BACKGROUND: Duodenal polyposis is a manifestation of adenomatous polyposis that predisposes to duodenal or ampullary adenocarcinoma. Duodenal polyposis is monitored by upper GI endoscopies and may require iterative resections and prophylactic radical surgical treatment when malignancy is threatening.
OBJECTIVE: The purpose of this study was to evaluate severity scoring for surveillance and treatment in a large series of duodenal polyposis.
DESIGN: From 1982 to 2014, every patient surveyed by upper GI endoscopies for duodenal polyposis was included.
SETTINGS: The study was conducted at a single tertiary care center.
PATIENTS: We performed 1912 upper GI endoscopies in 437 patients (median = 3; interquartile range, 2-6 endoscopies).
MAIN OUTCOME MEASURES: Conservative treatment was performed in 103 patients (159 endoscopic and 17 surgical resections), whereas radical surgical treatment (Whipple procedure or duodenectomy) was required in 52 (median age, 47.5 y; range, 43.0-57.3 y) because of high-grade dysplasia or unresectable lesions.
RESULTS: Genes involved were APC (n = 274; 62.7%) and MUTYH (n = 21; 4.8%). First upper GI endoscopies (median age, 32 y; range, 21-44 y) revealed duodenal polyposis in 190 (43.5%). Rates of low-grade dysplasia, high-grade dysplasia, and duodenal or ampulary adenocarcinoma at 5 years were 65% (range, 61.7%-66.9%), 12.1% (range, 10.3%-13.9%), and 2.4% (range, 1.5%-3.3%), whereas 10-year rates were 75.8% (range, 73.1%-78.5%), 20.8% (range, 18.2%-23.4%), and 5.4% (range, 3.8%-7.0%). The rate of ampullary abnormalities rose during surveillance from 18.3% at the first upper GI endoscopies to 47.4% at the fourth. Predictive factors for high-grade dysplasia were age at first upper GI endoscopy, type and age of colorectal surgery, Spigelman score, presence of an ampullary abnormality, and number of endoscopic treatments. In multivariate analysis, only age at first upper GI endoscopy and presence of an ampullary abnormality were independent predictive factors. Histologic analysis after radical surgical treatment showed high-grade dysplasia in 30 patients and duodenal or ampulary adenocarcinoma in 11 (4 patients had lymph node involvement).
LIMITATIONS: The study was limited by its retrospective analysis of a prospective database.
CONCLUSIONS: More than 20% of patients developed high-grade dysplasia with duodenal polyposis after 10 years. Iterative endoscopic resections allowed extended control, but surgery remained necessary in 12% of the patients and happened too late in many cases; 20% of those operated had developed duodenal or ampulary adenocarcinoma, whereas 8% exhibited malignancy with lymph node involvement. The trigger for prophylactic surgery required a more accurate predictive score leading to closer endoscopic surveillance. Modifying the Spigelman score by accounting for ampullary abnormalities should be considered as a means to increase compliance with closer endoscopic follow-up in high-risk patients. See Video Abstract at http://links.lww.com/DCR/A430.
DescriptorName: GastrointestinalNeoplasms... AbstractText: In the phase 3 RADIANT-4 trial, everolimus increased progression-free survival compared with placebo in patients with advanced, progressive, non-functional, well-differentiated gastrointestinal or lung neuroendocrine tumours (NETs. We now report the health-related quality of life (HRQOL) secondary endpoint AbstractText: RADIANT-4 is a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial ...
... with statistically significant reduced risk of all cancers (HR, 0.91, 95% CI:0.84, 0.99. Both blood types B and AB were associated with significantly lower risk of gastrointestinalcancer and colorectal cancer, respectively... The findings of this study support a role of genetic traits related to ABO blood type in the development of cancers in the gastrointestinal and urinary tracts.
Oncology (11), Anti-Obesity and Weight Loss (1) Neoplasms (5), Colorectal Neoplasms (2), Stomach Neoplasms (2), more mentions
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Importance: Mailed fecal immunochemical test (FIT) outreach is more effective than colonoscopy outreach for increasing 1-time colorectal cancer (CRC) screening, but long-term effectiveness may need repeat testing and timely follow-up for abnormal results.
Objective: Compare the effectiveness of FIT outreach and colonoscopy outreach to increase completion of the CRC screening process (screening initiation and follow-up) within 3 years.
Design, Setting, and Participants: Pragmatic randomized clinical trial from March 2013 to July 2016 among 5999 participants aged 50 to 64 years who were receiving primary care in Parkland Health and Hospital System and were not up to date with CRC screenings.
Interventions: Random assignment to mailed FIT outreach (n = 2400), mailed colonoscopy outreach (n = 2400), or usual care with clinic-based screening (n = 1199). Outreach included processes to promote repeat annual testing for individuals in the FIT outreach group with normal results and completion of diagnostic and screening colonoscopy for those with an abnormal FIT result or assigned to colonoscopy outreach.
Main Outcomes and Measures: Primary outcome was screening process completion, defined as adherence to colonoscopy completion, annual testing for a normal FIT result, diagnostic colonoscopy for an abnormal FIT result, or treatment evaluation if CRC was detected. Secondary outcomes included detection of any adenoma or advanced neoplasia (including CRC) and screening-related harms (including bleeding or perforation).
Results: All 5999 participants (median age, 56 years; women, 61.9%) were included in the intention-to-screen analyses. Screening process completion was 38.4% in the colonoscopy outreach group, 28.0% in the FIT outreach group, and 10.7% in the usual care group. Compared with the usual care group, between-group differences for completion were higher for both outreach groups (27.7% [95% CI, 25.1% to 30.4%] for the colonoscopy outreach group; 17.3% [95% CI, 14.8% to 19.8%] for FIT outreach group), and highest in the colonoscopy outreach group (10.4% [95% CI, 7.8% to 13.1%] for the colonoscopy outreach group vs FIT outreach group; P < .001 for all comparisons). Compared with usual care, the between-group differences in adenoma and advanced neoplasia detection rates were higher for both outreach groups (colonoscopy outreach group: 10.3% [95% CI, 9.5% to 12.1%] for adenoma and 3.1% [95% CI, 2.0% to 4.1%] for advanced neoplasia, P < .001 for both comparisons; FIT outreach group: 1.3% [95% CI, -0.1% to 2.8%] for adenoma and 0.7% [95% CI, -0.2% to 1.6%] for advanced neoplasia, P < .08 and P < .13, respectively), and highest in the colonoscopy outreach group (colonoscopy outreach group vs FIT outreach group: 9.0% [95% CI, 7.3% to 10.7%] for adenoma and 2.4% [95% CI, 1.3% to 3.3%] for advanced neoplasia, P < .001 for both comparisons). There were no screening-related harms in any groups.
Conclusions and Relevance: Among persons aged 50 to 64 years receiving primary care at a safety-net institution, mailed outreach invitations offering FIT or colonoscopy compared with usual care increased the proportion completing CRC screening process within 3 years. The rate of screening process completion was higher with colonoscopy than FIT outreach.
Trial Registration: clinicaltrials.gov Identifier: NCT01710215.
INTRODUCTION: The optimal treatment strategy for RAS wild type (WT) mCRC is controversial. Our phase III study investigated the effect of introducing earlier (second-line) or later (third-line) cetuximab in patients progressed after FOLFIRI/bevacizumab first-line.
PATIENTS AND METHODS: mCRC patients progressing after FOLFIRI/bevacizumab first-line were randomised to receive second-line irinotecan/cetuximab followed by third-line FOLFOX-4 (arm A) or the reverse sequence (arm B). Primary end-point was progression-free survival (PFS).
RESULTS: About 54 and 56 patients were randomised in arm A and in arm B, respectively. After a median follow-up of 37.5 months, 100 PFS events were recorded. Median PFS was 9.9 months in arm A and 11.3 months in arm B (Hazard ratio [HR] 1.04, 95% confidence interval [CI]: 0.69-1.56, p = 0.854), while median overall survival was 12.3 months in arm A and 18.6 months in arm B (HR 0.84, 95% CI: 0.55-1.28; p = 0.411). No overall difference in side-effects were observed between the two treatment arms.
CONCLUSIONS: This trial did not meet the primary end-point (PFS). Like other preclinical and clinical evidences, our study seems to suggest a reduced activity of cetuximab after a first-line bevacizumab-based therapy.
BACKGROUND: Squamous cell cancers of the anus are rare GI malignancies for which neoadjuvant chemoradiation is the first-line treatment for nonmetastatic disease. Squamous cancers of the rectum are far less common, and it is unclear to what degree chemoradiotherapy improves their outcomes.
OBJECTIVE: The purpose of this study was to compare stage-specific survival for anal and rectal squamous cancers stratified by treatment approach.
DESIGN: This was a retrospective cohort study.
SETTINGS: The study was conducted at Commission on Cancer designated hospitals.
PATIENTS: Patients (2006-2012) identified in the National Cancer Database with pretreatment clinical stage I to III cancers who underwent chemoradiotherapy, with and without subsequent salvage surgical resection (low anterior resection or abdominoperineal resection), ≥12 weeks after chemoradiotherapy were included in the study.
MAIN OUTCOME MEASURES: Overall survival and the need for salvage surgery were measured.
RESULTS: Anal cancers (n = 11,224) typically presented with stage II (45.7%) or III (36.3%) disease, whereas rectal cancer stages (n = 1049) were more evenly distributed (p < 0.001). More patients with rectal cancer underwent low anterior or abdominoperineal resections 12 weeks or later after chemoradiotherapy versus those undergoing abdominoperineal resection for anal cancer (3.8% versus 1.2%; p < 0.001). Stage I and II rectal cancer was associated with poorer survival compared with anal cancer (stage I, p = 0.017; stage II, p < 0.001); survival was similar for stage III disease. Salvage surgery for anal cancer was associated with worse survival for stage I to III cancers; salvage surgery did not significantly affect survival for rectal cancer.
LIMITATIONS: This was a retrospective study without cancer-specific survival measures.
CONCLUSIONS: Squamous rectal cancers are associated with significantly worse survival than squamous cancers of the anus for clinical stage I and II disease. Despite both cancers exhibiting squamous histology, rectal cancers may be less radiosensitive than anal cancers, as suggested by the greater incidence of salvage surgery that does not appear to significantly improve overall survival. See Video Abstract at http://links.lww.com/DCR/A422.
Oncology (11) Rectal Neoplasms (5), Anus Neoplasms (4), Neoplasms (4), more mentions
BACKGROUND: In patients with squamous cell carcinoma of the anus (SCCA), lymph node positivity (LNP) indicates poor prognosis for survival and is central to radiotherapy planning. Over the past three decades, LNP proportion has increased, mainly reflecting enhanced detection with newer imaging modalities; a process known as nodal stage migration. If accompanied by constant T stage distributions, prognosis for both lymph node-positive and lymph node-negative groups may improve without any increase in overall survival for individual patients; a paradox termed the Will Rogers phenomenon. Here, we aim to systematically evaluate the impact of nodal stage migration on survival in SCCA and address a novel hypothesis that this phenomenon results in reduced prognostic discrimination.
METHODS: We did a systematic review and meta-regression to quantify changes in LNP over time and the impact of this change on survival and prognostic discrimination. We searched MEDLINE, Embase, and the Cochrane Library to identify randomised trials and observational studies in patients with SCCA published between Jan 1, 1970, and Oct 11, 2016. Studies were eligible if patients received chemoradiotherapy or radiotherapy as the main treatment, reported LNP proportions (all studies), and reported overall survival (not necessarily present in all studies). We excluded studies with fewer than 50 patients. We extracted study-level data with a standardised, piloted form. The primary outcome measure was 5-year overall survival. To investigate scenarios in which reduced prognostic discrimination might occur, we simulated varying true LNP proportions and true overall survival, and compared these with expected observed outcomes for varying levels of misclassification of true nodal state.
FINDINGS: We identified 62 studies reporting LNP proportions, which included 10 569 patients. From these, we included 45 studies (6302 patients) with whole cohort 5-year overall survival, 11 studies with 5-year survival stratified by nodal status, and 20 studies with hazard ratios in our analyses of temporal changes. In 62 studies, the LNP proportions increased from a mean estimate of 15·3% (95% CI 10·5-20·1) in 1980 to 37·1% (34·0-41·3) in 2012 (p<0·0001). In 11 studies with prognostic data, increasing LNP was associated with improved overall survival in both lymph node-positive and lymph node-negative categories, whereas the proportions with combined tumour stage T3 and T4 remained constant. In 20 studies, across a range of LNP proportions from 15% to 40%, the hazard ratios for overall survival of lymph node-positive versus lymph node-negative patients decreased significantly from 2·5 (95% CI 1·8-3·3) at 15% LNP to 1·3 (1·2-1·9; p=0·014) at 40% LNP. The simulated scenarios reproduced this effect if the true LNP proportions were 20% or 25%, but not if the true LNP proportions were 30% or greater.
INTERPRETATION: We describe a consequence of staging misclassification in anal cancer that we have termed reduced prognostic discrimination. We used this new observation to infer that the LNP proportions of more than 30% seen in modern clinical series (11 out of 15 studies with a median year since 2007) are higher than the true LNP proportion. The introduction of new staging technologies in oncology might misclassify true disease stage, spuriously informing disease management and ultimately increasing the risk of overtreatment.
FUNDING: Bowel Disease Research Foundation.
Oncology (5) Anus Neoplasms (3), Squamous Cell Carcinoma (1), Neoplasm Invasiveness (1), more mentions
Diabetic nephropathy (DN) is a leading cause of end-stage kidney disease nowadays. Certain cancers are more common in patients with diabetes mellitus. However, there are no data concerning the cancer pattern in patients with DN. The aim of this study is to investigate the site-specific cancer risk and mortality in these patients.A retrospective cohort study of 5643 DN patients between 2000 and 2015 was conducted in 2 large hospitals in Hong Kong. Incidence and mortality of various cancers were compared with those of general population using standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs) respectively.With 24,726 person-years follow-up, 250 cancers were diagnosed. Overall cancer incidence was similar between DN patients and the general population (SIR 1.05, 95% confidence interval [CI] 0.92-1.19). However, certain site-specific cancers are increased in DN patients: the highest risk was observed for laryngeal cancer (SIR 3.03, 95% CI 1.11-6.60), followed by cancers of liver (SIR 1.96, 95% CI 1.35-2.76) and colorectum (SIR 1.92, 95% CI 1.53-2.37), but the risk of prostate cancer was lower (SIR 0.48, 95% CI 0.21-0.95) in the males with DN. The SMR of all cancers was 1.17 (95% CI 1.01-1.37). For individual specific site, only colorectal cancer carried a significant higher mortality risk (SMR 2.45, 95% CI 1.82-3.23).Our data suggested that DN is associated with increased incidence of cancers of colorectum, liver, and larynx but decreased incidence of prostate cancer. Moreover, there is increased mortality of colorectal cancer in patients with DN.
There is limited available information on patterns of utilization and efficacy of alternative medicine (AM) for patients with cancer. We identified 281 patients with nonmetastatic breast, prostate, lung, or colorectal cancer who chose AM, administered as sole anticancer treatment among patients who did not receive conventional cancer treatment (CCT), defined as chemotherapy, radiotherapy, surgery, and/or hormone therapy. Independent covariates on multivariable logistic regression associated with increased likelihood of AM use included breast or lung cancer, higher socioeconomic status, Intermountain West or Pacific location, stage II or III disease, and low comorbidity score. Following 2:1 matching (CCT = 560 patients and AM = 280 patients) on Cox proportional hazards regression, AM use was independently associated with greater risk of death compared with CCT overall (hazard ratio [HR] = 2.50, 95% confidence interval [CI] = 1.88 to 3.27) and in subgroups with breast (HR = 5.68, 95% CI = 3.22 to 10.04), lung (HR = 2.17, 95% CI = 1.42 to 3.32), and colorectal cancer (HR = 4.57, 95% CI = 1.66 to 12.61). Although rare, AM utilization for curable cancer without any CCT is associated with greater risk of death.
DescriptorName: Female. DescriptorName: Gastrointestinal Stromal Tumors... Abstract: Gastrointestinal stromal tumors (GISTs) that are not driven by kinase mutations, as are most GISTs, often show loss of function of the succinate dehydrogenase (SDH) complex and are considered SDH-deficient GISTs. SDH-deficient GISTs share many distinct characteristics compared with conventional GISTs.
BACKGROUND: There are many previous reports for using the internal pudendal artery perforator flap in vulvovaginal reconstruction; however, reports of this flap for perineal reconstruction after abdominoperineal excision of the rectum are scarce.
OBJECTIVE: The purpose of this study was to evaluate the outcomes of immediate internal pudendal artery perforator flap reconstruction for irradiated abdominoperineal resection defects.
DESIGN: This was a prospective case series.
SETTINGS: This flap could represent a step forward over other perineal flap approaches or primary closure.
PATIENTS: A total of 73 consecutive patients with anorectal tumors were included.
INTERVENTIONS: The study included immediate perineal reconstruction using 122 internal pudendal artery perforator flaps after abdominoperineal excision of the rectum.
MAIN OUTCOME MEASURES: Dimensions of the perineal defect (in centimeters squared), hospital stay (days), healing time (days), and postoperative complications (Clavien-Dindo grades) were measured.
RESULTS: The means of the perineal defect, hospital stay, and healing time were 51.62 cm, 15.94 days, and 38.52 days. The higher the patient BMI, the longer healing time (p = 0.02); Clavien-Dindo complications grades III to IV were greater in patients with perineal defect ≥60 cm (p = 0.03; OR = 10.56); postoperative complications were higher both in patients with anal squamous cell carcinoma (p = 0.005; OR = 6.09) and in patients with comorbidities (p = 0.04; OR = 2.78); hospital stay (p= 0.001) and healing time (p < 0.001) were higher in patients who had postoperative complications. The complete perineal wound healing at 12 weeks was achieved by 95% of patients, and our 30-day mortality rate was 4%.
LIMITATIONS: As a nonrandomized study, our results have to be interpreted with caution.
CONCLUSIONS: Multiple previously described advantages associated with internal pudendal artery perforator flap were also observed here, reinforcing the idea that it is reliable, versatile, and a useful option for perineal reconstruction after abdominoperineal excision of the rectum. Therefore, we propose that this flap could be considered as the first choice for perineal reconstruction in selected patients with moderate and some large defects after abdominoperineal excision of the rectum. See Video Abstract at http://links.lww.com/DCR/A367.
Squamous Cell Carcinoma (1), Anus Neoplasms (1), Carcinoma (1), more mentions
Genetic and epigenetic alterations mark colorectal cancer (CRC). Global hypomethylation is observed in nearly all CRC, but a distinct subset of CRC show the CpG Island Methylator Phenotype (CIMP). These tumors show DNA hypermethylation of a specific subset of CpG islands, resulting in transcriptional downregulation of nearby genes. Recently we reported the establishment of novel CRC cell lines derived from primary and metastatic CRC tissues. In this study we describe the DNA methylation profiling of these low passage CRC cell lines. We generated global DNA methylation profiles with Infinium HumanMethylation450 BeadChips and analysed them in conjunction with matching gene expression profiles. Multidimensional scaling of the DNA methylation and gene expression datasets showed that BRAF mutated cell lines form a distinct group. In this group we investigated the 706 loci which we have previously identified to be hypermethylated in BRAF mutant CRC. We validated the significant findings in the The Cancer Genome Atlas colon adenocarcinoma dataset. Our analysis identified ELOVL5, FAM127B, MTERF1, ZNF606 to be subject to transcriptional downregulation through DNA hypermethylation in CRC. We further investigated ELOVL5 with qPCR and immunohistochemical staining, validating our results, but did not find a clear relation between ELOVL5 expression and tumor stage or relapse free survival. ELOVL5, FAM127B, MTERF1, ZNF606 are involved in important cellular processes such as apoptosis, lipogenesis and the downstream transcriptional effect of the MAPK-pathway. We have identified a DNA methylation profile regulating key cellular processes in CRC, resulting in a growth advantage to the tumor cells.
RATIONALE: Cronkhite-Canada Syndrome (CCS) is an idiopathic, nonhereditary syndrome haracterized by gastrointestinal (GI) polyposis and ectodermal changes including alopecia, onychatrophia, and pigmentation. CCS colon polyps were previously considered to be benign neoplasms. However, serrated adenoma was reported to be associated with malignant neoplasms in some cases of gastric and colorectal carcinomas, and esophageal cancers. Although malignant colon and gastric cancer have been reported in CCS, reports of distant metastasis have been rare in CCS.
PATIENT CONCERNS: A 58-year-old male was referred from a nearby hospital with diarrhea and weight loss. The patient was hypoproteinemia (17.9 g/L), and multiple polyps were observed in the large intestine. He also had alopecia, onychatrophia, and dysgeusia.
DIAGNOSES: The presence of multiple polyps and associated symptoms of alopecia, onychatrophia, pigmentation, and dysgeusia informed the diagnosis of CCS.
INTERVENTIONS: He was treated with 20mg dexamethasone acetate per day for about 3 months, 10 mg for about 9 month, 5 mg for about 1 year, and then maintained on 5 mg daily. Three years after starting treatment, colonoscopy revealed colon cancer and colon adenomas. A sigmoidectomy revealed 4 well-differentiated adenocarcinomas of the ulcerating type in the sigmoid colon, and tubularadenomas throughout the rest of the large intestine. He was treated with FOLFOX6 for 6 months. At this stage liver metastasis was found. A right hepatectomy was performed confirming hepatic metastasis of colonic adenocarcinoma, which was GPC-3(-), CD34(-), CK20(+), CDX-2(+), Hep(-), CK19(+), and CK8(+).The patient received 3 courses of hepatic arterial infusion chemotherapy.
OUTCOMES: The patient's status has been stable for more than 2 years, and there was no tumor recurrence or metastasis occurred.
LESSONS: CCS is a rare cause of multiple polyposis most often treated with hormone therapy. Regular follow-ups are very important to ensure discovery of malignant tumors at an early stage. Studies with longer-term observations and larger sample sizes will be required to confirm these observations. However, characterization of molecular markers for the early detection of malignant transformation that might allow less invasive and more cost-effective surveillance of colon cancer is urgently sought.
Oncology (8), Anti-Obesity and Weight Loss (2) Alopecia (4), Colonic Neoplasms (4), Adenocarcinoma (3), more mentions
OBJECTIVE: The aim of this study was to compare the accuracy of CT colonography versus optical colonoscopy for neoplastic involvement at the surgical anastomosis 1 year after curative-intent colorectal cancer resection.
DESIGN, SETTING, PATIENTS, AND INTERVENTIONS: Two hundred one patients (mean age, 58.6 years; 117 men, 84 women) underwent same-day contrast-enhanced CT colonography and colonoscopy approximately 1 year (mean, 12.1 months; median, 11.9 months) after colorectal cancer resection as part of a prospective, multicenter trial. All patients enrolled were without clinical evidence of disease and considered low risk for recurrence (stage I-III).
MAIN OUTCOME MEASURES: Suspected neoplastic lesions within 5 cm of the colonic anastomosis were recorded at CT colonography, with subsequent colonoscopy performed for the same, with segmental unblinding of colonography findings. Anastomotic region biopsy or polypectomy was performed at the endoscopist's discretion.
RESULTS: None of the 201 patients had intraluminal anastomotic cancer recurrence or advanced neoplasia (or metachronous cancers). CT colonography detected extramural perianastomotic recurrence in 2 patients (1.0%); neither was detected at colonoscopy. Only 2 patients (1.0%; 2/201) were called positive at CT colonography for intraluminal anastomotic nondiminutive lesions (7- to 8-mm polyps), which were confirmed at colonoscopy but nonneoplastic at histopathology. At optical colonoscopy, the anastomosis was deemed abnormal and/or biopsied in 10.0% (20/201), yielding only 1 nondiminutive benign neoplasm (7-mm tubular adenoma).
LIMITATIONS: The lack of luminal cancer recurrence in our lower-risk cohort precludes assessment of sensitivity for detection, rendering the study underpowered in this regard. Potential cost savings of combined CT/CT colonography over the standard CT/colonoscopy approach were not assessed.
CONCLUSIONS: Relevant intraluminal anastomotic pathology appears to be very uncommon 1 year after colorectal cancer resection in lower-risk cohorts. Unlike colonoscopy, diagnostic contrast-enhanced CT colonography effectively evaluates both the intra- and extraluminal aspects of the anastomosis. See Video Abstract at http://links.lww.com/DCR/A471.
Our main aim was to elucidate the molecular mechanism responsible for the development and metastasis of colorectal cancer. Furthermore, we also identified the key genes participating in this molecular mechanism and stimulating the progression of colorectal cancer. In our experiment, the ANOS1 gene showed up-regulated expression levels continuously, whereas the methylation level showed downregulated levels when the colorectal cancer progressed through the four clinical stages of development and metastasis. We obtained this information by analyzing the expression profile data and methylation data of ANOS1 gene in colorectal cancer. This phenomenon indicates that ANOS1 gene shows continuous activation during the progression of colorectal cancer. According to the results of survival analysis, the expression of ANOS1 gene is closely related to the overall survival rate of patients (p = 0.003); moreover, the expression of ANOS1 gene is also strongly associated with the disease-specific survival rate (p = 0.001). When the expression of ANOS1 gene is high, the survival rate is low in patients. When the expression of ANOS1 gene is low, the survival rate of patients is high. To elucidate the possible molecular mechanism of ANOS1, we performed GSEA enrichment analysis based on the expression value of ANOS1 gene. We found that gene with an up-regulated expression was mainly involved in Wnt signaling pathway; these up-regulated genes were present in the group of high ANOS1 expression. Although several genes were involved in Wnt signaling pathway, CTHRC1 gene was of higher occurrence frequency. By co-expression analysis, we found that both expression value and expression extent of CTHRC1 were associated with ANOS1. All these results indicate that ANOS1 possibly promotes the activation of Wnt signaling pathway with its co-expression partner CTHRC1. Thus, ANOS1 and CTHRC1 genes promote the development and metastasis of colorectal cancer.
Oncology (11) Colorectal Neoplasms (8), Neoplasms (1), more mentions
AbstractText: Colorectal cancer (CRC) is a malignant gastrointestinaltumor with a high mortality rate, including both colon and rectal cancer. In order to provide clinical guidance for the treatment of CRC, this study is conducted to investigate the correlations of intercellular adhesion molecule 1 (ICAM-1) gene polymorphisms with susceptibility and multidrug resistance (MDR) of colorectal cancer (CRC) AbstractText: A ...
BACKGROUND: Protective effects of calcium supplementation against colorectal adenomas have been documented in systematic reviews; however, the results have not been conclusive. Our objective was to update and systematically evaluate the evidence for calcium supplementation taking into consideration the risks of systematic and random error and to GRADE the evidence.
METHODS: The study comprised a systematic review with meta-analysis and trial sequential analysis (TSA) of randomized controlled trials (RCTs). We searched for RCTs published up until September 2016. Retrieved trials were evaluated using risk of bias. Primary outcome measures were the incidences of any recurrent adenomas and of advanced adenomas. Meta-analytic estimates were calculated with the random-effects model and random errors were evaluated with trial sequential analyses (TSAs).
RESULTS: Five randomized trials (2234 patients with a history of adenomas) were included. Two of the 5 trials showed either unclear or high risks of bias in most criteria. Meta-analysis of good quality RCTs suggest a moderate protective effect of calcium supplementation on recurrence of adenomas (relative risk [RR], 0.88 [95% CI 0.79-0.99]); however, its effects on advanced adenomas did not show statistical significance (RR, 1.02 [95% CI 0.67-1.55]). Subgroup analyses demonstrated a greater protective effect on recurrence of adenomas with elemental calcium dose ≥1600 mg/day (RR, 0.74 [95% CI 0.56-0.97]) compared to ≤1200 mg/day (RR, 0.84 [95% CI 0.73-0.97]). No major serious adverse events were associated with the use of calcium, but there was an increase in the incidence of hypercalcemia (P = .0095). TSA indicated a lack of firm evidence for a beneficial effect. Concerns with directness and imprecision rated down the quality of the evidence to "low."
CONCLUSION: The available good quality RCTs suggests a possible beneficial effect of calcium supplementation on the recurrence of adenomas; however, TSA indicated that the accumulated evidence is still inconclusive. Using GRADE-methodology, we conclude that the quality of evidence is low. Large well-designed randomized trials with low risk of bias are needed.
BACKGROUND: The clinical efficacy of gadoxetic acid-enhanced liver MRI as a routine preoperative procedure for all patients with colorectal cancer remains unclear.
OBJECTIVE: The purpose of this study was to evaluate the efficacy of preoperative gadoxetic acid-enhanced liver MRI for the diagnosis of liver metastasis in patients with colorectal cancer.
DESIGN: This was a retrospective analysis from a prospective cohort database.
SETTINGS: All of the patients were from a subspecialty practice at a tertiary referral hospital.
PATIENTS: Patients who received preoperative gadoxetic acid-enhanced liver MRI after CT and attempted curative surgery for colorectal cancer were included.
MAIN OUTCOME MEASURES: The number of equivocal hepatic lesions based on CT and gadoxetic acid-enhanced liver MRI and diagnostic use of the gadoxetic acid-enhanced liver MRI were measured.
RESULTS: We reviewed the records of 690 patients with colorectal cancer. Equivocal hepatic lesions were present in 17.2% of patients based on CT and in 4.5% based on gadoxetic acid-enhanced liver MRI. Among 496 patients with no liver metastasis based on CT, gadoxetic acid-enhanced liver MRI detected equivocal lesions in 15 patients and metastasis in 3 patients. Among 119 patients who had equivocal liver lesions on CT, gadoxetic acid-enhanced liver MRI indicated hepatic lesions in 103 patients (86.6%), including 90 with no metastasis and 13 with metastasis. Among 75 patients who had liver metastasis on CT, gadoxetic acid-enhanced liver MRI indicated that the hepatic lesions in 2 patients were benign, in contrast to CT findings. The initial surgical plans for hepatic lesions according to CT were changed in 17 patients (3%) after gadoxetic acid-enhanced liver MRI.
LIMITATIONS: This study was limited by its retrospective design.
CONCLUSIONS: The clinical efficacy of gadoxetic acid-enhanced liver MRI as a routine preoperative procedure for all patients with colorectal cancer is low, in spite of its high diagnostic value for detecting liver metastasis. However, this study showed gadoxetic acid-enhanced liver MRI was helpful in characterizing equivocal hepatic lesions identified in CT and could lead to change in treatment plans for some patients. See Video Abstract at http://links.lww.com/DCR/A420.
Oncology (13) Colorectal Neoplasms (7), Liver Neoplasms (1), more mentions
Cancer stem cells (CSCs) correlate with recurrence, metastasis and poor survival in clinical studies. Encouraging results from clinical trials of CSC inhibitors have further validated CSCs as therapeutic targets. ONC201 is a first-in-class small molecule imipridone in Phase I/II clinical trials for advanced cancer. We have previously shown that ONC201 targets self-renewing, chemotherapy-resistant colorectal CSCs via Akt/ERK inhibition and DR5/TRAIL induction. In this study, we demonstrate that the anti-CSC effects of ONC201 involve early changes in stem cell-related gene expression prior to tumor cell death induction. A targeted network analysis of gene expression profiles in colorectal cancer cells revealed that ONC201 downregulates stem cell pathways such as Wnt signaling and modulates genes (ID1, ID2, ID3 and ALDH7A1) known to regulate self-renewal in colorectal, prostate cancer and glioblastoma. ONC201-mediated changes in CSC-related gene expression were validated at the RNA and protein level for each tumor type. Accordingly, we observed inhibition of self-renewal and CSC markers in prostate cancer cell lines and patient-derived glioblastoma cells upon ONC201 treatment. Interestingly, ONC201-mediated CSC depletion does not occur in colorectal cancer cells with acquired resistance to ONC201. Finally, we observed that basal expression of CSC-related genes (ID1, CD44, HES7 and TCF3) significantly correlate with ONC201 efficacy in >1000 cancer cell lines and combining the expression of multiple genes leads to a stronger overall prediction. These proof-of-concept studies provide a rationale for testing CSC expression at the RNA and protein level as a predictive and pharmacodynamic biomarker of ONC201 response in ongoing clinical studies.
Oncology (9), Stem Cell Research (5) Neoplasms (9), Colorectal Neoplasms (3), Glioblastoma (3), more mentions
BACKGROUND: The oestrogen receptor beta (ERβ) is the predominant oestrogen receptor in the normal colon mucosa and has been reported to exert anti-proliferative and pro-apoptotic effects. However, the role of ERβ in colorectal cancer (CRC) progression remains unclear.
AIM: To investigate the role of ERβ and its association with hormone status and lifestyle indicators in a female cohort of patients with CRC.
METHODS: Tissue microarrays of primary CRC tumour samples from 320 female patients were conducted with a monoclonal anti-ERβ antibody. The staining intensity was evaluated using immunohistochemistry. The association of ERβ expression with overall survival, disease-free survival, hormone status and lifestyle was evaluated, and effect estimators with 95% confidence intervals (CIs) were reported.
RESULTS: Among the 314 samples with successfully detected ERβ, 182 (58%) had low expression and 132 (42%) had high expression. The Cox multivariate analysis indicated that patients with high ERβ expression had a decreased risk of overall mortality by 50% (hazard ratio [HR], 0.50; CI, 0.30-0.83) and of cancer recurrence by 76% (HR, 0.24; CI, 0.11-0.52) after adjusting for age, tumour-node-metastasis stage and tumour intravascular invasion. Furthermore, high ERβ expression was significantly correlated with shorter breastfeeding time and longer use of hormone replacement therapy. No association was found between ERβ expression and lifestyle indicators.
CONCLUSION: Elevated ERβ expression is independently associated with a better prognosis and hormone status but not lifestyle indicators in female CRC patients.
Oncology (11) Colorectal Neoplasms (4), Neoplasms (3), more mentions