3CA breast cancer initiation., SCOPUS: ar.j, info:eu-repo/semantics/published

Introduction: Brain death (BD) triggers sympathetic storm with a torrent of circulatory catecholamines. Neurogenic pulmonary edema (NPE) and ventricular dysfunction can be achieved in return. Inflammation may be implicated in the pathogenesis of the condition but its precise role remains uncertain. We developed a model of brain death in pig to study the development of NPE and right ventricular (RV) dysfunction . Methods & results: Sixteen pigs were randomized to placebo (n=9) or corticosteroids (n=7) 1.5 mg/kg before BD induced by slow intracranial blood infusion. Four hours after BD, the animals underwent a hemodynamic evaluation followed by lung and RV tissue sampling for rtq-PCR for the inflammatory modulator HO-1 and the pro-inflammatory ratio IL-6 / IL10, and lung histopathologic injury score. A control group (n=9) was studied. After 4 hours, BDincreased cardiac frequency, pulmonary pressure, pulmonary vascular resistance, pulmonary arterial impedance at 0Hz, and capillary pressure. Right ventricular end-systolic elastance (Ees) increased but not in proportion to pulmonary arterial elastance (Ea) so that Ees/Ea ratio decreased. Systemic arterial pressure was decreased while cardiac output, occluded pulmonary arterial pressure, right auricular pressure and characteristic impedance did not change. The ratio of partial pressure arterial oxygen and fraction of inspired oxygen collapsed. BD was associated with an increase in IL-6/IL-10 and with a decrease in HO-1 gene expression in lung and RV tissue. BD increased the lung injury score. Conclusions: BD causes lung injury pulmonary and RV dysfunction associated with up-regulation of IL-6/IL-10 and down-regulation HO-1.

Introduction: In lung transplantation, neurogenic pulmonary edema (NPE) is a major impediment to lung harvesting. Corticosteroids may mitigate pulmonary edema but the role of inflammation in the pathogenesis of the condition remains uncertain. In a model of brain death (BD), we studied the role of inflammation in the NPE pathobiology. Methods & results: Sixteen pigs were randomized to placebo (n=9) or corticosteroids (n=7) 1.5 mg/kg before BD induced by slow intracranial blood infusion. Four hours after BD, the animals underwent a hemodynamic evaluation followed by lung tissue sampling for rtq-PCR for HO-1 and the pro-inflammatory ratio IL-6 / IL10, and lung histopathologic injury score. A control group (n=9) was studied. BD increased pulmonary pressure (PAP), pulmonary vascular resistance (PVR), capillary pressure (Pcap), pulmonary arterial impedance at 0Hz (Z0), and pulmonary arterial elastance (Ea). Systemic arterial pressure (SAP) was decreased while occluded pulmonary arterial pressure, right auricular pressure and characteristic impedance did not change. The ratio of partial pressure arterial oxygen and fraction of inspired oxygen (Pa02/Fi02) collapsed. BD was associated with an increase in IL-6/IL-10 and a decrease in HO-1 gene expression. The injury score was increased in BD group. Corticosteroids therapy totally prevented changes in PAP, PVR, Pcap, Z0, Ea, and IL6/IL10 and HO-1 gene expression in lung tissue. Changes in Pa02/iF02 and injury score were partially prevented. Conclusions: BD is responsible for neurogenic pulmonary edema. Corticosteroids prevent hemodynamics and partially prevent biological changes in neurogenic pulmonary edema.

Introduction: Brain death triggers sympathetic storm with a torrent of circulatory catecholamines. Pulmonary edema and ventricular dysfunction can be achieved in return. We developed a model of brain death in pigs and studied right ventricular (RV) function with or without corticosteroids therapy. Heme oxygenase-1 (HO1) is an inflammatory modulator and may play a role in right ventricular dysfunction pathobiology. Methods & results: Sixteen pigs (+/- 45 Kg) were randomized to placebo (n=9) or to corticosteroids (n=7) 1.5 mg/kg before brain death (BD). BD was induced by slow intracranial blood (250cc) infusion. Four hours after BD declaration, the animals underwent a hemodynamic evaluation followed by cardiac tissue sampling for real-time quantitative PCR for HO-1. A control group (n=9) was also studied. Brain death increased cardiac frequency (CF), pulmonary pressure (PAP), pulmonary vascular resistance (PVR), capillary pressure (Pcap) and total RV working (Wtot). Right ventricular end-systolic elastance (Ees) increased but not in proportion to pulmonary arterial elastance (Ea) so that Ees/Ea ratio collapsed. Systemic arterial pressure was decreased while occluded pulmonary arterial pressure did not change. BD was associated with a decrease in RV HO-1 gene expression . Corticosteroids therapy totally prevented changes in CF, PAP, PVR, Pcap, Wtot and Ees/Ea. Corticosteroids therapy was associated with an increased RV HO-1 gene expression beyond control animals. Conclusions: BD is responsible for RV dysfunction and HO-1 gene expression down regulation. Corticosteroids would maintain the RV-arterial coupling and increased gene expression of the inflammatory modulator HO-1.

The upper (suburothelial) lamina propria (ULP) is a distinct region in the human bladder with dense populations of interstitial cells (IC), fine vascular networks and variable development of muscularis mucosae (MM). It is more and more obvious that the ULP plays an important role in bladder physiology and bladder disease, and in the present study we have quantified changes in the cellular key players of the ULP in bladders from patients with carcinoma in situ (CIS), multiple sclerosis (MS) and bladder pain syndrome (BPS). Tissue samples for the different patient groups were obtained from radical cystectomy-specimens. Standardized immunohistochemistry with a panel of specific cell markers was used to characterise the ULP cellular structures, followed by digitalised morphometry and quantitative staining analysis. Alterations in the ULP area were most pronounced in MS bladders, but also present in BPS and CIS bladders. We observed an increased thickness and increased variability in thickness of the ULP IC area in MS and BPS bladders; a significantly increased development of MM in MS bladders; a changed organization of vascular plexuses in the lamina propria in most pathologic bladders and a changed phenotype of ULP IC: a significantly decreased expression of progesterone receptor in MS bladders and a trend towards decreased expression of alpha-smooth muscle actin in BPS bladders. We show here for the first time the presence of disease-specific changes in organisation and/or phenotype of the different key players of the ULP area in human bladder. The present findings further support the hypothesis that the ULP area is involved and altered in different bladder diseases., SCOPUS: ar.j, info:eu-repo/semantics/published

To evaluate the efficiency of the UCA1 test as a diagnostic tool for the detection of bladder cancer., SCOPUS: ar.j, info:eu-repo/semantics/published

Despite advances in surgical and adjuvant treatments, overall survival of glioblastoma (GBM) patients remains poor. The cancer stem cell concept suggests that a rare stem cell population, called glioma stem cells (GSCs), has high ability to self-renewal leading to recurrence in GBM. The identification of specific markers of GSCs would provide a powerful tool to detect and to characterise them in order to develop targeted therapies. We carried out a comparative analysis based on the identification of inter-study concordances to identify the genes that exhibit at best differential levels of expression between GSC-enriched cell cultures and differentiated tumour cell cultures from independent studies using DNA chip microarray technologies. We finally studied the protein expression of the marker we considered the most specific by immunohistochemistry and semi-quantitative analysis on a retrospective series of 18 GBMs. Of the selected studies, 32 genes were retained. Among them, eight genes were identified to be overexpressed in GSC-enriched cultures compared to differentiated tumour cell cultures. Finally, among the eight genes, oligodendrocyte lineage transcription factor 2 (OLIG2) was characterised by the most different expression level in the "GSC model" compared to the "differentiated tumour cells model". Our approach suggests that OLIG2 is the most specific GSC marker; additional investigations with careful considerations about methodology and strategies of validation are, however, mandatory., SCOPUS: ar.j, * Anne-Laure Trépant and Christelle Bouchart contributed equally to this work., info:eu-repo/semantics/published

The treatment of locally advanced metastasized melanoma is challenging because there is no level 1 evidence to guide clinical decision-making. Moreover, the treatment options available fail to improve overall survival and are associated with considerable morbidity. Here, we show that systemic treatment with BRAF inhibitor vemurafenib substituted by dual BRAF/MEK inhibition (dabrafenib and trametinib) before surgery can offer the potential to cure the initially difficult or inoperable melanoma. A 62-year-old woman was diagnosed with an AJCC stage IIIB melanoma harboring the BRAF V600E mutation after a complete initial evaluation. Clinically, the patient presented a large primary lesion that was surrounded by ∼25 secondary epidermotropic lesions both satellite and 'in transit' with a diameter between 1 and 6 mm. Following multidisciplinary consultation, the patient was started on 960 mg twice-daily vemurafenib, which was stopped and resumed at 720 mg twice daily, and finally substituted with the combination dabrafenib and trametinib to reduce the persistent side effects. Successive clinical examinations had shown a progressive reduction in the thickness of the melanoma lesions. After about 5 months of therapy, surgery was performed and the histopathological analysis showed an almost complete regression of tumor cells. The treatment with dabrafenib/trametinib was continued only 3 months after surgery and stopped at the patient's request. The patient currently remains in complete remission at 8 months after surgery. The case presented here supports the use of neoadjuvant treatment with BRAF inhibitors in advanced 'in transit' melanoma.

Object The aim of this study was to evaluate the integration of positron emission tomography (PET) scanning data into the image-guided resection of brain tumors. Methods Positron emission tomography scans obtained using fluorine-18 fluorodeoxyglucose (FDG) and l-[methyl-11C]methionine (MET) were combined with magnetic resonance (MR) images in the navigational planning of 103 resections of brain tumors (63 low-grade gliomas [LGGs] and 40 high-grade gliomas [HGGs]). These procedures were performed in 91 patients (57 males and 34 females) in whom tumor boundaries could not be accurately identified on MR images for navigation-based resection. The level and distribution of PET tracer uptake in the tumor were analyzed to define the lesion contours, which in turn yielded a PET volume. The PET scanning–demonstrated lesion volume was subsequently projected onto MR images and compared with MR imaging data (MR volume) to define a final target volume for navigation-based resection—the tumor contours were displayed in the microscope’s eyepiece. Maximal tumor resection was accomplished in each case, with the intention of removing the entire area of abnormal metabolic activity visualized during surgical planning. Early postoperative MR imaging and PET scanning studies were performed to assess the quality of tumor resection. Both pre- and postoperative analyses of MR and PET images revealed whether integrating PET data into the navigational planning contributed to improved tumor volume definition and tumor resection. Metabolic information on tumor heterogeneity or extent was useful in planning the surgery. In 83 (80%) of 103 procedures, PET studies contributed to defining a final target volume different from that obtained with MR imaging alone. Furthermore, FDG-PET scanning, which was performed in a majority of HGG cases, showed that PET volume was less extended than the MR volume in 16 of 21 cases and contributed to targeting the resection to the hypermetabolic (anaplastic) area in 11 (69%) of 16 cases. Performed in 59 LGG cases and 23 HGG cases, MET-PET demonstrated that the PET volume did not match the MR volume and improved the tumor volume definition in 52 (88%) of 59 and 18 (78%) of 23, respectively. Total resection of the area of increased PET tracer uptake was achieved in 54 (52%) of 103 procedures. Conclusions Imaging guidance with PET scanning provided independent and complementary information that helped to assess tumor extent and plan tumor resection better than with MR imaging guidance alone. The PET scanning guidance could help increase the amount of tumor removed and target image-guided resection to tumor portions that represent the highest evolving potential.

Purpose To evaluate in brain gliomas the relationship between tumor vascularity measured by MR-based maximum regional cerebral blood volume (rCBV) and tumor amino-acid metabolism based on maximum carbon-11 methionine (MET) uptake on positron emission tomography (PET). Materials and Methods Eighteen patients with histologically proven primary brain gliomas were included in the study. In addition to conventional MR sequences, dynamic MR images, including a first-pass gadopentetate dimeglumine T2*-weighted echo-planar perfusion sequence and a PET study using MET, were acquired. Eleven patients had low-grade gliomas, and seven had high-grade gliomas. rCBV ratios and MET uptake ratios normalized to the contralateral white matter (WM) corresponding values were measured in each tumor. Both maximum rCBV ratios and maximum MET uptake ratios were correlated to histopathology. The maximum rCBV ratios were correlated to the maximum MET uptake ratios. Results Both the maximum rCBV ratios and maximum MET uptake ratios of high-grade gliomas were significantly higher than those of low-grade gliomas (P < 0.05). There was a significant positive correlation between maximum rCBV ratios and maximum MET uptake ratios (Spearman: r = 0.89, P < 0.00001). Conclusion The maximum rCBV ratio and maximum MET uptake ratio are significantly correlated in gliomas, reflecting a close link between amino acid uptake and vascularity in these tumors. J. Magn. Reson. Imaging 2006. © 2006 Wiley-Liss, Inc.

Idiopathic pulmonary fibrosis is characterized by a progressive and irreversible respiratory failure. Validated noninvasive methods able to assess disease activity are essential for prognostic purposes as well as for the evaluation of emerging antifibrotic treatments. METHODS: C57BL/6 mice were used in a murine model of pulmonary fibrosis induced by an intratracheal instillation of bleomycin (control mice were instilled with a saline solution). At different times after instillation, PET/CT with (18)F-FDG- or (18)F-4-fluorobenzamido-N-ethylamino-maleimide ((18)F-FBEM)-labeled leukocytes was performed to assess metabolic activity and leukocyte recruitment, respectively. RESULTS:In bleomycin-treated mice, a higher metabolic activity was measured on (18)F-FDG PET/CT scans from day 7 to day 24 after instillation, with a peak of activity measured at day 14. Of note, lung mean standardized uptake values correlated with bleomycin doses, histologic score of fibrosis, lung hydroxyproline content, and weight loss. Moreover, during the inflammatory phase of the model (day 7), but not the fibrotic phase (day 23), bleomycin-treated mice presented with an enhanced leukocyte recruitment as assessed by (18)F-FBEM-labeled leukocyte PET/CT. Autoradiographic analysis of lung sections and CD45 immunostaining confirm the higher and early recruitment of leukocytes in bleomycin-treated mice, compared with control mice. CONCLUSION: 18)F-FDG- and (18)F-FBEM-labeled leukocyte PET/CT enable monitoring of metabolic activity and leukocyte recruitment in a mouse model of pulmonary fibrosis. Implications for preclinical evaluation of antifibrotic therapy are expected.

Diabetes is characterized by a progressive decline of the pancreatic beta cell mass (BCM), which is responsible for insufficient insulin secretion and hyperglycaemia. There are currently no reliable methods to measure non-invasively the BCM in diabetic patients. Our work describes a phage display-derived peptide (P88) that is highly specific to (FXYD2)γa expressed by human beta cells and is proposed as a molecular vector for the development of functionalized imaging probes. P88 does not bind to the exocrine pancreas and is able to detect down to ~156 human pancreatic islets/mm(3) in vitro after conjugation to ultra-small particles of iron oxide (USPIO), as proven by the R2 measured on MR images. For in vivo evaluation, MRI studies were carried out on nude mice bearing Capan-2 tumours that also express (FXYD2)γa. A strong negative contrast was obtained subsequent to the injection of USPIO-P88, but not in negative controls. On human histological sections, USPIO-P88 seems to be specific to pancreatic beta cells, but not to duodenum, stomach or kidney tissues. USPIO-P88 thus represents a novel and promising tool for monitoring pancreatic BCM in diabetic patients. The quantitative correlation between BCM and R2 remains to be demonstrated in vivo, but the T2 mapping and the black pixel estimation after USPIO-P88 injection could provide important information for the future pancreatic BCM evaluation by MRI.

Object. The aim of this study was to analyze the cellular immune response and histopathological changes in secondary brain tumors after gamma knife surgery (GKS). Methods. Two hundred ten patients with cerebral metastases underwent GKS. Seven patients underwent subsequent craniotomy for tumor removal between 1 and 33 months after GKS. Four of these patients had one tumor, two patients had two tumors, and one patient had three. Histological and immunohistochemical investigations were performed. In addition to routine H & E and Mallory trichrome staining, immunohistochemical reactions were conducted to characterize the phenotypic nature of the cell population contributing to the tissue immune response to neoplastic deposits after radiosurgery. Light microscopy revealed an intensive lymphocytic infiltration in the parenchyma and stroma of tumor samples obtained in patients in whom surgery was performed over 6 months after GKS. Contrary to this, extensive areas of tissue necrosis with either an absent or scanty lymphoid population were observed in the poorly controlled neoplastic specimens obtained in cases in which surgery was undertaken in patients less than 6 months after GKS. Immunohistochemical characterization demonstrated the predominance of CD3-positive T cells in the lymphoid infiltration. Conclusions. Histopathological findings of the present study are consistent with a cellular immune response of natural killer cells against metastatic brain tumors, presumably stimulated by the ionizing energy of focused radiation.

Purpose: This study aims to investigate the role of gastrin-17 (G17) on angiogenesis features in gliomas both in vitro and in vivo. Experimental Design: The influences of G17 and G17 receptor antagonists were characterized in vitro in terms of angiogenesis on human umbilical vein endothelial cell (HUVEC) tubulogenesis processes on Matrigel and in vivo with respect to U373 orthotopic glioma xenografts. The influence of phosphatidylinositol 3′-kinase, protein kinase C, and nuclear factor-κB inhibitors was characterized in vitro on G17-mediated HUVEC tubulogenesis. G17-mediated release of interleukin (IL)-8 from HUVECs and G17-induced modifications in nuclear factor-κB DNA binding activity were characterized by means of specific enzyme-linked immunosorbent assays. The influence of G17 on E- and P-selectin expression was determined by means of computer-assisted microscopy, whereas the influence of E- and P-selectin on HUVEC migration was approached by means of antisense oligonucleotides. The chemotactic influence of G17 and IL-8 on HUVEC migration was characterized by means of computer-assisted videomicroscopy with Dunn chambers. Results: Messenger RNAs for cholecystokinin (CCK)A, CCKB, and CCKC receptors were present in HUVECs and microvessels dissected from a human glioblastoma. Whereas G17 significantly increased the levels of angiogenesis in vivo in the U373 experimental glioma model and in vitro in the HUVECs, the CCKB receptor antagonist L365,260 significantly counteracted the G17-mediated proangiogenic effects. G17 chemoattracted HUVECs, whereas IL-8 failed to do so. IL-8 receptor α (CXCR1) and IL-8 receptor β (CXCR2) mRNAs were not detected in these endothelial cells. Gastrin significantly (but only transiently) decreased the level of expression of E-selectin, but not P-selectin, whereas IL-8 increased the expression of E-selectin. Specific antisense oligonucleotides against E- and P-selectin significantly decreased HUVEC tubulogenesis processes in vitro on Matrigel. Conclusions: The present study shows that gastrin has marked proangiogenic effects in vivo on experimental gliomas and in vitro on HUVECs. This effect depends in part on the level of E-selectin activation, but not on IL-8 expression/release by HUVECs.

Resume Introduction La prise en charge des gliomes de bas grade represente un veritable « challenge » pour les neurochirurgiens et oncologues. Quand faut-il les operer, leur administrer de la radiotherapie et de la chimio-therapie ? Afin d’essayer de repondre a ces questions, nous avons revu 65 patients porteurs d’un gliome de bas grade pour lesquels une imagerie TEP avait ete effectue. Nous avons voulu confirmer la TEP comme un facteur pronostique ainsi qu’etablir la sensibilite et la specificite de la TEP au FDG et a la MET. Materiel et methode Soixante-cinq patients porteurs d’un gliome de bas grade ont beneficie avant tout traitement d’un TEP au FDG et/ou a la MET. Une confirmation histologique a ete obtenue pour tous les patients. Un suivi regulier par l’examen clinique et imagerie (TEP et IRM) a ete pratique. Resultats La presence d’une captation elevee de FDG a la TEP est statistiquement correlee a un intervalle libre plus court (p = 0,001) et il en est de meme pour la survie (p = 0,0003). Les resultats obtenus pour la MET sont comparables a ceux du FDG puisque plus une tumeur capte la MET plus son intervalle libre est court (p = 0,0076). Trente-six patients ont beneficie d’un TEP au FDG et a la MET. La TEP au FDG a une sensibilite de 66 % et une specificite de 94 % tandis que la TEP METa une sensibilite de 100 % et une specificite de 53 %. Conclusions Nous confirmons sur une serie importante que la TEP au FDG et a la MET sont des facteurs pronostiques independants de l’histologie. La TEP MET est l’examen de choix dans le suivi des gliomes de bas grade et permet de separer les gliomes de bas grade agressifs des autres.

A dermoid cyst of the posterior fossa in a 73-year-old man is reported. The presentation of the cyst was unusual because of the age of the patient, the spontaneously hyperdense aspect of the mass on CT, the partial rim enhancement of the lesion, and the presence of perilesional edema. On pathologic examination, the cyst contained small amount of fat, hairs, necrosis, and small areas of hemorrhage. The amount of hemorrhage found could not explain the spontaneous hyperdensity of the lesion found on CT. The hyperdensity may be related to high protein content of the lesion.

Introduction La glomerulonephrite extramembraneuse (GEM) idiopathique se caracterise par la presence d’anticorps (Ac) anti-PLA2R dans le serum dans ± 70 % des cas. En immunofluorescence (IF), une fixation granulaire et diffuse d’IgG et C3 le long des membranes basales glomerulaires est classique. Un immunomarquage positif avec toutes les classes des Ig (pattern « full house ») peut etre retrouve et erronement interprete. Observation Nous presentons une serie de 3 cas de syndrome nephrotique floride dont le diagnostic histologique de GEM lupique a ete propose sur base de ce pattern. En absence de tout tableau clinicobiologique evocateur de lupus, la presence d’Ac anti-PLA2R a rectifie le diagnostic. Le Tableau 1 reprend les principales caracteristiques des patients. Discussion Un pattern « full house » a l’IF peut erronement conduire a un diagnostic de GEM lupique. La recherche d’Ac anti-PLA2R sur serum et l’expression des PLA2Recepteurs sur tissu renal permettent d’orienter le diagnostic vers une GEM idiopathique. A notre connaissance, un seul cas de GEM idiopathique associant Ac anti-PLA2R et pattern « full house » a l’IF a ete decrit. La recherche et la description d’une telle association est utile au diagnostic et permet d’affiner au mieux le traitement immunosuppresseur. Dans notre experience, le developpement d’un lupus n’a pas ete observe et le pronostic renal est mediocre. Conclusion La positivite des Ac anti-PLA2R dans une GEM avec pattern « full house » a l’IF confirme le diagnostic de GEM idiopathique.

Exposure to aristolochic acid (AA, IARC Group 1 carcinogen) present in some traditional herbal medicines leads to aristolochic acid nephropathy (AAN), often complicated by development of multiple urothelial carcinomas of sequential onset. We used genome-scale mutational signature analysis of multiple urinary tract tumors of AAN cases from a unique patient group to determine the relationships of the patients’ late-onset second cancers to the AA exposure as well as to the first cancers. Aristolactam-DNA adduct-positive AAN patients (n=4) who developed cancer within 8 years following the initial exposure to AA were chosen for analysis of their first cancers (upper tract urothelial carcinomas, UTUC) and second cancers of delayed onset (1-9 years after first-cancer diagnosis, involving the bladder or ureteral meatus). All patients had received a kidney transplant before developing the second cancers and had a functional renal graft prior to prophylactic nephroureterectomy. Genomic DNAs were isolated from FFPE sections of the renal cortex and from the upper and lower tract tumors of each patient using laser capture micro-dissection or macro-dissection of the tumor areas. Low-coverage (~15x) exome 100-bp paired-end sequencing was performed using Illumina HiSeq2500. Customized variant calling identified somatic variants absent in non-tumor tissues. Non-negative matrix factorization was applied to extract mutational signatures in the tumor tissues. In all cases, we established the mutational signature of AA (the COSMIC signature 22) in the first UTUC as well as second cancers involving the bladder or lower ureter (meatus). Additionally, the first and second cancers harbored considerable overlaps in exposure-specific (A>T) somatic mutations. This finding provides evidence that the delayed onset of bladder urothelial carcinomas in AAN patients is likely due to distal seeding of cancer cells originating from the primary UTUC tumors. Our first-of-its-kind study addresses the risk as well as mechanistic factors leading to the second, late-onset bladder urothelial carcinomas following kidney transplantation and primary UTUC development. Our results underline the importance of long-term bladder follow-up in high-risk populations with established or suspected AA exposure. Funding: IARC; NYU Genome Technology Center is partially supported by the NIH/NCI (P30CA016087) grant. Citation Format: Xavier Castells, Maude Ardin, Sandrine Rorive, Nilufer Broeders, Yan Song, Stephanie Villar, Christine Carreira, Pierre-Paul Bringuier, Adriana Heguy, Thierry Quackels, Thierry Roumeguere, Joelle Nortier, Jiri Zavadil. Tracking the genetic relationship between first and late-onset second urothelial cancers by mutational signature analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5738. doi:10.1158/1538-7445.AM2017-5738

Intravesical instillation of bacillus Calmette-Guerin (BCG) is the treatment of choice for non-muscle-invasive bladder cancer (NMIBC) of high grade and/or carcinoma in situ. This study evaluated the feasibility, efficacy, and tolerance of BCG instillations in eight kidney recipients for end-stage aristolochic acid nephropathy (AAN), a condition at high risk of urothelial carcinoma, and diagnosed for NMIBC. Five of them had relapsed after mitomycin C treatment. Tolerance to BCG was evaluated clinically and regular follow-up with fluorescence cystoscopy was performed along with renal graft function monitoring. Immunosuppression doses were adjusted and prophylactic anti-tuberculous treatment given to reduce risks of graft rejection and infection. After a mean follow-up period of 50 months, seven of the eight patients are free of relapse and kidney graft function remained unchanged. Tolerance was good, except for one episode of fever and one early discontinuation because of subjective discomfort. No systemic tuberculous infection was observed. This is the first clinical observation of successful BCG therapy for NMIBC in patients given transplant for end-stage AAN. Under standardized conditions, immunotherapy based on intravesical BCG is feasible, effective, and well tolerated in renal transplantation.

Aristolochic acid (AA) causes aristolochic acid nephropathy (AAN), first described in women in Belgium accidently prescribed Aristolochia fangchi in a slimming treatment, and also Balkan endemic nephropathy (BEN), through probable dietary contamination with Aristolochia clematitis seeds. Both nephropathies have a high risk of urothelial cancer, with AA being the causative agent. In tissues of AAN and BEN patients, a distinct DNA adduct, 7-(deoxyadenosin-N6-yl)-aristolactam I (dA-AAI), has been detected. DNA adducts can be removed through DNA repair, they can result in mutations through erroneous DNA replication or they can cause cell death. The dA-AAI adduct induces AT to TA transversions in the tumor-suppressor TP53 gene in experimental systems, matching TP53 mutations observed in urothelial tumors from AAN cancer cases. Using thin-layer chromatography 32P-postlabeling and mass spectrometric analysis we report the detection of dA-AAI in renal DNA from 11 Belgian AAN patients over 20 years after exposure to AA had ceased. Our results showed that dA-AAI is an established biomarker of AA exposure, and that this biomarker can be demonstrated to be persistent decades after a distinct AA exposure. Further, the persistence of dA-AAI adducts appears to be a critical determinant for the AA mutational fingerprint frequently found in oncogenes and tumor suppressor genes recently identified by whole genome sequencing of AA-associated urothelial tumors. The potential for exposure to AA worldwide is high; the unprecedented long-term persistence of dA-AAI provides a useful long-term biomarker of exposure and attests to the role of AA in human urothelial malignancy.

Despite advances in diagnosis and treatment, the overall outcomes for patients with brain tumors remain unpredictable. New prognostic markers are still needed to identify high-risk patients for whom the standard treatment has poor outcomes and would thus be well suited for more aggressive therapies. Neovascularization has long been implicated as a salient feature of glioma progression. In fact, high-grade gliomas are among the most vascular of all solid tumors, and vascular proliferation is a pathological hallmark of glioblastomas. Galectins are known to play important roles in cancer biology, including cancer cell migration, tumor immune escape or tumor angiogenesis. Moreover, galectins were reported to be involved in glioma progression. Given the key role of angiogenesis in brain tumors, the expression of galectins in tumor-associated endothelial cells (EC) and the implication of galectins in angiogenesis, the present review will focus on the expression of galectins in ECs of normal brain and brain tumors.

Aims The assessment of thyroid nodules is a common clinical challenge. Fine-needle aspiration (FNA) is the standard pre-operative tool for thyroid nodule diagnosis. However, up to 30% of the samples are classified as indeterminate. This often leads to unnecessary surgery. In this study, we evaluated the added value of next-generation sequencing (NGS) for helping in the diagnosis of FNA samples. Methods and results We analysed retrospectively 34 indeterminate FNA samples for which surgical resection was performed. DNA was obtained from cell blocks or from stained smears and subjected to NGS to analyse mutations in 50 genes. Mutations in BRAF, NRAS, KRAS and PTEN, that are known to be involved in thyroid cancer biology, were detected in seven FNA samples. The presence of a mutation in these genes was a strong indicator of cancer because five (71%) of the mutation-positive FNA samples had a malignant diagnosis after surgery. Moreover, there was only an 8% cancer risk in nodules with an indeterminate cytological diagnosis but with a negative molecular test. Conclusion This study demonstrates that thyroid FNA can be analysed successfully by NGS. The detection of mutations known to be involved in thyroid cancer improves the sensitivity of thyroid FNA diagnosis.

Whole slide scanners are novel devices that enable high-resolution imaging of an entire histological slide. Furthermore, the imaging is achieved in only a few minutes, which enables image rendering of large-scale studies involving multiple immunohistochemistry biomarkers. Although whole slide imaging has improved considerably, locally poor focusing causes blurred regions of the image. These artifacts may strongly affect the quality of subsequent analyses, making a slide review process mandatory. This tedious and time-consuming task requires the scanner operator to carefully assess the virtual slide and to manually select new focus points. We propose a statistical learning method that provides early image quality feedback and automatically identifies regions of the image that require additional focus points., SCOPUS: ar.j, info:eu-repo/semantics/published

The nuclear DNA content (DNA ploidy) level was determined in a series of 83 human brain metastases, for which 35 complete clinical follow-ups were available. The DNA ploidy level determination was carried out by means of DNA histogram types. The results show that certain brain metastases were diploid, while others exhibited aneuploidy levels ranging from low to very high. The present study also shows that a significant proportion, i.e. 18%, of the 83 brain metastases, exhibited very high levels of aneuploidy, i.e. hypertetraploidy, hyperpentaploidy and octoploidy. We have previously observed that this feature appeared only rarely, i.e. in less than 2% of primary nervous tumours. Furthermore, the present study shows that DNA ploidy level in brain metastases is related significantly (P0.001) to patient survival. Indeed, while 9/13 (69%) patients with diploid brain metastases survived longer than 9 months, none (0%) of the 22 patients with aneuploid brain metastases survived longer than the 9 months following the diagnosis of their brain metastases.

SCOPUS: no.j, info:eu-repo/semantics/published

BACKGROUND: Aristolochic acids are nephrotoxins and predispose to upper-tract urothelial carcinoma. The risk of bladder urothelial carcinoma after kidney transplantation and its relationship to upper-tract urothelial carcinoma is not well defined. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: Single-center cohort of 38 women given kidney transplants for end-stage aristolochic acid nephropathy. OUTCOMES & MEASUREMENTS: The prevalence of upper urinary tract urothelial carcinoma was determined by collecting pathological results of specimens obtained by means of bilateral ureteronephrectomy. We also established the cumulative incidence of bladder urothelial carcinoma in biopsies performed during prospective screening cystoscopies during a 15-year follow-up. RESULTS: Upper-tract urothelial carcinoma was found in 17 patients with aristolochic acid nephropathy (44.7%). During follow-up, bladder urothelial carcinoma was diagnosed in 15 patients 68 to 169 months after cessation of aristolochic acid exposure (39.5%): 8 urothelial carcinoma in situ, 4 noninvasive low-grade papillary urothelial carcinoma, and 3 infiltrating urothelial carcinoma. 12 of 17 patients (71%) with a history of upper-tract urothelial carcinoma developed bladder urothelial carcinoma during follow-up, whereas this occurred in only 3 of 21 patients (14%) without upper-tract urothelial carcinoma (P < 0.01). Despite local and/or systemic chemotherapy, 3 patients died and 2 radical cystectomies were performed. LIMITATIONS: Small sample size of this case series. CONCLUSIONS: Upper-tract and bladder urothelial carcinoma are dramatic complications in kidney transplant recipients with aristolochic acid nephropathy, confirming the carcinogenic properties of aristolochic acids. We identified upper-tract urothelial carcinoma as a potent risk factor for the subsequent development of bladder urothelial carcinoma after kidney transplantation for aristolochic acid nephropathy. Because this complication may occur years after aristolochic acid discontinuation, we suggest regular cystoscopies in addition to the bilateral ureteronephrectomy in kidney transplant recipients with aristolochic acid nephropathy.

The influence of five anti-hormone and/or anti-growth factor neutralizing antibodies on the in vitro proliferation of four human astrocytic tumor cell lines (U87, U138, U373, H4) is quantitatively described by means of a new tool which makes it possible to evaluate cell growth and cell clone architecture concomitantly. This tool relies upon the combined use of the digital cell image analyses of Feulgen-stained nuclei and the Delaunay and Voronoi mathematical triangulation and paving techniques. Of the five anti-hormone and/or anti-growth factors tested here, the anti-luteinizing hormone-releasing hormone (LHRH) antibody induced the most marked perturbation in the U138 and U373 cell lines, whereas this role was played by the anti-epidermal growth factor (EGF) antibody in the U87 and H4 cell lines. The anti-gastrin (G) antibody significantly modified the growth and/or cell clone architecture of the U138, U87 and H4 cell lines, as did the anti-transforming growth factor alpha (TGFalpha) antibody. The anti-transforming growth factor beta (TGFbeta) antibody modified the growth and/or cell clone architecture of the four cell lines under study. If the five antibodies are taken into consideration, the results strongly suggest that four (the anti-G, the anti-EGF, the anti-LHRH and the anti-TGFalpha) act as inhibitory agents on some glioma cell line proliferation, while the fifth one, i.e. the anti-TGFbeta, act as a stimulator of cell proliferation, perhaps by abrogating the inhibitory effects of TGFbeta on proliferation. A comparison of cell growth data with cell clone architecture characteristics provided further evidence of some specific influence exercised by a given hormone and/or growth factor on glioma cell proliferation. Indeed, the anti-LHRH antibody caused the most pronounced perturbations in the U138 and U373 cell clone architecture; this feature was observed in the H4 cell line and, to a lesser extent in the U87 one after the anti-EGF antibody had been used.

Whole-slide scanners allow the digitization of an entire histological slide at very high resolution. This new acquisition technique opens a wide range of possibilities for addressing challenging image analysis problems, including the identification of tissue-based biomarkers. In this study, we use whole-slide scanner technology for imaging the proliferating activity patterns in tumor slides based on Ki67 immunohistochemistry. Faced with large images, pathologists require tools that can help them identify tumor regions that exhibit high proliferating activity, called "hot-spots" (HSs). Pathologists need tools that can quantitatively characterize these HS patterns. To respond to this clinical need, the present study investigates various clustering methods with the aim of identifying Ki67 HSs in whole tumor slide images. This task requires a method capable of identifying an unknown number of clusters, which may be highly variable in terms of shape, size, and density. We developed a hybrid clustering method, referred to as Seedlink. Compared to manual HS selections by three pathologists, we show that Seedlink provides an efficient way of detecting Ki67 HSs and improves the agreement among pathologists when identifying HSs.

Background More than 25% of bladder cancer (BC) cases are still muscle-invasive at first diagnosis. Screening is unproven to enable the detection of more non–muscle-invasive tumors. BC association with aristolochic acid nephropathy (AAN) was reported after intake of slimming pills containing Chinese herbs. Objective We evaluated whether a BC screening protocol in a high-risk and unique patient population had an impact on the stage of tumor presentation. Design, setting, and participants Forty-eight AAN-affected patients were enrolled in a screening program, establishing BC incidence during prospective screening cystoscopies and biopsies biannually for up to 10 yr. Two patients were lost to follow-up, and three refused screening after consenting. Measurements Patients were evaluated for presence of BC and tumor stage at diagnosis. Results and limitations BC was diagnosed in 25 patients (52%). Among 43 patients who underwent screening cystoscopies (median follow-up: 94 mo), 22 were first diagnosed with non–muscle-invasive BC but none with muscle-invasive tumors and none died of BC. Three women who declined follow-up were diagnosed and died with advanced metastatic disease. The limitations of our findings include the small sample size of this case series, the absence of a real control group, and the particular risk factor in these patients that differs from the usual risk factors, such as smoking or industrial chemicals. Conclusions BC screening in high-risk groups may allow identification of tumors before muscle invasion. The optimal screening schedule and the relevance of the present findings in smoking-related BC remain to be defined.

Objective Integrating positron emission tomographic (PET) images into the image-guided resection of high-grade gliomas (HGG) has shown that metabolic information on tumor heterogeneity and distribution are useful for planning surgery, improve tumor delineation, and provide a final target contour different from that obtained with magnetic resonance imaging (MRI) alone in about 80% of the procedures. Moreover, PET guidance helps to increase the amount of tumor removed and to target image-guided resection to anaplastic tissue areas. The present study aims to evaluate whether PET-guided volumetric resection (VR) in supratentorial HGG might add benefit to the patient's outcome. Methods PET images using [18F]fluorodeoxyglucose (n=23) and [11C]methionine (n=43) were combined with MRI scans in the planning of VR procedures performed at the initial stage in 66 consecutive patients (43 M/23 F) with supratentorial HGG according to the technique previously described. In all cases (35 anaplastic gliomas [20 astrocytomas, 10 oligoastrocytomas, 5 oligodendrogliomas] and 31 glioblastomas [GBM]), level and distribution of PET tracer uptake were analyzed to define a PET contour projected on MRI scans to define a final target contour for VR. Maximal tumor resection was accomplished in each case, with the intention to remove the entire abnormal metabolic area comprised in the surgical planning. Early postoperative MRI and PET assessed tumor resection. Survival analysis was performed separately in anaplastic gliomas and glioblastoma multiforme according to the presence or absence of residual tracer uptake on postoperative PET and according to the presence or absence of residual contrast enhancement on postoperative MRI. Results Preoperatively, metabolic information helped the surgical planning. In all procedures, PET contributed to define a final target contour different from that obtained with MRI alone. Postoperatively, 46 of 66 patients had no residual PET tracer uptake (total PET resection), 23 of 66 had no residual MRI contrast enhancement. No additional neurological morbidity due to the technique was reported. A total PET tracer uptake resection was associated with a significantly longer survival in anaplastic gliomas (P = 0.0071) and in glioblastoma multiforme (P = 0.0001), respectively. A total MRI contrast enhancement resection was not correlated with a significantly better survival, neither in anaplastic gliomas (P = 0.6089) nor in glioblastoma multiforme (P = 0.6806). Conclusions Complete resection of the increased PET tracer uptake prolongs the survival of HGG patients. Because PET information represents a more specific marker than MRI enhancement for detecting anaplastic tumor tissue, PET-guidance increases the amount of anaplastic tissue removed in HGG.

Insulin-like growth factor II (IGFII) acts as a potent mitogen for several tumor types and has been reported to positively influence astrocytoma cell growth and motility. In the central nervous system, IGFII bioavailability is mainly modulated by insulin-like growth factor binding protein 2 (IGFBP2), which sequestrates IGFII and therefore prevents its interaction with the type-1 IGF receptor (IGF-IR). Proteolysis of IGFBP2 is the predominant mechanism recognized to reduce the binding affinity of IGFBP2 for IGFII, thus favoring dissociation of IGFII from the IGFBP2-IGFII complex. It is known that certain proteases involved in astrocytoma malignancy, such as matrix metalloproteinase-7 (MMP-7), plasmin, and cathepsin D, are able to proteolyze IGFBP2 in vitro. The present study aims to investigate whether other proteases expressed by astrocytomas, specifically MMP-2, MMP-9, and membrane-type 1 matrix metalloprotease (MT1-MMP), are able to proteolyze the IGFBP2-IGFII complex. Our results show the following: (i) MMP-9 proteolyzes the IGFBP2-IGFII complex in vitro, while MMP-2 and MT1-MMP do not; (ii) this MMP-9-induced IGFBP2-IGFII complex proteolysis releases free IGFII, which contributes to enhance the motility and the growth of LN229 astrocytoma cells. Furthermore, this study also highlights that the formation of the IGFBP2-IGFII complex inhibits IGFBP2's cell motility promoting effect by reducing the pool of free IGFBP2. In conclusion, MMP-9-induced IGFBP2 proteolysis may be regarded as an important post-translational event involved in astrocytoma aggressiveness. These new findings support drug targeting of MMP-9 as an interesting approach in the treatment of astrocytoma., Journal Article, Research Support, Non-U.S. Gov't, FLWIN, info:eu-repo/semantics/published

Von Hippel-Lindau (VHL) disease is a dominant autosomal disorder inducing the development of many tumors, such as hemangioblastomas in the central nervous system and retina, cysts or tumors (benign or malignant) in the kidneys and/or the pancreas. We report the case of a pregnant woman who presented with a voluminous hemorrhagic cyst of the right kidney with an exophytic lesion detected in the lower median part of the cyst wall. As an anamnestic inquiry resulted in a familial history of VHL disease, a screening imaging was performed and detected three medullary hemangioblastomas. Considering the active bleeding of the renal cyst and its potential malignancy, a unilateral nephrectomy was carried out after pregnancy interruption. Histological analysis confirmed a multilocular clear cell renal carcinoma. This case underlines the importance of screening procedures such as abdominal ultrasonography and medullary magnetic resonance imaging in all pregnant women with a familial history of VHL disease.

Skin rejection after hand transplantation is characterized by a maculopapular erythematous rash that may be diffuse, patchy or focal, and distributed over forearms and dorsum of the hands. This 'classical' pattern of rejection usually spares the skin of the palm and does not affect the nails. Herein, we report the experience on four cases presenting with an 'atypical' pattern of rejection that is novel in involving the palmar skin and the nails. All patients were young and exposed to repetitive and persistent mechanical stress of the palm. Characteristic features of rejection included a desquamative rash associated with dry skin, red papules, scaling and lichenification localized to the palm. Skin lesions were associated with nail dystrophy, degeneration, deformation or loss. Histology of the skin and nail bed revealed a lymphocytic infiltrate with predominance of T cells (CD3+, CD4+ and CD8+), with small numbers of B cells (CD20+ and CD79a+) and a low number of Forkhead transcription factor 3 (FOXP3)-positive cells in one patient. The lesions persisted over weeks to months, responded poorly to steroid treatment and were managed with antithymocyte globulin (ATG; Thymoglobulin, Genzyme, Cambridge, MA), alemtuzumab and/or intensified maintenance immunosuppression.

Aims: Tenascin-C (TN-C) is an extracellular matrix brain glycoprotein for which conflicting in vitro and in vivo results are reported in the literature dealing with its involvement in astrocytoma aggressiveness, in particular astrocytoma invasion. In view of these conflicting results and the lack of data available on low-grade astrocytomas, the present study focuses on pilocytic World Health Organization (WHO) grade I, and diffuse WHO grade II astrocytomas, that is, two histological entities associated with very different invasive abilities. Methods: Using real-time reverse transcription polymerase chain reaction and immunohistochemistry, we analysed the TN-C expression in normal brain tissue as well as in a series of 54 pilocytic and 53 grade II astrocytomas. Conclusions: Our data on normal brain showed that while TN-C is largely expressed in supratentorial white matter, it was largely absent in infratentorial white matter. Paralleling these observations, we showed that TN-C expression in low-grade astrocytomas similarly varies according to tumour site. Cox regression analysis evidenced that TN-C provided an independent prognostic value which is enhanced in the case of grade II astrocytomas for which positive TN-C expression is associated with a higher risk of recurrence. We also analysed TN-C expression specifically in vascular areas of low-grade astrocytomas without demonstrating any prognostic value for this additional feature. Results: Similarly to normal brain, low-grade astrocytomas exhibit variations in TN-C expression with site, and this expression is associated with an independent prognostic value in terms of recurrence.

Systematic human pathological background to brain tumor radiosurgery explaining biological and pathophysiological effects of focused irradiation barely exists. The goal of this study was to explore histopathological changes evoked by single high-dose irradiation in a set of different brain tumors following Gamma Knife radiosurgery (GKRS). Light microscopy revealed that GKRS evokes degenerative and proliferative pathological changes in the parenchyma, stroma and vessels of the irradiated tumors. Three main histological types of gamma radiolesions, that is acute, subacute and chronic variants of tissue reactions were recognized in different neoplasms irrespective of their ontogenetic nature. Acute type gamma radiolesions were characterized mainly with necrotic changes and appeared either early or in a delayed time interval. Subacute type gamma radiolesions expressed resorptive activity also with early or delayed chronology. Chronic type lesions showed a reparative tendency but presented only at the delayed stage. These changes seem to follow each other consecutively. There was no significant relation between morphological characteristics of the generated tissue reaction and the time interval elapsed after GKRS. This relative time and environment autonomy of the developed pathological lesions with similar histological picture in different neoplasms suggests either a vascular mechanism or/and a genetically directed origin presumably induced by the ionizing energy of high-dose irradiation.

Systematic human pathological background to brain tumor radiosurgery explaining biological and pathophysiological effects of focused irradiation barely exists. The goal of this study was to explore histopathological changes evoked by single high-dose irradiation in a set of different brain tumors following Gamma Knife radiosurgery (GKRS). Light microscopy revealed that GKRS evokes degenerative and proliferative pathological changes in the parenchyma, stroma and vessels of the irradiated tumors. Three main histological types of gamma radiolesions, that is acute, subacute and chronic variants of tissue reactions were recognized in different neoplasms irrespective of their ontogenetic nature. Acute type gamma radiolesions were characterized mainly with necrotic changes and appeared either early or in a delayed time interval. Subacute type gamma radiolesions expressed resorptive activity also with early or delayed chronology. Chronic type lesions showed a reparative tendency but presented only at the delayed stage. These changes seem to follow each other consecutively. There was no significant relation between morphological characteristics of the generated tissue reaction and the time interval elapsed after GKRS. This relative time and environment autonomy of the developed pathological lesions with similar histological picture in different neoplasms suggests either a vascular mechanism or/and a genetically directed origin presumably induced by the ionizing energy of high-dose irradiation.

The pathophysiology of atypical haemolytic-uraemic syndrome (aHUS) occurring de novo after renal transplantation may include genetic mutations of regulators of complement activation, but they are still rarely determined. A 41-year-old female renal transplant recipient presented two very different episodes of thrombotic microangiopathy. The first episode was associated with antibody-mediated rejection and the second was an isolated, acute aHUS, successfully treated with eculizumab. The diagnosis included a genetic analysis and we found a synonymous variant in the Complement Factor H (CFH) gene, c2634C>T (p.His878=) and low factor H (FH) activity during both events. In conclusion, the diagnosis of aHUS should be considered when TMA is associated with an AMR episode. In this setting, a silent polymorphism of factor H may be responsible for these rare cases of "de novo" aHUS after transplantation.

OBJECTIVE: To evaluate the interest of integrating positron emission tomography (PET) images with the radiolabeled tracer [11C]methionine (Met) into the image-guided navigation planning of infiltrative low-grade brain tumors (LGBTs) in children. METHODS: Twenty-two children underwent combined Met-PET with magnetic resonance imaging (MRI) scans in the planning of a navigation procedure. These children presented an LGBT (astrocytomas, 10; oligodendrogliomas, 4; ependymomas, 4; gangliogliomas, 4) located close to functional areas. Tumor boundaries were ill-defined on MRI (including T2-weighted and fluid-attenuated inversion-recovery scans) and could not be clearly identified for allowing a complete, or at least a large, image-guided resection. The PET tracer Met was chosen because of its higher sensitivity and specificity than MRI to detect tumor tissue. The level and extension of MET uptake were analyzed to define the PET contour, subsequently projected onto MRI scans to define a final target contour for volumetric resection. The quality of tumor resection was assessed by an early postoperative MRI and Met-PET workup. RESULTS: In 20 of the 22 children with ill-defined LGBTs, PET improved tumor delineation and contributed to define a final target contour different from that obtained with MRI alone. Met-PET guidance allowed a total resection of Met uptake in 17 cases that were considered total tumor resections because the operative margin left in place contained nontumor tissue. CONCLUSION: These data suggested that Met-PET guidance could help to improve the number of total resections and the amount of tumor removed in infiltrative LGBTs in children.

Laser-assisted microdissection has become a unique technique for an accurate gene-expression profiling analysis in human tissues. The introduction of this approach requires the development of a reliable, efficient, and reproducible procedure for tissue processing. We report a systematic evaluation of the different relevant steps required to obtain sufficient quantity and good quality RNA for reverse transcriptase-polymerase chain reaction when using frozen surgical pathologic tissues as starting material. We propose an optimized and very efficient method with respect to time and effort that can easily be put into practice in research laboratory as well as in any pathology laboratory.

In the mouse and the rat brain, the Ets transcription factor pet-1 is exclusively expressed in the central serotonin (5-hydroxytryptaminergic: 5-HT) system. In pet-1 null mice, the defect of this factor induces early disruption of the 5-HT function, resulting in an increase in anxiety and aggression; thus indicating its pivotal role in this system. Here, we studied the expression of fev, the homologue of pet-1, in the human brain. We showed that this transcription factor is exclusively expressed in the midline part of the human brainstem containing raphe nuclei, which also specifically expressed 5-HT transporter (sert) and tryptophan hydroxylase (tph), two markers of the 5-HT neurotransmitter system. This clearly suggests that fev is expressed in human serotonergic neurons. While the deficiency of the central serotonergic signaling is a major factor involved in the development of some psychiatric disorders, Fev could be a good diagnosis marker as well as a good target for pharmacological treatments of these patients.

Pleomorphic xanthoastrocytoma (PXA) is a rare brain glial tumour found in young patients. Most cases are reported as evolving low-grade neoplasms associated with a long survival after complete surgical resection. Some PXAs, however, can demonstrate secondary malignant transformation or progress with a short survival. Anaplastic histological features at first presentation or secondary meningeal dissemination have rarely been reported.We describe the case of a cerebral PXA in a 7-year-old girl presenting with anaplastic histological features and craniospinal meningeal dissemination that progressed rapidly with a poor outcome.