Predictive modelling of response to neoadjuvant therapy in HER2+ breast cancer.

HER2-positive (HER2+) breast cancer accounts for 20-25% of all breast cancers. Predictive biomarkers of neoadjuvant therapy response are needed to better identify patients with early stage disease who may benefit from tailored treatments in the adjuvant setting. As part of the TCHL phase-II clinical trial (ICORG10-05/NCT01485926) whole exome DNA sequencing was carried out on normal-tumour pairs collected from 22 patients. Here we report predictive modelling of neoadjuvant therapy response using clinicopathological and genomic features of pre-treatment tumour biopsies identified age, estrogen receptor (ER) status and level of immune cell infiltration may together be important for predicting response. Clonal evolution analysis of longitudinally collected tumour samples show subclonal diversity and dynamics are evident with potential therapy resistant subclones detected. The sources of greater pre-treatment immunogenicity associated with a pathological complete response is largely unexplored in HER2+ tumours. However, here we point to the possibility of APOBEC associated mutagenesis, specifically in the ER-neg/HER2+ subtype as a potential mediator of this immunogenic phenotype.

A systematic analysis of splicing variants identifies new diagnoses in the 100,000 Genomes Project.

BACKGROUND: Genomic variants which disrupt splicing are a major cause of rare genetic diseases. However, variants which lie outside of the canonical splice sites are difficult to interpret clinically. Improving the clinical interpretation of non-canonical splicing variants offers a major opportunity to uplift diagnostic yields from whole genome sequencing data. METHODS: Here, we examine the landscape of splicing variants in whole-genome sequencing data from 38,688 individuals in the 100,000 Genomes Project and assess the contribution of non-canonical splicing variants to rare genetic diseases. We use a variant-level constraint metric (the mutability-adjusted proportion of singletons) to identify constrained functional variant classes near exon-intron junctions and at putative splicing branchpoints. To identify new diagnoses for individuals with unsolved rare diseases in the 100,000 Genomes Project, we identified individuals with de novo single-nucleotide variants near exon-intron boundaries and at putative splicing branchpoints in known disease genes. We identified candidate diagnostic variants through manual phenotype matching and confirmed new molecular diagnoses through clinical variant interpretation and functional RNA studies. RESULTS: We show that near-splice positions and splicing branchpoints are highly constrained by purifying selection and harbour potentially damaging non-coding variants which are amenable to systematic analysis in sequencing data. From 258 de novo splicing variants in known rare disease genes, we identify 35 new likely diagnoses in probands with an unsolved rare disease. To date, we have confirmed a new diagnosis for six individuals, including four in whom RNA studies were performed. CONCLUSIONS: Overall, we demonstrate the clinical value of examining non-canonical splicing variants in individuals with unsolved rare diseases.

Cost and Capability Compromises in STEM Instrumentation for Low-Voltage Imaging.

Low-voltage transmission electron microscopy (≤80 kV) has many applications in imaging beam-sensitive samples, such as metallic nanoparticles, which may become damaged at higher voltages. To improve resolution, spherical aberration can be corrected for in a scanning transmission electron microscope (STEM); however, chromatic aberration may then dominate, limiting the ultimate resolution of the microscope. Using image simulations, we examine how a chromatic aberration corrector, different objective lenses, and different beam energy spreads each affect the image quality of a gold nanoparticle imaged at low voltages in a spherical aberration-corrected STEM. A quantitative analysis of the simulated examples can inform the choice of instrumentation for low-voltage imaging. We here demonstrate a methodology whereby the optimum energy spread to operate a specific STEM can be deduced. This methodology can then be adapted to the specific sample and instrument of the reader, enabling them to make an informed economical choice as to what would be most beneficial for their STEM in the cost-conscious landscape of scientific infrastructure.

Prismatic 2.0 - Simulation software for scanning and high resolution transmission electron microscopy (STEM and HRTEM).

Scanning transmission electron microscopy (STEM), where a converged electron probe is scanned over a sample's surface and an imaging, diffraction, or spectroscopic signal is measured as a function of probe position, is an extremely powerful tool for materials characterization. The widespread adoption of hardware aberration correction, direct electron detectors, and computational imaging methods have made STEM one of the most important tools for atomic-resolution materials science. Many of these imaging methods rely on accurate imaging and diffraction simulations in order to interpret experimental results. However, STEM simulations have traditionally required large calculation times, as modeling the electron scattering requires a separate simulation for each of the typically millions of probe positions. We have created the Prismatic simulation code for fast simulation of STEM experiments with support for multi-CPU and multi-GPU (graphics processing unit) systems, using both the conventional multislice and our recently-introduced PRISM method. In this paper, we introduce Prismatic version 2.0, which adds many new algorithmic improvements, an updated graphical user interface (GUI), post-processing of simulation data, and additional operating modes such as plane-wave TEM. We review various aspects of the simulation methods and codes in detail and provide various simulation examples. Prismatic 2.0 is freely available both as an open-source package that can be run using a C++ or Python command line interface, or GUI, as well within a Docker container environment.

Phase Ib Trial of Copanlisib, A Phosphoinositide-3 Kinase (PI3K) Inhibitor, with Trastuzumab in Advanced Pre-Treated HER2-Positive Breast Cancer "PantHER".

BACKGROUND: Activation of the phosphoinositide-3 kinase (PI3K) pathway is a resistance mechanism to anti-human epidermal growth factor receptor 2 (HER2) therapy. This phase Ib trial was conducted to determine the maximum tolerated dose (MTD) of copanlisib, an intravenous (IV) pan-class I PI3K inhibitor, combined with trastuzumab. METHODS: Patients with advanced HER2-positive breast cancer and disease progression following at least one prior line of HER2 therapy in the metastatic setting were treated with copanlisib (45 or 60 mg) IV on days 1, 8 and 15 of a 28-day cycle with a fixed dose of trastuzumab 2 mg/kg weekly. RESULTS: Twelve patients were enrolled. The MTD was determined as copanlisib 60 mg plus trastuzumab 2 mg/kg weekly. The most common adverse events of any grade occurring in more than two patients were hyperglycaemia (58%), fatigue (58%), nausea (58%) and hypertension (50%). Stable disease was confirmed at 16 weeks in six participants (50%). PIK3CA mutations were detected in archival tumour of six participants (50%). PIK3CA hotspot mutations, were detectable in pre- and on-treatment plasma of all participants. Pre- and post-treatment tumour biopsies for two patients identified temporal genomic heterogeneity, somatic mutations in the TRRAP gene, which encodes a PI3K-like protein kinase, and emergent somatic mutations related to protein kinase signalling. CONCLUSION: Copanlisib and trastuzumab can be safely administered with fair overall tolerability. Preliminary evidence of tumour stability was observed in patients with heavily pre-treated, metastatic HER2 positive breast cancer. Several potential biomarkers were identified for further study in the current phase 2 clinical trial. NCT: 02705859.

Systematic Literature Review of Economic Evaluations, Costs/Resource Use, and Quality of Life in Patients with Mantle Cell Lymphoma.

BACKGROUND: Mantle cell lymphoma (MCL) is a rare and aggressive subtype of non-Hodgkin's lymphoma. While treatment of patients with MCL and their outcomes are previously published, the availability of heath economics evidence is unclear. OBJECTIVE: The aim of this paper was to conduct a comprehensive review of studies relating to economic evaluations, costs and resource use, and health-related quality of life (HRQoL) in patients with MCL. METHODS: Search strategies were designed to capture studies reporting economic or HRQoL outcomes published in the previous 11 years (2007-2018). The following electronic databases were searched: MEDLINE, Embase, NHS Economic Evaluation Database (NHS EED), and EconLit. In addition, we reviewed congress abstracts presented over the previous 2 years (2015 and 2016; where 2017 proceedings had occurred, these were searched instead of 2015). Publications were screened in duplicate by two reviewers and supplementary searches were carried out on health technology assessment websites. Searches were first conducted in October 2017 and updated in March 2018. FINDINGS: The systematic literature review identified 11 economic evaluations (in 16 publications), seven studies reporting data relating to costs or resource use, and five relating to HRQoL. Four economic evaluations presented results for patients with MCL modelled in the first-line setting, while seven modelled patients in the relapsed/refractory setting. The majority of economic evaluations were conducted using a Markov model with three to five health states. Seven studies assessed resource use and reported adverse events as key drivers of increased costs and resource use. Across the five studies reporting HRQoL, disparate measures were used. Two studies reported improvement in Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) total scores following treatment and found that clinical response to treatment was associated with improvement in overall HRQoL. CONCLUSIONS AND RELEVANCE: The published economic and HRQoL evidence in MCL, although scarce, reveals that the economic and HRQoL burden associated with MCL is substantial. In highlighting this evidence, this analysis underlines a critical unmet need for more effective treatments with improved outcomes in MCL.

Whole-exome sequencing of long-term, never relapse exceptional responders of trastuzumab-treated HER2+ metastatic breast cancer.

Trastuzumab has significantly improved the overall survival of patients with HER2+ metastatic breast cancer (MBC). However, outcomes can vary, with patients progressing within 1 year of treatment or exceptional cases of complete response to trastuzumab for ≥10 years. Identification of the underlying genomic aberrations of "exceptional responders (ExRs)" compared to "rapid non-responders (NRs)" increases our understanding of the mechanisms involved in MBC progression and identification of biomarkers of trastuzumab response and resistance. Whole-exome sequencing was performed on six ExRs compared to five NR. The overall fraction of genome copy number alteration (CNA) burden was higher in NR patients (P = 0.07), while more significantly pronounced in copy number gains (P = 0.03) in NR compared to ExRs. Delineation of the distribution of CNA burden across the genome identified a greater degree of CNA burden in NR within Chr8 (P = 0.02) and in Chr17 (P = 0.06) and conferred a statistically significant benefit in overall survival. Clinical trial number: NCT01722890 [ICORG 12/09].

Distribution and Function of Prostaglandin E2 Receptors in Mouse Uterus: Translational Value for Human Reproduction.

Prostaglandin (PG) E analogs are used clinically to ripen the cervix and induce labor. However, selective receptor agonists may have potential to improve induction response rates or manage unwanted uterine hypercontractility in conditions such as dysmenorrhea and preterm labor. To characterize their therapeutic value, PGE2 analogs were used to investigate the functional E-type prostanoid (EP) receptor population in isolated human uterus. Responsiveness in mouse tissues was also examined to validate its use as a preclinical model. Uterine samples were obtained from mice at dioestrus (n = 12), term gestation (n = 14), and labor (n = 12) and from the lower uterus of women undergoing hysterectomy (n = 12) or Caesarean section (n = 18). Vehicle and agonist effects were assessed using superfusion and immersion techniques. PGE2 evoked predominant excitatory responses in mouse and relaxation in human tissues. Selective EP4 agonists inhibited tissue activity in both nonpregnant species, while the EP2 mimetic CP533536 also attenuated uterine contractions throughout gestation. The uterotonic effects of the EP3/1 agonist sulprostone were more pronounced than the EP1 agonist ONO-D1-004, corresponding to abundant EP3 receptor expression in all samples. The contractile phenotype in mouse compared with human uteri may relate to regional differences as well as high expression of EP3 receptor transcripts. Similarities in nonpregnant and gestational tissues across species suggest that EP3 may represent a valuable translational drug target for preventing uterine hypercontractility by employing a selective antagonist. SIGNIFICANCE STATEMENT: This research validates the use of nonpregnant mice for preclinical drug discovery of uterine EP receptor targets. To determine the utility of novel drugs and delivery systems at term pregnancy and labor, pharmacological agents interacting with EP3 receptors have clear translational value.

Systematic literature review of the global burden of illness of mantle cell lymphoma.

Background: Mantle cell lymphoma (MCL), a rare and aggressive disease, accounts for approximately 5% of all B-cell non-Hodgkin's lymphomas. Evidence on the burden of this disease, for patients and healthcare providers, is scarce.Methods: Four systematic literature reviews were developed to identify epidemiological, real-world clinical, economic and humanistic burden data on patients with MCL. Electronic databases searched included MEDLINE and Embase, NHS EED and Econlit.Results: Eight epidemiological studies, 19 clinical burden, 2 economic impact and 0 quality of life studies were identified. The range of standardized MCL incidence rates was 0.1-1.27/100,000. Overall survival rates of patients at 3 years differed by age at diagnosis (≤65 years: 76-81%, >65 years: 46-64%) and disease stage (stage I: 73-80%, stage IV: 48-53%). Outcomes were poorer in previously treated patients, and those with later stage or blastoid disease, and improved with more recent diagnosis/treatment. Hospitalization is a major contributor to healthcare cost and differs by therapy toxicity.Conclusions: We identified significant data gaps for many G20 countries for epidemiology, real-world clinical, economic and humanistic burden. These literature reviews demonstrate the ongoing unmet need for MCL patients globally. Future research to further understand the real-world impact of MCL is needed along with new therapeutic options to improve patient outcomes.

Cost-Effectiveness Analyses, Costs and Resource Use, and Health-Related Quality of Life in Patients with Follicular or Marginal Zone Lymphoma: Systematic Reviews.

BACKGROUND: Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are types of indolent non-Hodgkin lymphoma (NHL) that develop in the B lymphocytes (also known as B cells). OBJECTIVE: The aim of this study was to conduct a comprehensive review of studies relating to cost effectiveness, costs and resource use, and health-related quality of life (HRQoL) in patients with FL or MZL. METHODS: Three separate systematic reviews were conducted to identify all published evidence on cost effectiveness, costs and resource use, and HRQoL between 2007 and March 2017 using the MEDLINE®, MEDLINE in-process, E-pubs ahead of print (Ovid SP®), Embase (Ovid SP®), NHS EED, and EconLit databases. Select congress proceedings were also searched. Two systematic reviewers independently reviewed titles, abstracts, and full papers against eligibility criteria. Relevant data were extracted into bespoke data extraction templates (DETs) by a single systematic reviewer; these data were then validated for accuracy by a second reviewer against clean copies of the relevant publications. RESULTS: A total of 25 cost-effectiveness studies (24 in FL; 1 in FL and MZL) met the eligibility criteria. Markov models were the most utilised cost-effectiveness model. US FL studies reported an incremental cost-effectiveness ratio (ICER) of $28,565/QALY for first-line rituximab-cyclophosphamide, vincristine, and prednisone (R-CVP) versus CVP, and $43,000/QALY for second-line obinutuzumab plus bendamustine (G + B) followed by G maintenance versus B. In the UK, ICERs were £1529-10,834/quality-adjusted life-year (QALY) for first-line rituximab + chemotherapy versus chemotherapy, £27,988/QALY for second-line G + B + G-maintenance versus B, and £62,653/QALY for second-line idelalisib versus chemotherapy and/or rituximab. Five costs/resource use and four HRQoL studies were identified in FL, and none in MZL. US mean lifetime costs in first-line patients ranged from $108,000 (rituximab) to $130,300 (rituximab-cyclophosphamide, doxorubicin hydrochloride, vincristine and prednisolone [CHOP]), and from £2185 (watch-and-wait) to £17,054 (chemotherapy) in the UK. In a multinational study, more rituximab-refractory patients receiving G + B + G-maintenance reported a meaningful improvement in total FACT-Lym scores compared with patients receiving B. In the UK, total FACT-Lym scores were meaningfully higher for newly diagnosed patients compared with patients with progression (136.04 vs. 109.7). CONCLUSIONS AND RELEVANCE: We found a small body of evidence of quality of life, and potentially cost-effective treatment options for FL; however, no evidence was reported on MZL specifically. The significant data gaps in knowledge in these diseases demonstrate a marked need for further studies.

Burden of illness of follicular lymphoma and marginal zone lymphoma.

Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are two subtypes of indolent B cell non-Hodgkin lymphoma (NHL) that account for approximately 20% and 12% of all NHLs, respectively. FL and MZL are rare conditions with orphan disease designations. We conducted a comprehensive review of the burden of FL and MZL that encompasses the epidemiological, real world clinical, economic, and humanistic impact of these diseases globally. A targeted literature search identified 31 eligible studies for review. Epidemiological coverage was poor, with data obtained for studies from only seven countries. The incidences of both subtypes were low: age-standardized incidence rates of FL ranged from 2.1/100,000 in France to 4.3/100,000 in the USA, while for MZL it varied geographically from 0.5/100,000 in Australia to 2.6/100,000 in the UK. The cumulative total direct healthcare costs for FL were higher for patients with progressive disease compared to those without ($30,890 vs. $8704 at 12 months, respectively) and main driver of costs related to the use of chemotherapy. Five-year overall survival was improved in patients with FL compared with MZL (e.g., 76.5% vs 60.7% in one study that reported on both subtypes). Mortality rates were particularly lower in female patients with FL aged < 60 years. However, limited outcome data for MZL patients were identified. FL and MZL contribute significant burden on healthcare systems and on patients globally, with delays in progression potentially leading to cost savings. More rigorous characterization of these two NHL subtypes, new and more effective treatments, and standardization of reporting would lead to a more robust understanding of future data in this disease area.

Survey among ESGE members on leiomyosarcoma morcellation incidence.

BACKGROUND: Increased awareness of leiomyosarcoma (LMS) risk during myomectomy or hysterectomy is essential. Objective and correct reasoning should prevail on any decision regarding the extent and type of surgery to employ. The anticipated risk of a sarcoma after myoma or uterus morcellation is low, and the frequency of leiomyosarcoma especially in women below the age of 40 is very rare. The prevalence data has a wide range and is therefore not reliable. The European Society of Gynaecological Endoscopy (ESGE) initiated a survey among its members looking into the frequency of morcellated leiomyosarcoma after endoscopic surgery.The ESGE Central office sent 3422 members a structured electronic questionnaire with multiple answer choices for each question. After 3 months, the answers were classified with a unique number in the EXCEL spread sheet. Statistical analysis was done using the SPSS v.18. RESULTS: Out of 3422 members, 294 (8.6%) gynaecologists replied to the questionnaire; however, only 240 perform myomectomies by laparoscopy and hysteroscopy and hysterectomies by laparoscopy. The reported experience in performing laparoscopic myomectomy, hysteroscopic myomectomy, laparoscopic hysterectomy (LH), and laparoscopic subtotal hysterectomy (LSH) on an average was 10.8 (1-32) years. The vast majority of 67.1% had over 5 years of practice in laparoscopic surgery. The total number of 221 leiomyosarcoma was reported among 429,777 minimally invasive surgeries (laparoscopic and hysteroscopic myomectomies and LH and LSH), performed by all doctors in their lifetime. The overall reported sarcoma risk of all types of endoscopic myoma surgeries has been estimated to be 1.5% of operations which is very rare. Categorizing by type, 57 (0.06%) LMS were operated by laparoscopic myomectomy and 54 (0.07%) by hysteroscopic myomectomy, while 38 (0.13%) leiomyosarcoma operated by laparoscopic subtotal hysterectomy and 72 (0.31%) by laparoscopic hysterectomy. The probability of a sarcoma after morcellation to be falsely diagnosed by histopathology as a benign tumour and later identified as a sarcoma in a later examination has been reported and calculated to be 0.2%. The low risk of a sarcoma is also reflected by the small number of surgeries, where only 32 doctors reported that they operated once, 29 twice, and 18 operated on 3-10 sarcomas by laparoscopy during their lifetime. CONCLUSION: The survey demonstrated that myomectomy by hysteroscopy or laparoscopy has similar risks of sarcoma with an estimated incidence of 0.07%, much lower than that by laparoscopic hysterectomy and subtotal hysterectomy. Hence, for young patients with myoma infertility problem and low risk for LMS, myomectomy by MIS can be the first option of treatment. The fact that only 12.5% (216/1728) of uterine sarcoma cases are operated laparoscopically demonstrates the surgeons' awareness and alertness about LMS and the potential of spreading sarcomatous cells after myoma/uterus power morcellation.

Gynaecological endoscopic surgical education and assessment. A diploma programme in gynaecological endoscopic surgery.

In recent years, training and education in endoscopic surgery has been critically reviewed. Clinicians, both surgeons as gynaecologist who perform endoscopic surgery without proper training of the specific psychomotor skills, are at higher risk to increased patient morbidity and mortality. Although the apprentice-tutor model has long been a successful approach for training of surgeons, recently, clinicians have recognised that endoscopic surgery requires an important training phase outside the operating theatre. The Gynaecological Endoscopic Surgical Education and Assessment programme (GESEA) recognises the necessity of this structured approach and implements two separated stages in its learning strategy. In the first stage, a skill certificate on theoretical knowledge and specific practical psychomotor skills is acquired through a high-stake exam; in the second stage, a clinical programme is completed to achieve surgical competence and receive the corresponding diploma. Three diplomas can be awarded: (a) the Bachelor in Endoscopy, (b) the Minimally Invasive Gynaecological Surgeon (MIGS) and (c) the Master level. The Master level is sub-divided into two separate diplomas: the Master in Laparoscopic Pelvic Surgery and the Master in Hysteroscopy. The complexity of modern surgery has increased the demands and challenges to surgical education and the quality control. This programme is based on the best available scientific evidence, and it counteracts the problem of the traditional surgical apprentice-tutor model. It is seen as a major step toward standardisation of endoscopic surgical training in general.

Prevention of intrauterine post-surgical adhesions in hysteroscopy. A systematic review.

OBJECTIVE: The purpose of the present review is to provide a survey of the various measures of preventing adhesions used in hysteroscopic surgery. STUDY DESIGN: A systematic computerized literature search was conducted to provide a survey of the various measures used in hysteroscopic surgery to prevent adhesions. Finally, 29 studies were included in the analysis, showing a wide variety of methods and agents advocated in international literature. They are explained in various sections, based on the IUA prevention approach adopted (surgical technique, early second-look hysteroscopy, barrier method, pharmacological therapy). RESULTS: The results of our review show that (i) use of surgical techniques which reduce the use of electrosurgery should be preferred whenever possible (Level of evidence: 4); (ii) an early second-look hysteroscopy would appear to be an effective preventive, as well as therapeutic, strategy regarding IUA but studies on the topic are too few for relevant evidence; (iii) barriers methods are the most widely used and, among these, gel barriers have been proven to have a significant clinical effect on IUA prevention, because of higher adhesiveness and prolonged residence time on the injured surface (Level of evidence: 1b); (iv) the role of hormonal and antibiotic therapy in the prevention of post-operative IUA is difficult to evaluate as it has been used in association with other prevention strategies in most studies included in our review. CONCLUSIONS: Robust and high quality randomized trials to assess the effectiveness of different anti-adhesion therapies are still needed before one or more of these strategies may be strongly recommended for improving clinical outcomes in women treated by operative hysteroscopy.

Gynaecological Endoscopic Surgical Education and Assessment. A diploma programme in gynaecological endoscopic surgery.

In recent years, training and education in endoscopic surgery has been critically reviewed. Clinicians, both surgeons as gynaecologist who perform endoscopic surgery without proper training of the specific psychomotor skills are at higher risk to increased patient morbidity and mortality. Although the apprentice-tutor model has long been a successful approach for training of surgeons, recently, clinicians have recognised that endoscopic surgery requires an important training phase outside the operating theatre. The Gynaecological Endoscopic Surgical Education and Assessment programme (GESEA), recognises the necessity of this structured approach and implements two separated stages in its learning strategy. In the first stage, a skill certificate on theoretical knowledge and specific practical psychomotor skills is acquired through a high stake exam; in the second stage, a clinical programme is completed to achieve surgical competence and receive the corresponding diploma. Three diplomas can be awarded: (a) the Bachelor in Endoscopy; (b) the Minimally Invasive Gynaecological Surgeon (MIGS); and (c) the Master level. The Master level is sub-divided into two separate diplomas: the Master in Laparoscopic Pelvic Surgery and the Master in Hysteroscopy. The complexity of modern surgery has increased the demands and challenges to surgical education and the quality control. This programme is based on the best available scientific evidence and it counteracts the problem of the traditional surgical apprentice tutor model. It is seen as a major step toward standardization of endoscopic surgical training in general.

Options on fibroid morcellation: a literature review.

In laparoscopy, specimens have to be removed from the abdominal cavity. If the trocar opening or the vaginal outlet is insufficient to pass the specimen, the specimen needs to be reduced. The power morcellator is an instrument with a fast rotating cylindrical knife which aims to divide the tissue into smaller pieces or fragments. The Food and Drug Administration (FDA) issued a press release in April 2014 that discouraged the use of these power morcellators. This article has the objective to review the literature related to complications by power morcellation of uterine fibroids in laparoscopy and offer recommendations to laparoscopic surgeons in gynaecology. This project was initiated by the executive board of the European Society of Gynaecological Endoscopy. A steering committee on fibroid morcellation was installed and experienced ESGE members requested to chair an action group to address distinct clinical questions. Clinical questions were formulated with regards to the sarcoma risk in presumed uterine fibroids, diagnosis of sarcoma, complications of morcellation and future research. A literature review on the different subjects was conducted, systematic if appropriate and feasible. It was concluded that the true prevalence of uterine sarcoma in presumed fibroids is not known given the wide range of prevalences (0.45-0.014 %) from meta-analyses mainly based on retrospective trials. Age and certain imaging characteristics such as 'lacunes' suggesting necrosis and increased central vascularisation of the tumour are associated with a higher risk of uterine sarcoma, although the risks remain low. There is not enough evidence to estimate this risk in individual patients. Complications of morcellation are rare. Reported are direct morcellation injuries to vessels and bowel, the development of so-called parasitic fibroids requiring reintervention and the spread of sarcoma cells in the abdominal cavity, which may possibly or even likely upstaging the disease. Momentarily in-bag morcellation is investigated as it may possibly prevent morcellation complications. Because of lack of evidence, this literature review cannot give strong recommendations but offers only options which are condensed in a flow chart. Prospective data collection may clarify the issue on sarcoma risk in presumed fibroids and technology to extract tissue laparoscopically from the abdominal cavity should be perfected.

The CROWN Initiative: journal editors invite researchers to develop core outcomes in women's health.

Clinical trials, systematic reviews and guidelines compare beneficial and non-beneficial outcomes following interventions. Often, however, various studies on a particular topic do not address the same outcomes, making it difficult to draw clinically useful conclusions when a group of studies is looked at as a whole. This problem was recently thrown into sharp focus by a systematic review of interventions for preterm birth prevention, which found that among 103 randomised trials, no fewer than 72 different outcomes were reported. There is a growing recognition among clinical researchers that this variability undermines consistent synthesis of the evidence, and that what is needed is an agreed standardised collection of outcomes - a "core outcomes set" - for all trials in a specific clinical area. Recognising that the current inconsistency is a serious hindrance to progress in our specialty, the editors of over 50 journals related to women's health have come together to support The CROWN (CoRe Outcomes in WomeN's health) Initiative.

The CROWN initiative: journal editors invite researchers to develop core outcomes in women's health.

Clinical trials, systematic reviews and guidelines compare beneficial and non-beneficial outcomes following interventions. Often, however, various studies on a particular topic do not address the same outcomes, making it difficult to draw clinically useful conclusions when a group of studies is looked at as a whole. This problem was recently thrown into sharp focus by a systematic review of interventions for preterm birth prevention, which found that among 103 randomised trials, no fewer than 72 different outcomes were reported. There is a growing recognition among clinical researchers that this variability undermines consistent synthesis of the evidence, and that what is needed is an agreed standardised collection of outcomes--a "core outcomes set"--for all trials in a specific clinical area. Recognising that the current inconsistency is a serious hindrance to progress in our specialty, the editors of over 50 journals related to women's health have come together to support The CROWN (CoRe Outcomes in WomeN's health) Initiative.

Learning Layouts for Single-Page Graphic Designs.

This paper presents an approach for automatically creating graphic design layouts using a new energy-based model derived from design principles. The model includes several new algorithms for analyzing graphic designs, including the prediction of perceived importance, alignment detection, and hierarchical segmentation. Given the model, we use optimization to synthesize new layouts for a variety of single-page graphic designs. Model parameters are learned with Nonlinear Inverse Optimization (NIO) from a small number of example layouts. To demonstrate our approach, we show results for applications including generating design layouts in various styles, retargeting designs to new sizes, and improving existing designs. We also compare our automatic results with designs created using crowdsourcing and show that our approach performs slightly better than novice designers.