The APSY-SED study: protocol of an observational, longitudinal, mixed methods and multicenter study exploring the psychological adjustment of relatives and healthcare providers of patients with cancer with continuous deep sedation until death.

BACKGROUND: Since 2016, France is the only country in the World where continuous deep sedation until death (CDSUD) is regulated by law. CDSUD serves as a response to refractory suffering in palliative situations where the patients' death is expected to occur in the following hours or days. Little is known on the psychological adjustment surrounding a CDSUD procedure for healthcare providers (HCPs) and relatives. Our study aims to gather qualitative and quantitative data on the specific processes behind the psychological adjustment of both relatives and HCPs, after the administration of CDSUD for patients with cancer. METHODS: The APSY-SED study is a prospective, longitudinal, mixed-methods and multicenter study. Recruitment will involve any French-speaking adult cancer patient for who a CDSUD is discussed, their relatives and HCPs. We plan to include 150 patients, 150 relatives, and 50 HCPs. The evaluation criteria of this research are: 1/ Primary criterion: Psychological adjustment of relatives and HCPs 6 and 13 months after the death of the patient with cancer (psychological adjustment = intensity of anxiety, depression and grief reactions, CDSUD-related distress, job satisfaction, Professional Stress and Professional experience). Secondary criteria: a)occurrence of wish for a CDSUD in patients in palliative phase; b)occurrence of wish for hastened death in patients in palliative phase; c)potential predictors of adjustment assessed after the discussion concerning CDSUD as an option and before the setting of the CDSUD; d) Thematic analysis and narrative account of meaning-making process concerning the grief experience. DISCUSSION: The APSY-SED study will be the first to investigate the psychological adjustment of HCPs and relatives in the context of a CDSUD procedure implemented according to French law. Gathering data on the grief process for relatives can help understand bereavement after CDSUD, and participate in the elaboration of specific tailored interventions to support HCPs and relatives. Empirical findings on CDSUD among patients with cancer in France could be compared with existing data in other countries and with results related to other medical fields where CDSUD is also conducted. TRIAL REGISTRATION: This protocol received the National Registration Number: ID-RCB2021-A03042-39 on 14/12/2021.

Analysis of 3297 individuals suggests that the pathogenic germline 5'-UTR variant BRCA1 c.-107A > T is not common in south-east Germany.

In this study we aim to determine the prevalence of the recently identified pathogenic BRCA1 variant c.-107A > T in the south-east German population. This variant causes the epigenetic silencing of the BRCA1 promotor and has been detected in two independent families from the UK without a germline BRCA1 or BRCA2 pathogenic variant. A total of 3297 individuals with suspicion of hereditary breast and ovarian cancer and fulfilling the clinical criteria necessary for genetic testing in Germany were analyzed for presence of the variant by a Kompetitive Allele-Specific PCR (KASP) assay or direct Sanger sequencing. Since we did not detect an individual carrying the variant we conclude that BRCA1 c.-107A > T is not a common variant in the south-east German population.

The prognostic potential of alternative transcript isoforms across human tumors.

BACKGROUND: Phenotypic changes during cancer progression are associated with alterations in gene expression, which can be exploited to build molecular signatures for tumor stage identification and prognosis. However, it is not yet known whether the relative abundance of transcript isoforms may be informative for clinical stage and survival. METHODS: Using information theory and machine learning methods, we integrated RNA sequencing and clinical data from The Cancer Genome Atlas project to perform the first systematic analysis of the prognostic potential of transcript isoforms in 12 solid tumors to build new signatures for stage and prognosis. This study was also performed in breast tumors according to estrogen receptor (ER) status and melanoma tumors with proliferative and invasive phenotypes. RESULTS: Transcript isoform signatures accurately separate early from late-stage groups and metastatic from non-metastatic tumors, and are predictive of the survival of patients with undetermined lymph node invasion or metastatic status. These signatures show similar, and sometimes better, accuracies compared with known gene expression signatures in retrospective data and are largely independent of gene expression changes. Furthermore, we show frequent transcript isoform changes in breast tumors according to ER status, and in melanoma tumors according to the invasive or proliferative phenotype, and derive accurate predictive models of stage and survival within each patient subgroup. CONCLUSIONS: Our analyses reveal new signatures based on transcript isoform abundances that characterize tumor phenotypes and their progression independently of gene expression. Transcript isoform signatures appear especially relevant to determine lymph node invasion and metastasis and may potentially contribute towards current strategies of precision cancer medicine.

Identification of recurring tumor-specific somatic mutations in acute myeloid leukemia by transcriptome sequencing.

Genetic lesions are crucial for cancer initiation. Recently, whole genome sequencing, using next generation technology, was used as a systematic approach to identify mutations in genomes of various types of tumors including melanoma, lung and breast cancer, as well as acute myeloid leukemia (AML). Here, we identify tumor-specific somatic mutations by sequencing transcriptionally active genes. Mutations were detected by comparing the transcriptome sequence of an AML sample with the corresponding remission sample. Using this approach, we found five non-synonymous mutations specific to the tumor sample. They include a nonsense mutation affecting the RUNX1 gene, which is a known mutational target in AML, and a missense mutation in the putative tumor suppressor gene TLE4, which encodes a RUNX1 interacting protein. Another missense mutation was identified in SHKBP1, which acts downstream of FLT3, a receptor tyrosine kinase mutated in about 30% of AML cases. The frequency of mutations in TLE4 and SHKBP1 in 95 cytogenetically normal AML patients was 2%. Our study demonstrates that whole transcriptome sequencing leads to the rapid detection of recurring point mutations in the coding regions of genes relevant to malignant transformation.

[A retrospective study of six patients with late-onset Pompe disease]. / Forme adulte de la maladie de Pompe: à propos de six cas de la région du Languedoc-Roussillon.

INTRODUCTION: Pompe's disease, also called glycogen storage disease type II or acid maltase deficiency, is an autosomal recessive disease caused by an enzymatic deficiency of acid-alpha-glucosidase (GAA). This deficiency causes an accumulation of intralysosomal glycogen in different organs. The classic form appears in the newborn with a very severe hypotonia and cardiomyopathy, which lead to death before age two. Less frequently, the disease appears only in childhood or in adult life, so called late-onset Pompe's disease. This form causes a very progressive limb-girdle myopathy and restrictive respiratory failure. The diagnosis is based on a low level of GAA either in the muscle biopsy or in the leucocytes. We report six cases of late-onset Pompe's disease from the Languedoc-Roussillon district. METHOD: Our work was a retrospective analysis of all cases of Pompe disease diagnosed in adults between 1975 and 2006 at the Montpellier and Nîmes University Hospital. We describe the clinical presentation and course of this form and explain the diagnostic approach. Results. The mean age at onset was 44.3 years (range: 36-60 years). The first symptom was fatigability (50%), gait difficulty (50%) and dyspnea (16%). The mean delay from symptom onset to diagnosis was 8.4 years (range: 17 years). Fatal outcome due to respiratory failure was noted in three patients. The mean time between symptom onset and death (four patients) was 20.75 years (range: 37 years). The diagnosis was made on the muscle biopsy showing a low level of GAA. Muscle was strictly normal on the morphologic study in one patient, pointing out the requirement for enzymatic analysis. Molecular confirmation was available in one patient. DISCUSSION: Late-onset Pompe's disease is a possible cause of limb-girdle myopathy. Respiratory involvement is a characteristic feature. Enzymatic assay of GAA activity on the muscle biopsy is required for certain diagnosis. CONCLUSION: It is very important to recognize the adult form of Pompe's disease, a possible cause of limb-girdle myopathy, in order to search for respiratory failure and propose non-invasive ventilation if necessary. Moreover, substitutive therapy (recombinant acid-alpha-glucosidase) has shown efficiency for the classical infantile form of Pompe's disease and such treatment could be proposed for the adult form if larger studies confirm its efficacy.

[Adult onset nemaline myopathy revealed by respiratory insufficiency]. / Révélation d'une myopathie à bâtonnets par une insuffisance respiratoire de l'adulte.

INTRODUCTION: We report a case of nemaline myopathy revealed in adulthood by a respiratory insufficiency. CASE REPORT: A 26-year-old patient, without past history, was admitted with respiratory and right cardiac insufficiency which appeared in a few days. There was a severe restrictive lung impairment with nocturnal hypoventilation. Minor skeletal abnormalities and areflexia suggested a congenital myopathy. Muscle biopsy revealed a nemaline myopathy. CONCLUSION: Respiratory insufficiency is common in nemaline myopathy with infancy or childhood onset, but very rare in adults. It may be explained by multiple mechanisms.

[Non-Hodgkin's malignant lymphoma of the peripheral nervous system: clinicopathological correlations in ten patients]. / Lymphomes malins non Hodgkiniens du système nerveux périphérique. Corrélations anatomo-cliniques dans 10 observations.

INTRODUCTION: Identifying tumor infiltration or compression in patients with non-Hodgkin's malignant lymphoma presenting peripheral neuropathy can be a difficult task. METHODS: We collected a series of patients with peripheral neuropathy with demonstrated lymphomatous infiltration or compression managed between October 1977 and October 2001 to search for clinico-pathological correlations. RESULTS: Ten cases were reviewed. Neurological manifestations were the inaugural symptom of the disease in 7 patients. Clinical presentations included 5 focal (3 cranial nerve palsies, 2 brachial radiculopathies) and 5 diffuse neuropathies (3 polyradiculoneuropathies, 1 polyneuropathy and 1 mononeuritis multiplex). The mechanisms of peripheral nerve involvement were classified into lymphomatous meningoradiculitis (5 cases), involvement of cranial nerves or spinal roots in their extraneuraxial course (3 cases) and infiltration of distal peripheral nerves (2 cases). Four long lasting survivals after treatment were observed. CONCLUSIONS: Prognosis depends much more on the haematological disease than on the neurological symptoms or tumor location.

Autosomal-dominant hypophosphatemic rickets (ADHR) mutations stabilize FGF-23.

BACKGROUND: The gene for the renal phosphate wasting disorder autosomal-dominant hypophosphatemic rickets (ADHR) is FGF23, which encodes a secreted protein related to the fibroblast growth factors (FGFs). We previously detected missense mutations R176Q, R179W, and R179Q in FGF23 from ADHR kindreds. The mutations replace R residues within a subtilisin-like proprotein convertase (SPC) cleavage site 176RHTR-179 (RXXR motif). The goal of these studies was to determine if the ADHR mutations lead to protease resistance of FGF-23. METHODS: The ADHR mutations were introduced into human FGF-23 cDNA clones with or without an N-terminal FLAG tag by site-directed mutagenesis and were transiently transfected into HEK293 cells. Protein expression was determined by Western analyses. RESULTS: Antibodies directed toward the C-terminal portion of FGF-23 revealed that the native FGF-23 protein resolved as 32 kD and 12 kD species in HEK293 conditioned media; however, the three mutated proteins were detected only as the 32 kD band. An N-terminal FLAG-tagged native FGF-23 resolved as two bands of 36 kD and 26 kD when detected with a FLAG antibody, whereas the R176Q mutant resolved primarily as the 36 kD protein species. Cleavage of FGF-23 was not enhanced by extracellular incubation of FGF-23 with HEK293 cells. Native and mutant FGF-23s bound heparin. CONCLUSIONS: FGF-23 proteins containing the ADHR mutations are secreted, and produce polypeptides less sensitive to protease cleavage than wild-type FGF-23. Therefore, the ADHR mutations may protect FGF-23 from proteolysis, thereby potentially elevating circulating concentrations of FGF-23 and leading to phosphate wasting in ADHR patients.

[Laparoscopic excision of a duodenal neuroendocrine tumor]. / Exérèse laparoscopique d'une tumeur neuroendocrine duodénale.

A 75-year-old woman with melena was found to have a carcinoid tumor in the posterior wall of the duodenal bulb. The biology was normal. The tumor measured 10 mm in size, and endoscopic ultrasonography showed only submucosal involvement. There was no liver metastasis and no regional lymph nodes. Tumoral resection was performed laparoscopically with success. Postoperative course was uneventful. Laparoscopic resection could be an appropriate minimally invasive treatment for selected small size duodenal tumors.

Congenital muscular dystrophy and cerebellar atrophy.

Two siblings and two other unrelated patients had congenital muscular weakness and dystrophic changes but normal immunocytochemical stainings for merosin, dystrophin, and dystrophin-related proteins on muscle biopsy. All had marked ataxia and cerebellar atrophy or hypoplasia. Cerebral white matter and cortical organization appeared normal.

McArdle's disease in childhood: report of a new case.

McArdle's disease (glycogenosis type V) is an inherited glycogen storage disease characterized clinically by myalgia, cramps and sometimes myoglobinuria, triggered by exercise. The onset of exercise intolerance is usually in late childhood or adolescence and diagnosis is exceptionally established during infancy. We report the case of a 6-year-old girl who had been complaining of aching muscles for a long time, and who presented after a near-drowning incident, with extensive muscle necrosis, probably secondary to myophosphorylase deficiency-induced cramps. These unusual manifestations led to the diagnosis of this rare disorder. We compare the clinical findings of this case to nine previous reports. This highlights the heterogeneous spectrum of this disease in childhood and supports the distinction of three clinical pictures in childhood: a neonatal form rapidly fatal, a milder form with congenital myopathic symptoms and a benign classical form with myalgia, cramps and pigmenturia.

[Surgical treatment of ruptures of the Achilles tendon. Apropos of 42 cases treated by Bosworth's technique]. / Traitement chirurgical des ruptures du tendon d'Achille. A propos de 42 cas traités selon la technique de Bosworth.

PURPOSE OF THE STUDY: There is no consensus on the treatment of acute ruptures of the Achilles tendon. We have chosen surgical technique with early muscle stimulation. This study analyses possibilities of functional recovery and complications in Athletes. MATERIALS AND METHODS: Between 1983 and 1994, we treated surgically 42 Athletes who had Achilles tendon ruptures with early musculo-tendinous stimulation. The 39 male and 4 female patients had a mean age of 41 years (range, 15 to 70). We have always used Bosworth's technique with gastrocnemius flap procedure. Immediately after surgery, weightbearing with below-the-knee cast was initiated for 6 weeks followed by rehabilitation. RESULTS: There was no local major complication, deep vein thrombosis or pulmonary embolism. Only one patient suffered from a traumatic rerupture one month after surgery. Mean value of the calf atrophy was less than 1 cm. 93 per cent of patients returned to previous activity levels and 78.5 per cent of patients returned to their usual sport activity. DISCUSSION: Like this study recent results confirm the low complication and recurrence rate of the surgical treatment. Percutaneous technique and conservative treatments seem to be worse for rerupture and sportive functional recovery. Early muscle stimulation decrease morbidity and calf atrophy. Our protocol with weightbearing in ankle neutral position reduces calf atrophy. CONCLUSION: A rigid and stable reconstruction, allowing early weightbearing without equinus position seems to be a rational treatment for Achilles tendon rupture in athletes.

Thyroid spindle epithelial tumor with thymus-like differentiation (the "SETTLE" tumor). An immunohistochemical and electron microscopic study.

An intrathyroid primary epithelial spindle-cell tumor with mucous cysts is described in a 9-year-old child. Histologically, this well-circumscribed tumor exhibited a nodular pattern, a prominent spindle cell component with minimal pleomorphism, and well-differentiated mucinous glands within fibrous bands. The spindle cells demonstrated diffuse immunopositivity for cytokeratin and vimentin. Electron microscopy of tissue sections demonstrated that cells contained bundles of cytoplasmic tonofilaments and numerous desmosomes. The light and electron microscopic features and immunohistochemical profile of this tumor were similar to those of recently described thyroid tumors that have been called "SETTLE" tumors (i.e., spindle epithelial tumor with thymus-like differentiation). These uncommon tumors can be considered intrathyroid thymoblastomas and must be regarded as potentially malignant lesions.

Cathepsin D immunostaining in paraffin-embedded breast cancer cells and macrophages: correlation with cytosolic assay.

High cathepsin D (cath-D) concentration in breast cancer cytosol is associated with increased risk of metastasis. To specify the relative contribution of the different cells types responsible for cath-D level in cytosol, we validated semiquantitative cath-D immunoperoxidase staining on formalin-fixed, paraffin-embedded sections, using the M1G8 monoclonal antibody, one of the two antibodies of the cytosolic assay. Using computer-aided image analysis, cath-D level in cancer cells was estimated by integrating both staining intensity in each cell and proportion of stained cells. We confirmed on 41 primary breast cancers a higher expression of cath-D in cancer cells compared with peritumoral mammary glands. Cancer cell staining was mostly in lysosomes and for some invasive ductal carcinomas in large vesicles corresponding to phagosomes. Lymphocytes and fibroblasts were not or were only weakly stained. Macrophages also were stained for cath-D, generally on the periphery of the tumor area. The cytosolic cath-D level was correlated with cath-D expression in cancer cells (r = .76; P = 1 x 10(-4)) rather than with the number of macrophages in the tumor (r = .29; P = .09), as determined by use of the specific anti-CD68 antibody. There was a significant increase in the tissue cath-D level in tumors containing large vesicles compared with tumors without large vesicles. This approach provides a means to separately estimate the prognostic significance of cath-D expression in cancer cells and macrophages when evaluating risk of metastasis.

[Congenital cystic adenomatoid malformation of the lung. Apropos of 7 cases]. / Malformation adénomatoïde kystique congénitale du poumon. A propos de sept observations.

Seven new cases of congenital cystic adenomatoid malformation of the lung have been observed in our institution during the past twelve years. The diagnosis was made in five cases on stillborn fetuses between 16 to 23 weeks of gestation and in two cases in a three-day-old infant and in a two-month-old baby. Adopting the histological classification proposed by Stocker, the seven cases observed were type II. A review of the literature on this malformation reveals the most important characteristics of this entity (clinical aspects, macroscopic and microscopic features, associated malformations) and provides certain elements of the pathogenesis which remains unclear. Finally, only histological examination can confirm the diagnosis of this malformation.

[Natural history of cardiac rhabdomyoma. Presentation of 2 cases with immunohistochemical study and review of the literature]. / Histoire naturelle du rhabdomyome cardiaque. Présentation de deux observations avec étude immunohistochimique et revue de la littérature.

Two cases of cardiac rhabdomyoma have recently been observed in foetuses. The cardiac and muscular nature of the cells was confirmed by immunohistochemistry using monoclonal antibodies. A review of the literature shows that cardiac rhabdomyomas are usually considered to be hamartomas which are composed of primitive myocardial cells. Their spontaneous regression is often observed and apoptosis has been proposed as a possible mechanism of such a phenomenon. We propose that cardiac rhabdomyomas should be better considered as developmental vestiges rather than as true hamartomas. These vestigial structures would result either from a defect in differentiation, or from a defect in regression of primitive myocardial cells.

[Primary lymphoma of the central nervous system. Multiple remission with corticosteroid therapy]. / Lymphome primitif du système nerveux central. Rémissions multiples sous corticoïdes.

A primary T-cell lymphoma of the central nervous system was diagnosed at autopsy in a 73-year-old woman. The course of the illness was made of multiple neurological episodes: hypersomnia, palsies of cranial nerves, aphasia, hemiparesis, epileptic fits during 4 years, with fast recoveries under corticosteroid therapy. CT scan and MRI abnormalities were also dramatically improved by the treatment.

[Cervical thymic choristoma ]. / Chorista thymiques cervicaux.

Neck and thyroid tumors probably of thymic origin are more frequently reported since two years. It is therefore of interest to specify incidence and way of production of cervical ectopic tissue from they issue. So, authors studied 763 autopsies of fetus of various ages, newborns and infants and surgical pieces of 8 children and adults. Analysis of 72 cases of cervical thymic chorista.