Treatment interval in curative treatment of colon cancer, does it impact (cancer free) survival? A non-inferiority analysis.

BACKGROUND: In treatment of colon cancer, strict waiting-time targets are enforced, leaving professionals no room to lengthen treatment intervals when advisable, for instance to optimise a patient's health status by means of prehabilitation. Good quality studies supporting these targets are lacking. With this study we aim to establish whether a prolonged treatment interval is associated with a clinically relevant deterioration in overall and cancer free survival. METHODS: This retrospective multicenter non-inferiority study includes all consecutive patients who underwent elective oncological resection of a biopsy-proven primary non-metastatic colon carcinoma between 2010 and 2016 in six hospitals in the Southern Netherlands. Treatment interval was defined as time between diagnosis and surgical treatment. Cut-off points for treatment interval were ≤35 days and ≤49 days. FINDINGS: 3376 patients were included. Cancer recurred in 505 patients (15.0%) For cancer free survival, a treatment interval >35 days and >49 days was non-inferior to a treatment interval ≤35 days. Results for overall survival were inconclusive, but no association was found. CONCLUSION: For cancer free survival, a prolonged treatment interval, even over 49 days, is non-inferior to the currently set waiting-time target of ≤35 days. Therefore, the waiting-time targets set as fundamental objective in current treatment guidelines should become directional instead of strict targets.

A retrospective analysis of the association of effort-independent cardiopulmonary exercise test variables with postoperative complications in patients who underwent elective colorectal surgery.

PURPOSE: This study aimed to investigate the association of effort-independent variables derived from the preoperative cardiopulmonary exercise test (CPET) with 30-day postoperative complications after elective colorectal surgery. METHODS: A multicenter (n=4) retrospective explorative study was performed using data of patients who completed a preoperative CPET and underwent elective colorectal surgery. The preoperative slope of the relation between minute ventilation and carbon dioxide production (VE/VCO2-slope) and the oxygen uptake efficiency slope (OUES), as well as 30-day postoperative complications, were assessed. Multivariable logistic regression analyses and receiver operating characteristic (ROC) curves were used to investigate the prognostic value of the relationship between these preoperative CPET-derived effort-independent variables and postoperative complications. RESULTS: Data from 102 patients (60.1% males) with a median age of 72.0 (interquartile range 67.8-77.4) years were analyzed. Forty-four patients (43.1%) had one or more postoperative complications (of which 52.3% general and 77.3% surgical complications). Merely 10 (9.8%) patients had a general complication only. In multivariate analysis adjusted for surgical approach (open versus minimally invasive surgery), the VE/VCO2-slope (odds ratio (OR) 1.08, confidence interval (CI) 1.02-1.16) and OUES (OR 0.94, CI 0.89-1.00) were statistically significant associated with the occurrence of 30-day postoperative complications. CONCLUSION: The effort-independent VE/VCO2-slope and OUES might be used to assist in future preoperative risk assessment and could especially be of added value in patients who are unable or unwilling to deliver a maximal cardiorespiratory effort. Future research should reveal the predictive value of these variables individually and/or in combination with other prognostic (CPET-derived) variables for postoperative complications. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT05331196.

Node-negative colon cancer: histological, molecular, and stromal features predicting disease recurrence.

BACKGROUND: Within the group of node-negative colon cancer patients, presumed to have a good prognosis, a significant percentage of patients develops cancer-recurrence. Current high-risk features prove inadequate to select these particular high-risk patients. In the process of tailor-made care and shared decision-making the need to identify these patients grows. In this study we investigate the value of adding molecular markers and the tumour-stroma ratio (TSR) to conventional histological tumour staging methods to improve the selection of high risk patients. METHODS: We retrospectively analysed 201 patients diagnosed with TNM-stage I-II colon cancer and treated by complete oncological resection between November 1st 2002 and December 31st 2012 at the Jeroen Bosch Hospital. Conventional histological tumour staging, BRAF mutations, KRAS mutations, MSI status and TSR were determined. Differences between groups based on TSR and mutation status, in disease free survival were analysed using Cox-Regression analyses. RESULTS: Poorly differentiated histology (p = 0.002), high-TSR (p = 0.033), BRAF-mutation (p = 0.008) and MSI (p = 0.011) were identified as significant risk factors for cancer recurrence. The risk of recurrence increased in the presence of both a BRAF-mutation and high-TSR compared to the absence of both factors or presence of only one factor (HR = 3.66 BRAF-mt/TSR-low (p = 0.006), HR 2.82 BRAF-wt/TSR-high (p = 0.015), HR = 4.39 BRAF-mt/TSR-high (p = 0.023)). This was also seen in tumours with MSI and high-TSR (HR = 2.46 MSS/TSR-high (p = 0.041), HR = 3.31 MSI/TSR-high (p = 0.045). CONCLUSION: Judging by the higher HR for the combination of the prognostic factors TSR and BRAF compared to the HRs of these prognostic factors individually, the prognostication for disease free survival can be improved by determining both TSR and BRAF instead of BRAF alone, as is done in current daily practise. In this study MSI also shows additional value to TSR in the prognostication of disease free survival. Adopting TSR into daily diagnostics will be of additional value next to currently used molecular markers in risk stratification of patients with node negative colon cancer and is therefore advised.

Evaluation of National Surgical Practice for Lateral Lymph Nodes in Rectal Cancer in an Untrained Setting.

BACKGROUND: Involved lateral lymph nodes (LLNs) have been associated with increased local recurrence (LR) and ipsi-lateral LR (LLR) rates. However, consensus regarding the indication and type of surgical treatment for suspicious LLNs is lacking. This study evaluated the surgical treatment of LLNs in an untrained setting at a national level. METHODS: Patients who underwent additional LLN surgery were selected from a national cross-sectional cohort study regarding patients undergoing rectal cancer surgery in 69 Dutch hospitals in 2016. LLN surgery consisted of either 'node-picking' (the removal of an individual LLN) or 'partial regional node dissection' (PRND; an incomplete resection of the LLN area). For all patients with primarily enlarged (≥7 mm) LLNs, those undergoing rectal surgery with an additional LLN procedure were compared to those  undergoing only rectal resection. RESULTS: Out of 3057 patients, 64 underwent additional LLN surgery, with 4-year LR and LLR rates of 26% and 15%, respectively. Forty-eight patients (75%) had enlarged LLNs, with corresponding recurrence rates of 26% and 19%, respectively. Node-picking (n = 40) resulted in a 20% 4-year LLR, and a 14% LLR after PRND (n = 8; p = 0.677). Multivariable analysis of 158 patients with enlarged LLNs undergoing additional LLN surgery (n = 48) or rectal resection alone (n = 110) showed no significant association of LLN surgery with 4-year LR or LLR, but suggested higher recurrence risks after LLN surgery (LR: hazard ratio [HR] 1.5, 95% confidence interval [CI] 0.7-3.2, p = 0.264; LLR: HR 1.9, 95% CI 0.2-2.5, p = 0.874). CONCLUSION: Evaluation of Dutch practice in 2016 revealed that approximately one-third of patients with primarily enlarged LLNs underwent surgical treatment, mostly consisting of node-picking. Recurrence rates were not significantly affected by LLN surgery, but did suggest worse outcomes. Outcomes of LLN surgery after adequate training requires further research.

Influence of different data-averaging methods on mean values of selected variables derived from preoperative cardiopulmonary exercise testing in patients scheduled for colorectal surgery.

INTRODUCTION: Patients with a low cardiorespiratory fitness (CRF) undergoing colorectal cancer surgery have a high risk for postoperative complications. Cardiopulmonary exercise testing (CPET) to assess CRF is the gold standard for preoperative risk assessment. To aid interpretation of raw breath-by-breath data, different methods of data-averaging can be applied. This study aimed to investigate the influence of different data-averaging intervals on CPET variables used for preoperative risk assessment, as well as to evaluate whether different data-averaging intervals influence preoperative risk assessment. METHODS: A total of 21 preoperative CPETs were interpreted by two exercise physiologists using stationary time-based data-averaging intervals of 10, 20, and 30 seconds and rolling average intervals of 3 and 7 breaths. Mean values of CPET variables between different data averaging intervals were compared using repeated measures ANOVA. The variables of interest were oxygen uptake at peak exercise (VO2peak), oxygen uptake at the ventilatory anaerobic threshold (VO2VAT), oxygen uptake efficiency slope (OUES), the ventilatory equivalent for carbon dioxide at the ventilatory anaerobic threshold (VE/VCO2VAT), and the slope of the relationship between the minute ventilation and carbon dioxide production (VE/VCO2-slope). RESULTS: Between data-averaging intervals, no statistically significant differences were found in the mean values of CPET variables except for the ventilatory equivalent for carbon dioxide at the ventilatory anaerobic threshold (P = 0.001). No statistically significant differences were found in the proportion of patients classified as high or low risk regardless of the used data-averaging interval. CONCLUSION: There appears to be no significant or clinically relevant influence of the evaluated data-averaging intervals on the mean values of CPET outcomes used for preoperative risk assessment. Clinicians may choose a data-averaging interval that is appropriate for optimal interpretation and data visualization of the preoperative CPET. Nevertheless, caution should be taken as the chosen data-averaging interval might lead to substantial within-patient variation for individual patients. CLINICAL TRIAL REGISTRATION: Prospectively registered at ClinicalTrials.gov (NCT05353127).

Feasibility of a tele-prehabilitation program in high-risk patients with colon or rectal cancer undergoing elective surgery: a feasibility study.

BACKGROUND: Prehabilitation appears to be an effective strategy to reduce postoperative complications and enhance recovery after colorectal surgery. Although many patients prefer (unsupervised) home-based prehabilitation, adherence can be problematic. Combining home-based prehabilitation with tele-monitoring might demonstrate a higher adherence than unsupervised prehabilitation; however, evidence on its feasibility and effectiveness in patients with colorectal cancer scheduled for elective surgery who are at high risk for postoperative complications is lacking. The aim of this study was to assess the feasibility of a bimodal tele-prehabilitation program in patients with colorectal cancer at high risk for postoperative complications. METHODS: High-risk patients (oxygen uptake at the ventilatory anaerobic threshold ≤11 mL/kg/min or oxygen uptake at peak exercise ≤ 18 mL/kg/min) with colorectal cancer were included in a home-based bimodal tele-prehabilitation program. The program consisted of a personalized tele-monitored moderate to high-intensity interval training intervention and nutritional counseling. Feasibility was measured by participation rate, dropout rate, adherence to the physical exercise training session's frequency, intensity, and time, and retention rate. Patient appreciation was measured by a patient appreciation questionnaire. Changes in preoperative physical fitness as secondary outcomes were quantified by time to exhaustion on a constant work rate (cycle) test, number of repetitions on the 30-s chair-stand test, and walking speed on the 4-m gait speed test. RESULTS: The participation rate was 81%, there were no adverse events, and all participants managed to complete the tele-prehabilitation program (retention rate of 100%). Adherence with regard to the exercise program's frequency, intensity, and time was respectively 91%, 84%, and 100%. All participants appreciated the tele-prehabilitation program. Time to exhaustion on the constant work rate test improved (not statistically significant) from a pre-prehabilitation median score of 317 seconds to a post-prehabilitation median score of 412 seconds (p = 0.24). Median number of repetitions on the 30-s chair-stand test improved from 12 to 16 (p = 0.01). CONCLUSIONS: Tele-prehabilitation seems feasible in high-risk patients with colorectal cancer, but efforts should be made to further improve adherence to physical exercise training intensity. More research is needed to establish the (cost-)effectiveness of tele-prehabilitation regarding preoperative improvements in preoperative aerobic fitness and postoperative reduction of complications. TRIAL REGISTRATION: ISRCTN, ISRCTN64482109 . Registered 09 November 2021 - Retrospectively registered.

Longitudinal Associations between Inflammatory Markers and Fatigue up to Two Years after Colorectal Cancer Treatment.

BACKGROUND: Fatigue is often reported by colorectal cancer survivors and largely impacts their quality of life. Inflammation has been linked to fatigue mainly in patients with breast cancer. Therefore, we investigated how inflammation is longitudinally associated with fatigue in colorectal cancer survivors, up to 2 years posttreatment. METHODS: A total of 257 patients from the ongoing Energy for life after ColoRectal cancer cohort study were included in the analysis. Plasma levels of IL6, IL8, IL10, TNFα, high-sensitivity C-reactive protein (hsCRP), and fatigue were measured at 6 weeks, 6, 12, and 24 months posttreatment. Fatigue was measured through the validated Checklist Individual Strength (CIS; total, 20-140), consisting of four subscales - subjective fatigue (8-56), motivation (4-28), physical activity (3-21), and concentration (5-35), and the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 fatigue subscale (0-100). Linear mixed-models were used to assess the confounder-adjusted longitudinal associations between inflammatory markers and overall fatigue along with the subscales. RESULTS: Mean levels of CIS fatigue decreased from 62.9 at 6 weeks to 53.0 at 24 months. In general, levels of inflammatory markers also decreased over time. No statistically significant longitudinal associations were found between IL6, IL8, IL10, TNFα, and fatigue. Higher levels of hsCRP were associated with more CIS fatigue (ß per SD 3.21, 95% confidence interval (CI), 1.42-5.01) and EORTC fatigue (ß 2.41, 95% CI, 0.72-4.10). CONCLUSIONS: Increased levels of hsCRP are longitudinally associated with more posttreatment fatigue in colorectal cancer survivors. IMPACT: These findings suggest that low-grade inflammation may play a role in fatigue reported by colorectal cancer survivors up to 2 years posttreatment.

A prospective cohort study to evaluate continuous wound infusion with local analgesics within an enhanced recovery protocol after colorectal cancer surgery.

AIM: To reduce detrimental opioid-related side effects, minimising the postoperative opioid consumption is needed, especially in older patients. Continuous wound infusion (CWI) with local analgesics appears to be an effective opioid-sparing alternative. However, the added value of CWI to an enhanced recovery protocol after colorectal cancer (CRC) surgery is unclear. The aim of this study was to evaluate the outcomes of CWI after CRC surgery within a strictly adhered to enhanced recovery protocol. METHODS: In this multicentre prospective observational cohort study, patients who underwent CRC surgery between May 2019 and January 2021 were included. Patients were treated with CWI as adjunct to multimodal pain management within an enhanced recovery protocol. Postoperative opioid consumption, pain scores and outcomes regarding functional recovery were evaluated. RESULTS: A cohort of 130 consecutive patients were included, of whom 36.2% were ≥75 years. Postoperative opioids were consumed by 80 (61.5%) patients on postoperative day 0, and by 28 (21.5%), 27 (20.8%), and 18 (13.8%) patients on postoperative days 1, 2, and 3, respectively. Median pain scores were <4 on all days. The median time until first passage of stool was 1.0 (IQR: 1.0-2.0) day. Postoperative delirium occurred in 0.8%. Median length of hospital stay was 3.0 days (IQR: 2.0-5.0). CONCLUSION: In patients treated with CWI, low amounts of postoperative opioid consumption, adequate postoperative pain control, and enhanced recovery were observed. CWI seems a beneficial opioid-sparing alternative and may further improve the outcomes of an enhanced recovery protocol after CRC surgery, which seems especially valuable for older patients.

Inter-observer agreement of preoperative cardiopulmonary exercise test interpretation in major abdominal surgery.

BACKGROUND: Accurate determination of cardiopulmonary exercise test (CPET) derived parameters is essential to allow for uniform preoperative risk assessment. The objective of this prospective observational study was to evaluate the inter-observer agreement of preoperative CPET-derived variables by comparing a self-preferred approach with a systematic guideline-based approach. METHODS: Twenty-six professionals from multiple centers across the Netherlands interpreted 12 preoperative CPETs of patients scheduled for hepatopancreatobiliary surgery. Outcome parameters of interest were oxygen uptake at the ventilatory anaerobic threshold (V̇O2VAT) and at peak exercise (V̇O2peak), the slope of the relationship between the minute ventilation and carbon dioxide production (V̇E/V̇CO2-slope), and the oxygen uptake efficiency slope (OUES). Inter-observer agreement of the self-preferred approach and the guideline-based approach was quantified by means of the intra-class correlation coefficient. RESULTS: Across the complete cohort, inter-observer agreement intraclass correlation coefficient (ICC) was 0.76 (95% confidence interval (CI) 0.57-0.93) for V̇O2VAT, 0.98 (95% CI 0.95-0.99) for V̇O2peak, and 0.86 (95% CI 0.75-0.95) for the V̇E/V̇CO2-slope when using the self-preferred approach. By using a systematic guideline-based approach, ICCs were 0.88 (95% CI 0.74-0.97) for V̇O2VAT, 0.99 (95% CI 0.99-1.00) for V̇O2peak, 0.97 (95% CI 0.94-0.99) for the V̇E/V̇CO2-slope, and 0.98 (95% CI 0.96-0.99) for the OUES. CONCLUSIONS: Inter-observer agreement of numerical values of CPET-derived parameters can be improved by using a systematic guideline-based approach. Effort-independent variables such as the V̇E/V̇CO2-slope and the OUES might be useful to further improve uniformity in preoperative risk assessment in addition to, or in case V̇O2VAT and V̇O2peak are not determinable.

Higher vitamin B6 status is associated with improved survival among patients with stage I-III colorectal cancer.

BACKGROUND: Folate-mediated 1-carbon metabolism requires several nutrients, including vitamin B6. Circulating biomarker concentrations indicating high vitamin B6 status are associated with a reduced risk of colorectal cancer (CRC). However, little is known about the effect of B6 status in relation to clinical outcomes in CRC patients. OBJECTIVES: We investigated survival outcomes in relation to vitamin B6 status in prospectively followed CRC patients. METHODS: A total of 2031 patients with stage I-III CRC participated in 6 prospective patient cohorts in the international FOCUS (folate-dependent 1-carbon metabolism in colorectal cancer recurrence and survival) Consortium. Preoperative blood samples were used to measure vitamin B6 status by the direct marker pyridoxal 5'-phosphate (PLP), as well as the functional marker HK-ratio (HKr)[3'-hydroxykynurenine: (kynurenic acid + xanthurenic acid + 3'-hydroxy anthranilic acid + anthranilic acid)]. Using Cox proportional hazards regression, we examined associations of vitamin B6 status with overall survival (OS), disease-free survival (DFS), and risk of recurrence, adjusted for patient age, sex, circulating creatinine concentrations, tumor site, stage, and cohort. RESULTS: After a median follow-up of 3.2 y for OS, higher preoperative vitamin B6 status as assessed by PLP and the functional marker HKr was associated with 16-32% higher all-cause and disease-free survival, although there was no significant association with disease recurrence (doubling in PLP concentration: HROS, 0.68; 95% CI: 0.59, 0.79; HRDFS, 0.84; 95% CI: 0.75, 0.94; HRRecurrence, 0.96; 95% CI: 0.84, 1.09; HKr: HROS, 2.04; 95% CI: 1.67, 2.49; HRDFS, 1.56; 95% CI: 1.31, 1.85; HRRecurrence, 1.21; 95% CI: 0.96,1. 52). The association of PLP with improved OS was consistent across colorectal tumor site (right-sided colon: HROS, 0.75; 95% CI: 0.59, 0.96; left-sided colon: HROS, 0.71; 95% CI: 0.55, 0.92; rectosigmoid junction and rectum: HROS, 0.61; 95% CI: 0.47, 0.78). CONCLUSION: Higher preoperative vitamin B6 status is associated with improved OS among stage I-III CRC patients.

Functional Bowel Complaints and the Impact on Quality of Life After Colorectal Cancer Surgery in the Elderly.

BACKGROUND: The Low Anterior Resection Syndrome (LARS) is commonly reported after colorectal cancer surgery and significantly impairs quality of life. The prevalence and impact of LARS in the elderly after rectal cancer as well as colon cancer surgery is unclear. We aimed to describe the prevalence of LARS complaints and the impact on quality of life in the elderly after colorectal cancer surgery. MATERIALS AND METHODS: Patients were included from seven Dutch hospitals if they were at least one year after they underwent colorectal cancer surgery between 2008 and 2015. Functional bowel complaints were assessed by the LARS score. Quality of life was assessed by the EORTC QLQ-C30 and EORTC QLQ-CR29 questionnaires. Outcomes in patients ≥70 years were compared to a reference group of patients <70 years. RESULTS: In total 440 rectal cancer and 1183 colon cancer patients were eligible for analyses, of whom 133 (30.2%) rectal and 536 (45.3%) colon cancer patients were ≥70 years. Major LARS was reported by 40.6% of rectal cancer and 22.2% of colon cancer patients ≥70 years. In comparison, patients <70 years reported major LARS in 57.3% after rectal cancer surgery (p=0.001) and in 20.4% after colon cancer surgery (p=0.41). Age ≥70 years was independently associated with reduced rates of major LARS after rectal cancer surgery (OR 0.63, p=0.04). Patients with major LARS reported significantly impaired quality of life on almost all domains. CONCLUSION: Elderly should not be withheld a restorative colorectal cancer resection based on age alone. However, a substantial part of the elderly colorectal cancer patients develops major LARS after surgery, which often severely impairs quality of life. Since elderly frequently consider quality of life and functional outcomes as one of the most important outcomes after treatment, major LARS and its impact on quality of life should be incorporated in the decision-making process.

Moderate-intensity exercise training or high-intensity interval training to improve aerobic fitness during exercise prehabilitation in patients planned for elective abdominal cancer surgery?

Low preoperative aerobic fitness is associated with an increased risk of postoperative complications and delayed recovery in patients with abdominal cancer. Surgical prehabilitation aims to increase aerobic fitness preoperatively to improve patient- and treatment-related outcomes. However, an optimal physical exercise training program that is effective within the short time period available for prehabilitation (<6 weeks) has not yet been established. In this comparative review, studies (n = 8) evaluating the effect of short-term (<6 weeks) moderate-intensity exercise training (MIET) or high-intensity interval training (HIIT) on objectively measured aerobic fitness were summarized. The content of exercise interventions was critically appraised regarding the frequency, intensity, time, type, volume, and - monitoring of - progression (FITT-VP) principles. Three out of four studies evaluating HIIT showed statistically significant improvements in oxygen uptake at peak exercise (VO2peak) by more than 4.9%, the coefficient of variation for VO2peak. None of the two studies investigating short-term MIET showed statistically significant pre-post changes in VO2peak. Although short-term HIIT seems to be a promising intervention, concise description of performed exercise based on the FITT-VP principles was rather inconsistent in studies. Hence, interpretation of the results is challenging, and a translation into practical recommendations is premature. More emphasis should be given to individual responses to physical exercise training. Therefore, adequate risk assessment, personalized physical exercise training prescription using the FITT-VP principles, full reporting of physical exercise training adherence, and objective monitoring of training progression and recovery is needed to ensure for a personalized and effective physical exercise training program within a multimodal prehabilitation program.

Associations between alcohol consumption and anxiety, depression, and health-related quality of life in colorectal cancer survivors.

PURPOSE: Alcohol consumption is a major risk factor for colorectal cancer (CRC). It is currently poorly understood, however, how alcohol and different alcoholic beverage types are related to psychosocial outcomes in CRC survivors. METHODS: We used data of N = 910 CRC survivors from the pooled EnCoRe and PROCORE cohorts and harmonized them into five time points: at diagnosis and 3, 6, 12, and 24 months post-diagnosis. Generalized estimated equation models were used to examine longitudinal associations of alcohol consumption, including consumption of beer, wine, and liquor, with anxiety, depression, and health-related quality of life (HRQoL), while correcting for sociodemographic, lifestyle, and clinical factors. RESULTS: Survivors were on average 67 years and 37% was female. In the first 2 years post-diagnosis, survivors who consumed more alcoholic drinks/week reported lower anxiety and depressive symptoms and better HRQoL on all domains and symptom scales. This was the case for moderate and heavy amounts of alcohol and mostly for consuming beer and wine, but not for liquor. Associations were more often significant for men and for younger persons (< 67 years at baseline). CONCLUSIONS: Generally, alcohol consumption was observed to be longitudinally related to less anxiety and depression and better HRQoL in CRC survivors. IMPLICATIONS FOR CANCER SURVIVORS: Although alcohol consumption is generally unfavorable due to increased risk of carcinogenesis and worse prognosis after CRC, it seems to be associated with better psychosocial outcomes in the first 2 years after diagnosis and treatment. More research is needed to gain knowledge about reasons for drinking and causality.

Heart-rate-variability (HRV), predicts outcomes in COVID-19.

BACKGROUND: Patients with COVID-19 present with a variety of clinical manifestations, ranging from mild or asymptomatic disease to severe illness and death. Whilst previous studies have clarified these and several other aspects of COVID-19, one of the ongoing challenges regarding COVID-19 is to determine which patients are at risk of adverse outcomes of COVID-19 infection. It is hypothesized that this is the result of insufficient inhibition of the immune response, with the vagus nerve being an important neuro-immuno-modulator of inflammation. Vagus nerve activity can be non-invasively indexed by heart-rate-variability (HRV). Therefore, we aimed to assess the prognostic value of HRV, as a surrogate marker for vagus nerve activity, in predicting mortality and intensive care unit (ICU) referral, in patients hospitalized with COVID-19. METHODS: A retrospective cohort study including all consecutive patients (n = 271) diagnosed and hospitalized with COVID-19 between March 2020 and May 2020, without a history of cardiac arrhythmias (including atrial and ventricular premature contractions), pacemaker, or current bradycardia (heart rate <50 bpm) or tachycardia (heart rate >110 bpm). HRV was based on one 10s ECG recorded at admission. 3-week survival and ICU referral were examined. RESULTS: HRV indexed as standard deviation of normal to normal heartbeat intervals (SDNN) predicted survival (H.R. = 0.53 95%CI: 0.31-0.92). This protective role was observed only in patients aged 70 years and older, not in younger patients. HRV below median value also predicted ICU referral within the first week of hospitalization (H.R = 0.51, 95%CI: 0.29-0.90, P = 0.021). CONCLUSION: Higher HRV predicts greater chances of survival, especially in patients aged 70 years and older with COVID-19, independent of major prognostic factors. Low HRV predicts ICU indication and admission in the first week after hospitalization.

The Association Between Treatment Interval and Survival in Patients With Colon or Rectal Cancer: A Systematic Review.

BACKGROUND: Surgery for colon or rectal cancer is associated with a high incidence of complications, especially in patients with a low aerobic fitness. Those patients might benefit from a comprehensive preoperative workup including prehabilitation. However, time between diagnosis and treatment is often limited due to current treatment guidelines. To date, it is unclear whether the treatment interval can be extended without compromising survival. METHODS: A systematic review concerning the association between treatment intervals and survival in patients who underwent elective curative surgery for colon or rectal cancer was performed. A search up to December 2020 was conducted in PubMed, Cinahl and Embase. Original research articles were eligible. Quality assessment was performed using the Downs and Black checklist. RESULTS: Eleven observational studies were included (897 947 patients). In colon cancer, treatment intervals that were statistically significant associated with reduced overall survival or cancer-specific survival ranged between > 30 and > 84 days. In rectal cancer, only one out of four studies showed that treatment intervals > 49 days was associated with reduced cancer-specific survival. CONCLUSIONS: This systematic review identified that studies investigating the association between treatment intervals and survival are heterogeneous with regard to treatment interval definitions, treatment interval time intervals and used outcome measures. These aspects need standardization before a reliable estimate of an optimal treatment interval can be made. In addition, further research should focus on establishing optimal treatment intervals in patients at high risk for postoperative complications, as particularly these patients might benefit from extended diagnosis to treatment intervals permitting comprehensive preoperative preparation.

Longitudinal associations of sociodemographic, lifestyle, and clinical factors with alcohol consumption in colorectal cancer survivors up to 2 years post-diagnosis.

PURPOSE: Alcohol consumption can lead to worse prognosis and mortality among colorectal cancer (CRC) patients. We investigated alcohol consumption of CRC survivors up to 2 years post-diagnosis, and how sociodemographic, lifestyle, and clinical factors were associated longitudinally with these habits. METHODS: We pooled longitudinal data of 910 CRC survivors from the ongoing PROCORE and EnCoRe studies with data collected at diagnosis (baseline) and 3, 6, 12, and 24 months post-diagnosis. Both studies assessed alcohol consumption, including beer, wine, and liquor. Generalized estimated equation models were used to examine changes over time in alcohol consumption and multivariable longitudinal associations of sociodemographic, lifestyle, and clinical factors with alcohol consumption. RESULTS: At baseline, participants were on average 67 years old, 332 (37%) were female, and alcohol was consumed by 79%. Most survivors (68-71%) drank less at all follow-ups. Beer, wine, and liquor were consumed by 51%, 58%, and 25% at baseline, respectively, and these declined over time. Males consumed more alcohol, and higher education, more physical activity, and not having a (permanent) stoma were associated with consuming more alcohol. CONCLUSION: CRC survivors decreased their alcohol consumption in the 2 years post-diagnosis. Future studies should take the significant factors that were associated with alcohol post-diagnosis consumption into account, when they investigate CRC health outcomes or for identifying subgroups for interventions. Males with higher education, more physical activity, and no stoma should be reminded after diagnosis for reducing their alcohol consumption.

Circulating Folate and Folic Acid Concentrations: Associations With Colorectal Cancer Recurrence and Survival.

BACKGROUND: Folates, including folic acid, may play a dual role in colorectal cancer development. Folate is suggested to be protective in early carcinogenesis but could accelerate growth of premalignant lesions or micrometastases. Whether circulating concentrations of folate and folic acid, measured around time of diagnosis, are associated with recurrence and survival in colorectal cancer patients is largely unknown. METHODS: Circulating concentrations of folate, folic acid, and folate catabolites p-aminobenzoylglutamate and p-acetamidobenzoylglutamate were measured by liquid chromatography-tandem mass spectrometry at diagnosis in 2024 stage I-III colorectal cancer patients from European and US patient cohort studies. Multivariable-adjusted Cox proportional hazard models were used to assess associations between folate, folic acid, and folate catabolites concentrations with recurrence, overall survival, and disease-free survival. RESULTS: No statistically significant associations were observed between folate, p-aminobenzoylglutamate, and p-acetamidobenzoylglutamate concentrations and recurrence, overall survival, and disease-free survival, with hazard ratios ranging from 0.92 to 1.16. The detection of folic acid in the circulation (yes or no) was not associated with any outcome. However, among patients with detectable folic acid concentrations (n = 296), a higher risk of recurrence was observed for each twofold increase in folic acid (hazard ratio = 1.31, 95% confidence interval = 1.02 to 1.58). No statistically significant associations were found between folic acid concentrations and overall and disease-free survival. CONCLUSIONS: Circulating folate and folate catabolite concentrations at colorectal cancer diagnosis were not associated with recurrence and survival. However, caution is warranted for high blood concentrations of folic acid because they may increase the risk of colorectal cancer recurrence.

Plasma metabolites associated with colorectal cancer stage: Findings from an international consortium.

Colorectal cancer is the second most common cause of cancer-related death globally, with marked differences in prognosis by disease stage at diagnosis. We studied circulating metabolites in relation to disease stage to improve the understanding of metabolic pathways related to colorectal cancer progression. We investigated plasma concentrations of 130 metabolites among 744 Stages I-IV colorectal cancer patients from ongoing cohort studies. Plasma samples, collected at diagnosis, were analyzed with liquid chromatography-mass spectrometry using the Biocrates AbsoluteIDQ™ p180 kit. We assessed associations between metabolite concentrations and stage using multinomial and multivariable logistic regression models. Analyses were adjusted for potential confounders as well as multiple testing using false discovery rate (FDR) correction. Patients presented with 23, 28, 39 and 10% of Stages I-IV disease, respectively. Concentrations of sphingomyelin C26:0 were lower in Stage III patients compared to Stage I patients (pFDR < 0.05). Concentrations of sphingomyelin C18:0 and phosphatidylcholine (diacyl) C32:0 were statistically significantly higher, while citrulline, histidine, phosphatidylcholine (diacyl) C34:4, phosphatidylcholine (acyl-alkyl) C40:1 and lysophosphatidylcholines (acyl) C16:0 and C17:0 concentrations were lower in Stage IV compared to Stage I patients (pFDR < 0.05). Our results suggest that metabolic pathways involving among others citrulline and histidine, implicated previously in colorectal cancer development, may also be linked to colorectal cancer progression.