CD4(+) T cells can "help" or "license" conventional type 1 dendritic cells (cDC1s) to induce CD8(+) cytotoxic T lymphocyte (CTL) anticancer responses, as proven in mouse models. We recently... Show moreCD4(+) T cells can "help" or "license" conventional type 1 dendritic cells (cDC1s) to induce CD8(+) cytotoxic T lymphocyte (CTL) anticancer responses, as proven in mouse models. We recently identified cDC1s with a transcriptomic imprint of CD4(+) T-cell help, specifically in T-cell-infiltrated human cancers, and these cells were associated with a good prognosis and response to PD-1-targeting immunotherapy. Here, we delineate the mechanism of cDC1 licensing by CD4(+) T cells in humans. Activated CD4(+) T cells produce IFN beta via the STING pathway, which promotes MHC-I antigen (cross-)presentation by cDC1s and thereby improves their ability to induce CTL anticancer responses. In cooperation with CD40 ligand (L), IFN beta also optimizes the costimulatory and other functions of cDC1s required for CTL response induction. IFN-I-producing CD4(+) T cells are present in diverse T-cell-infiltrated cancers and likely deliver "help" signals to CTLs locally, according to their transcriptomic profile and colocalization with "helped/licensed" cDCs and tumor-reactive CD8(+) T cells. In agreement with this scenario, the presence of IFN-I-producing CD4(+) T cells in the TME is associated with overall survival and the response to PD-1 checkpoint blockade in cancer patients. Show less
Jongh, C. de; Triemstra, L.; Veen, A. van der; Brosens, L.A.; Nieuwenhuijzen, G.A.; Stoot, J.H.; ... ; Group, L.S.G.L.S. 2023
Background: Quality of gastric cancer surgery is crucial for favorable prognosis. Generally, prospective trials lack quality control measures. This study assessed surgical quality and a novel D2... Show moreBackground: Quality of gastric cancer surgery is crucial for favorable prognosis. Generally, prospective trials lack quality control measures. This study assessed surgical quality and a novel D2-lymphadenectomy photo-scoring in the LOGICA-trial.Methods: The multicenter LOGICA-trial randomized laparoscopic versus open total/distal D2-gastrectomy for resectable gastric cancer (cT1-4aN0-3M0) in 10 Dutch hospitals. During the trial, two reviewers prospectively analyzed intraoperative photographs of dissected nodal stations for quality control, and provided centers weekly feedback on their D2-lymphadenectomy, as continuous quality-enhancing incentive. After the trial, these photographs were reanalyzed to develop a photo-scoring for future trials, rating the D2-lymphadenectomy dissection quality (optimal-good-suboptimal-unevaluable). Interobserver variability was calculated (weighted kappa). Regression analyses related the photo-scoring to nodal yield, recurrence and 5-years survival.Results: Between 2015 and 2018, 212 patients underwent total/distal D2-gastrectomy (n = 122/n = 90), and 158 (75%) received neoadjuvant chemotherapy. R0-resection rate was 95%. Rate of =15 retrieved lymph nodes was 95%. Moderate agreement was obtained in stations 8 + 9 (? = 0.522), 11p/11d (? = 0.446) and 12a (? = 0.441). Consensus was reached for discordant cases (30%). Stations 8 + 9, 11p/11d and 12a were rated 'optimal' in 76%, 63% and 68%. Laparoscopic photographs could be rated better than open (2% versus 12% 'unevaluable'; 73% versus 50% 'optimal'; p = 0.042). The photo-scoring did not show associations with nodal yield (p = 0.214), recurrence (p = 0.406) and survival (p = 0.988).Conclusions: High radicality and nodal yield demonstrated good quality of D2-gastrectomy. The prospective quality control probably contributed to this. The photo-scoring did not show good performance, but can be refined. Laparoscopic D2-gastrectomy was better suited for standardized surgical photo-evaluation than open surgery. Show less
Veen, A. van der; Ramaekers, M.; Marsman, M.; Brenkman, H.J.F.; Seesing, M.F.J.; Luyer, M.D.P.; ... ; LOGICA Study Grp 2023
Background Laparoscopic gastrectomy could reduce pain and opioid consumption, compared to open gastrectomy. However, it is difficult to judge the clinical relevance of this reduction, since these... Show moreBackground Laparoscopic gastrectomy could reduce pain and opioid consumption, compared to open gastrectomy. However, it is difficult to judge the clinical relevance of this reduction, since these outcomes are reported in few randomized trials and in limited detail.Methods This secondary analysis of a multicenter randomized trial compared laparoscopic versus open gastrectomy for resectable gastric adenocarcinoma (cT1-4aN0-3bM0). Postoperative pain was analyzed by opioid consumption in oral morphine equivalents (OME, mg/day) at postoperative day (POD) 1-5, WHO analgesic steps, and Numeric Rating Scales (NRS, 0-10) at POD 1-10 and discharge. Regression and mixed model analyses were performed, with and without correction for epidural analgesia.Results Between 2015 and 2018, 115 patients in the laparoscopic group and 110 in the open group underwent surgery. Some 16 patients (14%) in the laparoscopic group and 73 patients (66%) in the open group received epidural analgesia. At POD 1-3, mean opioid consumption was 131, 118, and 53 mg OME lower in the laparoscopic group, compared to the open group, respectively (all p < 0.001). After correcting for epidural analgesia, these differences remained significant at POD 1-2 (47 mg OME, p = 0.002 and 69 mg OME, p < 0.001, respectively). At discharge, 27% of patients in the laparoscopic group and 43% patients in the open group used oral opioids (p = 0.006). Mean highest daily pain scores were between 2 and 4 at all PODs, < 2 at discharge, and did not relevantly differ between treatment arms.Conclusion In this multicenter randomized trial, postoperative pain was comparable between laparoscopic and open gastrectomy. After laparoscopic gastrectomy, this was generally achieved without epidural analgesia and with fewer opioids. Show less
Veen, A. van der; Meulen, M.P. van der; Seesing, M.F.J.; Brenkman, H.J.F.; Haverkamp, L.; Luyer, M.D.P.; ... ; Laparoscopic Vs Open Gastrectomy G 2022
IMPORTANCE Laparoscopic gastrectomy is rapidly being adopted worldwide as an alternative to open gastrectomy to treat gastric cancer. However, laparoscopic gastrectomy might be more expensive as a... Show moreIMPORTANCE Laparoscopic gastrectomy is rapidly being adopted worldwide as an alternative to open gastrectomy to treat gastric cancer. However, laparoscopic gastrectomy might be more expensive as a result of longer operating times and more expensive surgical materials. To date, the cost-effectiveness of both procedures has not been prospectively evaluated in a randomized clinical trial. OBJECTIVE To evaluate the cost-effectiveness of laparoscopic compared with open gastrectomy. DESIGN, SETTING, AND PARTICIPANTS In this multicenter randomized clinical trial of patients undergoing total or distal gastrectomy in 10 Dutch tertiary referral centers, cost-effectiveness data were collected alongside a multicenter randomized clinical trial on laparoscopic vs open gastrectomy for resectable gastric adenocarcinoma (cT1-4aN0-3bM0). A modified societal perspective and 1-year time horizon were used. Costs were calculated on the individual patient level by using hospital registry data and medical consumption and productivity loss questionnaires. The unit costs of laparoscopic and open gastrectomy were calculated bottom-up. Quality-adjusted life-years (QALYs) were calculated with the EuroQol 5-dimension questionnaire, in which a value of 0 indicates death and 1 indicates perfect health. Missing questionnaire data were imputed with multiple imputation. Bootstrapping was performed to estimate the uncertainty surrounding the cost-effectiveness. The study was conducted from March 17, 2015, to August 20, 2018. Data analyses were performed between September 1, 2020, and November 17, 2021. INTERVENTIONS Laparoscopic vs open gastrectomy. MAIN OUTCOMES AND MEASURES Evaluations in this cost-effectiveness analysis included total costs and QALYs. RESULTS Between 2015 and 2018, 227 patients were included. Mean (SD) age was 67.5 (11.7) years, and 140 were male (61.7%). Unit costs for initial surgery were calculated to be euro8124 (US $8087) for laparoscopic total gastrectomy, euro7353 (US $7320) for laparoscopic distal gastrectomy, euro6584 (US $6554) for open total gastrectomy, and euro5893 (US $5866) for open distal gastrectomy. Mean total costs after 1-year follow-up were euro26 084 (US $25 965) in the laparoscopic group and euro25 332 (US $25 216) in the open group (difference, euro752 [US $749; 3.0%]). Mean (SD) QALY contributions during 1 year were 0.665 (0.298) in the laparoscopic group and 0.686 (0.288) in the open group (difference, -0.021). Bootstrapping showed that these differences between treatment groups were relatively small compared with the uncertainty of the analysis. CONCLUSIONS AND RELEVANCE Although the laparoscopic gastrectomy itself was more expensive, after 1-year follow-up, results suggest that differences in both total costs and effectiveness were limited between laparoscopic and open gastrectomy. These results support centers' choosing, based on their own preference, whether to (de)implement laparoscopic gastrectomy as an alternative to open gastrectomy. Show less
Background: Patients with inborn errors of immunity (IEI) are at increased risk of severe coronavirus disease-2019 (COVID-19). Effective vaccination against COVID-19 is therefore of great... Show moreBackground: Patients with inborn errors of immunity (IEI) are at increased risk of severe coronavirus disease-2019 (COVID-19). Effective vaccination against COVID-19 is therefore of great importance in this group, but little is known about the immunogenicity of COVID-19 vaccines in these patients.Objectives: We sought to study humoral and cellular immune responses after mRNA-1273 COVID-19 vaccination in adult patients with IEI.Methods: In a prospective, controlled, multicenter study, 505 patients with IEI (common variable immunodeficiency [CVID], isolated or undefined antibody deficiencies, X-linked agammaglobulinemia, combined B- and T-cell immunodeficiency, phagocyte defects) and 192 controls were included. All participants received 2 doses of the mRNA-1273 COVID-19 vaccine. Levels of severe acute respiratory syndrome coronavirus-2-specific binding antibodies, neutralizing antibodies, and T-cell responses were assessed at baseline, 28 days after first vaccination, and 28 days after second vaccination.Results: Seroconversion rates in patients with clinically mild antibody deficiencies and phagocyte defects were similar to those in healthy controls, but seroconversion rates in patients with more severe IEI, such as CVID and combined B- and T-cell immunodeficiency, were lower. Binding antibody titers correlated well to the presence of neutralizing antibodies. T-cell responses were comparable to those in controls in all IEI cohorts, with the exception of patients with CVID. The presence of noninfectious complications and the use of immunosuppressive drugs in patients with CVID were negatively correlated with the antibody response.Conclusions: COVID-19 vaccination with mRNA-1273 was immunogenic in mild antibody deficiencies and phagocyte defects and in most patients with combined B- and T-cell immunodeficiency and CVID. Lowest response was detected in patients with X-linked agammaglobulinemia and in patients with CVID with noninfectious complications. The assessment of longevity of immune responses in these vulnerable patient groups will guide decision making for additional vaccinations. Show less
Beekman, K.M.; Veldhuis-Vlug, A.G.; Veen, A. van der; Heijer, M. den; Maas, M.; Kerckhofs, G.; ... ; Bravenboer, N. 2019
Introduction: The aim of this study is to provide insight in accuracy of diagnosing, current treatment and survival in patients with resectable esophageal and gastric neuroendocrine- and mixed... Show moreIntroduction: The aim of this study is to provide insight in accuracy of diagnosing, current treatment and survival in patients with resectable esophageal and gastric neuroendocrine- and mixed adenoneuroendocrine carcinomas (NEC, MANEC).Methods: All patients with esophageal or gastric (MA)NEC, who underwent surgical resection between 2006 and 2016, were identified from the Dutch national registry for histo-and cytopathology (PALGA). Patients with a neuroendocrine tumor lower than grade 3 were excluded. Data on patients, treatment and outcomes were retrieved from the patient records. Diagnosis by endoscopic biopsy was compared with diagnosis by resection specimen. Kaplan Meier survival analysis was performed.Results: A total of 49 patients were identified in 25 hospitals, including 21 patients with esophageal (MA)NEC and 26 patients with gastric (MA)NEC on resection specimen. Biopsy diagnosis of (MA)NEC was correct in 23/27 patients. However, 20/47 patients with definitive diagnosis of (MA)NEC, were misdiagnosed on biopsy. Neoadjuvant therapy was administered in 13 (62%) esophageal (MA)NEC5 and 12 (46%) gastric (MA)NECs. Survival curves were similar with and without neoadjuvant therapy. One (4.8%) esophageal (MA)NEC and 4 (15%) gastric (MA)NEC5 died within 90 days postoperatively. For esophageal (MA)NEC the median overall survival (OS) after surgery was 37 months and 1-, 3- and 5-year OS were 71%, 50% and 35%, respectively. For gastric (MA)NEC, the median OS was 23 months and 1-, 3- and 5-year OS were 62%, 50% and 39%, respectively.Conclusion: Localized esophageal and gastric (MA)NEC are often misdiagnosed on endoscopic biopsies. After resection, long-term survival was achieved in respectively 35% and 39% of patients. (C) 2018 Published by Elsevier Ltd. Show less
Brinkman, S.; Abu-Hanna, A.; Veen, A. van der; Jonge, E. de; Keizer, N.F. de 2012
