Response and survival of metastatic melanoma patients treated with immune checkpoint inhibition for recurrent disease on adjuvant dendritic cell vaccination

Vaccination with autologous dendritic cells (DC) loaded ex vivo with melanoma-associated antigens is currently being tested as an adjuvant treatment modality for resected locoregional metastatic (stage III) melanoma. Based on its mechanism of action, DC vaccination might potentiate the clinical efficacy of concurrent or sequential immune checkpoint inhibition (ICI). The purpose of this study was to determine the efficacy of ICI administered following recurrent disease during, or after, adjuvant DC vaccination. To this end, we retrospectively analyzed clinical responses of 51 melanoma patients with either irresectable stage III or stage IV disease treated with first- or second-line ICI following recurrence on adjuvant DC vaccination. Patients were analyzed according to the form of ICI administered: PD-1 inhibition monotherapy (nivolumab or pembrolizumab), ipilimumab monotherapy or combined treatment with ipilimumab and nivolumab. Treatment with first- or second-line PD-1 inhibition monotherapy after recurrence on adjuvant DC vaccination resulted in a response rate of 52%. In patients treated with ipilimumab monotherapy and ipilimumab-nivolumab response rates were 35% and 75%, respectively. In conclusion, ICI is effective in melanoma patients with recurrent disease on adjuvant DC vaccination

Identifying Host Genetic Risk Factors in the Context of Public Health Surveillance for Invasive Pneumococcal Disease

Host genetic factors that modify risk of pneumococcal disease may help target future public health interventions to individuals at highest risk of disease. We linked data from population-based surveillance for invasive pneumococcal disease (IPD) with state-based newborn dried bloodspot repositories to identify biological samples from individuals who developed invasive pneumococcal disease. Genomic DNA was extracted from 366 case and 732 anonymous control samples. TagSNPs were selected in 34 candidate genes thought to be associated with host response to invasive pneumococcal disease, and a total of 326 variants were successfully genotyped. Among 543 European Americans (EA) (182 cases and 361 controls), and 166 African Americans (AA) (53 cases and 113 controls), common variants in surfactant protein D (SFTPD) are consistently underrepresented in IPD. SFTPD variants with the strongest association for IPD are intronic rs17886286 (allelic OR 0.45, 95% confidence interval (CI) [0.25, 0.82], with p = 0.007) in EA and 5′ flanking rs12219080 (allelic OR 0.32, 95%CI [0.13, 0.78], with p = 0.009) in AA. Variants in CD46 and IL1R1 are also associated with IPD in both EA and AA, but with effects in different directions; FAS, IL1B, IL4, IL10, IL12B, SFTPA1, SFTPB, and PTAFR variants are associated (p≤0.05) with IPD in EA or AA. We conclude that variants in SFTPD may protect against IPD in EA and AA and genetic variation in other host response pathways may also contribute to risk of IPD. While our associations are not corrected for multiple comparisons and therefore must be replicated in additional cohorts, this pilot study underscores the feasibility of integrating public health surveillance with existing, prospectively collected, newborn dried blood spot repositories to identify host genetic factors associated with infectious diseases

Adjuvant dendritic cell vaccination induces tumor-specific immune responses in the majority of stage III melanoma patients.

Purpose To determine the effectiveness of adjuvant dendritic cell (DC) vaccination to induce tumor-specific immunological responses in stage III melanoma patients.Experimental design Retrospective analysis of stage III melanoma patients, vaccinated with autologous monocyte-derived DC loaded with tumor-associated antigens (TAA) gp100 and tyrosinase after radical lymph node dissection. Skin-test infiltrating lymphocytes (SKILs) obtained from delayed-type hypersensitivity skin-test biopsies were analyzed for the presence of TAA-specific CD8(+) T cells by tetrameric MHC-peptide complexes and by functional TAA-specific T cell assays, defined by peptide-recognition (T2 cells) and/or tumor-recognition (BLM and/or MEL624) with specific production of Th1 cytokines and no Th2 cytokines.Results Ninety-seven patients were analyzed: 21 with stage IIIA, 34 with stage IIIB, and 42 had stage IIIC disease. Tetramer-positive CD8(+) T cells were present in 68 patients (70%), and 24 of them showed a response against all 3 epitopes tested (gp100:154-162, gp100:280-288, and tyrosinase:369-377) at any point during vaccinations. A functional T cell response was found in 62 patients (64%). Rates of peptide-recognition of gp100:154-162, gp100:280-288, and tyrosinase:369-377 were 40%, 29%, and 45%, respectively. Median recurrence-free survival and distant metastasis-free survival of the whole study population were 23.0 mo and 36.8 mo, respectively.Conclusions DC vaccination induces a functional TAA-specific T cell response in the majority of stage III melanoma patients, indicating it is more effective in stage III than in stage IV melanoma patients. Furthermore, performing multiple cycles of vaccinations enhances the chance of a broader immune response

Thirty-minute compared to standardised office blood pressure measurement in general practice.

Item does not contain fulltextBackground Although blood pressure measurement is one of the most frequently performed measurements in clinical practice, there are concerns about its reliability. Serial, automated oscillometric blood pressure measurement has the potential to reduce measurement bias and white-coat effect' Aim To study agreement of 30-minute office blood pressure measurement (OBPM) with standardised OBPM, and to compare repeatability Design and setting Method comparison study in two general practices in the Netherlands Method Thirty-minute and standardised OBPM was carried out with the same, validated device in 83 adult patients, and the procedure was repeated after 2 weeks. During 30-minute OBPM, blood pressure was measured automatically every 3 minutes, with the patient in a sitting position, alone in a quiet room. Agreement between 30-minute and standardised OBPM was assessed by Bland-Altman analysis. Repeatability of the blood pressure measurement methods after 2 weeks was expressed as the mean difference in combination with the standard deviation of difference (SDD) Results Mean 30-minute OBPM readings were 7.6/2.5 mmHg (95% confidence interval [CI] = 6.1 to 9.1/1.5 to 3.4 mmHg) lower than standardised OBPM readings. The mean difference and SDD between repeated 30-minute OBPMs (mean difference = 3/1 mmHg, 95% CI = 1 to 5/0 to 2 mmHg; SDD 9.5/5.3 mmHg) were lower than those of standardised OBPMs (mean difference = 6/2 mmHg, 95% CI = 4 to 8/1 to 4 mmHg; SDD 10.9/6.3 mmHg). Conclusion Thirty-minute OBPM resulted in lower readings than standardised OBPM and had a better repeatability. These results suggest that 30-minute OBPM better reflects the patient's true blood pressure than standardised OBPM does.01 september 201

Thirty-minute compared to standardised office blood pressure measurement in general practice

Background: Although blood pressure measurement is one of themost frequently performed measurements in clinical practice, there are concerns about its reliability. Serial, automated oscillometric blood pressure measurement has the potential to reduce measurement bias and 'white-coat effect'. Aim: To study agreement of 30-minute office blood pressure measurement (OBPM) with standardised OBPM, and to compare repeatability. Design and setting: Method comparison study in two general practices in the Netherlands. Method: Thirty-minute and standardised OBPM was carried out with the same, validated device in 83 adult patients, and the procedure was repeated after 2 weeks. During 30-minute OBPM, blood pressure was measured automatically every 3minutes, with the patient in a sitting position, alone in a quiet room. Agreement between 30-minute and standardised OBPM was assessed by Bland-Altman analysis. Repeatability of the blood pressure measurement methods after 2 weeks was expressed as the mean difference in combination with the standard deviation of difference (SDD). Results: Mean 30-minute OBPM readings were 7.6/2.5 mmHg (95% confidence interval [CI] = 6.1 to 9.1/1.5 to 3.4 mmHg) lower than standardised OBPM readings. The mean difference and SDD between repeated 30-minute OBPMs (mean difference = 3/1 mmHg, 95%CI = 1 to 5/0 to 2 mmHg; SDD 9.5/5.3 mmHg) were lower than those of standardised OBPMs (mean difference = 6/2 mmHg, 95%CI = 4 to 8/1 to 4 mmHg; SDD 10.9/6.3 mmHg). Conclusion: Thirty-minute OBPM resulted in lower readings than standardised OBPM and had a better repeatability. These results suggest that 30-minute OBPM better reflects the patient's true blood pressure than standardised OBPM does

Immune-related Adverse Events of Dendritic Cell Vaccination Correlate With Immunologic and Clinical Outcome in Stage III and IV Melanoma Patients

Contains fulltext : 172741.pdf (Publisher’s version ) (Open Access)The purpose of this study was to determine the toxicity profile of dendritic cell (DC) vaccination in stage III and IV melanoma patients, and to evaluate whether there is a correlation between side effects and immunologic and clinical outcome. This is a retrospective analysis of 82 stage III and 137 stage IV melanoma patients, vaccinated with monocyte-derived or naturally circulating autologous DCs loaded with tumor-associated antigens gp100 and tyrosinase. Median follow-up time was 54.3 months in stage III patients and 12.9 months in stage IV patients. Treatment-related adverse events occurred in 84% of patients; grade 3 toxicity was present in 3% of patients. Most common adverse events were flu-like symptoms (67%) and injection site reactions (50%), and both correlated with the presence of tetramer-positive CD8 T cells (both P<0.001). In stage III melanoma patients experiencing flu-like symptoms, median overall survival (OS) was not reached versus 32.3 months in patients without flu-like symptoms (P=0.009); median OS in patients with an injection site reaction was not reached versus 53.7 months in patients without an injection site reaction (P<0.05). In stage IV melanoma patients (primary uveal and mucosal melanomas excluded), median OS in patients with or without flu-like symptoms was 13.1 versus 8.9 months, respectively (P=0.03); median OS in patients with an injection site reaction was 15.7 months versus 9.8 months in patients without an injection site reaction (P=0.003). In conclusion, DC vaccination is safe and tolerable and the occurrence of the immune-related side effects, such as flu-like symptoms and injection site reactions, correlates with immunologic and clinical outcome