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We previously demonstrated that intake of low-fat dairy, but not high-fat dairy, was associated with a decreased colorectal cancer (CRC) recurrence risk. These risks, however, may differ by sex, primary tumour location, and disease stage. Combining data from two similar prospective cohort studies of people with stage I-III CRC enabled these subgroup analyses. Participants completed a food frequency questionnaire at diagnosis (n = 2283). We examined associations between low- and high-fat dairy intake and recurrence risk using multivariable Cox proportional hazard models, stratified by sex, and primary tumour location (colon and rectum), and disease stage (I/II and III). Upper quartiles were compared to lower quartiles of intake, and recurrence was defined as a locoregional recurrence and/or metastasis. During a median follow-up of 5.0 years, 331 recurrences were detected. A higher intake of low-fat dairy was associated with a reduced risk of recurrence (hazard ratio [HR]: 0.60, 95% confidence interval [CI]: 0.43-0.83), which seemed more pronounced in men (HR: 0.51, 95% CI: 0.34-0.77) than in women (HR: 0.84, 95% CI: 0.47-1.49). A higher intake of high-fat dairy was associated with an increased risk of recurrence in participants with colon cancer (HR: 1.60, 95% CI: 1.03-2.50), but not rectal cancer (HR: 0.88, 95% CI: 0.54-1.45). No differences in associations were observed between strata of disease stage. Concluding, our findings imply that dietary advice regarding low-fat dairy intake may be especially important for men with CRC, and that dietary advice regarding high-fat dairy intake may be specifically important in people with colon cancer.
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Neoplasias Colorretais , Laticínios , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Humanos , Masculino , Feminino , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/epidemiologia , Pessoa de Meia-Idade , Neoplasias Colorretais/patologia , Neoplasias Colorretais/epidemiologia , Idoso , Estudos Prospectivos , Gorduras na Dieta/administração & dosagem , Gorduras na Dieta/efeitos adversos , Fatores Sexuais , Fatores de Risco , Modelos de Riscos Proporcionais , Dieta Hiperlipídica/efeitos adversosRESUMO
BACKGROUND: Low muscle mass and skeletal muscle mass (SMM) loss are associated with adverse patient outcomes, but the time-consuming nature of manual SMM quantification prohibits implementation of this metric in clinical practice. Therefore, we assessed the feasibility of automated SMM quantification compared to manual quantification. We evaluated both diagnostic accuracy for low muscle mass and associations of SMM (change) with survival in colorectal cancer (CRC) patients. METHODS: Computed tomography (CT) images from CRC patients enrolled in two clinical studies were analyzed. We compared i) manual vs. automated segmentation of preselected slices at the third lumbar [L3] vertebra ("semi-automated"), and ii) manual L3-slice-selection + manual segmentation vs. automated L3-slice-selection + automated segmentation ("fully-automated"). Automated L3-selection and automated segmentation was performed with Quantib Body Composition v0.2.1. Bland-Altman analyses, within-subject coefficients of variation (WSCVs) and Intraclass Correlation Coefficients (ICCs) were used to evaluate the agreement between manual and automatic segmentation. Diagnostic accuracy for low muscle mass (defined by an established sarcopenia cut-off) was calculated with manual assessment as the "gold standard". Using either manual or automated assessment, Cox proportional hazard ratios (HRs) were used to study the association between changes in SMM (>5% decrease yes/no) during first-line metastatic CRC treatment and mortality adjusted for prognostic factors. SMM change was also assessed separately in weight-stable (<5%, i.e. occult SMM loss) patients. RESULTS: In total, 1580 CT scans were analyzed, while a subset of 307 scans were analyzed in the fully-automated comparison. Included patients (n = 553) had a mean age of 63 ± 9 years and 39% were female. The semi-automated comparison revealed a bias of -2.41 cm2, 95% limits of agreement [-9.02 to 4.20], a WSCV of 2.25%, and an ICC of 0.99 (95% confidence intervals (CI) 0.97 to 1.00). The fully-automated comparison method revealed a bias of -0.08 cm2 [-10.91 to 10.75], a WSCV of 2.85% and an ICC of 0.98 (95% CI 0.98 to 0.99). Sensitivity and specificity for low muscle mass were 0.99 and 0.89 for the semi-automated comparison and 0.96 and 0.90 for the fully-automated comparison. SMM decrease was associated with shorter survival in both manual and automated assessment (n = 78/280, HR 1.36 [95% CI 1.03 to 1.80] and n = 89/280, HR 1.38 [95% CI 1.05 to 1.81]). Occult SMM loss was associated with shorter survival in manual assessment, but not significantly in automated assessment (n = 44/263, HR 1.43 [95% CI 1.01 to 2.03] and n = 51/2639, HR 1.23 [95% CI 0.87 to 1.74]). CONCLUSION: Deep-learning based assessment of SMM at L3 shows reliable performance, enabling the use of CT measures to guide clinical decision making. Implementation in clinical practice helps to identify patients with low muscle mass or (occult) SMM loss who may benefit from lifestyle interventions.
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BACKGROUND: Although animal experiments suggest beneficial effects of physical activity (PA) on antitumor immunity, little is known about the effects of PA on immune checkpoint inhibitor (ICI) toxicity and effectiveness in humans. We assessed the association of PA with immune-related adverse events (irAE) and survival in patients undergoing ICI. METHODS: Patients receiving ICI who completed the Dutch short questionnaire to assess health enhancing physical activity (SQUASH) questionnaire at the start of treatment as part of the prospective UNICIT study in an academic hospital were included. PA was quantified by calculating total metabolic equivalent task hours per week (total PA) and hours per week of moderate- to vigorous-intensity PA during sport and leisure time (MVPA-SL). Associations of PA with severe irAE occurrence within 1 year and overall survival (OS) were evaluated using logistic regression and Cox proportional hazard regression, respectively, with adjustment for probable confounders. RESULTS: In total, 251 patients were included, with a median follow-up of 20 months. Moderate and high levels of total PA were associated with lower odds of severe irAE occurrence compared to low levels of total PA (adjusted OR: 0.34 [95% CI = 0.12 to 0.90] and 0.19 [95% CI = 0.05 to 0.55], respectively). Moderate and high levels of total PA were also associated with prolonged survival (adjusted HR: 0.58 [95% CI = 0.32 to 1.04] and 0.48 [95% CI = 0.27 to 0.89], respectively). Similar associations were observed in patients who performed more MVPA-SL. CONCLUSIONS: Higher physical activity levels at the start of ICI treatment are associated with lower risk of severe irAEs and probably prolonged survival. Randomized controlled trials are needed to investigate whether patients indeed benefit from increasing PA levels after diagnosis.
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Exercício Físico , Humanos , Estudos Prospectivos , Estudos RetrospectivosRESUMO
AIM: The aim of this study was to longitudinally investigate dietary and lifestyle inflammation scores and their interaction in relation to risk of colorectal cancer (CRC) recurrence and all-cause mortality. METHODS: Data of two prospective cohort studies among CRC survivors was used. Information about diet and/or lifestyle was available for 2739 individuals for at least one of the following time points: at diagnosis, six months after diagnosis and two years after diagnosis. The dietary and lifestyle inflammation scores (DIS and LIS) were used to evaluate the inflammatory potential of diet and lifestyle. Joint modelling, combining mixed models and Cox proportional hazards regression, were used to assess associations between DIS and LIS over time and CRC recurrence and all-cause mortality. Interactions between DIS and LIS were assessed using time-dependent Cox proportional hazard regression. RESULTS: The median follow-up time was 4.8 (IQR 2.9-6.9) years for recurrence and 5.7 (IQR 3.5-8.5) years for all-cause mortality, with 363 and 453 events, respectively. A higher DIS as well as LIS was associated with a higher risk of all-cause mortality (HRDIScontinuous 1.09 95%CI 1.02; 1.15; HRLIScontinuous 1.24 95%CI 1.05; 1.46). Individuals who were in the upper tertile of both DIS and LIS had the highest all-cause mortality risk (HR 1.62 95%CI 1.16; 2.28), compared to the individuals in the lowest tertile of both DIS and LIS. No consistent associations with recurrence were observed. CONCLUSION: A more pro-inflammatory diet and lifestyle was associated with a higher risk of all-cause mortality, but not recurrence, in CRC survivors.
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INTRODUCTION: Physical activity (PA) is associated with higher quality of life and probably better prognosis among colorectal cancer (CRC) patients. This study focuses on determinants of PA among CRC patients from diagnosis until 5 yr postdiagnosis. METHODS: Sociodemographic and disease-related factors of participants of two large CRC cohort studies were combined. Moderate-to-vigorous PA during sport and leisure time (MVPA-SL) was measured at diagnosis (T0) and 6, 12, 24, and 60 months (T6 to T60) postdiagnosis, using the SQUASH questionnaire. Mixed-effects models were performed to identify sociodemographic and disease-related determinants of MVPA-SL, separately for stage I-III colon (CC), stage I-III rectal cancer (RC), and stage IV CRC (T0 and T6 only). Associations were defined as consistently present when significant at ≥4 timepoints for the stage I-III subsets. MVPA-SL levels were compared with an age- and sex-matched sample of the general Dutch population. RESULTS: In total, 2905 CC, 1459 RC and 436 stage IV CRC patients were included. Patients with higher fatigue scores, and women compared with men had consistently lower MVPA-SL levels over time, regardless of tumor type and stage. At T6, having a stoma was significantly associated with lower MVPA-SL among stage I-III RC patients. Systemic therapy and radiotherapy were not significantly associated with MVPA-SL changes at T6. Compared with the general population, MVPA-SL levels of CRC patients were lower at all timepoints, most notably at T6. CONCLUSIONS: Female sex and higher fatigue scores were consistent determinants of lower MVPA-SL levels among all CRC patients, and MVPA-SL levels were lowest at 6 months postdiagnosis. Our results can inform the design of intervention studies aimed at improving PA, and guide healthcare professionals in optimizing individualized support.
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Neoplasias Colorretais , Qualidade de Vida , Masculino , Humanos , Feminino , Exercício Físico , Estudos de Coortes , Neoplasias Colorretais/diagnóstico , FadigaRESUMO
BACKGROUND: S-1 is an oral fluoropyrimidine that is increasingly used in Western countries for the treatment of metastatic colorectal cancer (mCRC). We conducted a non-inferiority meta-analysis on the efficacy of S-1-based therapy versus 5-fluorouracil (5-FU)- or capecitabine-based therapy in the treatment of patients with mCRC. METHODS: MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and Opengrey were searched for randomised clinical trials until May 2021. Data were extracted for progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and adverse events. Pooled effect estimates, stratified by treatment line, with corresponding 99% confidence intervals (CI) were presented. For PFS, a pre-defined non-inferiority margin (ΔNI) of 1.25 was selected. RESULTS: Ten studies (n = 2117) were included, of which six studies reported PFS and OS data and 10 studies reported ORR data. S-1-based therapy was shown to be non-inferior to 5-FU/capecitabine-based therapy in terms of PFS (HRtotal 0.95, 99% CI 0.83-1.08) with its CI upper limit well below ΔNI, and at least as efficacious in terms of OS (HRtotal 0.93, 99% CI 0.81-1.07), and ORR (RRtotal 1.06, 99% CI 0.90-1.24). CONCLUSIONS: S-1-based therapy is non-inferior to 5-FU/capecitabine-based therapy in the treatment of mCRC regarding PFS and at least as efficacious as 5-FU/capecitabine-based therapy in terms of ORR and OS. These data support the use of S-1 in mCRC patients who are intolerant to 5-FU/capecitabine-based treatment.
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Neoplasias Colorretais , Fluoruracila , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Capecitabina/efeitos adversos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Fluoruracila/efeitos adversos , HumanosRESUMO
BACKGROUND: Genomic loci where recurrent pathogenic copy number variants are associated with psychiatric phenotypes in the population may also be sensitive to the collective impact of multiple functional low-frequency single nucleotide variants (SNVs). METHODS: We examined the cumulative impact of low-frequency, functional SNVs within the 22q11.2 region on schizophrenia risk in a discovery cohort and an independent replication cohort (N = 1933 and N = 11,128, respectively), as well as the impact on educational attainment (EA) in a third, independent, general population cohort (N = 2081). In the discovery and EA cohorts, SNVs were identified using genotyping arrays; in the replication cohort, whole-exome sequencing was available. For verification, we compared the regional SNV count for schizophrenia cases in the discovery cohort with a normative count distribution derived from a large population dataset (N = 26,500) using bootstrap procedures. RESULTS: In both schizophrenia cohorts, an increased regional SNV burden (≥4 low-frequency SNVs) in the 22q11.2 region was associated with schizophrenia (discovery cohort: odds ratio = 7.48, p = .039; replication cohort: odds ratio = 1.92, p = .004). In the EA cohort, an increased regional SNV burden at 22q11.2 was associated with decreased EA (odds ratio = 4.65, p = .049). Comparing the SNV count for schizophrenia cases with a normative distribution confirmed the unique nature of the distribution for schizophrenia cases (p = .002). CONCLUSIONS: In the general population, an increased burden of low-frequency, functional SNVs in the 22q11.2 region is associated with schizophrenia risk and a decrease in EA. These findings suggest that in addition to structural variation, a cumulative regional burden of low-frequency, functional SNVs in the 22q11.2 region can also have a relevant phenotypic impact.
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Esquizofrenia , Estudos de Coortes , Variações do Número de Cópias de DNA/genética , Humanos , Fenótipo , Esquizofrenia/genéticaRESUMO
Regular physical activity (PA) is associated with improved overall survival (OS) in stage I-III colorectal cancer (CRC) patients. This association is less defined in patients with metastatic CRC (mCRC). We therefore conducted a study in mCRC patients participating in the Prospective Dutch Colorectal Cancer cohort. PA was assessed with the validated SQUASH questionnaire, filled-in within a maximum of 60 days after diagnosis of mCRC. PA was quantified by calculating Metabolic Equivalent Task (MET) hours per week. American College of Sports and Medicine (ACSM) PA guideline adherence, tertiles of moderate to vigorous PA (MVPA), and sport and leisure time MVPA (MVPA-SL) were assessed as well. Vital status was obtained from the municipal population registry. Cox proportional-hazards models were used to study the association between PA determinants and all-cause mortality adjusted for prognostic patient and treatment-related factors. In total, 293 mCRC patients (mean age 62.9 ± 10.6 years, 67% male) were included in the analysis. Compared to low levels, moderate and high levels of MET-hours were significantly associated with longer OS (fully adjusted hazard ratios: 0.491, (95% CI 0.299-0.807, p value = 0.005) and 0.485 (95% CI 0.303-0.778, p value = 0.003), respectively), as were high levels of MVPA (0.476 (95% CI 0.278-0.816, p value = 0.007)) and MVPA-SL (0.389 (95% CI 0.224-0.677, p value < 0.001)), and adherence to ACSM PA guidelines compared to non-adherence (0.629 (95% CI 0.412-0.961, p value = 0.032)). The present study provides evidence that higher PA levels at diagnosis of mCRC are associated with longer OS.