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Purpose Rectal cancer and its treatment have a negative impact on health-related quality of life (HRQoL). If risk factors for sustained low HRQoL could be identified early, ideally before the start of treatment, individualised interventions could be identified and implemented to maintain or improve HRQoL. The study aimed to develop a multivariable prediction model for global HRQoL 12 months after rectal cancer treatment. Methods Within COLOR II, a randomised, multicentre, international trial of laparoscopic and open surgery for rectal cancer, a sub-study on HRQoL included 385 patients in 12 hospitals and five countries. The HRQoL study was optional for hospitals in the COLOR II trial. EORTC QLQ-C30 and EORTC QLQ-CR38 were analysed preoperatively and at 1 and 12 months postoperatively. In exploratory analyses, correlations between age, sex, fatigue, pain, ASA classification, complications, and symptoms after surgery to HRQoL were studied. Bivariate initial analyses were followed by multivariate regression models. Results Patient characteristics and clinical factors explained 4–10% of the variation in global HRQoL. The patient-reported outcomes from EORTC QLQ-C30 explained 55–65% of the variation in global HRQoL. The predominant predictors were fatigue and pain, which significantly impacted global HRQoL at all time points measured. Conclusion We found that fatigue and pain were two significant factors associated with posttreatment global HRQoL in patients treated for rectal cancer T1-T3 Nx. Interventions to reduce fatigue and pain could enhance global HRQoL after rectal cancer treatment., CC BY 4.0 DEEDEva Haglind eva.haglind@vgregion.seThis trial is registered with ClinicalTrials.gov No. NCT00297791Open access funding provided by University of Gothenburg. The study received financial support from the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-138751; ALFGBG-4307771; ALFGBG-718221; ALFGBG-965245), the Swedish Cancer Society (CAN 2010/593CAN 2013/497; CAN 2016/362; Pj19 0303), the Alice Swenson Foundation, Anna-Lisa and Bror Björnsson Foundation, Axel Linders Foundation, Assar Gabrielsson Foundation, and the Gothenburg Medical Society.

Mutation analysis of circulating tumor DNA (ctDNA) has applications in monitoring of colorectal cancer (CRC) patients for recurrence. Considering the low tumor fraction of ctDNA in cell-free DNA (cfDNA) isolated from blood plasma, the sensitivity of the detection method is important. Here, plasma DNA collected at diagnosis and follow-up from 25 CRC patients was analyzed using a multiplex superRCA mutation detection assay. The assay was also performed on genomic DNA (gDNA) from tumor and normal tissue from 20 of these patients. The lower limit of detection for most sequence variants was in the range of 10−5, while when analyzing cfDNA from plasma with a typical input of 33 ng, the practical detection limit was ~10−4 or 0.01% mutant allele frequency (MAF). In 17 of 19 patients with identified hotspot mutations in tumor gDNA, at least one hotspot mutation could be detected in plasma DNA at the time of diagnosis. The MAF increased at subsequent time points in four of the patients who experienced a clinical relapse. Multiplex superRCA analysis of the remaining six patients did not reveal any hotspot mutations. In conclusion, multiplex superRCA assays proved suitable for monitoring CRC patients by analyzing hotspot mutations in cfDNA, and dynamic changes in MAF were observed in patients with clinical relapse.

Simple Summary The concept of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy perfusion for the treatment of colorectal cancer peritoneal metastases has been debated based on the results of recent controlled trials. In this review, we describe the development of this "package" treatment and discuss various aspects of the selection and indications, as well as future fields of research.Abstract Peritoneal metastases (PM) are observed in approximately 8% of patients diagnosed with colorectal cancer, either synchronously or metachronously during follow-up. PM often manifests as the sole site of metastasis. PM is associated with a poor prognosis and typically shows resistance to systemic chemotherapy. Consequently, there has been a search for alternative treatment strategies. This review focuses on the global evolution of the combined approach involving cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for the management of PM. It encompasses accepted clinical guidelines, principles for patient selection, surgical and physiological considerations, biomarkers, pharmacological protocols, and treatment outcomes. Additionally, it integrates the relevant literature and findings from previous studies. The role of CRS and HIPEC, in conjunction with other therapies such as neoadjuvant and adjuvant chemotherapy, is discussed, along with the management of patients presenting with oligometastatic disease. Furthermore, potential avenues for future development in this field are explored.

Resistin is a protein involved in inflammation and angiogenesis processes and may play a role in the progression of colorectal cancer (CRC). However, it remains unclear whether resistin is associated with increased mortality after CRC diagnosis. We examined pre-diagnostic serum resistin concentrations in relation to CRC-specific and all-cause mortality among 1343 incident CRC cases from the European Prospective Investigation into Cancer and Nutrition cohort. For CRC-specific mortality as the primary outcome, hazard ratios (HRs) and 95% confidence intervals (95% CI) were estimated from competing risk analyses based on cause-specific Cox proportional hazards models and further in sensitivity analyses using Fine–Gray proportional subdistribution hazards models. For all-cause mortality as the secondary outcome, Cox proportional hazards models were used. Subgroup analyses were performed by sex, tumor subsite, tumor stage, body mass index and time to CRC diagnosis. Resistin was measured on a median of 4.8 years before CRC diagnosis. During a median follow-up of 8.2 years, 474 deaths from CRC and 147 deaths from other causes were observed. Resistin concentrations were not associated with CRC-specific mortality (HRQ4vsQ1 = 0.95, 95% CI: 0.73–1.23; Ptrend =.97; and HRper doubling of resistin concentration = 1.00; 95% CI: 0.84–1.19; P =.98) or all-cause mortality. Results from competing risk (sensitivity) analysis were similar. No associations were found in any subgroup analyses. These findings suggest no association between pre-diagnostic circulating resistin concentrations and CRC-specific or all-cause mortality among persons with CRC, and the potential insignificance of resistin in CRC progression.

Mutation analysis of circulating tumor DNA (ctDNA) has applications in monitoring of colorectal cancer (CRC) patients for recurrence. Considering the low tumor fraction of ctDNA in cell-free DNA (cfDNA) isolated from blood plasma, the sensitivity of the detection method is important. Here, plasma DNA collected at diagnosis and follow-up from 25 CRC patients was analyzed using a multiplex superRCA mutation detection assay. The assay was also performed on genomic DNA (gDNA) from tumor and normal tissue from 20 of these patients. The lower limit of detection for most sequence variants was in the range of 10−5, while when analyzing cfDNA from plasma with a typical input of 33 ng, the practical detection limit was ~10−4 or 0.01% mutant allele frequency (MAF). In 17 of 19 patients with identified hotspot mutations in tumor gDNA, at least one hotspot mutation could be detected in plasma DNA at the time of diagnosis. The MAF increased at subsequent time points in four of the patients who experienced a clinical relapse. Multiplex superRCA analysis of the remaining six patients did not reveal any hotspot mutations. In conclusion, multiplex superRCA assays proved suitable for monitoring CRC patients by analyzing hotspot mutations in cfDNA, and dynamic changes in MAF were observed in patients with clinical relapse.

Simple Summary The concept of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy perfusion for the treatment of colorectal cancer peritoneal metastases has been debated based on the results of recent controlled trials. In this review, we describe the development of this "package" treatment and discuss various aspects of the selection and indications, as well as future fields of research.Abstract Peritoneal metastases (PM) are observed in approximately 8% of patients diagnosed with colorectal cancer, either synchronously or metachronously during follow-up. PM often manifests as the sole site of metastasis. PM is associated with a poor prognosis and typically shows resistance to systemic chemotherapy. Consequently, there has been a search for alternative treatment strategies. This review focuses on the global evolution of the combined approach involving cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for the management of PM. It encompasses accepted clinical guidelines, principles for patient selection, surgical and physiological considerations, biomarkers, pharmacological protocols, and treatment outcomes. Additionally, it integrates the relevant literature and findings from previous studies. The role of CRS and HIPEC, in conjunction with other therapies such as neoadjuvant and adjuvant chemotherapy, is discussed, along with the management of patients presenting with oligometastatic disease. Furthermore, potential avenues for future development in this field are explored.

Bakgrund: Kolorektalcancer är globalt vanlig och påverkar patienternas livskvalitet negativt. Sjuksköterskor står inför utmaningar att möta patienternas behov på ett tillfredsställande sätt.Syfte: Studien syftar till att belysa vuxna patienters upplevelser i samband med diagnosbeskedet till början av behandling av kolorektalcancer.Metod: En litteraturstudie baserad på 10 kvalitativa artiklar genomfördes med användning av kvalitativ innehållsanalys från PubMed och CINAHL.Resultat: Litteraturstudien resulterade i två huvudkategorier: Emotionella reaktionen och vikten av stöd. Emotionella reaktionen hade subkategorierna tankar och känslor om framtiden, chockreaktion och ångest och osäkerhet. Vikten av stöd hade subkategorierna vikten av familjestöd, vikten av information och vikten av vård.Slutsats: Kolorektalcancerpatienter genomgår emotionella utmaningar och betonar behovet av stöd. Studiens resultat kan öka sjuksköterskors förståelse och förbättra deras möjlighet att ge patienterna ett effektivt och empatiskt bemötande., Background: Colorectal cancer significantly affects patients' quality of life and poses challenges for nurses in addressing patient needs.Objective: The study aims to illuminate the experiences of adult patients in connection with the diagnosis of colorectal cancer through the beginning of treatment. Method: Conducted through qualitative content analysis of 10 relevant articles sourced from PubMed and CINAHL databases.Results: The literature study resulted in two main categories: Emotional reactions and the importance of support. Emotional reactions had subcategories of thoughts and feelings about the future, shock reaction, and anxiety and uncertainty. The importance of support included subcategories of the importance of family support the importance of information and the importance of care. Conclusion: Colorectal cancer patients experience emotional turmoil, affecting their journey from diagnosis to treatment. Understanding these experiences enhances nurses' ability to provide empathetic care.

Purpose Rectal cancer and its treatment have a negative impact on health-related quality of life (HRQoL). If risk factors for sustained low HRQoL could be identified early, ideally before the start of treatment, individualised interventions could be identified and implemented to maintain or improve HRQoL. The study aimed to develop a multivariable prediction model for global HRQoL 12 months after rectal cancer treatment. Methods Within COLOR II, a randomised, multicentre, international trial of laparoscopic and open surgery for rectal cancer, a sub-study on HRQoL included 385 patients in 12 hospitals and five countries. The HRQoL study was optional for hospitals in the COLOR II trial. EORTC QLQ-C30 and EORTC QLQ-CR38 were analysed preoperatively and at 1 and 12 months postoperatively. In exploratory analyses, correlations between age, sex, fatigue, pain, ASA classification, complications, and symptoms after surgery to HRQoL were studied. Bivariate initial analyses were followed by multivariate regression models. Results Patient characteristics and clinical factors explained 4–10% of the variation in global HRQoL. The patient-reported outcomes from EORTC QLQ-C30 explained 55–65% of the variation in global HRQoL. The predominant predictors were fatigue and pain, which significantly impacted global HRQoL at all time points measured. Conclusion We found that fatigue and pain were two significant factors associated with posttreatment global HRQoL in patients treated for rectal cancer T1-T3 Nx. Interventions to reduce fatigue and pain could enhance global HRQoL after rectal cancer treatment., CC BY 4.0 DEEDEva Haglind eva.haglind@vgregion.seThis trial is registered with ClinicalTrials.gov No. NCT00297791Open access funding provided by University of Gothenburg. The study received financial support from the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-138751; ALFGBG-4307771; ALFGBG-718221; ALFGBG-965245), the Swedish Cancer Society (CAN 2010/593CAN 2013/497; CAN 2016/362; Pj19 0303), the Alice Swenson Foundation, Anna-Lisa and Bror Björnsson Foundation, Axel Linders Foundation, Assar Gabrielsson Foundation, and the Gothenburg Medical Society.

Mutation analysis of circulating tumor DNA (ctDNA) has applications in monitoring of colorectal cancer (CRC) patients for recurrence. Considering the low tumor fraction of ctDNA in cell-free DNA (cfDNA) isolated from blood plasma, the sensitivity of the detection method is important. Here, plasma DNA collected at diagnosis and follow-up from 25 CRC patients was analyzed using a multiplex superRCA mutation detection assay. The assay was also performed on genomic DNA (gDNA) from tumor and normal tissue from 20 of these patients. The lower limit of detection for most sequence variants was in the range of 10−5, while when analyzing cfDNA from plasma with a typical input of 33 ng, the practical detection limit was ~10−4 or 0.01% mutant allele frequency (MAF). In 17 of 19 patients with identified hotspot mutations in tumor gDNA, at least one hotspot mutation could be detected in plasma DNA at the time of diagnosis. The MAF increased at subsequent time points in four of the patients who experienced a clinical relapse. Multiplex superRCA analysis of the remaining six patients did not reveal any hotspot mutations. In conclusion, multiplex superRCA assays proved suitable for monitoring CRC patients by analyzing hotspot mutations in cfDNA, and dynamic changes in MAF were observed in patients with clinical relapse.

Resistin is a protein involved in inflammation and angiogenesis processes and may play a role in the progression of colorectal cancer (CRC). However, it remains unclear whether resistin is associated with increased mortality after CRC diagnosis. We examined pre-diagnostic serum resistin concentrations in relation to CRC-specific and all-cause mortality among 1343 incident CRC cases from the European Prospective Investigation into Cancer and Nutrition cohort. For CRC-specific mortality as the primary outcome, hazard ratios (HRs) and 95% confidence intervals (95% CI) were estimated from competing risk analyses based on cause-specific Cox proportional hazards models and further in sensitivity analyses using Fine–Gray proportional subdistribution hazards models. For all-cause mortality as the secondary outcome, Cox proportional hazards models were used. Subgroup analyses were performed by sex, tumor subsite, tumor stage, body mass index and time to CRC diagnosis. Resistin was measured on a median of 4.8 years before CRC diagnosis. During a median follow-up of 8.2 years, 474 deaths from CRC and 147 deaths from other causes were observed. Resistin concentrations were not associated with CRC-specific mortality (HRQ4vsQ1 = 0.95, 95% CI: 0.73–1.23; Ptrend =.97; and HRper doubling of resistin concentration = 1.00; 95% CI: 0.84–1.19; P =.98) or all-cause mortality. Results from competing risk (sensitivity) analysis were similar. No associations were found in any subgroup analyses. These findings suggest no association between pre-diagnostic circulating resistin concentrations and CRC-specific or all-cause mortality among persons with CRC, and the potential insignificance of resistin in CRC progression.

Bakgrund: Kolorektalcancer är globalt vanlig och påverkar patienternas livskvalitet negativt. Sjuksköterskor står inför utmaningar att möta patienternas behov på ett tillfredsställande sätt.Syfte: Studien syftar till att belysa vuxna patienters upplevelser i samband med diagnosbeskedet till början av behandling av kolorektalcancer.Metod: En litteraturstudie baserad på 10 kvalitativa artiklar genomfördes med användning av kvalitativ innehållsanalys från PubMed och CINAHL.Resultat: Litteraturstudien resulterade i två huvudkategorier: Emotionella reaktionen och vikten av stöd. Emotionella reaktionen hade subkategorierna tankar och känslor om framtiden, chockreaktion och ångest och osäkerhet. Vikten av stöd hade subkategorierna vikten av familjestöd, vikten av information och vikten av vård.Slutsats: Kolorektalcancerpatienter genomgår emotionella utmaningar och betonar behovet av stöd. Studiens resultat kan öka sjuksköterskors förståelse och förbättra deras möjlighet att ge patienterna ett effektivt och empatiskt bemötande., Background: Colorectal cancer significantly affects patients' quality of life and poses challenges for nurses in addressing patient needs.Objective: The study aims to illuminate the experiences of adult patients in connection with the diagnosis of colorectal cancer through the beginning of treatment. Method: Conducted through qualitative content analysis of 10 relevant articles sourced from PubMed and CINAHL databases.Results: The literature study resulted in two main categories: Emotional reactions and the importance of support. Emotional reactions had subcategories of thoughts and feelings about the future, shock reaction, and anxiety and uncertainty. The importance of support included subcategories of the importance of family support the importance of information and the importance of care. Conclusion: Colorectal cancer patients experience emotional turmoil, affecting their journey from diagnosis to treatment. Understanding these experiences enhances nurses' ability to provide empathetic care.

Mutation analysis of circulating tumor DNA (ctDNA) has applications in monitoring of colorectal cancer (CRC) patients for recurrence. Considering the low tumor fraction of ctDNA in cell-free DNA (cfDNA) isolated from blood plasma, the sensitivity of the detection method is important. Here, plasma DNA collected at diagnosis and follow-up from 25 CRC patients was analyzed using a multiplex superRCA mutation detection assay. The assay was also performed on genomic DNA (gDNA) from tumor and normal tissue from 20 of these patients. The lower limit of detection for most sequence variants was in the range of 10−5, while when analyzing cfDNA from plasma with a typical input of 33 ng, the practical detection limit was ~10−4 or 0.01% mutant allele frequency (MAF). In 17 of 19 patients with identified hotspot mutations in tumor gDNA, at least one hotspot mutation could be detected in plasma DNA at the time of diagnosis. The MAF increased at subsequent time points in four of the patients who experienced a clinical relapse. Multiplex superRCA analysis of the remaining six patients did not reveal any hotspot mutations. In conclusion, multiplex superRCA assays proved suitable for monitoring CRC patients by analyzing hotspot mutations in cfDNA, and dynamic changes in MAF were observed in patients with clinical relapse.

Simple Summary The concept of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy perfusion for the treatment of colorectal cancer peritoneal metastases has been debated based on the results of recent controlled trials. In this review, we describe the development of this "package" treatment and discuss various aspects of the selection and indications, as well as future fields of research.Abstract Peritoneal metastases (PM) are observed in approximately 8% of patients diagnosed with colorectal cancer, either synchronously or metachronously during follow-up. PM often manifests as the sole site of metastasis. PM is associated with a poor prognosis and typically shows resistance to systemic chemotherapy. Consequently, there has been a search for alternative treatment strategies. This review focuses on the global evolution of the combined approach involving cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for the management of PM. It encompasses accepted clinical guidelines, principles for patient selection, surgical and physiological considerations, biomarkers, pharmacological protocols, and treatment outcomes. Additionally, it integrates the relevant literature and findings from previous studies. The role of CRS and HIPEC, in conjunction with other therapies such as neoadjuvant and adjuvant chemotherapy, is discussed, along with the management of patients presenting with oligometastatic disease. Furthermore, potential avenues for future development in this field are explored.

FBXW7 is an E3 ubiquitin ligase that targets proteins for proteasome-mediated degradation and is mutated in various cancer types. Here, we use CRISPR base editors to introduce different FBXW7 hotspot mutations in human colon organoids. Functionally, FBXW7 mutation reduces EGF dependency of organoid growth by ~10,000-fold. Combined transcriptomic and proteomic analyses revealed increased EGFR protein stability in FBXW7 mutants. Two distinct phosphodegron motifs reside in the cytoplasmic tail of EGFR. Mutations in these phosphodegron motifs occur in human cancer. CRISPR-mediated disruption of the phosphodegron motif at T693 reduced EGFR degradation and EGF growth factor dependency. FBXW7 mutant organoids showed reduced sensitivity to EGFR-MAPK inhibitors. These observations were further strengthened in CRC-derived organoid lines and validated in a cohort of patients treated with panitumumab. Our data imply that FBXW7 mutations reduce EGF dependency by disabling EGFR turnover.

Resistin is a protein involved in inflammation and angiogenesis processes and may play a role in the progression of colorectal cancer (CRC). However, it remains unclear whether resistin is associated with increased mortality after CRC diagnosis. We examined pre-diagnostic serum resistin concentrations in relation to CRC-specific and all-cause mortality among 1343 incident CRC cases from the European Prospective Investigation into Cancer and Nutrition cohort. For CRC-specific mortality as the primary outcome, hazard ratios (HRs) and 95% confidence intervals (95% CI) were estimated from competing risk analyses based on cause-specific Cox proportional hazards models and further in sensitivity analyses using Fine-Gray proportional subdistribution hazards models. For all-cause mortality as the secondary outcome, Cox proportional hazards models were used. Subgroup analyses were performed by sex, tumor subsite, tumor stage, body mass index and time to CRC diagnosis. Resistin was measured on a median of 4.8 years before CRC diagnosis. During a median follow-up of 8.2 years, 474 deaths from CRC and 147 deaths from other causes were observed. Resistin concentrations were not associated with CRC-specific mortality (HR Q4vsQ1 = 0.95, 95% CI: 0.73-1.23; P trend = .97; and HR per doubling of resistin concentration = 1.00; 95% CI: 0.84-1.19; P = .98) or all-cause mortality. Results from competing risk (sensitivity) analysis were similar. No associations were found in any subgroup analyses. These findings suggest no association between pre-diagnostic circulating resistin concentrations and CRC-specific or all-cause mortality among persons with CRC, and the potential insignificance of resistin in CRC progression.

Background: Literature suggests colonic resection and primary anastomosis (RPA) instead of Hartmann’s procedure (HP) for the treatment of left-sided colonic emergencies. We aim to evaluate the surgical options globally used to treat patients with acute left-sided colonic emergencies and the factors that leading to the choice of treatment, comparing HP and RPA. Methods: This is a prospective, international, multicenter, observational study registered on ClinicalTrials.gov. A total 1215 patients with left-sided colonic emergencies who required surgery were included from 204 centers during the period of March 1, 2020, to May 31, 2020. with a 1-year follow-up. Results: 564 patients (43.1%) were females. The mean age was 65.9 ± 15.6 years. HP was performed in 697 (57.3%) patients and RPA in 384 (31.6%) cases. Complicated acute diverticulitis was the most common cause of left-sided colonic emergencies (40.2%), followed by colorectal malignancy (36.6%). Severe complications (Clavien-Dindo ≥ 3b) were higher in the HP group (P < 0.001). 30-day mortality was higher in HP patients (13.7%), especially in case of bowel perforation and diffused peritonitis. 1-year follow-up showed no differences on ostomy reversal rate between HP and RPA. (P = 0.127). A backward likelihood logistic regression model showed that RPA was preferred in younger patients, having low ASA score (≤ 3), in case of large bowel obstruction, absence of colonic ischemia, longer time from admission to surgery, operating early at the day working hours, by a surgeon who performed more than 50 colorectal resections. Conclusions: After 100 years since the first Hartmann’s procedure, HP remains the most common treatment for left-sided colorectal emergencies. Treatment’s choice depends on patient characteristics, the time of surgery and the experience of the surgeon. RPA should be considered as the gold standard for surgery, with HP being an exception.

Background: Colorectal cancer (CRC) remains a significant global health challenge, influenced by both dietary factors and genetic predispositions. Dairy/milk consumption has been suggested to be involved in CRC pathogenesis, yet the underlying mechanisms, particularly in ethnically diverse populations, remain poorly understood. This research aims to unravel the complex relationships between dairy/milk consumption, genetic polymorphisms related to dairy/milk digestion, and the influence of circulating proteins on CRC risk and progression.Objectives and Specific Aims: The study aims to: 1) Assess the association between dairy/milk intake (including lactose, calcium, and vitamin D) and CRC incidence and mortality across race/ethnicity; 2) Investigate the associations between genetic polymorphisms in LCT, MCM6, CASR, and VDR genes and CRC risk, including gene-diet interactions; 3) Explore the causal relationship between circulating proteins and CRC risk.Methods: Data from the Multiethnic Cohort study, involving 215,634 participants, were analyzed for dietary associations. Genetic analyses involved candidate SNPs on a sub-cohort of 70,000 participants. Proteomic Mendelian Randomization (MR) analyses leveraged summary-level statistics from various GWAS studies.Results: Higher consumption of dairy/milk and their key components was linked to a 13-17% reduced CRC risk. There was a weak association between dairy/milk intake and mortality among CRC patients. While no evident racial/ethnic heterogeneity was observed in incidence, significant differences were noted across racial/ethnic groups in mortality. No interaction was found between dairy/milk consumption and lactase persistence status. Several SNPs within LCT, MCM6, CASR, and VDR were associated with CRC risk across the different racial/ethnic groups. Elevated genetically determined lactase-phlorizin hydrolase levels were inversely associated with CRC risk. Four unique proteins (GREM1, LPH, PDE5A, LIMA1) were associated w

PURPOSE: To examine the association of a traditional Mexican diet score with risk of total, breast, and colorectal cancer among women of Mexican ethnic descent in the Womens Health Initiative (WHI). METHODS: Participants were WHI enrollees who self-identified as being of Mexican descent. Data from food frequency questionnaires self-administered at study baseline were used to calculate the MexD score, with higher scores indicating greater adherence to an a priori-defined traditional Mexican diet (high in dietary fiber, vegetables, and legumes). Incident cancers were self-reported by participants from 1993 to 2020 and adjudicated by trained physicians. We used multivariable-adjusted Cox proportional hazards models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Among 2,343 Mexican descent women (median baseline age: 59 years), a total of 270 cancers (88 breast, 37 colorectal) occurred during a mean follow-up of 14.4 years. The highest tertile of MexD score was associated with a lower risk of all-cancer incidence (HR: 0.67; 95% CI 0.49-0.91; p-trend: 0.01) and colorectal cancer (HR: 0.38; 95% CI 0.14-0.998; p-trend < 0.05), with each unit increase in the MexD score associated with a 6% lower risk of all-cancer incidence (HR: 0.94; 95% CI 0.88-0.99). There was no statistically significant association with risk of breast cancer. CONCLUSION: Consumption of a traditional Mexican diet was associated with a significantly lower risk of all-cancer incidence and colorectal cancer. Confirmation of these findings in future studies is important, given the prevalence of colorectal cancer and a growing U.S. population of women of Mexican descent.

Although incidence and mortality rates of colorectal cancer (CRC) in the United States (US) have declined in recent years, all populations have not benefited equally of improvements in screening and treatment. Racial and ethnic minoritized groups, low-income people and uninsured persons face the highest burden of this disease. Recent developments in cancer research have highlighted the need for evaluating neighborhood and social level factors in addition to individual characteristics, as they capture information on access to resources that are key elements of cancer risk. The overarching goal of this dissertation was to evaluate the relationship between the social environment and CRC screening and stage at diagnosis in the US, and to determine the role of public health policy in reducing racial and ethnic disparities.Residential segregation has shaped the history of the US, providing resources and better opportunities to people residing in some neighborhoods, while disinvestment have taken place in other areas (mostly inhabited by Black and other racial and ethnic minoritized groups). On the other hand, with the Medicaid expansion provision of the Patient Protection and Affordable Care Act (ACA), access to health insurance has been facilitated to underserved people. Yet, many states have decided not adopting it. This dissertation used national datasets representative of all areas in the US and a novel measure of residential segregation to capture the social environment of individuals and its association with CRC outcomes (Chapters 1 and 2). This dissertation also evaluated the effect of Medicaid expansion in reducing health inequities after the implementation of the ACA (Chapter 3).

Today, colorectal cancer (CRC) diagnosis is performed using colonoscopy, which is the current, most effective screening method. However, colonoscopy poses risks of harm to the patient and is an invasive process. Recent research has proven metabolomics as a potential, non-invasive detection method, which can use identified biomarkers to detect potential cancer in a patients body. The aim of this study is to develop a machine-learning (ML) model based on chemical descriptors that will recognize CRC-associated metabolites. We selected a set of metabolites found as the biomarkers of CRC, confirmed that they participate in cancer-related pathways, and used them for training a machine-learning model for the diagnostics of CRC. Using a set of selective metabolites and random compounds, we developed a range of ML models. The best performing ML model trained on Stage 0-2 CRC metabolite data predicted a metabolite class with 89.55% accuracy. The best performing ML model trained on Stage 3-4 CRC metabolite data predicted a metabolite class with 95.21% accuracy. Lastly, the best-performing ML model trained on Stage 0-4 CRC metabolite data predicted a metabolite class with 93.04% accuracy. These models were then tested on independent datasets, including random and unrelated-disease metabolites. In addition, six pathways related to these CRC metabolites were also distinguished: aminoacyl-tRNA biosynthesis; glyoxylate and dicarboxylate metabolism; glycine, serine, and threonine metabolism; phenylalanine, tyrosine, and tryptophan biosynthesis; arginine biosynthesis; and alanine, aspartate, and glutamate metabolism. Thus, in this research study, we created machine-learning models based on metabolite-related descriptors that may be helpful in developing a non-invasive diagnosis method for CRC.

Claudins (CLDN1-CLDN24) are a family of tight junction proteins whose dysregulation has been implicated in tumorigeneses of many cancer types. In colorectal cancer (CRC), CLDN1, CLDN2, CLDN4, and CLDN18 have been shown to either be upregulated or aberrantly expressed. In the normal colon, CLDN1 and CLDN3-7 are expressed. Although a few claudins, such as CLDN6 and CLDN7, are expressed in CRC their levels are reduced compared to the normal colon. The present review outlines the expression profiles of claudin proteins in CRC and those that are potential biomarkers for prognostication.

INTRODUCTION: Non-Hispanic Black (NHB) Americans have a higher incidence of colorectal cancer (CRC) and worse survival than non-Hispanic white (NHW) Americans, but the relative contributions of biological versus access to care remain poorly characterized. This study used two nationwide cohorts in different healthcare contexts to study health system effects on this disparity. METHODS: We used data from the Surveillance, Epidemiology, and End Results (SEER) registry as well as the United States Veterans Health Administration (VA) to identify adults diagnosed with colorectal cancer between 2010 and 2020 who identified as non-Hispanic Black (NHB) or non-Hispanic white (NHW). Stratified survival analyses were performed using a primary endpoint of overall survival, and sensitivity analyses were performed using cancer-specific survival. RESULTS: We identified 263,893 CRC patients in the SEER registry (36,662 (14%) NHB; 226,271 (86%) NHW) and 24,375 VA patients (4,860 (20%) NHB; 19,515 (80%) NHW). In the SEER registry, NHB patients had worse OS than NHW patients: median OS of 57 months (95% confidence interval (CI) 55-58) versus 72 months (95% CI 71-73) (hazard ratio (HR) 1.14, 95% CI 1.12-1.15, p = 0.001). In contrast, VA NHB median OS was 65 months (95% CI 62-69) versus NHW 69 months (95% CI 97-71) (HR 1.02, 95% CI 0.98-1.07, p = 0.375). There was significant interaction in the SEER registry between race and Medicare age eligibility (p < 0.001); NHB race had more effect in patients <65 years old (HR 1.44, 95% CI 1.39-1.49, p < 0.001) than in those ≥65 (HR 1.13, 95% CI 1.11-1.15, p < 0.001). In the VA, age stratification was not significant (p = 0.21). DISCUSSION: Racial disparities in CRC survival in the general US population are significantly attenuated in Medicare-aged patients. This pattern is not present in the VA, suggesting that access to care may be an important component of racial disparities in this disease.

BACKGROUND: Both defects in mismatch repair (dMMR) and high microsatellite instability (MSI-H) have been recognised as crucial biomarkers that guide treatment strategies and disease management in colorectal cancer (CRC). As MMR and MSI tests are being widely conducted, an increasing number of MSI-H tumours have been identified in CRCs with mismatch repair proficiency (pMMR). The objective of this study was to assess the clinical features of patients with pMMR/MSI-H CRC and elucidate the underlying molecular mechanism in these cases. METHODS: From January 2015 to December 2018, 1684 cases of pMMR and 401 dMMR CRCs were enrolled. Of those patients, 93 pMMR/MSI-H were identified. The clinical phenotypes and prognosis were analysed. Frozen and paraffin-embedded tissue were available in 35 patients with pMMR/MSI-H, for which comprehensive genomic and transcriptomic analyses were performed. FINDINGS: In comparison to pMMR/MSS CRCs, pMMR/MSI-H CRCs exhibited significantly less tumour progression and better long-term prognosis. The pMMR/MSI-H cohorts displayed a higher presence of CD8+ T cells and NK cells when compared to the pMMR/MSS group. Mutational signature analysis revealed that nearly all samples exhibited deficiencies in MMR genes, and we also identified deleterious mutations in MSH3-K383fs. INTERPRETATION: This study revealed pMMR/MSI-H CRC as a distinct subgroup within CRC, which manifests diverse clinicopathological features and long-term prognostic outcomes. Distinct features in the tumour immune-microenvironment were observed in pMMR/MSI-H CRCs. Pathogenic deleterious mutations in MSH3-K383fs were frequently detected, suggesting another potential biomarker for identifying MSI-H. FUNDING: This work was supported by the Science and Technology Commission of Shanghai Municipality (20DZ1100101).

BackgroundThe Affordable Care Act expanded Medicaid coverage for people with low income in the United States. Expanded insurance coverage could promote more timely access to cancer treatment, which could improve overall survival (OS), yet the long-term effects of Medicaid expansion (ME) remain unknown. We evaluated whether ME was associated with improved timely treatment initiation (TTI) and 3-year OS among patients with breast, cervical, colon, and lung cancers who were affected by the policy.MethodsMedicaid-insured or uninsured patients aged 40-64 with stage I-III breast, cervical, colon, or non-small cell lung cancer within the National Cancer Database (NCDB). A difference-in-differences (DID) approach was used to compare changes in TTI (within 60 days) and 3-year OS between patients in ME states versus nonexpansion (NE) states before (2010-2013) and after (2015-2018) ME. Adjusted DID estimates for TTI and 3-year OS were calculated using multivariable linear regression and Cox proportional hazards regression models, respectively.ResultsME was associated with a relative increase in TTI within 60 days for breast (DID = 4.6; p < 0.001), cervical (DID = 5.0 p = 0.013), and colon (DID = 4.0, p = 0.008), but not lung cancer (p = 0.505). In Cox regression analysis, ME was associated with improved 3-year OS for breast (DID hazard ratio [HR] = 0.82, p = 0.009), cervical (DID-HR = 0.81, p = 0.048), and lung (DID-HR = 0.87, p = 0.003). Changes in 3-year OS for colon cancer were not statistically different between ME and NE states (DID-HR, 0.77; p = 0.075).ConclusionsFindings suggest that expanded insurance coverage can improve treatment and survival outcomes among low income and uninsured patients with cancer. As the debate surrounding ME continues nationwide, our findings serve as valuable insights to inform the development of policies aimed at fostering accessible and affordable healthcare for all.

Colorectal cancer is one of the most common and deadly cancers nowadays. Luckily an early detection allows an optimal and successful treatment. To facilitate the detection, MiWEndo is working on a microwave imaging device to enhance colorectal cancer detec- tion via colonoscopy. A fundamental part of their device are the antennas. To optimize the device, a design improvement on a meander slot antenna for medical colonoscopy diagnosis is developed on this thesis. The improvement mainly consists in two upgrades. First one is modifying the shape of the slot pattern and feeder to make them rounded avoiding right angles and therefore reducing manufacturing tolerance errors on the Printed Circuit Board (PCB) etching process. Second one consists of adopting on the meander slot a new bowtie shape to enhance bandwidth. Result simulations of the new design show that bandwidth is indeed enhanced over a 60% and manufacturing is more robust. Such design is going to be implemented by the company MiWEndo Solutions, Barcelona, Spain, on future device manufacturing due to its advantages. Next step will be phantom tests with the new design.

Two independent exome sequencing initiatives aimed to identify new genes involved in the predisposition to nonpolyposis colorectal cancer led to the identification of heterozygous loss-of-function variants in NPAT, a gene that encodes a cyclin E/CDK2 effector required for S phase entry and a coactivator of histone transcription, in two families with multiple members affected with colorectal cancer. Enrichment of loss-of-function and predicted deleterious NPAT variants was identified in familial/early-onset colorectal cancer patients compared to non-cancer gnomAD individuals, further supporting the association with the disease. Previous studies in Drosophila models showed that NPAT abrogation results in chromosomal instability, increase of double strand breaks, and induction of tumour formation. In line with these results, colorectal cancers with NPAT somatic variants and no DNA repair defects have significantly higher aneuploidy levels than NPAT-wildtype colorectal cancers. In conclusion, our findings suggest that constitutional inactivating NPAT variants predispose to mismatch repair-proficient nonpolyposis colorectal cancer., This study was funded by the Spanish Ministry of Science and Innovation (Agencia Estatal de Investigación), co-funded by FEDER funds a way to build Europe [PID2020-112595RB-I00(LV)]; Instituto de Salud Carlos III [CIBERONC CB16/12/00234 (LV, GC)]; Government of Catalonia [AGAUR 2021SGR01112 (LV, GC), CERCA Program for institutional support (IDIBELL)]; Scientific Foundation “Asociación Española Contra el Cáncer” [AECC Investigador(MT)]; the Dutch Digestive Foundation [MLDS FP13-13 (TvW)]; Stichting Sacha Swarttouw-Hijmans (TvW); Fight Colorectal Cancer-Michael’s Mission-AACR Fellowship in Young Onset, Late-Stage Colorectal Cancer Research 2015 [15-40-1645-DEMI (NFCCdM)], the KWF Bas Mulder Award UL [2015-7664 (NFCCdM)] and the ZonMw Veni grant [016.176.l44(NFCCdM)], Peer Reviewed, "Article signat per 16 autors/es: Mariona Terradas, Stephanie A. Schubert, Julen Viana-Errasti, Dina Ruano, Gemma Aiza, Maartje Nielsen, Paula Marciel, Carli M. Tops, Genís Parra, Hans Morreau, David Torrents, Monique E. van Leerdam, Gabriel Capellá, Noel F. C. C. de Miranda, Laura Valle & Tom van Wezel", Postprint (author's final draft)

Background: Colorectal cancer (CRC) is the third-most-common cancer worldwide and its rates are increasing. Elevated body mass index (BMI) is an established risk factor for CRC, although the molecular mechanisms behind this association remain unclear. Using the Mendelian randomization (MR) framework, we aimed to investigate the mediating effects of putative biomarkers and other CRC risk factors in the association between BMI and CRC. Methods: We selected as mediators biomarkers of established cancer-related mechanisms and other CRC risk factors for which a plausible association with obesity exists, such as inflammatory biomarkers, glucose homeostasis traits, lipids, adipokines, insulin-like growth factor 1 (IGF1), sex hormones, 25-hydroxy-vitamin D, smoking, physical activity (PA) and alcohol consumption. We used inverse-variance weighted MR in the main univariable analyses and performed sensitivity analyses (weighted-median, MR–Egger, Contamination Mixture). We used multivariable MR for the mediation analyses. Results: Genetically predicted BMI was positively associated with CRC risk [odds ratio per SD (5 kg/m2) ¼ 1.17, 95% CI: 1.08–1.24, P-value ¼ 1.4 × 10−5] and robustly associated with nearly all potential mediators. Genetically predicted IGF1, fasting insulin, low-density lipoprotein cholesterol, smoking, PA and alcohol were associated with CRC risk. Evidence for attenuation was found for IGF1 [explained 7% (95% CI: 2–13%) of the association], smoking (31%, 4–57%) and PA (7%, 2–11%). There was little evidence for pleiotropy, although smoking was bidirectionally associated with BMI and instruments were weak for PA. Conclusions: The effect of BMI on CRC risk is possibly partly mediated through plasma IGF1, whereas the attenuation of the BMI–CRC association by smoking and PA may reflect confounding and shared underlying mechanisms rather than mediation.

Recent research shows that non-coding RNA transcripts of protein-coding genes could be an emerging novel class of diagnostic biomarkers. This study aimed to identify the most promising biomarkers for colorectal cancer (CRC) screening among upregulated non-coding transcripts of protein-coding genes in malignant CRC cells in comparison to non-malignant cells grown in 3D. Malignant CRC cell lines HCT116, DLD-1 and SW620, and a non-malignant human colon epithelial cell line HCEC-1CT, were cultivated in 3D as spheroids in 24-well plates with low attachment surface for 7 days. RNA sequencing was performed on ribosomal-depleted total RNA using Illumina’s NovaSeq6000 platform that generated paired-end 150bp reads. Highly upregulated transcripts (>10 FPKM) present in all malignant cell lines and absent in non-malignant cell line were filtered and analyzed by a set of in silico tools to filter the best candidates for further validation studies. The publicly available GSE164541 set consisting of triplicate tissue samples of normal, adenoma and primary CRC tissues collected from five patients with CRC was used for validation. As a result, 5 transcripts with retained introns ANXA3-204, LLGL2- 207, KRT19-204, KRT18-206 and KRT8-213 were analyzed by in silico tools. Only ANXA3-204 was classified as non-coding according to both CPC2 and LGC online coding potential prediction tools. Nucleus was predicted as subcellular localization for ANXA3- 204 by AnnoLnc2. Additionally, ANXA3-204 expression was upregulated in adenoma (p=0.04) and CRC tissue samples, although statistical significance was not reached for CRC, in comparison to normal tissue samples in the validation set. Transcriptomic analysis revealed that non-coding ANXA3-204 transcript was highly upregulated in malignant CRC cell lines and adenomas compared to control samples, making ANXA3-204 a potential candidate for early CRC screening. Further studies are needed to confirm diagnostic potential and regulatory role of ANXA3-20

ackground: The pervasive role of alternative promoters in context-specific isoform expression and the importance of promoter choice over its level of transcriptional activity have been recently implied based on pan-cancer in silico studies. We aimed to explore this phenomenon at the cellular level on the example of a major tumor suppressor SMAD4 in search of molecular mechanisms in colorectal cancer that could be exploited for novel biomarkers or therapeutic approaches. Methods: Multi-omics technologies, in silico tools and in vitro functional assays were applied to analyze the transcripts expression and the alternative promoters’ function of the SMAD4 gene in colon cell lines HCEC-1CT, HCT116, DLD-1, SW480 and SW620. Results: High expression of the transcript SMAD4-213 emerged as a hallmark of colon cancer cells, while in silico tools point to its possible additional role and potential for sponging miRNAs. Based on the observed dysregulation of SMAD4-209 and SMAD4-213 in malignant vs. non-malignant colon cells, we propose that their expression ratio might be a solid biomarker candidate for colorectal cancer detection. Conclusions: A differential pattern of the respective promoters’ activity was observed that corresponds to the expression of transcripts, confirming the role of alternative promoters in context-specific isoform expression. The investigated SMAD4 promoters and transcripts harbor translational potential that should be further investigated.

We previously demonstrated that intake of low-fat dairy, but not high-fat dairy, was associated with a decreased colorectal cancer (CRC) recurrence risk. These risks, however, may differ by sex, primary tumour location, and disease stage. Combining data from two similar prospective cohort studies of people with stage I–III CRC enabled these subgroup analyses. Participants completed a food frequency questionnaire at diagnosis (n = 2283). We examined associations between low- and high-fat dairy intake and recurrence risk using multivariable Cox proportional hazard models, stratified by sex, and primary tumour location (colon and rectum), and disease stage (I/II and III). Upper quartiles were compared to lower quartiles of intake, and recurrence was defined as a locoregional recurrence and/or metastasis. During a median follow-up of 5.0 years, 331 recurrences were detected. A higher intake of low-fat dairy was associated with a reduced risk of recurrence (hazard ratio [HR]: 0.60, 95% confidence interval [CI]: 0.43–0.83), which seemed more pronounced in men (HR: 0.51, 95% CI: 0.34–0.77) than in women (HR: 0.84, 95% CI: 0.47–1.49). A higher intake of high-fat dairy was associated with an increased risk of recurrence in participants with colon cancer (HR: 1.60, 95% CI: 1.03–2.50), but not rectal cancer (HR: 0.88, 95% CI: 0.54–1.45). No differences in associations were observed between strata of disease stage. Concluding, our findings imply that dietary advice regarding low-fat dairy intake may be especially important for men with CRC, and that dietary advice regarding high-fat dairy intake may be specifically important in people with colon cancer.

Aim: The aim of this study was to longitudinally investigate dietary and lifestyle inflammation scores and their interaction in relation to risk of colorectal cancer (CRC) recurrence and all-cause mortality. Methods: Data of two prospective cohort studies among CRC survivors was used. Information about diet and/or lifestyle was available for 2739 individuals for at least one of the following time points: at diagnosis, six months after diagnosis and two years after diagnosis. The dietary and lifestyle inflammation scores (DIS and LIS) were used to evaluate the inflammatory potential of diet and lifestyle. Joint modelling, combining mixed models and Cox proportional hazards regression, were used to assess associations between DIS and LIS over time and CRC recurrence and all-cause mortality. Interactions between DIS and LIS were assessed using time-dependent Cox proportional hazard regression. Results: The median follow-up time was 4.8 (IQR 2.9–6.9) years for recurrence and 5.7 (IQR 3.5–8.5) years for all-cause mortality, with 363 and 453 events, respectively. A higher DIS as well as LIS was associated with a higher risk of all-cause mortality (HRDIScontinuous 1.09 95%CI 1.02; 1.15; HRLIScontinuous 1.24 95%CI 1.05; 1.46). Individuals who were in the upper tertile of both DIS and LIS had the highest all-cause mortality risk (HR 1.62 95%CI 1.16; 2.28), compared to the individuals in the lowest tertile of both DIS and LIS. No consistent associations with recurrence were observed. Conclusion: A more pro-inflammatory diet and lifestyle was associated with a higher risk of all-cause mortality, but not recurrence, in CRC survivors.

Background: Colorectal cancer (CRC) prognosis is determined by the disease stage with low survival rates for advanced stages. Current CRC screening programs are mainly using colonoscopy, limited by its invasiveness and high cost. Therefore, non-invasive, cost-effective, and accurate alternatives are urgently needed. Objective and design: This retrospective multi-center plasma proteomics study was performed to identify potential blood-based biomarkers in 36 CRC patients and 26 healthy volunteers by high-resolution mass spectrometry proteomics followed by the validation in an independent CRC cohort (60 CRC patients and 44 healthy subjects) of identified selected biomarkers. Results: Among the 322 identified plasma proteins, 37 were changed between CRC patients and healthy volunteers and were associated with the complement cascade, cholesterol metabolism, and SERPIN family members. Increased levels in CRC patients of the complement proteins C1QB, C4B, and C5 as well as pro-inflammatory proteins, lipopolysaccharide-binding protein (LBP) and serum amyloid A4, constitutive (SAA4) were revealed for first time. Importantly, increased level of C5 was verified in an independent validation CRC cohort. Increased C4B and C8A levels were correlated with cancer-associated inflammation and CRC progression, while cancer-associated inflammation was linked to the acute-phase reactant leucine-rich alpha-2-glycoprotein 1 (LRG1) and ceruloplasmin. Moreover, a 4-protein signature including C4B, C8A, apolipoprotein C2 (APO) C2, and immunoglobulin heavy constant gamma 2 was changed between early and late CRC stages. Conclusion: Our results suggest that C5 could be a potential biomarker for CRC diagnosis. Further validation studies will aid the application of these new potential biomarkers to improve CRC diagnosis and patient care.

Background: Careful macroscopic assessment of surgical scars is needed to avoid routine scar resection during cytoreductive surgery (CRS) for peritoneal metastases (PM). This study aimed to analyze the correlation between macroscopically suspected and microscopically confirmed scar metastases (SMs), and to analyze the prognostic impact of not undergoing routine scar resection. Method: All patients with previous surgery, treated with CRS and hyperthermic intraperitoneal chemotherapy, for colorectal PM or pseudomyxoma peritonei (PMP), at Uppsala University Hospital in 2013–2021, were included. Macroscopic SMs in surgical reports were compared with histopathological analyses. Results: In total, 227 patients were included. Among colorectal PM patients (n = 156), SM was macroscopically suspected in 41 (26%) patients, and 63 (40%) underwent scar resection. SM was confirmed in 19 (30%). Among patients with macroscopic suspicion, 45% had confirmed SM (positive predictive value, PPV). A total of 1 of 23 (4%) patients with no macroscopic suspicion had SM (negative predictive value, NPV = 96%). Among the PMP patients (n = 71), SM was macroscopically suspected in 13 (18%), and 28 (39%) underwent scar resection, of whom 12 (43%) had SM. The PPV was 77%. Occult SM was found in 1 of 14 (NPV = 93%). Not undergoing routine scar resection did not affect recurrence-free survival (RFS, p = 0.2) or overall survival (OS, p = 0.1) in colorectal PM patients or PMP patients (RFS p = 0.7, OS p = 0.7). Conclusion: Occult SM is uncommon and scar resection does not affect RFS or OS. Therefore, macroscopically benign-appearing scars can be left without resection, though resection should be performed upon suspicion or uncertainty.

Background: Secondary treatment of recurrent colorectal peritoneal metastases after previous cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is poorly investigated. Objectives: To evaluate the overall survival outcome of secondary (repeat) CRS + HIPEC compared to palliative treatment in recurrent peritoneal disease. Methods: Patients with colorectal peritoneal metastases treated with an index CRS + HIPEC and subsequently having recurrent peritoneal disease were identified from the prospective Swedish national HIPEC registry. Patients were divided into interventional group (secondary CRS + HIPEC) or palliative group. Multivariable logistic regression, propensity-score matching, and survival outcomes were calculated. Results: Among 575 patients who underwent complete CRS between 2010 and 2021, 208 (36 %) were diagnosed with a subsequent recurrent peritoneal disease. Forty-two patients (20 %) were offered secondary CRS + HIPEC. Propensity-score matching of secondary interventional cases with palliative cases succeeded in 88 % (n = 37) in which female sex, lower peritoneal cancer index at index surgery, longer disease-free interval, and absence of extra-peritoneal metastases were identified as the most relevant matching covariates. Median OS from date of recurrence was 38 months (95%CI 30-58) in the interventional group and 19 months (95%CI: 15-24) in the palliative group (HR 0.35 95%CI: 0.20-0.63, p = 0.0004). Sensitivity analyses confirmed the results. As reference, the median OS from index CRS + HIPEC in the whole colorectal registry (n = 575) was 41 months (95%CI: 38-45). Conclusion: After matching for relevant factors, the hazard ratio for death was significantly reduced in patients who were offered a secondary CRS + HIPEC procedure for recurrent peritoneal disease. Selection bias is inherent, but survival outcomes were comparable to those achieved after the initial procedure.

The rapidly evolving landscape of biomarkers for colorectal cancer (CRC) necessitates an integrative, updated repository. In response, we constructed the Colorectal Cancer Biomarker Database (CBD), which collected and displayed the curated biomedicine information for 870 CRC biomarkers in the previous study. Building on CBD, we have now developed CBD2, which includes information on 1569 newly reported biomarkers derived from different biological sources (DNA, RNA, protein, and others) and clinical applications (diagnosis, treatment, and prognosis). CBD2 also incorporates information on nonbiomarkers that have been identified as unsuitable for use as biomarkers in CRC. A key new feature of CBD2 is its network analysis function, by which users can investigate the visible and topological network between biomarkers and identify their relevant pathways. CBD2 also allows users to query a series of chemicals, drug combinations, or multiple targets, to enable multidrug, multitarget, multipathway analyses, toward facilitating the design of polypharmacological treatments for CRC. CBD2 is freely available at http://www.eyeseeworld.com/cbd

Timely accurate and cost-efficient detection of colorectal cancer (CRC) is of great clinical importance. This study aims to establish prediction models for detecting CRC using plasma cell-free DNA (cfDNA) fragmentomic features. Whole-genome sequencing (WGS) was performed on cfDNA from 620 participants, including healthy individuals, patients with benign colorectal diseases and CRC patients. Using WGS data, three machine learning methods were compared to build prediction models for the stratification of CRC patients. The optimal model to discriminate CRC patients of all stages from healthy individuals achieved a sensitivity of 92.31% and a specificity of 91.14%, while the model to separate early-stage CRC patients (stage 0-II) from healthy individuals achieved a sensitivity of 88.8% and a specificity of 96.2%. Additionally, the cfDNA fragmentation profiles reflected disease-specific genomic alterations in CRC. Overall, this study suggests that cfDNA fragmentation profiles may potentially become a noninvasive approach for the detection and stratification of CRC. © 2024 The Authors

Multimodal prehabilitation seems to be the new kid on the block in perioperative optimalisation. This thesis aims to study the hypothesis that multimodal prehabilitation results in an enhanced and faster recovery after colorectal cancer surgery. Amongst other studies, the results of a systematic review about the colorectal cancer treatment interval, a Cochrane review comparing multimodal prehabilitation before colorectal cancer surgery with a control group and a randomised clinical trial studying a 4-week multimodal prehabilitation in patients undergoing surgery for nonmetastasised colorectal cancer are described and discussed in this thesis.

Early cancer detection is pivotal for improving treatment outcomes and reducing the impact on society. This thesis explores the potential of natural language processing (NLP) techniques to enhance the early detection of colorectal cancer by leveraging primary care data from electronic health records in Sweden. By harnessing the information contained within physician notes, the aim is to develop an NLP model capable of identifying subtle patterns indicative of early-stage cancer, which may be overlooked by human perception. NLP techniques, including Topic Modeling, Named Entity Recognition (NER), and Text Classification, are employed to extract relevant features from the physician notes. The features are then incorporated into existing algorithms to evaluate their impact on cancer detection performance. Additionally, the study assesses the effectiveness of clinical notes for cancer detection three months prior to the diagnosis date, and explores the suitability of existing Swedish language models for text classification of clinical language data. While the study encountered limitations related to data quality, quantity, and project timeframe constraints, the results demonstrate the potential of NLP for cancer detection. Clinical notes were successfully transformed into machine learning features, resulting in improved performance across most metrics. The utilization of clinical notes for cancer detection three months prior to the diagnosis date also increased performance across most metrics, albeit with lower overall predictive power due to the absence of strongly correlated symptoms during that period. The findings suggest that NLP could serve as a valuable source of information for machine learning models in cancer detection, as highly relevant information is present in the analyzed clinical notes. However, the current performance metrics indicate that further refinement and the acquisition of additional data are necessary before the developed models can be deemed, Tidig upptäckt av cancer är avgörande för att förbättra patientens prognos och minska påverkan på samhället. Detta arbete utforskar potentialen av naturlig språkbehandlingsteknik (NLP) för att facilitera tidig upptäckt av kolorektal cancer med primärvårdsdata från elektroniska journaler i Sverige. Genom att tillvarata informationen i patientjournalerna är målet att utveckla en NLP-modell som kan identifiera subtila mönster som tyder på tidig cancer, vilka kan förbises av mänsklig perception. Informationen extraheras från patientjournalerna med NLP-teknikerna Temamodellering (Topic Modeling), Named Entity Recognition (NER) och Textklassificering. Informationens inverkan på prestandan för cancerdetektering utvärderas sedan i befintliga algoritmer. För att simulera realistiska kliniska tillstånd utvärderades modellen även med en mindre mängd data, där information tre månader före diagnos uteslöts. Slutligen utforskar arbetet befintliga svenska språkmodeller för textklassificering av kliniskt språk. Trots begränsningar relaterade till datakvalitet, kvantitet och projektets tidsram, visar resultaten potentialen av NLP för cancerdetektering. Informationen extraherades framgångsrikt ur de kliniska anteckningarna, vilket resulterade i en ökad prestanda för de flesta mätvärdena. Användningen av kliniska anteckningar för cancerdetektering tre månader före diagnosdatum ökade också prestandan av de flesta mätvärden, även om den övergripande prediktiva kraften var lägre på grund av att starkt korrelerade symtom var frånvarande under den perioden. Resultaten tyder på att NLP kan utgöra en värdefull informationskälla för maskininlärningsmodeller vid cancerdetektering, då högst relevant information återfanns i de kliniska anteckningarna. De nuvarande prestandamåtten indikerar dock att ytterligare vidareutveckling och en större datamängd är nödvändig innan eventuell klinisk implementering.

Colorectal cancer is one of the most prevalent malignancies globally and recently introduced digital pathology enables the use of machine learning as an aid for fast diagnostics. This project aimed to develop a deep neural network model to specifically identify and differentiate dysplasia in the epithelium of colorectal polyps and was posed as a binary classification problem. The available dataset consisted of 80 whole slide images of different H&E-stained polyp sections, which were parted info smaller patches, annotated by a pathologist. The best performing model was a pre-trained ResNet-18 utilising a weighted sampler, weight decay and augmentation during fine tuning. Reaching an area under precision-recall curve of 0.9989 and 97.41% accuracy on previously unseen data, the model’s performance was determined to underperform compared to the task’s intra-observer variability and be in alignment with the inter-observer variability. Final model made publicly available at https://github.com/stinabr/classification-of-colorectal-polyps.

Bakgrund: Att få cancer kan rubba den grundläggande tilliten i tillvaron. Sexuell hälsa är en viktig aspekt av individens övergripande livskvalitet och välbefinnande. Patienter med kolorektalcancer får ofta biverkningar av behandlingen som kan påverka den sexuella funktionen och deras livskvalitet. Syfte: Att beskriva vilka sexuella problem patienter kan drabbas av efter att ha behandlats för kolorektalcancer och hur det kan påverka deras livskvalitet. Metod: En allmän litteraturöversikt valdes som metod med vetenskapliga kvantitativa artiklar. Artikelsökningar har skett i databaserna CINAHL, PubMed och PsycINFO. Artiklarna kvalitetsgranskades för att bedöma för risk för bias med hjälp av SBU:s granskningsmallar. Resultat: 15 artiklar inkluderades och resultatet presenteras utifrån tre teman: ”Manlig sexuell dysfunktion”, ”Kvinnlig sexuell dysfunktion” och ” Försämrad sexuell funktion och dess påverkan på livskvalitén”. Till teman ”Manlig sexuell dysfunktion” samt teman ”Kvinnlig sexuell dysfunktion” kunde tre respektive fem subteman identifieras. Samtliga studier bedömdes ha medel eller hög metodologisk kvalitet och låg risk för bias. Slutsats: Resultaten visade att både kirurgisk och medicinsk cancerbehandling negativt påverkade patienternas sexualitet och livskvalitet. Specialistsjuksköterskor har en viktig roll att erbjuda stöd till patienter kring sexuell hälsa genom samtal. Nyckelord: kolorectal cancer, livskvalité, sexuell dysfunktion, sexuell funktion., Background: Getting cancer has a negative influence on life. Sexual health is an important aspect of an individual's overall quality of life and well-being. Patients with colorectal cancer often experience side effects from the treatment that may affect sexual function and their quality of life. Aim: To describe what sexual problems patients may suffer from after being treated for colorectal cancer and how it can affect their quality of life. Method: A general literature review was chosen as the method where quantitative articles were included. The searches have been made in the databases CINAHL, PubMed and PsycINFO. Articles were quality reviewed for risk of bias using SBU's review templates. Results: 15 articles were included and the results are presented based on three themes: "Male sexual dysfunction", "Female sexual dysfunction" and "Impaired sexual function and its impact on quality of life". For the themes "Male sexual dysfunction" and the themes "Female sexual dysfunction" three and five subthemes could be identified, respectively. All studies were assessed as medium or high methodological quality and low risk of bias. Conclusion: The results showed that both surgical and medical cancer treatment negatively affected the patients' sexuality and quality of life. Specialist nurses have an important role in offering support to patients about sexual health through conversation

Background: There is an urgent need to evaluate the quality of healthcare systems to improve and deliver high-quality care. Clinical registries have become important platforms for performance measurements, improvements, and clinical research. Hence, the quality of data in registries is crucial. This study aimed to assess the validity of data in the Swedish Colorectal Cancer Register (SCRCR). Methods: Seven hundred patients from 12 hospitals were randomly selected and proportionally distributed among three different hospital categories in Sweden using two-stage cluster sampling. Validity was assessed by re-abstracting data from the medical files of patients reported to the SCRCR in 2015. Data on histopathology, postoperative complications, and a 3-year follow-up were selected for validation. Re-abstracted data were defined as source data, and validity was defined as the proportion of cases in the SRCRC dataset that agreed with the source data. Validity was expressed as the percentage of exact agreement of non-missing data in both data sets, and Cohens kappa coefficient (kappa) was used to measure the strength of the agreement. Results: The median agreement of the categorical histopathology variables was 93.4% (kappa = 0.83). The general postoperative complication variable showed substantial agreement (84.3%, kappa = 0.61). Likewise, the variable for overall cancer recurrence showed an almost perfect agreement (95.7%, kappa = 0.86), whereas specific variables for local recurrence and distant recurrence displayed only moderate and fair agreement (85.9% and 89.1%, kappa = 0.58 and 0.34, respectively). Conclusion: Validation of the SCRCR data showed high validity of pathology data and recurrence rates, whereas detailed data on recurrence were not as good. Data on postoperative complications were less reliable, although the incidence and Clavien-Dindo grading of severe complications (grade 3b or higher) were reliable.

Background: Secondary treatment of recurrent colorectal peritoneal metastases after previous cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is poorly investigated. Objectives: To evaluate the overall survival outcome of secondary (repeat) CRS + HIPEC compared to palliative treatment in recurrent peritoneal disease. Methods: Patients with colorectal peritoneal metastases treated with an index CRS + HIPEC and subsequently having recurrent peritoneal disease were identified from the prospective Swedish national HIPEC registry. Patients were divided into interventional group (secondary CRS + HIPEC) or palliative group. Multivariable logistic regression, propensity-score matching, and survival outcomes were calculated. Results: Among 575 patients who underwent complete CRS between 2010 and 2021, 208 (36 %) were diagnosed with a subsequent recurrent peritoneal disease. Forty-two patients (20 %) were offered secondary CRS + HIPEC. Propensity-score matching of secondary interventional cases with palliative cases succeeded in 88 % (n = 37) in which female sex, lower peritoneal cancer index at index surgery, longer disease-free interval, and absence of extra-peritoneal metastases were identified as the most relevant matching covariates. Median OS from date of recurrence was 38 months (95%CI 30-58) in the interventional group and 19 months (95%CI: 15-24) in the palliative group (HR 0.35 95%CI: 0.20-0.63, p = 0.0004). Sensitivity analyses confirmed the results. As reference, the median OS from index CRS + HIPEC in the whole colorectal registry (n = 575) was 41 months (95%CI: 38-45). Conclusion: After matching for relevant factors, the hazard ratio for death was significantly reduced in patients who were offered a secondary CRS + HIPEC procedure for recurrent peritoneal disease. Selection bias is inherent, but survival outcomes were comparable to those achieved after the initial procedure.

Background: Colorectal cancer (CRC) prognosis is determined by the disease stage with low survival rates for advanced stages. Current CRC screening programs are mainly using colonoscopy, limited by its invasiveness and high cost. Therefore, non-invasive, cost-effective, and accurate alternatives are urgently needed. Objective and design: This retrospective multi-center plasma proteomics study was performed to identify potential blood-based biomarkers in 36 CRC patients and 26 healthy volunteers by high-resolution mass spectrometry proteomics followed by the validation in an independent CRC cohort (60 CRC patients and 44 healthy subjects) of identified selected biomarkers. Results: Among the 322 identified plasma proteins, 37 were changed between CRC patients and healthy volunteers and were associated with the complement cascade, cholesterol metabolism, and SERPIN family members. Increased levels in CRC patients of the complement proteins C1QB, C4B, and C5 as well as pro-inflammatory proteins, lipopolysaccharide-binding protein (LBP) and serum amyloid A4, constitutive (SAA4) were revealed for first time. Importantly, increased level of C5 was verified in an independent validation CRC cohort. Increased C4B and C8A levels were correlated with cancer-associated inflammation and CRC progression, while cancer-associated inflammation was linked to the acute-phase reactant leucine-rich alpha-2-glycoprotein 1 (LRG1) and ceruloplasmin. Moreover, a 4-protein signature including C4B, C8A, apolipoprotein C2 (APO) C2, and immunoglobulin heavy constant gamma 2 was changed between early and late CRC stages. Conclusion: Our results suggest that C5 could be a potential biomarker for CRC diagnosis. Further validation studies will aid the application of these new potential biomarkers to improve CRC diagnosis and patient care.

Background/Aim: Matrix metalloproteinase 13 (MMP13) has been reported to be involved in tumor development and progression, including of colorectal cancer (CRC). This study aimed at evaluating whether the MMP13 rs2252070 gene polymorphism is associated with clinicopathological factors and its influence on long-term survival in Swedish patients with CRC. Patients and Methods: A total of 723 patients with CRC were genotyped using TaqMan single nucleotide polymorphism assays based on polymerase chain reaction. Results: Assessing clinicopathological factors, we demonstrated that having the G/G genotype for MMP13 rs2252070 was significantly associated with poor differentiation, higher serum level of carcinoembryonic antigen and higher lymph node status. Moreover, the presence of a G allele was significantly related to larger tumor size in rectal cancer but had a significantly protective role against mucinous cancer, perineural invasion and lymphovascular invasion. Kaplan-Meier analysis showed no difference between genotypes regarding cancerspecific survival. Conclusion: Our findings highlight the potential of MMP13 rs2252070 polymorphism as a useful predictor of poor differentiation, serum level of carcinoembryonic antigen, lymph node status, tumor size, mucinous cancer, perineural invasion and lymphovascular invasion in patients with CRC.

Background and Objectives: Disparities between tumors arising via different sporadic carcinogenetic pathways have not been studied systematically. This retrospective multicenter cohort study evaluated the differences in the risk for non-colorectal malignancy between sporadic colorectal cancer (CRC) patients from different DNA mismatch repair status. Methods: A retrospective European multicenter cohort study including in total of 1706 CRC patients treated between 1996 and 2019 in three different countries. The proficiency (pMMR) or deficiency (dMMR) of mismatch repair was determined by immunohistochemistry. Cases were analyzed for tumor BRAFV600E mutation, and BRAF mutated tumors were further analyzed for hypermethylation status in the promoter region of MLH1 to distinguish between sporadic and hereditary cases. Swedish and Finish patients were matched with their respective National Cancer Registries. For the Czech cohort, thorough scrutiny of medical files was performed to identify any non-colorectal malignancy within 20 years before or after the diagnosis of CRC. Poisson regression analysis was performed to identify the incidence rates of non-colorectal malignancies. For validation purposes, standardized incidence ratios were calculated for the Swedish cases adjusted for age, year, and sex. Results: Of the 1706 CRC patients included in the analysis, 819 were female [48%], median age at surgery was 67 years [interquartile range: 60–75], and sporadic dMMR was found in 188 patients (11%). Patients with sporadic dMMR CRC had a higher incidence rate ratio (IRR) for non-colorectal malignancy before and after diagnosis compared to patients with a pMMR tumor, in both uni- (IRR = 2.49, 95% confidence interval [CI] = 1.89–3.31, p = 0.003) and multivariable analysis (IRR = 2.24, 95% CI = 1.67–3.01, p = 0.004). This association applied whether or not the non-colorectal tumor developed before or after the diagnosis of CRC in both uni- (IRR = 1.91, 95% CI = 1.28–2.98, p = 0.004)

The rapidly evolving landscape of biomarkers for colorectal cancer (CRC) necessitates an integrative, updated repository. In response, we constructed the Colorectal Cancer Biomarker Database (CBD), which collected and displayed the curated biomedicine information for 870 CRC biomarkers in the previous study. Building on CBD, we have now developed CBD2, which includes information on 1569 newly reported biomarkers derived from different biological sources (DNA, RNA, protein, and others) and clinical applications (diagnosis, treatment, and prognosis). CBD2 also incorporates information on nonbiomarkers that have been identified as unsuitable for use as biomarkers in CRC. A key new feature of CBD2 is its network analysis function, by which users can investigate the visible and topological network between biomarkers and identify their relevant pathways. CBD2 also allows users to query a series of chemicals, drug combinations, or multiple targets, to enable multidrug, multitarget, multipathway analyses, toward facilitating the design of polypharmacological treatments for CRC. CBD2 is freely available at http://www.eyeseeworld.com/cbd

Aim Population-based data on incidence and risk factors of adhesive small bowel obstruction (SBO) are limited. The aims of this study were to assess the risk of SBO and SBO surgery after bowel resection for colorectal cancer (CRC) and to assess whether this risk is modified by minimally invasive surgery (MIS) and radiotherapy in a retrospective national study. Methods CRCBaSe, a nationwide register linkage originating from the Swedish Colorectal Cancer Register, was used to identify Stage I–III CRC patients who underwent resection in 2007–2016, with follow-up throughout 2017. Matched CRC-free comparators (1:6) were included as a reference of SBO and SBO surgery incidence. The association between MIS and preoperative radiotherapy and the incidence rate of SBO was evaluated in adjusted multivariable Cox regression models. Results Among 33 632 CRC patients and 198 649 comparators, the 5-year cumulative incidence of SBO and SBO surgery was 7.6% and 2.2% among patients and 0.6% and 0.2% among comparators, with death as a competing risk. In all patients, MIS was associated with a reduced incidence of SBO (hazard ratio [HR] 0.7, 95% CI 0.6–0.8) and SBO surgery (HR 0.5, 95% CI 0.3–0.7). In rectal cancer patients, radiotherapy was associated with an increased incidence of SBO (HR 1.6, 95% CI 1.4–1.8) and SBO surgery (HR 1.7, 95% CI 1.3–2.3). Discussion Colorectal cancer surgery is associated with a marked increase in risk of SBO, compared with the general population. The incidence is further increased if open surgery or radiotherapy is performed., Authors in the list of papers of Thorbjörn B. Sakari's thesis: T. Sakari, F. Sköldberg, C. Weibull, C. Nordenvall, U. Karlbom

Background: Colorectal cancer (CRC) is the third-most-common cancer worldwide and its rates are increasing. Elevated body mass index (BMI) is an established risk factor for CRC, although the molecular mechanisms behind this association remain unclear. Using the Mendelian randomization (MR) framework, we aimed to investigate the mediating effects of putative biomarkers and other CRC risk factors in the association between BMI and CRC. Methods: We selected as mediators biomarkers of established cancer-related mechanisms and other CRC risk factors for which a plausible association with obesity exists, such as inflammatory biomarkers, glucose homeostasis traits, lipids, adipokines, insulin-like growth factor 1 (IGF1), sex hormones, 25-hydroxy-vitamin D, smoking, physical activity (PA) and alcohol consumption. We used inverse-variance weighted MR in the main univariable analyses and performed sensitivity analyses (weighted-median, MR–Egger, Contamination Mixture). We used multivariable MR for the mediation analyses. Results: Genetically predicted BMI was positively associated with CRC risk [odds ratio per SD (5 kg/m2) ¼ 1.17, 95% CI: 1.08–1.24, P-value ¼ 1.4 × 10−5] and robustly associated with nearly all potential mediators. Genetically predicted IGF1, fasting insulin, low-density lipoprotein cholesterol, smoking, PA and alcohol were associated with CRC risk. Evidence for attenuation was found for IGF1 [explained 7% (95% CI: 2–13%) of the association], smoking (31%, 4–57%) and PA (7%, 2–11%). There was little evidence for pleiotropy, although smoking was bidirectionally associated with BMI and instruments were weak for PA. Conclusions: The effect of BMI on CRC risk is possibly partly mediated through plasma IGF1, whereas the attenuation of the BMI–CRC association by smoking and PA may reflect confounding and shared underlying mechanisms rather than mediation.