MLL3/MLL4 methyltransferase activities control early embryonic development and embryonic stem cell differentiation in a lineage-selective manner.

H3K4me1 methyltransferases MLL3 (KMT2C) and MLL4 (KMT2D) are critical for enhancer activation, cell differentiation and development. However, roles of MLL3/4 enzymatic activities and MLL3/4-mediated enhancer H3K4me1 in these processes remain unclear. Here we report that constitutive elimination of both MLL3 and MLL4 enzymatic activities prevents initiation of gastrulation and leads to early embryonic lethality in mice. However, selective elimination of MLL3/4 enzymatic activities in embryonic, but not extraembryonic, lineages leaves gastrulation largely intact. Consistent with this, embryonic stem cells (ESCs) lacking MLL3/4 enzymatic activities can differentiate toward the three embryonic germ layers but show aberrant differentiation to extraembryonic endoderm (ExEn) and trophectoderm. The failure in ExEn differentiation can be attributed to markedly reduced enhancer-binding of the lineage-determining transcription factor GATA6. Furthermore, we show that MLL3/4-catalyzed H3K4me1 is largely dispensable for enhancer activation during ESC differentiation. Together, our findings suggest a lineage-selective, but enhancer activation-independent, role of MLL3/4 methyltransferase activities in early embryonic development and ESC differentiation.

An epigenome atlas of neural progenitors within the embryonic mouse forebrain.

A comprehensive characterization of epigenomic organization in the embryonic mouse forebrain will enhance our understanding of neurodevelopment and provide insight into mechanisms of neurological disease. Here we collected single-cell chromatin accessibility profiles from four distinct neurogenic regions of the embryonic mouse forebrain using single nuclei ATAC-Seq (snATAC-Seq). We identified thousands of differentially accessible peaks, many restricted to distinct progenitor cell types or brain regions. We integrated snATAC-Seq and single cell transcriptome data to characterize changes of chromatin accessibility at enhancers and promoters with associated transcript abundance. Multi-modal integration of histone modifications (CUT&Tag and CUT&RUN), promoter-enhancer interactions (Capture-C) and high-order chromatin structure (Hi-C) extended these initial observations. This dataset reveals a diverse chromatin landscape with region-specific regulatory mechanisms and genomic interactions in distinct neurogenic regions of the embryonic mouse brain and represents an extensive public resource of a 'ground truth' epigenomic landscape at this critical stage of neurogenesis.

Extensive co-binding and rapid redistribution of NANOG and GATA6 during emergence of divergent lineages.

Fate-determining transcription factors (TFs) can promote lineage-restricted transcriptional programs from common progenitor states. The inner cell mass (ICM) of mouse blastocysts co-expresses the TFs NANOG and GATA6, which drive the bifurcation of the ICM into either the epiblast (Epi) or the primitive endoderm (PrE), respectively. Here, we induce GATA6 in embryonic stem cells-that also express NANOG-to characterize how a state of co-expression of opposing TFs resolves into divergent lineages. Surprisingly, we find that GATA6 and NANOG co-bind at the vast majority of Epi and PrE enhancers, a phenomenon we also observe in blastocysts. The co-bound state is followed by eviction and repression of Epi TFs, and quick remodeling of chromatin and enhancer-promoter contacts thus establishing the PrE lineage while repressing the Epi fate. We propose that co-binding of GATA6 and NANOG at shared enhancers maintains ICM plasticity and promotes the rapid establishment of Epi- and PrE-specific transcriptional programs.

Clinical Utility of Epigenetic Changes in Pancreatic Adenocarcinoma.

Pancreatic cancer is a molecularly heterogeneous disease. Epigenetic changes and epigenetic regulatory mechanisms underlie at least some of this heterogeneity and contribute to the evolution of aggressive tumor biology in patients and the tumor's intrinsic resistance to therapy. Here we review our current understanding of epigenetic dysregulation in pancreatic cancer and how it is contributing to our efforts in early diagnosis, predictive and prognostic biomarker development and new therapeutic approaches in this deadly cancer.

Beta-hydroxy beta-methylbutyrate/arginine/glutamine (HMB/Arg/Gln) supplementation to improve the management of cachexia in patients with advanced lung cancer: an open-label, multicentre, randomised, controlled phase II trial (NOURISH).

BACKGROUND: Cancer cachexia causes significant morbidity and mortality in advanced lung cancer patients. Clinical benefit of ß-hydroxy-ß-methylbutyrate, arginine, and glutamine (HMB/Arg/Gln) was assessed in newly diagnosed patients. METHODS: NOURISH, a prospective, two-arm, open-label, multi-centre, randomised controlled phase II trial compared cachexia in patients who received HMB/Arg/Gln with those who did not. All patients received structured nutritional, exercise and symptom control via a Macmillan Durham Cachexia Pack. Conducted in five UK centres, patients aged > 18 years, with newly diagnosed advanced small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC), who were able to take oral nutrition, with a performance status of 0-to-2 and a life expectancy > 4 months were eligible for trial entry. Patients suitable for treatment with curative intent were ineligible. The trial was designed as a signal-seeking pilot study with target recruitment of 96 patients. One-to-one randomisation was stratified by diagnosis (SCLC or NSCLC), stage of disease (locally advanced or metastatic) and performance status. The primary outcome measure was treatment success defined as a patient being alive without significant loss of lean body mass (not > 5%) by 12 weeks. Secondary outcome measures included quality of life. RESULTS: Between February-2012 and February-2013, 38 patients were recruited, 19 to each arm. Baseline characteristics were balanced. The trial was halted due to slow accrual and partial adherence. Trial data demonstrated no evidence of treatment benefit. No serious adverse events were reported during the trial. CONCLUSIONS: Further evaluation of HMB/Arg/Gln in this setting could not be recommended on the basis of this trial. CLINICAL TRIAL REGISTRATION: ISRCTN registry: 39911673; 14-Apr-2011 https://doi.org/10.1186/ISRCTN39911673 .

Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation.

Reversible modification of proteins with linkage-specific ubiquitin chains is critical for intracellular signaling. Information on physiological roles and underlying mechanisms of particular ubiquitin linkages during human development are limited. Here, relying on genomic constraint scores, we identify 10 patients with multiple congenital anomalies caused by hemizygous variants in OTUD5, encoding a K48/K63 linkage-specific deubiquitylase. By studying these mutations, we find that OTUD5 controls neuroectodermal differentiation through cleaving K48-linked ubiquitin chains to counteract degradation of select chromatin regulators (e.g., ARID1A/B, histone deacetylase 2, and HCF1), mutations of which underlie diseases that exhibit phenotypic overlap with OTUD5 patients. Loss of OTUD5 during differentiation leads to less accessible chromatin at neuroectodermal enhancers and aberrant gene expression. Our study describes a previously unidentified disorder we name LINKED (LINKage-specific deubiquitylation deficiency-induced Embryonic Defects) syndrome and reveals linkage-specific ubiquitin cleavage from chromatin remodelers as an essential signaling mode that coordinates chromatin remodeling during embryogenesis.

Knowledge and use of the ICM global standards for midwifery education.

OBJECTIVE: To explore how the International Confederation of Midwives Global Standards for Midwifery Education are currently used and their influence, if any, on the development of education programs globally. Secondarily, to identify current challenges to midwifery education. DESIGN: Cross-sectional exploratory descriptive qualitative study using focus groups and one-on-one interviews to collect data about knowledge of and use of the Education Standards and participants perceived current challenges to midwifery education. Interviews conducted in English, Spanish, and French. SETTING AND PARTICIPANTS: Midwife educators, education directors, or regulators attending one of four national/international conferences or one-on-one interviews in person or via internet. Thematic analysis was employed using the Framework approach for data analysis. FINDINGS: There were 11 focus groups and 19 individual interviews involving 145 midwives from 61 countries. There was a general awareness of the Education Standards amongst the participants although knowledge about the specifics of the document was lacking. The Standards were mainly used as a reference and greater use was made when developing new educational programs. The Standards identified as most difficult to meet included: organization and administration of the program, ensuring that teachers were formally prepared as teachers, meeting targets for teacher to student ratios and that 50% of educational time took place in the clinical setting. Universally endorsed challenges to midwifery education were: 1) inability to accommodate the increase in curricular content without compromising prior content or lengthening programs; 2) insufficient resources including lack of classroom and clinical teachers; 3) medicalization of childbirth and health system changes limiting student exposure to the midwifery care model; 4) role conflict and competition for clinical experience with other health professionals. KEY CONCLUSIONS: The Education Standards need to be more widely disseminated and implemented. Stronger collaborations with clinical settings and government systems are required to solve the current challenges to midwifery education. IMPLICATION OF PRACTICE: Well-educated midwives can provide the majority of maternal and neonatal care, however it will require an investment in strengthening midwifery programs globally for this goal to be achieved.

Safety and Efficacy of the Addition of Lapatinib to Perioperative Chemotherapy for Resectable HER2-Positive Gastroesophageal Adenocarcinoma: A Randomized Phase 2 Clinical Trial.

IMPORTANCE: Perioperative chemotherapy and surgery are a standard of care for operable gastroesophageal adenocarcinoma. Anti-HER2 therapy improves survival in patients with advanced HER2-positive disease. The safety and feasibility of adding lapatinib to perioperative chemotherapy should be assessed. OBJECTIVES: To assess the safety of adding lapatinib to epirubicin, cisplatin, and capecitabine (ECX) chemotherapy and to establish a recommended dose regimen for a phase 3 trial. DESIGN, SETTING, AND PARTICIPANTS: Phase 2 randomized, open-label trial comparing standard ECX (sECX: 3 preoperative and 3 postoperative cycles of ECX with modified ECX plus lapatinib (mECX+L). This multicenter national trial was conducted in 29 centers in the United Kingdom in patients with histologically proven, HER2-positive, operable gastroesophageal adenocarcinoma. Registration for ERBB/HER2 testing took place from February 25, 2013, to April 19, 2016, and randomization took place between May 24, 2013, and April 21, 2016. Data were analyzed May 10, 2017, to May 25, 2017. INTERVENTIONS: Patients were randomized 1:1 open-label to sECX (3 preoperative and 3 postoperative cycles of 50 mg/m2 of intravenous epirubicin on day 1, 60 mg/m2 intravenous cisplatin on day 1, 1250 mg/m2 of oral capecitabine on days 1 through 21) or mECX+L (ECX plus lapatinib days 1 through 21 in each cycle and as 6 maintenance doses). The first 10 patients in the mECX+L arm were treated with 1000 mg/m2 of capecitabine and 1250 mg of lapatinib per day, after which preoperative toxic effects were reviewed according to predefined criteria to determine doses for subsequent patients. MAIN OUTCOMES AND MEASURES: Proportion of patients experiencing grade 3 or 4 diarrhea with mECX+L. A rate of 20% or less was considered acceptable. No formal comparison between arms was planned. RESULTS: Between February 2013, and April 2016, 441 patients underwent central HER2 testing and 63 (14%) were classified as HER2 positive. Forty-six patients were randomized; 44 (24 sECX, 20 mECX+L) are included in this analysis. Two of the first 10 patients in the mECX+L arm reported preoperative grade 3 diarrhea; thus, no dose increase was made. The primary endpoint of preoperative grade 3 or 4 diarrhea rates were 0 of 24 in the sECX arm (0%) and 4 of 20 in the mECX+L arm (21%). One of 24 in the sECX arm and 3 of 20 in the mECX+L arm stopped preoperative treatment early, and for 4 of 19 in the mECX+L arm, lapatinib dose was reduced. Postoperative complication rates were similar in each arm. CONCLUSIONS AND RELEVANCE: Administration of 1250 mg of lapatinib per day in combination with ECX chemotherapy was feasible with some increase in toxic effects, which did not compromise operative management. TRIAL REGISTRATION: ISRCTN.org identifier: 46020948; clinicaltrialsregister.eu identifier: 2006-000811-12.

Integrating the Epigenome to Identify Drivers of Hepatocellular Carcinoma.

Disruption of epigenetic mechanisms has been intimately linked to the etiology of human cancer. Understanding how these epigenetic mechanisms (including DNA methylation [5mC], hydroxymethylation [5hmC], and histone post-translational modifications) work in concert to drive cancer initiation and progression remains unknown. Hepatocellular carcinoma (HCC) is increasing in frequency in Western countries but lacks efficacious treatments. The epigenome of HCC remains understudied. To better understand the epigenetic underpinnings of HCC, we performed a genome-wide assessment of 5mC, 5hmC, four histone modifications linked to promoter/enhancer function (H3K4me1, H3K27ac, H3K4me3, and H3K27me3), and transcription across normal, cirrhotic, and HCC liver tissue. Implementation of bioinformatic strategies integrated these epigenetic marks with each other and with transcription to provide a comprehensive epigenetic profile of how and when the liver epigenome is perturbed during progression to HCC. Our data demonstrate significant deregulation of epigenetic regulators combined with disruptions in the epigenome hallmarked by profound loss of 5hmC, locus-specific gains in 5mC and 5hmC, and markedly altered histone modification profiles, particularly remodeling of enhancers. Data integration demonstrates that these marks collaborate to influence transcription (e.g., hyper-5hmC in HCC-gained active enhancers is linked to elevated expression) of genes regulating HCC proliferation. Two such putative epigenetic driver loci identified through our integrative approach, COMT and FMO3, increase apoptosis and decrease cell viability in liver-derived cancer cell lines when ectopically re-expressed. Conclusion: Altogether, integration of multiple epigenetic parameters is a powerful tool for identifying epigenetically regulated drivers of HCC and elucidating how epigenome deregulation contributes to liver disease and HCC.

ZBTB24 is a transcriptional regulator that coordinates with DNMT3B to control DNA methylation.

The interplay between transcription factors and epigenetic writers like the DNA methyltransferases (DNMTs), and the role of this interplay in gene expression, is being increasingly appreciated. ZBTB24, a poorly characterized zinc-finger protein, or the de novo methyltransferase DNMT3B, when mutated, cause Immunodeficiency, Centromere Instability, and Facial anomalies (ICF) syndrome, suggesting an underlying mechanistic link. Chromatin immunoprecipitation coupled with loss-of-function approaches in model systems revealed common loci bound by ZBTB24 and DNMT3B, where they function to regulate gene body methylation. Genes coordinately regulated by ZBTB24 and DNMT3B are enriched for molecular mechanisms essential for cellular homeostasis, highlighting the importance of the ZBTB24-DNMT3B interplay in maintaining epigenetic patterns required for normal cellular function. We identify a ZBTB24 DNA binding motif, which is contained within the promoters of most of its transcriptional targets, including CDCA7, AXIN2, and OSTC. Direct binding of ZBTB24 at the promoters of these genes targets them for transcriptional activation. ZBTB24 binding at the promoters of RNF169 and CAMKMT, however, targets them for transcriptional repression. The involvement of ZBTB24 targets in diverse cellular programs, including the VDR/RXR and interferon regulatory pathways, suggest that ZBTB24's role as a transcriptional regulator is not restricted to immune cells.

Distinctive epigenomes characterize glioma stem cells and their response to differentiation cues.

BACKGROUND: Glioma stem cells (GSCs) are a subpopulation of stem-like cells that contribute to glioblastoma (GBM) aggressiveness, recurrence, and resistance to radiation and chemotherapy. Therapeutically targeting the GSC population may improve patient survival, but unique vulnerabilities need to be identified. RESULTS: We isolate GSCs from well-characterized GBM patient-derived xenografts (PDX), characterize their stemness properties using immunofluorescence staining, profile their epigenome including 5mC, 5hmC, 5fC/5caC, and two enhancer marks, and define their transcriptome. Fetal brain-derived neural stem/progenitor cells are used as a comparison to define potential unique and common molecular features between these different brain-derived cells with stem properties. Our integrative study reveals that abnormal expression of ten-eleven-translocation (TET) family members correlates with global levels of 5mC and 5fC/5caC and may be responsible for the distinct levels of these marks between glioma and neural stem cells. Heterogenous transcriptome and epigenome signatures among GSCs converge on several genes and pathways, including DNA damage response and cell proliferation, which are highly correlated with TET expression. Distinct enhancer landscapes are also strongly associated with differential gene regulation between glioma and neural stem cells; they exhibit unique co-localization patterns with DNA epigenetic mark switching events. Upon differentiation, glioma and neural stem cells exhibit distinct responses with regard to TET expression and DNA mark changes in the genome and GSCs fail to properly remodel their epigenome. CONCLUSIONS: Our integrative epigenomic and transcriptomic characterization reveals fundamentally distinct yet potentially targetable biologic features of GSCs that result from their distinct epigenomic landscapes.

Extracellular signal regulated kinase 5 and inflammasome in progression of mesothelioma.

Malignant mesothelioma is an aggressive cancer in desperate need of treatment. We have previously shown that extracellular signaling regulated kinase 5 (ERK5) plays an important role in mesothelioma pathogenesis using ERK5 silenced human mesothelioma cells exhibiting significantly reduced tumor growth in immunocompromised mice. Here, we used a specific ERK 5 inhibitor, XMD8-92 in various in vitro and in vivo models to demonstrate that inhibition of ERK5 can slow down mesothelioma tumorigenesis. First, we show a dose dependent toxicity of XMD8-92 to 2 human mesothelioma cell lines growing as a monolayer. We also demonstrate the inhibition of ERK5 phosphorylation in various human mesothelioma cell lines by XMD8-92. We further confirmed the toxicity of XMD8-92 towards mesothelioma cell lines grown as spheroids in a 3-D model as well as in intraperitoneal (immune-competent) and intrapleural (immune-deficient) mouse models with and without chemotherapeutic drugs. To ascertain the mechanism, we explored the role of the nod-like receptor family member containing a pyrin domain 3 (NLRP3) inflammasome in the process. We found XMD8-92 attenuated naïve and chemotherapeutic-induced inflammasome priming and activation in mesothelioma cells. It can thus be concluded that ERK5 inhibition attenuates mesothelioma tumor growth and this phenomenon in part is regulated by the inflammasome.

Carboplatin versus two doses of cisplatin in combination with gemcitabine in the treatment of advanced non-small-cell lung cancer: Results from a British Thoracic Oncology Group randomised phase III trial.

BACKGROUND: Platinum-based combination chemotherapy is standard treatment for the majority of patients with advanced non-small-cell lung cancer (NSCLC). The trial investigates the importance of the choice of platinum agent and dose of cisplatin in relation to patient outcomes. METHODS: The three-arm randomised phase III trial assigned patients with chemo-naïve stage IIIB/IV NSCLC in a 1:1:1 ratio to receive gemcitabine 1250 mg/m2 on days 1 and 8 of a 3-week cycle with cisplatin 80 mg/m2 (GC80) or cisplatin 50 mg/m2 (GC50) or carboplatin AUC6 (GCb6) for a maximum of four cycles. Primary outcome measure was survival time, aiming to test for a difference between treatment arms and also assess non-inferiority with pre-defined margin selected as hazard ratio (HR) of 1.2. Secondary outcome measures included response rate, adverse events and quality of life (QoL). FINDINGS: The trial recruited 1363 patients. Survival time differed significantly across the three treatment arms (p = 0.046) with GC50 worst with median 8.2 months compared to 9.5 for GC80 and 10.0 for GCb6. HRs (adjusted) for GC50 compared to GC80 was 1.13 (95% confidence interval [CI] 0.99-1.29) and for GC50 compared to GCb6 was 1.23 (95% CI: 1.08-1.41). GCb6 was significantly non-inferior to GC80 (HR = 0.93, upper limit of one-sided 95% CI 1.04). Adjusting for QoL did not change the findings. Best objective response rates were 29% (GC80), 20% (GC50) and 27% (GCb6), p < 0.007. There were more dose reductions and treatment delays in the GCb6 arm and more adverse events (60% with at least one grade 3-4 compared to 43% GC80 and 30% GC50). INTERPRETATION: In combination with gemcitabine, carboplatin at AUC6 is not inferior to cisplatin at 80 mg/m2 in terms of survival. Carboplatin was associated with more adverse events and not with better quality of life. Cisplatin at the lower dose of 50 mg/m2 has worse survival which is not compensated by better quality of life. CLINICALTRIALS. GOV IDENTIFIER: NCT00112710. EUDRACT NUMBER: 2004-003868-30. CANCER RESEARCH UK TRIAL IDENTIFIER: CRUK/04/009.

Neoadjuvant cisplatin and fluorouracil versus epirubicin, cisplatin, and capecitabine followed by resection in patients with oesophageal adenocarcinoma (UK MRC OE05): an open-label, randomised phase 3 trial.

BACKGROUND: Neoadjuvant chemotherapy before surgery improves survival compared with surgery alone for patients with oesophageal cancer. The OE05 trial assessed whether increasing the duration and intensity of neoadjuvant chemotherapy further improved survival compared with the current standard regimen. METHODS: OE05 was an open-label, phase 3, randomised clinical trial. Patients with surgically resectable oesophageal adenocarcinoma classified as stage cT1N1, cT2N1, cT3N0/N1, or cT4N0/N1 were recruited from 72 UK hospitals. Eligibility criteria included WHO performance status 0 or 1, adequate respiratory, cardiac, and liver function, white blood cell count at least 3 × 109 cells per L, platelet count at least 100 × 109 platelets per L, and a glomerular filtration rate at least 60 mL/min. Participants were randomly allocated (1:1) using a computerised minimisation program with a random element and stratified by centre and tumour stage, to receive two cycles of cisplatin and fluorouracil (CF; two 3-weekly cycles of cisplatin [80 mg/m2 intravenously on day 1] and fluorouracil [1 g/m2 per day intravenously on days 1-4]) or four cycles of epirubicin, cisplatin, and capecitabine (ECX; four 3-weekly cycles of epirubicin [50 mg/m2] and cisplatin [60 mg/m2] intravenously on day 1, and capecitabine [1250 mg/m2] daily throughout the four cycles) before surgery, stratified according to centre and clinical disease stage. Neither patients nor study staff were masked to treatment allocation. Two-phase oesophagectomy with two-field (abdomen and thorax) lymphadenectomy was done within 4-6 weeks of completion of chemotherapy. The primary outcome measure was overall survival, and primary and safety analyses were done in the intention-to-treat population. This trial is registered with the ISRCTN registry (number 01852072) and ClinicalTrials.gov (NCT00041262), and is completed. FINDINGS: Between Jan 13, 2005, and Oct 31, 2011, 897 patients were recruited and 451 were assigned to the CF group and 446 to the ECX group. By Nov 14, 2016, 327 (73%) of 451 patients in the CF group and 302 (68%) of 446 in the ECX group had died. Median survival was 23·4 months (95% CI 20·6-26·3) with CF and 26·1 months (22·5-29·7) with ECX (hazard ratio 0·90 (95% CI 0·77-1·05, p=0·19). No unexpected chemotherapy toxicity was seen, and neutropenia was the most commonly reported event (grade 3 or 4 neutropenia: 74 [17%] of 446 patients in the CF group vs 101 [23%] of 441 people in the ECX group). The proportions of patients with postoperative complications (224 [56%] of 398 people for whom data were available in the CF group and 233 [62%] of 374 in the ECX group; p=0·089) were similar between the two groups. One patient in the ECX group died of suspected treatment-related neutropenic sepsis. INTERPRETATION: Four cycles of neoadjuvant ECX compared with two cycles of CF did not increase survival, and cannot be considered standard of care. Our study involved a large number of centres and detailed protocol with comprehensive prospective assessment of health-related quality of life in a patient population confined to people with adenocarcinomas of the oesophagus and gastro-oesophageal junction (Siewert types 1 and 2). Alternative chemotherapy regimens and neoadjuvant chemoradiation are being investigated to improve outcomes for patients with oesophageal carcinoma. FUNDING: Cancer Research UK and Medical Research Council Clinical Trials Unit at University College London.

Management of ceritinib therapy and adverse events in patients with ALK-rearranged non-small cell lung cancer.

Anaplastic lymphoma kinase rearrangement (ALK+) occurs in approximately 2-7% of patients with non-small cell lung cancer (NSCLC), contributing to a considerable number of patients with ALK+ NSCLC worldwide. Ceritinib is a next generation ALK inhibitor (ALKi), approved by the European Medicines Agency in 2015. In the first-in-human, phase I study, ceritinib demonstrated rapid and durable responses in ALK patients previously treated with a different ALKi and in those who were ALKi-naive. As ceritinib is starting to be used routinely for the treatment of patients with ALK+ NSCLC, experience is growing with regard to ideal therapy management. In this review we provide a brief background to the development of ceritinib. The optimal treatment management and adverse events associated with ceritinib in clinical trials and in clinical practice are then discussed in detail, and where applicable, an expert consensus on specific recommendations are made. In clinical trials, the most common adverse events related to ceritinib are nausea, vomiting, and diarrhea. However, the majority of these are mild and, in the opinion of the authors, can be effectively managed with dose modifications. Based on clinical data, ceritinib has demonstrated efficacy as a first-line therapy and in patients who have relapsed on crizotinib, including those with brain metastases at baseline. Unfortunately, at some point, all patients experience progressive disease, with the central nervous system being a common site of metastases. Recommendations are made for continuing treatment beyond disease progression as long as a clinical benefit to patients is observed. Here, we review management of ceritinib treatment and adverse events and make recommendations on optimal management of patients.

Exploring global recognition of quality midwifery education: Vision or fiction?

BACKGROUND: Midwifery education is the foundation for preparing competent midwives to provide a high standard of safe, evidence-based care for women and their newborns. Global competencies and standards for midwifery education have been defined as benchmarks for establishing quality midwifery education and practice worldwide. However, wide variations in type and nature of midwifery education programs exist. AIM: To explore and discuss the opportunities and challenges of a global quality assurance process as a strategy to promote quality midwifery education. DISCUSSION: Accreditation and recognition as two examples of quality assurance processes in education are discussed. A global recognition process, with its opportunities and challenges, is explored from the perspective of four illustrative case studies from Ireland, Kosovo, Latin America and Bangladesh. The discussion highlights that the establishment of a global recognition process may assist in promoting quality of midwifery education programs world-wide, but cannot take the place of formal national accreditation. In addition, a recognition process will not be feasible for many institutions without additional resources, such as financial support or competent evaluators. In order to achieve quality midwifery education through a global recognition process the authors present 5 Essential Challenges for Quality Midwifery Education. CONCLUSION: Quality midwifery education is vital for establishing a competent workforce, and improving maternal and newborn health. Defining a global recognition process could be instrumental in moving toward this goal, but dealing with the identified challenges will be essential.

Gefitinib and EGFR Gene Copy Number Aberrations in Esophageal Cancer.

Purpose The Cancer Esophagus Gefitinib trial demonstrated improved progression-free survival with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib relative to placebo in patients with advanced esophageal cancer who had disease progression after chemotherapy. Rapid and durable responses were observed in a minority of patients. We hypothesized that genetic aberration of the EGFR pathway would identify patients benefitting from gefitinib. Methods A prespecified, blinded molecular analysis of Cancer Esophagus Gefitinib trial tumors was conducted to compare efficacy of gefitinib with that of placebo according to EGFR copy number gain (CNG) and EGFR, KRAS, BRAF, and PIK3CA mutation status. EGFR CNG was determined by fluorescent in situ hybridization (FISH) using prespecified criteria and EGFR FISH-positive status was defined as high polysomy or amplification. Results Biomarker data were available for 340 patients. In EGFR FISH-positive tumors (20.2%), overall survival was improved with gefitinib compared with placebo (hazard ratio [HR] for death, 0.59; 95% CI, 0.35 to 1.00; P = .05). In EGFR FISH-negative tumors, there was no difference in overall survival with gefitinib compared with placebo (HR for death, 0.90; 95% CI, 0.69 to 1.18; P = .46). Patients with EGFR amplification (7.2%) gained greatest benefit from gefitinib (HR for death, 0.21; 95% CI, 0.07 to 0.64; P = .006). There was no difference in overall survival for gefitinib versus placebo for patients with EGFR, KRAS, BRAF, and PIK3CA mutations, or for any mutation versus none. Conclusion EGFR CNG assessed by FISH appears to identify a subgroup of patients with esophageal cancer who may benefit from gefitinib as a second-line treatment. Results of this study suggest that anti-EGFR therapies should be investigated in prospective clinical trials in different settings in EGFR FISH-positive and, in particular, EGFR-amplified esophageal cancer.

Multicenter, Phase III, Randomized, Double-Blind, Placebo-Controlled Trial of Pravastatin Added to First-Line Standard Chemotherapy in Small-Cell Lung Cancer (LUNGSTAR).

Purpose Treating small-cell lung cancer (SCLC) remains a therapeutic challenge. Experimental studies show that statins exert additive effects with agents, such as cisplatin, to impair tumor growth, and observational studies suggest that statins combined with anticancer therapies delay relapse and prolong life in several cancer types. To our knowledge, we report the first large, randomized, placebo-controlled, double-blind trial of a statin with standard-of-care for patients with cancer, specifically SCLC. Patients and Methods Patients with confirmed SCLC (limited or extensive disease) and performance status 0 to 3 were randomly assigned to receive daily pravastatin 40 mg or placebo, combined with up to six cycles of etoposide plus cisplatin or carboplatin every 3 weeks, until disease progression or intolerable toxicity. Primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS), response rate, and toxicity. Results Eight hundred forty-six patients from 91 United Kingdom hospitals were recruited. The median age of recruited patients was 64 years of age, 43% had limited disease, and 57% had extensive disease. There were 758 deaths and 787 PFS events. No benefit was found for pravastatin, either in all patients or in several subgroups. For pravastatin versus placebo, the 2-year OS rate was 13.2% (95% CI, 10.0 to 16.7) versus 14.1% (95% CI, 10.9 to 17.7), respectively, with a hazard ratio of 1.01 (95% CI, 0.88 to 1.16; P = .90. The median OS was 10.7 months v 10.6 months, respectively. The median PFS was 7.7 months v 7.3 months, respectively. The median OS (pravastatin v placebo) was 14.6 months in both groups for limited disease and 9.1 months versus 8.8 months, respectively, for extensive disease. Adverse events were similar between groups. Conclusion Pravastatin 40 mg combined with standard SCLC therapy, although safe, does not benefit patients. Our conclusions are the same as those found in all four much smaller, randomized, placebo-controlled trials specifically designed to evaluate statin therapy in patients with cancer.