T-786C single nucleotide polymorphism of the endothelial nitric oxide synthase gene as a risk factor for endothelial dysfunction in polymyalgia rheumatica.

OBJECTIVES: We investigated the association of the T-786C single nucleotide polymorphism (SNP) of the endothelial nitric oxide synthase gene (NOS3), which is characterised by reduced expression of the enzyme in response to shear stress or interleukin-10 stimulation and significantly associated with coronary heart disease or rheumatoid arthritis, with the occurrence of isolated polymyalgia rheumatica. METHODS: A cohort of 78 patients who had presented at a rheumatological specialist practice in Heidelberg was tested for the T-786C SNP by means of restriction fragment length polymorphism analysis, and the result was compared with the data of a control cohort (n=2061) compiled from the genotyping of umbilical cord arteries from newborns. Patients were tested for an association with the genotype and their clinical characteristics obtained at the time of the initial presentation and during the first year of treatment. RESULTS: The T-786C SNP of the NOS3 gene was significantly associated with isolated PMR (p=0.0009; OR 2.475). The C-allele frequency in patients with PMR was higher than in patients with rheumatoid arthritis, who also showed a significant association with the T-786C SNP (PMR 0.481 vs. 0.422 RA). A significant association with clinical features of the patients could not be detected. CONCLUSIONS: The T-786C SNP of the NOS3 gene, which predisposes towards the development of endothelial dysfunction, is significantly associated with polymyalgia rheumatica manifesting itself without any clinically detectable vascular involvement.

The iTOP trial: Comparing immediate techniques of oncoplastic surgery with conventional breast surgery in women with breast cancer - A prospective, controlled, single-center study.

INTRODUCTION: Oncoplastic techniques allow resection of larger tumors, permitting breast conservation in cases otherwise requiring mastectomy. We sought to prospectively compare quality of life (QoL) in patients undergoing oncoplastic surgery as compared to conventional breast conservation (CBC) or mastectomy is lacking. METHODS: Patients diagnosed with BIRADS IV-VI lesion were eligible if resection of ≥10% of the breast volume was planned. Patients were allowed to decide whether they wanted to undergo CBC or oncoplastic breast conservation (OBC). Patients who underwent mastectomy and immediate breast reconstruction (IBR) were also included for comparison. The primary endpoint was breast self-esteem using the Breast Image Scale (BIS) at 12 months, secondary endpoints were perioperative morbidity and QoL using the BREAST-Q questionnaire. RESULTS: From 2011 to 2016, 205 patients were included in the study. 116 patients (56.6%) received CBC, 46 (22.4%) OBC and 43 (21%) MIBR. Women in the OBC group were more likely to have tumors ≥ 2 cm than those in the CBC group (34.7% vs. 17.5%, respectively). Women who underwent MIBR were more likely to have tumors > 5 cm than those in the CBC and OBC groups (23% vs 1% and 10%, respectively). The BIS and BREAST-Q improved in each group after 12 months but did not differ significantly between groups at any time point. Surgical complications (seroma, bleeding, infection, necrosis) were numerically more likely in the OBC and MIBR groups. CONCLUSION: OBC and the MIBR allow for resection of larger tumors with a similar quality of life as CBC.

Characterization of humoral immune responses against p16, p53, HPV16 E6 and HPV16 E7 in patients with HPV-associated cancers.

The cellular tumor suppressor p16 is strongly overexpressed in cervical cancers and precancers. We have previously demonstrated that infiltrating T lymphocytes reactive against p16 can be found in cervical cancer patients. Here, we analyzed whether p16 induces humoral immune responses. Sera of patients with cervical cancer, oropharyngeal cancer, colorectal cancer and autoimmune disease were included. A total of 919 sera were analyzed, including 486 matched sera from a cervical cancer case control study. p16 antibodies were analyzed in Western blot and a newly developed peptide ELISA covering the complete p16 protein. In addition, a Luminex-based multiplex assay was used for simultaneous detection of antibodies directed against p16, p53, HPV16 E6 and HPV16 E7. In all entities, only low p16 antibody reactivity was observed. Epitope mapping revealed 2 predominant epitope regions of the p16 protein. No significant difference in p16 antibody frequency (OR = 0.9; 95% CI = 0.6-1.3) and p53 antibody frequency (OR = 0.6; 95% CI = 0.3-1.2) was found between patients and healthy controls in the cervical cancer case control study. Antibodies against the HPV16 oncoproteins E6 and E7 were detected more frequently in cervical cancer patients when compared with healthy controls (E6 OR = 27.8; 95% CI = 11.1-69.7, E7 OR = 5.7; 95% CI = 2.9-11.1). In conclusion, despite the strong expression of p16 and the observed induction of cellular immune responses, antibody reactivity against p16 was observed only at very low levels independent of the disease background.

Immunogenicity, efficacy and adverse events of adalimumab in RA patients.

To assess the immunogenicity of adalimumab, a human anti-TNF-alpha mAb, we evaluated the formation of antibodies to adalimumab, efficacy and adverse events among 15 patients with highly active rheumatoid arthritis. Four patients were treated with adalimumab as monotherapy, and 11 patients with concomitant DMARDs. Disease activity was measured by DAS28. The antibodies were detected by ELISA. Thirteen (87%) patients withdrew from therapy within 45 weeks and overall 13 (87%) patients showed antibodies to adalimumab including 11 patients who withdrew from therapy. In four patients without concomitant DMARDs and in nine patients with concomitant DMARDs, we detected anti-adalimumab antibodies. Overall, five of seven patients with adverse drug reactions and all nine patients with lack of efficacy were associated with the formation of antibodies. Two antibody-positive patients developed an exantheme. The results indicate that adalimumab is, in spite of its fully human sequences, immunogenic and induces antibodies in a high rate of adalimumab-treated patients.