Metabolomics and detection of colorectal cancer in humans: a systematic review

Metabolomics represents one of the new omics sciences and capitalizes on the unique presence and concentration of small molecules in tissues and body fluids to construct a 'fingerprint' that can be unique to the individual and, within that individual, unique to environmental influences, including health and disease states. As such, metabolomics has the potential to serve an important role in diagnosis and management of human conditions. Colorectal cancer is a major public health concern. Current population-based screening methods are suboptimal and whether metabolomics could represent a new tool of screening is under investigation. The purpose of this systematic review is to summarize existing literature on metabolomics and colorectal cancer, in terms of diagnostic accuracies and distinguishing metabolites. Eight studies are included. A total of 12 metabolites (taurine, lactate, choline, inositol, glycine, phosphocholine, proline, phenylalanine, alanine, threonine, valine and leucine) were found to be more prevalent in colorectal cancer and glucose was found to be in higher proportion in control specimens using tissue metabolomics. Serum and urine metabolomics identified several other differential metabolites between controls and colorectal cancer patients. This article highlights the novelty of the field of metabolomics in colorectal oncology.     

Using molecular markers in sputum for the early detection of lung cancer: a review

Recent exciting advances have been made in identifying potential molecular markers in sputum which may soon be ready for validation trials to indicate high risk for lung cancer, especially central airway squamous cell lung cancer. Hopefully, a set of biomarkers will be identified with higher sensitivity, specificity, and enough lead-time compared to traditional cytopathology to justify endobronchial evaluation and local therapy to help reduce lung-cancer mortality in high-risk patients.     

Diagnostic markers for early detection of ovarian cancer.

PURPOSE: Early detection would significantly decrease the mortality rate of ovarian cancer. In this study, we characterize and validate the combination of six serum biomarkers that discriminate between disease-free and ovarian cancer patients with high efficiency. EXPERIMENTAL DESIGN: We analyzed 362 healthy controls and 156 newly diagnosed ovarian cancer patients. Concentrations of leptin, prolactin, osteopontin, insulin-like growth factor II, macrophage inhibitory factor, and CA-125 were determined using a multiplex, bead-based, immunoassay system. All six markers were evaluated in a training set (181 samples from the control group and 113 samples from OC patients) and a test set (181 sample control group and 43 ovarian cancer). RESULTS: Multiplex and ELISA exhibited the same pattern of expression for all the biomarkers. None of the biomarkers by themselves were good enough to differentiate healthy versus cancer cells. However, the combination of the six markers provided a better differentiation than CA-125. Four models with <2% classification error in training sets all had significant improvement (sensitivity 84%-98% at specificity 95%) over CA-125 (sensitivity 72% at specificity 95%) in the test set. The chosen model correctly classified 221 out of 224 specimens in the test set, with a classification accuracy of 98.7%. CONCLUSIONS: We describe the first blood biomarker test with a sensitivity of 95.3% and a specificity of 99.4% for the detection of ovarian cancer. Six markers provided a significant improvement over CA-125 alone for ovarian cancer detection. Validation was performed with a blinded cohort. This novel multiplex platform has the potential for efficient screening in patients who are at high risk for ovarian cancer.     

Analysis of blood markers for early colorectal cancer diagnosis

BackgroundColorectal cancer (CRC) is a very common tumor worldwide. Its mortality can be limited by early diagnosis through screening programs. These programs are based on fecal occult blood testing and colonoscopy. Our objective was to find a model based on the determination of blood biomarkers that was efficacious enough to become part of the early diagnosis of CRC.MethodsIn a total of 221 patients who underwent a colonoscopy, two types of markers were identified (I) classic: carcinoembryonic antigen (CEA), CA19.9, α-fetoprotein, CA125, CA72.4, and ferritin; and (II) experimental: neutrophil gelatinase-associated lipocalin (NGAL), estimated glomerular filtration rate (EGFR), 8-hydroxydeoxyguanosine (8OHdG), calprotectin, and cysteine-rich 61 (Cyr61). We divided the patients into four groups according to colonoscopy results: a control group (n=83) with normal colonoscopy, a polyp group (n=56), a CRC group (n=45), and an inflammatory disease group (n=37). We built an algorithm based on multivariate logistic regression analysis.ResultsA total of 51.6% were males, and the median age was 63 years. We designed an algorithm based on the combination of several markers that discriminated CRC patients from the rest of the patients with a performance of 94%, a sensitivity of 95.6%, and a specificity of 80.6%. Discriminating by sex also resulted in two powerful algorithms, although it performed better in males (97% vs. 91%).ConclusionsOur study has devised a predictive model with high efficacy based on the determination of several biomarkers. We think that it could be incorporated into the set of methods used in CRC screening.     

Indocyanine green fluorescence imaging for sentinel lymph node detection in colorectal cancer: A systematic review

Indocyanine green fluorescence-imaging (ICG-FI) has emerged as a potential tool for increasing the accuracy of staging of patients with primary colorectal cancer (CRC) through the detection of sentinel lymph nodes (SLNs). Here, we report the results of a systematic review of the available literature in the clinical setting of ex vivo and in vivo ICG-FI for the detection of SLNs in primary colorectal cancer. PubMed, Scopus, and Cochrane literature databases were searched for original articles on the use of ICG in the setting of clinical studies of CRC. Eighty studies were identified and screened, 23 were assessed for eligibility and 10 were included for review. Both ex vivo and in vivo ICG-FI are reported to be feasible for the detection of SLNs in CRC. The reported sensitivity of both techniques remains low, varying from 0% to 100% for the in vivo technique and 57% for the ex vivo technique. ICG-FI has not yet been shown to perform better than the standard blue dye technique. In addition, large variability among reported studies in terms of techniques used (ICG dose, type of injection), type of pathologic analyses performed (HE, IHC, serial section), and definition of positive LN status for sensitivity calculations made them difficult to compare directly. ICG-FI is a promising technique for the detection of SLNs in the setting of CRC but more work needs to be done to clearly define protocols and indications for its use and to test its efficacy in larger patient populations.     

Blood levels of vitamin D and early stage breast cancer prognosis: a systematic review and meta-analysis

Vitamin D regulates expression of genes important in development and progression of breast cancer. The association of vitamin D with breast cancer outcomes among breast cancer patients is controversial. We conducted a systematic review and meta-analysis of this association in early stage breast cancer outcome. We searched MEDLINE (1982–May 1, 2013), the American Society of Clinical Oncology (2009–2012), and the San Antonio Breast Cancer Symposium (2010–2012) for abstracts, using the following keywords: “breast cancer” and “prognosis” or “survival”, and “vitamin D” or” calcitriol” to identify studies reporting the associations of blood vitamin D levels (drawn close to diagnosis) with breast cancer outcomes. Meta-analyses were performed using an inverse-variance weighted fixed-effects model with Stata Version 12. Eight studies including 5,691 patients were identified. Vitamin D deficiency was variably categorized across studies; a median of 36.8 % of patients were classified as deficient. Low vitamin D levels were associated with a pooled hazard ratio of 2.13 (95 % CI 1.64–2.78) and 1.76 (95 % CIs 1.35–2.30) for recurrence (six studies) and death (four studies), respectively, with no evidence of significant heterogeneity across studies. There was potential evidence of a publication bias in studies examining associations with death (but not in those examining associations with recurrence). These findings support an association of low levels of vitamin D with increased risk of recurrence and death in early stage breast cancer patients. Given the observational nature of the included studies, it cannot be concluded that this association is causal. Further research is warranted to investigate the potential beneficial effects of vitamin D in breast cancer.     

Prognostic significance of detection of microscopic peritoneal disease in colorectal cancer: A systematic review

BackgroundFree intraperitoneal tumour cells are an independent indicator of poor prognosis, and are encorporated in current staging systems in upper gastrointestinal cancers, but not colorectal cancer. This systematic review aimed to evaluate the role and prognostic significance of positive peritoneal lavage in colorectal cancer.MethodsA search was undertaken of PUBMED/Medline and Cochrane databases for English language articles from 1990 to 2012 using a predefined search strategy. Both detection of free tumour cells and/or detection of tumour-associated antigens in peritoneal lavage fluid were considered a positive lavage. Primary endpoints were rates of positive lavage, recurrence and survival.ResultsOf 3805 articles identified by title, 18 met inclusion criteria (n = 3197 patients, 59.5% colon, 40.5% rectal cancer). There was heterogeneity across studies in method of detection of peritoneal disease with 7 studies using more than one method (conventional cytology (14 studies), immunological techniques (6 studies), molecular techniques (4 studies)). The rate of positive lavage varied from 2.1% to 52% across studies, with a weighted mean rate of positive lavage of 13.17% overall (95% CI 12.74–13.59). In 10 studies (n = 2017) positive peritoneal lavage was associated with worse survival, and with increased recurrence in 12 (n = 2371). Clinicopathological factors frequently associated with positive lavage included macroscopic peritoneal disease, increasing tumour stage and nodal disease.ConclusionPositive peritoneal lavage is a negative prognostic factor in colorectal cancer. However, its utility in staging colorectal cancer is currently limited by wide variation in rates of positive lavage between studies due to differences in methods of peritoneal lavage fluid analysis.     

A systematic review of microbial markers for risk prediction of colorectal neoplasia

Background Substantial evidence indicates that dysbiosis of the gut microbial community is associated with colorectal neoplasia. This review aims to systematically summarise the microbial markers associated with colorectal neoplasia and to assess their predictive performance.Methods A comprehensive literature search of MEDLINE and EMBASE databases was performed to identify eligible studies. Observational studies exploring the associations between microbial biomarkers and colorectal neoplasia were included. We also included prediction studies that constructed models using microbial markers to predict CRC and adenomas. Risk of bias for included observational and prediction studies was assessed.Results Forty-five studies were included to assess the associations between microbial markers and colorectal neoplasia. Nine faecal microbiotas (i.e., Fusobacterium, Enterococcus, Porphyromonas, Salmonella, Pseudomonas, Peptostreptococcus, Actinomyces, Bifidobacterium and Roseburia), two oral pathogens (i.e., Treponema denticola and Prevotella intermedia) and serum antibody levels response to Streptococcus gallolyticus subspecies gallolyticus were found to be consistently associated with colorectal neoplasia. Thirty studies reported prediction models using microbial markers, and 83.3% of these models had acceptable-to-good discrimination (AUROC > 0.75). The results of predictive performance were promising, but most of the studies were limited to small number of cases (range: 9–485 cases) and lack of independent external validation (76.7%).Conclusions This review provides insight into the evidence supporting the association between different types of microbial species and their predictive value for colorectal neoplasia. Prediction models developed from case-control studies require further external validation in high-quality prospective studies. Further studies should assess the feasibility and impact of incorporating microbial biomarkers in CRC screening programme.Subject terms: Prognostic markers, Microbiome     

Social disparities across the continuum of colorectal cancer: a systematic review

Objective:The purpose of this review is to evaluate the published literature to assess social inequalities in colorectal cancer using the cancer disparities grid. Methods: Three computerized databases were searched from January 1990 to January 2004 to identify published English language articles that collected data from study participants living in the United States. Abstracts were reviewed and articles that dealt with social inequality and colorectal cancer were selected. A total of 46 articles were identified and classified into the appropriate cell of the cancer disparities grid. Results: The majority of research identified for the grid has focused primarily in one domain of inequality, race/ethnicity and racism, and within one column of the cancer continuum, cancer screening. About one-third of the articles focused on multiple aspects of social inequalities. There were few or no published research articles within many of the domains of social inequality along the continuum of colorectal cancer prevention, treatment, and outcomes. Conclusions: This review found only a modest amount of research has been conducted that has examined the influence of social inequalities on colorectal cancer. Findings suggest that a multidisciplinary approach is needed to measure and remedy these social inequalities.Address correspondence to: Richard C. Palmer, DFCI-CCBR, 44 Binney Street, Smith 272, Boston, MA 02115, USA; Ph.: 617-632-4223; Fax: 617-632-3161; e-mail: richard_palmer@dfci.harvard.edu     

Blood autoantibodies against tumor-associated antigens as biomarkers in early detection of colorectal cancer

Multiple studies have shown that cancer patients produce detectable autoantibodies against certain tumor-associated antigens, which might be promising blood biomarkers for early detection of colorectal cancer (CRC). We aimed to provide an overview of published studies on blood autoantibody markers for early detection of CRC and to summarize their diagnostic performance. A systematic literature search was performed in PubMed, ISI Web of Knowledge and EMBASE to find relevant studies published until 23 July 2013. Relevant information, such as study population characteristics, autoantibodies studied, analytical methods and diagnostic performance characteristics was independently extracted by two reviewers. Overall, 67 studies evaluating 109 autoantibody markers were included. Most individual markers showed low sensitivity (below 25%) for detecting CRC, along with high specificity close to 100%. Occasionally reported higher sensitivities for specific antibodies are yet to be replicated in independent studies. Generally, more promising results were seen for combinations of multiple autoantibody markers. But again, these promising results are yet to be replicated in other samples. In conclusion, autoantibody signatures may become a promising approach to noninvasive CRC screening. Optimized marker panels are yet to be developed, and promising results require validation in large screening populations.     

Receipt of recommended surveillance among colorectal cancer survivors: a systematic review

Purpose

Regular surveillance decreases the risk of recurrent cancer in colorectal cancer (CRC) survivors. However, studies suggest that receipt of follow-up tests is not consistent with guidelines. This systematic review aimed to: (1) examine receipt of recommended post-treatment surveillance tests and procedures among CRC survivors, including adherence to established guidelines, and (2) identify correlates of CRC surveillance.

Methods

Systematic searches of Medline, PubMed, PsycINFO, CINAHL Plus, and Scopus databases were conducted using terms adapted for each database’s keywords and subject headings. Studies were screened for inclusion using a three-step process: (1) lead author reviewed abstracts of all eligible studies; (2) coauthors reviewed random 5 % samples of abstracts; and (3) two sets of coauthors reviewed all “maybe” abstracts. Discrepancies were adjudicated through discussion.

Results

Thirty-four studies are included in the review. Overall adherence ranged from 12 to 87 %. Within the initial 12 to 18 months post-treatment, adherence to recommended office visits was 93 %. Adherence ranged from 78 to 98 % for physical exams, 18–61 % for colonoscopy, and 17–71 % for carcinoembryonic antigen (CEA) testing. By 2 to 3 years post-treatment, cumulative adherence ranged from 70 to 88 % for office visits, 89–93 % for physical exams, 49–94 % for colonoscopy, and 7–79 % for CEA testing. Between 18 and 28 % of CRC survivors received greater than recommended overall surveillance; overuse of physical exams (42 %), colonoscopy (24–76 %), and metastatic disease testing (1–29 %) was also prevalent. Studies of correlates of CRC surveillance focused on sociodemographic and disease/treatment characteristics, and patterns of association were inconsistent across studies.

Conclusions

Deviation from surveillance recommendations includes both under- and overuse. Examination of modifiable determinants is needed to inform interventions targeting appropriate and timely receipt of recommended surveillance.

Implications for Cancer Survivors

Among CRC survivors, it remains unclear what modifiable psychosocial factors are associated with the observed under- and overuse of surveillance. Understanding and intervening with these psychosocial factors is critical to improving adherence to guideline-recommended surveillance and thereby reducing mortality among this group of survivors.     

Bevacizumab combined with chemotherapy for patients with advanced colorectal cancer: a systematic review

BackgroundFluoropyrimidine-based chemotherapy is considered standard treatment of advanced colorectal cancer. Recent studies indicate benefit to the addition of bevacizumab, a recombinant monoclonal antibody targeting vascular endothelial growth factor.MethodsMedline, EMBASE, Cochrane Library, and conference proceedings were searched to identify randomized trials in advanced colorectal cancer comparing chemotherapy plus bevacizumab with chemotherapy alone. A meta-analysis of published data was carried out.ResultsFive trials comparing chemotherapy plus bevacizumab with chemotherapy alone as first- or second-line treatment were identified. Our meta-analysis indicates an advantage in favor of the addition of bevacizumab to chemotherapy in terms of overall survival (OS) [hazard ratio (HR) 0.79; 95% confidence interval (CI) 0.69–0.90; P = 0.0005], progression-free survival (PFS) (HR 0.63; 95% CI 0.49–0.81, P = 0.0004), and response rate (RR 1.50; 95% CI 1.06–2.10, P = 0.02). The most commonly observed adverse effects related to bevacizumab included hypertension, proteinuria, bleeding, and thrombosis. Gastrointestinal perforation and poor wound healing were also observed; however, their incidence was rare.ConclusionsFor patients with advanced colorectal cancer receiving first- or second-line fluoropyrimidine-based chemotherapy, the addition of bevacizumab improves PFS and OS at the expense of increased incidence of toxicity. The magnitude of benefit may differ based on the chemotherapy regimen with which bevacizumab is partnered.     

Thymidylate synthase expression and prognosis in colorectal cancer: a systematic review and meta-analysis.

PURPOSE: A number of studies have investigated the relationship between thymidylate synthase (TS) expression and survival in colorectal cancer (CRC) patients. Although most have reported poorer overall and progression-free survival with high TS expression, estimates of the hazard ratio (HR) between studies differ wildly. To derive a more precise estimate of the prognostic significance of TS expression, we have reviewed published studies and carried out a meta-analysis. MATERIALS AND METHODS: Twenty studies stratifying overall survival and/or progression-free survival in CRC patients by TS expression status were eligible for analysis. The principal outcome measure was the HR. Data from these studies were pooled using standard meta-analysis techniques. RESULTS: Thirteen studies investigated outcome in a total of 887 cases with advanced CRC, and seven studies investigated outcome in a total of 2,610 patients with localized CRC. A number of methods were used both to assess TS expression and to assign TS status. Sample sizes varied greatly, small sample sizes being a feature of the advanced disease studies. The combined HR estimate for overall survival (OS) was 1.74 (95% CI, 1.34 to 2.26) and 1.35 (95% CI, 1.07 to 1.80) in the advanced and adjuvant settings, respectively, but there was evidence of heterogeneity and possible publication bias. CONCLUSION: Tumors expressing high levels of TS appeared to have a poorer OS compared with tumors expressing low levels. Additional studies with consistent methodology are needed to define the precise prognostic value of TS.     

Noninvasive diagnostic modalities for early detection of colorectal cancer

Colorectal cancer (CRC) screening strategies currently approved are colonoscopy every 10 years, annual fecal occult blood testing (FOBT), flexible sigmoidoscopy every 5 years, annual FOBT plus flexible sigmoidoscopy, and double-contrast barium enema every 5 years. Colonoscopy has been shown to be preferable, but it is invasive, needs bowel preparation, entails a risk of perforation, and is highly operator-dependent. Several noninvasive strategies are being developed as alternatives to colonoscopy. CT colonography (CTC), also known as virtual colonoscopy, has widely variable results but has been shown to have acceptable cost-effectiveness at either 5-year or 10-year intervals, whether it is performed using two-dimensional or three-dimensional techniques. Fecal immunochemical tests have now been shown to have clearly superior performance compared with guaiac-based testing and may become the FOBT of choice. Stool DNA (sDNA) testing has been improved by the addition to the commercial assay of gel-based DNA capture and buffering solutions for DNA stabilization. Simplified sDNA assays (for vimentin methylation and long DNA only) may also improve sensitivity. Advances in our understanding of the molecular genetic changes involved in neoplastic transformation have led to new noninvasive methods to detect tumors. The future of CRC screening will be driven by the performance characteristics of these technologies, which will be more clearly understood as additional data emerge.