Midline fascial plication under continuous digital transrectal control: which factors determine anatomic outcome?

Contains fulltext : 88897.pdf (publisher's version ) (Closed access)INTRODUCTION AND HYPOTHESIS: The aim of the study was to report anatomic and functional outcome of midline fascial plication under continuous digital transrectal control and to identify predictors of anatomic failure. METHODS: Prospective observational cohort. Anatomic success defined as POP-Q stage or= II underwent midline fascial plication under continuous digital transrectal control. Median follow-up was 14 months (12-35 months), and anatomic success was 80.3% (95% CI 75-86). Independent predictors of failure were posterior compartment POP stage >or= III [OR 8.7 (95% CI 2.7-28.1)] and prior colposuspension [OR 5.6 (95% CI 1.1-27.8)]. Sixty-three percent of patients bothered by obstructed defaecation experienced relief after surgery. CONCLUSIONS: Anatomic and functional outcomes were good. Risk factors for anatomic failure were initial size of posterior POP (stage >or= III) and prior colposuspension.1 juni 201

Intensified dose of cyclophosphamide with G-CSF support versus standard dose combined with platinum in first-line treatment of advanced ovarian cancer a randomised study from the GINECO group

ICON3 trial results have suggested that CAP and carboplatin–taxol regimens as first-line treatment of advanced ovarian cancer (AOC) yield similar survival. We explored the impact of increased dose of cyclophosphamide in a modified CAP regimen on the disease-free survival (DFS) and overall survival (OS) of AOC patients. From February 1994 to June 1997, 164 patients were randomised to receive six cycles every 3 weeks of either standard CEP (S) combining cyclophosphamide (C), 500 mg m−2, epirubicin (E) 50 mg m−2, and cisplatin (P) 75 mg m−2 or intensive CEP (I) with E and P at the same doses, but with (C) 1800 mg m−2 and filgrastim 5 μg kg−1 per day × 10 days. Response was evaluated at second-look surgery. Patient characteristics were well balanced. Except for grade 3–4 neutropaenia (S: 54%, I: 38% of cycles), Arm1 presented a significantly more important toxicity: infection requiring antibiotics, grade 3–4 thrombocytopaenia, anaemia, nausea-vomiting, diarrhoea, mucositis. Median follow-up was 84 months. DFS (15.9 vs 14.8 months) and OS (33 vs 30 months) were not significantly different between S and I (P>0.05). Increasing cyclophosphamide dose by more than 3 times with filgrastim support in the modified CAP regimen CEP induces more toxicity but not better efficacy in AOC

Resistance to HSP90 inhibition involving loss of MCL1 addiction

YesInhibition of the chaperone heat-shock protein 90 (HSP90) induces apoptosis, and it is a promising anti-cancer strategy. The mechanisms underpinning apoptosis activation following HSP90 inhibition and how they are modified during acquired drug resistance are unknown. We show for the first time that, to induce apoptosis, HSP90 inhibition requires the cooperation of multi BH3-only proteins (BID, BIK, PUMA) and the reciprocal suppression of the pro-survival BCL-2 family member MCL1, which occurs via inhibition of STAT5A. A subset of tumour cell lines exhibit dependence on MCL1 expression for survival and this dependence is also associated with tumour response to HSP90 inhibition. In the acquired resistance setting, MCL1 suppression in response to HSP90 inhibitors is maintained; however, a switch in MCL1 dependence occurs. This can be exploited by the BH3 peptidomimetic ABT737, through non-BCL-2-dependent synthetic lethality

Robot-assisted surgery for the management of apical prolapse: a bicentre prospective cohort study

Objective: Robot‐assisted surgery is a recognized treatment for pelvic‐organ prolapse. Many of the surgical subgroup outcomes for apical prolapse are reported together leading to a paucity of homogenous data. Design: Prospective observational cohort study (https://clinicaltrials.gov; identifier NCT01598467) assessing outcomes for homogeneous subgroups of robot‐assisted apical prolapse surgery. Setting: Two European tertiary referral hospitals. Population: Consecutive patients undergoing robot‐assisted sacrocolpopexy (RASC) and supracervical hysterectomy with sacrocervicopexy (RSHS). Methods: Anatomical cure (simplified Pelvic Organ Prolapse Quantification (sPOPQ) stage 1,), subjective cure (symptoms of bulge) and quality of life (Pelvic Floor Impact Questionnaire [PFIQ‐7]). Main Outcome measures: Primary outcome: anatomical and subjective cure. Secondary outcomes: surgical safety and intraoperative variables. Results: Total 305 patients included (RASC N=188, RSHS N=117). Twelve months follow‐up available for 144 (RASC 76.6%) and 109 (RSHS 93.2%). Anatomical success of the apical compartment occurred in 91% (RASC) and in 99% (RSHS). In all compartments, success percentages were 67% and 65% respectively. Most recurrences were anterior compartment (15.7% RASC [symptomatic 12.1%]; 22.9% RSHS [symptomatic 4.8%]). Symptoms of bulge improved from 97.4% to 17.4% (p<0.0005). PFIQ‐7 scores improved from 76.7 ± 62.3 to 13.5 ± 31.1 (p<0.0005). Duration of surgery increased significantly in RSHS (183.1 ± 38.2 versus 145.3 ± 29.8 [p<0.0005]). Intraoperative complications and conversion rates were low (RASC: 5.3% and 4.3%; RSHS: 0.0% and 0.0%). Four severe postoperative complications occurred after RASC (2.1%) and one after RSHS (1.6%). Conclusion: This is the largest reported prospective cohort study on robot‐assisted apical prolapse surgery. Both procedures are safe, with durable results

Therapy for metastatic melanoma: the past, present, and future

Metastatic melanoma is the most aggressive form of skin cancer with a median overall survival of less than one year. Advancements in our understanding of how melanoma evades the immune system as well as the recognition that melanoma is a molecularly heterogeneous disease have led to major improvements in the treatment of patients with metastatic melanoma. In 2011, the US Food and Drug Administration (FDA) approved two novel therapies for advanced melanoma: a BRAF inhibitor, vemurafenib, and an immune stimulatory agent, ipilimumab. The success of these agents has injected excitement and hope into patients and clinicians and, while these therapies have their limitations, they will likely provide excellent building blocks for the next generation of therapies. In this review we will discuss the advantages and limitations of the two new approved agents, current clinical trials designed to overcome these limitations, and future clinical trials that we feel hold the most promise

The impact of viral mutations on recognition by SARS-CoV-2 specific T cells.

We identify amino acid variants within dominant SARS-CoV-2 T cell epitopes by interrogating global sequence data. Several variants within nucleocapsid and ORF3a epitopes have arisen independently in multiple lineages and result in loss of recognition by epitope-specific T cells assessed by IFN-γ and cytotoxic killing assays. Complete loss of T cell responsiveness was seen due to Q213K in the A∗01:01-restricted CD8+ ORF3a epitope FTSDYYQLY207-215; due to P13L, P13S, and P13T in the B∗27:05-restricted CD8+ nucleocapsid epitope QRNAPRITF9-17; and due to T362I and P365S in the A∗03:01/A∗11:01-restricted CD8+ nucleocapsid epitope KTFPPTEPK361-369. CD8+ T cell lines unable to recognize variant epitopes have diverse T cell receptor repertoires. These data demonstrate the potential for T cell evasion and highlight the need for ongoing surveillance for variants capable of escaping T cell as well as humoral immunity.This work is supported by the UK Medical Research Council (MRC); Chinese Academy of Medical Sciences(CAMS) Innovation Fund for Medical Sciences (CIFMS), China; National Institute for Health Research (NIHR)Oxford Biomedical Research Centre, and UK Researchand Innovation (UKRI)/NIHR through the UK Coro-navirus Immunology Consortium (UK-CIC). Sequencing of SARS-CoV-2 samples and collation of data wasundertaken by the COG-UK CONSORTIUM. COG-UK is supported by funding from the Medical ResearchCouncil (MRC) part of UK Research & Innovation (UKRI),the National Institute of Health Research (NIHR),and Genome Research Limited, operating as the Wellcome Sanger Institute. T.I.d.S. is supported by a Well-come Trust Intermediate Clinical Fellowship (110058/Z/15/Z). L.T. is supported by the Wellcome Trust(grant number 205228/Z/16/Z) and by theUniversity of Liverpool Centre for Excellence in Infectious DiseaseResearch (CEIDR). S.D. is funded by an NIHR GlobalResearch Professorship (NIHR300791). L.T. and S.C.M.are also supported by the U.S. Food and Drug Administration Medical Countermeasures Initiative contract75F40120C00085 and the National Institute for Health Research Health Protection Research Unit (HPRU) inEmerging and Zoonotic Infections (NIHR200907) at University of Liverpool inpartnership with Public HealthEngland (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford.L.T. is based at the University of Liverpool. M.D.P. is funded by the NIHR Sheffield Biomedical ResearchCentre (BRC – IS-BRC-1215-20017). ISARIC4C is supported by the MRC (grant no MC_PC_19059). J.C.K.is a Wellcome Investigator (WT204969/Z/16/Z) and supported by NIHR Oxford Biomedical Research Centreand CIFMS. The views expressed are those of the authors and not necessarily those of the NIHR or MRC

Independent indistinguishable quantum light sources on a reconfigurable photonic integrated circuit

We report a compact, scalable, quantum photonic integrated circuit realised by combining multiple, tuneable InGaAs/GaAs quantum dot single photon sources with a silicon oxynitride waveguide circuit. Each waveguide in the circuit is addressed by a separate, electrically controlled quantum dot-containing diode. We show that the quantum dot emission from neighbouring diodes can be independently tuned to degeneracy using the Stark Effect and that the resulting photon streams are indistinguishable. This enables on-chip Hong-Ou-Mandel-type interference, as required for many photonic quantum information processing schemes