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

Genetic aspects and molecular testing in prostate cancer: a report from a Dutch multidisciplinary consensus meeting

Background: Germline and tumour genetic testing in prostate cancer (PCa) is becoming more broadly accepted, but testing indications and clinical consequences for carriers in each disease stage are not yet well defined.Objective: To determine the consensus of a Dutch multidisciplinary expert panel on the indication and application of germline and tumour genetic testing in PCa.Design, setting, and participants: The panel consisted of 39 specialists involved in PCa management. We used a modified Delphi method consisting of two voting rounds and a virtual consensus meeting.Outcome measurements and statistical analysis: Consensus was reached if >75% of the panellists chose the same option. Appropriateness was assessed by the RAND/UCLA appropriateness method.Results and limitations: Of the multiple-choice questions, 44% reached consensus. For men without PCa having a relevant family history (familial PCa/BRCA-related hered-itary cancer), follow-up by prostate-specific antigen was considered appropriate. For patients with low-risk localised PCa and a family history of PCa, active surveil-lance was considered appropriate, except in case of the patient being a BRCA2 germ -line pathogenic variant carrier. Germline and tumour genetic testing should not be done for nonmetastatic hormone-sensitive PCa in the absence of a relevant family history of cancer. Tumour genetic testing was deemed most appropriate for the identification of actionable variants, with uncertainty for germline testing. For tumour genetic testing in metastatic castration-resistant PCa, consensus was not reached for the timing and panel composition. The principal limitations are as fol-lows: (1) a number of topics discussed lack scientific evidence, and therefore the recommendations are partly opinion based, and (2) there was a small number of experts per discipline.Conclusions: The outcomes of this Dutch consensus meeting may provide further guidance on genetic counselling and molecular testing related to PCa.Patient summary: A group of Dutch specialists discussed the use of germline and tumour genetic testing in prostate cancer (PCa) patients, indication of these tests (which patients and when), and impact of these tests on the management and treatment of PCa.(c) 2022 The Author(s). Published by Elsevier B.V. on behalf of European Association of Urology. This is an open access article under the CC BY license (http://creativecommons. org/licenses/by/4.0/).Experimentele farmacotherapi

Generalizability of the Results of Efficacy Trials in First-Episode Schizophrenia: Comparing Outcome and Study Discontinuation of Groups of Participants in the Optimization of Treatment and Management of Schizophrenia in Europe (OPTiMiSE) Trial

Objective: In the majority of randomized controlled trials (RCTs) conducted in schizophrenia populations, patients suffering from a substance use disorder (SUD) or suicidality are excluded. Excluding these patients from RCTs might impact the generalizability of results. The aim of this study is to determine whether excluding patients with suicidality and/or SUD impacts RCT results on symptomatic remission, premature study discontinuation, symptom severity, and social functioning. Methods: Across Europe and Israel, 481 patients with first-episode schizophrenia, schizophreniform disorder, or schizoaffective disorder, based on DSM-IV criteria, were recruited between May 26, 2011, and May 15, 2016, for the Optimization of Treatment and Management of Schizophrenia in Europe (OPTiMiSE) trial. Baseline characteristics and follow-up assessments were compared between patients with versus without baseline SUD and/or suicidality. Results: A total of 446 patients met eligibility criteria for the OPTiMiSE trial and initiated amisulpride treatment, of whom 404 (91%) had data available on suicidality, SUD, duration of illness, and CDS score. Of the 360 eligible patients with baseline data on suicidality and SUD, 106 patients had comorbid suicidality and/or SUD while 254 patients had neither of these comorbidities. No significant differences in the likelihood to achieve symptomatic remission or to prematurely discontinue the study were found when comparing comorbid versus non-comorbid patients (P= .27). There were no significant differences in symptom severity and social functioning between the groups. Comorbid patients had a higher level of depressive symptoms and more impaired social functioning compared to non-comorbid patients. Discussion: Excluding first-episode schizophrenia patients with comorbidities from clinical trials unlikely affects key outcome measures. It is recommended to include patients with comorbidities in clinical trials while carefully monitoring suicidality and implementing safety plans to gain insight into efficacy and safety of treatment in this substantial patient population

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