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.

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.

[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.

[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.

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).

[Placental features in intrauterine growth retardation]. / L'examen du placenta dans le retard de croissance intra-utérin.

OBJECTIVE: To evaluate the placental pathological patterns in intrauterine growth restriction (IUGR) in order to determinate which placental lesions are linked to clinically significant anomalies and to predict the child outcome and the mother risk of recurrence. METHODS: Bibliographic review using the Medline and PubMed databases. RESULTS: Placental studies designed in order to provide macroscopic and microscopic information about the mechanism of IUGR are not numerous and retrospective; files are most of the time very small. Meta-analyses are an exception. Maternal vascular underperfusion is admitted to be the most frequent etiology of IUGR. None of the associated placental lesions is pathognomonic but the combination of a number of placental changes is. Low placental weight and microscopic lesions are more frequent than gross anomalies. Other pathophysiological groups of placental pathologies are reported to be linked to fetal growth restriction: umbilical cord anomalies, fetal thrombotic vasculopathy, chronic villitis of unknown etiology and chronic histiocytic intervillositis. Some placental lesions have been reported associated with infants with neurologic impairment and can be as different as vascular lesions, villitis of unknown origin with stem villi vasculopathy, fetal thrombotic vasculopathy or umbilical cord anomalies. However, there is no direct link between a type of placental pathology and the infant's adverse outcome or his neurological risk. The maternal risk of recurrence is not easily predictable except for the chronic histiocytic intervillositis in which the estimated recurrence rate is very high. CONCLUSION: Placental morphological findings can play a critical role in explaining the IUGR. They always need to be correlated with clinical findings.

Array-CGH Analysis Suggests Genetic Heterogeneity in Rhombencephalosynapsis.

Rhombencephalosynapsis is an uncommon, but increasingly recognized, cerebellar malformation defined as vermian agenesis with fusion of the hemispheres. The embryologic and genetic mechanisms involved are still unknown, and to date, no animal models are available. In the present study, we used Agilent oligonucleotide arrays in a large series of 57 affected patients to detect candidate genes. Four different unbalanced rearrangements were detected: a 16p11.2 deletion, a 14q12q21.2 deletion, an unbalanced translocation t(2p;10q), and a 16p13.11 microdeletion containing 2 candidate genes. These genes were further investigated by sequencing and in situ hybridization. This first microarray screening of a rhombencephalosynapsis series suggests that there may be heterogeneous genetic causes.

[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.

[Neuropathies associated with monoclonal IgM anti-MAG antibodies]. / Neuropathies associées à une IgM monoclonale anti-MAG.

Monoclonal IgM anti-MAG associated peripheral neuropathies are part of demyelinating dysimmune peripheral neuropathies. The hematological disease probably does not influence the outcome of the neuropathy. Neuropathies associated with IgM anti-MAG antibodies are predominantly sensory and distal polyneuropathies associated with ataxia, unsteadiness and tremor. The neurophysiological features include a symmetric sensorimotor demyelinating neuropathy with more slowing of conduction in the distal than in the proximal nerve segments, a length-dependence, and a variable degree of denervation. High titers of IgM anti-MAG antibodies confirm the diagnosis. The natural history is mostly slow with mild to moderate functional impairment. However, some patients have a faster evolution associated with a more severe handicap. Immunotherapies studies have failed to demonstrate significant efficacy of these treatments. Furthermore, severe adverse effects are not uncommon with any of these therapies. Thus, the risk of possible severe adverse effects must be balanced against any possible benefits. More research is needed to improve the management of anti-MAG neuropathies: research on treatment, on prognostic factors, and development of specific assessment scales adapted to the particularities of anti-MAG neuropathies.

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.

[Placenta and preeclampsia: relationships between anatomical lesions and clinical symptoms]. / Placenta de la prééclampsie : lésions anatomiques et corrélations anatomocliniques.

The histopathological examination of the placenta is part of the investigational workout since it is a convenient method of examining the central organ involved in the disease process. Characteristic lesions are the vascular placental lesions, and even though their discovery is neither necessary nor specific, they become all the more suggestive of the disease as they are found to be numerous. These vascular lesions are characterized by a microscopic involvement of the basal layer also termed atherosis, associated with uteroplacental artery displasia and its consequences: Infarction, retroplacental haematoma plus all other microscopic injuries of the placenta. These are mainly found in the severe forms of the disease and are usually associated with a placental underdevelopment and IUGR.

Fatal congenital tuberculosis due to a Beijing strain in a premature neonate.

Congenital tuberculosis (TB) remains a rare disease but is fatal if untreated. Early detection is difficult because of the non-specific nature of the symptoms in TB during pregnancy and infancy. This report summarizes a case of congenital TB in a very premature infant, born at 25 weeks gestation. Miliary TB was diagnosed in the mother when the neonate was 20 days old. Antituberculous therapy allowed a rapid improvement in the mother. The infant died at 27 days old. A Beijing genotype strain of Mycobacterium tuberculosis was isolated both in the mother, from pulmonary and urine specimens, and in the infant, from peritoneal fluid.

Severe epilepsy as the major symptom of new mutations in the mitochondrial tRNA(Phe) gene.

OBJECTIVE: To present 2 families with maternally inherited severe epilepsy as the main symptom of mitochondrial disease due to point mutations at position 616 in the mitochondrial tRNA(Phe) (MT-TF) gene. METHODS: Histologic stainings were performed on skeletal muscle slices from the 2 index patients. Oxidative phosphorylation activity was measured by oxygraphic and spectrophotometric methods. The patients' complete mitochondrial DNA (mtDNA) and the relevant mtDNA region in maternal relatives were sequenced. RESULTS: Muscle histology showed only decreased overall COX staining, while a combined respiratory chain defect, most severely affecting complex IV, was noted in both patients' skeletal muscle. Sequencing of the mtDNA revealed in both patients a mutation at position 616 in the MT-TF gene (T>C or T>G). These mutations disrupt a base pair in the anticodon stem at a highly conserved position. They were apparently homoplasmic in both patients, and had different heteroplasmy levels in the investigated maternal relatives. CONCLUSIONS: Deleterious mutations in the mitochondrial tRNA(Phe) may solely manifest with epilepsy when segregating to homoplasmy. They may be overlooked in the absence of lactate accumulation and typical mosaic mitochondrial defects in muscle.

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.