Treatment Of Colorectal Cancer Research Articles

Mechanisms of myeloid-derived suppressor cell-mediated immunosuppression in colorectal cancer and related therapies

Severe immunosuppression is a hallmark of colorectal cancer (CRC). Myeloid-derived suppressor cells (MDSCs), one of the most abundant components of the tumor stroma, play an important role in the invasion, metastasis, and immune escape of CRC. MDSCs create an immunosuppressive microenvironment by inhibiting the proliferation and activation of immunoreactive cells, including T and natural killer cells, as well as by inducing the proliferation of immunosuppressive cells, such as regulatory T cells and tumor-associated macrophages, which, in turn, promote the growth of cancer cells. Thus, MDSCs are key contributors to the emergence of an immunosuppressive microenvironment in CRC and play an important role in the breakdown of antitumor immunity. In this narrative review, we explore the mechanisms through which MDSCs contribute to the immunosuppressive microenvironment, the current therapeutic approaches and technologies targeting MDSCs, and the therapeutic potential of modulating MDSCs in CRC treatment. This study provides ideas and methods to enhance survival rates in patients with CRC.

Fisetin and/or capecitabine causes changes in apoptosis pathways in capecitabine-resistant colorectal cancer cell lines.

Capecitabine is recommended as one of the first-line chemotherapy treatments for advanced or metastatic colorectal cancer. Researches have been conducted on capecitabine's impact on the viability of human colon cancer cells and its potential to induce apoptosis. However, even in cases initially responsive to treatment, the development of acquired resistance significantly limits its efficacy. Challenges still exist in effectively treating patients with chemotherapy, and developing new cytotoxic drugs is hindered by drug resistance. Fisetin alters the cell cycle, inducing apoptosis, inhibiting cancer cell proliferation, and enhancing the therapeutic effectiveness of chemotherapy drugs. This work aims to create a plan for reversing capecitabine resistance. For this purpose, the role of capecitabine and/or fisetin combinations in cell proliferation and apoptosis has been determined in both wild-type and capecitabine-resistant HT29 cells (CR/HT29). We developed capecitabine-resistant cell line from wild-type HT29 cells. This study demonstrated the effects of capecitabine, fisetin, and their combinations on both resistant and wild-type cells through experiments including cell survival skills, cell proliferation, wound healing, colony formation, hoechst staining, and western blot analysis.We established capecitabine-resistant cell lines. P-gp expression increased in CR/HT29 cells. Capecitabine effects on a CR/HT29 cells less than wild-type HT29 cells. The combination of fisetin and capecitabine in cell proliferation caused greater reductions in wild-type HT29 cells than in capecitabine-resistant cells. Fisetin has also additive effects on the apoptotic pathway in CR/HT29 cells.This study provides new perspectives on the combination of capecitabine and/or flavonoid treatment in resistant cells.

A novel colorectal cancer screening framework with feature interpretability to identify high-risk populations for colonoscopy.

Risk assessment is of paramount importance for the detection and treatment of colorectal cancer. We developed and validated a feature interpretability screening framework to identify high-risk populations and recommend colonoscopy for them. We utilized a training cohort consisting of 1252605 participants who underwent colonoscopies in Shanghai from 2013 to 2015 to develop the screening framework. We incorporated Shapley additive explanation values into feature selection to provide interpretability for the framework. Two sampling methods were separately employed to mitigate potential model bias caused by class imbalance. Furthermore, we employed various machine learning algorithms to construct risk assessment models and compared their performance. We tested the screening models on an external validation cohort of 359462 samples and conducted comprehensive evaluation and statistical analysis of the validation results. The external validation results demonstrated that the models in the proposed framework achieved sensitivity over 0.734, specificity over 0.790, and area under the receiver operating characteristic curve ranging from 0.808 to 0.859. In the predictions of the best-performing model, the prevalence rates of colorectal cancer were 0.059% and 1.056% in the low- and high-risk groups, respectively. If colonoscopies were performed only on the high-risk group predicted by the model, only 14.36% of total colonoscopies would be needed to detect 74.86% of colorectal cancer cases. We developed and validated a novel framework to identify populations at high risk for colorectal cancer. Those classified as high risk should undergo colonoscopy for further diagnosis.

The impact of pre-, pro- and synbiotics supplementation in colorectal cancer treatment: a systematic review

The impact of pre-, pro- and synbiotics supplementation in colorectal cancer treatment: a systematic review

Approaches and considerations in the endoscopic treatment of T1 colorectal cancer.

The detection of early colorectal cancer (CRC) is increasing through the implementation of screening programs. This increased detection enhances the likelihood of minimally invasive surgery and significantly lowers the risk of recurrence, thereby improving patient survival and reducing mortality rates. T1 CRC, the earliest stage, is treated endoscopically in cases with a low risk of lymph node metastasis (LNM). The advantages of endoscopic treatment compared with surgery include minimal invasiveness and limited tissue disruption, which reduce morbidity and mortality, preserve bowel function to avoid colectomy, accelerate recovery, and improve cost-effectiveness. However, T1 CRC has a risk of LNM. Thus, selection of the appropriate treatment between endoscopic treatment and surgery, while avoiding overtreatment, is challenging considering the potential for complete resection, LNM, and recurrence risk.

Retraction Note: Molecular mechanism study and tumor heterogeneity of Chinese angelica and Fructus aurantii in the treatment of colorectal cancer through computational and molecular dynamics.

Retraction Note: Molecular mechanism study and tumor heterogeneity of Chinese angelica and Fructus aurantii in the treatment of colorectal cancer through computational and molecular dynamics.

Identification of DNA methylation characteristics associated with metastasis and prognosis in colorectal cancer

Colorectal cancer (CRC) is prone to metastasis and recurrence after surgery, which is one of the main causes for its poor treatment and prognosis. Therefore, it is essential to identify biomarkers associated with metastasis and recurrence in CRC. DNA methylation has a regulatory role in cancer metastasis, tumor immune microenvironment (TME), and prognosis and may be one of the most valuable biomarkers for predicting CRC metastasis and prognosis. We constructed a diagnostic model and nomogram that can effectively predict CRC metastasis based on the differential methylation CpG sites (DMCs) between metastatic and non-metastatic CRC patients. Then, we identified 17 DMCs associated with progression free survival (PFS) of CRC and constructed a prognostic model. The prognosis model based on 17 DMCs can predict the PFS of CRC with medium to high accuracy. The results of immunohistochemical analysis indicated that the protein expression levels of the genes involved in prognostic DMCs were different between normal and colorectal cancer tissues. According to the results of immune-related analysis, we found that the low-risk patients had better immunotherapy response. In addition, high risk scores were negatively correlated with high tumor mutation burden (TMB) levels, and patients with low TMB levels in the high-risk group had the worst PFS. Our work shows the clinical value of DNA methylation in predicting CRC metastasis and PFS, as well as their correlation with TME, immunotherapy, and TMB, which helps understand the changes of DNA methylation in CRC metastasis and improving the treatment and prognosis of CRC.

Updates on the Management of Colorectal Cancer in Older Adults

Colorectal cancer (CRC) poses a significant global health challenge. Notably, the risk of CRC escalates with age, with the majority of cases occurring in those over the age of 65. Despite recent progress in tailoring treatments for early and advanced CRC, there is a lack of prospective data to guide the management of older patients, who are frequently underrepresented in clinical trials. This article reviews the contemporary landscape of managing older individuals with CRC, highlighting recent advancements and persisting challenges. The role of comprehensive geriatric assessment is explored. Opportunities for treatment escalation/de-escalation, with consideration of the older adult’s fitness level. are reviewed in the neoadjuvant, surgical, adjuvant, and metastatic settings of colon and rectal cancers. Immunotherapy is shown to be an effective treatment option in older adults who have CRC with microsatellite instability. Promising new technologies such as circulating tumor DNA and recent phase III trials adding later-line systemic therapy options are discussed. Clinical recommendations based on the data available are summarized. We conclude that deliberate efforts to include older individuals in future colorectal cancer trials are essential to better guide the management of these patients in this rapidly evolving field.

Orally available dextran-aspirin nanomedicine modulates gut inflammation and microbiota homeostasis for primary colorectal cancer therapy

Reversing the aggravated immunosuppression hence overgrowth of colorectal cancer (CRC) caused by the gut inflammation and microbiota dysbiosis is pivotal for effective CRC therapy and metastasis inhibition. However, the low delivery efficiency and severe dose-limiting off-target toxicities caused by unsatisfied drug delivery systems remain the major obstacles in precisely modulating gut inflammation and microbiota in CRC therapy. Herein, a multifunctional oral dextran-aspirin nanomedicine (P3C-Asp) was utilized for oral treatment of primary CRC, as it could release salicylic acid (SA) while scavenging reactive oxygen species (ROS) and held great potential in modulating gut microbiota with prebiotic (dextran). Oral P3C-Asp retained in CRC tissues for over 12 h and significantly increased SA accumulation in CRC tissues over free aspirin (10.8-fold at 24 h). The enhanced SA accumulation and ROS scavenging of P3C-Asp cooperatively induced more potent inflammation relief over free aspirin, characterized as lower level of cyclooxygenase-2 and immunosuppressive cytokines. Remarkably, P3C-Asp promoted the microbiota homeostasis and notably increased the relative abundance of strengthening systemic anti-cancer immune response associated microbiota, especially lactobacillus and Akkermansia to 6.66- and 103- fold over the control group. Additionally, a demonstrable reduction in pathogens associated microbiota (among 96% to 79%) including Bacteroides could be detected. In line with our findings, inflammation relief along with enhanced abundance of lactobacillus was positively correlated with CRC inhibition. In primary CRC model, P3C-Asp achieved 2.1-fold tumor suppression rate over free aspirin, with an overall tumor suppression rate of 85%. Moreover, P3C-Asp cooperated with αPD-L1 further reduced the tumor weight of each mouse and extended the median survival of mice by 29 days over αPD-L1 alone. This study unravels the synergistic effect of gut inflammation and microbiota modulation in primary CRC treatment, and unlocks an unconventional route for immune regulation in TME with oral nanomedicine.

Dual ionotropic crosslinked biopolymer magnetic nanocomposites as 5‐Fluorouracil nanocarrier for potential colorectal cancer treatment

AbstractThis study aimed to synthesize dual‐crosslinked chitosan‐alginate nanocomposites (Cs‐Alg/IO NCs) using green‐synthesized iron oxide nanoparticles (IO, Fe3O4 NPs) for drug delivery application. The NCs, formed via ionotropic gelation with sodium tripolyphosphate (TPP) and calcium chloride (CaCl2) as crosslinking agents for Cs and Alg, respectively, and further characterized for physiochemical properties. The presence of Fe3O4 NPs and 5‐Fluorouracil (5FU) increased hydrodynamic size (153.12 ± 0.57 to 207.64 ± 3.59 nm). Morphological studies revealed NC agglomeration within nanoscales. 5FU‐loaded Cs‐Alg/IO NCs (Cs‐Alg/IO 5FU NCs) exhibited superparamagnetic behavior and sustained drug release under various pH conditions. Cytotoxicity assays on colon cancer cells (HCT116 and HT‐29) and normal colon cells (CCD‐112) indicated higher cancer cell selectivity (selectivity index, SI = 1.91) in 2D models. Elevated IC50 values in 3D models were linked to lower drug loading capacity (LC) and encapsulation efficiency (EE). Overall, the study highlights the potential of dual‐crosslinked biopolymer NCs with green‐synthesized Fe3O4 NPs for developing an anticancer drug delivery system in colorectal cancer treatment.Highlights Synthesis of 5FU‐loaded dual crosslinked Cs‐Alg/IO NCs and Cs‐Alg IPN. Physicochemical characterization of cross‐linked magnetic nanocarriers. Investigation of sustained drug release using superparamagnetic nanocarriers. Evaluation of selective cytotoxicity for Cs‐Alg/IO 5FU NCs.

Modulators of the Nrf2 Signaling Pathway Enhance the Cytotoxic Effect of Standard Chemotherapeutic Drugs on Organoids of Metastatic Colorectal Cancer.

The activity of known modulators of the Nrf2 signaling pathway (bardoxolone and brusatol) was studied on cultures of tumor organoids of metastatic colorectal cancer previously obtained from three patients. The effect of modulators was studied both as monotherapy and in combination with standard chemotherapy drugs used to treat colorectal cancer. The Nrf2 inhibitor brusatol and the Nrf2 activator bardoxolone have antitumor activity. Moreover, bardoxolone and brusatol also significantly enhance the effect of the chemotherapy drugs 5-fluorouracil, oxaliplatin, and irinotecan metabolite SN-38. Thus, bardoxolone and brusatol can be considered promising candidates for further preclinical and clinical studies in the treatment of colorectal cancer.

Treatment of colorectal cancer by traditional Chinese medicine: prevention and treatment mechanisms

Colorectal cancer (CRC) is a significant global health burden, with high morbidity and mortality rates. It is often diagnosed at middle to advanced stage, affecting approximately 35% of patients at the time of diagnosis. Currently, chemotherapy has been used to improve patient prognosis and increase overall survival. However, chemotherapy can also have cytotoxic effects and lead to adverse reactions, such as inhibiting bone marrow hematopoiesis, causing digestive dysfunction, hand-foot syndrome, and even life-threatening conditions. In response to these adverse effects, researchers have proposed using Traditional Chinese Medicine (TCM) as an option to treat cancer. TCM research focuses on prescriptions, herbs, and components, which form essential components of the current research in Chinese medicine. The study and implementation of TCM prescriptions and herbs demonstrate its distinctive holistic approach to therapy, characterized by applying multi-component and multi-target treatment. TMC components have advantages in developing new drugs as they consist of single ingredients, require smaller medication dosages, have a precise measure of pharmacodynamic effects, and have a clear mechanism of action compared to TCM prescriptions and herbs. However, further research is still needed to determine whether TMC components can fully substitute the therapeutic efficacy of TCM prescriptions. This paper presents a comprehensive analysis of the research advancements made in TCM prescriptions, herbs, and components. The findings of this study can serve as a theoretical basis for researchers who are interested in exploring the potential of TCM for the treatment of colorectal cancer.

Neoadjuvant treatment of colorectal cancer: comprehensive review.

Neoadjuvant therapy has an established role in the treatment of patients with colorectal cancer. However, its role continues to evolve due to both advances in the available treatment modalities, and refinements in the indications for neoadjuvant treatment and subsequent surgery. A narrative review of the most recent relevant literature was conducted. Short-course radiotherapy and long-course chemoradiotherapy have an established role in improving local but not systemic disease control in patients with rectal cancer. Total neoadjuvant therapy offers advantages over short-course radiotherapy and long-course chemoradiotherapy, not only in terms of increased local response but also in reducing the risk of systemic relapses. Non-operative management is increasingly preferred to surgery in patients with rectal cancer and clinical complete responses but is still associated with some negative impacts on functional outcomes. Neoadjuvant chemotherapy may be of some benefit in patients with locally advanced colon cancer with proficient mismatch repair, although patient selection is a major challenge. Neoadjuvant immunotherapy in patients with deficient mismatch repair cancers in the colon or rectum is altering the treatment paradigm for these patients. Neoadjuvant treatments for patients with colon or rectal cancers continue to evolve, increasing the complexity of decision-making for patients and clinicians alike. This review describes the current guidance and most recent developments.

Trends in incidence, treatment, and relative survival of colorectal cancer in the Netherlands between 2000 and 2021

BackgroundThe epidemiology of colorectal cancer (CRC) has changed rapidly over the years. The aim of this study was to assess the trends in incidence, treatment, and relative survival (RS) of patients diagnosed with CRC in the Netherlands between 2000 and 2021. Patients and methods2 75667 patients diagnosed with CRC between 2000 and 2021 were included from the Netherlands Cancer Registry. Analyses were stratified for disease extent (localised: T1-3N0M0; regional: T4N0M0/T1-4N1-2M0; distant: T1-4N0-2M1) and localisation (colon; rectum). Trends were assessed with joinpoint regression. ResultsCRC incidence increased until the mid-2010s but decreased strongly thereafter to rates comparable with the early 2000s. Amongst other trend changes, local excision rates increased for patients with localised colon (2021: 13.6 %) and rectal cancer (2021: 34.9 %). Moreover, primary tumour resection became less common in patients with distant colon (2000–2021: 60.9–12.5 %) or rectal cancer (2000–2021: 47.8–6.9 %), while local treatment of metastases rates increased. Five-year RS improved continuously for localised and regional colon (97.7 % and 72.0 % in 2017, respectively) and rectal cancer (95.2 % and 76.3 % in 2017, respectively). The rate of anti-cancer treatments decreased in distant colon (2010–2021: 80.3 % to 67.2 %; p < 0.001) and rectal cancer (2011–2021: 86.0 % to 77.0 %; p < 0.001). The improvement of five-year RS stagnated for distant colon (2010–2017: 11.2 % to 11.9 %; average percentage of change [APC]: 2.1, 95 % confidence interval [CI]: −7.6, 4.7) and rectal cancer (2009–2017: 12.7 % to 15.6 %; APC: 1.4, 95 % CI: −19.1, 5.5). ConclusionsMajor changes in the incidence and treatment of CRC between 2000 and 2021 were identified and quantified. Five-year RS increased continuously for patients with localised and regional CRC, but stagnated for patients with distant CRC, likely caused by decreased rates of anti-cancer treatment in this group.

Trends in patterns of treatment and survival of colorectal cancer patients using cancer registry data in Japan: 1995-2015.

Recent advances in treating colorectal cancer (CRC) have increased the importance of multidisciplinary treatment. This study aimed to clarify trends in the treatment and survival of CRC using population-based cancer registry data in Japan. We analyzed the survival of CRC cases diagnosed from 1995 through 2015 from a population-based cancer registry of six prefectures. The year of diagnosis was classified into five periods, and the trends in the detailed categorization of treatments and survival were identified. We calculated net survival and excess hazard of death from cancer using data on 256,590 CRC patients. The use of laparoscopic surgery has been increasing since 2005 and accounts for the largest proportion of treatment types in the most recent period. Net survival of CRC patients diagnosed after 2005 remained high for laparoscopic surgery and endoscopic surgery (endoscopic mucosal resection or endoscopic submucosal dissection). There was an upward trend in treatment with chemotherapy in addition to open and laparoscopic surgery. Using the excess hazard ratio at the regional stage since 2005, there has been a significant improvement in survival in the younger age group and the rectum cancer group. By type of treatment, there was a tendency toward significant improvement in the open surgery + chemotherapy group. We clarified the trends in treating CRC and the associated trends in survival. Continuous survey based on population-based data helps monitor the impact of developments in treatment.

CircHIF1A induces cetuximab resistance in colorectal cancer by promoting HIF1α-mediated glycometabolism alteration

Epidermal growth factor receptor (EGFR)-targeted therapy is an important treatment for RAS wild-type metastatic colorectal cancer (mCRC), but the resistance mechanism remains unclear. Here, the differential expression of circRNAs between Cetuximab sensitive and resistant cell lines was analyzed using whole-transcriptome sequencing. We identified that the expression of circHIF1A was significantly higher in LIM1215-R than in LIM1215. When treated with Cetuximab, downregulation of circHIF1A level weakened the proliferation and clonal formation ability of LIM1215-R, caused more cells to enter G0-G1 phase, and significantly reduced the basal respiration, ATP production, and maximal respiration, as well as the glycolytic capacity and glycolytic reserve. The response rate and prognosis of circHIF1A-positive patients were inferior to those of negative patients. Mechanistically, circHIF1A can upregulate the level of hypoxia-inducible factor 1 A (HIF1A) by competitively binding to miR-361-5p, inducing the overexpression of enzymes such as glucose transporter 1 (GLUT1) and lactate dehydrogenase A (LDHA). In a xenograft model, inhibition of circHIF1A expression increased the sensitivity to Cetuximab treatment. In conclusion, circHIF1A can promote HIF1α-mediated glycometabolism alteration to induce Cetuximab resistance in CRC. It has the potential to become a screening indicator for the Cetuximab beneficial population in mCRC and a new therapeutic target for enhancing treatment efficacy.

Hydroxygenkwanin suppresses peritoneal metastasis in colorectal cancer by modulating tumor-associated macrophages polarization

Peritoneal metastasis is an important cause of high mortality and poor prognosis in colorectal cancer (CRC) patients. Therefore, the development of compounds with unique anti-CRC Peritoneal metastasis activities is urgently needed to improve the survival of CRC patients. Hydroxygenkwanin (HGK),a natural flavonoid compound, have been shown to display anti-inflammatory, antioxidant, antitumor, and immunoregulatory effects. Here, we employed CRC peritoneal metastasis mouse model with MC38 cells to examine the antitumor activity of HGK. The result showed that HGK not only inhibited peritoneal metastasis, but also significantly increased the proportion of M1-like macrophages while decreasing the proportion of M2-like macrophages within the tumor microenvironment (TME). Furthermore, we demonstrated that the inhibitory effect of HGK on peritoneal metastasis of CRC depended on macrophages in vitro and in vivo. Moreover, we revealed that HGK promoted the polarization of TAMs into M1-like macrophages and inhibited their polarization into M2-like macrophages in a LPS- or IL-4-induced bone marrow-derived macrophages (BMDMs) model and co-culture system. Finally, we also investigated the regulatory mechanism of HGK on TAMs polarization that HGK may active p-STAT5, p–NF–κB signaling in M1-like macrophages and inhibit p-STAT6, JMJD3, PPARγ expression in M2-like macrophages. Taken together, our findings suggest that HGK is a natural candidate for effective prevention of peritoneal metastasis in colorectal cancer, which provides a potential strategy for clinical treatment of colorectal cancer.

Modified Lichong decoction intervenes in colorectal cancer by modulating the intestinal flora and the Wnt/β-catenin signaling pathway

BackgroundThe pathogenesis and treatment of colorectal cancer (CRC) continue to be areas of ongoing research, especially the benefits of traditional Chinese medicine (TCM) in slowing the progression of CRC. This study was conducted to investigate the effectiveness and mechanism of action of modified Lichong decoction (MLCD) in inhibiting CRC progression.MethodsWe established CRC animal models using azoxymethane/dextran sodium sulfate (AOM/DSS) and administered high, medium, or low doses of MLCD or mesalazine (MS) for 9 weeks to observe MLCD alleviation of CRC. The optimal MLCD dose group was then subjected to metagenomic and RNA sequencing (RNA-seq) to explore the differentially abundant flora and genes in the control, model and MLCD groups. Finally, the mechanism of action was verified using WB, qRT‒PCR, immunohistochemistry and TUNEL staining.ResultsMLCD inhibited the progression of CRC, and the optimal effect was observed at high doses. MLCD regulated the structure and function of the intestinal flora by decreasing the abundance of harmful bacteria and increasing that of beneficial bacteria. The differentially expressed genes were mainly associated with the Wnt/β-catenin pathway and the cell cycle. Molecular biology analysis indicated that MLCD suppressed the Wnt/β-catenin pathway and the epithelial–mesenchymal transition (EMT), inhibited abnormal cell proliferation and promoted intestinal epithelial cell apoptosis.ConclusionMLCD mitigated the abnormal growth of intestinal epithelial cells and promoted apoptosis, thereby inhibiting the progression of CRC. This inhibition was accomplished by modifying the intestinal microbiota and disrupting the Wnt/β-catenin pathway and the EMT. Therefore, MLCD could serve as a potential component of TCM prescriptions for CRC treatment.

Exploring the Relationship Between KRAS, NRAS, and BRAF Mutations and Clinical Characteristics in Iranian Colorectal Cancer Patients.

Patients with colorectal cancer can benefit from anti-EGFR (epidermal growth factor receptor) therapy. However, this therapy is not effective for treating colorectal cancers with constitutive activating mutations in the KRAS, NRAS, and BRAF genes. Molecular analysis of tumor tissue frequently informs treatment decisions for colorectal cancer. This study aims to identify KRAS, NRAS, and BRAF mutations in Iranian patients diagnosed with colorectal cancer and to assess the prevalence of these mutations relative to the tumor differentiation stage within these populations. From April 2018 to December 2022, 2000 specimens from patients with colorectal cancer were collected. Data on sex, age, and tumor differentiation stage were recorded for all samples. For mutation detection, the KRAS and NRAS exons (2, 3, and 4) were amplified using the Diatech kit, and a specific primer was used to amplify BRAF exon 15. Pyrosequencing was then performed. Analysis of samples revealed that 1105 specimens (55.3%) contained mutations in at least one of the screened genes. Among the genes studied, the highest occurrence was the KRAS mutation at 47.4%, followed by NRAS at 5.3% and BRAF at 2.7%. Most KRAS mutations were found in exon 2 (89.7%), with the G12D mutation being the most prevalent at 32% of cases. There was a significant difference in the rate of KRAS mutations in women (52.5%) compared to men (43.5%) (P =  0.02). For NRAS, the majority mutations were observed in exon 3 (76.2%), with the Q61H mutation being the most prevalent at 28.5% of cases. There were no significant associations between the clinicopathological parameters and mutations. The study's findings indicate a rising frequency of mutations in these genes in Iran, highlighting the need to screening mutations in the main exons of all three genes for effective colorectal cancer treatment strategies.

Longitudinal associations of diurnal rest-activity rhythms with fatigue, insomnia, and health-related quality of life in survivors of colorectal cancer up to 5 years post-treatment

BackgroundThere is a growing population of survivors of colorectal cancer (CRC). Fatigue and insomnia are common symptoms after CRC, negatively influencing health-related quality of life (HRQoL). Besides increasing physical activity and decreasing sedentary behavior, the timing and patterns of physical activity and rest over the 24-h day (i.e. diurnal rest-activity rhythms) could also play a role in alleviating these symptoms and improving HRQoL. We investigated longitudinal associations of the diurnal rest-activity rhythm (RAR) with fatigue, insomnia, and HRQoL in survivors of CRC.MethodsIn a prospective cohort study among survivors of stage I-III CRC, 5 repeated measurements were performed from 6 weeks up to 5 years post-treatment. Parameters of RAR, including mesor, amplitude, acrophase, circadian quotient, dichotomy index, and 24-h autocorrelation coefficient, were assessed by a custom MATLAB program using data from tri-axial accelerometers worn on the upper thigh for 7 consecutive days. Fatigue, insomnia, and HRQoL were measured by validated questionnaires. Confounder-adjusted linear mixed models were applied to analyze longitudinal associations of RAR with fatigue, insomnia, and HRQoL from 6 weeks until 5 years post-treatment. Additionally, intra-individual and inter-individual associations over time were separated.ResultsData were available from 289 survivors of CRC. All RAR parameters except for 24-h autocorrelation increased from 6 weeks to 6 months post-treatment, after which they remained relatively stable. A higher mesor, amplitude, circadian quotient, dichotomy index, and 24-h autocorrelation were statistically significantly associated with less fatigue and better HRQoL over time. A higher amplitude and circadian quotient were associated with lower insomnia. Most of these associations appeared driven by both within-person changes over time and between-person differences in RAR parameters. No significant associations were observed for acrophase.ConclusionsIn the first five years after CRC treatment, adhering to a generally more active (mesor) and consistent (24-h autocorrelation) RAR, with a pronounced peak activity (amplitude) and a marked difference between daytime and nighttime activity (dichotomy index) was found to be associated with lower fatigue, lower insomnia, and a better HRQoL. Future intervention studies are needed to investigate if restoring RAR among survivors of CRC could help to alleviate symptoms of fatigue and insomnia while enhancing their HRQoL.Trial registrationEnCoRe study NL6904 (https://www.onderzoekmetmensen.nl/).