CD133, Stem Cells, and Cancer Stem Cells: Myth or Reality?

CD133, a member of the prominin family, is found in a variety of tissues with at least three variants. The function of CD133 is not well understood, but its expression is subject to changes in the microenvironment cues including bioenergetic stress. Knockout of CD133 does not affect renewal, but mammary gland branching. A point mutation of CD133 (R733C) leads to retinal disorder. CD133 is found in embryonic stem cells, normal tissue stem cells, stem cell niches, and circulating endothelial progenitors as well as cancer stem cells. Maintenance of stemness in cancer may be attributable to asymmetric cell division in association with a set of embryonic expression signatures in CD133+ tumor cells. CD133 could enrich cancer stem cells, which are associated with chemo- and radiation resistance phenotype. High CD133 is associated with poor survival in a variety of solid tumors, including lung, colon, prostate, etc. Monitoring CD133+ cells in peripheral blood, and targeting CD133 in cancer, may further predict and improve the clinical outcomes.     

Margin Status,Local Recurrence,and Survival: Correlation or Causation?

The relationship between surgical margin status and outcomes in sarcoma has been an area of controversy for years. Some question whether a positive margin represents inadequate surgery or perhaps is a marker of aggressive cancer biology. This article reviews the literature regarding the natural history of positive margins and its possible influence on sarcoma recurrence and survival.     

Screening for Colorectal Cancer: When, how, and by Whom?

Screening the average-risk population is recommended to reduce CRC-related mortality. Several CRC screening tests are available, stool-based tests or structural endoscopic and radiologic examinations, all with their specific advantages and disadvantages. In this review, we discuss the screening test options for the average-risk population, when, how and by whom? We evaluate the growing body of evidence that support the implementation of FIT and endoscopic modalities in national screening programmes and we discuss the advances in newer screening tests.     

Colorectal Cancer Surveillance: What Is the Optimal Frequency of Follow-up and Which Tools Best Predict Recurrence?

Purpose of Review

Up to 50% of patients with stage II or III colon cancer are estimated to develop locoregional recurrence, distant metastasis, or metachronous colon cancers within 5 years of initial treatment. Given the high risk of recurrence, surveillance is critical, but what is the optimal frequency and testing of surveillance, and is it possible to tailor surveillance plans based on risk prediction tools?

Recent Findings

We reviewed the current national guidelines from 6 reputable oncologic organizations, as well as 10 randomized controlled trials and numerous meta-analyses in the last 22 years evaluating more intensive to less intensive surveillance to answer this question. Currently available adjunct testing, such as genomic testing, and risk calculators were also evaluated.

Summary

Overall, high-frequency surveillance, to a limit, has been established as superior to less frequency surveillance. Future research will likely demonstrate evidence for adjunct testing for personalized surveillance screening based on individual recurrence risk.

     

TOP2A Amplification in Breast Cancer in the Absence of That of HER-2: Myth or Reality?

Confusion between topoisomerase IIα gene amplification and topoisomerase mRNA overexpression is proposed as possibly leading to misinerpretation in a study by Glynn et al. published in an earlier issue of The Oncologist.     

Colorectal Cancer: What Should Patients and Families Be Told to Lower the Risk of Colorectal Cancer?

Colorectal cancer (CRC) is the second most common cause of cancer-related death in the United States. CRC, however, is potentially preventable, and several strategies may be employed to decrease the incidence of and mortality from CRC. Understanding of individual risk and adherence to screening and surveillance recommendations undoubtedly will reduce CRC-associated deaths. Several natural and synthetic chemopreventive agents may prove effective for both primary and secondary CRC chemoprevention. Finally, dietary modifications (ie, increased dietary fiber, fruits and vegetables, and decreased red meat) and other lifestyle changes (i.e., increased physical activity, weight maintenance, avoidance of smoking, and moderation of alcohol intake) also may lower the risk of developing CRC.     

Aspirin and Colorectal Cancer Prevention and Treatment: Is It for Everyone?

There is now a considerable body of data supporting the hypothesis that aspirin could be effective in the prevention and treatment of colorectal cancer, and a number of phase III randomised controlled trials designed to evaluate the role of aspirin in the treatment of colorectal cancer are ongoing. Although generally well tolerated, aspirin can have adverse effects, including dyspepsia and, infrequently, bleeding. To ensure a favourable balance of benefits and risks from aspirin, a more personalised assessment of the advantages and disadvantages is required. Emerging data suggest that tumour PIK3CA mutation status, expression of cyclo-oxygenase-2 and human leukocyte antigen class I, along with certain germline polymorphisms, might all help to identify individuals who stand to gain most. We review both the underpinning evidence and current data, on clinical, molecular and genetic biomarkers for aspirin use in the prevention and treatment of colorectal cancer, and discuss the opportunities for further biomarker research provided by ongoing trials.     

Are NSAIDs Coming Back to Colorectal Cancer Therapy or Not?

Despite adjuvant chemotherapy, between 20 and 50 % of patients with stage II/III colorectal cancer (CRC) will suffer recurrence, usually as incurable metastatic disease. Attempts to improve the efficacy of adjuvant regimens with addition of biologics have failed, and there is therefore a pressing need for novel therapeutic approaches. Inflammatory mediators, including the cyclooxygenase (COX) enzyme family, are commonly upregulated in CRC and known to promote tumour growth in preclinical models. COX inhibition by aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) may exert an antineoplastic effect. Despite considerable evidence in CRC prevention and emerging data demonstrating that regular aspirin reduces the frequency of metastases following CRC resection, its use has not become widespread due to concerns regarding toxicities. However, the recent identification of biomarkers that may predict aspirin benefit has renewed interest in the field. Large, randomised controlled trials underway/in set-up should provide definitive evidence of the efficacy of aspirin/NSAIDs as adjuvant therapy in CRC. This review examines the field to date, with focus on the biomarkers which may help refine the risk-benefit ratio.     

Comparison of Survival between Patients with Hereditary Non Polyposis Colorectal Cancer (HNPCC) and Sporadic Cancer

Background: Hereditary non polyposis colorectal cancer (HNPCC) appears to have a better prognosis thansporadic cancer. In the present study we evaluated the clinical outcomes of HNPCC patients with their sporadiccolorectal cancer counterparts arising from the general population recorded in a population-based cancer registryin Iran. Patients and methods: The population studied consisted of 121 individuals including 61 patients withsporadic colorectal cancer and 60 with HNPCC who were followed-up between 2003 and 2008 in TaleghaniHospital Tehran. The subjects with HNPCC were screened according to Amsterdam criteria II and BethesdaGuidelines. Subjects with sporadic cancer had no familial history of colorectal cancer. Observed survival wasestimated using the Kaplan-Meier method and compared with the log rank test. Multivariate analysis wasperformed using Cox’ regression analysis. Results: In the HNPCC group, 85.0% showed tumors in the colon, vs.68.9% in the sporadic cancer group. The 5-year survival was 82.5% in the HNPCC study group compared withonly 56.4% in the sporadic colorectal cancer group (P=0.044). The age distribution at diagnosis of sporadicpatients was significantly higher than HNPCC patients (mean 50.1 years vs 44.3 years P=0.008). The hazardratio for sporadic cases was 2.93 (95% CI 1.06-8.11) compared with the HNPCC group (P=0.038). Conclusion:Our findings corroborate the results of previous studies which showed overall survival of colorectal cancer inpatients with HNPCC is better than with sporadic CRC patients.     

Colorectal cancer follow-up: Useful or useless?

Follow-up of surgically treated colorectal cancer patients is not supported by objectively certain data. Despite the thousands of investigations reported in the scientific literature, only six randomized prospective studies and two meta-analysis of randomized studies provide data suggesting clear conclusions. Our review of the literature revealed that intensive colorectal follow-up should be performed even if the long-term survival benefit is small. The timing and investigations conducted in follow-ups diverge. The inconsistency of follow-ups is revealed by the fact that the leading USA and European societies propose different guidelines. One datum that the literature agrees on is that pancolonoscopy performed at 3-5 year intervals in colorectal cancer surgery patients supports diagnosis of adenomatous polyps and metachronous cancers. Cost analysis have shown that intensive follow-up would certainly exceed the cut-off point level set for every additional year of good quality of life.     

Best Strategy in the Approach of Advanced Colorectal Cancer: Aggressive or Non-aggressive Chemotherapy?

Teatment for metastatic colorectal cancer has advanced beyond single-agent fluoropyrimidine to include various cytotoxic agents, with or without targeted therapies. However, cure rates are still low and limited to those patients who are able to undergo surgery for resection of metastases. The number of possible drug combinations with activity against the disease has skyrocketed and the decision on which treatment to use has become a challenge. Additionally, there is growing agreement that not all tumors present and behave the same way, and that there is a need for further individualization of therapy. Questions remain about how to further optimize therapy between three distinct groups of patients: initially resectable, potentially resectable and definitively unresectable. In this review, we will discuss which patients might benefit better from each strategy.     

Dietary Patterns and Colorectal Cancer Risk: a Review of 17 Years of Evidence (2000–2016)

Purpose of Review

Colorectal cancer (CRC) is a global public health problem, with an estimated 1.4 million cases diagnosed worldwide in 2012. Evidence suggests that diet may be important for primary prevention.

Recent Findings

The 2017 WCRF/AICR Continuous Update Project on colorectal cancer concluded that there is convincing evidence linking several individual dietary factors with CRC risk but the evidence for dietary patterns was limited and inconclusive. In addition, previous reviews and meta-analyses have not critically synthesized various dietary patterns. This review synthesized data from dietary patterns studies over a 17-year period from 2000 to 2016.

Summary

We included 49 studies (28 cohort and 21 case-control) that examined the association of index-based and empirically derived dietary patterns and CRC risk. A synthesis of food group components comprising the different index-based and empirically derived patterns revealed two distinct dietary patterns associated with CRC risk. A “healthy” pattern, generally characterized by high intake of fruits and vegetables, whole grains, nuts and legumes, fish and other seafood, milk, and other dairy products, was associated with lower CRC risk. In contrast, the “unhealthy” pattern, characterized by high intakes of red meat, processed meat, sugar-sweetened beverages, refined grains, desserts, and potatoes was associated with higher CRC risk. It is notable that the number of food groups, the intake quantity, and the exact types of foods in each food group differed between populations, yet the two dietary patterns remained consistent across regions, especially in empirically derived patterns, an indication of the high reproducibility of these patterns. However, findings for CRC risk in both index-based and empirically derived patterns, differed by sex, with stronger associations among men than women; study design, a higher proportion of case-control studies reported significant findings compared to prospective studies. Consuming a dietary pattern high in fruits and vegetables and low in meats and sweets is protective against CRC risk. However, important questions remain about the mechanisms underlying differences by sex; life-course timing of exposure to dietary patterns; interaction of dietary patterns with the microbiome or with lifestyle factors including physical activity; and elucidation of subsite differences.

     

Transportation — A Vehicle or Roadblock to Cancer Care for VA Patients With Colorectal Cancer?

BackgroundPatients must have transportation to the treatment site before they can access appropriate cancer care. This article describes factors associated with patients experiencing transportation-related barriers to accessing cancer care.Patients and MethodsThe Cancer Care Assessment &; Responsive Evaluation Studies (C-CARES) questionnaire was mailed to Veterans Affairs (VA) patients with colorectal cancer (CRC) during the fall of 2009. Eligible patients were diagnosed at any VA facility in 2008, they were men, and alive at the time of the mailing. A total of 1409 surveys were returned (approximately 67% response rate). To assess transportation barriers, patients were asked how often it was difficult to get transportation to or from treatment. Symptoms were assessed using validated Patient-Reported Outcomes Measurement Information System (PROMIS) scales for fatigue, pain, and depression. Multivariate logistic regression was used to examine determinants of transportation barriers.ResultsA minority of respondents (19%) reported transportation barriers. Patients experiencing pain (OR, 1.04; 95% CI, 1.02-1.06) had greater odds of transportation barriers than patients without this symptom. Patients who reported no primary social support (OR, 6.13; 95% CI, 3.10-12.14) or nonspousal support (OR, 2.00; 95% CI, 1.40-2.87) were more likely to experience transportation barriers than patients whose spouses provided social support.DiscussionPatients with uncontrolled pain or less social support have greater odds of transportation barriers. The directional association between social support, symptoms, and transportation cannot be determined in this data.ConclusionInquiring about accessible transportation should become a routine part of cancer care, particularly for patients with known risk factors.     

Immunotherapy in Colorectal Cancer: Where Are We Now?

Purpose of Review

This review examines the current state of colorectal cancer (CRC) immunotherapy across multiple treatment modalities and discusses some of the most promising approaches.

Recent Findings

CRC immunotherapy involving viral vector and dendritic cell vaccines, checkpoint blockade, and adoptive cell therapy has been explored from preclinical to clinical studies. Despite successes in other malignancies, including melanoma, leukemia, lung, and renal cancers, immunotherapies have been FDA approved for only a small subset of CRCs. Recent studies leveraging greater understanding of cellular and molecular mechanisms underlying colorectal tumorigenesis and immunotherapeutic mechanism of action may be exploited in upcoming trials.

Summary

While immune infiltration of CRC has been an established indicator of patient outcomes, immunotherapeutic strategies to date have not exploited its potential immunogenicity to benefit patients. New vaccine, checkpoint inhibitor, and CAR-T cell therapy paradigms promise to change that. With continued research, we could see a rapid increase in the number of FDA-approved immunotherapies for CRC in the coming years.

     

Comparison of Beta-catenin with TGF-beta1, HIF-1alpha and Patients’ Disease-free Survival in Human Colorectal Cancer

Beta-catenin accumulation is suppressed by TGF-beta1 (transforming growth factor beta1) in intestinal epithelium suggesting negative feedback between these two factors. Besides that, beta-catenin interacts with HIF-1alpha (hypoxia-inducible factor-1alpha) at the promoter region of HIF-1 target genes. Our study was aimed at comparison of beta-catenin with HIF-1alpha, TGF-beta1, Ki67 and survival of sporadic colorectal cancer patients. Expressions of beta-catenin, TGF-beta1, HIF-1alpha, Ki67 were evaluated in triads of specimens of each primary tumor of 72 sporadic colorectal cancers with immunohistochemistry due to limited availability of tissue material. Disease-free survival was analyzed in case of all 100 beta-catenin stained tumors, in 85 cancers stained for HIF-1 and in 72 neoplasms with TGFbeta1 staining. Beta-catenin, TGF-beta1 and HIF-1alpha accumulated in 72 colorectal cancer cells. Beta-catenin correlated both with HIF-1alpha and TGF-beta1 in all colorectal cancers (p < 0.009, r = 0.307 and p = 0.003, r = 0.342, respectively) and in subgroups of different clinico-pathological profile. Beta-catenin failed to correlate with Ki67. In case of beta-catenin, TGF-beta1 and HIF-1alpha, disease-free survival curves failed to show any statistically significant differences between groups of marker negative tumors, cancers with low expression and neoplasms with higher protein expression. Positive correlations between beta-catenin and TGF-beta1 may indicate ineffective attempts of TGF-beta1 to reduce intracellular level of beta-catenin in colorectal cancer. Associations between beta-catenin and HIF-1alpha reflect previously detected interactions between HIF-1alpha with beta-catenin and are confirmative for presence of such reactions in human colorectal cancer.