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Although tumorigenesis is dependent on the reprogramming of cellular metabolism, the metabolic pathways engaged in the formation of metastases remain largely unknown. The transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) plays a pleiotropic role in the control of cancer cell metabolism and has been associated with a good prognosis in prostate cancer. Here, we show that PGC1α represses the metastatic properties of prostate cancer cells via modulation of the polyamine biosynthesis pathway. Mechanistically, PGC1α inhibits the expression of c-MYC and ornithine decarboxylase 1 (ODC1), the rate-limiting enzyme for polyamine synthesis. Analysis of in vivo metastases and clinical data from patients with prostate cancer support the proposition that the PGC1α/c-MYC/ODC1 axis regulates polyamine biosynthesis and prostate cancer aggressiveness. In conclusion, downregulation of PGC1α renders prostate cancer cells dependent on polyamine to promote metastasis. Significance: These findings show that a major regulator of mitochondrial metabolism controls polyamine synthesis and prostate cancer aggressiveness, with potential applications in therapy and identification of new biomarkers.

Background Currently, there are no histological criteria to diagnose irritable bowel syndrome (IBS). Our aims were (i) to examine the distribution of inflammatory cells in the colon of healthy and IBS subjects and (ii) to find histological diagnosis criteria for IBS. Methods Colonic biopsies were taken from four distinct regions of the colon from 20 controls (HC) and 11 patients with IBS (4 with constipation (IBS-C) and 7 with diarrhea (IBS-D) and embedded in paraffin. Macrophages, mast cells, eosinophils, and T lymphocytes were immunostained and positive cells counted. Key Results In both HC and IBS patients, global cellularity decreased from the cecum to the rectum (P

Introduction Cancer population studies require reliable and complete baseline data, which should theoretically be available by collecting histopathology records. The completeness of such a collection was evaluated using capture–recapture analysis based on three data sources concerning breast and colorectal cancers over an identical period and within the same geographical area. Method The total number of breast and colon cancer cases was estimated using capture–recapture analysis based on the number of cases which were common or not between sources recording screened, diagnosed and treated cancers in the French Alpes Maritimes district. Result The estimated total number of new cases of breast cancer diagnosed among Alpes Maritimes residents women aged 50–75 was 791 (95% CI: 784–797) in 2008. Of these 791 cases, 729 were identified through histopathology records, thus amounting to 92.2% completeness (95% CI: 91.5–93.0%). The total estimated number of new cases of colorectal cancer diagnosed among Alpes Maritimes residents aged 50–75 was 527 (95% CI: 517–536). Of these 527 cases, 481 were identified through histopathology records, thus amounting to 91.3% completeness (95% CI: 89.7–93.0%). Conclusion The estimated completeness of cancer records collected from histopathology laboratories was higher than 90% for new cases of breast and colorectal cancer within the age range concerned by the screening programme. A verified and validated histopathology data collection may be useful for cancer population studies.

Testicular germ cell cancers are the most common solid malignancies in young men, but their pathogenesis remains undetermined although some epidemiological data have implicated both environmental and genetic factors. Glial cell-derived neurotrophic factor (GDNF) is secreted by Sertoli cells, and promotes germ stem cell proliferation by activating RET, a tyrosine kinase receptor. Over-expression of GDNF in adult transgenic mice induces the development of testicular tumours that mimic human seminoma, the most frequent testicular germ cell tumour. Activating mutations of RET were previously reported in several types of cancer, including thyroid, pituitary, adrenal and melanoma cancer. Both mouse experimental model and clinical studies suggested that mutations or selective polymorphisms of RET might be associated with human seminoma. To verify this hypothesis, we conducted this study in a French University Hospital and carried out an association study using tissue samples from 66 paraffin-embedded seminoma tumours. The most frequently mutated exons of the RET proto-oncogene were sequenced to identify mutations or selective polymorphisms. No somatic mutations were identified. The polymorphic variants frequencies did not differ from those in a control Caucasian population. Human classical seminoma that occurs in young men does not appear to be linked with mutations or relevant polymorphisms of RET.

Le diagnostic et le grading histologiques jouent un role important dans la prise en charge des cancers prostatiques. Une mise a jour de la classification OMS a ete publiee en 2004. Les cancers prostatiques sont classes en plusieurs types en fonction de leur site presume d’origine et de leur aspects morphologiques: (i) les adenocarcinomes acineux. Il s’agit de la forme la plus frequente. La majorite des etudes concernant le grade, le stade et la prise en charge therapeutique concernent ces tumeurs. Il existe des variantes histologiques correspondant aux formes atrophiques, pseudohyperplasiques, a cellules spumeuses, a cellules oncocytaires, aux formes de type lymphoepithelial et de type sarcomatoide. Le profil immunohistochimique de ces tumeurs est defini par plusieurs marqueurs: antigene prostatique specifique, phosphatase acide prostatique et alpha-methyl-CoA racemase. On utilise les anticorps anti cytokeratine 34βE12 et p63 pour mettre en evidence les cellules basales pour le diagnostic differentiel avec les lesions glandulaires benignes; (ii) les adenocarcinomes canalaires, les carcinomes urotheliaux et squameux, les carcinomes a cellules basales, les tumeurs neuroendocrines, qui sont des tumeurs rares et agressives; (iii) les tumeurs mesenchymateuses.

The altered metabolism of cancer cells is a treasure trove to discover new antitumoral strategies. The gene (SLC7A5) encoding system L amino-acid transporter 1 (LAT1) is overexpressed in murine lymphoma cells generated via T-cell deletion of the pten tumor suppressor, and also in human T-cell acute lymphoblastic leukemia (T-ALL)/lymphoma (T-LL) cells. We show here that a potent and LAT1 selective inhibitor (JPH203) decreased leukemic cell viability and proliferation, and induced transient autophagy followed by apoptosis. JPH203 could also alter the in vivo growth of luciferase-expressing-tPTEN-/- cells xenografted into nude mice. In contrast, JPH203 was nontoxic to normal murine thymocytes and human peripheral blood lymphocytes. JPH203 interfered with constitutive activation of mTORC1 and Akt, decreased expression of c-myc and triggered an unfolded protein response mediated by the C/EBP homologous protein (CHOP) transcription factor associated with cell death. A JPH203-resistant tPTEN-/-clone appeared CHOP induction deficient. We also demonstrate that targeting LAT1 may be an efficient broad spectrum adjuvant approach to treat deadly T-cell malignancies as the molecule synergized with rapamycin, dexamethasone, doxorubicin, velcade and l-asparaginase to alter leukemic cell viability.

Introduction Le pronostic des carcinomes epidermoides cutanes (CEC) inoperables est pejoratif. Le cetuximab est utilise hors AMM dans les CEC localement evolues ou metastatiques. Le statut mutationnel des genes KRAS et NRAS est utilise comme marqueur predictif de l’efficacite du cetuximab dans les cancers colorectaux metastatiques (CCRm). L’objectif principal de ce travail etait de determiner la prevalence des mutations KRAS , NRAS , BRAF , HRAS et EGFR dans les CEC et de determiner l’impact de ces mutations sur la reponse au cetuximab. L’objectif secondaire etait d’etudier l’efficacite du cetuximab en monotherapie. Materiel et methodes Etude retrospective chez des patients traites par cetuximab en monotherapie ces dix dernieres annees dans trois centres d’oncologie cutanee et pour lesquels nous disposions d’une biopsie cutanee avant traitement. L’analyse mutationnelle faite sur les genes EGFR (exons 18 a 21), KRAS (exons 2, 3, 4), NRAS (exons 2, 3), HRAS (exons 2 et 3) et BRAF (exon 15), a ete realisee dans le laboratoire de genetique des tumeurs solides du CHU de Nice. Resultats Trente patients ont ete inclus (21H, 9F) avec un âge median de 86 ans (48–96). La majorite des patients (70 %) avait un CEC de l’extremite cephalique. Onze avaient un CEC localement evolue, 13 une atteinte ganglionnaire et 6 metastatique. Pour 26 d’entre eux, le cetuximab etait la 1 re ligne de traitement systemique. Le suivi median etait de 6,5 mois. Le taux de controle de la maladie a 6 semaines de traitement etait de 63 %, avec 1 reponse complete, 13 reponses partielles, 5 stabilites et 11 progressions tumorales. Une seule mutation, dans l’exon 2 du gene NRAS (codon 12 : C35.G > A), a ete detectee chez une patiente ayant eu une reponse partielle apres 6 semaines de cetuximab. Aucune mutation des genes KRAS , EGFR ou BRAF n’a ete observee. L’analyse mutationnelle du gene HRAS est en cours de realisation. Discussion Les etudes relatives au statut mutationnel du CEC sont peu nombreuses et ont ete realisees sur de faibles effectifs. Notre serie de 30 patients est, a notre connaissance, la plus importante a ce jour. Nous rapportons la premiere mutation du gene NRAS (c35.G > A) d’un CEC, sans qu’elle soit predictive d’une resistance au traitement puisqu’une reponse partielle a ete observee chez cette patiente. Bien que les mutations du gene EGFR aient ete decrites dans 3 % des CEC, aucune n’a ete trouvee dans notre serie. Sous reserve du resultat de l’analyse des mutations HRAS , cette etude souligne le faible pourcentage de mutations dans ces genes. Le taux de controle de la maladie de 63 % est comparable aux donnees de la litterature. Conclusion Compte tenu de la prevalence tres faible des mutations dans les genes KRAS , NRAS , BRAF et EGFR dans les CEC, leur recherche comme facteur predictif de reponse au cetuximab n’apparait pas pertinente.

The majority of endodermal cysts occur in the cervicothoracic spine, ventral to the cord. Intracranial locations are rare. We report a case involving the foramen magnum in a 14-year-old child, which was an incidental finding following a traumatic head injury. A review of the literature revealed six other cases involving this same location. These lesions are asymptomatic for a long time, and may cause brain stem medullary compression. Treatment is surgical. Effective simple removal can be achieved by a posterior approach.

The evoked expression of the immediate-early gene-encoded proteins c-Fos and Krox-24 was used to study activation of mesodiencephalic structures as a function of the development of cyclophosphamide (CP) cystitis in behaving rats. This article is the third of a series and completes previously published data obtained at both spinal and hindbrain levels. CP-injected animals received a single dose of 100 mg/kg i.p. under transient volatile anesthesia and survived for 1-4 h in order to cover the entire postinjection period during which the disease develops. Survival times longer than 4 h were not used owing to ethical considerations. Results from CP-injected groups are compared with those from either noninjected controls or saline-injected animals having survived for the same times as CP-injected ones. Quantitative results come from c-fos expression. At mesodiencephalic levels a high and widespread basal c-fos expression was observed in control animals; maximum staining was observed at the midthalamic level. Four groups of nuclei were identified with regard to the density of staining. The first group included nuclei showing clustered, intensely labeled cells; these areas were restricted in extent and related to the maintenance of circadian rythms (intergeniculate leaf, suprachiasmatic nucleus, dorsal parts of either paraventricular thalamic nuclei or central gray), sleep-arousal cycle (supramamillary nucleus), or changes in arterial pressure (laterodorsal tegmental nucleus). The second group included nuclei showing scattered, moderately labeled cells; these areas were widespread at all rostrocaudal levels and related to either autonomic/neuroendocrine regulations (central gray, lateral habenula, hypothalamus) or motor behavior, orienting reflex and oculomotor coordination (unspecific subdivisions of both colliculi and their adjoining mesencephalic regions, zona incerta dorsal). The third group included nuclei with evenly distributed, faintly labeled cells; these areas, which, with few exceptions, covered almost the entire diencephalon, mainly concerned nuclei of multisensory convergence having functions in either discriminative tasks (laterodorsal and lateroposterior thalamic nuclei) or emotional responses (intralaminar and midline thalamic nuclei). The fourth group included nuclei free of labeling; these were areas that received the bulk of unimodal sensory/motor inputs (central inferior colliculus, pretectal optic nuclei, ventral medial geniculate nucleus, ventral anterior pretectal nucleus, dorsal lateral geniculate nucleus, ventrobasal complex; zona incerta ventral, parafascicular thalamic nucleus) and are thus the most discriminative regarding specific modalities. Variations in staining were of the same magnitude in both saline- and CP-injected animals. A sequential study spanning every postinjection hour revealed maximum staining at 1 h postinjection, which was followed by a progressive, time-related decrease. Increases in the number of labeled cells 1 h postinjection were significant in only a restricted number of nuclei showing low basal expression (Edinger-Westphal nucleus and paraventricular, supraoptic, and lateral hypothalamic nuclei); time-related reductions in staining that were correlated to sleep or quiescence behaviors finally resulted in staining equal to or below that seen in control animals. No structures showed significantly increased staining in relation to the full development of cystitis, i.e., with the increase of visceronociceptive inputs. Comparing the present results with those previously obtained at more caudal levels, it appears that subtelencephalic levels primarily driven by visceronociceptive inputs, i.e., those that increase and/or maintain their activity in parallel with the degree of nociception, are confined to brainstem-spinal cord junction levels and only comprise certain subdivisions of the nucleus of the solitary tract (nucleus medialis, nucleus commissuralis, and ventralmost part of area po

The evoked expression of the immediate early gene-encoded proteins c-Fos and Krox-24 was used to study activation of hindbrain neurons as a function of the development of cyclophosphamide (CP) cystitis in behaving rats. CP-injected animals received a single dose of 100 mg/kg i.p. under transient volatile anesthesia and survived for 1 to 4 h in order to cover the whole postinjection period during which the disease develops. CP-injected groups included: (1) animals with minor simple chorionic edema, an early characteristic of inflammation (1 h postinjection); (2) animals with well-developed simple chorionic edema (2 h postinjection); (3) animals with mild inflammation (chorionic edema accompanied by epithelial cleavage; 3 h postinjection); and (4) animals with complete inflammation (4 h postinjection). In addition to onset of chorionic edema, the earliest postinjection period also included the general aspects of the nervous reaction consecutive to the injection process (handling, transient volatile anesthesia and postanesthesia awakening, abdominal pinprick, CP-blood circulating effects). Controls included both noninjected animals and saline-injected animals surviving for the same times as CP-injected ones. Quantitative results come from c-Fos expression. It has been shown that: (1) saline injection is a significant stimulus for only nucleus O and central gray pars alpha and nucleus medialis of the dorsal vagal complex; (2) all structures driven by CP injection (nucleus O and central gray pars alpha, locus coeruleus, Barrington's nucleus and parabrachial area mostly in its ventral and lateral subdivisions, dorsal vagal complex, ventrocaudal portion of lateral bulbar reticular formation) responded vigorously shortly after injection, but only two (dorsal vagal complex, ventrocaudal portion of lateral bulbar reticular formation) showed increased or renewed activity when cystitis completely developed, i.e., when noxious visceral inputs reached highest levels. Regarding the sequential activation of these structures in relation to postinjection time, evidence is given that: (1) a large variety of hindbrain structures are differentially involved in either the general reaction consecutive to the injection process or to various degrees of cystitis; (2) these structures extend from the brain-spinal cord to the pons-mesencephalon transitional junction levels; (3) the two structures most powerfully driven by visceronociceptive inputs are also the most caudal ones, being located at the brain-spinal cord junction level; and (4) the dorsal vagal complex could be the main hindbrain visceral pain center, with three particular subdivisions, the nucleus medialis, nucleus commissuralis, and ventralmost part of area postrema, being involved.

The evoked expression of the immediate early gene (IEG)-encoded proteins c-Fos and Krox-24 was used to monitor spinal visceronociceptive processing that results from cyclophosphamide cystitis in behaving rats. Animals received a single dose of 100 mg/kg i.p. of cyclophosphamide and survived for 30 min to 5 h. Longer survival times were not considered because of ethical considerations. Cyclophosphamide-injected animals developed characteristic behavioral signs in parallel with development of bladder lesions and spinal evoked expression of IEG-encoded proteins. Histological examination of the urinary bladder was used to evaluate the degree of cystitis and as a criterion for selection of groups of animals to be quantitatively analyzed. Controls consisted of freely behaving animals including control (uninjected), sham (saline-injected) or diuretic (furosemide-injected) animals. Behavioral modifications consisted of lacrimation, piloerection, assumption of a peculiar “rounded-back” posture, which was accompanied by head immobility and various brief “crises” (tail hyperextension, abdominal retractions, licking of the lower abdomen, backward withdrawal movements). Abnormal behaviors, which first appeared (lacrimation, piloerection) at the end of postinjection hour 1, progressively increased in severity (rounded-back posture) over the following 90 min to reach a plateau at about postinjection hour 2; the rounded-back posture was maintained up to time of death. Histological modifications of bladder tissue were assessed using a 4-grade scale in a blind setting. The 1st grade consisted of control or sham animals with no bladder lesion; 2nd grade, animals with simple chorionic edema; 3rd grade, animals with chorionic edema associated with mucosal abrasion, fibrin deposit, and onset of polymorphonuclear leukocyte infiltration; 4th grade, animals with complete cystitis corresponding to an increase in severity and spread of all the signs of cystitis described above plus petechial hemorrhage. Simple chorionic edema was observed from 30 min to 3 h post-injection, but with a progressive increase in severity over time. Edema accompanied by epithelial abrasion was observed for animals that survived 3–4 h postinjection; complete inflammation was observed in animals that survived 4–5 h postinjection. The study of c-Fos- and Krox-24-encoded protein expression demonstrated that few lumbosacral spinal areas were specifically involved in the processing of visceral inputs in response to bladder stimulation. These areas were the parasympathetic column (SPN), the dorsal gray commissure (DGC as the caudal extent of lamina X), and superficial layers of the dorsal horn. Differential basal and evoked labeling between c-Fos and Krox-24 allowed a functional distinction between these spinal subregions: Krox-24 was an indicator of the first signs of inflammation (simple chorionic edema); c-Fos was an indicator of more pronounced impairments. DGC, which displayed a high level of basal Krox-24 expression and in which both Krox-24 and c-Fos were evoked in relation to disease evolution, probably codes inputs from both physiological (progressive bladder filling) and all types of pathological (inflammatory processes, overdistension) conditions. SPN, which, except for basal Krox-24 expression, responded like DGC and contains preganglionic motor cells, probably codes inputs involved in eliciting motor activity that results in bladder emptying as needed from natural filling and/or pathological situations. Laminae I and II, which responded like DGC and SPN with respect to Krox-24 expression, may code inputs from physiopathological changes of the bladder, though lamina I would be primarily involved in pain processing as it was the only region in which c-Fos expression increased during abrasion and complete inflammation. The cyclophosphamide-cystitis model has the following unique features compared with other visceral models: first, the stimulus is a “pure” visceral one, confined to one viscus (bladder; no somatic stimulation is induced by either introducing a stimulating device or from surgical wounds, and no anesthesia is required); second, it is the exact replica of a human disease, and its evolution can be efficently monitored through behavioral and histological observations; third, it can be used in behaving animals without departing from ethical rules.

In Europe, human dirofilariasis refers to a group of autochtonous parasitic infections caused by tissue nematodes of the genus Dirofilaria, responsible for two distinct clinical presentations: Dirofilaria immitis usually presenting as pulmonary lesions and Dirofilaria repens as subcutaneous nodules. Rare in humans, genital involvement manifests itself as pseudotumor nodules affecting the scrotum, epididymis, or spermatic cord. We report on two cases of Dirofilaria repens infections, involving the spermatic cord and epididymis.

Pineal parenchymal tumours (PPTs) are rare neoplasms that are divided into pineocytoma (PC), pineoblastoma (PB) and PPT of intermediate differentiation (PPTID). Factors affecting the survival of patients with PPTs are morphological subtype and histological grading according to mitotic index and neurofilament immunostaining. Grading criteria to distinguish PPTIDs are difficult to define, particularly when using small specimens. The Ki67 labelling index (LI) might be helpful in distinguishing between grade II and III PPTIDs. Our study was performed to assess the predictive value of the Ki67 LI in a large cooperative series of PPTs and to evaluate whether inclusion of this data would improve and refine the World Health Organization classification.A retrospective analysis of 33 PPTs was performed. The histological features of the tumours were reviewed and Ki67 LI scoring was evaluated by immunohistochemistry. Data were correlated with the patients' survival.The mean Ki67 LI was significantly different for tumour grades (0 in PC, 5.2 ± 0.4 in PPTID grade II, 11.2 ± 2.0 in PPTID grade III, 36.4 ± 6.2 in PB; P0.0001). However, there was no statistically significant difference in either overall or disease-free survival evaluated by the Kaplan-Meier method for patients with different grade tumours or Ki67 LI, possibly due to the different clinical management of patients in different centres.The Ki67 LI may be a useful additional tool for grading PPTs, more particularly in small tumour samples.

The diagnosis of malignant melanoma is based upon the histological evaluation of the lesion. As such, the morphological interpretation relies on the expertise of a dermatopathologist. Infrared microimaging is emerging as a new powerful tool to investigate tissue biochemistry. Infrared spectra probe the biochemical constitution of the sample and are real tissue-specific spectroscopic fingerprints.To assess the potential of infrared microimaging to aid in the analysis of tissue sections from primary cutaneous melanomas.Ten samples of melanoma sections from the main histological subtypes were investigated using infrared microimaging combined with multivariate statistical analyses.This methodology yielded highly contrasted colour-coded images that permitted to highlight tissue architecture without any staining. It was possible to discriminate tumour areas from normal epidermis automatically, and intratumoral heterogeneity as revealed by our approach was correlated with the aggressiveness of the tumour.This proof-of-concept study shows that infrared microimaging could help in the diagnosis of primary cutaneous melanoma.

OBJECTIVE--To evaluate the prevalence of cardiac toxoplasmosis in a series of 182 necropsies performed between 1987 and 1991 on patients infected with the human immunodeficiency virus (HIV), to correlate this prevalence with the ante mortem diagnosis of cardiac involvement, and to assess the role of such cardiac lesions in the immediate cause of death. PATIENTS AND METHODS--Complete necropsies of 182 HIV-infected patients (48 women, 134 men) were performed consecutively between 1987 and 1991. Risk factors, identified in 174 cases, included drug abuse (111/182), homosexuality (51/182), and blood transfusions (12/182). 16 samples were systematically obtained from each heart for histological study. If trophozoites or lymphocytic myocarditis were seen, immunohistochemical investigations were carried out with polyclonal antibodies for Toxoplasma gondii. An ultrastructural study was performed in four patients with toxoplasma myocarditis. Myocardial lesions were defined by the Dallas classification. Clinical data (and information on electrocardiograms and echocardiograms) were obtained from medical records. RESULTS--Cardiac toxoplasmosis was diagnosed at necropsy in 21 (12%) patients. Cardiac lesions were associated with toxoplasmic encephalitis in 18 patients and were solitary in three patients. Acute diffuse myocarditis was present in 6/21, rare foci of myocarditis were seen in 8/21, and intramyocytic toxoplasmic cysts without any inflammatory reaction or necrosis were seen in 4/21. Anti-toxoplasma immunolabelling showed cardiac toxoplasmosis in three patients with lymphocytic myocarditis. Particles with the ultrastructural characteristics of Toxoplasma gondii trophozoites were seen in four cases. Six patients had presented with cardiac symptoms, confirmed by electrocardiographic and echocardiographic abnormalities during their disease course, and their cardiac lesions were directly responsible for the death. CONCLUSION--Cardiac toxoplasmosis was common in this necropsy series of HIV-infected patients. Cardiac toxoplasmosis had been suspected clinically in four patients. Myocardial lesions were generally asymptomatic and were not discovered until necropsy. Solitary cardiac involvement was not uncommon reflecting parasite reactivation at a myocardial site. The incidence of cardiac toxoplasmosis in this group of immunodepressed subjects from an area with a high prevalence of this parasitic disease justifies regular follow up of such patients by electrocardiography and echocardiography as well as immediate administration of anti-toxoplasma treatment should sudden heart failure occur.

International audience; Testicular germ cell cancers are the most common solid malignancies in young men, but their pathogenesis remains undetermined although some epidemiological data have implicated both environmental and genetic factors. Glial cell-derived neurotrophic factor (GDNF) is secreted by Sertoli cells, and promotes germ stem cell proliferation by activating RET, a tyrosine kinase receptor. Over-expression of GDNF in adult transgenic mice induces the development of testicular tumours that mimic human seminoma, the most frequent testicular germ cell tumour. Activating mutations of RET were previously reported in several types of cancer, including thyroid, pituitary, adrenal and melanoma cancer. Both mouse experimental model and clinical studies suggested that mutations or selective polymorphisms of RET might be associated with human seminoma. To verify this hypothesis, we conducted this study in a French University Hospital and carried out an association study using tissue samples from 66 paraffin-embedded seminoma tumours. The most frequently mutated exons of the RET proto-oncogene were sequenced to identify mutations or selective polymorphisms. No somatic mutations were identified. The polymorphic variants frequencies did not differ from those in a control Caucasian population. Human classical seminoma that occurs in young men does not appear to be linked with mutations or relevant polymorphisms of RET.

Cushing's disease is usually associated with higher mortality rate, especially from cardiovascular causes. Development or exacerbation of autoimmune or inflammatory diseases is known to occur in patients with hypercortisolism after cure. We report for the first time a 34-year old woman with a psychiatric background, who developed four months after the surgical cure of Cushing's disease an acute disseminated encephalomyelitis (ADEM) presenting initially as a psychiatric illness. We hypothesize that the recent correction of hypercortisolism triggered ADEM and that the atypical presentation, responsible for diagnosis delay, led to the death of this patient.

Regenerating gene (Reg), encodes a secretory protein with growth and differentiation stimulating effects mostly in digestive tissues. Overexpression of Reg proteins and specifically of Reg I, one member of the Reg family, is associated with several human diseases and cancers. In the present study we analyzed the expression of Reg I in normal rodent and human testes where germ cells normally proliferate and differentiate into spermatozoa, and in seminoma testis, the most common cancer of young men. Western blot analyses demonstrated the presence of a specific band at 19 kDa in human and rodent testis extracts. Immunofluorescence and deconvolution microscopy demonstrated that Reg I was present within the seminiferous tubules in both Sertoli and germ cells. By using a Sertoli cell line we demonstrated that Reg I was localized at the plasma membrane even in the absence of contact between neighboring cells and appeared before the tight junction associated protein ZO-1 was revealed at this location. Reg I was strongly expressed in human seminoma testis tissue and in a human tumor germ cell line where the immunoreactive signal was mainly detected at the plasma membrane level. These data showing for the first time the weak presence of Reg I in the normal testis and its strong expression in the testis cancer suggest a potential role of Reg I in normal and neoplastic germ cell proliferation.

Incidences of opportunistic infections of the epididymus and the testicule have already been reported in patients suffering from AIDS for over 10 years. Here we have reported the first description of microsporadic orchiepididymitis diagnosed at the university hospital (CHU) of Nice in 2005. We look at the epidemiology, the physiology and the treatment of this extremely rare infection.

We collected 6 case-reports of symptomatric non removable low grade fibrillary astrocytoma of adults treated with a procarbazine-CCNU-vincristine chemotherapy regimen. All patients had drug-resistant epilepsy but brain imaging was stable. Total gross resection was rejected because of Volume or tumor location. After 4 to 7 cycles of chemotherapy, 2 patients had partial response and one minor response on brain MRI. All of them were seizure-free. Progression free survival was not reached at 5 Years. Up-front chemotherapy for low-grade astrocytomas may be useful and has to be prospectively evaluated.

Although infectious causes are the most common source of pulmonary nodules in HIV-infected patients, malignant diseases such as Kaposi sarcoma and lymphoma must also be considered.A 40 year-old man, diagnosed with HIV infection 16 years earlier and with a satisfactory viro-immunological control, was hospitalized for bilateral pulmonary nodules and a dorsal lytic mass. Bone and pleural biopsies showed a malignant epithelioid hemangioendothelioma.Epithelioid hemangioendothelioma is an uncommon low grade vascular tumor. We report the first case in an HIV-infected patient. Bilateral pulmonary nodules are common in this malignant disease but are not specific. In a HIV-infected patient, such clinical presentation is associated with numerous differential diagnoses and must be interpreted in relation to the immune status.In HIV-patients without immunosuppression, pulmonary nodules are often malignant. With the increased survival of these patients, these etiologies closer to those of non-infected patients.

Favorable prognostic factors for oligodendroglial tumors include age younger than 40 years, low tumor grade, and extent of resection.To assess survival time and prognostic factors of 100 patients with oligodendrogliomas diagnosed between 1995 and 2002.The tumors were rated histologically by the WHO classification as low grade (grade II) or anaplastic (grade III). One hundred patients were categorized into three groups: group A: grade II, group B: secondary grade III (low grade with anaplastic transformation during the follow-up), group C: de novo grade III. All patients were symptomatic at presentation and underwent neurosurgical procedure for histologic diagnosis. Follow-up was performed with clinical assessment, brain MRI, and MIBI scintigraphy.There were 66 men and 34 women (mean age at diagnosis 46.7 years). The most common first symptom was partial epileptic seizure (75%). Fifty-six patients had initial gadolinium enhancement (A: 15.6%; B: 36.8% as grade II, 95% as grade III; C: 90%), generally associated with MIBI hypermetabolism (p0.0001). Survival rates at 2, 5, and 10 years were A: 88%, 88%, 85%; B: 79%, 64%, 42%; C: 43%, 16%, 15%.Secondary anaplastic oligodendroglioma patients were younger than patients with de novo anaplastic oligodendrogliomas. Histologic confirmation is mandatory because some low grade oligodendrogliomas had gadolinium enhancement on MRI and some anaplastic did not. Survival time was longer for secondary than for de novo anaplastic oligodendrogliomas without difference in the duration of the malignant phase of the disease.

Neuroepithelial dysembryoplastic tumor (DNT) is usually considered as a supratentorial benign neoplasm. DNT of the posterior fossa is a very rare entity and only four previous cases were reported in the literature. We describe a case of a 26-Year-old woman presenting recurrent episodes of vertigo. Magnetic resonance imaging revealed four cystic lesions located in the cerebellum, hypointense on T1-weighted images and hyperintense on T2-weighted images, without gadolinium enhancement. After partial resection, histological examination showed small glial cells, oligodendrocytes-like, lying in an eosinophilic alveolar matrix with some floating neurons. Due to this specific glioneuronal element, the diagnosis of DNT was retained. We discuss the clinical and radiological particularities of this infratentorial location and compare our case with those previously described in the literature.

Connexins, the constitutive proteins of gap junctions, are considered to be tumour suppressive agents and are often impaired in the tumourigenic processes. In the present study, the expression of connexin 43 (Cx43), which is involved in the control of spermatogenesis through Sertoli/germ cell coupling, has been investigated in human testicular seminoma cells (tumours and the JKT-1 cell line). Cx43 was immunolocalized in the Golgi apparatus without membrane expression and was detected by immunoblotting in JKT-1 as exclusive 70 kD bands. No mutation could be found by sequencing the transcript obtained by RT-PCR. Transfection with a Cx43-V5 vector reproduced the same gel shift, identifying these 70 kD bands as Cx43. The Cx43-70 kD bands were also expressed in normal testicular tissue, associated with the classical 43 kD isoforms. Stable transfection of JKT-1 with a Cx43-GFP vector allowed restoration of Cx43 membrane expression, functional cell coupling, and inhibition of the cell proliferation rate. Storage of Cx43 in the Golgi apparatus may correspond during spermatogenesis to an intermittent physiological process that becomes permanent in malignant seminoma cells as a result of the tumourigenic process. By preventing Cx43 membrane expression, this disrupted traffic may itself participate in tumour promotion.

Tumoral growth effects on brain circuitry and neurochemical activities remain poorly documented. This study evaluates C6 graft effects on striatal dopaminergic afferent projections at both anatomical and functional levels. Immunohistochemistry was performed to investigate changes in neurofilament (NF), tyrosine hydroxylase (TH) and dopamine transporter (DAT) expression. Dopaminergic turnover was assessed using multiprobe microdialysis in freely-moving rat. In C6 graft striatum, dopamine (DA) catabolites were reduced in glioblastoma (DOPAC: −61%, HVA: −62%). In contrast, the DA level remained unchanged. Staining for NF, TH and DAT was drastically decreased inside the tumor. Our histological data report that striatal tumoral growth is associated with a decrease in the density of dopaminergic endings which can explain, at least in part, the decrease in DA turnover. The decrease in DAT transporter expression and the lack of change in DA level may result from an increase in DA diffusion from the peripheral areas of the tumor. In conclusion, glioblastoma growth has major consequences on the local neuronal circuitry and its neurochemistry. Changes in inter-connections and neurotransmitter turnover may result in abnormal neuronal firing activity and participate in clinical disorders associated with glioblastoma diagnosis.

We reviewed a series of 14 cases of filum terminale ependymoma and 264 cases in the literature, to study the characteristics of these tumors and specifically to determine factors influencing recurrence.This series analyzed data between 1984 and 1998. The mean follow-up period was 5.5 years and the median age 40 years. Pain was the first symptom, except in one case, with progressive sensitive-motor deficit. Four patients had a myelography and a CT scan, and ten a MRI. All patients were operated with a total resection in 12 cases. All tumors, except one, were a myxopapillary ependymoma.Clinical results were excellent in 2 cases, good in 8, stable in 2 and worse in 2. Two patients had a recurrence after an initial sub-total resection, both were operated on again, followed by post-operative radiotherapy. Among the 278 filum terminale ependymoma, removal was total in 200 (72%). A recurrence occurred in 15% of them after total removal, and in 43% after partial removal (p0.001). Among patients with partial removal, recurrence was observed in 33% of them if they had post-operative radiotherapy, and in 55% of them if they did not have post-operative radiotherapy (p0.05).The extent of tumor removal has a statistically significant effect upon recurrence. This review is in favor of post-operative radiotherapy in case of partial removal, but this systematic attitude can be discussed after a critical analysis of this study. Long term follow-up is mandatory due to the possibility of late recurrence.

To compare ambulatory ultrasound-guided transrectal biopsy and finger-guided transperineal biopsy.From June 1997 to October 1999, 51 patients were simultaneously biopsied by the two techniques and by the same operator, 30 min after antibiotic prophylaxis with 200 mg of Ciprofloxacin by intravenous injection. Transperineal biopsies were performed first, followed by ultrasound-guided transrectal biopsies. Six cores were obtained with each technique, from the apex, the middle and the base of each lobe.For a PSA level between 4 and 10 ng/ml, 6 cancers were detected in 23 patients (26%) and one cancer was only detected via the transrectal route. For a PSA level greater than 10 ng/ml, 17 cancers were detected in 28 patients (60%), 15 (53%) by transperineal biopsy and 11 (39%) by transrectal biopsy. Six cancers were only detected by transperineal biopsy and two were only detected by transrectal biopsy. No statistically significant difference was observed between the numbers of positive biopsies obtained with the two techniques.The use of ultrasonography is not essential to perform systematic biopsies. Rather than the technique used, the detection of prostate cancer is improved by performing 12 cores instead of 6.

The purpose of this study is to investigate the in vivo tumoral brain metabolism in free moving rats using microdialysis. Cells from C6 glioma cell line were inoculated in one striatum 15 days before the microdialysis experimentation. Then, using a new system allowing perfusion of several microdialysis probes in free moving rat, normalised dialysate levels of glucose, lactate and pyruvate were monitored in both glioma and control striatum. At the end of the procedure, animals were sacrificed for histological study. Data shows that probe functioning is similar in both tissues. The results for normalised glucose level were in striatum control: 2.14 mM, in tumoral striatum: 1.71 mM (P0.1); for lactate, respectively, 0.86 and 1.65 mM (P0.05) and for pyruvate, respectively, 65.56 and 140. 94 microM (P0.05). This data clearly shows a significant increase of pyruvate and lactate in tumoral striatum compared to normal striatum, correlating previous in vitro studies on glioma metabolism. We conclude that this microdialysis technique is of value in tumoral brain and could constitute an interesting tool for a better understanding of glioma metabolism.

We describe a case of pacemaker infection due to two fungal species: Candida albicans and C. glabrata. Transthoracic echocardiography showed a large vegetation on the intraventricular wires. Because of severe underlying diseases, surgery was believed to be contraindicated. The patient was treated using high dose of fluconazole, resulting in clinical improvement and negative blood cultures. However, 2 months later, the patient underwent a fatal stroke. At autopsy, a large vegetation was found only all along the wires. Postmortem culture of the infected material was positive for both C. albicans and C. glabrata.

Intestinal microsporidiosis caused by Enterocytozoon bieneusi is a cause of chronic diarrhoea in patients with HIV infection for which there is no current therapy. This study was designed to assess the safety and efficacy of oral fumagillin in this infection.A dose-escalation trial.Twenty-nine HIV-infected patients with E. bieneusi infection were consecutively enrolled in the trial. Oral doses of fumagillin were given to four groups of patients for 14 days: 10 mg/day (group 1), 20 mg/day (group 2), 40 mg/day (group 3), and 60 mg/day (group 4). Patients were seen at weeks 1, 2, 4 and 6 to assess safety and efficacy. Efficacy was assessed primarily by the clearance of microsporidia from stools and follow-up duodenal biopsies.Thirteen patients complained of abdominal cramps, vomiting or diarrhoea during the study, and three patients had fumagillin withdrawn because of adverse events. Thrombocytopenia, neutropenia and hyperlipasaemia were the most frequent biological adverse events. Twenty-one out of 29 patients transiently cleared microsporidia from their stools during the study. By week 6, however, all patients in groups 1, 2 and 3 had parasitic relapse. Interestingly, eight out of 11 (72%) patients treated with 60 mg/day (group 4) apparently cleared microsporidia from their gastrointestinal tract and gained weight. No parasitic relapse was documented in these eight patients during a mean follow-up of 11.5 months.Treatment with fumagillin at 60 mg/day for 14 days has promise as an effective oral treatment for E. bieneusi infections.

We report 2 cases of solid and pseudopapillary tumors of the pancreas occurring in female children. Lesions were made of uniform small cells arranged in solid areas associated with pseudopapillary and cystic patterns. Immunohistochemistry study was positive for neuron-specific enolase, alpha-1 anti-trypsin and vimentin. Ultrastructural study showed an abundant cytoplasm, rich in mitochondria, containing a lot of granules of variable sizes, often disintegrated, and some lipid droplets. The differential diagnosis of this lesion included endocrine tumor, pancreatoblastoma and acinar cell carcinoma. It is a rare tumor of the pancreas with a favorable prognosis after complete resection.

The authors report a child male case of secretory carcinoma of the breast, associated with a abnormal tumoral karyotype (monosomy 22). The diagnosis was made by histopathological examination. This breast carcinoma is characterized by an abundant intra and extracellulary secretory material, which present a reactivity with antimilk proteins antibodies and includes spherical dense bodies, identified by ultrastructural study. The prognosis is not bad, whatever the age of the patient, particularly for the children and young women, displaying an locoregional aggressivity. The signification of a monosomy 22 in secretory carcinoma is unknown.

We report an histological study from term placentas of 286 HIV positive women born in Rwanda. We observed chorioamnionitis without any pathogen in 15% of the cases, cocci Gram positive infection in 12 observations and malaria infection in 75% of placentas. We noted 71 cases of active malaria infection with Plasmodium falciparum trophozoites in the erythrocytes of the intervillous spaces, and 135 cases of chronic infection with malaria pigment without any parasite. An ultrastructural study performed in 8 cases of active malaria infection showed characteristic features of trophozoites and schizontes, and malaria pigment. No viral particle were seen. We did not observe any significative difference concerning the incidence of chorioamnionitis and of malaria infection in 275 HIV negative placentas. In the literature as well as in the present study, the main lesions observed in the placentas of AIDS patients were chorioamnionitis. Opportunistic infections and neoplasias of the placenta are exceptional. Detection of HIV proteins by immunochemistry or in situ hybridization is possible, but the HIV could not be identified in the trophoblast by electron microscopy. Mechanisms of the materno-fetal transmission for HIV are currently unknown.

Kimura's disease, a chronic inflammatory condition of unknown cause, occurs predominantly in young Asian adult men. The disease involves subcutaneous tissues and lymph nodes in the head and neck region. We report a new case occurring in a young woman. The diagnosis was made late on a retroauricular lymph node examination. Immunohistochemical study showed that B lymphoid area remained, located in the germinal center showing some fibrosis involvement, and in the subcortex. T lymphoid zones were observed in the paracortex. Strong IgE positivity was noted in germinal centers. Vessels were positive with CD31, CD34, factor VIII and smooth muscle actin antibodies. Warthin-Finkeldey cells were negative for lymphoid and macrophagic markers used in this study. Differential diagnosis is discussed.

There is substantial evidence demonstrating the aggravating effect of human immunodeficiency virus (HIV) infection on the progression of chronic hepatitis C virus (HCV) infection. There is however, little data on the affect of certain factors which could affect liver pathology findings in patients with concomitant HIV infection such as the duration of HIV infection or T-cell subpopulation counts. We examined pathology findings in patients with concomitant HIV and HCV infections to determine the impact of immunodepression.We reviewed liver pathology data collected in patients with concomitant HIV and HCV infections grouping patients according to severity of the liver pathology: group 1 = cirrhosis or active hepatitis; group 2 = minimally active hepatitis or histologically normal liver. Transparietal liver biopsies were obtained for the work-up of viral hepatitis or because of long-term unexplained fever or suspected lymphoma. Epidemiological and biological data were obtained from medical files. The duration of the liver disease was estimated from the date of exposure to risk of immunodepression as determined by the peripheral CD4+ and CD8+ counts. All pathology specimens were read by two pathologists who established the Knodell score for each patient.Fifty patients were included: 23 were classed in group 1 and 28 in group 2. The Knodell score was significantly different between the two groups, 11 +/- 4 and 4 +/- 3 respectively (p0.0001). Disease duration was similar for the two groups: mean 8 years. Mean CD4+ count was significantly higher in group 1: 312/mm3 versus 110/mm3 for group 2 (p = 0.0057); as was the mean CD8+ count (758/mm3 versus 360/mm3, p = 0.0013). For the entire study population, there was a significantly negative correlation (p0.05) between the Knodell score and the CD4+ count (r = 0.31) and for the CD8+ count (r = 0.41).HCV-related liver pathology in patients co-infected with HIV depends on the level of immunodepression. CD8+ counts are better correlated with pathology findings than with CD4+ counts.

This article is the fifth of a series aimed at mapping brain activities as they result from the development of cyclophosphamide (CP) cystitis in behaving rats using c-fos and Krox-24 expression. The inactive hepatic metabolites of CP are metabolized in the kidney to produce acrolein, which generates cystitis. Data come from animals which were injected once i.p. with either 1 ml saline (sham) or 100 mg/kg CP in 1 ml saline under transient volatile anesthesia and which behaved freely for 1-4 h postinjection, 4 h being the minimum time for cystitis to completely develop. Survival times longer than 4 h were not studied owing to ethical considerations. The first 2 h postinjection cover a period of time over which inputs of multifactorial origin (stress and pain due to the intraperitoneal injection process, possible effects due to the presence of hepatic CP metabolites in blood, cystitis onset) interact in an indistinguishable way; the last 2 h are more cystitis specific as the other effects have vanished. Complete screening of telencephalic levels has been performed. These data complete previously published data at both spinal and subtelencephalic levels. Of all the telencephalic structures, only the bed nucleus of the stria terminalis in the dorsal part of its lateral division (BSTLd) and, to a lesser degree, the nucleus centralis of the amygdala, mostly in its caudal portion (cCeA), appeared to be significantly driven over the most specific cystitis period. Both of these structures had related, but not identical patterns of expression. They both reacted shortly after CP injection, but, while cCeA maintained its activity throughout cystitis development, BSTLd showed a rebound, reaching a peak value when cystitis was fully developed. Both of these areas are the only telencephalic areas to contain high PACAP38 immunoreactivity. This is evidence that, (1) both the BSTLd and cCeA could be the most rostral areas that visceronociceptive inflow would reach when cystitis genesis is under way, and (2) PACAP38 could be one of the neurochemical agents involved in telencephalic visceronociceptive processing. From our complete mapping of brain activities under a fully developed cystitis situation (4 h postinjection), it appears that the activities in BSTLd and cCeA are concomitant with those of both the dorsal vagal complex (DVC), paratrigeminal nucleus (PaT), and the ventrocaudal bulbar reticular formation (vcBRF) at brainstem levels, suggesting they all form the main part of the neural network that subserves the central processing of cystitis-related inputs, comprising pain and associated pseudoaffective responses. Both the DVC and BSTLd, which are the most powerfully driven areas, would be particularly important in such a way. The origin of these activities should be found in both vagal (as sensed through PaT activity) and spinal (pelvic) influences. This network profoundly differs from those reported for painful situations, either somatic or visceral, which controversally accompany positive cardiac inotropism.

The authors report a case of a 70 year-old man with a past of myelodysplasia and presenting a voluminous lesion of the thigh corresponding to a cutaneous malacoplakia. Histologic study showed a dermo-hypoderma granuloma with numerous Von Hansemann cells containing some Michaelis-Gutmann bodies. Immunohistochemical study showed a positivity of these cells with the antibodies against CD68 (KP1, Mac 387, PGM1), the lysozyme and the alpha-chemotrypsine. Ultrastructural study confirmed the histiocytic origin of this infiltration by showing some regular and voluminous inclusions with a clear center and a peripheral and dense ring, and also some bacteria measuring 3 to 5 microns. Bacteriological study isolated an Escherichia coli. The evolution was favourable after surgical excision and antibiotherapy. Cutaneous malacoplakia is a very rare disease, usually with a perineal localization, and occurring in immunodeficient host. Michaelis-Gutmann bodies are sometimes difficult to identify by light microscopy underlying the rule of the immunohistochemical and the ultrastructural studies to perform the diagnosis.

The majority of endodermal cysts occur in the cervicothoracic spine, ventral to the cord. Intracranial locations are rare. We report a case involving the foramen magnum in a 14-year-old child, which was an incidental finding following a traumatic head injury. A review of the literature revealed six other cases involving this same location. These lesions are asymptomatic for a long time, and may cause brain stem medullary compression. Treatment is surgical. Effective simple removal can be achieved by a posterior approach.

Intravascular lymphomatosis is characterized by a proliferation of malignant lymphoid cells within the lumen of arteriola, capillaria or venula. It is a very rare neoplasia (less than 200 cases reported). Many organs can be involved, but preferentially the central nervous system. The diagnosis is sometimes performed only by a post mortem study. We report a case of a 74 year-old man with biological markers of inflammation, progressive dyspnea and myalgia. A muscular biopsy revealed the diagnosis.

Intestinal microsporidiosis due to Enterocytozoon bieneusi is a frequent cause of chronic diarrhoea in patients with HIV infection for which there is no available therapy. This study was designed to search for a drug with activity against this organism.Prospective open-labelled Phase II multicentre study.University hospitals.Sixty HIV-infected men with intestinal E. bieneusi infection.Ten drug regimens were consecutively tested orally for 3 weeks: albendazole plus metronidazole, sulphadiazine plus pyrimethamine, atovaquone, doxycycline plus nifuroxazide, itraconazole, flubendazole, chloroquine, paromomycin, sparfloxacin and fumagillin. Nine evaluable patients per regimen were required, but each patient could be enrolled up to three times in the study.Efficacy was assessed primarily by the clearance of E. bieneusi from stools and intestinal biopsies. The safety of each regimen was also assessed.Only purified fumagillin was able to clear E. bieneusi from stools as well as intestinal biopsies, whereas all other regimens failed to show antiparasitic efficacy. However, only four patients received fumagillin because of drug-induced thrombocytopenia. The four patients who received fumagillin remained free of E. bieneusi infection after a mean follow-up of 10 months.Eradication of E. bieneusi from the intestinal tract of patients with HIV infection and persistent immunosuppression is an achievable goal. Our study allowed the identification of oral fumagillin as a potential treatment for intestinal microsporidiosis due to E. bieneusi.