Publications by authors named "Michael Hoffmeister"

330 Publications

Deep learning can predict lymph node status directly from histology in colorectal cancer.

Eur J Cancer 2021 Oct 11;157:464-473. Epub 2021 Oct 11.

Digital Biomarkers for Oncology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address:

Background: Lymph node status is a prognostic marker and strongly influences therapeutic decisions in colorectal cancer (CRC).

Objectives: The objective of the study is to investigate whether image features extracted by a deep learning model from routine histological slides and/or clinical data can be used to predict CRC lymph node metastasis (LNM).

Methods: Using histological whole slide images (WSIs) of primary tumours of 2431 patients in the DACHS cohort, we trained a convolutional neural network to predict LNM. In parallel, we used clinical data derived from the same cases in logistic regression analyses. Subsequently, the slide-based artificial intelligence predictor (SBAIP) score was included in the regression. WSIs and data from 582 patients of the TCGA cohort were used as the external test set.

Results: On the internal test set, the SBAIP achieved an area under receiver operating characteristic (AUROC) of 71.0%, the clinical classifier achieved an AUROC of 67.0% and a combination of the two classifiers yielded an improvement to 74.1%. Whereas the clinical classifier's performance remained stable on the TCGA set, performance of the SBAIP dropped to an AUROC of 61.2%. Performance of the clinical classifier depended strongly on the T stage.

Conclusion: Deep learning-based image analysis may help predict LNM of patients with CRC using routine histological slides. Combination with clinical data such as T stage might be useful. Strategies to increase performance of the SBAIP on external images should be investigated.
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http://dx.doi.org/10.1016/j.ejca.2021.08.039DOI Listing
October 2021

Weakly supervised annotation-free cancer detection and prediction of genotype in routine histopathology.

J Pathol 2021 Sep 24. Epub 2021 Sep 24.

Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.

Deep Learning is a powerful tool in computational pathology: it can be used for tumor detection and for predicting genetic alterations based on histopathology images alone. Conventionally, tumor detection and prediction of genetic alterations are two separate workflows. Newer methods have combined them, but require complex, manually engineered computational pipelines, restricting reproducibility and robustness. To address these issues, we present a new method for simultaneous tumor detection and prediction of genetic alterations: The 'Slide-Level Assessment Model' (SLAM) uses a single off-the-shelf neural network to predict molecular alterations directly from routine pathology slides without any manual annotations, improving upon previous methods by automatically excluding normal and non-informative tissue regions. SLAM requires only standard programming libraries and is conceptually simpler than previous approaches. We have extensively validated SLAM for clinically relevant tasks using two large multicentric cohorts of colorectal cancer patients, DACHS from Germany and YCR-BCIP from the United Kingdom. We show that SLAM yields reliable slide-level classification of tumor presence with an area under the receiver operating curve (AUROC) of 0.980 (confidence interval 0.975, 0.984; N = 2297 tumor and N = 1281 normal slides). In addition, SLAM can detect microsatellite instability (MSI) / mismatch repair deficiency (dMMR) or microsatellite stability (MSS) /mismatch repair proficiency (pMMR) with an AUROC of 0.909 (0.888, 0.929; N = 2039 patients) and BRAF mutational status with an AUROC of 0.821 (0.786, 0.852; N = 2075 patients). The improvement with respect to previous methods was validated in a large external testing cohort in which MSI/dMMR status was detected with an AUROC of 0.900 (0.864, 0.931; N = 805 patients). In addition, SLAM provides human-interpretable visualization maps, enabling the analysis of multiplexed network predictions by human experts. In summary, SLAM is a new simple and powerful method for computational pathology which could be applied to multiple disease contexts. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/path.5800DOI Listing
September 2021

Strongly Divergent Impact of Adherence Patterns on Efficacy of Colorectal Cancer Screening: The Need to Refine Adherence Statistics.

Clin Transl Gastroenterol 2021 Sep 10;12(9):e00399. Epub 2021 Sep 10.

Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Introduction: The performance of colorectal cancer (CRC) screening programs depends on the adherence to screening offers. However, identical adherence levels may result from varying patterns of the population's screening behavior. We quantified the effects of different adherence patterns on the long-term performance of CRC screening for annual fecal immunochemical testing and screening colonoscopy at 10-year intervals.

Methods: Using a multistate Markov model, we simulated scenarios where, while at the same overall adherence level, a certain proportion of the population adheres to all screening offers (selective adherence) or the entire population uses the screening offers at some point(s) of time, albeit not in the recommended frequency (sporadic adherence). Key outcomes for comparison were the numbers of prevented CRC cases and prevented CRC deaths after 50 simulated years.

Results: For screening with annual fecal immunochemical testing at adherence levels of 10%-50%, ratios of prevented CRC cases (CRC deaths) resulting from a sporadic vs a selective pattern ranged from 1.8 to 4.4 (1.9-5.3) for men and from 1.7 to 3.6 (1.8-4.4) for women, i.e., up to 4-5 times more CRC cases and deaths were prevented when the population followed a sporadic instead of a selective adherence pattern. Comparisons of simulated scenarios for screening colonoscopy revealed similar patterns.

Discussion: Over a lifelong time frame, large numbers of irregular screening attendees go along with much larger preventive effects than small numbers of perfectly adhering individuals. In clinical practice, efforts to reach as many people as possible at least sporadically should be prioritized over efforts to maximize adherence to repeat screening offers.
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http://dx.doi.org/10.14309/ctg.0000000000000399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8437219PMC
September 2021

Association of Polypharmacy with Colorectal Cancer Survival Among Older Patients.

Oncologist 2021 Sep 3. Epub 2021 Sep 3.

Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg, Germany.

Background: In geriatric oncology, polypharmacy is often assessed during a comprehensive geriatric assessment. Previous studies about its association with survival among patients with colorectal cancer (CRC) were inconclusive and had high risk for indication bias.

Patients And Methods: A cohort study was conducted with 3,239 patients with CRC, aged ≥65 years, who were recruited in Germany between 2003 and 2016, while being hospitalized for CRC surgery. We defined polypharmacy as the concurrent use of five or more drugs, and excessive polypharmacy (EPP) as concurrent use of eight or more drugs. Cox proportional hazards regression models were performed to assess the associations of polypharmacy with 5-year overall (OS), CRC-specific (CSS), and non-cancer-specific survival (NCS) with rigorous adjustment for morbidity to minimize indication bias (e.g., for cancer stage, functional status, and 13 common diseases/conditions).

Results: The prevalence of polypharmacy was 54.7% and that of EPP was 24.2%. During up to 5 years of follow-up, 1,070 participants died, among whom 615 died of CRC and 296 died of other causes than cancer. EPP was statistically significantly associated with poorer up-to-5-year OS (hazard ratio [HR], 1.23; 95% confidence interval [CI], 1.02-1.47) and CSS (HR, 1.31; 95% CI, 1.03-1.68). HR point estimate for NCS was higher than 1 (1.22) but not statistically significant.

Conclusion: Polypharmacy was very common and EPP was a weak risk factor for mortality in this large cohort of older patients with CRC. Clinical trials are needed to address the causality of this relationship because older patients with CRC might benefit from deprescribing drugs without an indication.

Implications For Practice: The results of this study support the hypothesis that excessive polypharmacy, defined as use of eight or more concurrently used active substances, has a negative impact on the prognosis of older patients with colorectal cancer (CRC). This study suggests to oncologists that performing a medication review for older patients with CRC with eight drugs or more is indicated (especially when a broader comprehensive geriatric assessment is being performed). Such a medication review should not only focus on reducing the number of medications (by deprescribing drugs without an indication) but also check the appropriateness of indicated drugs for older patients with cancer.
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http://dx.doi.org/10.1002/onco.13961DOI Listing
September 2021

Gastrointestinal cancer classification and prognostication from histology using deep learning: Systematic review.

Eur J Cancer 2021 Sep 11;155:200-215. Epub 2021 Aug 11.

Digital Biomarkers for Oncology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address:

Background: Gastrointestinal cancers account for approximately 20% of all cancer diagnoses and are responsible for 22.5% of cancer deaths worldwide. Artificial intelligence-based diagnostic support systems, in particular convolutional neural network (CNN)-based image analysis tools, have shown great potential in medical computer vision. In this systematic review, we summarise recent studies reporting CNN-based approaches for digital biomarkers for characterization and prognostication of gastrointestinal cancer pathology.

Methods: Pubmed and Medline were screened for peer-reviewed papers dealing with CNN-based gastrointestinal cancer analyses from histological slides, published between 2015 and 2020.Seven hundred and ninety titles and abstracts were screened, and 58 full-text articles were assessed for eligibility.

Results: Sixteen publications fulfilled our inclusion criteria dealing with tumor or precursor lesion characterization or prognostic and predictive biomarkers: 14 studies on colorectal or rectal cancer, three studies on gastric cancer and none on esophageal cancer. These studies were categorised according to their end-points: polyp characterization, tumor characterization and patient outcome. Regarding the translation into clinical practice, we identified several studies demonstrating generalization of the classifier with external tests and comparisons with pathologists, but none presenting clinical implementation.

Conclusions: Results of recent studies on CNN-based image analysis in gastrointestinal cancer pathology are promising, but studies were conducted in observational and retrospective settings. Large-scale trials are needed to assess performance and predict clinical usefulness. Furthermore, large-scale trials are required for approval of CNN-based prediction models as medical devices.
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http://dx.doi.org/10.1016/j.ejca.2021.07.012DOI Listing
September 2021

Association Between Smoking and Molecular Subtypes of Colorectal Cancer.

JNCI Cancer Spectr 2021 Aug 14;5(4):pkab056. Epub 2021 Jun 14.

Departments of Cancer Biology and Genetics and Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.

Background: Smoking is associated with colorectal cancer (CRC) risk. Previous studies suggested this association may be restricted to certain molecular subtypes of CRC, but large-scale comprehensive analysis is lacking.

Methods: A total of 9789 CRC cases and 11 231 controls of European ancestry from 11 observational studies were included. We harmonized smoking variables across studies and derived sex study-specific quartiles of pack-years of smoking for analysis. Four somatic colorectal tumor markers were assessed individually and in combination, including mutation, mutation, CpG island methylator phenotype (CIMP), and microsatellite instability (MSI) status. A multinomial logistic regression analysis was used to assess the association between smoking and risk of CRC subtypes by molecular characteristics, adjusting for age, sex, and study. All statistical tests were 2-sided and adjusted for Bonferroni correction.

Results: Heavier smoking was associated with higher risk of CRC overall and stratified by individual markers ( < .001). The associations differed statistically significantly between all molecular subtypes, which was the most statistically significant for CIMP and . Compared with never-smokers, smokers in the fourth quartile of pack-years had a 90% higher risk of CIMP-positive CRC (odds ratio = 1.90, 95% confidence interval = 1.60 to 2.26) but only 35% higher risk for CIMP-negative CRC (odds ratio = 1.35, 95% confidence interval = 1.22 to 1.49; = 2.1 x 10). The association was also stronger in tumors that were positive, MSI high, or wild type when combined ( < .001).

Conclusion: Smoking was associated with differential risk of CRC subtypes defined by molecular characteristics. Heavier smokers had particularly higher risk of CRC subtypes that were CIMP positive and MSI high in combination, suggesting that smoking may be involved in the development of colorectal tumors via the serrated pathway.
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http://dx.doi.org/10.1093/jncics/pkab056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346704PMC
August 2021

Association of Body Mass Index With Risk of Early-Onset Colorectal Cancer: Systematic Review and Meta-Analysis.

Am J Gastroenterol 2021 Jul 23. Epub 2021 Jul 23.

Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Introduction: Incidence of colorectal cancer (CRC) in young adults has been increasing in recent decades in many countries for still widely unclear reasons. Suspected candidates include increasing prevalence of overweight and obesity, but specific evidence on their role for early-onset CRC (EOCRC) is sparse. We conducted a systematic review and meta-analysis to summarize available evidence on the association of body mass index (BMI) with EOCRC.

Methods: We systematically searched PubMed, EMBASE, and Web of Science up to February 2021 for studies that evaluated the association of BMI (before diagnosis but not near diagnosis) with CRC risk and reported specific results for EOCRC. Results from studies with similar BMI groupings were summarized in meta-analyses using random-effects models.

Results: Twelve studies were eligible and included. Results of 6 studies were pooled in meta-analyses, which yielded a higher risk of EOCRC for overweight and obesity (BMI ≥25 kg/m2) compared with normal weight (odds ratio [OR] 1.42, 95% confidence interval [CI] 1.19-1.68). An increasing risk with increasing BMI was observed, with much higher risk for obesity (OR 1.88, 95% CI 1.40-2.54) than for overweight (OR 1.32, 95% CI 1.19-1.47).

Discussion: Obesity is a strong risk factor for EOCRC, and its increasing prevalence in younger generations is likely to substantially contribute to the increase in EOCRC. Efforts to limit the obesity epidemic in adolescents and younger adults may be crucial for reducing CRC incidence in future generations of adults.
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http://dx.doi.org/10.14309/ajg.0000000000001393DOI Listing
July 2021

Consistent Major Differences in Sex- and Age-Specific Diagnostic Performance among Nine Faecal Immunochemical Tests Used for Colorectal Cancer Screening.

Cancers (Basel) 2021 Jul 16;13(14). Epub 2021 Jul 16.

German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Division of Preventive Oncology, 69120 Heidelberg, Germany.

Evidence on diagnostic performance of faecal immunochemical tests (FITs) by sex and age is scarce. We aimed to evaluate FIT performance for detection of advanced colorectal neoplasia (AN) by sex and age across nine different FIT brands in a colonoscopy-controlled setting. The faecal samples were obtained from 2042 participants of colonoscopy screening. All eligible cases with AN ( 216) and 300 randomly selected participants without AN were included. Diagnostic performance for detection of AN was assessed by sex and age (50-64 vs. 65-79 years for each of the nine FITs individually and for all FITs combined. Sensitivity was consistently lower, and specificity was consistently higher for females as compared with males (pooled values at original FIT cutoffs, 25.7% vs. 34.6%, = 0.12 and 96.2% vs. 90.8%, < 0.01, respectively). Positive predictive values (PPVs) were similar between both sexes, but negative predictive values (NPVs) were consistently higher for females (pooled values, 91.8% vs. 86.6%, < 0.01). Sex-specific cutoffs attenuated differences in sensitivities but increased differences in predictive values. According to age, sensitivities and specificities were similar, whereas PPVs were consistently lower and NPVs were consistently higher for the younger participants. A negative FIT is less reliable in ruling out AN among men than among women and among older than among younger participants. Comparisons of measures of diagnostic performance among studies with different sex or age distributions should be interpreted with caution.
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http://dx.doi.org/10.3390/cancers13143574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306133PMC
July 2021

Striving to optimize colorectal cancer prevention.

Nat Rev Gastroenterol Hepatol 2021 Oct;18(10):677-678

Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.

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http://dx.doi.org/10.1038/s41575-021-00494-6DOI Listing
October 2021

To what extent is male excess risk of advanced colorectal neoplasms explained by known risk factors? Results from a large German screening population.

Int J Cancer 2021 Dec 31;149(11):1877-1886. Epub 2021 Jul 31.

Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Colorectal cancer (CRC) incidence and prevalence of its precursors are substantially higher among males than among females in most countries but the reasons for the male excess risk are incompletely understood. We aimed to assess to what extent it is explained by known risk factors. Prevalence of advanced neoplasia (AN, ie, CRC or advanced adenoma) and CRC risk and preventive factors were ascertained among 15 985 participants of screening colonoscopy aged 55-79 years in Germany. Logistic regression was used to calculate odds ratios (ORs) for the association between male sex and AN with and without adjustment for known risk and preventive factors. In age-adjusted comparisons, men had 2-fold increased risk for AN compared to women (OR = 1.98, 95% confidence interval [CI] 1.79-2.19). After comprehensive adjustment for medical, lifestyle and dietary factors, the OR was reduced to 1.52 (95% CI 1.30-1.77), suggesting that these factors accounted for 47% of male excess risk. Male excess risk increased from proximal colon to distal colon and rectum, with age-adjusted ORs (95% CI) of 1.63 (1.38-1.91), 2.13 (1.85-2.45) and 2.36 (1.95-2.85), respectively, and with the proportion of excess risk explained by covariates being lower for AN in the rectum (26%) than for AN in the proximal (52%) or distal colon (46%). Male excess risk was somewhat lower (age-adjusted OR 1.87) and explained excess risk was smaller (36%) when men were compared to women who never used hormone replacement therapy. In conclusion, most of the male excess risk and the potential to overcome it remain to be explored by further research.
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http://dx.doi.org/10.1002/ijc.33742DOI Listing
December 2021

Association of co-medication quality with chemotherapy-related adverse drug reactions and survival in older colorectal cancer patients.

J Gerontol A Biol Sci Med Sci 2021 Jul 12. Epub 2021 Jul 12.

Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: Evidence about the clinical relevance of appropriate co-medication among older colorectal cancer (CRC) patients is sparse.

Methods: A cohort study was conducted with 3,239 CRC patients aged 65 years and older. To assess co-medication quality, we calculated the total Fit fOR The Aged (FORTA) score and its sub-scores for medication overuse, underuse, and potentially inappropriate medication use. Multivariable Cox proportional hazards or logistic regression models were performed to evaluate the association of co-medication quality with up to 5-year overall survival, CRC-specific survival, and chemotherapy-related adverse drug reactions (ADRs).

Results: Overall, 3,239 and 1,209 participants were included in analyses on survival and ADRs, respectively. The hazard ratios [95%-confidence intervals] for the total FORTA score ≥ 7 vs. 0-1 points were 1.83 [1.40-2.40] and 1.76 [1.22-2.52] for up to 5-year overall and CRC-specific survival, respectively. Worse up to 5-year OS and CSS was also evident for FORTA sub-scores for PIM use and overuse whereas no association was observed for underuse. Although results for the total FORTA and potentially inappropriate medication score were much stronger among patients receiving chemotherapy, no significant associations with chemotherapy-related ADRs were observed. Moreover, associations were particularly strong among men and rectal cancer patients as compared to women and colon cancer patients.

Conclusions: Poor total co-medication quality was significantly associated with worse up to 5-year overall and CRC-specific survival. Randomized controlled trials are needed to test whether improved cancer co-medication management in older CRC patients prolongs survival.
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http://dx.doi.org/10.1093/gerona/glab198DOI Listing
July 2021

Risk Factors of Inadequate Bowel Preparation for Screening Colonoscopy.

J Clin Med 2021 Jun 21;10(12). Epub 2021 Jun 21.

Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.

The success of a colonoscopy in detecting and removing pre-cancerous and cancerous lesions depends heavily on the quality of bowel preparation. Despite efforts, 20-44% of colonoscopy participants have an inadequate bowel preparation. We aimed to assess and compare risk factors for inadequate bowel preparation and for the presence of advanced colorectal neoplasms in routine screening practice. In this cross-sectional study, among 8125 participants of screening colonoscopy in Germany with a comprehensive assessment of sociodemographic factors, lifestyle and medical history, we examined factors associated with inadequate bowel preparation and with findings of advanced neoplasms using adjusted log-binomial regression models. Among the identified risk factors assessed, three factors were identified that were significantly associated with inadequate bowel preparation: age ≥ 70 years (adjusted prevalence ratios, aPR, 1.50 95%CI 1.31-1.71), smoking (aPR 1.29 95%CI 1.11-1.50) and abdominal symptoms (aPR 1.14 95%CI 1.02-1.27). The same risk factors were also associated with the prevalence of advanced neoplasms in our study (aPR 1.72, 1.62 and 1.44, respectively). The risk factors associated with inadequate bowel preparation in this study were also associated with a higher risk for advanced neoplasms. Inadequate bowel preparation for colonoscopy might lead to missed colorectal cancer (CRC) precursors and the late diagnosis of CRC. People at high risk of advanced neoplasms are in particular need of enhanced bowel preparation.
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http://dx.doi.org/10.3390/jcm10122740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233947PMC
June 2021

DNA Methylation-Based Estimates of Circulating Leukocyte Composition for Predicting Colorectal Cancer Survival: A Prospective Cohort Study.

Cancers (Basel) 2021 Jun 12;13(12). Epub 2021 Jun 12.

Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, 69120 Heidelberg, Germany.

Leukocytes are involved in the progression of colorectal cancer (CRC). The proportion of six major leukocyte subtypes can be estimated using epigenome-wide DNA methylation (DNAm) data from stored blood samples. Whether the composition of circulating leukocytes can be used as a prognostic factor is unclear. DNAm-based leukocyte proportions were obtained from a prospective cohort of 2206 CRC patients. Multivariate Cox regression models and survival curves were applied to assess associations between leukocyte composition and survival outcomes. A higher proportion of lymphocytes, including CD4+ T cells, CD8+ T cells, B cells, and NK cells, was associated with better survival, while a higher proportion of neutrophils was associated with poorer survival. CD4+ T cells outperformed other leukocytes in estimating the patients' prognosis. Comparing the highest quantile to the lowest quantile of CD4+ T cells, hazard ratios (95% confidence intervals) of all-cause and CRC-specific mortality were 0.59 (0.48, 0.72) and 0.59 (0.45, 0.77), respectively. Furthermore, the association of CD4+ T cells and prognosis was stronger among patients with early or intermediate CRC or patients with colon cancer. In conclusion, the composition of circulating leukocytes estimated from DNAm, particularly the proportions of CD4+ T cells, could be used as promising independent predictors of CRC survival.
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http://dx.doi.org/10.3390/cancers13122948DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231262PMC
June 2021

Characteristics of Early-Onset vs Late-Onset Colorectal Cancer: A Review.

JAMA Surg 2021 Sep;156(9):865-874

Department of Surgery, Skåne University Hospital, Malmö, Sweden.

Importance: The incidence of early-onset colorectal cancer (younger than 50 years) is rising globally, the reasons for which are unclear. It appears to represent a unique disease process with different clinical, pathological, and molecular characteristics compared with late-onset colorectal cancer. Data on oncological outcomes are limited, and sensitivity to conventional neoadjuvant and adjuvant therapy regimens appear to be unknown. The purpose of this review is to summarize the available literature on early-onset colorectal cancer.

Observations: Within the next decade, it is estimated that 1 in 10 colon cancers and 1 in 4 rectal cancers will be diagnosed in adults younger than 50 years. Potential risk factors include a Westernized diet, obesity, antibiotic usage, and alterations in the gut microbiome. Although genetic predisposition plays a role, most cases are sporadic. The full spectrum of germline and somatic sequence variations implicated remains unknown. Younger patients typically present with descending colonic or rectal cancer, advanced disease stage, and unfavorable histopathological features. Despite being more likely to receive neoadjuvant and adjuvant therapy, patients with early-onset disease demonstrate comparable oncological outcomes with their older counterparts.

Conclusions And Relevance: The clinicopathological features, underlying molecular profiles, and drivers of early-onset colorectal cancer differ from those of late-onset disease. Standardized, age-specific preventive, screening, diagnostic, and therapeutic strategies are required to optimize outcomes.
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http://dx.doi.org/10.1001/jamasurg.2021.2380DOI Listing
September 2021

Incidence and Mortality of Proximal and Distal Colorectal Cancer in Germany.

Dtsch Arztebl Int 2021 04;118(16):281-287

Division of Preventive Oncology, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg; Faculty of Medicine Heidelberg, University of Heidelberg; Division of Clinical Epidemiology and Aging Research, German Cancer Research Center, Heidelberg; German Cancer Consortium, German Cancer Research Center, Heidelberg.

Background: The use of colonoscopy has increased and colorectal cancer (CRC) incidence has decreased after the introduction of screening colonoscopy in Germany. However, it remains unknown to what extent progress has been achieved in the prevention of cancer in the proximal colon, distal colon, and rectum.

Methods: We analyzed trends in CRC incidence (2000-2016) and mortality (2000-2018) in Germany by sex, age, and tumor location.

Results: The age-standardized incidence of CRC declined by 22.4% (from 65.3 to 50.7 per 100 000) in men and by 25.5% (from 42.7 to 31.8 per 100 000) in women. CRC mortality declined by 35.8% (from 29.6 to 19.0 per 100 000) in men and by 40.5% (19.0 to 11.3 per 100 000) in women. Despite demographic changes, the annual numbers of CRC cases and deaths still decreased from about 60 400 to 58 300 and from around 28 700 to 24 200, respectively. The decline in incidence was greatest in groups aged ≥ 55 years. While the incidence of cancer in the distal colon and rectum decreased by 34.5% and 26.2%, respectively, in men and by 41.0% and 27.9% in women, the incidence of proximal colon cancer remained stable in men and decreased by only 7.0% in women. However, a major shift towards earlier stages was observed for the proximal cancers.

Conclusion: The results support the assumption that the increased use of colo - noscopy has contributed to substantial reductions in the incidence of distal CRC incidence and the mortality from cancers in the entire colon and rectum.
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http://dx.doi.org/10.3238/arztebl.m2021.0111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287758PMC
April 2021

Inpatient rehabilitation therapy among colorectal cancer patients - utilization and association with prognosis: a cohort study.

Acta Oncol 2021 Aug 17;60(8):1000-1010. Epub 2021 Jun 17.

Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.

Background: Inpatient rehabilitation therapy (IRT) is commonly offered to cancer patients during or after cancer treatment in Germany. However, little is known about utilization and long-term effects of this offer in colorectal cancer (CRC) patients. We aimed to assess IRT utilization, determinants of utilization and the association between IRT and survival in CRC patients.

Materials And Methods: CRC patients diagnosed in 2005-2014 recruited in the population-based DACHS study in South West Germany were included. Determinants of IRT utilization were assessed by multivariable logistic regression. Hazard ratios (HRs) of the association of IRT with overall and disease-specific survival were estimated by adjusted Cox proportional hazards models. Modified landmark approach was applied to avoid immortal time biased results.

Results: Among the included CRC patients ( = 3704), 43.6% underwent IRT. Patients who did not live in a relationship with a partner, worked as employee and who reported higher levels of physical activity were more likely to undergo IRT. Patients were less likely to undergo IRT if they had private health insurance, were diagnosed with cancer stage IV, received no or laparoscopic cancer surgery or were treated in a hospital with medium vs. high surgical volume. The median follow-up time was 4.4 years (post-landmark). Utilization of IRT was associated with better overall (HR 0.81, 95% confidence interval 0.72-0.92) and disease-specific survival (HR 0.72, 95% confidence interval 0.61-0.85).

Conclusion: Almost every other CRC patient underwent IRT. Next to clinical characteristics, identified social and lifestyle characteristics seemed to play an essential role in the decision-making. Use of IRT was associated with better overall and disease-specific survival.
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http://dx.doi.org/10.1080/0284186X.2021.1940274DOI Listing
August 2021

Non-steroidal anti-inflammatory drugs, polygenic risk score and colorectal cancer risk.

Aliment Pharmacol Ther 2021 07 11;54(2):167-175. Epub 2021 Jun 11.

Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: The regular use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with reduced colorectal cancer (CRC) risk.

Aim: To explore whether this association varies according to background polygenic risk for CRC.

Methods: Data were collected from a large population-based case-control study on CRC in Germany. A polygenic risk score (PRS) based on 140 CRC-related risk loci was used to quantify the genetic risk. The associations of regular use of NSAIDs (≥2times per week for at least 1 year) with CRC risk were estimated in the whole population and in subgroups according to PRS levels using multivariable logistic regression. The impact of NSAIDs on CRC risk was compared to PRS using the 'genetic risk equivalent' (GRE), a recently developed metric for effective risk communication.

Results: In total 5129 CRC cases and 4093 controls were included in this analysis. The regular use of NSAIDs (including aspirin) was associated with reduced CRC risk [odds ratio (OR) 0.66, 95% confidence interval (CI) 0.59, 0.74], as was regular use of aspirin only (OR 0.73, 95% CI 0.65, 0.83), without indication of interaction with the PRS (P = 0.10 and 0.22 respectively). The effect of NSAID use was equivalent to the effect of having a 32 percentiles lower PRS (GRE -32, 95% CI -41, -22).

Conclusions: The regular use of NSAIDs is associated with greatly reduced CRC risk regardless of individual genetic profile. With an equivalent reduction of relative risk across all polygenic risk groups, absolute risk reduction would be expected to be strongest among those with the highest polygenic risk score.
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http://dx.doi.org/10.1111/apt.16438DOI Listing
July 2021

Colorectal cancer incidence, mortality, and stage distribution in European countries in the colorectal cancer screening era: an international population-based study.

Lancet Oncol 2021 07 25;22(7):1002-1013. Epub 2021 May 25.

Department of Research and Development, Netherlands Comprehensive Cancer Organisation, Utrecht, Netherlands; Department of Public Health, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands.

Background: Colorectal cancer screening programmes and uptake vary substantially across Europe. We aimed to compare changes over time in colorectal cancer incidence, mortality, and stage distribution in relation to colorectal cancer screening implementation in European countries.

Methods: Data from nearly 3·1 million patients with colorectal cancer diagnosed from 2000 onwards (up to 2016 for most countries) were obtained from 21 European countries, and were used to analyse changes over time in age-standardised colorectal cancer incidence and stage distribution. The WHO mortality database was used to analyse changes over time in age-standardised colorectal cancer mortality over the same period for the 16 countries with nationwide data. Incidence rates were calculated for all sites of the colon and rectum combined, as well as the subsites proximal colon, distal colon, and rectum. Average annual percentage changes (AAPCs) in incidence and mortality were estimated and relevant patterns were descriptively analysed.

Findings: In countries with long-standing programmes of screening colonoscopy and faecal tests (ie, Austria, the Czech Republic, and Germany), colorectal cancer incidence decreased substantially over time, with AAPCs ranging from -2·5% (95% CI -2·8 to -2·2) to -1·6% (-2·0 to -1·2) in men and from -2·4% (-2·7 to -2·1) to -1·3% (-1·7 to -0·9) in women. In countries where screening programmes were implemented during the study period, age-standardised colorectal cancer incidence either remained stable or increased up to the year screening was implemented. AAPCs for these countries ranged from -0·2% (95% CI -1·4 to 1·0) to 1·5% (1·1 to 1·8) in men and from -0·5% (-1·7 to 0·6) to 1·2% (0·8 to 1·5) in women. Where high screening coverage and uptake were rapidly achieved (ie, Denmark, the Netherlands, and Slovenia), age-standardised incidence rates initially increased but then subsequently decreased. Conversely, colorectal cancer incidence increased in most countries where no large-scale screening programmes were available (eg, Bulgaria, Estonia, Norway, and Ukraine), with AAPCs ranging from 0·3% (95% CI 0·1 to 0·5) to 1·9% (1·2 to 2·6) in men and from 0·6% (0·4 to 0·8) to 1·1% (0·8 to 1·4) in women. The largest decreases in colorectal cancer mortality were seen in countries with long-standing screening programmes.

Interpretation: We observed divergent trends in colorectal cancer incidence, mortality, and stage distribution across European countries, which appear to be largely explained by different levels of colorectal cancer screening implementation.

Funding: German Cancer Aid (Deutsche Krebshilfe) and the German Federal Ministry of Education and Research.
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http://dx.doi.org/10.1016/S1470-2045(21)00199-6DOI Listing
July 2021

Nongenetic Determinants of Risk for Early-Onset Colorectal Cancer.

JNCI Cancer Spectr 2021 Jun 20;5(3):pkab029. Epub 2021 May 20.

Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.

Background: Incidence of early-onset (younger than 50 years of age) colorectal cancer (CRC) is increasing in many countries. Thus, elucidating the role of traditional CRC risk factors in early-onset CRC is a high priority. We sought to determine whether risk factors associated with late-onset CRC were also linked to early-onset CRC and whether association patterns differed by anatomic subsite.

Methods: Using data pooled from 13 population-based studies, we studied 3767 CRC cases and 4049 controls aged younger than 50 years and 23 437 CRC cases and 35 311 controls aged 50 years and older. Using multivariable and multinomial logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) to assess the association between risk factors and early-onset CRC and by anatomic subsite.

Results: Early-onset CRC was associated with not regularly using nonsteroidal anti-inflammatory drugs (OR = 1.43, 95% CI = 1.21 to 1.68), greater red meat intake (OR = 1.10, 95% CI = 1.04 to 1.16), lower educational attainment (OR = 1.10, 95% CI = 1.04 to 1.16), alcohol abstinence (OR = 1.23, 95% CI = 1.08 to 1.39), and heavier alcohol use (OR = 1.25, 95% CI = 1.04 to 1.50). No factors exhibited a greater excess in early-onset compared with late-onset CRC. Evaluating risks by anatomic subsite, we found that lower total fiber intake was linked more strongly to rectal (OR = 1.30, 95% CI = 1.14 to 1.48) than colon cancer (OR = 1.14, 95% CI = 1.02 to 1.27;  = .04).

Conclusion: In this large study, we identified several nongenetic risk factors associated with early-onset CRC, providing a basis for targeted identification of those most at risk, which is imperative in mitigating the rising burden of this disease.
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http://dx.doi.org/10.1093/jncics/pkab029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8134523PMC
June 2021

Early discontinuation and dose reduction of adjuvant chemotherapy in stage III colon cancer patients.

Ther Adv Med Oncol 2021 22;13:17588359211006348. Epub 2021 Apr 22.

Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, Heidelberg, 69120, Germany.

Background: The benefit of chemotherapy in colon cancer patients is well documented but depends largely on whether patients complete the planned treatment regimen. We evaluated predictors of early discontinuation (EDChemo) and dose reduction of chemotherapy, especially the role of adverse treatment effects, in stage III patients who received adjuvant chemotherapy.

Methods: Stage III colon cancer patients who were diagnosed in 2003-2014 and recruited into a population-based study in Germany and received FOLFOX [5-fluorouracil (5-FU), leucovorin (LV), and oxaliplatin], capecitabine monotherapy (CapMono), or 5-FU/LV were included. We assessed determinants of EDChemo and dose reduction using multivariable logistic regression. Also, we estimated proportions of EDChemo and dose reduction that are attributable to adverse effects using attributable fractions.

Results: EDChemo and dose reduction rates were 52% and 17% for FOLFOX, 28% and 9% for CapMono, and 45% and 6% for 5-FU/LV, respectively. Predictors of EDChemo were low-grade tumor and treatment in a medium-volume hospital (for FOLFOX), obesity (for CapMono), and increasing age, T4 stage, and treatment in a medium-volume hospital (for 5-FU/LV). Adverse effects were particularly strongly associated with EDChemo and contributed to about 63%, 51%, and 32% of EDChemo of FOLFOX, CapMono, and 5-FU/LV, respectively. Of the various adverse effects, gastrointestinal events showed the strongest associations with EDChemo and accounted for about 7%, 26%, and 20% of EDChemo of FOLFOX, CapMono, and 5-FU/LV, respectively. Adverse effects were, moreover, a strong determinant of dose reduction and accounted for about 82% of all cases.

Conclusions: EDChemo is common in stage III colon cancer patients receiving chemotherapy and more than half of the cases of EDChemo and dose reduction are due to adverse treatment effects. Further research should address the potential for reducing EDChemo and dose reduction rates by close monitoring of patients for early signs and enhanced management of adverse effects, especially gastrointestinal events.
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http://dx.doi.org/10.1177/17588359211006348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8072866PMC
April 2021

Genetically Predicted Circulating C-Reactive Protein Concentration and Colorectal Cancer Survival: A Mendelian Randomization Consortium Study.

Cancer Epidemiol Biomarkers Prev 2021 Jul 10;30(7):1349-1358. Epub 2021 May 10.

Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Background: A positive association between circulating C-reactive protein (CRP) and colorectal cancer survival was reported in observational studies, which are susceptible to unmeasured confounding and reverse causality. We used a Mendelian randomization approach to evaluate the association between genetically predicted CRP concentrations and colorectal cancer-specific survival.

Methods: We used individual-level data for 16,918 eligible colorectal cancer cases of European ancestry from 15 studies within the International Survival Analysis of Colorectal Cancer Consortium. We calculated a genetic-risk score based on 52 CRP-associated genetic variants identified from genome-wide association studies. Because of the non-collapsibility of hazard ratios from Cox proportional hazards models, we used the additive hazards model to calculate hazard differences (HD) and 95% confidence intervals (CI) for the association between genetically predicted CRP concentrations and colorectal cancer-specific survival, overall and by stage at diagnosis and tumor location. Analyses were adjusted for age at diagnosis, sex, body mass index, genotyping platform, study, and principal components.

Results: Of the 5,395 (32%) deaths accrued over up to 10 years of follow-up, 3,808 (23%) were due to colorectal cancer. Genetically predicted CRP concentration was not associated with colorectal cancer-specific survival (HD, -1.15; 95% CI, -2.76 to 0.47 per 100,000 person-years; = 0.16). Similarly, no associations were observed in subgroup analyses by stage at diagnosis or tumor location.

Conclusions: Despite adequate power to detect moderate associations, our results did not support a causal effect of circulating CRP concentrations on colorectal cancer-specific survival.

Impact: Future research evaluating genetically determined levels of other circulating inflammatory biomarkers (i.e., IL6) with colorectal cancer survival outcomes is needed.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1848DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254760PMC
July 2021

Strong Reduction of Colorectal Cancer Incidence and Mortality After Screening Colonoscopy: Prospective Cohort Study From Germany.

Am J Gastroenterol 2021 05;116(5):967-975

Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Introduction: A claimed advantage of colonoscopy over sigmoidoscopy in colorectal cancer (CRC) screening is prevention of CRC not only in the distal colon and rectum but also in the proximal colon. We aimed to assess the association of screening colonoscopy use with overall and site-specific CRC incidence and associated mortality.

Methods: Information on use of screening colonoscopy as well as potential confounding factors was obtained at baseline in 2000-2002, updated at 2-, 5-, 8-, and 17-year follow-up from 9,207 participants aged 50-75 years without history of CRC in a statewide cohort study in Saarland, Germany. Covariate-adjusted associations of screening colonoscopy with CRC incidence and mortality, which were obtained through record linkage with the Saarland Cancer Registry and mortality statistics up to 2018, were assessed by Cox proportional hazards models with time-varying exposure information.

Results: During a median follow-up of 17.2 years, 268 participants were diagnosed with CRC and 98 died from CRC. Screening colonoscopy was associated with strongly reduced CRC incidence (adjusted hazard ratio [aHR] 0.44, 95% confidence interval [CI] 0.33-0.57) and mortality (aHR 0.34, 95% CI 0.21-0.53), with stronger reduction for distal (aHRs 0.36, 95% CI 0.25-0.51, and 0.33, 95% CI 0.19-0.59, respectively) than for proximal cancer (aHRs 0.69, 95% CI 0.42-1.13, and 0.62, 95% CI 0.26-1.45, respectively). Nevertheless, strong reduction of mortality from proximal cancer was also observed within 10 years after screening colonoscopy (aHR 0.31, 95% CI 0.10-0.96).

Discussion: In this large prospective cohort study from Germany, screening colonoscopy was associated with strong reduction in CRC incidence and mortality.
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http://dx.doi.org/10.14309/ajg.0000000000001146DOI Listing
May 2021

Second-generation colon capsule endoscopy for detection of colorectal polyps: Systematic review and meta-analysis of clinical trials.

Endosc Int Open 2021 Apr 12;9(4):E562-E571. Epub 2021 Apr 12.

Dr. Margarete Fischer Bosch Institute of Clinical Pharmacology, Clinical Pharmacogenomics and Cancer, Stuttgart, Germany.

Adherence to colorectal cancer (CRC) screening is still unsatisfactory in many countries, thereby limiting prevention of CRC. Colon capsule endoscopy (CCE), a minimally invasive procedure, could be an alternative to fecal immunochemical tests or optical colonoscopy for CRC screening, and might increase adherence in CRC screening. This systematic review and meta-analysis evaluates the diagnostic accuracy of CCE compared to optical colonoscopy (OC) as the gold standard, adequacy of bowel preparation regimes and the patient perspective on diagnostic measures. We conducted a systematic literature search in PubMed, EMBASE and the Cochrane Register for Clinical Trials. Pooled estimates for sensitivity, specificity and the diagnostic odds ratio with their respective 95 % confidence intervals (CI) were calculated for studies providing sufficient data. Of 840 initially identified studies, 13 were included in the systematic review and up to 9 in the meta-analysis. The pooled sensitivities and specificities for polyps ≥ 6 mm were 87 % (95 % CI: 83 %-90 %) and 87 % (95 % CI: 76 %-93 %) in 8 studies, respectively. For polyps ≥ 10 mm, the pooled estimates for sensitivities and specificities were 87 % (95 % CI: 83 %-90 %) and 95 % (95 % CI: 92 %-97 %) in 9 studies, respectively. A patients' perspective was assessed in 31 % (n = 4) of studies, and no preference of CCE over OC was reported. Bowel preparation was adequate in 61 % to 92 % of CCE exams. CCE provides high diagnostic accuracy in an adequately cleaned large bowel. Conclusive findings on patient perspectives require further studies to increase acceptance/adherence of CCE for CRC screening.
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http://dx.doi.org/10.1055/a-1353-4849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041571PMC
April 2021

Polymorphisms within Autophagy-Related Genes Influence the Risk of Developing Colorectal Cancer: A Meta-Analysis of Four Large Cohorts.

Cancers (Basel) 2021 Mar 12;13(6). Epub 2021 Mar 12.

Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.

The role of genetic variation in autophagy-related genes in modulating autophagy and cancer is poorly understood. Here, we comprehensively investigated the association of autophagy-related variants with colorectal cancer (CRC) risk and provide new insights about the molecular mechanisms underlying the associations. After meta-analysis of the genome-wide association study (GWAS) data from four independent European cohorts (8006 CRC cases and 7070 controls), two loci, ( = 2.19 × 10) and ( = 6.28 × 10) were associated with the risk of CRC. Mechanistically, the allele was associated with IL1 β levels after the stimulation of peripheral blood mononuclear cells (PBMCs) with ( = 0.002), CD24 + CD38 + CD27 + IgM + B cell levels in blood ( = 0.0038) and serum levels of en-RAGE ( = 0.0068). allele was associated with TNF α and IL1 β levels after the stimulation of PBMCs with LPS ( = 0.0088 and = 0.0076, respectively), CD14+CD16- cell levels in blood ( = 0.0068) and serum levels of CCL19 and cortisol ( = 0.0052 and = 0.0074, respectively). Interestingly, no association with autophagy flux was observed. These results suggested an effect of the and loci in the pathogenesis of CRC, likely through the modulation of host immune responses.
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http://dx.doi.org/10.3390/cancers13061258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998818PMC
March 2021

The Effects of Different Invitation Schemes on the Use of Fecal Occult Blood Tests for Colorectal Cancer Screening: Systematic Review of Randomized Controlled Trials.

Cancers (Basel) 2021 Mar 25;13(7). Epub 2021 Mar 25.

German Cancer Research Center (DKFZ), Division of Clinical Epidemiology and Aging Research, 69120 Heidelberg, Germany.

Personal invitations for fecal occult blood tests (nowadays mostly fecal immunochemical tests) are increasingly used to raise their usage for colorectal cancer screening. However, there is a large heterogeneity in applied invitation schemes. We aimed to review evidence for the effectiveness of various invitation schemes. The main outcome was the fecal occult blood test usage rate. A systematic search was performed in Medline and Web of Science (up to 9 July 2020). Randomized controlled trials or cluster-randomized controlled trials were eligible, which reported on general invitations for fecal occult blood test-based colorectal cancer screening sent to the general population at average colorectal cancer risk. (PROSPERO 2020 CRD42020169409). Overall, 34 studies were included. Invitations with an attached, i.e., mailed fecal occult blood test consistently increased test usage by 4-19.7% points, compared to other methods of test provision. Likewise, the introduction of advance notification consistently led to a higher usage rate, with an increase of 3.3-10.8% points. Reminders showed positive but varying effects by method. With an increase of 8.5-15.8% points, letter or email reminders were more effective than reminders by phone call or text message (0.6-6.5% points). Inconsistent results were found for financial incentives ((-8.4)-20% points) and for added or changed invitation material ((-3.5)-11.8% points). With 3.5-24.7% points, the strongest increases in use were achieved by multifaceted invitation, implementing multiple components. Any invitation scheme was superior over no invitation. Advance notification, mailing of fecal occult blood test, and reminders were consistently shown to have major, complementary potential to increase participation in fecal occult blood test-based colorectal cancer screening settings.
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http://dx.doi.org/10.3390/cancers13071520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037417PMC
March 2021

Pan-cancer image-based detection of clinically actionable genetic alterations.

Nat Cancer 2020 Aug 27;1(8):789-799. Epub 2020 Jul 27.

Division of Gastroenterology, Hepatology and Gastrointestinal On-cology, University Hospital RWTH Aachen, Aachen, Germany.

Molecular alterations in cancer can cause phenotypic changes in tumor cells and their micro-environment. Routine histopathology tissue slides - which are ubiquitously available - can reflect such morphological changes. Here, we show that deep learning can consistently infer a wide range of genetic mutations, molecular tumor subtypes, gene expression signatures and standard pathology biomarkers directly from routine histology. We developed, optimized, validated and publicly released a one-stop-shop workflow and applied it to tissue slides of more than 5000 patients across multiple solid tumors. Our findings show that a single deep learning algorithm can be trained to predict a wide range of molecular alterations from routine, paraffin-embedded histology slides stained with hematoxylin and eosin. These predictions generalize to other populations and are spatially resolved. Our method can be implemented on mobile hardware, potentially enabling point-of-care diagnostics for personalized cancer treatment. More generally, this approach could elucidate and quantify genotype-phenotype links in cancer.
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http://dx.doi.org/10.1038/s43018-020-0087-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610412PMC
August 2020

Genetically predicted circulating concentrations of micronutrients and risk of colorectal cancer among individuals of European descent: a Mendelian randomization study.

Am J Clin Nutr 2021 06;113(6):1490-1502

Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: The literature on associations of circulating concentrations of minerals and vitamins with risk of colorectal cancer is limited and inconsistent. Evidence from randomized controlled trials (RCTs) to support the efficacy of dietary modification or nutrient supplementation for colorectal cancer prevention is also limited.

Objectives: To complement observational and RCT findings, we investigated associations of genetically predicted concentrations of 11 micronutrients (β-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B-6, vitamin B-12, and zinc) with colorectal cancer risk using Mendelian randomization (MR).

Methods: Two-sample MR was conducted using 58,221 individuals with colorectal cancer and 67,694 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. Inverse variance-weighted MR analyses were performed with sensitivity analyses to assess the impact of potential violations of MR assumptions.

Results: Nominally significant associations were noted for genetically predicted iron concentration and higher risk of colon cancer [ORs per SD (ORSD): 1.08; 95% CI: 1.00, 1.17; P value = 0.05] and similarly for proximal colon cancer, and for vitamin B-12 concentration and higher risk of colorectal cancer (ORSD: 1.12; 95% CI: 1.03, 1.21; P value = 0.01) and similarly for colon cancer. A nominally significant association was also noted for genetically predicted selenium concentration and lower risk of colon cancer (ORSD: 0.98; 95% CI: 0.96, 1.00; P value = 0.05) and similarly for distal colon cancer. These associations were robust to sensitivity analyses. Nominally significant inverse associations were observed for zinc and risk of colorectal and distal colon cancers, but sensitivity analyses could not be performed. None of these findings survived correction for multiple testing. Genetically predicted concentrations of β-carotene, calcium, copper, folate, magnesium, phosphorus, and vitamin B-6 were not associated with disease risk.

Conclusions: These results suggest possible causal associations of circulating iron and vitamin B-12 (positively) and selenium (inversely) with risk of colon cancer.
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http://dx.doi.org/10.1093/ajcn/nqab003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168352PMC
June 2021

The association of vitamin D with survival in colorectal cancer patients depends on antioxidant capacity.

Am J Clin Nutr 2021 06;113(6):1458-1467

Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.

Background: Vitamin D plays a role in detoxifying free radicals, which might explain the previously reported lower mortality in colorectal cancer (CRC) patients with higher vitamin D concentrations.

Objectives: We aimed to assess whether the associations of 25-hydroxyvitamin D [25(OH)D] with prognosis in CRC patients differ by total thiol concentration (TTC), a biomarker of antioxidant capacity.

Methods: CRC patients who were diagnosed from 2003 to 2010 and recruited into a population-based study in southern Germany (n = 2,592) were followed over a period of 6 y. 25(OH)D and TTC were evaluated from blood samples collected shortly after CRC diagnosis. Associations of 25(OH)D with all-cause and CRC mortality according to TTC were estimated using multivariable Cox proportional hazards regression.

Results: There was a weak positive correlation between 25(OH)D and TTC (r = 0.26, P < 0.001). 25(OH)D was inversely associated with mortality among patients in the lowest and middle TTC tertiles, but no associations were found among patients in the highest TTC tertile (P-interaction = 0.01). Among patients in the lowest/middle TTC tertiles, those in the middle and highest (compared with lowest) 25(OH)D tertiles had 31% and 44% lower all-cause mortality (P < 0.001) and 25% and 45% lower CRC mortality (P < 0.001), respectively. However, in the highest TTC tertile, 25(OH)D was not associated with all-cause (P = 0.638) or CRC mortality (P = 0.395).

Conclusions: The survival advantages in CRC patients with adequate vitamin D strongly depend on antioxidant capacity and are most pronounced in cases of low antioxidant capacity. These findings suggest that TTC and other biomarkers of antioxidant status may be useful as the basis for enhanced selection criteria of patients for vitamin D supplementation, in addition to the conventional judgment based on blood 25(OH)D concentrations, and also for refining selection of patients for clinical trials aiming to estimate the effect of vitamin D supplementation.
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http://dx.doi.org/10.1093/ajcn/nqaa405DOI Listing
June 2021

Circulating B-vitamin biomarkers and B-vitamin supplement use in relation to quality of life in patients with colorectal cancer: results from the FOCUS consortium.

Am J Clin Nutr 2021 06;113(6):1468-1481

Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.

Background: 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.

Objectives: 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.

Methods: 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.

Results: 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.

Conclusions: 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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http://dx.doi.org/10.1093/ajcn/nqaa422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168355PMC
June 2021
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