The Prevalence, Dental Complications, and Effects of Infant Oral Mutilation.

OBJECTIVE: The aim of this scoping review on infant oral mutilation (IOM) was to study the prevalence, dental complications, and immediate and long-term effects of this practice, in addition to providing a systematic overview on existing knowledge and analysis of identified knowledge gaps on IOM. METHODS: Five electronic bibliographic databases (OVID/Medline, Embase.com, Clarivate Analytics/Web of Science Core Collection, SCOPUS, and Global Index Medicus) were searched for relevant studies. Data were entered in a bespoke data-charting form. The risk of bias was assessed by 2 independent reviewers. RESULTS: A total of 478 studies were identified from the search, out of which 42 studies were included in this review. Of the 42 studies, 19 were prevalence studies published between 1969 and 2019 which were additionally assessed for the risk of bias. We found the prevalence of IOM in Uganda was 2% to 30%; Ethiopia, 12% to 86%; Sudan, 10%; Kenya, 61% to 87%; and Tanzania 0% to 24%. Based on the prevalence studies, we observed that the most common factor motivating IOM was diarrhoea. The immediate effects of IOM were found to be infection, bleeding, anaemia, pneumonia, septicaemia, osteomyelitis, meningitis, tetanus, and blood-borne diseases, with some infants dying from these effects. Missing canines, enamel hypoplasia, malformations, abnormal eruption of permanent teeth, occlusal discrepancies, midline shift, chronic periapical infections, rotations, canine transposition, or odontomas were the long-term effects found in relation to IOM. CONCLUSIONS: IOM is a practice with serious immediate and long-term consequences that is mainly performed in East Africa (or by people originated from this region) in children aged 4 to 8 months. Most frequently affected are the deciduous canines and mostly the mandibular teeth. It is important to create professional and public awareness of the procedure in low- and high-income countries. Furthermore, there is a need for more research on the prevalence of IOM in Africa and other areas of the world to determine the long-term consequences of the practice.

Birt-Hogg-Dubé syndrome in apparent primary spontaneous pneumothorax patients; results and recommendations for clinical practice.

BACKGROUND: Birt-Hogg-Dubé syndrome (BHD) is an inherited disease caused by pathogenic variants in the FLCN gene. One of the characteristics is the increased risk for spontaneous pneumothorax, likely due to the presence of pulmonary cysts mainly distributed under the carina. Due to variable expression and lack of awareness, BHD is likely to be underdiagnosed. We aimed to examine the prevalence of BHD in patients presenting with an apparent primary spontaneous pneumothorax and to evaluate the contribution of chest CT in establishing the diagnosis. METHODS: Patients who presented with apparent primary spontaneous pneumothorax between 2004 and 2017 in a large Dutch teaching hospital were enrolled in this quantitative cross-sectional study. A questionnaire was sent to eligible patients. Patients who completed the questionnaire and consented to further participation were invited to visit the hospital for genetic testing and low dose, volumetric chest CT. RESULTS: Genetic testing was performed in 88 patients with apparent primary spontaneous pneumothorax. Three patients were found to have a pathogenic variant in the FLCN gene (3.4%). No variants of unknown significance were detected. Pulmonary cysts were detected in 14 out of 83 participants with an available chest CT, six had more than one cyst. All three patients with BHD had multiple pulmonary cysts. CONCLUSIONS: Based on previous literature and the present study, we believe that performing a chest CT in every patient presenting with primary spontaneous pneumothorax is justified. Subsequent genetic testing of the FLCN gene should be considered when multiple pulmonary cysts are present. TRIAL REGISTRATION: The study was registered at clinicaltrials.gov with reference NCT02916992. Three out of 88 patients with an apparent primary spontaneous pneumothorax were diagnosed with Birt-Hogg-Dubé syndrome in this study and all three had multiple pulmonary cysts. We believe that performing a chest CT in every patient with an apparent primary spontaneous pneumothorax is justified to identify underlying diseases.

Angiogenic markers during preeclampsia: Are they associated with hypertension 1 year postpartum?

OBJECTIVES: Preeclampsia is associated with hypertension in later life, but the underlying pathophysiological mechanisms remain uncertain. We aimed to explore whether the angiogenic markers soluble Fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) measured in women with preeclampsia could be associated with hypertension 1 year after delivery. METHODS: This is a secondary analysis of a prospective cohort study, originally aimed to evaluate the use of sFlt-1/PlGF ratio to predict adverse outcome in women with (suspected) preeclampsia. Office blood pressure (BP) was evaluated at 1 year postpartum in women who had a confirmed diagnosis of preeclampsia within one week of biomarker measurement. RESULTS: Eighty women were included with a median (interquartile range) gestational age (GA) at biomarker measurement of 30 (27-33) weeks. Twenty-three (29%) women had hypertension 1 year postpartum. These women showed higher median SBP during their pregnancy and lower GA at PE diagnosis compared to women without hypertension. Median PlGF levels were lower in women with hypertension 1 year postpartum compared to women without hypertension (23 vs. 48 pg/mL, p = 0.017), while no differences in sFlt-1 or sFlt-1/PlGF ratio were observed. Multivariable analysis adjusted for GA did not show significant association between PlGF (nor sFlt-1, sFlt-1/PlGF ratio) and hypertension 1 year postpartum (OR [95% CI] 0.9 [0.2-4.4], p = 0.97). CONCLUSION: Our data indicate that sFlt-1, PlGF or their ratio measured during pregnancy are not suitable for the prediction of hypertension 1 year postpartum and hence guiding follow-up of women with previous preeclampsia.

Declining detection rates for APC and biallelic MUTYH variants in polyposis patients, implications for DNA testing policy.

This study aimed to determine the prevalence of APC-associated familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) in a large cohort, taking into account factors as adenoma count and year of diagnosis. All application forms used to send patients in for APC and MUTYH variant analysis between 1992 and 2017 were collected (n = 2082). Using the data provided on the application form, the APC and biallelic MUTYH prevalence was determined and possible predictive factors were examined using multivariate multinomial logistic regression analysis in SPSS. The prevalence of disease causing variants in the APC gene significantly increases with adenoma count while MAP shows a peak prevalence in individuals with 50-99 adenomas. Logistic regression analysis shows significant odds ratios for adenoma count, age at diagnosis, and, interestingly, a decline in the chance of finding a variant in either gene over time. Moreover, in 22% (43/200) of patients with FAP-related extracolonic manifestations a variant was identified. The overall detection rates are above 10% for patients with >10 adenomas aged <60 and >20 adenomas aged <70. Patients with variants outside these criteria had FAP-related extracolonic manifestations, colorectal cancer aged <40, somatic KRAS c.34G > T variant in the tumor or a first-degree relative with >10 adenomas. Therefore, APC and MUTYH testing in patients with >10 adenomas aged <60 and with >20 adenomas aged <70 is advised. Almost all FAP and MAP patients not meeting these criteria showed other characteristics that can be used as an indication to prompt genetic testing.

No evidence for increased prevalence of colorectal carcinoma in 399 Dutch patients with Birt-Hogg-Dubé syndrome.

BACKGROUND: Previously, it has been suggested that colorectal polyps and carcinomas might be associated with Birt-Hogg-Dubé syndrome. We aimed to compare the occurrence of colorectal neoplasms between Dutch patients with Birt-Hogg-Dubé syndrome and their relatives without Birt-Hogg-Dubé syndrome. METHODS: In all, 399 patients with a pathogenic FLCN mutation and 382 relatives without the familial FLCN mutation were included. Anonymous data on colon and rectum pathology was provided by PALGA: the Dutch Pathology Registry. RESULTS: No significant difference in the percentage of individuals with a history of colorectal carcinoma was found between the two groups (3.6% vs 2.6%, p = 0.54). There was also no significant difference between the age at diagnosis, diameter, differentiation and location of the colorectal carcinomas. Significantly more individuals with Birt-Hogg-Dubé syndrome underwent removal of colorectal polyps (12.2% vs 6.3%, p = 0.005). However, there was no significant difference between the number of polyps per person, the histology, grade of dysplasia and location of the polyps. CONCLUSION: Our data do not provide evidence for an increased risk for colorectal carcinoma in Birt-Hogg-Dubé syndrome, arguing against the need for colorectal surveillance. The difference in polyps might be due to a bias caused by a higher number of colonoscopies in patients with Birt-Hogg-Dubé syndrome.

Renal imaging in 199 Dutch patients with Birt-Hogg-Dubé syndrome: Screening compliance and outcome.

Birt-Hogg-Dubé syndrome is associated with an increased risk for renal cell carcinoma. Surveillance is recommended, but the optimal imaging method and screening interval remain to be defined. The main aim of our study was to evaluate the outcomes of RCC surveillance to get insight in the safety of annual US in these patients. Surveillance data and medical records of 199 patients with Birt-Hogg-Dubé syndrome were collected retrospectively using medical files and a questionnaire. These patients were diagnosed in two Dutch hospitals and data were collected until June 2014. A first screening for renal cell carcinoma was performed in 172/199 patients (86%). Follow-up data were available from 121 patients. The mean follow-up period per patient was 4.2 years. Of the patients known to be under surveillance, 83% was screened at least annually and 94% at least every two years. Thirty-eight renal cell carcinomas had occurred in 23 patients. The mean age at diagnosis of the first tumour was 51. Eighteen tumours were visualized by ultrasound. Nine small tumours (7-27 mm) were visible on MRI or CT and not detected using ultrasound. Our data indicate that compliance to renal screening is relatively high. Furthermore, ultrasound might be a sensitive, cheap and widely available alternative for MRI or part of the MRIs for detecting clinically relevant renal tumours in BHD patients,but the limitations should be considered carefully. Data from larger cohorts are necessary to confirm these observations.

Pediatric Diamond-Blackfan anemia in the Netherlands: An overview of clinical characteristics and underlying molecular defects.

INTRODUCTION: Diamond-Blackfan anemia (DBA) is characterized by hypoplastic anemia, congenital anomalies, and a predisposition for malignancies. Most of our understanding of this disorder stems from molecular studies combined with extensive data input from international patient registries. OBJECTIVES: To create an overview of the pediatric DBA population in the Netherlands. METHODS: Forty-three patients diagnosed with DBA from all Dutch university pediatric hospitals were included in this study, and their clinical and genetic characteristics were collected from patient records. RESULTS: Congenital malformations were present in 24 of 43 patients (55.8%). An underlying genetic defect was identified in 26 of 43 patients (60.5%), the majority of which were found in the RPS19 gene (12 of 43, 27.9%) with 1 patient carrying a mutation in a novel DBA candidate gene, RPL9. In 31 of 35 (88.6%) patients, an initial response to glucocorticoid treatment was observed. Six patients (14.0%) underwent hematopoietic stem cell transplantation, and eleven patients (11 of 43, 25.6%) became treatment-independent spontaneously. CONCLUSION: In agreement with previous reports, the Dutch pediatric DBA population is both clinically and genetically heterogeneous. National and international registries, together with more extensive genetic testing, are crucial to increase our understanding of genotype and phenotype correlations of this intriguing disorder.

Low dose aspirin in the prevention of recurrent spontaneous preterm labour - the APRIL study: a multicenter randomized placebo controlled trial.

BACKGROUND: Preterm birth (birth before 37 weeks of gestation) is a major problem in obstetrics and affects an estimated 15 million pregnancies worldwide annually. A history of previous preterm birth is the strongest risk factor for preterm birth, and recurrent spontaneous preterm birth affects more than 2.5 million pregnancies each year. A recent meta-analysis showed possible benefits of the use of low dose aspirin in the prevention of recurrent spontaneous preterm birth. We will assess the (cost-)effectiveness of low dose aspirin in comparison with placebo in the prevention of recurrent spontaneous preterm birth in a randomized clinical trial. METHODS/DESIGN: Women with a singleton pregnancy and a history of spontaneous preterm birth in a singleton pregnancy (22-37 weeks of gestation) will be asked to participate in a multicenter, randomized, double blinded, placebo controlled trial. Women will be randomized to low dose aspirin (80 mg once daily) or placebo, initiated from 8 to 16 weeks up to maximal 36 weeks of gestation. The primary outcome measure will be preterm birth, defined as birth at a gestational age (GA) < 37 weeks. Secondary outcomes will be a composite of adverse neonatal outcome and maternal outcomes, including subgroups of prematurity, as well as intrauterine growth restriction (IUGR) and costs from a healthcare perspective. Preterm birth will be analyzed as a group, as well as separately for spontaneous or indicated onset. Analysis will be performed by intention to treat. In total, 406 pregnant women have to be randomized to show a reduction of 35% in preterm birth from 36 to 23%. If aspirin is effective in preventing preterm birth, we expect that there will be cost savings, because of the low costs of aspirin. To evaluate this, a cost-effectiveness analysis will be performed comparing preventive treatment with aspirin with placebo. DISCUSSION: This trial will provide evidence as to whether or not low dose aspirin is (cost-) effective in reducing recurrence of spontaneous preterm birth. TRIAL REGISTRATION: Clinical trial registration number of the Dutch Trial Register: NTR 5675 . EudraCT-registration number: 2015-003220-31.

Comprehensive Mutation Analysis of PMS2 in a Large Cohort of Probands Suspected of Lynch Syndrome or Constitutional Mismatch Repair Deficiency Syndrome.

Monoallelic PMS2 germline mutations cause 5%-15% of Lynch syndrome, a midlife cancer predisposition, whereas biallelic PMS2 mutations cause approximately 60% of constitutional mismatch repair deficiency (CMMRD), a rare childhood cancer syndrome. Recently improved DNA- and RNA-based strategies are applied to overcome problematic PMS2 mutation analysis due to the presence of pseudogenes and frequent gene conversion events. Here, we determined PMS2 mutation detection yield and mutation spectrum in a nationwide cohort of 396 probands. Furthermore, we studied concordance between tumor IHC/MSI (immunohistochemistry/microsatellite instability) profile and mutation carrier state. Overall, we found 52 different pathogenic PMS2 variants explaining 121 Lynch syndrome and nine CMMRD patients. In vitro mismatch repair assays suggested pathogenicity for three missense variants. Ninety-one PMS2 mutation carriers (70%) showed isolated loss of PMS2 in their tumors, for 31 (24%) no or inconclusive IHC was available, and eight carriers (6%) showed discordant IHC (presence of PMS2 or loss of both MLH1 and PMS2). Ten cases with isolated PMS2 loss (10%; 10/97) harbored MLH1 mutations. We confirmed that recently improved mutation analysis provides a high yield of PMS2 mutations in patients with isolated loss of PMS2 expression. Application of universal tumor prescreening methods will however miss some PMS2 germline mutation carriers.

Fetal fibronectin status and cervical length in women with threatened preterm labor and the effectiveness of maintenance tocolysis.

OBJECTIVE: To assess the effect of maintenance tocolysis in women who are at high or low risk for preterm delivery according to fetal fibronectin (fFN) status and cervical length (CL). STUDY DESIGN: We compared the risk of preterm delivery in fFN pos and fFN neg women and in women with a CL <15 mm and ≥15 mm, by using the Cox regression. Differences between the effectiveness of maintenance tocolysis in high- and low-risk women were assessed by using an interaction term. RESULTS: 122 fFN tests were taken, of which 50 were fFN pos. CL was measured in 236 women, of whom 52 women had a CL <15 mm. The median gestational age at delivery was lower in fFN pos women; fFN pos women had a higher hazard for preterm delivery at any point of time (HR 4.7; 95% CI 2.9 to 7.6). Comparable results were seen for CL. Neither fFN status nor CL did alter the effect of maintenance tocolysis, which was ineffective in the total randomized group, on the risk of preterm delivery (p for interaction = 0.87 for fFN and 0.18 for CL). CONCLUSION: Maintenance tocolytic therapy with nifedipine is ineffective and not dependent on fFN or CL status.

Predictive Factors for Delivery within 7 Days after Successful 48-Hour Treatment of Threatened Preterm Labor.

Objective The aim of this study was to assess which characteristics and results of vaginal examination are predictive for delivery within 7 days, in women with threatened preterm labor after initial treatment. Study Design A secondary analysis of a randomized controlled trial on maintenance nifedipine includes women who remained undelivered after threatened preterm labor for 48 hours. We developed one model for women with premature prelabor rupture of membranes (PPROM) and one without PPROM. The predictors were identified by backward selection. We assessed calibration and discrimination and used bootstrapping techniques to correct for potential overfitting. Results For women with PPROM (model 1), nulliparity, history of preterm birth, and vaginal bleeding were included in the multivariable analysis. For women without PPROM (model 2), maternal age, vaginal bleeding, cervical length, and fetal fibronectin (fFN) status were in the multivariable analysis. Discriminative capability was moderate to good (c-statistic 0.68; 95% confidence interval [CI] 0.60-0.77 for model 1 and 0.89; 95% CI, 0.84-0.93 for model 2). Conclusion PPROM and vaginal bleeding in the current pregnancy are relevant predictive factors in all women, as are maternal age, cervical length, and fFN in women without PPROM and nulliparity, history of preterm birth in women with PPROM.

Behavioural and neurodevelopmental outcome of 2-year-old children after preterm premature rupture of membranes: follow-up of a randomised clinical trial comparing induction of labour and expectant management.

OBJECTIVE: We recently reported that induction of labour does not improve short term neonatal outcome in women with late preterm premature rupture of membranes (PPROM) as compared to expectant management (PPROMEXIL trial). In this study the neurodevelopmental and behavioural outcome of the children from this trial at 2 years of age was studied. STUDY DESIGN: We studied outcome of offspring of women randomised in the PPROMEXIL study. These women had >24h of ruptured membranes and were between 34 and 37 weeks of pregnancy when they were randomised to induction of labour (IoL) or expectant management (EM). Two years after delivery, the parents received the ages and stages questionnaire (ASQ), the child behaviour checklist (CBCL) and a general questionnaire. RESULTS: Follow-up data were obtained from 234 children (121 after IoL, 113 after EM, response rate 59% (44% of the original 532 randomised women)). In the IoL group 16 children (14%) had an abnormal score in ≥1 domains of the ASQ, versus 27 (26%) in the EM group (difference in percentage -11.4 (95% CI -21.9 to -0.98; p=0.033)). For the CBCL, an abnormal score was found in 13% (n=15) in the IoL group and in 15% (n=16) in the EM group (difference in percentage -2.13 (95% CI -11.2 to 6.94; p=0.645)). CONCLUSION: Although a policy of induction of labour in women with late PPROM does not improve short term neonatal outcome, it might be associated with a decrease in neurodevelopmental difficulties at the age of two years as compared to expectant management. Expectant management did not lead to a difference in behavioural problems.

The Sleeve Bypass Trial: a multicentre randomized controlled trial comparing the long term outcome of laparoscopic sleeve gastrectomy and gastric bypass for morbid obesity in terms of excess BMI loss percentage and quality of life.

BACKGROUND: Obesity is an increasing disease worldwide. Bariatric surgery is the only effective therapy to induce sufficient long-term weight loss for morbidly obese patients. Laparoscopic Roux-en-Y Gastric Bypass (LRYGB) is the gold standard surgical technique. Laparoscopic Sleeve Gastrectomy (LSG) is a new promising bariatric procedure which has the advantage of maintaining an intact gastrointestinal tract. The aim of this study is to evaluate the efficiency of both techniques. Our hypothesis is that LSG has a similar percentage excess BMI loss (%EBMIL) after 5 years compared to LRYGB. METHODS/DESIGN: The Sleeve Bypass Trial is a randomized multicentre clinical trial: patients eligible for bariatric surgery are randomized to either LSG or LRYGB. Patients with a body mass index (BMI) ≥ 40 kg/m(2) or BMI 35 kg/m(2) with obesity related comorbidity (T2 DM, sleep apnoea, hypertension) are eligible for randomization. At randomization patients are stratified for centre, sex, T2 DM and BMI ≥ 50 kg/m(2). A total number of 620 patients will be enrolled and equally (1:1) randomized to both treatment arms. Only surgeons experienced in both operation techniques will participate in the Sleeve Bypass trial. The primary endpoint is the 5-year weight loss (%EBMIL) of LSG and LRYGB. Secondary endpoints are resolution of obesity related comorbidity, complications, revision bariatric surgery and quality of life (QOL) defined in various questionnaires. DISCUSSION: Long-term %EBMIL between the two treatment strategies used to be in favour of LRYGB, but more recent results throughout the world show similar %EBMIL in both techniques. If weight loss is comparable, obesity-related comorbidity and QOL after bariatric procedures should be taken into account when deciding on which surgical technique is to be preferred for certain subgroups in the future. TRIAL REGISTRATION: Dutch Trial Register: NTR 4741.

Study protocol of the DUCATI-study: a randomized controlled trial investigating the optimal common channel length in laparoscopic gastric bypass for morbid obese patients.

BACKGROUND: Morbid obesity has become one of the most frequent chronic medical disorders in Western countries, affecting 1.5-2 % of the Dutch population. Currently, the laparoscopic Roux-Y gastric bypass is considered to be the most effective bariatric treatment option for morbid obesity as it results in adequate weight loss and a significant decrease in comorbidity. Although this technique has been applied for years, the optimal lengths of the three bowel limbs (alimentary limb, biliopancreatic limb, and common channel) in order to achieve maximal percentage excess weight loss with minimal side effects (i.e. malabsorption symptoms), are unknown. As 'normal' sized gastric bypasses achieve an average of 60 - 80 % excess weight loss after one year, one could hypothesize that afferent limb lengths should be longer in order to reduce the common channel length, thereby improving outcome in terms of excess weight loss. The aim of the current study is to investigate the effect of the length of the common channel in gastric bypass surgery for morbid obesity. In this randomized controlled trial the very long Roux limb gastric bypass will be compared to the standard gastric bypass, in order to conclude which option is the optimal therapeutic strategy in the morbidly obese patient. METHODS/DESIGN: In this multicentre trial patients will be randomized either to a very long Roux limb gastric bypass with a fixed common channel length of 100 cm, or to a standard gastric bypass with a variable common channel length. The primary objective is to evaluate whether the very long Roux limb gastric bypass is superior in terms of percentage excess weight loss after one year follow-up compared to the standard gastric bypass. Secondary endpoints are quality-of-life, cure /improvement of obesity related comorbidity, complications, malnutrition, re-admission rate, and re-operation rate. DISCUSSION: We hypothesize that our proposed distal LRYGB will provide for improved results concerning % EWL with an acceptable rate of (metabolic) complications. Our main point of interest is to determine if the distal LRYGB is a superior alternative to standard LRYGB in terms of percentage excess weight loss and to put more focus on the role of the common channel. Therefore we will perform this randomized controlled trial comparing both techniques, with % EWL as a primary outcome. TRIAL REGISTRATION: CCMO registration number: NL43951.101.13 and Netherlands Trial Registry number: NTR4466.

Maintenance treatment with capecitabine and bevacizumab in metastatic colorectal cancer (CAIRO3): a phase 3 randomised controlled trial of the Dutch Colorectal Cancer Group.

BACKGROUND: The optimum duration of first-line treatment with chemotherapy in combination with bevacizumab in patients with metastatic colorectal cancer is unknown. The CAIRO3 study was designed to determine the efficacy of maintenance treatment with capecitabine plus bevacizumab versus observation. METHODS: In this open-label, phase 3, randomised controlled trial, we recruited patients in 64 hospitals in the Netherlands. We included patients older than 18 years with previously untreated metastatic colorectal cancer, with stable disease or better after induction treatment with six 3-weekly cycles of capecitabine, oxaliplatin, and bevacizumab (CAPOX-B), WHO performance status of 0 or 1, and adequate bone marrow, liver, and renal function. Patients were randomly assigned (1:1) to either maintenance treatment with capecitabine and bevacizumab (maintenance group) or observation (observation group). Randomisation was done centrally by minimisation, with stratification according to previous adjuvant chemotherapy, response to induction treatment, WHO performance status, serum lactate dehydrogenase concentration, and treatment centre. Both patients and investigators were aware of treatment assignment. We assessed disease status every 9 weeks. On first progression (defined as PFS1), patients in both groups were to receive the induction regimen of CAPOX-B until second progression (PFS2), which was the study's primary endpoint. All endpoints were calculated from the time of randomisation. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00442637. FINDINGS: Between May 30, 2007, and Oct 15, 2012, we randomly assigned 558 patients to either the maintenance group (n=279) or the observation group (n=279). Median follow-up was 48 months (IQR 36-57). The primary endpoint of median PFS2 was significantly improved in patients on maintenance treatment, and was 8·5 months in the observation group and 11·7 months in the maintenance group (HR 0·67, 95% CI 0·56-0·81, p<0·0001). This difference remained significant when any treatment after PFS1 was considered. Maintenance treatment was well tolerated, although the incidence of hand-foot syndrome was increased (64 [23%] patients with hand-foot skin reaction during maintenance). The global quality of life did not deteriorate during maintenance treatment and was clinically not different between treatment groups. INTERPRETATION: Maintenance treatment with capecitabine plus bevacizumab after six cycles of CAPOX-B in patients with metastatic colorectal cancer is effective and does not compromise quality of life. FUNDING: Dutch Colorectal Cancer Group (DCCG). The DCCG received financial support for the study from the Commissie Klinische Studies (CKS) of the Dutch Cancer Foundation (KWF), Roche, and Sanofi-Aventis.

[Timing of Advance Care Planning in frail elderly patients: when to start?]. / Kwetsbare ouderen en advance care planning: wanneer beginnen?

Advance Care Planning (ACP) is the process of discussing and recording patient preferences concerning goals for end-of-life care and to facilitate decision-making. ACP is an essential element of care for frail elderly patients because frailty increases the risks of negative health outcomes and loss of function. In this article, we present three patient cases to illustrate how general practitioners (GPs) can perform ACP and to demonstrate the importance of early and iterative end-of-life discussions with frail elderly patients. Good timing is decisive for the success of the intervention. GPs are in a key position to identify and discuss ACP matters at an early stage, supported by the geriatrician if necessary. Posing the 'surprise question' has proved helpful to determine timing. Complex ACP interventions contribute to care which is better adapted to the needs of frail elderly patients.

Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951.

PURPOSE: Anaplastic oligodendroglioma are chemotherapy-sensitive tumors. We now present the long-term follow-up findings of a randomized phase III study on the addition of six cycles of procarbazine, lomustine, and vincristine (PCV) chemotherapy to radiotherapy (RT). PATIENTS AND METHODS: Adult patients with newly diagnosed anaplastic oligodendroglial tumors were randomly assigned to either 59.4 Gy of RT or the same RT followed by six cycles of adjuvant PCV. An exploratory analysis of the correlation between 1p/19q status and survival was part of the study. Retrospectively, the methylation status of the methyl-guanine methyl transferase gene promoter and the mutational status of the isocitrate dehydrogenase (IDH) gene were determined. The primary end points were overall survival (OS) and progression-free survival based on intent-to-treat analysis. RESULTS: A total of 368 patients were enrolled. With a median follow-up of 140 months, OS in the RT/PCV arm was significantly longer (42.3 v 30.6 months in the RT arm, hazard ratio [HR], 0.75; 95% CI, 0.60 to 0.95). In the 80 patients with a 1p/19q codeletion, OS was increased, with a trend toward more benefit from adjuvant PCV (OS not reached in the RT/PCV group v 112 months in the RT group; HR, 0.56; 95% CI, 0.31 to 1.03). IDH mutational status was also of prognostic significance. CONCLUSION: The addition of six cycles of PCV after 59.4 Gy of RT increases both OS and PFS in anaplastic oligodendroglial tumors. 1p/19q-codeleted tumors derive more benefit from adjuvant PCV compared with non-1p/19q-deleted tumors.

Antimicrobial and antibiofilm activity of LL-37 and its truncated variants against Burkholderia pseudomallei.

The Gram-negative bacterium Burkholderia pseudomallei is the aetiological agent of melioidosis, which is an endemic disease in tropical areas of Southeast Asia and Northern Australia. Burkholderia pseudomallei has intrinsic resistance to a number of commonly used antibiotics and has also been reported to develop a biofilm. Resistance to killing by antimicrobial agents is one of the hallmarks of bacteria grown in biofilm. The aim of this study was to determine the antimicrobial activity and mechanisms of action of LL-37 and its truncated variants against B. pseudomallei both in planktonic and biofilm form, as LL-37 is an antimicrobial peptide that possessed strong killing activity against several pathogens. Antimicrobial assays revealed that LL-31, a truncated variant of LL-37 lacking the six C-terminus residues, exhibited the strongest killing effect. Time-kill experiments showed that 20 µM LL-31 can reach the bactericidal endpoint within 2h. Freeze-fracture electron microscopy of bacterial cells demonstrated that these peptides disrupt the membrane and cause leakage of intracellular molecules leading to cell death. Moreover, LL-31 also possessed stronger bactericidal activity than ceftazidime against B. pseudomallei grown in biofilm. Thus, LL-31 should be considered as a potent antimicrobial agent against B. pseudomallei both in planktonic and biofilm form.

Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers.

Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77-0.95, P = 0.003). Promoter in vitro assays of the major BRCA1 haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of BRCA1 modify risk of breast cancer among carriers of BRCA1 mutations, possibly by altering the efficiency of BRCA1 transcription.

Randomized phase II study comparing efficacy and safety of combination-therapy trastuzumab and docetaxel vs. sequential therapy of trastuzumab followed by docetaxel alone at progression as first-line chemotherapy in patients with HER2+ metastatic breast cancer: HERTAX trial.

BACKGROUND: Because chemotherapy for metastatic breast cancer (MBC) is associated with relevant toxicity, sequential monotherapy trastuzumab followed by cytotoxic therapy at disease progression might be an attractive approach. METHODS: In a multicenter phase II trial, 101 patients with overexpression of human epidermal growth factor receptor 2 (HER2(+)) MBC were randomized between combination-therapy trastuzumab (Herceptin) plus docetaxel (H+D) and sequential therapy of single-agent trastuzumab followed at disease progression by docetaxel alone (H→D) as first-line chemotherapy for metastatic disease. The primary endpoint was progression-free survival (PFS) after completed sequential or combination therapy. RESULTS: For the H+D group the median PFS was 9.4 vs. 9.9 months for the H→D group and 1-year PFS rates were 44% vs. 35%, respectively. However the overall response rates (ORRs) were 79% vs. 53%, respectively (P = .016), and overall survival was 30.5 vs. 19.7 months, respectively (P = .11). In the H→D group, response rates to monotherapy trastuzumab and subsequent docetaxel were 34% and 39%, respectively, with a median PFS during single-agent trastuzumab of 3.9 months. The incidence and severity of neuropathy were significantly higher in the H+D group. Retrospective analysis of trastuzumab treatment beyond progression (applied in 46% of patients in the H+D group and 37% in the H→D group) showed a correlation with longer overall survival in both treatment arms (36.0 vs. 18.0 months and 30.3 vs. 18.6 months, respectively). CONCLUSION: First-line treatment in patients with MBC with H→D resulted in a similar PFS compared with H+D, but the response rate was lower and the overall survival nonsignificantly shorter.