Genotype phenotype classification of hepatocellular adenoma

Studies that compare tumor genotype with phenotype have provided the basis of a new histological/molecular classification of hepatocellular adenomas. Based on two molecular criteria （presence of a TCFI/HNF1α or β-catenin mutation）, and an additional histological criterion （presence or absence of an inflammatory infiltrate）, subgroups of hepatocellular adenoma can be defined and distinguished from focal nodular hyperplasia. Analysis of 96 hepatocellular adenomas performed by a French collaborative network showed that they can be divided into four broad subgroups： the first one is defined by the presence of mutations in TCF1 gene inactivating the hepatocyte nuclear factor 1 （HNF1α）, the second by the presence of β-catenin activating mutations; the category without mutations of HNF1α or β-catenin is further divided into 2 subgroups depending on the presence or absence of inflammation. Therefore, the approach to the diagnosis of problematic benign hepatocytic nodules may be entering a new era directed by new molecular information. It is hoped that immunohistological tools will improve significantly diagnosis of liver biopsy in our ability to distinguish hepatocellular adenoma from focal nodular hyperplasia （FNH）, and to delineate clinically meaningful entities within each group to define the best clinical management. The optimal care of patients with a liver nodule will benefit from the recent knowledge coming from molecular biology and the combined expertise of hepatologists, pathologists, radiologists, and surgeons.

Characterization of focal liver lesions with SonoVue~-enhanced sonography: International multicenter-study in comparison to CT and MRI

AIM： To evaluate in a multicenter study whether the sonographic characterization of focal liver lesions can be improved using SonoVue-enhancement; and to compare this method with computed tomography （CT） and magnetic resonance imaging （MRI）. METHODS： One hundred and thirty four patients withone focal liver lesion detected in baseline ultrasound （US） were examined with conventional US, contrastenhanced US （n = 134）, contrast-enhanced CT （n = 115） and/or dynamic contrast-enhanced MRI （n = 70）. The lesions were classified as malignant, benign or indeterminate and the type of lesion was determined. The final diagnosis based on the combined information of all imaging examinations, clinical information and histology （n = 32） was used. Comparisons were made to see whether the addition of contrast-enhanced US led to the improvement of the characterization of doubtful focal liver lesions.RESULTS： In comparison with unenhanced US, SonoVue markedly improves sensitivity and specificity for the characterization （malignant/benign） of focal liver lesions. In comparison with CT and/or dynamic MRI, SonoVue -enhanced sonography applied for characterization of focal liver lesions was 30.2% more sensitive in the recognition of malignancy and 16.1% more specific in the exclusion of malignancy and overall 22.9% more accurate. In the subgroup with confirmative histology available （n = 30）, sensitivity was 95.5% （CEUS）, 72.2% （CT） and 81.8% （MRI）, and specificity was 75.0% （CEUS）, 37.5% （CT） and 42.9% （MRI）. The sensitivity and specificity of CEUS for the identification of focal nodular hyperplasia （FNH） and hemangiomas was 100% and 87%, resulting in an accuracy of 94.5%.CONCLUSION： SonoVue-enhanced sonography emerges as the most sensitive, ost specific and thus most accurate imaging modality for the characterization of focal liver lesions.

Local transgene expression and whole-body transgenesis to model brain diseases in nonhuman primate

Animal model is an essential tool in the life sciences research, notably in understanding the pathogenesis of the diseases and for further therapeutic intervention success. Rodents have been the most frequently used animals to model human disease since the establishment of gene manipulation technique. However, they remain inadequate to fully mimic the pathophysiology of human brain disease, partially due to huge differences between rodents and humans in terms of anatomy, brain function, and social behaviors. Nonhuman primates are more suitable in translational perspective. Thus, genetically modified animals have been generated to investigate neurologic and psychiatric disorders. The classical transgenesis technique is not efficient in that model; so, viral vector-mediated transgene delivery and the new genome-editing technologies have been promoted. In this review, we summarize some of the technical progress in the generation of an ad hoc animal model of brain diseases by gene delivery and real transgenic nonhuman primate.

Sexual health and fertility for individuals with inflammatory bowel disease

The impact of a chronic disease such as inflammatory bowel disease (IBD) on sexual functioning and body image can significantly impair the quality of life of patients. This review considers the sexual and fertility aspects of IBD patients and their daily management. Modern IBD healthcare management should include appropriate communication on sexuality and consider psychological, physiological, and biological issues. Patients with IBD have less children than the general population, and voluntary childlessness is frequent. The most influential factors reported by IBD patients who experience fertility alteration are psychological and surgery-related problems. Pregnancy is a major concern for patients, and any pregnancy for IBD patients should be closely followed-up to keep the chronic disease in a quiescent state. Preconceptional consultation is of great help.

Smoothelin,a new marker to determine the origin of liver fibrogenic cells

AIM: To explore this hypothesis that smooth muscle cells may be capable of acquiring a myofibroblastic phenotype, we have studied the expression of smoothelin in fibrotic conditions.

TP53基因突变参与成人肝脏未分化(胚胎)肉瘤的生成,不同于Wnt和端粒酶途径:3例病例的免疫组化研究及2例病例的基因相关研究

Background/Aims: Hepatic undifferentiated (embryonal) sarcoma (HUS) is an exc eptional hepatic malignant tumor in adults. Genetic studies were never reported in adult cases. Methods: In this study concerning three cases of HUS occurring i n adult, we studied the three classical ways of carcinogenesis i.e. the TP53 (p5 3), Wnt (CTNNB1/β - catenin and AXIN1) and telomerase (hTERT) pathways. We stu died the expression of p53, β - catenin and telomerase catalytic subunit hTERT by immunohistochemistry in the three cases; we determined TP53 gene mutation in two cases and the genome- wide allelotype, AXIN1, and CTNNB1/β - catenin gen e mutation in one case. Results: Immunohistochemistry showed an overexpression o f p53 in more than 80% of tumoral cells; furthermore, mutations of TP53 were o bserved in two cases, involving the sequence- specific DNA binding domain. In c ontrast, no mutation was found in CTNNB1/β - catenin and AXIN1 genes. Tumoral cells did not show hTERT staining nor nuclear expression of β - catenin. In ad dition, allelotype analysis in one case showed loss of heterozygosity of chromos ome 7p, 11p, 17p, 22q, and allelic imbalance of 1p, 8p, 20q. Conclusions: In thi s report of HUS in three adult patients, we emphasize the role of TP53 pathway i n carcinogenesis of this rare tumor. This point could be of interest for therape utic strategies.

Pandemic influenza 2009: Impact of vaccination coverage on critical illness in children, a Canada and France observational study

AIM To study the impact of vaccination critical illness due to H1N1pdm09, we compared the incidence and severity of H1N1pdm09 infection in Canada and France.METHODS We studied two national cohorts that included children with documented H1N1pdm09 infection, admitted to a pediatric intensive care unit(PICU) in Canada and in France between October 1, 2009 and January 31, 2010.RESULTS Vaccination coverage prior to admission to PICUs was higher in Canada than in France(21% vs 2% of children respectively, P < 0.001), and in both countries, vaccination coverage prior to admission of these critically ill patients was substantially lower than in the general pediatric population(P < 0.001). In Canada, 160 children(incidence = 2.6/100000 children) were hospitalized in PICU compared to 125 children(incidence = 1.1/100000) in France(P < 0.001). Mortality rates were similar in Canada and France(4.4% vs 6.5%, P = 0.45, respectively), median invasive mechanical ventilation duration and mean PICU length of stay were shorter in Canada(4 d vs 6 d, P = 0.02 and 5.7 d vs 8.2 d, P = 0.03, respectively). H1N1pdm09 vaccination prior to PICU admission was associated with a decreased risk of requiring invasive mechanical ventilation(OR = 0.30, 95%CI: 0.11-0.83, P = 0.02).CONCLUSION The critical illness due to H1N1pdm09 had a higher incidence in Canada than in France. Critically ill children were less likely to have received vaccination prior to hospitalization in comparison to general population and children vaccinated had lower risk of ventilation.

Current view and perspectives in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis（ALS）, identified as a distinct clinical entity by Charcot since the end of the nineteenth century, is a devastating and fatal neurodegenerative disorder that affects motor neurons in the brain, brainstem and spinal cord. Survival of patients with ALS is associated with several factors such as clinical phenotype, age at onset, gender, early presence of respiratory failure, weight loss and treatment with Riluzole（the only disease-modifying drug approved for this disease）. Nowadays, there is still no curative treatment for ALS： palliative care and symptomatic treatment are therefore essential components in the management of these patients. Nevertheless, the scientific knowledge in the field of ALS motor neuron degeneration is growing, with the prospect of new treatments. Based on this physiopathological knowledge, several new therapeutic targets are being studied, involving various mechanisms such as excitotoxicity, neuroinflammation, mitochondrial dysfunction, oxidative stress, RNA metabolism and other attractive concepts. Moreover, it is also important to identify reliable biomarkers that will be essential components for future therapeutic development and study design in ALS. In this review, we present the main recent advances and promising therapeutics and biomarkers in the field of ALS.

Unexpected discovery of 2 cases of hepatocyte nuclear factor 1α-mutated infracentimetic adenomatosis

We present 2 cases of hepatocyte nuclear factor 1α (HNF1α)-mutated adenomatosis, discovered for reasons unrelated to this disease, and identified using immunohistochemical methods. These new tools may further our understanding of the link between adenomas/adenomatosis subtypes and their complications, and their association with other abnormalities.

Factors associated with DAA virological treatment failure and resistance-associated substitutions description in HIV/HCV coinfected patients

AIMTo describe factors associated with treatment failure and frequency of resistance-associated substitutions （RAS）.METHODSHuman immunodefciency virus （HIV）/hepatitis C virus （HCV） coinfected patients starting a first direct-acting antiviral （DAA） regimen before February 2016 and included in the French ANRS CO13 HEPAVIH cohort were eligible. Failure was defned as： （1） non-response [HCV-RNA remained detectable during treatment, at end of treatment （EOT）]; and （2） relapse （HCV-RNA suppressed at EOT but detectable thereafter）. Sequencing analysis was performed to describe prevalence of drug class-specifc RAS. Factors associated with failure were determined using logistic regression models.RESULTSAmong 559 patients, 77% had suppressed plasmaHIV-RNA 〈 50 copies/mL at DAA treatment initiation41% were cirrhotic, and 68% were HCV treatmentexperienced. Virological treatment failures occurred in22 patients and were mainly relapses （17, 77%） thenundefined failures （3, 14%） and non-responses （29%）. Mean treatment duration was 16 wk overall. Posttreatment NS3, NS5A or NS5B RAS were detected in10/14 patients with samples available for sequencinganalysis. After adjustment for age, sex, ribavirin useHCV genotype and treatment duration, low platelecount was the only factor signifcantly associated with ahigher risk of failure （OR： 6.5; 95%CI： 1.8-22.6）. CONCLUSIONOnly 3.9% HIV-HCV coinfected patients failed DAAregimens and RAS were found in 70% of those failingLow platelet count was independently associated withvirological failure.

皮肤CD8阳性鳞状T细胞大疱性淋巴瘤

Introduction. Bullous forms of cutaneous T- cell lymphomas are rare. A new group of cutaneous T- cell lymphomas has recently been identified as a distinct clinicopathological and immunophenotype entity. These cutaneous T- cell lymphomas express a CD8+ phenotype, rarely expressed in other cutaneous T- cell lymphomas. Case report. We describe a cutaneous CD8+ squamous T- cell lymphoma with polymorphic clinical features, strongly epidermotropic lymphoid infiltrate and spongiosis, classical for this type of lymphoma. Discussion. Bullous lesions in cutaneous T- cell lymphoma should evoke the possibilityofacutaneousCD8+ T- celllymphoma,onceotherbullous diseases have been excluded. Spongiosis, rare in other types of T- cell lymphoma, and strongly epidermotropic pleomorphic lymphoid infiltrate are classical histological features. The association of polymorphic lesions, bullas and atypical CD8+ epidermotropic phenotype should evoke this diagnosis even at the early stage. Treatment is difficult and classical chemotherapy often fails. Prognosis is poor with a mean overall survival of 32 months.

X-Ray and Mössbauer Study of Magnetic Black Sand from Mayotte Island

Natural magnetic black sands are known from several sites often located in areas of volcanic origin. Their elemental and mineral composition provides information on the geology of their territory and depends on several factors occurred during their formation. A sample of black sand was collected on the seashore of the island of Mayotte in the Indian Ocean and its magnetic part was investigated by means of energy dispersive X-ray spectroscopy (EDS), powder X-ray diffraction (XRD), and M&#214;ssbauer spectroscopy at room temperature. The mineral composition is dominantly magnetite, in good agreement with samples collected in other sites of volcanic origin. Contrary to pure magnetite, a relevant fraction of Ti was detected by EDS. The 16% Ti and 1% Mn content increase the magnetite lattice parameter to 8.4312 (25) &#197;. The broadening of XRD lines pointed towards a significant degree of disorder. This was confirmed by M&#214;ssbauer spectroscopy and is attributed to the presence of Ti replacing Fe in the magnetite lattice. The presence of Ti modifies the local magnetic field on the Fe sites, leading to a broader and more complex M&#214;ssbauer transmission spectrum with respect to the one of pure magnetite. To study the effect of temperature, samples were heated for 12 hours to 600&deg;C and 800&deg;C in argon and to 1000&deg;C in air. Annealing in argon did not improve the crystallinity while annealing in air caused a complete decomposition of magnetite into hematite and pseudobrookite.

Management of skin toxicities during panitumumab treatment in metastatic colorectal cancer

BACKGROUND Anti-epidermal growth factor receptor therapy is associated with skin adverse events not previously reported with conventional chemotherapy. Prophylactic actions are recommended, but routine clinical management of these toxicities and their impact on quality of life remain unknown. AIM To assess the dermatological toxicities reported after panitumumab initiation, their impact on the quality of life and the clinical practices for their management. METHODS Patients included in this prospective multicenter observational study were over 18 years of age and began treatment with panitumumab for wild-type KRAS metastatic colorectal cancer. The incidence of dermatological toxicities, clinical practices for their management and impact on quality of life were recorded during a 6-mo follow-up. RESULTS Overall, 229 patients (males, 57.6%;mean age, 66.2 years) were included. At day 15, 59.3% of patients had dermatological toxicity;the rate peaked at month 2 (74.7%) and decreased at month 6 (46.5%). The most frequent dermatological toxicities were rash/acneiform rash, xerosis and skin cracks. At least one preventive treatment was administered to 65.9% of patients (oral antibiotics, 84.1%;emollients, 75.5%;both, 62.9%). The rates of patients who received at least one curative treatment peaked at month 2 (63.4%) and decreased at month 6 (44.8%). The impact of the dermatological toxicities on quality of life was limited as assessed with Dermatology Life Quality Index scores and inconvenience visual analogic scale score. The rates of topical corticosteroids administration and visits to specialists were low. CONCLUSION The rates of the different skin toxicities peaked at various times and were improved at the end of follow-up. Nevertheless, their clinical management could be optimized with a better adherence to current recommendations. The impact of skin toxicities on patient’s quality of life appeared to be limited.

结肠系膜血管球瘤

Glomus tumors are rare distinctive benign neoplasms, which arise from modified smooth muscle cells of the normal glomus body and are most commonly located in the subungual region of the finger. Intraabdominal locations are relatively rare. We report a case of glomus tumor of the mesocolon in a 10- yearold girl. Surgical exploration showed a lesion in the transverse mesocolon, which was excised. Histopathology showed it to be a glomus tumor of the mesocolon.

嗜碱性白细胞CD4^+,CD56^+血液皮肤肿瘤:新病例报道1例

Background. "Agranular CD4+CD56+hematodermic neoplasm"are rare hematologic neoplasms which were recently shown to correspond to the plasmocytoid dendritic cells. Case report. A 83-year-old presented isolated skin lesions purple, infiltrating the dermis. The biopsy has shown a dense dermal infiltration with malignant cells CD4+CD56+CD43+. There were no bone marrow involvement and no circulating blood cells. A chemotherapy permitted a clinical remission after six courses. Unfortunately, skin and blood relapses appear four months later. After a short success of chemotherapy by DHAP, the patient died three month later. Discussion. "Agranular CD4+CD56+hematodermic neoplasm"is a distinct entity from the cutaneous primary lymphomas. Recently plasmocytoid monocyte cells have been identified as the precursor of the malignant population with the high expression of CD123, IL-3 receptor. It is a distinct clinicopathologic entity by its clinical presentation with skin tropism, bone marrow involvement with or without leukemic phase and poor prognosis independent of the kind of treatment and its particular phenotype CD4+CD56+CD43+. It would be interesting to use antibodies linked to CD123 in therapeutic because any treatment have efficacity in this disease.

1例11月龄女婴先天性胆总管囊肿自发性破裂

Choledochal cysts are rare congenital malformations of the biliary tract. Though most cysts are diagnosed incidentally, some present directly with complications. We report on the case of an 11-month-old girl admitted for abdominal pain, fever and vomiting. Ultrasonography revealed intraabdominal fluid and the absence of a choledochal cyst diagnosed 2 months earlier. Laparotomy for suspected rupture of a choledochal cyst was planned and a choledochojejunostomy with Roux-en-Y was performed. Spontaneous rupture of a choledochal cyst is rare and occurs most frequently in children under the age of 4. The exact cause is yet unknown and several factors have been implicated. The most probable cause is the combination of pancreatic reflux and epithelial irritation of a weakened cyst wall. Choledochal cysts should preferably be treated as soon as the child is 6 months old. Complete excision of the cyst is mandatory because of the risk of malignant transformation.

儿科临床中一项实用的检测方法:粪胰肽酶E-1的测定

- To study fecal elastase- 1 (E1F) and chymotrypsin (ChT) in stools for the diagnosis of pancreatic insufficiency in pediatric practice. - Materials and methods. - E1F and ChT were measured in stools of 198 children divided in 3 groups: 49 children without any digestive disease (group A), 71 children with pancreatic diseases (group B), and 78 children with nonpancreatic digestive diseases (group C). Results. - In group B, E1F values were very low in 64 children and normal in 7 children without pancreatic insufficiency (6 children with cystic fibrosis and 1 with chronic pancreatitis). ChT values were normal in children without pancreatic insufficiency but also in half of children treated with pancreatic enzymes. Decreased E1F values were seen in 2 children (4% ) in the group A and 22 children (28% ) in the group C, especially those with acute gastroenteritis or celiac disease. Conclusion. - E1F is a simple, non-invasive, useful tool for the diagnosis of pancreatic insuffi ciency in children with growth failure or chronic diarrhea, and those with cystic fibrosis. Nevertheless, low values may be found in diseases with villous atrophy or very liquid stools.

Identifying High-Risk Medication Prescriptions to Prevent Potentially Severe Adverse Drug Events in Primary-Care Patients with Chronic Multimorbidities:The Polychrome Study

Background:The association between multimorbidities and polypharmacy among elderly individuals is well documented,and polypharmacy has been shown to increase the risk of adverse drug events(ADEs).However,little information is available about the risks associated with the lifelong use of medications to treat chronic multimorbidities.Objective:To determine the prevalence and nature of high-risk prescriptions among primary-care patients with chronic multimorbidities.Methods:We studied a weighted stratified random sample of 105 prescriptions for different patients with chronic multimorbidities taken from the Polychrome database established using information from the French primary-care record database(Observatoire de la Médecine Générale).A medication review was conducted to identify contra-indications and potential drug-drug interactions for each prescription.Results:Contra-indications were identified for 60(57.1%)prescriptions,potential drug-drug interactions for 70(66.7%),absolute contra-indications for 9(8.6%),and inadvisable drug combinations for 11(10.5%).In all,19(18.1%)different patients were at risk for major ADEs.Cardiovascular and nervous-system drugs contributed 66.2% of contra-indications and 69.3% of potential drug-drug interactions.Conclusions:This exploratory study confirms the high prevalence and potential seriousness of prescriptions at risk for ADEs in a population of primary-care patients with chronic multimorbidities.The high prevalence of interactions involving the cardiovascular and nervous systems indicates that efforts to improve prescription practices should target these two categories of conditions and drugs in patients with chronic multimorbidities.

α-Synuclein-carrying astrocytic extracellular vesicles in Parkinson pathogenesis and diagnosis

Background The accumulation ofα-synuclein(α-syn),an essential step in PD development and progression,is observed not only in neurons but also in glia,including astrocytes.The mechanisms regulating astrocyticα-syn level and aggregation remain unclear.More recently,it has been demonstrated that a part ofα-syn spreading occurs through extracellular vesicles(EVs),although it is unknown whether this process is involved in astrocytes of PD.It is known,however,that EVs derived from the central nervous system exist in the blood and are extensively explored as biomarkers for PD and other neurodegenerative disorders.Methods Primary astrocytes were transfected with A53Tα-syn plasmid or exposed toα-syn aggregates.The level of astrocyte-derived EVs(AEVs)was assessed by nanoparticle tracking analysis and immunofluorescence.The lysosomal function was evaluated by Cathepsin assays,immunofluorescence for levels of Lamp1 and Lamp2,and LysoTracker Red staining.The Apogee assays were optimized to measure the GLT-1+AEVs in clinical cohorts of 106 PD,47 multiple system atrophy(MSA),and 103 healthy control(HC)to test the potential of plasma AEVs as a biomarker to differentiate PD from other forms of parkinsonism.Results The number of AEVs significantly increased in primary astrocytes withα-syn deposition.The mechanism of increased AEVs was partially attributed to lysosomal dysfunction.The number ofα-syn-carrying AEVs was significantly higher in patients with PD than in HC and MSA.The integrative model combining AEVs with total and aggregatedα-syn exhibited efficient diagnostic power in differentiating PD from HC with an AUC of 0.915,and from MSA with an AUC of 0.877.Conclusions Pathologicalα-syn deposition could increase the astrocytic secretion of EVs,possibly throughα-syninduced lysosomal dysfunction.Theα-syn-containing AEVs in the peripheral blood may be an effective biomarker for clinical diagnosis or differential diagnosis of PD.

Clustering of prostate cancer healthcare pathways in the French National Healthcare database

Background:Healthcare pathways of patients with prostate cancer are heterogeneous and complex to apprehend using traditional descriptive statistics.Clustering and visualization methods can enhance their characterization.Methods:Patients with prostate cancer in 2014 were identified in the French National Healthcare database(Système National des Données de Santé—SNDS)and their data were extracted with up to 5 years of history and 4 years of follow‐up.Fifty‐one‐specific encounters constitutive of prostate cancer management were synthesized into four macro‐variables using a clustering approach.Their values over patient follow‐ups constituted healthcare pathways.Optimal matching was applied to calculate distances between pathways.Partitioning around medoids was then used to define consistent groups across four exclusive cohorts of incident prostate cancer patients:Hormone‐sensitive(HSPC),metastatic hormone‐sensitive(mHSPC),castration‐resistant(CRPC),and metastatic castration‐resistant(mCRPC).Index plots were used to represent pathways clusters.Results:The repartition of macro‐variables values—surveillance,local treatment,androgenic deprivation,and advanced treatment—appeared to be consistent with prostate cancer status.Two to five clusters of healthcare pathways were observed in each of the different cohorts,corresponding for most of them to relevant clinical patterns,although some heterogeneity remained.For instance,clustering allowed to distinguish patients undergoing active surveillance,or treated according to cancer progression risk in HSPC,and patients receiving treatment for potentially curative or palliative purposes in mHSPC and mCRPC.Conclusion:Visualization methods combined with a clustering approach enabled the identification of clinically relevant patterns of prostate cancer management.Characterization of these care pathways is an essential element for the comprehension and the robust assessment of healthcare technology effectiveness.