Association between CTLA-4 + 49A > G and – 318C > T single-nucleotide polymorphisms and susceptibility to thyroid neoplasm

Abstract

Purpose

Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4 or CD152) is among the immune checkpoint molecules and its abnormal expression in cancer predisposed individuals might make the person more susceptible to tumor initiation and progression. Considering the implication of single-nucleotide polymorphisms (SNPs) in CTLA-4 gene expression and probably protein function, one can assume the involvement of these SNPs in neoplastic diseases. rs5742909 ( − 318C > T) and rs231775 ( + 49 A > G) are among the most commonly studied SNPs and have been considered as genetic factors related to thyroid diseases. In this cross-sectional study, we aimed to elucidate the association between these SNPs and susceptibility to various types of thyroid cancers.

Methods

We investigated the genetic polymorphisms of − 318C > T and + 49 A > G in the CTLA-4 gene by means of ARMS-PCR and RFLP-PCR, respectively, in 167 patients with thyroid carcinomas (papillary, follicular, and anaplastic). The results were then compared with a group of 100 age-sex matched healthy individuals.

Results

A statistically significant association was observed between the presence of G allele in + 49 A > G locus and thyroid carcinoma, when comparing cases and controls (OR = 2.10; 95% CI = 1.35–3.28; P = 0.001) and the frequency of heterozygotes (AG) was higher than homozygotes for allele A (AA), in patients with and papillary thyroid carcinoma (PTC). Regarding Hashimoto's thyroiditis, the frequencies of A allele and AA genotype in PTC patients were higher than Hashimoto patients with no history of cancer (OR = 4.67, 95% CI = 2.70–8.08, P < 0.0001; and, OR = 4.68, 95% CI = 1.84–11.91, P = 0.0012; respectively). However; we observed no difference among allele/genotype frequencies in regards to locus – 318C > T.

Conclusion

In this study, we observed that G allele in + 49 A > G and possibly lower expression of mutated CTLA-4 molecule, is associated with higher susceptibility to thyroid carcinoma. Although the G allele frequency was higher in thyroid cancer patients, when justified for the presence of lymphocytic thyroiditis, the presence of A allele seemed to increase the odds for PTC in patients with Hashimoto's disease.

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Association between CTLA-4 + 49A > G and – 318C > T single-nucleotide polymorphisms and susceptibility to thyroid neoplasm

Abstract

Purpose

Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4 or CD152) is among the immune checkpoint molecules and its abnormal expression in cancer predisposed individuals might make the person more susceptible to tumor initiation and progression. Considering the implication of single-nucleotide polymorphisms (SNPs) in CTLA-4 gene expression and probably protein function, one can assume the involvement of these SNPs in neoplastic diseases. rs5742909 ( − 318C > T) and rs231775 ( + 49 A > G) are among the most commonly studied SNPs and have been considered as genetic factors related to thyroid diseases. In this cross-sectional study, we aimed to elucidate the association between these SNPs and susceptibility to various types of thyroid cancers.

Methods

We investigated the genetic polymorphisms of − 318C > T and + 49 A > G in the CTLA-4 gene by means of ARMS-PCR and RFLP-PCR, respectively, in 167 patients with thyroid carcinomas (papillary, follicular, and anaplastic). The results were then compared with a group of 100 age-sex matched healthy individuals.

Results

A statistically significant association was observed between the presence of G allele in + 49 A > G locus and thyroid carcinoma, when comparing cases and controls (OR = 2.10; 95% CI = 1.35–3.28; P = 0.001) and the frequency of heterozygotes (AG) was higher than homozygotes for allele A (AA), in patients with and papillary thyroid carcinoma (PTC). Regarding Hashimoto's thyroiditis, the frequencies of A allele and AA genotype in PTC patients were higher than Hashimoto patients with no history of cancer (OR = 4.67, 95% CI = 2.70–8.08, P < 0.0001; and, OR = 4.68, 95% CI = 1.84–11.91, P = 0.0012; respectively). However; we observed no difference among allele/genotype frequencies in regards to locus – 318C > T.

Conclusion

In this study, we observed that G allele in + 49 A > G and possibly lower expression of mutated CTLA-4 molecule, is associated with higher susceptibility to thyroid carcinoma. Although the G allele frequency was higher in thyroid cancer patients, when justified for the presence of lymphocytic thyroiditis, the presence of A allele seemed to increase the odds for PTC in patients with Hashimoto's disease.

https://ift.tt/2MezQX9

Impact of Genomic Assay Testing and Clinical Factors on Chemotherapy Use After Implementation of Standardized Testing Criteria

AbstractBackground.For clinically appropriate early‐stage breast cancer patients, reflex criteria for Oncotype DX ordering ("the intervention") were implemented at our comprehensive cancer center, which reduced time‐to‐adjuvant chemotherapy initiation. Our objective was to evaluate Oncotype DX ordering practices and chemotherapy use before and after implementation of the intervention.Materials and Methods.We examined medical records for 498 patients who had definitive breast cancer surgery at our center. The post‐intervention cohort consisted of 232 consecutive patients who had Oncotype DX testing after reflex criteria implementation. This group was compared to a retrospective cohort of 266 patients who were diagnosed and treated prior to reflex criteria implementation, including patients who did and did not have Oncotype DX ordered. Factors associated with Oncotype DX ordering pre‐ and post‐intervention were examined. We used multivariate logistic regression to evaluate factors associated with chemotherapy receipt among patients with Oncotype DX testing.Results.The distribution of Oncotype DX scores, the proportion of those having Oncotype DX testing (28.9% vs. 34.1%) and those receiving chemotherapy (14.3% vs. 19.4%), did not significantly change between pre‐ and post‐intervention groups. Age ≤65 years, stage II, grade 2, 1–3+ nodes, and tumor size >2 cm were associated with higher odds of Oncotype DX testing. Among patients having Oncotype DX testing, node status and Oncotype DX scores were significantly associated with chemotherapy receipt.Conclusion.Our criteria for reflex Oncotype DX ordering appropriately targeted patients for whom Oncotype DX would typically be ordered by providers. No significant change in the rate of Oncotype DX ordering or chemotherapy use was observed after reflex testing implementation.Implications for Practice.This study demonstrates that implementing multidisciplinary consensus reflex criteria for Oncotype DX ordering maintains a stable Oncotype DX ordering rate and chemotherapy rate, mirroring what was observed in a specific clinical practice, while decreasing treatment delays due to additional testing. These reflex criteria appropriately capture patients who would likely have had Oncotype DX ordered by their providers and for whom the test results are predicted to influence management. This intervention serves as a potential model for other large integrated, multidisciplinary oncology centers to institute processes targeting patient populations most likely to benefit from genomic assay testing, while mitigating treatment delays.

https://ift.tt/2Oa4z8t

Interferon‐α Is Effective for Treatment of Minimal Residual Disease in Patients with t(8;21) Acute Myeloid Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation: Results of a Prospective Registry Study

AbstractBackground.RUNX1‐RUNX1T1 transcript levels were established as a powerful marker for predicting relapse in patients with t(8;21) acute myeloid leukemia (AML). We aimed to identify the efficacy of minimal residual disease (MRD)‐directed interferon‐alpha (IFN‐α) treatment in patients with t(8;21) AML who were positive for MRD after allogeneic hematopoietic stem cell transplantation (allo‐HSCT; n=42).Subjects, Materials, and Methods.MRD‐positive status was defined as a <4.5‐log reduction from diagnosis in RUNX1‐RUNX1T1 transcripts and/or the loss of a ≥4.5‐log reduction after 3 months after HSCT. Patients with positive MRD received six cycles of IFN‐α treatment (twice or thrice weekly of every 4 weeks cycle).Results.The 1‐year cumulative incidence of severe acute and chronic graft‐versus‐host disease after MRD‐directed IFN‐α treatment was 7.1% and 4.8%, respectively. After the treatment, 15 (35.7%), 5 (11.9%), 3 (7.1%), and 9 (21.5%) patients achieved MRD negativity at 1, 2, 3, and >3 months, respectively. Three patients relapsed after the IFN‐α treatment, in which the 1‐year cumulative incidence of relapse was 7.2%. One patient died of severe infection at 460 days after treatment. The 1‐year probabilities of event‐free survival, disease‐free survival, and overall survival after treatment were 76.0%, 92.4%, and 92.5%, respectively. The clinical outcomes in patients who received MRD‐directed IFN‐α treatment were significantly better than those of the MRD‐positive patients without any interventions in the historical cohort.Conclusion.MRD‐directed IFN‐α treatment is effective for patients with t(8;21) AML who were MRD‐positive after allo‐HSCT. The study was registered at https://ift.tt/KkipBP as NCT02027064.Implications for Practice.In patients with t(8;21) acute myeloid leukemia (AML), the presence of post‐allogeneic hematopoietic stem cell transplantation (allo‐HSCT) minimal residual disease (MRD), measured by RUNX1‐RUNX1T1 transcript levels, has been established as a powerful marker for predicting relapse. Interferon‐alpha (IFN‐α) could exert a relatively strong graft‐versus‐leukemia effect, and MRD‐directed IFN‐α treatment is effective for patients with t(8;21) AML who were MRD‐positive after allo‐HSCT.

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Non‐Small Cell Lung Cancer in Countries of Central and Southeastern Europe: Diagnostic Procedures and Treatment Reimbursement Surveyed by the Central European Cooperative Oncology Group

AbstractThis article analyzes the availability of different diagnostic procedures of non‐small cell lung cancer (NSCLC) and the reimbursement landscape of drugs for NSCLC in countries of central and southeastern Europe (CEE). A survey was conducted by the Central European Cooperative Oncology Group. Results of the survey show that both availability and reimbursement of diagnoses of molecular alterations in NSCLC, the detection of which is essential for therapeutic decisions, varies widely between countries of CEE. Not only is "reflex" testing often substituted by analyses performed only "on demand," but reimbursement of such assessments varies widely between unavailability and payments by the health care system or even pharmaceutical companies. It was concluded that a structured access to testing and reimbursement should be the aim in order to provide patients with appropriate therapeutic options.Implications for Practice.This article provides an overview of the limitations in lung cancer treatment in countries of central and southeastern Europe, as well as the reimbursement status of various lung cancer treatment regimens in these countries, which directly impacts treatment options.

https://ift.tt/2nfSbIN

NGR‐hTNF and Doxorubicin as Second‐Line Treatment of Patients with Small Cell Lung Cancer

AbstractBackground.Relapsed small cell lung cancer (SCLC) patients have limited treatment options and poor outcomes. NGR‐hTNF is a vascular‐targeting agent, which increases intratumoral chemotherapy penetration and T‐lymphocyte infiltration.Methods.Twenty‐eight patients relapsing after at least one platinum‐based regimen with a treatment‐free interval shorter (n = 16; platinum‐resistant) or longer (n = 12; platinum‐sensitive) than 3 months received NGR‐hTNF 0.8 μg/m2 plus doxorubicin 75 mg/m2 every 3 weeks. The primary endpoint of this single‐arm phase II trial was progression‐free survival (PFS), and safety, response rate, and survival were secondary endpoints.Results.The most common grade 3–4 toxicities were neutropenia (53%) and anemia (21%). Median PFS was 3.2 months for all patients, 2.7 months for platinum‐resistant patients, and 4.1 months for platinum‐sensitive patients. Seven patients had partial responses (25%), including four (25%) with platinum‐resistant and three (25%) with platinum‐sensitive relapse. Mean changes from baseline in tumor burden (after two, four, and six cycles) did not differ between platinum‐resistant (−9%, −29%, and −32%) and platinum‐sensitive (−11%, −20%, and −43%) cohorts. Overall survival was associated only with baseline lymphocyte counts, with median survival times of 13.1 and 5.2 months for lymphocyte counts above or below the median, respectively.Conclusion.NGR‐hTNF plus doxorubicin showed manageable toxicity and promising activity in patients with relapsed SCLC.

https://ift.tt/2Odg92L

Serum Myostatin is Upregulated in Obesity and Correlates with Insulin Resistance in Humans

Exp Clin Endocrinol Diabetes
DOI: 10.1055/a-0641-5546

Obesity and type 2 diabetes mellitus have reached an epidemic level, thus novel treatment concepts need to be identified. Myostatin, a myokine known for restraining skeletal muscle growth, has been associated with the development of insulin resistance and type 2 diabetes mellitus. Yet, little is known about the regulation of myostatin in human obesity and insulin resistance. We aimed to investigate the regulation of myostatin in obesity and uncover potential associations between myostatin, metabolic markers and insulin resistance/sensitivity indices. Circulating active myostatin concentration was measured in the serum of twenty-eight severely obese non-diabetic patients compared to a sex and age matched lean and overweight control group (n=22). Insulin resistance/sensitivity was assessed in the obese group. Skeletal muscle and adipose tissue specimens from the obese group were collected during elective bariatric surgery. Adipose tissue samples from lean and overweight subjects were collected during elective abdominal surgery. Myostatin concentration was increased in obese compared to lean individuals, while myostatin adipose tissue expression did not differ. Muscle myostatin gene expression strongly correlated with expression of metabolic genes such as IRS1, PGC1α, SREBF1. Circulating myostatin concentration correlated positively with insulin resistance indices and negatively with insulin sensitivity indices. The best correlation was obtained for the oral glucose insulin sensitivity index. Our results point to an interesting correlation between myostatin and insulin resistance/sensitivity in humans, and emphasize its need for further evaluation as a pharmacological target in the prevention and treatment of obesity-associated metabolic complications.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
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Subcutaneous Administration of Insulin is Associated With Regional Differences in Injection Depot Variability and Kinetics in The Rat

Exp Clin Endocrinol Diabetes
DOI: 10.1055/a-0658-1089

Background In humans, subcutaneous administration of insulin in the abdominal region or arm is associated with a faster absorption compared to the thigh or buttocks. We hypothesised that this is partly caused by differences in injection depot structure and kinetics and that the variability in insulin exposure differs between injection sites. Material and methods Regional effects on insulin pharmacokinetics were evaluated in a series of studies in Sprague Dawley rats dosed subcutaneously with insulin aspart in the neck or flank. Injection depots were visualised using µCT after subcutaneous dosing with insulin aspart mixed with the contrast agent iomeprol, and insulin exposure was determined between the scans by Luminescent Oxygen Channeling Immunoassay. Results Insulin absorption was significantly delayed by subcutaneous dosing in the flank compared to the neck region (p<0.01 or less). This delay was associated with smaller depots, as measured by reduced depot volume and surface area (p<0.001). Furthermore, the delayed absorption correlated with a slower depot disappearance (p<0.001). Regional differences in depot variability were not reflected by similar differences in pharmacokinetic variability. Conclusion Structure and kinetics of subcutaneous injection depots—as detected by µCT scans—predict insulin exposure and may thus contribute to the regional differences in insulin pharmacokinetics. The present methodology is applicable for visualisation of insulin injection depots in vivo. Our results did however not support a link between the variability in depot size and insulin pharmacokinetics.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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Positive Effects of Practical Nutrition Lessons in a Primary School Setting with a High Proportion of Migrant School Children

Exp Clin Endocrinol Diabetes
DOI: 10.1055/a-0661-1919

Background Children with migration background are at increased risk for overweight, partly due to less favorable dietary habits compared to their German counterparts. We examined the effects of practical nutrition lessons among children with a high proportion of migration background in a primary school setting. Methods Ten 3rd and 4th grade classes (n=166 children, 73% with migration background) received the intervention and nine school classes (n=139 children, 76% with migration background) served as control. Before, shortly after (only among the intervention group) and three months after the three-day practical nutrition lessons, the nutrition-related skills, behavior, attitudes, and knowledge of the children were assessed using a questionnaire. Changes between baseline and 1st follow-up among children of the intervention group were calculated using linear mixed models. Differences between the two groups for changes between baseline and 2nd follow-up were tested using linear regression analyses. Models were adjusted for potential confounders. Results Shortly after the practical nutrition lessons, the children of the intervention group had improved their knowledge (β=1.7; 95% CI: 1.0; 2.4, P<0.001) and skills (β=1.8; 95% CI: 1.4; 2.2, P<0.001). These changes were sustainable and larger in the intervention compared to the control group (knowledge: β=1.6; 95% CI: 0.7; 2.5, P<0.001; skills: β=1.3; 95% CI: 0.7; 1.9, P<0.001). Changes in nutrition-related behavior and attitudes did not differ between the groups. Conclusions Providing practical nutrition lessons in a primary school setting with a high proportion of children with immigrational background improved the children's nutrition-related knowledge and skills.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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Linking Sleep Disturbance To Idiopathic Male Infertility

Recently published data suggests that male fertility has declined over the past four decades. The reasons for the decline are unclear with up to 50% of cases of male infertility remaining unexplained (idiopathic male infertility). Whilst environmental factors and rising rates of obesity have been implicated, there is now growing evidence that sleep disturbance may be an independent causative factor. Indeed, the prevalence of sleep disturbance appears to be increasing in parallel with deterioration in population sperm quality, a commonly used surrogate marker of male fertility.

https://ift.tt/2M2lk7W

Climate Change and Sleep: A Systematic Review of the Literature and Conceptual Framework

From disaster related stress causing insomnia, to poor air quality causing sleep related breathing problems, climate change poses a potentially serious threat to human sleep. We conducted a systematic review evaluating the relationship between climate change and human sleep in the PubMed, Scopus, and Cochrane databases from 1980 through 2017 following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Inclusion criteria included epidemiologic studies published in English that reported observational population data on human sleep and its relationship to climate change, temperature, extreme weather events and climate related disasters (e.g.

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Targeting volume overload and overnight rostral fluid shift: a new perspective to treat sleep apnea

Sleep apnea is a common condition associated with increased morbidity and mortality. Continuous positive airway pressure and oral appliances are efficient for treating sleep apnea; however, they are often poorly tolerated. Therefore, alternative therapies are needed. Overnight rostral fluid shift has been implicated in the pathogenesis of sleep apnea, particularly in conditions associated with fluid overload. Fluid shift predisposes to both obstructive and central sleep apnea, with the type of sleep apnea being related to whether the fluid shifts from the legs into the neck or chest, respectively.

https://ift.tt/2M2q8u6

Cross-section investigation and analysis of anxiety and depression in preoperative patients in outpatient department of aesthetic plastic surgery in a general hospital in China

Objective: This study was designed to evaluate the anxiety and depression disorders and investigate the prevalence and risk factors in preoperative patients who came to cosmetic plastic surgery clinic. Methods: Using the field survey method, the estimate of anxiety and depression in preoperative patients was made by the Hospital Anxiety and Depression Scale from July 2016 to July 2017 in the outpatient department of plastic surgery in a general hospital. The demographic information was collected.

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Reconstruction of columellar defects: which surgical technique to choose ? A retrospective study of 18 patients

The reconstruction of the columella is challenging and poorly evaluated in the literature. Our study aimed to evaluate retrospectively the different techniques used in our center and to propose an algorithm of reconstruction adapted to each patient. We report a retrospective cohort study included 18 patients (9 men and 9 women; 53 years-old in average) with columellar reconstruction treated from 1999 through 2014. Six different techniques were used: chondrocutaneous graft, nasolabial flap, paramedian forehead flap and scalping flap according to the Converse technique or the Raulo technique.

https://ift.tt/2Mj55jQ

Nipple-sparing mastectomy with different approaches: surgical incisions, complications and cosmetic results. Preliminary results of 100 consecutive patients at a single center

Nipple areola sparing mastectomy is a novel surgical approach that preserves the nipple areola complex. Patients with moderate and/or severe breast ptosis are usually not eligible for this surgical approach. In this study we are aimed to demonstrate the feasibility of non-conventional surgical approaches for nipple sparing mastectomy.One hundred consecutive patients were enrolled for this study, with diagnosed primary breast cancer. Clinical and pathological data, such as body mass index, smoking status, breast ptosis, complications and aesthetic satisfaction (Breast-Q test) were considered.

https://ift.tt/2vhV3cl

Sensory and functional morbidity following sural nerve harvest in paediatric patients

The sural nerve is a common donor site for nerve reconstruction. The only study describing outcomes in paediatric patients was following bilateral sural nerve harvest prior to the age of one. Bilateral nerve harvest at such a young age may limit patients' ability to perceive a sensory difference. The objective of this study was to understand the sensory and functional deficit after unilateral sural nerve harvest in paediatric patients.

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Negative-Pressure Wound Therapy: An Effective Adjunctive Treatment to Assist Flap Survival and Wound Closure

Dear Sir,

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The impact of orthognathic surgery on velopharyngeal function by evaluating speech and cephalometric radiographs

: Maxillary retrognathia is a well-known consequence of abnormal facial growth in patients with cleft lip and palate. Orthognathic surgery improves facial appearance and occlusion, but may induce velopharyngeal insufficiency. The aim of the study was to evaluate the effect of orthognathic surgery on velopharyngeal function using speech analysis and lateral cephalometric radiographs.

https://ift.tt/2O5VihF

Autologous fat grafting for enhancement of breast reconstruction with a transverse myocutaneous gracilis flap: A cohort study

The transverse myocutaneous gracilis (TMG) flap is a viable option for reconstruction of small to moderate breasts. The purpose of this series was to examine outcomes of fat grafting to breast and donor site secondary to breast reconstruction with a TMG flap.

https://ift.tt/2LXrfLz

Post oncological lacrimal duct reconstruction; a practical classification system for reconstructive planning and short-term results of a case series.

: Surgical resection of skin tumors in the medial canthal area may damage the lacrimal duct and can result in chronic ephiphora. Post oncologic reconstruction of the lacrimal duct has not been studied extensively. The current study discusses the anatomical and functional features of the lacrimal duct. It describes short-term functional outcomes after monocanalicular reconstruction of the lacrimal duct in a case series of 10 patients.

https://ift.tt/2O8Cmik