Clinical Germline Testing Results of Men With Prostate Cancer: Patient-Level Factors and Implications of NCCN Guideline Expansion.

Germline likely pathogenic or pathogenic variants (PVs) have been identified in up to 17% of men with prostate cancer (PC) and may drive disease severity or be targetable by novel therapies. National Comprehensive Cancer Network (NCCN) guidelines encouraging germline testing in metastatic PC were recently expanded to include all men with high-risk, very high-risk, or regional PC. Our aim was to assess the impact of expanded NCCN guidelines on the detection rate of germline PVs and to determine patient-level factors associated with a PV germline testing result. PATIENTS AND METHODS: Men with PC underwent multigene germline genetic testing for PVs from June 2016 to December 2018, and trends were compared. The association of patient-level factors with a PV germline testing result, where ≥ 1 PV was identified, was assessed using analysis of variance and univariate logistic regression. Sensitivity analyses were limited to clinically actionable variants and those associated with disease severity or progression (BRCA1/2 and ATM). RESULTS: Of 408 men undergoing germline testing, 42 (10.3%) men had PVs and 366 (89.7%) men did not have PVs identified. The proportion of men identified with a germline PV remained stable following testing criteria expansion (9.4% v 10.6%, P = .73). No patient-level factors were significantly associated with increased odds of a PV germline testing result, including age at diagnosis, race, pretreatment prostate-specific antigen, Gleason grade group, NCCN risk group, and family history of cancer (breast and/or ovarian, prostate, or any cancer). CONCLUSION: This study demonstrated a stable PV detection rate in men with PC using expanded criteria aligned to the updated NCCN testing guidelines. However, we did not find strong evidence to suggest that patient-level factors are associated with PV germline testing results. These findings support the recent expansion of NCCN germline testing guidelines in PC.

Short-term transcutaneous non-invasive vagus nerve stimulation may reduce disease activity and pro-inflammatory cytokines in rheumatoid arthritis: results of a pilot study.

Objective: Rheumatoid arthritis (RA) is a chronic, autoimmune, inflammatory disease. Studies suggest that pro-inflammatory cytokines may be attenuated by the vagus nerve through the cholinergic anti-inflammatory pathway. We aimed to evaluate the anti-inflammatory effects of short-term transcutaneous non-invasive vagus nerve stimulation (n-VNS) applied to the cervical vagus nerve in patients with RA. Method: We conducted a single-centre, open-label, preliminary proof-of-concept study of n-VNS in two cohorts of participants with RA: one with high disease activity (n = 16) and one with low disease activity (n = 20). Disease Activity Score based on 28-joint count-C-reactive protein (DAS28-CRP), cardiac vagal tone, and pro-inflammatory cytokines were measured at baseline and after 1 and 4 days of n-VNS. Results: In the high disease activity group, n-VNS resulted in reductions in DAS28-CRP (4.1 to 3.8, p = 0.02), CRP (8.2 to 6 mg/mL, p = 0.01), and interferon-γ (29.8 to 22.5 pg/mL, p = 0.02). In the low disease activity group, there was no effect on DAS28-CRP, and n-VNS was associated with a decrease in cardiac vagal tone (p = 0.03) and a reduction in interleukin-10 (0.8 to 0.6 pg/mL, p = 0.02). Participants with high disease activity had lower baseline cardiac vagal tone than those with low disease activity (3.6 ± 2 vs 4.9 ± 3 linear vagal scale, p = 0.03). Cardiac vagal tone was negatively associated with DAS28-CRP (r = -0.37, p = 0.03). Overall, n-VNS was well tolerated. Conclusion: This study provides preliminary support for an anti-inflammatory effect of n-VNS in patients with RA. These findings warrant further investigation in larger placebo-controlled trials.

Transcutaneous cervical vagal nerve stimulation modulates cardiac vagal tone and tumor necrosis factor-alpha.

The vagus nerve is a central component of cholinergic anti-inflammatory pathways. We sought to evaluate the effect of bilateral transcutaneous cervical vagal nerve stimulation (t-VNS) on validated parameters of autonomic tone and cytokines in 20 healthy subjects. 24 hours after t-VNS, there was an increase in cardiac vagal tone and a reduction in tumor necrosis factor-α in comparison to baseline. No change was seen in blood pressure, cardiac sympathetic index or other cytokines. These preliminary data suggest that t-VNS exerts an autonomic and a subtle antitumor necrosis factor-α effect, which warrants further evaluation in larger controlled studies.

[Imatinib--a possible therapeutic option for cervical carcinoma: results of a preclinical phase I study]. / Imatinib - eine mogliche Therapieoption beim Zervixkarzinom: Ergebnisse einer praklinischen Phase-I-Studie.

BACKGROUND: In the last few years, the therapy of cervical carcinoma has progressed substantially due to the use of simultaneous platinum- containing radiochemotherapy. However, there are no data which evaluate an individualized treatment adapted to tumor biology, in spite of the fact that patients show remarkably different responses to chemotherapy. Therefore this preclinical phase I study aims at finding therapeutic alternatives to the current cytostatic drugs to treat cervical carcinoma. MATERIAL AND METHODS: In a tumor chemosensitivity assay, 8 drugs were tested on freshly isolated tumor cells of 16 patients [carbo- and cisplatin, topotecan, paclitaxel as well as the 2 tyrosine kinase inhibitors imatinib (Glivec) and gefitinib (Iressa (R) ) and the 2 monoclonal antibodies cetuximab (Erbitux) and trastuzumab (Herceptin (R) )]. RESULTS: Overall the test was evaluable for 16 specimens (100%). Ten of 15 tumor samples (66.6%) were sensitive to imatinib. A sensitive therapeutic response could be demonstrated in all tested FIGO stages. An interindividual comparison could establish sensitivity to cetuximab in 12.5% of cases, to gefitinib in 6.25%, to trastuzumab in 6.6%, to cisplatin in 13.3%, to carboplatin in 7.6%, to paclitaxel in 93.8% and to topotecan in 25%. CONCLUSION: Imatinib seems to be an efficacious therapeutic option for patients with cervical carcinoma, independently of tumor subtype.

Beneficial effects of a soy-based dietary supplement on lipid levels and cardiovascular risk markers in type 2 diabetic subjects.

OBJECTIVE: Consumption of soy protein has recently been shown to improve the blood lipid levels in nondiabetic subjects. The purpose of this study was to evaluate if a dietary supplement of soy protein, isoflavones, and cotyledon fiber (Abalon) affects cardiovascular risk markers, blood glucose, and insulin levels in type 2 diabetic subjects. RESEARCH DESIGN AND METHODS: Twenty type 2 diabetic subjects participated in a crossover trial. They were randomized to double-blind supplementation for 6 weeks with Abalon (soy protein [50 g/day] with high levels of isoflavones [minimum 165 mg/day] and cotyledon fiber [20 g/day]) or placebo (casein [50 g/day] and cellulose [20 g/day]), separated by a 3-week wash-out period. RESULTS: The results are expressed as means +/- SD. The percentage mean treatment difference between Abalon and placebo demonstrated significantly lower mean values after Abalon for LDL cholesterol (10 +/- 15%, P < 0.05), LDL/UHDL ratio (12 +/- 18%, P < 0.05), apolipoprotein (apo) B100 (30 +/- 38%, P < 0.01), triglycerides (22 +/- 10%, P < 0.05), and homocysteine (14 +/- 21%, P < 0.01), whereas the total cholesterol value tended to be less significant but still lower (8 +/- 15%, P < 0.08). No change occurred in HDL cholesterol, apo B100/apo A1 ratio, plasminogen activator inhibitor 1, factor VIIc, von Willebrand factor, fibrinogen, lipoprotein(a), glucose, HbA1c, or 24-h blood pressure. CONCLUSIONS: These results indicate beneficial effects of dietary supplementation with Abalon on cardiovascular risk markers in type 2 diabetic subjects. This improvement is seen even in individuals with near-normal lipid values.