Long-term oncological outcomes after local excision of T1 rectal cancer.

BACKGROUND: A growing proportion of patients with early rectal cancer is treated by local excision only. The aim of this study was to evaluate long-term oncological outcomes and the impact of local recurrence on overall survival for surgical local excision in pT1 rectal cancer. METHODS: Patients who only underwent local excision for pT1 rectal cancer between 1997 and 2014 in two Dutch tertiary referral hospitals were included in this retrospective cohort study. The primary outcome was the local recurrence rate. Secondary outcomes were distant recurrence, overall survival and the impact of local recurrence on overall survival. RESULTS: A total of 150 patients (mean age 68.5 ± 10.7 years, 57.3% males) were included in the study. Median length of follow-up was 58.9 months (range 6-176 months). Local recurrence occurred in 22.7% (n = 34) of the patients, with a median time to local recurrence of 11.1 months (range 2.3-82.6 months). The vast majority of local recurrences were located in the lumen. Five-year overall survival was 82.0%, and landmark analyses showed that local recurrence significantly impacted overall survival at 6 and 36 months of follow-up (6 months, p = 0.034, 36 months, p = 0.036). CONCLUSIONS: Local recurrence rates after local excision of early rectal cancer can be substantial and may impact overall survival. Therefore, clinical decision-making should be based on patient- and tumour characteristics and should incorporate patient preferences.

Functional complaints and quality of life after transanal total mesorectal excision: a meta-analysis.

BACKGROUND: Total mesorectal excision (TME) gives excellent oncological results in rectal cancer treatment, but patients may experience functional problems. A novel approach to performing TME is by single-port transanal minimally invasive surgery. This systematic review evaluated the functional outcomes and quality of life after transanal and laparoscopic TME. METHODS: A comprehensive search in PubMed, the Cochrane Library, Embase and the trial registers was conducted in May 2019. PRISMA guidelines were used. Data for meta-analysis were pooled using a random-effects model. RESULTS: A total of 11 660 studies were identified, from which 14 studies and six conference abstracts involving 846 patients (599 transanal TME, 247 laparoscopic TME) were included. A substantial number of patients experienced functional problems consistent with low anterior resection syndrome (LARS). Meta-analysis found no significant difference in major LARS between the two approaches (risk ratio 1·13, 95 per cent c.i. 0·94 to 1·35; P = 0·18). However, major heterogeneity was present in the studies together with poor reporting of functional baseline assessment. CONCLUSION: No differences in function were observed between transanal and laparoscopic TME.

ANTECEDENTES: La escisión total del mesorrecto (total mesorectal excision, TME) proporciona excelentes resultados oncológicos en el tratamiento del cáncer de recto, pero los pacientes pueden presentar trastornos funcionales. Un abordaje novedoso para realizar la TME es mediante cirugía transanal mínimamente invasiva de puerto único. En esta revisión sistemática se evaluaron los resultados funcionales y la calidad de vida después de TME transanal (TaTME) y TME laparoscópica (LapTME). MÉTODOS: En mayo de 2019 se realizó una búsqueda exhaustiva en las bases de datos de Pubmed, Biblioteca Cochrane, EMBASE y en los registros de ensayos clínicos. Se utilizaron las guías PRISMA. Los datos para el metaanálisis se agruparon utilizando un modelo de efectos aleatorios. RESULTADOS: Se identificaron un total de 11.660 estudios, de los cuales se incluyeron 14 estudios y 6 resúmenes de congresos con 846 pacientes (599 TaTME/247 LapTME). Un número sustancial de pacientes presentó trastornos funcionales consistentes con el síndrome de resección anterior baja (low anterior resection syndrome, LARS). El metaanálisis no encontró diferencias significativas en los porcentajes de LARS grave entre los dos abordajes (razón de oportunidades, odds ratio, OR 1,13; i.c. del 95% 0,94-1,35; P = 0,18). Sin embargo, los estudios globalmente presentaron una gran heterogeneidad, así como una deficiente información sobre la evaluación funcional basal. CONCLUSIÓN: No se observaron diferencias en la función entre TaTME y LapTME.

Local recurrence after local excision of early rectal cancer: a meta-analysis of completion TME, adjuvant (chemo)radiation, or no additional treatment.

BACKGROUND: The risks of local recurrence and treatment-related morbidity need to be balanced after local excision of early rectal cancer. The aim of this meta-analysis was to determine oncological outcomes after local excision of pT1-2 rectal cancer followed by no additional treatment (NAT), completion total mesorectal excision (cTME) or adjuvant (chemo)radiotherapy (aCRT). METHODS: A systematic search was conducted in PubMed, Embase and the Cochrane Library. The primary outcome was local recurrence. Statistical analysis included calculation of the weighted average of proportions. RESULTS: Some 73 studies comprising 4674 patients were included in the analysis. Sixty-two evaluated NAT, 13 cTME and 28 aCRT. The local recurrence rate for NAT among low-risk pT1 tumours was 6·7 (95 per cent c.i. 4·8 to 9·3) per cent. There were no local recurrences of low-risk pT1 tumours after cTME or aCRT. The local recurrence rate for high-risk pT1 tumours was 13·6 (8·0 to 22·0) per cent for local excision only, 4·1 (1·7 to 9·4) per cent for cTME and 3·9 (2·0 to 7·5) per cent for aCRT. Local recurrence rates for pT2 tumours were 28·9 (22·3 to 36·4) per cent with NAT, 4 (1 to 13) per cent after cTME and 14·7 (11·2 to 19·0) per cent after aCRT. CONCLUSION: There is a substantial risk of local recurrence in patients who receive no additional treatment after local excision, especially those with high-risk pT1 and pT2 rectal cancer. The lowest recurrence risk is provided by cTME; aCRT has outcomes comparable to those of cTME for high-risk pT1 tumours, but shows a higher risk for pT2 tumours.

ANTECEDENTES: Tras una resección temprana de un cáncer de recto localizado, hay que considerar el equilibrio entre el riesgo de recidiva local y la morbilidad relacionada con el tratamiento. El objetivo de este metaanálisis era determinar los resultados oncológicos tras la resección de un cáncer de recto pT1-T2 seguida de ningún tratamiento adicional (no additional treatment, NAT), escisión total del mesorrecto (completion total mesorectal excision, cTME) o quimiorradioterapia adyuvante (adjuvant chemoradiotherapy, aCRT). METHODS: Se llevó a cabo una búsqueda sistemática en PubMed, Embase y biblioteca Cochrane. La variable principal de resultado era la recidiva local (local recurrence, LR). En el análisis estadístico se calcularon las medias ponderadas de proporciones. RESULTADOS: Se incluyeron en el análisis 76 estudios con un total de 4.793 pacientes. NAT fue evaluada en 72 estudios, cTME en 13 y aCRT en 28. La tasa de LR para NAT en tumores pT1 de bajo riesgo era de 6,7% (i.c. del 95% 4,8-9,3). No se observaron casos de LR en tumores pT1 de bajo riesgo tras cTME o aCRT. La tasa de LR para tumores pT1 de alto riesgo fue de 13,6% (i.c. del 95% 8,0-22,0) para la resección local como único tratamiento, 4,1% (i.c. del 95% 1,7-9,4) para cTME y 3,9% (i.c. del 95% 2,0-7,5) para aCRT. La tasa de LR para tumores pT2 fue de 28,9% (i.c. del 95% 22,3-36,4) para NAT, 4,3% (i.c. del 95% 1,4-12,5) para cTME y 14,7% (i.c. del 95% 11,2-19,0) para aCRT. CONCLUSIÓN: Tras la resección local de cáncer pT1 de alto riesgo y pT2, existe un riesgo sustancial de recidiva local en ausencia de tratamiento adicional. La escisión total del mesorrecto se asocia con el menor riesgo de recidiva. La quimiorradioterapia adyuvante ofrece resultados similares a la escisión total del mesorrecto en tumores pT1 de alto riesgo, pero presenta un mayor riesgo en tumores pT2.

Association of culture medium with growth, weight and cardiovascular development of IVF children at the age of 9 years.

STUDY QUESTION: Is embryo culture media used during an IVF/ICSI treatment associated with differences in growth, body composition and cardiovascular development as determined in 9-year-old singleton IVF children? SUMMARY ANSWER: The choice of in vitro culture medium for human embryos is associated with differences in body weight, BMI, truncal adiposity, waist circumference and waist/hip ratio at the age of 9, while no significant differences were observed in cardiovascular development. WHAT IS KNOWN ALREADY: Children born after IVF/ICSI have an increased risk of low birthweight, which is correlated with a higher risk of cardiovascular diseases. Some studies show that IVF children exhibit a significantly higher systolic and diastolic blood pressure and higher fasting glucose levels compared to naturally conceived children. After alternating assignment to G1™ Version 3 (Vitrolife) or K-SICM (Cook) embryo culture media, birthweight of the resulting children was significantly higher in the Vitrolife group and they remained heavier during the first 2 years of life. STUDY DESIGN, SIZE, DURATION: In this observational cohort study (MEDIUM-KIDS), parents of singletons from a previous study were approached for further follow-up after the ninth birthday of their child. The singletons were born after fresh embryo transfer of cleavage stage embryos resulting from an IVF/ICSI treatment performed between July 2003 and December 2006 in our clinic, when two different culture media were used alternately: either G1™ Version 3 (Vitrolife) or K-SICM (Cook). Follow-up measurements were performed between March 2014 and December 2016. PARTICIPANT/MATERIALS, SETTINGS, METHODS: Parents were invited to attend our clinic with their child for a single visit lasting ~2.5 h. Two experienced clinicians performed all measurements as part of the MEDIUM-KIDS study in a standardized way. Height and weight of the child was measured using calibrated scales, 4-point skinfold thickness measurements were measured in triplicate and waist and hip circumference were measured using a tape measure. The following cardiovascular parameters were measured in a standardized way: blood pressure, heart rate and endothelial function by skin laser-Doppler with iontophoresis using vasodilatory drugs. Cortisol and cortisone concentrations in hair were measured. A blood sample was taken after an overnight fast for insulin, glucose, TSH and lipid analysis. Blood samples of the IVF children were compared with a non-IVF control group. Differences between culture medium groups were analysed by Student's t-test and effects of confounders were analysed using multivariable regression analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 294 eligible children (168 Vitrolife and 126 Cook), 136 children (75 Vitrolife and 61 Cook) participated in the study. Baseline characteristics of the participating children from the Vitrolife and Cook group were similar. Birthweight was higher in the Vitrolife group, in keeping with the full cohort. After correction for confounders, the difference in weight and BMI attributable to culture medium was 1.58 kg (95% CI: 0.01-3.14) and 0.84 kg/m2 (95% CI: 0.02-1.67), respectively, with the Vitrolife children being heavier. Height and height corrected for age and gender (SDS scores) were similar in both groups. Furthermore, waist circumference was significantly higher in the Vitrolife group with a corrected difference of 3.21 cm (95%CI: 0.60-5.81) leading to a 0.03 increase (95% CI: 0.01-0.05) in waist/hip ratio. Subscapular skinfolds combined with suprailiacal skinfolds (defined as truncal adiposity), was also significantly higher in Vitrolife children (adjusted difference 3.44 cm [95% CI: 0.27-6.62]). Both systolic (adj. beta 0.364 [95% CI: -2.129 to 2.856],) and diastolic (adj. beta 0.275 [95% CI: -2.105 to 2.654]) blood pressures (mmHg) were comparable for the two groups. After an overnight fast, cholesterol, glucose, insulin, low and high-density lipoprotein, triglycerides and TSH were normal and similar in the two groups. Endothelial function in the microcirculation was compared by using maximum perfusion units corrected for the baseline value as a measure for vasodilatory capacity. There were no significant differences between the two groups. Cortisol and cortisone concentration in hair samples were comparable. LIMITATIONS, REASONS FOR CAUTION: A limitation of the original study was its pseudo-randomized design. This and the dwindling enthusiasm of families for participation (47.7% after 9 years) prevent us from drawing robust causal conclusions from the observed association. Nevertheless, to date this is oldest cohort of IVF/ICSI children where culture medium was allocated alternatingly and used in a blinded setting, to be studied. We believe that our participants are representative for the full cohort. The current number of participants was sufficient to rule out differences as little as 3 mmHg in systolic and diastolic blood pressures. WIDER IMPLICATIONS OF THE FINDINGS: This study underlines the importance of structured follow-up of IVF/ICSI children to further elucidate possible long-term health effects. Health professionals and culture medium manufacturers should be aware that small changes in culture conditions and culture medium composition for the early embryo can have long-term health effects. The similar cardiovascular results for the two groups are reassuring but the children may still be too young to detect differences in cardiovascular development. Prolonged follow-up and structured investigations up until adulthood are necessary to gain more insight and reassurance in the cardiovascular development of IVF offspring, although long-term follow-up will become more complicated by confounding life-style and environmental factors possibly influencing development. STUDY FUNDING/COMPETING INTEREST(S): The study was financially supported by the March of Dimes (Grant number #6-FY13-153). The sponsor of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: NTR4220.

BRCA1 mutation carriers have a lower number of mature oocytes after ovarian stimulation for IVF/PGD.

PURPOSE: The aim of this study was to determine whether BRCA1/2 mutation carriers produce fewer mature oocytes after ovarian stimulation for in vitro fertilization (IVF) with preimplantation genetic diagnosis (PGD), in comparison to a PGD control group. METHODS: A retrospective, international, multicenter cohort study was performed on data of first PGD cycles performed between January 2006 and September 2015. Data were extracted from medical files. The study was performed in one PGD center and three affiliated IVF centers in the Netherlands and one PGD center in Belgium. Exposed couples underwent PGD because of a pathogenic BRCA1/2 mutation, controls for other monogenic conditions. Only couples treated in a long gonadotropin-releasing hormone (GnRH) agonist-suppressive protocol, stimulated with at least 150 IU follicle stimulating hormone (FSH), were included. Women suspected to have a diminished ovarian reserve status due to chemotherapy, auto-immune disorders, or genetic conditions (other than BRCA1/2 mutations) were excluded. A total of 106 BRCA1/2 mutation carriers underwent PGD in this period, of which 43 (20 BRCA1 and 23 BRCA2 mutation carriers) met the inclusion criteria. They were compared to 174 controls selected by frequency matching. RESULTS: Thirty-eight BRCA1/2 mutation carriers (18 BRCA1 and 20 BRCA2 mutation carriers) and 154 controls proceeded to oocyte pickup. The median number of mature oocytes was 7.0 (interquartile range (IQR) 4.0-9.0) in the BRCA group as a whole, 6.5 (IQR 4.0-8.0) in BRCA1 mutation carriers, 7.5 (IQR 5.5-9.0) in BRCA2 mutation carriers, and 8.0 (IQR 6.0-11.0) in controls. Multiple linear regression analysis with the number of mature oocytes as a dependent variable and adjustment for treatment center, female age, female body mass index (BMI), type of gonadotropin used, and the total dose of gonadotropins administered revealed a significantly lower yield of mature oocytes in the BRCA group as compared to controls (p = 0.04). This finding could be fully accounted for by the BRCA1 subgroup (BRCA1 mutation carriers versus controls p = 0.02, BRCA2 mutation carriers versus controls p = 0.50). CONCLUSIONS: Ovarian response to stimulation, expressed as the number of mature oocytes, was reduced in BRCA1 but not in BRCA2 mutation carriers. Although oocyte yield was in correspondence to a normal response in all subgroups, this finding points to a possible negative influence of the BRCA1 gene on ovarian reserve.

Dyspareunia and depressive symptoms are associated with impaired sexual functioning in women with endometriosis, whereas sexual functioning in their male partners is not affected.

STUDY QUESTION: To what extent are endometriosis and its related physical and mental symptoms associated with the perceived level of sexual functioning in women and their male partners? SUMMARY ANSWER: Dyspareunia and depressive symptoms are associated with impaired sexual functioning in women with endometriosis, whereas sexual functioning in their male partners is not affected. WHAT IS KNOWN ALREADY: Women with endometriosis suffer from more dyspareunia, lower sexual functioning, and lower quality of life. In qualitative studies, partners of women with endometriosis report that endometriosis affected their quality of life and produced relational distress. STUDY DESIGN SIZE, DURATION: In this cross-sectional study, sexual functioning in women with endometriosis (n = 83) and their partners (n = 74) was compared with sexual functioning in a control group of women attending the outpatient department for issues related to contraception (n = 40), and their partners (n = 26). PARTICIPANTS/MATERIALS, SETTING, METHODS: Women and partners were recruited in the Maastricht University Medical Centre (MUMC) and the VieCuri Medical Centre Venlo between June 2011 and December 2012. All participants were asked to complete a set of online questionnaires. MAIN RESULTS AND THE ROLE OF CHANCE: Response rates were 59.3% (83/140) for women with endometriosis and 52.3% (74/140) for their partners. Response rates in the control group were respectively 43.2% and 27.4% (41/95 and 27/95), of whom 40 women and 26 partners could be included in the study. Women with endometriosis as compared with the control group, reported significantly more frequent pain during intercourse (53% versus 15%, P < 0.001); higher levels of chronic pain (median VAS 2.0 cm versus 0.0 cm, P < 0.001); more impairment of sexual functioning (median Female Sexual Function Index 25.4 versus 30.6, P < 0.001); more impairment of quality of life (median Short Form-12 66.3 versus 87.2, P < 0.001); more pain catastrophizing (mean Pain Catastrophizing Scale 17.8 versus 8.5, P < 0.001), more depression and anxiety symptoms (median Hospital Anxiety and Depression Scale for depression 7 versus 4, P < 0.001 and for anxiety 4 versus 1, P < 0.001). Sexual functioning was comparable between male partners of women with endometriosis and male partners of the control group based on the International Index of Erectile Function. Logistic regression analyses showed that dyspareunia (OR 0.54; 95% CI 0.39-0.75) and depressive symptoms (OR 0.761; 95% CI 0.58-0.99) were independent and significant negative predictors for sexual functioning. Chronic pelvic pain (OR 0.53; 95% CI 0.35-0.81) and depressive symptoms (OR 0.65; 95% CI 0.44-0.96) were independent and significant negative predictors for quality of life. LIMITATIONS, REASONS FOR CAUTION: Patient recruitment was performed in one tertiary care centre and to a lesser extent one general hospital, possibly leading to an over-representation of patients with more severe endometriosis. All participating women had a partner and are therefore 'survivors' in relationship terms. This may have led to an underestimation of the impact of endometriosis on sexual functioning. WIDER IMPLICATIONS OF THE FINDINGS: It would be worthwhile to further explore the role of depressive symptoms in women with symptomatic endometriosis and to assess the effect of treatment of depressive symptoms on sexual functioning and quality of life. The fact that the partners did not report impaired sexual functioning could be a reassuring thought to women that might be discussed in the consulting room. STUDY FUNDING/COMPETING INTERESTS: The study was funded by the MUMC. An unconditional research grant was given by the Dutch Society of Psychosomatic Obstetrics and Gynaecology (21 June 2011). TRIAL REGISTRATION NUMBER: Not applicable.

Trajectories of cognitive decline in different types of dementia.

BACKGROUND: To investigate trajectories of cognitive decline in patients with different types of dementia compared to controls in a longitudinal study. METHOD: In 199 patients with Alzheimer's disease (AD), 10 with vascular dementia (VaD), 26 with dementia with Lewy bodies (DLB), 20 with behavioural variant frontotemporal dementia (bvFTD), 15 with language variant frontotemporal dementia (lvFTD) and 112 controls we assessed five cognitive domains: memory, language, attention, executive and visuospatial functioning, and global cognition (Mini-Mental State Examination, MMSE). All subjects had at least two neuropsychological assessments (median 2, range 2-7). Neuropsychological data were standardized into z scores using baseline performance of controls as reference. Linear mixed models (LMMs) were used to estimate baseline cognitive functioning and cognitive decline over time for each group, adjusted for age, gender and education. RESULTS: At baseline, patients with dementia performed worse than controls in all cognitive domains (p < 0.05) except visuospatial functioning, which was only impaired in patients with AD and DLB (p < 0.001). During follow-up, patients with AD declined in all cognitive domains (p < 0.001). DLB showed decline in every cognitive domain except language and global cognition. bvFTD showed rapid decline in memory, language, attention and executive functioning (all p < 0.01) whereas visuospatial functioning remained fairly stable. lvFTD declined mostly in attention and executive functioning (p < 0.01). VaD showed decline in attention and executive functioning. CONCLUSIONS: We show cognitive trajectories of different types of dementia. These estimations of natural disease course have important value for the design of clinical trials as neuropsychological measures are increasingly being used as outcome measures.

Routine labour epidural analgesia versus labour analgesia on request: a randomised non-inferiority trial.

OBJECTIVE: To assess the effect on mode of delivery of the routine use of labour epidural analgesia (EA) compared with analgesia on request. DESIGN: Randomised non-inferiority trial. SETTING: One university and one non-university teaching hospital in The Netherlands. POPULATION: Women with a singleton pregnancy in cephalic presentation beyond 36 + 0 weeks' gestation. METHODS: Participants were randomly allocated to receive either routine EA or analgesia on request. Intention-to-treat (ITT) and per-protocol (PP) analyses were performed, with confidence intervals (CI) calculated for the differences in percentages or means. MAIN OUTCOME MEASURES: Rate of operative delivery (instrumental vaginal or caesarean), labour characteristics, and adverse labour and neonatal outcomes. RESULTS: A total of 488 women were randomly allocated to the routine EA (n = 233) or analgesia on request group (n = 255). In the routine EA group, 89.3% (208/233) received EA. According to ITT analysis, 34.8% (81/233) women in the routine EA group had an operative delivery, compared with 26.7% (68/255) in the analgesia on request group (difference 8.1%, 95% CI -0.1 to 16.3). The difference in rate of operative deliveries according to the PP analysis was statistically significant (difference 8.9%, 95% CI 0.4 to 17.4). Inferiority of EA could not be rejected, as in both analyses the upper bound of the confidence interval exceeded the pre-specified inferiority criterion of +10%. Women in the routine EA group had more adverse effects, including hypotension (difference 9.5%, 95% CI 4.2 to 14.9), and motor blockade (difference 6.8%, 95% CI 1.1 to 12.5). CONCLUSION: Non-inferiority of routine EA could not be demonstrated in this trial. Routine EA use is likely to lead to more operative deliveries and more maternal adverse effects. The results of our study do not justify routine use of EA.

Predicting successful intended vaginal delivery after previous caesarean section: external validation of two predictive models in a Dutch nationwide registration-based cohort with a high intended vaginal delivery rate.

OBJECTIVE: To externally validate two models from the USA (entry-to-care [ETC] and close-to-delivery [CTD]) that predict successful intended vaginal birth after caesarean (VBAC) for the Dutch population. DESIGN: A nationwide registration-based cohort study. SETTING: Seventeen hospitals in the Netherlands. POPULATION: Seven hundred and sixty-three pregnant women, each with one previous caesarean section and a viable singleton cephalic pregnancy without a contraindication for an intended VBAC. METHODS: The ETC model comprises the variables maternal age, prepregnancy body mass index (BMI), ethnicity, previous vaginal delivery, previous VBAC and previous nonprogressive labour. The CTD model replaces prepregnancy BMI with third-trimester BMI and adds estimated gestational age at delivery, hypertensive disease of pregnancy, cervical examination and induction of labour. We included consecutive medical records of eligible women who delivered in 2010. For validation, individual probabilities of women who had an intended VBAC were calculated. MAIN OUTCOME MEASURES: Discriminative performance was assessed with the area under the curve (AUC) of the receiver operating characteristic and predictive performance was assessed with calibration plots and the Hosmer-Lemeshow (H-L) statistic. RESULTS: Five hundred and fifteen (67%) of the 763 women had an intended VBAC; 72% of these (371) had an actual VBAC. The AUCs of the ETC and CTD models were 68% (95% CI 63-72%) and 72% (95% CI 67-76%), respectively. The H-L statistic showed a P-value of 0.167 for the ETC model and P = 0.356 for the CTD model, indicating no lack of fit. CONCLUSION: External validation of two predictive models developed in the USA revealed an adequate performance within the Dutch population.

Vaginal birth after a caesarean section: the development of a Western European population-based prediction model for deliveries at term.

OBJECTIVE: To develop and internally validate a model that predicts the outcome of an intended vaginal birth after caesarean (VBAC) for a Western European population that can be used to personalise counselling for deliveries at term. DESIGN: Registration-based retrospective cohort study. SETTING: Five university teaching hospitals, seven non-university teaching hospitals, and five non-university non-teaching hospitals in the Netherlands. POPULATION: A cohort of 515 women with a history of one caesarean section and a viable singleton pregnancy, without a contraindication for intended VBAC, who delivered at term. METHODS: Potential predictors for a vaginal delivery after caesarean section were chosen based on literature and expert opinions. We internally validated the prediction model using bootstrapping techniques. MAIN OUTCOME MEASURES: Predictors for VBAC. For model validation, the area under the receiver operating characteristic curve (AUC) for discriminative capacity and calibration-per-risk-quantile for accuracy were calculated. RESULTS: A total of 371 out of 515 women had a VBAC (72%). Variables included in the model were: estimated fetal weight greater than the 90(th) percentile in the third trimester; previous non-progressive labour; previous vaginal delivery; induction of labour; pre-pregnancy body mass index; and ethnicity. The AUC was 71% (95% confidence interval, 95% CI = 69-73%), indicating a good discriminative ability. The calibration plot shows that the predicted probabilities are well calibrated, especially from 65% up, which accounts for 77% of the total study population. CONCLUSION: We developed an appropriate Western European population-based prediction model that is aimed to personalise counselling for term deliveries.

Peri-partum reference ranges for ROTEM(R) thromboelastometry.

BACKGROUND: Post-partum haemorrhage (PPH) causes rapidly developing deficiencies in clotting factors and contributes to substantial maternal morbidity and mortality. Rotational thromboelastometry (ROTEM(®)) is increasingly used as a point of care coagulation monitoring device in patients with massive haemorrhage; however, there are limited data on reference ranges in the peri-partum period. These are required due to the haemostatic changes in pregnancy. METHODS: In a Dutch multi-centre trial, 161 subjects were included; blood samples were obtained during labour (T1) and within 1 h of delivery (T2). Reference ranges of ROTEM(®) INTEM, EXTEM, FIBTEM, and APTEM were set and correlation with laboratory results was investigated using the guidelines of the International Federation of Clinical Chemistry. RESULTS: Reference ranges were obtained for clotting time (CT), clot formation time (CFT), α-angle, clot firmness at 10 and 20 min (A10, A20), maximum clot firmness (MCF), and maximum lysis (ML). These were comparable from centre to centre, and between T1 and T2. Reference ranges T1: EXTEM: CT 31-63 s, CFT 41-120 s, and MCF 42-78 mm. INTEM: CT 109-225 s, CFT 40-103, and MCF 63-78 mm. FIBTEM: CT 31-79 s and MCF 13-45 mm. APTEM: CT 33-62 s, CFT 42-118, and MCF 61-79 mm. CONCLUSIONS: Reference values for ROTEM(®) parameters are reported. The previously published correlation between FIBTEM parameters and plasma fibrinogen levels by the Clauss method is confirmed. Further research is needed to define threshold values for haemostatic therapy in the course of PPH. Clinical trial registration NTR 2515 (http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2515).

The proper delivery pressure for cardioplegic solution in neonatal cardiac surgery - an investigation of biomechanical and structural properties of neonatal and adult coronary arteries.

When cardioplegic solution is injected into coronary arteries with a pump in order to ensure myocardial protection, it is necessary to determine the correct delivery pressure to avoid damage of the heart. Biomechanical and structural properties of the neonatal coronary artery wall should be taken into account when determining the delivery pressure. We investigated twelve coronary artery specimens without cardiac pathology retrieved from autopsies of neonates 9.3 ± 9.7 days old and compared them to adult specimens with no detected atherosclerosis. There was a rapid increase in the strain until the inner pressure reached 80 - 100 mmHg, whilst the increase of stress in the wall of the neonatal coronary arteries was less rapid. When the pressure exceeded 100 mmHg, the increase in the strain slowed down, whilst the wall stress and modulus of elasticity began to increase rapidly. Morphologic examination of tensile properties revealed prominent affection of the vascular wall of the neonates, with accentuated redistribution (loosening) of medial myocytes and the adventitial vasa vasorum. Collectively, a raised inner pressure applied to cardioplegic solution injected into the coronary artery of a neonate may increase the risk of structural damage to the vascular wall.

Disrupted modular brain dynamics reflect cognitive dysfunction in Alzheimer's disease.

The relation between pathology and cognitive dysfunction in dementia is still poorly understood, although disturbed communication between different brain regions is almost certainly involved. In this study we combine magneto-encephalography (MEG) and network analysis to investigate the role of functional sub-networks (modules) in the brain with regard to cognitive failure in Alzheimer's disease. Whole-head resting-state (MEG) was performed in 18 Alzheimer patients (age 67 ± 9, 6 females, MMSE 23 ± 5) and 18 healthy controls (age 66 ± 9, 11 females, MMSE 29 ± 1). We constructed functional brain networks based on interregional synchronization measurements, and performed graph theoretical analysis with a focus on modular organization. The overall modular strength and the number of modules changed significantly in Alzheimer patients. The parietal cortex was the most highly connected network area, but showed the strongest intramodular losses. Nonetheless, weakening of intermodular connectivity was even more outspoken, and more strongly related to cognitive impairment. The results of this study demonstrate that particularly the loss of communication between different functional brain regions reflects cognitive decline in Alzheimer's disease. These findings imply the relevance of regarding dementia as a functional network disorder.

Local recurrence at the site of the Lone Star device through implantation of exfoliated cells during local excision for early rectal cancer: A case report.

INTRODUCTION: Invasive procedures for colorectal cancer can cause iatrogenic tumor cell seeding. Implantation of these exfoliated cells in the surrounding tissue can result in locoregional cancer recurrence. This has been described in endoscopic procedures and major surgical resections, however recurrence in iatrogenic lesions of the anal canal during minimal invasive rectal surgery has not been shown in literature yet. This is the first reported case of recurrent rectal cancer that developed into an anal metastasis at the site where hooks of the Lone Star Retractor disrupted the epithelial lining of the anal canal during a local excision of early rectal cancer using TAMIS. PRESENTATION OF CASE: A 57 year old male was diagnosed with a high risk early stage rectal adenocarcinoma. He was treated with transanal minimally invasive surgery (TAMIS) with the use of a Lone Star retractor and he received subsequent chemo-radiotherapy. 23 months later the patient developed a bleeding mass bulging out of the anus. A true cut and incision biopsy was performed and the pathology report revealed localization of adenocarcinoma at the anal canal which was similar to the earlier diagnosed rectal carcinoma. The patient underwent an abdominal perineal resection and left-sided lymph node dissection. DISCUSSION AND CONCLUSION: This shows that local recurrence through implantation of exfoliated tumor cells can occur in iatrogenic lesions of the anal canal not only in major but also in minimal invasive rectal surgery. Careful tissue handling and rectal washout may reduce the chance of this implantation metastasis.

Early versus late epidural analgesia and risk of instrumental delivery in nulliparous women: a systematic review.

OBJECTIVE: Review of the literature regarding the relation between the timing of epidural analgesia and the rate of caesarean or instrumental vaginal deliveries. SEARCH STRATEGY: Pubmed, Embase and the Cochrane Library were searched for articles published until 31 July 2010. SELECTION CRITERIA: Studies were selected in which the effects of early latent phase (defined as a cervical dilatation of 3 cm or less) epidural analgesia (including combined-spinal epidural) and late active phase epidural analgesia on the mode of delivery in nulliparous women at 36 weeks of gestation or more were evaluated. DATA COLLECTION AND ANALYSIS: Data extraction was completed by using a data-extraction form. Risk ratio and its 95% confidence intervals were calculated for caesarean delivery and instrumental vaginal delivery. Pooled data were calculated. MAIN RESULTS: The search retrieved 20 relevant articles, of which six fulfilled the selection criteria of inclusion. These six studies reported on 15,399 nulliparous women in spontaneous or induced labour with a request for analgesia. Risk of caesarean delivery (pooled risk ratio 1.02, 95% CI 0.96-1.08) or instrumental vaginal delivery (pooled risk ratio 0.96, 95% CI 0.89-1.05) was not significantly different between groups. AUTHORS' CONCLUSIONS: This systematic review showed no increased risk of caesarean delivery or instrumental vaginal delivery for women receiving early epidural analgesia at cervical dilatation of 3 m or less in comparison with late epidural analgesia.

Early-pregnancy changes in cardiac diastolic function in women with recurrent pre-eclampsia and in previously pre-eclamptic women without recurrent disease.

OBJECTIVE: To compare early-pregnancy changes in cardiac diastolic function between formerly pre-eclamptic women with (RECUR) and without (NORECUR) recurrent pre-eclampsia. DESIGN: Retrospective observational cohort study. SETTING: Tertiary referral centre. POPULATION: Pregnant women with a history of early-onset pre-eclampsia (n = 34). METHODS: The peak mitral filling velocity in early diastole (E) and at atrial contraction (A), and the E/A ratio were assessed before and at 12, 16 and 20 weeks of gestation in the next pregnancy. Differences in early-pregnancy alterations between women with (RECUR) and without (NORECUR) recurrent pre-eclampsia were evaluated by use of mixed design analysis of covariance. MAIN OUTCOME MEASURES: Cardiac function and recurrent pre-eclampsia. RESULTS: In ten women (29%) pre-eclampsia recurred. By 12 weeks of gestation the E/A ratio had increased in the RECUR group, but not in the NORECUR group (P < 0.01). Moreover, from 16 weeks of gestation onwards, the RECUR group had a lower cardiac output and higher systemic vascular resistance as compared with the NORECUR group (P < 0.05). CONCLUSION: Our results suggest that formerly pre-eclamptic women destined to develop recurrent pre-eclampsia differ from their counterparts who do not develop recurrent pre-eclampsia by impaired first-trimester adaptation of cardiac diastolic function.

A tumefactive demyelinating lesion in a person with MS after five years of fingolimod.

A 38-year-old man with relapsing remitting multiple sclerosis (RRMS) developed a tumefactive demyelinating lesion (TDL) after being clinically and radiologically stable on fingolimod for the last five years. TDLs in MS tend to occur early on in the disease and are uncommon in longstanding MS. Compared to other immune modifying drugs used in MS, there is a relatively high and still increasing number of reports describing the development of TDL under treatment with fingolimod, suggesting a causal relation.

Minimally invasive perineal redo surgery for rectovesical and rectovaginal fistulae: A case series.

INTRODUCTION: Iatrogenic recto-urogenital fistulae are refractory complications that rarely heal without surgical intervention. The ongoing local infection causes pain, discomfort and substantially impacts quality of life. Surgical repair requires adequate exposure and space to fill with healthy tissue, which is a major challenge in pelvic redo surgery. An abdominal approach to repair the fistula is associated with major morbidity and often fails to expose the deep pelvis. In our experience a novel transperineal minimally invasive approach a utilizing single incision laparoscopic surgery (SILS) technique could offer improved results. PRESENTATION OF CASES: In the present study, three cases of patients with recto-urogenital fistulae after pelvic surgery are described. Two patients were diagnosed with a rectovesical fistula and one patient with a rectovaginal fistula. In all three cases, a minimally invasive perineal approach, using a SILS port, was used to perform surgical repair. The closure of the fistulae involved: a separate repair of the urethra/bladder or vaginal defect and the rectal defect, followed by interposition of vascularized tissue by either a pudendal thigh fasciocutaneous flap or omentoplasty. DISCUSSION AND CONCLUSION: This study is the first to report on a minimally invasive perineal approach, utilizing a SILS technique for recto-urogenital fistulae repair after previous pelvic surgery. The current approach improves exposure, creates surgical space, optimizes view and allows the interposition of vascularized tissue, without causing substantial blood loss and avoiding major abdominal surgery.

Lengthening adalimumab dosing interval in quiescent Crohn's disease patients: protocol for the pragmatic randomised non-inferiority LADI study.

INTRODUCTION: Adalimumab is effective for maintenance of remission in patients with Crohn's disease (CD) at a dose of 40 mg subcutaneously every 2 weeks. However, adalimumab is associated with (long-term) adverse events and is costly. The aim of this study is to demonstrate non-inferiority and cost-effectiveness of disease activity guided adalimumab interval lengthening compared to standard dosing of every other week (EOW). METHODS AND ANALYSIS: The Lengthening Adalimumab Dosing Interval (LADI) study is a pragmatic, multicentre, open label, randomised controlled non-inferiority trial. Non-inferiority is reached if the difference in cumulative incidence of persistent (>8 weeks) flares does not exceed the non-inferiority margin of 15%. 174 CD patients on adalimumab maintenance therapy in long-term (>9 months) clinical and biochemical remission will be included (C-reactive protein (CRP) <10 mg/L, faecal calprotectin (FC) <150 µg/g, Harvey-Bradshaw Index (HBI) <5). Patients will be randomised 2:1 into the intervention (adalimumab interval lengthening) or control group (adalimumab EOW). The intervention group will lengthen the adalimumab administration interval to every 3 weeks, and after 24 weeks to every 4 weeks. Clinical and biochemical disease activity will be monitored every 12 weeks by physician global assessment, HBI, CRP and FC. In case of disease flare, dosing will be increased. A flare is defined as two of three of the following criteria; FC>250 µg/g, CRP≥10 mg/l, HBI≥5. Secondary outcomes include cumulative incidence of transient flares, adverse events, predictors for successful dose reduction and cost-effectiveness. ETHICS AND DISSEMINATION: The study is approved by the Medical Ethics Committee Arnhem-Nijmegen, the Netherlands (registration number NL58948.091.16). Results will be published in peer-reviewed journals and presented at international conferences. TRIAL REGISTRATION NUMBERS: EudraCT registry (2016-003321-42); Clinicaltrials.gov registry (NCT03172377); Dutch trial registry (NTRID6417).