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Background: Fluoropyrimidine drugs are widely used in chemotherapy to treat solid tumors. However, severe toxicity has been reported in 10% to 40% of patients. The DPYD gene encodes the rate-limiting enzyme dihydropyrimidine dehydrogenase responsible for fluoropyrimidine catabolism. The DPYD variants resulting in decreased or no enzyme activity are associated with increased risk of fluoropyrimidine toxicity. This study aims to develop a pharmacogenetic test for screening DPYD variants to guide fluoropyrimidine therapy. Methods: A multiplex allele-specific polymerase chain reaction (AS-PCR) assay, followed by capillary electrophoresis, was developed to detect 5 common DPYD variants (c.557A > G, c.1129–5923C > G, c.1679T > G, c.1905 + 1G > A, and c.2846A > T). Deidentified population samples were used for screening positive controls and optimizing assay conditions. Proficiency testing samples with known genotypes were analyzed for test validation. All variants detected were confirmed by Sanger sequencing. Results: From the deidentified population samples, 5 samples were heterozygous for c.557A > G, 2 samples were heterozygous for c.1129–5923C > G (HapB3), and 1 sample was heterozygous for c.2846A > T. The 20 proficiency samples matched with their assigned genotypes, including 13 wild-type samples, 3 samples heterozygous for c.1679T > G, 2 samples heterozygous for c.1905 + 1G > A, and 2 samples heterozygous for c.2846A > T. One of the 3 patient samples was heterozygous for c.1129–5923C > G (HapB3). All the variants detected by the multiplex AS-PCR assay were concordant with Sanger sequencing results. Conclusions: A robust multiplex AS-PCR assay was developed to rapidly detect 5 variants in the DPYD gene. It can be used for screening DPYD variants to identify patients with increased risk of toxicity when prescribed fluoropyrimidine therapy. [ABSTRACT FROM AUTHOR]

Study Question: What is the recommended diagnostic work-up of female genital anomalies according to the European Society of Human Reproduction and Embryology (ESHRE)/European Society for Gynaecological Endoscopy (ESGE) system?Summary Answer: The ESHRE/ESGE consensus for the diagnosis of female genital anomalies is presented.What Is Known Already: Accurate diagnosis of congenital anomalies still remains a clinical challenge because of the drawbacks of the previous classification systems and the non-systematic use of diagnostic methods with varying accuracy, some of them quite inaccurate. Currently, a wide range of non-invasive diagnostic procedures are available enriching the opportunity to accurately detect the anatomical status of the female genital tract, as well as a new objective and comprehensive classification system with well-described classes and sub-classes.Study Design, Size, Duration: The ESHRE/ESGE CONgenital UTerine Anomalies (CONUTA) Working Group established an initiative with the goal of developing a consensus for the diagnosis of female genital anomalies. The CONUTA working group and imaging experts in the field have been appointed to run the project.Participants/materials, Setting, Methods: The consensus is developed based on: (i) evaluation of the currently available diagnostic methods and, more specifically, of their characteristics with the use of the experts panel consensus method and of their diagnostic accuracy by performing a systematic review of evidence and (ii) consensus for the definition of where and how to measure uterine wall thickness and the recommendations for the diagnostic work-up of female genital anomalies, based on the results of the previous evaluation procedure, with the use of the experts panel consensus method.Main Results and the Role Of Chance: Uterine wall thickness is defined as the distance between the interostial line and external uterine profile at the midcoronal plane of the uterus; alternatively, if a coronal plane is not available, the mean anterior and posterior uterine wall thickness at the longitudinal plane could be used. Gynecological examination and two-dimensional ultrasound (2D US) are recommended for the evaluation of asymptomatic women. Three-dimensional (3D) US is recommended for the diagnosis of female genital anomalies in 'symptomatic' patients belonging to high risk groups for the presence of a female genital anomaly and in any asymptomatic woman suspected to have an anomaly from routine evaluation. Magnetic resonance imaging (MRI) and endoscopic evaluation are recommended for the subgroup of patients with suspected complex anomalies or in diagnostic dilemmas. Adolescents with symptoms suggestive for the presence of a female genital anomaly should be thoroughly evaluated with 2D US, 3D US, MRI and endoscopically.Limitations, Reasons For Caution: The various diagnostic methods should always be used in the proper way and evaluated by experts to avoid mis-, over- and underdiagnosis.Wider Implications Of the Findings: The role of a combined US examination and outpatient hysteroscopy should be prospectively evaluated. It is a challenge for further research, based on diagnosis, to objectively evaluate the clinical consequences related to various degrees of uterine deformity.Study Funding/competing Interests: None. [ABSTRACT FROM AUTHOR]

Background Febrile neutropenia is a serious toxicity of cancer chemotherapy that is usually treated in hospital. We assessed the cost-effectiveness of filgrastim and pegfilgrastim as primary prophylaxis against febrile neutropenia in diffuse large B-cell lymphoma (DLBCL) patients undergoing chemotherapy. Metiods We used a Markov model that followed patients through induction chemotherapy to compare the three prophylaxis strategies: 1) no primary prophylaxis against febrile neutropenia; 2) primary prophylaxis with 10 days of filgrastim therapy; and 3) primary prophylaxis with a single dose of pegfilgrastim. The target population was a hypothetical cohort of 64-year-old men and women with DLBCL. Data sources included published literature and current clinical practice. The analysis was conducted from a publicly funded health-care system perspective. The main outcome measures included costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). Results In the base-case analysis, costs associated with no primary prophylaxis, primary prophylaxis with 10 days of filgrastim, and primary prophylaxis with pegfilgrastim were CaD $7314, CaD $13947, and CaD $16290, respectively. The QALYs associated with the three strategies were 0.2004, 0.2015, and 0.2024, respectively. The ICER for the filgrastim vs no primary prophylaxis strategy was CaD $5796000 per QALY. The ICER for the pegfilgrastim vs filgrastim primary prophylaxis strategy was CaD $2611 000 per QALY. All one-way sensitivity analyses yielded ICERs greater than CaD $400000 per QALY. Cost-effectiveness acceptability curves show that 20.0% of iterations are cost-effective at a willingness-to-pay threshold of CaD $1 595000 for the filgrastim strategy and CaD $561 000 for the pegfilgrastim strategy. Conclusions Primary prophylaxis against febrile neutropenia with either filgrastim or pegfilgrastim is not cost-effective in DLBCL patients. [ABSTRACT FROM AUTHOR]

Study Question: What classification system is more suitable for the accurate, clear, simple and related to the clinical management categorization of female genital anomalies?Summary Answer: The new ESHRE/ESGE classification system of female genital anomalies is presented.What Is Known Already: Congenital malformations of the female genital tract are common miscellaneous deviations from normal anatomy with health and reproductive consequences. Until now, three systems have been proposed for their categorization but all of them are associated with serious limitations.Study Design, Size and Duration: The European Society of Human Reproduction and Embryology (ESHRE) and the European Society for Gynaecological Endoscopy (ESGE) have established a common Working Group, under the name CONUTA (CONgenital UTerine Anomalies), with the goal of developing a new updated classification system. A scientific committee (SC) has been appointed to run the project, looking also for consensus within the scientists working in the field.Participants/materials, Setting, Methods: The new system is designed and developed based on (i) scientific research through critical review of current proposals and preparation of an initial proposal for discussion between the experts, (ii) consensus measurement among the experts through the use of the DELPHI procedure and (iii) consensus development by the SC, taking into account the results of the DELPHI procedure and the comments of the experts. Almost 90 participants took part in the process of development of the ESHRE/ESGE classification system, contributing with their structured answers and comments.Main Results and the Role Of Chance: The ESHRE/ESGE classification system is based on anatomy. Anomalies are classified into the following main classes, expressing uterine anatomical deviations deriving from the same embryological origin: U0, normal uterus; U1, dysmorphic uterus; U2, septate uterus; U3, bicorporeal uterus; U4, hemi-uterus; U5, aplastic uterus; U6, for still unclassified cases. Main classes have been divided into sub-classes expressing anatomical varieties with clinical significance. Cervical and vaginal anomalies are classified independently into sub-classes having clinical significance.Limitations, Reasons For Caution: The ESHRE/ESGE classification of female genital anomalies seems to fulfill the expectations and the needs of the experts in the field, but its clinical value needs to be proved in everyday practice.Wider Implications Of the Findings: The ESHRE/ESGE classification system of female genital anomalies could be used as a starting point for the development of guidelines for their diagnosis and treatment.Study Funding/competing Interest(s): None. [ABSTRACT FROM AUTHOR]

Background: Diagnostic hysteroscopy has not yet been generally accepted as a well-tolerated office procedure. The aim of our study was to verify compliance, side-effects and haemodynamic variations when a mini-hysteroscope is used.Methods: A prospective randomized trial on office hysteroscopy was performed by comparing the use of a traditional 5 mm hysteroscope (group A) and of a 3.3 mm mini-hysteroscope (group B). Two patient groups (A and B), each comprising 100 cases, were formed on the basis of a randomized computer-generated list.Results: A marked reduction in the mean (+/- SD) pelvic pain score during office hysteroscopy was seen in group B (2.3 +/- 2.1) as compared with group A (4.6 +/- 2.2) (P < 0.0001, Mann-Whitney test). This result was also confirmed when using an alternative approach: four classes of pelvic pain at the visual analogue score (VAS). A significant reduction was observed in the incidence of moderate and severe pelvic pain in group B at the end of the examination (P = 0.001) and 5-10 min later (P < 0.05).Conclusions: The use of mini-hysteroscopes (3.3 mm with diagnostic sheath) lowers considerably the level of pelvic pain the patients feel: it is halved in comparison with traditional calibre hysteroscopes (2.3 +/- 2.1, on a 0-10 VAS). Furthermore the outpatient hysteroscopy failure rate is less than half (2%) with the mini-hysteroscope compared with the traditional 5 mm hysteroscope (5%). As for side-effects and haemodynamic parameters, no differences were observed except for an increase (P < 0.05) in bradycardia in group B. The advantage of this technique is self-evident, if the patients' compliance is taken into account: in many cases the introduction or withdrawal of the vaginal speculum was reported as the greatest discomfort. [ABSTRACT FROM AUTHOR]