Conservative surgical treatment in cervical dysplastic lesions associated with cystorectocele

The treatment of cervical intraepithelial neoplasia aims at removing the squamocolumnar junction area, including abnormal tissues, up to the healthy tissue. Old postpartum perineal tears associated with cystorectocele, hypertrophic cervical elongation, and first and second degree uterine prolapse are pelvic static disorders. Particular aspects of pelvic-genital static disorder are related to the vulnerability of the pelvic-perineal floor during birth. On the occasion of birth, especially when there are different forms of dystocia during labor, the degradation of soft pelvic, genital, and vaginal-perineal tissues can occur. The objective of this study was to re-evaluate the conservative treatment of cervical dysplasia, depending on the degree of cervical lesions, the surface extension, the age of the patients, and the pathology associated with cervical lesions – colpocele, cystorectocele, and urinary incontinence in the old postpartum perineal tears. In order to solve the three types of concomitant lesions, we used the Manchester operation: the anterior colporrhaphy with the recalibration of the urethra and the suspension of the cystocele, the minimal colpectomy, the lesional cervical amputation with the anterior fixation of the parameters, and the posterior colpoperineorrhaphy with high myorrhaphy of the levator ani muscles. The decision on the management of cervical dysplasia has taken into account the degree of cervical lesions, the extension on the surface, the patients’ age and the pregnancy planning, and the pathology associated with cervical lesions. The Manchester operation is a conservative surgical procedure, effective in women under 45 years old, multiparous, with present genital activity, with dysplastic cervical lesions and cystorectocele. It also solves cystorectocele, cervical dysplasia, hypertrophic cervical elongation, and first and second degree uterine prolapse

Conservative surgical treatment in cervical dysplastic lesions associated with cystorectocele

The treatment of cervical intraepithelial neoplasia aims at removing the squamocolumnar junction area, including abnormal tissues, up to the healthy tissue. Old postpartum perineal tears associated with cystorectocele, hypertrophic cervical elongation, and first and second degree uterine prolapse are pelvic static disorders. Particular aspects of pelvic-genital static disorder are related to the vulnerability of the pelvic-perineal floor during birth. On the occasion of birth, especially when there are different forms of dystocia during labor, the degradation of soft pelvic, genital, and vaginal-perineal tissues can occur. The objective of this study was to re-evaluate the conservative treatment of cervical dysplasia, depending on the degree of cervical lesions, the surface extension, the age of the patients, and the pathology associated with cervical lesions – colpocele, cystorectocele, and urinary incontinence in the old postpartum perineal tears. In order to solve the three types of concomitant lesions, we used the Manchester operation: the anterior colporrhaphy with the recalibration of the urethra and the suspension of the cystocele, the minimal colpectomy, the lesional cervical amputation with the anterior fixation of the parameters, and the posterior colpoperineorrhaphy with high myorrhaphy of the levator ani muscles. The decision on the management of cervical dysplasia has taken into account the degree of cervical lesions, the extension on the surface, the patients’ age and the pregnancy planning, and the pathology associated with cervical lesions. The Manchester operation is a conservative surgical procedure, effective in women under 45 years old, multiparous, with present genital activity, with dysplastic cervical lesions and cystorectocele. It also solves cystorectocele, cervical dysplasia, hypertrophic cervical elongation, and first and second degree uterine prolapse

Prediction Tools for Unfavourable Outcomes in Clostridium difficile Infection: A Systematic Review

CONTEXT: Identifying patients at risk for adverse outcomes of Clostridium difficile infection (CDI), including recurrence and death, will become increasingly important as novel therapies emerge, which are more effective than traditional approaches but very expensive. Clinical prediction rules (CPRs) can improve the accuracy of medical decision-making. Several CPRs have been developed for CDI, but none has gained a widespread acceptance. METHODS: We systematically reviewed studies describing the derivation or validation of CPRs for unfavourable outcomes of CDI, in medical databases (Medline, Embase, PubMed, Web of Science and Cochrane) and abstracts of conferences. RESULTS: Of 2945 titles and abstracts screened, 13 studies on the derivation of a CPR were identified: two on recurrences, five on complications (including mortality), five on mortality alone and one on response to treatment. Two studies on the validation of different severity indices were also retrieved. Most CPRs were developed as secondary analyses using cohorts assembled for other purposes. CPRs presented several methodological limitations that could explain their limited use in clinical practice. Except for leukocytosis, albumin and age, there was much heterogeneity in the variables used, and most studies were limited by small sample sizes. Eight models used a retrospective design. Only four studies reported the incidence of the outcome of interest, even if this is essential to evaluate the potential usefulness of a model in other populations. Only five studies performed multivariate analyses to adjust for confounders. CONCLUSIONS: The lack of weighing variables, of validation, calibration and measures of reproducibility, the weak validities and performances when assessed, and the absence of sensitivity analyses, all led to suboptimal quality and debatable utility of those CPRs. Evidence-based tools developed through appropriate prospective cohorts would be more valuable for clinicians than empirically-developed CPRs

Investigations of a mechanically failed cable insulation used in indoor conditions

This paper presents the investigation work on different polymeric materials used as insulation materials of conductors in a multicore instrumentation cable. Among differently colored materials, only the white one presented cracks after a few years of use. Isothermal and non-isothermal DSC measurements were performed on initial (non-used) and aged (in service used or laboratory aged) materials as well as on raw materials in order to characterize their stability and the ageing state after storage, use in service or laboratory ageing. As shown by the oxidation induction time values, a pronounced antioxidant loss occurred for all materials during storage or service; plus a strong effect of the ambient light on stability was observed for the white insulation material. Around 3\% of filler, consisting mainly of TiO(2) particles (as revealed by SEM-XRF elemental analysis), was found in the white material. The higher degradability of the white material can be related to both the photocatalytic effect of the TiO(2) particles and rapid loss of stabilizers. (C) 2010 Elsevier Ltd. All rights reserved

A randomised double-blind placebo-controlled phase II study of AGI004 for control of chemotherapy-induced diarrhoea

BACKGROUND: AGI004 is a controlled-release transdermal patch preparation of mecamylamine. We conducted a randomised placebo-controlled phase II study of two dose levels of AGI004 in chemotherapy-induced diarrhoea (CID). METHODS: Adult patients receiving chemotherapy who had experienced diarrhoea (NCI grade 1–2) during previous cycles of chemotherapy were eligible. In all, 64 patients were randomised to receive AGI004 4 mg then 8 mg per 24 h transdermal patch or placebo for two sequential cycles of chemotherapy. Patients' severity of diarrhoea was physician-assessed using NCI grade of diarrhoea and patient-assessed using information recorded in daily diaries of bowel movements. RESULTS: Overall AGI004 doubled the odds of a response to treatment on the first day of chemotherapy based on physician assessment of NCI grade of diarrhoea compared with placebo (odds ratio=2.0, 90% confidence interval: 0.9–4.5) and there was a trend to improved response rates for AGI004 for the full treatment cycle although these results were not statistically significant. There was also evidence of significantly improved response rates based on patient assessment of diarrhoea both overall (P=0.05) and at the 8-mg dose level (P=0.02) compared with placebo. CONCLUSION: AGI004 demonstrated effectiveness in reducing chemotherapy-associated diarrhoea, with results suggesting response across multiple measurements of diarrhoea. Treatment was well tolerated with no drug-related adverse events. Further evaluation of this agent in the management of CID is warranted

Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: A randomized clinical trial

IMPORTANCE Low-molecular-weight heparin is recommended over warfarin for the treatment of acute venous thromboembolism (VTE) in patients with active cancer largely based on results of a single, large trial. OBJECTIVE To study the efficacy and safety of tinzaparin vs warfarin for treatment of acute, symptomatic VTE in patients with active cancer. DESIGN, SETTINGS, AND PARTICIPANTS A randomized, open-label study with blinded central adjudication of study outcomes enrolled patients in 164 centers in Asia, Africa, Europe, and North, Central, and South America between August 2010 and November 2013. Adult patients with active cancer (defined as histologic diagnosis of cancer and receiving anticancer therapy or diagnosed with, or received such therapy, within the previous 6 months) and objectively documented proximal deep vein thrombosis (DVT) or pulmonary embolism, with a life expectancy greater than 6 months and without contraindications for anticoagulation, were followed up for 180 days and for 30 days after the last study medication dose for collection of safety data. INTERVENTIONS Tinzaparin (175 IU/kg) once daily for 6 months vs conventional therapy with tinzaparin (175 IU/kg) once daily for 5 to 10 days followed by warfarin at a dose adjusted to maintain the international normalized ratio within the therapeutic range (2.0-3.0) for 6 months. MAIN OUTCOMES AND MEASURES Primary efficacy outcome was a composite of centrally adjudicated recurrent DVT, fatal or nonfatal pulmonary embolism, and incidental VTE. Safety outcomes included major bleeding, clinically relevant nonmajor bleeding, and overall mortality. RESULTS Nine hundred patients were randomized and included in intention-to-treat efficacy and safety analyses. Recurrent VTE occurred in 31 of 449 patients treated with tinzaparin and 45 of 451 patients treated with warfarin (6-month cumulative incidence, 7.2% for tinzaparin vs 10.5% for warfarin; hazard ratio [HR], 0.65 [95% CI, 0.41-1.03]; P = .07). There were no differences in major bleeding (12 patients for tinzaparin vs 11 patients for warfarin; HR, 0.89 [95% CI, 0.40-1.99]; P = .77) or overall mortality (150 patients for tinzaparin vs 138 patients for warfarin; HR, 1.08 [95% CI, 0.85-1.36]; P = .54). A significant reduction in clinically relevant nonmajor bleeding was observed with tinzaparin (49 of 449 patients for tinzaparin vs 69 of 451 patients for warfarin; HR, 0.58 [95% CI, 0.40-0.84]; P = .004). CONCLUSIONS AND RELEVANCE Among patients with active cancer and acute symptomatic VTE, the use of full-dose tinzaparin (175 IU/kg) daily compared with warfarin for 6 months did not significantly reduce the composite measure of recurrent VTE and was not associated with reductions in overall mortality or major bleeding, but was associated with a lower rate of clinically relevant nonmajor bleeding. Further studies are needed to assess whether the efficacy outcomes would be different in patients at higher risk of recurrent VTE

Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial

Background: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings. Methods: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1–3c (modified to stage 2–3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1–3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants. Findings: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1–5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57–0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3–91·8) in the neratinib group and 87·7% (85·7–89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3–4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [<1%] grade 4 with neratinib vs 23 [2%] grade 3 with placebo), vomiting (grade 3: 47 [3%] vs five [<1%]), and nausea (grade 3: 26 [2%] vs two [<1%]). Treatment-emergent serious adverse events occurred in 103 (7%) women in the neratinib group and 85 (6%) women in the placebo group. No evidence of increased risk of long-term toxicity or long-term adverse consequences of neratinib-associated diarrhoea were identified with neratinib compared with placebo. Interpretation: At the 5-year follow-up, 1 year of extended adjuvant therapy with neratinib, administered after chemotherapy and trastuzumab, significantly reduced the proportion of clinically relevant breast cancer relapses—ie, those that might lead to death, such as distant and locoregional relapses outside the preserved breast—without increasing the risk of long-term toxicity. An analysis of overall survival is planned after 248 events