In-depth investigation of the molecular pathogenesis of bladder cancer in a unique 26-year old patient with extensive multifocal disease: A case report

Background. The molecular characteristics and the clinical disease course of bladder cancer (BC) in young patients remain largely unresolved. All patients are monitored according to an intensive surveillance protocol and we aim to gain more insight into the molecular pathways of bladder tumors in young patients that could ultimately contribute to patient stratification, improve patient quality of life and reduce associated costs. We also determined whether a biomarker-based surveillance could be feasible. Case Presentation. We report a unique case of a 26-year-old Caucasian male with recurrent non-muscle invasive bladder tumors occurring at a high frequency and analyzed multiple tumors (maximal pTaG2) and urine samples of this patient. Analysis included FGFR3 mutation detection, FGFR3 and TP53 immunohistochemistry, mircosatellite analysis of markers on chromosomes 8, 9, 10, 11 and 17 and a genome wide single nucleotide polymorphism-array (SNP). All analyzed tumors contained a mutation in FGFR3 and were associated with FGFR3 overexpression. None of the tumors showed overexpression of TP53. We found a deletion on chromosome 9 in the primary tumor and this was confirmed by the SNP-array that showed regions of loss on chromosome 9. Detection of all recurrences was possible by urinary FGFR3 mutation analysis. Conclusions. Our findings would suggest that the BC disease course is determined by not only a patient's age, but also by the molecular characteristics of a tumor. This young patient contained typical genetic changes found in tumors of older patients and implies a clinical disease course comparable to older patients. We demonstrate that FGFR3 mutation analysis on voided urine is a simple non-invasive method and could serve as a feasible follow-up approach for this young patient presenting with an FGFR3 mutant tumor

Potato Consumption and Risk of Cardiovascular Mortality and Type 2 Diabetes After Myocardial Infarction : A Prospective Analysis in the Alpha Omega Cohort

Background: Higher potato intake, especially French fries, was unfavorably associated with cardiometabolic endpoints in population-based studies. Little is known about this in patients with ischemic heart disease (IHD). Objective: Total and boiled potatoes and French fries intake were examined in relation to cardiovascular disease (CVD) mortality, all-cause mortality, and type 2 diabetes mellitus (T2DM) risk in Dutch post-myocardial infarction (MI) patients of the Alpha Omega Cohort. Methods: We analyzed 3,401 patients (60–80 years, 78% male), free from T2DM at baseline, with an MI ≤ 10 years before enrolment. Diet was assessed at baseline (2002–2006) using a 203-item validated Food Frequency Questionnaire (FFQ) that includes potato preparation methods. Cause-specific mortality was monitored through December 2018, and T2DM incidence (self-reported physician diagnosis and/or prescribed anti-diabetes medication) was monitored during the first 40 months of follow-up. Multivariable Cox models were used to obtain hazard ratios (HRs) for fatal endpoints and incident T2DM in tertiles of potato intake. Results: Patients had a median total potato intake (mainly boiled) of 111 g/d, 96% consumed >1 serving (200 g) per week. French fries were consumed by 48% of the patients (median of 6 g/d among consumers). During >12 years of follow-up (38,987 person-years), 1,476 deaths occurred of which 641 were from CVD, 394 were from IHD, and 119 were from a stroke. Total and boiled potatoes were not associated with CVD mortality, but a higher risk of all-cause mortality was observed (HR: 1.07; 95% CI: 1.01, 1.14; per 50 g/d). Potato consumption tended to be positively associated with incident T2DM (186 cases; HR: 1.11, 95% CI: 0.94, 1.32; per 50 g/d). Results for French fries were inconsistent for all outcomes. Conclusion: In Dutch post-MI patients, potatoes (mainly boiled) were not associated with CVD mortality but possibly adversely associated with all-cause mortality and T2DM risk. These findings warrant confirmation in other IHD patient cohorts. The Alpha Omega Cohort is registered at ClinicalTrials.gov as NCT03192410

Design and Development of Digital Learning Material for Applied Data Analysis

Digital learning material was developed to help students acquire the necessary skills for the preparation and implementation of a data analysis protocol. The learning material focused on the relation between the main experimental and observational study types in human nutrition research and the appropriate methods of data analysis. This article describes the main guidelines derived from theories on learning and instruction and illustrates how they were used to develop the digital learning material. Evaluation of the learning material in an academic context indicated that students appreciated the learning material and achieved the learning objective

Alcohol intake and long-term mortality risk after myocardial infarction in the Alpha Omega Cohort

BACKGROUND: Population-based studies generally show J-shaped associations between alcohol intake and mortality from cardiovascular disease (CVD). Little is known about alcohol and long-term mortality risk after myocardial infarction (MI). OBJECTIVES: We examined alcohol intake in relation to all-cause, CVD, and ischemic heart disease (IHD) mortality in Dutch post-MI patients of the Alpha Omega Cohort. METHODS: The analysis comprised 4365 patients (60-80 years; 79% male) with an MI ≤ 10 years before study enrolment. We used a 203-item FFQ to assess alcohol (total ethanol) and dietary intakes over the past month. Patients were classified as nondrinkers (0 g/d; n = 956) or very light (>0 to 2 g/d; n = 385), light (M: >2 to 10 g/d; F: >2 to 5 g/d; n = 1125), moderate (M: >10 to 30 g/d; F: >5 to 15 g/d; n = 1207), or heavy drinkers (M: >30 g/d; F: >15 g/d; n = 692). HRs of mortality for alcohol intake were obtained from Cox models, adjusting for age, sex, education, smoking, BMI, physical activity, and dietary factors. RESULTS: Alcohol was consumed by 83% of males and 61% of females. During ∼12 years of follow-up, 2035 deaths occurred, of which 903 were from CVD and 558 were from IHD. Compared to the (combined) reference group of nondrinkers and very light drinkers, HRs for all-cause mortality were 0.87 (95% CI, 0.78-0.98), 0.85 (95% CI, 0.75-0.96), and 0.91 (95% CI, 0.79-1.04) for light, moderate, and heavy drinkers, respectively. For CVD mortality, corresponding HRs were 0.80 (95% CI, 0.67-0.96), 0.82 (95% CI, 0.69-0.98), and 0.87 (95% CI, 0.70-1.08) for light, moderate, and heavy drinkers, respectively. Findings for IHD mortality were similar. HRs did not materially change when nondrinkers or very light drinkers were taken as the reference, or after exclusion of former drinkers or patients with diabetes or poor/moderate self-rated health. CONCLUSIONS: Light and moderate alcohol intakes were inversely associated with mortality risk in stable post-MI patients. These observational findings should be cautiously interpreted in light of the total evidence on alcohol and health. The Alpha Omega Cohort is registered at clinicaltrials.gov as NCT03192410

GRPr antagonist 68Ga‐SB3 PET/CT‐imaging of primary prostate cancer in therapy-naive patients

The gastrin releasing peptide receptor (GRPr) is overexpressed in prostate cancer (PCa) cells, making it an excellent tool for targeted imaging. The gallium-68 labeled GRPr antagonist SB3 (68Ga-SB3) has shown excellent results in (pre)clinical studies and was selected for further clinical investigation. The aims of this phase I study were to investigate 68Ga-SB3 PET/CT-imaging of primary PCa tumors and assess safety. More aims included biodistribution, dosimetry, comparison with pathology and GRPr expression. MATERIALS AND METHODS: Ten therapy-naive, biopsy-confirmed PCa patients planned for prostatectomy were included. A 3-hour extensive PET/CT-imaging protocol was performed, within 2 weeks prior to prostatectomy. Prostate tissue was evaluated for tumor localization, Gleason Score and in vitro autoradiography was performed to determine GRPr expression. Available MRI scans performed within 3 months prior to the study were matched. For dosimetry residence times were estimated and effective dose to the body as well as absorbed doses to organs were calculated using the IDAC dose 2.1 model. RESULTS: Administration of 68Ga-SB3 (187.4 ± 40.0 MBq, 40±5 μg) was well tolerated, no significant changes in vital signs or laboratory results were observed. 68Ga-SB3 PET/CT showed lesions in 8 out of 10 patients. Pathological analysis revealed a total of 16 tumor lesions of which PET/CT showed 14, resulting in a sensitivity of 88%. 68Ga-SB3 PET/CT-imaging showed uptake in 2 large prostatic intraepithelial neoplasia foci, considered a precursor of PCa, resulting in an 88% specificity. Autoradiography of tumor lesions revealed heterogeneous GRPr expression and was negative in 4 patients. Both PET/CT-negative patients had a GRPr-negative tumor. In autoradiography-positive tumors, level of GRPr expression showed significant correlation to tracer uptake on PET/CT. Dosimetry calculations estimated the effective dose to be 0.0144 mSv/MBq, similar to other 68Ga labeled radiopeptides. Highest absorbed dose was detected in the physiological GRPr-expressing pancreas (0.198 mGy/MBq), followed by bladder wall and kidneys. CONCLUSION: 68Ga-SB3 PET/CT is a safe imaging method and a promising tool for early PCa imaging

Immediate treatment vs. active-surveillance in very-low-risk prostate cancer: the role of patient-, tumour-, and hospital-related factors

Background: To provide insight in the treatment variation of very-low-risk prostate cancer patients and to assess the role of hospital-related factors. Methods: All patients diagnosed with very-low-risk prostate cancer (cT1c-cT2a, PSA < 10 ng/ml, Gleason score <7 and <3 positive cores) in 2015 and 2016 were identified through the population-based Netherlands Cancer Registry. Multilevel logistic regression analyses were performed to examine the crude and case-mix adjusted probability of immediate treatment vs. active-surveillance (AS) according to hospital of diagnosis and to evaluate the effect of patient-, tumour-, and hospital-related factors. Results: In all, 2047 (85.4%) of the 2396 patients with very-low-risk prostate cancer were managed with AS. The crude proportion of patients with AS varied from 33.3 to 100% between hospitals. Case-mix adjusted probability varied from 71 to 97%. Tumour stage cT2a vs. cT1c (OR 2.0, 95%CI 1.1−3.6), two vs. one positive core (OR 2.8, 95%CI 1.6−4.7), diagnostic MRI (OR 2.8, 95%CI 1.5−5.2), discussion of a patient in a multi-disciplinary team (OR 2.2, 95%CI 1.1−4.5), discussion of treatment options with the patient (OR 3.3, 95%CI 1.5−7.4) and type of hospital (non-university referral hospital vs. community hospital: OR 0.5, 95%CI 0.2−0.9) were associated with immediate treatment. Conclusion: The majority of Dutch very-low-risk prostate cancer patients is managed with AS but variation between hospitals exists. Part of the variation is explained by patient- and tumour characteristics but also hospital-related factors play a role. This implies that clinical practice could be improved