Higher concentrations of 25-hydroxyvitamin D3 25(OH)D3 at diagnosis are associated with a lower mortality risk in colorectal cancer (CRC) patients. However, magnesium and calcium are important in ...vitamin D metabolism.
We aimed to investigate 25(OH)D3, magnesium, or calcium and their interaction among patients with CRC in relation to recurrence and all-cause mortality.
The study population included 1169 newly diagnosed stage I–III CRC patients from 2 prospective cohorts. Associations between 25(OH)D3 concentrations, magnesium or calcium intake through diet and/or supplements at diagnosis, and recurrence and all-cause mortality were evaluated using multivariable Cox proportional hazard models. The interaction between 25(OH)D3 and magnesium or calcium was assessed by investigating 1) joint compared with separate effects, using a single reference category; and 2) the effect estimates of 1 factor across strata of another.
Serum 25(OH)D3, calcium, and magnesium, alone and their interactions, were not associated with recurrence. Serum 25(OH)D3 concentrations seemed to be associated with all-cause mortality. An inverse association between magnesium intake (HRQ3 vs. Q1: 0.55; 95% CI: 0.32, 0.95 and HRQ4 vs. Q1: 0.65; 95% CI: 0.35, 1.21), but not calcium intake, and all-cause mortality was observed. When investigating the interaction between 25(OH)D3 and magnesium, we observed the lowest risk of all-cause mortality in patients with sufficient vitamin D concentrations (≥50 nmol/L) and a high magnesium intake (median split) (HR: 0.53; 95% CI: 0.31, 0.89) compared with patients who were vitamin D deficient (<50 nmol/L) and had a low magnesium intake. No interactions between calcium and vitamin D in relation to all-cause mortality were observed.
Our findings suggest that the presence of an adequate status of 25(OH)D3 in combination with an adequate magnesium intake is essential in lowering the risk of mortality in CRC patients, yet the underlying mechanism should be studied. In addition, diet and lifestyle intervention studies are needed to confirm our findings. The COLON study was registered at clinicaltrials.gov as NCT03191110. The EnCoRe study was registered at trialregister.nl as NTR7099.
An unhealthy lifestyle is associated with the risk of colorectal cancer (CRC), but it is unclear whether overall lifestyle after a CRC diagnosis is associated with risks of recurrence and mortality.
...To examine associations between postdiagnosis lifestyle and changes in lifestyle after a CRC diagnosis with risks of CRC recurrence and all-cause mortality.
The study population included 1425 newly diagnosed, stage I–III CRC patients from 2 prospective cohort studies enrolled between 2010 and 2016. Lifestyle, including BMI, physical activity, diet, and alcohol intake, was assessed at diagnosis and at 6 months postdiagnosis. We assigned lifestyle scores based on concordance with 2 sets of cancer prevention guidelines—from the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) and the American Cancer Society (ACS)—and national disease prevention guidelines. Higher scores indicate healthier lifestyles. We computed adjusted HRs and 95% CIs using Cox regression.
We observed 164 recurrences during a 2.8-year median follow-up and 171 deaths during a 4.4-year median follow-up. No associations were observed for CRC recurrence. A lifestyle more consistent with the ACS recommendations was associated with a lower all-cause mortality risk (HR per +1 SD, 0.85; 95% CI: 0.73–0.995). The same tendency was observed for higher WCRF/AICR (HR, 0.92; 95% CI: 0.78–1.08) and national (HR, 0.90; 95% CI: 0.77–1.05) lifestyle scores, although these associations were statistically nonsignificant. Generally, no statistically significant associations were observed for BMI, physical activity, diet, or alcohol. Improving one’s lifestyle after diagnosis (+1 SD) was associated with a lower all-cause mortality risk for the ACS (HR, 0.80; 95% CI: 0.67–0.96) and national (HR, 0.84; 95% CI: 0.70–0.999) scores, yet was statistically nonsignificant for the WCRF/AICR score (HR, 0.94; 95% CI: 0.78–1.13).
A healthy lifestyle after CRC diagnosis and improvements therein were not associated with the risk of CRC recurrence, but were associated with a decreased all-cause mortality risk.
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Outer membrane vesicles (OMVs) are nanoparticles released by Gram-negative bacteria and can be used as vaccines. Often, detergents are used to promote release of OMVs and to remove the toxic ...lipopolysaccharides. Lipopolysaccharides can be detoxified by genetic modification such that vesicles spontaneously produced by bacteria can be directly used as vaccines. The use of spontaneous OMVs has the advantage that no separate extraction step is required in the purification process. However, the productivity of spontaneous OMVs by bacteria at optimal growth conditions is low. One of many methods for increasing OMV formation is to reduce the linkage of the outer membrane to the peptidoglycan layer by knocking out the rmpM gene. A previous study showed that for Neisseria meningitidis this resulted in release of more OMVs. Furthermore, cysteine depletion was found to trigger OMV release and at the same time cause reduced growth and oxidative stress responses. Here we study the effect of growth rate and oxidative stress on OMV release.
First, we identified using chemostat and accelerostat cultures of N. meningitidis that increasing the growth rate from 0.03 to 0.18 h
has a limited effect on OMV productivity. Thus, we hypothesized that oxidative stress is the trigger for OMV release and that oxidative stress can be introduced directly by increasing the dissolved oxygen tension of bacterial cultures. Slowly increasing oxygen concentrations in a N. meningitidis changestat showed that an increase from 30 to 150% air saturation improved OMV productivity four-fold. Batch cultures controlled at 100% air saturation increased OMV productivity three-fold over batch cultures controlled at 30% air saturation.
Increased dissolved oxygen tension induces the release of outer membrane vesicles in N. meningitidis cultures. Since oxygen concentration is a well-controlled process parameter of bacterial cultures, this trigger can be applied as a convenient process parameter to induce OMV release in bacterial cultures. Improved productivity of OMVs not only improves the production costs of OMVs as vaccines, it also facilitates the use of OMVs as adjuvants, enzyme carriers, or cell-specific drug delivery vehicles.
Background Conservative management of acute type B aortic dissection (ABAD) is often associated with aortic dilatation during follow-up increasing the risk of aortic rupture. The goal of this study ...was to investigate whether morphologic characteristics of the dissection can predict aortic growth. Methods All conservatively managed ABAD patients from four referral centers were included (2000 to 2010). Aortic diameters were measured at five levels at baseline and at the last follow-up computed tomography angiography, and annual aortic growth rates were calculated for all segments. Linear regression was used to study the influence of aortic morphologic characteristics for aortic dilatation. Results Included were 62 patients (41 men) with a mean age of 60.3 ± 10.7 years. Among the 310 analyzed aortic segments, 248 (80.0%) were dissected, of which 211 (85.1%) showed aortic growth. Overall, the mean diameter increased from 36.1 ± 9.4 to 40.2 ± 11.1 mm ( P < .01), which corresponds with a mean aortic growth rate of 3.1 ± 6.3 mm/y. Multivariate linear regression analysis showed that male sex (95% confidence interval CI, 0.60-4.04; P = .005) and a saccular false lumen (95% CI, 2.07-7.81: P = .001) were associated with a significantly increased aortic growth rate. Increasing age (95% CI, −0.23 to −0.04; P = .005), increased number of entry tears (95% CI, −2.40 to −0.43; P = .005), false lumen located on the aortic outer curvature (95% CI, −4.30 to −0.38; P = .019), and a circular configuration of the true lumen (95% CI, −5.35 to −0.32; P = .027) were associated with a decreased aortic growth rate. Conclusions Multiple morphologic characteristics appear to predict aortic dilatation in ABAD patients treated medically. Early assessment of these morphologic signs may be useful in the selection of ABAD patients who might benefit from closer radiologic surveillance or prophylactic intervention.
Objective To identify an optimal imaging strategy for the accurate detection of urgent conditions in patients with acute abdominal pain.Design Fully paired multicentre diagnostic accuracy study with ...prospective data collection.Setting Emergency departments of two university hospitals and four large teaching hospitals in the Netherlands.Participants 1021 patients with non-traumatic abdominal pain of >2 hours’ and <5 days’ duration. Exclusion criteria were discharge from the emergency department with no imaging considered warranted by the treating physician, pregnancy, and haemorrhagic shock.Intervention All patients had plain radiographs (upright chest and supine abdominal), ultrasonography, and computed tomography (CT) after clinical and laboratory examination. A panel of experienced physicians assigned a final diagnosis after six months and classified the condition as urgent or non-urgent.Main outcome measures Sensitivity and specificity for urgent conditions, percentage of missed cases and false positives, and exposure to radiation for single imaging strategies, conditional imaging strategies (CT after initial ultrasonography), and strategies driven by body mass index and age or by location of pain.Results 661 (65%) patients had a final diagnosis classified as urgent. The initial clinical diagnosis resulted in many false positive urgent diagnoses, which were significantly reduced after ultrasonography or CT. CT detected more urgent diagnoses than did ultrasonography: sensitivity was 89% (95% confidence interval 87% to 92%) for CT and 70% (67% to 74%) for ultrasonography (P<0.001). A conditional strategy with CT only after negative or inconclusive ultrasonography yielded the highest sensitivity, missing only 6% of urgent cases. With this strategy, only 49% (46% to 52%) of patients would have CT. Alternative strategies guided by body mass index, age, or location of the pain would all result in a loss of sensitivity.Conclusion Although CT is the most sensitive imaging investigation for detecting urgent conditions in patients with abdominal pain, using ultrasonography first and CT only in those with negative or inconclusive ultrasonography results in the best sensitivity and lowers exposure to radiation.
•Several factors were associated with 25(OH)D3 levels in colorectal cancer patients.•Colorectal cancer treatment was the strongest determinant of 25(OH)D3 levels.•Chemotherapy was associated with ...decreasing 25(OH)D3 levels over time.•Vitamin D supplement use was associated with increasing 25(OH)D3 levels over time.
Vitamin D metabolites, including 25-hydroxyvitamin D3 (25(OH)D3), may inhibit colorectal cancer (CRC) progression. Here we investigated cross-sectional and longitudinal associations of demographic, lifestyle and clinical characteristics with 25(OH)D3 serum concentrations in CRC patients at diagnosis and six months later. In 1201 newly-diagnosed stage I-III CRC patients, 25(OH)D3 levels were analysed twice. Multivariable linear regression was used to assess demographic, lifestyle and clinical determinants of 25(OH)D3 levels at diagnosis and six months later. Linear mixed models were used to assess characteristics associated with changes in 25(OH)D3 levels over time.
Results of our study showed that vitamin D intake from diet or supplements, use of calcium supplements, BMI and disease stage were associated with 25(OH)D3 levels at both time points. Six months after diagnosis, gender and having received chemo- and/or radiotherapy were also associated with 25(OH)D3 levels. A stronger decrease in 25(OH)D3 levels was observed in patients who underwent chemotherapy, compared to surgery only (β-6.9 nmol/L 95 %CI -9.8; -4.0). Levels of 25(OH)D3 levels increased in patients using vitamin D supplements compared to non-users (β 4.0 nmol/L 95 %CI 1.2; 6.8).
In conclusion, vitamin D supplement use and treatment appear to be important determinants of 25(OH)D3 levels during the first six months after CRC diagnosis, although the difference in 25(OH)D3 levels was minor.
ClinicalTrials.gov Identifier: NCT03191110
B vitamins have been associated with the risk and progression of colorectal cancer (CRC), given their central roles in nucleotide synthesis and methylation, yet their association with quality of life ...in established CRC is unclear.
To investigate whether quality of life 6 months postdiagnosis is associated with: 1) circulating concentrations of B vitamins and related biomarkers 6 months postdiagnosis; 2) changes in these concentrations between diagnosis and 6 months postdiagnosis; 3) B-vitamin supplement use 6 months postdiagnosis; and 4) changes in B-vitamin supplement use between diagnosis and 6 months postdiagnosis.
We included 1676 newly diagnosed stage I–III CRC patients from 3 prospective European cohorts. Circulating concentrations of 9 biomarkers related to the B vitamins folate, riboflavin, vitamin B6, and cobalamin were measured at diagnosis and 6 months postdiagnosis. Information on dietary supplement use was collected at both time points. Health-related quality of life (global quality of life, functioning scales, and fatigue) was assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 6 months postdiagnosis. Confounder-adjusted linear regression analyses were performed, adjusted for multiple testing.
Higher pyridoxal 5′-phosphate (PLP) was cross-sectionally associated with better physical, role, and social functioning, as well as reduced fatigue, 6 months postdiagnosis. Associations were observed for a doubling in the hydroxykynurenine ratio 3-hydroxykynurenine: (kynurenic acid + xanthurenic acid + 3-hydroxyanthranilic acid + anthranilic acid); an inverse marker of vitamin B6 and both reduced global quality of life (β = −3.62; 95% CI: −5.88, −1.36) and worse physical functioning (β = −5.01; 95% CI: −7.09, −2.94). Dose–response relations were observed for PLP and quality of life. No associations were observed for changes in biomarker concentrations between diagnosis and 6 months. Participants who stopped using B-vitamin supplements after diagnosis reported higher fatigue than nonusers.
Higher vitamin B6 status was associated with better quality of life, yet limited associations were observed for the use of B-vitamin supplements. Vitamin B6 needs further study to clarify its role in relation to quality of life.
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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.
We investigated survival outcomes in relation to vitamin B6 status in prospectively followed CRC patients.
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.
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).
Higher preoperative vitamin B6 status is associated with improved OS among stage I–III CRC patients.
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We investigated whether preoperative and postoperative levels of inflammation markers, which have mechanistically been linked to colorectal cancer progression, were associated with recurrence and ...all-cause mortality in patients with colorectal cancer.
Data of two prospective cohort studies were used. For the current analysis, patients with stage I to III colorectal cancer were considered. Data on inflammation IL6, IL8, IL10, TNFα, high-sensitivity C-reactive protein (hsCRP), and a combined inflammatory
-score were available for 747 patients before surgery and for 614 patients after surgery. The associations between inflammation marker levels and colorectal cancer recurrence and all-cause mortality were examined using multivariable Cox proportional hazard regression models, considering patient characteristics and clinical and lifestyle factors.
Higher preoperative and postoperative hsCRP levels were associated with a higher risk of recurrence HR
(95% CI), 1.15 (1.02-1.30) and 1.34 (1.16-1.55) and all-cause mortality HR
(95% CI) 1.13 (1.01-1.28) and 1.15 (0.98-1.35). A doubling in IL8 levels (preoperative levels HR = 1.23; 95% CI, 1.00-1.53 and postoperative levels HR = 1.61; 95% CI, 1.23-2.12) and a higher combined inflammatory
-score (preoperative HR
= 1.39; 95% CI, 1.03-1.89 and postoperative HR
= 1.56; 95% CI, 1.06-2.28) were associated with a higher risk of all-cause mortality, but not recurrence. No associations between IL6, IL10, and TNFα and recurrence or all-cause mortality were observed.
Preoperative and postoperative levels of specific inflammation markers were associated with recurrence and/or all-cause mortality.
The complex role of inflammation in cancer recurrence merits further elucidation by investigating local inflammation at the tumor site.
ABSTRACT
Objectives
To compare the diagnostic accuracy of conditional computed tomography (CT), i.e. CT when initial ultrasound findings are negative or inconclusive, and immediate CT for patients ...with suspected appendicitis.
Methods
Data were collected within a prospective diagnostic accuracy study on imaging in adults with acute abdominal pain. All patients underwent ultrasound and CT, read by different observers who were blinded from the other modality. Only patients with clinical suspicion of appendicitis were included. An expert panel assigned a final diagnosis to each patient after 6 months of follow-up (clinical reference standard).
Results
A total of 422 patients were included with final diagnosis appendicitis in 251 (60 %). For 199 patients (47 %), ultrasound findings were inconclusive or negative. Conditional CT imaging correctly identified 241 of 251 (96 %) appendicitis cases (95 %CI, 92 % to 98 %), versus 238 (95 %) with immediate CT (95 %CI, 91 % to 97 %). The specificity of conditional CT imaging was lower: 77 % (95 %CI, 70 % to 83 %) versus 87 % for immediate CT (95 %CI, 81 % to 91 %).
Conclusion
A conditional CT strategy correctly identifies as many patients with appendicitis as an immediate CT strategy, and can halve the number of CTs needed. However, conditional CT imaging results in more false positives.
Key Points
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Conditional CT (CT after negative/inconclusive ultrasound findings) can be used for suspected appendicitis
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Half the number of CT examinations is needed with a conditional strategy
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Conditional CT correctly identifies as many patients with appendicitis as immediate CT
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Conditional imaging results in more false positive appendicitis cases
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