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Background High-risk medulloblastoma is defined by the presence of metastatic disease and/or incomplete resection and/or unfavorable histopathology and/or tumors with MYC amplification. We aimed to assess the 3-year progression-free survival (PFS) and define the molecular characteristics associated with PFS in patients aged 5–19 years with newly diagnosed high-risk medulloblastoma treated according to the phase II trial PNET HR+5. Methods All children received postoperative induction chemotherapy (etoposide and carboplatin), followed by 2 high-dose thiotepa courses (600 mg/m2) with hematological stem cell support. At the latest 45 days after the last stem cell rescue, patients received risk-adapted craniospinal radiation therapy. Maintenance treatment with temozolomide was planned to start between 1–3 months after the end of radiotherapy. The primary endpoint was PFS. Outcome and safety analyses were per protocol (all patients who received at least one dose of induction chemotherapy). Results Fifty-one patients (median age, 8 y; range, 5–19) were enrolled. The median follow-up was 7.1 years (range: 3.4–9.0). The 3 and 5-year PFS with their 95% confidence intervals (95% CI) were 78% (65–88) and 76% (63–86), and the 3 and 5-year OS were 84% (72–92) and 76% (63–86), respectively. Medulloblastoma subtype was a statistically significant prognostic factor (P-value = 0.039) with large-cell/anaplastic being of worse prognosis, as well as a molecular subgroup (P-value = 0.012) with sonic hedgehog (SHH) and group 3 being of worse prognosis than wingless (WNT) and group 4. Therapy was well tolerated. Conclusions This treatment based on high-dose chemotherapy and conventional radiotherapy resulted in a high survival rate in children with newly diagnosed high-risk medulloblastoma.

PURPOSE To assess the 3-year EFS rate of children younger than 5 years of age with high-risk medulloblastoma (MB) treated according to the prospective multicenter trial HR MB-5. PATIENTS AND METHODS After surgery, all children received 2 cycles of Etoposide- Carboplatine. If partial (PR) or complete response (CR) was achieved after induction chemotherapy, children received 2 courses of thiotepa (600mg/m²) with stem cell rescue. For patients in CR after high-dose chemotherapy, they received one course of Cyclophosphamide – Busilvex with stem cell rescue (Phase I part). The others patients (not in PR after induction or in CR after thiotepa) were treated with 2 cycles of Temozolomide-Irinotecan followed by age-adapted craniospinal irradiation and maintenance treatment. RESULTS 28 children (2 to 4 years; median: 3.0 years) were enrolled. Group 3 MB were most common (57%). The response rate to Etoposide-Carboplatine was 60.7%. Among 20 patients treated with Thiotepa, 13 children were in CR and received Cyclophosphamide – Busilvex without radiotherapy. Out of them, 9 patients (45%) are alive in CR without craniospinal irradiation (median follow-up 5 years). Among 15 patients treated with radiotherapy, 8 patients are alive (median follow-up 3.8 years). The study was prematurely stopped for an excess of events. The median follow-up was 4 years (range 1.5 - 6.1). The 3-year EFS and OS were 42.3% [25.9 - 60.6] and 71.3% [52.7 - 84.7], respectively. CONCLUSIONS This risk-adapted strategy did not improve EFS in young children with high-risk MB. However, the study shows that good responders to chemotherapy can be cured without recourse to irradiation.

Noonan syndrome (NS), an autosomal dominant disorder, is characterized by short stature, congenital heart defects, developmental delay, and facial dysmorphism. PTPN11 mutations are the most common cause of NS. PTPN11 encodes a non-receptor protein tyrosine phosphatase, SHP2. Hematopoietic malignancies and solid tumors are associated with NS. Among solid tumors, brain tumors have been described in children and young adults but remain rather rare. We report a 16-year-old boy with PTPN11-related NS who, at the age of 12, was incidentally found to have a left temporal lobe brain tumor and a cystic lesion in the right thalamus. He developed epilepsy 2 years later. The temporal tumor was surgically resected because of increasing crises and worsening radiological signs. Microscopy showed nodules with specific glioneuronal elements or glial nodules, leading to the diagnosis of dysembryoplastic neuroepithelial tumor (DNT). Immunohistochemistry revealed positive nuclear staining with Olig2 and pERK in small cells. SHP2 plays a key role in RAS/MAPK pathway signaling which controls several developmental cell processes and oncogenesis. An amino-acid substitution in the N-terminal SHP2 domain disrupts the self-locking conformation and leads to ERK activation. Glioneuronal tumors including DNTs and pilocytic astrocytomas have been described in NS. This report provides further support for the relation of DNTs with RASopathies and for the implication of RAS/MAPK pathways in sporadic low-grade glial tumors including DNTs. © 2017 Wiley Periodicals, Inc.

A 21-day-old male infant was admitted with signs of intracranial hypertension. Brain magnetic resonance imaging (MRI) revealed a voluminous mass in the posterior fossa with an intense peripheral enhancement on T1 images with gadolinium. The child was treated secondarily by surgical decompression of the posterior fossa and the lesion was biopsied. The pathological findings indicated infantile hemangioma. Treatment with oral prednisolone was initiated at 3 months, given the lack of tumor involution. Six months after corticotherapy was stopped, repeated MRIs indicated a significant reduction in tumor size and then complete disappearance. Psychometric evaluation was performed at the age of 15 years, showing heterogeneous cognitive disabilities, with verbal abilities superior to nonverbal abilities and delayed motor development. Neurological examination was normal with no focal deficit. To our knowledge, this is the first published case reporting the long-term evolution of a patient with neonatal intracerebral hemangioma. We conclude that psychometric evaluations should be part of the long-term follow-up of children who have had an intracranial capillary hemangioma.

Amyloid-β (Aβ) is a peptide deposited in the brain parenchyma in Alzheimer’s disease and in the wall of small cortical and leptomeningeal vessels in cerebral amyloid angiopathy (CAA). Sporadic CAA is prevalent in an ageing population and is a major cause of intracerebral haemorrhage and dementia. There is evidence of Aβ transmission through medical procedures, such as injection of cadaver-derived growth hormone (GH) or cadaveric dura mater graft in humans, in the context of iatrogenic Creutzfeldt-Jakob disease (iCJD).1 Interestingly, there is increasing evidence to suggest that Aβ transmission may also occur in the absence of iCJD through neurosurgical procedures.2 3 This paper describes a case of early onset, pathologically proven CAA presenting with multiple symptomatic intracerebral haemorrhages occurring three decades after cardiac surgery involving a cadaveric dura mater patch. A young male with multiple intracerebral haemorrhages underwent an extensive multimodal evaluation including clinical examination, cerebral MRI, amyloid positron emission tomography using 18F-florbetapir, apolipoprotein E (APOE) genotype, genetic testing for mutations or duplication causing hereditary CAA (amyloid precursor protein (APP), gelsolin, transthyretin and cystatin 3) and neuropathological examination of a brain biopsy. Sporadic CAA was confirmed pathologically. Childhood exposure to cadaveric dura mater was suspected based on the surgical history for congenital heart disease, then confirmed. The patient’s informed consent was obtained. A man aged 34 years presented with multiple symptomatic lobar intracerebral haemorrhages. He had a medical history of transposition of the great arteries, requiring neonatal cardiac surgery with the Rashkind procedure. At 2 years of age, the patient underwent repeat surgery with a Senning …

International audience

Medulloblastoma may occur in a context of APC germline mutation and familial adenomatous polyposis. We aimed to describe clinical features of patients with medulloblastoma occurring in this context. We performed a multicentric retrospective review of French and Belgian patients treated for medulloblastoma with identified or highly suspected (personal or familial history) APC germline mutation. Genetic status, clinical and histological characteristics, treatments and outcome were reported. Eleven patients with known or suspected APC germline mutation, mostly on exon 15 (N=6/9 available data), were diagnosed with medulloblastoma at a median age of 10.6 years [6-32]. Medulloblastomas were mainly non-metastatic (N=9/11), classic (N=9/9 available data, central review ongoing), with no significant residual tumor after surgery (N=9/11). All patients underwent radiotherapy (median craniospinal dose: 35 Gy), combined with chemotherapy for 10 patients. No relapse was noticed (median follow-up: 11 years). Secondary tumors (N=8) occurred in 7 patients, including 1 lethal malignant Triton tumor in the irradiation field, 1 thyroid carcinoma, and 6 desmoid tumors (5 abdominal tumors, 1 occipital tumor in the irradiation field). Pre-symptomatic polyposis was diagnosed for 9 patients at a median age of 15.5 years, prior to medulloblastoma for 2 of them. Medulloblastomas associated with APC germline mutation have favorable clinical outcome, even for metastatic tumors, with no relapse in this small series of patients, in line with WNT-medulloblastomas’ profile. Yet, long-term survival is clouded by second tumor occurrence, with potential radiation-induced tumors. These findings raise the question of applying de-escalation therapeutic protocol for these patients with reduced intensity craniospinal irradiation.

Pineoblastoma (PB) is a rare but aggressive pediatric brain tumour arising from the pineal gland. Outcomes remain dismal with long-term survival rates between 10–40% despite intensive treatment regimens. Although germline RB1 and DICER1 alterations have been reported in a small proportion of PB, the clinical significance of such alterations and the biology of sporadic cases remains unknown. We undertook global methylation profiling of 75 PB cases, and discovered that PBs comprise four molecular sub-types, designated groups 1 to 4 with characteristic copy number alterations and mutational patterns. Molecular sub-groups of PB also exhibited distinct clinical features and survival outcomes. While PBs group 1–3 arose in older children (median ages 5.2–12.6 years), group 4 PB was restricted to much younger children (median age 1.4 years). Group 4 PB exhibited the highest incidence of metastases (53%) and had the worst 5-year event-free survival (EFS) and overall survival (OS), respectively 7.7% and 16.7%. In contrast, group 2 patients had a 5-year EFS and OS of 100%, while group 1 and 3 had intermediate outcomes (68.1%, 53.3% respectively). These findings demonstrate significant clinical and molecular heterogeneity in PB and underscore the critical need to define mechanisms underlying PB, so that precise patient stratification and selection of biology-informed therapies can be undertaken in future clinical trials.

Anti-amyloid-beta immunization leads to amyloid clearance in patients with Alzheimer's disease, but the effect of vaccination on amyloid-beta-induced neuronal pathology has not been quantitatively examined. The objectives of this study were to address the effects of anti-amyloid-beta active immunization on neurite trajectories and the pathological hallmarks of Alzheimer's disease in the human hippocampus. Hippocampal sections from five patients with Alzheimer's disease enrolled in the AN1792 Phase 2a trial were compared with those from 13 non-immunized Braak-stage and age-matched patients with Alzheimer's disease, and eight age-matched non-demented controls. Analyses included neurite curvature ratio as a quantitative measure of neuritic abnormalities, amyloid and tau loads, and a quantitative characterization of plaque-associated neuritic dystrophy and astrocytosis. Amyloid load and density of dense-core plaques were decreased in the immunized group compared to non-immunized patients (P < 0.01 and P < 0.001, respectively). The curvature ratio in non-immunized patients with Alzheimer's disease was elevated compared to non-demented controls (P < 0.0001). In immunized patients, however, the curvature ratio was normalized when compared to non-immunized patients (P < 0.0001), and not different from non-demented controls. In the non-immunized patients, neurites close to dense-core plaques (within 50 microm) were more abnormal than those far from plaques (i.e. beyond 50 microm) (P < 0.0001). By contrast, in the immunized group neurites close to and far from the remaining dense-core plaques did not differ, and both were straighter compared to the non-immunized patients (P < 0.0001). Compared to non-immunized patients, dense-core plaques remaining after immunization had similar degree of astrocytosis (P = 0.6060), more embedded dystrophic neurites (P < 0.0001) and were more likely to have mitochondrial accumulation (P < 0.001). In addition, there was a significant decrease in the density of paired helical filament-1-positive neurons in the immunized group as compared to the non-immunized (P < 0.05), but not in the density of Alz50 or thioflavin-S positive tangles, suggesting a modest effect of anti-amyloid-beta immunization on tangle pathology. Clearance of amyloid plaques upon immunization with AN1792 effectively improves a morphological measure of neurite abnormality in the hippocampus. This improvement is not just attributable to the decrease in plaque load, but also occurs within the halo of the remaining dense-core plaques. However, these remaining plaques still retain some of their toxic potential. Anti-amyloid-beta immunization might also ameliorate the hippocampal tau pathology through a decrease in tau phosphorylation. These data agree with preclinical animal studies and further demonstrate that human anti-amyloid-beta immunization does not merely clear amyloid from the Alzheimer's disease brain, but reduces some of the neuronal alterations that characterize Alzheimer's disease.

International audience; Background - Anaplastic gangliogliomas (GGGs) are rare tumors whose natural history is poorly documented. We aimed to define their clinical and imaging features and to identify prognostic factors. Methods - Consecutive cases of anaplastic GGGs in adults prospectively entered into the French Brain Tumor Database between March 2004 and April 2014 were screened. After diagnosis was confirmed by pathological review, clinical, imaging, therapeutic, and outcome data were collected retrospectively. Results - Forty-three patients with anaplastic GGG (median age, 49.4 y) from 18 centers were included. Presenting symptoms were neurological deficit (37.2%), epileptic seizure (37.2%), or increased intracranial pressure (25.6%). Typical imaging findings were unifocal location (94.7%), contrast enhancement (88.1%), central necrosis (43.2%), and mass effect (47.6%). Therapeutic strategy included surgical resection (95.3%), adjuvant radiochemotherapy (48.8%), or radiotherapy alone (27.9%). Median progression-free survival (PFS) and overall survival (OS) were 8.0 and 24.7 months, respectively. Three- and 5-year tumor recurrence rates were 69% and 100%, respectively. The 5-year survival rate was 24.9%. Considering unadjusted significant prognostic factors, tumor midline crossing and frontal location were associated with shorter OS. Temporal and parietal locations were associated with longer and shorter PFS, respectively. None of these factors remained statistically significant in multivariate analysis. Conclusions - We report a large series providing clinical, imaging, therapeutic, and prognostic features of adult patients treated for an intracerebral anaplastic GGG. Our results show that pathological diagnosis is difficult, that survivals are only slightly better than for glioblastomas, and that complete surgical resection followed with adjuvant chemoradiotherapy offers longer survival.

The aim of this study was to review and describe therapeutic approaches in children with choroid plexus tumor (CPT) based on a nationwide series. The World Health Organization classification subdivides these rare tumors into three histological subtypes corresponding to three grades of malignancy: low grade (grade I) choroid plexus papilloma (CPP), intermediate grade (grade II) atypical choroid plexus papilloma (aCPP) and high grade (grade III) choroid plexus carcinoma (CPC). This retrospective study included 102 French children younger than 18 years, treated from 2000 to 2012: 54 CPP, 26 aCPP and 22 CPC. The 5 year overall survival was 100% in CPP, 96.2% in aCPP and 64.7% in CPC. In patients with localized disease, complete surgical resection was achieved in 48/52 CPP, 20/26 aCPP and 7/14 CPC. In this group, patients with complete surgical resection had better event free survival than patients with partial resection (88.9 vs. 41.6%). 28 patients (1 CPP, 6 aCPP and 22 CPC) had adjuvant chemotherapy. 2 aCPP and 9 CPC had radiotherapy. We underlined the need for a central histological review to accurately analyze clinical data; we reported a much higher overall survival for CPC than in most previous CPT series probably including atypical teratoid rhabdoid tumors. In our series, the 5 years overall survival in CPC (64.7%) was higher than event free survival (25.2%) and could be interpreted as a clue for the efficiency of adjuvant/salvage therapy even if the heterogeneity of applied treatments in this retrospective series does not allow for meaningful statistical comparisons.

A 27-year-old man suddenly died in hospital of acute respiratory distress syndrome secondary to severe systemic vasculitis. Multi-phase post-mortem computed tomography angiography followed by scientific autopsy of the thoracic and abdominal cavity and histology was performed, illustrating the advantages and drawbacks of such techniques. Imaging enabled us to examine the cranium, as the family refused cerebral dissection. MPMCTA revealed absence of opacification of the left middle cerebral artery. But parenchymal findings of thoracic and abdominal organs were still difficult to interpret after both imaging and macroscopic examination during the autopsy. Microscopic examination provided the definitive diagnosis of cause of death. Analysis revealed systemic vasculitis of the lung complicated by diffuse alveolar, mediastinal, splenic and retroperitoneal lesions. We were unable to determine the type of vasculitis, whether polyarteritis nodosa or microscopic polyangiitis, because of artifactual glomerular collapse. We observed some structural changes in tissue secondary to contrast agent injection, affecting the vascular system and renal parenchyma in particular. Such artifacts must be known in order to avoid misinterpreting them as pathological findings. MPMCTA and conventional autopsy are two complementary techniques showing both their specific advantages and limits which have to be known in order to choose the appropriate technique. One limit of both techniques is the detection of microscopic findings which can only be obtained by additional histological examination. This case report underlines this fact and demonstrates that caution is required in some cases if microscopic analyses are carried out after contrast agent injection.

Objectives To evaluate HBME-1, cytokeratin-19 (CK-19) and Ki-67 immunomarkers in order to increase the diagnostic accuracy of preoperative thyroid fine needle aspiration (FNA) cytology. Methods Immunocytochemistry against HBME-1, CK-19 and Ki-67 was performed on 123 thyroid FNAs processed by liquid-based cytology (LBC). Statistical analysis was carried out on 61 cases with histological control and sufficient material for one or more of the three markers. The Bethesda System was used for cytological diagnosis. Results Taking into account all the cytological categories, with a cut-off of 30% of positive cells, HBME-1 (n = 47) and CK-19 (n = 53) showed a sensitivity for malignancy of 66.7% (95% confidence interval, 53.2–80.1) and 90.5% (82.6–98.4) and a specificity of 90.6% (82.3–99) and 75% (63.3–86.7), respectively. For Ki-67 (n = 54) with a cut-off of 1% of positive cells, the sensitivity was 85.0% (75.5–94.5) and the specificity 70.6% (58.4–82.7). In the follicular neoplasm/suspicious for follicular neoplasm (FN/SFN) category (n = 37), which was the focus of the study, papillary thyroid carcinomas (PTCs) were less numerous (four cases, three of which were the follicular variant), the positivity of the three immunomarkers combined showed an overall accuracy of 91% (21/23). The mean percentage of Ki-67-positive cells was increased in malignant lesions, with the exception of follicular variant PTCs: 16% ± 15.6% in two follicular carcinomas, 4.8% ± 3.2% in 13 classical PTCs, 1% ± 1.2% in five follicular variant PTCs and 0.5% ± 1.9% in 34 non-malignant lesions. Conclusions Immunocytochemistry using HBME-1, CK-19 and the Ki-67 proliferative index increased the diagnostic accuracy of FNA in the FN/SFN category of the Bethesda System, which may help to distinguish lesions in this category with a low or high risk of malignancy. Thus, clinical management would be improved.

Background Based on our previous results showing the involvement of the farnesylated form of RhoB in glioblastoma radioresistance, we designed a phase II trial associating the farnesyltransferase inhibitor Tipifarnib with radiotherapy in patients with glioblastoma and studied the prognostic values of the proteins which we have previously shown control this pathway. Patients and methods Patients were treated with 200 mg Tipifarnib (recommended dose (RD)) given continuously during radiotherapy. Twenty-seven patients were included in the phase II whose primary end-point was time to progression (TTP). Overall survival (OS) and biomarker analysis were secondary end-points. Expressions of αvβ3, αvβ5 integrins, FAK, ILK, fibroblast growth factor 2 (FGF2) and fibroblast growth factor receptor 1 (FGFR1) were studied by immuno-histochemistry in the tumour of the nine patients treated at the RD during the previously performed phase I and on those of the phase II patients. We evaluated the correlation of the expressions of these proteins with the clinical outcome. Results For the phase II patients median TTP was 23.1 weeks (95%CI = [15.4; 28.2]) while the median OS was 80.3 weeks (95%CI = [57.8; 102.7]). In the pooled phase I and II population, median OS was 60.4w (95%CI = [47.3; 97.6]) while median TTP was 18.1w (95%CI = [16.9; 25.6]). FGFR1 over-expression (HR = 4.65; 95%CI = [1.02; 21.21], p = 0.047) was correlated with shorter TTP while FGFR1 (HR = 4.1 (95% CI = [1.09–15.4]; p = 0.036)) and αvβ3 (HR = 10.38 (95%CI = [2.70; 39.87], p = 0.001)) over-expressions were associated with reduced OS. Conclusion Association of 200 mg Tipifarnib with radiotherapy shows promising OS but no increase in TTP compared to historical data. FGFR1 and αvβ3 integrin are independent bad prognostic factors of OS and TTP.

Given the failure of chemo- and biotherapies to fight advanced pancreatic cancer, one major challenge is to identify critical events that initiate invasion. One priming step in epithelia carcinogenesis is the disruption of epithelial cell anchorage to the basement membrane which can be provided by hemidesmosomes (HDs). However, the existence of HDs in pancreatic ductal epithelium and their role in carcinogenesis remain unexplored. HDs have been explored in normal and cancer pancreatic cells, and patient samples. Unique cancer cell models where HD assembly can be pharmacologically manipulated by somatostatin/sst2 signaling have been then used to investigate the role and molecular mechanisms of dynamic HD during pancreatic carcinogenesis. We surprisingly report the presence of mature type-1 HDs comprising the integrin α6β4 and bullous pemphigoid antigen BP180 in the human pancreatic ductal epithelium. Importantly, HDs are shown to disassemble during pancreatic carcinogenesis. HD breakdown requires phosphoinositide 3-kinase (PI3K)-dependent induction of the matrix-metalloprotease MMP-9, which cleaves BP180. Consequently, integrin α6β4 delocalizes to the cell-leading edges where it paradoxically promotes cell migration and invasion through S100A4 activation. As S100A4 in turn stimulates MMP-9 expression, a vicious cycle maintains BP180 cleavage. Inactivation of this PI3K-MMP-9-S100A4 signaling loop conversely blocks BP180 cleavage, induces HD reassembly and inhibits cell invasion. We conclude that mature type-1 HDs are critical anchoring structures for the pancreatic ductal epithelium whose disruption, upon PI3K activation during carcinogenesis, provokes pancreatic cancer cell migration and invasion.

We report the case of a 63-year-old patient with muscular weakness in the context of a myasthenia gravis evolving for 4 years. Although myasthenia gravis was under control, aggravation of muscular weakness led to perform a muscular biopsy. It showed a giant cell myositis, which is usually described in sarcoidosis but can also be found in a context of myositis associated with myasthenia gravis.

International audience; We report the case of a 37-year-old man suffering from insidious visual agnosia and spastic paraparesis due to a PSEN1 mutation. His mother was diagnosed with Alzheimer disease after a biopsy. He was assessed by multimodal neuroimaging, including new in vivo positron emission tomography amyloid imaging (F-AV45). His data were compared with those from healthy participants and patients with sporadic predemential Alzheimer disease. He exhibited posterior cortical thickness reduction, posterior hypometabolism, and increased amyloid ligand uptake in the posterior cortex and the striatum. We show that F-AV45 positron emission tomography allows visualization of the unusual pattern of amyloid deposits that co-localize with cortical atrophy in this genetic form of Alzheimer disease.

The problem of identifying the wounding agent in forensic cases is recurrent. Moreover, when several tools are involved, distinguishing the origin of lesions can be difficult. Scanning electron microscopy (SEM)/energy dispersive X-ray analysis (EDS) equipment is increasingly available to the scientific and medical community, and some studies have reported its use in forensic anthropology. However, at our knowledge, no study has reported the use of SEM-EDS in forensic cases involving glass tools, whether in case reports or experiments. We performed an experimental study on human rib fragments, on which we manually created wounds using fragments of window and mirror glass. SEM-EDS was executed on samples without any further preparation on low vacuum mode, then on the same samples after defleshing them completely by boiling them. Window and mirror glass particles were detected on experimental wounds. Both had silica in their spectra, and the opaque side of the mirror contained titanium, allowing for their identification. Boiling and defleshing the bone samples involved a loss of information in terms of the number of wounds detected as positive for glass particles and in the number of glass particles detected, for both window and mirror glass. We suggest the analysis of wounds with suspected glass particles using low vacuum mode and with no defleshment by boiling.

The aim of this study was to better define the clinical and biopathological features of patients with desmoplastic/nodular medulloblastoma (DNMB) and to further characterize this subgroup. 17 children aged < 5 years, with initial DNMB treated according to the HIT-SKK protocol, were evaluated. A retrospective central radiological review, a pathological and immunohistochemical study, and array-CGH and sequencing of germline SUFU and PTCH1 genes were performed. 15 histologically reviewed cases were confirmed as DNMB including three cases of medulloblastoma with extensive nodularity. Median age at diagnosis was 26 months. Radiology showed five cases with a vermis location and one with T2 hyperintensity. All cases showed a SHH immuno-profile. A 9q deletion was found in 6 cases, a MYCN–MYCL amplification in 1 case, and a SUFU germline mutation in 1 case (/9). The presence of SUFU and PTCH1 germline mutations agreed with previous reports. At 3 years, progression-free survival and overall-survival rates were 72 ± 15% and 85 ± 10%, respectively. The rate of recurrence was relatively high (4 patients). This may have been because chemotherapy was delayed in two cases. Age > 3 years, and residual tumor may also have been an explanation for recurrence.

International audience; Purposes The purpose of this study was to retrospectively study embryonal tumors with multilayered rosettes (ETMR), a rare new entity that gathers ETAN-TR (embryonal tumor with abundant neuropil and true rosettes), ependymoblastomas, and medulloepitheliomas, in order to improve their descriptions and try to better define therapeutic modalities. Methods: Patients with ETMR, ETAN-TR, ependymoblastoma, and medulloepithelioma treated in SFCE centres (Société Française de lutte contre les Cancers et les leucémies de l'Enfant et de l'adolescent) since 2000 were collected. Data were retrieved from clinical charts.Results: Thirty-eight patients were included in the analysis. Seventeen had an ETAN-TR, 13 had a medulloepithelioma, and 8 had an ETMR. No ependymoblastoma was included. The median age at diagnosis was 31 months (range, 2.8–141 months). The predominant tumor location was supratentorial (66 %); 18.4 % patients had metastatic lesion. LIN28A expression was positive in 11/11 patients. Amplification of the locus 19q13.42 was positive in 10/12 patients. Thirty patients were treated according to the primitive neuroectodermal tumors of high risk (PNET-HR) protocol. The median time of follow-up was 0.9 years (range 0.1 to 15.3 years). The 1-year event-free survival (EFS) and overall survival (OS) were, respectively, 36 % CI 95 % (23–55) and 45 % CI 95 % (31–64). On multivariate analysis, complete surgical resection, radiotherapy, and high-dose chemotherapy were associated with a better overall survival with a relative risk of, respectively, 7.9 CI 95 % (2.6–23.5) p < 0.0002, 41.8 CI 95 % (9.4–186) p < 0.0001, and 3.5 CI 95 % (1.3–9.5) p = 0.012.Conclusion: Prognosis of ETMR remains dismal despite multimodal therapy. LIN28A immunostaining and 19q13.42 amplification should be systematically done to secure the diagnosis. Complete surgical resection, radiotherapy, and high-dose chemotherapy are associated with better outcome.

Malignant transformation of a fibrous dysplasia into an osteosarcoma is very rare. We report the case of an 84-year-old man with telangiectatic osteosarcoma of the upper femur arising in a previous fibrous dysplasia also known as liposclerosing myxofibrous tumor. The tumor was expressing the epithelial membrane antigen. This is the first described case of a malignant transformation into an osteosarcoma arising in a liposclerosing myxofibrous tumor. We discuss the main differential diagnosis with a review.

Based on epidemiological, clinical, and preclinical data, lung carcinogenesis can be distinctive in women, suggesting that women should be treated differently depending on the expression of various specific biomarkers. We aimed to describe the hormonal and genetic profile of lung cancer in both men and women to identify gender specificities. Primary lung-tumor tissues from surgically treated patients, (50 men, 50 women) were analyzed and compared for expression of estrogen receptors (ER) α and β, progesterone receptors (PR), epidermal growth-factor receptor (EGFR), and HER2 (for EGFR and K-Ras mutations). These data were combined with clinical and outcome data. Fewer women with lung cancer were smokers (p=0.001) and they smoked fewer cigarettes (p=0.001). We observed a higher rate of EGFR mutations (p=0.02) and ERα expression (p=0.006) in women. ERβ and EGFR were also expressed more frequently in women (p=0.29 and p=0.16). HER2 was overexpressed regardless of gender in three men and two women. K-Ras was mutated in 16% of both men and women. Interestingly, there was a positive link between EGFR expression and expression of ERα (p=0.028) and ERβ (p=0.047) in both men and women. Expression of ERα was associated with improved disease-free survival (p=0.007). Our findings provide further evidence on the specificities of lung cancer in women. The differential expression of specific biomarkers, which could be targeted by therapy, favors the development of gender-based treatment guided by biomarker expression.

Characterization of sharp-force trauma on human bones can be extremely useful in providing information regarding the nature and context of death. Nevertheless, in the identification of weapons used to cause sharp-force trauma and analysis of bone wounds, challenging tasks still remain. Current analysis attempting to dissect bone wound characteristics varied quite a lot and mixed different criteria, thus leading sometimes to conflicting results. In this context, the aim of our study is to clarify qualitative aspects of cut marks induced by sharp weapons on human bones. For that purpose, we analyzed bone samples via an original approach based on bone autofluorescence with an epifluorescence macroscope and compared it to previous existing methods. In this study, we used bone sections from human clavicles on which three different kinds of lesions were manually implemented, using different weapons. The bone wounds were analyzed by three different methodologies, light microscopy, scanning electron microscopy (SEM), and micro-computed tomography, and were compared with epifluorescence macroscopy. We paid attention more significantly to the aspect of walls and floor of the kerf, so as to conclude on the nature and distinguish between weapons used. Among all technologies used in this study, the most precise and efficient methods were epifluorescence macroscopy and SEM. Nonetheless, epifluorescence macroscopy is faster, cheaper, and more accessible than SEM. More significantly, this technique, which has the potential to accurately document the nature of the damage, is nondestructive, and could thus be highly useful in forensic science as anthropology.

International audience; We report the case of a 62-year-old asymptomatic carrier of AβPP gene duplication. He was investigated by MRI and the amyloid ligand 18F-AV45, and compared to Alzheimer's disease patients (n = 11) and healthy controls (n = 11). The neuropsychological examination was normal. Cortical thickness and AV45 retention were comparable to Alzheimer's disease patients. AβPP duplication was diagnosed because cerebral amyloid angiopathy and Alzheimer's disease pathology were found on the neuropathological examination of his youngest brother, who died at 42 from intracerebral hemorrhage. This is the first description of a pre-symptomatic AβPP duplication carrier over 60, despite widespread cerebral amyloid angiopathy, "Alzheimer's like" atrophy, and amyloid deposition.

M. Fevre-Montange, A. Vasiljevic, D. Frappaz, J. Champier, A. Szathmari, M.-H. Aubriot Lorton, F. Chapon, A. Coulon, I. Quintin Roue, M.-B. Delisle, D. Figarella-Branger, A. Laquerriere, C. Miquel, J.-F. Michiels, M. Peoch, M. Polivka, F. Fauchon and A. Jouvet (2012) Neuropathology and Applied Neurobiology38, 87–94 Utility of Ki67 immunostaining in the grading of pineal parenchymal tumours: a multicentre study Aims: 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. Methods: 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. Results: 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; P

Purpose This study aims to determine prognostic factors for patients who have non–small-cell lung cancer (NSCLC) that is treated with definitive chemoradiation therapy. Materials and Methods Seventy-eight patients has been treated with radiation therapy and concomitant or sequential chemotherapy between 2000 and 2005. Paraffin-embedded biopsy specimens were obtained before treatment from 73 patients and reviewed by two independent pathologists. Complete follow-up data were collected. The impact of clinical and pathological factors and treatment modality on survival was studied using the χ 2 and Fisher exact tests. A multivariate analysis was performed using the Cox proportional hazard model. Results Seventy-three patients were evaluated, 58 men and 15 women. Median age was 62 years. Most had locally advanced disease (42 stage IIIB and 24 stage IIIA), whereas 7 were medically inoperable stage I-II patients. Lymphovascular invasion (LVI) was identified in 20 biopsy specimens (27.4 %). Radiotherapy delivered a median dose of 66 Gy (range, 60 to 70 Gy). The median overall survival was 20.5 months. Relapse-free and overall survival were significantly higher in the concomitant arm than in the sequential arm ( P = .025 and P = .031, respectively). We found an independent association between the presence of LVI and both the risk of death with an adjusted hazard ratio (HR) of 2.69 (95% confidence interval [CI] 1.50-4.83) and the risk of metastatic progression (adjusted HR=3.01; 95% CI 1.58-5.72). Conclusion The presence of LVI on stage III NSCLC biopsy specimens was the only independent prognostic factor for poor outcome and may, therefore, be helpful in identifying patients at high risk of metastatic disease.

We report a case of basaloid squamous carcinoma with a spindle cell component of the hypopharynx, in a 61-years-old-man. An excisional biopsy of a pedonculated and polypoid tumour was performed by endoscopy. The histologic examination revealed a biphasic tumour with both a basaloid carcinomatous and a spindle cell component. Focally, osseous metaplasia was seen. The spindle cell component demonstrated immunoreactivity with the p63 epithelial marker. The patient was treated with chemotherapy followed by radiotherapy. The patient has been free of disease for one year. It's the ninth case reported in the literature of a biphasic carcinoma with both a basaloid squamous and a spindle cell component and the first case with osseous metaplasia.

L. Lacoste-Collin, G. Martin-Blondel, C. Basset-Leobon, V. Lauwers-Cances, D. d’Aure, J. Aziza, A. Berry, B Marchou, M.B. Delisle and M. Courtade-Saidi Investigation of the significance of Oil Red O-positive macrophage excess in bronchoalveolar lavage fluid during HIV infection Objective: To assess the significance of increased levels of Oil Red O-positive macrophages (ORO-PM) in bronchoalveolar lavage fluids (BALFs) from HIV-positive patients. Methods: Cytological data for seventy BALF samples from 66 consecutive HIV-infected patients were analysed according to antiretroviral therapy regimen, presence of Pneumocystis jiroveci infection, blood CD4+T cell count, HIV-1 viral load and plasma lipid levels. Non-parametric tests were used to compare the values between groups. Results: The percentages of ORO-PM were high in this group: 40% [6–80] (median [interquartile range]). They were positively correlated with the BALF total cell count, 21% [5–48.5] for 300 cells/mm3 (P

International audience; The clinical management of osteosarcoma differs significantly from that of chondrosarcoma; therefore, it is extremely important to diagnose these 2 types of bone tumor accurately. In the absence of a specific marker, differential diagnosis by histochemistry is sometimes impossible, especially between chondroblastic osteosarcoma and conventional chondrosarcoma. We analyzed 165 bone sarcomas by immunohistochemical staining of tissue microarrays for expression of the galectin-1 (GAL1) lectin and by Western blot experiments. We found that GAL1 was abundant in normal human osteoblasts from benign proliferations and in osteosarcomas, including chondroblastic osteosarcomas, but not in chondrosarcomas. There was a highly significant statistical difference in the percentage of stained cells (P < 10(-4)) and in the staining intensity (P < 10(-3)) of chondroblastic osteosarcomas compared to conventional chondrosarcomas. This discriminatory potential of GAL1 staining for osteosarcoma-derived tumors was confirmed by Western blotting. We propose a diagnostic test for bone tumors that takes into account the optimal discriminative values for the percentage of cells stained and the intensity of staining. The positive and negative predictive values were 85.7% (trust interval of 63.7%-97%) and 90% (trust interval of 80%-95.9%), respectively, demonstrating the pertinence of the test. Altogether, our data indicate that GAL1 is a powerful diagnostic marker that distinguishes chondroblastic osteosarcomas from conventional chondrosarcomas.

2028Background: Pineoblastoma (PB) is a rare but aggressive pediatric brain tumour arising from the pineal gland. Overall survival rates are estimated at 50-60%, with younger patients ( < 5 years o...

Resume Introduction La maladie de Moyamoya est rare et mal connue dans les populations non asiatiques. Nous rapportons 12 nouveaux cas chez des adultes francais. Patients et methods Nous avons identifie les patients adultes atteints d’une maladie de Moyamoya idiopathique suivis dans les services de neurologie du CHU de Toulouse depuis 1998 et analyse les donnees cliniques et radiologiques. Resultats Douze patients (dont dix femmes) ont ete inclus. L’âge moyen au moment du diagnostic etait de 31,1 ans. La pathologie a ete revelee par un accident vasculaire cerebral (AVC) ischemique dans dix cas. La duree moyenne de suivi a ete de 52,4 mois. Cinq patients ont eu des recidives d’AVC. La probabilite cumulee de premiere recidive d’AVC etait de 50 % a un et a cinq ans. Au terme du suivi, quatre patients n’avaient pas de sequelle fonctionnelle (score de Rankin 0 ou 1), sept avaient un handicap modere (score de Rankin 2–3) et un etait decede. Six patients presentaient des troubles cognitifs evoquant un syndrome dysexecutif. Conclusion La maladie de Moyamoya chez l’adulte non asiatique est une affection grave en raison du risque eleve de recidive d’AVC et de la frequence des troubles cognitifs.

Resume La decouverte d’un infarctus du myocarde d’origine ischemique lors d’une autopsie scientifique ou medicolegale est parfois deroutante surtout lorsqu’il s’agit d’un sujet jeune. Elle pose le probleme de l’etiologie des lesions vasculaires pour la mise en route d’eventuelles mesures de prevention dans la famille. En post mortem des examens complementaires sont realisables afin de preciser le diagnostic d’infarctus du myocarde et d’approcher son etiopathogenie. Ces examens, souvent exploites en Medecine Legale, sont rarement utilises par les pathologistes lors des autopsies scientifiques. Pourtant certains milieux biologiques sont suffisamment stables pour permettre une analyse biologique, biochimique voire genetique. Nous proposons une mise au point sur ces examens post mortem en insistant sur leurs apports et leurs limites.

Pathological diagnosis of brain tumors provides an index of brain disease severity and guides clinical practice in their treatment. Diagnoses are often made from biopsy material obtained using stereotactic techniques with the difficulty of making a histological diagnosis in small samples. In our experience, the estimation of the degree of malignancy on the basis of in vitro1H magnetic resonance spectroscopy (1H MRS) appears to well correlate with histology and clinical evolution. We report two cases with a discordance between the diagnoses on the basis of histology examination and in vitro 1H MRS whose evolution seems to correlate better with the data of1H MRS.

Abnormal accumulation of ferritin was found to be associated with an autosomal dominant slowly progressing neurodegenerative disease clinically characterized by tremor, cerebellar ataxia, parkinsonism and pyramidal signs, behavioral disturbances, and cognitive decline. These symptoms may appear sequentially over a period of 4 decades. Pathologically, intranuclear and intracytoplasmic bodies were found in glia and subsets of neurons in the central nervous system as well as in extraneural tissue. Biochemical analyses of these bodies isolated from the striatum and cerebellar cortex revealed that ferritin light polypeptide (FTL) and ferritin heavy polypeptide (FTH1) were the main constituents. Molecular genetic studies revealed a 2-bp insertion mutation in exon 4 of the FTL gene. The resulting mutant polypeptide is predicted to have a carboxy terminus that is altered in amino-acid sequence and length. In tissue sections, the bodies were immunolabeled by anti-ferritin and anti-ubiquitin antibodies and were stained by Perls' method for ferric iron. Synthetic peptides homologous to the altered and wild-type carboxy termini were used to raise polyclonal antibodies. These novel antibodies as well as an antibody recognizing FTH1 immunolabeled the bodies. This study of this disorder has provided additional knowledge and insights in the growing area of ferritin-related neurodegeneration.

Prognostic value of p27 Kip1 immunohistochemical expression was evaluated in a series of 95 bladder carcinomas. Low p27 Kip1 expression was correlated with higher tumor grade ( P =0.01) and stage ( P =0.009), associated with poor overall survival ( P =0.01) and, for superficial cancers, with disease-free survival ( P =0.05). Thirty-five cases exhibited a heterogeneous expression related in some instances to tumoral architecture. Seventeen cases showed a cytoplasmic reactivity related to low nuclear expression ( P =0.057). Loss of p27 Kip1 expression is a pejorative event in bladder tumors and inhibition of p27 Kip1 degradation could offer new therapeutic ways.

Background & Aims: To explore the pancreatic function of CCK2/gastrin receptor, we created ElasCCK2 transgenic mice expressing the human receptor in pancreatic exocrine cells. In previous studies, the transgenic CCK2/gastrin receptor was demonstrated to mediate enzyme release and protein synthesis. We now report results of phenotypic and long-term studies. Methods: Pancreas was characterized using morphometry and immunohistochemistry. ElasCCK2 mice were crossed with INS-GAS mice expressing gastrin in pancreatic β cells to achieve continuous stimulation of the CCK2/gastrin receptor. Results: The pancreatic weight of ElasCCK2 mice was increased by 40% and correlated with an increase in the area of exocrine tissue. Alterations in pancreatic histology were apparent from postnatal day 50. Crossing the ElasCCK2 mice with INS-GAS mice resulted in development of morphologic changes in younger animals. Malignant transformation occurred in 3 of 20 homozygous ElasCCK2 mice. Although tumors had different phenotypes, they all developed through an acinar-ductal carcinoma sequence. Conclusions: Our data show that transgenic expression of a G protein–coupled receptor can lead to cancer. This study also supports a key role of the CCK2/gastrin receptor in the development of pre- and neoplastic lesions of the pancreas. ElasCCK2 mice provide a model for carcinogenesis by transformation and dedifferentiation of acinar cells. GASTROENTEROLOGY 2002;122:428-437

Lymphocytic Hypophysitis is a rare autoimmune disease of the pituitary presenting mainly with features of a mass lesion and loss of pituitary function. Its cousre is quite unpredictable and its treatment is still controversial as experience in the field remains scarce. We describe a 45 year-old woman with a history of recurrent fever and meningeal symptoms who was referred 3 years later to our department for pituitary insufficiency Hormonal studies revealed an anterior pituitary deficiency and autoimmune thyroiditis. Pituitary hypertrophy as evidenced by magnetic resonance imaging showed complete regression upon hydrocortisone substitution therapy. Two years later, fever and meningeal symptoms recurred as well as pituitary hypertrophy. Cerebrospinal fluid analysis revealed an aseptic lymphocytic meningitis. Pituitary biopsy confirmed the diagnosis of LH. The patient was started on prednisone 70 mg per day. She improved clinically and radiologically and remained free of symptoms thereafter. At a recent follow up the MRI showed an empty sella turcica. Hereby we illustrate a yet unreported pattern of LH presenting as a recurrent aseptic meningitis. We also describe one of the long-term course of the disease which is still unpredictable.

Differentiating iatrogenic Creutzfeldt-Jakob disease (iCJD) from sporadic CJD (sCJD) would be useful for the identification and prevention of human-to-human prion transmission. Currently, the diagnosis of iCJD depends on identification of a recognized source of contamination to which patients have been exposed, in addition to fulfilling basic requirements for the establishment of diagnosis of CJD. Attempts to identify differences in clinical manifestations, neuropathological changes and pathological prion protein (PrPSc) between iCJD and sCJD have been unsuccessful. In the present study, using a variety of more sophisticated methods including sucrose step gradient sedimentation, conformational stability immunoassay, protein misfolding cyclic amplification (PMCA), fragment-mapping, and transmission study, we show no significant differences in gel profiles, oligomeric state, conformational stability and infectivity of PrPSc between iCJD and sCJD. However, using PMCA, we find that convertibility and amplification efficiency of PrPSc is greater in iCJD than in sCJD in a polymorphism-dependent manner. Moreover, two protease-resistant PrP C-terminal fragments (termed PrP-CTF12/13) were detected in all 9 cases of sCJD but not in 6 of 8 cases of iCJD tested in this study. The use of fragment mapping- and PMCA-based assays thus provides a means to distinguish most cases of iCJD from sCJD.

Primary sinonasal intestinal-type adenocarcinomas (ITAC) are defined on the basis of their morphological similarities to colorectal adenocarcinomas (CRA). Thus, differential diagnosis with sinonasal metastasis of CRA could be a real challenge. Neuroendocrine differentiation has been variably described in several types of adenocarcinomas and notably in ITACs and CRAs. In a series of 25 ITACs and 25 lymph node metastasis of CRAs (nmCRA), we analysed neuroendocrine differentiation by immunohistochemistry with anti-chromogranin A and synaptophysin antibodies. Neuroendocrine differentiation (chromogranin A and/or synaptophysin positivity) was significantly different (p=0.0002) in ITACs (72%) and in nmCRAs (20%). In conclusion, presence of neuroendocrine cells seems more in favour of a sinonasal intestinal-type adenocarcinoma, than metastatic CRA. This immunohistochemical study could be useful in difficult cases and should be an interesting complement in a clinical discussion.

Aims To improve the cytological diagnosis of retinal lymphoma on vitreous fluid using improved cell collection and systematic analyses. Methods and results Since October 2010, we have developed and optimized in our department a method with which to perform the diagnosis of retinal lymphoma. The vitreous sample was collected in a tube containing RPMI-1640 medium, decomplemented fetal bovine serum, and gentamicin. The transport and technical steps were performed at 4°C. Systematically, cytological examination with May–Grunwald–Giemsa staining and immunocytochemistry (mainly anti-CD3, anti-CD20 and anti-CD68 antibodies) were performed on cytospins. Whenever possible, determination of B-cell clonality, flow cytometry and determination of the interleukin (IL)-10/IL-6 ratio were performed. From October 2010 to June 2013, with this optimized protocol, 38 vitreous cytological samples from 32 patients were analysed, and a final diagnosis was possible, avoiding a biopsy, in all cases except one. Conclusion The preservation of vitreous fluid cells on culture medium led to the diagnosis of retinal lymphoma in 10 of 12 cases, and exclusion of this diagnosis in 26 cases. This protocol may be applied even when the delay in shipping from the surgery to the pathology departments exceeds 1 h.

Background Mammary analog secretory carcinoma (MASC) of the salivary gland has been recently described according to morphological, immunohistochemical, and molecular (ETV6-NTRK3 translocation) similarities with the mammary secretory carcinoma. The most important differential diagnostic considerations of MASC are low-grade adenocarcinoma not otherwise specified (NOS), cystadenocarcinoma, and acinic cell carcinoma (AciCC). These tumors may share an overlapping morphology with MASC, and additional immunohistochemical studies are required to reinforce the diagnosis. Mammaglobin, GCDFP-15, and p63 staining have been reported in MASC. Our study was designed to check the specificity of these antibodies in MASC compared to other frequent tumors of salivary glands. Methods A series of 62 salivary gland tumors [10 MASCs, 5 adenocarcinomas NOS and 2 cystadenocarcinomas with MASC features and without ETV6 rearrangement, one low-grade cribriform cystadenocarcinoma (LGCCC), 9 AciCCs, 10 MECs, 10 adenoid cystic carcinomas (AdeCCs), 5 polymorphous low-grade adenocarcinomas (PLGAs), and 10 pleomorphic adenomas (PAs)] was analyzed by immunohistochemistry with mammaglobin, GCDFP-15, and p63 antibodies. Results Positivity for mammaglobin was observed in all MASCs, cystadenocarcinomas, LGCCC, and PLGAs, in some adenocarcinomas NOS, PAs, and MECs, rarely in AciCCs and never in AdeCCs. Positivity for GCDFP-15 was observed in most of the tumor types except in AdeCCs. Interestingly, cytoplasmic positivity for p63 was observed in most of MASCs and PLGAs while rarely in adenocarcinomas NOS and PAs, and never in the other tumor types. Conclusion Our study revealed the usefulness of mammaglobin and p63 cytoplasmic staining to define which tumors are worth to be screened for ETV6 rearrangement.

Embryonal tumor with multilayered rosettes (ETMR), including embryonal tumor with abundant neuropil and true rosettes (ETANTR), and ependymoblastoma (EBL) constitute a distinct entity of the primitive neuroectodermal tumor (PNET) family. The presence of a focal amplification at chromosome region 19q13.42 associated with an up-regulation of the oncogenic miRNA cluster C19MC suggests that they may represent a histological spectrum of a single biological entity. Their histopathological spectrum is wide, including medulloepithelioma, their location may be supra- or infra-tentorial, their prognosis is poor. Recent data on molecular subgroups of PNETs have led to new insights on diagnosis and treatment of these tumors. Subsequently, LIN28A immunoexpression was identified as a highly specific marker for ETMR. In this study, we report 4 cases diagnosed initially as ETANTR with CGH-array data, including 19q13.42 gain with absence of other amplicons, particularly of the MYC gene family, and inconstant gain of whole chromosome 2. Immunohistochemical positive expression of LIN28A and absence of Olig2 expression were observed. We summarize the literature on ETMR, pointing out on the nosological evolution of this entity and the findings on genetic hallmarks of this particular tumor. Our results emphasize the usefulness of immunohistochemistry as a highly sensitive and fast diagnostic tool for ETMR and for genetic data, especially for 19q13.42 locus. Biological features may offer new therapeutic options for these embryonal tumors that do not usually respond to conventional treatments of PNETs.

We report on a boy with a BMD phenotype presenting with a deletion of exons 45-49 in the DMD gene. Immunofluorescence and Western blot analysis of a skeletal muscle sample revealed, as expected, truncated dystrophin with loss in the central rod domain, but with an unusual severe deficiency in the sarcoglycan complex, as in severe DMD. We discuss possible neighboring between dystrophin and associated proteins within their complex organization at the muscle membrane.

Central neurocytoma (CN) is described as a rare intra-ventricular benign neuronal tumor of the brain. Two primary tumors first diagnosed as malignant and extra-ventricular neurocytomas are reported here. Histologically, the tumor of the first patient, a forty-one-year-old man, consisted of monotonous cells with round nuclei, but no fibrillar background. The second tumor, in a nineteen-year-old girl, showed areas of moderately pleomorphic round cells, with numerous rosettes and ganglion cell differentiation, in an abundant fibrillary network. Both presented calcifications. Mitoses were more frequent in recurrences and spinal locations than in the primaries. All tumors stained strongly for synaptophysin, and GFAP was partly positive in the first case only. Patients received post-surgical radiotherapy and were still alive eight and six years, respectively, after initial surgery. The interpretation of atypical cases, such as ours is not easy: the diagnoses finally retained were oligodendroglioma in the first case and ganglioneuroblastoma in the second case. Furthermore, neurocytomas atypical either by their unusual topographical or histological presentation or by their poor prognosis, have been frequently entitled in this way on synaptophysin positivity. So, we were prompted to reassess the entity of CN, seventeen years after the first description, to re-appreciate the reality of anatomo-clinical variants and to discuss the value of synaptophysin positivity in these tumors. In conclusion, it seems preferable to individualize true classical CN, which has a favorable outcome, from so-called extra-ventricular, atypical and anaplastic, clinically malignant neurocytomas for which complementary treatment is required.

Recently intronic and exonic mutations in the Tau gene have been found to be associated with familial neurodegenerative syndromes characterized not only by a predominantly frontotemporal dementia but also by the presence of neurological signs consistent with the dysfunction of multiple subcortical neuronal circuitries. Among families, the symptomatology appears to vary in quality and severity in relation to the specific Tau gene mutation and often may include parkinsonism, supranuclear palsies, and/or myoclonus, in addition to dementia. We carried out molecular genetic and neuropathological studies on two patients from a French family presenting, early in their fifth decade, a cognitive impairment and supranuclear palsy followed by an akinetic rigid syndrome and dementia. The proband died severely demented 7 years after the onset of the symptoms; currently, his brother is still alive although his disease is progressing. In both patients, we found a Tau gene mutation in exon 10 at codon 279, resulting in an asparagine to lysine substitution (N279K). Neuropathologically, widespread neuronal and glial tau accumulation in the cortex, basal ganglia, brain stem nuclei as well as in the white matter were the hallmark of the disease. These deposits were shown by immunohistochemistry and immunoelectron microscopy, using a battery of antibodies to phosphorylation-dependent and phosphorylation-independent epitopes present in multiple tau regions. In the neocortex, tau-immunopositive glial cells were more numerous than immunopositive neurons; the deeper cortical layers as well as the white matter adjacent to the cortex contained the largest amount of immunolabeled glial cells. In contrast, some brain stem nuclei contained more neurons with tau deposits than immunolabeled glial cells. The correlation of clinical, neuropathological and molecular genetic findings emphasize the phenotypic heterogeneity of diseases caused by Tau gene mutations. Furthermore, to test the effect of the N279K mutation and compare it with the effect of the P301L exon 10 mutation on alternative splicing of Tau exon 10, we used an exon amplification assay. Our results suggest that the N279K mutation affects splicing similar to the intronic mutations, allowing exon 10 to be incorporated more frequently in the Tau transcript.

Adenoid cystic carcinoma generally arises from the salivary glands and is rarely found in the female genital tract. Infection with HPV is implicated in this cervical lesion. Differential diagnosis includes adenoid basal carcinoma, polymorphous low-grade adenocarcinoma and basaloid squamous cell carcinoma. Only one case of vaginal localisation was previously described. We report a case of adenoid cystic carcinoma in a 48-year-old woman with previous cervical HPV infection. Histological examination revealed nests of cells with peripheral palisading organisation and glandular lumina containing material produced by the tumor cells.