Lessons learned during implementation of MR-guided High-Intensity Focused Ultrasound treatment of uterine fibroids.

BACKGROUND: Although promising results have been reported for Magnetic Resonance image-guided High-Intensity Focused Ultrasound (MR-HIFU) treatment of uterine fibroids, this treatment is not yet widely implemented in clinical practice. During the implementation of a new technology, lessons are learned and an institutional learning-curve often has to be completed. The primary aim of our prospective cohort study was to characterize our learning-curve based on our clinical outcomes. Secondary aims included identifying our lessons learned during implementation of MR-HIFU on a technical, patient selection, patient counseling, medical specialists and organizational level. RESULTS: Our first seventy patients showed significant symptom reduction and improvement of quality of life at 3, 6 and 12 months after MR-HIFU treatment compared to baseline. After the first 25 cases, a clear plateau phase was reached in terms of failed treatments. The median non-perfused volume percentage of these first 25 treatments was 44.6% (range: 0-99.7), compared to a median of 74.7% (range: 0-120.6) for the subsequent treatments. CONCLUSIONS: Our findings describe the learning-curve during the implementation of MR-HIFU and include straightforward suggestions to shorten learning-curves for future users. Moreover, the lessons we learned on technique, patient selection, patient counseling, medical specialists and organization, together with the provided supplements, may be of benefit to other institutions aiming to implement MR-HIFU treatment of uterine fibroids. Trial registration ISRCTN14634593. Registered January 12, 2021-Retrospectively registered, https://www.isrctn.com/ISRCTN14634593 .

Impact of Hypertension and Preeclampsia Intervention Trial At Near Term-I (HYPITAT-I) on obstetric management and outcome in The Netherlands.

OBJECTIVE: The Hypertension and Preeclampsia Intervention Trial At near Term-I (HYPITAT-I) randomized controlled trial showed that, in women with gestational hypertension or mild pre-eclampsia at term, induction of labor, compared with expectant management, was associated with improved maternal outcome without compromising neonatal outcome. The aim of the current study was to evaluate the impact of these findings on obstetric management and maternal and perinatal outcomes in The Netherlands. METHODS: We retrieved data for the period 2000-2014 from the Dutch National Perinatal Registry, including 143 749 women with gestational hypertension or pre-eclampsia and a singleton fetus in cephalic presentation, delivered between 36 + 0 and 40 + 6 weeks of gestation (hypertensive disorder of pregnancy (HDP) group). Pregnant women without HDP were used as the reference group (n = 1 649 510). The HYPITAT-I trial was conducted between 2005 and 2008. To study the impact of HYPITAT-I, we compared rate of induction of labor, mode of delivery and maternal and perinatal outcomes in the periods before (2000-2005) and after (2008-2014) the trial. We also differentiated between hospitals that participated in HYPITAT-I and those that did not. RESULTS: In the HDP group, the rate of induction of labor increased from 51.1% before the HYPITAT-I trial to 64.2% after it (relative risk (RR), 1.26; 95% CI, 1.24-1.27). Maternal mortality decreased from 0.022% before the trial to 0.004% after it (RR, 0.20; 95% CI, 0.06-0.70) and perinatal death decreased from 0.49% to 0.27% (RR, 0.54; 95% CI, 0.45-0.65), which was attributable mostly to a decrease in fetal death. Both the increase in induction rate and the reduction in hypertensive complications were more pronounced in hospitals that participated in the HYPITAT-I trial than in those that did not. Following HYPITAT-I, the rate of induction of labor also increased (by 4.6 percentage points) in the reference group; however, the relative increase in the HDP group (13.1 percentage points) was significantly greater (P < 0.001 for the interaction). The reduction in maternal and perinatal deaths did not differ significantly between the HDP and reference groups. There was a decreased incidence of placental abruption in both HDP and reference groups, which was significantly greater in the HDP than in the reference group (P < 0.001 for the interaction). There was also an increased incidence of emergency Cesarean section in both HDP and reference groups; however, this change was significantly greater in the reference than in the HDP group (P < 0.001 for the interaction). CONCLUSION: Following the HYPITAT-I trial, there was a higher rate of induction of labor and improved obstetric outcome in term pregnancies complicated by HDP in The Netherlands. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Maternal mortality due to cardiovascular disease in the Netherlands: a 21-year experience.

OBJECTIVE: Cardiovascular disorders are the leading cause of indirect maternal mortality in Europe. The aim of this study is to present an extensive overview concerning the specific cardiovascular causes of maternal death and to identify avoidable contributing care factors related to these deaths. METHODS: We assessed all cases of maternal death due to cardiovascular disorders collected by a systematic national confidential enquiry of maternal deaths published by the Dutch Maternal Mortality and Morbidity Committee on behalf of the Netherlands Society of Obstetrics and Gynaecology over a 21-year period (1993-2013) in the Netherlands. RESULTS: There were 96 maternal cardiovascular deaths (maternal mortality rate due to cardiovascular diseases 2.4/100,000 liveborn children). Causes were aortic dissection (n = 20, 21%), ischaemic heart disease (n = 17, 18%), cardiomyopathies (including peripartum cardiomyopathy and myocarditis, n = 20, 21%) and (unexplained) sudden death (n = 27, 28%). Fifty-five percent of the deaths occurred postpartum (n = 55, 55%). Care factors that may have contributed to the adverse outcome were identified in 27 cases (28%). These factors were patient-related in 40% (pregnancy against medical advice, underestimation of symptoms) and healthcare-provider-related in 60% (symptoms not recognised, delay in diagnosis, delay in referral). CONCLUSION: The maternal cardiovascular mortality ratio is low in the Netherlands and the main causes of maternal cardiovascular mortality are in line with other European reports. In a minority of cases, care factors that were possibly preventable were identified. Women with cardiovascular disease should be properly counselled about the risks of pregnancy and the symptoms of complications. Education of care providers regarding the incidence, presentation and diagnosis of cardiovascular disease during pregnancy is recommended.

[Trisomy 18: how lethal is 'lethal'?] / Trisomie 18: hoe lethaal is 'lethaal'?

Should active treatment be available for children with trisomy 18? In the Netherlands, trisomy 18 is described as a lethal condition leading to death during or immediately after birth. The Dutch course of action for trisomy 18 is termination of pregnancy, almost without exception, or passive treatment without medical interventions. But that approach might be outdated. We present a case that inspired physicians and parents to rethink the perception of trisomy 18.

Fertility and obstetric outcomes after curettage versus expectant management in randomised and non-randomised women with an incomplete evacuation of the uterus after misoprostol treatment for miscarriage.

OBJECTIVE: To assess fertility and obstetric outcomes in women treated with curettage or undergoing expectant management for an incomplete miscarriage after misoprostol treatment. STUDY DESIGN: Between June 2012 and July 2014, we conducted a multicentre randomised clinical trial (RCT) with a parallel cohort study for non-randomised women, treated according to their preference. In the RCT 30 women were allocated curettage and 29 expectant management. In the cohort 197 women participated; 65 underwent curettage and 132 women underwent expectant management. Primary outcome was curation, defined as either an empty uterus on sonography at six weeks or an uneventful clinical follow-up. We used questionnaires to assess fertility and obstetric outcome of the first new pregnancy subsequent to study enrolment. RESULTS: Curation was seen in 91/95 women treated with curettage (95.8%) versus 134/161 women managed expectantly (83.2%) (p=0.003). The response rate was 211/255 (82%). In 198 women pursuing a new pregnancy, conception rates were 92% (67/73) in the curettage group versus 96% (120/125) in the expectant management group (OR 0.96, 95% CI 0.89;1.03, p=0.34), with ongoing pregnancy rates of 87% (58/67) versus 78% (94/120), respectively (OR 1.12, 95% CI 0.99;1.28, p=0.226). Preterm birth rates were 1/46 in the curettage group versus 8/81 in the expectant management group (OR 0.22, 95% CI 0.03;1.71 P=0.15). Caesarean section rates were 23% and 24% for women in the curettage group and expectant management group respectively. CONCLUSION: In women with an incomplete evacuation of the uterus after misoprostol treatment, curettage and expectant management does not lead to different fertility and pregnancy outcomes, as compared to expectant management.

GFI1 as a novel prognostic and therapeutic factor for AML/MDS.

Genetic and epigenetic aberrations contribute to the initiation and progression of acute myeloid leukemia (AML). GFI1, a zinc-finger transcriptional repressor, exerts its function by recruiting histone deacetylases to target genes. We present data that low expression of GFI1 is associated with an inferior prognosis of AML patients. To elucidate the mechanism behind this, we generated a humanized mouse strain with reduced GFI1 expression (GFI1-KD). Here we show that AML development induced by onco-fusion proteins such as MLL-AF9 or NUP98-HOXD13 is accelerated in mice with low human GFI1 expression. Leukemic cells from animals that express low levels of GFI1 show increased H3K9 acetylation compared to leukemic cells from mice with normal human GFI1 expression, resulting in the upregulation of genes involved in leukemogenesis. We investigated a new epigenetic therapy approach for this subgroup of AML patients. We could show that AML blasts from GFI1-KD mice and from AML patients with low GFI1 levels were more sensitive to treatment with histone acetyltransferase inhibitors than cells with normal GFI1 expression levels. We suggest therefore that GFI1 has a dose-dependent role in AML progression and development. GFI1 levels are involved in epigenetic regulation, which could open new therapeutic approaches for AML patients.

Bivalent promoter marks and a latent enhancer may prime the leukaemia oncogene LMO1 for ectopic expression in T-cell leukaemia.

LMO1 is a transcriptional regulator and a T-acute lymphoblastic leukaemia (T-ALL) oncogene. Although first identified in association with a chromosomal translocation in T-ALL, the ectopic expression of LMO1 occurs far more frequently in the absence of any known mutation involving its locus. Given that LMO1 is barely expressed in any haematopoietic lineage, and activation of transcriptional drivers in leukaemic cells is not well described, we investigated the regulation of this gene in normal haematopoietic and leukaemic cells. We show that LMO1 has two promoters that drive reporter gene expression in transgenic mice to neural tissues known to express endogenous LMO1. The LMO1 promoters display bivalent histone marks in multiple blood lineages including T-cells, and a 3' flanking region at LMO1 +57 contains a transcriptional enhancer that is active in developing blood cells in transgenic mouse embryos. The LMO1 promoters become activated in T-ALL together with the 3' enhancer, which is bound in primary T-ALL cells by SCL/TAL1 and GATA3. Taken together, our results show that LMO1 is poised for expression in normal progenitors, where activation of SCL/TAL1 together with a breakdown of epigenetic repression of LMO1 regulatory elements induces ectopic LMO1 expression that contributes to the development and maintenance of T-ALL.

Sorafenib as third- or fourth-line treatment of advanced gastrointestinal stromal tumour and pretreatment including both imatinib and sunitinib, and nilotinib: A retrospective analysis.

BACKGROUND: Tyrosine kinase inhibitors (TKI) improve the outcome of patients with advanced gastrointestinal stromal tumour (GIST), but treatment failure is frequent, and prognosis then bleak. Smaller trials in this setting suggested activity for sorafenib, a multikinase inhibitor of receptor tyrosine kinases and RAF serine/threonine kinases. PATIENTS AND METHODS: We retrospectively evaluated the efficacy of sorafenib, starting dose 400mg twice daily, in a large community-based cohort of 124 patients treated in 12 European and one United States (U.S.) cancer centre. All but one patient had a WHO performance score 0-2. All had failed both imatinib and sunitinib, 68 patients nilotinib and 26 had failed investigational therapy, too. RESULTS: Twelve (10%) patients responded to sorafenib and 70 (57%) patients achieved disease stabilisation. Sorafenib was moderately tolerated, and toxicity reported in 56% of the patients. Rash, hand-foot-syndrome and diarrhea occurred frequently. Sorafenib dosage was reduced in a third of patients, but this did not have an impact on progression-free survival (PFS) (p=0.15). Median PFS was 6.4 months (95% confidence interval [CI], 4.6-8.0 months) and median overall survival (OS) 13.5 months (95% CI, 10.0-21.0 months). Patients with a good performance status and those who responded to sorafenib had a significant better PFS. CONCLUSION: We conclude that sorafenib is active in GIST resistant to imatinib, sunitinib and nilotinib. These results warrant further investigation of sorafenib or similar molecules in GIST.

Fatal meningitis during pregnancy in the Netherlands: a nationwide confidential enquiry.

OBJECTIVE: To determine the incidence of maternal deaths attributable to meningitis in the Netherlands, and to assess clinical features and risk factors. DESIGN: Confidential enquiry into the causes of maternal deaths. SETTING: Nationwide in the Netherlands. POPULATION: A total of 4 784 408 live births. METHODS: Analysis of all maternal deaths due to meningitis in pregnancy and puerperium from 1983 up to and including 2007 reported to the Maternal Mortality Committee of the Dutch Society of Obstetrics and Gynaecology. MAIN OUTCOME MEASURES: Incidence, clinical features and risk factors. RESULTS: Fifteen maternal deaths occurred due to meningitis, representing 4.4% of all maternal deaths. Twelve women (80%) presented with meningitis during pregnancy, 8 (66%) of them in the third trimester. Presenting symptoms were altered mental status (11; 73%), fever (9; 60%), nuchal rigidity (5; 33%) and headache (13; 87%). Nine women (60%) had otolaryngological infection at presentation or in the previous days or weeks. Twelve women (80%) underwent radiological examination, of which 5 (33%) showed distinct abnormalities. Cerebrospinal fluid (CSF) examination showed infected CSF in 8 (53%) women. In ten women (67%) Streptococcus pneumoniae was isolated. Substandard care was identified in 4 (27%) women. CONCLUSION: Pregnant or puerperal women presenting with classical symptoms of meningitis, particularly those with a history of otolaryngological infection or headache, should undergo thorough investigation and radiological and CSF examinations. Early diagnosis and immediate antibiotic treatment are imperative because of rapid deterioration in pregnant women. In case of doubt, the threshold for antibiotic treatment should be low and close monitoring is warranted.

A randomised phase II trial of the Polo-like kinase inhibitor BI 2536 in chemo-naïve patients with unresectable exocrine adenocarcinoma of the pancreas - a study within the Central European Society Anticancer Drug Research (CESAR) collaborative network.

BACKGROUND: BI 2536, a novel Polo-like kinase 1 inhibitor, was assessed in patients with unresectable advanced exocrine adenocarcinoma of the pancreas. METHODS: The study employed a two-stage design. Randomised first-line patients received BI 2536 200 mg on day 1 (n=43) or 60 mg on days 1-3 (n=43) every 21 days. Recruitment of second-line patients was planned for a second stage dependent on an interim analysis demonstrating ≥ 2 responses in the first 18 evaluable patients following 12 weeks of treatment and/or tumour control ≥ 12 weeks in 5 patients per schedule. Primary end point was objective response rate (ORR). RESULTS: By independent review, ORR was 2.3% (all partial) and 24.4% had stable disease as confirmed best response. The second stage was not initiated. Median overall and progression-free survivals were 149 (95% confidence interval (CI), 91-307) and 46 days (95% CI, 44-56). Most common drug-related adverse events were neutropenia (37.2%), leukopenia (29.1%), fatigue (29.1%) and nausea (22.1%); most common grade 3/4-related events were neutropenia (36.0%), leukopenia (27.9%) and thrombocytopenia (8.1%). CONCLUSION: Given the low ORR and poor survival, further development of BI 2536 monotherapy is not warranted in this population.

Regional differences in Dutch maternal mortality.

OBJECTIVE: To study regional differences in maternal mortality in the Netherlands. DESIGN: Confidential inquiry into the causes of maternal mortality. SETTING: Nationwide. POPULATION: A total of 3 108 235 live births and 337 maternal deaths. METHODS: Data analysis of all maternal deaths in the period 1993-2008. MAIN OUTCOME MEASURE: Maternal mortality. RESULTS: The overall national maternal mortality ratio was 10.8 per 100 000 live births. In the 12 provinces of the Netherlands, the maternal mortality ratio ranged from 6.2 in Noord Brabant to 16.3 per 100 000 live births in Zeeland. In the four largest cities, maternal mortality varied from 9.3 in Amsterdam to 21.0 in Rotterdam. At a national level, the most frequent direct cause was pre-eclampsia. Increased risks for maternal mortality were found for women living in deprived neighbourhoods (RR 1.41), women from non-Western origin (RR 1.59), and women who were 35 years or older (RR 1.61). CONCLUSION: There are significant variations in maternal mortality ratios in the Netherlands between cities, provinces, and neighbourhoods. In addition, higher maternal mortality was observed in women of non-Western origin and in women who were 35 years of age or older.

Maternal mortality attributable to vascular dissection and rupture in the Netherlands: a nationwide confidential enquiry.

OBJECTIVE: To determine the incidence of maternal deaths attributable to vascular dissection and rupture in the Netherlands, and to assess clinical features, risk factors and the frequency of substandard care in the cases identified. DESIGN: Confidential enquiry into the causes of maternal deaths. SETTING: Nationwide in the Netherlands. POPULATION: A total of 3,108,235 live births. METHODS: Data analysis of all cases of maternal death from vascular dissection and rupture in the period 1993-2008. A literature review was also performed. MAIN OUTCOME MEASURES: Incidence, clinical features, risk factors and frequency of substandard care. RESULTS: A total of 23 maternal deaths attributable to vascular dissection and rupture were reported. In most cases the location was aortic (n=13), followed by coronary (n=4) and splenic (n=3) arteries. Clinical features were various, but most women presented with sudden unexplainable pain. Risk factors were present in 14 cases (61%), with hypertension being most frequently reported in ten cases (43%). Substandard care was determined to have been received in 13 cases (56%), inadequate assessment of complaints and a delay in diagnosis being the most frequent problems identified. CONCLUSIONS: Vascular dissection and rupture in pregnancy, although rare, carry a high risk of maternal and fetal morbidity and mortality. Because of the rarity of this condition and its variety in presentation, diagnosis is easily missed. A high index of suspicion when a woman presents with suggestive complaints, leading to an early diagnosis, may improve the prognosis for the woman and her child.

Modification of a commercial atomic force microscopy for low-noise, high-resolution frequency-modulation imaging in liquid environment.

A key issue for high-resolution frequency-modulation atomic force microscopy imaging in liquids is minimizing the frequency noise, which requires a detailed analysis of the corresponding noise contributions. In this paper, we present a detailed description for modifying a commercial atomic force microscope (Bruker MultiMode V with Nanoscope V controller), aiming at atomic-resolution frequency-modulation imaging in ambient and in liquid environment. Care was taken to maintain the AFMs original stability and ease of operation. The new system builds upon an optimized light source, a new photodiode and an entirely new amplifier. Moreover, we introduce a home-built liquid cell and sample holder as well as a temperature-stabilized isolation chamber dedicated to low-noise imaging in liquids. The success of these modifications is measured by the reduction in the deflection sensor noise density from initially 100 fm/√Hz to around 10 fm/√Hz after modification. The performance of our instrument is demonstrated by atomically resolved images of calcite taken under liquid conditions.

Maternal death related to IVF in the Netherlands 1984-2008.

BACKGROUND: We assessed all deaths in the Netherlands that might have been related to IVF or to an IVF pregnancy in order to investigate this most serious complication. METHODS: All deaths related to IVF, within 1 year after IVF, from 1984 to 2008 were collected by sending a letter to all gynaecologists, and by retrieving data from a large cohort study examining the late effects of ovarian stimulation (OMEGA) and from the Dutch Maternal Mortality Committee. RESULTS: Six deaths were directly related to IVF (6/100,000), 17 deaths were directly related to the IVF pregnancy (42.5/100,000) and eight deaths were neither related to the IVF nor to the IVF-related pregnancy. The overall mortality in patients undergoing IVF procedures was lower than in the general population, whereas the overall mortality related to IVF pregnancies was higher than the maternal mortality in the general population. CONCLUSION: The decreased mortality is probably the result of a 'healthy female effect' in women undergoing IVF. The high maternal mortality in IVF pregnancies is probably related to the high number of multiple pregnancies and to the fact that (donor egg) IVF is successfully used in women who are older. The fact that only a few deaths directly related to IVF are reported in the literature whereas we observed six in the Netherlands indicates worldwide under-reporting of IVF-related mortality. We underline the importance of reporting all lethal cases to the European Society of Human Reproduction and Embryology Committee 'Safety and Quality after IVF'.

Cardiac arrest in pregnancy: increasing use of perimortem caesarean section due to emergency skills training?

OBJECTIVE: Management of cardiac arrest in pregnancy is recommended to include perimortem caesarean section (PMCS) in the Managing Obstetric Emergencies and Trauma (MOET) course. In this study, we aimed to assess maternal and neonatal outcome of all cases of PMCS in the Netherlands performed in the last 15 years, and to test the hypothesis that PMCS was used more often since the introduction of the MOET-course in 2004. DESIGN: Retrospective cohort study. SETTING: Nationwide assessment of all cases of PMCS inside or outside hospitals. POPULATION: All known cases of PMCS in the Netherlands from 1993 to 2008. METHODS: Data collection through contacting all Dutch obstetricians and all MOET and Advanced Trauma Life Support instructors. All cases of cardiac arrest during pregnancy were collected by cross-checking with data from the Dutch Maternal Mortality Committee and a nationwide severe maternal morbidity study. MAIN OUTCOME MEASURES: Incidence and case fatality rate of PMCS. Incidence of PMCS before and after introduction of the MOET course. Maternal and neonatal outcome and the process of the PMCS were analysed. RESULTS: During the study period, 55 women had a cardiac arrest, 12 of whom underwent a PMCS. Before the introduction of the MOET course, four PMCSs were performed (0.36/year), compared with eight cases after its introduction (1.6/year, P = 0.01). No PMCS was performed within the recommended 5 minutes after starting resuscitation. Eight of the twelve women (67%) regained cardiac output after PMCS, with two maternal and five neonatal survivors. Maternal case fatality rate was 83%. Neonatal case fatality rate was 58%. CONCLUSIONS: Since the introduction of the MOET course, the use of PMCS has increased. Outcome, however, was still poor. An important factor to improve outcome is more timely application of this potentially life-saving procedure.

Rise in maternal mortality in the Netherlands.

OBJECTIVE: To assess causes, trends and substandard care factors in maternal mortality in the Netherlands. Design Confidential enquiry into the causes of maternal mortality. SETTING: Nationwide in the Netherlands. POPULATION: 2,557,208 live births. METHODS: Data analysis of all maternal deaths in the period 1993-2005. MAIN OUTCOME MEASURES: Maternal mortality. RESULTS: The overall maternal mortality ratio was 12.1 per 100 000 live births, which was a statistically significant rise compared with the maternal mortality ratio of 9.7 in the period 1983-1992 (OR 1.2, 95% CI 1.0-1.5). The most frequent direct causes were (pre-)eclampsia, thromboembolism, sudden death in pregnancy, sepsis, obstetric haemorrhage and amniotic fluid embolism. The number of indirect deaths also increased, mainly caused by an increase in cardiovascular disorders (OR 2.5, 95% CI 1.4-4.6). Women younger than 20 years and older than 45 years, those with high parity or from nonwestern immigrant populations were at higher risk. Most substandard care was found in women with pre-eclampsia (91%) and in immigrant populations (62%). CONCLUSIONS: Maternal mortality in the Netherlands has increased since 1983-1992. Pre-eclampsia remains the number one cause. Groups at higher risk for complications during pregnancy should be better identified early in pregnancy or before conception, in order to receive preconception advice and more frequent antenatal visits. There is an urgent need for the better education of women and professionals concerning the danger signs, and for the training of professionals in order to improve maternal health care.

An open-label expanded access study of lapatinib and capecitabine in patients with HER2-overexpressing locally advanced or metastatic breast cancer.

BACKGROUND: The Lapatinib Expanded Access Program (LEAP) was designed to provide access to lapatinib plus capecitabine for HER2-positive metastatic breast cancer patients who previously received an anthracycline, a taxane, and a trastuzumab and had no other treatment options. PATIENTS AND METHODS: LEAP opened globally and enrollment continued until lapatinib received regulatory approval in each participating country. Patients were assessed for progression-free survival (PFS) and overall survival (OS) and monitored for serious adverse events (SAEs). RESULTS: As of 30 September 2008, 4283 patients from 45 countries enrolled in LEAP. The median treatment duration was 24.7 weeks. The most common drug-related SAEs were diarrhea (9.7%), vomiting (4.3%), and nausea (2.4%) and were mainly grade 3 or higher. The incidences of special interest SAEs were decreased left ventricle ejection fraction (0.5%), interstitial lung disease/pneumonitis (0.2%), and serious hepatobiliary events (0.4%). This safety profile is consistent with the overall lapatinib program. The median PFS and OS were 21.1 [95% confidence interval (CI) = 20.1-22.3] and 39.6 (95% CI = 37.7-40.7) weeks, respectively (n = 4006). Subgroup analysis showed longer PFS and OS in patients who had not received prior capecitabine. CONCLUSIONS: These results demonstrate the safety and efficacy of lapatinib in a broader patient population compared with a clinical trial.

Concept for support and cleavage of brittle crystals.

We report on sample holders for crystals to be cleaved for the preparation of surfaces with large atomically flat terraces. The concept for mounting sample crystals is based on a vicelike clamping mechanism to securely hold the crystal in position while reducing the risk of fragmentation. Sample holders based on this concept and made of suitable materials allow preparation and cleavage of crystals in the ultrahigh vacuum at high or low temperatures. To cleave the crystal, we employ a scalpel blade mounted on a wobble stick to generate a highly localized stress field initiating the cleavage process. The sample holders are used for experiments of highest resolution scanning force microscopy, however, the concept can be transferred to any other system where cleavage faces of crystals are of interest. Exemplarily, scanning force microscopy results demonstrate that (111) cleavage faces of CaF2 crystals can be prepared with steps only a few F-Ca-F triple-layers high and atomically flat terraces extending over areas of several microm2.

Maternal mortality and serious maternal morbidity in Jehovah's witnesses in The Netherlands.

OBJECTIVE: To determine the risk of maternal mortality and serious maternal morbidity because of major obstetric haemorrhage in Jehovah's witnesses in The Netherlands. DESIGN: A retrospective study of case notes. SETTING: All tertiary care centres, general teaching hospitals and other general hospitals in The Netherlands. SAMPLE: All cases of maternal mortality in The Netherlands between 1983 and 2006 and all cases of serious maternal morbidity in The Netherlands between 2004 and 2006. METHODS: Study of case notes using two different nationwide enquiries over two different time periods. MAIN OUTCOME MEASURES: Maternal mortality ratio (MMR) and risk of serious maternal mortality. RESULTS: The MMR for Jehovah's witnesses was 68 per 100,000 live births. We found a risk of 14 per 1000 for Jehovah's witnesses to experience serious maternal morbidity because of obstetric haemorrhage while the risk for the total pregnant population was 4.5 per 1000. CONCLUSIONS: Women who are Jehovah's witnesses are at a six times increased risk for maternal death, at a 130 times increased risk for maternal death because of major obstetric haemorrhage and at a 3.1 times increased risk for serious maternal morbidity because of obstetric haemorrhage, compared to the general Dutch population.