TT Patients Research Articles

Comparison of clinical characteristics of testicular tumor between children and adult population: a retrospective analysis

ObjectiveTesticular tumor (TT) is a uncommon disease posing serious health problem. There are differences in some aspects between adult and pediatric TT. The study was to compare their differences of clinical and histological characteristics through the analysis of the long-term experiences in TT patients from two institutions.Materials and methodsThe clinical data of hospitalized patients was collected and analyzed retrospectively from January 2014 to January 2024 at a pediatric and an adult institution, respectively. The data included composition, gender, age, initial presentation, tumor size, tumor markers, pathological diagnosis.ResultsA total of 195 hospitalized patients were included. There were 135 children and 60 adult with TT, respectively. Of these children, patients were aged from 1 month to 14 years, with a mean age of 2.32 years. More cases (37.04%) were diagnosed at age younger than 1 years. 69 cases were left-sided, 65 cases were right-side and only 1 case was bilateral. Pediatric TTs mainly included 82 prepubertal teratomas, 37 had prepubertal yolk sac tumors and 3 mixed malignant germ tumors. Testicular surgeries included testicular-sparing surgery (TSS) (n = 73), radical orchiectomy (n = 60), and testicular biopsy (n = 2). There were 24 patients receiving postoperative chemotherapy. Adult TTs mainly contained 17 seminomas, 10 prepubertal teratomas,7 postpubertal teratomas, 6 stromal tumors and 3 embryonal carcinomas. The average age was 34.08 years. There were 29 right-sided, 27 left-sided and 4 bilateral tumors. TSS (n = 26), radical orchiectomy (n = 33), and testicular biopsy (n = 1) were performed in these TT patients. Only 6 patients received postoperative chemotherapy. The most common symptom was a painless scrotal mass at initial diagnosis in both groups. In addition, we found that significant differences were explored between histological type and age, tumor size (P < 0.05). Yolk sac tumor and seminoma were the most common malignant TT in pediatric and adult population, respectively. After two year follow-up, two children with yolk sac tumor and 4 adults with seminoma died of their diseases.ConclusionsThe majority of pediatric cases were benign compared to adult. The most common type was prepubertal teratoma and yolk sac tumor. Pediatric TTs often occurred under the age of 1 year. Seminomas and prepubertal teratomas were commonly found in adult TTs, especially for young adult. We found that pediatric tumor type was associated with age and tumor size. TSS should be considered for benign TTs based on frozen biopsy findings in children.

Pro-fibrotic effect of the susceptible gene PCSK5 in vascular fibrosis of Takayasu arteritis via TGF-β and SMAD3 signaling pathway activation

BackgroundVascular fibrosis directly causes vascular thickening in Takayasu arteritis (TAK), in which sustained transforming growth factor beta (TGF-β) activation is critical. Understanding TGF-β activation regulation and blocking it might yield a therapeutic effect in TAK. Proprotein convertase subtilisin/kexin type 5 (PCSK5) rs6560480 (T/C) is associated with TAK development. In this study, we assessed the association between the PCSK5 rs6560480 genotype and PCSK5 expression in TAK and explored its molecular role in TGF-β activation and vascular fibrosis development. MethodsIn TAK patients, PCSK5 and TGF-β expression in plasma and aortic tissue was examined by ELISA and immunohistochemical staining, and PCSK5 rs6560480 was genotyped. The correlation between PCSK5 and extracellular matrix (ECM) expression was examined by Western blotting (WB) and immunohistochemistry staining. Detection by co-immunoprecipitation was performed to detect the interaction between PCSK5 and TGF-β in adventitial fibroblasts (AAFs). Downstream signaling pathways were detected by WB and validated with appropriate inhibitors. Potential immunosuppressive agents to inhibit the effects of PCSK5 were explored in cell culture and TAK patients. ResultsPatients with PCSK5 rs6560480 TT patients had significantly higher PCSK5 levels and more thickened vascular lesions than patients with PCSK5 rs6560480 CT. PCSK5 expression was significantly increased in alpha smooth muscle actin (α-SMA)-positive myofibroblasts in TAK vascular lesions. Overexpressing PCSK5 facilitated TGF-β and downstream SMAD2/3 activation and ECM expression in AAFs and aorta in in-vitro culture. The mechanistic study supported that PCSK5 activated precursor TGF-β (pro-TGF-β) to the mature form by binding the pro-TGF-β cleavage site. Leflunomide inhibited PCSK5 and pro-TGF-β binding, decreasing TGF-β activation and ECM expression, which was also partially validated in leflunomide-treated patients. ConclusionThe findings revealed a novel pro-fibrotic mechanism of PCSK5 in TAK vascular fibrosis via TGF-β and downstream SMAD2/3 pathway activation. Leflunomide might be anti-fibrotic by disrupting PCSK5 and pro-TGF-β binding, presenting a new TAK treatment approach.

Association between polymorphism in the MTHFR gene and encephaloduroarteriosynangiosis-induced collateral circulation formation.

This study aimed to investigate whether high homocysteine (Hcy) levels associated with the MTHFR gene influence the formation of the collateral vascular network in patients with moyamoya disease (MMD) after encephaloduroarteriosynangiosis (EDAS) by influencing the number of endothelial progenitor cells (EPCs) in peripheral blood. A total of 118 Chinese patients with bilateral primary MMD were prospectively included. Blood samples were collected from the anterior cubital vein before surgery, and MTHFR rs9651118 was genotyped using high-throughput mass spectrometry to determine the genotype of the test specimen. Serum Hcy and EPC levels were measured, the latter with flow cytometry. Digital subtraction angiography was performed 6 months after EDAS, and the formation of collateral circulation was evaluated using the Matsushima grade system. The correlations between MTHFR rs9651118 genotype, Hcy and EPC levels, and Matsushima grade were compared. Among the 118 patients, 53 had the TT genotype (wild type) of MTHFR rs9651118, 33 TC genotype (heterozygous mutation), and 32 CC genotype (homozygous mutation). The mean ± SD Hcy level was 13.4 ± 9.5 μmol/L in TT patients, 9.8 ± 3.2 μmol/L in TC patients, and 8.9 ± 2.9 μmol/L in CC patients (p < 0.001). The level of EPCs in the venous blood of TT patients was 0.039% ± 0.016%, that of TC patients 0.088% ± 0.061%, and that of CC patients 0.103% ± 0.062% (p < 0.001). When the rs9651118 gene locus was mutated, Matsushima grade was better (p < 0.001) but there was no difference between heterozygous and homozygous mutations. The results suggest that the MTHFR rs9651118 polymorphism is a good biomarker for collateral vascular network formation after EDAS in MMD patients.

Comparing clinical course and patients out comes in patients undergoing Open surgical Versus Thoracoscopic closure of the atrial and ventricular septal defects in children

The current study is aimed at evaluation of the impact of different surgical approaches while correcting congenital heart diseases (CHD). Clinical outcomes like; operative time, complications, hospital stay were evaluated in children undergoing surgical repair of atrial septal defect (ASD) and ventricular septal defect (VSD).&#x0D; Patients and methods: Between 2015 and 2019, a total of 111 patients surgically managed for CHD with male: female ratio of…. and mean age 10.42±3.24 years. Two surgical approaches: open either right anterolateral thoracotomy or sternotomy and thoracoscopic were used. The study conducted to determine the operative time, ICU stay, complications, recovery period and long term follow up of the patients in both the groups.&#x0D; Results: 67 patients with ASD and 44 patients with VSD underwent cardiac surgery. Mean operation time was significantly longer in TS patients in comparison with TT and ST groups. However, mean intensive care unit (ICU) stay and hospital stay were significantly shorter in TS group in comparison with TT and ST patients.&#x0D; Conclusion: TS approach in repair of congenital heart defects not only resulted of good cosmetic effect, but also reduces time in ICU and hospital stay in comparison with “classical” operational techniques. In this article we tried to show the whole results of research.&#x0D; Bangladesh Journal of Medical Science Vol. 23 No. 01 January’24 Page : 115-120

Effects of the SNAP-25 Mnll variant on hippocampal functional connectivity in children with attention deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most widespread and highly heritable neurodevelopmental disorders affecting children worldwide. Although synaptosomal-associated protein 25 (SNAP-25) is a possible gene hypothesized to be associated with working memory deficits in ADHD, little is known about its specific impact on the hippocampus. The goal of the current study was to determine how variations in ADHD's SNAP-25 Mnll polymorphism (rs3746544) affect hippocampal functional connectivity (FC). A total of 88 boys between the ages of 7 and 10 years were recruited for the study, including 60 patients with ADHD and 28 healthy controls (HCs). Data from resting-state functional magnetic resonance imaging (rs-fMRI) and clinical information were acquired and assessed. Two single nucleotide polymorphisms (SNP) in the SNAP-25 gene were genotyped, according to which the study's findings separated ADHD patients into two groups: TT homozygotes (TT = 35) and G-allele carriers (TG = 25). Based on the rs-fMRI data, the FC of the right hippocampus and left frontal gyrus was evaluated using group-based comparisons. The corresponding sensitivities and specificities were assessed. Following comparisons between the patient groups, different hippocampal FCs were identified. When compared to TT patients, children with TG had a lower FC between the right precuneus and the right hippocampus, and a higher FC between the right hippocampus and the left middle frontal gyrus. The fundamental neurological pathways connecting the SNAP-25 Mnll polymorphism with ADHD via the FC of the hippocampus were newly revealed in this study. As a result, the hippocampal FC may further serve as an imaging biomarker for ADHD.

Adjuvant treatment and outcome of stage III melanoma patients: Results of a multicenter real-world German Dermatologic Cooperative Oncology Group (DeCOG) study

PurposeClinical trials demonstrated significantly improved recurrence-free survival (RFS) of melanoma patients receiving adjuvant treatment. As data from controlled trials are based on selected populations, we investigated adjuvantly treated stage III melanoma patients under real-world conditions. Patients and methodsIn a prior multicenter cohort study, stage III-IV melanoma patients were analysed for their choice of adjuvant therapy. In this follow-up study, we examined RFS, overall and melanoma-specific survival (MSS) and response to the subsequent treatment of 589 stage III patients (232 BRAF-mutated) receiving adjuvant PD-1 inhibitors (PD1; n = 479) or targeted therapy (TT; n = 110). ResultsThe median follow-up of the total cohort was 25.7 months. The main reason for premature discontinuation of adjuvant therapy was disease progression in PD1- (28.8%, n = 138/479) and adverse events in TT-treated patients (28.2%, n = 31/110).Among BRAF-mutated patients, RFS at 24 months was 49% (95% CI 40.6–59.0%) for PD1- and 67% (95% CI 58–77%) for TT-treated patients. The risk of recurrence was higher for BRAF-mutated PD1 than TT (hazard ratio 1.99; 95% CI 1.34–2.96; hazard ratio adjusted for age, sex and tumour stage, 2.21; 95% CI 1.48–3.30). Twenty-four months MSS was 87% (95% CI 81.0–94.1) for PD1 and 92% (95% CI 86.6–97.0) for TT.Response to subsequent systemic treatment for unresectable disease was 22% for all PD1- and 16% for TT-treated patients. ConclusionsPD1-treated patients had more and earlier recurrences than TT patients. In BRAF-mutated patients, adjuvant TT might prevent early recurrences more effectively than PD1 treatment. Management of recurrence despite adjuvant treatment is challenging, with low response to current therapeutic options.

Patient characteristics and treatment patterns in BRAF-mutated unresectable or metastatic melanoma in the United States: A snapshot from real-world data.

e21506 Background: BRAF mutations are found in 40-60% of patients with unresectable/metastatic melanoma (m-melanoma). Recently, several new BRAF-targeted therapies (TT) have been approved, transforming the treatment landscape for patients with BRAF-mutated (BRAFm) unresectable/m-melanoma. This analysis aimed to describe patient characteristics and treatment patterns in BRAFm unresectable/m-melanoma patients receiving treatment during November 2015-June 2021. Methods: A retrospective analysis using Flatiron Health’s database was conducted. Adult patients with unresectable/m-melanoma who had evidence of the BRAF-V600 activating mutation were included. Patients were indexed at first-line (1L) therapy initiation. Treatments of interest were classified into immuno-oncology (IO) therapies and TT. All analyses were descriptive. Results: 671 unresectable/m-melanoma patients (average age: 62.7 years, 64.1% male) were included. Among them, 64.4% of patients received IO, 34.4% received TT, and 1.2% received IO+TT. In 1L, ipilimumab+nivolumab and dabrafenib+trametinib were the most common IO (50.9%) and TT (71.9%), respectively. The median duration of 1L was 8.0 months (9.7 months in IO and 6.7 months in TT). Among IO-treated patients, 28.5% had Eastern Cooperative Oncology Group (ECOG)≥1, 23.4% had elevated lactate dehydrogenase (LDH) levels, and 4.9% had 3+ metastases identified. Among TT-treated patients, 42.9% had ECOG≥1, 27.3% had elevated LDH, and 7.8% had 3+ metastases identified. Approximately one-third of the patients (n = 204) received their 1L treatment prior to being tested for BRAF mutation; the majority of whom (90.2%) received IO. 273 patients (40.7%) advanced to a second line (2L). In 2L, 14.3% of patients received the same class of therapy as in 1L, 44.7% switched from 1L IO to 2L TT, and 35.2% switched from 1L TT to 2L IO. In 2L, ipilimumab+nivolumab (50.0%) in IO and dabrafenib+trametinib (60.7%) in TT were the most common combinations. The median duration of 2L was 5.0 months (3.7 months in IO and 6.5 months in TT). Conclusions: Despite the recent availability of TT combinations for BRAFm unresectable/m-melanoma, IO is about twice as frequently prescribed than TT in 1L. One-third of the patients received treatment before BRAFm testing results were available and most of them were prescribed IO. These findings along with elevated ECOG scores, the proportion of 3+ metastases, and elevated LDH levels seen in TT patients, suggest TT is often offered to patients with a high disease burden in the current practice settings.

Leptin Deficiency May Influence the Divergence of Cell-Mediated Immunity Between Lepromatous and Tuberculoid Leprosy Patients.

Leprosy is a disease caused by an intracellular bacillus bacterium called Mycobacterium leprae which lives and multiplies in the hosts' macrophages and Schwann cells. Depending on the degree of the host's cell-mediated immunity (CMI) response to the bacilli, the disease manifests itself in five clinical spectra ranging from polar tuberculoid (TT) to polar lepromatous leprosy (LL). A very high level of T helper 1 (Th1) driven bacilli-specific CMI is seen in the TT form, whereas this response is essentially nonexistent in the LL form. As a result, there is very low or absent bacillary load and localized nodular lesions in TT patients. On the contrary, LL patients presented with high bacillary load and generalized lesions due to low CMI response. The mechanism underlying this divergence of CMI response is not clearly elucidated yet. However, mounting evidence links it to an elevated number of Th1 and Th17 suppressing CD4+ CD25+ FOXP3+ T regulatory cells (Treg cells) which are abundantly found in LL than in TT patients. The predominance of these cells in LL patients is partly attributed to a deficiency of leptin, the cytokine-like peptide hormone, in these patients. Becausea normal level of leptin promotes the proliferation and preferential differentiation of effector T cells (Th1 and Th17) while inhibiting the growth and functional responsiveness of the Treg cells. In contrast, leptin deficiency or neutralization was reported to exert the opposite effect on Treg cells and effector T cells. Other smaller subsets of lymphocytes such as gamma delta (γδ) T cells and B regulatory cells are also modulated by leptin level in the pathogenesis of leprosy. Leptin may therefore regulate the divergence of CMI between TT and LL patients by regulating the homeostasis of effector T cells and Treg cells, and this review will examine the underlying mechanism for this.

Evaluation of testicular torsion management in Ogbomoso, South-Western Nigeria and surgical detorsion-augmented treatment with phytochemical fractions of Corchorus olitorius leaf in experimental rats

BackgroundThere is need to investigate whether phytochemicals along with surgical detorsion could serve as better managements options in TT patients rather than surgical detorsion (SD) alone. MethodsThe descriptive cross-sectional part of this study is questionnaire-based addressing sociodemographic characteristics of participants and their experience in management of TT. In the experimental part, male rats (n = 32) were grouped into: sham, Ischemia-reperfusion injury (IRI), dichloromethane (DCM) and ethanol fraction (100 mg/kg) of CO. Evaluation of tissue GPx, total thiol, SOD, MDA and H2O2 was done. Serum estimations of nitrite, TNF-α and IL-6, MPO, sperm motility, count and viability was also carried out. Tissue expression of bax and caspase 3 was assessed. Results68.9 % respondents agreed that SD alone is non-effective in the management of TT while 83.6 % reported a need to augment surgery with medications. Oxidative stress markers like H2O2, MDA and nitrite increased by IRI were decreased in post-treatment groups, along with a significant increase in the tissue level of GSH, GST, SOD, GPx, and total thiol. Inflammatory mediators were elevated in IRI while post-treatment rats showed significant decrease. IRI decreased sperm count significantly this was reversed by post-treatment. Bax and caspase 3 was increased in IRI rats and post-treatment with CO fractions reduced them. ConclusionsQuantitative cross-sectional study has revealed through experience of clinicians that surgical detorsion alone is not effective in managing TT. Augmented treatment with CO leaf fractions suppressed testicular IRI through inhibition of pro-apoptotic proteins expression, oxidative stress and inflammation.

Clinical Study on the Relationship between the SNP rs8192675 (C/C) Site of SLC2A2 Gene and the Hypoglycemic Effect of Metformin in Type 2 Diabetes.

This study investigates the correlation between the gene polymorphism of rs8192675 (C/C) locus of SLC2A2 in patients with type 2 diabetes (T2DM) and the efficacy of metformin. For this purpose, we have selected 110 T2DM patients (T2DM group) and 110 healthy people (control group) who were treated in our hospital from January 2019 to January 2020 as the research subjects. PCR-restriction fragment length polymorphism (PCR-RFLP) method detects the distribution frequency of gene polymorphism. The patients in the T2DM group were treated with metformin and followed up for 90 days to analyze the relationship between the efficacy of metformin and the SLC2A2 gene polymorphism. The genotypes of SLC2A2 rs8192675 in the control group and in the T2DM group conformed to the Hardy–Weinberg equilibrium law. Compared with the control group, the CT type and the CC type at rs8192675 in the T2DM group were significantly higher (P < 0.05). For rs8192675, there was no significant difference in TT, CT, CC FPG, 2hPBG, and HbA1c levels before treatment (P > 0.05); after metformin treatment, the reduction in FPG, 2hPBG, and HbA1c in CC patients was lower than that of TT and CT patients (P < 0.05). SLC2A2 gene polymorphism site rs8192675 CC type T2DM patients are sensitive to metformin and have a better hypoglycemic effect.

Should haematological inflammatory markers be included as an adjuvant in the differential diagnosis of acute scrotal pathologies?

The aim of this study was to determine discriminative role of haematological inflammatories between acute scrotal pathologies and malignancies. In addition, it was aimed to search for a predictive marker of testicular survival in the TT group. Medical data of 141 patients with acute scrotal pathology and 63TTm patients who presented to our clinic between January 2015 and July 2019 were retrospectively reviewed and compared in terms of haematological values and demographic parameters following the inclusion of 92 healthy controls. In the TTm group, NLR was the discriminative parameter with a median of 2.42 (0.25-8.42), whereas discriminative median values of MCV for TT and CRP for EO were 83.65 (56.9-98.16) and 59.5 (2.9-337) respectively. NLR, PLR, MER and RDW values were statistically lower in the control group compared to the patients groups. In TT subgroup analysis, monocyte count, MER and CRP were found to be statistically higher in the orchiectomy group, while multivariate logistic regression analysis performed for testicular viability revealed monocyte count to be the only significant variable (Odds Ratio [95% Confidence Interval]=0.046 (0.006-0.366), p<0.004). While our study demonstrated both diagnostic and discriminative values of haematological parameters, it also showed that monocyte count could predict testicular salvage in TT patients. However, further prospective studies are required.

GALNT14 genotype-guided chemoembolization plus sorafenib therapy in hepatocellular carcinoma: a randomized trial.

GALNT14-rs9679162 "TT" genotype is associated with favorable clinical outcomes in hepatocellular carcinoma (HCC) treated by transarterial chemoembolization (TACE). We investigated whether patients with GALNT14-rs9679162 "non-TT" unfavorable genotype benefited from chemoembolization plus sorafenib combination therapy. Intermediate stage HCC patients were recruited for GALNT14-rs9679162 genotyping before TACE. Patients with "TT" genotype received only TACE, labeled as TT (TACE) group. Patients with "non-TT" genotype ("GG" or "GT") were randomized to receive either TACE alone, labeled as Non-TT (TACE) group, or TACE plus sorafenib, labeled as Non-TT (TACE + Sora) group. The latter group received sorafenib 400mg daily plus TACE. From October 2015 to April 2019, 103 HCC patients scheduled to receive chemoembolization were screened. Of them, 84 met inclusion criteria and were assigned to TT (TACE) (n = 25), Non-TT (TACE) (n = 30) and Non-TT (TACE + Sora) (n = 29) groups according to their GALNT14 genotypes. Repeated TACE sessions were performed on-demand and patients were followed until November 2020. It was found that TT (TACE) and Non-TT (TACE + Sora) patients had shorter time-to-complete response compared with that in Non-TT (TACE) patients (p < 0.001 and 0.009, respectively). These two groups also had longer time-to-TACE progression (p < 0.001 and 0.006, respectively) and longer progression-free survival (p = 0.001 and 0.021, respectively). However, TT (TACE) patients harbored longer overall survival compared with those in non-TT (TACE + Sora) and non-TT (TACE) patients (p = 0.028, < 0.001, respectively). Combination of sorafenib and TACE for "non-TT" patients partially overcame the genetic disadvantage on treatment outcomes in terms of time-to-complete response, time-to-TACE progression and progression-free survival. ClinicalTrials.gov NCT02504983.

Fatigue in breast cancer patients on chemotherapy: a cross-sectional study exploring clinical, biological, and genetic factors

BackgroundCancer-related fatigue (CRF) is one of the most common and distressing complaints reported by cancer patients during chemotherapy considerably impacting all aspects of a patient’s life (physical, psychosocial, professional, and socioeconomic). The aim of this study was to assess the severity of cancer-related fatigue in a group of breast cancer patients undergoing chemotherapy and explore the association between fatigue scores and sociodemographic, clinical, biological, psychiatric, and genetic factors.MethodsA cross-sectional pilot study carried out at the oncology outpatient unit of Hôtel-Dieu de France University Hospital recruited 67 breast cancer patients undergoing chemotherapy between November 2017 and June 2019 to evaluate fatigue using the EORTC QLQ-C30 scale (European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire). Genotyping for seven gene polymorphisms (COMT, DRD2, OPRM1, CLOCK, PER2, CRY2, ABCB1) was performed using the Lightcycler® (Roche).ResultsThe prevalence of fatigue was 46.3%. Multivariable analysis taking the fatigue score as the dependent variable showed that a higher number of cycles and a lower hemoglobin level were significantly associated with higher odds of exhibiting fatigue. Moreover, having at least one C allele for DRD2 SNP (vs. TT) was significantly associated with a 4.09 higher odds of expressing fatigue compared to TT patients. Finally, patients with at least one C allele for CLOCK SNP tended to display higher fatigue levels than TT patients.ConclusionsOur study showed that anemic breast cancer patients with a high number of chemotherapy cycles and those carrying at least one C allele for DRD2 and CLOCK SNPs are at greater risk of exhibiting fatigue. Since no previous research has reported such genetic results, future studies are necessary to confirm our findings.

HLA-B Leader Dimorphism Impacts on Outcomes of HLA-Matched Related/Unrelated Transplantation: Analysis of the Japanese Society for Transplantation and Cellular Therapy

HLA-B Leader Dimorphism Impacts on Outcomes of HLA-Matched Related/Unrelated Transplantation: Analysis of the Japanese Society for Transplantation and Cellular Therapy

ANNUAL EXPENDITURES AMONG PATIENTS WITH COPD INITIATING TIOTROPIUM/OLODATEROL VS TRIPLE THERAPY

TOPIC: Obstructive Lung Diseases TYPE: Original Investigations PURPOSE: In 2018, 16.4 million U.S. adults reported a diagnosis of Chronic Obstructive Pulmonary Disease (COPD) with annual healthcare costs projected to reach $49 billion by 2020. Up to 70% of COPD-related healthcare expenditures are attributable to acute COPD exacerbations. The 2018 Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommends long-acting muscarinic antagonists/beta2-agonists (LAMA+LABA) as next-in-line therapy for symptomatic COPD patients on mono-maintenance therapy. The addition of inhaled corticosteroids and escalation to Triple Therapy [TT] should be reserved for those experiencing further exacerbations and after risk/benefit (e.g., pneumonia) assessment. However, evidence reveals TT is over-prescribed in discordance with GOLD recommendations. The purpose of this study is to compare COPD-related plan paid costs among matched cohorts of TIO+OLO (a fixed-dose LAMA+LABA inhaler) vs. TT initiators in a U.S. Medicare Advantage population: a) naïve to maintenance treatment and b) stratified by baseline exacerbation history (proxy for COPD severity): no=0 exacerbation; single=1 moderate exacerbation; multiple/severe=≥2 moderate or ≥1 severe exacerbation(s). METHODS: This retrospective, observational post-hoc analysis included COPD patients aged ≥40 years initiating TIO+OLO or TT from 01 Jan 2014 to 31 Mar 2018 (treatment initiation date = index date). 12 months pre-index and ≥30 days post-index continuous medical/pharmacy coverage was required. Cohorts were propensity score matched 1:1. Multivariable analyses were used to estimate adjusted annualized post-index mean costs after matching. RESULTS: Among patients naïve to maintenance treatment, TIO+OLO patients had lower mean COPD-related total ($9,422 vs. $16,753; p<0.001), medical ($5,845 vs. 10,009; p<0.001) and pharmacy ($3,669 vs. $7,084; p<0.001) costs. TIO+OLO patients with no exacerbations had significantly lower mean COPD-related total costs ($7,342 vs $16,005; p<0.001) than patients who initiated TT, with lower medical ($3,675 vs. $9,199; p<0.001), and pharmacy ($3,685 vs. $7,032; p<0.001) costs. Among patients in the 'single' exacerbation group, TIO+OLO patients also had lower mean COPD-related total ($8,398 vs. $15,058; p<0.001), medical ($4,954 vs. $8,422; p<0.02) and pharmacy ($3,545 vs. $6,912; p<0.001) costs than TT patients. Among patients in the 'multiple/severe' group, TIO+OLO patients had lower mean COPD-related pharmacy costs ($3,761 vs. $7,249; p<0.001) but no significant difference in total costs ($17,262 vs. 22,979; p=0.1). CONCLUSIONS: Patients initiating TIO+OLO who were either naïve to maintenance treatment, and/or had no or single exacerbations prior to initiation had significantly lower medical and pharmacy costs versus those initiating TT. CLINICAL IMPLICATIONS: This real-world cost analysis illustrates the financial impact of prescribing TT, inconsistent with GOLD recommendations. DISCLOSURES: Employee relationship with Optum Please note: 09/2014 to present Added 05/04/2021 by Amy Anderson, source=Web Response, value=Salary Optum research sponsor relationship with Boehringer Ingelheim Please note: 2017 to current Added 05/04/2021 by Amy Anderson, source=Web Response, value=Research funding to Optum Employee relationship with Optum Please note: 11/2006 to current Added 04/26/2021 by Ami Buikema, source=Web Response, value=Salary Optum research sponsor relationship with Boehringer Ingelheim Please note: 2017 to current Added 04/26/2021 by Ami Buikema, source=Web Response, value=Research funding to Optum Employee relationship with Boehringer Ingelheim Corporation Please note: 2015-2021 Added 04/26/2021 by jess franchino-elder, source=Web Response, value=Salary No relevant relationships by Monica Frazer, source=Web Response no disclosure on file for Lisa Le;Employee relationship with Boehringer Ingelheim Pharmaceuticals, Inc. Please note: 08/07/17 to current Added 04/26/2021 by Swetha Palli, source=Web Response, value=Salary Employee relationship with Boehringer Ingelheim Pharmaceuticals, Inc. Please note: Aug 2017 - Current Added 04/26/2021 by Swetha Palli, source=Web Response, value=Salary

A nuclear polymorphism at the 8q24 region is associated with improved survival time and chemo-response in high-grade serous ovarian cancer.

The 8q24 chromosomal region is strongly associated with an increased risk of ovarian cancer. One single nucleotide polymorphism that is associated with ovarian cancer in this region is rs6983267, located within the long non-coding RNA colon cancer associated transcript 2 (CCAT2). The aim of the present study was to assess the association between rs6983267 and clinical outcomes in patients with high-grade serous ovarian cancer (HGSOC). The present retrospective genetic association study utilized Sanger sequencing to determine the genotype at the rs6983267 locus (GG, GT, TT) in 98 patients with HGSOC. Survival time and chemotherapy responses between patients were compared with the TT genotype and patients with a genotype containing a G allele (GT, GG). Survival analyses were performed using Cox proportional hazard ratio analysis. Association with chemo-response was performed using a logistic regression. The results revealed that patients with HGSOC and the TT genotype at the rs6983267 locus had improved survival time compared with patients with genotypes containing a G allele [hazard ratio=0.59; 95% confidence interval (CI), 0.36–0.97; P=0.039] and were significantly associated with International Federation of Gynecology and Obstetrics stage [odds ratio (OR)=5.34; 95% CI, 1.50–22.62; P=0.014] and positive chemo-response (OR=4.51; 95% CI, 1.40–18.00; P=0.018). In summary, patients with HGSOC and the TT genotype at the rs6983267 locus had improved survival time compared with those with a G allele, despite being associated with more advanced disease; this was possibly due to an improved response to chemotherapy.

PACSIN2 rs2413739 Polymorphism and Thiopurine Pharmacokinetics: Validation Studies in Pediatric Patients

Thiopurines such as thioguanine (TG), mercaptopurine (MP) and its prodrug azathioprine (AZA) are key antileukemic and immunosuppressive drugs in the treatment of several pediatric diseases such as acute lymphoblastic leukemia (ALL) and inflammatory bowel disease (IBD): their therapeutic action is affected by the enzyme thiopurine-S-methyltransferase (TPMT) whose encoding gene is polymorphic and whose enzymatic activity is also trans -regulated by the intronic single nucleotide polymorphism (SNP) rs2413739 (T>C) in the PACSIN2 gene.This study was aimed at validating the impact of PACSIN2 rs2413739 on thiopurine pharmacokinetic and pharmacodynamic parameters in two Italian pediatric cohorts: the first cohort was multicentric, consisted of 297 pediatric patients newly diagnosed with ALL (median (IQ) age: 4.8 (3.0-9.2) years; male: 54.9%) treated according to the AIEOP-BFM ALL 2009 protocol; the second consisted of 119 pediatric IBD patients (median age (interquartile range (IQ)): 15.1 (12.3-16.9) years; male: 52.1%) treated continuously with daily weight-based AZA therapy for at least three months before enrollment at the Gastroenterology Unit of the Pediatric Hospital IRCCS “Burlo Garofolo” in Trieste. Moreover, the role of rs2413739 polymorphism on TPMT and PACSIN2 protein expression was evaluated in peripheral blood mononuclear cells (PBMC) of adult healthy donors.The presence of the PACSIN2 rs2413739 T allele significantly reduced the TPMT activity only in the ALL cohort (p=0.026, linear mixed-effect model, multivariate analysis considering the TPMT SNP rs1142345 and rs1800460), without affecting MP metabolites levels in patients' erythrocytes: the PACSIN2 rs2413739 genetic effect on TPMT activity was particularly evident within TPMT heterozygotes (linear mixed-effect model, p=0.041). Interestingly, TPMT enzymatic function was significantly higher in ALL patients undergoing a long-term thiopurine-based therapy compared to IBD patients (p=0.032, linear mixed-effect model). In IBD patients, treatment response to AZA was significantly affected by PACSIN2 genotype: AZA effectiveness was reduced in patients carrying the T allele of the SNP rs2413739 (linear mixed effects, p=0.018; genotyping results: CC in 19, CT in 29 and TT in 20 patients): indeed, a clinically active disease was observed in ~40% of TT patients, in 30% of those with the CT genotype and in 20% of the CC subjects. For ALL patients, clinical data are still under collection and are not available at the time of preparation of the abstract.To evaluate the role of PACSIN2 SNP rs2413739 on TPMT and PACSIN2 protein expression, 20 adult healthy donors were genotyped for the SNP of interest, and Western-blot analysis against human TPMT and human PACSIN2 were performed on their PBMCs lysates. No significant contribution of the polymorphism was found on TPMT and PACSIN2 protein expression in this small population. In contrast, a significant direct correlation between the TPMT and PACSIN2 levels was observed (linear mixed effect, p = 0.045), suggesting a putative coordination in their protein expression in PBMCs.These results support the role of PACSIN2 polymorphism on TPMT activity, although this effect may be tissue-specific or dependent on the patients' clinical condition. DisclosuresNo relevant conflicts of interest to declare.

A Crohn's Disease-associated IL2RA Enhancer Variant Determines the Balance of T Cell Immunity by Regulating Responsiveness to IL-2 Signalling.

Background and AimsDifferential responsiveness to interleukin [IL]-2 between effector CD4+ T cells [Teff] and regulatory T cells [Treg] is a fundamental mechanism of immunoregulation. The single nucleotide polymorphism [SNP] rs61839660, located within IL2RA [CD25], has been associated with the development of Crohn’s disease [CD]. We sought to identify the T cell immune phenotype of IBD patients who carry this SNP.MethodsTeff and Treg were isolated from individuals homozygous [TT], heterozygous [CT], or wild-type [CC] for the minor allele at rs61839660, and used for phenotyping [flow cytometry, Cytometry Time Of Flight] functional assays or T cell receptor [TCR] sequencing. Phosphorylation of signal transducer and activator of transcription 5 [STAT5] was assessed in response to IL-2, IL-7, and in the presence of basiliximab, a monoclonal antibody directed against CD25. Teff pro-inflammatory cytokine expression levels were assessed by reverse transcription quantitative polymerase chain reaction after IL-2 and/or TCR stimulation.ResultsPresence of the minor T allele enhances CD25 expression, leading to increased STAT5 phosphorylation and pro-inflammatory cytokine transcript expression by Teff in response to IL-2 stimulation in vitro. Teff from TT individuals demonstrate a more activated gut homing phenotype. TCR sequencing analysis suggests that TT patients may have a reduced clonal capacity to mount an optimal regulatory T cell response.Conclusionsrs61839660 regulates the responsiveness of T cells to IL-2 signalling by modulating CD25 expression. As low-dose IL-2 is being trialled as a selective Treg modulator in CD, these findings highlight the potential for adverse effects in patients with this genotype.

HLA-DRB1, IRF5, and CD28 gene polymorphisms in Egyptian patients with rheumatoid arthritis: susceptibility and disease activity.

This study was established to assess the effects of IRF5 rs10488631 and CD28 rs1980422 single-nucleotide polymorphisms (SNPs) and HLA-DRB1 shared epitope (SE) allele on the prognosis and disease activity of rheumatoid arthritis (RA) patients. A total of 150 RA patients and 150 healthy controls were genotyped for the selected SNPs by real-time PCR. HLA-DRB1 SE was determined using LAB Type SSO Class II DRB1 typing. Our results suggest that HLA-DRB1, CD28, and IRF5 significantly discriminated (p < 0.001) RA patients and healthy controls (OR of single HLA-DRB1 SE allele = 2.431, CI = 1.467-4.027, OR of two SE alleles = 11.152, CI = 2.479-50.159), (OR of CD28 risk allele C = 2.794, 95% CI = 1.973-3.956) and (OR of IRF5 risk allele C = 4.925, CI = 3.26-7.439). Rheumatoid factor (RF) seropositivity was associated with HLA-DRB1 SE (p < 0.001) and IRF5 risk allele (p < 0.001). ACPA was significantly associated only with IRF5 risk allele (p < 0.001). A better response to methotrexate therapy was found in HLA-DRB1 SE non-carriers, and CD28 TT patients. This study demonstrated associations of HLA-DRB1 SE, CD28, and IRF5 with the risk of RA. HLA-DRB1 SE and CD28 rs1980422 can be used as predictors of methotrexate therapy response.

Association between interleukin 28B polymorphism and sustained virological response to sofosbuvir plus daclatasvir in chronic hepatitis C genotype 4 Egyptian patients

Sofosbuvir has been approved as the first nonstructural protein 5Bpolymerase inhibitor with pan-genotypic activity against the hepatitis C (HCV) virus. Daclatasvir is a first-in-class hepatitis C virus nonstructural protein 5A replication complex inhibitor. We aimed to evaluate the usefulness of the reference single nucleotide polymorphism (rs12979860) interleukin 28B (CC genotype) for predicting sustained virological response to sofosbuvir plus daclatasvir in Egyptian patients infected with HCV-4. Samples were collected at week zero. One hundred and thirty-one patients who reached the end of treatment (at week 12) were divided into three groups, according to their interleukin 28B genotype: Group A included 31 patients (CC genotype), group B included 79 patients (CT genotype) and group C had 21 patients (TT genotype). All patients received treatment for 3months in the form of sofosbuvir plus daclatasvir with ribavirin (in case of cirrhotic patients) or without ribavirin (in case of non-cirrhotic patients). Sustained virological response rate was significantly higher in patients with IL28B (CC genotype) vs. (non-CC genotype) (100 vs.88%) (p<0.0001).These patients also showed lower rates of post-treatment relapse and non-response, compared with the CT and TT patients (0% vs. (7.59% and 28.5%, respectively) (p<0.0001). Also, patients with CC genotype showed higher sustained virological response than non-CC genotypes on both cirrhotic (100% vs. 68.75%) and non-cirrhotic patients (100% vs. 91.66%) (p≤0.0001). Our results suggest that IL28B genotype contributes to the prediction of response to sofosbuvir plus daclatasvir.