Chemoradiotherapy in gastric cancer

Verheij, M. [Promotor]Bartelink, G.M.M. [Promotor]Cats, A. [Copromotor

Germline DLST variants promote epigenetic modifications in pheochromocytoma-paraganglioma

Context: Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors in which altered central metabolism appears to be a major driver of tumorigenesis, and many PPGL genes encode proteins involved in the tricarboxylic acid (TCA) cycle.Objective/design: While about 40% of PPGL cases carry a variant in a known gene, many cases remain unexplained. In patients with unexplained PPGL showing clear evidence of a familial burden or multiple tumors, we aimed to identify causative factors using genetic analysis of patient DNA and functional analyses of identified DNA variants in patient tumor material and engineered cell lines.Patients and Setting: Patients with a likely familial cancer burden of pheochromocytomas and/or paragangliomas and under investigation in a clinical genetic and clinical research setting in university hospitals.Results: While investigating unexplained PPGL cases, we identified a novel variant, c.1151C>T, p.(Pro384Leu), in exon 14 of the gene encoding dihydrolipoamide S-succinyltransferase (DLST), a component of the multi-enzyme complex 2-oxoglutarate dehydrogenase. Targeted sequence analysis of further unexplained cases identified a patient carrying a tumor with compound heterozygous variants in DLST, consisting of a germline variant, c.1121G>A, p.(Gly374Glu), together with a somatic missense variant identified in tumor DNA, c.1147A>G, p.(Thr383Ala), both located in exon 14. Using a range of in silico and functional assays we show that these variants are predicted to be pathogenic, profoundly impact enzyme activity, and result in DNA hypermethylation.Conclusions: The identification and functional analysis of these DLST variants further validates DLST as an additional PPGL gene involved in the TCA cycle.MTG

Prognostic value of tumor markers and ctDNA in patients with resectable gastric cancer receiving perioperative treatment: results from the CRITICS trial

Aim To evaluate the prognostic value of tumor markers in a European cohort of patients with resectable gastric cancer. Methods We performed a post hoc analysis of the CRITICS trial, in which 788 patients received perioperative therapy. Association between survival and pretreatment CEA, CA 19-9, alkaline phosphatase, neutrophils, hemoglobin and lactate dehydrogenase were explored in uni- and multivariable Cox regression analyses. Likelihoods to receive potentially curative surgery were investigated for patients without elevated tumor markers versus one of the tumor markers elevated versus both tumor markers elevated. The association between tumor markers and the presence of circulating tumor DNA (ctDNA) was explored in 50 patients with available ctDNA data. Results In multivariable analysis, in which we corrected for allocated treatment and other baseline characteristics, elevated pretreatment CEA (HR 1.43; 95% CI 1.11-1.85, p < 0.001) and CA 19-9 (HR 1.79; 95% CI 1.42-2.25, p < 0.001) were associated with worse OS. Likelihoods to receive potentially curative surgery were 86%, 77% and 60% for patients without elevated tumor marker versus either elevated CEA or CA 19-9 versus both elevated, respectively (p < 0.001). Although both preoperative presence of ctDNA and tumor markers were prognostic for survival, no association was found between these two parameters. Conclusion CEA and CA 19-9 were independent prognostic factors for survival in a large cohort of European patients with resectable gastric cancer. No relationship was found between tumor markers and ctDNA. These factors could potentially guide treatment choices and should be included in future trials to determine their definitive position.Surgical oncolog

Adjuvant chemotherapy is superior to chemoradiation after D2 surgery for gastric cancer in the per-protocol analysis of the randomized CRITICS trial

Background: The Intergroup 0116 and the MAGIC trials changed clinical practice for resectable gastric cancer in the Western world. In these trials, overall survival improved with post-operative chemoradiotherapy (CRT) and perioperative chemotherapy (CT). Intention-to-treat analysis in the CRITICS trial of post-operative CT or post-operative CRT did not show a survival difference. The current study reports on the per-protocol (PP) analysis of the CRITICS trial.Patients and methods: The CRITICS trial was a randomized, controlled trial in which 788 patients with stage Ib-Iva resectable gastric or esophagogastric adenocarcinoma were included. Before start of preoperative CT, patients from the Netherlands, Sweden and Denmark were randomly assigned to receive post-operative CT or CRT. For the current analysis, only patients who started their allocated post-operative treatment were included. Since it is uncertain that the two treatment arms are balanced in such PP analysis, adjusted proportional hazards regression analysis and inverse probability weighted analysis were used to minimize the risk of selection bias and to estimate and compare overall and event-free survival.Results: Of the 788 patients, 478 started post-operative treatment according to protocol, 233 (59%) patients in the CT group and 245 (62%) patients in the CRT group. Patient and tumor characteristics between the groups before start of the post-operative treatment were not different. After a median follow-up of 6.7 years since the start of post-operative treatment, the 5-year overall survival was 57.9% (95% confidence interval: 51.4% to 64.3%) in the CT group versus 45.5% (95% confidence interval: 39.2% to 51.8%) in the CRT group (adjusted hazard ratio CRT versus CT: 1.62 (1.24-2.12), P = 0.0004). Inverse probability weighted analysis resulted in similar hazard ratios.Conclusion: After adjustment for all known confounding factors, the PP analysis of patients who started the allocated post-operative treatment in the CRITICS trial showed that the CT group had a significantly better 5-year overall survival than the CRT group (NCT00407186).Surgical oncolog

Effectiveness and cost-effectiveness of proactive and multidisciplinary integrated care for older people with complex problems in general practice: an individual participant data meta-analysis

Purpose to support older people with several healthcare needs in sustaining adequate functioning and independence, more proactive approaches are needed. This purpose of this study is to summarise the (cost-) effectiveness of proactive, multidisciplinary, integrated care programmes for older people in Dutch primary care. Methods design individual patient data (IPD) meta-analysis of eight clinically controlled trials. Setting primary care sector. Interventions combination of (i) identification of older people with complex problems by means of screening, followed by (ii) a multidisciplinary integrated care programme for those identified. Main outcome activities of daily living, i.e. a change on modified Katz-15 scale between baseline and 1-year follow-up. Secondary outcomes quality of life (visual analogue scale 0–10), psychological (mental well-being scale Short Form Health Survey (SF)-36) and social well-being (single item, SF-36), quality-adjusted life years (Euroqol-5dimensions-3level (EQ-5D-3L)), healthcare utilisation and cost-effectiveness. Analysis intention-to-treat analysis, two-stage IPD and subgroup analysis based on patient and intervention characteristics. Results included were 8,678 participants: median age of 80.5 (interquartile range 75.3; 85.7) years; 5,496 (63.3%) women. On the modified Katz-15 scale, the pooled difference in change between the intervention and control group was −0.01 (95% confidence interval −0.10 to 0.08). No significant differences were found in the other patient outcomes or subgroup analyses. Compared to usual care, the probability of the intervention group to be cost-effective was less than 5%. Conclusion compared to usual care at 1-year follow-up, strategies for identification of frail older people in primary care combined with a proactive integrated care intervention are probably not (cost-) effective

Effectiveness and cost-effectiveness of proactive and multidisciplinary integrated care for older people with complex problems in general practice: An individual participant data meta-analysis

Purpose: to support older people with several healthcare needs in sustaining adequate functioning and independence, more proactive approaches are needed. This purpose of this study is to summarise the (cost-) effectiveness of proactive, multidisciplinary, integrated care programmes for older people in Dutch primary care. Methods design: individual patient data (IPD) meta-analysis of eight clinically controlled trials. Setting: primary care sector. Interventions: combination of (i) identification of older people with complex problems by means of screening, followed by (ii) a multidisciplinary integrated care programme for those identified. Main outcome: activities of daily living, i.e. a change on modified Katz-15 scale between baseline and 1-year follow-up. Secondary outcomes: quality of life (visual analogue scale 0-10), psychological (mental well-being scale Short Form Health Survey (SF)-36) and social well-being (single item, SF-36), quality-adjusted life years (Euroqol-5dimensions-3level (EQ-5D-3L)), healthcare utilisation and cost-effectiveness. Analysis: intention-to-treat analysis, two-stage IPD and subgroup analysis based on patient and intervention characteristics. Results: included were 8,678 participants: median age of 80.5 (interquartile range 75.3; 85.7) years; 5,496 (63.3%) women. On the modified Katz-15 scale, the pooled difference in change between the intervention and control group was -0.01 (95% confidence interval -0.10 to 0.08). No significant differences were found in the other patient outcomes or subgroup analyses. Compared to usual care, the probability of the intervention group to be cost-effective was less than 5%. Conclusion: compared to usual care at 1-year follow-up, strategies for identification of frail older people in primary care combined with a proactive integrated care intervention are probably not (cost-) effective

Case of spontaneous regression of carotid body tumor in a SDHD mutant: a discussion on potential mechanisms based on a review of the literature

Diabetes mellitus: pathophysiological changes and therap

No difference in phenotype of the main Dutch SDHD founder mutations

Molecular tumour pathology - and tumour genetic

Imaging strategies in the management of gastric cancer: current role and future potential of MRI

Contains fulltext : 207166.pdf (Publisher’s version ) (Open Access)Accurate preoperative staging of gastric cancer and the assessment of tumor response to neoadjuvant treatment is of importance for treatment and prognosis. Current imaging techniques, mainly endoscopic ultrasonography (EUS), computed tomography (CT) and (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET), have their limitations. Historically, the role of magnetic resonance imaging (MRI) in gastric cancer has been limited, but with the continuous technical improvements, MRI has become a more potent imaging technique for gastrointestinal malignancies. The accuracy of MRI for T- and N-staging of gastric cancer is similar to EUS and CT, making MRI a suitable alternative to other imaging strategies. There is limited evidence on the performance of MRI for M-staging of gastric cancer specifically, but MRI is widely used for diagnosing liver metastases and shows potential for diagnosing peritoneal seeding. Recent pilot studies showed that treatment response assessment as well as detection of lymph node metastases and systemic disease might benefit from functional MRI (e.g. diffusion weighted imaging and dynamic contrast enhancement). Regarding treatment guidance, additional value of MRI might be expected from its role in better defining clinical target volumes and setup verification with MR-guided radiation treatment