[Meta-analysis of clinical trials against colorectal cancer--report of the First Colorectal Cancer Collaboration Meeting in Oxford].
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Clinical Trials as Topic↗
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The role of heredity in the etiology of large bowel cancer: data from the Melbourne Colorectal Cancer Study.
Family history data of colorectal cancer, heart disease, and stroke were obtained on near relatives (parents, siblings, and children) in 702 colorectal cancer cases and 710 age-/sex-matched community controls as part of a large, comprehensive, population-based epidemiological and clinicopathological study of colorectal cancer conducted in Melbourne (the Melbourne Colorectal Cancer Study). There was a statistically significant higher family history rate of colorectal cancer in cases than in controls (relative risk = 2.13; 95% confidence interval = 1.53-2.96; p less than 0.001). This family history effect was more pronounced for colon cancer than for rectal cancer and there was an earlier age of detection of colorectal cancer in those with a family history of this cancer when compared with those without such a history. Dietary risk factors for colorectal cancer, which were previously described in the Melbourne study, were separate and independent from the family history effects. It is concluded that a family history of colorectal cancer is an important indication to screen individuals for this cancer, and also that while heredity has a definite role in the etiology of colorectal cancer, this hereditary effect is either likely to be small, or else likely to be important in only a proportion (perhaps 20%) of cases.
Adenocarcinoma↗
The risk of endometrial cancer in hereditary nonpolyposis colorectal cancer.
PURPOSE: Hereditary nonpolyposis colorectal cancer (HNPCC) is characterized by increased risk for cancer, especially colorectal cancer. It has been recommended that colon cancer control programs for family members be expanded to include endometrial cancer, the commonest extracolonic cancer observed in HNPCC families. We estimated the age-specific and cumulative endometrial cancer risk for women at high risk for HNPCC. PATIENTS AND METHODS: Family history data from three large HNPCC registries were combined for this study. High risk family members were identified without regard to extracolonic cancer. Life table methods were used to calculate estimates of risk. RESULTS: One thousand eighteen women from 86 families were included in the study. Cumulative incidence was 20% by age 70, compared to 3% in the general population. Risk was highest in women most likely to carry the HNPCC gene (P < 0.001). In this group, during the highest risk years (age 40 to 60), average annual risk exceeded 1%. There was no significant difference among the registries, despite different ascertainment practices regarding endometrial cancer. CONCLUSION: Interventions to reduce endometrial cancer morbidity and mortality are justified by the risk levels observed. Prophylactic total hysterectomy and bilateral salpingo-oophorectomy should be recommended to women in HNPCC families who have a syndrome cancer or offspring with a syndrome cancer. Endometrial cancer screening should be available to women at high risk. Studies of screening protocols are needed.
Colorectal Neoplasms, Hereditary Nonpolyposis↗
[Radiological findings of cancerous invasion in colorectal cancer less than 3 cm in diameter].
131 colorectal cancers, less than 3 cm in diameter, experienced at Juntendo University Hospital in Oct. 1977 through Dec. 1988 were studied with respect to their radiological and macroscopic features. Macroscopic features of the cancers were classified into type a (a lesion with a long stalk), type b (a subpedunculated or sessile lesion), type c (a plaque-like lesion) and type d (a lesion with a depression). Type a is early cancer. An early cancer of type b was mostly demonstrated as a lobular pattern of tumor surface, and an advanced cancer as a nodular pattern. Type c less than 1 cm in diameter was seen a sm cancer. A sm cancer of type d was mostly demonstrated as a faint barium fleck of the depression, an advanced cancer as a mild barium fleck. By deformed colonic wall in profile view, an early cancer was mostly demonstrated as a thorn shape deformity, sm or pm cancer as an arch shaped deformity and a cancer with deeper cancerous invasion than pm as a trapezoid deformity.
Colorectal Neoplasms↗
Glycosylation profiles of the human colorectal cancer A33 antigen naturally expressed in the human colorectal cancer cell line SW1222 and expressed as recombinant protein in different insect cell lines.
The A33 antigen is a cell surface glycoprotein expressed in human gastrointestinal epithelium and in 95% of colorectal cancers. We have compared the N-linked glycosylation profile of A33 antigen naturally expressed in a human colorectal cancer cell line with recombinant human A33 antigen (rA33) produced in insect cell culture using the baculovirus expression vector. N-Linked glycans were enzymatically released from the protein, and glycan composition was analyzed by HPLC. In three insect cell lines tested (Sf-21, Tn5B1-4, and Tn-4s), glycosylation of rA33 was dominated by high mannose structures (M5Gn2 to M9Gn2; 78-95% of total N-linked glycans), with M8Gn2 being the single most abundant glycoform. A33 antigen naturally expressed in the SW1222 human colon cancer cell line (A33) also possessed a high abundance of high mannose glycans (72%). No complex glycosylation was detected on rA33 expressed in insect cells. Natural A33 was galactosylated to a small extent (6%). These results illustrate a case of similar glycosylation of a glycoprotein between a recombinant version produced in insect cell culture and its counterpart naturally expressed in human cell culture.
Animals↗
Cluster randomization trial of sequence mass screening for colorectal cancer.
PURPOSE: Colorectal cancer is a major cause of death worldwide. To reduce the incidence and mortality from rectal cancer, an individual quantitative risk-assessment model (hereafter referred to as the Attributive Degree Value) and reverse passive hemagglutination fecal occult blood test were used in a randomized, controlled, population-based trial that was conducted in Jiashan County, People's Republic of China. METHODS: All residents of Jiashan County aged 30 years or older were enrolled in the study, and 21 townships in the county were randomized to either a screening (n = 10 townships) or control (n = 11 townships) group. Participants in the screened group submitted a one-article-per-slide stool sample and completed a structured risk-assessment questionnaire from which their attributive degree value was computed. According to study protocol, 4,299 participants were defined as high risk and underwent diagnostic evaluation with 60-cm flexible sigmoidoscopy and, in some cases, an additional screening with colonoscopy. RESULTS: From 1989 to 1996, cumulative mortality from colon cancer was 90 (95 percent confidence interval, 83-97) per 100,000 in the screened group and 83 (95 percent confidence interval, 76-90) per 100,000 in the control group (log-rank P = 1.49, P = 0.222). Mortality from rectal cancer during this time was 110 (95 percent confidence interval, 102-118) per 100,000 in the screened group, which differed significantly from the control group mortality rate of 161 (95 percent confidence interval, 152-170) per 100,000 (log-rank P = 0.003). CONCLUSION: Mass screening with a reverse passive hemagglutination fecal occult blood test along with an individual attributive degree value score was effective in reducing mortality from rectal cancer but not in reducing mortality from colon cancer or the incidence of colorectal cancer.
Adult↗
Cathepsin B in the growth of colorectal cancer: increased activity of cathepsin B in human colorectal cancer.
Cathepsin B, a thiol protease, is involved in cancer metastasis. To clarify the role of cathepsin B in tumor progression in human colorectal cancer, the relationship between its activity, immunohistochemical staining, and clinical tumor progression was investigated. Cathepsin B activity in adenocarcinomas was significantly elevated compared with that in the tumor-bearing tissue. Furthermore, the tumor/tumor-bearing tissue (T/Tb) ratio of the activity was significantly higher than that of colorectal adenoma. Immunohistochemical studies demonstrated intense staining in the cancerous tissue. With respect to the clinical stage of tumors, the activity tended to be higher in tumors that had invaded the serosa or subserosa than in those that invaded the proper muscle. The results suggest that cathepsin B participates in the progression of human colorectal cancer, and its increased expression is a sensitive marker of the differentiation between colorectal adenoma and adenocarcinoma.
Adenocarcinoma↗
Cannabinoids and cancer: potential for colorectal cancer therapy.
Despite extensive research into the biology of CRC (colorectal cancer), and recent advances in surgical techniques and chemotherapy, CRC continues to be a major cause of death throughout the world. Therefore it is important to develop novel chemopreventive/chemotherapeutic agents for CRC. Cannabinoids are a class of compounds that are currently used in the treatment of chemotherapy-induced nausea and vomiting, and in the stimulation of appetite. However, there is accumulating evidence that they could also be useful for the inhibition of tumour cell growth by modulating key survival signalling pathways. The chemotherapeutic potential for plant-derived and endogenous cannabinoids in CRC therapy is reviewed.
Antiemetics↗
Integrative subtyping by bile acid metabolism identifies CLCA1/UGT2A3/ZG16 as markers of immune dysfunction and poor prognosis in colorectal cancer.
BACKGROUND: Colorectal cancer (CRC) is the primary driver of cancer-related death and illness across the world. Despite the full-scale shift of the treatment approach for some colorectal cancer patients due to the use of immune checkpoint inhibitors (ICIs), primary resistance still poses a huge challenge to clinicians. Bile acid metabolism is involved in the pathogenesis of CRC. However, its particular function in shaping the tumor immune microenvironment (TIME) and its effect on prognosis and immune treatment response remain unclear. METHODS: Based on the transcriptome and clinical data from The Cancer Genome Atlas-Colon Adenocarcinoma (TCGA-COAD) cohort, we performed unsupervised consensus clustering and classified patients into different molecular subtypes according to bile acid metabolism. We subsequently compared overall survival (OS), immune cell infiltration levels, and differentially expressed genes among the subtypes. In addition, protein-protein interaction (PPI) network and Cox proportional hazards regression were used to identify key hub genes. Finally, the expression of these crucial hub genes was validated in the Gene Expression Omnibus (GEO) cohort and independent clinical patients. RESULTS: The bile-low group showed a significant reduction in OS time (p = 0.0049). The infiltration levels of CD8+ T cells (p < 0.05) and M1 macrophages (p < 0.01) were significantly higher in the bile-low group than in the bile-high group. We identified three key genes-CLCA1, UGT2A3, and ZG16-and found that they all were downregulated in tumor tissues across the TCGA-COAD and GEO datasets, as well as in independent clinical samples. Survival analysis showed that high CLCA1 expression was significantly associated with favorable overall survival (p < 0.001), whereas UGT2A3 (p = 0.23) and ZG16 (p = 0.17) did not reach statistical significance. The three hub genes were negatively correlated with the (TIDE) score (CLCA1: R = - 0.24, p < 0.001; UGT2A3: R = - 0.15, p = 0.0022; ZG16: R = - 0.14, p = 0.0039). CONCLUSION: Our findings suggest that bile acid metabolism could shape the TIME via key genes CLCA1, UGT2A3, and ZG16, and subsequently modify CRC prognosis and immunotherapy responses. These genes may serve as potential prognostic indicators and mechanistic mediators linking bile acid metabolism to T-cell dysfunction, offering insights for future combination strategies targeting the metabolism-barrier-immunity axis.
CLCA1↗
Quality of life in colorectal cancer patients with colectomy and the validation of the Functional Assessment of Cancer Therapy-Colorectal (FACT-C), Version 4.
The purpose of this study was to determine whether the Functional Assessment of Cancer Therapy-Colorectal (the FACT-C), a disease-specific tool for the assessment of colorectal cancer patients' QOL, is a valid assessment tool for measuring QOL changes. Ninety-eight colorectal cancer patients performed the assessment at baseline and 52 of these patients completed the instrument at one month and six months after colectomy. In addition to the FACT-C, the shortened forms of the Profile of Mood States, the Eastern Cooperative Oncology Group Performance Status Rating, Neuroticism Scale in the Eysenck Personality Questionnaire, and Functional Living Index-Cancer were completed. We found convergent and divergent validity and good reliability of the FACT-C. Patients' overall QOL was lower at one month after colectomy and recovered to the pre-surgery level at six months after colectomy.
Colectomy↗
Colorectal cancer risk, chronic illnesses, operations, and medications: case control results from the Melbourne Colorectal Cancer Study.
The associations between colorectal cancer risk and several chronic illnesses, operations, and various medications were examined in 715 colorectal cancer cases and 727 age/sex-matched controls in data derived from a large, comprehensive, population-based study of this cancer conducted in Melbourne, Australia. There was a statistically significant deficit among cases of hypertension, heart disease, stroke, chronic chest disease, and chronic arthritis and a statistically significant excess of "hemorrhoids" among cases, and all of these differences were consistent for both colon and rectal cancer and for both males and females. Although no statistically significant differences were found for other cancers, there were twice as many breast cancers among cases (16) than among controls and also there were 9 uterine cancers among cases and only 2 among controls. There was a statistically significant deficit among cases in the use of aspirin-containing medication and vitamin supplements, and this was consistent for both colon and rectal cancer and for both males and females. There was a statistically significant excess of large bowel polypectomy among cases. The modeling of these significant associations simultaneously in a logistic regression equation indicated that hypertension, heart disease, chronic arthritis, and aspirin use were each independent effects and consistent for both colon and rectal cancer for both males and females and also that these effects were independent of dietary risk factors previously described in the Melbourne study. The possible relevance of these findings towards an understanding of colorectal cancer risk and etiology is discussed.
Aged↗
An international multidisciplinary approach to the management of advanced colorectal cancer. The International Working Group in Colorectal Cancer (IWGCRC) (1)
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Colorectal Neoplasms↗
An international, multidisciplinary approach to the management of advanced colorectal cancer. The International Working Group in Colorectal Cancer (IWGCRC)(2).
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Colorectal Neoplasms↗
Randomised study of sequential versus combination chemotherapy with capecitabine, irinotecan and oxaliplatin in advanced colorectal cancer, an interim safety analysis. A Dutch Colorectal Cancer Group (DCCG) phase III study.
BACKGROUND: Results on overall survival in randomised studies of mono- versus combination chemotherapy in advanced colorectal cancer patients may have been biased by an imbalance in salvage treatments. This is the first randomised study that evaluates sequential versus combination chemotherapy with a fluoropyrimidine, irinotecan and oxaliplatin. PATIENTS AND METHODS: A total of 820 patients were randomised between first-line capecitabine, second-line irinotecan and third-line capecitabine + oxaliplatin (arm A) versus first-line capecitabine + irinotecan, and second-line capecitabine + oxaliplatin (arm B). The primary end point was overall survival. We present the results of an interim analysis on the safety data in the first 400 patients. RESULTS: In first-line the incidence of grade 3-4 diarrhoea, nausea, vomiting and febrile neutropenia was significantly higher in arm B. However, when toxicity over all lines was considered only grade 3 hand-foot syndrome occurred more frequently in arm A (12% versus 6%, respectively, P = 0.041). The incidence of cardiovascular toxicity was low. In two out of five patients with sudden death (one in arm A, four in arm B) cardiovascular risk factors were present. CONCLUSIONS: Both treatment arms had an acceptable safety profile. These data imply that the results on survival will be the major determinant for the selection of either strategy. Capecitabine plus irinotecan appears to be a feasible first-line treatment for patients with advanced colorectal carcinoma.
Adult↗
Modulation of the tumor microenvironment by the ubiquitin-proteasome system in colorectal cancer.
BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, with the tumor microenvironment (TME) playing a pivotal role in its progression and therapeutic resistance. The ubiquitin-proteasome system (UPS), a central regulator of intracellular protein degradation, is increasingly recognized for its involvement in cancer pathogenesis, though its specific role in modulating the CRC TME remains to be fully elucidated. This review aims to systematically summarize current evidence on how the UPS influences the immunosuppressive network within the CRC TME and to evaluate its potential as a therapeutic target. METHODS: We conducted a comprehensive literature search in PubMed, Web of Science, and Scopus databases for original research articles and reviews published between January 2010 and August 2025, using keywords including "ubiquitin-proteasome system," "colorectal cancer," "tumor microenvironment,""immune escape,"and "targeted therapy." Studies were selected based on their relevance to UPS-mediated regulatory mechanisms in CRC TME remodeling, immune cell function, and treatment response. RESULTS: Our analysis of preclinical and clinical evidence reveals that the UPS critically regulates immune evasion in CRC through multiple mechanisms: (1) USP14 stabilizes indoleamine 2,3-dioxygenase 1 (IDO1), enhancing tryptophan catabolism and kynurenine accumulation, which suppresses T-cell activity; (2) E3 ligases including SPOP, C-Cbl, KLHL22, and FBW7 modulate PD-L1/PD-1 protein stability via ubiquitination, thereby influencing immune checkpoint signaling; and (3) ZFP91 facilitates K63-linked ubiquitination of PP2Ac, impairing mTORC1-mediated glycolysis in T cells and reinforcing regulatory T-cell immunosuppression. Additionally, the UPS intersects with key oncogenic pathways such as Wnt/β-catenin, NF-κB, and p53, further shaping the immunosuppressive landscape of CRC. CONCLUSIONS: Targeting the UPS represents a promising strategy to reverse immunosuppression and overcome therapy resistance in CRC. The primary advantage of this approach lies in its ability to simultaneously disrupt multiple immunosuppressive pathways within the TME, offering a potential solution to the limitations of single-target therapies. Current approaches include proteasome inhibitors, E3 ligase modulators, and deubiquitinating enzyme inhibitors, with combination regimens-such as UPS inhibitors with immune checkpoint blockade-showing synergistic efficacy in preclinical models. Future efforts should focus on enhancing the selectivity of UPS-targeting agents, minimizing off-target effects, and integrating genomic profiling to guide personalized treatment. While current evidence strongly supports the therapeutic potential of UPS targeting, its establishment as a reliable alternative therapy in the clinic will depend on overcoming these challenges and validating efficacy in human trials. This review underscores the UPS as a central regulator of the CRC TME and provides a rational basis for novel therapeutic development.
Humans↗
MLH1 and MSH2 constitutional mutations in colorectal cancer families not meeting the standard criteria for hereditary nonpolyposis colorectal cancer.
Genetic diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) may have a significant impact on the clinical management of patients and their at-risk relatives. At present, clinical criteria represent the simplest and most useful method for the identification of HNPCC families and for the selection of candidates for genetic testing. However, reports of mismatch repair (MMR) gene mutations in families not fulfilling the minimal diagnostic criteria point out the necessity to identify additional clinical parameters suggestive of genetic predisposition to colorectal cancer (CRC) related to MMR defects. We thus investigated a series of 32 Italian putative HNPCC individuals selected on the basis of one of the following criteria: 1) family history of CRC and/or other extracolonic tumors; 2) early-onset CRC; and 3) presence of multiple primary malignancies in the same individual. These patients were investigated for the presence of MLH1 and MSH2 mutations by single-strand conformation polymorphism analysis. Pathogenetic truncating mutations were identified in 4 (12.5%) cases, 3 of them involving MSH2 and 1 MLH1. In addition, 2 missense MLH1 variants of uncertain significance were observed. All pathogenetic mutations were associated with early age (<40 years) at onset and proximal CRC location. Our results support the contention that constitutional MMR mutations can also occur in individuals without the classical HNPCC pattern. Moreover, evaluation of the clinical parameters associated with MMR mutations indicates that early onset combined with CRC location in the proximal colon can be definitely considered suggestive of MMR-related hereditary CRC and should be included among the guidelines for referring patients for genetic testing.
Adaptor Proteins, Signal Transducing↗
Recommendations on population screening for colorectal cancer in New Zealand. Members of the National Health Committee Working Party on Population Screening for Colorectal Cancer.
The National Advisory Committee on Health and Disability invited a working party to make recommendations on population screening for colorectal cancer in New Zealand. Recent results from randomised controlled trials of screening with guaiac faecal occult blood tests have provided evidence that population screening could reduce mortality from colorectal cancer. However, given the modest potential level of benefit, the considerable commitment of health sector resources, and the small but real potential for harm, the working party does not recommend population screening for colorectal cancer with faecal occult blood tests in New Zealand. The working party does nto recommend pilot colorectal cancer screening programmes in New Zealand because pilot programmes cannot address the issues of concern: the modest potential benefit and the small, but real, potential for harm. The working party does not recommend faecal occult blood testing as a screening test for colorectal cancer in average-risk individuals outside a population screening programme. Those requesting screening by faecal occult blood test should be given information about the potential risks and benefits. Follow-up bowel investigations in the public health system cannot be guaranteed without an increased allocation of resources. As there is yet no evidence from randomised controlled trials that screening with flexible sigmoidoscopy, colonoscopy or double-contrast barium enema produces a reduction in colorectal cancer mortality, the working party does not recommend population screening with these modalities. Wider consultation and further consideration should be undertaken to develop appropriate advice on surveillance recommendations for groups identified to be at increased risk of colorectal cancer. These decisions should be reviewed as evidence of benefit from new types of faecal occult blood test and other screening modalities becomes available. The working party recognises that colorectal cancer is an important cause of morbidity and mortality and recommends that New Zealand participate in international research in this area.
Colonoscopy↗
Assessing the quality of colorectal cancer staging: documenting the process in improving the staging of node-negative colorectal cancer.
HYPOTHESIS: Examination of 14 or more nodes is the optimal criterion to accurately stage node-negative colorectal cancer and predict outcome. DESIGN: Case series. SETTING: Three university-affiliated community medical centers. PATIENTS: A total of 2149 individuals with apparently localized, invasive colorectal cancer examined between January 1, 1990, and December 31, 2002. INTERVENTION: Study of tumor registry data. MAIN OUTCOME MEASURES: Nodal status and disease-specific survival. RESULTS: The number of nodes examined ranged from 0 to 97 (mean +/- SD, 18 +/- 15 nodes). The mean number of nodes examined in node-positive individuals was 21.0 vs 16.6 in node-negative individuals (P<.001). The mean number of nodes examined at medical center A was 22.3; center B, 17.9; and center C, 14.0. The mean number of nodes examined for T3 and T4 tumors at center A was 26; center B, 20; and center C, 16 (P<.001). The node-positive rate for all T3 and T4 lesions was 49.7% at center A, 57.8% at center B, and 50.0% at center C (P<.001). Despite significant differences in the mean number of nodes examined between medical centers, the overall survival in patients with node-negative colorectal cancer in the 3 medical centers was not statistically different (P = .79). The criterion of examining 14 or more nodes distinguished between individuals at low risk for recurrence and those at increased risk. CONCLUSIONS: Variability exists between medical centers in the pathological analysis of colorectal cancer specimens. However, within an institution, examining a mean of 14 or more nodes accurately stages apparently node-negative colorectal cancer and accurately predicts outcome.
Adult↗