Publications by authors named "Pascale Marcorelles"

136 Publications

A recurrent RYR1 mutation associated with early-onset hypotonia and benign disease course.

Acta Neuropathol Commun 2021 09 17;9(1):155. Epub 2021 Sep 17.

Laboratoire de Biochimie et Génétique Moléculaire, Pôle de Biologie, CHU Grenoble Alpes, Grenoble, France.

The ryanodine receptor RyR1 is the main sarcoplasmic reticulum Ca channel in skeletal muscle and acts as a connecting link between electrical stimulation and Ca-dependent muscle contraction. Abnormal RyR1 activity compromises normal muscle function and results in various human disorders including malignant hyperthermia, central core disease, and centronuclear myopathy. However, RYR1 is one of the largest genes of the human genome and accumulates numerous missense variants of uncertain significance (VUS), precluding an efficient molecular diagnosis for many patients and families. Here we describe a recurrent RYR1 mutation previously classified as VUS, and we provide clinical, histological, and genetic data supporting its pathogenicity. The heterozygous c.12083C>T (p.Ser4028Leu) mutation was found in thirteen patients from nine unrelated congenital myopathy families with consistent clinical presentation, and either segregated with the disease in the dominant families or occurred de novo. The affected individuals essentially manifested neonatal or infancy-onset hypotonia, delayed motor milestones, and a benign disease course differing from classical RYR1-related muscle disorders. Muscle biopsies showed unspecific histological and ultrastructural findings, while RYR1-typical cores and internal nuclei were seen only in single patients. In conclusion, our data evidence the causality of the RYR1 c.12083C>T (p.Ser4028Leu) mutation in the development of an atypical congenital myopathy with gradually improving motor function over the first decades of life, and may direct molecular diagnosis for patients with comparable clinical presentation and unspecific histopathological features on the muscle biopsy.
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http://dx.doi.org/10.1186/s40478-021-01254-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8447513PMC
September 2021

Detection of NTRK fusions in glioblastoma: fluorescent in situ hybridisation is more useful than pan-TRK immunohistochemistry as a screening tool prior to RNA sequencing.

Pathology 2021 Sep 10. Epub 2021 Sep 10.

CHRU Brest, Department of Pathology, Brest, France; Univ Brest, Inserm, CHU de Brest, LBAI, UMR1227, Brest, France. Electronic address:

Glioblastomas are frequent malignant brain tumours with a very poor prognosis and a need for new and efficient therapeutic strategies. With the approval of anti-TRK targeted therapies to treat patients with advanced NTRK-rearranged cancers, independent of the type of cancer, potential new treatment opportunities are available for the 0.5-5% of patients with NTRK-rearranged glioblastomas. Identification of these rare NTRK-rearranged glioblastomas requires efficient diagnostic tools and strategies which are evaluated in this study. We compared the results of NTRK1, NTRK2 and NTRK3 fluorescent in situ hybridisation (FISH) assays to those of pan-TRK immunohistochemistry (IHC) using two EPR17341 and A7H6R clones in a set of 196 patients with glioblastomas. Cases with at least 15% of positive nuclei using FISH analyses were further analysed using RNA sequencing. Above the 15% threshold, seven positive glioblastomas (3.57%) were identified by FISH assays (4 NTRK1, 3 NTRK2, no NTRK3). NTRK rearrangements were confirmed by RNA sequencing analyses in four cases [1 LMNA-NTRK1, 1 PRKAR2A-NTRK2, 1 SPECC1L-NTRK2 and 1 NACC2-NTRK2 fusions, i.e., 4/196 (2%) of NTRK-rearranged tumours in our series] but no rearrangement was detected in three samples with less than 30% of positive tumour nuclei as determined by NTRK1 FISH. Pan-TRK immunostaining showed major discrepancies when using either the EPR17341 or the A7H6R clones for the following criteria: main intensity, H-Score based scoring and homogeneity/heterogeneity of staining (Kappa values <0.2). This led to defining adequate criteria to identify NTRK-rearranged gliomas exhibiting strong and diffuse immunostaining contrasting to the variable and heterogeneous staining in non-NTRK-rearranged gliomas (p<0.0001). As assessing NTRK rearrangements has become crucial for glioma therapy, FISH seems to be a valuable tool to maximise access to TRK testing in patients with glioblastomas. In contrast to other cancers, pan-TRK IHC appears of limited interest in this field because there is no 'on/off' IHC positivity criterion to distinguish between NTRK-rearranged and non-NTRK-rearranged gliomas. RNA sequencing analyses are necessary in FISH positive cases with less than 30% positive nuclei, to avoid false positivity when scoring is close to the detection threshold.
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http://dx.doi.org/10.1016/j.pathol.2021.05.100DOI Listing
September 2021

Xanthogranulomatous endometritis: A case report and literature review.

Clin Case Rep 2021 Jun 24;9(6):e04299. Epub 2021 Jun 24.

Gynecology and Obstetrics Department Brest University Hospital Brest France.

Xanthogranulomatous endometritis is a rare benign pathology mimicking endometrial carcinoma.
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http://dx.doi.org/10.1002/ccr3.4299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223691PMC
June 2021

Neuropathological hallmarks of fetal hydrocephalus linked to CCDC88C pathogenic variants.

Acta Neuropathol Commun 2021 06 6;9(1):104. Epub 2021 Jun 6.

UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics and Reference Center for Developmental Disorders, Normandy Center for Genomic and Personalized Medicine, Normandie Univ, 76000, Rouen, France.

The prevalence of congenital hydrocephalus has been estimated at 1.1 per 1000 infants when including cases diagnosed before 1 year of age after exclusion of neural tube defects. Classification criteria are based either on CSF dynamics, pathophysiological mechanisms or associated lesions. Whereas inherited syndromic hydrocephalus has been associated with more than 100 disease-causing genes, only four genes are currently known to be linked to congenital hydrocephalus either isolated or as a major clinical feature: L1CAM, AP1S2, MPDZ and CCDC88C. In the past 10 years, pathogenic variants in CCDC88C have been documented but the neuropathology remains virtually unknown. We report the neuropathology of two foetuses from one family harbouring two novel compound heterozygous pathogenic variants in the CCDC88C gene: a maternally inherited indel in exon 22, c.3807_3809delinsACCT;p.(Gly1270Profs*53) and a paternally inherited deletion of exon 23, c.3967-?_c.4112-?;p.(Leu1323Argfs*10). Medical termination of pregnancy was performed at 18 and 23 weeks of gestation for severe bilateral ventriculomegaly. In both fetuses, brain lesions consisted of multifocal atresia-forking along the aqueduct of Sylvius and the central canal of the medulla, periventricular neuronal heterotopias and choroid plexus hydrops. The second fetus also presented lumbar myelomeningocele, left diaphragmatic hernia and bilateral renal agenesis. CCDC88C encodes the protein DAPLE which contributes to ependymal cell planar polarity by inhibiting the non-canonical Wnt signaling pathway and interacts with MPDZ and PARD3. Interestingly, heterozygous variants in PARD3 result in neural tube defects by defective tight junction formation and polarization process of the neuroepithelium. Besides, during organ formation Wnt signalling is a prerequisite for planar cell polarity pathway activation, and mutations in planar cell polarity genes lead to heart, lung and kidney malformations. Hence, candidate variants in CCDC88C should be carefully considered whether brain lesions are isolated or associated with malformations suspected to result from disorders of planar cell polarity.
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http://dx.doi.org/10.1186/s40478-021-01207-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183048PMC
June 2021

MSI-High RAS-BRAF wild-type colorectal adenocarcinomas with MLH1 loss have a high frequency of targetable oncogenic gene fusions whose diagnoses are feasible using methods easy-to-implement in pathology laboratories.

Hum Pathol 2021 Aug 19;114:99-109. Epub 2021 May 19.

CHU de la Martinique, Service d'anatomie et Cytologie Pathologiques, Fort-de-France, F-97261, France; Univ Brest, Inserm, CHU de Brest, LBAI, UMR1227, Brest, 29200, France. Electronic address:

Targetable kinase fusions are extremely rare (<1%) in colorectal cancers (CRCs), making their diagnosis challenging and often underinvestigated. They have been shown particularly frequently among MSI-High, BRAF/KRAS/NRAS wild-type CRCs with MLH1 loss (MLH1 MSI-High wild-type). We searched for NTRK1, NTRK2, NTRK3, ALK, ROS1, BRAF, RET, and NRG1 kinase fusions in CRCs using methods easy-to-implement in pathology laboratories: immunohistochemistry (IHC), fluorescent in situ hybridization (FISH), and fully automated real-time PCR targeted analyses. RNA-sequencing analyses were used for confirmation. Among 84 selected MLH1 deficient (IHC) CRCs cases, MLH1 MSI-High wild-type CRCs consisted first in 19 cases after Idylla™ analyses and finally in 18 cases (21%) after RNA-sequencing (detection of one additional KRASG12D mutation). FISH (and when relevant, IHC) analyses concluded in 5 NTRK1, 3 NTRK3, 1 ALK, 2 BRAF, and 2 RET FISH positive tumors. ALK and NTRK1 rearranged tumors were IHC positive, but pan-TRK IHC was negative in the 3 NTRK3 FISH positive tumors. RNA-sequencing analyses confirmed 12 of 13 fusions with only one false positive RET FISH result. Finally, 12/18 (67%) of MLH1 MSI-High wild-type CRCs contained targetable kinase fusions. Our study demonstrates the feasibility, but also the cost-effectiveness, of a multistep but rapid diagnostic strategy based on nonsequencing methods to identify rare and targetable kinase fusions in patients with advanced CRCs, as well as the high prevalence of these kinase fusions in MLH1 MSI-High wild-type CRCs. Nevertheless, confirmatory RNA-sequencing analyses are necessary in case of low FISH positive nuclei percentage to rule out FISH false-positive results.
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http://dx.doi.org/10.1016/j.humpath.2021.05.006DOI Listing
August 2021

Fluorescent In Situ Hybridization Must be Preferred to pan-TRK Immunohistochemistry to Diagnose NTRK3-rearranged Gastrointestinal Stromal Tumors (GIST).

Appl Immunohistochem Mol Morphol 2021 09;29(8):626-634

Department of Pathology.

Tyrosine kinase inhibitors have revolutionized the treatment of patients with gastrointestinal stromal tumors (GISTs). Nevertheless, some GISTs do not contain any targetable KIT or PDGFRA mutations classically encountered in this field. Novel approved therapies targeting TRK chimeric proteins products of NTRK genes fusions consist in a promising approach to treat some patients with GISTs lacking any identified driver oncogenic mutation in KIT, PDGFRA or BRAF genes. Thus, an adequate testing strategy permitting to diagnose the rare NTRK-rearranged GISTs is required. In this work, we studied about the performances of pan-TRK immunohistochemistry (IHC) and NTRK1/2/3 fluorescent in situ hybridization in a series of 39 GISTs samples. Among 22 patients with GISTs lacking KIT or PDGFRA mutations, BRAFV600E IHC permitted to diagnose 2/22 (9%) BRAFV600E-mutated GISTs and, among the 20 KIT, PDGFRA, and BRAF wild type tumors, 1/20 (5%), NTRK3-rearranged tumor was diagnosed using NTRK3 fluorescent in situ hybridization. Pan-TRK IHC using EPR17341 and A7H6R clones was negative in this NTRK3-rearranged sample. Pan-TRK IHC was frequently positive in NTRK not rearranged tumors without (24 samples analyzed) or with (15 samples analyzed) KIT or PDGFRA mutations with major discrepancies between the 2 IHC clones (intraclass correlation coefficient of 0.3042). Given the new therapeutic opportunity offered by anti-TRK targeted therapies to treat patients with advanced cancers including GISTs, it is worth to extend molecular analysis to NTRK fusions testing in KIT, PDGFRA, and BRAF wild type GISTs. Pan-TRK IHC appears not relevant in this field but performing a simple NTRK3 fluorescent in situ hybridization test consists in a valuable approach to identify the rare NTRK3-rearranged GISTs treatable using anti-TRK therapies.
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http://dx.doi.org/10.1097/PAI.0000000000000933DOI Listing
September 2021

Factors associated with poor fetal outcome in placental abruption.

Pregnancy Hypertens 2021 Mar 25;23:59-65. Epub 2020 Nov 25.

Service d'Anatomopathologie, CHU de Brest, Hôpital Morvan, 29200 Brest, France; EA 4685 LIEN, Université Bretagne Loire, 29200 Brest, France.

Objectives: We aimed at describing placental abruption in our county and at evaluating factors associated with poor fetal outcome.

Study Design: In this case-control study, women with placental abruption were identified from two databases of Brest University Hospital between January 2013 and December 2018.

Main Outcome Measures: Placental histological findings, course of pregnancies, maternal and fetal characteristics were described and compared between cases (placental abruption with stillbirth or neonatal death) and controls.

Results: We identified 135 placental abruption, of whom 24.4% were complicated with stillbirth and 6.5% with neonatal death. Forty percent of women were smokers and 14.1% had a history of vasculoplacental disorder. Pregnancies were complicated with 42.2% of pre-eclampsia and 43% of intrauterine growth restriction. Cases were associated with more autoimmune diseases in mother (20.0% versus 3.2%, P = 0.003), more aspirin or heparin use during pregnancy (20.0% versus 6.3%, P = 0.03), less pre-eclampsia (25.0% versus 49.5%, P = 0.01) and more deliveries ≤ 34 weeks of gestation (80.0% versus 43.2%, P = 0.0001) than controls. Placentas from cases showed more placental indentation ≥ 30% (42.5% versus 5.3%, P < 0.0001) and less histological chronic inflammation, especially less chronic chorioamniotitis (2.5% versus 24.2%, P = 0.002) than controls. In multivariate analysis, factors negatively associated with poor fetal outcome were placental histological chronic inflammation (P = 0.01) and macroscopic infarcts (P = 0.01).

Conclusions: Poor fetal outcome is negatively associated with certain placental histological chronic lesions, but not with pre-eclampsia, what suggests various pathophysiological processes among placental abruption.
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http://dx.doi.org/10.1016/j.preghy.2020.11.004DOI Listing
March 2021

Prenatal alcohol exposure is a leading cause of interneuronopathy in humans.

Acta Neuropathol Commun 2020 11 30;8(1):208. Epub 2020 Nov 30.

Department of Pathology, Normandie Univ, UNIROUEN, INSERM U1245 and Rouen University Hospital, Normandy Centre for Genomic and Personalized Medicine, 76000, Rouen, France.

Alcohol affects multiple neurotransmitter systems, notably the GABAergic system and has been recognised for a long time as particularly damaging during critical stages of brain development. Nevertheless, data from the literature are most often derived from animal or in vitro models. In order to study the production, migration and cortical density disturbances of GABAergic interneurons upon prenatal alcohol exposure, we performed immunohistochemical studies by means of the proliferation marker Ki67, GABA and calretinin antibodies in the frontal cortical plate of 17 foetal and infant brains antenatally exposed to alcohol, aged 15 weeks' gestation to 22 postnatal months and in the ganglionic eminences and the subventricular zone of the dorsal telencephalon until their regression, i.e., 34 weeks' gestation. Results were compared with those obtained in 17 control brains aged 14 weeks of gestation to 35 postnatal months. We also focused on interneuron vascular migration along the cortical microvessels by confocal microscopy with double immunolabellings using Glut1, GABA and calretinin. Semi-quantitative and quantitative analyses of GABAergic and calretininergic interneuron density allowed us to identify an insufficient and delayed production of GABAergic interneurons in the ganglionic eminences during the two first trimesters of the pregnancy and a delayed incorporation into the laminar structures of the frontal cortex. Moreover, a mispositioning of GABAergic and calretininergic interneurons persisted throughout the foetal life, these cells being located in the deep layers instead of the superficial layers II and III. Moreover, vascular migration of calretininergic interneurons within the cortical plate was impaired, as reflected by low numbers of interneurons observed close to the cortical perforating vessel walls that may in part explain their abnormal intracortical distribution. Our results are globally concordant with those previously obtained in mouse models, in which alcohol has been shown to induce an interneuronopathy by affecting interneuron density and positioning within the cortical plate, and which could account for the neurological disabilities observed in children with foetal alcohol disorder spectrum.
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http://dx.doi.org/10.1186/s40478-020-01089-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706035PMC
November 2020

Breast cancer tumor heterogeneity has only little impact on the estimation of the Oncotype DX® recurrence score using Magee Equations and Magee Decision Algorithm™.

Hum Pathol 2021 02 24;108:51-59. Epub 2020 Nov 24.

CHRU Brest, Department of Pathology, Brest, F-29220, France; Univ Brest, Inserm, CHU de Brest, LBAI, UMR1227, Brest, France. Electronic address:

Oncotype DX® assay is used to guide therapeutic decisions in early-stage invasive breast carcinoma but remains expensive. Magee Equations (MEs) and Magee Decision Algorithm (MDA) predict the Oncotype DX® recurrence score (RS) on the basis of histopathological parameters. The influence of intratumor heterogeneity on MEs and MDA remains uncertain. We compared Ki-67, estrogen and progesterone receptors, and human erb-b2 receptor tyrosine kinase 2 (HER2) status on tissue microarray cores with the corresponding findings on the whole slides to calculate MEs scores and to decide if Oncotype DX® testing was required as per MDA in two sets of 175 and 59 tumors, without and with Oncotype DX® results, respectively. Agreements in the interpretation of Ki-67, estrogen and progesterone receptors, and HER2 status were very good between limited areas and whole-slide analyses. This resulted also in very good agreements about the results of MEs and MDA. For 7 of 175 (4%) and 3 of 59 (5.1%) cases, MEs and MDA results in different tumor areas would have changed the indication to perform or not perform Oncotype DX® assays. Oncotype DX® RSs were significantly correlated with MEs and MDA results, but among cases initially predicted to have an RS ≤25 using MDA, 3 of 34 cases (8.8%) had in fact an RS >25. Tumor heterogeneity appears to have little impact on the estimation of the Oncotype DX® RS using MEs and MDA and would have permitted to avoid half of Oncotype DX® assays in our series. Caution is nevertheless required in discarding Oncotype DX® assay in cases with ME scores >18 associated with low mitotic activity.
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http://dx.doi.org/10.1016/j.humpath.2020.11.006DOI Listing
February 2021

A fatal case after an intravenous injection of levamisole.

Forensic Sci Med Pathol 2021 Mar 12;17(1):130-135. Epub 2020 Nov 12.

Angers University, UFR santé, medicine department, Angers, France.

Levamisole is a drug originally prescribed as an antihelmintic. Because of the occurrence of severe cases of agranulocytosis and leukoencephalitis it was removed from the French market in 1998 for human use, while it remains available for veterinary use. Nowadays in France its only use in humans is regulated by authorization for temporary use for its immunomodulatory properties in the treatment of nephritic syndrome.A 52-year-old man was found dead at his farm. Injection points were observed on his arm and a syringe containing a dark orange-brown liquid was found near the body. At his home, the discovery of a letter highlighted suicidal intent. Analysis of the aforementioned liquid, peripheral blood and urine confirmed the unique presence of levamisole. The femoral blood concentration of levamisole was of 25 mg/L whereas the femoral blood concentrations reported in cases of fatalities after cocaine use do not exceed 0.0056 mg/L. In humans, levamisole can be detected in biological samples after cocaine use as this drug is also an adulterant and one of its metabolites (aminorex) seems to have amphetamine-like properties. In this case, the man consumed levamisole from time to time for its stimulant and strengthening effects.Cases of fatal poisoning using levamisole are very rare and poorly documented, which makes the interpretation of postmortem blood levamisole concentration difficult.
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http://dx.doi.org/10.1007/s12024-020-00336-yDOI Listing
March 2021

Keratinocytes Communicate with Sensory Neurons via Synaptic-like Contacts.

Ann Neurol 2020 12 10;88(6):1205-1219. Epub 2020 Oct 10.

Univ Brest, LIEN, Brest University, F-29200 Brest, France.

Objective: Pain, temperature, and itch are conventionally thought to be exclusively transduced by the intraepidermal nerve endings. Although recent studies have shown that epidermal keratinocytes also participate in sensory transduction, the mechanism underlying keratinocyte communication with intraepidermal nerve endings remains poorly understood. We sought to demonstrate the synaptic character of the contacts between keratinocytes and sensory neurons and their involvement in sensory communication between keratinocytes and sensory neurons.

Methods: Contacts were explored by morphological, molecular, and functional approaches in cocultures of epidermal keratinocytes and sensory neurons. To interrogate whether structures observed in vitro were also present in the human epidermis, in situ correlative light electron microscopy was performed on human skin biopsies.

Results: Epidermal keratinocytes dialogue with sensory neurons through en passant synaptic-like contacts. These contacts have the ultrastructural features and molecular hallmarks of chemical synaptic-like contacts: narrow intercellular cleft, keratinocyte synaptic vesicles expressing synaptophysin and synaptotagmin 1, and sensory information transmitted from keratinocytes to sensory neurons through SNARE-mediated (syntaxin1) vesicle release.

Interpretation: By providing selective communication between keratinocytes and sensory neurons, synaptic-like contacts are the hubs of a 2-site receptor. The permanent epidermal turnover, implying a specific en passant structure and high plasticity, may have delayed their identification, thereby contributing to the long-held concept of nerve endings passing freely between keratinocytes. The discovery of keratinocyte-sensory neuron synaptic-like contacts may call for a reassessment of basic assumptions in cutaneous sensory perception and sheds new light on the pathophysiology of pain and itch as well as the physiology of touch. ANN NEUROL 2020;88:1205-1219.
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http://dx.doi.org/10.1002/ana.25912DOI Listing
December 2020

In utero alcohol exposure exacerbates endothelial protease activity from pial microvessels and impairs GABA interneuron positioning.

Neurobiol Dis 2020 11 3;145:105074. Epub 2020 Sep 3.

Normandie Univ, UNIROUEN, INSERM U1245 and Rouen University Hospital, Department of Neonatal Paediatrics and Intensive Care, F 76000, Normandy Centre for Genomic and Personalized Medicine, Rouen, France. Electronic address:

In utero alcohol exposure can induce severe neurodevelopmental disabilities leading to long-term behavioral deficits. Because alcohol induces brain defects, many studies have focused on nervous cells. However, recent reports have shown that alcohol markedly affects cortical angiogenesis in both animal models and infants with fetal alcohol spectrum disorder (FASD). In addition, the vascular system is known to contribute to controlling gamma-aminobutyric acid (GABA)ergic interneuron migration in the developing neocortex. Thus, alcohol-induced vascular dysfunction may contribute to the neurodevelopmental defects in FASD. The present study aimed at investigating the effects of alcohol on endothelial activity of pial microvessels. Ex vivo experiments on cortical slices from mouse neonates revealed that in endothelial cells from pial microvessels acute alcohol exposure inhibits both glutamate-induced calcium mobilization and activities of matrix metalloproteinase-9 (MMP-9) and tissue plasminogen activator (tPA). The inhibitory effect of alcohol on glutamate-induced MMP-9 activity was abrogated in tPA-knockout and Grin1/VeCad mice suggesting that alcohol interacts through the endothelial NMDAR/tPA/MMP-9 vascular pathway. Contrasting with the effects from acute alcohol exposure, in mouse neonates exposed to alcohol in utero during the last gestational week, glutamate exacerbated both calcium mobilization and endothelial protease activities from pial microvessels. This alcohol-induced vascular dysfunction was associated with strong overexpression of the N-methyl-d-aspartate receptor subunit GluN1 and mispositioning of the Gad67-GFP interneurons that normally populate the superficial cortical layers. By comparing several human control fetuses with a fetus chronically exposed to alcohol revealed that alcohol exposure led to mispositioning of the calretinin-positive interneurons, whose density was decreased in the superficial cortical layers II-III and increased in deepest layers. This study provides the first mechanistic and functional evidence that alcohol impairs glutamate-regulated activity of pial microvessels. Endothelial dysfunction is characterized by altered metalloproteinase activity and interneuron mispositioning, which was also observed in a fetus with fetal alcohol syndrome. These data suggest that alcohol-induced endothelial dysfunction may contribute in ectopic cortical GABAergic interneurons, that has previously been described in infants with FASD.
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http://dx.doi.org/10.1016/j.nbd.2020.105074DOI Listing
November 2020

Amniotic fluid peptides predict postnatal kidney survival in developmental kidney disease.

Kidney Int 2021 03 1;99(3):737-749. Epub 2020 Aug 1.

Department of Pediatrics, Hôpital Nord, CHU de Saint Etienne, Saint Etienne, France.

Although a rare disease, bilateral congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of end stage kidney disease in children. Ultrasound-based prenatal prediction of postnatal kidney survival in CAKUT pregnancies is far from accurate. To improve prediction, we conducted a prospective multicenter peptidome analysis of amniotic fluid spanning 140 evaluable fetuses with CAKUT. We identified a signature of 98 endogenous amniotic fluid peptides, mainly composed of fragments from extracellular matrix proteins and from the actin binding protein thymosin-β4. The peptide signature predicted postnatal kidney outcome with an area under the curve of 0.96 in the holdout validation set of patients with CAKUT with definite endpoint data. Additionally, this peptide signature was validated in a geographically independent sub-cohort of 12 patients (area under the curve 1.00) and displayed high specificity in non-CAKUT pregnancies (82 and 94% in 22 healthy fetuses and in 47 fetuses with congenital cytomegalovirus infection respectively). Change in amniotic fluid thymosin-β4 abundance was confirmed with ELISA. Knockout of thymosin-β4 in zebrafish altered proximal and distal tubule pronephros growth suggesting a possible role of thymosin β4 in fetal kidney development. Thus, recognition of the 98-peptide signature in amniotic fluid during diagnostic workup of prenatally detected fetuses with CAKUT can provide a long-sought evidence base for accurate management of the CAKUT disorder that is currently unavailable.
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http://dx.doi.org/10.1016/j.kint.2020.06.043DOI Listing
March 2021

The ratio of maximal handgrip force and maximal cycloergometry power as a diagnostic tool to screen for metabolic myopathies.

Sci Rep 2020 06 1;10(1):8865. Epub 2020 Jun 1.

Department of Sport Medicine and Functional Explorations-CRNH Auvergne, Clermont-Ferrand University Hospital, G. Montpied Hospital, Clermont-Ferrand, F-63000, France.

Metabolic myopathies comprise a diverse group of inborn errors of intermediary metabolism affecting skeletal muscle, and often present clinically as an inability to perform normal exercise. Our aim was to use the maximal mechanical performances achieved during two functional tests, isometric handgrip test and cycloergometer, to identify metabolic myopathies among patients consulting for exercise-induced myalgia. Eighty-three patients with exercise-induced myalgia and intolerance were evaluated, with twenty-three of them having a metabolic myopathy (McArdle, n = 9; complete myoadenylate deaminase deficiency, n = 10; respiratory chain deficiency, n = 4) and sixty patients with non-metabolic myalgia. In all patients, maximal power (MP) was determined during a progressive exercise test on a cycloergometer and maximal voluntary contraction force (MVC) was assessed using a handgrip dynamometer. The ratio between percent-predicted values for MVC and MP was calculated for each subject (MVC%pred:MP%pred ratio). In patients with metabolic myopathy, the MVC%pred:MP%pred ratio was significantly higher compared to non-metabolic myalgia (1.54 ± 0.62 vs. 0.92 ± 0.25; p < 0.0001). ROC analysis of MVC%pred:MP%pred ratio showed AUC of 0.843 (0.758-0.927, 95% CI) for differentiating metabolic myopathies against non-metabolic myalgia. The optimum cutoff was taken as 1.30 (se = 69.6%, sp = 96.7%), with a corresponding diagnostic odd ratio of 66.3 (12.5-350.7, 95% CI). For a pretest probability of 15% in our tertiary reference center, the posttest probability for metabolic myopathy is 78.6% when MVC%pred:MP%pred ratio is above 1.3. In conclusion, the MVC%pred:MP%pred ratio is appropriate as a screening test to distinguish metabolic myopathies from non-metabolic myalgia.
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http://dx.doi.org/10.1038/s41598-020-65797-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264313PMC
June 2020

Exercise efficiency impairment in metabolic myopathies.

Sci Rep 2020 05 29;10(1):8765. Epub 2020 May 29.

Department of Sport Medicine and Functional Explorations-CRNH Auvergne, Clermont-Ferrand University Hospital, G. Montpied Hospital, Clermont-Ferrand, F-63000, France.

Metabolic myopathies are muscle disorders caused by a biochemical defect of the skeletal muscle energy system resulting in exercise intolerance. The primary aim of this research was to evaluate the oxygen cost (∆V'O/∆Work-Rate) during incremental exercise in patients with metabolic myopathies as compared with patients with non-metabolic myalgia and healthy subjects. The study groups consisted of eight patients with muscle glycogenoses (one Tarui and seven McArdle diseases), seven patients with a complete and twenty-two patients with a partial myoadenylate deaminase (MAD) deficiency in muscle biopsy, five patients with a respiratory chain deficiency, seventy-three patients with exercise intolerance and normal muscle biopsy (non-metabolic myalgia), and twenty-eight healthy controls. The subjects underwent a cardiopulmonary exercise test (CPX Medgraphics) performed on a bicycle ergometer. Pulmonary V'O was measured breath-by-breath throughout the incremental test. The ∆V'O/∆Work-Rate slope for exercise was determined by linear regression analysis. Lower oxygen consumption (peak percent of predicted, mean ± SD; p < 0.04, one-way ANOVA) was seen in patients with glycogenoses (62.8 ± 10.2%) and respiratory chain defects (70.8 ± 23.3%) compared to patients with non-metabolic myalgia (100.0 ± 15.9%) and control subjects (106.4 ± 23.5%). ∆V'O/∆Work-Rate slope (mLO.min.W) was increased in patients with MAD absent (12.6 ± 1.5), MAD decreased (11.3 ± 1.1), glycogenoses (14.0 ± 2.5), respiratory chain defects (13.1 ± 1.2), and patients with non-metabolic myalgia (11.3 ± 1.3) compared with control subjects (10.2 ± 0.7; p < 0.001, one-way ANOVA). In conclusion, patients with metabolic myopathies display an increased oxygen cost during exercise and therefore can perform less work for a given VO consumption during daily life-submaximal exercises.
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http://dx.doi.org/10.1038/s41598-020-65770-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260200PMC
May 2020

p57-discordant villi in hydropic products of conception: a clinicopathological study of 70 cases.

Hum Pathol 2020 07 6;101:18-30. Epub 2020 May 6.

Department of Pathology, Lyon Sud University Hospital, Hospices Civils de Lyon, Pierre Bénite, Lyon, 69495, France; French Reference Center for Gestational Trophoblastic Diseases, Lyon Sud University Hospital, Hospices Civils de Lyon, Pierre-Bénite, 69495, France. Electronic address:

p57 immunostaining is performed on hydropic products of conception to diagnose hydatidiform moles (HMs), which can progress to gestational trophoblastic neoplasia. Partial hydatidiform mole (PHM) and hydropic abortion (HA) display positive staining in stromal and cytotrophoblastic cells, whereas complete hydatidiform mole (CHM) is characterized by loss of p57 expression in both cell types. In some cases, an aberrant pattern is observed, called discordant p57 expression, with positive cytotrophoblast staining and negative stromal staining, or vice versa. The aim of this study was to describe the clinical, biological, and pathological characteristics of p57-discordant villi (p57DV) and other associated populations in cases of divergent p57 expression and to compare the evolutions of p57DV-associated and classic CHMs. Seventy cases of p57DV diagnosed by referent pathologists were divided into two groups, G1: p57DV ± non-CHM component (n = 22) and G2: p57DV + CHM component (n = 48). p57DV morphology was similar in the two groups. Observation of more than two populations and hybrid villi on p57 immunostaining were significantly more frequent in G2. The clinical, ultrasound, and biological presentations of p57DV-associated and classic CHMs were similar. The initial pathological diagnosis was more frequently incorrect, missing the CHM component, for the p57DV-associated CHMs. Molecular genotyping was informative in seven cases and identified as androgenetic/biparental mosaicism in four cases. These results show that p57DV are a diagnostic challenge for pathologists and that most are associated with a CHM component. However, the clinical management of p57DV-associated CHMs should be the same as that of classic CHMs.
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http://dx.doi.org/10.1016/j.humpath.2020.04.011DOI Listing
July 2020

Evaluation of , and mutational status and microsatellite instability in early colorectal carcinomas invading the (pT1): towards an in-house molecular prognostication for pathologists?

J Clin Pathol 2020 Nov 9;73(11):741-747. Epub 2020 Apr 9.

Pathology, CHRU de Brest, Brest, France

Aim: We aimed to study the prognostic value of , , mutations and microsatellite stable (MSS)/instable (MSI) in the field of colorectal cancer invading the (ie, pT1 colorectal cancer (CRC)).

Methods: We led a case-control study in tumour samples from 60 patients with pT1 CRC with (20 cases) and without (40 cases) metastatic evolution (5 years of follow-up) which were analysed for , , mutations (Idylla testing and next generation sequencing, NGS) and MSS/MSI status (Idylla testing and expression of mismatch repair (MMR) proteins using immunohistochemistry).

Results: mutations were encountered in 11/20 (55%) cases and 21/40 (52.5%) controls (OR=1.11 (0.38 to 3.25), p=0.8548), mutations in 1/20 (5%) cases and 3/40 (7.5%) controls (OR=3.08 (0.62 to 15.39), p=0.1698) and mutations in 3/20 (15%) cases and 6/40 (15%) controls (OR=1.00 (0.22 to 4.5), p=1.00). A MSI status was diagnosed in 3/20 (15%) cases and 5/40 (12.5%) controls (OR=1.2353 (0.26 to 5.79), p=0.7885). Beyond the absence of significant association between the metastatic evolution and any of the studied molecular parameters, we observed a very good agreement between methods analysing and mutations (Kappa value of 0.849 (0.748 to 0.95) between Idylla and NGS) and MSS/MSI (Idylla)-proficient MMR/deficient MMR (immunohistochemistry) status (Kappa value of 1.00).

Conclusion: Although being feasible using the fully automated Idylla method as well as NGS, the molecular testing of and MSS/MSI status does not seem useful for prognostic purpose in the field of pT1 CRC.
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http://dx.doi.org/10.1136/jclinpath-2020-206496DOI Listing
November 2020

EPR17341 and A7H6R pan-TRK Immunohistochemistry Result in Highly Different Staining Patterns in a Series of Salivary Gland Tumors.

Appl Immunohistochem Mol Morphol 2020 10;28(9):719-724

CHRU Brest, Department of Pathology, Brest.

Patients with NTRK-rearranged tumors can be now treated using anti-TRK-targeted therapies making NTRK testing important for treatment choices in patients with advanced cancers. Pan-TRK immunohistochemistry (IHC) could be a valuable premolecular screening strategy in this field. The choice of 1 IHC method or another requires to investigate for intermethod comparison. A high frequency of pan-TRK positive tumors among salivary gland tumors makes these tumors particularly appropriate for such a technical study. In this work, we studied the intermethod agreement for 2 pan-TRK IHC methods (using A7H6R and EPR17341 clones) in a file of salivary gland tumors of different subtypes. Among 71 tumors, pan-TRK IHC was diagnosed as positive (ie, H score ≥5) in 23 and 18 cases using EPR17341 and A7H6R clones, respectively, with a good intermethod agreement in terms of positive/negative result (κ, 0.70) but only a moderate agreement considering the H score values themselves (intraclass correlation coefficient of 0.5399). Beyond the intensity of staining and the percentages of stained cells, major differences were also observed between the location and type of cells stained in positive cases between the 2 clones. The single NTRK-rearranged case in our series (ie, a NTRK3-rearranged salivary secretory carcinoma) was positive with the 2 pan-TRK antibodies. Future studies including molecularly proven NTRK-rearranged tumors remain required to further study and compare the performances of different pan-TRK clones in the screening of NTRK-rearranged cancers but it is now obvious that the staining patterns of A7H6R and EPR17341 clones are not strictly identical.
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http://dx.doi.org/10.1097/PAI.0000000000000825DOI Listing
October 2020

PD-L1 Copy Number Variation Does Not Correlate With PD-L1 Expression or Response to Anti-PD-1 Immunotherapy In Patients With Advanced Melanomas.

Appl Immunohistochem Mol Morphol 2020 02;28(2):161-165

Department of Pathology, CHRU Brest.

Predicting the response to PD-1/PD-L1 immune checkpoint blockade in patients with metastatic melanoma remains challenging. In this study, we have investigated for the relationships between PD-L1 expression, PD-L1 copy number variations, and the response to anti-PD-1 therapies. We studied the formalin-fixed paraffin-embedded tumor samples of 36 patients with metastatic melanoma using PD-L1 immunohistochemistry (IHC) and PD-L1/chromosome 9 fluorescent in situ hybridization (FISH). PD-L1 IHC was positive in 3 patients (8.33%, with >5% stained tumor cells) and PD-L1 FISH test revealed 5 (13.8%) PD-L1 amplifications, 8 (22.2%) PD-L1 gains, and 2 (5.5%) PD-L1 losses. Among 14 responders and 13 nonresponders to anti-PD-1 immunotherapy, we concluded that there was no significant relationship between PD-L1 expression, PD-L1 copy number variations, and the response to anti-PD-1 therapies. In our study, the determination of PD-L1 expression using IHC and PD-L1 copy number using FISH was insufficient to predict the response to PD-1/PD-L1 immune checkpoint blockade in patients with advanced melanomas.
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http://dx.doi.org/10.1097/PAI.0000000000000712DOI Listing
February 2020

Intra-epidermal nerve endings progress within keratinocyte cytoplasmic tunnels in normal human skin.

Exp Dermatol 2020 04 14;29(4):387-392. Epub 2020 Feb 14.

Univ Brest, LIEN, Brest, France.

Intra-epidermal nerve endings, responsible for cutaneous perception of temperature, pain and itch, are conventionally described as passing freely between keratinocytes, from the basal to the granular layers of the epidermis. However, the recent discovery of keratinocyte contribution to cutaneous nociception implies that their anatomical relationships are much more intimate than what has been described so far. By studying human skin biopsies in confocal laser scanning microscopy, we show that intra-epidermal nerve endings are not only closely apposed to keratinocytes, but can also be enwrapped by keratinocyte cytoplasms over their entire circumference and thus progress within keratinocyte tunnels. As keratinocytes must activate intra-epidermal nerve endings to transduce nociceptive information, these findings may help understanding the interactions between the keratinocytes and nervous system. The discovery of these nerve portions progressing in keratinocyte tunnels is a strong argument to consider that contacts between epidermal keratinocytes and intra-epidermal nerve endings are not incidental and argue for the existence of specific and rapid paracrine communication from keratinocytes to sensory neurons.
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http://dx.doi.org/10.1111/exd.14081DOI Listing
April 2020

Correlation of biological parameters with placental parameters and pregnancy outcomes in pre-eclamptic women.

Pregnancy Hypertens 2020 Jan 26;19:61-66. Epub 2019 Dec 26.

Service d'anatomopathologie, CHU de Brest, Hôpital Morvan, Brest Cedex, France; EA 4685 LIEN, Université de Bretagne Occidentale, Brest Cedex, France.

Introduction: Pre-eclampsia is characterized by maternal vascular malperfusion and chronic inflammation in placenta. Our purpose was to investigate the potential correlation of biological parameters with placental parameters and pregnancy outcomes in pre-eclamptic women.

Methods: Pre-eclamptic women were identified by interrogation of the Medical Registry Department in six French maternities between April 2013 and June 2018. Histological parameters in placentas (weight, macroscopic and microscopic lesions), baseline maternal characteristics and pregnancy outcomes (course of pregnancy, newborns' characteristics) were collected. Biological parameters were blood cell ratios (Platelet-to-Lymphocyte Ratio (PLR), Neutrophil-to-Lymphocyte Ratio (NLR)) collected at delivery and Placental growth factor (PlGF) measured in women with an available first trimester serum sample. Correlations of blood cell ratios and PlGF levels with placental parameters and pregnancy outcomes were assessed by Pearson's correlation test for quantitative parameters and by logistic regression analysis for qualitative parameters.

Results: 202 pregnancies were included, among which 68 had a first trimester PlGF quantification. No correlation was found between biological parameters and placental lesions. Low PLR was correlated with low placental weight (r = 0.156, p = 0.036) and with low birth weight (r = 0.179, p = 0.015). Low PlGF was correlated with long time from pre-eclampsia diagnosis to delivery (r = -0.250, p = 0.048).

Conclusions: There is no correlation between biological parameters and placental lesions in pre-eclamptic women. Yet, low PLR at delivery is correlated with low placental and birth weights. Moreover, low first trimester PlGF is correlated with long time from pre-eclampsia diagnosis to delivery.
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http://dx.doi.org/10.1016/j.preghy.2019.12.008DOI Listing
January 2020

Nonpuerperal uterine inversion due to adenomyosis: A case report and a literature review.

Clin Case Rep 2019 Dec 5;7(12):2420-2424. Epub 2019 Nov 5.

Gynecology and Obstetrics Department Brest University Hospital Brest France.

Nonpuerperal uterine inversion is a very rare event. We reported on the first ever case of nonpuerperal uterine inversion due to adenomyosis. Magnetic resonance imaging is recommended in cases with an unusual vaginal mass, so that this possible uterine etiology can be taken into consideration.
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http://dx.doi.org/10.1002/ccr3.2530DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935629PMC
December 2019

[Fetal alcohol exposure: when placenta would help to the early diagnosis of child brain impairments].

Med Sci (Paris) 2019 Nov 17;35(11):859-865. Epub 2019 Dec 17.

Inserm U1245, Équipe 4, Rouen Université, Normandie Université, Rouen, France.

Alcohol consumption during pregnancy constitutes a major cause of neurodevelopmental and behavioral disabilities. Whereas it is possible for clinicians to establish a perinatal diagnosis of fetal alcohol syndrome, the more severe expression of fetal alcohol spectrum disorder (FASD), most FASD children are late or mis-diagnosed due to a lack of clear morphological and neurodevelopmental abnormalities. Several precious years of care are consequently lost. Recent data revealed a functional placenta-brain axis involved in the control of the fetal brain angiogenesis which is impaired by in utero alcohol exposure. Because in the developing fetal brain a correct angiogenesis is required for a correct neurodevelopment, these preclinical and clinical advances pave the way for a new generation of placental biomarkers for early diagnosis of FASD.
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http://dx.doi.org/10.1051/medsci/2019167DOI Listing
November 2019

Clinical, neuroimaging and biochemical findings in patients and patient fibroblasts expressing ten novel GFM1 mutations.

Hum Mutat 2020 02 11;41(2):397-402. Epub 2019 Nov 11.

Laboratory for Genetics of Mitochondrial Disorders, INSERM U1163, Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, Paris, France.

Pathogenic GFM1 variants have been linked to neurological phenotypes with or without liver involvement, but only a few cases have been reported in the literature. Here, we report clinical, biochemical, and neuroimaging findings from nine unrelated children carrying GFM1 variants, 10 of which were not previously reported. All patients presented with neurological involvement-mainly axial hypotonia and dystonia during the neonatal period-with five diagnosed with West syndrome; two children had liver involvement with cytolysis episodes or hepatic failure. While two patients died in infancy, six exhibited a stable clinical course. Brain magnetic resonance imaging showed the involvement of basal ganglia, brainstem, and periventricular white matter. Mutant EFG1 and OXPHOS proteins were decreased in patient's fibroblasts consistent with impaired mitochondrial translation. Thus, we expand the genetic spectrum of GFM1-linked disease and provide detailed clinical profiles of the patients that will improve the diagnostic success for other patients carrying GFM1 mutations.
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http://dx.doi.org/10.1002/humu.23937DOI Listing
February 2020

Testing for fusions in patients with advanced // wild-type melanomas permits to identify patients who could benefit of anti-MEK targeted therapy.

J Clin Pathol 2020 Feb 10;73(2):116-119. Epub 2019 Sep 10.

Department of Pathology, CHRU Brest, Brest, France

Beyond targeted therapy for patients with -mutated melanomas and immunotherapy in patients lacking mutations, anti-MEK therapy has been proposed in patients with advanced melanomas harbouring fusions. fusions diagnosis in patients with advanced melanomas is the subject of the present study. Using fluorescent in situ hybridisation (FISH), we searched for fusions in 74 samples of 66 patients with advanced // wild-type melanomas. We identified 2/66 (3%) patients with fusions in a brain metastasis of one patient and in a lymph node metastasis and in a cutaneous metastasis for the second patient with 90%-95% of tumour nuclei containing isolated 3'- FISH signals. As a result, we conclude that FISH in patients with advanced // wild-type melanomas is a valuable and easy-to-perform test to diagnose fusions and to identify patients who could benefit of anti-MEK targeted therapy.
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http://dx.doi.org/10.1136/jclinpath-2019-206026DOI Listing
February 2020

First trimester serum biomarkers in pregnancies complicated with placental chronic inflammation.

Eur J Obstet Gynecol Reprod Biol 2019 Oct 23;241:119-125. Epub 2019 Aug 23.

Service d'anatomopathologie, CHU de Brest, Hôpital Morvan, Brest Cedex, France; EA 4685 LIEN, Université Bretagne Loire, Brest Cedex, France.

Objective: This study aimed at determining if first trimester serum biomarkers could predict adverse pregnancy outcomes associated with villitis (VUE) and chronic intervillositis of unknown etiology (CIUE).

Study Design: Between January 2013 and June 2018, we selected from pathology department files placentas with VUE or CIUE associated with VUE and control placentas with available first trimester Down syndrome screening results. First trimester PAPP-A and βhCG levels were recorded. Placental growth factor (PlGF) levels were measured in patients with an available first trimester serum sample. Histological findings in placentas, course of pregnancies and newborns' characteristics were compared between cases and controls.

Results: 78 cases and 75 controls were included. In cases, there were 21,8% intrauterine growth restriction (IUGR), 30,8% small for gestational age (SGA). Compared to controls, placentas from cases were smaller (425 g [IQR 370-480] vs 460 g [IQR 390-523], p = 0,03), showed more maternal vascular malperfusion features (79,5% vs 22,7%, p < 0,0001) and more fetal vascular malperfusion features (33,3% vs 12%, p = 0,002). Cases had lower PlGF (29,74 pg/ml [IQR 19,74-36,17] vs 36,37 pg/ml [IQR 27,36-49,13], p = 0,007) and βhCG levels (0,74 MoM [IQR 0,53-1,12] vs 1,00 MoM [IQR 0,72-1,53], p = 0,002) than controls. These differences resulted from lower PlGF levels in VUE patients compared to CIUE associated with VUE patients and controls (28,35 vs 34,05 and 36,37 pg/ml, p = 0,01) and from lower βhCG levels in CIUE associated with VUE patients compared to VUE patients and controls (0,65 vs 0,86 and 1, p = 0,005).

Conclusion: Low first trimester PlGF levels in cases, especially in VUE patients, suggest that reduced angiogenesis is involved in adverse pregnancy outcomes related to VUE.
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http://dx.doi.org/10.1016/j.ejogrb.2019.08.014DOI Listing
October 2019

PD-L1 Immunohistochemistry-Discrepant Results Between Synchronous Tumor Samples May Cause More Treatment Choice Dilemmas Than Molecular Heterogeneity in Patients With Advanced Non-Small Cell Lung Cancers.

Appl Immunohistochem Mol Morphol 2020 07;28(6):437-443

Department of Pathology, CHRU Brest, Brest.

Biomarker analyses have become mandatory for treatment choices in patients with advanced non-small cell lung cancers. PD-L1 expression for immunotherapy as well as oncogenic molecular alterations for targeted therapies must be analyzed in tumor samples. Intersample heterogeneity may cause dilemmas in treatment choices when faced with discrepant biomarker results. We led a retrospective study evaluating the potential impact on guideline-based therapeutic decisions of biomarker analyses performed in several synchronous tumor samples per patient. We collected retrospective data about patients with advanced non-small cell lung cancers, and synchronous tumor paired samples were analyzed for PD-L1 immunohistochemistry (IHC) and oncogene molecular statuses. Among 34 patients, none had a discrepant result between paired samples with respect to oncogene molecular statuses. At the opposite, intersample-discrepant PD-L1 IHC results may have caused treatment choice dilemmas for 6 (17.6%) patients discussing first-line therapy options (ie, immune checkpoint inhibitor therapy versus other systemic therapy with regard to the threshold of ≥50% PD-L1 IHC-positive tumor cells). In addition, for 6 (17.6%) other patients, different PD-L1 IHC results may have also influenced the choice of one therapy or another in second-line therapy (ie, with regard to the threshold of ≥1% PD-L1 IHC-positive tumor cells). In our case series, discrepant results with regard to PD-L1 IHC between paired tumor samples could generate more treatment choice dilemmas than the molecular heterogeneity of oncogenic drivers.
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http://dx.doi.org/10.1097/PAI.0000000000000768DOI Listing
July 2020

Tubular aggregate myopathy and Stormorken syndrome: Mutation spectrum and genotype/phenotype correlation.

Hum Mutat 2020 01 15;41(1):17-37. Epub 2019 Sep 15.

Department of translational medicine and Neurogenetics, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France.

Calcium (Ca ) acts as a ubiquitous second messenger, and normal cell and tissue physiology strictly depends on the precise regulation of Ca entry, storage, and release. Store-operated Ca entry (SOCE) is a major mechanism controlling extracellular Ca entry, and mainly relies on the accurate interplay between the Ca sensor STIM1 and the Ca channel ORAI1. Mutations in STIM1 or ORAI1 result in abnormal Ca homeostasis and are associated with severe human disorders. Recessive loss-of-function mutations impair SOCE and cause combined immunodeficiency, while dominant gain-of-function mutations induce excessive extracellular Ca entry and cause tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK). TAM and STRMK are spectra of the same multisystemic disease characterized by muscle weakness, miosis, thrombocytopenia, hyposplenism, ichthyosis, dyslexia, and short stature. To date, 42 TAM/STRMK families have been described, and here we report five additional families for which we provide clinical, histological, ultrastructural, and genetic data. In this study, we list and review all new and previously reported STIM1 and ORAI1 cases, discuss the pathomechanisms of the mutations based on the known functions and the protein structure of STIM1 and ORAI1, draw a genotype/phenotype correlation, and delineate an efficient screening strategy for the molecular diagnosis of TAM/STRMK.
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http://dx.doi.org/10.1002/humu.23899DOI Listing
January 2020

Foci of Programmed Cell Death-Ligand 1 (PD-L1)-positive Tumor Areas With Tumor-infiltrating Leukocytes (TILs) Evocative of a PD-1/PD-L1-related Adaptive Immune Resistance are Frequent in Merkel Cell Carcinoma.

Appl Immunohistochem Mol Morphol 2020 01;28(1):17-22

Departments of Pathology.

Immune checkpoint inhibitors (ICIs) targeting the programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis have revolutionized the treatment of patients with Merkel cell carcinoma (MCC). To date, no biomarker conditions access to these ICIs in MCC. We compared the tumor microenvironment of PD-L1 and PD-L1 areas in a case series of MCC searching for foci evocative of PD-1/PD-L1 adaptive immune resistance. Among 58 tumors studied on digitalized serial tissue sections, 11 (19%) were concluded as "PD-L1 tumors" [≥1% positive tumor cells (TCs) using PD-L1 immunohistochemistry in the whole tumor slide]. In addition, among the remaining 47 (81%) "PD-L1 tumors," we nevertheless also identified "PD-L1 FOV" (ie, "field of view" of about 3 mm² containing ≥1% positive TCs) in 22 (38%) additional tumors. Comparison between paired "PD-L1 field of view (FOV)" and "PD-L1 FOV" within tumors, and between "PD-L1 tumors" and "PD-L1 tumors", revealed correlations between PD-L1 positivity and the abundance of tumor-infiltrating leukocytes, arguing for areas of PD-1/PD-L1-related adaptive immune resistance at least in some foci of "PD-L1 tumors" and also in "PD-L1 tumors." Tumor heterogeneity consists in a challenge searching for biomarkers able to predict the response/nonresponse to ICIs. Progress in digital pathology and multiplex immunolabeling may permit to overcome this challenge by better analyzing the interactions between TCs and immune and nonimmune non-TCs in the same tissue section. This approach of tumor heterogeneity may contribute to elucidate and to predict why some patients respond impressively to ICIs, whereas others do not.
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http://dx.doi.org/10.1097/PAI.0000000000000792DOI Listing
January 2020

[A NTRK1-rearranged mammary carcinoma].

Ann Pathol 2020 Jan 26;40(1):42-45. Epub 2019 Jun 26.

CHRU Brest, service d'anatomie et cytologie pathologiques, 29220 Brest, France. Electronic address:

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http://dx.doi.org/10.1016/j.annpat.2019.05.009DOI Listing
January 2020
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