A novel lethal recognizable polymicrogyric syndrome caused by ATP1A2 homozygous truncating variants.

Polymicrogyria is a heterogeneous malformation of cortical development microscopically defined by an excessive folding of the cortical mantle resulting in small gyri with a fused surface. Polymicrogyria is responsible for a wide range of neurological symptoms (e.g. epilepsy, intellectual disability, motor dysfunction). Most cases have a supposed environmental clastic vascular or infectious origin but progress in genomics has revealed new monogenic entities. We report four cases from two independent families sharing a common recognizable lethal syndromic polymicrogyria of autosomal recessive inheritance. Beyond diffuse polymicrogyria detected prenatally, pathological examination revealed a common pattern associating meningeal arterial calcifications, necrotic and calcified areas in basal ganglia, dentato-olivary dysplasia and severe hypoplasia/agenesis of the pyramidal tracts. In all affected cases, exome sequencing showed a pathogenic homozygous nonsense ATP1A2 variant. This resulted in absence of immunodetectable ATP1A2 protein in two brains analysed. ATP1A2 encodes the alpha-2 isoform of the Na+/K+-ATPase, which is highly expressed in brain tissues and has previously been related to familial hemiplegic migraine (MIM#602481) and alternating hemiplegia of childhood (MIM#104290). Through the description of this genetic entity, we emphasize the possibility of dual mode of transmission for disease-causing genes and provide the key neuropathological features that should prompt geneticists to test for mutations in the ATP1A2 gene.

Bardet-Biedl syndrome: Antenatal presentation of forty-five fetuses with biallelic pathogenic variants in known Bardet-Biedl syndrome genes.

Bardet-Biedl syndrome (BBS) is an emblematic ciliopathy associated with retinal dystrophy, obesity, postaxial polydactyly, learning disabilities, hypogonadism and renal dysfunction. Before birth, enlarged/cystic kidneys as well as polydactyly are the hallmark signs of BBS to consider in absence of familial history. However, these findings are not specific to BBS, raising the problem of differential diagnoses and prognosis. Molecular diagnosis during pregnancies remains a timely challenge for this heterogeneous disease (22 known genes). We report here the largest cohort of BBS fetuses to better characterize the antenatal presentation. Prenatal ultrasound (US) and/or autopsy data from 74 fetuses with putative BBS diagnosis were collected out of which molecular diagnosis was established in 51 cases, mainly in BBS genes (45 cases) following the classical gene distribution, but also in other ciliopathy genes (6 cases). Based on this, an updated diagnostic decision tree is proposed. No genotype/phenotype correlation could be established but postaxial polydactyly (82%) and renal cysts (78%) were the most prevalent symptoms. However, autopsy revealed polydactyly that was missed by prenatal US in 55% of the cases. Polydactyly must be carefully looked for in pregnancies with apparently isolated renal anomalies in fetuses.

Impact of micrometastasis or isolated tumor cells on recurrence and survival in patients with early cervical cancer: SENTICOL Trial.

OBJECTIVES: The aim of this study was to evaluate the impact of micrometastasis and isolated tumor cells on disease recurrence in patients with early-stage cervical cancer. METHODS: We included patients with International Federation of Gynecology and Obstetrics (FIGO) stage IA1 with lymphvascular space invasion, stage IA2, and IB1 who participated in the SENTICOL1 trial. A centralized histologic analysis with re-reading and ultrastaging was performed 3 months after surgery and treatment was not impacted by findings from our study. Patients were followed for 3 years and outcomes were compared according to prognostic factors. RESULTS: A total of 139 patients were included and 13 recurrences were found. There were two recurrences in patients with positive sentinel lymph node (SLN) (one macrometastases and one micrometastases) and 11 recurrences in patients with negative lymph nodes (sentinel or non-sentinel). Among patients with positive SLN for micrometastases there was only one recurrence. No patient with isolated tumor cells on their lymph nodes experienced a recurrence. There was a significant decrease in disease-free survival in patients aged >50 years (p = 0.01). CONCLUSION: Evidence of micrometastasis or isolated tumor cells in the SLN of untreated patients with early cervical cancer in the SENTICOL1 trial did not impact progression-free survival.

Vaginal Neoplasia Induced by an Unusual Papillomavirus Subtype in a Woman with Inherited Chromosomally Integrated Human Herpesvirus Type 6A.

We describe here a case of high-grade vaginal squamous lesion in a 54-year-old woman with a papillomaviruses (HPV) genital infection that developed from a cervical low-grade squamous intraepithelial lesion (SIL) to a high-grade SIL (H-SIL) on cytological examination. A colposcopy exam led to the detection of suspect vaginal lesions with granulomatous infiltrations, which were classified as a Vaginal Intra-Epithelial Neoplasia grade 2 after pathologists' analyses. After a laser vaginal surgery and a loop excision of the transformation zone, the analyses of the anatomical pieces using a near-complete HPV screening panel revealed an HPV-4 infection that was not detected before in cervical smears. This HPV-infection is associated with a high human herpesvirus type 6A (HHV-6A) viral load in the same anatomical piece. The presence of an inherited chromosomally integrated HHV-6A (iciHHV-6A) was proved in this patient by real-time polymerase chain reaction on hair follicles and nail. This case suggests reconsidering both the benign nature of low-grade lesions in the female genital tract and the well-known "good" prognosis of low-risk HPV infection, especially when iciHHV-6A is diagnosed. This clinical course insists on the benefits of the multiplex panel use or global sequencing in order to optimize biological testing sensitivity, and so enhance clinical management of infection-induced neoplasia.

Fetal anomalies associated with HNF1B mutations: report of 20 autopsy cases.

OBJECTIVES: To describe macroscopic and microscopic anomalies present in fetuses carrying hepatocyte nuclear factor-1 ß mutation, their frequency, and genotype/phenotype correlations. METHODS: Clinical data, ultrasound findings, genetic studies, and autopsy reports of 20 fetal autopsies were analyzed. Histology was reviewed by two pathologists. RESULTS: Macroscopic findings were typically unilateral or bilateral renal enlargement and cortical cysts. Renal lesions were associated with congenital anomalies of the kidney and urinary tract in 25% of cases. Microscopic renal anomalies were dominated by glomerulocystic kidney and renal dysplasia. Extra-renal manifestations such as pancreatic hypoplasia (75%) and genital anomalies (68%) were only detected at autopsy. In 40% of cases, there was heterozygous deletion of the whole gene. There were de novo mutations in 40%. CONCLUSION: This study underlines the importance of considering hepatocyte nuclear factor-1 ß mutations in fetuses with congenital anomalies of the kidney and urinary tract, especially when associated with pancreatic hypoplasia. No correlation between phenotype and genotype was found, highlighting high intra-familial variability in cases with inherited mutations. © 2016 John Wiley & Sons, Ltd.

The incidence and clinical significance of the micrometastases in the sentinel lymph nodes during surgical staging for early endometrial cancer.

INTRODUCTION: The status of regional node remains one of the most important factors to guide adjuvant therapy in endometrial cancer (EC). Pelvic recurrence occurs in up to 15% of early EC patients with negative pelvic lymph nodes (LNs). The prognostic significance of detecting micrometastases (µM) in LN is debated. This retrospective case-control study performed in the Oncological Gynecology Department in Lyon between December 1998 and June 2012 reports the incidence and the clinical significance of µM detected during ultrastaging of negative sentinel lymph node (SLN) in EC. PATIENTS AND METHODS: Ninety-three patients affected by type I and II EC were submitted to surgery with SLN. Dual-labeling method was used to detect SLN. All the SLNs were subjected to ultrastaging researching µM. The patients with a locoregional or distant relapse represented the case-series (CS). The patients without locoregional or distant recurrences were the case-controls (CC).They were matched (1:2 ratio) according to age, International Federation of Gynecology and Obstetrics stage, and histopathologic features. RESULTS: Ten patients presenting a relapse represented CS. In the remaining 83 patients without recurrence, 20 CC were individualized. The detection rate of SLN per hemipelvis was of 17 (85%) of 20 hemipelvis and of 33 (82.5%) of 40 hemipelvis for CS and CC, respectively. Two SLN of CS arm were positives at frozen section. One of the 8 patients of CS arm with negative SLNs was positive for µM by immunohistochemistry analysis. CONCLUSIONS: Lymph node status is one of the most important histopathologic features to determine the adjuvant treatment. The SLN technique could be proposed in selected patients affected by early EC. The µM in SLN could be researched and could help to modulate the following treatment. The multicenter study must be performed to clarify the optimal method of research of SLN in EC and the significance of µM in the LN.

The sentinel node technique detects unexpected drainage pathways and allows nodal ultrastaging in early cervical cancer: insights from the multicenter prospective SENTICOL study.

BACKGROUND: Sentinel lymph node (SLN) biopsy may improve nodal staging in cervical cancer. The aims of this study are to determine the rate of unusual patterns of cervical lymphatic drainage, to determine the rates of micrometastases and isolated tumor cells (ITCs) in SLNs, and to assess the clinical impact of SLN biopsy. METHODS: Multicenter prospective study conducted between January 2005 and June 2007 in women undergoing laparoscopic surgery for early cervical cancer. Combined technetium/Patent Blue labeling was used. Lymphoscintigraphy was performed before surgery. SLN location was recorded, and factors associated with location were explored. SLNs underwent step sectioning ± immunohistochemistry. RESULTS: 145 patients were enrolled and 139 included in a modified intention-to-diagnose analysis. Although 80.6 % of SLNs were in external iliac and interiliac areas, 38.2 % of patients had at least one SLN in an unexpected area and 5.1 % had SLNs only in unexpected areas. In unexpected areas, the number of SLNs per patient was not significantly different between lymphoscintigraphy and intraoperative detection (0.79 [0.62-1.02] versus 0.50 [0.37-0.68]; P = 0.096). In expected locations, there were significantly more blue and hot SLNs per patient than blue or hot SLNs (1.70 [1.45-1.99], 0.42 [0.30-0.57], 0.52 [0.39-0.69]). Of 28 metastatic SLNs, 17 contained micrometastases or ITCs. SLN involvement was found only by immunohistochemistry in 39.1 % of patients with positive nodes, and involved SLNs were located in unexpected areas in 17 % of those patients. CONCLUSIONS: Sentinel lymph node biopsy detects unusual drainage pathways and micrometastases in a substantial proportion of patients, thus improving nodal staging.

Early invasive cervical cancer during pregnancy: different therapeutic options to preserve fertility.

INTRODUCTION: Cervical cancer is the second most common cancer diagnosed during pregnancy. Conservative management is possible, and different options should be discussed with patients. The main decision parameters are stage of disease, lymph node status, trimester of pregnancy and wishes of the patient. We reviewed our experience on cases of early-stage cervical cancer discovered during pregnancy and treated with different options of fertility-sparing management. MATERIALS AND METHODS: Between 1990 and 2010, 5 patients with early-stage cervical cancer diagnosed during pregnancy were referred to our department for fertility-sparing treatment. The mean age at diagnosis was 28.6 years (range, 26-30 years). The stages of the tumors according to the International Federation of Gynecology and Obstetrics were IA2 in 2 women and IB1 in 3 women. The histological type was squamous carcinoma in 3 cases and adenocarcinoma in 2 cases. All patients willing to preserve their fertility were treated with vaginal radical trachelectomy (VRT) and pelvic lymph nodes dissection (PLN-D). RESULTS: Three procedures were performed in the first trimester: 1 patient was treated with medical abortion and then VRT and PLN-D, 2 patients were submitted to VRT and PLN-D during the first trimester, and 1 patient's case was complicated by spontaneous abortion. One patient was observed during the second trimester (20 weeks of gestation) and treated with VRT and PLN-D during pregnancy. Because this patient had pelvic lymph nodes positive for cancer, a cesarean delivery (CD) with radical hysterectomy and para-aortic lymph nodes dissection was performed followed by chemoradiotherapy. The last patient was evaluated during the third trimester of her pregnancy. Treatment included CD followed by VRT and PLN-D, which was delayed, to allow fetal maturity. CONCLUSIONS: Diagnosis of cervical cancer can occur during pregnancy. Different options of fertility-sparing treatment can be discussed on the basis of several factors: tumor stage, gestational age, and the patient's desire regarding fertility and pregnancy sparing.

Lymph Node Involvement in Early-Stage Cervical Cancer: Is Lymphangiogenesis a Risk Factor? Results from the MICROCOL Study.

Background: In patients with cervical cancer, the presence of tumoral lymph-vascular space invasion (LVSI) is the main risk factor for pelvic lymph node metastasis (PLNM). The objective of this study was to evaluate the presence of several markers of lymphangiogenesis in early-stage cervical cancer and their correlation with PLNM and tumoral recurrence. Materials and Methods: Seventy-five patients with early-stage cervical carcinoma underwent sentinel lymph node (SLN) sampling in association with complete pelvic lymph node dissection. Primary tumors were stained with the following markers: Ki67, D2-40, CD31 and VEGF-C. A 3-year follow-up was performed to evaluate the disease-free survival. Results: Overall, 14 patients (18.6%) had PLNM. Positive LVSI was seen in 29 patients (38.6%). There was a significant correlation between LVSI evidenced by H/E staining and PLNM (p < 0.001). There was no correlation between high Ki67, CD31, D2-40, and VEGF-C staining with PLNM or tumor recurrence. Conclusions: Our data support that lymphatic spread does not require the proliferation of new lymphatic endothelial cells in early-stage cervical cancer. These results emphasize the importance of pre-existing peritumoral lymphatic vessels in the metastatic process in early cervical cancer. None of the markers of lymphangiogenesis and proliferation assessed in this study were predictive of PLNM or recurrence.

Neoadjuvant chemotherapy and vaginal radical trachelectomy for fertility-sparing treatment in women affected by cervical cancer (FIGO stage IB-IIA1).

OBJECTIVES: The aim of the present report is to support the feasibility and the safety of a new fertility-sparing treatment in young women affected by bulky cervical cancer. METHODS: Between February 2007 and October 2010, seven patients presenting large IB-IIA1 tumors (30-45 mm) were scheduled for conservative treatment. All patients underwent neoadjuvant chemotherapy (NACT) followed by laparoscopic pelvic lymphadenectomy and vaginal radical trachelectomy (VRT). RESULTS: One patient presented hematological toxicity during NACT (grade 3). All patients showed complete disappearance of tumor (n=4/7) or partial response (a 50% or more decrease in total tumor size, n=3/7) to neoadjuvant treatment, and they were all treated with pelvic lymphadenectomy and VRT. Additional treatment (interstitial brachytherapy) was offered to only one woman because of a persistent parametrial tumoral lesion. After a mean follow up of 22 months (range 5-49), no relapse was observed. To date, only one woman in our study attempted to conceive and she is currently pregnant. CONCLUSIONS: Neoadjuvant chemotherapy for fertility sparing treatment is an innovative approach which is potentially quite interesting for many young women affected by bulky cervical cancer. These women, i.e. those with tumors larger than 2 cm (2-5 cm), are traditionally not offered fertility sparing treatment, thus the preliminary data we report here might have a promising impact. Nevertheless, for these patients it may be suitable to use the more radical, and time-tested, conservative surgical approach to allow for a complete and conservative excision of the residual tumor after neoadjuvant treatment. Studies with a larger number of patients and adequate follow-up are required to validate this conservative approach and to define clearly the good indications for this treatment.

Diagnostic value of intraoperative examination of sentinel lymph node in early cervical cancer: a prospective, multicenter study.

OBJECTIVES: Sentinel lymph node (SLN) biopsy is a surgical procedure proposed in early cervical cancer. This technique yields the potential interest to reduce the morbidity of complete lymphadenectomy, which could then be performed only in case of positive SLN. Intraoperative examination has a major per-operative role in predicting nodal involvement and preventing a second step procedure. The aim of this study was to assess the diagnostic value of intraoperative examination with frozen section (FS) or imprint cytology (IC) of SLNs in early cervical cancer. METHODS: Prospective study in 7 centers (01/2005-06/2007) including patients with stage IA1 and lymphovascular space involvement to IB1 cervical cancer (squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma). SLNs were detected with a combined method (Tc99m+blue dye) and then removed laparoscopically. Intraoperative examination (FS or IC) was not systematically performed but recommended in case of macroscopical nodal enlargement in 5 centers. Results of intraoperative examination were compared with final histology performed by Hematoxylin-Eosin-Safran staining and immunohistochemistry. The diagnostic value of intraoperative examination was calculated. RESULTS: One hundred and thirty-nine patients were analyzed in the study. The combined detection rate was 97.8% per patient, with 454 detected SLNs. One hundred and two patients (73.4%) had an intraoperative examination (97 patients with FS and 5 with IC). Among patients with intraoperative examination, 5 SLNs were positive (all with macrometastasis at final histology), as compared with 22 metastatic nodes at final result. The 17 false negative SLNs were: 4 macrometastasis, 4 micrometastasis and 9 isolated tumor cells. Sensitivity of the intraoperative examination per node was 20.7% [95%CI: 7.8%-45.4%] and the negative predictive value 93.0% [95%CI: 89.0%-95.9%]. CONCLUSIONS: Intraoperative examination of SLNs by FS and IC has a poor diagnostic value. This is mainly related to micrometastasis and isolated tumor cells, which are not detected by intraoperative techniques. Other techniques, like new molecular assays, should be investigated to improve intraoperative assessment of SLNs.

BBS10 mutations are common in 'Meckel'-type cystic kidneys.

BACKGROUND: Bardet-Biedl syndrome (BBS) is a genetically heterogeneous, multisystemic disorder characterised by progressive retinal dystrophy, obesity, hypogenitalism, learning difficulties, renal abnormalities and postaxial polydactyly, with only the last two antenatally observable. BBS is inherited as an autosomal recessive disorder, and 14 genes have been identified to date (BBS1-BBS14). In addition, a complex digenic inheritance has been established in some families. Mutations of the BBS10 gene on chromosome 12q21.2 account for 20% of BBS cases. METHODS: Given the fact that mutations in BBS genes have already been found in Meckel-like fetuses, and in light of the major contribution of BBS10 to BBS, the BBS10 gene was sequenced in 20 fetal cases and a child diagnosed antenatally presenting with characteristic renal anomalies and polydactyly, but without biliary dysgenesis. RESULTS: Recessive mutations were identified at the BBS10 locus in five cases: four fetuses and a child. Interestingly, one of them had situs ambiguus, a rare feature in BBS. In the child, BBS gene screening identified a heterozygous BBS6 nonsense mutation in addition to the homozygous BBS10 mutation, in accordance with the suggested multigenic inheritance of the disease. CONCLUSIONS: These results confirm that BBS is underdiagnosed antenatally and should systematically be suspected in fetuses with severe cystic kidneys leading to oligoamnios and fetal or perinatal death. Moreover, this study confirms the high frequency of BBS10 mutations, particularly of the p.Cys91LeufsX5 allele, including severe lethal cases.

Inbag Morcellation Applied to the Laparoscopic Surgery of Leiomyoma: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the efficacy and safety of an endoscopic bag during laparoscopic morcellation of leiomyoma or myomatous uterus. MATERIALS AND METHODS: A total of 48 patients with symptomatic leiomyoma were randomized for laparoscopic morcellation in two groups: group A with a specific endoscopic bag or group B without any bag. The primary outcome measure was the detection of smooth muscle cells from washing after power morcellation determined by peritoneal cytology and immunohistochemistry (IHC). RESULTS: Cytology and IHC from group A did not revealed any smooth muscle cells, while 29% of cases (7/24) from group B were positive (p = .009). The duration of the surgical procedure was the same in both groups. The duration of positioning the bag did not change significantly during the study. Only in one case the use of the bag was difficult due to a low pneumoperitoneum. CONCLUSIONS: The use of a morcellation bag is efficient to prevent the spread of smooth muscle cells during the morcellation of leiomyoma or myomatous uterus. This study confirms the feasibility and the safety of the laparoscopic inbag morcellation versus open morcellation.

Neonatal Alloimmune Thrombocytopenia With Amegakaryocytosis, B Lymphopenia, and Villitis.

Neonatal alloimmune thrombocytopenia (NAIT) is a common but significant challenge for neonatologists and a potentially devastating disease that may lead to intracranial bleeding. The underlying mechanism of thrombocytopenia is expected to be mediated by accelerated clearance of antibody-opsonized fetal platelets. We report severe recurrent NAIT related to human platelet antigen (HPA)-15 systems in 2 consecutive siblings. The first child presented with intracranial hemorrhage at birth and subsequently died. The diagnosis of NAIT, although initially suspected, was ruled out after negative investigation of only HPA-1, HPA-3, and HPA-5 systems. The second child experienced a clinically milder presentation but a profound thrombocytopenia. In both siblings, NAIT was unexpectedly associated with amegakaryocytosis, suggesting that alloimmunization could extend at the megakaryocyte level. In addition, both siblings presented with drastic abnormalities in the B-cell compartment, which led to broad investigations for an immune-deficiency syndrome and provided a novel pathophysiologic hypothesis. Both placental examinations revealed major lymphoid infiltration involving the villous placenta, which is consistent with the diagnosis of villitis of unknown etiology. Severe thrombocytopenia in an otherwise healthy newborn should raise high the suspicion of NAIT. The diagnosis of NAIT should not be ruled out until extensive human platelet antigen systems have been investigated to screen for fetal-maternal antigen incompatibility. This is crucial not only for the newborn to allow optimal lifesaving treatments but also for effective management of future pregnancies. Interestingly, antibodies to HPA-15 have previously been reported with severe NAIT-related thrombocytopenia, but we are the first to report associated in vivo amegakaryocytosis.

Opportunistic Salpingectomy at the Time of Benign Laparoscopic Hysterectomy: Assessment of Possible Complications and Histopathological p53-Signatures.

INTRODUCTION: The aim of this study is to assess the prevalence of tubal histopathological abnormalities (serous tubal intraepithelial carcinoma STIC and p53 signatures) and the prevalence of perioperative and postoperative complications related to opportunistic laparoscopic salpingectomy in a low risk population. MATERIALS AND METHODS: In this observational prospective cohort, prophylactic bilateral salpingectomy during benign laparoscopic hysterectomy was systematically performed in 100 consecutive women. Peri- and postoperative complications were registered. Duration of salpingectomy and post-salpingectomy blood loss were also measured. Histopathological and immunohistochemical analysis with anti-p53 antibody were performed on the whole fallopian tubes according to a specific and validated protocol. RESULTS: Laparoscopic salpingectomy was always possible without any peri- or postoperative complication attributable to the salpingectomy itself. The mean duration was 428 seconds (354 - 596) and the blood loss was 9 cm 3 (2 - 15). Using histopathological and immunohistochemical assessment with anti-p53 antibody on 199 fallopian tubes (99 bilateral salpingectomies and one unilateral salpingectomy because of previous salpingectomy for ectopic pregnancy), there was a prevalence of 5.52% (11/199) of p53 signatures. No STIC were observed and no associated cancer. CONCLUSIONS: Laparoscopic salpingectomy is both feasible and innocuous during benign hysterectomy. Meticulous histopathologic examination of the tubes may reveal specific abnormalities.

How to manage chickenpox during pregnancy: case reports.

Chickenpox is a human infection that occurs mainly during childhood. Infection during pregnancy is therefore rare but may cause a congenital infection with malformation in less than 1% of cases. A specific management should be proposed at diagnosis in order to reduce materno-fetal transmission and morbimortality. Three cases were herein presented focusing on the main at-risk situations for pregnant women, whom immunological status against varicella was unknown. The first case focused on a varicella eruption during early pregnancy that leads to a lethal outcome. The second one described the management of varicella contact during early pregnancy. This woman was treated by specific immunoglobulins, leading to a positive outcome. The third case focused on another varicella contact, at the end of pregnancy. The woman was treated by acyclovir, before and after delivery, to limit materno-fetal consequences. In conclusion, after a suspicious contact, a serology assay has to be performed to know the immune status of the pregnant woman against varicella. In case of seronegativity, prevention against varicella infection should be carried out using specific immunoglobulins or valacyclovir. Clinical varicella does not require virology confirmation but requires immediate treatment with valacyclovir especially when it occurs during the first trimester.

Dynamic real-time in vivo confocal laser endomicroscopy of the fallopian tube during laparoscopy in the prevention of ovarian cancer.

OBJECTIVES: Recently it has been postulated that most ovarian cancers have a tubal origin. The identification of preinvasive tubal lesions would be of great interest in the early diagnosis of ovarian cancer. Optical biopsy has been developed and validated in the detection of precancerous lesions (such as Barrett's oesophagus). The first objective of this study was to assess the feasibility of optical biopsy in the study of fallopian tubes during laparoscopy. The second objective was to describe the images in benign premalignant and malignant tubes with a histopathological and immunohistochemical (p53 and Ki67 expressions) correlation. STUDY DESIGN: In this prospective study, 40 patients undergoing laparoscopic salpingectomy for benign conditions (benign hysterectomy), prophylactic conditions (BRCA mutation) or in case of pelvic cancers were included after obtaining informed and signed consent prior to surgery. The optical biopsy was performed on the fimbria of each tube in and ex vivo. A correlation was made with the histopathological and immunohistochemical analysis. RESULTS: The feasibility of optical biopsy was always confirmed during laparoscopy. The optical biopsy iconography revealed different images in benign tubal epithelium (well-defined black and grey structure), in adenomatoid tumour (tortuous architectural organization), in STIC precancerous lesion (enlarged, irregular and pleomorphic cells, dilated and distorted vessels) and in tubal metastasis of high grade serous ovarian cancer (dark neoplastic cells irregular in size and shape) CONCLUSIONS: Optical biopsy may be the first emerging mini-invasive technology that could detect tubal lesions and may be considered as a promising tool in the early detection of ovarian cancer.

Brain protection at the blood-cerebrospinal fluid interface involves a glutathione-dependent metabolic barrier mechanism.

The choroid plexuses (CPs) form a protective interface between the blood and the ventricular cerebrospinal fluid (CSF). To probe into the pathways by which CPs provide brain protection, we sought to evaluate the efficiency of glutathione conjugation in this barrier as a mechanism to prevent the entry of blood-borne electrophilic, potentially toxic compounds into the CSF, and we investigated the fate of the resulting metabolites. Rat CPs, as well as human CPs from both fetal and adult brains, displayed high glutathione-S-transferase activities. Using an in vitro model of the blood-CSF barrier consisting of choroidal epithelial cells cultured in a two-chambered device, we showed that glutathione conjugation can efficiently prevent the entry of 1-chloro-2,4-dinitrobenzene (CDNB) into the CSF, a model for electrophilic compounds. The duration of this enzymatic protection was set by the concentration of CDNB to which the epithelium was exposed, and this barrier effect was impaired only on severe epithelial intracellular glutathione and cysteine depletion. The conjugate was excreted from the choroidal cells in a polarized manner, mostly at the blood-facing membrane, via a high-capacity transport process, which is not a rate-limiting step in this detoxification pathway, and which may involve transporters of the ATP-binding cassette c(Abcc) and/or solute carrier 21 (Slc21) families. Supplying the choroidal epithelium at the blood-facing membrane with a therapeutically relevant concentration of N-acetylcysteine sustained this neuroprotective effect. Thus, glutathione conjugation at the CP epithelium coupled with the basolateral efflux of the resulting metabolites form an efficient blood-CSF enzymatic barrier, which can be enhanced by pharmacologically increasing glutathione synthesis within the epithelial cells.

Small Cell Carcinoma of the Ovary, Hypercalcemic Type: Report of a Bilateral Case in a Teenager Associated with SMARCA4 Germline Mutation.

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a highly aggressive neoplasm that typically occurs in young females. Paraneoplastic hypercalcemia is associated in two thirds of the cases. Recent studies demonstrated that this rare tumor harbors the same molecular features of malignant rhabdoid tumor secondary to SMARCA4/BRG1 mutations. We illustrate herein a typical bilateral case of SCCOHT with comprehensive molecular characterization in a 14-year-old girl. We also discuss the value of SMARCA4 immunostaining in the diagnostic approach of undifferentiated ovarian and pelvic malignancies.