Overexpression of certain transient receptor potential and Orai channels in prostate cancer is associated with decreased risk of systemic recurrence after radical prostatectomy.

BACKGROUND: Several studies had suggested the potential role of calcium signaling in prostate cancer (PCa) prognosis and agressiveness. We aimed to investigate selected proteins contributing to calcium (Ca2+ ) signaling, (Orai, stromal interaction molecule (STIM), and transient receptor potential (TRP) channels) and involved in cancer hallmarks, as independent predictors of systemic recurrence after radical prostatectomy (RP). METHODS: A case-control study including 112 patients with clinically localized PCa treated by RP between 2002 and 2009 and with at least 6-years' follow-up. Patients were divided into two groups according to the absence or presence of systemic recurrence. Expression levels of 10 proteins involved in Ca2+ signaling (TRPC1, TRPC4, TRPV5, TRPV6, TRPM8, STIM1, STIM2, Orai1, Orai2, and Orai3), were assessed by immunohistochemistry using tissue microarrays (TMAs) constructed from paraffin-embedded PCa specimens. The level of expression of the various transcripts in PCa was assessed using quantitative polymerase chain reaction (qPCR) analysis. RNA samples for qPCR were obtained from fresh frozen tissue samples of PCa after laser capture microdissection on RP specimens. Relative gene expression was analyzed using the 2-▵▵Ct method. RESULTS: Multivariate analysis showed that increased expression of TRPC1, TRPC4, TRPV5, TRPV6, TRPM8, and Orai2 was significantly associated with a lower risk of systemic recurrence after RP, independently of the prostate-specific antigen (PSA) level, percentage of positive biopsies, and surgical margin (SM) status (P = .007, P = .01, P < .001, P = .0065, P = .007, and P = .01, respectively). For TRPC4, TRPV5, and TRPV6, this association was also independent of Gleason score and pT stage. Moreover, overexpression of TRPV6 and Orai2 was significantly associated with longer time to recurrence after RP (P = .048 and .023, respectively). Overexpression of TRPC4, TRPV5, TRPV6, and Orai2 transcripts was observed in group R- (3.71-, 5.7-, 1.14-, and 2.65-fold increase, respectively). CONCLUSIONS: This is the first study to suggest the independent prognostic value of certain proteins involved in Ca2+ influx in systemic recurrence after RP: overexpression of TRPC1, TRPC4, TRPV5, TRPV6, TRPM8, and Orai2 is associated with a lower risk of systemic recurrence. TRPC4, TRPV5, and TRPV6 appear to be particularly interesting, as they are independent of the five commonly used predictive factors, that is, PSA, percentage of positive biopsies, SM status, Gleason score, and pT stage.

Exercise testing-based algorithms to diagnose McArdle disease and MAD defects.

OBJECTIVE: As exercise intolerance and exercise-induced myalgia are commonly encountered in metabolic myopathies, functional screening tests are commonly used during the diagnostic work-up. Our objective was to evaluate the accuracy of isometric handgrip test (IHT) and progressive cycle ergometer test (PCET) to identify McArdle disease and myoadenylate deaminase (MAD) deficiency and to propose diagnostic algorithms using exercise-induced lactate and ammonia variations. METHODS: A prospective sample of 46 patients underwent an IHT and a PCET as part of their exercise-induced myalgia and intolerance evaluation. The two diagnostics tests were compared against the results of muscle biopsy and/or the presence of mutations in PYGM. A total of 6 patients had McArdle disease, 5 a complete MAD deficiency (MAD absent), 12 a partial MAD deficiency, and 23 patients had normal muscle biopsy and acylcarnitine profile (disease control). RESULTS: The two functional tests could diagnose all McArdle patients with statistical significance, combining a low lactate variation (IHT: <1 mmol/L, AUC = 0.963, P < .0001; PCET: <1 mmol/L, AUC = 0.990, P < .0001) and a large ammonia variation (IHT: >100 µmol/L, AUC = 0.944, P = .0005; PCET: >20 µmol/L, AUC = 1). PCET was superior to IHT for MAD absent diagnosis, combining very low ammonia variation (<10 µmol/L, AUC = 0.910, P < .0001) and moderate lactate variation (>1 mmol/L). CONCLUSIONS: PCET-based decision tree was more accurate than IHT, with respective generalized squared correlations of 0.796 vs 0.668. IHT and PCET are both interesting diagnostic tools to identify McArdle disease, whereas cycle ergometer exercise is more efficient to diagnose complete MAD deficiency.

[Exercise-induced muscle pain due to phosphofrutokinase deficiency: Diagnostic contribution of metabolic explorations (exercise tests, 31P-nuclear magnetic resonance spectroscopy)]. / Intolérance musculaire à l'effort par déficit en phosphofructokinase : apport au diagnostic du bilan métabolique musculaire (tests d'effort, spectroscopie RMN du P31).

INTRODUCTION: Muscle phosphofructokinase deficiency, the seventh member of the glycogen storage diseases family, is also called Tarui's disease (GSD VII). METHODS: We studied two patients in two unrelated families with Tarui's disease, analyzing clinical features, CK level, EMG, muscle biopsy findings and molecular genetics features. Metabolic muscle explorations (forearm ischemic exercise test [FIET]; bicycle ergometer exercise test [EE]; 31P-nuclear magnetic resonance spectroscopy of calf muscle [31P-NMR-S]) are performed as appropriate. RESULTS: Two patients, a 47-year-old man and a 38-year-old woman, complained of exercise-induced fatigue since childhood. The neurological examination was normal or showed light weakness. Laboratory studies showed increased CPK, serum uric acid and reticulocyte count without anemia. There was no increase in the blood lactate level during the FIET or the EE although there was a light increase in the respiratory exchange ratio during the EE. 31P-NMR-S revealed no intracellular acidification or accumulated intermediates such as phosphorylated monoesters (PME) known to be pathognomic for GSD VII. Two new mutations were identified. DISCUSSION: FIET and EE were non-contributive to diagnosis, but 31P-NMR provided a characteristic spectra of Tarui's disease, in agreement with phosphofructokinase activity level in erythrocytes. Muscle biopsy does not always provide useful information for diagnosis. In these two cases, genetic studies failed to establish a genotype-phenotype correlation. CONCLUSION: The search for phosphofructokinase deficiency should be continued throughout life in adults experiencing fatigability or weakness because of the severe disability for daily life activities caused by the late onset form.

Rationale and design of the multicentric, double-blind, double-placebo, randomized trial APrepitant versus HYdroxyzine in association with cytoreductive treatments for patients with myeloproliferative neoplasia suffering from Persistent Aquagenic Pruritus. Trial acronym: APHYPAP.

BACKGROUND: Aquagenic pruritus (AP), an intense sensation of scratching induced after water contact, is the most troublesome aspect of BCR-ABL1-negative myeloproliferative neoplasms (MPNs). Mostly described in polycythemia vera (PV, ~ 40%), it is also present in essential thrombocythemia (ET) and primary myelofibrosis (PMF) (10%). Even if this symptom can decrease or disappear under cytoreductive treatments, 30% of treated MPN patients still persist with a real impact on the quality of life (QoL). Because its pathophysiology is poorly understood, efficient symptomatic treatments of AP are missing. The neuropeptide substance P (SP) plays a crucial role in the induction of pruritus. Several studies showed the efficacy of aprepitant, an antagonist of SP receptor (NK-1R), in the treatment of chronic pruritus but never evaluated in AP. The objectives of APHYPAP are twofold: a clinical aim with the evaluation of the efficacy of two drugs in the treatment of a persistent AP for MPN patients and a biological aim to find clues to elucidate AP pathophysiology. METHODS/DESIGN: A multicentric, double-blind, double-placebo, randomized study will include 80 patients with MPN (PV or ET or PMF) treated since at least 6 months for their hemopathy but suffering from a persistent AP (VAS intensity ≥6/10). Patients will be randomized between aprepitant (80 mg daily) + placebo to match to hydroxyzine OR hydroxyzine (25 mg daily) + placebo to match to aprepitant for 14 days. At D0, baseline information will be collected and drugs dispense. Outcome measures will be assessed at D15, D30, D45, and D60. The primary study endpoint will be the reduction of pruritus intensity below (or equal) at 3/10 on VAS at D15. Secondary outcome measures will include the number of patients with a reduction or cessation of AP at D15 or D60; evaluation of QoL and AP characteristics at D0, D15, D30, D45, and D60 with MPN-SAF and AP questionnaires, respectively; modification of plasmatic concentrations of cytokines and neuropeptides at D0, D15, D30, and D60; and modification of epidermal innervation density and pruriceptor expression at D0 and D15. DISCUSSION: The APHYPAP trial will examine the efficacy of aprepitant vs hydroxyzine (reference treatment for AP) to treat persistent AP in MPN patients. The primary objective is to demonstrate the superiority of aprepitant vs hydroxyzine to treat persistent AP of MPN patients. The treatment received will be considered efficient if the AP intensity will be reduced at 3/10 or below on VAS after 14 days of treatment. The results of this study may provide a new treatment option for this troublesome symptom and also give us more insights in the pathophysiology understanding of AP. TRIAL REGISTRATION: APHYPAP. NCT03808805 , first posted: January 18, 2019; last update posted: June 10, 2021. EudraCT 2018-090426-66.

Late-onset cervicoscapular muscle atrophy and weakness after radiotherapy for Hodgkin disease: a case series.

Patients with cervical or mediastinal Hodgkin disease (HD) classically underwent chemotherapy plus extended-field radiation therapy. We report six patients who gradually developed severe atrophy and weakness of cervical paraspinal and shoulder girdle muscles 5-30 years after mantle irradiation for HD. Although clinical presentation was uniform, including a dropped head syndrome, electrophysiological and pathological findings were rather heterogeneous. Either neurogenic or myogenic processes may be involved and sometimes combined. We discuss the pathophysiological mechanisms underlying these cervicoscapular motor complications of mantle irradiation in HD.

Nemaline bodies as unique pathological feature in the course of treated dermatomyositis.

Dermatomyositis was diagnosed on clinical and muscle histological criteria in a 42-year-old woman. Despite treatment, the patient complained of deterioration of her muscle condition. Since her symptoms were discordant with the rest of the data, muscle biopsy was performed and disclosed rod-bearing non-atrophic fibers as the unique and predominant pathological feature. Their significance is examined in this paper.

[Small fiber neuropathy]. / La neuropathie des petites fibres.

Small fiber neuropathy (SFN) is still unknown. Characterised by neuropathic pain, it typically begins by burning feet, but could take many other expression. SFN affects the thinly myelinated Aδ and unmyelinated C-fibers, by an inherited or acquired mechanism, which could lead to paresthesia, thermoalgic disorder or autonomic dysfunction. Recent studies suggest the preponderant role of ion channels such as Nav1.7. Furthermore, erythromelalgia or burning mouth syndrome are now recognized as real SFN. Various aetiologies of SFN are described. It could be isolated or associated with diabetes, impaired glucose metabolism, vitamin deficiency, alcohol, auto-immune disease, sarcoidosis etc. Several mutations have recently been identified, like Nav1.7 channel leading to channelopathies. Diagnostic management is based primarily on clinical examination and demonstration of small fiber dysfunction. Laser evoked potentials, Sudoscan®, cutaneous biopsy are the main test, but had a difficult access. Treatment is based on multidisciplinary management, combining symptomatic treatment, psychological management and treatment of an associated etiology.

Molecular heterogeneity in fetal forms of type II lissencephaly.

Type II lissencephaly (type II LIS) is a group of autosomal recessive congenital muscular dystrophies (CMD) associated with defects in alpha-DG O-glycosylation, which comprises Walker-Warburg syndrome, Fukuyama cerebral and muscular dystrophy, or muscle-eye-brain disease. The most severe forms of these diseases often have a fetal presentation and lead to a pregnancy termination. We report here the first molecular study on fetal type II LIS in a series of 47 fetuses from 41 unrelated families. Sequencing of the different genes known to be involved in alpha-DG O-glycosylation allowed the molecular diagnosis in 22 families: involvement of POMT1 was demonstrated in 32% of cases, whereas POMGNT1 and POMT2 were incriminated in 15% and in 7% of cases, respectively. We found 30 different mutations in these three genes, 25 were described herein for the first time, 15 in POMT1, and five in POMT2 and POMGNT1. Despite sequencing of FKRP, FCMD, and LARGE, no definitive molecular diagnosis could be made for the other half of our cases. Preliminary results concerning genotype-phenotype correlations show that the choice of the first gene sequenced should depend on the clinical severity of the type II LIS; POMT1 and POMT2 for severest clinical picture and POMGNT1 for milder disease. The other genes, FKRP, FCMD, and LARGE, seem not to be implicated in the fetal form of CMD.

[Anti-HMG-CoA reductase necrotizing myopathy: A report of 4 cases]. / Myopathies nécrosantes à anti-HMG-CoA réductase : à propos de 4 observations.

INTRODUCTION: Anti-3-hydroxy-3-méthylglutaryl-coenzyme A reductase antibody-associated necrotizing autoimmune myopathy has been recently described (2011). This myopathy is distinct from statin toxic myopathy. Our objective is to report on the clinical and para-clinical characteristics of this myopathy and to show the difficulties of therapeutic care. CASE REPORTS: We describe 4 cases of patients followed-up in Brittany, France. All data have been analyzed retrospectively. The mean age of our patients was 59.5 years, with a sex ratio of 1. The clinical presentation was homogeneous, with a subacute painful proximal and symmetrical weakness, without extra-muscular involvement. Other presentations have been described (including pseudo-dystrophic presentation). All patients had a previous statin medication (mean duration of 3.75 years) although this criteria is not a requisite. All patients had high levels of creatine kinase and abnormal electromyographic examination. The pathological pattern on muscular biopsy was a necrotizing myopathy without significant inflammatory cells infiltration. Cardio-respiratory function was normal and no associated neoplasia was found. Over the follow-up, we observed a marked corticosteroid-dependence, not improved by immunosuppressive drugs (azathioprine and methotrexate). The benefit of intravenous immunoglobulin was clear with, sometimes, prolonged responses. CONCLUSION: An early diagnosis of this myopathy is necessary in order to introduce an immunotherapy associated with a close monitoring. The therapeutic strategy (within which the stead of intravenous immunoglobulin seems increased) remains to be defined and long-term prospective studies are thus needed.

Cerebellar-pulmonary embolism, cause of death in the newborn.

A 28-year-old woman delivered twin girls. The first twin was delivered without any difficulty. The head of the second twin failed to descend with pushing. A special kind of obstetrical forceps, Thierry's spatulas, were used to extract the second twin in the occipito-posterior vertex position. She was declared dead after recording Apgar scores of 0 and 0 and after 35 min of resuscitation. An autopsy was performed for medico-legal reasons. Macroscopic examination of the brain showed a small area of leptomeningeal haemorrhage in the left sylvian fossa and the base of the brain. Histopathological studies demonstrated cerebellar tissue emboli in meningeal and pulmonary arteries. Excessive pressure on the suboccipital region during delivery can cause traumatic separation of the occipital chondral junctions, which may lead to separation of the occipital squama from lateral parts of the occipital bones. The inferior part of the occipital squama is displaced forward and upward into the posterior fossa. This produces tearing of the duramater and occipital sinuses leading to leptomeningeal haemorrhage in the posterior cranial fossa, often associated with cerebellar lesions. Major stretching and tearing of the posterior aspect of tentorium cerebelli in contact with the sinuses and the cerebellar cortex may also occur, inducing slight movement of the occipital bones and subsequent emboli. This case study is that of a newborn death due to pulmonary cerebellar tissue embolism occurring during delivery with Thierry's forceps, which are considered less traumatic to the foetal cranium. A review of the literature identified 17 other published cases. In difficult deliveries this pathology should sought carefully. Brain, lung and placenta tissue sections must be studied.

Fetal aqueductal glioneuronal hamartoma: a clinicopathological and physiopathological study of three cases.

UNLABELLED: Fetal hydrocephalus due to aqueductal stenosis is classified into two main groups: congenital (X-linked, atresia, septa and forking) and acquired (post-infectious or post-hemorrhagic, gliosis and tumors). MATERIAL AND METHODS: We report three fetal cases presenting with severe hydrocephalus, two of which being apparently sporadic, and the third possibly inherited. On macroscopic examination, no associated malformations were identified, either craniofacial dysmorphy, or visceral abnormalities. Neuropathological study revealed massive hydrocephalus caused by narrowing of the Aqueduct of Sylvius. Histological examination evidenced a nodular, well-demarcated mass producing into the aqueductal lumen, and containing numerous immature proliferating glioneuronal cells. Immunohistochemical analyses did not suggest a developmental abnormality of the subcommissural organ but rather a hamartomatous malformative process. RESULTS: Hamartoma of the posterior fossa has been rarely reported. Post-natal cases have been described in the cerebello-pontine angle or in the quadrigeminal plate, and have always been diagnosed as pilocytic or low-grade astrocytomas. In our cases, the lesions could be related to so-called pencil glioma, sometimes associated with type 1 neurofibromatosis and, to our knowledge, have never been described prior to birth. The occurrence during fetal life and the progressive maturation of the nodules are more likely in favor of a hamartomatous process. CONCLUSION: Even though they could sporadically occur, an accurate genetic counseling should be required in order to ensure that there is no familial history of Recklinghausen disease, and to provide a more precise evaluation of recurrence risk.

Fetal growth restriction and intra-uterine growth restriction: guidelines for clinical practice from the French College of Gynaecologists and Obstetricians.

Small for gestational age (SGA) is defined by weight (in utero estimated fetal weight or birth weight) below the 10th percentile (professional consensus). Severe SGA is SGA below the third percentile (professional consensus). Fetal growth restriction (FGR) or intra-uterine growth restriction (IUGR) usually correspond with SGA associated with evidence indicating abnormal growth (with or without abnormal uterine and/or umbilical Doppler): arrest of growth or a shift in its rate measured longitudinally (at least two measurements, 3 weeks apart) (professional consensus). More rarely, they may correspond with inadequate growth, with weight near the 10th percentile without being SGA (LE2). Birthweight curves are not appropriate for the identification of SGA at early gestational ages because of the disorders associated with preterm delivery. In utero curves represent physiological growth more reliably (LE2). In diagnostic (or reference) ultrasound, the use of growth curves adjusted for maternal height and weight, parity and fetal sex is recommended (professional consensus). In screening, the use of adjusted curves must be assessed in pilot regions to determine the schedule for their subsequent introduction at national level. This choice is based on evidence of feasibility and the absence of any proven benefits for individualized curves for perinatal health in the general population (professional consensus). Children born with FGR or SGA have a higher risk of minor cognitive deficits, school problems and metabolic syndrome in adulthood. The role of preterm delivery in these complications is linked. The measurement of fundal height remains relevant to screening after 22 weeks of gestation (Grade C). The biometric ultrasound indicators recommended are: head circumference (HC), abdominal circumference (AC) and femur length (FL) (professional consensus). They allow calculation of estimated fetal weight (EFW), which, with AC, is the most relevant indicator for screening. Hadlock's EFW formula with three indicators (HC, AC and FL) should ideally be used (Grade B). The ultrasound report must specify the percentile of the EFW (Grade C). Verification of the date of conception is essential. It is based on the crown-rump length between 11 and 14 weeks of gestation (Grade A). The HC, AC and FL measurements must be related to the appropriate reference curves (professional consensus); those modelled from College Francais d'Echographie Fetale data are recommended because they are multicentere French curves (professional consensus). Whether or not a work-up should be performed and its content depend on the context (gestational age, severity of biometric abnormalities, other ultrasound data, parents' wishes, etc.) (professional consensus). Such a work-up only makes sense if it might modify pregnancy management and, in particular, if it has the potential to reduce perinatal and long-term morbidity and mortality (professional consensus). The use of umbilical artery Doppler velocimetry is associated with better newborn health status in populations at risk, especially in those with FGR (Grade A). This Doppler examination must be the first-line tool for surveillance of fetuses with SGA and FGR (professional consensus). A course of corticosteroids is recommended for women with an FGR fetus, and for whom delivery before 34 weeks of gestation is envisaged (Grade C). Magnesium sulphate should be prescribed for preterm deliveries before 32-33 weeks of gestation (Grade A). The same management should apply for preterm FGR deliveries (Grade C). In cases of FGR, fetal growth must be monitored at intervals of no less than 2 weeks, and ideally 3 weeks (professional consensus). Referral to a Level IIb or III maternity ward must be proposed in cases of EFW <1500g, potential birth before 32-34 weeks of gestation (absent or reversed umbilical end-diastolic flow, abnormal venous Doppler) or a fetal disease associated with any of these (professional consensus). Systematic caesarean deliveries for FGR are not recommended (Grade C). In cases of vaginal delivery, fetal heart rate must be monitored continuously during labour, and any delay before intervention must be faster than in low-risk situations (professional consensus). Regional anaesthesia is preferred in trials of vaginal delivery, as in planned caesareans. Morbidity and mortality are higher in SGA newborns than in normal-weight newborns of the same gestational age (LE3). The risk of neonatal mortality is two to four times higher in SGA newborns than in non-SGA preterm and full-term infants (LE2). Initial management of an SGA newborn includes combatting hypothermia by maintaining the heat chain (survival blanket), ventilation with a pressure-controlled insufflator, if necessary, and close monitoring of capillary blood glucose (professional consensus). Testing for antiphospholipids (anticardiolipin, circulating anticoagulant, anti-beta2-GP1) is recommended in women with previous severe FGR (below third percentile) that led to birth before 34 weeks of gestation (professional consensus). It is recommended that aspirin should be prescribed to women with a history of pre-eclampsia before 34 weeks of gestation, and/or FGR below the fifth percentile with a probable vascular origin (professional consensus). Aspirin must be taken in the evening or at least 8h after awakening (Grade B), before 16 weeks of gestation, at a dose of 100-160mg/day (Grade A).

[The fetal head: from screening to diagnosis]. / Le pôle céphalique foetal: du dépistage au diagnostic.

The implementation of a prenatal screening ultrasound program to the general population requires a few rules. The sonographers must be adequately trained and the required imaging planes of the fetal head must be easy to acquire and be readily reproducible irrespective of the technology used. Screening for the presence of a potential local or global anomaly can be mainly established from a reference image. The diagnosis of an anomaly is confirmed from a different medical approach and is usually done during the second trimester (21 weeks GA).

[Sudden death of a two-year-old boy with influenza A virus infection: study of an autopsy case]. / Décès brutal et infection à virus Influenza A chez un enfant de deux ans: étude d'un cas autopsique.

UNLABELLED: Influenza A virus infections are common in childhood and infancy and are often underdiagnosed while serious or lethal forms are rare. CASE-REPORT: We describe a case of sudden death in a two-year-old boy. Pathologic findings at autopsy were consistent with Myxovirus influenzae A virus infection and the virus was isolated by post mortem PCR. CONCLUSION: In the case of sudden death in infants, especially if pathologic findings are compatible with a viral infection, PCR may allow identification of the causative virus.

[Primary pure carcinoid tumor of the breast: a case report. Review of the literature]. / Tumeur carcinoïde primitive pure du sein: une observation. Revue de la littérature.

The authors present a case of primary pure carcinoid tumour of the breast and point out how rare it is and how they made their diagnosis mainly by histology. A review of the literature makes it possible to assess the prognosis which should be good and they also describe the anatomo-pathological findings in these tumours. Finally these tumours show a strange histogenesis which if it is understood makes it possible to understand certain processes of cellular differentiation in breast tissue.