Implication of the SH3TC2 gene in Charcot-Marie-Tooth disease associated with deafness and/or scoliosis: Illustration with four new pathogenic variants.

The autosomal recessive demyelinating form of Charcot-Marie-Tooth can be due to SH3TC2 gene pathogenic variants (CMT4C, AR-CMTde-SH3TC2). We report on a series of 13 patients with AR-CMTde-SH3TC2 among a French cohort of 350 patients suffering from all type of inheritance peripheral neuropathy. The SH3TC2 gene appeared to be the most frequently mutated gene for demyelinating neuropathy in this series by NGS. Four new pathogenic variants have been identified: two nonsense variants (p.(Tyr970*), p.(Trp1199*)) and two missense variants (p.(Leu1126Pro), p.(Ala1206Asp)). The recurrent variant p.Arg954* was present in 62%, and seems to be a founder mutation. The phenotype is fairly homogeneous, as all these patients, except the youngest ones, presented scoliosis and/or hearing loss.

[Transverse reductional anomaly and atypical fibrodysplasia ossificans progressiva: A case diagnosed late]. / Anomalie réductionnelle transverse et fibrodysplasie ossifiante progressive atypique, à propos d'un cas de diagnostic tardif.

Fibrodysplasia ossificans progressiva (FOP) is a rare disease characterized by the association of congenital bone abnormalities and extraskeletal ossification flare-ups occurring in muscles and fasciae. Early diagnosis is important to prevent ossification flare-ups, but some atypical presentations can lead to errors in diagnosis and therefore delay. Here, we report on a case of an atypical presentation of FOP in a girl, in whom prominent transverse reductional abnormalities delayed diagnosis. The patient developed extraskeletal ossifications and progressive fibrosis that led to motor restrictions. Since early diagnosis is important, we discuss the clinical presentations of FOP and the differential diagnoses.

[Lumpectomy vs oncoplastic surgery for breast-conserving therapy of cancer. A prospective study about 99 patients]. / Traitement conservateur des cancers du sein: zonectomie vs oncoplastie. Etude prospective à propos de 99 patientes.

UNLABELLED: The integration of oncoplastic techniques with a concomitant contralateral symmetrization procedure is a novel surgical approach that allows wide excisions and prevents breast deformities. AIM OF THE STUDY: This prospective study was undertaken to compare the accuracy of breast resection, between standard narrow lumpectomy and oncoplastic surgery. PATIENTS AND METHODS: Ninety-nine consecutive women undergoing breast cancer resection were enrolled in a prospective study comparing oncoplastic surgery (42 women) and standard lumpectomy (57 women). The size of the glandular resection, the width of the nearest margins, the ratio of clear margins and the need for further surgery were recorded. RESULTS: The oncoplastic approach resulted in significantly greater glandular resection and wider free histological margins than did standard lumpectomy. The need for re-exicsional surgery was significantly lower in the oncoplastic group than in the lumpectomy group. Furthermore, a trend towards fewer secondary mastectomies was seen for the oncoplastic approach versus standard lumpectomy. CONCLUSIONS: The use of oncoplastic techniques and concomitant symmetrization of the contralateral breast allows extensive resections for conservative treatment of breast carcinoma achieves accurate tumour resection and reduces the need for further surgery.

Differential expression of estrogen receptor-alpha and -beta messenger RNAs as a potential marker of ovarian carcinogenesis.

Although estrogen receptor (ER)-alpha is expressed in both benign and malignant ovarian tumors, the role of ER in ovarian carcinogenesis of epithelial tumors is still unknown. In view of the recent characterization of ER-beta, a second form of ER that seems to be highly expressed in ovaries, we reexamined this issue by studying the relative expression of ER-alpha and -beta in human ovarian tumor progression. We developed a competitive PCR assay based on coamplification of the two ERs in target nucleotide sequences displaying a high homology (exons 3 and 4). Coamplification experiments with varying amounts of plasmids containing ER-alpha and -beta cDNAs showed that this assay was reliable for discriminating as little as a 2-fold difference in the initial ER-alpha:ER-beta cDNA ratio. The relative expression of ER-alpha compared with ER-beta mRNAs was studied in human ovarian cancer cell lines (n = 5) and in normal ovaries (n = 6), then in human benign and malignant tumor samples including ovarian cysts (n = 24), borderline tumors (n = 3), and cancers (n = 10). In normal ovaries, ER-beta mRNA was the predominant ER form, whereas in ovarian cancer cell lines ER-alpha mRNA was markedly increased as compared with ER-beta. In benign and borderline tumors, ER-beta mRNA was detected in 78% of tumors, whereas ER-alpha mRNA was detected in 29%. In ovarian carcinomas, both ER-alpha and -beta mRNAs were expressed in 80% of tumors. The ER-alpha:ER-beta mRNA ratio was >1 in only one cyst sample (4%). In contrast, the ER-alpha:ER-beta mRNA ratio was markedly increased in ovarian cancers because 60% showed an ER-alpha:ER-beta mRNA >1. In situ hybridization experiments showed overlapping tissular distribution of ER-beta and -alpha expression in cancers and cysts, with a main localization in the epithelium and only a low level of expression in stromal cells. In summary, we found an increase in the ER-alpha:ER-beta mRNA ratio in ovarian carcinomas as compared with normal ovaries and cysts. These data suggest that overexpression of ER-alpha relative to ER-beta mRNA may be a marker of ovarian carcinogenesis.

[Ovarian cancer: incidence and mortality in France]. / Les cancers de l'ovaire: incidence et mortalité en France.

OBJECTIVES: To describe the ovarian cancer incidence and mortality trends in France from 1980 to 2000. MATERIALS AND METHODS: Incidence data were obtained from 9 French departments covered by cancer registries which systematically record all cancers, of which those of the ovary. Mortality data has been provided by INSERM bureau in charge of the analysis of death certificates. RESULTS: With 4500 incident cases and 3500 deaths for the year 2000 in France, ovarian cancer still shows a poor prognosis. Age adjusted incidence and mortality rates are almost stable over the study period at an annual rate of 9 by 100000 for incidence and 5.5 by 100000 for mortality. However the risk of developing this cancer and the risk of dying from it, steadily decreased for the cohort born in 1930 to 1950, and the beginning of this reduction corresponds exactly to the beginning of oral contraception. We present comparisons between departments and analyze the border-line tumors in parallel with invasive cancers. CONCLUSION: The cancer of the ovary represents only a small part of female cancers (3.8%) in France and its incidence is stable over time, but its prognosis is very bad.

Cathepsin-D in human endometrium: induction by progesterone and potential value as a tumor marker.

Using an immunoenzymatic assay, cathepsin-D concentrations were measured in the cytosol of human endometrium biopsies. The level of cathepsin-D was higher in the luteal phase than in the follicular phase (P less than 0.01), suggesting increased accumulation by progesterone. Induction by progestin was confirmed by immunoprecipitation of cathepsin-D from a lysate of epithelial endometrial cells previously treated in primary culture with R5020 (10 nM); estradiol (10 nM) had no effect. Immunohistochemistry showed that cathepsin-D is mainly localized in the epithelium and that its level is higher in the luteal phase. The plasma level of cathepsin-D was stable during the menstrual cycle, ranging between 2.5-10 pmol/mL, but increased slightly during pregnancy. The mean level of cathepsin-D was higher in 19 endometrial carcinoma than in 20 normal endometrium, but was not correlated with steroid receptor status. However, using 15 pmol/mg protein as a cut-off level, the cathepsin-D status (high or low) was correlated with the degree of myometrial invasion (greater than or equal to one third) by adenocarcinoma cells, whereas steroid receptor status was not. We conclude that cathepsin-D is induced by progesterone in human endometrium, as it is in normal rat uterus, and we suggest that a low concentration of cathepsin-D in the cytosol of endometrial adenocarcinoma may indicate a favorable prognosis, since it is correlated with low myometrial invasion.

Immunohistochemical detection of the estrogen-regulated 52,000 mol wt protein in primary breast cancers but not in normal breast and uterus.

An estrogen regulated glycoprotein of molecular weight 52,000 is released by metastatic human breast cancer cells in culture. In order to detect this protein directly in human tissues, several high affinity monoclonal antibodies were produced against the 52,000 mol wt protein. Frozen sections of human breast cancer samples were stained by the peroxidase-anti-peroxidase method using these antibodies. In 20 of 25 samples, specific immunoperoxidase staining was observed in the cytoplasm of epithelial cells with six monoclonal antibodies to the 52,000 mol wt protein. The 5 samples that were not stained contained no detectable estrogen receptor. Epithelial cells were not stained in 6 normal mammary glands collected during reduction mammoplasties and in 9 normal uteri, whether tissues were collected during the follicular or luteal phase. The demonstration that the 52,000 mol wt estrogen regulated protein is present in the cytoplasm of some primary breast cancers but absent in normal mammary tissue and uterus indicates its possible use as a tumor marker.

Ultrastructural and enzyme histochemical study of ovarian hilar cells in women and their relationships with sympathetic nerves.

The ultrastructure of normal ovarian hilar cells, both during the reproductive era and after the menopause, shows evidence of steroid hormone synthesis. In this respect these cells are very similar to Leydig cells in that they contain mitochondria with a dense matrix, a highly developed smooth endoplasmic reticulum, Reinke crystals, and microcystalline inclusions. The latter are much more numerous than in the normal testis. Their enzymatic activities are quite similar to those of Leydig cells. Ovarian hilar cells seem to originate from progressive metamorphosis of fibroblastic cells under the induction of sympathetic nervous structures. Their relations with hilar nerves are of three types: simple direct membrane contact without a Schwann cell sheath, intimate intracytoplasmic relationships, and specialized contacts, which are comparable to a synapse.

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.

Dissociated overexpression of cathepsin D and estrogen receptor alpha in preinvasive mammary tumors.

The role of estrogen as a promoter agent of sporadic breast cancer has been considered by assaying, in benign breast disease (BBD) and in situ carcinomas (CIS), 2 markers, the estrogen receptor alpha (ERalpha) and cathepsin D (cath-D) involved in estrogen action on mammary tissue. ERalpha and cath-D were assayed by quantitative immunohistochemistry using an image analyzer in 170 lesions of varying histological risk (94 BBD and 76 CIS), and in "normal" glands close to these lesions. The ERalpha level increased significantly in proliferative BBD with atypia (P < .001), in non-high-grade CIS (P < .001), and in adjacent "normal" glands. ERalpha level was decreased in high-grade ductal CIS (DCIS) and also in adjacent "normal" glands. Cath-D level increased in ductal proliferative BBD (P < or = .01) and in high-grade DCIS (P < or = .003), but not in the other lesions. After menopause, ERalpha level was increased (P = .012) but not cath-D level. According to Mac Neman test, the high-grade DCIS were predominantly ERalpha negative and cath-D positive (P = .0017), and the other CIS were predominantly ERalpha positive and cath-D negative (P = .0002). The 2 markers are overexpressed early in premalignant lesions, but independently. This dissociation suggests a branched model of mammary carcinogenesis involving 1 estrogen-independent pathway with high cath-D and low ERalpha levels (including high-grade DCIS) and 1 estrogen-dependent pathway, with high ERalpha level (including proliferative BBD with atypia and low-grade DCIS). We propose that ERalpha-negative breast cancers may develop directly from high-grade DCIS and that ERalpha assay in preinvasive lesions should be considered in prevention trials with antiestrogens.

Ultrasound-assisted laparoscopic creation of a neovagina by modification of Vecchietti's operation.

BACKGROUND: In performing Vecchietti's operation laparoscopically, it is important to ensure bladder and rectum integrity. We report new techniques of ultrasonography and suture retrieval that simplify and improve the ease and speed of this operation. TECHNIQUE: The pneumoperitoneum is emptied and the bladder filled with 200 mL of sterile water. The ultrasound probe is placed on the suprapubic wall for a sagittal image. The needle progresses medially through the vesicorectal space, with ultrasound guidance, and its emergence into the pelvis is controlled with laparoscopy. The nylon sutures carrying the dilation ball are threaded through the needle and brought back through the abdominal wall. EXPERIENCE: Seven patients with vaginal aplasia had this procedure. There were no complications, and the mean operative time was 43 minutes (range 35-55). Mean vaginal length was 7 cm (range 6-10). Four women defined sexual intercourse as very satisfying and two as moderately satisfying. CONCLUSION: This original technique was used for easy, safe, and rapid creation of neovaginas.

Cervical ripening with mifepristone before labor induction: a randomized study.

OBJECTIVE: To determine the efficacy and safety of mifepristone for cervical ripening in post-term pregnancies. METHODS: Women with post-term pregnancies and Bishop scores less than 6 were assigned randomly to mifepristone (41 patients) or placebo (42 patients). Mifepristone was given orally in a dose of 400 mg. Efficacy was assessed by change in the Bishop score within 48 hours after treatment; a score of 6 or greater was considered a "strict" success. An "extended" success rate was defined, including all patients with scores of at least 6 or those who delivered within 48 hours of treatment. Antenatal safety was assessed by fetal heart rate testing before and throughout labor. Neonatal safety was assessed by Apgar score, arterial or venous pH of cord blood, and blood glucose level during the first 48 hours. Analysis used Student t test for continuous variables, Kruskal-Wallis test for ordinal data, and chi2 for categoric variables. RESULTS: Strict success was achieved in 10 of 18 mifepristone patients (55%) evaluated for Bishop score on day 2 versus 8 of 29 placebo patients (27.5%) (P=.004). Extended success was achieved in 33 mifepristone patients (80.5%) and 21 placebo patients (50.0%) (P=.004). There were no statistical differences with regard to number of cesareans or fetal and neonatal safety. CONCLUSION: Mifepristone proved effective for cervical ripening and reduced the time to delivery compared with placebo, but it did not improve the rate of cesarean. Our study did not include enough pregnancies to reach conclusions about fetal or neonatal safety.

Clinical and biologic prognostic factors in breast cancer diagnosed during postmenopausal hormone replacement therapy.

OBJECTIVE: To ascertain the influence of hormone replacement therapy on clinical and biologic prognostic factors of breast cancer. METHODS: Between 1976-1992, we treated 1081 postmenopausal women for breast cancer at our institution. Of these, 68 were undergoing postmenopausal hormone replacement therapy at the time of diagnosis. These patients were compared with a matched control group of 272 breast cancer patients who had not undergone prior hormone replacement therapy. RESULTS: Patients who developed breast cancer during hormone replacement therapy had fewer locally advanced cancers (large tumors and extensive lymph node involvement) and more well-differentiated cancers (infiltrating lobular cancers and grade 1 cancer). The number of patients with estradiol or progesterone receptors was lower in the hormone-treated group. Metastasis-free survival curves showed a tendency (P = .05) for better prognosis in hormone-treated patients both overall and in stage T2. CONCLUSIONS: Hormone replacement therapy per se does not affect the prognosis of breast cancer. Regular surveillance during hormone replacement therapy reduces the number of locally advanced cancers and thus improves the survival rate. The higher number of well-differentiated cancers and the distribution of hormone receptivity may reflect interaction between neoplastic tissue and exogenous hormones.

Successful in vitro fertilization-surrogate pregnancy in a patient with ovarian transposition who had undergone chemotherapy and pelvic irradiation.

OBJECTIVE: To present a case of IVF-surrogate pregnancy in a patient with ovarian transposition who had undergone chemotherapy and total pelvic irradiation. DESIGN: Case report. SETTING: Teaching hospital. PATIENT(S): A 29-year-old woman who had undergone Wertheim's hysterectomy for a bulky carcinoma of the uterine cervix. INTERVENTION(S): Ovarian transposition before chemotherapy and total pelvic irradiation. Standard IVF treatment, transabdominal oocyte retrieval, and transfer to the surrogate mother. MAIN OUTCOME MEASURE(S): Results of the IVF cycle. RESULT(S): A twin pregnancy at the first cycle and two live newborns. CONCLUSION(S): This is the first reported case of ovulation induction and oocyte retrieval performed on a transposed ovary.

Effects of selective reduction in triplet gestation: a comparative study of 80 cases managed with or without this procedure.

OBJECTIVE: To evaluate the effect of selective termination in triplet pregnancies. DESIGN: Comparative, prospective, nonrandomized study. SETTING: All 80 pregnancies were managed in a single tertiary center by the same obstetrical team. PATIENTS: Eighty women with triplet pregnancies were divided into two groups: group I consisted of 48 women who wished to continue their pregnancies without reduction; in group II were 32 women who choose reduction generally to obtain twins. INTERVENTIONS: Selective terminations were performed after an average term of 9.6 weeks of gestation by transcervical or transabdominal approaches. MAIN OUTCOME MEASUREMENTS: The rate of miscarriage and prematurity, fetal growth, perinatal morbidity and mortality, and maternal complications in the two groups. RESULTS: Prematurity was lower in reduced pregnancies (95.5% in triplets versus 53.5%), especially between 24 to 32 weeks' gestation where prematurity was reduced by half. Birth weight was > 450 g higher in the reduced group. The perinatal mortality rate was lower for reduced pregnancies, but this difference was not statistically significant. Five life-threatening maternal complications occurred in triplets, with none in the reduced group. CONCLUSIONS: Selective terminations are effective in decreasing the rate of prematurity, improving fetal growth, and avoiding maternal complications. The procedure thus could be used in triplet gestations. The ultimate decision should be taken by the couple who must be well informed of the risks of the procedure before deciding.

Pre-operative arterial embolisation of a uterine rhabdomyosarcoma in a 14-year-old girl.

We report a young patient suffering from a uterine rhabdomyosarcoma. Particular features of the present case are: accuracy of the tumour spread evaluation performed by MRI of the pelvis; and the use of pre-operative arterial embolisation. The present multimodal management highlights the usefulness of cooperation between surgeons and radiologists in lowering operative bleeding and finally permitting uterine conservation.

Prenatal diagnosis of an abdomino-pelvic hydrometrocolpos; a case report.

The authors describe a case of prenatal diagnosis of hydrometrocolpos performed at 35 weeks of ammenorhea. Diagnosis was based on fetal images of a rounded, solid, pelvic mass increasing rapidly, which evoked vaginal and uterine distension. No associated anomaly was found. This very unusual genital malformation required treatment at birth. This case shows that hydrometrocolpos can be evidenced by prenatal ultra-sonography allowing early treatment and prevention of complications.

The effects of mifepristone on uterine sensitivity to oxytocin and on fetal heart rate patterns.

OBJECTIVE: To compare the incidences of tachysystole, hypertonia and fetal heart rate (FHR) abnormalities in women treated by mifepristone plus prostaglandins (PGs), mifepristone alone or PGs alone for an unfavourable cervix. STUDY DESIGN: In this retrospective study, all women between 37 and 42 weeks were eligible for the study if they had undergone cervical ripening prior to labour induction. In group 1, the women were treated with mifepristone plus PGs (n=103). Group 2 women were treated with mifepristone alone (n=96) and group 3 women with PGs alone (n=100). Incidences of tachysystole, hypertonia and FHR abnormalities were compared. RESULTS: During induction of labour, tachysystole and hypertonia occurred more frequently in women treated with mifepristone. Severe bradycardia and recurrent late decelerations were more frequent after the initiation of oxytocin in groups 1 and 2 than in group 3. CONCLUSIONS: In this study, mifepristone increased the incidences of tachysystole, hypertonia and FHR abnormality.

Early prenatal diagnosis of congenital cystic adenomatoid malformation of the lung (Stocker's type I); a case report.

A congenital cystic adenomatoid malformation was diagnosed by ultrasound examination at 20 week's gestation. The entire right lung was cystic and elements of poor prognosis such as hydrops fetalis and polyhydramnios were present. After verification of the karyotype, abortion was performed and autopsy confirmed prenatal findings and Stocker's type I. Cystic congenital adenomatoid malformation of the lung is a rare form of congenital pulmonary disease. Our case shows that this malformation can be accurately diagnosed during the midtrimester of pregnancy by ultrasound examination. Ultrasound examination permits an evaluation of the three types described by Stocker and may reveal certain lesions associated with poor prognosis, such as anasarca or polyhydramnios. Also, it offers the possibility to save some fetuses by surgical decompression in the immediate postnatal period, or to terminate earlier pregnancies by abortion.