[Primitive myxoid melanoma: An unusual histological aspect]. / Mélanome myxoïde primitif : une forme histologique inhabituelle.

BACKGROUND: Myxoid melanoma is a rare variant of melanoma that must be recognised. Herein we describe a new metastatic case. PATIENTS AND METHODS: A 78-year-old woman consulted for a firm, pinkish nodule measuring 25mm and present for six months on her left leg. Analysis of the biopsy revealed achromic fusiform tumour cells separated by large myxoid plaques. Labeling of SOX10, HMB45 and PS100 was diffuse and of moderate to strong intensity. A diagnosis of myxoid melanoma was considered, with Breslow thickness of 9mm. Surgery was carried out with a 2-cm margin and confirmed the diagnosis. Dermatological follow-up at one year revealed metastatic spread to the ganglia, pleura, liver and bone. DISCUSSION: Few cases of primary myxoid melanoma have been described, and the condition is probably underdiagnosed. The classic clinical presentation of this condition consists of a solitary achromic nodule found chiefly on the limbs. The microscopic appearance is relatively non-specific. Immunohistochemical analysis may indicate melanocytic involvement: cells exhibit expression of SOX10, diffuse expression of protein S100, and less consistent and more variable expression of HMB45. The increasingly common use of anti-SOX10 is of value since it is expressed in the nucleus of melanocytes. Mastocytes and TGF-ß secretion appear to be involved in myxoid stroma production. In the absence of specific codification, management of myxoid melanoma is comparable to that of other types of melanoma. There is uncertainty about the prognosis, with the involvement of TGF-ß possibly indicating the aggressive potential of this type of tumour.

Severe COVID-19 and its cardiopulmonary effects 6 and 18 months after hospital discharge.

Introduction: SARS-CoV-2 infection affects the cardiopulmonary system in the acute as well as long-term phase. The aim of the present study was to comprehensively assess symptoms and possible long-term impairments 6 and 18 months after hospitalization for severe COVID-19 infection. Methods: This prospective registry included patients with PCR-confirmed COVID-19 infection requiring hospitalization. Follow-up approximately 6 months post discharge comprised a detailed patient history, clinical examination, transthoracic echocardiography, electrocardiogram, cardiac magnetic resonance imaging (cMRI), chest computed tomography (CT) scan, pulmonary function test (PFT), six-minute walk test (6MWT) and a laboratory panel. At the time of the second follow-up visit at 18 months, patients without pathologic findings during the first study visit were contacted by phone to inquire about the course of their symptoms. In all other patients all initial examinations were repeated. Results: Two hundred Patients, who were hospitalized for COVID-19, were contacted by phone and were recruited for the study. Due to dropouts the second study visit was performed in 170 patients. A comparison between the two study visits at 6 and 18 months post discharge showed the following results: Six months after discharge, 73% and 18 months after discharge 52% fulfilled the criteria for Long COVID with fatigue being the most common symptom (49%). Echocardiography at 6 months post discharge showed an impaired left ventricular function in 8% of which 80% returned to normal. Six months post discharge, cMRI revealed pericardial effusion in 17% which resolved in 47% of the 15 patients who underwent a control cMRI. Signs of peri- or myocarditis were present in 5% of the patients and were resolved in all 4 patients who attended control studies. At 6 months, chest CT scans identified post-infectious residues in 24%. In the 25 repeated chest CT scans 20% showed full recovery. Length of in-hospital stay was identified as a significant predictor for persisting Long COVID (95% CI: 1.005-1.12, p = 0.03). Conclusion: Comparing 6 to 18 months, the prevalence of Long COVID decreased over time, but a high symptom burden remained. Structural and functional abnormalities were less frequent than the portrayed symptoms, and it thus remains a challenge to substantiate the symptoms.

Effects of enzyme replacement therapy on cardiac function in classic infantile Pompe disease.

OBJECTIVE: Patients with classic infantile Pompe disease are born with a hypertrophic cardiomyopathy, which resolves after treatment with Enzyme replacement therapy (ERT). We aimed to assess potential deterioration of cardiac function over time using myocardial deformation analysis. METHODS: Twenty-seven patients treated with ERT were included. Cardiac function was assessed at regular time intervals (before and after start with ERT) using conventional echocardiography and myocardial deformation analysis. Separate linear mixed effect models were used to asses temporal changes within the first year and the long-term follow-up period. Echocardiograms of 103 healthy children served as controls. RESULTS: A total of 192 echocardiograms were analyzed. Median follow-up was 9.9 years (IQR: 7.5-16.3). Mean LVMI before start of ERT was increased 292.3 g/m2 (95% CI: 202.8-381.8, mean Z-score + 7.6) and normalized after 1 year of ERT 87.3 g/m2 (CI: 67.5-107.1, mean Z-score + 0.8, p < 0.001). Mean shortening fraction was within normal limits before start of ERT, up to 22 years of follow-up. Cardiac function measured by RV/LV longitudinal, and circumferential strain was diminished before start of ERT, but normalized (<-16%) within 1 year after start of ERT, and all remained within normal limits during follow-up. Only LV circumferential strain gradually worsened in Pompe patients (+0.24%/year) during follow-up compared to controls. LV longitudinal strain was diminished in Pompe patients, but did not change significantly over time compared to controls. CONCLUSION: Cardiac function, measured using myocardial deformation analysis, normalizes after start of ERT, and seems to remain stable over a median follow-up period of 9.9 years.

Facial-muscle weakness, speech disorders and dysphagia are common in patients with classic infantile Pompe disease treated with enzyme therapy.

Classic infantile Pompe disease is an inherited generalized glycogen storage disorder caused by deficiency of lysosomal acid α-glucosidase. If left untreated, patients die before one year of age. Although enzyme-replacement therapy (ERT) has significantly prolonged lifespan, it has also revealed new aspects of the disease. For up to 11 years, we investigated the frequency and consequences of facial-muscle weakness, speech disorders and dysphagia in long-term survivors. Sequential photographs were used to determine the timing and severity of facial-muscle weakness. Using standardized articulation tests and fibreoptic endoscopic evaluation of swallowing, we investigated speech and swallowing function in a subset of patients. This study included 11 patients with classic infantile Pompe disease. Median age at the start of ERT was 2.4 months (range 0.1-8.3 months), and median age at the end of the study was 4.3 years (range 7.7 months -12.2 years). All patients developed facial-muscle weakness before the age of 15 months. Speech was studied in four patients. Articulation was disordered, with hypernasal resonance and reduced speech intelligibility in all four. Swallowing function was studied in six patients, the most important findings being ineffective swallowing with residues of food (5/6), penetration or aspiration (3/6), and reduced pharyngeal and/or laryngeal sensibility (2/6). We conclude that facial-muscle weakness, speech disorders and dysphagia are common in long-term survivors receiving ERT for classic infantile Pompe disease. To improve speech and reduce the risk for aspiration, early treatment by a speech therapist and regular swallowing assessments are recommended.

Rate of progression and predictive factors for pulmonary outcome in children and adults with Pompe disease.

Respiratory insufficiency is a serious threat to patients with Pompe disease, a neuromuscular disorder caused by lysosomal acid alpha-glucosidase deficiency. Innovative therapeutic options which may stabilize pulmonary function have recently become available. We therefore determined proportion and severity of pulmonary involvement in patients with Pompe disease, the rate of progression of pulmonary dysfunction, and predictive factors for poor respiratory outcome. In a single-center, prospective, cohort study, we measured vital capacity (VC) in sitting and supine positions, as well as maximum inspiratory (MIP) and expiratory (MEP) mouth pressures, and end expiratory CO(2) in 17 children and 75 adults with Pompe disease (mean age 42.7 years, range 5-76 years). Seventy-four percent of all patients, including 53% of the children, had some degree of respiratory dysfunction. Thirty-eight percent had obvious diaphragmatic weakness. Males appeared to have more severe pulmonary involvement than females: at a group level, their mean VC was significantly lower than that of females (p<0.001), they used mechanical ventilation more often than females (p=0.042) and the decline over the course of the disease was significantly different between males and females (p=0.003). Apart from male gender, severe skeletal muscle weakness and long disease duration were the most important predictors of poor respiratory status. During follow-up (average 1.6 years, range 0.5-4.2 years), three patients became ventilator dependent. Annually, there were average decreases in VC in upright position of 0.9% points (p=0.09), VC in supine position of 1.2% points (p=0.049), MIP of 3.2% points (p=0.018) and MEP of 3.8% points (p<0.01). We conclude that pulmonary dysfunction in Pompe disease is much more common than generally thought. Males, patients with severe muscle weakness, and those with advanced disease duration seem most at risk.

[Contribution of the pre-operative Mri-coloscan couple in the surgical planning of deep digestive pelvic endometriosis]. / Apport du couple IRM-coloscanner pré-opératoire dans la planification chirurgicale de l'endométriose digestive.

INTRODUCTION: The digestive involvement of endometriosis accounts for up to 20-25% of deep localisations. Precise mapping of digestive lesions is essential in order to plan surgery and specialized teams. The aim of this study is to assess the contribution of the MRI-coloscan couple in the preoperative assessment of digestive endometriosis. METHODS: We analyzed 45 files of patients referred for suspected digestive endometriosis. They had all undergone a preoperative MRI and coloscan associated with surgery throughout the year. We first compared the data collected in imaging, and then compared the synthesis of this data with the surgical procedure performed. RESULTS: 35 patients required digestive surgery. 24 of 45 files were concordant in MRI and coloscanner. Data from MRI alone matched with surgery in 69% of cases, against 84% for the coloscan. The synthesis allowed a concordance of 89%. 25 segmental resections, 2 discoid and 16 shaving were performed. The use of coloscan made up for nine extra cases: the detection of four additional cases of multifocality, a single undiagnosed case of a deep lesion, and allowed to specify the depth of the involvement in four cases. On the contrary, the MRI was correct compared to the CT in four cases. The presence of a digestive surgeon was necessary in 53% of cases. CONCLUSION: In the era of imaging staging, it would seem interesting to turn towards a subclassification of the digestive involvement of endometriosis in order to decide which surgery to perform. In our experience, the coloscan is a useful complement of MR, especially to assess the depth of involvement and the multifocality.

Efficacy of sonic hedgehog inhibitors rechallenge, after initial complete response in recurrent advanced basal cell carcinoma: a retrospective study from the CARADERM database.

BACKGROUND: Smoothened (SMO) inhibitors, blocking the sonic hedgehog pathway, have been approved for advanced basal cell carcinoma (aBCC). Safety analyses reveal a high rate of adverse events (AEs) and, most of the time, vismodegib is most commonly stopped when the best overall response is reached. The long-term evolution of aBCC after vismodegib discontinuation is poorly described. The aim of this study is to evaluate the efficacy and safety of the SMO inhibitors (SMOis) available (vismodegib and sonidegib) following rechallenge after complete response (CR) following an initial treatment by vismodegib. MATERIALS AND METHODS: This real-life, retrospective, multicenter and descriptive study is based on an extraction from the CARADERM accredited database, including 40 French regional hospitals, of patients requiring BCC systemic treatment. RESULTS: Of 303 patients treated with vismodegib, 110 achieved an initial CR. The vast majority of these patients (98.2%) stopped vismodegib, notably due to poorly tolerated AEs. The CARADERM database provided a median follow-up of 21 months (13.5-36.0 months) after CR. Of the 110 patients, 48.1% relapsed after a median relapse-free survival of 24 months (13.0-38.0 months). Among them, 35 patients were retreated by an SMOi and the overall response rate was 65.7% (34.3% of CR and 31.4% of partial response). The median duration of retreatment was 6.0 months (4.0-9.5 months). CONCLUSION: Our real-life study, carried out on patients with complex clinical pictures, shows that after treatment discontinuation, 48.1% of patients achieved CR relapse within an average of 24 months (13.0-38.0 months). It emphasized that even though rechallenge can be considered as a therapeutic option, efficacy seems to decrease, suggesting the development of resistance mechanisms.

How reproducible are classical and new CT-pelvimetry measurements?

PURPOSE: The objective of this study was to assess the reliability and reproducibility of existing and new computed tomography (CT)-pelvimetry measurements. MATERIAL AND METHODS: A retrospective cohort study of 63 women with a mean age of 33.9±5.2 (SD) years (range: 19-49 years) was conducted. Classical pelvimetry measurements were collected including the obstetric conjugate (OC), median transverse diameter (MTD), and interspinous diameter (ISD). Additionally, we used multiplanar reconstruction (MPR) mode to define two oblique planes: inlet pelvic plane (IPP) and mid-pelvic plane (MPP) and measure new pelvic parameters, including anteroposterior (APD), transverse diameters and circumference of both IPP and MPP (inletAPD, inletMTD, inletCIRC and midAPD, ISD, midCIRC, respectively). The reproducibility (intra- and inter-observer) of our results were assessed. Multivariate analyses using principal component analysis and clustering methods were conducted to analyze the association between pelvimetry measurements and identify patient sub-groups. RESULTS: All linear measurements (OC, inletAPD, MTD, inletMTD, midAPD, and ISD) showed statistically "almost perfect" intra- and inter-observer correlation coefficients (range: 0.924-0.980). Circumferences (inletCIRC and midCIRC) showed statistically "almost perfect" intra- (range: 0.847-0.857) and inter-observer correlation coefficients (range: 0.923-0.957). The measurement of 6 pelvimetric parameters allowed determining three groups of pelvis size. CONCLUSION: New pelvic measurements have excellent reproducibility and are similar to the classical measurements, based on the MPR analysis of CT planes adjusted to the inner bony pelvis.

Eight years experience with enzyme replacement therapy in two children and one adult with Pompe disease.

Pompe disease (type 2 glycogenosis, acid maltase deficiency) is a disorder affecting skeletal and cardiac muscle, caused by deficiency of acid alpha-glucosidase. In 2006 enzyme therapy with recombinant human alpha-glucosidase received marketing approval based on studies in infants. Results in older children and adults are awaited. Earlier we reported on the 3-year follow-up data of enzyme therapy in two adolescents and one adult. In the present study these patients were followed for another 5 years. Two severely affected patients, wheelchair and ventilator dependent, who had shown stabilization of pulmonary and muscle function in the first 3 years, maintained this stabilization over the 5-year extension period. In addition patients became more independent in daily life activities and quality of life improved. The third moderately affected patient had shown a remarkable improvement in muscle strength and regained the ability to walk over the first period. He showed further improvement of strength and reached normal values for age during the extension phase. The results indicate that both long-term follow-up and timing of treatment are important topics for future studies.

Cardiac evaluation in children and adults with Pompe disease sharing the common c.-32-13T>G genotype rarely reveals abnormalities.

BACKGROUND AND OBJECTIVE: Pompe disease is an inherited metabolic disorder caused by deficiency of acid alpha-glucosidase. All affected neonates have a severe hypertrophic cardiomyopathy, leading to cardiac failure and death within the first year of life. We investigated the presence and extent of cardiac involvement in children and adults with Pompe disease with the common c.-32-13T>G genotype to determine the usefulness of cardiac screening in these patients with relatively 'milder' phenotypes. METHODS: Cardiac dimensions and function were evaluated through echocardiography, electrocardiography and Holter monitoring. The total group comprised 68 patients with Pompe disease, of whom 22 patients had disease onset before the age of 18. RESULTS: Two patients (3%) had cardiac abnormalities possibly related to Pompe disease: Electrocardiography showed a Wolff-Parkinson-White pattern in an 8-year-old girl, and one severely affected adult patient had a mild hypertrophic cardiomyopathy. This hypertrophy did not change during treatment with recombinant human alpha-glucosidase. In addition, four adult patients showed minor cardiac abnormalities which did not exceed the prevalence in the general population and were attributed to advanced age, hypertension or pre-existing cardiac pathology unrelated to Pompe disease. CONCLUSIONS: Cardiac involvement is rare in Pompe patients with the common c.-32-13T>G genotype. The younger patients were not more frequently affected than the adults. Electrocardiographic evaluation appears to be appropriate as initial screening tool. Extensive cardiac screening seems indicated only if the electrocardiogram is abnormal or the patient has a history of cardiac disease.

Childhood Pompe disease: clinical spectrum and genotype in 31 patients.

BACKGROUND: As little information is available on children with non-classic presentations of Pompe disease, we wished to gain knowledge of specific clinical characteristics and genotypes. We included all patients younger than 18 years, who had been evaluated at the Pompe Center in Rotterdam, the Netherlands, between 1975 and 2012, excluding those with the classic-infantile form. None were treated with enzyme replacement therapy at the time of evaluation. We collected information on first symptoms, diagnosis, use of a wheelchair and/or respirator, and enzyme and mutation analysis and assessed muscle strength, pulmonary function, and cardiac parameters. RESULTS: Thirty-one patients participated. Median age at symptom onset was 2.6 years (range 0.5-13y) and at diagnosis 4.0 years. Most first problems were delayed motor development and problems related to limb-girdle weakness. Fatigue, persistent diarrhea and problems in raising the head in supine position were other first complaints. Ten patients were asymptomatic at time of diagnosis. Five of them developed symptoms before inclusion in this study. Over 50 % of all patients had low or absent reflexes, a myopathic face, and scoliosis; 29 % were underweight. Muscle strength of the neck flexors, hip extensors, hip flexors, and shoulder abductors were most frequently reduced. Pulmonary function was decreased in over 48 % of the patients; 2 patients had cardiac hypertrophy. Patients with mutations other than the c.-32-13T > G were overall more severely affected, while 18 out of the 21 patients (86 %) with the c.-32-13T > G/'null' genotype were male. CONCLUSIONS: Our study shows that Pompe disease can present with severe mobility and respiratory problems during childhood. Pompe disease should be considered in the differential diagnosis of children with less familiar signs such as disproportional weakness of the neck flexors, unexplained fatigue, persistent diarrhea and unexplained high CK/ASAT/ALAT. Disease presentation appears to be different from adult patients. The majority of affected children with GAA genotype c.-32-13T > G/'null' appeared to be male.

A real-time experimental prototype for enhancement of vision rehabilitation using auditory substitution.

The rehabilitation of blindness, using noninvasive methods, requires sensory substitution. A theoretical frame for sensory substitution has been proposed which consists of a model of the deprived sensory system connected to an inverse model of the substitutive sensory system. This paper addresses the feasibility of this conceptual model in the case of auditory substitution, and its implementation as a rough model of the retina connected to an inverse linear model of the cochlea. We have developed an experimental prototype. It aims at allowing optimization of the sensory substitution process. This prototype is based on a personal computer which is connected to a miniature head-fixed video camera and to headphones. A visual scene is captured. Image processing achieves edge detection and graded resolution. Each picture element (pixel) of the processed image is assigned a sinusoidal tone; weighted summation of these sinewaves builds up a complex auditory signal which is transduced by the headphones. On-line selection of various parameters and real-time functioning of the device allow optimization of parameters during psychophysical experimentations. Assessment of this implementation has been initiated, and has so far demonstrated prototype usefulness for pattern recognition. An integrated circuit of this system is to be developed.

Effect of enzyme therapy in juvenile patients with Pompe disease: a three-year open-label study.

Pompe disease is a rare neuromuscular disorder caused by deficiency of acid α-glucosidase. Treatment with recombinant human α-glucosidase recently received marketing approval based on prolonged survival of affected infants. The current open-label study was performed to evaluate the response in older children (age 5.9-15.2 years). The five patients that we studied had limb-girdle muscle weakness and three of them also had decreased pulmonary function in upright and supine position. They received 20-mg/kg recombinant human α-glucosidase every two weeks over a 3-year period. No infusion-associated reactions were observed. Pulmonary function remained stable (n = 4) or improved slightly (n = 1). Muscle strength increased. Only one patient approached the normal range. Patients obtained higher scores on the Quick Motor Function Test. None of the patients deteriorated. Follow-up data of two unmatched historical cohorts of adults and children with Pompe disease were used for comparison. They showed an average decline in pulmonary function of 1.6% and 5% per year. Data on muscle strength and function of untreated children were not available. Further studies are required.

Neurofibromatosis presenting with a cherubism phenotype.

We report on a child who presented clinical manifestations of both neurofibromatosis type 1 (NF1) and cherubism. With genetic testing, we found a mutation in the NF-1 gene, confirming the neurocutaneous disorder. Histology when correlated with radiological evaluation of a mandibular biopsy was consistent with cherubism. This is the first report in the literature of a child with proven neurofibromatosis type 1 and cherubism without extragnathic lesions. This emphasises that cherubism is a clinical phenotype that can be associated with a number of germline mutations involving SH3BP2, PTPN11 and NF1.

Standardization of platelet counts--problems and pitfalls.

In a previous work, we have compared two automated techniques for platelet-rich plasma using a thrombocounter or whole blood with the continuous flow instrument Auto-analyzer (AA). More recently, we have tested two instruments using whole blood: the first one, fully automated: Coulter S+; and the other one, semi-automated: Clay-Adams. In the present work, these 4 methods are compared to the phase contrast microscope technique, used as reference. The coefficients of variation ranged between 2 and 13 per cent. The coefficients of correlation between the different methods were between 0.92 and 0.96. Platelet distribution curves for platelet volumes obtained in parallel with platelet-rich plasma and with whole blood in 30 controls, show that platelet population are not significantly different. These instruments count particles and, therefore, necessitate a calibration made by means of platelet standards. Different platelet standards have been studied: these containing latex particles seem to give better results than suspensions of human or animal platelets.

[Platelet count and distribution of platelet volume in whole blood using a Coulter S Plus. Demonstration of errors not detected by the apparatus]. / La numération des plaquettes et la répartition des volumes plaquettaires sur sang total au Coulter S Plus. Mise en évidence d'erreurs non signalées par l'appareil.

The Coulter Counter S Plus is a reliable instrument for performing platelet counts, platelet sizing and different platelet indices. A critical analysis of platelet indices, mean red cell volume and platelet histograms indicates the presence of small erythrocytes thus avoiding any errors.