Molecular characterization of disseminated pilocytic astrocytomas.

AIM: Pilocytic astrocytomas represent the most common paediatric tumours of the central nervous system. Dissemination through the ventricular system occurs rarely in patients with pilocytic astrocytomas; however, it is more common in infants with diencephalic tumours, and is associated with a poor outcome. Despite histological similarities with classic pilocytic astrocytomas, it is still unclear whether disseminated pilocytic astrocytomas may have specific molecular features. METHODS: Seventeen disseminated pilocytic astrocytomas were investigated using the molecular inversion probe array and screened for the presence of gene fusions (KIAA1549-BRAF) and mutations (BRAF, RAS and FGFR1). RESULTS: Along with evidence of a constitutive MAPK activation in all cases, the molecular inversion probe array, fluorescence in situ hybridization analysis and mutational study revealed KIAA1549-BRAF fusions in 66% and BRAF(V600E) mutations in 5% of cases. No KRAS, HRAS, NRAS or FGFR1 mutations were found. CONCLUSIONS: disseminated pilocytic astrocytomas showed genetic features similar to classic pilocytic astrocytoma, including a similar incidence of KIAA1549-BRAF fusions, BRAF mutations and a stable genetic profile. Given common activation of the MAPK pathway, the use of specific inhibitors can be hypothesized for the treatment of disseminated pilocytic astrocytomas, along with standard chemo- and/or radiotherapy.

Fertility, pregnancy and gynecological outcomes after fetoscopic surgery for congenital diaphragmatic hernia.

STUDY QUESTION: What is the impact of fetoscopic surgery for isolated Congenital Diaphragmatic Hernia (CDH) on future reproductive and gynecological outcomes? SUMMARY ANSWER: We did not observe an increase of obstetric or gynecological problems after fetoscopic surgery nor was there an increased risk for subsequent infertility. WHAT IS KNOWN ALREADY: The reproductive and gynecological outcomes of patients undergoing open maternal-fetal surgery are known. The most relevant counseling items are the elevated risk for uterine dehiscence and rupture (up to 14%). STUDY DESIGN, SIZE, DURATION: Bi-centric study over a 10-year period including 371 women carrying a fetus with isolated CDH either managed expectantly (n = 167) or operated in utero (n = 204). PARTICIPANTS/MATERIALS, SETTING, METHODS: Consenting patients filled out a survey with 23 questions (2 open and 21 multiple choice). Questionnaires were custom designed to obtain information on subsequent reproductive or gynecological problems as well as psychological impact. MAIN RESULTS AND THE ROLE OF CHANCE: The response rate was 40% (147/371). More women in the FETO group attempted a subsequent pregnancy: 70% (62/89) when compared with 47% (27/58) in controls (P = 0.009). This coincided with a longer follow-up in the FETO group (76 versus 59 months; P < 0.001) and a lower survival rate in the index pregnancy (53 versus 72%; P = 0.028). There was no difference in the number of nulliparous or parous women, neither in the conception rate. In total, there were 129 subsequent pregnancies. Nobody reported secondary fertility problems. Four women in the FETO group and one in the control reported a congenital anomaly in a subsequent pregnancy. Twenty-one pregnancies were reported with at least one complication (FETO: 23% (14/60), controls 27% (7/26)). During delivery or in the post-partum period 11 patients reported at least 1 complication (FETO 17% (10/59), controls 4% (1/24)). New onset gynecological problems occurred in 14 participants (10%). None of these events were more likely in one or the other group. Psychological and emotional impacts were frequent in both the FETO (41%) and the control groups (46%) (P = 0.691). LIMITATIONS, REASONS FOR CAUTION: The response rate was 40% (147/371), less than desired. The use of unvalidated self-reported outcomes may skew exact determination of the nature and severity of medical complications. The number of observations for uncommon events was low. The mean follow-up period to detect gynecological complications may be too short. WIDER IMPLICATIONS OF THE FINDINGS: This is the first evidence that fetoscopic surgery for CDH does not compromise future reproductive potential or obstetrical outcome when compared with expectant management. A pregnancy complicated by a serious congenital birth defect, such as CDH, frequently has a measurable psychological impact. STUDY FUNDING/COMPETING INTEREST: The authors have no conflicts to declare. J.D. receives a fundamental clinical research grant of the Fonds Wetenschappelijk Onderzoek - Vlaanderen (FWO; 18.01207). A.C.E. is supported by the Erasmus+Program of the European Union (Framework agreement number 2013-0040; contract 1011990). This was presented at the 61st meeting of the Society of Gynaecologic Investigation, in Florence, March 2014 (F-111).

Sonographic detection of central nervous system defects in the first trimester of pregnancy.

The fetal central nervous system can already be examined in the first trimester of pregnancy. Acrania, alobar holoprosencephaly, cephaloceles, and spina bifida can confidently be diagnosed at that stage and should actively be looked for in every fetus undergoing first-trimester ultrasound. For some other conditions, such as vermian anomalies and agenesis of the corpus callosum, markers have been identified, but the diagnosis can only be confirmed in the second trimester of gestation. For these conditions, data on sensitivity and more importantly specificity and false positives are lacking, and one should therefore be aware not to falsely reassure or scare expecting parents based on first-trimester findings. This review summarizes the current knowledge of first-trimester neurosonography in the normal and abnormal fetus and gives an overview of which diseases can be diagnosed.

[Transcervical Embryoscopy after Missed Abortion in Monoamniotic Twins with Discordant Exencephaly]. / Transzervikale Embryoskopie nach verhaltenem Abort in monoamnioten Zwillingen mit diskordanter Exenzephalie.

INTRODUCTION: Monoamniotic twins are considered a cause of high-risk pregnancies. Thereby, discordant malformations do occur rarely. A discordant exencephaly has been described in only a few cases. Transcervical embryoscopy can be performed in cases of monoamniotic twins with missed abortion directly before the abort-curettage. CASE REPORT: The case of a 35-year-old G1/P0 women in the 12(th) week of pregnancy is described. She had a monoamniotic twin pregnancy with discordant exencephaly and missed abortion diagnosed at 11+2 weeks. A transcervical embryoscopy was performed immediately before the abort-curettage and identified the discordant exencephaly and an additional umbilical cord knot of the 2 foetuses as a probable cause for the abortion. DISCUSSION: The transcervical embryoscopy lead in our case report to the diagnosis of a umbilical cord knot in a monoamniotic twin pregnancy with missed abortion. We also identified a discordant exencephaly by embryoscopy. With blunt access to the amniotic cavity, the transcervical embryoscopy applies only a minor additional risk to the abort-curettage. However, it should only be performed when the patient explicitly asks for enhanced diagnostics. CONCLUSION: Transcervical embryoscopy can be performed as an additional diagnostic tool in cases of monoamniotic twins with missed abortion. However, a detailed risk-benefit analysis should be done upfront in consultation with the patient.

Collagen plug sealing of iatrogenic fetal membrane defects after fetoscopic surgery for congenital diaphragmatic hernia.

OBJECTIVES: To investigate the efficacy of collagen plugs at reducing the risk of preterm premature rupture of membranes (PPROM) after fetoscopic surgery for congenital diaphragmatic hernia (CDH). METHODS: This was a single-center cohort study on all consecutive cases undergoing fetoscopic endoluminal tracheal occlusion (FETO) for severe or moderate CDH, between April 2002 and May 2011 (n = 141). Cases either received a collagen plug for sealing the fetal membrane defect after FETO or did not, depending on the operating surgeon. The principal outcome measure was the time from fetal surgery to PPROM, further referred to as 'latency'. A multivariable Cox regression model was used to investigate the association between collagen plug and latency while adjusting for risk factors for PPROM. RESULTS: Of the 141 cases, 54 (38%) received a collagen plug and 87 (62%) did not. Sixty cases experienced PPROM, 26 among cases with and 34 among cases without a plug (48 vs 39%). The hazard ratio of plug use was 1.29 (95% CI, 0.76-2.19), which does not exclude a potentially increased risk for PPROM when a collagen plug is used. For cases with a plug, 24% had PPROM before balloon removal and 24% had PPROM after elective balloon removal. For cases without a plug, these rates were 30 and 9%, respectively. Perinatal outcomes were similar in both groups. CONCLUSIONS: No evidence was found that collagen plugs reduce the risk of PPROM after FETO for CDH.

In vitro sealing of iatrogenic fetal membrane defects by a collagen plug imbued with fibrinogen and plasma.

OBJECTIVES: We aimed to demonstrate local thrombin generation by fetal membranes, as well as its ability to generate fibrin from fibrinogen concentrate. Furthermore, we aimed to investigate the efficacy of collagen plugs, soaked with plasma and fibrinogen, to seal iatrogenic fetal membrane defects. METHODS: Thrombin generation by homogenized fetal membranes was measured by calibrated automated thrombography. To identify the coagulation caused by an iatrogenic membrane defect, we analyzed fibrin formation by optical densitometry, upon various concentrations of fibrinogen. The ability of a collagen plug soaked with fibrinogen and plasma was tested in an ex vivo model for its ability to seal an iatrogenic fetal membrane defect. RESULTS: Fetal membrane homogenates potently induced thrombin generation in amniotic fluid and diluted plasma. Upon the addition of fibrinogen concentrate, potent fibrin formation was triggered. Measured by densiometry, fibrin formation was optimal at 1250 µg/mL fibrinogen in combination with 4% plasma. A collagen plug soaked with fibrinogen and plasma sealed an iatrogenic membrane defect about 35% better than collagen plugs without these additives (P = 0.037). CONCLUSIONS: These in vitro experiments suggest that the addition of fibrinogen and plasma may enhance the sealing efficacy of collagen plugs in closing iatrogenic fetal membrane defects.

Effect of finite size of ion chambers used for neutron dosimetry.

The effective point of measurement for spherical ionisation chambers was determined free-in-air for d + T neutrons and inside a human water phantom for d + T neutrons and 60Co gamma rays. Measurements were performed with spherical chambers of different diameters and a disc-type chamber. For spherical ion chambers free-in-air, the geometrical centre of the chamber was found to be the point of measurement for sufficiently great distances from the neutron source. In-phantom for spherical ion chambers, displacement correction factors of 1 - (0.25 +/- 0.06) x 10(-2) r for d + T neutrons and of 1 - (0.37 +/- 0.04) x 10(-2) r for 60Co gamma rays (r being the cavity radius in mm) were observed. The differences in displacement for d + T neutrons and 60Co gamma rays can be attributed to differences in attenuation and scatter characteristics of these radiation qualities. The replacement of phantom material by the cavity of an ion chamber was simulated by introducing Styrofoam spheres of comparable dimensions into the phantom. The dose distributions measured over the cavities could explain the different displacement corrections for 60Co gamma rays and 15 MeV neutrons.

Effective measuring point of ion chambers for photon dosimetry in phantoms.

The effective point of measurement for spherical ionization chambers has been determined for 60Co and 137Cs gamma rays and for 300 kV X rays inside a water phantom. For reasons of comparison, measurements were also performed with a thimble-type Baldwin-Farmer ion chamber. For spherical ion chambers the displacement correction factors were 1-(0.37 +/- 0.04) r. 10(-2) for 60Co gamma rays and 1-(0.22 +/- 0.05) r. 10(-2) for 137 Cs gamma rays, where r is expressed in mm, whereas no displacement was observed for X rays. The differences in displacement obtained for the various types of radiation can be attributed to differences in attenuation and scatter characteristics of the various radiation qualities.