Search

The immune-specialized environment of the healthy brain is tightly regulated to prevent excessive neuroinflammation. However, after cancer development, a tissue-specific conflict between brain-preserving immune suppression and tumor-directed immune activation may ensue. To interrogate potential roles of T cells in this process, we profiled these cells from individuals with primary or metastatic brain cancers via integrated analyses on the single-cell and bulk population levels. Our analysis revealed similarities and differences in T cell biology between individuals, with the most pronounced differences observed in a subgroup of individuals with brain metastasis, characterized by accumulation of CXCL13-expressing CD39+ potentially tumor-reactive T (pTRT) cells. In this subgroup, high pTRT cell abundance was comparable to that in primary lung cancer, whereas all other brain tumors had low levels, similar to primary breast cancer. These findings indicate that T cell-mediated tumor reactivity can occur in certain brain metastases and may inform stratification for treatment with immunotherapy.

Human tissue samples represent an invaluable source of information for the analysis of disease-specific cellular alterations and their variation between different pathologies. In cancer research, advancing a comprehensive understanding of the unique characteristics of individual tumor types and their microenvironment is of considerable importance for clinical translation. However, investigating human brain tumor tissue is challenging due to the often-limited availability of surgical specimens. Here we describe a multimodule integrated pipeline for the processing of freshly resected human brain tumor tissue and matched blood that enables analysis of the tumor microenvironment, with a particular focus on the tumor immune microenvironment (TIME). The protocol maximizes the information yield from limited tissue and includes both the preservation of bulk tissue, which can be performed within 1 h following surgical resection, as well as tissue dissociation for an in-depth characterization of individual TIME cell populations, which typically takes several hours depending on tissue quantity and further downstream processing. We also describe integrated modules for immunofluorescent staining of sectioned tissue, bulk tissue genomic analysis and fluorescence- or magnetic-activated cell sorting of digested tissue for subsequent culture or transcriptomic analysis by RNA sequencing. Applying this pipeline, we have previously described the overall TIME landscape across different human brain malignancies, and were able to delineate disease-specific alterations of tissue-resident versus recruited macrophage populations. This protocol will enable researchers to use this pipeline to address further research questions regarding the tumor microenvironment. Bulk tumor preservation and dissociation enable multiple analyses of the brain tumor immune microenvironment via immunofluorescent staining and cell sorting followed by transcriptomics, genomics or in vitro culture of specific cell populations.

Primary non-neuroendocrine tumours of the pituitary gland and sella are rare lesions often challenging to diagnose. We describe two cases of clinically aggressive primary glomus tumour of the pituitary gland. The lesions occurred in a 63-year-old male and a 30-year-old female who presented with headache, blurred vision and hypopituitarism. Neuroimaging demonstrated large sellar and suprasellar tumours invading the surrounding structures. Histologically, the lesions were characterised by angiocentric sheets and nests of atypical cells that expressed vimentin, smooth muscle actin and CD34. Perivascular deposition of collagen IV was also a feature. Case 2 expressed synaptophysin. INI-1 (SMARCB1) expression was preserved. Both lesions were mitotically active and demonstrated a Ki-67 labelling index of 30%. Next-generation sequencing performed in case 1 showed no mutations in the reading frame of 37 commonly mutated oncogenes, including BRAF and KRAS. Four pituitary glomus tumours have previously been reported, none of which showed features of malignant glomus tumour. Similar to our two patients, three previous examples displayed aggressive behaviour.

The invasive behavior of glioblastoma, the most aggressive primary brain tumor, is considered highly relevant for tumor recurrence. However, the invasion zone is difficult to visualize by Magnetic Resonance Imaging (MRI) and is protected by the blood brain barrier, posing a particular challenge for treatment. We report biological features of invasive growth accompanying tumor progression and invasion based on associated metabolic and transcriptomic changes observed in patient derived orthotopic xenografts (PDOX) in the mouse and the corresponding patients’ tumors. The evolution of metabolic changes, followed in vivo longitudinally by 1H-Magnetic Resonance Spectroscopy (MRS) at ultra-high field, reflected growth and the invasive properties of the human glioblastoma transplanted into the brains of mice (PDOX). Comparison of MRS derived metabolite signatures, reflecting temporal changes of tumor development and invasion in PDOX, revealed high similarity to spatial metabolite signatures of combined multi-voxel MRS analyses sampled across different areas of the patients’ tumors. Pathway analyses of the transcriptome associated with the metabolite profiles of the PDOX, identified molecular signatures of invasion, comprising extracellular matrix degradation and reorganization, growth factor binding, and vascular remodeling. Specific analysis of expression signatures from the invaded mouse brain, revealed extent of invasion dependent induction of immune response, recapitulating respective signatures observed in glioblastoma. Integrating metabolic profiles and gene expression of highly invasive PDOX provided insights into progression and invasion associated mechanisms of extracellular matrix remodeling that is essential for cell-cell communication and regulation of cellular processes. Structural changes and biochemical properties of the extracellular matrix are of importance for the biological behavior of tumors and may be druggable. Ultra-high field MRS reveals to be suitable for in vivo monitoring of progression in the non-enhancing infiltration zone of glioblastoma.

Aims: We sought to develop a reproducible animal model for acute myocardial infarction (AMI) in adult atherosclerosis-prone pigs. Methods and results: A coil was placed in the right coronary artery or the left anterior descending artery in 26 downsized spontaneously hypercholesterolaemic pigs and left untreated until thrombotic occlusion. Then, we crossed the thrombotic occlusion with a guidewire, followed by predilatation, thrombus visualisation with optical coherence tomography (OCT) imaging and, finally, deployment of a stent and repeated OCT. After revascularisation, we calculated the index of microcirculatory resistance (IMR). After a feasibility phase (six animals), acute thrombotic occlusion was achieved in all 20 pigs. Eighteen animals were successfully revascularised and survived until sacrifice. Thrombus formation was confirmed by OCT, measurement of thrombin-antithrombin complexes and pathology examination. Myocardial necrosis was confirmed by troponin T elevation, myocardial staining and pathology examination. Distal thrombotic embolisation and microvascular obstruction were supported by increased IMR and pathology examination. Conclusions: A porcine model of thrombotic occlusion AMI in miniaturised adult spontaneously atherosclerosis-prone pigs is feasible by percutaneous intracoronary placement of a coil. The reperfusion by angioplasty completed this model which mirrors human pathological conditions with myocardial infarction, necrosis and distal embolisation.

Spinal angiolipomas (SALs) are rare extradural tumors frequently located at the level of the thoracic spine and they are associated with spinal cord compromise that might result in severe myelopathy. While the first macroscopic description dates 1890, histologically these tumors where not described as angiolipomas until 1986 by Haddad et al. Occurrence in pregnancy is even more infrequent. Since their first macroscopic description, spinal angiolipomas were reported anecdotally in pregnant women. We present a case of spinal angiolipoma in pregnancy with confirmed histologic diagnosis. In the present paper, we reviewed the literature regarding spinal angiolipomas in order to characterize their clinical manifestation, natural history, radiologic and histologic appearance. We add also a further case of spinal angiolipoma in a pregnant woman. Finally, we provide suggestions for the management of such rare tumors in pregnancy.

Human tissue samples represent an invaluable source of information for the analysis of disease-specific cellular alterations and their variation between different pathologies. In cancer research, advancing a comprehensive understanding of the unique characteristics of individual tumor types and their microenvironment is of considerable importance for clinical translation. However, investigating human brain tumor tissue is challenging due to the often-limited availability of surgical specimens. Here we describe a multimodule integrated pipeline for the processing of freshly resected human brain tumor tissue and matched blood that enables analysis of the tumor microenvironment, with a particular focus on the tumor immune microenvironment (TIME). The protocol maximizes the information yield from limited tissue and includes both the preservation of bulk tissue, which can be performed within 1 h following surgical resection, as well as tissue dissociation for an in-depth characterization of individual TIME cell populations, which typically takes several hours depending on tissue quantity and further downstream processing. We also describe integrated modules for immunofluorescent staining of sectioned tissue, bulk tissue genomic analysis and fluorescence- or magnetic-activated cell sorting of digested tissue for subsequent culture or transcriptomic analysis by RNA sequencing. Applying this pipeline, we have previously described the overall TIME landscape across different human brain malignancies, and were able to delineate disease-specific alterations of tissue-resident versus recruited macrophage populations. This protocol will enable researchers to use this pipeline to address further research questions regarding the tumor microenvironment.

Central nervous system involvement in Hodgkin lymphoma is extremely rare, especially in nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), which usually carries a favorable prognosis. Here we report a case of a young patient with NLPHL, who developed a progressive and fatal neurological deterioration requiring a very extensive work-up including two biopsies to obtain the diagnosis of T-cell/histiocyte-rich large B-cell lymphoma like transformation. This report, which includes post-mortem analysis, highlights the correlations between clinical, radiological, and biological data but also the difficulties encountered in reaching the correct diagnosis.

Brain malignancies encompass a range of primary and metastatic cancers, including low-grade and high-grade gliomas and brain metastases (BrMs) originating from diverse extracranial tumors. Our understanding of the brain tumor microenvironment (TME) remains limited, and it is unknown whether it is sculpted differentially by primary versus metastatic disease. We therefore comprehensively analyzed the brain TME landscape via flow cytometry, RNA sequencing, protein arrays, culture assays, and spatial tissue characterization. This revealed disease-specific enrichment of immune cells with pronounced differences in proportional abundance of tissue-resident microglia, infiltrating monocyte-derived macrophages, neutrophils, and T cells. These integrated analyses also uncovered multifaceted immune cell activation within brain malignancies entailing converging transcriptional trajectories while maintaining disease- and cell-type-specific programs. Given the interest in developing TME-targeted therapies for brain malignancies, this comprehensive resource of the immune landscape offers insights into possible strategies to overcome tumor-supporting TME properties and instead harness the TME to fight cancer.

Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating, mostly lethal complication due to an opportunistic infection of the central nervous system (CNS) by John Cunningham polyo...

Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) of the gallbladder are generally composed of adenocarcinoma and neuroendocrine carcinoma (NEC). Rare cases associated with intracholecystic papillary neoplasm (ICPN) have been reported. Although recent molecular data suggest that the different components of digestive MiNENs originate from a common precursor stem cell, this aspect has been poorly investigated in gallbladder MiNENs. We describe the clinicopathologic and molecular features of a MiNEN composed of ICPN, adenocarcinoma, and NEC. A 66-year-old woman presented with severe abdominal pain. She underwent radical cholecystectomy and an intracholecystic mass was found. Histologically, it was composed of ICPN associated with adenocarcinoma and large cell neuroendocrine carcinoma (LCNEC). The three components were positive for DNA repair proteins and p53. EMA was positive in the ICPN and adenocarcinoma components, while it was negative in the LCNEC. Heterogeneous expression of Muc5AC, cytokeratin 20, and CDX2 was only observed in the ICPN component. Cytokeratin 7 was diffusely positive in both adenocarcinoma and LCNEC components, while it was heterogeneously expressed in the ICPN. The copy number variation analysis showed overlapping results between the adenocarcinoma and LCNEC components with some minor differences with the ICPN component. The three tumor components showed the same mutation profile including TP53 mutation c.700T > C (p. Tyr234His), without mutations in other 51 genes known to be frequently altered in cancer pathogenesis and growth. This finding may support the hypothesis of a monoclonal origin of the different tumor components. We have also performed a review of the literature on gallbladder MiNENs.

A previously healthy 9-year-old boy presented with a history of fatigue for 3 weeks, pain in both calves for 2 days, and a mild cough, without fever. His medical history was negative and vaccinations were up to date. Examination by his pediatrician only showed decreased deep tendon reflexes (DTR) in both lower limbs. Blood count (white blood cells [WBC] 5.4 G/L, hemoglobin [Hb] 138 g/L, thrombocytes [Tc] 251 G/L), thyroid-stimulating hormone (1.76 mU/L), creatine kinase (CK) level (104 U/L), and erythrocyte sedimentation rate (3 mm/h) were all normal. Epstein-Barr virus monotest was negative and blood serology suggested a past infection.

Aim: To describe four novel primary epithelial tumours of the sella with papillary architecture and Thyroid Transcription Factor 1 (TTF-1) expression. Methods: Paraffin-embedded tissue from the four cases and recurrence of patient 1 was investigated with haematoxylin–eosin, special histochemical stains, immunohistochemistry with a broad panel of antibodies and next-generation sequencing. The ultrastructure of one tumour was studied in tissue retrieved from paraffin. Results: The lesions occurred in three females aged 20, 26 and 42years and a male aged 49 years. They presented with signs and symptoms secondary to pituitary stalk compression. Preoperative neuroimaging documented mixed solid and cystic, enhancing sellar masses with suprasellar extension. Histologically, the tumours showed thin papillae lined by a single layer of cytokeratin and TTF-1-positive cuboidal and cylindrical cells with mildly atypical nucleus. Next-generation sequencing performed in three cases did not identify any mutations. The main differential diagnosis included metastasis from lung or thyroid carcinoma, extraventricular choroid plexus papilloma and sellar ependymoma. Conclusion: We suggest the descriptive term of primary papillary epithelial tumour of the sella (PPETS) for this entity and propose that it could represent the intracranial equivalent of thyroid-like low-grade nasopharyngeal papillary adenocarcinoma. The cell of origin of PPETS remains undetermined although the intense and ubiquitous expression of TTF-1 may suggest a derivation from the infundibulum or ventricular recess. Our study expands the spectrum of sellar TTF-1-positive tumour and challenges the view that they all derive from pituicytes.

Background The invasive behavior of glioblastoma is considered highly relevant for recurrence. However, the invasion zone is difficult to visualize, typically lies outside the resected and irradiated area, and is protected by the blood brain barrier, posing a particular challenge for treatment. We present biological features of invasive growth accompanying tumor progression and invasion based on associated metabolic and transcriptomic changes in patient derived orthotopic xenografts (PDOX) and corresponding patients. Methods Patients with suspected glioblastoma were enrolled (NCT02904525) and underwent 1H-MR spectroscopy and imaging (1H-MRS/I, 7T). Tissue obtained at surgery was transplanted orthotopically into immune-compromised mice. Longitudinal follow-up was performed by 1H-MRS/I (14.1T) on the injected and the contralateral side. The PDOX, the corresponding contralateral side, and the original human tumors underwent RNA-sequencing. Results The temporal changes of the metabolite profiles characterized the kinetics of invasive growth of PDOX, and were patient specific. Comparison of 1H-MRS derived metabolite signatures, reflecting temporal changes of tumor development and invasion in PDOX, revealed high similarity to spatial metabolite signatures of combined multi-voxel analyses of the patients’ tumors. Associations between the metabolite profiles and the combined transcriptome of the xenografts and the host, reflected molecular signatures of invasion, comprising extracellular matrix degradation and reorganization, growth factor binding, and vascular remodeling. Conclusion Integrating metabolic profiles and gene expression of highly invasive PDOX allows in vivo monitoring of progression in the non-enhancing tumor infiltration zone and provides insights into the remodeling of the extracellular matrix that is essential for cell-cell communication and regulation of cellular processes. The changes of the structural and biochemical properties of the extracellular matrix are of importance for the biological behavior of the tumors and may be subjected to therapeutic targeting.

This clinical vignette describes the interdisciplinary diagnostic approach to a patient with cystic brain lesions. The scope of this case is to develop the clinical reasoning skills of trainees in clinical neuroscience, taking into account alternative diagnoses and unusual clinical presentations.

The 2017 World Health Organization classification of central nervous system and endocrine tumors have introduced significant changes in the diagnostic criteria for pituitary lesions. The aim of our paper is to describe the epidemiological, clinico-pathological, and radiological features of a single consecutive institutional surgical series of rare pituitary lesions, using these new criteria. Of the 316 endoscopic endonasal trans-sphenoidal approaches performed for pituitary lesions between 2010 and 2018, 15 rare lesions were encountered. These included metastases, pituitary carcinomas, pituicytomas, granular cell tumor, primary pituitary lymphomas, germinoma, mixed gangliocytoma-adenoma, hypophysitis, and pituitary hyperplasia. Their clinical, radiological, and pathological features are herewith presented along with a literature review that enabled us to propose an algorithm to facilitate a diagnosis for rare pituitary lesions.

Breast cancer is a highly heterogeneous disease. The efficacy of tailored therapeutic strategies relies on the precise detection of diagnostic biomarkers by immunohistochemistry (IHC). Therefore, considering the increasing incidence of breast cancer cases, a concomitantly time-efficient and accurate diagnosis is clinically highly relevant. Microfluidics is a promising innovative technology in the field of tissue diagnostic, enabling for rapid, reliable, and automated immunostaining. We previously reported the microfluidic-based HER2 (human epidermal growth factor receptor 2) detection in breast carcinomas to greatly correlate with the HER2 gene amplification level. Here, we aimed to develop a panel of microfluidic-based IHC protocols for prognostic and therapeutic markers routinely assessed for breast cancer diagnosis, namely HER2, estrogen/progesterone receptor (ER/PR), and Ki67 proliferation factor. The microfluidic IHC protocol for each marker was optimized to reach high staining quality comparable to the standard procedure, while concomitantly shortening the staining time to 16 min-excluding deparaffinization and antigen retrieval step-with a turnaround time reduction up to 7 folds. Comparison of the diagnostic score on 50 formaldehyde-fixed paraffin-embedded breast tumor resections by microfluidic versus standard staining showed high concordance (overall agreement: HER2 94%, ER 95.9%, PR 93.6%, Ki67 93.7%) and strong correlation (ρ coefficient: ER 0.89, PR 0.88, Ki67 0.87; p

IgG4-related hypophysitis (IgG4-RH) is a rare disease, which can occur singularly or as manifestation of a systemic IgG4-related disease (IgG4-RD). Less than one hundred cases have been reported in the literature, very few of which were histopathologically documented. We analyzed the clinical, radiological, and histopathological features of two cases of IgG4-RH, the former observed in a 66-year-old man in the context of an IgG4-RD, and the latter affecting a 21-year-old woman, as an isolated lesion. In addition, we performed a comprehensive review of the previously published histopathologically documented cases of IgG4-RH. Pituitary samples from both patients showed dense lymphoplasmacytic infiltration, interstitial and storiform fibrosis, and high numbers of IgG4-positive plasma cells, consistent with IgG4-RH. From the literature review, we retrieved 18 papers reporting a total of 22 cases of histopathologically documented IgG4-RH. The revision of these cases, also including the two reported herein, showed an equal distribution of IgG4-RH in the two sexes, albeit significant clinico-pathological variation was found between cases arisen in female and male patients, respectively. In detail, IgG4-RH females were affected in their second-third decade of life, with a solitary pituitary lesion, low IgG4 serum level, and frequent association with autoimmune disorders. By contrast, IgG4-RH in men was a disease of the elderly, often in the context of a systemic IgG4-RD, with high IgG4 serum levels. Our study shows that IgG4-RH, as currently defined, is a clinically heterogenous disease, with different features in the two sexes. Indeed, cases diagnosed in young women, as our case 2, mostly do not present other evidence of IgG4-RD and might be better classified as lymphocytic hypophysitis with abundant IgG4+ plasma cells. For this reason, the histopathological examination of the pituitary lesion, particularly in female patients, may still be useful for a correct differential diagnosis with other variants of primary hypophysitis.

Burkitt’s lymphoma is the commonest childhood malignancy in tropical Africa and is rare outside of Africa. Cavernous sinus lymphoma is a rare occurence and Burkitt’slymphoma of the cavernous sinus is uncommon. We review the case of a 52-year-old non-african and immunocompetent woman who developed over a period of 2 weeks an ocular pain, diplopia and ptosis. Physical examination revealed breast tumors. CT scan and MRI disclosed a bilateral cavernous sinus mass and work-up of the tumor showed additionnal tumor within the pelvis. Biopsy of breast tumor showed findings consistent with Burkitt’s Lymphoma and there was positivity to Epstein-Barr EBER-1. Chemotherapy led to complete and asymptomatic remission of the cavernous sinuses lesions. The disease had a highly aggressive course and the patient died 11 months after diagnosis. We discuss the MRI findings and the differential diagnosis of cavernous sinuses lesions.The case herein reported emphasizes this extremely rare location of Burkitt’s lymphoma, the MR findings and the need of considering the diagnosis of Burkitt’s Lymphoma in cavernous sinuses lesions.

Cryptococcosis is a serious infection, possibly lethal, of worldwide distribution. It mainly affects immunosuppressed patients resulting with pulmonary and/or meningeal involvements or disseminated infections. Due to the rarity of visceral and osseous infections, and to the absence of specific clinical symptoms, this diagnosis is often deferred. Resulting of diagnostic errors, samples are often directed to the department of pathology and more rarely to the department of mycology. Histopathological examination appears crucial, highlighting encapsulated yeasts with alcian blue staining. Once the diagnosis is performed, an appropriate antifungal therapy must be quickly introduced because these infections are associated with a high mortality rate. The aim of our work was to report five extra-cerebral and extra-pulmonary cryptococcosis cases, to describe their histopathological features, to evoke diagnostic techniques and to discuss the differential diagnoses.

Background Sequestered disc fragments may present as a lesion with peripheral enhancement on magnetic resonance imaging. When located in the psoas muscle compartment, this finding could mimic an abscess. Case description We describe a case of a 52-year-old man who returned from Togo after 2 years of living in precarious conditions. He was afebrile and complaining of lumbar back pain. The magnetic resonance imaging showed L3 and L4 vertebral body enhancement with bilateral psoas lesions in continuity with the disc space, suggesting spondylodiscitis with a differential diagnosis of inflammatory herniated disc. A computed tomography-guided biopsy of the right psoas lesion was performed to rule out spondylodiscitis. Histology was compatible with extruded disc material. Conclusion Herniated disc fragments should be considered as a differential diagnosis of psoas abscesses. Coronal plane images may show the continuity of bilateral herniated disc fragments, mimicking psoas abscesses.

International audience; IntroductionAim was to develop a full automatic clustering approach of the time-activity curves (TAC) from dynamic 18F-FET PET and evaluate its association with IDH1 mutation status and survival in patients with gliomas.MethodsThirty-seven patients (mean age: 45±13 y) with newly diagnosed gliomas and dynamic 18F-FET PET before any histopathologic investigation or treatment were retrospectively included. Each dynamic 18F-FET PET was realigned to the first image and spatially normalized in the Montreal Neurological Institute template. A tumor mask was semi-automatically generated from Z-score maps. Each brain tumor voxel was clustered in one of the 3 following centroids using dynamic time warping and k-means clustering (centroid #1: slowly increasing slope; centroid #2: rapidly increasing followed by slowly decreasing slope; and centroid #3: rapidly increasing followed by rapidly decreasing slope). The percentage of each dynamic 18F-FET TAC within tumors and other conventional 18F-FET PET parameters (maximum and mean tumor-to-brain ratios [TBRmax and TBRmean], time-to-peak [TTP] and slope) was compared between wild-type and IDH1 mutant tumors. Their prognostic value was assessed in terms of progression free-survival (PFS) and overall survival (OS) by Kaplan-Meier estimates.ResultsTwenty patients were IDH1 wild-type and 17 IDH1 mutant. Higher percentage of centroid #1 and centroid #3 within tumors were positively (P = 0.016) and negatively (P = 0.01) correlated with IDH1 mutated status. Also, TBRmax, TBRmean, TTP, and slope discriminated significantly between tumors with and without IDH1 mutation (P range 0.01 to 0.04). Progression occurred in 22 patients (59%) at a median of 13.1 months (7.6–37.6 months) and 13 patients (35%) died from tumor progression. Patients with a percentage of centroid #1 > 90% had a longer survival compared with those with a percentage of centroid #1 < 90% (P = 0.003 for PFS and P = 0.028 for OS). This remained significant after stratification on IDH1 mutation status (P = 0.029 for PFS and P = 0.034 for OS). Compared to other conventional 18F-FET PET parameters, TTP and slope were associated with PFS and OS (P range 0.009 to 0.04).ConclusionsBased on dynamic 18F-FET PET acquisition, we developed a full automatic clustering approach of TAC which appears to be a valuable noninvasive diagnostic and prognostic marker in patients with gliomas.

The revised WHO classification 2016 of central nervous system tumours incorporates molecular biomarkers in addition to histological features in an « integrated diagnosis ». Thus, it refines classification with more homogenous diagnosis groups in order to improve prognosis and to guide treatment, notably for gliomas. This article firstly summarized the new concept of this revised classification, some basis of the molecular genetics of gliomas and practical application of the « integrated diagnosis ». It analyses the impact of this classification on the diagnosis and outcome of gliomas performed at the University Institute of Pathology - CHUV, Lausanne from October 2015 to November 2016.La nouvelle classification OMS 2016 des tumeurs du système nerveux central amène un grand renouveau puisqu’elle prend maintenant en compte des données de biologie moléculaire et aboutit à un « diagnostic intégré ». Elle définit ainsi des groupes diagnostiques plus homogènes en termes de pronostic et de valeur prédictive à un traitement, notamment pour les gliomes. Après un rappel sur le concept de cette nouvelle classification, les notions de base sur la génétique moléculaire des gliomes et l’application pratique du diagnostic intégré, une analyse de l’impact de cette classification sur le diagnostic et le devenir des gliomes portés à l’Institut universitaire de pathologie du CHUV d’octobre 2015 à novembre 2016 est rapportée.

Background Endoplasmic reticulum (ER) calcium storage and release play important roles in B lymphocyte maturation, survival, antigen-dependent cell activation and immunoglobulin synthesis. Calcium is accumulated in the endoplasmic reticulum (ER) by Sarco/Endoplasmic Reticulum Calcium ATPases (SERCA enzymes). Because lymphocyte function is critically dependent on SERCA activity, it is important to understand qualitative and quantitative changes of SERCA protein expression that occur during B lymphoid differentiation and leukemogenesis. Methods In this work we investigated the modulation of SERCA expression during the pharmacologically induced differentiation of leukemic precursor B lymphoblast cell lines that carry the E2A-PBX1 fusion oncoprotein. Changes of SERCA levels during differentiation were determined and compared to those of established early B lymphoid differentiation markers. SERCA expression of the cells was compared to that of mature B cell lines as well, and the effect of the direct inhibition of SERCA-dependent calcium transport on the differentiation process was investigated. Results We show that E2A-PBX1+ leukemia cells simultaneously express SERCA2 and SERCA3-type calcium pumps; however, their SERCA3 expression is markedly inferior to that of mature B cells. Activation of protein kinase C enzymes by phorbol ester leads to phenotypic differentiation of the cells, and this is accompanied by the induction of SERCA3 expression. Direct pharmacological inhibition of SERCA-dependent calcium transport during phorbol ester treatment interferes with the differentiation process. Conclusion These data show that the calcium pump composition of the ER is concurrent with increased SERCA3 expression during the differentiation of precursor B acute lymphoblastic leukemia cells, that a cross-talk exists between SERCA function and the control of differentiation, and that SERCA3 may constitute an interesting new marker for the study of early B cell phenotype. Electronic supplementary material The online version of this article (doi:10.1186/s13046-017-0556-7) contains supplementary material, which is available to authorized users.

Expression profile of SERCA3 and SERCA2 mRNA in key normal early B cell populations in the mouse, adapted from the Immunological Genome project transcriptomic database. (PPTX 1190Â kb)

Expression profile of CD19, CD20 CD22, CD34, TdT and of β-actin in key normal early B cell populations in the mouse, adapted from the Immunological Genome project transcriptomic database. (PPTX 566 kb)

Name, hematological origin and molecular type of the cell lines used in this study. (DOCX 18Â kb)

Benign soft tissue tumors of the vulva are relatively rare in adult patients. We present the magnetic resonance (MR) imaging features of an angiolipoma of the labia majora that developed in a 58-year-old woman. MR imaging showed a well-circumscribed lesion that was hyperintense on T1-weighted and T2-weighted MR images, and hypointense on fat-suppressed MR images, consistent with fat content. High apparent diffusion coefficient was noticed on diffusion-weighted MR images. Dynamic gadolinium-chelate enhanced MR imaging showed progressive enhancement. Histopathologically, the lesion was predominantly made of mature adipose tissue and contained thin walled vascular channels consistent with angiolipoma.

Background The status of the surgical margins of lumpectomy is one of the most important determinants of local recurrence in breast cancer. Systematically practicing cavity margin resection is debated but may avoid surgical re-excision and allow the diagnosis of multifocality. Methods This multicentric retrospective study included 294 patients who underwent conservative management of breast cancer with 2–4 systematic cavity shavings. Clinico-biological characteristics of the patients were collected in order to establish whether surgical management was modified by systematic cavity shaving. Local recurrence rate with a long-term follow up of minimum 4 years was evaluated. Results Cavity shaving avoided the need for re-excision in 25% of cases and helped in the diagnosis of multifocality in 8% of cases. Resection volume was not associated with usefulness of the cavity shaving. No predictive factor of positive cavity shaving was found. The rate of local recurrence was 3.7% and appeared in a median time of 3 years and 8 month. Only one quarter of the patients with local recurrence had initially positive lumpectomy margins but negative cavity shaving. Discussion Systematic cavity shaving can change surgical management of conservative treatment. No specific target population for useful cavity shaving was found, such that we recommend utilising it systematically.

Frau A. F., 80 Jahre alt, leidet an seropositiver rheumatoider Polyarthritis, die seit einem Jahr mit Methotrexat behandelt wird. Infolge einer Grippeschutzimpfung entwickelte sie eine Dyspnoe, Husten, weisslichen Auswurf und einen fluktuierenden Status febrilis.

Madame A.F., 80 ans, souffre d’une polyarthrite rhumatoide seropositive traitee par methotrexate depuis une annee. A la suite d’un vaccin contre la grippe, elle developpe une dyspnee, une toux, des expectorations blanchâtres et un etat febrile fluctuant.

Although preventing excessive hyperglycemia during critical illness may provide clinical neuroprotection, it remains debated whether normoglycemia is without risk for the brain.To address this question, we compared the neuropathological alterations in microglia, astrocytes, and neurons, with uncontrolled hyperglycemia, moderately controlled hyperglycemia, and normoglycemia during human critical illness. We further investigated the time course in an animal model.We analyzed brain specimens from patients who died in the intensive care unit and from critically ill rabbits randomized to hyper- or normoglycemia. PATIENTS/OTHER PARTICIPANTS: We compared 10 critically ill patients randomized to normoglycemia (104 ±9 mg/dl) or moderate hyperglycemia (173 ±32 mg/dl), and five patients with uncontrolled hyperglycemia (254 ±83 mg/dl) with 16 controls (out of hospital sudden deaths). Critically ill rabbits were randomized to hyperglycemia (315 ±32 mg/dl) or normoglycemia (85 ±13 mg/dl) and studied after 3 and 7 d.Insulin was infused to control blood glucose.Patients with uncontrolled hyperglycemia showed 3.7-6-fold increased microglial activation, 54-95% reduced number and activation of astrocytes, more than 9-fold increased neuronal and glial apoptosis, and a 1.5-2-fold increase in damaged neurons in hippocampus and frontal cortex (all P ≤ 0.05). Most of these abnormalities were attenuated with moderate hyperglycemia and virtually absent with normoglycemia. Frontal cortex of hyperglycemic rabbits that had been critically ill for 3 d only revealed microglial activation, followed after 7 d by astrocyte and neuronal abnormalities similar to those observed in patients, all prevented by normoglycemia.Preventing hyperglycemia with insulin during critical illness reduced neuropathological abnormalities, with microglial activation being the earliest preventable event. Whether these pathological findings associate with neurological outcome remains unknown.

The endoplasmic reticulum (ER) is a major intracellular calcium storage pool and a multifunctional organelle that accomplishes several calcium-dependent functions involved in many homeostatic and signaling mechanisms. Calcium is accumulated in the ER by Sarco/Endoplasmic Reticulum Calcium ATPase (SERCA)-type calcium pumps. SERCA activity can determine ER calcium content available for intra-ER functions and for calcium release into the cytosol, and can shape the spatiotemporal characteristics of calcium signals. SERCA function therefore constitutes an important nodal point in the regulation of cellular calcium homeostasis and signaling, and can exert important effects on cell growth, differentiation and survival. In several cell types such as cells of hematopoietic origin, mammary, gastric and colonic epithelium, SERCA2 and SERCA3-type calcium pumps are simultaneously expressed, and SERCA3 expression levels undergo significant changes during cell differentiation, activation or immortalization. In addition, SERCA3 expression is decreased or lost in several tumor types when compared to the corresponding normal tissue. These observations indicate that ER calcium homeostasis is remodeled during cell differentiation, and may present defects due to decreased SERCA3 expression in tumors. Modulation of the state of differentiation of the ER reflected by SERCA3 expression constitutes an interesting new aspect of cell differentiation and tumor biology.

Impaired arginine vasopressin (AVP) synthesis and release by the neurohypophyseal system, which includes the neurohypophysis and magnocellular neurons of the paraventricular and supraoptic nuclei, have been postulated in septic shock, but changes in this system have never been assessed in human septic shock, and only partially experimentally. We investigated AVP synthesis and release by the neurohypophyseal system in 9 patients who died from septic shock and 10 controls, and in 20 rats with fecal peritonitis-induced sepsis and 8 sham-operation controls. Ten rats died spontaneously from septic shock, and the others were sacrificed. In patients with septic shock, as in rats that died spontaneously following sepsis induction, AVP immunohistochemical expression was decreased in the neurohypophysis and supraoptic magnocellular neurons, whereas it was increased in the paraventricular magnocellular neurons. No significant change was observed in AVP messenger RiboNucleic Acid (mRNA) expression assessed by in situ hybridization in either paraventricular or supraoptic magnocellular cells. This study shows that both in human and experimental septic shock, AVP posttranscriptional synthesis and transport are differently modified in the magnocellular neurons of the supraoptic and paraventricular nuclei. This may account for the inappropriate AVP release in septic shock and suggests that distinct pathogenic mechanisms operate in these nuclei.