Improved prognosis of young patients with breast cancer undergoing breast-conserving surgery

Background

The aim of the present study was to evaluate how breast cancer prognosis has evolved over time in young women treated with breast-conserving surgery (BCS).

Methods

Data from patients younger than 40 years who had BCS and whole-breast radiotherapy in a single cancer centre between 1997 and 2010 were analysed. The patients were followed until 2016. Endpoints were local recurrence, any breast cancer-related event and death from any cause.

Results

A total of 1331 patients were included in the study. After a median follow-up of 9·3 years, 114 local recurrences, 289 breast cancer-related events and 138 deaths had occurred. Women were divided into three groups of similar size based on tertiles of the date of diagnosis: 1997–2002 (524 patients), 2003–2005 (350) and 2006–2010 (457). The risk of local recurrence was 1·42 per 100 person-years in women diagnosed in the first interval, 0·85 per 100 person-years in the second and 0·48 per 100 person-years in the third (P for trend = 0·028). The respective values were 3·01, 2·52 and 2·07 per 100 person-years for any breast cancer-related event (P = 0·004), and 1·59, 1·22 and 0·64 per 100 person-years for death (P = 0·003). Each passing year was associated with a decreasing risk of local recurrence (hazard ratio (HR) 0·93, 95 per cent c.i. 0·87 to 1·00), any breast cancer-related event (HR 0·94, 0·91 to 0·98) and death (HR 0·89, 0·83 to 0·94). A major improvement in prognosis was observed after 2005, when the classification of breast cancer molecular subtypes and use of trastuzumab were implemented in routine clinical practice.

Conclusion

In the past two decades, both local control and overall prognosis have improved significantly in young women (aged less than 40 years) with breast cancer who undergo BCS.

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Prox1-GFP/Flt1-DsRed transgenic mice: an animal model for simultaneous live imaging of angiogenesis and lymphangiogenesis

Abstract

The roles of angiogenesis in development, health, and disease have been studied extensively; however, the studies related to lymphatic system are limited due to the difficulty in observing colorless lymphatic vessels. But recently, with the improved technique, the relative importance of the lymphatic system is just being revealed. We bred transgenic mice in which lymphatic endothelial cells express GFP (Prox1-GFP) with mice in which vascular endothelial cells express DsRed (Flt1-DsRed) to generate Prox1-GFP/Flt1-DsRed (PGFD) mice. The inherent fluorescence of blood and lymphatic vessels allows for direct visualization of blood and lymphatic vessels in various organs via confocal and two-photon microscopy and the formation, branching, and regression of both vessel types in the same live mouse cornea throughout an experimental time course. PGFD mice were bred with CDh5CreERT2 and VEGFR2lox knockout mice to examine specific knockouts. These studies showed a novel role for vascular endothelial cell VEGFR2 in regulating VEGFC-induced corneal lymphangiogenesis. Conditional deletion of vascular endothelial VEGFR2 abolished VEGFA- and VEGFC-induced corneal lymphangiogenesis. These results demonstrate the potential use of the PGFD mouse as a powerful animal model for studying angiogenesis and lymphangiogenesis.

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Slow Versus Fast Robot-Assisted Locomotor Training After Severe Stroke: A Randomized Controlled Trial.

Background and Purpose: Robot-assisted locomotor training on a bodyweight-supported treadmill is a rehabilitation intervention that compels repetitive practice of gait movements. Standard treadmill speed may elicit rhythmic movements generated primarily by spinal circuits. Slower-than-standard treadmill speed may elicit discrete movements, which are more complex than rhythmic movements and involve cortical areas. Objective: Compare effects of fast (i.e., rhythmic) versus slow (i.e., discrete) robot-assisted locomotor training on a bodyweight-supported treadmill in subjects with chronic, severe gait deficit after stroke. Methods: Subjects (N = 18) were randomized to receive 30 sessions (5 d/wk) of either fast or slow robot-assisted locomotor training on a bodyweight-supported treadmill in an inpatient setting. Functional ambulation category, time up and go, 6-min walk test, 10-m walk test, Berg Balance Scale, and Fugl-Meyer Assessment were administered at baseline and postintervention. Results: The slow group had statistically significant improvement on functional ambulation category (first quartile-third quartile, P = 0.004), 6-min walk test (95% confidence interval [CI] = 1.8 to 49.0, P = 0.040), Berg Balance Scale (95% CI = 7.4 to 14.8, P

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Cauda Equina Syndrome Due to Vigorous Back Massage With Spinal Manipulation in a Patient With Pre-Existing Lumbar Disc Herniation: A Case Report and Literature Review.

Cauda equina syndrome (CES) resulting from acute lumbar disc herniation due to spinal massage is extremely rare. We present a case of CES caused by the acute worsening of a lumbar disc herniation after a vigorous back massage that included spinal manipulation. After vigorous back massage with spinal manipulation performed by a massage therapist, a 38-yr-old male patient experienced CES with severe numbness in both lower limbs, inability to walk due to weakness of bilateral lower limbs, and incontinence of urine and feces. The magnetic resonance imaging and computer tomography scan results showed that the L4-5 disc herniated down into the spinal canal, extensively compressing the ventral dural sac. The patient was successfully treated with an emergency operation including laminectomy, spinal canal decompression, discectomy, interbody fusion, and pedicle screw fixation. The muscle power in both lower limbs of the patient recovered rapidly to support standing only 1 wk later. Moreover, he regained continence of urine and feces. In conclusion, this case brings us novel knowledge that spinal massage or manipulation may worsen pre-existing disc herniation causing CES, and a timely emergency surgery is necessary and effective for treatment of CES-related symptoms. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Is early recurrence of hepatocellular carcinoma in HCV cirrhotic patients affected by treatment with direct-acting antivirals? A prospective multicentre study

Summary

Background

Data on HCV-related hepatocellular carcinoma (HCC) early recurrence in patients whose HCC was previously cured, and subsequently treated by direct-acting antivirals (DAAs), are equivocal.

Aim

To assess the risk of HCC early recurrence after DAAs exposure in a large prospective cohort of HCV-cirrhotic patients with previous successfully treated HCC, also looking for risk factors for cancer early recurrence.

Methods

We enrolled 143 consecutive patients with complete response after curative treatment of HCC, subsequently treated with DAAs and monitored by the web-based RESIST-HCV database. Clinical, biological, and virological data were collected. The primary endpoint was the probability of HCC early recurrence from DAA starting by Kaplan-Meier method.

Results

Eighty-six per cent of patients were in Child-Pugh class A and 76% of patients were BCLC A. Almost all patients (96%) achieved sustained virological response. Twenty-four HCC recurrences were observed, with nodular or infiltrative pattern in 83% and 17% of patients, respectively. The 6-, 12- and 18-month HCC recurrence rates were 12%, 26.6% and 29.1%, respectively. Main tumour size and history of prior HCC recurrence were independent risk factors for HCC recurrence by Cox multivariate model.

Conclusions

Probability of HCC early recurrence in patients who had HCC previously cured remains high, despite HCV eradication by DAAs. Risk was comparable but not higher to that reported in literature in DAA-untreated patients. Previous HCC recurrence and tumour size can be used to stratify the risk of HCC early recurrence. Further studies are needed to assess impact of DAAs on late recurrence and mortality.

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Issue Information

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Cost-effectiveness analysis of potentially curative and combination treatments for hepatocellular carcinoma with person-level data in a Canadian setting

Abstract

Patients with early-stage hepatocellular carcinoma (HCC) are potential candidates for curative treatments such as radiofrequency ablation (RFA), surgical resection (SR), or liver transplantation (LT), which have demonstrated a significant survival benefit. We aimed to estimate the cost-effectiveness of curative and combination treatment strategies among patients diagnosed with HCC during 2002–2010. This study used Ontario Cancer Registry-linked administrative data to estimate effectiveness and costs (2013 USD) of the treatment strategies from the healthcare payer's perspective. Multiple imputation by logistic regression was used to handle missing data. A net benefit regression approach of baseline important covariates and propensity score adjustment were used to calculate incremental net benefit to generate incremental cost-effectiveness ratio (ICER) and uncertainty measures. Among 2,222 patients diagnosed with HCC, 10.5%, 14.1%, and 10.3% received RFA, SR, and LT monotherapy, respectively; 0.5–3.1% dual treatments; and 0.5% triple treatments. Compared with no treatment (53.2%), transarterial chemoembolization (TACE) + RFA (average $2,465, 95% CI: −$20,000–$36,600/quality-adjusted life years [QALY]) or RFA monotherapy ($15,553, 95% CI: $3,500–$28,500/QALY) appears to be the most cost-effective modality with lowest ICER value. The cost-effectiveness acceptability curve showed that if the relevant threshold was $50,000/QALY, RFA monotherapy and TACE+ RFA would have a cost-effectiveness probability of 100%. Strategies using LT delivered the most additional QALYs and became cost-effective at a threshold of $77,000/QALY. Our findings found that TACE+ RFA dual treatment or RFA monotherapy appears to be the most cost-effective curative treatment for patients with potential early stage of HCC in Ontario. These findings highlight the importance of identifying and measuring differential benefits, costs, and cost-effectiveness of alternative HCC curative treatments in order to evaluate whether they are providing good value for money in the real world.

The aim of this article was to estimate the cost-effectiveness of mutually exclusive potentially curative monotherapies such as radiofrequency ablation (RFA), surgical resection (SR), or liver transplantation (LT) and combination therapies with palliative treatment (transarterial chemoembolization, TACE) among patients diagnosed with hepatocellular carcinoma (HCC) during 2002–2010. Compared with no treatment, TACE plus RFA (average $2,465, 95% CI: −$20,000–$36,600/quality-adjusted life years [QALY]) or RFA monotherapy ($15,553, 95% CI: $3,500–$28,500/QALY) appears to be the most cost-effective modality with lowest incremental cost-effectiveness ratio (ICER) value. Our findings found that TACE plus RFA dual treatment or RFA monotherapy appears to be the most cost-effective curative treatment for patients with potential early stage of HCC in Ontario, which may potentially provide good value for money in the real world within the context of an organized healthcare system.

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The Patterns of Non-vitamin K Antagonist Oral Anticoagulants (NOACs) Use in Patients with Atrial Fibrillation in Seven Balkan Countries: a Report from the BALKAN-AF Survey

Abstract

Introduction

Data on management of atrial fibrillation (AF) in the Balkan Region are scarce. To capture the patterns in AF management in contemporary clinical practice in the Balkan countries a prospective survey was conducted between December 2014 and February 2015, and we report results pertinent to the use of non-vitamin K antagonist oral anticoagulants (NOACs).

Methods

A 14-week prospective, multicenter survey of consecutive AF patients seen by cardiologists or internal medicine specialists was conducted in Albania, Bosnia and Herzegovina, Bulgaria, Croatia, Montenegro, Romania, and Serbia (a total of about 50 million inhabitants).

Results

Of 2712 enrolled patients, 2663 (98.2%) had complete data relevant to oral anticoagulant (OAC) use (mean age 69.1 ± 10.9 years, female 44.6%). Overall, OAC was used in 1960 patients (73.6%) of whom 338 (17.2%) received NOACs. Malignancy [odds ratio (OR), 95% confidence interval (CI) 2.06, 1.20–3.56], rhythm control (OR 1.64, 1.25–2.16), and treatment by cardiologists were independent predictors of NOAC use (OR 2.32, 1.51–3.54) [all p < 0.01)], whilst heart failure and valvular disease were negatively associated with NOAC use (both p < 0.01). Individual stroke and bleeding risk were not significantly associated with NOAC use on multivariate analysis.

Conclusions

NOACs are increasingly used in AF patients in the Balkan Region, but NOAC use is predominantly guided by factors other than evidence-based decision-making (e.g., drug availability on the market or reimbursement policy). Efforts are needed to establish an evidence-based approach to OAC selection and to facilitate the optimal use of OAC, thus improving the outcomes in AF patients in this large region.

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Health-Related Quality of Life in Individuals with Down Syndrome: Results from a Non-Interventional Longitudinal Multi-National Study

Abstract

Introduction

To date, there is little research on health-related quality of life (HRQoL) in Down syndrome (DS), and existing research is variable with regard to reported HRQoL in DS. There are also no HRQoL measures developed specifically to be used with individuals with Down syndrome.

Methods

A multi-national, longitudinal, 24-week non-interventional study was conducted in adolescents and adults with DS. HRQoL was assessed (n = 90) using the parent-report KIDSCREEN-27 questionnaire.

Results

HRQoL domain scores were found to be similar to those in the KIDSCREEN-27 European normative group data set on the Physical Well-being, Psychological Well-being, Autonomy and Parent Relations domains. Compared with the normative data set, the adolescent participants with DS in the current study were found to have lower scores on the Social Support and Peers domain and higher scores than the normative group on the School Environment domain. The test-retest reliability of the KIDSCREEN-27 was also examined using the intraclass correlation coefficient (ICC) in a subgroup of stable participants. The KIDSCREEN-27 demonstrated poor-to-moderate test-retest reliability; however, test-retest reliability was assessed using a long time interval between assessment time points.

Conclusion

The findings of this study underline that further research is needed to better understand the nature of HRQoL in DS. Further research using a shorter time interval between assessment time points to examine test-retest reliability is also required.

Funding

F. Hoffmann-La Roche Ltd.

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Circumferential bone grafting around an absorbable gelatin sponge core reduced the amount of grafted bone in the induced membrane technique for critical-size defects of long bones

Publication date: Available online 8 August 2017
Source:Injury
Author(s): Jae-Woo Cho, Jinil Kim, Won-Tae Cho, Jin-Kak Kim, Jong Hoon Song, Hyung-Jin Kim, Alain C. Masquelet, Jong-Keon Oh
ObjectivesThe objectives of the study were to introduce a circumferential bone graft around an absorbable gelatin sponge core using an induced membrane technique, to assess its ability to reduce the required amount of graft and to maintain the bone graft, and to evaluate the clinical outcomes in the management of critical-size bone defects.Patients and MethodsCircumferential bone grafting using a staged induced membrane technique for managing critical-size bone defects was performed in 21 patients. Postoperative computed tomography scans were performed 7days after Hemovac drain removal and 3 months after bone grafting. Volumetric measurements of the defect size, gelatin sponge proportion, and amount of grafted bone were performed by two independent observers using three-dimensional (3D) software.ResultsThe critical-size defects were located at the metadiaphyseal area of 11 tibias, eight femurs, and two humeri. The average defect size was 8.9cm in length and 65.2cm³ in volume. The absorbable gelatin sponge core replaced 21.4% (average) of the defect volume. There was no significant deterioration in the shape of the grafted bone among the serial 3D models. Eighteen patients (86%) were healed radiographically at 9.1 months (average).ConclusionOur study suggests that circumferential bone grafting in association with the induced membrane technique could reduce the required amount of bone graft and adequately maintain graft position and shape, with favourable clinical outcomes.



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The Pararectus approach provides secure access to the deep circumflex iliac vessel for harvest of a large sized and vascularized segment of the iliac crest

Publication date: Available online 8 August 2017
Source:Injury
Author(s): C.E. Dumont, M.J. Keel, V. Djonov, P. Haefeli, T. Schmid, R. Olariu, J.L. Cullmann, J.D. Bastian
BackgroundThe feasibility of harvesting a vascularized iliac crest utilizing the Pararectus approach was assessed in cadavers and then this new technique was implemented in a clinical case.MethodsBilaterally in five cadavers the branches of both external iliac arteries were injected with colored silicone to assess their position to each other and to harvest a bone graft vascularized by the deep circumflex iliac artery (DCIA) through the Pararectus approach. This technique was implemented in a 68-years-old female patient, initially admitted to a level-I-trauma center after sustaining multiple injuries by falling from great height. For definitive treatment of a severely contaminated medially open (Gustilo-Anderson Type 3A) calcaneal luxation fracture (Sanders type IIIBC) in this patient a vascularized iliac crest autograft harvest by the Pararectus approach was used for reconstructive surgery.ResultsThe DCIA and the deep inferior epigastric vessels (DIEV: vascularizing the rectus abdominis muscle and main pedicle of the inferiorly based rectus abdominis myocutaneous flap) are very close on the lateral and medial border of the external iliac artery, respectively. As a consequence, the retrograde dissection of the DIEV towards the DCIA through the Pararectus approach made the dissection of the vascularized iliac crest more amenable, preserving both the lateral femoral cutaneous and the genitofemoral nerves. Four months after the surgery the patient was able to fully weight-bear in orthopedic shoes. Radiographs and CT scans showed correct hind foot alignment and bony integration of the vascularized iliac crest graft into the residual calcaneal body.ConclusionThe Pararectus approach allowed for secure collection of large vascularized iliac grafts. The presented technique was successful as a salvage procedure in a clinical case with substantial bone loss after an open calcaneal fracture.



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Dried blood spots from finger prick facilitate therapeutic drug monitoring of adalimumab and anti-adalimumab in patients with inflammatory diseases

Abstract

Background

Development of a self-sampling method for therapeutic drug monitoring (TDM) of biologicals will enhance TDM implementation in routine care and pharmacokinetic knowledge.

Aim

To compare adalimumab and anti-adalimumab antibody (ADA) concentration measurements in dried blood spots (DBS) obtained from finger prick with measurements in serum obtained via venepuncture, from patients with rheumatic inflammatory diseases.

Methods

In this cross–sectional study, 161 consecutive patients were included. For clinical validation, DBS from finger prick and serum from venepuncture were collected simultaneously and adalimumab and ADA concentration were assessed by ELISA and antigen binding test (ABT), respectively. To convert DBS eluate results to values which can be compared to serum concentrations, five different methods were investigated, using a marker protein or a volumetric approach.

Results

Adalimumab and ADA concentrations obtained from the finger prick/DBS method correlated well with serum results from the same patient (correlation coefficient >0.87). Interestingly, antibody concentrations (either adalimumab, ADA or total immunoglobulin G) in DBS from finger prick, but not albumin, were systematically lower compared to serum. Spike experiments demonstrated a quantitative recovery for all tested proteins in DBS, suggesting a slightly different protein composition of blood collected via finger prick vs venepuncture. We established a correction factor to relate finger prick/DBS values with serum values (approximately 1.2).

Conclusions

We show here for the first time that adalimumab and ADA serum concentrations can be satisfactorily estimated by measuring concentrations in DBS eluates, collected by finger prick. This method offers great opportunity to simplify TDM of adalimumab.

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Prognostic Implications of miR-302a/b/c/d in Human Gastric Cancer

Abstract

Background: The microRNA (miR)-302 family consisting four members, miR-302a, miR-302b, miR-302c and miR-302d, plays an important role in diverse biological processes, and regulates many pathological changes, including cancer. However, the involvement of the miR-302 family into human gastric cancer (GC) remains unclear. The aim of this study was to investigate the expression patterns of miR-302a/b/c/d and determine their clinical significance in GC. Materials and methods: Expression levels of miR-302a/b/c/d in 160 pairs of human GC and matched normal mucosa tissues were detected by quantitative real-time polymerase chain reaction. Then, the associations of miR-302a/b/c/d expression with various clinicopathological characteristics and patients' prognosis were statistically evaluated. Results: The expression levels of miR-302a, miR-302b and miR-302c in GC tissues were all significantly lower than those in matched normal mucosa (all P < 0.001), but miR-302d expression had no significant differences between cancer and normal groups. Additionally, GC patients with low miR-302a, miR-302b and miR-302c expression more frequently had positive lymph node metastasis (all P < 0.05), advanced TNM stage (all P < 0.05) and great depth of invasion (all P < 0.05). More importantly, low miR-302a, miR-302b and miR-302c expression in GC tissues were significantly associated with shorter disease-free and overall survivals of GC patients (all P < 0.05). Further multivariate analysis identified miR-302a, miR-302b and miR-302c as independent prognostic markers for GC patients. Conclusions: GC patients with the decreased expression of miR-302a, miR-302b and miR-302c may had aggressive cancer progression and unfavorable prognosis. Further rigorous validation based on a large cohort of clinical cases should be performed.

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Protein Intake in Chronic Kidney Disease

Abstract

Purpose of Review

The purpose of this review is to better understand the protein needs in patients with chronic kidney disease (CKD) not on dialysis. Protein energy wasting is common in patients with chronic kidney disease, and the incidence increases as the kidney function declines. Typically, protein intake in patients with CKD is lower than the daily-recommended allowance for healthy adults, and that poor nutritional status has been associated with increase in morbidity and mortality. It is of interest to note that the current guidelines for protein intake vary in terms of both quantity as well as the quality, thus making it confusing for the practicing nephrologist.

Recent Findings

Recent studies show that very low protein intake when supplemented by keto-analogues of essential amino acid could be helpful in slowing the progression of chronic kidney disease. However, it is important to understand that recommending low protein intake could be harmful in CKD patients especially those with poor nutritional status or during an acute illness.

Summary

In summary, it is important for the physician to understand that patients with chronic kidney disease have very complex nutritional requirements, and that recommendations for protein intake should be based on the individual patient needs.

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-Alcohol Length Governs Shift in - Mixing Temperatures in Synthetic and Cell-Derived Membranes

A persistent challenge in membrane biophysics has been to quantitatively predict how membrane physical properties change upon addition of new amphiphiles (e.g., lipids, alcohols, peptides, or proteins) in order to assess whether the changes are large enough to plausibly result in biological ramifications. Because of their roles as general anesthetics, n-alcohols are perhaps the best-studied amphiphiles of this class. When n-alcohols are added to model and cell membranes, changes in membrane parameters tend to be modest.

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Papillary fibroelastoma diagnosed through multimodality cardiac imaging: a rare tumour in an uncommon location with review of literature

We describe the case of a woman presenting with transient ischaemic attack, who was found to have a papillary fibroelastoma arising from the aortic wall, an extremely rare location. We describe the multimodality imaging techniques used in diagnosing this patient and review the most recent literature on evaluation and management of patients with cardiac papillary fibroelastomas.

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Evaluating Brain-Computer Interface Performance Using Color in the P300 Checkerboard Speller

A Brain Computer Interface (BCI) is a specific type of human-machine interaction. BCI is a direct link between the human brain and a computer. BCIs can be defined as invasive utilizing techniques requiring implantation such as electrocorticography (ECoG), or non-invasive techniques utilizing techniques requiring surface electrodes such as electroencephalography (EEG [Wolpaw et al. 2003]). A BCI can provide an important communication outlet for those who are "locked-in" by amyotrophic lateral sclerosis (ALS), brain stem stroke, or head trauma.

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Inter-chromosomal Transfer of Immune Regulation During Infection of Barley with the Powdery Mildew Pathogen

Powdery mildew pathogens colonize over 9,500 plant species, causing critical yield loss. The Ascomycete fungus, Blumeria graminis f. sp. hordei (Bgh), causes powdery mildew disease in barley (Hordeum vulgare L.). Successful infection begins with penetration of host epidermal cells, culminating in haustorial feeding structures, facilitating delivery of fungal effectors to the plant and exchange of nutrients from host to pathogen. We used expression Quantitative Trait Locus (eQTL) analysis to dissect the temporal control of immunity-associated gene expression in a doubled haploid barley population challenged with Bgh. Two highly significant regions possessing trans eQTL were identified near the telomeric ends of chromosomes 2HL and 1HS. Within these regions reside diverse resistance loci derived from barley landrace, H. laevigatum (MlLa), and H. vulgare cv. Algerian (Mla1); which associate with the altered expression of 961 and 3,296 genes during fungal penetration of the host and haustorial development, respectively. Regulatory control of transcript levels for 299 of the 961 genes is re-prioritized from MlLa on 2HL to Mla1 on 1HS as infection progresses; with 292 of the 299 alternating the allele responsible for higher expression, including Adaptin Protein-2 subunit μ AP2M and Vesicle Associated Membrane Protein VAMP72 subfamily members VAMP721/722. AP2M mediates effector-triggered immunity via endocytosis of plasma membrane receptor components. VAMP721/722 and SNAP33 form a SNARE complex with SYP121 (PEN1), which is engaged in PAMP-triggered immunity via exocytosis. We postulate that genes regulated by alternate chromosomal positions are repurposed as part of conserved immune complex to respond to different pathogen attack scenarios.

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Complementary value of contralateral parenchymal enhancement on DCE-MRI to prognostic models and molecular assays in high-risk ER+HER2- breast cancer

Purpose: To determine whether markers of healthy breast stroma are able to select a subgroup of patients at low risk of death or metastasis from patients considered at high risk according to routine markers of the tumor. <p>Experimental Design: Patients with ER-positive/HER2-negative breast cancer were consecutively included for retrospective analysis. The contralateral parenchyma was segmented automatically on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), whereupon the average of the top-10% late enhancement was calculated. This contralateral parenchymal enhancement (CPE) was analyzed with respect to routine prognostic models and molecular assays (Nottingham Prognostic Index, Dutch clinical chemotherapy-selection guidelines, 70-gene signature, and 21-gene recurrence score). CPE was split in tertiles and tested for overall and distant disease-free survival. CPE was adjusted for patient and tumor characteristics, as well as systemic therapy, using inverse probability weighting (IPW). Subanalyses were performed in patients at high risk according to prognostic models and molecular assays.</p> <p>Results: Four-hundred-and-fifteen patients were included, constituting the same group in which the association between CPE and survival was discovered. Median follow-up was 85 months, 34/415(8%) patients succumbed. After IPW-adjustment for patient and tumor characteristics, patients with high CPE had significantly better overall survival than those with low CPE in groups at high risk according to the Nottingham Prognostic Index (HR(95%CI):0.08(0.00-0.40),P<.001); Dutch clinical guidelines (HR(95%CI):0.22(0.00-0.81),P=.021); and 21-gene recurrence score (HR(95%CI):0.14(0.00-0.84),P=.030). One group showed a trend (70-gene signature:HR(95%CI):0.25(0.00-1.02),P=.054).</p> Conclusions: In patients at high risk based on the tumor, subgroups at relatively low risk were identified using pretreatment enhancement of the stroma on breast DCE-MRI.

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ANTI-CD137 AND PD-1/PD-L1 ANTIBODIES IN ROUTE TOWARDS CLINICAL SYNERGY.

T-cell co-stimulation and co-inhibition can be exploited  by blocking and agonist monoclonal antibodies (mAbs) respectively. Both strategies can be synergistically combined in mouse models. Early clinical results from combinations of anti-PD-1 mAbs in conjunction with agonist anti-CD137 (4-1BB) mAbs show excellent safety and promising efficacy.

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In Vivo Validation of PAPSS1 (3'-phosphoadenosine 5'-phosphosulfate synthase 1) as a Cisplatin-Sensitizing Therapeutic Target

Introduction: Our previous screening efforts found that inhibition of PAPSS1 increases the potency of DNA damaging agents in non-small cell lung cancer (NSCLC) cell lines. Here, we explored the clinical relevance of PAPSS1 and further investigated it as a therapeutic target in pre-clinical model systems. Methods: PAPSS1 expression and cisplatin IC₅₀ values were assessed in 52 lung adenocarcinoma (LAC) cell lines. Effects of PAPSS1 inhibition on A549 cisplatin sensitivity under hypoxic and starvation conditions, in 3D spheroids, as well as in zebrafish and mouse xenografts, were evaluated. Finally, the association between PAPSS1 expression levels and survival in patients treated with standard chemotherapy was assessed. Results: Our results show a positive correlation between low PAPSS1 expression and increased cisplatin sensitivity in LAC. In vitro, the potentiation effect was greatest when A549 cells were serum-starved under hypoxic conditions. When treated with low-dose cisplatin, PAPSS1-deficient A549 spheroids showed a 58% reduction in size compared to control cells. In vivo, PAPSS1 suppression and low-dose cisplatin treatment inhibited proliferation of lung tumor cells in zebrafish xenografts and significantly delayed development of subcutaneous tumors in mice. Clinical data suggest that NSCLC and ovarian cancer patients with low PAPSS1 expression survive longer following platinum-based chemotherapy. Conclusions: These results suggest that PAPSS1 inhibition enhances cisplatin activity in multiple pre-clinical model systems and that low PAPSS1 expression may serve as a biomarker for platin sensitivity in cancer patients. Developing strategies to target PAPSS1 activity in conjunction with platinum-based chemotherapy may offer an approach to improving treatment outcomes.

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Burden and profile of somatic mutation in duodenal adenomas from patients with familial adenomatous- and MUTYH-associated polyposis

Purpose: Duodenal polyposis and cancer are important causes of morbidity and mortality in familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). This study aimed to comprehensively characterize somatic genetic changes in FAP and MAP duodenal adenomas to better understand duodenal tumorigenesis in these disorders.<br /><br />Experimental Design: Sixty-nine adenomas were biopsied during endoscopy in 16 FAP and 10 MAP patients with duodenal polyposis. Ten FAP and 10 MAP adenomas and matched blood DNA samples were exome sequenced, 42 further adenomas underwent targeted sequencing and 47 were studied by array comparative genomic hybridization. Findings in FAP and MAP duodenal adenomas were compared to each other and to the reported mutational landscape in FAP and MAP colorectal adenomas.<br /><br />Results: MAP duodenal adenomas had significantly more protein-changing somatic mutations (P = 0.018), truncating mutations (P = 0.006) and copy number variants (P = 0.005) than FAP duodenal adenomas, even though MAP patients had lower Spigelman stage duodenal polyposis. Fifteen genes were significantly recurrently mutated. Targeted sequencing of APC, KRAS, PTCHD2 and PLCL1 identified further mutations in each of these genes in additional duodenal adenomas. In contrast to MAP and FAP colorectal adenomas, neither exome nor targeted sequencing identified WTX mutations (P=0.0017).<br /><br />Conclusions: The mutational landscapes in FAP and MAP duodenal adenomas overlapped with, but had significant differences to those reported in colorectal adenomas. The significantly higher burden of somatic mutations in MAP than FAP duodenal adenomas despite lower Spigelman stage disease could increase cancer risk in the context of apparently less severe benign disease.

http://ift.tt/2wGoXFg

MSH2 Loss in Primary Prostate Cancer

Purpose: Inactivation of mismatch repair (MMR) genes may predict sensitivity to immunotherapy in metastatic prostate cancers. We studied primary prostate tumors with MMR defects. Experimental Design: 1133 primary prostatic adenocarcinomas and 43 prostatic small cell carcinomas (NEPC) were screened by MSH2 immunohistochemistry with confirmation by next-generation sequencing (NGS). Microsatellite instability (MSI) was assessed by PCR and NGS (mSINGS). Results: Of primary adenocarcinomas and NEPC, 1.2% (14/1176) had MSH2 loss. Overall, 8% (7/91) of adenocarcinomas with primary Gleason pattern 5 (Gleason score 9-10) had MSH2 loss compared to 0.4% (5/1042) of tumors with any other scores (p<0.05). 5% (2/43) of NEPC had MSH2 loss. MSH2 was generally homogenously lost, suggesting it was an early/clonal event. NGS confirmed MSH2 loss-of-function alterations in all (12/12) samples, with bi-allelic inactivation in 83% (10/12) and hypermutation in 83% (10/12). Overall, 61% (8/13) and 58% (7/12) of patients had definite MSI by PCR and mSINGS, respectively. Three patients (25%) had germline mutations in MSH2. Tumors with MSH2 loss had a higher density of infiltrating CD8+ lymphocytes compared to grade-matched controls without MSH2 loss (390 vs. 76 cells/mm²; p=0.008), and CD8+ density was correlated with mutation burden among cases with MSH2 loss (r=0.72, p=0.005). T-cell receptor sequencing on a subset revealed a trend towards higher clonality in cases versus controls. Conclusion: Loss of MSH2 protein is correlated with MSH2 inactivation, hypermutation and higher tumor-infiltrating lymphocyte density, and appears most common among very high-grade primary tumors, where routine screening may be warranted if validated in additional cohorts.

http://ift.tt/2vNiUT1

Neurotensin receptor 1 antagonist SR48692 improves response to carboplatin by enhancing apoptosis and inhibiting drug efflux in ovarian cancer

Purpose: The high affinity receptor 1 (NTSR1) and its agonist, neurotensin (NTS), is correlated with tumor cell aggressiveness in most solid tumors. As chemo-resistance and tumor aggressiveness are often related; we decided to study the role of the NTSR1 complex within platinum-based chemotherapy responses. In an ovarian model, we studied carboplatin because it is the main standard of care for ovarian cancer (OC).Experimental Design: Experimental tumors and in vitro studied were performed using SKOV3 and A2780 cells treated with carboplatin, with or without a very specific NTSR1 antagonist, SR48692. We measured the effects of these treatments on cell apoptosis and apoptosis related proteins, platinum accumulation in the cell and nucleus, and the expression and localization of platinum transporters. NTS and NTSR1 labelling was measured in patients with ovarian cancer. Results: SR48692 enhanced the response to carboplatin in OC cells and experimental tumors. When SR48692 is combined to carboplatin, we noted a major improvement of platinum induced DNA damage and cell death, as well as a decrease in tumor growth. The relationship of these results to clinic studies was made by the detection of NTS and NTSR1 in 72% and 74% of OC, respectively. Furthermore, in a large series of high grade OC, NTSR1 mRNA was shown to correlate with higher stages and platinum resistance. Conclusions: This study strongly suggests that the addition of NTSR1 inhibitor in combination with platinum salt-based therapy will improve the response to the drug.

http://ift.tt/2wGuHz8

Amiloride, an old diuretic drug, is a potential therapeutic agent for multiple myeloma

Purpose: <br />The search for new drugs that control the continuous relapses of multiple myeloma is still required. Here, we report for the first time the potent anti-myeloma activity of amiloride, an old potassium-sparing diuretic approved for the treatment of hypertension and edema due to heart failure.<br /><br />Experimental Design:  <p>Myeloma cell lines and primary samples were used to evaluate cytotoxicity of amiloride. In vivo studies were carried out in a xenograft mouse model. The mechanisms of action were investigated using RNA-Seq, qRT-PCR, immunoblotting and immunofluorescence assays.</p> Results: <p>Amiloride-induced apoptosis was observed in a broad panel of MM cell lines and in a xenograft mouse model. Moreover, amiloride also had a synergistic effect when combined with dexamethasone, melphalan, lenalidomide and pomalidomide. RNA-Seq experiments showed that amiloride not only significantly altered the level of transcript isoforms and alternative splicing events, but also deregulated the spliceosomal machinery. Additionally, disruption of the splicing machinery in immunofluorescence studies was associated with the inhibition of myeloma cell viability after amiloride exposure. Although amiloride was able to induce apoptosis in myeloma cells lacking p53 expression, activation of p53 signaling was observed in wild-type and mutated TP53 cells after amiloride exposure. On the other hand, we did not find a significant systemic toxicity in mice treated with amiloride. </p> <br />Conclusions: <p>Overall, our results demonstrate the anti-myeloma activity of amiloride and provide a mechanistic rationale for its use as an alternative treatment option for relapsed MM patients, especially those with 17p deletion or TP53 mutations that are resistant to current therapies.

http://ift.tt/2vNc682

Differential toxicity in patients with and without DNA repair mutations: Phase I Study of Carboplatin and Talazoparib in advanced solid tumors

<p>Purpose: The PARP inhibitor, talazoparib, may potentiate activity of chemotherapy in cells vulnerable to DNA damage. Experimental Design: This phase 1 study evaluated the safety, tolerability, pharmacokinetics (PK), and efficacy of talazoparib and carboplatin. Pharmacokinetic-modeling explored associations between dosing and hematological toxicity. Results: 24 patients with solid tumors were enrolled in 4 cohorts at 0.75mg and 1mg daily talazoparib and weekly carboplatin (AUC 1 and 1.5, Q2W or Q3W). Dose-limiting toxicities included grade 3 fatigue and grade 4 thrombocytopenia; the maximum tolerated dose was not reached. Grade 3/4 toxicities included fatigue (13%), neutropenia (63%), thrombocytopenia (29%), and anemia (38%). Post-cycle 2 dose modifications were required in all patients. One complete and two partial responses occurred in germline BRCA1/2 (gBRCA1/2) patients. Four patients showed stable disease beyond four months, three of which had mutations in DNA repair pathways. Pharmacokinetic-toxicity modeling showed that after 3 cycles of carboplatin AUC 1.5 Q3W and talazoparib 1mg daily, neutrophil counts decreased 78% (CI: 87 to 68%) from baseline in gBRCA carriers and 63% (CI: 72 to 55%) in non-carriers (p<0.001). This modeling suggests an intermittent, pulse dosing schedule of PARP inhibition, differentiated by gBRCA mutation status may improve tolerance of combination therapy. Conclusions: In order to optimize efficacy and minimize toxicity, we feel that the combination of carboplatin and talazoparib is likely best pursued using differentiated dosing schedules for patients with somatic DNA repair mutations vs. gBRCA mutations.

http://ift.tt/2wGu8p3

Replication stress leading to apoptosis within the S-phase contributes to synergism between vorinostat and AZD1775 in HNSCC harboring high risk TP53 mutation

Purpose: The cure rate for patients with advanced head and neck squamous cell carcinoma (HNSCC) remains poor due to resistance to standard therapy primarily consisting of chemoradiation. Since mutation of TP53 in HNSCC occurs in 60-80% of non-HPV associated cases and is in turn associated with resistance to these treatments, more effective therapies are needed. In this study, we evaluated the efficacy of a regimen combining vorinostat and AZD1775 in HNSCC cells with a variety of p53 mutations. <p>Experimental Design: Clonogenic survival assays and an orthotopic mouse model of oral cancer were used to examine the in vitro and in vivo sensitivity of high-risk mutant p53 HNSCC cell lines to vorinostat in combination with AZD1775. Cell cycle, replication stress, homologous recombination (HR), live cell imaging, RNA-sequencing, and apoptosis analyses were performed to dissect molecular mechanisms.</p> <p>Results: We found that vorinostat synergizes with AZD1775 in vitro to inhibit growth of HNSCC cells harboring high-risk mutp53. These drugs interact synergistically to induce DNA damage, replication stress associated with impaired Rad51-mediated homologous recombination through activation of CDK1 and inhibition of Chk1 phosphorylation, culminating in an early apoptotic cell death during the S-phase of the cell cycle. The combination of vorinostat and AZD1775 inhibits tumor growth and angiogenesis in vivo in an orthotopic mouse model of oral cancer and prolongs animal survival.</p> <p>Conclusions: Vorinostat synergizes with AZD1775 in HNSCC cells with mutant p53 in vitro and in vivo. A strategy combining HDAC and WEE1 inhibition deserves further clinical investigation in patients with advanced HNSCC.

http://ift.tt/2vNoSDE

Cyclophilin A Maintains Glioma-Initiating Cell Stemness by Regulating Wnt/{beta}-catenin Signaling

Purpose: Glioma-initiating cells (GICs) are glioma stem-like cells that contribute to glioblastoma (GBM) development, recurrence, and resistance to chemotherapy and radiotherapy. They have recently become the focus of novel treatment strategies. Cyclophilin A (CypA) is a cytosolic protein that belongs to the peptidyl-prolyl isomerase (PPIase) family and the major intracellular target of the immunosuppressive drug cyclosporin A (CsA). In this study, we investigate the functions of CypA and its mechanism of action in GICs' development. Experimental Design: We analyzed differences in CypA expression between primary tumors and neurospheres from the GDS database, both before and after GIC differentiation. A series of experiments was conducted to investigate the role of CypA in GIC stemness, self-renewal, proliferation, radiotherapy resistance, and mechanism. We then designed glutathione S-transferase (GST) pull-down and co-immunoprecipitation assays to detect signaling activity. Results: In this study, we demonstrated that CypA promotes GIC stemness, self-renewal, proliferation, and radiotherapy resistance. Mechanistically, we found that CypA binds β-catenin and is recruited to Wnt target gene promoters. By increasing the interaction between β-catenin and TCF4, CypA enhances transcriptional activity. Conclusions: Our results demonstrate that CypA enhances GIC stemness, self-renewal, and radio-resistance through Wnt/β-catenin signaling. Due to its promotive effects on GICs, CypA is a potential target for future glioma therapy.

http://ift.tt/2wGggLe

Prospective Validation of Molecular Prognostic Markers in Cutaneous Melanoma: A Correlative Analysis of E1690

Purpose: To validate the prognostic impact of combined expression levels of three markers (SPP1, RGS1, and NCOA3) in melanoma specimens from patients enrolled in the E1690 clinical trial of high-dose or low-dose interferon alpha-2b (IFN) versus observation. <p>Experimental Design: Tissue was available from 248 patients. Marker expression was determined by digital imaging of immunohistochemically stained slides. The prognostic impact of each marker was first assessed by recording its expression value relative to the median. A multi-marker index was then developed to combine marker expression levels by counting for each patient the number of markers with high expression. The impact of the multi-marker index on relapse-free survival (RFS) and overall survival (OS) was assessed using Kaplan-Meier analysis, and both univariate and multivariate Cox regression analyses.</p> <p>Results: By Kaplan-Meier analysis, high multi-marker expression scores were significantly predictive of RFS (P<0.001) and OS (P<0.001). Stepwise multivariate Cox regression analysis with backward elimination that included routine clinical and histological prognostic factors revealed high multi-marker expression scores and tumor thickness as the only factors significantly and independently predicting RFS and OS. Stepwise multivariate Cox regression analyses that also included treatment type and number of positive lymph nodes generated identical results for both RFS and OS. In the molecularly defined low-risk subgroup, patients treated with high-dose IFN had a significantly improved RFS compared with patients in the other two subgroups (P<0.05).</p> <p> </p> Conclusions: These results validate the independent impact of combined expression levels of SPP1, RGS1, and NCOA3 on survival of melanoma in a prospectively collected cohort.

http://ift.tt/2vN4iTN

Targeted proteomics identifies proteomic signatures in liquid-biopsies of the endometrium to diagnose endometrial cancer and assist in the prediction of the optimal surgical treatment

Purpose: Endometrial cancer (EC) diagnosis relies on the observation of tumor cells in endometrial biopsies obtained by aspiration i.e., uterine aspirates), but it is associated with 22% undiagnosed patients and up to 50% of incorrectly assigned EC histotype and grade. We aimed to identify biomarker signatures in the fluid fraction of these biopsies to overcome these limitations. Experimental Design: The levels of 52 proteins were measured in the fluid fraction of uterine aspirates from 116 patients by LC-PRM, the latest generation of targeted mass-spectrometry acquisition. A logistic regression model was used to assess the power of protein panels to differentiate between EC and non-EC patients and between EC histological subtypes. The robustness of the panels was assessed by the "leave-one-out" cross-validation procedure performed within the same cohort of patients and an independent cohort of 38 patients. Results: The levels of 28 proteins were significantly higher in EC patients (n=69) compared to controls (n=47). The combination of MMP9 and KPYM exhibited 94% sensitivity and 87% specificity for detecting EC cases. This panel perfectly complemented the standard diagnosis, achieving 100% of correct diagnosis in this dataset. Nine proteins were significantly increased in endometrioid EC (n=49) compared to serous EC (n=20). The combination of CTNB1, XPO2 and CAPG achieved 95% sensitivity and 96% specificity for the discrimination of these subtypes. Conclusions: We developed two uterine aspirate-based signatures to diagnose EC and classify tumors in the most prevalent histological subtypes. This will improve diagnosis and assist in the prediction of the optimal surgical treatment.

http://ift.tt/2vio3RL

n-Alcohol Length Governs Shift in Lo-Ld Mixing Temperatures in Synthetic and Cell-Derived Membranes

A persistent challenge in membrane biophysics has been to quantitatively predict how membrane physical properties change upon addition of new amphiphiles (e.g., lipids, alcohols, peptides, or proteins) in order to assess whether the changes are large enough to plausibly result in biological ramifications. Because of their roles as general anesthetics, n-alcohols are perhaps the best-studied amphiphiles of this class. When n-alcohols are added to model and cell membranes, changes in membrane parameters tend to be modest.

http://ift.tt/2unBsox

Blimp1 induces transient metastatic heterogeneity in pancreatic cancer [Research Articles]

Pancreatic ductal adenocarcinoma (PDAC) is one of the most metastatic and deadly cancers. Despite the clinical significance of metastatic spread, our understanding of molecular mechanisms that drive PDAC metastatic ability remains limited. Using a novel genetically engineered mouse model of human PDAC, we uncover a transient subpopulation of cancer cells with exceptionally high metastatic ability. Global gene expression profiling and functional analyses uncovered the transcription factor Blimp1 as a key driver of PDAC metastasis. The highly metastatic PDAC subpopulation is enriched for hypoxia-induced genes and hypoxia-mediated induction of Blimp1 contributes to the regulation of a subset of hypoxia-associated gene expression programs. These findings support a model in which up-regulation of Blimp1 links microenvironmental cues to a metastatic stem cell character.

http://ift.tt/2unNnH9

Notch Shapes the Innate Immunophenotype in Breast Cancer [Research Articles]

Notch activation, which is associated with basal-like breast cancer (BLBC), normally directs tissue patterning, suggesting that it may shape the tumor microenvironment (TME). Here we show that Notch in tumor cells regulates the expression of two powerful pro-inflammatory cytokines, IL1β and CCL2, and the recruitment of tumor-associated macrophages (TAMs). Notch also regulates TGFβ-mediated activation of tumor cells by TAMs, closing a Notch-dependent paracrine signaling loop between these two cell types. We use a novel mouse model in which Notch can be regulated in spontaneous mammary carcinoma to confirm that IL1β and CCL2 production, and macrophage recruitment are Notch-dependent. In human disease, expression array analyses demonstrate a striking association between Notch activation, IL1β and CCL2 production, macrophage infiltration and BLBC. These findings place Notch at the nexus of a vicious cycle of macrophage infiltration and amplified cytokine secretion and provide novel immunotherapeutic opportunities in BLBC.

http://ift.tt/2uEl1DI

GSK 3 inhibition drives maturation of NK cells and enhances their antitumor activity

Maturation of human natural killer cells (NK cells) as defined by accumulation of cell surface expression of CD57 is associated with increased cytotoxic character and TNF and IFN-γ production upon target cell recognition. Notably, multiple studies point to a unique role for CD57+ NK cells in cancer immunosurveillance, yet there is scant information about how they mature. In this study, we show that pharmacological inhibition of GSK3 kinase in peripheral blood NK cells expanded ex vivo with IL-15 greatly enhances CD57 upregulation and late-stage maturation. GSK3 inhibition elevated the expression of several transcription factors associated with late-stage NK cell maturation including T-BET, ZEB2 and BLIMP-1 without affecting viability or proliferation. When exposed to human cancer cells, NK cell expanded ex vivo in the presence of a GSK3 inhibitor exhibited significantly higher production of TNF and IFN-γ, elevated natural cytotoxicity, and increased antibody-dependent cellular cytotoxicity (ADCC). In an established mouse xenograft model of ovarian cancer, adoptive transfer of NK cells conditioned in the same way also displayed more robust and durable tumor control. Our findings show how GSK3 kinase inhibition can greatly enhance the mature character of NK cells most desired for effective cancer immunotherapy.

http://ift.tt/2hHqE2F

ATM deficiency generating genomic instability sensitizes pancreatic ductal adenocarcinoma cells to therapy-induced DNA damage

Pancreatic adenocarcinomas (PDAC) harbour recurrent functional mutations of the master DNA damage response kinase ATM which has been shown to accelerate tumorigenesis and epithelial-mesenchymal transition. To study how ATM deficiency affects genome integrity in this setting, we evaluated the molecular and functional effects of conditional Atm deletion in a mouse model of PDAC. ATM deficiency was associated with increased mitotic defects, recurrent genomic rearrangements and deregulated DNA integrity checkpoints, reminiscent of human PDAC. We hypothesized that altered genome integrity might allow synthetic lethality-based options for targeted therapeutic intervention. Supporting this possibility, we found that the PARP inhibitor olaparib or ATR inhibitors reduced the viability of PDAC cells in vitro and in vivo associated with a genotype-selective increase in apoptosis. Overall, our results offered a preclinical mechanistic rationale for the use of PARP and ATR inhibitors to improve treatment of ATM-mutant PDAC.

http://ift.tt/2fqke7o

Liquid Drug Products Manufactured by PharmaTech and Distributed by Rugby Laboratories and Possibly Other Companies: FDA Advisory - Not to Use

Audience: Pharmacy, Patient, Health Professional ISSUE: FDA is advising health care professionals and patients not to use any liquid product manufactured by PharmaTech LLC, Davie, Florida, due to Burkholderia cepacia contamination and the potential...

http://ift.tt/2wrTdEK

Zanthoxylum heitzii Modulates Ferric Nitrilotriacetate-Dependent Oxidative Alterations in Four Vital Organs: An In Vitro Organoprotective Model

Ferric nitrilotriacetate (Fe-NTA) is a highly reactive compound used to induce degenerative disorders through oxidative stress (OS). Zanthoxylum heitzii (Z. heitzii) is a spice used as a medicinal plant to treat a variety of illnesses. This study investigated the ability of extracts from the leaves, fruits, roots, and barks of Z. Heitzii to inhibit Fe-NTA mediated oxidative damage in rats. The supernatant of rat liver homogenates was pretreated with the extracts for one hour before the induction of oxidative damage using a solution of Fe-NTA (400 mM). The activities of superoxide dismutase (SOD), catalase, and peroxidases were measured together with the marker of lipid peroxidation and the level of glutathione. The pretreated groups showed a significant increase in the activity of SOD, catalase, and peroxidases. The methanolic extract from the leaves of Z. heitzii (36.78 ± 3.30) and aqueous extract from the fruits (37.01 ± 2.52) showed the highest activities of SOD in the liver. The lowest concentration of MDA was found in the liver, and the glutathione was greater in the brain. Conclusively, these results suggest that Z. heitzii might be a chemoprotector which may be used in for prevention of distinct types of diseases induced by oxidative stress.

http://ift.tt/2vLxmtV

Re-bleeding rates and survival after early transjugular intrahepatic portosystemic shunt (TIPS) in clinical practice

Early implantation (<72hours) of a transjugular intrahepatic portosystemic shunt (TIPS) after acute variceal bleeding (AVB) improves survival in highly selected patients.

http://ift.tt/2vk1vOX

ENDOSCOPIC FINDINGS AND COLONIC PERFORATION IN MICROSCOPIC COLITIS; A SYSTEMATIC REVIEW

Microscopic colitis (MC) is a clinical syndrome of severe watery diarrhoea with few or no endoscopic abnormalities. The incidence of MC is reported similar to that of other inflammatory bowel diseases. The need for histological confirmation of MC frequently guides reimbursement health policies. With the advent of high-definition (HD) coloscopes, the incidence of reporting distinct endoscopic findings in MC has risen. This has the potential to improve timely diagnosis and cost-effective MC management and diminish the workload and costs of busy modern endoscopy units.

http://ift.tt/2vCslEk

Palliative Care and Human Rights: A Decade of Evolution in Standards

Human rights standards to address palliative care have developed over the last decade.

http://ift.tt/2vk5via

A survey to evaluate facilitators and barriers to quality measurement and improvement: Adapting tools for implementation research in palliative care programs

Though critical for improving patient outcomes, palliative care quality indicators are not yet widely used. Better understanding of facilitators and barriers to palliative care quality measurement and improvement might improve their use and program quality.

http://ift.tt/2vDbbGQ

Pain and Policy Studies Group: Two decades of working to address regulatory barriers to improve opioid availability and accessibility around the world

For two decades, the Pain & Policy Studies Group (PPSG), a global research program at the University of Wisconsin Carbone Cancer Center, has worked passionately to fulfil its mission of improving pain relief by achieving balanced access to opioids worldwide. PPSG's early work highlighted the conceptual framework of balance leading to the development of the seminal guidelines and criteria for evaluating opioid policy. It has collaborated at the global level with UN agencies to promote access to opioids and has developed a unique model of technical assistance to help national governments assess regulatory barriers to essential medicines for pain relief and amend existing or develop new legislation that facilitates appropriate and adequate opioid prescribing according to international standards.

http://ift.tt/2vk2nTt

Promoting Palliative Care Internationally: Building Leaders to Promote Education, Practice, and Advocacy

In February 2000, nine nursing educators, practitioners, and researchers met in Nashville, TN to develop a palliative care curriculum specifically for nurses. The following month, twenty-two advisors from nursing organizations across the United States convened in Washington, DC to review the recommended curriculum development and dissemination plans for end-of-life care throughout nursing schools, hospitals, hospices, homecare, and geriatric settings. The Robert Wood Johnson Foundation (RWJF) provided funding for curriculum and competency development and for 6 national train-the-trainer courses to be held from 2001 to 2003.

http://ift.tt/2vCPiax

Legal Support for Palliative Care Patients

Palliative care patients face legal issues which impact their quality of life. Legal support, embedded in holistic palliative care services, has developed globally over the last decade to address this.

http://ift.tt/2vjRgdr

Palliative Care Development in Ukraine

There are approximately 1 million cancer patients in Ukraine and 90,000 cancer deaths a year, 35% of these are diagnosed in the late stage of disease. Ukraine has the most severe HIV epidemic in the region with more than 200,000 persons living with HIV/AIDS and 6000-10000 deaths annually.The morphine consumption rate is among the lowest in the. The first palliative care services were established in 1996 and the number has slowly increased with services provided in inpatient units, home and day care programs and by a range of health care providers.

http://ift.tt/2vDb9ic

Palliative Care in Kazakhstan

In Kazakhstan, like most ex-Soviet Union countries palliative care began in the late 1990's with the opening of the Almaty Hospice in 1999. Since that time, several palliative care services have opened in urban centers but there is little coverage in rural areas. Palliative care has grown due to the collaborative work of Parliament leaders, Ministry of Health, local governments officials, Public Health Higher School, National Center for Health Development, academic medical institutions, oncology and palliative care experts, NGO's, Soros Foundation Kazakhstan, and international experts.

http://ift.tt/2vkaxLR

WHO Public Health Model: A Roadmap for Palliative Care Development

The Open Society Foundation's International Palliative Care Initiative (IPCI) began to support palliative care development in Central and Eastern Europe and the Former Soviet Union in 1999. Twenty-eight country representatives were invited to discuss the need for palliative care in their countries and to identify key areas that should be addressed to improve the care of adults and children with life-limiting illnesses. As a public health concern, progress in palliative care requires integration into health policy, education and training of health care professionals, availability of essential pain relieving medications, and health care services.

http://ift.tt/2vCwbNZ

The Palliative Care Journey In Kenya And Uganda

Palliative care is "an approach that improves the quality of life of patients and their families facing the problems associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual. This update is aimed at examining palliative care development/achievements and challenges in Kenya and Uganda and the role of various actors in palliative care establishment in the region.

http://ift.tt/2vkjnsS

International Children’s Palliative Care Network: A Global Action Network for Children with Life-Limiting Conditions

The International Children's Palliative Care Network (ICPCN) is a global network of individuals and organisations working together to reach the estimated 21 million children with life-limiting conditions and life-threatening illnesses. The drive to establish the ICPCN was born from the recognition of the gaps in service provision for children's palliative care and the need to collaborate, network and share resources. Established in 2005 during a meeting in Seoul, South Korea, the ICPCN has developed over the years into an established network with a global membership.

http://ift.tt/2vCD3dW

Examining the effects of a home-based palliative heart failure program on quality of life, symptom burden, satisfaction with care and caregiver burden among patients with end-stage heart failure

Provision of home-based palliative care for seriously ill patients is important, yet few home-based palliative care services specifically or exclusively focus on end-stage heart failure (ESHF) patients.

http://ift.tt/2vk95Jc

Liquid Drug Products Manufactured by PharmaTech and Distributed by Rugby Laboratories and Possibly Other Companies: FDA Advisory - Not to Use

[Posted 08/08/2017] AUDIENCE: Pharmacy, Patient, Health Professional ISSUE: FDA is advising health care professionals and patients not to use any liquid product manufactured by PharmaTech LLC, Davie, Florida, due to Burkholderia cepacia...

http://ift.tt/2wrTdEK

Non-invasive prediction of recurrence in bladder cancer by detecting somatic TERT promoter mutations in urine

http://ift.tt/2vNdOWP

Detection of phosphatidylserine-positive exosomes for the diagnosis of early-stage malignancies

http://ift.tt/2wFMjet

Lifestyle predictors for non-participation and outcome in the second round of faecal immunochemical test in colorectal cancer screening

http://ift.tt/2vN8O4x

MiR-646 inhibited cell proliferation and EMT-induced metastasis by targeting FOXK1 in gastric cancer

http://ift.tt/2wFSord

Geriatric assessment is superior to oncologists’ clinical judgement in identifying frailty

http://ift.tt/2vMLSmh

LIM kinase 1 interacts with myosin-9 and alpha-actinin-4 and promotes colorectal cancer progression

http://ift.tt/2wG2NmU

Integrating cytokines and angiogenic factors and tumour bulk with selected clinical criteria improves determination of prognosis in advanced renal cell carcinoma

http://ift.tt/2vN88wi

HYPE or HOPE: the prognostic value of infiltrating immune cells in cancer

http://ift.tt/2wFZf3O

Harmonisation of biobanking standards in endometrial cancer research

http://ift.tt/2vMVuxc

UV radiation promotes melanoma dissemination mediated by the sequential reaction axis of cathepsins–TGF-β1–FAP-α

http://ift.tt/2wG7Ao2

Kinase-driven metabolic signalling as a predictor of response to carboplatin–paclitaxel adjuvant treatment in advanced ovarian cancers

http://ift.tt/2vN4kuI

KIBRA attains oncogenic activity by repressing RASSF1A

http://ift.tt/2wGfD4m

TOPK modulates tumour-specific radiosensitivity and correlates with recurrence after prostate radiotherapy

http://ift.tt/2vN8Lpn

Clinical study of genomic drivers in pancreatic ductal adenocarcinoma

http://ift.tt/2wFV6Nl

Modulating cancer cell survival by targeting intracellular cholesterol transport

http://ift.tt/2vN8T8w

Pre-diagnostic statin use, lymph node status and mortality in women with stages I–III breast cancer

http://ift.tt/2wGgdzk

Role of Plasma D-Dimer Levels in Breast Cancer Patients and Its Correlation with Clinical and Histopathological Stage

Abstract

Breast cancer, the most common female malignancy, represents a heterogeneous group of tumors, which presen both varied behaviors and response to therapy. This study was done with an attempt to evaluate the role of D-dimer in patients of carcinoma breast, in predicting lymph node metastasis in carcinoma patients and to look for relationship of these markers with histopathologic parameters. Clinical data was obtained from clinical examination of patients admitted in the Department of Surgery with history of breast lump and confirmed with fine needle aspiration cytology (FNAC). Clinical staging was done using TNM staging. D-dimer level was measured prior to commencement of treatment, i.e., modified radical mastectomy (MRM) or neoadjuvant chemotherapy and finally 6 months after surgery or completion of 6 cycles of chemotherapy. The characteristics of the study population Out of 60 study cases minimum age of the patient being 30 years and maximum being 74 years. Of all histopathologic variables examined, D-dimer levels directly correlated with extent of lymph node involvement and lymphovascular invasion, D-dimer levels correlated strongest with the number of positive lymph nodes, but not with tumor size, estrogen receptor status, and progesterone receptor status. This study clearly shows that plasma D-Dimer levels are elevated in carcinoma breast patients. Increased D-Dimer levels are an important marker of clinical stage, lymphovascular invasion, lymph node involvement, and tumor metastasis.

http://ift.tt/2uEu4of

Functional imaging and circulating biomarkers of response to regorafenib in treatment-refractory metastatic colorectal cancer patients in a prospective phase II study

Objective

Regorafenib demonstrated efficacy in patients with metastatic colorectal cancer (mCRC). Lack of predictive biomarkers, potential toxicities and cost-effectiveness concerns highlight the unmet need for better patient selection.

Design

Patients with RAS mutant mCRC with biopsiable metastases were enrolled in this phase II trial. Dynamic contrast-enhanced (DCE) MRI was acquired pretreatment and at day 15 post-treatment. Median values of volume transfer constant (K^trans), enhancing fraction (EF) and their product KEF (summarised median values of K^transx EF) were generated. Circulating tumour (ct) DNA was collected monthly until progressive disease and tested for clonal RAS mutations by digital-droplet PCR. Tumour vasculature (CD-31) was scored by immunohistochemistry on 70 sequential tissue biopsies.

Results

Twenty-seven patients with paired DCE-MRI scans were analysed. Median KEF decrease was 58.2%. Of the 23 patients with outcome data, >70% drop in KEF (6/23) was associated with higher disease control rate (p=0.048) measured by RECIST V. 1.1 at 2 months, improved progression-free survival (PFS) (HR 0.16 (95% CI 0.04 to 0.72), p=0.02), 4-month PFS (66.7% vs 23.5%) and overall survival (OS) (HR 0.08 (95% CI 0.01 to 0.63), p=0.02). KEF drop correlated with CD-31 reduction in sequential tissue biopsies (p=0.04). RAS mutant clones decay in ctDNA after 8 weeks of treatment was associated with better PFS (HR 0.21 (95% CI 0.06 to 0.71), p=0.01) and OS (HR 0.28 (95% CI 0.07–1.04), p=0.06).

Conclusions

Combining DCE-MRI and ctDNA predicts duration of anti-angiogenic response to regorafenib and may improve patient management with potential health/economic implications.

http://ift.tt/2wrXKHt

Insomnia, postpartum depression and estradiol in women after delivery

Abstract

After childbirth, women may develop symptoms of depression with the associated sleep disturbances. This study assessed the relationship between insomnia and both depression symptoms and blood estradiol levels in women during the early postpartum period. 84 patients were assessed 24–48 h after labor. The main assessment methods were the following psychometric scales: Beck Depression Inventory (BDI), Edinburgh Postnatal Depression Scale (EPDS) and Athens Insomnia Scale (AIS). Serum estradiol levels were measured using ELISA assay. Women who developed postpartum insomnia significantly more often reported insomnia during pregnancy (P = 0.001), were more likely to have suffered from depression in the past (P = 0.007) and had significantly higher BDI (P = 0.002) and EPDS (P = 0.048) scores. Our study demonstrated no significant association between Restless Legs Syndrome (RLS) during pregnancy and postpartum insomnia. The groups of women with and without postpartum RLS showed no significant differences in the incidence of postpartum insomnia. No significant differences in estradiol levels were observed in women with and without postpartum insomnia. The study showed the following factors to play a major role in development of postpartum insomnia: an increase in Beck Depression Inventory score, a history of depression and a history of insomnia during pregnancy.

http://ift.tt/2vLt06b

Metabolic Tumor Volume of Primary Tumor Predicts Survival Better than T Classification in the Larynx Preservation Approach

Abstract

We aimed to determine whether pretreatment metabolic tumor volume of the primary tumor (T-MTV) or T classification would be a better predictor of laryngectomy-free survival (LFS) and overall survival (OS) after chemoradiotherapy in patients with locally advanced laryngeal or hypopharyngeal cancer requiring total laryngectomy. We analyzed 85 patients using a Cox proportional hazards model and evaluated its usefulness by Akaike's information criterion. A T-MTV cutoff value was determined by time-dependent receiver operating characteristic curve analysis. Interobserver reliability for measuring T-MTV was estimated by the intraclass correlation coefficient (ICC). After adjustment for covariables, T-MTV, irrespective of whether a continuous or dichotomized variable, and T classification remained independent predictors of LFS and OS. Large T-MTV (>28.7 ml) was associated with inferior LFS [hazard ratio (HR), 4.16; 95% confidence interval (CI), 1.97–8.70; P = 0.0003] and inferior OS (HR, 3.18; 95% CI, 1.47–6.69; P = 0.004) compared with small T-MTV (≤28.7 ml). The T-MTV model outperformed the T classification model in predicting LFS and OS (P = 0.007 and 0.01, respectively). The 3-year LFS and OS rates for patients with small versus large T-MTV were 68% versus 9% (P < 0.0001) and 77% versus 25% (P < 0.0001), respectively, while those for patients with T2-T3 versus T4a were 61% versus 31% (P = 0.003) and 71% versus 48% (P = 0.10), respectively. The ICC was 0.99 (95% lower confidence bound, 0.99). Given the excellent interobserver reliability, T-MTV would serve better than T classification to identify patients who benefit from the larynx preservation approach.

This article is protected by copyright. All rights reserved.

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A combination of anti-CD4 antibody treatment and DLI ameliorates GVHD while preserving GVT effects in murine allo-HSCT

Abstract

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is not only a well-established immunotherapy for hematologic malignancies, but is potentially useful for treating solid tumors refractory to available therapies. However, application of allo-HSCT to solid tumors is limited, despite the beneficial anti-tumor effects, by the risk of graft-versus-host disease (GVHD). CD4⁺ T cells have been implicated in several aspects of GVHD, and suppress anti-tumor CD8⁺ T cell responses. In the present study, we investigated clinically applicable allo-HSCT protocols designed to maximize anti-tumor effects while reducing the risk of GVHD. We used a mouse model of allo-HSCT with subcutaneous tumors. We found that myeloablative conditioning was associated with better inhibition of tumor growth but with severe acute GVHD. Early administration of anti-CD4 mAb substantially ameliorated GVHD, while preserving anti-tumor effects, leading to improved survival in myeloablative allo-HSCT. Late administration of anti-CD4 mAb also ameliorated GVHD to some extent. Donor lymphocyte infusion (DLI) in GVHD mice treated with anti-CD4 mAb further suppressed tumor growth without exacerbating GVHD. Collectively, our results suggest that myeloablative allo-HSCT followed by anti-CD4 mAb treatment and DLI may be a potent and safe immunotherapy for patients with cancers refractory to available therapies.

This article is protected by copyright. All rights reserved.

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Efficacy and safety of a new elastic tourniquet cuff in total knee arthroplasty: a prospective randomized controlled study

The effects of cuff shape, timing of tourniquet application, and automated systems using limb occlusion pressure (LOP) have been reported to minimize the appropriate tourniquet pressure. However, studies on th...

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Remote monitoring of cardiorespiratory signals from a hovering unmanned aerial vehicle

Remote physiological measurement might be very useful for biomedical diagnostics and monitoring. This study presents an efficient method for remotely measuring heart rate and respiratory rate from video captur...

http://ift.tt/2hHPyiT

Reference-free determination of tissue absorption coefficient by modulation transfer function characterization in spatial frequency domain

Spatial frequency domain (SFD) measurement allows rapid and non-contact wide-field imaging of the tissue optical properties, thus has become a potential tool for assessing physiological parameters and therapeu...

http://ift.tt/2fqTNyA

Effect of athletic fatigue damage and the associated bone targeted remodeling in the rat ulna

Fatigue damage of the long bones is prevalent in running athletes and military recruits due to vigorous mid- and long-term physical activity. The current study attempted to know the features of bony athletic f...

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Progressive Occlusion of Small Saccular Aneurysms Incompletely Occluded After Stent-Assisted Coil Embolization

Abstract

Purpose

Incompletely occluded aneurysms after coil embolization are subject to recanalization but occasionally progress to a totally occluded state. Deployed stents may actually promote thrombosis of coiled aneurysms. We evaluated outcomes of small aneurysms (<10 mm) wherein saccular filling with contrast medium was evident after stent-assisted coiling, assessing factors implicated in subsequent progressive occlusion.

Methods

Between September 2012 and June 2016, a total of 463 intracranial aneurysms were treated by stent-assisted coil embolization. Of these, 132 small saccular aneurysms displayed saccular filling with contrast medium in the immediate aftermath of coiling. Progressive thrombosis was defined as complete aneurysmal occlusion at the 6‑month follow-up point. Rates of progressive occlusion and factors predisposing to this were analyzed via binary logistic regression.

Results

In 101 (76.5%) of the 132 intracranial aneurysms, complete occlusion was observed in follow-up imaging studies at 6 months. Binary logistic regression analysis indicated that progressive occlusion was linked to smaller neck diameter (odds ratio [OR] = 1.533; p = 0.003), hyperlipidemia (OR = 3.329; p = 0.036) and stent type (p = 0.031). The LVIS stent is especially susceptible to progressive thrombosis, more so than Neuroform (OR = 0.098; p = 0.008) or Enterprise (OR = 0.317; p = 0.098) stents. In 57 instances of progressive thrombosis, followed for ≥12 months (mean 25.0 ± 10.7 months), 56 (98.2%) were stable, with minor recanalization noted once (1.8%) and no major recanalization.

Conclusion

Aneurysms associated with smaller diameter necks, hyperlipidemic states and LVIS stent deployment may be inclined to possible thrombosis, if occlusion immediately after stent-assisted coil embolization is incomplete. In such instances, excellent long-term durability is anticipated.

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Is Dementia Screening of Apparently Healthy Individuals Justified?

Despite efforts to raise awareness and develop guidelines for care of individuals with dementia, reports of poor detection and inadequate management persist. This has led to a call for more identification of people with dementia, that is, screening individuals who may or may not complain of symptoms of dementia in both acute settings and primary care. The following should be considered before recommending screening for dementia among individuals in the general population. Dementia Tests. Low screening reduces positive predictive value of tests and screening tests will miss people who have dementia and identify people who do not have dementia in substantial numbers. Clinical Issues. The clinical course of dementia has not yet been shown to be amenable to intervention. Misdiagnosis and overdiagnosis can have significant long-term effects including stigmatization, loss of employment, and autonomy. Economic Issues. Health systems do not have the capacity to respond to increased demand resulting from screening. In conclusion, at present attention to life-course risk reduction and support in the community for frail and cognitively impaired older adults is a better use of limited healthcare resources than introduction of unevaluated dementia screening programs.

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9 steps to fostering EMS community support

By Thomas L. Little Every EMS service has many opportunities to build and maintain community support. Providing top-notch patient care is a priority, but public education and outreach pay big dividends, too. The demand for up-to-date, timely health and safety information is greater than ever before. Establishing your organization as a health and safety authority in the community is an effective method ...

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Local Allergic Rhinitis in Adult Patients with Chronic Nasal Symptoms

Background: Local allergic rhinitis (LAR) remains an underdiagnosed condition characterized by the local production of IgE antibodies during the natural exposure to aeroallergens. The prevalence of LAR in adult patients with a previous diagnosis of non-AR was assessed. Material and Methods: Eighty-four patients with perennial nasal allergy symptoms but a negative skin prick test and specific IgE antibodies against common inhalant allergens were included in the study. Nasal provocation tests were performed with the inhalant allergens Dermatophagoides pteronyssinus, Alternaria, and cat allergen, followed by the detection of nasal-specific IgE antibodies in the lavage during the challenge. Results: LAR was confirmed in 21 (25%) study patients. In the remaining 63 (75%) patients, non-AR was diagnosed. In addition, LAR was found following exposure to D. pteronyssinus in 19 (22.6%) patients, Alternaria in 3 (3.6%) patients, and the cat allergen in 1 (1.2%) patient. In 2 patients, concomitant allergies to D. pteronyssinus and Alternaria were observed. Conclusion: LAR can be a form of chronic perennial rhinitis that has previously been considered to be non-AR.
Int Arch Allergy Immunol 2017;173:165-170

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Association between Caesarean Delivery and Isolated Doses of Formula Feeding in Cow Milk Allergy

Background: Cow milk allergy (CMA) is the most common food allergy in breastfed infants. The aim of this study is to verify whether certain perinatal factors may influence the development of CMA immunoglobulin E (IgE)+. Methods: A retrospective, observational study of case and control groups was carried out. Information was collected of patients with CMA IgE+ from our department during the years 1990-2013. Patients of the same age and sex were recruited for the control group. Information on the following variables was collected: sex, age, pregnancy tolerance, duration of pregnancy, type of delivery, isolated doses of formula feeding in hospital (FFH), duration of breastfeeding, and family history of allergy (defined as ≥1 first-degree family member with allergic disease). Statistical analysis was performed using multivariate logistic regression techniques. Results: A total of 211 cases were included in this study. Multivariate analysis showed an influence of duration of breastfeeding, FFH to be a risk factor (OR 4.94; 95% CI 2.68-9.08), especially in caesarean delivery (OR 11.82; 95% CI 2.64-47.50), and prematurity (OR 0.29; 95% CI 0.09-0.92) to be a protective factor. Conclusions: Perinatal factors play a key role in the development of CMA IgE+, with an influence of breastfeeding duration, FFH and caesarean delivery as risk factors and prematurity as a protective factor. While family history had no important role, environmental factors were more decisive.
Int Arch Allergy Immunol 2017;173:147-152

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Modulation of CD4+ T Helper Cell Memory Responses in the Human Skin

Immunological memory is defined as the capacity to mount faster and more effective immune responses against antigenic challenges that have been previously encountered by the host. CD4+ T helper (Th) cells play central roles in the establishment of immunological memory as they assist the functions of other leukocytes. Th cells express polarized cytokine profiles and distinct migratory and seeding capacities, but also retain a certain functional plasticity that allows them to modulate their proliferation, activity, and homing behaviour upon need. Thus, in healthy individuals, T cell immunomodulation fulfils the task of eliciting protective immune responses where they are needed. At times, however, Th plasticity can lead to collateral tissue damage and progression to autoimmune diseases or, conversely, incapacity to reject malignant tissues and clear chronic infections. Furthermore, common immune players and molecular pathways of diseases can lead to different outcomes in different individuals. A mechanistic understanding of those pathways is therefore crucial for developing precise and curative medical interventions. Here, I focus on the skin microenvironment and comprehensively describe some of the cellular and molecular determinants of CD4+ T cell memory responses in homeostatic and pathological conditions. In discussing the cellular network orchestrating cutaneous immunity, I comprehensively describe the bidirectional interaction of skin antigen-presenting cells and mononuclear phagocytes with Th17 lymphocytes, and examine how the outcome of this interaction is influenced by endogenous skin molecules, including sodium salts and neuropeptides.
Int Arch Allergy Immunol 2017;173:121-137

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A Pilot Study Investigating Clinical Responses and Biological Pathways of Azelastine/Fluticasone in Nonallergic Vasomotor Rhinitis before and after Cold Dry Air Provocation

Background: Nonallergic vasomotor rhinitis (NAVMR) has been considered a diagnosis by exclusion due to unknown mechanisms or lack of diagnostic biomarkers. Methods: To determine clinical responses and biological pathways in NAVMR subjects challenged to cold dry air (CDA) in an environmental exposure chamber (EEC) pre- and posttreatment with azelastine/fluticasone (AzeFlu), 30 NAVMR subjects, prescreened for CDA-induced symptoms (approx. 14°C, n = 20) or placebo (n = 10) for 2 weeks. Total nasal symptoms scores, minimum cross-sectional area, cough, and conjunctival redness were recorded at visit 1 (pretreatment) and visit 2 (posttreatment) before, during, and after CDA challenge. At both visits, nasal lavage fluid (NLF) and nasal scrapings (NS) were collected pre- and post-CDA challenge. Substance P, neurokinin-A, and calcitonin gene-related peptide concentrations in NLF were analyzed pre- and postchallenge at each visit. Their relationship with CDA-induced symptoms was determined by statistical analysis. MicroRNA sequencing from NS determined differentially expressed miRNA between the treatment groups post-CDA challenge at each visit. Results: The minimum cross-sectional area (p p p Conclusions: This study demonstrated the feasibility of an EEC model to investigate CDA-induced clinical responses and pathobiology in NAVMR subjects pre- and posttreatment with AzeFlu. NAVMR disease mechanisms for other nonallergic triggers can be investigated similarly.
Int Arch Allergy Immunol 2017;173:153-164

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Molecular Recognition Profiles and Clinical Patterns of PR-10 Sensitization in a Birch-Free Mediterranean Area

Background: The order Fagales represents an important cause of tree-pollen allergy in northern countries. We investigated the IgE recognition profiles, mutual relationships, and association with clinical symptoms of a panel of allergens belonging to the PR-10 family, the main proteins responsible for Fagales allergy (Act d 8, Aln g 1, Api g 1, Ara h 8, Bet v 1, Cor a 1.0101, Cor a 1.0401, Gly m 4, Mal d 1, and Pru p 1). Methods: A total of 526 PR-10-reactive subjects living in central and southern Italy were studied by ImmunoCAP-ISAC-112 microarray analysis. Results: Overall, Bet v 1 reactivity was the most commonly (74%) observed among PR-10 proteins, but Cor a 1.0101 was the most prevalent in participants aged Conclusions: Testing IgE reactivity to a panel of PR-10s in a birch-free area discloses peculiar relationships between clinical phenotypes and sensitization profiles, allowing the identification of novel cluster patterns.
Int Arch Allergy Immunol 2017;173:138-146

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The Trend of Change of Allergic Diseases over the Years: Three Repeated Surveys from 1994 to 2014

Background: Although it is known that there has been an increase in asthma and allergic diseases among school-aged children, results vary between countries. The aim of this study was to examine trends in the prevalence of these diseases in the city of Adana (south Turkey) over the last 20 years based on the results of 3 cross-sectional studies. Methods: Three cross-sectional surveys were performed 10 years apart in south Turkey. Here, we compare the surveys conducted among children between the ages of 6 and 14 years from 1994, 2004, and 2014. The participants were randomly chosen among children attending participating primary schools in Adana. The questionnaire in the first survey contained almost the same questions as the ISAAC. In the 2 latter surveys, we used the ISAAC questionnaire to investigate the prevalence of asthma and other allergic diseases. Results: A total of 2,334 children in 1994, 3,728 children in 2004, and 3,209 children in 2014 were included in the final analysis. The results showed a statistically significant increase in the prevalence of physician-diagnosed allergic diseases across the years, respectively: asthma (5, 4.6, and 8.9%), allergic rhinitis (8.8, 11.4, and 15.6%), and atopic dermatitis (5, 9.9, and 7%). In contrast, the prevalence of parent-reported current wheeze (16.2, 13.2%) decreased in the last 10 years. Conclusions: Our findings were consistent with the increased prevalence of childhood asthma and other allergic diseases. However, this pattern did not occur in respiratory symptoms.
Int Arch Allergy Immunol 2017;173:178-182

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3 steps to properly documenting patient care in EMS

All members of the EMS team must commit to improving patient care documentation by expanding on the details and ensuring completion

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Boosting isoprene production via heterologous expression of the Kudzu isoprene synthase gene (kIspS) into Bacillus spp. cell factory

Isoprene represents a key building block for the production of valuable materials such as latex, synthetic rubber or pharmaceutical precursors and serves as basis for advanced biofuel production. To enhance th...

http://ift.tt/2vh7RAj

Early Onset Parkinson’s Disease in a family of Moroccan origin caused by a p.A217D mutation in PINK1: a case report

Bi-allelic mutations in the genes Parkin (PARK2), PINK1 (PARK6) and DJ-1 (PARK7) are established causes of autosomal recessive early-onset Parkinson's Disease (EOPD). PINK1 mutations are the second commonest caus...

http://ift.tt/2vMDXp2

Association between multiple sclerosis, cancer risk, and immunosuppressant treatment: a cohort study

The association between multiple sclerosis (MS) and cancer has long been investigated with conflicting results. Several reports suggest an increased cancer risk among MS patients treated with immunosuppressant...

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Development of novel genic microsatellite markers from transcriptome sequencing in sugar maple (Acer saccharum Marsh.)

Sugar maple (Acer saccharum Marsh.) is a hardwood tree species native to northeastern North America and economically valued for its wood and sap. Yet, few molecular genetic resources have been developed for this...

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Two years retrospective study of maxillofacial trauma at a tertiary center in North West Ethiopia

Maxillofacial injury poses a challenge to oral and maxillofacial surgeons working in developing countries with limited resource and human power. The present study aimed to determine the etiology, pattern, and ...

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Clinical profile and comorbidity of traumatic brain injury among younger and older men and women: a brief research notes

Comorbid disorders influence the course and outcomes of rehabilitation following traumatic brain injury (TBI), yet sex- and age-related disparities in the frequency distribution of these disorders remain poorl...

http://ift.tt/2uDngav

Oral pyridoxine can substitute for intravenous pyridoxine in managing patients with severe poisoning with isoniazid and rifampicin fixed dose combination tablets: a case report

Fixed drug combination of isoniazid and rifampicin is a rare cause of poisoning even in endemic countries for tuberculosis infection. Severe poisoning can cause severe morbidity and mortality if not treated pr...

http://ift.tt/2umKdDq

Mycobacterium iranicum bacteremia and hemophagocytic lymphohistiocytosis: a case report

Mycobacterium iranicum has recently been recognised as an opportunistic human pathogen. Although infectious conditions represent frequent triggers for hemophagocytic lymphohistiocytosi...

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Evidence of advanced stage colorectal cancer with longer diagnostic intervals: a pooled analysis of seven primary care cohorts comprising 11 720 patients in five countries

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Pre-clinical imaging of transgenic mouse models of neuroblastoma using a dedicated 3-element solenoid coil on a clinical 3T platform

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miR-125b predicts childhood acute lymphoblastic leukaemia poor response to BFM chemotherapy treatment

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GEIS-21: a multicentric phase II study of intensive chemotherapy including gemcitabine and docetaxel for the treatment of Ewing sarcoma of children and adults: a report from the Spanish sarcoma group (GEIS)

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miR-29a/b/c function as invasion suppressors for gliomas by targeting CDC42 and predict the prognosis of patients

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Right or left? Side selection for a totally implantable vascular access device: a randomised observational study

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Blood Pressure and Altitude: An Observational Cohort Study of Hypertensive and Nonhypertensive Himalayan Trekkers in Nepal

High Altitude Medicine & Biology , Vol. 0, No. 0.


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It's time to weigh in on EMS Scope of Practice revisions

If you ever wanted the opportunity to weigh in on the future of your profession, the time is now. The National Association of State EMS Officials is seeking input from across the nation during its revision process of the National EMS Scope of Practice. Your input will be valuable in helping to move our practice forward, from EMR to Paramedic level. A quick history of the EMS Scope of Practice If you ...

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Long-term daily temozolomide with dose-dependent efficacy in MGMT promotor methylation negative recurrent high-grade astrocytoma

Abstract

Temozolomide (TMZ) for malignant gliomas is traditionally dosed in 5 out of a 28-day cycle, however alternative regimens exist, including dose-dense. Continuous daily dosing is available, but the acceptable dose and duration of therapy is unknown. We document a 40-year-old male with recurrent anaplastic astrocytoma, IDH mutant and MGMT promotor methylation negative, who has well-tolerated continuous daily TMZ for 20 months at 100 mg per day for nearly the length of this period. A trial at 80 mg per day demonstrated disease progression with response upon return to 100 mg per day. Prior to the daily TMZ, the patient underwent three surgical resections, radiation therapy with concurrent TMZ according to the EORTC-NCIC protocol, and subsequently bevacizumab in combination with use of the Optune device. Long-term survival of patients with recurrent malignant gliomas is uncommon, and currently no standard treatment strategies exist for these patients. We present this case to demonstrate the tolerability and dose dependency of prolonged daily TMZ dosing as a therapeutic option for recurrent anaplastic astrocytomas.

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RGB and Spectral Root Imaging for Plant Phenotyping and Physiological Research: Experimental Setup and Imaging Protocols

An experimental protocol is presented for assessment of soil grown plant root systems with RGB and hyperspectral imaging. Combination of RGB image time series with chemometric information from hyperspectral scans optimizes insights into plant root dynamics.

http://ift.tt/2fpDOka

Systemic Delivery of Dysferlin Overlap Vectors Provides Long-Term Gene Expression and Functional Improvement for Dysferlinopathy

Human Gene Therapy , Vol. 0, No. 0.


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Feasibility of dose-dense epirubicin and cyclophosphamide with subcutaneous pegfilgrastim 3.6 mg support: a single-center prospective study in Japan

Abstract

Background

Dose-dense chemotherapy consisting of a combination of epirubicin and cyclophosphamide (EC) improves the survival of patients with breast cancer. Although pegfilgrastim was used at a subcutaneous dose of 6.0 mg in a pivotal study of dose-dense EC treatment, pegfilgrastim at a dose of 3.6 mg has been approved in Japan. We have assessed the feasibility of dose-dense EC treatment supported with a 3.6 mg dose of pegfilgrastim by evaluating the relative dose intensity (RDI) and safety of the treatment, together with measuring the pegfilgrastim concentrations remaining on the day of starting the next cycle of chemotherapy.

Methods

Patients with primary breast cancer received a total of 4 cycles of dose-dense EC treatment every 2 weeks, together with a subcutaneous injection of 3.6 mg pegfilgrastim on the day after chemotherapy. The serum granulocyte colony-stimulating factor (G-CSF) concentrations were measured on the 15th day of every chemotherapy cycle.

Results

From March 2015 through to July 2016, a total of 51 patients (median age 51 years; range 33–73 years) were studied. The mean RDI was 95.2% (range 60.0–100%). Although most adverse events were consistent with those reported in previous studies, pneumocystis pneumonia developed in two patients during the following course of docetaxel treatment. The median serum G-CSF concentration was 92.5 (range 30.4–440) pg/ml.

Conclusions

With support provided by pegfilgrastim injection at a dose of 3.6 mg, dose-dense EC is feasible and associated with maintenance of a high RDI. There was no clinically significant accumulation of serum G-CSF concentrations associated with the use of a 3.6 mg dose of pegfilgrastim at 2-week intervals.

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Be ready to save lives: Innovative, new tourniquet available at GideonTactical

COATESVILLE, Pa. - GideonTactical, the top-tier source for all things tactical, now offers a versatile tourniquet that effectively negates the risk of exsanguination (bleeding to death) from occurring: the SAM Medical XT Extremity Tourniquet. When dealing with a potentially life-threatening hemorrhage, every second counts. Many times, inappropriately applied tourniquets result in lost lives, with slack ...

http://ift.tt/2wFsPqd

Rescue Essentials announces the release of the QuikLitter Lite™

SALIDA, Colo. — RESCUE ESSENTIALS, a Colorado based tactical medical supply and training company, has recently released the newest addition to their popular QuikLitter line of soft litters, the QuikLitter Lite™. In response to the need for multiple litters at an MCI or active shooter incident, the QuikLitter Lite™ was specifically designed to be compact and lightweight. This highly ...

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Evaluation of muscle activity, bite force and salivary cortisol in children with bruxism before and after low level laser applied to acupoints: study protocol for a randomised controlled trial

Bruxism is a repetitive activity that causes tooth wear, audible sounds, and discomfort. Preventive measures have been studied for conditions that can exert a negative influence on physiological development in...

http://ift.tt/2um3QHT

Study protocol on comparative effectiveness of mindfulness meditation and qigong on psychophysiological outcomes for patients with colorectal cancer: a randomized controlled trial

Colorectal cancer imposes threats to patients' well-being. Although most physical symptoms can be managed by medication, psychosocial stressors may complicate survival and hamper quality of life. Mindfulness a...

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High-throughput Screening for Protein-based Inheritance in S. cerevisiae

This protocol describes a high-throughput methodology to functionally screen for protein-based inheritance in S. cerevisiae.

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4 Things PTs Need to Know About the Quality Payment Program (QPP)

Providers can get involved today through MIPS and alternate payment methods (APMs).

https://www.youtube.com/watch?v=CDfHAWMmwoY

Contrasting effects of cyclophosphamide on anti-CTLA-4 blockade therapy in two mouse tumor models

Summary

Immune checkpoint blockade is a promising anti-cancer therapy, but must be used in combination with other anti-cancer therapies to increase therapeutic efficacy. Cyclophosphamide (CP) is a chemotherapeutic drug that exhibits immune-modulating effects. In this study, we examined the effect of CP on anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade therapy in two mouse tumor models. Drastic tumor regression was observed in the CT26 colon carcinoma model after intraperitoneal (i.p.) injection of CP (100 mg/kg) followed by anti-CTLA-4 antibody. However, administration in the reverse order increased apoptosis in tumor-specific CD8⁺ T cells. In the RENCA renal carcinoma model, the anti-tumor effect of combination therapy was marginal and the tumor-bearing state reduced body weight with an increased serum level of interleukin (IL)-6. Interestingly, although CP monotherapy increased myeloid-derived suppressor cells (MDSCs) in the spleens of both models, subsequent anti-CTLA-4 therapy increased MDSCs only in RENCA-bearing mice. Additionally, the serum levels of chemokine ligand 2 (CCL2) and C-X-C motif chemokine 10 (CXCL10) were increased by the combination therapy only in RENCA-bearing mice and in vivo depletion of Gr-1⁺ cells augmented the anti-tumor effect to some degree. These results reveal a contrasting effect of CP on anti-CTLA-4 therapy between the two mouse tumor models. CP augments the anti-tumor effect of anti-CTLA-4 therapy in CT26-bearing hosts, whereas CP after anti-CTLA-4 therapy attenuates this effect via induction of apoptosis in tumor-reactive T cells. Alternatively, CP-induced MDSCs can be increased by anti-CTLA-4 therapy only in RENCA-bearing hosts with an elevated level of IL-6.

This article is protected by copyright. All rights reserved.

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Protocol for Assessing the Relative Effects of Environment and Genetics on Antler and Body Growth for a Long-lived Cervid

Phenotypic differences among cervid populations may be related to population-level genetics or nutrition; discerning which is difficult in the wild. This protocol describes how we designed a controlled study where nutritional variation was eliminated. We found that phenotypic variation of male white-tailed deer was more limited by nutrition than genetics.

http://ift.tt/2wETVO3

Germline variation of circadian pathway genes and prognosis of gastric cancer patients

As we have summarised in this journal,1 germline DNA variation has been long recognised as a key component of the risk to develop to gastric carcinoma, the discovery pace being greatly accelerated by genome-wide association studies.2 More recently, growing evidence is accumulating also on the association between genetic variation and prognosis of patients with gastric cancer.3 4 Furthermore, investigators have demonstrated that alterations of the circadian rhythm can predispose to a variety of illnesses, including different types of malignancies and gastrointestinal diseases.5 6

Putting together these observations, we studied the relationship between circadian genes germline variation and the overall survival of 460 patients with TNM stage I to IV gastric carcinoma. We considered 21 single nucleotide polymorphisms (SNPs) of 14 circadian pathway genes. Genotyping was performed with real-time quantitative PCR using patient peripheral blood samples. Expression quantitative trait locus...

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Card9 mediates susceptibility to intestinal pathogens through microbiota modulation and control of bacterial virulence

Objective

In association with innate and adaptive immunity, the microbiota controls the colonisation resistance against intestinal pathogens. Caspase recruitment domain 9 (CARD9), a key innate immunity gene, is required to shape a normal gut microbiota. Card9^–/– mice are more susceptible to the enteric mouse pathogen Citrobacter rodentium that mimics human infections with enteropathogenic and enterohaemorrhagic Escherichia coli. Here, we examined how CARD9 controls C. rodentium infection susceptibility through microbiota-dependent and microbiota-independent mechanisms.

Design

C. rodentium infection was assessed in conventional and germ-free (GF) wild-type (WT) and Card9^–/– mice. To explore the impact of Card9^–/–microbiota in infection susceptibility, GF WT mice were colonised with WT (WT->GF) or Card9^–/– (Card9^–/–->GF) microbiota before C. rodentium infection. Microbiota composition was determined by 16S rDNA gene sequencing. Inflammation severity was determined by histology score and lipocalin level. Microbiota–host immune system interactions were assessed by quantitative PCR analysis.

Results

CARD9 controls pathogen virulence in a microbiota-independent manner by supporting a specific humoral response. Higher susceptibility to C. rodentium-induced colitis was observed in Card9^–/–->GF mice. The microbiota of Card9^–/– mice failed to outcompete the monosaccharide-consuming C. rodentium, worsening the infection severity. A polysaccharide-enriched diet counteracted the ecological advantage of C. rodentium and the defective pathogen-specific antibody response in Card9^–/– mice.

Conclusions

CARD9 modulates the susceptibility to intestinal infection by controlling the pathogen virulence in a microbiota-dependent and microbiota-independent manner. Genetic susceptibility to intestinal pathogens can be overridden by diet intervention that restores humoural immunity and a competing microbiota.

http://ift.tt/2vMwar3

Smiths Detection technology protects first responders against the threat of fentanyl exposure

EDGEWOOD, Md. — Smiths Detection Inc. (SDI) is at the forefront of arming first responders with solutions to safeguard against the presence of fentanyl. Working directly with international law enforcement and hazmat agencies, SDI has adapted a range of existing technologies to be able to quickly and accurately detect fentanyl and its analogues on scene. Fentanyl, if inhaled, may lead to respiratory ...

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Doctor competing in Ironman performs CPR on fellow triathlete

Dr. Patricia DeLaMora, a pediatric infectious disease physician, stopped when she saw an unconscious man on the road

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The cost-effectiveness of active surveillance compared to watchful waiting and radical prostatectomy for low risk localised prostate cancer

Abstract

Background

Radical prostatectomy is the most common treatment for localised prostate cancer in New Zealand. Active surveillance was introduced to prevent overtreatment and reduce costs while preserving the option of radical prostatectomy. This study aims to evaluate the cost-effectiveness of active surveillance compared to watchful waiting and radical prostatectomy.

Methods

Markov models were constructed to estimate the life-time cost-effectiveness of active surveillance compared to watchful waiting and radical prostatectomy for low risk localised prostate cancer patients aged 45–70 years, using national datasets in New Zealand and published studies including the SPCG-4 study. This study was from the perspective of the Ministry of Health in New Zealand.

Results

Radical prostatectomy is less costly than active surveillance in men aged 45–55 years with low risk localised prostate cancer, but more costly for men aged 60–70 years. Scenario analyses demonstrated significant uncertainty as to the most cost-effective option in all age groups because of the unavailability of good quality of life data for men under active surveillance. Uncertainties around the likelihood of having radical prostatectomy when managed with active surveillance also affect the cost-effectiveness of active surveillance against radical prostatectomy.

Conclusions

Active surveillance is less likely to be cost-effective compared to radical prostatectomy for younger men diagnosed with low risk localised prostate cancer. The cost-effectiveness of active surveillance compared to radical prostatectomy is critically dependent on the 'trigger' for radical prostatectomy and the quality of life in men on active surveillance. Research on the latter would be beneficial.

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