Sex Differences in Neoplastic Progression in Barrett's Esophagus:A Multicenter Prospective Cohort Study

Recommendations in Barrett’s esophagus (BE) guidelines are mainly based on male patients. We aimed to evaluate sex differences in BE patients in (1) probability of and (2) time to neoplastic progression, and (3) differences in the stage distribution of neoplasia. We conducted a multicenter prospective cohort study including 868 BE patients. Cox regression modeling and accelerated failure time modeling were used to estimate the sex differences. Neoplastic progression was defined as highgrade dysplasia (HGD) and/or esophageal adenocarcinoma (EAC). Among the 639 (74%) males and 229 females that were included (median follow-up 7.1 years), 61 (7.0%) developed HGD/EAC. Neoplastic progression risk was estimated to be twice as high among males (HR 2.26, 95% CI 1.11–4.62) than females. The risk of HGD was found to be higher in males (HR 3.76, 95% CI 1.33–10.6). Time to HGD/EAC (AR 0.52, 95% CI 0.29–0.95) and HGD (AR 0.40, 95% CI 0.19–0.86) was shorter in males. Females had proportionally more EAC than HGD and tended to have higher stages of neoplasia at diagnosis. In conclusion, both the risk of and time to neoplastic progression were higher in males. However, females were proportionally more often diagnosed with (advanced) EAC. We should strive for improved neoplastic risk stratification per individual BE patient, incorporating sex disparities into new prediction models

Implementation of paediatric precision oncology into clinical practice: The Individualized Therapies for Children with cancer program ‘iTHER’

iTHER is a Dutch prospective national precision oncology program aiming to define tumour molecular profiles in children and adolescents with primary very high-risk, relapsed, or refractory paediatric tumours. Between April 2017 and April 2021, 302 samples from 253 patients were included. Comprehensive molecular profiling including low-coverage whole genome sequencing (lcWGS), whole exome sequencing (WES), RNA sequencing (RNA-seq), Affymetrix, and/or 850k methylation profiling was successfully performed for 226 samples with at least 20% tumour content. Germline pathogenic variants were identified in 16% of patients (35/219), of which 22 variants were judged causative for a cancer predisposition syndrome. At least one somatic alteration was detected in 204 (90.3%), and 185 (81.9%) were considered druggable, with clinical priority very high (6.1%), high (21.3%), moderate (26.0%), intermediate (36.1%), and borderline (10.5%) priority. iTHER led to revision or refinement of diagnosis in 8 patients (3.5%). Temporal heterogeneity was observed in paired samples of 15 patients, indicating the value of sequential analyses. Of 137 patients with follow-up beyond twelve months, 21 molecularly matched treatments were applied in 19 patients (13.9%), with clinical benefit in few. Most relevant barriers to not applying targeted therapies included poor performance status, as well as limited access to drugs within clinical trial. iTHER demonstrates the feasibility of comprehensive molecular profiling across all ages, tumour types and stages in paediatric cancers, informing of diagnostic, prognostic, and targetable alterations as well as reportable germline variants. Therefore, WES and RNA-seq is nowadays standard clinical care at the Princess Máxima Center for all children with cancer, including patients at primary diagnosis. Improved access to innovative treatments within biology-driven combination trials is required to ultimately improve survival

Implementation of paediatric precision oncology into clinical practice: The Individualized Therapies for Children with cancer program ‘iTHER’

iTHER is a Dutch prospective national precision oncology program aiming to define tumour molecular profiles in children and adolescents with primary very high-risk, relapsed, or refractory paediatric tumours. Between April 2017 and April 2021, 302 samples from 253 patients were included. Comprehensive molecular profiling including low-coverage whole genome sequencing (lcWGS), whole exome sequencing (WES), RNA sequencing (RNA-seq), Affymetrix, and/or 850k methylation profiling was successfully performed for 226 samples with at least 20% tumour content. Germline pathogenic variants were identified in 16% of patients (35/219), of which 22 variants were judged causative for a cancer predisposition syndrome. At least one somatic alteration was detected in 204 (90.3%), and 185 (81.9%) were considered druggable, with clinical priority very high (6.1%), high (21.3%), moderate (26.0%), intermediate (36.1%), and borderline (10.5%) priority. iTHER led to revision or refinement of diagnosis in 8 patients (3.5%). Temporal heterogeneity was observed in paired samples of 15 patients, indicating the value of sequential analyses. Of 137 patients with follow-up beyond twelve months, 21 molecularly matched treatments were applied in 19 patients (13.9%), with clinical benefit in few. Most relevant barriers to not applying targeted therapies included poor performance status, as well as limited access to drugs within clinical trial. iTHER demonstrates the feasibility of comprehensive molecular profiling across all ages, tumour types and stages in paediatric cancers, informing of diagnostic, prognostic, and targetable alterations as well as reportable germline variants. Therefore, WES and RNA-seq is nowadays standard clinical care at the Princess Máxima Center for all children with cancer, including patients at primary diagnosis. Improved access to innovative treatments within biology-driven combination trials is required to ultimately improve survival

Religious denomination as a symptom-formation factor of depression in older Dutch citizens

Objectives. The type of symptoms in depression is likely to be influenced by cultural environment. As religion represents an important cultural resource for older adults, it is hypothesised that religious denomination represents a symptom-formation factor of depression in the older generation. Focusing on older Dutch citizens, it is expected that depressed Calvinists report: (1) less depressed affect, (2) more vegetative symptoms, and (3) more guilt feelings, than Roman Catholics and non-church members. Methods and procedures. The Center for Epidemiologic Studies Depression Scale (CES-D) was used to distinguish depressed (N = 395) and non-depressed (N = 2333) older adults, and to assess depressive symptom-profiles. The Diagnostic Interview Schedule (DIS) was used to assess major depressive episodes and criterion-symptoms of depression. Results. Depressed Calvinists, especially males, had higher scores on the vegetative CES-D subscale. The same was found for non-church members with Calvinist parents. Among those who have a major depressive episode in later life (N = 84), support was found for all hypotheses. Feelings of guilt were also more prevalent among Roman Catholics. Conclusions. Religious denomination modified the type of symptoms in late-life depression. As a Calvinist background was associated with less depressive affect and more inhibition, there is a risk of underdiagnosis of major depression in older Calvinists in the Netherlands. Copyright (C) 2000 John Wiley and Sons, Ltd

Prayer and depressive symptoms in a period of secularization: Patterns among older adults in the Netherlands

Objective: Prayer is generally recognized as an important aspect of religiousness. Relatively few empiric studies examined the relation between prayer and depressive symptoms in later life, and findings so far are mixed. Method: Respondents, aged 60ĝ€"91 years, participated in the third (N ≤ 1,702) and fourths (N ≤ 1,346) assessment cycles, with three-year intervals, of the Longitudinal Aging Study Amsterdam. Data were collected on frequency of prayer, perceived meaningfulness of prayer, religious affiliation, church attendance, salience of religion, demographics, and health variables. Depressive symptoms were assessed with the Center for Epidemiologic Studiesĝ€"Depression Scale. Results: In the total sample, there was no significant association between frequency of prayer and depressive symptoms. Among those who were not religiously affiliated, prayer was associated with higher levels of depressive symptoms. The results were particularly pronounced among nonaffiliated widowed respondents; odds ratio for praying daily associated with having Center for Epidemiologic Studiesĝ€" Depression Scale scores of 16 and higher amounted to 3.59 (99% confidence interval: 1.01ĝ€"11.79). At three-year follow up, prayer did not predict change of depressive symptoms. Conclusions: As secularization in Western Europe progresses, the current results suggest that clinical exploration of private religiousness among older patients remains relevant, also among people who seem to be less religious

Religious involvement and 6-year course of depressive symptoms in older Dutch citizens: Results from the longitudinal aging study Amsterdam

Objectives: Expanding on cross-sectional studies, associations are examined between religious involvement and the 6-year course of depressive symptoms in older adults. Methods: Subjects are 1,840 community-dwelling older adults (aged 55 to 85) participating in three measurement cycles of the Longitudinal Aging Study, Amsterdam. Assessments include aspects of religious involvement, depressive symptoms, physical health, self-perceptions, social integration, urbanization, and alcohol use. Results: Church attendance is negatively associated with the course of depressive symptoms, also after adjustment for explanatory variables. Among respondents with functional limitations, lower depression scores are found for those who attend church on a regular basis. For respondents who are bereaved or nonmarried, however, slightly higher depression scores are found for those with high levels of orthodox beliefs. Discussion: There is a consistent negative association over time between church attendance and depressive symptoms in older Dutch citizens. Both stress-buffering as well as depression-evoking effects of religious involvement are found

Religious climate and geographical distribution of depressive symptoms in older Dutch citizens

This study examines whether the degree of conservatism of the religious climate affects the geographical distribution of late life depressive symptoms. A U-shaped relationship is hypothesized: high levels of depressive symptoms at the extremes (both a-religious and hyperconservative), and a low level in the middle (moderate-conservative). Subjects are 3051 older Dutch citizens (55-85 years), living in 11 municipalities. Depressive symptoms are assessed using the CES-D. Religious climate is estimated on the municipality level, using percentages votes on political parties with a Christian background (moderate-conservative versus hyperconservative). Using multi- level analysis, the results support the U-curve hypothesis

The natural history of late-life depression: A 6-year prospective study in the community

Background: Accurate assessment of the natural history of late-life depression requires frequent observation over time. In later life, depressive disorders fulfilling rigorous diagnostic criteria are relatively rare, while subthreshold disorders are common. The primary aim was to study the natural history of late-life depression, systematically comparing those who did with those who did not fulfill rigorous diagnostic criteria. Methods: Within the Longitudinal Aging Study Amsterdam, a large cohort of depressed elderly persons (n=277) was identified and followed up for 6 years, using 14 observations. Depression was measured using self-reports (the Center for Epidemiological Studies Depression Scale) and diagnostic interviews (the Diagnostic Interview Schedule). The natural history was assessed for symptom severity (Center for Epidemiological Studies Depression Scale score), symptom duration, clinical course type, and stability of diagnoses. Results: The average symptom severity remained above the 85th percentile of the population average for 6 years. Symptoms were short-lived in only 14%. There were remissions in 23%, an unfavorable but fluctuating course in 44%, and a severe chronic course in 32% (percentages do not total 100 because of rounding). Comparing the outcome, there was a clear gradient in which those with subthreshold disorders had the best outcome, followed by those with major depressive disorder, dysthymic disorder, and double depression. However, the prognosis of subthreshold disorders was unfavorable in most cases, while this group was at high risk of developing DSM affective disorders. Conclusions: The natural history of late-life depression in the community is poor. DSM affective disorders are relatively rare among elderly persons, but do identify those with the worst prognosis. However, subthreshold depression is serious and chronic in many cases

PTEN in colorectal cancer: a report on two Cowden syndrome patients

Kersseboom R, Dubbink HJ, Corver WE, van Tilburg AJP, Poley JW, van Leerdam ME, Atmodimedjo PN, van de Laar IMBH, Collee JM, Dinjens WNM, Morreau H, Wagner A. PTEN in colorectal cancer; a report on two Cowden syndrome patients. Heterozygous germline PTEN mutations cause Cowden syndrome. The risk of colorectal cancer in Cowden patients, however, remains a matter of debate. We describe two patients presenting with colorectal cancer at a young age (28 and 39 years) and dysmorphisms fitting the Cowden spectrum. Heterozygous germline mutations in PTEN were found in both patients. Moreover, analysis of the resected colorectal cancer specimens revealed loss of heterozygosity at the PTEN locus with retention of the mutated alleles, and greatly reduced or absent PTEN expression. Histologically and molecularly, the tumours showed resemblance with sporadic colorectal cancers, although they had prominent fibrotic stroma. Our data indicate that PTEN loss was involved in carcinogenesis in the two patients, supporting that colorectal cancer is part of the Cowden syndrome-spectrum. This is in line with data on sporadic colorectal cancer, mice studies and emerging epidemiological data on Cowden syndrome. Although the exact role of germline PTEN mutations in the carcinogenesis of colorectal cancer remains unclear, we think that Cowden syndrome should be in the differential diagnosis of colorectal cancer certainly in view of the possible prognostic and therapeutic consequences. Prospective follow-up and surveillance of PTEN mutation carriers from the age of 25 to 30 years in a study setting should clarify this issue