Epidemiology of and Risk Factors for BK Polyomavirus Replication and Nephropathy in Pediatric Renal Transplant Recipients: An International CERTAIN Registry Study

Background BK polyomavirus-associated nephropathy (BKPyVAN) constitutes a serious cause of kidney allograft failure, but large-scale data in pediatric renal transplant recipients and a comprehensive analysis of specific risk factors are lacking. Methods We analyzed data of 313 patients in the Cooperative European Paediatric Renal Transplant Initiative (CERTAIN) registry, with an observation period of 3.3 years (range, 1 – 5). The net state of immunosuppressive therapy was assessed by the modified Vasudev score. Results Presumptive BKPyVAN (defined as sustained (>3 weeks) high-level BK viremia >104 copies/mL) within 5 years posttransplant occurred in 49/311 (15.8%) of patients, and biopsy-proven BKPyVAN in 14/313 (4.5%). BKPyV viremia was observed in 115/311 patients (36.7%), of whom 11 of 115 (9.6%) developed viremia late, ie, after the second year posttransplant. In 6/48 patients (12.5%) with high-level viremia and in 3/14 (21.4%) with BKPyVAN this respective event occurred late. According to multivariable analysis, BKPyV viremia and/or BKPyVAN were associated with a higher net state of immunosuppression (OR 1.3, p

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Islet Allotransplantation in the Bone Marrow of Patients With Type 1 Diabetes: A Pilot Randomized Trial

Background Results in murine and nonhuman primate suggested that the bone marrow (BM) might be an alternative site for pancreatic islet transplantation. Methods We report the results of 2 clinical studies in patients with type 1 diabetes receiving an intra-BM allogeneic islet transplantation: a feasibility study in patients with hepatic contraindications for liver islet allotransplantation receiving a single intra-BM islet infusion (n=4) and a pilot randomized trial (1:1 allocation using blocks of size 6) in which patients were randomized to receive islets into either the liver (n=6) or BM (n=3) to evaluate islet transplant function and survival Results We observed no adverse events related to the intrabone injection procedure or the presence of islets in the BM. None of the recipient of an intra-BM allogeneic islet transplantation had a primary nonfunction, as shown by measurable post transplantation C-peptide levels and histopathological evidence of insulin-producing cells or molecular markers of endocrine tissue in BM biopsy samples collected during follow-up. All patients receiving islets in the BM except one lost islet function during the first 4 months after infusion (2 with an early graft loss). Based on biopsies and immuno-monitoring, we concluded that the islet loss was primarily caused by the recurrence of autoimmunity. Conclusion BM is not a suitable alternative site for pancreatic islet allotransplantation in patients with type 1 diabetes Correspondence to: Lorenzo Piemonti, Diabetes Research Institute, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan. Fax: 39 02 26432871. Tel: 39 02 26432706. E-mail: piemonti.lorenzo@hsr.it Trial registration. ClinicalTrials.gov NCT01345227 and NCT01722682 Authorship page P.M. and A.S. managed patients. M.P. and C.D performed the histopathological analysis of the bone marrow. R.N., R.M. and A.M. performed islet isolations. V.S. and S.P performed the molecular analysis of the bone marrow biopsy samples. M.S. reviewed and edited the manuscript and contributed to the discussion. J.P., C.M. and F.C. developed the intrabone marrow islet infusion method and performed the transplantations. P.M., S.B., B.R, A.N. and M.C. performed the cellular and humoral immunomonitoring. L.P. conceived the intrabone marrow strategy, developed the concept, designed the experiments, wrote the manuscript, promoted the study, and researched data. L.P. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Disclosure The authors of this manuscript have no conflicts of interest to disclose as described by Transplantation. Funding This study was supported by the Italian Minister of Health (Ricerca Finalizzata RF-2009-1469691) and by the European Commission (FP7 241883 and H2020 681070). P.M. is supported by a Career Development Award (5-CDA-2015-85-A-N) from JDRF. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Migrating From Universal to Personalized Prevention: Predicting the Risk of Cytomegalovirus Infection after Organ Transplantation

No abstract available

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Outcomes in Third and Fourth Kidney Transplants Based on the Type of Donor

Background An increasing number of patients are requiring multiple retransplants. We assessed outcomes of third and fourth kidney transplants, to aid decision-making on the most suitable donor type. Methods Data were collected retrospectively for 2561 transplants, including 69 third and 8 fourth, performed from 2000-2017. Demographics and outcomes for the combined third/fourth group were compared to first and second transplants. Within the third/fourth kidney transplant group, comparisons were made between deceased-donors (n=39), live-donor-HLA-compatible (n=23) and -incompatible (n=13) transplants, as well as between standard (n=25) and extended-criteria (n=14) deceased-donor transplants. Results Patient survival did not differ significantly by transplant number (p=0.532), whilst death-censored graft survival declined progressively, from 89% at 5 years in first, 85% in second and 74% in the third/fourth transplant group (p

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Obesity and Metabolic Syndrome in Kidney Transplantation: The Role of Dietary Fructose and Systemic Endotoxemia

Background The concepts that obesity is merely a consequence of overeating, and that metabolic health then reflects obesity, may be insufficient and potentially flawed. The role of fructose intake and metabolic endotoxemia have gained attention recently, but data in kidney transplantation are lacking. This study evaluated the risk factors for metabolic syndrome (MS), its components, and other associated markers in kidney transplant recipients (KTRs), focussing particularly on fructose intake and systemic endotoxemia. Methods This cross-sectional observational study enrolled 128 KTRs>1-year posttransplantation. Clinical, biochemical, anthropometric, and questionnaire assessments were undertaken. Results Obesity (body mass index≥30kg/m2) and MS (International Diabetes Federation Definition) were found in 36.7% and 50% of KTRs respectively. Both increased fructose intake (p=0.01) and endotoxin level (p=0.02) were independently associated with MS; and higher fructose intake was independently associated with obesity (p0.6), as well as relationships between increased fructose intake, inflammation and blood glucose (r>0.6). Conclusions Dietary modifications through decreasing fructose intake and addressing systemic endotoxemia are plausible targets for improving metabolic health of KTRs. Corresponding Author: Dr Richard Borrows, Department of Nephrology & Kidney Transplantation, Area 5, Level 7, Queen Elizabeth Hospital Birmingham, Mindelsohn Way, Edgbaston, Birmingham B15 2WB, UK. Tel: +44 (0) 121 371 6099, Fax: +44 (0) 121 371 5858. Email: Richard.Borrows@uhb.nhs.uk Author Contributions Winnie Chan and Richard Borrows designed the research. Winnie Chan, Byron Smith, Mark Stegall, and Richard Borrows wrote the manuscript. Winnie Chan and Richard Borrows conducted the research. Winnie Chan, Byron Smith, and Richard Borrows analysed the data and performed the statistical analysis. Richard Borrows had primary responsibility for the final content. Disclosure: The authors declare no conflict of interest. Funding Winnie Chan received a research grant from the British Renal Society and was awarded a PhD research training fellowship from the National Health Service West Midlands Strategic Healthy Authority. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Fosfomycin-Trometamol for Urinary Tract Infections in Kidney Transplant Recipients

Background The treatment of urinary tract infections (UTI's) in kidney transplant recipients (KTRs) with oral antibiotics is complicated by increasing resistance to trimethoprim-sulfamethoxazole, amoxicillin/clavulanic acid and ciprofloxacin. Fosfomycin-trometamol (FT) could be an alternative, but evidence on clinical effectiveness is scarce. We evaluated the use, effectiveness and safety of FT for UTI in KTRs. Methods Data were retrospectively collected in 2 Dutch transplant hospitals from adult KTRs that were treated with FT as initial treatment for lower-UTI or asymptomatic bacteriuria or as stepdown treatment for upper-UTI after initial intravenous antibiotics. Exclusion criteria were in vitro resistance to FT or concomitant antibiotic treatment. Endpoints were clinical cure within 14 days and severe clinical failure, microbiological cure, relapse, recurrence, and acquired resistance within 90 days postend of treatment. Results 53 episodes in 40 KTRs were included (ASB n=15; lower-UTI n=33; upper-UTI n=5). FT was used for a median short duration in a heterogeneous gift interval. FT resulted in microbiological cure in 25, 28 and 100% of ASB, lower-UTI and upper-UTI with initial positive culture and follow-up culture performed, respectively. Clinical cure rates were 67% for lower-UTI and 80% for upper-UTI. Relapses or recurrences occurred in 31% and 24% of symptomatic UTI episodes, without severe clinical failure. Acquired resistance to fosfomycin was observed in 6 episodes. Conclusions FT has a reasonable effectiveness as last-resort oral treatment for lower-UTI and stepdown treatment for upper-UTI in KTRs. Randomized controlled trials with optimal dosage regimens are warranted. Use of FT is not recommended for ASB. Authorship: TD, HW, SM, JS and MB participated in the research design. TD and JS participated in the collection of the data. TD and HW participated in the data analysis. All authors participated in the writing of the paper. Disclosure: The authors declare no conflicts of interest. Funding: No funding was received for this work. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Serum Factor V is a Continuous Biomarker of Graft Dysfunction and a Predictor of Graft Loss After Liver Transplantation

Background: Factor V has never been compared to a validated early allograft dysfunction (EAD) definition. We aimed to assess Factor V as a biomarker of EAD and a predictor of graft loss after liver transplantation (LT). Methods: We retrospectively assessed the serum Factor V levels on postoperative day 1 after LT. Patients were divided according to their Factor V levels into the ≤36.1U/mL and >36.1U/mL groups. The primary outcome was graft loss within 1, 3, and 6 months. The secondary outcome was EAD, as defined by Olthoff et al Predictors of outcomes were identified by multivariable logistic regression. Results: 227 patients were included in the study: 74 with Factor V ≤36.1U/mL and 153 with Factor V >36.1U/mL. EAD was diagnosed in 41/74 (55.4%) patients with Factor V ≤36.1U/mL and in 20/153 (13.1%) patients with Factor V >36.1U/mL (p36.1U/mL (p=0.001). Factor V was a continuous predictor for 3- and 6-month graft loss [(OR=0.96 (95%CI 0.94–0.99) and OR=0.97 (95% CI 0.94–0.99) per U/mL], whereas EAD was not significant when adjusted for Factor V. Conclusion: Factor V is an early marker for EAD and is a continuous predictor of short-term graft loss after LT. Corresponding Author: Dr. Cleber Rosito Pinto Kruel, Assistant Professor, Liver Transplant Program, Hospital de Clinical de Porto Alegre, 2350 Ramiro Barcelos Street, office 745, Porto Alegre, Brazil, Phone: +55 51 3359 8232. E-mail: crkruel@hcpa.edu.br Authorship: AG has contributed to the study's concept, design, data collection, data analysis, interpretation, and manuscript writing. CP and JEP have contributed to the data collection and approved the manuscript's final version. MFC, ANB, AA, TJMG, IL, ADC, and MRAS have all contributed to the data interpretation and critical appraisal, and they also approved the manuscript's final version. GS and CRPK have contributed to the study's concept, design, data interpretation, and manuscript writing. All authors have approved the manuscript's final version. Category of manuscript: Original investigation Financial Support: None Conflict of Interest: None Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Temporal Changes in the Impact of HLA Mismatching Among Pediatric Kidney Transplant Recipients

Background Allocation for pediatric deceased-donor kidney transplantation (pDDKT) in the United States now deemphasizes HLA matching to improve equality in access to transplantation, but other national systems still consider HLA matching due to concerns about graft survival. We hypothesized that the impact of HLA mismatching has decreased over time due to advances including improved immunosuppression. Methods Using SRTR data, we analyzed whether the association between the number of HLA mismatches and outcomes of first-time pDDKTs changed between 2 eras: 1995-2004 (N=2854) and 2005-2014 (N=4643). Results Between eras, the median number of mismatches increased from 4 to 5 (p

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CMV-specific Cell-Mediated Immunity at 3-month Prophylaxis Withdrawal Discriminates D+/R+ Kidney Transplants at risk of Late-onset CMV Infection Regardless the Type of Induction Therapy

Background Whether CMV-specific cell-mediated immunity (CMI) at prophylaxis cessation predicts D+/R+ kidney transplants (KTR) at risk of late-onset CMV infection after receiving distinct induction therapies is still not well characterized. Methods We prospectively assessed CMV-specific CMI predicting late-onset CMV infection at prophylaxis withdrawal and at earlier time-points, in 96 consecutive D+/R+ patients receiving either antiinterleukin 2-receptor antibody (anti-IL2RA; n=50) or rabbit antithymoglobulin (rATG; n=46). CMV-specific CMI was evaluated against CMV antigens (IE-1, pp65) using an IFN-γ ELISpot assay. Results 14/96(14.6%) patients developed late-onset CMV infection and 2/96(2.1%) displayed disease. At 3 months, CMV-specific CMI frequencies were significantly lower in patients developing late-onset CMV infection (p

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Factors Associated With Mortality and Response to Extracorporeal Photopheresis in Lung Allograft Recipients With Bronchiolitis Obliterans Syndrome

Background This study was designed to identify factors associated with clinical response to extracorporeal photopheresis (ECP) and mortality after ECP in lung allograft recipients with bronchiolitis obliterans (BOS). Methods FEV1 values obtained 6 months before (baseline) and 6 months after initiation of ECP were used to plot the linear relationship between FEV1 vs time before and after ECP. Response to ECP was assigned when a positive integer was derived after subtracting the baseline rate of decline from the rate of decline 6 months after ECP. Uni- and multivariate logistic regression analyses were used to identify demographic, treatment related factors or spirometric parameters and that may be associated with response to ECP or mortality at either 6 or 16 months after initiation of ECP. Results FEV1 just prior to ECP was associated with mortality (p=0.007) at 16 months after ECP initiation. An FEV1 ≤ 1.50L had a sensitivity of 87% and a specificity of 60% to identify patients who died within 16 months after ECP initiation. Patients whose FEV1 decline exceeded > 40 mL/month were 12 times more likely to have a response to ECP (p=0.0001). Patients whose decline in FEV1 before ECP was statistically significant (p40 mL/month) and statistical significance of the relationship between FEV1 vs time prior to ECP initiation. Therefore, earlier BOS detection and more timely implementation of ECP (ie, when FEV1 values > 1.5L) should be considered especially in patients with a more aggressive rate of decline of lung function. Correspondence: George Despotis, MD, Washington University School of Medicine, Department of Pathology & Immunology, Division of Laboratory & Genomic Medicine,425 S. Euclid Avenue, Campus Box 8118, Saint Louis, MO 63110. Email gjdespotis@wustl.edu Authorship Hope E. Karnes, MD, PhD: Participated in research design, performance of the research, writing of the paper, data analysis Emily I. Schindler, MD, PhD: Participated in research design, performance of the research, writing of the paper, data analysis Matt Morrell, MD: Participated in research design, performance of the research, writing of the paper, data analysis Ramsey R Hachem MD: Participated in research design, performance of the research, writing of the paper, data analysis Keith Berman, MPH, MPA: Participated in writing of the paper, data analysis Suresh Vedantham, MD: Participated in writing of the paper, data analysis Jeff Atkinson, MD: Participated in writing of the paper, data analysis Edward Spitznagel, PhD: Participated performance of the research, in writing of the paper, data analysis George Despotis, MD: Participated in research design, performance of the research, writing of the paper, data analysis Disclosure: Relationships with entities related to the topic are listed below: Hope E. Karnes, MD, PhD - None Emily I. Schindler, MD, PhD - None Matt Morrell, MD –Investigator for Investigator initiated grant from Therakos and Medicare for protocol Number CAG-00324R2 Ramsey Hachem, MD – Investigator for Investigator initiated grant from Therakos and Medicare for protocol Number CAG-00324R2, Served on advisory board for Theravance, Served on advisory board for Vectura, Serving on advisory board for Breath Keith Berman MPH, MBA: Consultant to Therakos and Barnes-Jewish Hospital Suresh Vedantham, MD – Investigator for Investigator initiated grant from Therakos and Medicare for protocol Number CAG-00324R2 Jeff Atkinson, MD - None Ed Spitznagel, PhD – Investigator for Investigator initiated grant from Therakos and Medicare for protocol Number CAG-00324R2 George Despotis, MD – Principle Investigator for Investigator initiated grant from Therakos and Medicare for protocol Number CAG-00324R2 Funding: No funding for the current work. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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The Effect of Histidine-Tryptophan-Ketoglutarate Solution (HTK) and University of Wisconsin Solution (UW): an Analysis of the Eurotransplant Registry

Background Both UW and HTK are currently used in the Eurotransplant region for preservation of liver allografts. Previous studies on their effect have led to a lot of discussion. This study aims to compare the effect of HTK and UW on graft survival. Methods First liver transplantations in recipients ≥18 years from 1.1.2007 until 31.12.2016 were included. Graft survival was compared for livers preserved with HTK and UW at 30 days, 1, 3 and 5-years. Multivariable analysis of risk factors was performed and outcome was adjusted for important confounders. Results Of all 10,628 first liver transplantations, 8,176 (77%) and 2,452 (23%) were performed with livers preserved with HTK and UW, respectively. Kaplan-Meier curves showed significant differences in graft survival between HTK and UW at 30 days (89% vs 93%, p=

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Proinflammatory/profibrotic effects of aldosterone in Gitelman’s syndrome, a human model opposite to hypertension

Abstract

Purpose

Aldosterone proinflammatory/profibrotic effects are mediated by the induction of mononuclear leucocytes (MNL) to express oxidative stress (OxSt)-related proteins, such as p22^phox, and by the activation of RhoA/Rho kinase pathway. Gitelman's syndrome (GS), an autosomal recessive tubulopathy, is an interesting opposite model to hypertension, being characterized by hypokalemia, activation of renin–angiotensin–aldosterone system yet normo/hypotension and lack of cardiovascular–renal remodeling. We aimed to evaluate the proinflammatory/profibrotic effect of aldosterone in MNL of 6 GS patients compared with 6 healthy subjects (HS).

Methods

p22^phox expression and MYPT-1 phosphorylation status, a marker of RhoA/Rho kinase pathway activation, were evaluated in MNL of GS patients and HS at baseline and after incubation with aldosterone (1 × 10⁻⁸ M) alone or with canrenone (1 × 10⁻⁶ M).

Results

At basal condition, p22^phox expression was significantly higher in HS than in GS patients (1.02 ± 0.05 densitometric unit (du) vs 0.40 ± 0.1 du, respectively). Aldosterone significantly increased p22^phox expression in HS and this effect was reversed by coincubation with canrenone (1.4 ± 0.05 du and 1.09 ± 0.03 du, respectively). No significant change was reported in GS after incubation of MNL with aldosterone and/or canrenone compared with basaline. Even MYPT-1 phosphorylation was significantly higher in HS compared with GS patients at basal condition (1.16 ± 0.1 du vs 0.69 ± 0.07, respectively). Aldosterone significantly increased MYPT-1 phosphorylation only in HS (1.37 ± 0.1 du vs 0.83 ± 0.12 du in GS).

Conclusions

GS patients seem to be protected by the OxSt status induced by aldosterone and revealed in HS. This human model could provide additional clues to highlight the proinflammatory/cardiovascular remodeling effects of aldosterone.

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Fulvestrant-Based Combination Therapy for Second-Line Treatment of Hormone Receptor-Positive Advanced Breast Cancer

Abstract

Fulvestrant is recommended for patients with hormone receptor-positive (HR+) advanced breast cancer (ABC) who progress after aromatase inhibitor therapy. As most patients in this setting have already developed mechanisms of resistance to endocrine therapy, targeting biological pathways associated with endocrine resistance in combination with fulvestrant may improve outcomes. Therefore, evidence supporting a combinatorial treatment approach in the second-line setting was investigated based on a search of PubMed and ClinicalTrials.gov. Twenty-eight studies of targeted therapies plus fulvestrant as second-line treatment for HR+ ABC were identified, including three and six key randomized trials exploring cyclin-dependent kinase 4/6 (CDK4/6) inhibitors and phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors plus fulvestrant respectively. Additional combinations with fulvestrant included inhibitors of epidermal growth factor receptors, androgen receptor, and the bromodomain and extra-terminal family of proteins. Across the studies reviewed with available data, the addition of targeted therapies to fulvestrant resulted in clinically meaningful improvements in progression-free survival compared with fulvestrant alone. While some challenging toxicities were observed, most adverse events could be effectively managed. Selection of second-line targeted therapy for use with fulvestrant should consider prior treatment as well as the mutation status of the tumor. In conclusion, available data indicate that fulvestrant combined with agents targeting mechanisms of endocrine resistance is a promising approach. The ongoing trials identified in this review will help further inform the selection of combination treatments with fulvestrant for HR+ ABC.

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Application of continuous-wave photoacoustic sensing to red blood cell morphology

Abstract

The feasibility of continuous wave laser-based photoacoustic (CWPA) response technique in detecting the morphological changes in cells during the biological studies, through the features extracted from CWPA signal (i.e., amplitude) is demonstrated here. Various hematological disorders (e.g., sickle cell anemia, thalesemia) produce distinct changes at the cellular level morphologically. In order to explore the photoacoustic response technique to detect these morphological changes, we have applied CWPA technique onto the blood samples. Results of our preliminary study show a distinct change in the signal amplitude of photoacoustic (PA) signal due to a change in the concentration of blood, which signifies the sensitivity of the technique towards red blood cell (RBC) count (related to hematological disease like anemia). Further hypotonic and hypertonic solutions were induced in blood to produce morphological changes in RBCs (i.e., swollen and shrink, respectively) as compared to the normal RBCs. Experiments were performed using continuous wave laser-based photoacoustic response technique to verify the morphological changes in these RBCs. A distinct change in the PA signal amplitude was found for the distinct nature of RBCs (swollen, shrink, and normal). Thus, this can serve as a diagnostic signature for different biological studies based on morphological changes at cellular level. The experiments were also performed using conventional pulsed laser photoacoustic response technique which uses nano-second pulsed laser and the results obtained from both PA techniques were validated to produce identical changes. This demonstrates the utility of continuous wave laser-based photoacoustic technique for different biological studies related to morphological cellular disorders.

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Pervious concrete reactive barrier containing nano-silica for nitrate removal from contaminated water

Abstract

In this research, the effectiveness of using pervious concrete as a reactive barrier to decrease the concentration of nitrates in polluted water was investigated. Parameters of concrete mix design including water to cement ratio (W/C), aggregate to cement ratio (A/C), the amount of nano-silica (NS), and fine aggregates (FA) were studied based on Taguchi method. Properties of concrete such as compressive strength, density, permeability, and porosity, as well as pH measurement and the column method were carried out to assess the nitrate removal capacity of pervious concrete. Also, SEM-EDX, XRD, and FTIR were used to analyze the results. It was found that the optimum mix design in terms of nitrate removal corresponded to the mix with W/C = 0.26, A/C = 5, NS = 6%, and FA = 20%. Based on the results, it can be said that adding NS (up to 6%) and FA (up to 20%) to pervious concrete had the best influence on nitrate removal and compressive strength. Addition of NS increased the nitrate removal capacity due to increase in surface positive charges and provision of new surface functional groups.

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Contribution of Sociodemographic Factors to Different Engagement of Children in Peer Violence

Violence and Gender, Ahead of Print.


https://ift.tt/2Pt9umk

Effects of Freeze-Dried Grape Powder on High-Density Lipoprotein Function in Adults with Metabolic Syndrome: A Randomized Controlled Pilot Study

Metabolic Syndrome and Related Disorders, Ahead of Print.


https://ift.tt/2MEkOxz

Relationship Between Handgrip Strength and Nonalcoholic Fatty Liver Disease: Nationwide Surveys

Metabolic Syndrome and Related Disorders, Ahead of Print.


https://ift.tt/2Nca4DG

High Body Mass Index Masks Body Composition Differences in Physically Active Versus Sedentary Participants

Metabolic Syndrome and Related Disorders, Ahead of Print.


https://ift.tt/2MGFPHY

Effect of Treadmill Walking on Leg Muscle Activation in Parkinson's Disease

Rejuvenation Research, Ahead of Print.


https://ift.tt/2PuMxPM

Patients with Benign Thyroid Diseases Experience and Impaired Sex Life

Thyroid, Ahead of Print.


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Follicular Thyroid Carcinoma: A Perspective

Thyroid, Ahead of Print.


https://ift.tt/2LjQuTY

MicroRNA-222 Promotes Invasion and Metastasis of Papillary Thyroid Cancer Through Targeting Protein Phosphatase 2 Regulatory Subunit B Alpha Expression

Thyroid, Ahead of Print.


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Update on the indications and results of sentinel node mapping in upper GI cancer

Abstract

The clinical utilization of sentinel node (SN) mapping for early esophageal cancer or gastric cancer has been unclear for a long time. However, previous investigations regarding SN mapping of these cancers have shown relatively good results with regard to the detection rate and diagnostic accuracy for determining the lymph node status. SN mapping helps obtain information about individual metastatic status and allows the modification of the operation in early-stage upper gastrointestinal (GI) disease. Radio-guided methods for identifying SNs in early esophageal cancer have been established via endoscopic injection of technetium-99m tin colloid. Previous studies have reported that the SN concept seems valid, and radio-guided SN mapping can be feasible in cT1N0 esophageal cancer. SN navigation surgery are believed to have potential as strategies for minimally invasive modified surgery for early esophageal cancer. A Japanese study group conducted a prospective multicenter trial of SN mapping for early gastric cancer using a dual tracer method with radioactive colloid and blue dyes; they demonstrated a high detection rate and accuracy for determining the metastatic status based on SN mapping. Subsequently, minimized gastrectomy, including partial gastrectomy and segmental gastrectomy with individualized selective and modified lymphadenectomy for early gastric cancer with a negative SN has been performed to evaluate the long-term survival and postoperative quality of life (QOL) in a multicenter prospective trial. This study verified the SN concept in early-stage upper GI disease with cN0 and found that function-preserving esophagectomy or gastrectomy may help maintain patients' post-surgical QOL.

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Diagnostic difficulties of primary angiosarcoma of the breast: a case report

Angiosarcoma of the breast is a rare tumor, which may be primary or secondary to breast surgery or irradiation. It is characterized by polymorphic and nonspecific clinical and radiological features. A patholog...

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Unklare, symptomarme Raumforderung im Bereich des Oropharynx

Laryngo-Rhino-Otol
DOI: 10.1055/a-0664-9045

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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Treatment of Unilateral PA by Adrenalectomy: Potential Reasons for Incomplete Biochemical Cure

Exp Clin Endocrinol Diabetes
DOI: 10.1055/a-0662-6081

The importance of an early diagnosis and appropriate management of patients with primary aldosteronism (PA) has become increasingly clear because of the adverse impact of the disorder on cardiovascular and cerebrovascular events and target organ damage. Adrenalectomy potentially cures patients with unilateral PA resulting in normalisation of blood pressure or significant clinical improvements in the majority of patients. Different criteria have been used to evaluate outcomes of unilateral adrenalectomy. Clinical remission (cure of hypertension) is observed in 6% to 86% of patients and clinical benefits from surgery are seen in the majority. Several factors have been identified that predict clinical success after surgery such as age, sex, anti-hypertensive medication dosage and known duration of hypertension. Biochemical remission of PA after unilateral adrenalectomy, characterised by the resolution of hyperaldosteronism and correction of pre-surgical hypokalaemia, is observed in 67% to 100% of patients with unilateral PA. In only a small proportion of patients, adrenalectomy fails to resolve hyperaldosteronism and inappropriate aldosterone production persists after surgery. In this review we discuss the potential reasons for failing to cure hyperaldosteronism after unilateral adrenalectomy for unilateral primary aldosteronism.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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Consensus on Postoperative Recommendations After Transsphenoidal Surgery

Exp Clin Endocrinol Diabetes
DOI: 10.1055/a-0664-7710

Background Guidelines for patient behavior following transsphenoidal surgery do not exist. To gain generally recommendations, the German pituitary working group conducted a study among pituitary surgeons to elucidate their opinions and customs of patients' counselling. Methods Questions concerning daily activities, exertion of sports and work life were addressed. It was asked to provide the postoperative time interval after which specific activities can be resumed both after a routine or an extended approach. Results Fourteen pituitary surgeons returned the completed questionnaire. Following routine operations, washing the hair was allowed within one week, blowing the nose after 3, flying on an airplane and driving a car after one, lifting heavy weights after 4, playing wind instruments after 6, use of CPAP (continuous positive airway pressure) device after 3, permit leisure sports after 2 to 4 weeks (except for scuba diving). Competitive sports can be resumed after 6 weeks. Occupation with mental demands was considered feasible after 2 weeks, with physical labor after 4 weeks. After extended transsphenoidal surgery, the recommended time interval was roughly twice as long compared to the routine approach. Driving a car was allowed within the first 4 weeks after surgery by some pituitary surgeons, while others allow driving only after 3 months analogous to the regulations after craniotomy. The risk of scuba diving was considered high. Conclusions The data of our study and the literature, and expert opinions from related scientific fields resulted in a consensus on recommendations for patients' conduct to minimize risks after transsphenoidal surgery.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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“The Adrenal Gland: Central Relay in Health and Disease - Current Challenges and Perspectives 2018” – Cushing’s Disease

Exp Clin Endocrinol Diabetes
DOI: 10.1055/a-0664-7632

Background Despite advances in diagnostic and therapeutic approach, Cushing's disease (CD) presents a challenging situation for the treating physician. Aims To elucidate current challenges, present strengths and pitfalls of existing diagnostic tests, enlighten the need for new diagnostic approaches, appraise the effects of surgery and available pharmacological agents and identify future perspectives regarding CD. Materials and methods Systematic search to PubMed and Medline databases for publications mainly over the last five years. Results Mutations in the ubiquitin specific peptidase 8 gene have been recently identified in functional sporadic corticotroph adenomas causing CD. Since the prevalence of obesity and metabolic syndrome is rapidly increasing, new diagnostic tests are necessary to differentiate these conditions. Next to the traditional tests, a cutoff of preoperative ACTH/cortisol ratio, an ultrasensitive late night salivary cortisol assay and the desmopressin test have been suggested as valid tools for the diagnosis and differential diagnosis of CD. Transsphenoidal surgery with variable remission and recurrence rates presents the treatment of choice for CD. Medical therapy consists of adrenal-targeted drugs e. g. ketoconazole, metyrapone, etomidate and mitotane and pituitary-targeted drugs e. g. pasireotide, cabergoline and retinoic acid. Conclusions CD is associated to a significant clinical burden, since numerous comorbidities persist after long-term biochemical control. These chronically ill patients show an increased mortality despite disease remission. Clinicians should treat comorbidities aggressively and seek for appropriate consultations. Structured consultation hours and expert excellence networks are needed in order to allow optimal, individualized care for affected patients, reverse increased morbidity and mortality and identify tumor recurrence early.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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FREE Public Health Forum – All are welcome

Thyroid Disease and You

…

Do you have any concerns about your thyroid function? Have you or a family member been diagnosed

with thyroid disease or have you noticed

a lump in your neck?

The American Thyroid Association and our Alliance Partners Invite Thyroid Patients and their Families to join us for the:

2018 ATA Alliance for Thyroid Patient Education Health Forum

Saturday, October 6, 2018
2:00 pm – 4:00 pm
Marriott Marquis
901 Massachusetts Ave NW – Tulip Room, 2nd Floor
Washington, DC

ATA Physician Members and our ATA Alliance Partners are available to meet with thyroid patients and their families during the forum. This program is free and open to the public, please register/confirm your participation here.

Who should attend?

Please come if you have questions, symptoms, or concerns about a thyroid problem. We invite anyone who has had an overactive or underactive thyroid, thyroiditis, a thyroid nodule, thyroid cancer, or a family history of thyroid problems or related d isorders, including rheumatoid arthritis, juvenile diabetes, or pernicious anemia. Free educational materials will be available for all.

Reservations requested. Walk-ins welcome. E-mail thyroid@thyroid.org with any questions or requests for additional information.

Flyer for printing, saving, and posting (PDF File, 232 KB)

 

 

The post FREE Public Health Forum – All are welcome appeared first on American Thyroid Association.

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Thyroid® High-Impact Articles

FREE ACCESS through September 3, 2018.

Read now:

Latest Impact Factor: 7.557
The Official Journal of: American Thyroid Association^®

Early Determinants of Thyroid Function Outcomes in Children with Congenital Hypothyroidism and a Normally Located Thyroid Gland: A Regional Cohort Study
Carole Saba, Sophie Guilmin-Crepon, Delphine Zénaty, Laetitia Martinerie, Anne Paulsen, Dominique Simon, Caroline Storey, Sophie Dos Santos, Jeremie Haignere, Damir Mohamed, Jean-Claude Carel, and Juliane Léger  

Comparing the Prognostic Value of the Eighth Edition of the American Joint Committee on Cancer/Tumor Node Metastasis Staging System Between Papillary and Follicular Thyroid Cancer
Evert F.S. van Velsen, Merel T. Stegenga, Folkert J. van Kemenade, Boen L.R. Kam, Tessa M. van Ginhoven, W. Edward Visser, and Robin P. Peeters

The Prognostic Impact of Tumor Size in Papillary Thyroid Carcinoma is Modified by Age
Bryan Tran, David Roshan, Earl Abraham, Laura Wang, Natalia Garibotto, James Wykes, Peter Campbell, and Ardalan Ebrahimi

Predicting Malignancy in Thyroid Nodules: Radiomics Score Versus 2017 American College of Radiology Thyroid Imaging, Reporting and Data System
Jinyu Liang, Xiaowen Huang, Hangtong Hu, Yihao Liu, Qian Zhou, Qinghua Cao, Wei Wang, Baoxian Liu, Yanling Zheng, Xin Li, Xiaoyan Xie, Mingde Lu, Sui Peng, Longzhong Liu, and Haipeng Xiao

Apparent Hyperthyroidism Caused by Biotin-Like Interference from IgM Anti-Streptavidin Antibodies
Leo Lam, Warwick Bagg, Geoff Smith, Weldon Wai Chiu, Martin James Middleditch, Julie Ching-Hsia Lim, and Campbell Vance Kyle  

 

The post <i>Thyroid^®</i> High-Impact Articles appeared first on American Thyroid Association.

https://ift.tt/2vZOAmy

FREE Public Health Forum – All are welcome

Thyroid Disease and You

…

Do you have any concerns about your thyroid function? Have you or a family member been diagnosed

with thyroid disease or have you noticed

a lump in your neck?

The American Thyroid Association and our Alliance Partners Invite Thyroid Patients and their Families to join us for the:

2018 ATA Alliance for Thyroid Patient Education Health Forum

Saturday, October 6, 2018
2:00 pm – 4:00 pm
Marriott Marquis
901 Massachusetts Ave NW – Tulip Room, 2nd Floor
Washington, DC

ATA Physician Members and our ATA Alliance Partners are available to meet with thyroid patients and their families during the forum. This program is free and open to the public, please register/confirm your participation here.

Who should attend?

Please come if you have questions, symptoms, or concerns about a thyroid problem. We invite anyone who has had an overactive or underactive thyroid, thyroiditis, a thyroid nodule, thyroid cancer, or a family history of thyroid problems or related d isorders, including rheumatoid arthritis, juvenile diabetes, or pernicious anemia. Free educational materials will be available for all.

Reservations requested. Walk-ins welcome. E-mail thyroid@thyroid.org with any questions or requests for additional information.

Flyer for printing, saving, and posting (PDF File, 232 KB)

 

 

The post FREE Public Health Forum – All are welcome appeared first on American Thyroid Association.

https://ift.tt/2N7MM1x

Thyroid® High-Impact Articles

FREE ACCESS through September 3, 2018.

Read now:

Latest Impact Factor: 7.557
The Official Journal of: American Thyroid Association^®

Early Determinants of Thyroid Function Outcomes in Children with Congenital Hypothyroidism and a Normally Located Thyroid Gland: A Regional Cohort Study
Carole Saba, Sophie Guilmin-Crepon, Delphine Zénaty, Laetitia Martinerie, Anne Paulsen, Dominique Simon, Caroline Storey, Sophie Dos Santos, Jeremie Haignere, Damir Mohamed, Jean-Claude Carel, and Juliane Léger  

Comparing the Prognostic Value of the Eighth Edition of the American Joint Committee on Cancer/Tumor Node Metastasis Staging System Between Papillary and Follicular Thyroid Cancer
Evert F.S. van Velsen, Merel T. Stegenga, Folkert J. van Kemenade, Boen L.R. Kam, Tessa M. van Ginhoven, W. Edward Visser, and Robin P. Peeters

The Prognostic Impact of Tumor Size in Papillary Thyroid Carcinoma is Modified by Age
Bryan Tran, David Roshan, Earl Abraham, Laura Wang, Natalia Garibotto, James Wykes, Peter Campbell, and Ardalan Ebrahimi

Predicting Malignancy in Thyroid Nodules: Radiomics Score Versus 2017 American College of Radiology Thyroid Imaging, Reporting and Data System
Jinyu Liang, Xiaowen Huang, Hangtong Hu, Yihao Liu, Qian Zhou, Qinghua Cao, Wei Wang, Baoxian Liu, Yanling Zheng, Xin Li, Xiaoyan Xie, Mingde Lu, Sui Peng, Longzhong Liu, and Haipeng Xiao

Apparent Hyperthyroidism Caused by Biotin-Like Interference from IgM Anti-Streptavidin Antibodies
Leo Lam, Warwick Bagg, Geoff Smith, Weldon Wai Chiu, Martin James Middleditch, Julie Ching-Hsia Lim, and Campbell Vance Kyle  

 

The post <i>Thyroid^®</i> High-Impact Articles appeared first on American Thyroid Association.

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Generation of Rat Monoclonal Antibodies Against a Deubiquitinase, Ovarian Tumor Domain-Containing Protein 1

Monoclonal Antibodies in Immunodiagnosis and Immunotherapy, Ahead of Print.


https://ift.tt/2N89mak

A continuous-time multistate Markov model to describe the occurrence and severity of diarrhea events in metastatic breast cancer patients treated with lumretuzumab in combination with pertuzumab and paclitaxel

Abstract

Purpose

To inform lumretuzumab and pertuzumab dose modifications in order to decrease the incidence, severity, and duration of the diarrhea events in metastatic breast cancer patients treated with a combination therapy of lumretuzumab (anti-HER3) in combination with pertuzumab (anti-HER2) and paclitaxel using quantitative clinical pharmacology modeling approaches.

Methods

The safety and pharmacokinetic (PK) data from three clinical trials (lumretuzumab monotherapy n = 47, pertuzumab monotherapy n = 78, and the combination therapy of lumretuzumab, pertuzumab and paclitaxel n = 35) were pooled together to develop a continuous-time discrete states Markov model describing the dynamics of the diarrhea events.

Results

The model was able to capture the time course of different severities of diarrhea reasonably well. The effect of lumretuzumab and pertuzumab was well described by an E_max function indicating an increased rate of transition from moderate to mild or more severe diarrhea with higher doses. The concentration needed to trigger or worsen diarrhea episodes was estimated to be 120-fold lower in combination therapy compared to monotherapy, suggesting strong synergy between the two monoclonal antibodies. The prophylactic effect of loperamide in a subset of patients was also well captured by the model with a clear tendency to reduce the occurrence of diarrhea events.

Conclusions

This work shows that PK-toxicity modeling provides insight into how the severity of key adverse events evolves over time and highlights the potential use to support decision making in drug development.

https://ift.tt/2LbAIKN

A population pharmacokinetic/toxicity model for the reduction of platelets during a 48-h continuous intravenous infusion of the histone deacetylase inhibitor belinostat

Abstract

Purpose

Belinostat is a second-generation histone deacetylase inhibitor (HDI) predominantly metabolized by UGT1A1-mediated glucuronidation. Two common polymorphisms (UGT1A1*28 and UGT1A1*60) were previously associated with impaired drug clearance and thrombocytopenia risk, likely from increased drug exposure. This latter phenomenon has been observed with other HDIs such as abexinostat, panobinostat, romidepsin, and vorinostat. It was the intention of this brief report to expand a population pharmacokinetic (PPK) model to include a pharmacodynamic (PD) model describing the change in platelet levels in patients with cancer administered belinostat as a 48-h continuous intravenous infusion, along with cisplatin and etoposide.

Methods

The PPK/PD model developed here introduced an additional rate constant to a commonly used mechanistic myelosuppression model to better describe the maturation of megakaryocytes into platelets before degradation and a feedback mechanism. The model employed a proportional error model to describe the observed circulating platelet data.

Results

Several covariates were explored, including sex, body weight, UGT1A1 genotype status, liver, and kidney function, but none significantly improved the model. Platelet levels rebounded to baseline within 21 days, before the next cycle of therapy. Simulations predicted that higher belinostat drug exposure does cause lower thrombocyte nadirs compared to lower belinostat levels. However, platelet levels rebound by the start of the next belinostat cycle.

Conclusions

This model suggests a q3week schedule allows for sufficient platelet recovery before the next belinostat infusion is optimal.

https://ift.tt/2Ps4RJd

A phase I study of LY3164530, a bispecific antibody targeting MET and EGFR, in patients with advanced or metastatic cancer

Abstract

Purpose

The phase I study characterized the safety, pharmacokinetics, anti-tumor activity, and recommended phase II dose/schedule of LY3164530 in patients with advanced or metastatic cancer.

Methods

Patients received LY3164530 on days 1 and 15 (Schedule 1: 300, 600, 1000, and 1250 mg) or Days 1, 8, 15, and 22 (Schedule 2: 500 and 600 mg) of each 28 days cycle. Dose escalation used a modified toxicity probability interval model.

Results

Dose escalation defined a maximum tolerated dose (MTD) of 1000 mg on Schedule 1 and 500 mg on Schedule 2. Treatment-emergent adverse events related to study treatment were consistent with epidermal growth factor receptor (EGFR) inhibition and included maculopapular rash/dermatitis acneiform (83%, Grade 3/4 17%), hypomagnesemia (55%, Grade 3/4 7%), paronychia (35%), fatigue (28%, Grade 3/4 3%), skin fissures (24%), and hypokalemia (21%, Grade 3/4 7%). Partial response was achieved in three patients on Schedule 2 with colorectal cancer (n = 2) or squamous cell cancer. Overall response rate (ORR) was 10.3%, disease control rate (ORR + stable disease [SD]) was 51.7 and 17.2% of patients had SD ≥ 4 months. The in vivo stability of the bispecific antibody was confirmed. Schedule 2 provided greater and more consistent inhibition of mesenchymal-epithelial transition (MET)/EGFR throughout the dosing interval than Schedule 1.

Conclusions

Although this study defined the LY3164530 MTD and pharmacokinetics on both schedules, significant toxicities associated with EGFR inhibition and lack of a potential predictive biomarker limit future development. Nonetheless, the results provide insight into the development of bispecific antibody therapy.

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Natural low- and high-density lipoproteins as mighty bio-nanocarriers for anticancer drug delivery

Abstract

Lipoproteins (LPs) are a set of naturally occurring bio-nanoparticles consisting of Apo-LPs, phospholipids, a highly hydrophobic core of cholesteryl esters and triglycerides that participate mainly in the targeted transport of cholesteryl esters and other hydrophobic molecules through the bloodstream. They also are able to recognize specific receptors on normal and abnormal cells. Therefore, LPs represent a relevant tool for targeted delivery of cancer diagnostics and therapeutics due to their native biocompatibility, biodegradability, nano-scale size and receptor-mediated uptake. The circulating LPs are categorized into five classes, each with its own characteristic protein and lipid composition. Low-density LPs (LDL) and high-density LPs (HDL) are two major subclasses of LPs which were extensively subjected to attractive and versatile vehicles for targeted delivery of anticancer drugs. This study focus to highlight the potential applications of LDL and HDL bio-nanocarriers in the field of specific target drug delivery to cancer cells.

https://ift.tt/2MpsNiK

Genetic polymorphisms in cyclin H gene are associated with oxaliplatin-induced acute peripheral neuropathy in South Indian digestive tract cancer patients

Abstract

Purpose

Digestive tract cancer patients treated with oxaliplatin are often associated with the development of peripheral neuropathy. The aim of the present study is to identify the influence of single-nucleotide polymorphisms (SNPs) in genes involved in oxaliplatin metabolism, cell cycle control, detoxification or excretion pathways with the development of oxaliplatin-induced acute peripheral neuropathy (acute OXAIPN) and its severity among digestive tract cancer patients treated with oxaliplatin-based chemotherapy.

Patients and methods

A total of 228 digestive tract cancer patients undergoing with the oxaliplatin-based chemotherapy between November 2014 and December 2016 were included in the current study. Genomic DNA was extracted from peripheral blood by standard phenol–chloroform method. Genotyping of five SNPs in four genes [GSTP₁ (rs1965), ABCG2 (rs3114018), CCNH (rs2230641, rs3093816), AGXT (rs4426527)] was carried out by Real-Time TaqMan SNP genotyping assay.

Results

We found that the two genetic variants rs2230641 and rs3093816 in cyclin H (CCNH) gene were significantly associated with both the incidence and severity of acute OXAIPN. For CCNH-rs2230641 (AA vs AG+GG; dominant model) Incidence: OR 2.62, 95% CI 1.44–4.75, p = 0.001, severity; OR 4.64, 95% CI 1.58–13.62, p = 0.002. For CCNH-rs3093816 (AA vs AG+GG; dominant model); incidence: OR 3.43, 95% CI 1.57–7.50, p = 0.001; severity: OR 2.36, 95% CI 1.05–5.30, p = 0.033.

Conclusions

The results of the present study found significant association between CCNH polymorphisms and acute OXAIPN development. However, further studies are warranted from independent groups to validate our study results.

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Lapatinib in combination with paclitaxel plays synergistic antitumor effects on esophageal squamous cancer

Abstract

Purpose

Paclitaxel-based chemoradiotherapy was proven to be efficacious in treating patients with advanced esophageal cancer. However, the toxicity and the development of resistance limited its anticancer efficiency. The present study was to evaluate the antitumor effects of lapatinib, a dual tyrosine inhibitor of both epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), combined with paclitaxel on the esophageal squamous cancer.

Methods

MTT assays were used to evaluate the effects of the combination of lapatinib and paclitaxel on the growth of esophageal squamous cancer cell lines (KYSE150, KYSE450, KYSE510 and TE-7). The activity of the combination of two agents on cell invasion, migration and apoptosis was measured by wound healing assay, transwell assay and Annexin V-FITC/PI stain assay. Western blot assay was used to analyze the effects of the two agents on the EGFR/HER2 signaling. The in vivo efficacy was evaluated in KYSE450 xenograft nude mouse model.

Results

The combination of lapatinib and paclitaxel was highly synergistic in inhibiting cell growth with a combination index of < 1, and suppressed significantly the invasion and migration capability of esophageal squamous cancer cells. Esophageal squamous cancer cells displayed increased rates of apoptosis after treatment with lapatinib plus paclitaxel. The phosphorylated EGFR and HER2 as well as the activation of downstream molecules MAPKs and AKT significantly decreased when exposed to lapatinib and paclitaxel. In vivo studies showed that the combination of two agents had greater antitumor efficacy than either agent alone.

Conclusions

The combination of lapatinib with paclitaxel showed synergistic antitumor activity, suggesting their potential in treating patients with esophageal squamous cancer.

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Association of OPG–RANKL ratio with left ventricular hypertrophy and geometric remodeling in male overweight/obese youths

Abstract

Purpose

Receptor activator of nuclear factor kappa B ligand/receptor activator of nuclear factor kappa B/osteoprotegerin (RANKL/RANK/OPG) axis has been hypothesized as a potential mediator of left ventricular hypertrophy (LVH). The aim of the study was to assess whether circulating concentrations of RANKL, RANK, and OPG were associated with early signs of morphological cardiac changes in overweight/obese youths.

Methods

We determined serum levels of RANKL, RANK and OPG by enzyme-linked immunosorbent assays in 188 overweight/obese children and adolescents. LV mass index (LVMI) and relative wall thickness (RWT) were estimated using M-mode echocardiography.

Results

OPG and RANKL levels were higher among girls than among boys [1.73 (1.64–1.86) and 3.28 (1.90–6.37) pmol/L, respectively, vs. 1.69 (1.59–1.82) and 2.12 (1.52–3.80) pmol/L; p = 0.02 and p = 0.0001, respectively], but the OPG/RANKL ratio was lower [0.52 (0.26–0.88) vs 0.77 (0.44–1.11); p = 0.001]. In gender-specific multivariate linear regression, OPG/RANKL ratio was associated with LVMI and RWT in boys but not in girls. In multiple logistic regression, after adjustment for clinical variables, OPG/RANKL ratio was associated with concentric remodeling, eccentric and concentric LVH in boys but not in girls.

Conclusion

OPG/RANKL ratio is independently associated with LVH and patterns of LV structural remodeling in male overweight/obese children and adolescents.

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Postoperative Rechtsstreitigkeiten bei Trägern von Cochleaimplantaten

Zusammenfassung

Hintergrund

Nach der Versorgung mit einem oder 2 Cochleaimplantaten (CI) ergeben sich oft weitere Probleme betreffend die Frage, welche Folgekosten die gesetzlichen Krankenversicherungen oder andere Kostenträger übernehmen müssen, z. B. im Rahmen der Eingliederungshilfe.

Zielsetzung/Fragestellung

Der Artikel gibt einen Überblick über Urteile der deutschen Sozialgerichte. Untersucht wurde, ob es sich für den einzelnen Patienten lohnt, den Klageweg zu beschreiten und mit welcher Verfahrensdauer gerechnet werden muss.

Material und Methoden

Ausgewertet wurden die beiden größten kommerziellen juristischen Datenbanken sowie die von der Sozialgerichtsbarkeit veröffentlichten Urteile. Suchparameter waren „Cochlear", „Cochlea", „Implant" und „Implantat". Die besprochenen Entscheidungen ergingen im Zeitraum zwischen 2002 und 2017.

Ergebnisse

Insgesamt wurden 13 Entscheidungen gefunden. Die Ergebnisse variierten je nach den Besonderheiten des Einzelfalls. Von den untersuchten Urteilen und Beschlüssen fielen 54 % positiv für den Patienten (Kläger) aus. Die Verfahren dauerten zwischen 0,2 Jahren (ab Klage, Antragsdatum hier nicht bekannt) und 6,11 Jahren.

Schlussfolgerung

Die Arbeit zeigt, dass ungewiss ist, ob nicht in direktem Zusammenhang mit der Operation bzw. der Nachsorge stehende Kosten erstattet werden oder nicht. Da jeder Fall im Prinzip einzigartig ist, variieren auch die Ergebnisse. Trotzdem wird empfohlen, im Falle der Ablehnung der Ansprüche nach sorgfältiger Abwägung den Klageweg zu beschreiten.

https://ift.tt/2PlPJx7

Lebensqualität nach funktionell-ästhetischer Septorhinoplastik in primärer Operation vs. in Revisionsoperation – eine monozentrische Studie

Zusammenfassung

Hintergrund

Subjektive Bewertungen der Lebensqualität haben als Ergebnisqualität in den letzten Jahrzehnten an Bedeutung gewonnen. Die Anzahl der prospektiven Studien zur Lebensqualitätsmessung mit krankheitsspezifischen Messinstrumenten ist überschaubar. Ziel war es, die Lebensqualität nach primärer und Revisionsseptorhinoplastik eines einzelnen Chirurgen in einem HNO(Hals-Nasen-Ohrenheilkunde)-Zentrum zu untersuchen.

Studiendesign und Untersuchungsmethoden

Präoperativ und mindestens ein Jahr postoperativ wurden 2 krankheitsspezifische Lebensqualitätsmessinstrumente eingesetzt: der ROE(„rhinoplasty outcome evaluation")- und der NOSE(„nasal obstruction symptome evaluation")-Score. Weitere Informationen, insbesondere Alter, Geschlecht und Voroperationen, wurden erfragt.

Ergebnisse

Es wurden 237 Patienten in die Studie eingeschlossen, 208 (87,8 %) weibliche, 29 (12,2 %) männliche. Das Durchschnittsalter lag bei 30,3 ± 8,9 Jahren, der durchschnittliche Beobachtungszeitraum bei 19,3 ± 7,4 Monaten. Alle Operationen wurden von demselben Chirurgen (F. R.) durchgeführt. Mit dem Messinstrument NOSE zeigte sich eine signifikante Verbesserung der Obstruktion im Gesamtkollektiv (präoperativ 49,8 ± 26,2, postoperativ 19,1 ± 21,3; p < 0,001), ohne signifikanten Unterschied in Bezug auf primäre vs. Revisionsoperation. Der ROE-Score verbesserte sich signifikant, beide Kollektive (primär und sekundär operierte) zeigten beide Kollektive eine signifikante Verbesserung nach der Intervention. Postoperativ fielen die Patienten mit einer Primärintervention durch eine signifikant höheren Lebensqualität (p < 0,001) auf.

Schlussfolgerung

Die krankheitsspezifische Lebensqualität nimmt nach primärer Septorhinoplastik wie nach Revisionsoperation signifikant zu. Der NOSE-Score stieg in beiden Interventionsgruppen postoperativ signifikant an.

https://ift.tt/2OSqi5i

Correlation of plasma erlotinib trough concentration with skin rash in Chinese NSCLC patients harboring exon 19 deletion mutation

Abstract

Purpose

Erlotinib is an essential drug for non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) activating mutations. The relationship between the pharmacokinetics and skin rash and diarrhea of erlotinib in Chinese patients with EGFR mutated NSCLC is unknown. In this study, we evaluated the variability in erlotinib trough concentration and its relationship with the severity of skin rash and diarrhea in patients with two common types of EGFR mutations: a deletion in exon 19 and point mutations in exon 21 L858R.

Patients and methods

EGFR mutation-positive Chinese patients (n = 52) treated with erlotinib were included in our study; the steady-state trough concentrations were assessed; and the occurrence and severity of skin rash and diarrhea after the onset of treatment with erlotinib were recorded. The patients were divided into two groups by mutation type (exon 19 deletions or exon 21 L858R point mutations). Occurrence and severity of skin rash and diarrhea was analyzed in both groups.

Results

The overall mean (± SD) steady-state trough concentration for erlotinib was 1380 ± 663 ng/mL, and there was no significant difference of erlotinib concentrations between the two mutation groups. Occurrence and severity of skin rash was significantly associated with trough concentration in patients with exon 19 deletions but not exon 21 L858R point mutations. Significant association of erlotinib concentrations with diarrhea was found neither in the exon 19 deletions group nor in the exon 21 L858R point mutation group.

Conclusions

The occurrence and severity of skin rash correlated with increase in erlotinib trough concentrations only in Chinese patients with exon 19 deletion; the erlotinib trough concentrations were not associated with diarrhea.

https://ift.tt/2N4tPNf

A safety, tolerability, and pharmacokinetic analysis of two phase I studies of multitargeted small molecule tyrosine kinase inhibitor XL647 with an intermittent and continuous dosing schedule in patients with advanced solid malignancies

Abstract

Purpose

To evaluate the safety, tolerability, and pharmacokinetics of XL647 and determine the maximum tolerated dose (MTD) of oral XL647 once-daily using intermittent or continuous dosing schedules.

Methods

Patients with advanced solid malignancies were enrolled in successive cohorts to receive escalating dose levels of oral once-daily XL647 using two different dosing schedules: 5 consecutive days of every 14-day cycle (study XL647-001) or continuously over 28-day cycles (study XL647-002). PK sampling was performed to determine C_max, and AUC. Patients remained on study until progressive disease or unacceptable AEs.

Results

In XL647-001, 42 individuals were enrolled across 9 dose levels. The most frequently occurring drug-related AEs were diarrhea, nausea, rash, and fatigue. Expansion of the 4.68 mg/kg cohort to 6 patients occurred without further dose-limiting toxicities (DLTs) and this was considered the MTD. In XL647-002, 31 patients were enrolled across 5 dose levels. A DLT of grade 3 pneumonitis occurred in 1/6 patients at 300 mg, which was declared the MTD. The most common AEs included grade 1/2 rash, diarrhea, fatigue, dysgeusia, and QTc prolongation. Levels of pharmacodynamic plasma markers were not consistently changed after XL647 and no conclusions could be drawn with this limited data set.

Conclusions

For oral XL647, the MTD was 4.68 mg/kg or 350 mg fixed dose when administered once-daily for 5 consecutive days of every 14-day cycle and was 300 mg when administered once-daily continuously. XL647 was well tolerated at doses up to the MTD.

https://ift.tt/2MEmAyt

Determination of optimum vitamin D3 levels for NK cell-mediated rituximab- and obinutuzumab-dependent cellular cytotoxicity

Abstract

Vitamin D3 (25-OH-D3) deficiency impairs rituximab-dependent cellular cytotoxicity and the outcome of patients with diffuse large B-cell and follicular lymphomas (DLBCL). Since the optimum 25-OH-D3 serum levels for NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) are unknown, we determined the 25-OH-D3 serum levels associated with maximum NK cell-mediated ADCC. CD20 antibody-loaded CD20⁺ B-cell lymphoma cell lines were cultured with NK cells and ADCC activity was determined by lactate dehydrogenase release assays. Using a newly developed formula, pre-defined 25-OH-D3 serum levels were achieved with high individual precision over a wide range. NK cells from 20 healthy individuals killed antibody-treated CD20⁺ lymphoma cells in a concentration- and E:T ratio-dependent manner with obinutuzumab displaying a stronger ADCC activity than rituximab. Maximum NK-cell activity and ADCC were observed at 65 ng/ml 25-OH-D3, the middle of the normal range (30–100 ng/ml). 25-OH-D3 serum levels around this range should be the target in interventional trials aiming at improving NK cell-mediated ADCC by 25-OH-D3 substitution. Lower levels do not provide significant ADCC improvements in individuals with 25-OH-D3 deficiency or insufficiency and might result in the failure of interventions with 25-OH-D3.

https://ift.tt/2OVWCUJ

Mitochondrial-Derived Peptides Exacerbate Senescence

Rejuvenation Research, Volume 21, Issue 4, Page 369-373, August 2018.


https://ift.tt/2PskcJR

Data and Corporate Governance in Pharma and Digital Health: A Necessary Regulatory Convergence

Rejuvenation Research, Volume 21, Issue 4, Page 291-293, August 2018.


https://ift.tt/2N45uqJ

Meetings Calendar

Rejuvenation Research, Volume 21, Issue 4, Page 380-385, August 2018.


https://ift.tt/2nWsvRN

Commentary on Some Recent Theses Relevant to Combating Aging: August 2018

Rejuvenation Research, Volume 21, Issue 4, Page 374-379, August 2018.


https://ift.tt/2N45kQ9

Cosmetics, Vol. 5, Pages 51: Caffeic Acid-layered Double Hydroxide Hybrid: A New Raw Material for Cosmetic Applications

Cosmetics, Vol. 5, Pages 51: Caffeic Acid-layered Double Hydroxide Hybrid: A New Raw Material for Cosmetic Applications

Cosmetics doi: 10.3390/cosmetics5030051

Authors: Maria Bastianini Caterina Faffa Michele Sisani Annarita Petracci

Bioactive ingredients from natural sources possess well-known positive effects in cosmetic applications. Among them, phenolic acids have emerged with very interesting potential. Caffeic acid (CAF) is one of the most promising active compounds because it possess antioxidant, anti-inflammatory, antitumoral and anti-wrinkle effects. In order to increase its local bioavailability in topical applications, the vehiculation of caffeic acid can lead to a new raw material of cosmetic interest. For this purpose, clay minerals possess excellent properties, such as low or null toxicity and good biocompatibility. Clays are able to host a wide range of active ingredients in the interlayer region, using a green process known as intercalation reaction. The hosting of cosmetic actives into the layered structure of anionic clays allows the preparation of new materials with enhanced stability towards oxidation and photodegradation, better local bioavailability, and easier workability. In this paper, the successful vehiculation of caffeic acid into anionic clay is presented. The obtained hybrid is very promising for the cosmetic market because of its higher bioavailability and prolonged antioxidant activity.

https://ift.tt/2MpyM6R

Hearing preservation in children with electric-acoustic stimulation after cochlear implantation

Abstract

Background

Cochlear implantation in patients with functional residual low-frequency hearing is performed according to an established hearing-preserving surgical technique in order to cause minimal trauma of inner ear structures. Due to the increasing number of cochlear implants in children, the preservation of residual hearing is becoming increasingly important in this patient collective.

Objectives

Short- and mid-term hearing preservation outcome in pediatric patients is investigated.

Materials and methods

A group of 9 children (12 ears) between 5 and 12 years of age were examined after hearing-assisted cochlear implantation with respect to the pure tone audiometric thresholds. Retrospectively, short-term hearing preservation (up to 3 months after surgery) was examined. In a subgroup of 5 children, mid-term hearing preservation (7.5 to 16 months after surgery) was also analyzed. The mean values of hearing preserved (HL%) and hearing loss (HL) due to electrode insertion were calculated as measured values.

Results

In the whole group, the mean values of the preoperative PTA_low were 29.8 dB and the short-term postoperative PTA_low 42.6 dB. The mean value of the HL% was 73.6%, corresponding to an HL of 9.4 dB. In the subgroup, the mean PTA_low postoperatively was 46.0 dB in the mid-term and the HL% at 80.7% with a HL of 6.6 dB.

Conclusions

The results in children are consistent with the results in adults. Electric-acoustic stimulation (EAS) should be used in the treatment of children with existing low-frequency residual hearing, as good residual hearing preservation can also be achieved in children after implantation.

https://ift.tt/2nXHOJY

Operative Therapie von Lidtumoren

Zusammenfassung

Tumoren der Lider sind oft Hauttumoren, sie können jedoch ihren Ursprung auch in anderen adnexalen Strukturen oder in der Konjunktiva haben. Die Therapie v. a. maligner Prozesse ist primär chirurgisch; hierbei wird die komplette Exzision zur Minimierung der Lokalrezidivrate angestrebt. In besonderen Fällen spielen adjuvante Therapien oder konservative Therapiealternativen (z. B. Radiatio, Kryotherapie, Immunmodulatoren) eine Rolle. Die Wiederherstellung der Lider hat die funktionelle und die ästhetische Rehabilitation zum Ziel. Im vorliegenden Beitrag werden Prinzipien und grundlegende Techniken für die Rekonstruktion der Periokularregion dargestellt.

https://ift.tt/2LekkJA

Long-Term Outcomes after Performing Tympanoplasty without Mastoidectomy for Active and Inactive Noncholesteatomatous Chronic Otitis Media

Objective: This study aimed to assess long-term outcomes after performing tympanoplasty without mastoidectomy (TWOM) for active and inactive noncholesteatomatous chronic otitis media (COM) and to estimate the optimal time for surgery. Methods: The patients were placed into an active ear group (group A) and an inactive ear group (group B). All patients were followed up for 5 years after TWOM. Results: Ninety-two cases among 113 achieved dry ears in half a month to 1 month. The tympanic pressure gradually improved 3–6 months after the operation. A total of 69/72 ears achieved dry ears in the active ear group, and 37 ears had effective hearing improvement. In all, 40/41 ears achieved dry ears in the inactive ear group, and 20 ears had effective hearing improvement. There was no difference in the recurrence rate or hearing improvement in the two groups. Conclusion: With good quality control of the surgical treatment of TWOM, there are no differences in long-term outcomes in noncholesteatomatous COM in different chronic infection conditions.
ORL

https://ift.tt/2nUIMGB

Role of PKM2 in directing the metabolic fate of glucose in cancer: a potential therapeutic target

Abstract

Background

Many of the hallmarks of cancer are not inherently unique to cancer, but rather represent a re-enactment of normal host responses and activities. A vivid example is aerobic glycolysis ('Warburg effect'), which is used not only by cancer cells but also by normal cells that undergo rapid proliferation. A common feature of this metabolic adaptation is a shift in the expression of pyruvate kinase (PK) isoform M1 to isoform M2. Here, we highlight the key role of PKM2 in shifting cancer metabolism between ATP production and biosynthetic processes. Since anabolic processes are highly energy dependent, the fate of glucose in energy production versus the contribution of carbon in biosynthetic processes needs to be finely synchronised. PKM2 acts to integrate cellular signalling and allosteric regulation of metabolites in order to align metabolic activities with the changing needs of the cell.

Conclusions

The central role of PKM2 in directing the flow of carbon between catabolic (ATP-producing) and anabolic processes provides unique opportunities for extending the therapeutic window of currently available and/or novel anti-neoplastic agents.

https://ift.tt/2knJBWV

Identification of biomarkers associated with partial epithelial to mesenchymal transition in the secretome of slug over-expressing hepatocellular carcinoma cells

Abstract

Background

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. Complete epithelial to mesenchymal transition (EMT) has long been considered as a crucial step for metastasis initiation. It has, however, become apparent that many carcinoma cells can metastasize without complete loss of epithelial traits or with incomplete gain of mesenchymal traits, i.e., partial EMT. Here, we aimed to determine the similarities and differences between complete and partial EMT through over-expression of the EMT-associated transcription factor Slug in different HCC-derived cell lines.

Methods

Slug over-expressing HCC-derived HepG2 and Huh7 cells were assessed for their EMT, chemo-resistance and stemness features using Western blotting, qRT-PCR, neutral red uptake, doxorubicin accumulation and scratch wound healing assays. We also collected conditioned media from Slug over-expressing HCC cells and analyzed its exosomal protein content for the presence of chemo-resistance and partial EMT markers using MALDI-TOF/TOF and ELISA assays, respectively.

Results

We found that Slug over-expression resulted in the induction of both complete and partial EMT in the different HCC-derived cell lines tested. Complete EMT was characterized by downregulation of E-cadherin and upregulation of ZEB2. Partial EMT was characterized by upregulation of E-cadherin and downregulation of vimentin and ZEB2. Interestingly, we found that Slug induced chemo-resistance through downregulation of the ATP binding cassette (ABC) transporter ABCB1 and upregulation of the ABC transporter ABCG2, as well as through expression of CD133, a stemness marker that exhibited a similar expression pattern in cells with either a complete or a partial EMT phenotype. In addition, we found that Slug-mediated partial EMT was associated with enhanced exosomal secretion of post-translationally modified fibronectin 1 (FN1), collagen type II alpha 1 (COL2A1) and native fibrinogen gamma chain (FGG).

Conclusions

From our data we conclude that the exosomal proteins identified may be considered as potential non-invasive biomarkers for chemo-resistance and partial EMT in HCC.

https://ift.tt/2OPL0CC

AAA+ ATPases Reptin and Pontin as potential diagnostic and prognostic biomarkers in salivary gland cancer - a short report

Abstract

Purpose

Salivary gland cancer (SGC) is a rare and heterogeneous disease with significant differences in recurrence and metastasis characteristics. As yet, little is known about the mechanisms underlying the initiation and/or progression of these diverse tumors. In recent years, the AAA+ ATPase family members Pontin (RuvBL1, Tip49a) and Reptin (RuvBL2, Tip49b) have been implicated in various processes, including transcription regulation, chromatin remodeling and DNA damage repair, that are frequently deregulated in cancer. The aim of this study was to assess the clinical and functional significance of Reptin and Pontin expression in SGC.

Methods

Immunohistochemical staining of Pontin, Reptin, β-catenin, Cyclin D1, TP53 and MIB-1 was performed on a collection of 94 SGC tumor samples comprising 13 different histological subtypes using tissue microarrays.

Results

We found that Reptin and Pontin were expressed in the majority of SGC samples across all histological subtypes. Patients with a high Reptin expression showed a significantly inferior 5-year overall survival rate compared to patients with a low Reptin expression (47.7% versus 78.3%; p = 0.033), whereas no such difference was observed for Pontin. A high Reptin expression strongly correlated with a high expression of the proliferation marker MIB-1 (p = 0.003), the cell cycle regulator Cyclin D1 (p = 0.006), accumulation of TP53 as a surrogate p53 mutation marker (p = 0.042) and cytoplasmic β-catenin expression (p = 0.002). Increased Pontin expression was found to significantly correlate with both cytoplasmic and nuclear β-catenin expression (p = 0.037 and p = 0.018, respectively), which is indicative for its oncogenic function.

Conclusions

Our results suggest a role of Reptin and Pontin in SGC tumor progression and/or patient survival. Therefore, SGC patients exhibiting a high Reptin expression may benefit from more aggressive therapeutic regimens. Future studies should clarify whether such patients may be considered for more radical surgery, extended adjuvant therapy and/or targeted therapy.

https://ift.tt/2nUhrEt

Potential of the dual mTOR kinase inhibitor AZD2014 to overcome paclitaxel resistance in anaplastic thyroid carcinoma

Abstract

Purpose

Anaplastic thyroid carcinoma (ATC) is an aggressive, chemo-resistant malignancy. Chemo-resistance is often associated with changes in activity of the RAS/MAPK/ERK and PI3K/AKT/mTOR pathways and/or a high expression of ATP binding cassette (ABC) transporters, such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). To assess the therapeutic efficacy in ATC of a combination of the dual mTOR kinase inhibitor vistusertib (AZD2014) and paclitaxel (PTX), we generated a new cell line (Rho-) via the selection of human thyroid carcinoma 8505C cells that exhibit a low accumulation of rhodamine 123, which serves as a P-gp and BCRP substrate.

Methods

Immunohistochemistry was used for P-gp and BCRP expression analyses in primary ATC patient samples. Spheroid formation and immunodeficient NSG mice were used for performing in vitro and in vivo tumorigenicity assays, respectively. MTT, flow-cytometry, fluorescent microscopy, cell death and proliferation assays, as well as migration, invasion and gelatin degradation assays, were used to assess the potential of AZD2014 to enhance the effects of PTX. ATC xenografts in SCID mice were used for evaluating in vivo treatment efficacies.

Results

Rho- cells were found to be 10-fold more resistant to PTX than 8505C cells and, in addition, to be more tumorigenic. We also found that AZD2014 sensitized Rho- cells to PTX by inhibiting proliferation and by inducing autophagy. The combined use of AZD2014 and PTX efficiently inhibited in vitro ATC cell migration and invasion. Subsequent in vivo xenograft studies indicated that the AZD2014 and PTX combination effectively suppressed ATC tumor growth.

Conclusions

Our data support results from recent phase I clinical trials using combinations of AZD2014 and PTX for the treatment of solid tumors. Such combinations may also be employed for the design of novel targeted ATC treatment strategies.

https://ift.tt/2kePYeU

Identification of subsets of actionable genetic alterations in KRAS-mutant lung cancers using association rule mining

Abstract

Background

Lung cancer is the leading cause of cancer-related death in both men and women. KRAS mutations occur in ~ 25% of patients with lung cancer, and the presence of these mutations is associated with a poor prognosis. Unfortunately, efforts to directly target KRAS or its associated downstream MAPK or PI3K/AKT/mTOR pathways have seen little or no benefits. Here, I hypothesize that KRAS-mutant tumors do not respond to KRAS pathway therapies due to the co-occurrence of other activated cell survival pathways and/or mechanisms.

Methods and results

To identify other potentially activated cell survival pathways in KRAS-mutant tumors, I performed association rule mining on somatic mutations in 725 metastatic lung cancer patient samples. I identified 67 additional genes that were mutated in at least 10% of the samples with KRAS mutations. This gene list was enriched with genes involved in the MAPK, AKT and STAT3 pathways, as well as in cell-cell adhesion, DNA repair, chromatin remodeling and the Wnt/β-catenin pathway. I also identified 160 overlapping subsets of three or more genes that code for oncogenic or tumor suppressive proteins that were mutated in at least 10% of the KRAS-mutant tumors.

Conclusions

I identified several genes that are co-mutated in primary KRAS-mutant lung cancer samples. I also identified subpopulations of KRAS-mutant lung cancers based on sets of genes that were co-mutated. Pre-clinical models that capture these subsets of KRAS-mutant tumors may enhance our understanding of lung cancer development and, in addition, facilitate the design of personalized treatment strategies for lung cancer patients carrying KRAS mutations.

https://ift.tt/2K2sLIH

Patched-2 functions to limit Patched-1 deficient skin cancer growth

Abstract

Purpose

Basal cell carcinoma (BCC) is one of the most common skin cancers, and is typically driven by an aberrantly activated Hedgehog (Hh) pathway. The Hh pathway is regulated by interactions between the Patched-1 (Ptch1) and Smoothened (Smo) receptors. Smo is an activating receptor and is subject to inhibition by Ptch1. Following ligand binding to Ptch1, its inhibitory action is relieved and pathway activation occurs. This receptor interaction is pivotal to restraining uncontrolled cellular growth. Both receptors have been found to be frequently mutated in BCCs. Ptch2 is a Ptch1 paralog that exhibits overlapping functions in both normal development and tissue homeostasis. As yet, its contribution to cancer growth is poorly defined. Here we set out to assess how Ptch2 inhibits BCC growth.

Methods

We used several in vitro readouts for transcriptional and chemotactic Hh signaling in BCC-derived ASZ001 cells, and a novel xenograft model to assess in vivo BCC tumor growth. Gene editing by TALEN was used to untangle the different Ptch2-dependent responses to its ligand sonic hedgehog (Shh).

Results

We first defined the signaling competence of Ptch2 in Ptch1-deficient ASZ001 cells in vitro, and found that Ptch2 ligand binding drives their migration rather than eliciting a transcriptional response. We found that subsequent targeting of Ptch2 abrogated the chemotaxic effect. Next, we tested the contribution of Ptch2 to in vivo tumor growth using a xenograft model and found that reduced Ptch function results in increased tumor growth, but that selective pressure appatently acts against complete Ptch2 ablation.

Conclusions

We conclude that like Ptch1, Ptch2 exerts a tumor-suppressive function in BCC cells, and that after targeting of both paralogs, ligand-independent activation of the Hh pathway contributes to tumor growth.

https://ift.tt/2N6lR6n

Successful treatment of life-threatening severe metabolic acidosis by continuous veno-venous hemodialysis in a child with diabetic ketoacidosis

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Issue: Ahead of print


https://ift.tt/2N6aBXv

Etiology of short stature in Indian children and an assessment of the growth hormone-insulin-like growth factor axis in children with idiopathic short stature

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Issue: Ahead of print


https://ift.tt/2PvOGuC

Poverty and immigration as a barrier to iodine intake and maternal adherence to iodine supplementation

Abstract

Purpose

Iodine deficiency still remains a significant health issue worldwide. Pregnant and lactating women are at risk for iodine deficiency when living in mild iodine-deficient areas such as Italy. This study aims at evaluating the consumption of iodized salt, iodine-rich-foods and maternal micronutrient supplements in a group of women with limited access to the Italian National Health System.

Methods

A cross-sectional survey was conducted among immigrant and Italian women living in poverty and referring to 40 Non-Governmental Organization throughout Italy for their health needs. 3483 women answered the ad hoc questionnaire between January 2017 and February 2018.

Results

The consumption of iodized salt was very low, and even lower among immigrant women. Determinants of iodized salt consumption were the period spent in Italy for immigrant women and living in a family-type setting, parity and, particularly, the degree of education for Italian ones. 17.5% of immigrant women and 8.6% of the Italian ones reported a diagnosis of thyroid disease. 521 women, 75.4% of whom were immigrants, were pregnant or breast-feeding. The majority (57.3%) had no specific maternal supplementation.

Conclusions

Both Italian and immigrating women with a low income or without access to the public health system have a poor adherence both to the salt iodization policy and to folic acid and iodine supplements in preconception and pregnancy. They also referred a low-frequency intake of iodine-rich-foods. The identification of barriers to health care access could be useful to promote specific health interventions in this target population.

https://ift.tt/2MHyveT

Study of Anlotinib Combined With Gemcitabine/Cisplatin in Advanced Nasopharyngeal Carcinoma

Conditions:   Recurrent Nasopharyngeal Carcinoma;   Metastatic Nasopharyngeal Carcinoma
Intervention:   Drug: Anlotinib plus gemcitabine/cisplatin
Sponsor:   Chinese Academy of Medical Sciences
Not yet recruiting

https://ift.tt/2NacKle

Modified Ramped Position for Intubation of Obese Females.

Conditions:   Obesity;   Anesthesia
Interventions:   Other: Modified ramped position;   Other: Ramped position
Sponsor:   Cairo University
Not yet recruiting

https://ift.tt/2PrQwwh

Chidamide Combined With Cisplatin in Head and Neck Adenoid Cystic Carcinoma (HNACC)

Conditions:   Adenoid Cystic Carcinomas;   Chidamide;   Cisplatin
Intervention:   Drug: Chidamide combined with cisplatin
Sponsor:   Fudan University
Recruiting

https://ift.tt/2Bys7m0

Psychological Impact of a Sophrological Accompaniment During the Announcement of Thyroid Cancer

Condition:   Follicular Thyroid Cancer
Intervention:   Other: sophrology sessions
Sponsor:   Assistance Publique Hopitaux De Marseille
Not yet recruiting

https://ift.tt/2MDIQbL

Attachment Systems for Implant Overdenture

Conditions:   Dental Implants;   Dental Prosthesis Failure
Interventions:   Device: OT Equators® (Rhein83);   Device: Locator® (Zest)
Sponsor:   Rhein 83 Srl
Recruiting

https://ift.tt/2Ps9HGA

Study of Anlotinib Combined With Gemcitabine/Cisplatin in Advanced Nasopharyngeal Carcinoma

Conditions:   Recurrent Nasopharyngeal Carcinoma;   Metastatic Nasopharyngeal Carcinoma
Intervention:   Drug: Anlotinib plus gemcitabine/cisplatin
Sponsor:   Chinese Academy of Medical Sciences
Not yet recruiting

https://ift.tt/2NacKle

Modified Ramped Position for Intubation of Obese Females.

Conditions:   Obesity;   Anesthesia
Interventions:   Other: Modified ramped position;   Other: Ramped position
Sponsor:   Cairo University
Not yet recruiting

https://ift.tt/2PrQwwh

Chidamide Combined With Cisplatin in Head and Neck Adenoid Cystic Carcinoma (HNACC)

Conditions:   Adenoid Cystic Carcinomas;   Chidamide;   Cisplatin
Intervention:   Drug: Chidamide combined with cisplatin
Sponsor:   Fudan University
Recruiting

https://ift.tt/2Bys7m0

Psychological Impact of a Sophrological Accompaniment During the Announcement of Thyroid Cancer

Condition:   Follicular Thyroid Cancer
Intervention:   Other: sophrology sessions
Sponsor:   Assistance Publique Hopitaux De Marseille
Not yet recruiting

https://ift.tt/2MDIQbL

Single word test for the assessment of speech sound production in Persian speaking children: Development, reliability and validity

Publication date: Available online 21 August 2018

Source: International Journal of Pediatric Otorhinolaryngology

Author(s): Akram Ahmadi, Abbas Ebadi, Mohammad Kamali, Talieh Zarifian, Mehdi Dastjerdi Kazemi, Reyhane Mohammadi

Abstract

Objectives

Single word tests are used frequently to determine clients' speech sound errors. These tools are user-friendly and popular for speech and language pathologists. The aim of this study was to design and validate a single word test for the assessment of speech sound production for Persian speaking children.

Methods

The present study included two phases. In phase I, test material was developed. Psychometric properties were evaluated in phase II. In the next phase, 525 typically developing Persian-speaking children with the age range of 3 to 5 years old were studied. Statistical Package for the Social Sciences, version 24.0 (SPSS, Inc., Chicago, IL) was used for statistical analysis of this study. The significance level was set at (p< 0.05).

Pilot study was performed by administrating the test on 25 typically developing children, construct validity: by administrating the test on 400 typically developing children and the comparison of performance of the children in 4 age groups (discriminative validity regarding age and by administration of this test and phonetic subtest of Persian version of diagnostic evaluation of articulation and phonology on 100 children (convergent validity). Inter-rater reliability was performed by transcription and scoring of samples of 25 children and calculation of Intra Correlation Coefficient (ICC) was calculated. Test-retest was completed by administrating the test two times on 100 children with two weeks intervals. Internal consistency was achieved by the calculation of the correlation of the items of test.

Results

The final version of the test includes 70 target words for assessment of the consonants in three positions, vowels in medial position and consonant clusters (CVCC). There was 80% or more than it for the percentage agreement between experts for the content validity. There wasn't any significant difference between experts' responses about items of the test.

4 pictures were revised based on children's responses for the pilot study. All of the reliability values (test-re test, internal consistency and inter-rater reliability) were higher than 0.85. There was a significant difference between the four age groups for the mean value of Persian single word test for speech sound production (p<0.0001). There was a high correlation between the score of this instrument and the scores of participants in the Phonetic sub-test of the Persian version of Diagnostic evaluation of articulation and phonology(r=0.934, p<0.0001).

Conclusion

It seems that the Persian Speech sound Production Test is a reliable and valid instrument that can be used to measure speech sound errors for Persian speaking children.

https://ift.tt/2LeT3qi

Diffusion tensor imaging in differentiation of residual head and neck squamous cell carcinoma from post-radiation changes

Publication date: Available online 21 August 2018

Source: Magnetic Resonance Imaging

Author(s): Ahmed Abdel Khalek Abdel Razek

Abstract

Background

Differentiation between residual head and neck squamous cell carcinoma and post-radiation changes is difficult with routine computed tomography and magnetic resonance imaging.

Purpose

To assess the reliability and reproducibility of mean diffusivity (MD) and fractional anisotropy (FA) parameters of diffusion tensor imaging in differentiation residual head and neck squamous cell carcinoma from post-radiation changes.

Material and methods

A retrospective analysis of diffusion tensor imaging of 43 patients with head and neck squamous cell carcinoma cancer after radiotherapy. The MD and FA of the lesion were calculated by the same reader at two-time points.

Results

There was a significantly lower difference (P = 0.001) in MD of both readings between residual head and neck squamous cell carcinoma (1.48 ± 0.06 and 1.47 ± 0.07 × 10⁻³ mm²/s) and post-radiation changes (1.72 ± 0.08 and 1.71 ± 0.11 × 10⁻³ mm²/s). The FA of residual head and neck squamous cell carcinoma of both readings (0.41 ± 0.09 and 0.42 ± 0.09) shows a significantly higher difference (P = 0.001) than post-radiation changes (0.17 ± 0.04 and 0.16 ± 0.03). There was excellent intra-reader agreement between both readings using MD (K = 0.958) and FA (K = 0.987). The threshold MD and FA used for differentiating the residual from post-radiation changes of both readings was 1.61, 1.65 × 10⁻³ mm²/s and 0.27, 0.25 with an area under the curve of 0.991, 0.934, 0.993 and 0.990 respectively.

Conclusion

MD and FA of diffusion tensor imaging are non-invasive reliable and reproducible parameters that can help in differentiation residual head and neck squamous cell carcinoma from post-radiation changes.

https://ift.tt/2Lc5MKF

The impact of institutional clinical trial recruitment versus hospital volume on survival outcomes of patients with head and neck cancer: An analysis of the PET-NECK trial outcomes, UKCRN portfolio, and Hospital Episode Statistics (HES) in England

Publication date: October 2018

Source: Oral Oncology, Volume 85

Author(s): Daniel J. Lin, Christopher C. McConkey, Paul Nankivell, Janet Dunn, Hisham Mehanna

Abstract

Objectives

High institutional clinical trial recruitment and high hospital volume are reported to be independent indicators of better patient outcomes following cancer treatment. However, their relationship in head and neck cancers (HNC) remains less clear.

Methods

We aimed to assess the relationship between institutional clinical trial recruitment, hospital throughput of HNC cases, and survival of patients with advanced HNC treated with primary chemoradiotherapy at hospitals which recruited to the PET-NECK trial (2008–2012). The impact on outcome was assessed using Cox's proportional hazards regression analysis and multivariate analysis.

Results

HNC RCT recruitment positively correlated with hospital throughput (r = 0.57, p < 0.0001). Low-recruiters (1–5 patients) had a 107% increased risk of death when compared to high-recruiters (>5 patients) (HR = 2.07, p = 0.05). There was no significant impact of hospital throughput on overall or disease-specific HNC survival. Multivariate analysis identified p16 status, N-stage, smoking, and RCT recruitment volume as the only significant predictors of survival. There was a significant difference in chemotherapy regimen between low and high-recruiters (p = 0.003) where a higher proportion of patients (50%, n = 13) in low-recruiting compared to high-recruiting hospitals (29%, n = 92) received neoadjuvant chemotherapy. A higher proportion of these patients died at low-recruiting hospitals (46% versus 23%).

Discussion

A significant association exists between high recruitment and better OS for patients with HNC. However, no significance was found between hospital throughput and outcomes. The significance of individual centre differences in chemotherapy regimen needs further investigation. Future studies need a greater number of patient outcome events to support the trends found in this study.

https://ift.tt/2N6zBhx

PD-1/PD-L1 co-inhibition shapes anticancer T cell immunodominance: facing the consequences of an immunological ménage à trois

Abstract

PD-1- and PD-L1-blocking monoclonal antibodies have shown significant promise in clinical settings and rekindled the hope for successful cancer immunotherapy. We recently demonstrated that interfering with PD-1/PD-L1 signaling selectively augments CD8⁺ T cell (T_CD8) responses to subdominant determinants (SDDs) of a model tumor antigen. This was likely due to decreased lysis of SDD-specific T_CD8 by neighboring immunodominant clones co-engaging the same antigen-presenting cells (APCs). We therefore proposed that PD-1-based checkpoint inhibitors widen the range of tumor determinants that can be effectively targeted by T_CD8. Subsequently and using different tumor models, Chen et al. reported, in Proceedings of the National Academy of Sciences of the United States of America, that PD-L1 protects APCs from the lytic function of immunodominant T_CD8 and that PD-L1 blockade narrows, rather than broadens, the overall anticancer T cell response. Here, we briefly compare and contrast the experimental systems employed by the two groups, which may account, at least partially, for the opposing conclusions drawn. We argue that the pathway(s) of tumor antigen presentation, direct presentation versus cross-presentation, and the intensity of PD-1 expression by immunodominant and subdominant T_CD8 must be taken into consideration in rational design of anti-PD-1/PD-L1-adjuvanted tumor vaccines and therapies.

https://ift.tt/2BwtlhE