Neuronal Distribution in Colorectal Cancer: Associations With Clinicopathological Parameters and Survival.

Over the past years, insights in the cancer neuroscience field increased rapidly, and a potential role for neurons in colorectal carcinogenesis has been recognized. However, knowledge on the neuronal distribution, subtypes, origin, and associations with clinicopathological characteristics in human studies is sparse. In this study, colorectal tumor tissues from the Netherlands Cohort Study on diet and cancer (n = 490) and an in-cohort validation population (n = 529) were immunohistochemically stained for the pan-neuronal markers neurofilament (NF) and protein gene product 9.5 (PGP9.5) to study the association between neuronal marker expression and clinicopathological characteristics. In addition, tumor and healthy colon tissues were stained for neuronal subtype markers, and their immunoreactivity in colorectal cancer (CRC) stroma was analyzed. NF-positive and PGP9.5-positive nerve fibers were found within the tumor stroma and mostly characterized by the neuronal subtype markers vasoactive intestinal peptide and neuronal nitric oxide synthase, suggesting that inhibitory neurons are the most prominent neuronal subtype in CRC. NF and PGP9.5 protein expression were not consistently associated with tumor stage, sublocation, differentiation grade, and median survival. NF immunoreactivity was associated with a worse CRC-specific survival in the study cohort (P = .025) independent of other prognostic factors (hazard ratio, 2.31; 95% CI, 1.33-4.03; P = .003), but these results were not observed in the in-cohort validation group. PGP9.5, in contrast, was associated with a worse CRC-specific survival in the in-cohort validation (P = .046) but not in the study population. This effect disappeared in multivariate analyses (hazard ratio, 0.81; 95% CI, 0.50-1.32; P = .393), indicating that this effect was dependent on other prognostic factors. This study demonstrates that the tumor stroma of CRC patients mainly harbors inhibitory neurons and that NF as a single marker is significantly associated with a poorer CRC-specific survival in the study cohort but necessitates future validation.

Diabetes and the risk of bladder cancer subtypes in men and women: results from the Netherlands Cohort Study.

Meta-analyses have shown modest positive associations between diabetes mellitus (DM) and bladder cancer risk, but results are heterogeneous. This might be due to lack of distinction between bladder cancer subtypes, between sexes, and possibly between Type 2 and Type 1 DM (T2DM and T1DM). The relationship of T2DM (and secondarily T1DM) characteristics with risk of bladder cancer subtypes (invasive versus noninvasive) was investigated in the Netherlands Cohort Study. In 1986, 120,852 men and women aged 55-69 years provided information on DM and lifestyle data. After 20.3 years of follow-up, multivariable case-cohort analyses were based on 1020 invasive and 1088 noninvasive bladder cancer cases, and 4267 subcohort members with complete data on DM and confounders. While T2DM was not associated with noninvasive bladder cancer, it was statistically significantly associated with invasive bladder cancer risk: the multivariable-adjusted was HR = 1.57 (95% CI 1.04-2.37), comparing participants with T2DM versus without DM. The association was only significant in women, and women showed a stronger association [HR = 2.19 (95% CI 1.10-4.34)] between T2DM and invasive bladder cancer than men [HR = 1.42 (95% CI 0.88-2.30)]; interaction by sex was nonsignificant. Associations were stronger positive in those whose age at diagnosis of T2DM was 55+ years, and in those diagnosed with T2DM less than five years before baseline. T2DM participants using antidiabetic medication had higher invasive bladder cancer risk than those without DM. Exploratory age-sex-adjusted analyses suggested a positive association between T1DM and invasive bladder cancer, but this was based on few cases. These findings suggest that T2DM and possibly T1DM are positively associated with invasive bladder cancer risk.

The out-of-pocket expenses of people with tinnitus in Europe.

BACKGROUND: Despite the high frequency of tinnitus and its impact on wellbeing, little is known about its economic burden and no data to our knowledge are available on out-of-pocket (OOP) expenses. METHODS: In 2022 a survey was conducted on OOP costs of tinnitus. We enrolled 679 participants with slight, moderate and severe tinnitus in Italy, United Kingdom, Netherlands, Germany and Spain. We estimated annual OOP expenses for tinnitus-related healthcare visits, treatments, medications and alternative medicine practices. Prevalence of tinnitus in the general population, obtained from a representative survey we conducted in Europe in 2017-2018, was used to generalise costs for people with any tinnitus at the national level. RESULTS: OOP expenses were 368€ (95% confidence intervals (CI), 78€-690€), 728€ (95% CI, 316€-1,288€), and 1,492€ (95% CI, 760€-2,688€) for slight, moderate, and severe tinnitus, respectively, with annual expenditure of 565€ for people with any tinnitus: 209€ for healthcare visits, 93€ for treatments, 16€ for drugs, 64€ for hearing supporting systems and 183€ for acupuncture, homeopathy and osteopathy. Individuals with slight, moderate, and severe tinnitus expressed a willingness to invest 1.6, 4.3, and 7.0 times their monthly income, respectively, to achieve complete relief from tinnitus. CONCLUSIONS: This study offers for the first time insights into the OOP expenses incurred by individuals with tinnitus. OOP expenses exhibited substantial variations based on severity status, accounting for more than 17 thousand million€ in the countries considered. In terms of financial burden, these findings align tinnitus to the recognised leading disabilities, including back pain and migraine.

The association between height and risk of lung cancer subtypes in men and women in the Netherlands Cohort Study.

OBJECTIVES: Previous studies found no or weak positive associations between height and lung cancer (LC) risk, with differences between sexes. Few studies stratified the association by smoking status and LC subtype. This prospective study investigated the association between height and risks of overall LC and LC subtypes (i.e., adenocarcinoma, squamous cell carcinoma, small cell carcinoma, large cell carcinoma) in Dutch men and women, with comprehensive adjustment for smoking, and stratified by smoking status. MATERIALS AND METHODS: Data originate from 120,852 Dutch participants aged 55-69 in 1986 in the Netherlands Cohort Study. Self-reported height and potential confounders were collected at baseline. After 20.3 years of follow-up, 3318 LC cases (2765 men; 553 women) and 4314 subcohort members were included in the multivariable Cox regression analysis. RESULTS: There were no significant associations between height and risks of overall LC and LC subtypes in men and women, except for an increased adenocarcinoma risk in taller women (HRquartile4 vs quartile1=1.62, 95% CI: 1.02-2.55, Ptrend=0.031). This positive association was borderline statistically significant in female current smokers only when stratifying on smoking status. No interaction by smoking status was shown in women for any LC risk. In men, smoking modified the association between height and risks of overall LC, large cell and squamous cell carcinoma, with the p-values for interaction of 0.037, 0.007 and 0.050, respectively. CONCLUSION: Positive associations between height and LC subtypes were predominantly seen in smokers. Further studies should focus on LC subtypes and stratify the association by smoking status.

Consequences of COVID-19 pandemic on weight gain and physical activity: a prospective cohort study from Italy.

INTRODUCTION: It is crucial to monitor changes in body weight and physical activity (PA) to understand if short-term effects of COVID-19 pandemic have had implications over time. METHODS: This longitudinal study is based on data from 4,831 Italians aged 18-74 years interviewed during the first phase of COVID-19 pandemic (April-May 2020) and two years later (February-March 2022). Changes in body weight and PA were assessed through multivariable analyses in association with socio-demographic and psychological characteristics. RESULTS: Over the two years, 17.4% reported a weight gain of at least 5 kg and 32.8% a decreased PA by at least 4 hours per week. Weight gain and decreased PA were more frequent in participants from the less wealthy areas, with lower educational level and those who reported a worsening in mental health. CONCLUSIONS: After two years from the start of the pandemic, in Italy we observed a trend toward a renormalization of body weight and PA. The segments of the population mostly affected by the pandemic are subjects with more disadvantaged socio-economic status and with an impaired mental health.

The relationship between Stroma AReactive Invasion Front Areas (SARIFA), Warburg-subtype and survival: results from a large prospective series of colorectal cancer patients.

BACKGROUND: Stroma AReactive Invasion Front Areas (SARIFA) is a recently identified haematoxylin & eosin (H&E)based histopathologic biomarker in gastrointestinal cancers, including colorectal cancer (CRC), defined as direct contact between tumour cells and adipocytes at the tumour invasion front. The current study aimed at validating the prognostic relevance of SARIFA in a large population-based CRC series as well as at investigating the relationship between SARIFA-status and previously established Warburg-subtypes, both surrogates of the metabolic state of the tumour cells. METHODS: SARIFA-status (positive versus negative) was determined on H&E slides of 1,727 CRC specimens. Warburg-subtype (high versus moderate versus low) data was available from our previous study. The associations between SARIFA-status, Warburg-subtype, clinicopathological characteristics and CRC-specific as well as overall survival were investigated. RESULTS: 28.7% (n=496) CRC were SARIFA-positive. SARIFA-positivity was associated with more advanced disease stage, higher pT category, and more frequent lymph node involvement (all p<0.001). SARIFA-positivity was more common in Warburg-high CRC. 44.2% (n=219) of SARIFA-positive CRCs were Warburg-high compared to 22.8% (n=113) being Warburg-low and 33.1% (n=164) being Warburg-moderate (p<0.001). In multivariable-adjusted analysis, patients with SARIFA-positive CRCs had significantly poorer CRC-specific (HRCRC-specific 1.65; 95% CI 1.41-1.93) and overall survival (HRoverall survival 1.46; 95% CI 1.28-1.67) independent of clinically known risk factors and independent of Warburg-subtype. Combining the SARIFA-status and the Warburg-subtype to a combination score (SARIFA-negative/Warburg-high versus SARIFA-positive/Warburg-low versus SARIFA-positive/Warburg-high, and so on) did not improve the survival prediction compared to the use of SARIFA-status alone (SARIFA-negative + Warburg-high: HRCRC-specific 1.08; 95% CI 0.84-1.38; SARIFA-positive + Warburg-low: HRCRC-specific 1.79; 95% CI 1.32-2.41; SARIFA-positive + Warburg-high: HRCRC-specific 1.58; 95% CI 1.23-2.04). CONCLUSIONS: Our current study is the by far largest external validation of SARIFA-positivity as a novel independent negative prognostic H&E-based biomarker in CRC. In addition, our study shows that SARIFA-positivity is associated with the Warburg-high subtype. Further research is warranted to provide a more mechanistic understanding of the underlying tumour biology. Based on our data, we conclude SARIFA-status should be implemented in pathologic routine practice to stratify CRC patients.

Association between long-term energy balance-related factors and survival in colorectal cancer overall and by metabolic Warburg-subtypes.

BACKGROUND: Long-term energy balance-related factors (i.e. lifestyle and physiological factors that influence the equilibrium between energy intake and energy expenditure over an extended period) like body mass index (BMI) are linked to colorectal cancer (CRC) risk, but their impact on CRC survival is unclear. We explored associations between these long-term energy balance-related factors and survival, and examined potential differences across metabolic Warburg-subtypes. METHODS: Associations between long-term energy balance-related factors and survival in the total series of CRC patients (n=2,347) obtained from the prospective Netherlands Cohort Study, as well as according to Warburg-subtype (Warburg-low: n=652, Warburg-moderate: n=802, Warburg-high: n=797), were investigated using Cox regression analysis. RESULTS: Among the long-term energy balance-related factors studied, only increasing pre-diagnostic BMI was associated with a borderline significant poorer overall survival in CRC patients (HR5kg/m2 1.07; 95%CI 0.99-1.15). Stratified analyses showed that pre-diagnostic weight gain (HR5kg 1.06; 95%CI 1.00-1.12), and potentially increased height (HR5cm 1.04; 95%CI 0.98-1.11), were associated with poor overall survival only in patients with Warburg-high CRC. Increasing pre-diagnostic BMI was associated with poor survival only in patients with Warburg-moderate CRC (CRC-specific: HR5kg/m2 1.12; 95%CI 0.96-1.32, overall: HR5kg/m2 1.20; 95%CI 1.05-1.36). No consistent patterns were observed across energy-restriction proxies. CONCLUSIONS: Maintaining a healthy pre-diagnostic BMI may be beneficial for CRC survival. Moreover, associations between pre-diagnostic BMI, weight change, early-life energy restriction, height and CRC survival differed according to Warburg-subtype. IMPACT: Understanding the biological pathways involved in associations between energy balance-related factors and CRC survival could help refine prevention strategies in the future.

Dietary Fiber Intake and Risk of Advanced and Aggressive Forms of Prostate Cancer: A Pooled Analysis of 15 Prospective Cohort Studies.

BACKGROUND: Evidence of an association between dietary fiber intake and risk of advanced and aggressive forms of prostate cancer (PC) and PC mortality is limited. OBJECTIVE: The aim of this study was to examine associations between intakes of dietary fiber overall and by food source and risk of advanced and aggressive forms of PC. DESIGN: The study design was a pooled analysis of the primary data from 15 cohorts in 3 continents. Baseline dietary fiber intake was assessed using a validated food frequency questionnaire or diet history in each study. PARTICIPANTS/SETTING: There were 842 149 men followed for up to 9 to 22 years between 1985 and 2009 across studies. MAIN OUTCOME MEASURES: The primary outcome measures were advanced (stage T4, N1, or M1 or PC mortality), advanced restricted (excluded men with missing stage and those with localized PC who died of PC), and high-grade PC (Gleason score ≥8 or poorly differentiated/undifferentiated) and PC mortality. STATISTICAL ANALYSIS PERFORMED: Study-specific multivariable hazard ratios (MVHR) were calculated using Cox proportional hazards regression and pooled using random effects models. RESULTS: Intake of dietary fiber overall, from fruits, and from vegetables was not associated with risk of advanced (n = 4863), advanced restricted (n = 2978), or high-grade PC (n = 9673) or PC mortality (n = 3097). Dietary fiber intake from grains was inversely associated with advanced PC (comparing the highest vs lowest quintile, MVHR 0.84; 95% CI 0.76-0.93), advanced restricted PC (MVHR 0.85; 95% CI 0.74-0.97), and PC mortality (MVHR 0.78; 95% CI 0.68-0.89); statistically significant trends were noted for each of these associations (P ≤ .03), and a null association was observed for high-grade PC for the same comparison (MVHR 1.00; 95% CI 0.93-1.07). The comparable results were 1.06 (95% CI 1.01-1.10; P value, test for trend = .002) for localized PC (n = 35,199) and 1.05 (95% CI 0.99-1.11; P value, test for trend = .04) for low/intermediate grade PC (n = 34 366). CONCLUSIONS: Weak nonsignificant associations were observed between total dietary fiber intake and risk of advanced forms of PC, high-grade PC, and PC mortality. High dietary fiber intake from grains was associated with a modestly lower risk of advanced forms of PC and PC mortality.

Association of glycaemic index and glycaemic load with type 2 diabetes, cardiovascular disease, cancer, and all-cause mortality: a meta-analysis of mega cohorts of more than 100 000 participants.

BACKGROUND: There is debate over whether the glycaemic index of foods relates to chronic disease. We aimed to assess the associations between glycaemic index (GI) and glycaemic load (GL) and type 2 diabetes, cardiovascular disease, diabetes-related cancers, and all-cause mortality. METHODS: We did a meta-analysis of large cohorts (≥100 000 participants) identified from the Richard Doll Consortium. We searched the Cochrane Library, MEDLINE, PubMed, Embase, Web of Science, and Scopus for cohorts that prospectively examined associations between GI or GL and chronic disease outcomes published from database inception to Aug 4, 2023. Full-article review and extraction of summary estimates data were conducted by three independent reviewers. Primary outcomes were incident type 2 diabetes, total cardiovascular disease (including mortality), diabetes-related cancers (ie, bladder, breast, colorectal, endometrial, hepatic, pancreatic, and non-Hodgkin lymphoma), and all-cause mortality. We assessed comparisons between the lowest and highest quantiles of GI and GL, adjusting for dietary factors, and pooling their most adjusted relative risk (RR) estimates using a fixed-effects model. We also assessed associations between diets high in fibre and whole grains and the four main outcomes. The study protocol is registered with PROSPERO, CRD42023394689. FINDINGS: From ten prospective large cohorts (six from the USA, one from Europe, two from Asia, and one international), we identified a total of 48 studies reporting associations between GI or GL and the outcomes of interest: 34 (71%) on various cancers, nine (19%) on cardiovascular disease, five (10%) on type 2 diabetes, and three (6%) on all-cause mortality. Consumption of high GI foods was associated with an increased incidence of type 2 diabetes (RR 1·27 [95% CI 1·21-1·34]; p<0·0001), total cardiovascular disease (1·15 [1·11-1·19]; p<0·0001), diabetes-related cancer (1·05 [1·02-1·08]; p=0·0010), and all-cause mortality (1·08 [1·05-1·12]; p<0·0001). Similar associations were seen between high GL and diabetes (RR 1·15 [95% CI 1·09-1·21]; p<0·0001) and total cardiovascular disease (1·15 [1·10-1·20]; p<0·0001). Associations between diets high in fibre and whole grains and the four main outcomes were similar to those for low GI diets. INTERPRETATION: Dietary recommendations to reduce GI and GL could have effects on health outcomes that are similar to outcomes of recommendations to increase intake of fibre and whole grain. FUNDING: Banting and Best and the Karuna Foundation.

Hypertension and Risk of Endometrial Cancer: A Pooled Analysis in the Epidemiology of Endometrial Cancer Consortium (E2C2).

BACKGROUND: The incidence rates of endometrial cancer are increasing, which may partly be explained by the rising prevalence of obesity, an established risk factor for endometrial cancer. Hypertension, another component of metabolic syndrome, is also increasing in prevalence, and emerging evidence suggests that it may be associated with the development of certain cancers. The role of hypertension independent of other components of metabolic syndrome in the etiology of endometrial cancer remains unclear. In this study, we evaluated hypertension as an independent risk factor for endometrial cancer and whether this association is modified by other established risk factors. METHODS: We included 15,631 endometrial cancer cases and 42,239 controls matched on age, race, and study-specific factors from 29 studies in the Epidemiology of Endometrial Cancer Consortium. We used multivariable unconditional logistic regression models to estimate ORs and 95% confidence intervals (CI) to evaluate the association between hypertension and endometrial cancer and whether this association differed by study design, race/ethnicity, body mass index, diabetes status, smoking status, or reproductive factors. RESULTS: Hypertension was associated with an increased risk of endometrial cancer (OR, 1.14; 95% CI, 1.09-1.19). There was significant heterogeneity by study design (Phet < 0.01), with a stronger magnitude of association observed among case-control versus cohort studies. Stronger associations were also noted for pre-/perimenopausal women and never users of postmenopausal hormone therapy. CONCLUSIONS: Hypertension is associated with endometrial cancer risk independently from known risk factors. Future research should focus on biologic mechanisms underlying this association. IMPACT: This study provides evidence that hypertension may be an independent risk factor for endometrial cancer.