[Inflammatory diseases : anatomo-pathological features]. / Maladies inflammatoires : aspects anatomo-pathologiques.

The aim of this article is to describe the role of anatomic pathology in the management of acute and chronic inflammatory diseases. Granulomatous pathologies will be also addressed as well as some dysimmune pathologies and recent data on the prognostic role of the antitumoral inflammatory response.

: Le but de cet article est de décrire le rôle joué par l'anatomie pathologique dans la prise en charge de maladies inflammatoires aiguës et chroniques. Les pathologies granulomateuses seront également abordées de même que certaines pathologies dysimmunitaires et des données récentes sur le rôle pronostique de la réponse inflammatoire antitumorale.

Unusual intra-rectal "laterally spreading tumour" in immunosuppressed patient with ulcerative colitis.

Condyloma acuminatum (CA) is a manifestation of Human Papillomavirus (HPV) infection which usually occurs in genital and perianal regions. We report a 46-year-old man with an ulcerative proctitis diagnosed four years earlier, asymptomatic for a long time under azathioprine but without any follow-up for three years. A colonoscopy was performed prior to potential immunosuppressive treatment discontinuation and showed a circumferential "laterally spreading tumour" in the rectum. Surprisingly biopsies revealed a CA with a very focally high-grade intra-epithelial lesion. Azathioprine was stopped and a transanal surgical resection was performed. At guided anamnesis, patient confirmed to be a former active "men who have sex with men". No recurrence of proctitis occurred despite azathioprine discontinuation. A retrospective review of the histological sections suggests that it was, in fact, an intestinal spirochetosis misdiagnosed as inflammatory bowel disease. Involvement of the rectal mucosa by HPV is a rare condition and this may have been promoted by inappropriate immunosuppressive treatment.

[Aid of artificial intelligence for the anatomo-pathological diagnosis of tumours]. / Intérêt de l'intelligence artificielle pour le diagnostic anatomo-pathologique des tumeurs.

The anatomo-pathological diagnosis of tumors is based on many criteria related mainly to image analysis. Currently, in most pathology laboratories, tissues or cells are placed on glass slides and directly analyzed with an optical microscope. Because of technological evolutions, it is currently possible to digitize slides (digital pathology). The digitization of whole slides has allowed the development of computer programs of artificial intelligence (AI) for image analysis. Applied to tumour pathology, this technology allows the detection, diagnosis or evaluation of the prognosis of neoplastic lesions. There are many challenges associated with the use of AI in routine pathology. These are mainly related to the amount of data to be analyzed and to the development of reliable algorithms. Nevertheless, this technology is promising and could become a valuable aid in the field of precision medicine for which the amount of data related to a patient is constantly increasing.

Le diagnostic anatomo-pathologique des tumeurs repose sur de nombreux éléments en relation principalement avec l'analyse d'images. Actuellement, dans la plupart des laboratoires d'anatomie pathologique, les tissus ou les cellules sont placés sur des lames en verre et directement analysés avec un microscope optique. Grâce aux évolutions technologiques, il est actuellement possible de numériser des lames (pathologie digitale). La digitalisation de lames entières a permis le développement de programmes informatiques d'intelligence artificielle (IA) d'analyse d'images. Appliquée à la pathologie tumorale, cette technologie permet, entre autres, la détection, le diagnostic ou l'évaluation du pronostic de lésions tumorales. Il existe de nombreux défis à l'utilisation de l'IA en anatomie pathologique de routine. Ceux-ci sont essentiellement liés à la quantité de données à analyser pour obtenir des résultats et au développement d'algorithmes fiables. Néanmoins, cette technologie est prometteuse et pourrait devenir une aide précieuse dans le cadre de la médecine de précision où la quantité de données liées à un patient s'accroît sans cesse.

[PD-L1 : a natural immunosuppressor related to carcinogenesis. A pathologist's point of view]. / Le PD-L1 : un immunosuppresseur naturel impliqué dans la carcinogenèse Le point de vue du pathologiste.

The goal of this article is to emphasize the role of anatomopathology for the intratumoral detection of the immune checkpoint PD-L1. This molecule is one of the main targets in the anti-cancer immunotherapy. The binding of PD-L1 to its receptor PD-1 results in the inactivation of the cytotoxic T-cells, thus providing a mechanism of keeping immune reactions under control. This process can be circumvented by tumour cells to evade immune system. By blocking PD-1/PD-L1 binding, it is possible to reactivate T-cells targeting tumour neo-antigens. This article focuses on how PD-L1 works, on its implication in neoplastic processes, on the general principles of its therapeutic blockade, on the biomarkers underlying the treatment efficacy and on the practical implications of these biomarkers, especially in the anatomopathological practice.

Le but de cet article est de démontrer le rôle de l'anatomie pathologique dans la détection intra-tumorale du checkpoint immunitaire PD-L1. Ce dernier est l'une des principales cibles de l'immunothérapie à visée oncologique. La liaison du ligand PD-L1 à son récepteur PD-1 permet d'inhiber l'action des lymphocytes T cytotoxiques et, ainsi, de garder sous contrôle les réactions immunitaires. Ce processus peut être détourné par les cellules tumorales pour échapper à l'immunosurveillance. En bloquant le couple PD-L1/PD-1, il est possible de réactiver les lymphocytes T dirigés contre les néo-antigènes tumoraux. Nous nous concentrons, dans cet article, sur le mode de fonctionnement général de PD-L1, sur son implication dans les processus néoplasiques, sur le principe de son blocage thérapeutique, sur les biomarqueurs de l'efficacité du traitement et sur l'utilisation pratique de ces biomarqueurs, particulièrement dans la pratique anatomo-pathologique.

Curative effect of second curettage for treatment of gestational trophoblastic disease - Results of the Belgian registry for gestational trophoblastic disease.

OBJECTIVE: We assessed the curative effect of a second curettage in patients with persistent hCG serum levels after first curettage for a gestational trophoblastic disease (GTD). STUDY DESIGN: This prospective observational study used the data of the Belgian register for GTD between July 2012 and January 2017. We analysed the data of patients who underwent a second curettage. We included 313 patients in the database. Primary endpoints were need for second curettage and chemotherapy. RESULTS: Thirty-seven patients of the study population (12 %) underwent a second curettage. 20 had persistent human chorionic gonadotropin hormone (hCG) elevation before second curettage. Of them, 9 patients (45 %) needed no further treatment afterwards. Eleven patients (55 %) needed further chemotherapy. Nine (82 %) were cured with single-agent chemotherapy and 2 patients (18 %) needed multi-agent chemotherapy. Of the 37 patients, patients with hCG levels below 5000 IU/L undergoing a second curettage were cured without chemotherapy in 65 % versus 45 % of patients with hCG level more than 5000 IU/L. Of the ten patients with a hCG level below 1000 IU/L, eight were cured without chemotherapy. CONCLUSIONS: Patients with post-mole gestational trophoblastic neoplasia can benefit from a second curettage to avoid chemotherapy, especially when the hCG level is lower than 5000 IU/L.

[Lung lesions in severe COVID-19 : anatomoclinical confrontation]. / Lésions pulmonaires dans la COVID-19 sévère : confrontation anatomoclinique.

We report the fatal outcome of two patients infected by SARS-CoV-2 and exhibiting severe lung lesions at the thoracic imaging and autopsic examination. We also describe the biosecurity measures to adopt when performing autopsies during the Covid-19 pandemia.

Nous rapportons l'évolution fatale de deux patients infectés par le SARS-CoV-2 et porteurs de lésions pulmonaires sévères à l'imagerie thoracique et à l'examen autopsique. Nous décrivons également les mesures de biosécurité à adopter pour la réalisation des autopsies au cours de la pandémie de la Covid-19.

[Kidney injury in COVID-19]. / Atteintes rénales de la COVID-19.

The SARS-CoV-2 virus causes a respiratory distress syndrome, the main symptom of COVID-19 (for "COronaVIrus Disease 2019"). This infectious disease has been causing a major health and socio-economic pandemic since December 2019. The pulmonary alveolus is regarded as the main target of SARS-CoV-2. However, this coronavirus is capable of directly or indirectly affecting other organs, including the kidneys. Here, we summarize the presumed pathophysiology of COVID-19 renal disease. The incidence of acute kidney injury ranges from 0,5 to 22 % of all patients infected with SARS-CoV-2. The need for renal replacement therapy is reported in 5-9 % of patients in intensive care. Histological analysis of renal biopsies mainly shows acute tubular necrosis of varying severity, as well as the congestion of glomerular and peri-tubular capillaries. Endothelitis has been described in few cases. Evidence for a factual inflammation of the glomerulus remains controversial. The medium/long term consequences of COVID-19 nephropathy are unknown and will deserve a tight follow-up.

Le virus SARS-CoV-2 provoque un syndrome de détresse respiratoire aiguë, le symptôme principal de l'infection COVID-19 (pour «COronaVIrus Disease 2019¼). Cette maladie infectieuse provoque une pandémie de gravité sanitaire et socio-économique majeure depuis décembre 2019. La cible principale du SARS-CoV-2 serait l'alvéole pulmonaire. Néanmoins, ce coronavirus est capable d'affecter directement ou indirectement d'autres organes, y compris les reins. Nous résumons ici la physiopathologie présumée de l'atteinte rénale de la COVID-19. L'incidence de l'insuffisance rénale aiguë varie entre 0,5 à 22 % de tous les patients infectés par le SARS-CoV-2. La nécessité d'une épuration extra-rénale est rapportée chez 5-9 % des patients pris en charge aux soins intensifs. L'analyse histologique de biopsies rénales montre, principalement, une nécrose tubulaire aiguë de sévérité variable, ainsi qu'une congestion des capillaires glomérulaires et péri-tubulaires. Une endothélite a parfois été décrite. L'atteinte inflammatoire du glomérule reste débattue. Les conséquences à moyen/long termes de la néphropathie COVID-19 sont inconnues et mériteront un suivi étroit.

[Erdheim-Chester disease : a case report]. / Cas clinique. Maladie d'Erdheim-Chester.

We report the case of a 47-year-old woman with unexplained inflammatory syndrome and asthenia. Imaging findings show bilateral abnormalities of femurs and tibias, suggesting an Erdheim-Chester disease, which is confirmed by a bone marrow biopsy of the left femur. The BRAF V600E mutation is detected, allowing the administration of targeted therapies such as BRAF and MEK inhibitors that lead to the improvement of symptoms.

Nous rapportons le cas d'une patiente de 47 ans explorée pour un syndrome inflammatoire inexpliqué et une asthénie chronique. Les examens en imagerie démontrent la présence d'importants remaniements osseux au niveau du périoste des deux fémurs et tibias, évoquant une maladie d'Erdheim-Chester. Celle-ci est confirmée par l'analyse d'une biopsie ostéomédullaire réalisée au niveau du fémur gauche. La détection de la mutation V600E du gène BRAF permet à la patiente de bénéficier d'un traitement ciblé anti-BRAF et anti-MEK, améliorant sa symptomatologie.

[Influence of clinical and pathological factors on lymph node harvesting in surgical specimens of colorectal cancer]. / Facteurs anatomo-cliniques influençant la collecte ganglionnaire dans les pièces de résection chirurgicale pour cancer colorectal.

In colorectal cancer staging, pathologic lymph node analysis is a crucial information for the clinician and must be performed with a maximal level of accuracy. Therefore, the surgical sample analysis needs harvesting of as many lymph nodes as possible from the mesentery. In this study, we analysed the influence of a series of clinical and pathological factors which could influence lymph node harvesting. A total of 239 patients were included in our study. The factors with a statistically significant influence on lymph node collection (pinferior to0.05) were the age, gender of the patient, size of the primitive neoplasm, size of the surgical specimen, expertise of the surgeon and the pathology department. The presence of a radiochimiotherapy did not have any influence on the lymph node collection. This study highlights the importance of lymph node harvesting in colorectal surgical specimens of colo-rectal cancers.

Dans la stadification de l'adénocarcinome colorectal, le statut ganglionnaire anatomopathologique constitue une information capitale pour le clinicien et doit être défini avec un maximum d'exactitude. L'analyse de la pièce de résection chirurgicale requiert la collecte au sein du méso du plus grand nombre possible de ganglions lymphatiques. Dans cette étude, nous avons analysé une série de facteurs anatomo-cliniques pouvant influencer la collecte ganglionnaire. Un total de 239 patients a été inclus dans notre étude. Les facteurs avec une influence statistiquement significative sur la collecte ganglionnaire (p inf�rieur a 0,05) ont été l'âge et le sexe du patient, la taille de la tumeur primitive, la taille de la pièce d'exérèse, le degré d'activité du chirurgien et le laboratoire d'anatomie pathologique. La présence ou non d'une radiochimiothérapie néo-adjuvante n'a pas eu d'impact sur le nombre de ganglions prélevés. Cette étude souligne l'importance de la collecte ganglionnaire au sein des pièces de résection chirurgicale d'un cancer colo-rectal.

[Sarcoidosis following tuberculosis. Is there a link between these granulomatous diseases?] / Une sarcoïdose dans le décours d'une tuberculose. Existe-t-il un lien étiologique entre ces deux maladies granulomateuses ?

We report the case of a 38-year old non-smoking female who initially presented to the hospital with frequent cough and sputum for several weeks. The investigations confirmed the diagnosis of tuberculosis and a triple therapy was introduced with clinical improvement. Two years later, the patient reported recurrence of respiratory symptoms. The new investigations concluded initially to a recurrence of tuberculosis and a quadriple therapy was introduced. The treatment was poorly tolerated and rapidly stopped. It was then decided to perform a biopsy through mediastinoscopy in the hilar ganglia, which confirmed the diagnosis of sarcoidosis. The etiology of sarcoidosis is not yet clearly established, one of the hypothesis would be the direct involvement of an infectious agent that would induce an excessive immune response. The clinical case below supports a possible role of Mycobacterium tuberculosis in the pathogenesis of sarcoidosis.

Nous rapportons le cas d'une patiente âgée de 38 ans, non fumeuse, qui s'est présentée à l'hôpital pour une symptomatologie de toux et d'expectorations depuis plusieurs semaines. Les différentes investigations ont permis d'établir un diagnostic de tuberculose et une trithérapie a été introduite avec une évolution favorable de la patiente. Deux ans plus tard, la patiente rapporte une récidive des plaintes respiratoires. Les nouveaux examens menés concluent, dans un premier temps, à une récidive de tuberculose et une quadrithérapie est instaurée. Le traitement fut mal toléré et stoppé rapidement. Il est alors décidé de réaliser une biopsie par médiastinoscopie au niveau des ganglions hilaires qui permettra de confirmer le diagnostic de sarcoïdose. L'étiologie de la sarcoïdose n'étant pas encore clairement établie, une des hypothèses est l'implication directe d'un agent infectieux qui induirait une réaction immunitaire excessive. Le cas clinique ci-dessous étaye la théorie selon laquelle le Mycobacterium tuberculosis pourrait être un des agents étiologiques de la sarcoïdose.

[Pulmonary tumour thrombotic microangiopathy associated with a gastric adenocarcinoma]. / Microangiopathie thrombotique tumorale pulmonaire associée à un adénocarcinome gastrique.

We report the case of a 67 years old patient with a history of gastric adenocarcinoma who died in a context of severe dyspnea and whose autopsy will confirm the diagnosis of a Pulmonary Tumor Thrombotic Microangiopathy (PTTM). PTTM is a fatal pulmonary complication associated to multiple cancers. It starts with an acute or subacute respiratory failure quickly evolving towards fatal thrombo-embolic pulmonary hypertension and right heart failure. Pre-mortem diagnosis is difficult and not frequent because the pathology is rare, the underlying neoplastic disease is not always known, clinical and radiological signs are not specific and progression is fast. When made soon enough, PTTM diagnosis avoids useless and sometimes harmful medication. In some cases, an improvement of patient's symptoms and comfort is observed. Some studies described several months of extended survival.

Nous rapportons le cas d'un patient de 67 ans avec un antécédent d'adénocarcinome gastrique décédé dans un contexte de dyspnée majeure et dont l'autopsie confirmera la présence d'une microangiopathie thrombotique tumorale pulmonaire (Pulmonary Tumor Thrombotic Microangiopathy - PTTM). La PTTM est une complication pulmonaire fatale associée à de multiples cancers. Elle se présente par une insuffisance respiratoire d'installation aiguë ou subaiguë, évoluant rapidement vers une hypertension thrombo-embolique pulmonaire et une insuffisance cardiaque droite fatales. Le diagnostic ante-mortem est difficile et rarement posé car la pathologie est rare. L'affection néoplasique sous-jacente n'est pas toujours connue, les signes cliniques et radiologiques sont peu spécifiques et son évolution est rapide. Réalisé à temps, le diagnostic permet, néanmoins, d'éviter une médication inefficace et parfois délétère. Dans certains cas, on observe une amélioration des symptômes et de l'inconfort du patient et, parfois, une survie prolongée de quelques mois.

Platelets contribute to the initiation of colitis-associated cancer by promoting immunosuppression.

Essentials Inflammation plays a key role in the development of colorectal cancer. Understanding mechanisms of cancer initiation might reveal new anticancer preventive strategy. Hyperactive platelets promote tumor formation by fostering immune evasion of cancer. Platelet inhibition by clopidogrel prevents carcinogenesis by restoring antitumor immunity. SUMMARY: Background Clinical and experimental evidence support a role for inflammation in the development of colorectal cancer, although the mechanisms are not fully understood. Beyond thrombosis and hemostasis, platelets are key actors in inflammation; they have also been shown to be involved in cancer. However, whether platelets participate in the link between inflammation and cancer is unknown. Objective To investigate the contribution of platelets and platelet-derived proteins to inflammation-elicited colorectal tumor development. Methods We used a clinically relevant mouse model of colitis-associated cancer. Platelet secretion and platelet reactivity to thrombin were assessed at each stage of carcinogenesis. We conducted an unbiased proteomic analysis of releasates of platelets isolated at the pretumoral stage to identify soluble factors that might act on tumor development. Plasma levels of the identified proteins were measured during the course of carcinogenesis. We then treated the mice with clopidogrel to efficiently inhibit platelet release reaction. Results At the pretumoral stage, hyperactive platelets constituted a major source of circulating protumoral serum amyloid A (SAA) proteins. Clopidogrel prevented the early elevation of the plasma SAA protein level, decreased colitis severity, and delayed the formation of dysplastic lesions and adenocarcinoma. Platelet inhibition hindered the expansion and function of immunosuppressive myeloid cells, as well as their infiltration into tumors, but increased the number of tissue CD8+ T cells. Platelets and releasates of platelets from mice with cancer were both able to polarize myeloid cells towards an immunosuppressive phenotype. Conclusions Thus, platelets promote the initiation of colitis-associated cancer by enhancing myeloid cell-dependent immunosuppression. Antiplatelet agents may help to prevent inflammation-elicited carcinogenesis by restoring antitumor immunity.

[The Mosan Study Group of Pigmented Tumours facing toward the oligometastatic cutaneous melanoma]. / Le Groupe Mosan d'étude des Tumeurs Pigmentaires face au mélanome cutané oligométastatique.

The oligometastatic melanoma is a peculiar stage of cancer progression which is initially restricted to the initial body area. In most instances, only a small number of metastases are simultaneously present. The oligometastatic stage is synchronous when metastases are disclosed at the time of initial diagnosis of the primary cancer. Metastases are metachronous when they are detected after the initial treatment of the primary neoplasm. A variant of the disease is called the smouldering disease when cutaneous metastases grow or regress in unison. The smouldering disease is granted to a condition when some metastases keep grooving when other metastases regress.

Le mélanome oligométastatique est un mode particulier de progression cancéreuse qui se cantonne initialement au territoire de drainage lymphatique du site du cancer primitif. Dans la majorité des cas, un très petit nombre de métastases seraient présentes simultanément. Le stade oligométastatique est synchrone lorsque les métastases sont découvertes au moment du diagnostic initial du cancer primitif. Les métastases sont dites métachrones lorsqu'elles surviennent après traitement initial. Une variante de ce processus, décrite sous le nom de maladie couveuse ou «smouldering disease¼, concerne des lésions métastatiques cutanées qui grandissent et régressent de concert sur ce même territoire.

[Skin carcinogenesis in renal transplant recipients]. / La cancérogenèse dans la peau de patients transplantés rénaux.

Organ transplants are bound to the induction and upkeep of immunosuppression. The immunomodulatory regimen modalities have changed over time with an improvement of the overage graft survival. The effects are also present on the skin and its cancerogenesis which is particularly activated for the squamous cell carcinoma. A review of the recent medical literature reveals the importance of searching squamous cell carcinomas, actinic keratoses, seborrheic keratoses and keratocanthomas before and after organ transplants. The severity of the carcinomas is due to their multiplicity and to the progressive occurrence of more aggressive lesions. Prevention relies on a strict adherence to sun protection after transplantation and on refined immunosuppressive strategies.

Toute greffe d'organe s'accompagne de l'induction et de l'entretien d'un état d'immunosuppression. Les modalités des traitements immunosuppresseurs ont évolué au cours du temps avec une amélioration de la survie des greffons. Les effets se marquent aussi au niveau de la peau et de sa cancérogenèse qui est particulièrement active pour le carcinome spinocellulaire. Un survol de la littérature médicale récente semble indiquer l'importance de répertorier les carcinomes spinocellulaires, les kératoses actiniques, les kératoses séborrhéiques et les kératoacanthomes avant et dans le suivi d'une greffe. La gravité des carcinomes tient à leur multiplicité et à la survenue progressive de lésions biologiquement plus agressives. La prévention des lésions repose sur une protection solaire stricte dès la transplantation et sur l'adoption de stratégies immunosuppressives adaptées.

Tyrosine kinase inhibition is an important factor for gene expression of CRTH2 in human eosinophils and lymphocytes: A novel mechanism for explaining eosinophils recruitment by the neuro-immune axis in allergic rhinitis.

We recently shown a novel neuro-immune competition between vasoactive intestinal peptide (VIP) and PGD2 for CRTH2 receptor, and that genistein augmented VIP and PGD2-induced eosinophil chemotaxis. However, there are neither studies on the CRTH2 gene expression in allergic rhinitis (AR) nor in the effect of tyrosine kinase inhibitors in CRTH2 gene regulation. Our Objectives were to study the gene expression modulation of CRTH2 receptor in AR patients and the effect of tyrosine kinase inhibitors (TKIs) on CRTH2 gene modulation. Nasal provocation tests, ELISA, qRT-PCR, western blot, flow cytometry and chemotaxis assays in modified micro-Boyden chambers, were all used, to achieve our objectives. Herein we show that AR patients increased the amounts of VIP and PGD2 in their nasal secretions in the early phase reaction, however CRTH2 gene expression from leukocytes recovered in their nasal secretions was upregulated only during the late phase reaction. The TKIs; Genistein, Erbstatin and Herbimycin A, induced the gene expression of CRTH2 and increased the protein content of CRTH2 in both human lymphocytes and eosinophils. This was functional as PGD2/VIP-induced eosinophil chemotaxis was augmented by the TKIs and inhibited by pervanadate, the tyrosine phosphatase inhibitor. These results open channels for therapeutic modalities targeting CRTH2 molecules in AR.

Myoferlin regulates cellular lipid metabolism and promotes metastases in triple-negative breast cancer.

Myoferlin is a multiple C2-domain-containing protein that regulates membrane repair, tyrosine kinase receptor function and endocytosis in myoblasts and endothelial cells. Recently it has been reported as overexpressed in several cancers and shown to contribute to proliferation, migration and invasion of cancer cells. We have previously demonstrated that myoferlin regulates epidermal growth factor receptor activity in breast cancer. In the current study, we report a consistent overexpression of myoferlin in triple-negative breast cancer cells (TNBC) over cells originating from other breast cancer subtypes. Using a combination of proteomics, metabolomics and electron microscopy, we demonstrate that myoferlin depletion results in marked alteration of endosomal system and metabolism. Mechanistically, myoferlin depletion caused impaired vesicle traffic that led to a misbalance of saturated/unsaturated fatty acids. This provoked mitochondrial dysfunction in TNBC cells. As a consequence of the major metabolic stress, TNBC cells rapidly triggered AMP activated protein kinase-mediated metabolic reprogramming to glycolysis. This reduced their ability to balance between oxidative phosphorylation and glycolysis, rendering TNBC cells metabolically inflexible, and more sensitive to metabolic drug targeting in vitro. In line with this, our in vivo findings demonstrated a significantly reduced capacity of myoferlin-deficient TNBC cells to metastasise to lungs. The significance of this observation was further supported by clinical data, showing that TNBC patients whose tumors overexpress myoferlin have worst distant metastasis-free and overall survivals. This novel insight into myoferlin function establishes an important link between vesicle traffic, cancer metabolism and progression, offering new diagnostic and therapeutic concepts to develop treatments for TNBC patients.

HDAC7 inhibition resets STAT3 tumorigenic activity in human glioblastoma independently of EGFR and PTEN: new opportunities for selected targeted therapies.

To date, the mutational status of EGFR and PTEN has been shown as relevant for favoring pro- or anti-tumor functions of STAT3 in human glioblastoma multiforme (GBM). We have screened genomic data from 154 patients and have identified a strong positive correlation between STAT3 and HDAC7 expression. In the current work we show the existence of a subpopulation of patients overexpressing HDAC7 and STAT3 that has particularly poor clinical outcome. Surprisingly, the somatic mutation rate of both STAT3 and HDAC7 was insignificant in GBM comparing with EGFR, PTEN or TP53. Depletion of HDAC7 in a range of GBM cells induced the expression of tyrosine kinase JAK1 and the tumor suppressor AKAP12. Both proteins synergistically sustained the activity of STAT3 by inducing its phosphorylation (JAK1) and protein expression (AKAP12). In absence of HDAC7, activated STAT3 was responsible for significant imbalance of secreted pro-/anti-angiogenic factors. This inhibited the migration and sprouting of endothelial cells in paracrine fashion in vitro as well as angiogenesis in vivo. In a murine model of GBM, induced HDAC7-silencing decreased the tumor burden by threefold. The current data show for the first time that silencing HDAC7 can reset the tumor suppressor activity of STAT3, independently of the EGFR/PTEN/TP53 background of the GBM. This effect could be exploited to overcome tumor heterogeneity and provide a new rationale behind the development of specific HDAC7 inhibitors for clinical use.

[How I explore . HLA class II by ultrastructure in toxic epidermal necrolysis]. / Comment j'explore les HLA de classe II par ultrastructure dans la nécrolyse épidermique toxique.

Toxic epidermal necrolysis (TEN, Lyell syndrome) is a severe paroxystic drug reaction whose inductive mechanisms remain poorly understood. The HLA glycoproteins are possibly involved in the disease process. Such investigations rely on biomolecular methods, and suggest specific interactions between some drugs or their metabolites and some HLA groups according to ethnicity of the TEN patients. Electron microscopy following the immunogold method for revealing HLA-DR did not disclose any evidence for distinguishing distinct patterns on Langerhans cell membrane between the initial and the resolution phases of TEN.

La nécrolyse épidermique toxique (NET, syndrome de Lyell) est une toxidermie paroxystique grave dont les mécanismes inducteurs restent mal élucidés. Les glycoprotéines HLA ont été potentiellement impliquées dans ce processus. Leur étude a bénéficié des méthodes biomoléculaires qui suggèrent des interactions spécifiques entre certains médicaments ou leurs métabolites et certains HLA en fonction du groupe ethnique du patient atteint de NET. La microscopie électronique, par la méthode «immunogold¼ afin d'évaluer les HLA-DR, n'a pas révélé de différences notoires dans leur distribution sur la paroi de cellules de Langerhans entre la phase initiale et celle de résolution de 5 cas de NET.

Human cytomegalovirus and primary intracranial tumours: frequency of tumour infection and lack of correlation with systemic immune anti-viral responses.

AIMS: Human cytomegalovirus (HCMV) is a ubiquitous beta human herpesvirus able to influence infected cell survival and proliferation and to modulate the host immune response. As there is accumulating evidence that HCMV is detected in primary intracranial astrocytic tumours, in this study we looked for the presence of HCMV in intracranial tumours and tried to correlate this eventual presence with the anti-HCMV systemic immunoreactivity and with the detection of HCMV in peripheral blood. METHODS: In this study, we analysed 43 glioblastomas (GBM), 14 oligodendrogliomas (OL) and 20 meningiomas (MG) by immunofluorescence (IF) targeting HCMV immediate early antigen (IE1) and by nested PCR (nPCR) amplifying HCMV glycoprotein B (gB). RESULTS: Detection of IE1 by IF showed the presence of HCMV in 70% of GBM, 57% of OL and 85% of MG, in contrast to gB nPCR, which detected HCMV in only 50% of GBM, 38% of OL and 46% of MG. Unexpectedly, HCMV DNA and antigens were detected within GBM, OL and MG of patients that exhibit negative viral serology. More surprisingly, PCR on the peripheral blood did not detect HCMV in patients with a HCMV-positive tumour. CONCLUSIONS: Our results are in agreement with previous observations demonstrating HCMV in glial tumours and highlight the presence of HCMV in meningiomas. We also showed that anti-HCMV specific systemic immunoreactivity and detection of HCMV in peripheral blood are not predictive of HCMV presence in primary intracranial tumours.

[Belgian register and reference centers for gestational trophoblastic diseases]. / REGISTRE BELGE ET CENTRES DE RÉFÉRENCE POUR LES MALADIES TROPHOBLASTIQUES GESTATIONNELLES.

Gestational trophoblastic diseases include placental pathologies comprising fertilization abnormalities (hydatidiform moles) and malignant lesions (choriocarcinoma, placental site trophoblastic tumor and epithelioid trophoblastic tumor). Due to their low incidence and heterogeneity, their diagnosis, management and treatment are not always optimal. Following the example of other European countries, a national registration system with two reference centers has been set up to guide physicians and patients and to propose individualized management. The centers offer their expertise through a systematic centralised pathology review by a panel of experts. HCG values are plotted in regression curves. In case of gestational trophoblastic neoplasia, an imaging work-up is proposed, from which the FIGO score and stage are derived and will guide the choice of treatment. Belgian centers offer a multidisciplinary approach, in partnership with the referent physician. More information for practitioners and patients is available on a web site: www.mole-chorio-bgog.eu, which also harbours a forum of discussion.