Medicine by Alexandros G.Sfakianakis: 10/16/17

Δευτέρα 16 Οκτωβρίου 2017

Determination of the absolute oral bioavailability of niraparib by simultaneous administration of a 14 C-microtracer and therapeutic dose in cancer patients

Abstract

Introduction

Niraparib (Zejula™) is a poly(ADP-ribose) polymerase inhibitor recently approved by the US Food and Drug Administration for the maintenance treatment of patients with recurrent platinum-sensitive epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. The pivotal phase III clinical trial has shown improved progression-free survival in patients receiving niraparib compared with those receiving placebo.

Purpose

Since niraparib is administered orally, it is of interest to investigate the oral bioavailability (F _po) of this novel compound, which is the aim of this study.

Methods

Six patients received an oral therapeutic dose of 300 mg niraparib, followed by a 15-min intravenous infusion of 100 µg ¹⁴C-niraparib with a radioactivity of approximately 100 nCi. The niraparib therapeutic dose was measured in plasma using a validated liquid chromatography–tandem mass spectrometry method, whereas the total ¹⁴C-radioactivity and ¹⁴C-niraparib plasma levels were measured by accelerator mass spectrometry and a validated high performance liquid chromatography assay with AMS.

Results

The F _po of niraparib was determined to be 72.7% in humans.

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Population pharmacokinetics of trastuzumab emtansine in previously treated patients with HER2-positive advanced gastric cancer (AGC)

Abstract

Purpose

Ado-trastuzumab emtansine (T-DM1) is an antibody–drug conjugate comprising trastuzumab conjugated via a stable thioether linker to DM1, a highly potent cytotoxic agent. A population pharmacokinetics (PK) analysis was performed to characterize T-DM1 PK and evaluate the impact of patient characteristics on T-DM1 PK in previously treated patients with HER2-positive advanced gastric cancer (AGC).

Methods

Following T-DM1 weekly or every three weeks dosing, T-DM1 concentration measurements (n = 780) were collected from 136 patients in the GATSBY (NCT01641939) study and analyzed using nonlinear mixed effects modeling. The influence of demographic, baseline laboratory, and disease characteristics on T-DM1 PK was examined.

Results

T-DM1 PK was best described by a two-compartment model with parallel linear and nonlinear (Michaelis–Menten) elimination from the central compartment. The final population model estimated linear clearance (CL) of 0.79 L/day, volume of distribution in the central compartment (V _c) of 4.48 L, distribution clearance (Q) of 0.62 L/day, volume of distribution in the peripheral compartment (V _p) of 1.49 L, nonlinear CL of 2.06 L/day, and KM of 1.63 μg/mL. Parameter uncertainty was low to moderate for fixed effects, except KM (estimated with poor precision). Patients with high body weight and low baseline trastuzumab concentrations had significantly faster linear CL; those with higher body weight had significantly larger V _c.

Conclusions

In a HER2-positive AGC population, T-DM1 PK was best described by a two-compartment model with parallel linear and nonlinear elimination. Baseline body weight and trastuzumab concentration were identified as significant covariates for T-DM1 PK in a HER2-positive AGC population.

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Cholecystokinin receptor antagonist alters pancreatic cancer microenvironment and increases efficacy of immune checkpoint antibody therapy in mice

Abstract

Advanced pancreatic ductal adenocarcinoma (PDAC) has typically been resistant to chemotherapy and immunotherapy; therefore, novel strategies are needed to enhance therapeutic response. Cholecystokinin (CCK) has been shown to stimulate growth of pancreatic cancer. CCK receptors (CCKRs) are present on pancreatic cancer cells, fibroblasts, and lymphocytes. We hypothesized that CCKR blockade would improve response to immune checkpoint antibodies by promoting influx of tumor-infiltrating lymphocytes (TILs) and reducing fibrosis. We examined the effects of CCKR antagonists or immune checkpoint blockade antibodies alone or in combination in murine models of PDAC. Monotherapy with CCKR blockade significantly decreased tumor size and metastases in SCID mice with orthotopic PDAC, and in C57BL/6 mice, it reduced fibrosis and induced the influx of TILs. Immune-competent mice bearing syngeneic pancreatic cancer (Panc02 and mT3-2D) that were treated with the combination of CCK receptor antagonists and immune checkpoint blockade antibodies survived significantly longer with smaller tumors. Tumor immunohistochemical staining and flow cytometry demonstrated that the tumors of mice treated with the combination regimen had a significant reduction in Foxp3+ T-regulatory cells and an increase in CD4+ and CD8+ lymphocytes. Masson's trichrome stain analysis revealed 50% less fibrosis in the tumors of mice treated with CCKR antagonist compared to controls and compared to checkpoint antibody therapy. CCKR antagonists given with immune checkpoint antibody therapy represent a novel approach for improving survival of PDAC. The mechanism by which this combination therapy improves the survival of PDAC may be related to the decreased fibrosis and immune cells of the tumor microenvironment.

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DDR2 and IFITM1 Are Prognostic Markers in Gallbladder Squamous Cell/Adenosquamous Carcinomas and Adenocarcinomas

Abstract

This study was conducted to investigate the expressions of DDR2 and IFITM1 and their clinical and pathological significances in the rare type squamous cell/adenosquamous carcinomas (SC/ASC) and ordinary adenocarcinomas (AC) of gallbladder cancers. DDR2 and IFITM1 expression was examined in 69 SC/ASCs and 146 ACs using EnVision immunohistochemistry. Results showed that the percentage of positive DDR2 and IFITM1 expression was significantly higher in SC/ASC patients with high TNM stage, lymph node metastasis, invasion, and no resection surgery compared to patients with low TNM stages, no lymph node metastasis, no invasion, and resection surgery (P < 0.05 or P < 0.01). The positive rate of DDR2 was significantly higher in SC/ASC patients with large tumor sizes than patients with small tumor sizes (p < 0.05). The percentage of positive DDR2 and IFITM1 expressions was significantly higher in AC patients with high TNM stages that didn't receive resection surgery compared to patients with low TNM stages that did receive resection surgery (P < 0.05 or P < 0.01). The positive rate of IFITM1 was significantly higher in AC patients with lymph node metastasis and invasion than in patients without metastasis and invasion (p < 0.05). Positive DDR2 and IFITM1 expression was closely associated with a decreased overall survival in SC/ASC and AC patients (P < 0.05 or P < 0.01). AUC analysis showed that DDR2 and IFITM1 was sensitive and specific for the diagnosis of SC/ASC (AUC = 0.740 and AUC =0.733, respectively) and AC (AUC = 0.710 and AUC =0.741, respectively). In conclusion, positive DDR2 and IFITM1 expression is a marker for the clinical severity, poor prognosis, and diagnosis of gallbladder SC/ASC and AC.

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Cholecystokinin receptor antagonist alters pancreatic cancer microenvironment and increases efficacy of immune checkpoint antibody therapy in mice

Abstract

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Corrigendum to “Interrelationship between Sleep and Exercise: A Systematic Review”

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Spinal Implant options to optimize fixation in patients with osteopenia/osteoporosis

Publication date: Available online 14 September 2017
Source:Seminars in Spine Surgery
Author(s): Sohrab Virk, Elizabeth Yu
The challenges presented by osteoporotic spines for creating a strong bone-implant interface are substantial. Many devices have been specifically designed to enhance fixation of screws, hooks, and cages in order to create an optimal healing environment for patients with low bone mineral density. Screw design has been enhanced via differing screw pitches, shapes, materials, coating and sizes in order to enhance fixation in both the posterior and anterior osteoporotic spine. Several novel designs for cages, plates, anchors, hooks and bands can be used to achieve fixation as well. With appropriate surgical technique, these technological advances can dramatically improve fixation for a construct to treat osteoporotic spines.

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Interpreting the DXA analysis: When should you hold off on spinal fusion?

Publication date: Available online 14 September 2017
Source:Seminars in Spine Surgery
Author(s): Nathan Wanderman, Brett Freedman, Bradford Currier, Paul Huddleston, Michael Yaszemski, Ahmad Nassr
Dual energy x-ray absorptiometry (DXA) is the standard assessment of bone mineral density (BMD) and is used for the diagnosis of osteoporosis and monitoring the effectiveness of osteoporosis treatment. Its results are predictive of both vertebral compression fractures and vertebral screw pullout strength. Though low BMD and the presence of osteoporosis are associated with failure of spinal instrumentation and junctional kyphosis, DXA scans are not universally obtained prior to spinal fusions, and there exists no consensus on T-score thresholds for determining if spinal fusions are a reasonable option in patients with diminished bone quality.

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Do bisphosphonates affect fusion rates? how to manage these medications in the perioperative time frame

Publication date: Available online 12 September 2017
Source:Seminars in Spine Surgery
Author(s): Emmanuel N. Menga, Antonio J. Webb, Addisu Mesfin
Various treatment options are available for the management of patients with osteoporosis including bisphosphonates. While bisphosphonates have demonstrated effectiveness at reducing the risk of vertebral osteoporotic fractures, their mechanisms of action may render them contraindicated in the setting of spinal arthrodesis. Research studies reporting on the effects of bisphosphonate osteoporotic medications on spinal fusion remain limited, inconsistent and controversial with no clear guidelines. Future randomized and multi-center studies are needed that further examine the questions of bisphosphonates and spinal fusion.

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What is the future of spinal surgery in patients with osteoporosis?

Publication date: Available online 12 September 2017
Source:Seminars in Spine Surgery
Author(s): Jason C. Eck, Scott D. Hodges
Spinal surgery in patients with osteoporosis has an increased risk for instrumentation failure. Many advancements are being developed in biological methods that manipulate cellular differentiation or cellular recruitment to the surgical site using bioactive coating and mechanical changes to the implants such as altering the surface roughness to enhance in-migration of bone through osteoinduction. The goal of this article is to summarize some of the potential advancement expected in the future related to spinal surgery in patients with osteoporosis.

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Can medical management with teriparatide improve spinal surgery outcomes in patients with spinal osteoporosis/osteopenia?

Publication date: Available online 12 September 2017
Source:Seminars in Spine Surgery
Author(s): Muhammad Shakib Akhter, Hussein Ali El-Khechen, Rakesh Patel, Ilyas S. Aleem
Osteopenia and osteoporosis have become increasingly common in the elderly population, as has the concern from treating spinal surgeons. Many adverse surgical outcomes have been associated with poor bone quality, including decreased fusion rates, hardware complications, and osteoporotic fractures. Teriparatide, a recombinant form of parathyroid hormone, has been used as a major pharmaceutical intervention in osteoporosis treatment. This article provides an overview of the mechanism of teriparatide followed by a detailed review of the literature concerning outcomes of medical management with teriparatide in both animal models and humans with osteoporosis/osteopenia. Improved fusion rates and duration, as well as reduced osteoporosis-related complications are evident upon reviewing clinical and radiographic outcomes of teriparatide therapy in spinal surgery patients.

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Secondary fracture prevention in spine surgery

Publication date: Available online 12 September 2017
Source:Seminars in Spine Surgery
Author(s): Paul A. Anderson, Kristyn Hare, Eeric Truumees
A fragility fracture is associated with high likelihood of further fracture and the risk is reduced by quality improvement programs to provide osteoporotic care and rehabilitation. Unfortunately, these treatments are offered to less than 20% of patients who have fragility fractures. Multiple types of secondary fracture prevention programs are available and all have been shown to increase diagnostic testing and pharmacologic treatments in a cost-effective manner. The American Orthopaedic Association's "Own the Bone" is one such comprehensive quality improvement program that provides leadership and offers patients access to preventive care. Spine surgeons should take the lead to make sure that patients with fragility spinal fractures receive secondary fracture prevention.

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Healthcare burden of osteoporosis

Publication date: Available online 12 September 2017
Source:Seminars in Spine Surgery
Author(s): Benjamin Weisenthal, Silky Chotai, Ahilan Sivaganesan, Jeffrey Hills, Clinton J. Devin
Osteoporosis is responsible for a global medical and economic burden that will grow as the elderly population doubles over the next 20 years. Measuring the cost of the effects of osteoporosis on treatment of spinal disorders is important as we prioritize distribution of resources in the healthcare community. This article examines the monetary cost of osteoporotic disorders associated with spinal care, specifically compression fractures, complications of spinal fusions, and medical treatment of osteoporosis. Examining these costs will allow us to focus further research into the primary cost drivers associated with osteoporosis.

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Complex spinal surgery in patients with osteoporosis: Tips and tricks for achieving adequate constructs and avoiding complications

Publication date: Available online 12 September 2017
Source:Seminars in Spine Surgery
Author(s): David P. Falk, Evan J. Smith, Sachin Gupta, Warren Yu, Joseph R. O'Brien
Osteoporosis presents a unique set of challenges for instrumentation and correction of spinal deformity, both due to the unique pathology created by the disease and the technical considerations for obtaining spinal fixation. As a result, the spine surgeon is faced with the challenge of needing a robust reduction method to achieve stability in a relatively weak medium. Complications from fixation failure most frequently present as pedicle screw pullout and junctional failure. Many solutions have been offered to improve construct strength from preoperative therapeutics to intraoperative surgical adjuncts. From our experience, we review several promising strategies.

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Introduction

Publication date: Available online 12 September 2017
Source:Seminars in Spine Surgery
Author(s): Ahmad Nassr, Bradford Currier

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Vertebral fracture management

Publication date: Available online 12 September 2017
Source:Seminars in Spine Surgery
Author(s): Arjun S. Sebastian, Jeffrey A. Rihn
Osteoporosis-related acute vertebral fragility fracture is a debilitating condition that can cause significant morbidity in elderly patients. Appropriate treatment requires a multimodal approach by spine care providers. Initial management should be directed at achieving adequate pain control to facilitate early mobilization. In patients refractory to nonoperative treatment, vertebral augmentation may be utilized. Back extensor exercises, postural training, and active orthoses can help not only with symptom control but also reduce the progression of kyphosis. Appropriate treatment of osteoporosis should be initiated as soon as possible to minimize the risk of future fracture.

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Contributors

Publication date: September 2017
Source:Seminars in Spine Surgery, Volume 29, Issue 3

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Enhanced DNA double-strand break repair of microbeam targeted A549 lung carcinoma cells by adjacent WI38 normal lung fibroblast cells via bi-directional signaling.

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Enhanced DNA double-strand break repair of microbeam targeted A549 lung carcinoma cells by adjacent WI38 normal lung fibroblast cells via bi-directional signaling.

Mutat Res. 2017 Oct;803-805:1-8

Authors: Kobayashi A, Tengku Ahmad TAF, Autsavapromporn N, Oikawa M, Homma-Takeda S, Furusawa Y, Wang J, Konishi T

Abstract
Understanding the mechanisms underlying the radiation-induced bystander effect (RIBE) and bi-directional signaling between irradiated carcinoma cells and their surrounding non-irradiated normal cells is relevant to cancer radiotherapy. The present study investigated propagation of RIBE signals between human lung carcinoma A549 cells and normal lung fibroblast WI38 cells in bystander cells, either directly or indirectly contacting irradiated A549 cells. We prepared A549-GFP/WI38 co-cultures and A549-GFP/A549 co-cultures, in which A549-GFP cells stably expressing H2BGFP were co-cultured with either A549 cells or WI38 cells, respectively. Using the SPICE-NIRS microbeam, only the A549-GFP cells were irradiated with 500 protons per cell. The level of γ-H2AX, a marker for DNA double-strand breaks (DSB), was subsequently measured for up to 24h post-irradiation in three categories of cells: (1) "targeted"/irradiated A549-GFP cells; (2) "neighboring"/non-irradiated cells directly contacting the "targeted" cells; and (3) "distant"/non-irradiated cells, which were not in direct contact with the "targeted" cells. We found that DSB repair in targeted A549-GFP cells was enhanced by co-cultured WI38 cells. The bystander response in A549-GFP/A549 cell co-cultures, as marked by γ-H2AX levels at 8h post-irradiation, showed a decrease to non-irradiated control level when approaching 24h, while the neighboring/distant bystander WI38 cells in A549-GFP/WI38 co-cultures was maintained at a similar level until 24h post-irradiation. Surprisingly, distant A549-GFP cells in A549-GFP/WI38 co-cultures showed time dependency similar to bystander WI38 cells, but not to distant cells in A549-GFP/A549 co-cultures. These observations indicate that γ-H2AX was induced in WI38 cells as a result of RIBE. WI38 cells were not only involved in rescue of targeted A549, but also in the modification of RIBE against distant A549-GFP cells. The present results demonstrate that radiation-induced bi-directional signaling had extended a profound influence on cellular sensitivity to radiation as well as the sensitivity to RIBE.

PMID: 28689138 [PubMed - indexed for MEDLINE]

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10 MRI Characteristics of Patients with Cervical SVA >40 mm. A Propensity Score-Matching Analysis of 1,500 Weight-Bearing MR Images

Publication date: October 2017
Source:The Spine Journal, Volume 17, Issue 10, Supplement
Author(s): Koji Tamai, Zorica Buser, Permsak Paholpak, Joshua Romanu, Phillip T. Grisdela, Hiroaki Nakamura, Jeffrey C. Wang

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18 Sources of Patients' Expectations of Lumbar Surgery

Publication date: October 2017
Source:The Spine Journal, Volume 17, Issue 10, Supplement
Author(s): Carol A. Mancuso, Roland Duculan, Frank P. Cammisa, Andrew A. Sama, Alexander P. Hughes, Darren R. Lebl, Federico P. Girardi

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Accumulation and localization of macrophage phenotypes with human intervertebral disc degeneration

Publication date: Available online 12 October 2017
Source:The Spine Journal
Author(s): Kenneth R. Nakazawa, Benjamin A. Walter, Damien M. Laudier, Divya Krishnamoorthy, Grace E. Mosley, Kara L. Spiller, James C. Iatridis
Background ContextChronic inflammation is an important component of intervertebral disc (IVD) degeneration, but there is limited knowledge about the identity and source of inflammatory cells involved with the degenerative processes. Macrophages can exhibit multiple phenotypes and are known inflammatory regulators in many tissues, but their phenotypes have not been characterized in IVD degeneration.PurposeTo characterize accumulation and localization of macrophages in IVD degeneration.Study Design/SettingExploratory study to characterize macrophage phenotypes in human cadaver IVDs and the effects of injury and degeneration using multiple immunohistochemistry methods.Patient SampleN.A.Outcome Measures% Positivity of immunohistochemical markers specific for CCR7, CD163 and CD206. Qualitative assessments of dual immunofluorescence and immunostaining localization.MethodsMacrophages were identified in human cadaveric IVDs with immunohistochemistry using cell surface markers CCR7, CD163, and CD206, which are associated with pro-inflammatory M1, remodeling M2c, and anti-inflammatory M2a phenotypes, respectively. Variations in the accumulation and localization of macrophage markers with degenerative grade across subjects and within donors are described. Federal grant funded project with no relevant conflicts.ResultsCells expressing all three macrophage markers were found in all degenerative IVDs, but not in the healthiest IVDs. Cells expressing CCR7 and CD163, but not CD206 significantly increased with degenerative grade. Many cells also coexpressed multiple macrophage markers. Across all degenerative grades, CCR7+ and CD163+ were significantly more present in unhealthy NP, AF, and EP regions exhibiting structural irregularities and defects. Positively stained cells in the NP and AF closely resembled resident IVD cells, suggesting that IVD cells can express macrophage cell surface markers. In the EP, there were increasing trends of positively stained cells with atypical morphology and distribution, suggesting a source for exogenous macrophage infiltration into the IVD.ConclusionsChronic inflammatory conditions of IVD degeneration appear to involve macrophages or macrophage-like cells, as expression of multiple macrophage markers increased with degeneration, especially around unhealthy regions with defects and the EP. Knowledge of macrophage phenotypes and their localization better elucidates the complex injury and repair processes in IVDs and may eventually lead to novel treatments.

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14 Identifying Sources of Improvement of Axial Pain in Corrective Cervical Deformity Surgery

Publication date: October 2017
Source:The Spine Journal, Volume 17, Issue 10, Supplement
Author(s): Peter G. Passias, Gregory W. Poorman, Samantha R. Horn, Eric O. Klineberg, Christopher I. Shaffrey, Virginie Lafage, Themistocles S. Protopsaltis, Christopher P. Ames, Justin S. Smith, Gregory M. Mundis, Brian J. Neuman, Robert A. Hart, Douglas C. Burton

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Prevention and the state of knowledge of tick-borne diseases among orienteers in Poland

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European Society for Gene and Cell Therapy—Inaugural Learned Society in the Field Worldwide: A Vision on Its Birth, Life, and Prospects for Sustainability

Human Gene Therapy Nov 2017, Vol. 28, No. 11: 941-950.

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Advances in Gene Therapy for Hemophilia

Human Gene Therapy Nov 2017, Vol. 28, No. 11: 1004-1012.

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Celebrating 25 Years of the European Society of Gene and Cell Therapy

Human Gene Therapy Nov 2017, Vol. 28, No. 11: 939-939.

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A Sophism in Vectorology: Turning Harmful Defective Retroviral Vectors into Helpful Replication-Competent Retroviruses Against Cancer

Human Gene Therapy Nov 2017, Vol. 28, No. 11: 954-957.

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Gene Therapy: From Birth to Maturity Requires Commitment to Science and Ethics

Human Gene Therapy Nov 2017, Vol. 28, No. 11: 958-958.

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Clinical Gene Therapy for Neurodegenerative Diseases: Past, Present, and Future

Human Gene Therapy Nov 2017, Vol. 28, No. 11: 988-1003.

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Twenty-Five Years of Gene Therapy: Prof. George Dickson on Past Progress and Future Promise

Human Gene Therapy Nov 2017, Vol. 28, No. 11: 960-963.

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Major Advances in the Development of Vectors for Clinical Gene Therapy of Hematopoietic Stem Cells from European Groups over the Last 25 Years

Human Gene Therapy Nov 2017, Vol. 28, No. 11: 964-971.

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Unraveling the Complex Story of Immune Responses to AAV Vectors Trial After Trial

Human Gene Therapy Nov 2017, Vol. 28, No. 11: 1061-1074.

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Twenty-Five Years of Gene Therapy for ADA-SCID: From Bubble Babies to an Approved Drug

Human Gene Therapy Nov 2017, Vol. 28, No. 11: 972-981.

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Diagnostic pathology of early systemic cancer: ERBB2 gene amplification in single disseminated cancer cells determines patient survival in operable esophageal cancer

Abstract

Early metastatic dissemination and evolution of disseminated cancer cells (DCCs) outside the primary tumor is one reason for the failure of adjuvant therapies because it generates molecular geno- and phenotypes different from primary tumors which still underlie therapy decisions. Since ERBB2 amplification in esophageal DCCs but not in primary tumor cells predict outcome, we aimed to establish an assay with diagnostic reliability for single DCCs or circulating tumor cells (CTCs). For this we evaluated copy number alterations of more than 600 single DCCs from multiple cancer types to define reference regions suitable for quantification of target regions, such as ERBB2. We then compared ERBB2 quantitative PCR (qPCR) measurements with fluorescent in situ hybridization (FISH) data of various breast cancer cell lines and identified the aberration-calling threshold. The method was applied to two independent cohorts of esophageal cancer patients from Hamburg (n = 59) and Düsseldorf (n = 53). We found a high correlation between the single cell qPCR assay and the standard FISH assay (R = 0.98) and significant associations between amplification and survival for both patient cohorts (Hamburg (HH), p = 0.033; Düsseldorf (D), p = 0.052; pooled HH+D, p = 0.002) when applied to DCCs of esophageal cancer patients. Detection of a single ERBB2-amplified DCC was the most important risk factor for death from esophageal cancer (relative risk = 4.16; 95% CI = 1.887- 9.184; p < 0.001). In our study, we detected ERBB2-amplified cells in 7% of patients. These patients could benefit from anti-ERBB2 targeting therapies. This article is protected by copyright. All rights reserved.

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The impact of socioeconomic status on stage specific prostate cancer survival and mortality before and after introduction of PSA test in Finland

Abstract

Socioeconomic status (SES) has an impact on prostate cancer (PCa) outcomes. Men with high SES have higher incidence and lower mortality of PCa versus lower SES males. PCa cases diagnosed in Finland in 1985-2014 (N=95076) were identified from the Finnish Cancer Registry. Information on education level (EL) was obtained from Statistics Finland. EL was assessed with three-tiered scale: basic, upper secondary and higher education. PCa stage at diagnosis was defined as localized, metastatic or unknown. Years of diagnosis 1985-1994 were defined as pre-PSA period and thereafter as post-PSA period. We report PCa-specific survival (PCSS) and relative risks (RR) for PCa specific mortality (PCSM) among cancer cases in Finland, where healthcare is 100% publicly reimbursed and inequality in healthcare services low. Men with higher EL had markedly better 10-year PCSS: 68% vs 63% in 1985-1994 and 90% vs 85% in 1995-2004 compared to basic EL in localized PCa. The RR for PCSM among men with localized PCa and higher EL compared to basic EL was 0.76(95%confidence interval (CI) 0.66-0.88) in 1985-1994 and 0.61(95%CI 0.53-0.70) in 1995-2004. Variation in PCSS and PCSM between EL categories was evident in metastatic PCa, too. The difference in PCSM between EL categories was larger in the first 10-year post-PSA period than before that but decreased thereafter in localized PCa, suggesting PSA testing became earlier popular among men with high EL. In summary, higher SES/EL benefit PCa survival both in local and disseminated disease and the effect of EL was more pronounced in early post-PSA period. This article is protected by copyright. All rights reserved.

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The human PKP2/Plakophilin-2 gene is induced by Wnt/β-catenin in normal and colon cancer-associated fibroblasts

Abstract

Colorectal cancer results from the malignant transformation of colonic epithelial cells. Stromal fibroblasts are the main component of the tumour microenvironment, and play an important role in the progression of this and other neoplasias. Wnt/β-catenin signalling is essential for colon homeostasis, but aberrant, constitutive activation of this pathway is a hallmark of colorectal cancer. Here we present the first transcriptomic study on the effect of a Wnt factor on human colonic myofibroblasts. Wnt3A regulates the expression of 1136 genes, of which 662 are upregulated and 474 are downregulated in CCD-18Co cells. A set of genes encoding inhibitors of the Wnt/β-catenin pathway stand out among those induced by Wnt3A, which suggests that there is a feedback inhibitory mechanism. We also show that the PKP2 gene encoding the desmosomal protein Plakophilin-2 is a novel direct transcriptional target of Wnt/β-catenin in normal and colon cancer-associated fibroblasts. PKP2 is induced by β-catenin/TCF through three binding sites in the gene promoter and one additional binding site located in an enhancer 20 kb upstream from the transcription start site. Moreover, Plakophilin-2 antagonizes Wnt/β-catenin transcriptional activity in HEK-293T cells, which suggests that it may act as an intracellular inhibitor of the Wnt/β-catenin pathway. Our results demonstrate that stromal fibroblasts respond to canonical Wnt signalling and that Plakophilin-2 plays a role in the feedback control of this effect suggesting that the response to Wnt factors in the stroma may modulate Wnt activity in the tumour cells. This article is protected by copyright. All rights reserved.

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CCDC6: The identity of a protein known to be partner in fusion

Abstract

Coiled Coil Domain Containing 6 gene, CCDC6, was initially isolated as part of a tumorigenic DNA originated by the fusion of CCDC6 with the tyrosine kinase of RET receptor, following a paracentric inversion of chromosome 10. For a long time CCDC6 has been considered as an accidental partner of the RET protooncogene, providing the promoter and the first 101 aa necessary for the constitutive activation of the oncogenic Tyrosine Kinase (TK) RET in thyroid cells. With the advent of more refined diagnostic tools and bioinformatic algorithms, an exponential growth in fusion genes discoveries has allowed the identification of CCDC6 as partner of genes other than RET in different tumor types.

CCDC6 gene product has a proper role in sustaining the DNA damage checkpoints in response to DNA damage. The inactivation of CCDC6 secondary to chromosomal rearrangements or gene mutations could enhance tumor progression by impairing the apoptotic response upon the DNA damage exposure, contributing to the generation of radio- and chemo-resistance. Preclinical studies indicate that the attenuation of CCDC6 in cancer, while conferring a resistance to cisplatinum, sensitizes the cancer cells to the small molecule inhibitors of Poly (ADP-ribose) polymerase (PARP1/2) with a synthetic lethal effect.

Several CCDC6 mutations and gene rearrangements have been described so far in different types of cancer and CCDC6 may represent a possible predictive biomarker of tumor resistance to the conventional anticancer treatments. Nevertheless, the detection of a CCDC6 impairment in cancer patients may help to select, in future clinical trials, those patients who could benefit of PARP-inhibitors treatment alone or in combination with other treatments. This article is protected by copyright. All rights reserved.

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Identification of somatic genetic alterations in ovarian clear cell carcinoma with next generation sequencing

Abstract

Ovarian clear cell carcinoma (OCCC) is the most refractory subtype of ovarian cancer and more prevalent in Japanese than Caucasians (25% and 5% of all ovarian cancer, respectively). The aim of this study is to discover the genomic alterations that may cause OCCC and effective molecular targets for chemotherapy. Paired genomic DNAs of 48 OCCC tissues and corresponding non-cancerous tissues were extracted from formalin-fixed, paraffin embedded specimens collected between 2007 and 2015 at Tohoku University Hospital. All specimens underwent exome sequencing and the somatic genetic alterations were identified. We divided the cases into three clusters based on the mutation spectra. Clinical characteristics such as age of onset and endometriosis are similar among the clusters but one cluster shows mutations related to APOBEC activation, indicating its contribution to subset of OCCC cases. There are three hypermutated cases (showing 12-fold or higher somatic mutations than the other 45 cases) and they have germline and somatic mismatch repair gene alterations. The frequently mutated genes are ARID1A (66.7%), PIK3CA (50%), PPP2R1A (18.8%) and KRAS (16.7%). Somatic mutations important for selection of chemotherapeutic agents, such as BRAF, ERBB2, PDGFRB, PGR, and KRAS are found in 27.1% of OCCC cases, indicating clinical importance of exome analysis for OCCC. Our study suggests that the genetic instability caused by either mismatch repair defect or activation of APOBEC play critical roles in OCCC carcinogenesis. This article is protected by copyright. All rights reserved.

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Targeted Deep Sequencing of Effusion Cytology Samples is Feasible, informs Spatiotemporal Tumor Evolution, and has Clinical and Diagnostic Utility

Abstract

During the course of disease, many cancer patients eventually present with metastatic disease including peritoneal or pleural spread. In this context, cytology specimens derived from ascites or pleural effusion may help to differentiate malignant from benign conditions and sometimes yield diagnosis of a malignancy. However, even when supported by immunohistochemistry, cytological interpretation can be challenging, especially if tumor cellularity is low. Here, we investigated whether targeted deep sequencing of formalin-fixed and paraffin embedded (FFPE) cytology specimens of cancer patients is feasible, and has diagnostic and clinical impact. To this end, a cohort of 20 matched pairs was compiled, each comprising a cytology sample (FFPE cell block) and at least one biopsy/surgical resection specimen serving as benchmark. In addition, 5 non-malignant effusions were sequenced serving as negative-controls. All samples yielded sufficient libraries and were successfully subjected to targeted sequencing employing a semiconductor based next-generation sequencing platform. Using gene panels of different size and composition, including the Oncomine Comprehensive Panel, for targeted sequencing, somatic mutations were detected in the tissue of all 20 cases. Of these, 15 (75%) harbored mutations that were also detected in the corresponding cytology samples. In four of these cases (20%), additional private mutations were detected in either cytology or tissue samples, reflecting spatiotemporal tumor evolution. Of the five remaining cases, three (15%) showed wild type alleles in cytology material whereas tumor tissue had mutations in interrogated genes. Two cases were discordant, showing different private mutations in the cytology and in the tissue sample, respectively.

In summary, sequencing of cytology specimens (FFPE cell block) reflecting spatiotemporal tumor evolution is feasible and yields adjunct genetic information that may be exploitable for diagnostics and therapy. This article is protected by copyright. All rights reserved.

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Xeroderma pigmentosum complementation group D polymorphism toward lung cancer susceptibility survival and response in patients treated with platinum chemotherapy

Future Oncology, Ahead of Print.

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Dissecting Nucleosome Function with a Comprehensive Histone H2A and H2B Mutant Library

Using a comprehensive library of histone H2A and H2B mutants, we assessed the biological function of each amino acid residue involved in various stress conditions including exposure to different DNA damage-inducing reagents, different growth temperatures and other chemicals. H2B N- and H2A C-termini were critical for maintaining nucleosome function and mutations in these regions led to pleiotropic phenotypes. Additionally, two screens were performed using this library, monitoring heterochromatin gene silencing and genome stability, to identify residues which could compromise normal function when mutated. Many distinctive regions within the nucleosome were revealed. Furthermore, we used the bar-seq method to profile the mutant composition of many libraries in one high-throughput sequencing experiment, greatly reducing the labor and increasing the capacity. This study not only demonstrates the applications of the versatile histone library, but also revealed many previously unknown functions of histone H2A and H2B.

http://ift.tt/2igGcva

In vitro combination of Isavuconazole with Echinocandins against Azole-Susceptible and --Resistant Aspergillus spp. [PublishAheadOfPrint]

The in vitro combinations of isavuconazole with echinocandins were evaluated against 30 Aspergillus spp. by a two-dimensional checkerboard microdilution method and an agar-based diffusion method. With the checkerboard method, the three combinations showed indifferent interactions for all the strains. With the agar-based method, indifferent interactions were found for all the strains for isavuconazole-micafungin and isavuconazole-anidulafungin. For the isavuconazole-caspofungin combination, indifference was found in 24/30 strains, synergy in 4/30 strains, and antagonism in 2/30 strains.

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CTX-M-15-producing Shewanella sp. clinical isolate expressing OXA-535, a chromosome-encoded OXA-48 variant, putative progenitor of the plasmid-encoded OXA-436 [PublishAheadOfPrint]

Shewanella spp. constitute a reservoir of antibiotic resistance determinants. In a bile sample, we have identified three Extended Spectrum β-lactamase (ESBL)-producing bacteria (Escherichia coli, Klebsiella pneumoniae and Shewanella sp. JAB-1) isolated from a child suffering from cholangitis. Our objectives were to characterize the genome and the resistome of the first ESBL-producing isolate of the genus Shewanella and determine whether plasmidic exchange occurred between the three-bacterial species. Bacterial isolates were characterized using MALDI-TOF, standard biochemical tools and antimicrobial susceptibility testing. Shewanella sp JAB-1 and ESBL gene-carrying plasmids were characterized using PacBio and Illumina whole genome sequencing, respectively. The Shewanella sp JAB-1 chromosome-encoded OXA-48-variant was cloned and functionally characterized.

Whole genome sequencing (WGS) of the Shewanella sp. clinical isolate JAB-1 revealed the presence of a 193-kb plasmid belonging to IncA/C incompatibility group and harboring two ESBL genes: bla_CTX-M-15 and bla_SHV-2a. bla_CTX-M-15 gene carrying plasmids belonging to IncY and IncR incompatibility groups were also found in the E. coli and K. pneumoniae isolates from the same patient, respectively. Comparison of the bla_CTX-M-15 genetic environment indicated the independent origin of these plasmids and dismissed in vivo transfers. Furthermore, characterization of the resistome of Shewanella sp. JAB-1 revealed the presence of a chromosome-encoded bla_OXA-535 gene, likely the progenitor of the plasmid-encoded bla_OXA-436 gene, a novel bla_OXA-48-like gene. Expression of bla_OXA-535 in E. coli showed the carbapenem-hydrolyzing activity of OXA-535. The production of OXA-535 in Shewanella sp. JAB-1 could be evidenced using molecular and immuno-enzymatic tests, but not with biochemical tests that monitor carbapenem-hydrolysis. In this study, we have identified a CTX-M-15-producing Shewanella species that was responsible of an hepatobiliary infection and that is likely the progenitor of OXA-436, a novel plasmid-encoded OXA-48-like class D carbapenemases.

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Intracellular Tenofovir-Diphosphate and Emtricitabine-Triphosphate in Dried Blood Spots following Directly Observed Therapy: the DOT-DBS Study [PublishAheadOfPrint]

Studies of daily emtricitabine-tenofovir disoproxil fumarate (FTC-TDF) for HIV pre-exposure prophylaxis (PrEP) in men who have sex with men (MSM) modeled intracellular tenofovir-diphosphate (TFV-DP) in dried blood spots (DBS) to assess adherence and corresponding PrEP outcomes. We conducted a prospective, randomized, cross-over pharmacokinetic study of TFV-DP in DBS during 33%, 67% or 100% of daily dosing, under directly observed therapy (DOT). Participants were assigned to two 12-week dosing regimens, separated by a 12-week washout. Forty-eight adults (24 women) from Denver and San Francisco were included. TFV-DP exhibited a median half-life of 17 days, reaching steady-state in 8 weeks. TFV-DP was dose-proportional with mean (SD) steady-state concentrations of 530 (159), 997 (267), and 1542 (405) fmol/punch for the 33%, 67% and 100% arms, respectively. Prior work in MSM demonstrated clinically meaningful TFV-DP thresholds of 350, 700, and 1250 fmol/punch, which were estimated 25^th percentiles for 2, 4, and 7 doses/wk. In the present study, corresponding TFV-DP was within 3% of the prior estimates and subgroups by site, race, and sex, were within 14% of prior estimates, although males had 17.6% (95%CI 6.5, 27.4%) lower TFV-DP compared with females. The thresholds of 350, 700, and 1250 fmol/punch were achieved by 75% of men taking ≥1.2, 3.1, and 6 doses/wk, and 75% of women taking ≥0.6, 2.1, and 5.3 doses/wk, indicating that lower dosing reached these thresholds for both sexes. In conclusion, TFV-DP arising from DOT was similar to previous estimates, and is useful for interpreting PrEP adherence and study outcomes.

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Targeting Human Cytomegalovirus-Infected Cells by Redirecting T Cells Using an Anti-CD3/Anti-gB Bispecific Antibody [PublishAheadOfPrint]

Host immune response to human cytomegalovirus (HCMV) is effective against HCMV reactivation from latency although not sufficient to clear the virus. T cells are primarily responsible for control of the viral reactivation. When host immune system is compromised, as in transplant recipients with immunosuppression, HCMV reactivation and progressive infection can cause serious morbidity and mortality. Adoptive T cell therapy is effective for control of HCMV infection in transplant recipients. However, it is a highly personalized therapeutic regimen, and difficult to implement in routine clinical practice. In this study, we explored a bispecific antibody strategy to direct non-HCMV-specific T cells to recognize and exert effector functions against HCMV-infected cells. Using a knobs-into-holes strategy, we constructed a bispecific antibody with one arm specific to CD3, which can trigger T cell activation, and the other specific to HCMV glycoprotein B (gB), which recognizes and marks the cells with HCMV infection based on their surface expression of viral gB. We showed that this bispecific antibody was able to redirect T cells with specificity to HCMV-infected cells in vitro. In the presence of HCMV infection, the engineered antibody was able to activate T cells with no HCMV-specificity for cytokine production, proliferation and expression of phenotype markers unique of T cell activation. The results suggested the potential of the engineered bispecific antibodies such as the construct described here as a prophylactic or therapeutic agent against HCMV reactivation and infection.

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A CTG clade Candida yeast genetically engineered for the genotype-phenotype characterization of azole antifungal resistance in human pathogenic yeasts [PublishAheadOfPrint]

A strain of the opportunistic pathogenic yeast Candida lusitaniae was genetically modified for its use as a cellular model for assessing by allele replacement the impact of lanosterol C14α-demethylase ERG11 mutations on azole resistance. Candida lusitaniae was chosen because it is susceptible to azole antifungals, it belongs to the CTG clade of yeast which includes most of the Candida species pathogenic for humans, and it is haploid and easily amenable to genetic transformation and molecular modeling. In this work, allelic replacement is targeted at the ERG11 locus by the reconstitution of a functional auxotrophic marker in the 3' intergenic region of ERG11. Homologous and heterologous ERG11 alleles are expressed from the resident ERG11 promoter of C. lusitaniae, allowing accurate comparison of the phenotypic change in azole susceptibility. As a proof of concept, we successfully expressed in C. lusitaniae different ERG11 alleles – bearing or not mutations retrieved from clinical context - from two phylogenetically distant yeasts, C. albicans and Kluyveromyces marxianus. Candida lusitaniae constitutes a high fidelity expression system, giving specific Erg11p-dependent fluconazole MICs very close to those observed with the ERG11 donor strain. This work led to characterize the phenotypic effect of two kinds of mutation: mutation conferring decreased fluconazole susceptibility in a species-specific manner, and mutation conferring fluconazole resistance in several yeast species. In particular, a missense mutation affecting the amino acid K143 of Erg11p in Candida species, and the equivalent position K151 in K. marxianus, plays a critical role in fluconazole resistance.

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Activity of Meropenem-Vaborbactam Against Carbapenem-resistant Enterobacteriaceae in a Murine Model of Pyelonephritis [PublishAheadOfPrint]

The recently approved combination of meropenem-vaborbactam (Vabomere™) is highly active against Gram-negative pathogens, especially KPC-producing, carbapenem-resistant Enterobacteriaceae. We evaluated the efficacy of meropenem-vaborbactam against three clinically relevant isolates in a murine polynephritis model. Data indicated that the combination of meropenem-vaborbactam significantly increased the bacterial killing compared to the untreated controls. These data suggest that this combination may have utility in the treatment of complicated urinary tract infections due to KPC-producing, carbapenem-resistant Enterobacteriaceae.

http://ift.tt/2yrkDMl

Thrombocytopenia with tedizolid and linezolid [PublishAheadOfPrint]

Several studies have suggested the risk of thrombocytopenia with tedizolid, a second-in-class oxazolidinone antibiotic (approved 06/2014), is less than that observed with linezolid (first-in-class oxazolidinone). Using data from the Food and Drug Administration Adverse Event Reporting System (07/2014-12/2016), we observed a significantly increased risk of thrombocytopenia of similar magnitude with both antibiotics: linezolid reporting odds ratio [ROR] 37.9 (95% confidence interval [CI] 20.78-69.17); tedizolid ROR 34.0 (95% CI 4.67- 247.30).

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Pharmacokinetic Modelling of Voriconazole to Develop an Alternative Dosing Regimen in Children [PublishAheadOfPrint]

Background. The pharmacokinetic variability of voriconazole in immunocompromised children is high and adequate exposure, particularly in the first days of therapy, is uncertain.

Methods. A population pharmacokinetic model was developed to explore VCZ exposure in plasma after alternative dosing regimens. Concentration data were obtained from a pediatric phase II study. Non-linear mixed effects modelling was used to develop the model. Monte Carlo simulations were performed to test an array of three times daily (TID) intravenous dosing regimens in children 2 to 12 years of age.

Results. A two compartment model with first order absorption, non-linear Michaelis-Menten elimination and allometric scaling best described the data (V_max= 51.5 mg/h/70 kg, V₁= 228 L/70 kg, Q= 21.9 L/h/70 kg, V₂= 1430 L/70 kg, F= 59.4%, K_m fixed to 1.15 mg/L, K_a fixed to 1.19 h^-1). Inter-individual variabilities were 63.6%, 45.4%, 67% and 1.34 on logit scale for V_max, V₁, Q and F, respectively, and residual variability was 37.8% (proportional error) and 0.0049 mg/L (additive error). Monte Carlo simulations of a regimen of 9 mg/kg TID simulated for 24, 48 and 72 h followed by 8 mg/kg twice daily (BID) resulted in improved early target attainment relative to the currently recommended BID dosing regimen but no increased rate of accumulation thereafter.

Conclusions. Pharmacokinetic modelling suggests that intravenous TID dosing at 9 mg/kg per dose for up to 3 days may result in a substantially higher percentage of children 2 to 12 years of age with adequate exposure of VCZ early during treatment. Before implementation of this regimen in patients, however, validation of exposure, safety and tolerability in a carefully designed clinical trial would be needed.

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Putative Integrative Mobile Elements that exploit the Xer Recombination Machinery Carrying blaIMI-type Carbapenemase Genes in the Enterobacter cloacae complex in Singapore [PublishAheadOfPrint]

Whole genome sequencing was performed on 16 isolates of carbapenemase-producing Enterobacter cloacae complex to determine the flanking regions of bla_IMI-type genes. Phylogenetic analysis of MLST targets separated the isolates into 4 clusters. The bla_IMI-type genes were all found on IMEX elements. The IMEX elements of 5 isolates were similar to those described in Canada, while the remainder were novel. Five isolates had IMEX elements lacking a resolvase and recombinase.

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In Vivo Bioluminescent Monitoring of Therapeutic Efficacy and Pharmacodynamic Target Assessment of Antofloxacin against Escherichia coli in a Neutropenic Murine Thigh Infection Model [PublishAheadOfPrint]

Antimicrobial resistance among uropathogens has increased infection-related morbidity and mortality. Antofloxacin is a novel fluoroquinolone with broad-spectrum antibacterial activity against urinary Gram-negative bacilli such as Escherichia coli. This study monitored the in vivo efficacy of antofloxacin using bioluminescence imaging and determined pharmacokinetic/pharmacodynamic (PK/PD) targets against E. coli isolates in a neutropenic murine thigh infection model. The PK properties were performed after subcutaneous antofloxacin administration of 2.5, 10, 40 and 160 mg/kg. Following thigh infection, mice were treated with 2-fold-increasing doses of antofloxacin from 2.5 to 80 mg/kg administered every 12 hours. Efficacy was assessed by quantitative bacterial burdens in thigh homogenates and was compared with bioluminescent density. Antofloxacin demonstrated both static and killing endpoints in relation to the initial burden against all study strains. The PK/PD index AUC/MIC correlated well with efficacy (R²=0.92), and the dose-response relationship was relatively steep as observed with escalating doses of antofloxacin. The mean free drug AUC/MIC targets necessary to produce a net bacterial stasis, 1-log₁₀ and 2-log₁₀ kill for each isolate were 38.7, 66.1 and 147.0 h, respectively. In vivo bioluminescence imaging showed a rapid decrease in bioluminescent density at free drug AUC/MIC exposures that exceeded the stasis targets. The integration of these PD targets combined with PK studies from humans will be useful in setting optimal dosing regimens for treatment of urinary tract infections due to E. coli.

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Fidaxomicin and OP-1118 inhibit C. difficile toxin A- and B-mediated inflammatory responses via inhibition of NF-{kappa}B activity. [PublishAheadOfPrint]

Objective: Clostridium difficile causes diarrhea and colitis by releasing toxin A and toxin B. In the human colon, both toxins cause intestinal inflammation and stimulate TNFα expression via activation of NF-B. It is well established that the macrolide antibiotic fidaxomicin is associated with reduced relapses of C. difficile infection. We showed that fidaxomicin and its primary metabolite, OP-1118, significantly inhibited toxin A-mediated intestinal inflammation in mice in vivo and toxin A-induced cell rounding in vitro. We aim to determine whether fidaxomicin and OP-1118 possess anti-inflammatory effects against toxin A and toxin B in the human colon and examine the mechanism of this response. Design: We used fresh human colonic explants, NCM460 human colonic epithelial cells, and RAW264.7 mouse macrophages to study the mechanism of fidaxomicin and OP-1118 against toxin A- and B-mediated cytokine expression and apoptosis. Results: Fidaxomicin and OP-1118 dose-dependently inhibited toxin A- and B-induced TNFα and IL-1β mRNA expression and histological damage in human colonic explants. Fidaxomicin and OP-1118 inhibited toxin A-mediated NF-B phosphorylation in human and mouse intestinal mucosa. Fidaxomicin and OP-1118 also inhibited toxin A-mediated NF-B phosphorylation and TNFα expression in macrophages, which was reversed by the NF-B activator PMA. Fidaxomicin and OP-1118 prevented toxin A- and B-mediated apoptosis in NCM460 cells, which was reversed by the addition of the PMA. PMA reversed the cytoprotective effect of fidaxomicin and OP-1118 in toxin-exposed human colonic explants. Conclusion: Fidaxomicin and OP-1118 inhibit C. difficile toxin A- and B-mediated inflammatory responses, NF-B phosphorylation, and tissue damage in human colon.

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Evaluation of Antifungal efficacy of three new cyclic lipopeptides of the class Bacillomycin from Bacillus subtilis RLID 12.1 [PublishAheadOfPrint]

New lipopeptide homologues (AF₃, AF₄ and AF₅) with antifungal activities against Candida and Cryptococcus spp. were purified from the cell free supernatant of Bacillus subtilis RLID 12.1. The lipopeptides AF₃, AF₄ and AF₅ were identified with the same peptide sequence Asn-Pro-Tyr-Asn-Gln-Thr-Ser with variations in the fatty acid branching type and chain length (anteiso-C₁₇, iso-C₁₇ and iso-C₁₈ respectively). Comparing the three homologues for minimum inhibitory concentrations (MIC) against 81 Candida (64 no.) and Cryptococcus (17 no.) clinical isolates and its cytotoxicity, AF₄ was found as the most promising antifungal lipopeptide which exhibited MIC_g of 3.31, 3.41, 3.48 and 2.83 μg/mL showing 100% inhibition against Candida albicans, Candida tropicalis, Candida auris and Cryptococcus neoformans respectively with low hemolysis value (<6%) and IC₅₀ values (13.31 μg/mL). The additive effects among the homologues AF₃, AF₄ and AF₅ were evaluated against 3 Candida species along with the cytotoxicity studies. Five combinations exhibited good additive interaction effects: AF₃, AF₄ (4, 4 μg/mL), AF₃, AF₅ (4, 4 μg/mL), AF₃, AF₅ (2, 4 μg/mL) AF₄, AF₅ (4, 4 μg/mL) and AF₄, AF₅ (2, 4 μg/mL) in planktonic cell inhibition and AF₃, AF₄ (4, 4 μg/mL), AF₃, AF₅ (4, 4 μg/mL) and AF₃, AF₅ (2, 4 μg/mL) in the inhibition of biofilm formation. However the combinations (AF₃, AF₄) and (AF₃, AF₅) showing >70% cell survival with low hemolysis (<5%) were found to be comparatively effective. To date this is the first study which describes the additive effects of lipopeptide homologues showing reduced cytotoxicity against mammalian cells and the combination might serve as a potent anti-biofilm forming substitute.

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Reduced chlorhexidine and daptomycin susceptibility in vancomycin-resistant Enterococcus faecium after serial chlorhexidine exposure [PublishAheadOfPrint]

Vancomycin-resistant Enterococcus faecium (VREfm) are critical public health concerns because they are among the leading causes of hospital-acquired bloodstream infections. Chlorhexidine (CHX) is a bisbiguanide cationic antiseptic that is routinely used for patient bathing and other infection control practices. VREfm are likely frequently exposed to CHX; however, the long-term effects of CHX exposure have not been studied in enterococci. In this study, we serially exposed VREfm to increasing concentrations of CHX for a period of 21 days in two independent experimental evolution trials. Reduced CHX susceptibility emerged (4-fold shift in CHX MIC). Sub-populations with reduced daptomycin (DAP) susceptibility were detected, which were further analyzed by genome sequencing and lipidomic analysis. Across the trials, we identified adaptive changes in genes with predicted or experimentally confirmed roles in chlorhexidine susceptibility (efrE), global nutritional stress response (relA), nucleotide metabolism (cmk), phosphate acquisition (phoU), and glycolipid biosynthesis (bgsB), among others. Moreover, significant alterations in membrane phospholipids were identified for some populations with reduced DAP susceptibility. Our results are clinically significant because they identify a link between serial sub-inhibitory CHX exposure and reduced DAP susceptibility. In addition, the CHX-induced genetic and lipidomic changes described in this study offer new insights into the mechanisms underlying the emergence of antibiotic resistance in VREfm.

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A Retrospective Analysis of Treatment and Clinical Outcomes among Patients with Methicillin-susceptible Staphylococcus aureus Bloodstream Isolates Possessing Detectable mecA by a Commercial PCR Assay Compared to Patients with Methicillin-resistant Staphylococcus aureus Bloodstream Isolates [PublishAheadOfPrint]

mecA-positive Staphylococcus aureus isolates phenotypically susceptible to cefoxitin (mecA-MSSA) have been identified. We describe treatment and outcomes among patients with mecA-MSSA bloodstream infections (BSI) and MRSA BSI patients matched 1:1 on age, BSI origin and BSI type (n=17 per group). Compared to MRSA BSI patients, mecA-MSSA BSI patients more often experienced clinical failure (58.8% and 11.8%, p=0.010), driven largely by persistent bacteremia (35.3% and 11.8%). mecA-MSSA BSI patients may be at higher risk for poor clinical outcomes.

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Population Pharmacokinetic Analysis of Cefiderocol, a Parenteral Siderophore Cephalosporin, in Healthy Subjects, Subjects with Varying Renal Function, and Patients with Complicated Urinary Tract Infection or Acute Uncomplicated Pyelonephritis [PublishAheadOfPrint]

Cefiderocol, a novel parenteral siderophore cephalosporin, exhibits potent efficacy against most Gram-negative bacteria including carbapenem-resistant strains. The aim of this study is to perform a population pharmacokinetic (PK) analysis based on plasma cefiderocol concentrations in healthy subjects, subjects with varying renal function, and patients with complicated urinary tract infection (cUTI) or acute uncomplicated pyelonephritis (AUP) caused by Gram-negative pathogens, and to calculate the fraction of time during the dosing interval where the free drug concentration in plasma exceeds the minimum inhibitory concentration (MIC) (fT>MIC).

Population PK models were developed with three renal function markers; body-surface-area-adjusted estimated glomerular filtration rate (eGFR), absolute eGFR, and creatinine clearance based on 2571 plasma concentration data from 91 subjects without infection and 238 patients with infection. The population PK models with each renal function marker adequately described plasma cefiderocol concentrations. Clear relationships of total clearance (CL) to all renal function markers were observed. Body weight and the disease status (with or without infection) were also significant covariates. The CL in patients with infection was 26% higher than that in subjects without infection. The fT>MIC values were more than 75% in all patients (100% in most patients), suggesting a sufficient exposure to cefiderocol was provided by the tested dose regimen (2 g q8hr as the standard dose regimen) for the treatment of cUTI or AUP caused by Gram-negative pathogens.

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Severe infusion-related adverse events and renal failure in patients receiving high-dose intravenous polymyxin B [PublishAheadOfPrint]

Very high doses of polymyxin B (PMB) have been addressed in in vitro experiments against carbapenem-resistant Gram-negative bacilli as a strategy to improve bacterial killing and suppress resistance emergence. However, the toxicities of very high doses in patients are unknown. This is a retrospective cohort study assessing patients receiving >3mg/kg/day or a total dose ≥250mg/day of PMB. The main outcomes were severe infusion-related adverse event according to Common Terminology Criteria for Adverse Criteria and renal failure category of RIFLE criteria for acute kidney injury (AKI) during treatment. A total of 222 were included for analysis of infusion-related events. The mean PMB dose was 3.61±0.97mg/kg/day (median total dose/day=268 mg). Severe infusion-related adverse events occurred in two patients determining an incidence of 0.9% (95% Confidence Interval, 0.2-3.2): one was classified as a life-threatening and one as severe adverse effect. Renal failure was analyzed in 115 patients: 25 (21.7%) patients presented renal failure (54 [47.0%] developed any degree of AKI, categorized as Risk [27.8%]; Injury [25.9%] and Failure [46.3%]). Vasoactive drug, concomitant nephrotoxic drugs and baseline creatinine clearance were independent risk factors for renal failure. Neither PMB daily dose scaled by body weight nor total daily dose were associated with renal failure. In-hospital mortality was 60% (134 patients): 26% (57 patients) occurred during treatment and none during infusion. Our data suggest that high dose schemes have acceptable safety profile and could be further tested in clinical trials assessing strategies to improve patients' outcomes and minimize the emergence of PMB resistance.

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Regression of an intramedullary spinal cord metastasis with a checkpoint inhibitor: a case report

CNS Oncology, Ahead of Print.

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Spontaneous isolated dissection of the superior mesenteric artery and aneurysm formation resulting from segmental arterial mediolysis: a case report

Spontaneous isolated dissection of the superior mesenteric artery (SMA) can lead to bowel ischemia, aneurysm rupture, or even death. Studies have suggested that mechanical or hemodynamic stress on the vascular...

http://ift.tt/2zfDEAq

Potentially inappropriate prescribing and its association with health outcomes in middle-aged people: a prospective cohort study in Ireland

Objectives

To determine the prevalence of potentially inappropriate prescribing (PIP) in a cohort of community-dwelling middle-aged people and assess the relationship between PIP and emergency department (ED) visits, general practitioner (GP) visits and quality of life (QoL).

Design

Prospective cohort study.

Setting

The Irish Longitudinal Study on Ageing (TILDA), a nationally representative cohort study of ageing.

Participants

Individuals aged 45–64 years recruited to TILDA who were eligible for the means-tested General Medical Services scheme and followed up after 2 years.

Exposure

PIP was determined in the 12 months preceding baseline and follow-up TILDA data collection by applying the PRescribing Optimally in Middle-aged People's Treatments (PROMPT) criteria to participants' medication dispensing data.

Outcome measures

At follow-up, the reported rates of ED and GP visits over 12 months (primary outcome) and the CASP-R12 (Control Autonomy Self-realisation Pleasure) measure of QoL (secondary outcome).

Analysis

Multivariate negative binomial (rates) and linear regression (CASP-R12) models controlling for potential confounders.

Results

At 2-year follow-up (n=808), PIP was detected in 42.9% by the PROMPT criteria. An ED visit was reported by 18.7% and 94.4% visited a GP (median 4 visits, IQR 2–6). Exposure to ≥2 PROMPT criteria was associated with higher rates of healthcare utilisation and lower QoL in unadjusted regression. However, in multivariate analysis, the associations between PIP and rates of ED visits (adjusted incidence rate ratio (IRR) 0.92, 95% CI 0.53 to 1.58), and GP visits (IRR 1.06, 95% CI 0.87 to 1.28), and CASP-R12 score (adjusted β coefficient 0.35, 95% CI –0.93 to 1.64) were not statistically significant. Numbers of medicines and comorbidities were associated with higher healthcare utilisation.

Conclusions

Although PIP was prevalent in this study population, there was no evidence of a relationship with ED and GP visits and QoL. Further research should evaluate whether the PROMPT criteria are related to these and other adverse outcomes in the general middle-aged population.

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Better early functional outcome after short stem total hip arthroplasty? A prospective blinded randomised controlled multicentre trial comparing the Collum Femoris Preserving stem with a Zweymuller straight cementless stem total hip replacement for the treatment of primary osteoarthritis of the hip

Objectives

Primary aim was to compare the functional results at 3 months and 2 years between short and conventional cementless stem total hip arthroplasty (THA). Secondary aim was to determine the feasibility of a double-blind implant-related trial.

Design

A prospective blinded randomised controlled multicentre trial in patients with osteoarthritis of the hip. All patients, research assistants, clinical assessors, investigators and data analysts were blinded to the type of prosthesis. Population: 150 patients between 18 and 70 years with osteoarthritis of the hip, 75 in the short stem and 75 in the conventional stem group. Mean age: 60 years (SD 7). Interventions: the Collum Femoris Preserving short stem versus the Zweymuller Alloclassic conventional stem.

Main outcome measures

The Dutch version of the Hip Disability and Osteoarthritis Outcome Score (HOOS). Secondary outcomes measures: Harris Hip Score, the Physical Component Scale of the SF12, the Timed Up and Go test, Pain and the EQ-5D. Feasibility outcomes: continued blinding, protocol adherence and follow-up success rate.

Results

No significant difference between the two groups. Mean HOOS total score in the short stem group increased 32.7 points from 36.6 (95% CI 32.9 to 40.2) preoperatively to 69.3 (95% CI 66.4 to 72.1) at 3 months follow-up. Mean HOOS total score in the conventional straight stem group increased 36.3 points from 37.1 (95% CI 33.9 to 40.3) preoperatively to 73.4 (95% CI 70.3 to 76.4) at 3 months follow-up. 91.2% of patients remained blinded at 2 years follow-up. Both protocol adherence and follow-up success rate were 98%.

Conclusions

Functional result at 3 months and 2 years after short stem THA is not superior to conventional cementless THA. There were more perioperative and postoperative complications in the short stem group. Direct comparison of two hip implants in a double-blinded randomised controlled trial is feasible.

Trial registration number

NTR1560.

http://ift.tt/2kSo8s9

Is overseas volunteering beneficial to the NHS? The analysis of volunteers responses to a feedback questionnaire following experiences in low-income and middle-income countries

Introduction

Locally requested and planned overseas volunteering in low-income and middle-income countries by National Health Service (NHS) staff can have benefits for the host or receiving nation, but its impact on the professional development of NHS staff is not proven. The Knowledge and Skills Framework (KSF) and Leadership Framework (LF) are two tools used by employers as a measure of individuals' development. We have used dimensions from both tools as a method of evaluating the benefit to NHS doctors who volunteer overseas.

Methods

88 NHS volunteers participating with local colleagues in Primary Trauma Care and orthopaedic surgical training courses in sub-Saharan Africa were asked to complete an online self-assessment questionnaire 6 months following their return to the UK. The survey consisted of questions based on qualities outlined in both the KSF and LF.

Results

85 completed responses to the questionnaire were received. In every KSF domain assessed, the majority of volunteers agreed that their overseas volunteering experience improved their practice within the NHS. Self-assessed pre-course and post-course scores evaluating the LF also saw a universal increase, notably in the 'working with others' domain.

Discussion

There is a growing body of literature outlining the positive impact of overseas volunteering on NHS staff. Despite increasing evidence that such experiences can develop volunteers' essential skills, individuals often find it difficult to gain support of their employers. Our study, in line with the current literature, shows that overseas volunteering by NHS staff can provide an opportunity to enhance professional and personal development. Skills gained from volunteering within international links match many of the qualities outlined in both KSF and LF, directly contributing to volunteers' continued professional development.

http://ift.tt/2xKEvgk

Awareness and willingness towards pre-exposure prophylaxis against HIV infection among individuals seeking voluntary counselling and testing for HIV in Taiwan: a cross-sectional questionnaire survey

Objectives

We aimed to investigate the awareness and willingness towards pre-exposure prophylaxis (PrEP) among individuals seeking voluntary counselling and testing (VCT) for HIV in Taiwan, where PrEP is currently not reimbursed by the insurance.

Methods

Between April and October 2016, a questionnaire interview was conducted among VCT clients to inquire about the attitudes towards PrEP against HIV infection. Multivariate logistic regression analysis was performed to identify the associated factors with willingness to initiate PrEP.

Results

During the 6-month period, 1173 VCT clients (99.8%) completed the interviews, with 67.4% being homosexual or bisexual male. While 67.2% of the clients knew of postexposure prophylaxis, 40.2% heard of PrEP. Overall, 546 clients (46.5%) were willing to initiate PrEP and 89.5% of them would choose event-driven PrEP. In multivariate analysis, male gender (OR 1.796; 95% CI 1.165 to 2.768), full-time job (OR 1.354; 95% CI 1.052 to 1.742), one-night stand (OR 1.374; 95% CI 1.043 to 1.810), having casual sex partners within 3 months (OR 1.329; 95% CI 1.031 to 1.714), condomless anal sex (OR 1.405; 95% CI 1.122 to 1.878) and ever having chemsex or attending a drug party in the past 1 year (OR 2.571; 95% CI 1.541 to 4.287), regular screening for HIV infection (OR 1.321; 95% CI 1.021 to 1.711) and knowledge of PrEP (OR 1.504; 95% CI, 1.159 to 1.953) were associated with willingness to initiate PrEP.

Conclusions

Understanding the willingness to initiate PrEP against HIV among the VCT clients in Taiwan, which was associated with male gender, risky sexual behaviours and awareness of PrEP, will help inform the implementation of PrEP programme.

http://ift.tt/2xKU6MY

Drugs and life-threatening ventricular arrhythmia risk: results from the DARE study cohort

Objectives

To establish a unique sample of proarrhythmia cases, determine the characteristics of cases and estimate the contribution of individual drugs to the incidence of proarrhythmia within these cases.

Setting

Suspected proarrhythmia cases were referred by cardiologists across England between 2003 and 2011. Information on demography, symptoms, prior medical and drug histories and data from hospital notes were collected.

Participants

Two expert cardiologists reviewed data for 293 referred cases: 130 were included. Inclusion criteria were new onset or exacerbation of pre-existing ventricular arrhythmias, QTc >500 ms, QTc >450 ms (men) or >470 ms (women) with cardiac syncope, all secondary to drug administration. Exclusion criteria were acute ischaemia and ischaemic polymorphic ventricular tachycardia at presentation, structural heart disease, consent withdrawn or deceased prior to study. Descriptive analysis of Caucasian cases (95% of included cases, n=124) and culpable drug exposures was performed.

Results

Of the 124 Caucasian cases, 95 (77%) were QTc interval prolongation-related; mean age was 62 years (SD 15), and 63% were female. Cardiovascular comorbidities included hypertension (53%) and patient-reported 'heart rhythm problems' (73%). Family history of sudden death (36%) and hypokalaemia at presentation (27%) were common. 165 culpable drug exposures were reported, including antiarrhythmics (42%), of which amiodarone and flecainide were the most common. Sotalol, a beta-blocking agent with antiarrhythmic activity, was also common (15%). 26% reported multiple drugs, of which 84% reported at least one cytochrome (CYP) P450 inhibitor. Potential pharmacodynamics interactions identified were mainly QT prolongation (59%).

Conclusions

Antiarrhythmics, non-cardiac drugs and drug combinations were found to be culpable in a large cohort of 124 clinically validated proarrhythmia cases. Potential clinical factors that may warn the prescriber of potential proarrhythmia include older women, underlying cardiovascular comorbidity, family history of sudden death and hypokalaemia.

http://ift.tt/2xLHPYP

Emotional reactions in parents of the youth who experienced the Utoya shooting on 22 July 2011; results from a cohort study

Objective and setting

The objective of this study was to provide knowledge about the emotional reactions in parents whose offspring experienced a mass shooting on Utøya island in Norway in 2011. The research questions included whether parents' reactions were influenced by their offspring's symptom level, age, living situation and parental gender.

Design

The study was designed as an open cohort study. The data were collected at two time points; 4–5 months and 14–15 months after the shooting.

Participants

The participants were 531 parents of youth exposed to the Utøya island attack.

Outcome measures

The Parental Emotional Reaction Questionnaire measured parents' reactions, and University of California, Los Angeles Post-traumatic Stress Disorder Reaction Index measured youths' post-traumatic stress symptoms.

Results

Parental emotional reactions were positively related to post-traumatic stress reactions in offspring at wave 1: Est.=0.20, 95% CI 0.10 to 0.30, p<0.001, over time (wave 1and wave 2 nested within individuals): Est.=0.23, CI 0.13 to 0.32, p<0.001, and at wave 2: Est.=0.26, CI 0.12 to 0.39, p<0.001. Youths' age was not significantly related to parental emotional reactions, neither at wave 1: Est.=0.19, CI –0.40 to 0.77, p=0.531, over time: Est.=0.26, CI –0.27 to 0.79, p=328, nor at wave 2: Est.=0.32, CI –0.41 to 1.05, p=0.389. Mothers were more emotionally upset than fathers both at wave 1: Est.=–5.66, CI –7.63 to –3.69, p<0.001, over time: Est.=–5.36, CI –7.18 to –3.55, p<0.001, and at wave 2: Est.=–5.33, CI –7.72 to –2.53, p<0.001.

Conclusions

The findings suggest that parenting after trauma should be addressed in outreach programmes and in planning of healthcare services.

http://ift.tt/2kUf2en

Effectiveness of an electronic patient-centred self-management tool for gout sufferers: a cluster randomised controlled trail protocol

Introduction

Gout is increasing despite effective therapies to lower serum urate concentrations to 0.36 mmol/L or less, which, if sustained, significantly reduces acute attacks of gout. Adherence to urate-lowering therapy (ULT) is poor, with rates of less than 50% 1 year after initiation of ULT. Attempts to increase adherence in gout patients have been disappointing. We aim to evaluate the effectiveness of use of a personal, self-management, 'smartphone' application (app) to achieve target serum urate concentrations in people with gout. We hypothesise that personalised feedback of serum urate concentrations will improve adherence to ULT.

Methods and analysisSetting and design

Primary care. A prospective, cluster randomised (by general practitioner (GP) practices), controlled trial.

Participants

GP practices will be randomised to either intervention or control clusters with their patients allocated to the same cluster.

Intervention

The intervention group will have access to the Healthy.me app tailored for the self-management of gout. The control group patients will have access to the same app modified to remove all functions except the Gout Attack Diary.

Primary and secondary outcomes

The proportion of patients whose serum urate concentrations are less than or equal to 0.36 mmol/L after 6 months. Secondary outcomes will be proportions of patients achieving target urate concentrations at 12 months, ULT adherence rates, serum urate concentrations at 6 and 12 months, rates of attacks of gout, quality of life estimations and process and economic evaluations. The study is designed to detect a ≥30% improvement in the intervention group above the expected 50% achievement of target serum urate at 6 months in the control group: power 0.80, significance level 0.05, assumed 'dropout' rate 20%.

Ethics and dissemination

This study has been approved by the University of New South Wales Human Research Ethics Committee. Study findings will be disseminated in international conferences and peer-reviewed journal.

Trial registration number

ACTRN12616000455460.

http://ift.tt/2xKTtmA

'What does that mean?: a qualitative exploration of the primary and secondary clinical care experiences of young people with continence problems in the UK

Objectives

To explore the clinical care experiences of young people with continence problems.

Design

In-depth semistructured qualitative interviews were conducted by Skype and telephone, with the addition of art-based participatory research techniques. Transcripts were analysed using inductive thematic analysis.

Setting

Primary and secondary care in the UK.

Participants

We interviewed 20 participants (9 females, 11 males) aged 11–20 years. There were six participants with bedwetting alone, five with daytime wetting alone, five with combined (day and night) wetting and four with soiling.

Results

We identified four themes: appointment experiences, treatment experiences, engagement with treatment and internalisation and externalisation of the continence problem. Patient-focused appointments using age-appropriate language were highly desirable. Continuity of care was highlighted as an important aspect of positive clinical experiences; however, this was found to be rare with many participants seeing a different person on each visit. Participants had tried a wide range of treatments for their continence problems with varying degrees of success. Relapse and treatment failure were common. Experiencing relapse was distressing and diminished participants' belief in the success of future treatments and undermined adherence. Participants would be seen to adopt two opposing coping strategies for dealing with their continence problem— internalisation and externalisation.

Conclusion

Incontinence in young people is challenging to manage. Young people may need to try a range of treatments before their symptoms improve. Due to challenges in treatment, there is an increased risk of poor adherence. During patient-focused appointments, clinicians should work to build rapport with patients and use age-appropriate language. Involving young people in their own care decisions is important. The way in which young people understand their continence problem can influence their coping strategies and adherence to treatment regimes.

http://ift.tt/2xKw4lo

Effect of point-of-care susceptibility testing in general practice on appropriate prescription of antibiotics for patients with uncomplicated urinary tract infection: a diagnostic randomised controlled trial

Objectives

To investigate the effect of adding point-of-care (POC) susceptibility testing to POC culture on appropriate use of antibiotics as well as clinical and microbiological cure for patients with suspected uncomplicated urinary tract infection (UTI) in general practice.

Design

Open, individually randomised controlled trial.

Setting

General practice.

Participants

Women with suspected uncomplicated UTI, including elderly patients above 65, patients with recurrent UTI and patients with diabetes. The sample size calculation predicted 600 patients were needed.

Interventions

Flexicult SSI-Urinary Kit was used for POC culture and susceptibility testing and ID Flexicult was used for POC culture only.

Main outcome measures

Primary outcome: appropriate antibiotic prescribing on the day after consultation defined as either (1) patient with UTI: to prescribe a first-line antibiotic to which the infecting pathogen was susceptible or a second line if a first line could not be used or (2) patient without UTI: not to prescribe an antibiotic. UTI was defined by typical symptoms and significant growth in a reference urine culture performed at one of two external laboratories.

Secondary outcomes: clinical cure on day five according to a 7-day symptom diary and microbiological cure on day 14. Logistic regression models taking into account clustering within practices were used for analysis.

Results

20 general practices recruited 191 patients for culture and susceptibility testing and 172 for culture only. 63% of the patients had UTI and 12% of these were resistant to the most commonly used antibiotic, pivmecillinam. Patients randomised to culture only received significantly more appropriate treatment (OR: 1.44 (95% CI 1.03 to 1.99), p=0.03). There was no significant difference in clinical or microbiological cure.

Conclusions

Adding POC susceptibility testing to POC culture did not improve antibiotic prescribing for patients with suspected uncomplicated UTI in general practice. Susceptibility testing should be reserved for patients at high risk of resistance and complications.

Trial registration number

NCT02323087; Results.

http://ift.tt/2xKgTZj

Non-invasive brain stimulation interventions for management of chronic central neuropathic pain: a scoping review protocol

Introduction

Pain can affect people regardless of age, gender or ethnicity. Chronic central neuropathic pain (CCNP) is a debilitating condition that affects populations such as stroke survivors, amputees, spinal cord injury patients and patients with multiple sclerosis, with prevalence rates between 30% and 80%. This condition can be caused by a lesion or disease affecting the somatosensory system. CCNP is notoriously drug resistant, and few effective CCNP treatment or management strategies exist. The emergence of non-invasive brain stimulation and neuromodulation techniques provide novel avenues for managing chronic central neuropathic pain. This scoping review aims to systematically identify the methods and effectiveness of non-invasive brain stimulation techniques for treating and managing chronic central neuropathic pain.

Methods and analysis

The following databases will be searched systematically: PubMed, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Institute of Electric and Electronic Engineers (IEEE), Association of Computing Machinary (ACM) and Scopus. Additional literature will be identified by searching the reference lists of identified studies. Studies will include reviews and original research in both published and grey literatures. Two reviewers will independently screen identified studies for final inclusion. A quantitative analysis on the intervention type, application and efficacy will be synthesised along with a qualitative analysis to describe the effectiveness of each intervention.

Ethics and dissemination

No primary data will be collected and hence formal ethics review is not required. The results of the scoping review will be presented at relevant national and international conferences, published in a peer-reviewed journal and provided to the stakeholders with plain language to be posted on their websites. This scoping review will provide a foundation to guide the development of future primary research on non-invasive brain stimulation and CCNP.

http://ift.tt/2kSnYkx

Effectiveness and meaningful use of paediatric surgical safety checklists and their implementation strategies: a systematic review with narrative synthesis

Objective

To examine the effectiveness and meaningful use of paediatric surgical safety checklists (SSCs) and their implementation strategies through a systematic review with narrative synthesis.

Summary background data

Since the launch of the WHO SSC, checklists have been integrated into surgical systems worldwide. Information is sparse on how SSCs have been integrated into the paediatric surgical environment.

Methods

A broad search strategy was created using Pubmed, Embase, CINAHL, Cochrane Central, Web of Science, Science Citation Index and Conference Proceedings Citation Index. Abstracts and full texts were screened independently, in duplicate for inclusion. Extracted study characteristic and outcomes generated themes explored through subgroup analyses and idea webbing.

Results

1826 of 1921 studies were excluded after title and abstract review (kappa 0.77) and 47 after full-text review (kappa 0.86). 20 studies were of sufficient quality for narrative synthesis. Clinical outcomes were not affected by SSC introduction in studies without implementation strategies. A comprehensive SSC implementation strategy in developing countries demonstrated improved outcomes in high-risk surgeries. Narrative synthesis suggests that meaningful compliance is inconsistently measured and rarely achieved. Strategies involving feedback improved compliance. Stakeholder-developed implementation strategies, including team-based education, achieved greater acceptance. Three studies suggest that parental involvement in the SSC is valued by parents, nurses and physicians and may improve patient safety.

Conclusions

A SSC implementation strategy focused on paediatric patients and their families can achieve high acceptability and good compliance. SSCs' role in improving measures of paediatric surgical outcome is not well established, but they may be effective when used within a comprehensive implementation strategy especially for high-risk patients in low-resource settings.

http://ift.tt/2kUeTrl

Association between malignancies and Marfan syndrome: a population-based, nested case-control study in Taiwan

Objective

Marfan syndrome (MFS) involves a deficiency of the structural extracellular matrix component fibrillin-1 and overactivation of the transforming growth factor-β (TGF-β) signalling pathway. The TGF-β signalling pathway also actively participates in malignant transformation. Although anecdotal case reports have suggested associations between MFS/MFS-like conditions and several haematological and solid malignancies, such associations have not been thoroughly evaluated in large-scale studies. We sought to use a nationwide healthcare insurance claim database to evaluate whether patients with MFS are at increased risk of malignancy.

Patients and methods

We conducted a nested case–control analysis using a database extracted from Taiwan's National Health Insurance Research Database. All medical conditions for each case and control were categorised using the International Classification of Diseases, 9th Revision classifications. ORs and 95% CIs for associations between MFS and malignancies were estimated using conditional logistic regression and adjusted for comorbidities.

Results

Our analyses included 1 153 137 cancer cases and 1 153 137 propensity score-matched controls. Relative to other subjects, patients with MFS had a significantly higher risk of having a malignancy (adjusted OR 3.991) and hypertension (adjusted OR 1.964) and were significantly more likely to be men. Malignancies originating from the head and neck and the urinary tract were significantly more frequent among patients with MFS than among subjects without MFS.

Conclusion

Patients with MFS are at increased risk of developing various malignancies. Healthcare professionals should be aware of this risk when treating such patients, and increased cancer surveillance may be necessary for these patients.

http://ift.tt/2kYeWTh

Association between polypharmacy and falls in older adults: a longitudinal study from England

Objectives

Assess the longitudinal association between polypharmacy and falls and examine the differences in this association by different thresholds for polypharmacy definitions in a nationally representative sample of adults aged over 60 years from England.

Design

Longitudinal cohort study.

Setting

The English Longitudinal Study of Ageing waves 6 and 7.

Participants

5213 adults aged 60 or older.

Main outcome measures

Rates, incidence rate ratio (IRR) and 95% CI for falls in people with and without polypharmacy.

Results

A total of 5213 participants contributed 10 502 person-years of follow-up, with a median follow-up of 2.02 years (IQR 1.9–2.1 years). Of the 1611 participants with polypharmacy, 569 reported at least one fall within the past 2 years (rate: 175 per 1000 person-years, 95% CI 161 to 190), and of the 3602 participants without polypharmacy 875 reported at least one fall (rate: 121 per 1000 person-years, 95% CI 113 to 129). The rate of falls was 21% higher in people with polypharmacy compared with people without polypharmacy (adjusted IRR 1.21, 95% CI 1.11 to 1.31). Using ≥4 drugs threshold the rate of falls was 18% higher in people with polypharmacy compared with people without (adjusted IRR 1.18, 95% CI 1.08 to 1.28), whereas using ≥10 drugs threshold polypharmacy was associated with a 50% higher rate of falls (adjusted IRR 1.50, 95% CI 1.34 to 1.67).

Conclusions

We found almost one-third of the total population using five or more drugs, which was significantly associated with 21% increased rate of falls over a 2-year period. Further exploration of the effects of these complex drug combinations in the real world with a detailed standardised assessment of polypharmacy is greatly required along with pragmatic studies in primary care, which will help inform whether the threshold for a detailed medication review should be lowered.

http://ift.tt/2xKTUxe

Avoid Futile Therapy

This case is not in the "gray zone." The patient (1) has incurable metastatic disease, has had one pointless thoracic operation, and should not have further meddlesome local therapy unless he is symptomatic. He should be offered further systemic treatment either now or when more metastases appear.

http://ift.tt/2xLi2jg

SABR Given Thoughtfully

The patient (1) has had a histologically proven lung metastasis excised 12 months previously, and the site and pattern of the new findings are consistent with progressive lung metastases.

http://ift.tt/2ztmVL9

Metastasis-Directed Therapy: Right for Some, but Not All, and Not Here

Metastasis-directed therapy should not be performed in this patient (1). Surgery or thermal ablation is not advisable based on location. No further evaluation is required, given the patient's prior pulmonary metastasectomy. Instead, standard systemic therapy should be given.

http://ift.tt/2xLK9is

In Reply to Liu and Li

To the Editor: We thank Drs. Li and Liu for sharing their interesting thoughts (1) on Lysenko's doctrine of species transmutation through acquired heritability. Although this discussion is clearly outside the scope of our review article (2), it is no doubt true that the passage of time often involves a reinterpretation of historical figures and their beliefs.

http://ift.tt/2zrNvnX

Meetings

December 5-9, 2017

http://ift.tt/2xJRA9X

Give Resection a Chance

Widespread metastatic disease is typically not amenable to localized therapy, but when limited to the lungs, localized treatments can be beneficial. Lung metastases develop in 5% to 15% of colorectal cancer patients, and resection is an integral part of treatment. Selection criteria for metastasectomy include primary tumor control, no extrathoracic metastatic disease, amenability to complete resection, patient's ability to tolerate resection, and absence of better alternative therapies.

http://ift.tt/2xLhTfI

Potential Role of the Quality Assurance Review Center Platform in Global Radiation Oncology

The 2014 World Health Organization (WHO) Cancer Report describes an alarming growth in the cancer burden worldwide and underscores that, of the 14 million new cases of cancer and 8.2 million cancer-related deaths per year, 60% and 70%, respectively, occur in low-income and middle-income countries (LMICs) (1). These countries are the least capable of dealing with cancer without some form of collaboration. The disparities in cancer-related deaths in part reflect poignant underlying inequalities in access to radiation oncology services; also, a majority of the population groups that experience disparities is significantly underrepresented in cancer clinical trials (2).

http://ift.tt/2ztyEJu

Neoadjuvant Chemoradiation in the Treatment of Locally Advanced Breast Cancer

Despite the clear benefit of neoadjuvant chemoradiation in multiple disease sites, including head and neck, lung, and gastrointestinal malignancies, its role in breast cancer remains unclear. In this issue of the International Journal of Radiation Oncology • Biology • Physics, 2 phase 2 trials examine the role of neoadjuvant chemoradiation in the treatment of patients with breast cancer. These 2 studies examine different treatment regimens and use very different eligibility criteria and different endpoints, making meaningful comparison between them difficult.

http://ift.tt/2xLhQAy

The Prickly Predicament of Pursuing Pulmonary Polymetastases

A 54-year-old non-smoking man presented with midrectal adenocarcinoma, which was staged thoroughly including whole-body 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET). He underwent neoadjuvant chemoradiation with 50.4 Gy delivered in 28 fractions with infusional 5-fluorouracil and total mesorectal excision with clear margins, final stage pT3N1M0. He then received a total of 8 of 12 planned cycles of adjuvant oxaliplatin, fluorouracil, and leucovorin chemotherapy (1), limited by treatment-related toxicity.

http://ift.tt/2ztmdgX

In Regard to Likhacheva et al

To the Editor: In their recent article, "The red beam: Past, present, and future of radiation oncology in Russia," Anna Likhacheva and colleagues mentioned Lysenkoism. According to their statement, Lysenko argued that a single generation of a crop could be "taught" certain advantageous characteristics, which would be transmitted to subsequent generations (1). We fear that this statement is not supported by historical evidence. Actually, Lysenko emphasized that more than 2 generations (usually 3 or 4 generations), instead of a single generation, were necessary for the inheritance of acquired characters.

http://ift.tt/2xLkJ4q

Stereotactic Body Radiation Therapy for Oligometastatic Prostate Cancer: The Hunt for the Silver Bullet

At the American Society for Radiation Oncology annual meeting in 2014 in San Francisco, significant excitement rose from a genitourinary oral session in which several abstracts discussed the potential for localized treatment of N1 prostate cancer to change anticipated survival outcomes (1-3). Since then, studies have been published on the utility of treatment for both N1 and true metastatic disease, arguing that prevention of "reseeding" from primary disease or current metastases can reduce future metastases (4).

http://ift.tt/2zuklEP

Let “Whitmore's Principle” be the Guide

As we try to balance what we can do versus what we should do for this patient (1), several of Willet Whitmore's quotes come to mind (2). "Is cure possible only when it is not necessary"; or in this context "is control possible only…." Does it do any good to control disease that is not symptomatic in someone who may have symptoms, and ultimately die, from progressive disease elsewhere? Perhaps "buying time is the name of the game"; with our goal to delay chemotherapy, or reduce the cost of prolonged bevacizumab? How about "tell me what you want to hear and I'll refer you to someone who will recommend it" versus "let's try to replace heated opinion with cold facts." The aim should not be to use stereotactic ablative body radiation therapy (SABR) for oligometastases because we can, but rather to prove it works before we use it routinely.

http://ift.tt/2xLRGhf

Estimating Survival in Melanoma Patients With Brain Metastases: An Update of the Graded Prognostic Assessment for Melanoma Using Molecular Markers (Melanoma-molGPA)

To update the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) for a markedly heterogeneous patient population, patients with melanoma and brain metastases, using a larger, more current cohort, including molecular markers.

http://ift.tt/2ztJdfT

Tissue Force Programs Cell Fate and Tumor Aggression [Reviews]

Biomechanical and biochemical cues within a tissue collaborate across length scales to direct cell fate during development and are critical for the maintenance of tissue homeostasis. Loss of tensional homeostasis in a tissue not only accompanies malignancy but may also contribute to oncogenic transformation. High mechanical stress in solid tumors can impede drug delivery and may additionally drive tumor progression and promote metastasis. Mechanistically, biomechanical forces can drive tumor aggression by inducing a mesenchymal-like switch in transformed cells so that they attain tumor-initiating or stem-like cell properties. Given that cancer stem cells have been linked to metastasis and treatment resistance, this raises the intriguing possibility that the elevated tissue mechanics in tumors could promote their aggression by programming their phenotype toward that exhibited by a stem-like cell.

Significance: Recent findings argue that mechanical stress and elevated mechanosignaling foster malignant transformation and metastasis. Prolonged corruption of tissue tension may drive tumor aggression by altering cell fate specification. Thus, strategies that could reduce tumor mechanics might comprise effective approaches to prevent the emergence of treatment-resilient metastatic cancers. Cancer Discov; 7(11); 1–14. ©2017 AACR.

http://ift.tt/2geDBgS

An Akt3 splice variant lacking the serine 472 phosphorylation site promotes apoptosis and suppresses mammary tumorigenesis

The Akt pathway is a well-known promoter of tumor malignancy. Akt3 is expressed as two alternatively spliced variants, one of which lacks the key regulatory serine 472 phosphorylation site. Whereas the function of full-length Akt3 isoform (Akt3/+S472) is well-characterized, that of Akt3/-S472 isoform remains unknown. Despite being expressed at a substantially lower level than Akt3/+S472 in triple negative breast cancer cells, specific ablation of Akt3/-S472, enhanced, whereas overexpression, suppressed mammary tumor growth-consistent with a significant association with patient survival duration relative to Akt3/+S472. These effects were due to induction of apoptosis, which was mediated by Bim upregulation, leading to conformational activation of Bax and caspase-3 processing. Bim accumulation was caused by endocytosis of EGF receptors with concomitant ERK attenuation, which stabilizes BIM. These findings demonstrate an unexpected function of an endogenously expressed Akt isoform in promoting - as opposed to suppressing - apoptosis, underscoring that Akt isoforms may exert dissonant functions in malignancy.

http://ift.tt/2zrLyrD

STK33 promotes growth and progression of pancreatic cancer as a critical downstream mediator of HIF-1{alpha}

The serine/threonine kinase STK33 has been implicated in cancer cell proliferation. Here we provide evidence of a critical role for STK33 in the pathogenesis and metastatic progression of pancreatic ductal adenocarcinoma (PDAC). STK33 expression in PDAC was regulated by the hypoxia-inducible transcription factor HIF-1α. In human PDAC specimens, STK33 was overexpressed and associated with poor prognosis. Enforced STK33 expression promoted PDAC proliferation, migration, invasion and tumor growth, whereas STK33 depletion exerted opposing effects. Mechanistic investigations showed that HIF-1α regulated STK33 via direct binding to a hypoxia response element in its promoter. In showing that dysregulated HIF-1α/STK33 signaling promotes PDAC growth and progression, our results suggest STK33 as a candidate therapeutic target to improve PDAC treatment.

http://ift.tt/2zfwWL8

ATR is a therapeutic target in synovial sarcoma

Synovial sarcoma (SS) is an aggressive soft-tissue malignancy characterised by expression of SS18-SSX fusions, where treatment options are limited. To identify therapeutically actionable genetic dependencies in SS, we performed a series of parallel, high-throughput small interfering RNA (siRNA) screens and compared genetic dependencies in SS tumor cells to those in >130 non-SS tumour cell lines. This approach revealed a reliance of SS tumor cells upon the DNA damage response serine/threonine protein kinase ATR. Clinical ATR inhibitors (ATRi) elicited a synthetic lethal effect in SS tumor cells and impaired growth of SS patient-derived xenografts. Oncogenic SS18-SSX family fusion genes are known to alter the composition of the BAF chromatin-remodeling complex, causing ejection and degradation of wild-type SS18 and the tumor suppressor SMARCB1. Expression of oncogenic SS18-SSX fusion proteins caused profound ATRi sensitivity and a reduction in SS18 and SMARCB1 protein levels, but a SSX18-SSX1 Δ71-78 fusion containing a C-terminal deletion did not. ATRi sensitivity in SS was characterized by an increase in biomarkers of replication fork stress (increased γH2AX, decreased replication fork speed, and increased R-loops), an apoptotic response, and a dependence upon Cyclin E expression. Combinations of cisplatin or PARP inhibitors enhanced the anti-tumor cell effect of ATRi, suggesting that either single agent ATRi or combination therapy involving ATRi might be further assessed as candidate approaches for SS treatment.

http://ift.tt/2ztQQTu

Administering xCT inhibitors based on circadian clock improves antitumor effects

Clock genes encoding transcription factors that regulate circadian rhythms may inform chrono-modulated chemotherapy, where time-dependent dose alterations might affect drug efficacy and reduce side effects. For example, inhibiting the essential cystine transporter xCT with sulfasalazine induces growth arrest in cancer cells. Although the anticancer effects of sulfasalazine have been studied extensively, its effects on transcriptional control of xCT expression have not been studied. Here we show that sulfasalazine administration during the period of increased xCT expression improves its anticancer effects, and that the Clock gene itself induces xCT expression and regulates its circadian rhythm. Our findings highlight the clinical potential of chrono-modulated chemotherapy and the importance of xCT-mediated transcriptional regulation in the utility of such strategies.

http://ift.tt/2zdRe7v

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Δευτέρα 16 Οκτωβρίου 2017

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