[Stretching and chylothorax]. / Stretching et chylothorax.

INTRODUCTION: Chylothorax is a rare cause of pleural effusion. The most common causes are iatrogenic or medical. We report an unusual and rare cause of bilateral chylothorax. CASE REPORT: A 73-year-old woman with no past history was admitted to the emergency department for sudden onset of dyspnoea. Chest X-ray and thoracic CT scan revealed large bilateral pleural effusions. Analysis of the fluid revealed a chylothorax. The patient was treated by chest tube drainage and a fat free (medium chain triglyceride) diet. This led to drying up of the effusions and rapid discharge. Complementary imaging examinations with chest-abdomen-pelvis CT, PET CT and pelvic MRI did not reveal any underlying cause. The final diagnosis was bilateral traumatic chylothorax caused by tearing of the thoracic duct during stretching exercises. CONCLUSION: Following a literature review, similar cases with the same clinical presentation were found. Combined treatment with thoracic drainage and medium chain triglyceride diet was effective in drying up the effusions. Our diagnosis was a diagnosis of exclusion. It is important to exclude a medical cause by thorough investigation.

[Thymomectomy by minimally invasive surgery. Comparative study videosurgery versus robot-assisted surgery]. / Traitement des thymomes par chirurgie mini-invasive. Étude comparative vidéochirurgie versus voie robot-assistée.

OBJECTIVES: To report the results of minimally invasive surgery in patients with stage I or II thymoma in the Masaoka classification. The reference technique is partial or complete thymectomy by sternotonomy. METHODS: A retrospective single-center study of a prospective database including all cases of thymoma operated from April 2009 to February 2015 by minimally invasive techniques: either videosurgery (VATS) or robot-assisted surgery (RATS). The surgical technique, type of resection, length of hospital stay, postoperative complications and recurrences were analysed. RESULTS: Our series consisted of 22 patients (15 women and 7 men). The average age was 53 years. Myasthenia gravis was present in 12 patients. Eight patients were operated on by VATS and 14 patiens by RATS. There were no conversions to sternotomy and no perioperative deaths. The mean operating time was 92min for VATS and 137min for RATS (P<0.001). The average hospital stay was 5 days. The mean weight of the specimen for the VATS group was 13.2 and 45.7mg for the RATS group. Twelve patients were classified Masaoka stage I and 10 were stage II. According to the WHO classification there were 7 patients type A, 5 type AB, 4 type B1, 4 type B2 4 and 2 type B3. As proposed by the Group ITMIG-IASLC in 2015 all patients corresponded to group I. The mean follow-up period was 36 months. We noted 3 major perioperative complications according to the Clavien-Dindo classification: one pneumonia, one phrenic nerve paralysis and one recurrent laryngeal nerve palsy. We observed one case of local recurrence at 22 months. Following surgery 4 patients were treated with radiotherapy and 2 patients with chemotherapy. CONCLUSIONS: The minimally invasive route is safe, relatively atraumatic and may be incorporated in the therapeutic arsenal for the treatment of Masaoka stage I and II thymoma as an alternative to conventional sternotomy. RATS and VATS are two minimally invasive techniques and the results in the short and medium term are acceptable. The clinical advantages of one over the other are sifficult to establish. RATS could handle larger and more complex lesions in view of the weight and size of the operating instrument.

Fetal phenotypes in otopalatodigital spectrum disorders.

Otopalatodigital spectrum disorders (OPDSD) include OPD syndromes types 1 and type 2 (OPD1, OPD2), Melnick-Needles syndrome (MNS), and frontometaphyseal dysplasia (FMD). These conditions are clinically characterized by variable skeletal dysplasia associated in males, with extra-skeletal features including brain malformations, cleft palate, cardiac anomalies, omphalocele and obstructive uropathy. Mutations in the FLNA gene have been reported in most FMD and OPD2 cases and in all instances of typical OPD1 and MNS. Here, we report a series of 10 fetuses and a neonatally deceased newborn displaying a multiple congenital anomalies syndrome suggestive of OPDSD and in whom we performed FLNA analysis. We found a global mutation rate of 44%. This series allows expanding the clinical and FLNA mutational spectrum in OPDSD. However, we emphasize difficulties to correctly discriminate OPDSD based on clinical criteria in fetuses due to the major overlap between these conditions. Molecular analyses may help pathologists to refine clinical diagnosis according to the type and the location of FLNA mutations. Discriminating the type of OPDSD is of importance in order to improve the genetic counseling to provide to families.

[Implementation of a robotic video-assisted thoracic surgical program]. / Mise en place d'un programme de chirurgie thoracique mini-invasive robot-assistée.

AIMS: Recent publications from North America have shown the benefits of robot-assisted thoracic surgery. We report here the process of setting up such a program in a French university centre and early results in a unit with an average treatment volume. METHODS: Retrospective review of a single institution database. The program was launched after a 6-month preparation period. RESULTS: From January 2012 to January 2013, totally endoscopic, full robot-assisted procedures were performed on 30 patients (17 males). Median age was 54 [Q1-Q3, 48-63] years and ASA score 2 [1,2]. Operative procedures included thymectomy (9 ; 30%), lobectomy with nodes resection (11 ; 38%), segmentectomy (4 ; 14%), lymphadenectomy (3 ; 10%), Bronchogenic cyst (2, 5%) and posterior mediastinal mass resection (1 ; 3%). No conversion was required. Median blood loss was 50mL [10-100]. Median operating time was 135 min (105-165) including 30 min [20-40] for docking, 90min for robot-assisted operating [70-120] and 15 min [10-15] for lesion extraction. CO2 insufflation was used in 28 cases (93%). Hospital stay was 4 days [4-6] with 6 minor complications (20%) (Grade 1 according to the Clavien-Dindo classification). After a median 4 months follow-up [2-7], all patients were alive and demonstrated a good quality of life. CONCLUSION: This series suggests that full robotic thoracic procedures are safe and effective treatment for various pathologies, with low morbidity and without a significant learning curve, even in a lower volume centre. This technology should accompany the development of minimally invasive thoracic surgery. The importance of robotic training should be emphasized to optimize procedures and costs.

[Pulmonary resection using video-assisted thoracoscopic surgery--20 years experience]. / Résections pulmonaires majeures par vidéothoracoscopie: 20 ans après les premières réalisations.

Major lung resection using minimally invasive techniques - video-assisted thoracoscopic surgery (VATS) - was first described 20 years ago. However, its development has been slow in many countries because the value of this approach has been questioned. Different techniques and definitions of VATS are used and this can be confusing for physicians and surgeons. The benefit of minimally invasive thoracic surgery was not always apparent, while many surgeons pointed to suboptimal operative outcomes. Recently, technological advances (radiology, full HD monitor and new stapler devices) have improved VATS outcomes. The objectives of this review are to emphasize the accepted definition of VATS resection, outline the different techniques developed and their results including morbidity and mortality compared to conventional approaches. Minimally invasive thoracic surgery has not been proven to give superior survival (level one evidence) compared to thoracotomy. A slight advantage has been demonstrated for short-term outcomes. VATS is not a surgical revolution but rather an evolution of surgery. It should be considered together with the new medical environment including stereotactic radiotherapy and radiofrequency. VATS seems to be more accurate in the treatment of small lung lesions diagnosed with screening CT scan. In the academic field, VATS allows easier teaching and diffusion of techniques.

[Traumatic pseudoaneurysm of the superficial temporal artery: a case report]. / Faux anévrisme post-traumatique de l'artère temporale superficielle : à propos d'un cas.

We report a case of traumatic pseudoaneurysm of the superficial temporal artery (STA) in an 87-year-old man. Surgical treatment was undertaken after failure of ultrasound-guided compression. In this report, we review briefly the pathogenic mechanism, presentation, diagnosis and treatment of this type of aneurysm. Traumatic pseudoaneurysms of the STA are rare injuries, generally occurring after a recent (weeks to months) episode of blunt head injury, and primarily in a young to middle-aged (60 %) male (80 %) population. Clinical diagnosis is straightforward when the patient presents with a pulsating painful mass in the STA area and a history of trauma. Doppler ultrasound, CT scan and MRI are useful to confirm diagnosis and exclude the other possible diagnoses (i.e. hematoma, abscess, lipoma, cyst, meningocele, etc.). Surgery remains the treatment of choice for these lesions, however, other treatments have been proposed: endovascular coil embolization, percutaneous thrombin embolization or ultrasound-guided compression.

SPG15 is the second most common cause of hereditary spastic paraplegia with thin corpus callosum.

OBJECTIVE: Hereditary spastic paraplegias (HSPs) are very heterogeneous inherited neurodegenerative disorders. Our group recently identified ZFYVE26 as the gene responsible for one of the clinical and genetic entities, SPG15. Our aim was to describe its clinical and mutational spectra. METHODS: We analyzed all exons of SPG15/ZFYVE26 gene by direct sequencing in a series of 60 non-SPG11 HSP subjects with associated mental or MRI abnormalities, including 30 isolated cases. The clinical data were collected through the SPATAX network. RESULTS: We identified 13 novel truncating mutations in ZFYVE26, 12 of which segregated at the homozygous or compound heterozygous states in 8 new SPG15 families while 1 was found at the heterozygous state in a single family. Two of 3 splice site mutations were validated on mRNA of 2 patients. The SPG15 phenotype in 11 affected individuals was characterized by early onset HSP, severe progression of the disease, and mental impairment dominated by cognitive decline. Thin corpus callosum and white matter hyperintensities were MRI hallmarks of the disease in this series. CONCLUSIONS: The mutations are truncating, private, and distributed along the entire coding sequence of ZFYVE26, which complicates the analysis of this gene in clinical practice. In our series of patients with hereditary spastic paraplegia-thin corpus callosum, the largest analyzed so far, SPG15 was the second most frequent form (11.5%) after SPG11. Both forms share similar clinical and imaging presentations with very few distinctions, which are, however, insufficient to infer the molecular diagnosis when faced with a single patient.

A large-scale international meta-analysis of paraoxonase gene polymorphisms in sporadic ALS.

BACKGROUND: Six candidate gene studies report a genetic association of DNA variants within the paraoxonase locus with sporadic amyotrophic lateral sclerosis (ALS). However, several other large studies, including five genome-wide association studies, have not duplicated this finding. METHODS: We conducted a meta-analysis of 10 published studies and one unpublished study of the paraoxonase locus, encompassing 4,037 ALS cases and 4,609 controls, including genome-wide association data from 2,018 ALS cases and 2,425 controls. RESULTS: The combined fixed effects odds ratio (OR) for rs662 (PON1 Q192R) was 1.09 (95% confidence interval [CI], 1.02-1.16, p = 0.01); the genotypic OR for RR homozygotes at Q192R was 1.25 (95% CI, 1.07-1.45, p = 0.0004); the combined OR for rs854560 (PON1 L55M) was 0.97 (95% CI, 0.86-1.10, p = 0.62); the OR for rs10487132 (PON2) was 1.08 (95% CI, 0.92-1.27, p = 0.35). Although the rs662 polymorphism reached a nominal level of significance, no polymorphism was significant after multiple testing correction. In the subanalysis of samples with genome-wide data from which population outliers were removed, rs662 had an OR of 1.06 (95% CI, 0.97-1.16, p = 0.22). CONCLUSIONS: In contrast to previous positive smaller studies, our genetic meta-analysis showed no significant association of amyotrophic lateral sclerosis (ALS) with the PON locus. This is the largest meta-analysis of a candidate gene in ALS to date and the first ALS meta-analysis to include data from whole genome association studies. The findings reinforce the need for much larger and more collaborative investigations of the genetic determinants of ALS.

Mutation and methylation analysis of TP53 in adrenal carcinogenesis.

AIM: To investigate the role of coding region mutation and promoter hypermethylation of TP53 in adrenocortical cancer formation. METHODS: Twenty sporadic adrenocortical cancers (ACCs) and five normal adrenal tissue samples were available for analysis. Coding region mutation of TP53 in 20 ACCs was examined by polymerase chain amplification using intronic primers for exons 2-11 and direct sequencing of the product. In 10 ACCs and five normal adrenal tissue specimens, methylation of the 16 CpG sites within the TP53 promoter was examined using bisulphite methylation sequencing. RESULTS: Coding region mutation in TP53 was demonstrated in 5 of 20 ACCs. There were four mis-sense mutations and one frameshift mutation. Four of 5 patients with a TP53 mutation had metastases at diagnosis or detected soon thereafter and 3 of 4 died of disease within 12 months of surgical resection. No methylation was seen in the TP53 promoter in 10 ACC and the five normal adrenal tissues examined. CONCLUSION: Coding region mutation in TP53 occurs in 25% of ACCs with a trend toward a poorer prognosis. Promoter methylation of TP53 is not present in ACC as a mechanism for tumour suppressor gene (TSG) inactivation and, therefore, other genes in the 17p13 region are implicated in adrenal carcinogenesis.

Allelic heterogeneity of SMARD1 at the IGHMBP2 locus.

Spinal Muscular Atrophy with Respiratory Distress (SMARD) is an autosomal recessive disorder characterized by neurogenic muscular atrophy due to progressive anterior horn cell degeneration and early life-threatening respiratory failure ascribed to diaphragmatic dysfunction. SMARD is clinically and genetically heterogeneous. SMARD type 1 is characterized by onset of respiratory failure within the first weeks of life and has been ascribed to mutations in the immunoglobulin mu-binding protein 2 (IGHMBP2) gene on chromosome 11q13-q21. We report here the identification of nine novel IGHMBP2 mutations in five SMARD1 patients, including seven missense [ c.587A>G (p.Gln196Arg), c.647C>T (p.Pro216Leu), c.752T>C (p.Leu251Pro), c.1693G>A (p.Asp565Asn), c.1730T>C (p.Leu577Pro), c.1807C>T (p.Arg603Cys), c.1909C>T (p.Arg637Cys)] and two nonsense mutations [ c.1488C>A (p.Cys496X), c.2368C>T (p.Arg790X)]. Interestingly, 7 of 9 mutations occurred at highly conserved residues of the putative DNA helicase domain. The identification of novel IGHMBP2 variants will hopefully help diagnosing SMARD1 and contribute to a better functional characterization of IGHMBP2 gene product.

Progressive and selective degeneration of motoneurons in a mouse model of SMA.

Spinal muscular atrophy (SMA), an autosomal recessive disorder characterized by the degeneration of motoneurons of the spinal cord and brainstem, results from loss-of-function mutations in the survival motor neuron gene (smn). The goal of these experiments was to analyse axons and cell bodies of motoneurons in different regions of the CNS during disease progression in a mouse model of SMA carrying a deletion of the exon 7 directed to neurons. These experiments demonstrate a progressive loss of motor axons and of motoneurons in the CNS. This is the first study that describes a selective neurodegeneration in this line of mice and underlines the importance of exon 7 in some populations of motoneurons for survival in vivo.

Closure of carotid bifurcation endarterectomy using a polyurethane patch. A multicentre prospective study with 252 patients.

BACKGROUND: In order to evaluate the results of carotid endarterectomy with closure using a polyurethane patch, a multicentre prospective study of 252 patients (263 interventions) undergoing this operation was performed between November 1996 and August 2001. METHODS: One hundred and seventy-one men and 81 women with a mean age of 70 years were studied. Fifty-five percent of the patients had neurological symptoms. The degree of carotid stenosis evaluated using the European carotid surgery trialist's collaborative group (ECST) criteria was greater than or equal to 70% in 95% of cases. RESULTS: The combined mortality-morbidity operation rate (CMMR) was 2% (1 death from cerebrovascular haemorrhage on Day 3, 1 non-regressive cerebrovascular accident (CVA), 3 regressive CVAs). The patients had follow-up clinical examinations and Doppler ultrasound scans for 2 years. Fifteen patients died during follow-up, 8 of these patients died from heart-related causes and 2 patients died from CVA. Four patients presented with CVAs ipsilateral or contralateral to the endarterectomy. Two false aseptic aneurysms and 1 false septic aneurysm required further surgery. Three asymptomatic carotid occlusions occurred during follow-up. The rate of restenosis greater than 50% was 1.2% at 6 months, 2.3% at 1 year and 5.3% at 2 years. CONCLUSIONS: These results confirm the value of po-lyurethane patch closure of carotid endarterectomy.

[Exhumations procedures for investigating the genetic link in bones]. / Procedimentos em exumações para investigação de vínculo genético em ossos.

OBJECTIVE: To identify technical problems in exhumations performed for DNA detection in bones and to propose solutions through a protocol. METHODS: A prospective and qualitative study of exhumations was carried out according to the methods proposed in the medical legal literature. From 1995 to 1998, were performed 10 exhumations to collect human remains for DNA extraction. Of them, seven cases were of civil interest and three of criminal. Alternatives were sought to overcome technical difficulties found during the execution of these procedures. RESULTS: For all cases, there was scarcity of useful information to identify the human remains. In half of them, identification was based on the individual's morphological characteristics, given by their relatives. Individual morphological characteristics contributed to identification in 50% of cases. In three cases, it was possible to determine only the sex, and in one of them, only the age. Lack of infrastructure and police security in the cemeteries impaired the examination. CONCLUSIONS: To assure the reliability of the DNA molecular examination, it is necessary to identify the individual to whom the exhumed mortal remains belonged. To an efficacious investigation, it is paramount to have a working protocol that will cover, among other issues, those concerning identification, infrastructure and staff safety at the site of examination.

Embolization of hypogastric artery aneurysm: 17 cases.

Surgical management of hypogastric artery aneurysm is associated with high morbidity due to hemorrhage and ischemia. Occlusion by embolization is an attractive alternative treatment. Between 1991 and 1995, we used Gianturco coils to embolize 17 hypogastric aneurysms in 14 patients. All patients were men with a mean age of 77 years. Ten patients had previously undergone aortic repair. Complete occlusion of the aneurysm was achieved in 16 cases but placement of an iliac stent was required in 1 case. Embolization failed in one case involving rupture of a large aneurysm. No complications were observed. Moderate buttock claudication was noted after bilateral embolization in three cases. Embolization of hypogastric artery aneurysm using coils resolves the long-term problems associated with surgical ligation. Extensive aneurysm of the origin to the bifurcation is the main indication for nonresective treatment but embolization can also be a useful alternative to open surgery for high-risk patients. Availability of stent grafts may extend the indication for endovascular treatment.

Characterisation of novel point mutations in the survival motor neuron gene SMN, in three patients with SMA.

We report two novel mutations in three cases of spinal muscular atrophy (SMA), including two distant cousins who followed an unexpectedly severe course. Diagnosis was confirmed by reduced SMN protein and full-length SMN mRNA levels. Sequencing of the non-deleted SMN1 gene revealed a single G insertion at the end of exon 1 in the two cousins and a novel G275S exon 6 missense mutation in the milder case.

Deletion of murine SMN exon 7 directed to skeletal muscle leads to severe muscular dystrophy.

Spinal muscular atrophy (SMA) is characterized by degeneration of motor neurons of the spinal cord associated with muscle paralysis and caused by mutations of the survival motor neuron gene (SMN). To determine whether SMN gene defect in skeletal muscle might have a role in SMA pathogenesis, deletion of murine SMN exon 7, the most frequent mutation found in SMA, has been restricted to skeletal muscle by using the Cre-loxP system. Mutant mice display ongoing muscle necrosis with a dystrophic phenotype leading to muscle paralysis and death. The dystrophic phenotype is associated with elevated levels of creatine kinase activity, Evans blue dye uptake into muscle fibers, reduced amount of dystrophin and upregulation of utrophin expression suggesting a destabilization of the sarcolemma components. The mutant mice will be a valuable model for elucidating the underlying mechanism. Moreover, our results suggest a primary involvement of skeletal muscle in human SMA, which may contribute to motor defect in addition to muscle denervation caused by the motor neuron degeneration. These data may have important implications for the development of therapeutic strategies in SMA.

Mouse models for Friedreich ataxia exhibit cardiomyopathy, sensory nerve defect and Fe-S enzyme deficiency followed by intramitochondrial iron deposits.

Friedreich ataxia (FRDA), the most common autosomal recessive ataxia, is characterized by degeneration of the large sensory neurons and spinocerebellar tracts, cardiomyopathy and increased incidence in diabetes. FRDA is caused by severely reduced levels of frataxin, a mitochondrial protein of unknown function. Yeast knockout models as well as histological and biochemical data from heart biopsies or autopsies of FRDA patients have shown that frataxin defects cause a specific iron-sulfur protein deficiency and intramitochondrial iron accumulation. We have recently shown that complete absence of frataxin in the mouse leads to early embryonic lethality, demonstrating an important role for frataxin during mouse development. Through a conditional gene-targeting approach, we have generated in parallel a striated muscle frataxin-deficient line and a neuron/cardiac muscle frataxin-deficient line, which together reproduce important progressive pathophysiological and biochemical features of the human disease: cardiac hypertrophy without skeletal muscle involvement, large sensory neuron dysfunction without alteration of the small sensory and motor neurons, and deficient activities of complexes I-III of the respiratory chain and of the aconitases. Our models demonstrate time-dependent intramitochondrial iron accumulation in a frataxin-deficient mammal, which occurs after onset of the pathology and after inactivation of the Fe-S-dependent enzymes. These mutant mice represent the first mammalian models to evaluate treatment strategies for the human disease.

Endovascular treatment of iliac aneurysms with covered stents.

The purpose of this retrospective, single-institution study was to analyze the results of endovascular treatment of iliac aneurysm using covered stents. Since January 1, 1996, a total of 34 iliac aneurysms have been treated with covered endovascular stents. The series included 9 isolated aneurysms, 29 aneurysms following repair of aortic aneurysm, and 3 false anastomotic aneurysms. The mean diameter of aneurysm was 42 mm (range, 21 to 120 mm). The aneurysm was either symptomatic or complicated in 11 cases. Three procedures were carried out under emergency conditions after acute rupture. Stent deployment was successful in 33 cases (technical success rate, 97.6%). Exclusion of the aneurysm was obtained in all cases with one (n = 26) or two overlapping (n = 7) covered stents. Mean procedure duration was 45 min (range, 25 to 75 min). The internal iliac artery was patent in 28 cases, but patency was preserved in only 4 cases. In the remaining 24 cases the internal iliac artery was excluded either preoperatively by embolization using Gianturco coils (n = 15) or intraoperatively by placement of the stent (n = 9). Endovascular treatment of iliac aneurysm with covered stents achieves good short- and middle-term results but usually requires exclusion of the internal iliac artery.

Hypermethylation of E-cadherin in leukemia.

E-cadherin gene is often termed a "metastasis suppressor" gene because the E-cadherin protein can suppress tumor cell invasion and metastasis. Inactivation of the E-cadherin gene occurs in undifferentiated solid tumors by both genetic and epigenetic mechanisms; however, the role of E-cadherin in hematologic malignancies is only now being recognized. E-cadherin expression is essential for erythroblast and normoblast maturation, yet expression is reduced or absent in leukemic blast cells. This study examined the messenger RNA (mRNA) and protein expression of the E-cadherin gene in bone marrow and blood samples from normal donors and patients with leukemia. We found that all normal donor samples expressed E-cadherin mRNA, whereas both samples of acute myelogenous leukemia and chronic lymphocytic leukemia had a significant reduction or absence of expression. However, normal blast counterparts expressed only a low level of E-cadherin surface protein. Sodium bisulphite genomic sequencing was used to fully characterize the methylation patterns of the CpG island associated with the E-cadherin gene promoter in those samples with matched DNA. All of the normal control samples were essentially unmethylated; however, 14 of 18 (78%) of the leukemia samples had abnormal hypermethylation of the E-cadherin CpG island. In fact both alleles of the E-cadherin gene were often hypermethylated. We conclude the E-cadherin gene is a common target for hypermethylation in hematologic malignancies.