Παρασκευή 21 Ιουλίου 2017
Long-term effectiveness of the preoperative smoking cessation programme at Western Health
Background
Smoking is associated with adverse effects in the perioperative period, including elevated risk of death. The perioperative period provides an opportunity to engage with patients who are smokers to encourage smoking cessation, often referred to as a 'teachable moment'. We developed a smoking intervention model for the pre-admission clinic (PAC) at Western Health, Victoria, Australia. This case series aimed to assess the impact of the smoking intervention model, which is standard of care, on the participant's smoking habits over four time points.
Methods
We enrolled 50 consecutive participants for elective surgery who were smokers and had attended PAC at Western Health, Footscray. All smokers were offered a standard intervention package to address their smoking. Participants underwent a brief interview to elicit their current smoking behaviour on their day of surgery, 3 and 12 months post-operatively.
Results
We found a reduction at each time point post-intervention in the average number of cigarettes smoked per day by all participants with a 43% reduction at 12 months compared with PAC. We found that the number of participants who had quit increased at each time point, with 29% abstinent at 12 months post-operatively. At 12 months, we found 71% of participants had either quit or reduced the number of cigarettes smoked compared with the amount reported at PAC.
Conclusion
This study adds to the evidence that a simple intervention preoperatively can contribute to long-term changes in smoking behaviour.
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Implant treatment in pharmacologically immunosuppressed liver transplant patients: A prospective-controlled study
Abstract
Objectives
The main objective of this prospective study was to evaluate the long-term outcome of implant therapy in liver transplant patients (LTP). The secondary goal was to assess several implant- and patient-dependent variables, such as peri-implantitis (PI), peri-implant mucositis (PIM), bone loss (BL), and immediate postoperative complications.
Material and methods
Two groups, including 16 pharmacologically immunosuppressed LTP and 16 matched controls, received 52 and 54 implants, respectively, between 1999 and 2008. After evaluating the postoperative healing, a mean follow-up of more than 8 years was carried out, and radiographic, clinical, and periodontal parameters were recorded to evaluate implant survival and implant- and patient-dependent outcomes.
Results
The early postsurgical complications were similar in both groups. Implant survival rate was 100% in the LTP group and 98.15% in the CG. PIM was diagnosed in 35.42% of the implants and 64.29% of the patients of LTP group (LTPG) and in 43.40% of the implants and 56.25% of the patients in the CG. PI was detected in 4.17% of the implants and 7.10% of the patients in the LTPG and in 9.43% of the implants and 18.80% of the patients in the CG.
Conclusion
Pharmacologically immunosuppression in liver transplant patients was not a risk factor for implant failure, nor for the incidence of peri-implant diseases. Liver transplant is not a contraindication for dental implant treatment, although these patients should be carefully monitored during follow-up care.
http://ift.tt/2tolieg
Outcomes of preexisting diabetes mellitus in breast, colorectal, and prostate cancer
Abstract
Purpose
Preexisting diabetes is associated with increased morbidity and mortality in cancer. We examined the impact of incident cancer on the long-term outcomes of diabetes.
Methods
Using the United Kingdom Clinical Practice Research Datalink, we identified three cohorts of diabetes patients subsequently diagnosed with breast, colorectal, or prostate cancer, each matched to diabetic noncancer controls. Patients were required to have survived at least 1 year after cancer diagnosis (cases) or a matched index date (controls), and were followed up to 10 years for incident microvascular and macrovascular complications and mortality. Multivariate competing risks regression analyses were used to compare outcomes between cancer patients and controls.
Results
Overall, there were 3382 cancer patients and 11,135 controls with 59,431 person-years of follow-up. In adjusted analyses, there were no statistically significant (p ≤ 0.05) differences in diabetes complication rates between cancer patients and their controls in any of the three cancer cohorts. Combined, cancer patients were less likely (adjusted hazard ratio [HR] 0.88; 95% CI = 0.79–0.98) to develop retinopathy. Cancer patients were more likely to die of any cause (including cancer), but prostate cancer patients were less likely to die of causes associated with diabetes (HR 0.61; 95% CI = 0.43–0.88).
Conclusions and implications
There is no evidence that incident cancer had an adverse impact on the long-term outcomes of preexisting diabetes.
Implications for Cancer Survivors
These findings are important for cancer survivors with preexisting diabetes because they suggest that substantial improvements in the relative survival of several of the most common types of cancer are not undermined by excess diabetes morbidity and mortality.
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Expression and function of the metabotropic purinergic P2Y receptor family in experimental seizure models and patients with drug-refractory epilepsy
Summary
Objective
ATP is released into the extracellular space during pathologic processes including increased neuronal firing. Once released, ATP acts on P2 receptors including ionotropic P2X and metabotropic P2Y receptors, resulting in changes to glial function and neuronal network excitability. Evidence suggests an involvement of P2Y receptors in the pathogenesis of epilepsy, but there has been no systematic effort to characterize the expression and function of the P2Y receptor family during seizures and in experimental and human epilepsy.
Methods
Status epilepticus was induced using either intra-amygdala kainic acid or pilocarpine to characterize the acute- and long-term changes in hippocampal P2Y expression. P2Y expression was also investigated in brain tissue from patients with temporal lobe epilepsy. Finally, we analyzed the effects of two specific P2Y agonists, ADP and UTP, on seizure severity and seizure-induced cell death.
Results
Both intra-amygdala kainic acid and pilocarpine-induced status epilepticus increased the transcription of the uracil-sensitive P2Y receptors P2ry2, P2ry4, and P2ry6 and decreased the transcription of the adenine-sensitive P2Y receptors P2ry1, P2ry12, P2ry13. Protein levels of P2Y1, P2Y2, P2Y4, and P2Y6 were increased after status epilepticus, whereas P2Y12 expression was decreased. In the chronic phase, P2ry1, P2ry2, and P2ry6 transcription and P2Y1, P2Y2, and P2Y12 protein levels were increased with no changes for the other P2Y receptors. In hippocampal samples from patients with temporal lobe epilepsy, P2Y1 and P2Y2 protein expression was increased, whereas P2Y13 levels were lower. Demonstrating a functional contribution of P2Y receptors to seizures, central injection of ADP exacerbated seizure severity, whereas treatment with UTP decreased seizure severity during status epilepticus in mice.
Significance
The present study is the first to establish the specific hippocampal expression profile and function of the P2Y receptor family after experimental status epilepticus and in human temporal lobe epilepsy and offers potential new targets for seizure control and disease modification.
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Implementation of the Canadian CT Head Rule and Its Association With Use of Computed Tomography Among Patients With Head Injury
Approximately 1 in 3 computed tomography (CT) scans performed for head injury may be avoidable. We evaluate the association of implementation of the Canadian CT Head Rule on head CT imaging in community emergency departments (EDs).
http://ift.tt/2uJke8O
Adolescents at Risk for Sexually Transmitted Infection Need More Than the Right Medicine
In the US, sexually transmitted infections (STIs) are a formidable public health issue, with nearly 20 million new cases annually, one-half of which occur among adolescents and young adults ages 15-24 years.1 Each year, STIs account for $16 billion in healthcare costs.2 Adolescents frequently seek care in emergency departments (EDs), and this population reports high rates of risky behaviors, including early sexual debut, multiple partners, and infrequent condom use.3-6 Rates of STIs are often higher among these youth compared with the general population4-6 and, for many, the ED may be their only contact with a healthcare provider.
http://ift.tt/2ujp3UZ
A Case of Oxalate Nephropathy: When a Single Cause Is Not Crystal Clear
Hyperoxaluria can result in oxalate nephropathy with intratubular calcium oxalate crystallization and acute tubular injury. Primary inherited enzymatic deficiency or secondary causes such as excessive dietary intake, enteric increased absorption, or high doses of vitamin C, which is metabolized to oxalate, may underlie hyperoxaluria and oxalate nephropathy. We report a case of acute kidney injury due to oxalate nephropathy in a patient using chelating therapy with oral ethylenediamine tetra acetic acid (EDTA), intravenous supplementation with vitamin C, and chronic diarrhea and discuss the potential kidney damage these factors can cause in particular settings.
http://ift.tt/2uKaAlE
Peptide Receptor Radionuclide Therapy–Induced Gitelman-like Syndrome
Peptide receptor radionuclide therapy (PRRT) is a molecular-targeted therapy in which a somatostatin analogue (a small peptide) is coupled with a radioligand so that the radiation dose is selectively administered to somatostatin receptor–expressing metastasized neuroendocrine tumors, particularly gastroenteropancreatic. Reported toxicities include myelotoxicity and nephrotoxicity, the latter manifesting as decreased kidney function, often developing months to years after treatment completion. We present a case of PRRT-induced kidney toxicity manifesting as a severe Gitelman-like tubulopathy with preserved kidney function.
http://ift.tt/2toTrdO
A novel functional splice variant of AKT3 defined by analysis of alternative splice expression in HPV-positive oropharyngeal cancers
The incidence of HPV-related oropharyngeal squamous cell carcinoma (OPSCC) has increased more than 200% in the past 20 years. Recent genetic sequencing efforts have elucidated relevant genes in head and neck cancer, but HPV-related tumors have consistently shown few DNA mutations. In this study, we sought to analyze alternative splicing events (ASE) that could alter gene function independent of mutations. To identify ASE unique to HPV-related tumors, RNA sequencing was performed on 46 HPV-positive OPSCC and 25 normal tissue samples. A novel algorithm using outlier statistics on RNA-sequencing junction expression identified 109 splicing events, which were confirmed in a validation set from the Cancer Genome Atlas (TCGA). Because the most common type of splicing event identified was an alternative start site (39%), MBD-seq genome-wide CpG methylation data were analyzed for methylation alterations at promoter regions. ASE in six genes showed significant negative correlation between promoter methylation and expression of an alternative transcriptional start site, including AKT3. The novel AKT3 transcriptional variant and methylation changes were confirmed using qRT-PCR and qMSP methods. In vitro silencing of the novel AKT3 variant resulted in significant growth inhibition of multiple head and neck cell lines, an effect not observed with wild type AKT3 knockdown. Analysis of ASE in HPV-related OPSCC identified multiple alterations likely involved in carcinogenesis, including a novel, functionally active transcriptional variant of AKT3. Our data indicate that ASEs represent a significant mechanism of oncogenesis with untapped potential for understanding complex genetic changes that result in development of cancer.
http://ift.tt/2toTfeG
Maternal SSRI discontinuation, use, psychiatric disorder and the risk of autism in children: A meta-analysis of cohort studies.
Summary
We undertook an exclusive meta-analysis of cohort studies investigating the possible link between prenatal SSRI exposure and autism spectrum disorders (ASD) in children to further investigate our previous suggestion of confounding by indication. The point estimates regarding the following cohorts were extracted and pooled: (1) Pregnant women who discontinued SSRI until 3 months before pregnancy. (2) Pregnant women who were exposed to SSRI during pregnancy. (3) Pregnant women with maternal psychiatric disorder but no exposure to SSRI during pregnancy. Although the pooled point estimate of the first cohort showed a trend for increase, it did not reach significance. The pooled point estimates of the latter cohorts showed a significant association with ASD which strengthens our previous suggestion of confounding by indication. Future studies should be adequately designed to differentiate whether the previously suggested association is a result of maternal psychiatric disorder or SSRI exposure or both.
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Population pharmacokinetics and exposure-response of trastuzumab emtansine in advanced breast cancer previously treated with ≥2 HER2-targeted regimens
Abstract
Aims
We conducted population pharmacokinetic (PopPK) and exposure-response analyses for trastuzumab emtansine (T-DM1) to assess the need for T-DM1 dose optimization in patients with low exposure by using TH3RESA study data (NCT01419197). The randomized phase III TH3RESA study investigated T-DM1 vs. treatment of physician's choice (TPC) in patients with heavily pretreated HER2-positive advanced breast cancer.
Methods
We compared a historical T-DM1 PopPK model with T-DM1 pharmacokinetics in TH3RESA and performed exposure-response analyses using model-predicted cycle 1 Cmax, cycle 1 Cmin, and AUCss. Kaplan–Meier analyses (OS, PFS) and logistic regression (overall response rate [ORR], safety) were stratified by T-DM1 exposure metrics. Survival hazard ratios (HRs) in the lowest exposure quartile (Q1) of cycle 1 Cmin were compared with matched TPC-treated patients.
Results
T-DM1 concentrations in TH3RESA were described well by the historical PopPK model. Patients with higher cycle 1 Cmin and AUCss exhibited numerically longer median OS and PFS and higher ORR than patients with lower exposure. Exposure-response relationships were less evident for cycle 1 Cmax. No relationship between exposure and safety was identified. HRs for the comparison of T-DM1–treated patients in the Q1 subgroup with matched TPC-treated patients were 0.96 (95% CI 0.63, 1.47) for OS and 0.92 (95% CI 0.64, 1.32) for PFS.
Conclusions
Exposure-response relationships for efficacy were inconsistent across exposure metrics. HRs for survival in patients in the lowest T-DM1 exposure quartile vs. matched TPC-treated patients suggest that, compared with TCP, the approved T-DM1 dose is unlikely to be detrimental to patients with low exposure.
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Hepatitis transmission risk in kidney transplantation (the HINT study): a cross-sectional survey of transplant clinicians in Australian and New Zealand.
Background: Interpreting hepatitis serology and virus transmission risk in transplantation can be challenging. Decisions must balance opportunity to transplant against potential infection transmission. We aimed to survey understanding among the Australian and New Zealand medical transplant workforce of hepatitis risk in kidney donors and recipients. Methods: An anonymous, self-completed, cross-sectional survey was distributed via electronic mailing lists to Australian and New Zealand clinicians involved in kidney transplantation (2014-2015). We compared interpretation of clinical scenarios with paired donor and recipient hepatitis B and C (HBV, HBC) serology to recommendations in clinical practice guidelines. We used logistic regression modelling to investigate characteristics associated with decisions on transplant suitability in scenarios with poor (
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http://ift.tt/2toFOeT
Monoclonal Gammopathy of Undetermined Significance after Kidney Transplantation: single-center experience.
Background: Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic premalignant plasma cell disorder. Prevalence and clinical outcomes of MGUS in kidney transplant (KT) recipients have been previously reported in few studies with conflicting results. Methods: We conducted a retrospective study in a population of 548 KT recipients transplanted between 1998 and 2015. Results: Thirty-nine subjects (8.1%) developed MGUS after KT. At diagnosis of MGUS, the average age was 52+/-9.2 years and 23% of patients were younger than 50 years. Occurrence of MGUS was not influenced by age and sex. After a mean follow-up of 7.8 years, only 1 patient (2.5%) progressed to multiple myeloma. We found no differences in the incidence of solid and hematological malignancies, serious infections, graft failure and mortality between KT patients with MGUS and a matched cohort of KT recipients without MGUS. The MGUS group had a significantly higher prevalence of Monoclonal B cell Lymphocytosis (MBL), premalignant condition poorly described in KT recipients. Prior history of glomerulonephritis or interstitial nephritis, as cause of renal failure, represented the only predictive factor for MGUS development. Conclusions: MGUS is a premalignant disorder frequently encountered in KT recipients; we found no differences in clinical outcomes between MGUS patients and KT controls. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.
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http://ift.tt/2uJVkVZ
Validation of the Prognostic Kidney Donor Risk Index (KDRI) Scoring System of Deceased Donors for Renal Transplantation in the Netherlands.
Background: The prognostic Kidney Donor Risk Index (KDRI)-developed and internally validated in the US-is a widely-used tool to predict transplant outcome of a deceased donor kidney. The KDRI is currently used for longevity matching between donors and recipients in the US. Methods: We aimed to externally validate the KDRI as proposed by Rao et al, (2009) containing 10 donor factors (KDRIdonor-only) and 1 with 4 additional transplant factors (KDRIfull), with stratification on recipient age and diabetes. We used the Dutch Organ Transplantation Registry to include 3201 adult recipients transplanted from 2002 to 2012. Results: The median Dutch KDRI was 1.21, and comparable with the year 2012 in the US (median of 1.24). The calibration-slope was 0.98 and 0.96 for the KDRIfull and KDRIdonor-only, respectively, indicating that predictions of graft failure were on average similar. The discriminative ability (Harrell's C) of the KDRIfull and the KDRIdonor-only at 5 years was 0.63 (95%CI 0.62-0.64), and 0.62 (95%CI 0.61-0.63), respectively. We found misspecification of 3 KDRI factors: age (p=.002), weight (p=.017), and cold ischemia time (p24h vs 12h, p=.059) could improve predictive ability. Conclusions: The KDRI performs equal in the Dutch population. Discriminative ability of the KDRI indicates limited clinical use for adequate individualized decisions. An updated KDRI may contribute to a standardized policy meeting the growing demand of donor kidneys in the Eurotransplant region. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.
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http://ift.tt/2tox0p0
C1-inhibitor Treatment Decreases Renal Injury in an Established Brain-dead Rat Model.
Background: Kidneys derived from brain-dead (BD) donors have lower graft survival rates compared to kidneys from living donors. Complement activation plays an important role in brain death. The aim of our study was therefore to investigate the effect of C1-inhibitor (C1-INH) on BD-induced renal injury. Methods: Brain death was induced in rats by inflating a subdurally placed balloon catheter. Thirty minutes after BD, rats were treated with saline, low-dose or high-dose C1-INH. Sham-operated rats served as controls. After 4 hours of brain death, renal function, injury, inflammation and complement activation was assessed. Results: High-dose C1-INH treatment of BD donors resulted in significantly lower renal gene expression and serum levels of IL-6. Treatment with C1-INH also improved renal function and reduced renal injury, reflected by the significantly lower KIM-1 gene expression and lower serum levels of LDH and creatinine. Furthermore, C1-INH effectively reduced complement activation by brain death and significantly increased functional levels. However, C1-INH treatment did not prevent renal cellular influx. Conclusions: Targeting complement activation after the induction of brain death reduced renal inflammation and improved renal function, before transplantation. Therefore, strategies targeting complement activation in human BD donors might clinically improve donor organ viability and renal allograft survival. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.
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http://ift.tt/2uKfYp1
Oral nucleos(t)ide Analogs Alone After Liver Transplantation in Chronic Hepatitis B with Preexisting rt204 Mutation.
Background: There is currently limited data regarding the use of oral antiviral therapy alone without HBIG for CHB patients with preexisting LAM-resistance (LAM-R) undergoing liver transplantation. Methods: This is a cohort study determining the effectiveness and long-term outcome in this group of patients. Results: Fifty-seven consecutive CHB patients with preexisting rt204 LAM-R mutations or virological load refractory to LAM undergoing liver transplantation were included, with a median follow-up of 73 months. Fifty-five (96.5%) patients received a regimen that included the use of nucleotide analogs. The cumulative rate of HBsAg seroclearance at 1, 5, and 10 years was 82%, 88%, and 91% respectively. At the time of transplantation, 39 (72%) patients had detectable HBV DNA, with a median of 4.5 log copies/mL. The cumulative rate of HBV undetectability was 91% at 1 year, increasing to 100% by 5 years. After 1 year of liver transplantation, over 90% of patients had undetectable HBV DNA, and from 8 years onwards, 100% had undetectable HBV DNA. The overall long-term survival was excellent, with a 12-year survival of 87%. There was no HBV-related graft loss, and no retransplantation or deaths due to HBV reactivation. Conclusion: Oral antiviral therapy alone without HBIG is highly effective in preventing HBV reactivation and graft loss from recurrent hepatitis B after liver transplantation in patients with preexisting lamivudine resistance HBV. The long-term outcome was excellent, with survival of 87% at 12 years after transplantation, without any mortality related to HBV reactivation. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.
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http://ift.tt/2tosl6w
Prognostic Factors in Lung Transplantation after Hematopoietic Stem Cell Transplantation.
Background: Lung transplantation is the final life-saving option for patients with pulmonary complications after hematopoietic stem cell transplantation (HSCT). Patients undergoing HSCT for hematologic diseases are thought to be high-risk candidates for lung transplantation; therefore, few lung transplants are performed for these patients, and few studies have been reported. This study aimed to describe the characteristics and outcomes of lung transplantation in patients with pulmonary complications after HSCT. Methods: We retrospectively investigated 62 patients who underwent lung transplantation after HSCT. All data were collected from 6 lung transplant centers in Japan. Results: Seventeen patients underwent cadaveric lung transplantation, whereas 45 underwent living-donor lobar lung transplantation (LDLLT). In the LDLLT group, 18 patients underwent LDLLT after HSCT in which 1 of the donors had also served as a donor for HSCT. Seven patients underwent single LDLLT for which the donor was the same as the patient from whom stem cells were obtained for HSCT. Preoperative hypercapnia was observed in 52 patients (84%). Thirteen patients (21%) required mechanical ventilation preoperatively. Fifty-five patients underwent HSCT for hematologic malignancies, and 4 (7%) relapsed after lung transplantation. The 5-year survival rate was 64.2%. In a multivariable analysis, patients younger than 45 years and those with the same donor for both procedures exhibited significantly better survival (p = 0.012 and 0.041, respectively). Conclusions: Lung transplantation for pulmonary complications after HSCT was performed safely and yielded better survival, especially in younger recipients for whom both lung transplantation and HSCT involved the same donor. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.
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http://ift.tt/2uKrxwj
New answers to old conundrums: what antibodies, exosomes and inflammasomes bring to the conversation. Canadian National Transplant Research Program international summit report.
Antibody-mediated injury is a major cause of allograft dysfunction and loss. Antibodies to ABH(O) blood group antigens are classical mediators of ABO-incompatible (ABOi) graft rejection, while donor-specific anti-HLA antibodies and, more recently, autoantibodies are appreciated as important contributors to allograft inflammation and dysfunction. In August 2016, the International Summit of the Canadian National Transplant Research Program focused on recent advances in the field of antibody-mediated rejection. Here, we describe work presented and discussed at the meeting, with a focus on 3 major themes: the importance of 1- Natural antibodies and autoantibodies, 2- tissue injury derived exosomes and autoimmunity, 3- inflammasome activation and innate immune responses in regulating allograft inflammation and dysfunction. Finally, we explore novel areas of therapeutic intervention that have recently emerged from these 3 major and overlapping fields of transplantation research. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.
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http://ift.tt/2uKiv2y
Terasaki epitope mismatch burden predicts the development of de novo DQ donor specific antibodies and are associated with adverse allograft outcomes.
Background: De novo DQ DSA are associated with antibody-mediated rejection and allograft loss. Given the lack of effective treatment of de novo DQ DSA, their prevention is vital if there is to be an improvement of long term allograft survival. Using the HLA Matchmaker programme, DQ epitope matching has been shown to be superior to HLA antigen mismatching in predicting de novo DQ DSA development. Whether DQ epitopes determined by Terasaki may more accurately predict de novo DQ development over HLA antigen matching is not known. Methods: We retrospectively analysed the immunogenicity of the different HLA antigens, DQB1 alleles and DQB1 Teraskai epitopes (TerEp) in a large cohort of renal transplant recipients, by comparing patient mismatches with de novo DSA development. Results: Patients mismatched at a DQB1 allele were at significantly higher risk of developing de novo DSA compared with other mismatched HLA antigens. Patients mismatched at the DQ7 allele appear to be at specific risk. For patients mismatched at a single DQB1 allele, the risk of de novo DQ DSA development increases with the number of TerEp mismatches. However, the immunogenicity of the different DQ TerEps, do not appear to be equal. Patients who develop antibodies against TerEps are at increased risk of adverse allograft outcomes, specifically antibody-mediated rejection. Conclusion: Epitope mismatch burden, determined by TerEps, helps predict risk of de novo DQ DSA development, and offers an alternative approach to predict an alloimmune response. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.
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http://ift.tt/2tobxN4
BAX Can Be Allosterically Sensitized to Promote Apoptosis [Research Watch]
An NMR-based fragment screen identified a BAX-interacting compound, BIF-44, that enhances BAX activity.
http://ift.tt/2toyaRG
Biallelic Germline Mutations in RFWD3 May Induce Fanconi Anemia [Research Watch]
The E3 ubiquitin ligase RFWD3 is mutated in a patient with Fanconi anemia lacking known Fanconi mutations.
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Frameshift Indels Generate Highly Immunogenic Tumor Neoantigens [Research Watch]
Renal clear cell carcinomas have the highest proportion of indels, which are linked to immune activation.
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CAMKII{gamma} Stabilizes MYC to Promote T-cell Lymphomagenesis [Research Watch]
Inhibition of CAMKII reduces MYC protein levels, T-cell lymphomagenesis, and tumor burden in vivo.
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GPX4 Blocks Ferroptosis to Drive the Survival of Chemoresistant Cells [Research Watch]
The lipid peroxidase GPX4 is critical for the survival of therapy-resistant ZEB1+ cancer cells.
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TCR Repertoire Intratumor Heterogeneity in Localized Lung Adenocarcinomas: an Association with Predicted Neoantigen Heterogeneity and Postsurgical Recurrence [Research Briefs]
Genomic intratumor heterogeneity (ITH) may be associated with postsurgical relapse of localized lung adenocarcinomas. Recently, mutations, through generation of neoantigens were shown to alter tumor immunogenicity through T cell responses. Here, we performed sequencing of the T cell receptor (TCR) in 45 tumor regions from 11 localized lung adenocarcinomas and observed substantial intratumor differences in T cell density and clonality with the majority of T cell clones restricted to individual tumor regions. TCR ITH positively correlated with predicted neoantigen ITH, suggesting that spatial differences in the T cell repertoire may be driven by distinct neoantigens in different tumor regions. Finally, a higher degree of TCR ITH was associated with an increased risk of postsurgical relapse and shorter disease-free survival, suggesting a potential clinical significance of T cell repertoire heterogeneity.
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MOlecular Screening for CAncer Treatment Optimization (MOSCATO-01) in pediatric patients: A single institutional prospective molecular stratification trial
Purpose: This single institutional feasibility study prospectively characterized genomic alterations in recurrent or refractory solid tumors of pediatric patients in order to select a targeted therapy.<br /><br />Experimental Design: Following treatment failure patients with signed consent and aged above 6 months, underwent tumor biopsy or surgical resection of primary or metastatic tumor site. These newly acquired samples were analyzed by comparative genomic hybridization array, next generation sequencing for 75 target genes, whole exome and RNA sequencing. Biological significance of the alterations and suggestion of most relevant targeted therapies available were discussed in a multidisciplinary tumor board.<br /><br />Results: From December 2012 to January 2016, 75 patients were included, 73 patients underwent 79 interventions, 56 of which were research biopsies with a low complication rate. All patients were pretreated, 37.0% had a brain tumor and 63.0% an extra-cranial solid tumor. Median tumor cell content was 70% (range 0-100%). Successful molecular analysis in 69 patients detected in 60.9% of patients an actionable alteration in various oncogenic pathways (42.4% with copy number change, 33.3% with mutation, 2.1% with fusion), and change in diagnosis in three patients. Fourteen patients received 17 targeted therapies; two had received a matched treatment prior to inclusion.<br /><br />Conclusions: Research biopsies are feasible in advanced pediatric malignancies that exhibit a considerable amount of potentially actionable alterations. Genetic events affecting different cancer hallmarks and limited access to targeted agents within pediatric clinical trials remain the main obstacles that are addressed in our two subsequent precision medicine studies MAPPYACTS and AcSé-ESMART.
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89Zr-lumretuzumab PET imaging before and during HER3 antibody lumretuzumab treatment in patients with solid tumors
Purpose: We evaluated biodistribution and tumor targeting of 89Zr-lumretuzumab before and during treatment with lumretuzumab, a human epidermal growth factor receptor 3 (HER3)-targeting monoclonal antibody. <p>Experimental design: 20 patients with histologically confirmed HER3-expressing tumors received 89Zr-lumretuzumab and underwent Positron Emission Tomography (PET). In Part A, 89Zr-lumretuzumab was given with additional, escalating doses of unlabeled lumretuzumab and scans were performed 2, 4 and 7 days postinjection to determine optimal imaging conditions. In Part B, patients were scanned following tracer injection before (baseline) and after a pharmacodynamic (PD)-active lumretuzumab dose for saturation analysis. HER3 expression was determined immunohistochemically in skin biopsies. Tracer uptake was calculated as standardized uptake value (SUV).</p> <p>Results: Optimal PET conditions were found to be 4 and 7 days after administration of 89Zr-lumretuzumab with 100 mg unlabeled lumretuzumab. At baseline using 100 mg unlabeled lumretuzumab, the tumor SUVmax was 3.4 (±1.9) at 4 days postinjection. SUVmean for normal blood, liver, lung and brain tissues were 4.9, 6.4, 0.9 and 0.2, respectively. Saturation analysis (n=7) showed that 4 days after lumretuzumab administration, tumor uptake decreased by 11.9% (±8.2), 10.0% (±16.5) and 24.6% (±20.9) at PD-active doses of 400, 800 and 1600 mg, respectively, when compared to baseline. Membranous HER3 was completely downregulated in paired skin biopsies already at and above 400 mg lumretuzumab.</p> <p>Conclusions: PET imaging showed biodistribution and tumor specific 89Zr-lumretuzumab uptake. Although, PD-active lumretuzumab doses decreased 89Zr-lumretuzumab uptake, there was no clear evidence of tumor saturation by PET imaging as the tumor SUV did not plateau with increasing doses.
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Direct metabolic interrogation of dihydrotestosterone biosynthesis from adrenal precursors in primary prostatectomy tissues
Purpose: A major mechanism of castration-resistant prostate cancer (CRPC) involves intratumoral biosynthesis of dihydrotestosterone (DHT) from adrenal precursors. We have previously shown that adrenal-derived androstenedione (AD) is the preferred substrate over testosterone (T) for 5α-reductase expressed in metastatic CRPC, bypassing T as an obligate precursor to DHT. However, the metabolic pathway of adrenal-derived DHT biosynthesis has not been rigorously investigated in the setting of primary disease in the prostate. <p>Experimental Design: Seventeen patients with clinically localized prostate cancer were consented for fresh tissues after radical prostatectomy. Prostate tissues were cultured ex vivo in media spiked with an equimolar mixture of AD and T, and stable isotopic tracing was employed to simultaneously follow the enzymatic conversion of both precursor steroids into nascent metabolites, detected by liquid chromatography-tandem mass spectrometry. CRPC cell line models and xenograft tissues were similarly assayed for comparative analysis. A tritium-labeled steroid radiotracing approach was used to validate our findings.</p> <p>Results: Prostatectomy tissues readily 5α-reduced both T and AD. Furthermore, 5α-reduction of AD was the major directionality of metabolic flux to DHT. However, AD and T were comparably metabolized by 5α-reductase in primary prostate tissues, contrasting the preference exhibited by CRPC in which AD was favored over T. 5α-reductase inhibitors effectively blocked the conversion of AD to DHT.</p> <p>Conclusions: Both AD and T are substrates of 5α-reductase in prostatectomy tissues, resulting in two distinctly non-redundant metabolic pathways to DHT. Furthermore, the transition to CRPC may coincide with a metabolic switch towards AD as the favored substrate.
http://ift.tt/2gRK0BO
Implementation of a model-based design in a phase 1b study of combined targeted agents
In recent years, investigators have recognized the rigidity of single agent, safety only, traditional designs, rendering them ineffective for conducting contemporary early-phase clinical trials, such as those involving combinations and /or biological agents. Novel approaches are required to address these research questions, such as those posed in trials involving targeted therapies. We describe the implementation of a model-based design for identifying an optimal treatment combination, defined by low toxicity and high efficacy, in an early-phase trial evaluating a combination of two oral targeted inhibitors in relapsed / refractory mantle cell lymphoma. <p>Operating characteristics demonstrate the ability of the method to effectively recommend optimal combinations in a high percentage of trials with reasonable sample sizes. The proposed design is a practical, early-phase, adaptive method for use with combined targeted therapies. This design can be applied more broadly to early-phase combination studies, as it was used in an ongoing study of a melanoma helper peptide vaccine plus novel adjuvant combinations.
http://ift.tt/2eCSQ5X
Dose Transition Pathways: The missing link between complex dose-finding designs and simple decision-making
The ever increasing pace of development of novel therapies mandates efficient methodologies for assessment of their tolerability and activity. Evidence increasingly support the merits of model-based dose-finding designs in identifying the recommended Phase II dose compared to conventional rule-based designs such as the 3+3 but despite this, their use remains limited. Here, we propose a useful tool, Dose Transition Pathways (DTP), which helps overcome several commonly-faced practical and methodological challenges in the implementation of model-based designs. DTP projects in advance the doses recommended by a model-based design for subsequent patients (stay, escalate, de-escalate or stop early), using all the accumulated information. After specifying a model with favourable statistical properties, we utilise the DTP to fine-tune the model to tailor it to the trial's specific requirements that reflect important clinical judgements. In particular, it can help to determine how stringent the stopping rules should be if the investigated therapy is too toxic. Its use to design and implement a modified Continual Reassessment Method is illustrated in an Acute Myeloid Leukaemia trial. DTP removes the fears of model-based designs as unknown, complex systems and can serve as a handbook, guiding decision-making for each dose-update. In the illustrated trial, the seamless, clear transition for each dose-recommendation aided the investigators' understanding of the design and facilitated decision-making to enable finer calibration of a tailored model. We advocate the use of the DTP as an integral procedure in the co-development and successful implementation of practical model-based designs by statisticians and investigators.
http://ift.tt/2gR343h
Overexpression of Rabl3 and Cullin7 is associated with pathogenesis and poor prognosis in hepatocellular carcinoma
The expression of Rabl3 and Cullin7 is relevant to the carcinogenesis of certain cancers. However, the relationship of this expression with hepatocellular carcinoma remains unclear. To study the protein expression of Rabl3 and Cullin7 and to evaluate their role in hepatocarcinogenesis, in 162 cases of hepatocellular carcinoma, we used immunohistochemistry to investigate the expression of Rabl3 and Cullin7 in both the cancer tissues and the normal hepatic tissues around the hepatocellular carcinoma.
http://ift.tt/2ujzWX6
Primary Signet Ring Stromal Tumor of the Testis: A Study of 13 Cases Indicating Their Phenotypic and Genotypic Analogy to Pancreatic Solid Pseudopapillary Neoplasm
Primary signet ring stromal tumor of the testis (PSRSTT) is an extremely rare tumor described only twice in the literature. Pancreatic-analogue solid pseudopapillary neoplasm (SPN) of the testis is a recently reported entity with morphological overlap with PSRSTT. We reviewed our files to find all cases of PSRSTT in order to better characterize this entity. We studied 13 cases of PSRSTTs using histological, immunohistochemical (IHC) and molecular genetic methods and compared the results with pancreatic SPN.
http://ift.tt/2vumSge
Increased Expression of EZH2 in Merkel Cell Carcinoma Is Associated with Disease Progression and Poorer Prognosis
Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that affects tumorigenesis by epigenetic gene silencing. Merkel cell carcinoma (MCC) is a rare cutaneous neuroendocrine carcinoma that has a high risk of disease progression with nodal and distant metastases. Here, we evaluated EZH2 expression by immunohistochemistry in a cohort of 85 MCC tumors (29 primary tumors, 41 lymph node metastases, 13 in-transit metastases, and 2 distant metastases) with clinical follow-up. We show strong/moderate EZH2 expression in 54% of tumors.
http://ift.tt/2ujqm6D
Salivary Gland Epithelial Neoplasms in Pediatric Population: a Single Institute Experience with a Focus on the Histologic Spectrum and Clinical Outcome
Salivary gland epithelial neoplasms are rare in children and adolescents with only a handful of large series have been published. A retrospective study was conducted for 57 cases in patients 20years or younger. The tumors were located in the parotid (n=36), submandibular gland (n=7), and minor salivary glands (n=14). 19 (33%) tumors were pleomorphic adenoma, while the remaining (67%) were malignant. The histologic types of carcinomas were mucoepidermoid carcinoma (MEC, n=19, 33%), acinic cell carcinoma (n=7, 12%), adenoid cystic carcinoma (n=6, 11%), secretory carcinoma (mammary analogue) (SC, n=4, 7%), and myoepithelial carcinoma (n=2, 4%).
http://ift.tt/2vtKwJF
Breast Implant Capsule-Associated Squamous Cell Carcinoma: A Report of Two Cases
The use of prosthetic implants for breast augmentation has become commonplace. While implants do not increase the risk of conventional mammary carcinoma, they are rarely associated with anaplastic large cell lymphoma. We report two cases of breast implant capsule-associated squamous cell carcinoma with poor clinical outcomes. Both patients (56-year-old female and 81-year-old female) had long-standing implants (>25years) and presented with acute unilateral breast enlargement. In both cases, squamous cell carcinoma arose in (focally dysplastic) squamous epithelium-lined breast implant capsules, and widely invaded surrounding breast parenchyma or chest wall.
http://ift.tt/2ujlMFj
Membrane Curvature and Lipid Composition Synergize To Regulate N-Ras Anchor Recruitment
Proteins anchored to membranes through covalently linked fatty acids and/or isoprenoid groups play crucial roles in all forms of life. Sorting and trafficking of lipidated proteins has traditionally been discussed in the context of partitioning to membrane domains of different lipid composition. We recently showed that membrane shape/curvature can in itself mediate the recruitment of lipidated proteins. However, exactly how membrane curvature and composition synergize remains largely unexplored.
http://ift.tt/2uIFpI7
Membrane Curvature and Lipid Composition Synergize To Regulate N-Ras Anchor Recruitment
Proteins anchored to membranes through covalently linked fatty acids and/or isoprenoid groups play crucial roles in all forms of life. Sorting and trafficking of lipidated proteins has traditionally been discussed in the context of partitioning to membrane domains of different lipid composition. We recently showed that membrane shape/curvature can in itself mediate the recruitment of lipidated proteins. However, exactly how membrane curvature and composition synergize remains largely unexplored.
http://ift.tt/2uIFpI7
Neuraxial drug delivery for the management of cancer pain: cost, updates, and society guidelines.
Purpose of review: The present study discusses the utilization of neuraxial drug delivery (NDD) for the management of cancer pain, based on recent trials, reviews, and guidelines with a focus on cost analysis. Recent findings: Almost all recent publications suggest that more stringent research is needed to improve evidence on NDD, particularly as conflicting reports exist regarding cost effectiveness of drug delivery systems. The combination of local anesthetics and opioids, with or without clonidine, continues to be reported as beneficial with the utilization of patient controlled systems providing an advantage over continuous ones. Interestingly, the use of opioids as an adjunct to local anesthetics may not enhance analgesia but the addition of dexamethasone is useful for incident cancer-related bone pain. Ziconitide remains supported as first-line therapy in districts where it is available - United States and Europe. Although new targeted drugs are being designed for cancer pain management, none have seen human clinical trials in the last year. Summary: The ability to demonstrate cost effectiveness of NDD is variable from region to region. Less expensive externalized systems may pose a viable alternative. With the exception of dexamethasone, no new drugs have been shown to provide any benefit to conventional medications. Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.
http://ift.tt/2ujgEky
http://ift.tt/2ujgEky
Management of complex spine surgery.
Purpose of review: The main objective of this article is to present the updated data regarding the perioperative management of patients undergoing major spine surgery in an era where the surgical techniques are changing and there is a high demand for these surgeries in older and high-risk patients. Recent findings: Preoperative assessment and stabilization is now more structured protocol and it is based on a multidisciplinary approach to the patient. The Enhanced Recovery After Surgery (ERAS) programs and the Perioperative Surgical Home on major spine surgery are not yet fully evidence based but it seems that the use of a perioperative optimization of patients and use of a drugs' bundle is more effective than using single drugs or interventions on the postoperative pain reduction and faster recovery from surgery. Fluid and pain-control protocols combined with an accurate blood management represent the key to success. Summary: A tailored approach to patients undergoing major spine surgeries seems to be effective improving the outcome and quality of life of patients. Future studies should aim to understand which elements of the ERAS can be improved to allow the patient to have a long-term good outcome. Video abstract: http://ift.tt/2vtcsgP Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.
http://ift.tt/2ujeGRp
http://ift.tt/2ujeGRp
The COOLER Code: A Novel Analytical Approach to Calculate Subcellular Energy Deposition by Internal Electron Emitters
Radiation Research, Volume 188, Issue 2, Page 204-220, August 2017.
http://ift.tt/2uIv7HH
Different Sequences of Fractionated Low-Dose Proton and Single Iron-Radiation-Induced Divergent Biological Responses in the Heart
Radiation Research, Volume 188, Issue 2, Page 191-203, August 2017.
http://ift.tt/2vtPNkk
Cellular Therapies for Treatment of Radiation Injury after a Mass Casualty Incident
Radiation Research, Volume 188, Issue 2, Page 242-245, August 2017.
http://ift.tt/2uHL1lW
Cellular Therapies for Treatment of Radiation Injury: Report from a NIH/NIAID and IRSN Workshop
Radiation Research, Volume 188, Issue 2, Page e54-e75, August 2017.
http://ift.tt/2vtGDEy
Subtype-Specific Radiation Response and Therapeutic Effect of FAS Death Receptor Modulation in Human Breast Cancer
Radiation Research, Volume 188, Issue 2, Page 169-180, August 2017.
http://ift.tt/2uIyRJm
Delayed Growth Suppression and Radioresistance Induced by Long-Term Continuous Gamma Irradiation
Radiation Research, Volume 188, Issue 2, Page 181-190, August 2017.
http://ift.tt/2vu2k7h
Radiation Exposure Enhances Hepatocyte Proliferation in Neonatal Mice but not in Adult Mice
Radiation Research, Volume 188, Issue 2, Page 235-241, August 2017.
http://ift.tt/2vto17F
Intrinsic LINE-1 Hypomethylation and Decreased Brca1 Expression are Associated with DNA Repair Delay in Irradiated Thyroid Cells
Radiation Research, Volume 188, Issue 2, Page 144-155, August 2017.
http://ift.tt/2uHXt50
The Exploitation of Low-Energy Electrons in Cancer Treatment
Radiation Research, Volume 188, Issue 2, Page 123-143, August 2017.
http://ift.tt/2vtyG22
Cellular Response to Exponentially Increasing and Decreasing Dose Rates: Implications for Treatment Planning in Targeted Radionuclide Therapy
Radiation Research, Volume 188, Issue 2, Page 221-234, August 2017.
http://ift.tt/2uIJvzU
Keep it clean: How to prevent on-scene, rehab carcinogen exposures
Firefighters should assume carcinogens are present during suppression and overhaul activities and take appropriate actions during and after the incident
http://ift.tt/2ukbRO4
Expression of Type I Cannabinoid Receptors at Different Stages of Neuronal Differentiation of Human Fibroblasts
Differential expression of type 1 cannabinoid receptors (CR1) was evaluated at different stages of human skin fibroblast transformation into terminally differentiated neurons. Immunocytochemical staining detected no CR1 on fibroblasts, but their transformation into induced pluripotent stem cells was accompanied by marked stimulation of CR1 expression. In neuronal precursors, the receptors were located mainly on cell bodies and at the base of their processes. This distribution was retained at the terminal stage of differentiation of induced pluripotent stem cells into neurons.
http://ift.tt/2ujlfDc
Ovarian Cancer in Young Women
Abstract
It is not clear how often epithelial tumours affect young women. This study aimed to evaluate the clinico-pathological pattern and survival outcome of women, 40 years and younger, with cancer ovary. Women 40 years and younger, operated between 2008 and 2012 for ovarian cancer, were retrospectively recruited and followed up. The study design was descriptive as well as a survival analysis. A hybrid of retrospective and prospective cohort design was used for risk factor analysis. Of the 115 women less than 40 years being operated for probable ovarian cancer, 22 were excluded for various reasons. Demographic details, clinical presentations, histopathological features, treatments and survival outcomes were studied. The primary outcomes looked for were death and recurrence. Secondary outcomes were complications of treatment and fertility. The predominant histology in the study population was epithelial tumour (70%), and serous adenocarcinoma was the commonest tumour type. The overall survival rate was 87%, and progression free survival was 63%. Time to death and recurrence were dependent on stage of disease, histology of tumour, primary treatment and residual disease at surgery. In multivariate analysis, the hazard ratio for recurrence in advanced stages was 12.6 (95% CI 3.5 to 45.5; p < 0.001) as compared to early stage disease. Epithelial ovarian cancers are common in young women. Death and recurrence are more likely in women with epithelial cancers, advanced stage disease and in those with residual tumour at cytoreductive surgery.
http://ift.tt/2uJpFUM
Predicting Gene Silencing Through the Spatiotemporal Control of siRNA Release from Photo-responsive Polymeric Nanocarriers
We present a novel method that uses photo-responsive block copolymers for more efficient spatiotemporal control of gene silencing with no detectable off-target effects. Additionally, changes in gene expression can be predicted using straightforward siRNA release assays and simple kinetic modeling.
http://ift.tt/2uQMxCr
ED-530XT Duodenoscopes by Fujifilm: Safety Communication - Recall Issued, Updated Design and Labeling
Audience: Gastroenterology, Risk Manager [Posted 07/21/2017] ISSUE: On July 21, 2017, Fujifilm issued an Urgent Medical Device Correction and Removal notification informing customers of its voluntary recall of all ED-530XT duodenoscopes. This...
http://ift.tt/2uilVcg
Intraperitoneal lactate/pyruvate ratio and the level of glucose and glycerol concentration differ between patients surgically treated for upper and lower perforations of the gastrointestinal tract: a pilot study
Secondary peritonitis is a condition associated with high morbidity and mortality. Continuous postoperative monitoring of patients to ensure timely intervention to treat complications without delay is importan...
http://ift.tt/2ujhWKJ
Sero-prevalence and vaccination status of hepatitis A and hepatitis B among adults with cirrhosis in Sri Lanka: a hospital based cohort study
As acute viral hepatitis can be fatal in patients with cirrhosis, vaccination against hepatitis A (HAV) and hepatitis B (HBV) is recommended for non-immune patients. With increasing affluence the incidence of ...
http://ift.tt/2uHv0MM
Microcrystallography of Protein Crystals and In Cellulo Diffraction
http://ift.tt/2tnjQc9
Evaluation of creatine kinase and liver enzymes in identification of severe dengue
Existing biomarkers such as AST, ALT and hematocrit have been associated with severe dengue but evidence are mixed. Recently, interests in creatine kinase as a dengue biomarker have risen. These biomarkers rep...
http://ift.tt/2vsGuky
Comparative assessment of clinical rating scales in Wilson’s disease
Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism resulting in multifaceted neurological, hepatic, and psychiatric symptoms. The objective of the study was to comparatively assess t...
http://ift.tt/2tncaqp
Penumbra 3D Revascularization Device by Penumbra: Class I Recall - Wire Material May Break or Separate During Use
Audience: Cardiology, Risk Manager [Posted 07/21/2017] ISSUE: Penumbra Inc. is recalling the Penumbra 3D Revascularization device because there is a risk of the delivery wire breaking or separating during use. Fractured pieces of the delivery wire...
http://ift.tt/2vsKkKK
ED-530XT Duodenoscopes by Fujifilm: Safety Communication - Recall Issued, Updated Design and Labeling
Audience: Gastroenterology, Risk Manager [Posted 07/21/2017] ISSUE: On July 21, 2017, Fujifilm issued an Urgent Medical Device Correction and Removal notification informing customers of its voluntary recall of all ED-530XT duodenoscopes. This...
http://ift.tt/2uilVcg
Assessing Autophagic Flux by Measuring LC3, p62, and LAMP1 Co-localization Using Multispectral Imaging Flow Cytometry
http://ift.tt/2tnbf9q
Episodic foresight beyond the very next event in 3- and 4-year-old children
Abstract
Testing episodic foresight in children generally involves presenting them with a problem in one location (e.g., Room A) and, after a spending a delay in a different location, telling them they will be returning to Room A. Before they go, children are presented with a number of items, one of which will allow them to solve the problem in Room A. At around 3 to 4 years of age children display episodic foresight, selecting the item that will allow them to solve the problem. To date, however, no study has assessed whether 3- and 4-year-old children can plan beyond the very next event, selecting the correct item when there is a delay before returning to Room A. Here, we show that 3- and 4-year-old children can pass when a delay is imposed but that their performance is significantly worse than when they are planning for an immediate event.
http://ift.tt/2uQv39o
Early response of C-reactive protein as a predictor of survival in patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors
Abstract
Background
Pretreatment C-reactive protein (CRP) has been shown to be an independent prognostic factor for metastatic renal cell carcinoma (mRCC) treated with tyrosine kinase inhibitors (TKIs). We further evaluated the early response of CRP after the initiation of TKIs.
Methods
A total of 103 patients (80 men and 23 women) were treated with TKIs for mRCC from 2008−2013. Patients were divided into three groups according to their early CRP kinetics—patients whose baseline CRP levels were <10 mg/L (non-elevated), patients whose baseline CRP levels were ≥10 mg/L and had decreased by >20% at 4 weeks after the initiation of TKIs (early CRP responder), and the remaining patients (non-early CRP responder). The endpoints were progression-free survival (PFS) and overall survival (OS).
Results
The median follow-up period was 21 (interquartile range 10–34) months. The numbers of patients classified as non-elevated, early CRP responder, and non-early CRP responder were 62, 19, and 22, respectively. The 1-year PFS rates of patients in the non-elevated, early CRP responder, and non-early CRP responder groups were 50, 23, and 9.7%, respectively (p < 0.001). The 1-year OS rates of patients in these three groups were 79, 62, and 36%, respectively (p < 0.001). In multivariate analysis, the early CRP kinetics assessment was a significant independent factor for PFS and OS.
Conclusions
Early CRP response at 4 weeks is predictive of survival for patients with mRCC treated with TKI.
http://ift.tt/2uHHdRl
Expression of the scaffold connector enhancer of kinase suppressor of Ras 1 (CNKSR1) is correlated with clinical outcome in pancreatic cancer
Abstract
Background
Despite the near universal occurrence of activating codon 12 KRAS somatic variants in pancreatic cancer, there is considerable heterogeneity in the molecular make-up, MAPK/ERK pathway activation states, and clinical outcome in this disease. We analyzed the expression levels of CNKSR1, a scaffold that influences MAPK/ERK pathway activity, in clinical pancreas cancer specimens and their impact on survival of patients with pancreatic cancer.
Methods
Immunohistochemical staining for CNKSR1 expression was performed on 120 specimens from three independent pancreatic cancer tissue registries, phospho-ERK levels were measured in 86 samples. Expression was divided into CNKSR1 low and CNKSR1 high and correlated with clinicopathological variables including overall survival using multivariate Cox proportional hazard ratio models.
Results
CNKSR1 expression was increased in tumors compared to matched normal uninvolved resection specimens (p = 0.004). 28.3% (34/120) of patient specimens stained as CNKSR1 low compared to 71.7% (86/120) of specimens which stained as CNKSR1 high. High CNKSR1 expression was more prevalent in low grade tumors (p = 0.04). In multivariate analysis, low CNKSR1 expression status was independently correlated with decreased overall survival (HR = 2.146; 95% CI 1.34 to 3.43). When stratifying primary, non-metastatic tumor biopsies by CNKSR1 expression, resection was associated with improved survival in patients with high CNKSR1 expression (p < 0.0001) but not low CNKSR1 expression (p = 0.3666). Pancreatic tumors with nuclear in addition to cytoplasmic CNKSR1 staining (32/107) showed increased nuclear phospho-ERK expression compared to tumor with cytoplasmic CNKSR1 staining only (p = 0.017).
Conclusion
CNKSR1 expression is increased in pancreatic tissue specimens and was found to be an independent prognostic marker of overall survival. CNKSR1 may help to identify patient subgroups with unfavorable tumor biology in order to improve risk stratification and treatment selection. Cellular distribution of CNKSR1 was correlated with nuclear pERK expression.
http://ift.tt/2uj1lXp
Cholangiocytes and the environment in primary sclerosing cholangitis: where is the link?
In primary sclerosing cholangitis (PSC), annular fibrosis around intrahepatic and extrahepatic bile ducts leads to progressive liver disease for which there is no effective therapy except liver transplantation.1 The concentric accumulation of connective tissue around bile ducts suggests that the cholangiocyte plays an integral role in PSC pathogenesis. However, what initiates changes in cholangiocyte phenotype and how cholangiocytes interact with cells in the peribiliary extracellular matrix like immune cells and stromal components is largely unknown. Over the last 10 years, genome-wide association studies in PSC have revealed >20 risk genes.2–5 A significant observation that can be derived from these data, which also applies to other non-Mendelian phenotypes, is that the predominant risk contribution is likely to come from one or more environmental sources, rather than the genetic aberrations. Indeed, in PSC, we estimate that <10% of the overall liability is...
http://ift.tt/2tNTkYR
EMS agency wraps ambulance in handprints of children with autism
The autism ambulance is the second ambulance specially wrapped as a joint project between the Whitley County Fiscal Court and Whitley EMS
http://ift.tt/2uiisuj
2017 Hooley™ Awards winners announced at ImageTrend Connect
LAKEVILLE, Minn. — ImageTrend, Inc. announced the winners of the 2017 Hooley™ Awards. Nominees were narrowed down to a field of nine finalists – three in each of three categories – from which the winners were selected by a panel of third-party judges. Judges cast votes via secret ballot for each category. ImageTrend extends congratulations to the nominees, finalists and winners ...
http://ift.tt/2tNW3RZ
Correlation of Transabdominal Ultrasonography and Cystoscopy in Follow-up of Patients with Non-muscle Invasive Bladder Cancer
Abstract
Cystoscopy (CS) is considered to be the gold standard in the follow-up of non-muscle invasive bladder cancer. However, CS is invasive, time-consuming, and expensive. On the other hand, modern sensitive transducers have improved the imaging of urinary tract rendering transabdominal ultrasonography (US) more effective in visualizing intraluminal filling defects in the bladder than it was in the past. Twenty-five follow-up patients of low-risk bladder cancer meeting the inclusion and exclusion criteria were included in study. Ultrasonography of the bladder was performed by a single senior radiologist, and subsequently, these patients were subjected to flexible cystoscopy under local anesthesia. Pain score was calculated for each of the cystoscopies done. Findings of transabdominal ultrasound of the bladder were correlated and compared with those of cystoscopy. Subjects with US and/or CS findings suggestive of recurrence underwent transurethral resection of bladder tumor (TURBT) under general anesthesia and confirmation of the bladder carcinoma was achieved by the histopathological examination. Mean patient age was 60.56 years with range of 29 to 77 years. The sensitivity of modern ultrasonographic techniques was found to be 84.61% with specificity of 91.7% taking flexible cystoscopy as the gold standard for detection of recurrence. The accuracy of US was 88% with positive predictive value of 91.7% and negative predictive value of 84.61%. Technological evolution has improved the accuracy of ultrasonography in diagnosis of bladder carcinoma. It represents a valuable surveillance tool in selected sub group of low risk non-muscle invasive bladder cancer patients.
http://ift.tt/2uJa9Z6
Measurement of Basal and Forskolin-stimulated Lipolysis in Inguinal Adipose Fat Pads
http://ift.tt/2gQnE3S
Endoscopic surgical technique for benign fibrotic strictures of the upper esophageal sphincter
Abstract
A 43-year-old man with complaints of increased difficulty of swallowing and weight loss underwent videofluorographic examination of swallowing, which revealed severely reduced cricopharyngeal opening. Endoscopic cricopharyngeal myotomy was performed using a modified technique (mECPM). A benign fibrotic stricture of the upper esophageal sphincter (UES) was identified under visualization of a distending operating laryngoscope. A vertical midline incision in the strictured mucosa and submucosal resection of the cricopharyngeal muscle were performed using a CO2 laser. The initial vertical mucosal incision was tightly sutured in the horizontal direction with absorbable surgical sutures. Histopathological examination of the cricopharyngeal muscle revealed infiltration of inflammatory cells. The patient started his oral intake on postoperative day 7. He has been symptom-free for two years with an improved body mass index, and postoperavite laryngoscopy revealed no salivary retention in the piriform sinuses. The technique presented here provides sufficient opening of the UES by eliminating the problem of restenosis. mECPM will be useful for treating benign fibrotic strictures of the UES.
This article is protected by copyright. All rights reserved.
http://ift.tt/2vs5JDJ
In vivo diagnosis of early-stage gastric cancer found after Helicobacter pylori eradication using probe-based confocal laser endomicroscopy
Abstract
Background and Aim
Early-stage gastric cancer (EGC) found after Helicobacter pylori (Hp) eradication often displays non-tumorous regenerative epithelium and/or maturated tumorous epithelium overlying the cancerous tissue, which may confuse endoscopic and histologic diagnosis. Probe-based confocal laser endomicroscopy (pCLE) enables in vivo real-time optical biopsy. We compared the diagnostic yields for these EGC cases using conventional white light endoscopy (WL), magnifying endoscopy with narrow-band imaging (ME-NBI), pCLE, and endoscopic biopsy; we also compared the accuracy of the horizontal extent diagnosis between ME-NBI and pCLE.
Methods
This study enrolled 30 patients with 36 EGC lesions after successful Hp eradication. The diagnostic yields of WL, ME-NBI, pCLE, and endoscopic biopsy were prospectively compared. Four points of cancerous margins (oral, anal, anterior, and posterior sites) were also prospectively evaluated with M-NBI and pCLE to determine the horizontal extent of the EGC.
Results
The diagnostic yield was significantly higher with pCLE than with WL and endoscopic biopsy (97 vs. 72%, 97 vs. 72%, P=0.0159, 0.0077, respectively), whereas it did not differ from ME-NBI (88.9%, P=0.371). The height of non-tumorous regenerative epithelium or maturated atypical glands was 104.7±34.2 μm in the pCLE-positive cases, whereas it was 188.3±27.1 μm in a pCLE-negative case (P=0.0004). The diagnostic accuracy of the horizontal margin of EGC was significantly higher with pCLE than with ME-NBI (92 vs. 70%, P=0.0159).
Conclusion
pCLE may be helpful for the diagnosis of ambiguous ECGs found after Hp eradication because it enables real-time scanning throughout the lesion and the detection of subsurface microstructure.
This article is protected by copyright. All rights reserved.
http://ift.tt/2gQet3r
GeneXpert HIV-1 quant assay, a new tool for scale up of viral load monitoring in the success of ART programme in India
Recent WHO guidelines identify virologic monitoring for diagnosing and confirming ART failure. In view of this, validation and scale up of point of care viral load technologies is essential in resource limited...
http://ift.tt/2twNnEn
Spatial and temporal patterns of diarrhoea in Bhutan 2003–2013
To describe spatiotemporal patterns of diarrhoea in Bhutan, and quantify the association between climatic factors and the distribution and dynamics of the disease.
http://ift.tt/2vs34tF
Exiguobacterium sp. A1b/GX59 isolated from a patient with community-acquired pneumonia and bacteremia: genomic characterization and literature review
Bacterial species belonging to the genus Exiguobacterium are facultative anaerobic, non-spore-forming, Gram-positive bacilli, and rarely associated with human infections. Herein, we reported the first case of com...
http://ift.tt/2twZ1yP
Staphylococcus aureus Prostatic abscess: a clinical case report and a review of the literature
Prostatic abscess is a rare complication of acute bacterial prostatitis and is most commonly caused by Enterobacteriaceae. We report on a case of prostatic abscess caused by Staphylococcus aureus and conduct a re...
http://ift.tt/2vsiYUW
Validity and reliability of the tuberculosis-related stigma scale version for Brazilian Portuguese
Stigma associated with tuberculosis (TB) has been an object of interest in several regions of the world. The behaviour presented by patients as a result of social discrimination has contributed to delays in di...
http://ift.tt/2twT7h7
PD-1 Checkpoint Blockade in Combination with an mTOR Inhibitor Restrains Hepatocellular Carcinoma Growth Induced by Hepatoma Cell-Intrinsic PD-1
ABSTRACT
Inhibitors of PD-1 administered as single agents have resulted in durable tumor regression in advanced cancer patients. However, only a minority of cancer patients respond to anti PD-1 immunotherapy. Here, we show that PD-1 expression in hepatocellular carcinoma (HCC) promotes tumor growth independently of adaptive immunity. Knockdown of PD-1 suppress tumor growth, whereas PD-1 overexpression enhances tumorigenesis in immunodeficient xenografted mice. Mechanistically, PD-1 binds the downstream mTOR effectors eukaryotic initiation factor 4E (eIF4E) and ribosomal protein S6 (S6), thus promoting their phosphorylation. Moreover, combining mTOR inhibition with anti-PD-1 antibody treatment results in more durable and synergistic tumor regression than either single agent alone, each of which presents only modest efficacy. Therefore, targeting mTOR pathways in combination with PD-1 may result in increased antitumor efficacy in cancer patients. This article is protected by copyright. All rights reserved.
http://ift.tt/2tNYW59
The Ecology of Exercise: Mechanisms Underlying Individual Variation in Behavior, Activity, and Performance: An Introduction to Symposium
Abstract
Wild animals often engage in intense physical activity while performing tasks vital for their survival and reproduction associated with foraging, avoiding predators, fighting, providing parental care, and migrating. In this theme issue we consider how viewing these tasks as "exercise"—analogous to that performed by human athletes—may help provide insight into the mechanisms underlying individual variation in these types of behaviors and the importance of physical activity in an ecological context. In this article and throughout this issue, we focus on four key questions relevant to the study of behavioral ecology that may be addressed by studying wild animal behavior from the perspective of exercise physiology: (1) How hard do individual animals work in response to ecological (or evolutionary) demands?; (2) Do lab-based studies of activity provide good models for understanding activity in free-living animals and individual variation in traits?; (3) Can animals work too hard during "routine" activities?; and (4) Can paradigms of "exercise" and "training" be applied to free-living animals? Attempts to address these issues are currently being facilitated by rapid technological developments associated with physiological measurements and the remote tracking of wild animals, to provide mechanistic insights into the behavior of free-ranging animals at spatial and temporal scales that were previously impossible. We further suggest that viewing the behaviors of non-human animals in terms of the physical exercise performed will allow us to fully take advantage of these technological advances, draw from knowledge and conceptual frameworks already in use by human exercise physiologists, and identify key traits that constrain performance and generate variation in performance among individuals. It is our hope that, by highlighting mechanisms of behavior and performance, the articles in this issue will spur on further synergies between physiologists and ecologists, to take advantage of emerging cross-disciplinary perspectives and technologies.http://ift.tt/2uhH1r6
Frailty and cancer: Implications for oncology surgery, medical oncology, and radiation oncology
Abstract
The concept of frailty has become increasingly recognized as one of the most important issues in health care and health outcomes and is of particular importance in patients with cancer who are receiving treatment with surgery, chemotherapy, and radiotherapy. Because both cancer itself, as well as the therapies offered, can be significant additional stressors that challenge a patient's physiologic reserve, the incidence of frailty in older patients with cancer is especially high—it is estimated that over one-half of older patients with cancer have frailty or prefrailty. Defining frailty can be challenging, however. Put simply, frailty is a state of extreme vulnerability to stressors that leads to adverse health outcomes. In reality, frailty is a complex, multidimensional, and cyclical state of diminished physiologic reserve that results in decreased resiliency and adaptive capacity and increased vulnerability to stressors. In addition, over 70 different measures of frailty have been proposed. Still, it has been demonstrated that frail patients are at increased risk of postoperative complications, chemotherapy intolerance, disease progression, and death. Although international standardization of frailty cutoff points are needed, continued efforts by oncology physicians and surgeons to identify frailty and promote multidisciplinary decision making will help to develop more individualized management strategies and optimize care for patients with cancer. CA Cancer J Clin 2017. © 2017 American Cancer Society.
http://ift.tt/2vrw58N
Long noncoding RNA expression profiles in sub-lethal heat-treated hepatoma carcinoma cells
Abstract
Background
Sub-lethal heat treatment characterizes a transition zone of radiofrequency ablation (RFA) which explains hepatocellular carcinoma (HCC) residual cancer occurrence in this area after RFA treatment. The biochemistry of residual cancer cell recurrence is poorly understood, but long noncoding RNAs (lncRNAs) may have aberrant expression that is associated with diverse cancers. Thus, we measured lncRNA gene expression in sub-lethally heat-treated HCC cells using microarray.
Method
Differentially expressed lncRNA and mRNA were measured with an Agilent Human lncRNA + mRNA Array V4.0 (4 × 180 K format) containing 41,000 lncRNAs and 34,000 mRNAs. Bioinformatics analysis was used to assess differentially expressed lncRNA and mRNA. Seven lncRNA and seven mRNA were validated by qRT-PCR analysis in HCC cells.
Results
Genome-wide lncRNA and mRNA expression data in sub-lethal heat-treated SMMC-7721 HCC cells 558 lncRNA and 250 mRNA were significantly up-regulated and 224 lncRNA and 1031 mRNA down-regulated compared to normal cultured SMMC-7721 cells. We demonstrated for the first time that ENST00000570843.1, ENST00000567668.1, ENST00000582249.1, ENST00000450304.1, TCONS_00015544, ENST00000602478.1, TCONS_00001266 and ARC, IL12RB1, HSPA6 were upregulated, whereas STAT3, PRPSAP1, MCU, URB2 were down-regulated in sub-lethally heat-treated HCC cells.
Conclusions
lncRNA expression data in sub-lethally heat-treated HCC cells will provide important insights about lncRNAs' contribution to HCC recurrence after RFA treatment.
http://ift.tt/2twXKaY
2015 Edition Certification Criteria Infographic Published
This document makes it easier to understand the sixty 2015 edition ceritifcation criteria.
http://ift.tt/2tngPIE
Internal quality control in an academic cytopathology laboratory for the introduction of a new reporting system for endometrial cytology
Abstract
Background
To evaluate reproducibility of a reporting system for endometrial cytology.
Methods
Cytologic slides from 49 patients, prepared via liquid based cytology, were blindly examined by five cytopathologists of various experience levels, applying a recently introduced reporting system as previously reported. The agreement among cytopathologists was evaluated via Kappa (κ) statistics and the Kendall's Coefficient of Variation (W); cytologic results were compared with the relevant histologic report.
Results
Substantial agreement among all five raters was found in the benign, ACE-L and malignant categories, fair agreement in inadequate and ACE-H categories, whereas only slight agreement in ACE-U. For the three more experienced cytopathologists, an almost perfect agreement was found in inadequate, benign, and ACE-L categories, substantial agreement in ACE-H and malignant categories and fair agreement in ACE-U category. Overall agreement for all five cytopathologists and for all categories was moderate, whereas it was very high for the three senior raters. Using the Kendall's test, both five cytopathologists (W = 0.81) and the three senior ones (W = 0.93) had very high agreement. Sensitivity: 83.33–92.59%, specificity: 83.33–94.74%, ROC area: 71.72–90.3%.
Conclusion
Application of appropriate statistical tests shows that integration of a new reporting cytologic system is effective with an overall accuracy around 90%. Both statistical tests applied disclosed lower agreement rates among both all five raters and the three most experienced ones in the intermediate categories constituting the gray zone, thus delineating the need for better training of cytopathologists to correctly identify diagnostic criteria for classification of a given case into these categories.
http://ift.tt/2twXvgg
Fatigue associated with newly approved vascular endothelial growth factor receptor tyrosine kinase inhibitors in cancer patients: an up-to-date meta-analysis
Abstract
The fatigue associated with five newly approved vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) (regorafenib, vandetanib, cabozantinib, lenvatinib, axitinib) is poorly understood. We conducted this systematic review to fully investigate the fatigue associated with these VEGFR-TKIs in cancer patients. Relevant studies of randomized controlled trials in cancer patients treated with the five VEGFR-TKIs were retrieved and a systematic evaluation was conducted. EMBASE, MEDLINE, and PubMed were searched for articles published until March 2017. Thirteen randomized controlled trials and 4395 patients were included. The current analysis suggested that the use of five newly approved VEGFR-TKIs increased the risk of all-grade fatigue (1.43; 95% CI 1.23–1.66; p < 0.00001) and high-grade (≥grade 3) fatigue (1.97; 95% CI1.44–2.70; p < 0.0001). On subgroup analysis, the risk ratio (RR) of all-grade fatigue varied significantly within drug type, but high-grade fatigue did not. The RR of all-grade and high-grade fatigue did not vary significantly according to cancer type, treatment line, and treatment duration. The risk of high-grade fatigue may vary with treatment duration, whereas all-grade fatigue may not. The available data suggest that the use of the five newly approved VEGFR-TKIs is associated with a significantly increased risk of fatigue in cancer patients. Physicians should be aware of this adverse effect and should monitor cancer patients receiving these drugs.
http://ift.tt/2vrT03M
FDA Clears Wider Use of Cooling Cap to Reduce Hair Loss during Chemotherapy
The FDA has cleared a cooling cap—a device designed to reduce hair loss during chemotherapy called the DigniCap Scalp Cooling System—for use by patients with any type of solid tumor.
http://ift.tt/2vs6A7B
Assessment of simplified ratio-based approaches for quantification of PET [ 11 C]PBR28 data
Abstract
Purpose
Kinetic modelling with metabolite-corrected arterial plasma is considered the gold standard for quantification of [11C]PBR28 binding to the translocator protein (TSPO), since there is no brain region devoid of TSPO that can serve as reference. The high variability in binding observed using this method has motivated the use of simplified ratio-based approaches such as standardised uptake value ratios (SUVRs) and distribution volume (VT) ratios (DVRs); however, the reliability of these measures and their relationship to VT have not been sufficiently evaluated.
Methods
Data from a previously published [11C]PBR28 test-retest study in 12 healthy subjects were reanalysed. VT was estimated using a two-tissue compartment model. SUVR and DVR values for the frontal cortex were calculated using the whole brain and cerebellum as denominators. Test-retest reliability was assessed for all measures. Interregional correlations were performed for SUV and VT, and principal component analysis (PCA) was applied. Lastly, correlations between ratio-based outcomes and VT were assessed.
Results
Reliability was high for VT, moderate to high for SUV and SUVR, and poor for DVR. Very high interregional correlations were observed for both VT and SUV (all R 2 > 85%). The PCA showed that almost all variance (>98%) was explained by a single component. Ratio-based methods correlated poorly with VT (all R 2 < 34%, divided by genotype).
Conclusions
The reliability was good for SUVR, but poor for DVR. Both outcomes showed little to no association with VT, questioning their validity. The high interregional correlations for VT and SUV suggest that after dividing by a denominator region, most of the biologically relevant signal is lost. These observations imply that results from TSPO PET studies using SUVR or DVR estimates should be interpreted with caution.
http://ift.tt/2uQ6EAM
Drug discovery and development for rare genetic disorders
Approximately 7,000 rare diseases affect millions of individuals in the United States. Although rare diseases taken together have an enormous impact, there is a significant gap between basic research and clinical interventions. Opportunities now exist to accelerate drug development for the treatment of rare diseases. Disease foundations and research centers worldwide focus on better understanding rare disorders. Here, the state-of-the-art drug discovery strategies for small molecules and biological approaches for orphan diseases are reviewed. Rare diseases are usually genetic diseases; hence, employing pharmacogenetics to develop treatments and using whole genome sequencing to identify the etiologies for such diseases are appropriate strategies to exploit. Beginning with high throughput screening of small molecules, the benefits and challenges of target-based and phenotypic screens are discussed. Explanations and examples of drug repurposing are given; drug repurposing as an approach to quickly move programs to clinical trials is evaluated. Consideration is given to the category of biologics which include gene therapy, recombinant proteins, and autologous transplants. Disease models, including animal models and induced pluripotent stem cells (iPSCs) derived from patients, are surveyed. Finally, the role of biomarkers in drug discovery and development, as well as clinical trials, is elucidated.
http://ift.tt/2uINYC8
Posterior osteosynthesis with monoaxial lateral mass screw-rod system for unstable c1 burst fractures
Publication date: Available online 21 July 2017
Source:The Spine Journal
Author(s): Yin-shun Zhang, Jian-xiang Zhang, Qing-guo Yang, Wei Li, Hui Tao, Cai-liang Shen
Background ContextSurgical treatment for unstable atlas fractures has evolved in recent decades from C1-C2 or C0-C2 fusion to motion-preservation techniques of open reduction and internal fixation (ORIF). However, regardless of transoral or posterior approach, the reduction is still not satisfactory.PurposeThe article describes and evaluates a new technique for treating the unstable atlas fractures by using a monoaxial screw-rod system.Study DesignThis is a retrospective studyPatient SampleThe sample includes adult patients with unstable C1 fractures treated with a posterior monoaxial screw-rod system.Outcome MeasuresVisual analog pain scale (VAS),radiographic reduction (lateral mass displacement), maintenance of reduction, C1-C2 instability (anterior atlanto-dens interval), and complications.MethodsFrom August 2013 to May 2016, 9 consecutive patients with unstable atlas fractures were retrospectively reviewed. All patients were treated with posterior ORIF by using a monoaxial screw-rod system. The medical records and the preoperative and postoperative radiographs were reviewed. The preoperative and postoperative computed tomography (CT) scans were used to specify the fracture types and to assess the reduction.ResultsAll 9 patients with a mean age of 50.3 years successfully underwent surgery with this technique, and a follow-up of 17.4±9.3 months was performed. Transverse atlantal ligament (TAL) injury was found in 8 of the 9 patients: 1 of type I and 7 of type II. The preoperative lateral mass displacement averaged 7.0±2.2 mm and was restored completely after surgery; all the fractures achieved bony healing without loss of reduction or implant failure. None of the patients had complications of neurological deficit, vertebral artery injury, or wound infection associated with the surgical procedure. Two patients complained of greater occipital nerve neuralgia after the operation, which gradually disappeared in 1 month. All patients had a well-preserved range of motion of the upper cervical spine at the final follow-up.ConclusionsPosterior osteosynthesis with a monoaxial screw-rod system is capable of almost anatomical reduction for the unstable atlas fractures. The TAL incompetence may be not a contraindication to ORIF for C1 fractures, but the long-term effect of C1-C2 instability remains to be further investigated.
http://ift.tt/2vsaP30
Risk factor analysis for predicting vertebral body re-collapse after posterior instrumented fusion in thoracolumbar burst fracture
Publication date: Available online 20 July 2017
Source:The Spine Journal
Author(s): Hae-Dong Jang, Jae Chul Lee, Jae-Wan Soh, Sung-Woo Choi, Hyeung-Kyu Cho, Byung-Joon Shin
Background ContextIn the posterior instrumented fusion surgery for thoracolumbar (T-L) burst fracture, early postoperative re-collapse of well-reduced vertebral body fracture could induces critical complications such as correction loss, post-traumatic kyphosis, metal failure, often lead to revision surgery. Furthermore, re-collapse is quite difficult to predict because of the variety of risk factors and no widely accepted accurate prediction systems existed. Although load sharing classification (LSC) has been known to help to decide the need for additional anterior column support, this radiographic scoring system has several critical limitations.Purpose1) To evaluate risk factors and predictors for postoperative re-collapse in T-L burst fractures. 2) Through the decision-making model, we aimed to predict re-collapse and prevent unnecessary additional anterior spinal surgery.Study DesignRetrospective comparative study.Patient SampleTwo-hundred and eight (104 men and 104 women) consecutive patients with thoracolumbar burst fracture who underwent posterior instrumented fusion were reviewed retrospectively. Burst fracture caused by high energy trauma (fall from a height and motor vehicle accident) with a minimum one-year follow-up were included. The average age at the time of surgery was 45.9 years (range, 15 to 79). With respect to the involved spinal level, 95 cases (45.6%) involved L1, 51 involved T12, 54 involved L2, and 8 involved T11. Mean fixation segments were 3.5 (range, 2 to 5). Pedicle screw instrumentation including fractured vertebra had been performed in 129 patients (62.3%).Outcome MeasuresClinical data using self-report measures (visual analogue scale score), radiographic measurements (plain radiograph, computed tomography, and magnetic resonance image), and functional measures using the Oswestry Disability Index were evaluated.MethodsBody height loss of fractured vertebra, body wedge angle and Cobb angle were measured in serial plain radiographs. We assigned patients to the re-collapse group if their body height loss was progressed greater than 20% at any follow-up time compared with immediate postoperative body height loss; we assigned the remaining patients to the well-maintained group. The χ2 test and t-test of SPSS were used for comparison of differences between two groups and multiple logistic regression analysis for risk factor evaluation. Through the decision tree analysis of statistical package R, decision-making model was composed and a cut-off value of revealed risk factors and re-collapse rate of each subgroup were identified. Present study was supported by University College of medicine Research Fund (University to which authors belong). There was no external funding source for this study. The authors have no conflict of interest to declare.ResultsRe-collapse occurred in 31 of 208 patients (14.9%). In this group, age, the proportion of male gender, preoperative height loss, and preoperative wedge angle were significantly greater than the well-maintained group. Multivariable logistic regression analysis identified two independent risk factors: age (adjusted odds ratio 1.084, p = 0.002) and body height loss (adjusted odds ratio 1.065, p = 0.003). According to decision-making tree, age (>43 years) was the most discriminating variable, and preoperative body height loss (> 54%) was the second. In this model, the re-collapse rate was zero in the ages less than 43 years and among the remains, nearly 80% patients greater than 54 % of body height loss belonged to the re-collapse group.ConclusionsThe independent predictors of re-collapse after posterior instrumented fusion for T-L burst fracture were the age at operation (> 43 years old) and preoperative body height loss (> 54%). Careful assessment using our decision-making model could help to predict re-collapse and prevent unnecessary additional spinal surgery for anterior column support, especially in young patients.
http://ift.tt/2uGM1Xh
Incidental durotomy during total en bloc spondylectomy
Publication date: Available online 20 July 2017
Source:The Spine Journal
Author(s): Noriaki Yokogawa, Hideki Murakami, Satoru Demura, Satoshi Kato, Katsuhito Yoshioka, Hiroyuki Tsuchiya
Background ContextThe incidence of incidental durotomy (ID) during total en bloc spondylectomy (TES) tends to be higher than that during other spinal surgeries because of the peculiarities of TES, including its highly invasive nature, epidural tumor extension, and use in patients who often have complicated medical backgrounds. However, there have been no detailed reports on ID associated with TES.PurposeThe study aimed to investigate ID during TES in detail.Study DesignA retrospective review of prospectively collected data.Patient SampleThe study included 105 consecutive spinal tumor patients who underwent TES between May 2010 and February 2015 (59 men, 46 women; mean age, 54.0 years [range, 14–75 years] at the time of surgery).Outcome MeasuresOutcome measures included the incidence, risk factors, anatomical location, intraoperative maneuvers, and postoperative course of ID associated with TES.MethodsMedical and operative records and imaging findings were reviewed. Univariate analysis and multivariable stepwise logistic regression models were used to identify independent risk factors for ID. There was no funding or conflicts of interest for this work.ResultsID occurred in 18 (17.1%) of the 105 patients. The univariate and multivariate analysis demonstrated that older age (adjusted odds ratio [aOR], 6.09; 95% confidence interval [CI], 1.17–31.76, P=0.03), radiotherapy (RT) history (aOR, 5.31; 95% CI, 1.46–19.49, P=0.01), and revision surgery (aOR, 19.42; 95% CI, 3.46–109.14, P<0.01) were independent risk factors for ID. ID was more likely to occur during dissection of tumor tissues in proximity to the nerve root. Although all of the ID cases were primarily sutured and covered with polyglycolic acid mesh and fibrin glue spray, 8 cases required additional intervention due to intractable postoperative cerebrospinal fluid leakage. Six of these 8 had a history of RT.ConclusionOur results may help better identify high-risk patients for ID during TES, which may aid surgeons with optimal surgical decision-making and counseling patients on perioperative complications.
http://ift.tt/2vrr7ZD
Cervical flexion and extension includes anti-directional cervical joint motion in healthy adults
Publication date: Available online 20 July 2017
Source:The Spine Journal
Author(s): Xu Wang, René Lindstroem, Maciej Plocharski, Lasse Riis Østergaaard, Thomas Graven-Nielsen
Background contextAnti-directional cervical joint motion has previously been demonstrated. However, quantitative studies of anti-directional and pro-directional cervical flexion and extension motions have not been published.PurposeQuantitative assessment of directional and anti-directional cervical joint motion in healthy subjects.Study designObservational study.Patients sampleEighteen healthy subjects.Outcome measuresAnti-directional and pro-directional cervical flexion and extension motion from each cervical joint in degrees.MethodsFluoroscopy videos of cervical flexion and extension motions (from neutral to end-range) were acquired from 18 healthy subjects. The videos were divided into 10% epochs of C0/C7 range of motion (ROM). The pro-directional and anti-directional motions in each 10% epoch were extracted, and the ratios of anti-directional motions with respect to the pro-directional motions (0% = no anti-directional movement) were calculated for joints and 10% epochs. This study was funded by University $ 2,000.ResultsThe flexion and extension ROM for C0/C7 were 51.9±9.3° and 57.2±12.2°. The anti-directional motions of flexion and extension ROM constituted 42.8±9.7% and 41.2±8.2% of the respective pro-directional movements. For flexion, the first three joints (C0/C1, C1/C2, C2/C3) demonstrated larger ratios compared to the last three joints (C4/C5, C5/C6, C6/C7) (P<0.03). For extension, C1/C2 and C2/C3 ratios were larger compared to C0/C1, C4/C5, and C5/C6 (P<0.03). Comparisons between flexion and extension motions showed larger C0/C1 ratio but smaller C5/C6 and C6/C7 ratios in extension (P<0.05).ConclusionsThis is the first report of quantified anti-directional cervical flexion and extension motion. The anti-directional motion is approximately 40% of the pro-directional motion. The results document that large proportions of anti-directional cervical flexion and extension motions were normal.
http://ift.tt/2uGPPb9
Traumatic subaxial cervical facet subluxation and dislocation: epidemiology, radiographic analyses and risk factors for spinal cord injury
Publication date: Available online 21 July 2017
Source:The Spine Journal
Author(s): Ryan D Quarrington, Claire F Jones, Petar Tcherveniakov, Jillian M Clark, Simon J I Sandler, Yu Chao Lee, Shabnam Torabiardakani, John J Costi, Brian J C Freeman
Background contextDistractive-flexion injuries (DFIs) of the subaxial cervical spine are major contributors to spinal cord injury (SCI). Prompt assessment and early intervention of DFIs associated with SCI is crucial to optimize patient outcome; however, neurological examination of patients with subaxial cervical injury is often difficult, as patients commonly present with reduced levels of consciousness. Therefore, it is important to establish potential associations between injury epidemiology and radiographic features, and neurological involvement.PurposeThe aim of this study was to describe the epidemiology and radiographic features of DFIs presenting to a major Australian tertiary hospital, and identify those factors predictive of SCI. The agreement and repeatability of radiographic measures of DFI severity were also investigated.Study design/settingThis is a combined retrospective case-control and reliability/agreement study.Patient sampleTwo hundred and twenty-six patients (median age 40 years [interquartile range ±34]; 72.1% male) who presented with a DFI of the subaxial cervical spine between 2003 and 2013 were reviewed.Outcome measuresEpidemiology and radiographic features of DFI, and risk-factors for SCI were identified. Inter- and intra-observer agreement of radiographic measurements was evaluated.MethodsMedical records, radiographs, computed tomography and magnetic resonance imaging scans were examined and the presence of SCI was evaluated. Radiographic images were analysed by two consultant spinal surgeons and the degree of vertebral translation, facet apposition, spinal canal occlusion and spinal cord compression were documented. Multivariable logistic regression models identified epidemiology and radiographic features predictive of SCI. Intra-class correlation coefficients (ICC) examined inter- and intra-observer agreement of radiographic measurements.ResultsThe majority of patients (56.2%) sustained unilateral (51.2%) or bilateral facet (48.8%) dislocation. The C6/C7 vertebral level was most commonly involved (38.5%). Younger adults were over-represented amongst motor-vehicle accidents, whilst falls contributed to a majority of DFIs sustained by older adults. Greater vertebral translation together with lower facet apposition distinguished facet dislocation from subluxation. Dislocation, bilateral facet injury, reduced Glasgow coma scale, spinal canal occlusion and spinal cord compression were predictive of neurological deficit. Radiographic measurements demonstrated at least "moderate" agreement (ICC>0.4), with most demonstrating "almost perfect" reproducibility.ConclusionsThis large-scale cohort investigation of DFIs in the cervical spine describes radiographic features that distinguish facet dislocation from subluxation, and associates highly reproducible anatomical and clinical indices to the occurrence of concomitant SCI.
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BMP-2/7 heterodimer strongly induces bone regeneration in the absence of increased soft tissue inflammation
Publication date: Available online 20 July 2017
Source:The Spine Journal
Author(s): Takashi Kaito, Tokimitsu Morimoto, Yuki Mori, Sadaaki Kanayama, Takahiro Makino, Shota Takenaka, Yusuke Sakai, Satoru Otsuru, Yoshichika Yoshioka, Hideki Yoshikawa
Background ContextBone morphogenetic protein (BMP)-2/7 heterodimer is a stronger inducer of bone regeneration than individual homodimers. However, clinical application of its potent bone induction ability may be hampered if its use is accompanied by excessive inflammatory reactions.PurposeWe sought to quantitatively evaluate bone induction and inflammatory reactions by BMP heterodimer and corresponding BMP homodimers using ultra-high resolution magnetic resonance imaging (MRI) and micro-computed tomography.Study DesignExperimental animal study.MethodsA total of 32 absorbable collagen sponge implantations into dorsal muscle were performed in rats of four different groups (control group, 0 µg BMP; recombinant human (rh)BMP-7 group, 3 µg rhBMP-7; rhBMP-2 group, 3 µg rhBMP-2; rhBMP-2/7 group, 3 µg rhBMP-2/7). Inflammatory reactions were evaluated by 11.7-T MRI (axial T2-weighted imaging using Rapid Acquisition with Relaxation Enhancement) at postoperative days 2 and 7. Bone volumes (BVs) of the induced ectopic bone were quantified at postoperative day 7. In addition, immunohistochemical staining for IL-1β, IL-6, and TNF-α was performed in samples obtained on postoperative day 2. Bone formation (BF)/inflammation (IM) ratios were calculated by dividing bone volumes by values of inflamed areas.ResultsAt postoperative day 2, the mean volume of T2 high area on MRI scans in BMP-2 group was significantly larger than that in control group. In contrast, the BMP-2/7 had no difference in the mean volume of T2 high area compared to the control group, however there was no difference between the BMP-2/7 compared to BMP-2 group. At postoperative day 7, the volumes of T2 high area were not different between the groups. Mean BV of the newly formed bone on postoperative day 7 was significantly greater in BMP-2/7 group than in BMP-7 groups. No new bone formation was observed in control group. BF/IM ratio in BMP-2/7 group was significantly higher than those in BMP-2 and BMP-7 homodimer groups. Immunohistochemistry experiments did not reveal differences in expression levels of IL-1β, IL-6, or TNF-α in samples from BMP-2, BMP-7, and BMP-2/7 groups.ConclusionsThis study demonstrated that BMP-2/7 heterodimer has stronger bone induction ability without accompanying increased inflammatory reactions (the increased bone formation to inflammation ratio) than those observed by BMP-2 or BMP-7 homodimers. These results suggest that BMP-2/7 heterodimer can be an alternative to BMP-2 and BMP-7 homodimers in clinical applications, although further translational studies including whether lower doses of BMP heterodimer may produce similar bone formation compared to the BMP homodimers but produce a reduced inflammatory response are required.
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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Alimentary Pharmacology &Therapeutics, EarlyView. https://ift.tt/2qECBIJ
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
