Longitudinal associations of plasma kynurenines and ratios with fatigue and quality of life in colorectal cancer survivors up to 12 months post-treatment.

Fatigue is prevalent in colorectal cancer (CRC) survivors, impacting their health-related quality of life (HRQoL). Inflammation-induced activation of the kynurenine pathway may play a role in cancer-related fatigue and HRQoL, but evidence is scarce. Therefore, we aimed to investigate longitudinal associations of plasma tryptophan, kynurenines, and ratios with fatigue and HRQoL in CRC survivors up to 12 months post-treatment. Repeated measurements at 6 weeks, 6 months, and 12 months post-treatment were performed in 249 stage I-III CRC survivors. Plasma tryptophan and eight kynurenines were analyzed using liquid chromatography-tandem mass spectrometry (LC/MS-MS). Fatigue and HRQoL outcomes were evaluated using validated questionnaires. Confounder-adjusted linear mixed models were conducted to analyze longitudinal associations, with false discovery rate (FDR) correction. Higher tryptophan (Trp), kynurenic acid (KA), and xanthurenic acid (XA) concentrations, as well as a higher kynurenic acid-to-quinolinic acid ratio (KA/QA), were associated with less fatigue and better functioning, while a higher kynurenine-to-tryptophan ratio (KTR) and 3-hydroxykynurenine ratio (HKr) were associated with more fatigue and worse functioning. Finally, higher KA and XA concentrations and a higher KA/QA ratio were associated with a higher overall HRQoL summary score, while a higher HKr was associated with a lower overall HRQoL summary score. In conclusion, we observed that tryptophan and several kynurenines were longitudinally associated with fatigue and HRQoL in CRC survivors up to 12 months post-treatment. Future research is needed to validate our findings and explore the potential of the kynurenine pathway as intervention target for reducing fatigue and enhancing HRQoL after CRC treatment.

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.

Longitudinal associations of circadian eating patterns with sleep quality, fatigue and inflammation in colorectal cancer survivors up to 24 months post-treatment.

Fatigue and insomnia, potentially induced by inflammation, are distressing symptoms experienced by colorectal cancer (CRC) survivors. Emerging evidence suggests that besides the nutritional quality and quantity, also the timing, frequency and regularity of dietary intake (chrono-nutrition) could be important for alleviating these symptoms. We investigated longitudinal associations of circadian eating patterns with sleep quality, fatigue and inflammation in CRC survivors. In a prospective cohort of 459 stage I-III CRC survivors, four repeated measurements were performed between 6 weeks and 24 months post-treatment. Chrono-nutrition variables included meal energy contribution, frequency (a maximum of six meals could be reported each day), irregularity and time window (TW) of energetic intake, operationalised based on 7-d dietary records. Outcomes included sleep quality, fatigue and plasma concentrations of inflammatory markers. Longitudinal associations of chrono-nutrition variables with outcomes from 6 weeks until 24 months post-treatment were analysed by confounder-adjusted linear mixed models, including hybrid models to disentangle intra-individual changes from inter-individual differences over time. An hour longer TW of energetic intake between individuals was associated with less fatigue (ß: -6·1; 95 % CI (-8·8, -3·3)) and insomnia (ß: -4·8; 95 % CI (-7·4, -2·1)). A higher meal frequency of on average 0·6 meals/d between individuals was associated with less fatigue (ß: -3·7; 95 % CI (-6·6, -0·8)). An hour increase in TW of energetic intake within individuals was associated with less insomnia (ß: -3·0; 95 % CI (-5·2, -0·8)) and inflammation (ß: -0·1; 95 % CI (-0·1, 0·0)). Our results suggest that longer TWs of energetic intake and higher meal frequencies may be associated with less fatigue, insomnia and inflammation among CRC survivors. Future studies with larger contrasts in chrono-nutrition variables are needed to confirm these findings.

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.

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.

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.

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.

Associations of Pretreatment Physical Status Parameters with Tolerance of Concurrent Chemoradiation and Survival in Patients with Non-small Cell Lung Cancer.

OBJECTIVE: The aim of this study was to evaluate associations between pretreatment physical status parameters and tolerance of concurrent chemoradiation (cCHRT) and survival among patients with stage III non-small cell lung cancer (NSCLC). METHODS: A retrospective cohort study was conducted among patients with stage III NSCLC who had received cCHRT between 2006 and 2015. Multivariate independent associations were analysed between the pretreatment parameters age, Charlson comorbidity index, World Health Organization performance status (WHO performance status), body mass index (BMI), fat-free mass index (FFMI), maximal handgrip strength, forced expiratory volume in one second and carbon monoxide lung diffusion capacity on the one hand with tolerance of cCHRT (defined as a received radiation dose at least equal to the prescribed radiation dose) and survival on the other hand. RESULTS: 527 of 577 patients (91.3%) tolerated cCHRT. A WHO performance status ≥ 2 (odds ratio (OR) 0.43) and BMI < 18.5 kg/m2 (OR 0.36) were associated with poorer tolerance of cCHRT. In the total group, a WHO performance status ≥ 2 (hazard ratio (HR) 1.73), low FFMI (HR 1.23) and intolerance of cCHRT (HR 1.55) were associated with poorer survival. CONCLUSION: In patients with stage III NSCLC receiving cCHRT, poor WHO performance status and BMI < 18.5 kg/m2 were independently associated with tolerance of cCHRT. Physical status parameters and intolerance of cCHRT were independently associated with poorer survival. Besides using this information for treatment decisions, optimizing physical status in patients at risk for intolerance of cCHRT might be a next step for improving treatment outcomes.

Diabetes mellitus, genetic variants in the insulin-like growth factor pathway and colorectal cancer risk.

Genetic variation in the insulin-like growth factor (IGF) pathway may further increase the risk of colorectal cancer (CRC) associated with type 2 diabetes mellitus (T2DM). Joint effects of T2DM and genetic variation in the IGF pathway on CRC risk can increase mechanistic insights. Participants from the Netherlands Cohort Study (n = 120, 852) completed a baseline questionnaire in 1986 when 55-69 years old (case-cohort, nsubcohort = 5,000, ncases = 3,441 after 16.3 years follow-up). Self-reported DM at baseline with onset at ≥30 years was classified as T2DM. Eighteen single nucleotide polymorphisms (SNPs) from the IGF pathway were aggregated in a genetic risk score (GRS). Cox proportional hazard ratios (HRs) for CRC were estimated according to combinations of T2DM status with GRS tertiles and categories of an IGF1 19-CA repeat polymorphism. Baseline T2DM prevalence was 3.1% in subcohort members and 3.8% in CRC cases. Comparison of combined categories with non-T2DM individuals in the lowest GRS tertile as reference showed that those in the highest GRS tertiles with and without T2DM had significantly increased CRC risks, particularly those with T2DM (HR = 2.28, 95% CI: 1.11, 4.66). As compared to IGF1 19-CA wild-type carriers without T2DM, carrying two IGF1 19-CA variant repeat alleles were associated with a significantly decreased CRC risk in those without T2DM (HR = 0.76, 95% CI: 0.63-0.91). This association was absent when T2DM was present. Our study of joint effects indicated that the presence of unfavorable alleles in the IGF pathway may further increase the risk of CRC associated with T2DM.

Geriatric Assessment for Older Patients with Non-small Cell Lung Cancer: Daily Practice of Centers Participating in the NVALT25-ELDAPT Trial.

INTRODUCTION: Geriatric assessment (GA) for older patients with lung cancer could provide insight into vulnerability, cognitive impairment, and risk of toxicity. Discontinuation and complications of intensive treatment could potentially be prevented in vulnerable and frail patients. This study aimed to evaluate current clinical practice of GA for older patients with lung cancer in the Netherlands and identify potential hurdles for implementation. METHODS: Pulmonologists and radiation oncologists participating in the NVALT25-ELDAPT trial completed an online questionnaire regarding current practice of GA, added value of GA for treatment decision-making and logistic barriers for patients with non-small cell lung cancer. RESULTS: 15 out of 17 centers responded. Three performed GA as standard procedure, three on indication, eight considered a frailty screening step before GA, and one did not perform GA. Suspicion of cognitive problems was mentioned most often as indication for GA and of added value for treatment decision-making, followed by older age, curative-intent treatment, and stage I-III lung cancer. Administered instruments for screening and extensive GA were diverse. Main barriers to implement GA in clinical practice were logistic problems (timescales and availability of trained personnel). CONCLUSION: The use of GA in clinical practice for patients with lung cancer varied widely across centers regarding instruments and domains. Physicians are uniform in their opinion about indications for GA and the added value for treatment decision-making. Research should focus on manageable instruments and important domains to assess for this heterogeneous group of older patients with lung cancer to optimize treatment selection. Trial registration The NVALT25-ELDAPT trial is registered under trial number NCT02284308. Details are available at http://www.eldapt.org (predominantly in Dutch).

Lung Cancer in the Oldest Old: A Nation-Wide Study in The Netherlands.

INTRODUCTION: An important step in improving research and care for the oldest patients with lung cancer is analyzing current data regarding diagnostic work-up, treatment choices, and survival. METHODS: We analyzed data on lung cancer from the Netherlands Cancer Registry (NCR-IKNL) regarding diagnostic work-up, treatment, and survival in different age categories; the oldest old (≥85 years of age) versus those aged 71-84 (elderly) and those aged ≤70 years (younger patients). RESULTS: 47,951 patients were included in the 2010-2014 NCR database. 2196 (5%) patients were aged ≥85 years. Histological diagnosis was obtained significantly less often in the oldest old (38%, p < 0.001), and less standard treatment regimen was given (8%, p < 0.001) compared to elderly and younger patients. 67% of the oldest old received best supportive care only versus 38% of the elderly and 20% of the younger patients (p < 0.001). For the oldest old receiving standard treatment, survival rates were similar in comparison with the elderly patients. In the oldest old, no survival differences were found when comparing standard or adjusted regimens for stage I and IV NSCLC; for stage III, oldest old receiving standard treatment had longer survival. No oldest old patients with stage II received standard treatment. CONCLUSION: Clinicians make limited use of diagnostics and invasive treatment in the oldest old; however, selected oldest old patients experienced similar survival rates as the elderly when receiving some form of anticancer therapy (standard or adjusted). More research is needed to further develop individualized treatment algorithms.

Comparability of the age and sex distribution of the UK Clinical Practice Research Datalink and the total Dutch population.

PURPOSE: The UK Clinical Practice Research Datalink (CPRD) is increasingly being used by Dutch researchers in epidemiology and pharmacoepidemiology. It is however unclear if the UK CPRD is representative of the Dutch population and whether study results would apply to the Dutch population. Therefore, as first step, our objective was to compare the age and sex distribution of the CPRD with the total Dutch population. METHODS: As a measure of representativeness, the age and sex distribution of the UK CPRD were visually and numerically compared with Dutch census data from the StatLine database of the Dutch National Bureau of Statistics in 2011. RESULTS: The age distribution of men and women in the CPRD population was comparable to the Dutch male and female population. Differences of more than 10% only occurred in older age categories (75+ in men and 80+ in women). CONCLUSIONS: Results from observational studies that have used CPRD data are applicable to the Dutch population, and a useful resource for decision making in the Netherlands. Nevertheless, differences in drug exposure likelihood between countries should be kept in mind, as these could still cause variations in the actual population studied, thereby decreasing its generalizability. Copyright © 2016 John Wiley & Sons, Ltd.

Sigmoid cancer versus chronic diverticular disease: differentiating features at CT colonography.

PURPOSE: To retrospectively identify morphologic findings at computed tomographic (CT) colonography that are the most reliable in the differentiation of masslike chronic diverticular disease from sigmoid carcinoma in a large patient cohort. MATERIALS AND METHODS: This study was approved by the institutional review boards. The need for signed consent was waived for this retrospective study. The cohort consisted of 212 patients (mean age, 68 years; 113 women, 99 men) with focal masslike findings in the sigmoid colon at CT colonography, representing chronic diverticular disease (n = 97) or sigmoid carcinoma (n = 115). CT colonography studies were scored according to presence or absence of potential discriminators by a panel of four readers in consensus. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated, and multivariate analysis was performed. RESULTS: Absence of diverticula in the affected segment showed high NPV and PPV (0.95 and 0.93, respectively). Also, shoulder phenomenon showed a high NPV (0.92) and PPV (0.75). Segment length of 10 cm or less (NPV, 0.85; PPV, 0.61) and destroyed mucosal folds (NPV, 1.00; PPV, 0.62) had a high NPV but a low PPV. Although segments affected by carcinoma often showed straightened and eccentric growth patterns, no thick fascia sign, and more and larger local-regional lymph nodes (all P < .05), NPV was insufficient for discrimination (NPV ≤ 0.66). Combination of absence of diverticula and presence of shouldering showed a high diagnostic certainty (93%). CONCLUSION: Carcinoma is best differentiated from masslike diverticular disease by the absence of diverticula in the affected segment and the presence of shoulder phenomenon.

The effect of 3% and 6% hypertonic saline in viral bronchiolitis: a randomised controlled trial.

Bronchiolitis is a common disorder in young children that often results in hospitalisation. Except for a possible effect of nebulised hypertonic saline (sodium chloride), no evidence-based therapy is available. This study investigated the efficacy of nebulised 3% and 6% hypertonic saline compared with 0.9% hypertonic saline in children hospitalised with viral bronchiolitis. In this multicentre, double-blind, randomised, controlled trial, children hospitalised with acute viral bronchiolitis were randomised to receive either nebulised 3%, 6% hypertonic saline or 0.9% normal saline during their entire hospital stay. Salbutamol was added to counteract possible bronchial constriction. The primary endpoint was the length of hospital stay. Secondary outcomes were need for supplemental oxygen and tube feeding. From the 292 children included in the study (median age 3.4 months), 247 completed the study. The median length of hospital stay did not differ between the groups: 69 h (interquartile range 57), 70 h (IQR 69) and 53 h (IQR 52), for 3% (n=84) and 6% (n=83) hypertonic saline and 0.9% (n=80) normal saline, respectively, (p=0.29). The need for supplemental oxygen or tube feeding did not differ significantly. Adverse effects were similar in the three groups. Nebulisation with hypertonic saline (3% or 6% sodium chloride) although safe, did not reduce the length of stay in hospital, duration of supplemental oxygen or tube feeding in children hospitalised with moderate-to-severe viral bronchiolitis.

Actual prognosis during follow-up of survivors of B-cell non-Hodgkin lymphoma in the Netherlands.

Survival rates determined at diagnosis are often too negative for cancer survivors. Conditional relative survival reflects actual prognosis during follow-up better. Data from all 54,015 patients newly diagnosed in the Netherlands with B-cell non-Hodgkin lymphoma during 1989-2008, aged 15-89 years (Netherlands Cancer Registry), were used. Five-year conditional relative survival was computed for every additional year of survival up to 16 years after diagnosis, according to entity, grade, gender, age, and Ann Arbor stage. The prognosis for survivors of indolent B-cell non-Hodgkin lymphoma improved slightly with each additional year survived up to 91%. For patients with aggressive non-Hodgkin lymphoma conditional relative survival improved strongly during the first year after diagnosis (from 48% to 68%) and gradually thereafter to 93% after 16 years. There were differences between morphological entities. Initial differences in conditional relative survival at diagnosis between groups with different disease stages became smaller with increasing number of years survived. Age remained a prognostic indicator, also after prolonged follow-up. These results help caregivers to plan optimal surveillance and inform patients about their actual prognosis during follow-up. Long-lasting excess mortality among patients with B-cell non-Hodgkin lymphoma indicates the need for additional care long after their diagnosis.

Patients with prostate cancer continue to have excess mortality up to 15 years after diagnosis.

OBJECTIVE: To estimate the population-based conditional 5-year relative survival rates for patients with prostate cancer (PCa). PATIENTS AND METHODS: All 98 672 patients, aged 45-89 years, diagnosed in the Netherlands with PCa (clinical T stage 1-4) in the period 1989-2008 were selected from the Netherlands Cancer Registry and followed up until 2010. The conditional 5-year relative survival rate was estimated for every subsequent year of survival up to 15 years after diagnosis. RESULTS: The conditional 5-year relative survival rate decreased with survival time from diagnosis. Excess mortality (conditional 5-year relative survival rate <95%) for patients with clinical T1 stage only became manifest 5 years after diagnosis and increased to almost 10% after 10 years. Patients with more advanced disease (cT2-cT4) were found to have an excess mortality rate of 6-12% at diagnosis, which increased to 15-22% after 10 years. Excess mortality occurred earlier for the older age groups. The 5-year relative survival rate at diagnosis was <90% for all age groups of patients with cT3/cT4 disease and excess mortality for this group increased to >20% for those who had already survived for 5 years since diagnosis. CONCLUSIONS: Patients with PCa were found to have excess mortality within 10 years of diagnosis. Excess mortality was found at an earlier timepoint for patients with a more advanced stage and for older age groups. Quantitative insight into conditional survival is useful for caregivers to help plan optimum cancer treatment and surveillance and to inform patients about their actual prognosis during follow-up, taking the current condition of the patient into account.

Prospective evaluation of the added value of imaging within the Dutch National Diagnostic Appendicitis Guideline--do we forget our clinical eye?

BACKGROUND: Annually 16,000 appendectomies are performed in the Netherlands, of which 15-20% are negative. In 2010, to reduce this unacceptable percentage of superfluous appendectomies, the Dutch Association for Surgery introduced the 'Appendicitis Guideline'. This guideline recommends the use of imaging. In this observational prospective study the added value of imaging in everyday clinical practice is evaluated. METHODS: All patients with suspected appendicitis were included at the emergency department of a Dutch teaching hospital during the period from September 2011 to May 2012 (n = 350; 237 adults and 113 children under 18 years). Adherence to the guideline was evaluated. RESULTS: 75 Patients (21%) were not referred for imaging because of a low suspicion or alternative diagnosis. In 16 patients (5%) the guideline was not followed. Of the 259 patients (74%) who underwent ultrasonography, 105 (30%) also underwent computed tomography (CT). 127 appendectomies were performed, showing appendicitis in 112 patients (88%); 15 appendectomies (12%) were negative. In the latter group, 12 were performed after false positive imaging results, and 3 following inconclusive imaging results. CONCLUSION: When using imaging in the diagnosis of appendicitis, the percentage of negative appendectomies remains close to the percentage declared as unacceptable by the publishers of the guideline.

Four screening instruments for frailty in older patients with and without cancer: a diagnostic study.

BACKGROUND: Frailty in older patients might influence treatment decisions. Frailty can be determined using a Comprehensive Geriatric Assessment (CGA), but this is time-consuming and expensive. Therefore we assessed the diagnostic value of four shorter screening instruments. METHODS: We tested the abbreviated CGA (aCGA), the Vulnerable Elders Survey-13 (VES-13), the Groningen Frailty Indicator (GFI) and the Geriatric 8 (G8). A full CGA including functional status, cognitive status, depression, nutrition and comorbidity was used as reference. A minimum of 85% for both sensitivity and specificity was predefined as acceptable. Data were collected through personal interviews by trained interviewers. We assessed people aged ≥ 70 years: 108 patients with recently diagnosed cancer recruited in hospitals and 290 without cancer recruited by general practitioners in the Netherlands and Belgium.Frailty was defined as having impairment in at least two domains of the full CGA. We used original cut-offs for the screening instruments and calculated sensitivity, specificity, positive and negative diagnostic values and the percentage classified as frail. RESULTS: Sensitivity of aCGA was 79% and 87% for patients with and without cancer; specificity was 59% and 64%. Sensitivity of VES-13 was 67% and 82% for patients with and without cancer; specificity was 70% and 79%. Sensitivity for GFI was 76% (in both groups) and specificity 73% (in both groups). Sensitivity for G8 was 87% and 75% for patients with and without cancer; specificity was 68% (in both groups). CONCLUSIONS: No screening instrument was acceptable according to our predefined minimum of 85% for both sensitivity and specificity. The diagnostic value of the investigated instruments is rather poor and one could wonder about their additional value to clinical judgment.

Longitudinal associations of plasma kynurenines and ratios with anxiety and depression scores in colorectal cancer survivors up to 12 months post-treatment.

INTRODUCTION: Colorectal cancer (CRC) survivors often experience neuropsychological symptoms, including anxiety and depression. Mounting evidence suggests a role for the kynurenine pathway in these symptoms due to potential neuroprotective and neurotoxic roles of involved metabolites. However, evidence remains inconclusive and insufficient in cancer survivors. Thus, we aimed to explore longitudinal associations of plasma tryptophan, kynurenines, and their established ratios with anxiety and depression in CRC survivors up to 12 months post-treatment. METHODS: In 249 stage I-III CRC survivors, blood samples were collected at 6 weeks, 6 months, and 12 months post-treatment to analyze plasma concentrations of tryptophan and kynurenines using liquid-chromatography tandem-mass spectrometry (LC/MS-MS). At the same timepoints, anxiety and depression were assessed using the Hospital Anxiety and Depression Scale (HADS). Confounder-adjusted linear mixed models were used to analyze longitudinal associations. Sensitivity analyses with false discovery rate (FDR) correction were conducted to adjust for multiple testing. RESULTS: Higher plasma tryptophan concentrations were associated with lower depression scores (ß as change in depression score per 1 SD increase in the ln-transformed kynurenine concentration: -0.31; 95%CI: -0.56,-0.05), and higher plasma 3-hydroxyanthranilic acid concentrations with lower anxiety scores (-0.26; -0.52,-0.01). A higher 3-hydroxykynurenine ratio (HKr; the ratio of 3-hydroxykynurenine to the sum of kynurenic acid, xanthurenic acid, anthranilic acid, and 3-hydroxyanthranilic acid) was associated with higher depression scores (0.34; 0.04,0.63) and higher total anxiety and depression scores (0.53; 0.02,1.04). Overall associations appeared to be mainly driven by inter-individual associations, which were statistically significant for tryptophan with depression (-0.60; -1.12,-0.09), xanthurenic acid with total anxiety and depression (-1.04; -1.99,-0.10), anxiety (-0.51; -1.01,-0.01), and depression (-0.56; -1.08,-0.05), and kynurenic-acid-to-quinolinic-acid ratio with depression (-0.47; -0.93,-0.01). In sensitivity analyses, associations did not remain statistically significant after FDR adjustment. CONCLUSION: We observed that plasma concentrations of tryptophan, 3-hydroxyanthranilic acid, xanthurenic acid, 3-hydroxykynurenine ratio, and kynurenic-acid-to-quinolinic-acid ratio tended to be longitudinally associated with anxiety and depression in CRC survivors up to 12 months post-treatment. Future studies are warranted to further elucidate the association of plasma kynurenines with anxiety and depression.