Treatment discontinuation among breast, colorectal, and prostate cancer patients in Alabama

Introduction. Cancer registries provide information about treatment initiation but not the full course of treatment. In an effort to identify patient reported reasons for discontinuing cancer treatment, patients with prostate, breast, and colorectal cancer were identified from Alabama State Cancer Registry (ASCR) -Alabama Medicare linked database for interview. This study has two specific aims: (1) determine whether the ASCR-Medicare database accurately reflects patients’ treatment experiences in terms of whether they started and completed treatment when compared to patient self-report and (2) determine which patient demographic and health care system factors are related to treatment completion as defined by patient self-report. ^ Methods. The ASCR-Medicare claims dataset supplemented patient interview responses to identify treatment initiation and completion among prostate, breast, and colorectal cancer patients in Alabama from 1999-2003. Kappa statistic was used to test for concordance of treatment initiation and completion between patient self-report and Medicare claims data. Patients who reported not completing treatment were asked questions to ascertain reasons for treatment discontinuation. Logistic regression models were constructed to explore the association of patient and tumor characteristics with discontinuation of radiation and chemotherapy. ^ Results. Overall, there was a fair agreement across all cancer sites about whether one had surgery (Kappa=.382). There was fair agreement between self-report and Medicare claims data for starting radiation treatment (Kappa=.278). For starting chemotherapy there was moderate agreement (Kappa=.414). There was no agreement for completing treatment for radiation and chemotherapy between the self-report and claims data. Patients most often reported doctor’s recommendation (40% for radiation treatment and 21.4% for chemotherapy) and side effects (30% for radiation treatment and 42.8% for chemotherapy) for discontinuing treatment. Females were less likely to complete radiation than males (OR=.24, 95% CI=.11–.50). Stage I patients were more likely to drop radiation treatment than stage III patients (OR=3.34, 95% CI=1.12–9.95). Younger patients were more likely to discontinue chemotherapy than older patients (OR=2.84 95%, CI=1.08–7.69) and breast cancer patients were less likely to discontinue chemotherapy than colorectal patients (OR=.13, 95% CI=.04–.46). ^ Conclusion. This study reveals that patients recall starting treatment more accurately than completing treatment and that there are several demographic and tumor characteristics that influence treatment discontinuation. Providing patients with treatment summaries and survivorship plans can help patients their follow-up care when there are gaps in treatment recall and discontinuation of treatment.^

Gender differences in colorectal cancer screening and incidence in large nationwide, population-based cohorts

Background. A few studies have reported gender differences along the colorectal cancer (CRC) continuum but none has done so longitudinally to compare a cancer and a non-cancer populations.^ Objectives and Methods. To examine gender differences in colorectal cancer screening (CRCS); to examine trends in gender differences in CRC screening among two groups of patients (Medicare beneficiaries with and without cancer); to examine gender differences in CRC incidence; and to examine for any differences over time. In Paper 1, the study population consisted of men and women, ages 67–89 years, with CRC (73,666) or without any cancer (39,006), residing in 12 U.S. Surveillance Epidemiology and End-Results (SEER) regions. Crude and age-adjusted percentages and odds ratios of receiving fecal occult blood test (FOBT), sigmoidoscopy (SIG), or colonoscopy (COL) were calculated. Multivariable logistic regression was used to assess gender on the odds of receiving CRC screening over time.^ In Paper 2, age-adjusted incidence rates and proportions over time were reported across race, CRC subsite, CRC stage and SEER region for 373,956 patients, ages 40+ years, residing in 9 SEER regions and diagnosed with malignant CRC. ^ Results. Overall, women had higher CRC screening rates than men and screening rates in general were higher in the SEER sample of persons with CRC diagnosis. Significant temporal divergence in FOBT screening was observed between men and women in both cohorts. Although the largest temporal increases in screening rates were found for COL, especially among the cohort with CRC, little change in the gender gap was observed over time. Receipt of FOBT was significantly associated with female gender especially in the period of full Medicare coverage. Receipt of COL was also significantly associated with male gender, especially in the period of limited Medicare coverage.^ Overall, approximately equal numbers of men (187,973) and women (185,983) were diagnosed with malignant CRC. Men had significantly higher age-adjusted CRC incidence rates than women across all categories of age, race, subsite, stage and SEER region even though rates declined in all categories over time. Significant moderate increases in rate difference occurred among 40-59 year olds; significant reductions occurred among patients age 70+, within subsite rectum, unstaged and distant stage CRC, and eastern and western SEER regions. ^ Conclusions. Persistent gender differences in CRC incidence across time may have implications for gender-based interventions that take age into consideration. A shift toward proximal cancer was observed over time for both genders, but the high proportion of men who develop rectal cancer suggests that a greater proportion of men may need to be targeted with newer screening methods such as fecal DNA or COL. Although previous reports have documented higher CRC screening among men, higher incidence of CRC observed among men suggests that higher risk categories of men are probably not being reached. FOBT utilization rates among women have increased over time and the gender gap has widened between 1998 and 2005. COL utilization is associated with male gender but the differences over time are small.^

Role of activation of the protein tyrosine kinase, Src, in colorectal cancer chemoresistance

Advances in therapy for colorectal cancer have been hampered by development of resistance to chemotherapy. The Src family of protein tyrosine kinases has been associated with colorectal cancer development and progression. Activation of the prototypic member of the family, Src, occurs in advanced colorectal cancer and is associated with a worse outcome. This work tests the hypotheses that Src activation contributes to chemoresistance in some colon tumors and that this resistance can be overcome by use of Src inhibitors. The aims of the proposal were to (1) determine if constitutive Src activation is sufficient to induce oxaliplatin resistance; (2) evaluate the role of reactive oxygen species (ROS) in the activation of Src after oxaliplatin treatment; (3) determine the frequency of Src activation in liver metastases after oxaliplatin treatment; and (4) evaluate the safety, preliminary efficacy, and pharmacodynamics of the combination of dasatinib with oxaliplatin-based therapy in patients with metastatic colorectal cancer. ^ Using a panel of colon cancer cell lines and murine models, I demonstrate that administration of oxaliplatin, a commonly utilized chemotherapy for colorectal cancer, results in an increased activation of Src. The activation occurs acutely in some, but not all, colorectal carcinoma cell lines. Cell lines selected for oxaliplatin resistance are further increased in Src activity. Treatment of cell lines with dasatinib, a non-selective pharmacologic inhibitor of the Src family kinases synergistically killed some, but not all cell lines. Cell lines with the highest acute activation of Src after oxaliplatin administration were the most sensitive to the combination therapy. Previous work demonstrated that siRNA to Src increased sensitivity to oxaliplatin, suggesting that the effects of dasatinib are primarily due to its ability to inhibit Src in these cell lines. ^ To examine the mechanism underlying these results, I examined the effects of reactive oxygen species (ROS), as previous studies have demonstrated that platinum chemotherapeutics result in intracellular oxidative stress. I demonstrated that oxaliplatin-induced reactive oxygen species were higher in the cell lines with Src activation, relative to those in which Src was not activated. This oxaliplatin-induced Src activation was blocked by the administration of anti-oxidants, thereby demonstrating that synergistic killing between dasatinib and oxaliplatin was associated with the ability of the latter to generate ROS. ^ In a murine model of colorectal cancer metastasis to the liver, the combination of dasatinib and oxaliplatin was more effective in reducing tumor volume than either agent alone. However, when oxaliplatin resistant cell lines were treated with a combination of oxaliplatin and AZD0530, an inhibitor in the clinic with increased specificity for Src, no additional benefit was seen, although Src was activated by oxaliplatin and Src substrates were inhibited. The indolent growth of oxaliplatin-resistant cells, unlike the growth of oxaliplatin resistant tumors in patients, precludes definitive interpretation of these results. ^ To further explore Src activation in patients with oxaliplatin exposure and resistance, an immunohistochemistry analysis of tumor tissue from resected liver metastases of colorectal cancer was performed. Utilizing a tissue microarray, staining for phosphorylated Src and FAK demonstrated strong staining of tumor relative to stromal and normal liver. In patients recently exposed to oxaliplatin, there was increased FAK activation, supporting the clinical relevance of the prior preclinical studies. ^ To pursue the potential clinical benefit of the combination of Src inhibition with oxaliplatin, a phase IB clinical trial was completed. Thirty patients with refractory metastatic colorectal cancer were treated with a combination of 5-FU, oxaliplatin, an epidermal-growth factor receptor monoclonal antibody, and dasatinib. The recommended phase II dose of dasatinib was established, and toxicities were quantified. Pharmacodynamic studies demonstrated increased phosphorylation of the Src substrate paxillin after dasatinib therapy. Tumor biopsies were obtained and Src expression levels were quantitated. Clinical benefit was seen with the combination, including a response rate of 20% and disease control rate of 56%, prompting a larger clinical study. ^ In summary, although Src is constitutively activated in metastatic colorectal cancer, administration of oxaliplatin chemotherapy can further increase its activity, through a reactive oxygen species dependent manner. Inhibition of Src in combination with oxaliplatin provides additional benefit in vitro, in preclinical animal models, and in the clinic. Further study of Src inhibition in the clinic and identification of predictive biomarkers of response will be required to further advance this promising therapeutic target. ^

Increasing awareness of colorectal cancer screening through targeted exam room based video messages

Colorectal cancer (CRC) is the third largest cause of cancer death in the United States. While the disease burden is high, there are proven methods to screen for CRC and detect it at a stage that is amenable to cure. Patients with low health literacy have difficulty navigating the health care system and are at increased risk to not receive preventive care services such as colorectal cancer screening (CRCS). To address this need, an exam-room based video was developed to be played for patients in the privacy of the exam room, while they are waiting to be seen by their medical provider. In roughly 2 minutes, the video informs the patient about CRC and CRCS and how they can successfully complete CRCS. One of the key barriers to completing CRCS is the need to increase patients' knowledge and improve attitudes surrounding CRCS. This study examines the impact of the video on patients' knowledge and attitudes about CRC and CRCS in a medically underserved patient population in Houston, Texas. ^ Sixty-one patients presenting for routine medical care were enrolled in the study. Depending on their randomization, the patients either received routine information about CRC and CRCS or they watched the video. We found that the patients who did watch the video did have improvements in their knowledge and improved attitudes about CRC and CRCS. Future studies will be needed to examine whether the video improves the patients' completion of CRCS.^

The role and impact of transitional care utilization in colorectal cancer

BACKGROUND Although one out of every five gastrointestinal cancer patients needs transitional care (home-based skilled care or placement in skilled nursing or rehabilitation facilities) following treatment, few studies have examined outcomes in this population compared to patients who return home without assistance. This study has two primary goals: 1. To evaluate long-term cancer-specific outcomes in colorectal cancer patients utilizing transitional care compared to those that return home without assistance following therapy 2. To compare results using standard regression techniques and propensity scores. ^ METHODS Patients undergoing curative surgery for colorectal adenocarcinoma will be identified using data from a tertiary care Veterans Administration hospital. Survival and recurrence will then be determined from VA records and the Social Security Death Index. ^ The association between transitional care utilization and overall and disease-free survival will be evaluated using Cox proportional hazards regression to adjust for confounding factors. Predictors of transitional care utilization will be assessed using multiple logistic regression to generate a propensity score which will also be used to assess differences in survival based on transitional care use. ^ POTENTIAL SIGNIFICANCE If transitional care utilization is associated with worse survival and recurrence following therapy then it will be important to subsequently assess the mechanism in order to target interventions to improve outcomes. If there is no difference in cancer-specific outcomes, then this project can potentially highlight benefits of supportive therapy following colorectal cancer resection.^

A case comparison study of dietary factors and risk of colorectal polyps

Little is known about the etiology of colorectal adenomatous polyps, although they are generally considered to be precursor lesions to colorectal carcinoma. To investigate the associations of colorectal adenomatous polyps with dietary intake of calcium, total fat and fiber, a case comparison study was conducted among 98 persons who had first occurrences of adenomatous polyps and 408 persons who did not have colorectal polyps.^ The study population comprised Black, White and Hispanic males and females ages 35 to 80 inclusive, who underwent a sigmoidoscopy or total colonoscopy at collaborating clinics in the Texas Medical Center at Houston between September 1991 and November 1992, and met the eligibility criteria. Case participants were those who had a first-time diagnosis of adenomatous polyps. Comparison participants were individuals who underwent the same diagnostic procedure as the cases and met the same eligibility criteria but had no colorectal polyps. A food frequency questionnaire was administered by interview to obtain information about diet during the 28 days preceding the interview.^ Dietary intake of total fiber was inversely associated with risk of adenomatous polyps. An increment of 15 gm/day in energy-adjusted intake of fiber was associated with a relative odds of 0.39 with a 95% confidence interval of 0.20 to 0.79, after adjustment for age, sex, ethnicity, body mass index, cigarette smoking, family history of colorectal cancer and intake of nonsteroidal anti-inflammatory drugs. No association between dietary intake of total fat and risk of adenomatous polyps was observed. When total fat was analyzed as percent of energy, an increment of 15.3% in intake was associated with a relative odds of 0.98 with a 95% confidence interval of 0.53 to 1.80. However, few persons in the study group had intakes below 25% of energy from total fat. An inverse association was observed between energy-adjusted intake of dietary calcium and risk of adenomatous polyps, but this was not statistically significant; an increment of 638 mg/day was associated with a relative odds of 0.77 with a 95% confidence interval of 0.41 to 1.38. Intake of calcium did not appear to strongly modify the association between intake of fat and risk of adenomatous polyps, perhaps because the study group included few people with calcium intake below 400 mg/day.^ These results support the idea that dietary fiber decreases risk of adenomatous polyps. Further studies are needed on the association of dietary calcium and fat with risk of colorectal adenomatous polyps in populations where individuals vary widely in intake of these nutrients. ^

Colorectal cancer: An insight on dietary factors

Aim. To assess the relationships between dietary factors and colorectal cancer risk. ^ Methods. We looked at all the systematic reviews published in last ten years on the topic. ^ Results. For fruits-vegetables some studies1 were significant for heterogeneity and others2 were not. In study by Aune at al3 only fruits were significant, although all the studies had protective RR between 0.90 to 0.94. For folate only case-control group of studies, the study by Sanjoaquin et al4 was significant with p heterogeneity being 0.01 and all of them had protective effect with RR between 0.75 to 0.95, for dietary as well as total folate. For fiber study by Park et al5 p was insignificant at 0.14 an RR was 0.84. Vitamin B6 study by Larsson et al6 had significant p with RR 0.90. For dietary fat both Alexander7 and Liu8 concluded that there is insufficient evidence that dietary fat is an independent causative risk factor. Only one study by Norat et al9 out of three was able to achieve significant p heterogeneity for meat. All the studies reported RR between 1.14 to 1.35, clearly implicating meat as culprit for increasing the risk of colorectal cancer. ^ Conclusions. We would recommend the use of fruits and vegetables to be protective against colorectal cancer. Also meat consumption increases the risk of colorectal cancer.^ *Please refer to dissertation for references/footnotes.^

"I understood what she meant when she said '21st century medicine'": A qualitative analysis of patient responses for plans for colorectal cancer screening following a recommendation from their physician

Although physician recommendation has been significantly associated with colorectal cancer screening (CRCS), it still does not motivate all patients to get CRCS. Although improved physician recommendation for CRCS has been shown to increase patient CRCS screening, questions remain about what elements of that discussion may lead to screening. The objective of this study is to describe patients' perceptions and interpretations about their physician's recommendation for CRCS during their annual wellness exam. A subset of patients (n=51) participating in a supplement study of a behavioral intervention trial designed to increase CRCS completed a follow-up, open-ended interview two to four weeks after their annual wellness visit. Using qualitative methods, transcripts of these interviews were analyzed. Findings suggest that most patients would follow their physician's recommendation for CRCS despite not engaging in much discussion. Patients may refrain from CRCS discussion because of a commitment to CRCS, awareness of screening guidelines, and trust in physician's honesty and beneficence. Yet many patients left their wellness exams with questions, refraining because of future plans to consult with their physicians, perceived time constraints or a lack of a patient-physician relationship. If patients are leaving their wellness exams with unanswered questions, interventions should prepare physicians for patient reticence, teaching physicians how to assure patients that CRCS is a primary care activity where all questions and concerns, including cost and scheduling, may be resolved.^

Cost-effectiveness analysis of stereotactic body radiotherapy and radiofrequency ablation for medically inoperable liver metastases from colorectal cancer

This report describes the development of a Markov model for comparing percutaneous radiofrequency ablation (RFA) and stereotactic body radiation therapy (SBRT) in terms of their cost-utility in treating isolated liver metastases from colorectal cancer. The model is based on data from multiple retrospective and prospective studies, available data on different utility states associated with treatment and complications, as well as publicly available Medicare costs. The purpose of this report is to establish a well-justified model for clinical management decisions. In comparison with SBRT, RFA is the most cost-effective treatment for this patient population. From the societal perspective, SBRT may be an acceptable alternative with an ICER of $28,673/QALY. ^

Colorectal cancer screening: Participation and determinants in West Texas

Early detection by screening is the key to colorectal cancer control. However, colorectal cancer screening and its determinants in rural areas have not been adequately studied. This goal of this study was to investigate the screening participation and determinants of colonoscopy, sigmoidoscopy, and/or fecal occult blood test (FOBT) in subjects of Project Frontier from the rural counties of Cochran, Bailey and Parmer, Texas. Subjects ( n=820 with 435 Hispanics, 355 Non-Hispanic Whites, 26 African Americans, and 4 unknown ethnicity; 255 males, 565 females, aged from 40 to 92 years) were from Project FRONTIER. Stepwise logistic regression analysis was performed. Explanatory variables included ethnicity (Hispanic, Non-Hispanic white and African American), gender, health insurance, smoking status, household income, education (years), physical activity, overweight, other health screenings, personal physicians, family history (first-degree relatives) of cancers, and preferred language (English vs. Spanish) for interview/testing. The screening percentage for ever having had a colonoscopy/sigmoidoscopy (51.8%) in this cohort aged 50 years or older is well below the percentage of the nation (65.2%) and Texas (64.6%) while the percentage for FOBT (29.2%) is higher than in the nation (17.2%) and Texas (14.9%). However, Hispanics had significantly lower participation than non-Hispanic whites for colonoscopy/sigmoidoscopy (37.0% vs. 66.0%) and FOBT (16.5% vs. 41.7%), respectively. Stepwise logistic regression showed that predictors for colonoscopy, sigmoidoscopy or FOBT included Hispanic race (p = 0.0045), age (p < 0.0001), other screening procedure (p < 0.0001), insurance status (p < 0.0001) and physician status (p = 0.0053). Screening percentage for colonoscopy/sigmoidoscopy in this rural cohort is well below the national and Texas level mainly due to the lower participation of Hispanics vs. Non-Hispanic whites. Health insurance, having had a personal physician, having had screenings for other cancers, race, and older age are among the main predictors.^

Assessing the patterns of colorectal cancer treatment, adherence to treatment guidelines and survival in Texas

Colorectal cancer (CRC) is the third leading cancer in both incidence and mortality in Texas. This study investigated the adherence of CRC treatment to standard treatment guidelines and the association between standard treatment and CRC survival in Texas. The author used Texas Cancer Registry (TCR) and Medicare linked data to study the CRC treatment patterns and factors associated with standard treatment in patients who were more than 65 years old and were diagnosed in 2001 through 2007. We also determined whether adherence to standard treatment affect patients' survival. Multiple logistic regression and Cox regression analysis were used to analyze our data. Both regression models are adjusted for demographic characteristics and tumor characteristics. We found that for the 3977 regional colon cancer patients 80 years old or younger, 60.2% of them received chemotherapy, in adherence to the recommended treatment guidelines. People with younger age, female gender, higher education and lower comorbidity score are more likely adherent to this surgery guideline. Patients' adherence to chemotherapy in this cohort have better survival compared to those who are not (HR: 0.76, 95% CI: 0.68-0.84). For the 12709 colon cancer patients treated with surgery, 49.3% have more than 12 lymph nodes removed, in adherence to the treatment guidelines. People with younger age, female gender, higher education, regional stage, lager tumor size and lower comorbidity score are more likely to adherent to this surgery guideline. Patients with more than 12 lymph nodes removed in this cohort have better survival (HR: 0.86, 95% CI: 0.82-0.91). For the 1211 regional rectal cancer patients 80 years old or younger, 63.2% of them were adherent to radiation treatment. People with smaller tumor size and lower comorbidity score are more likely to adherent to this radiation guideline. There is no significant survival difference between radiation adherent patients and non-adherent patients (HR: 1.03, 95% CI: 0.82-1.29). For the 1122 regional rectal cancer patients 80 years old or younger who were treated with surgery, 76.0% of them received postoperative chemotherapy, in adherence to the treatment guidelines. People with younger age and smaller comorbidity score are related with higher adherence rate. Patients adherent with adjuvant chemotherapy in this cohort have better survival than those were not adherent (HR: 0.60, 95% CI: 0.45-0.79).^

Activation of c -Met contributes to growth and metastasis of human colorectal carcinoma

c-Met is the protein tyrosine kinase receptor for hepatocyte growth factor/scatter factor (HGF/SF) and mediates several normal cellular functions including proliferation, survival, and migration. Overexpression of c-Met correlates with progression and metastasis of human colorectal carcinoma (CRC). The goals of this study were to determine if overexpression of c-Met directly contributes to tumorigenicity and liver metastatic potential of colon cancer, and what are the critical pathways regulated by c-Met in this process. The studies used two colon tumor cell lines, KM12SM and KM20, which express high levels of constitutively active c-Met and are highly metastatic in nude mice. To examine the effects of c-Met overexpression, subclones of theses lines with reduced c-Met expression were obtained following transfection with a c-Met specific targeting ribozyme. Reduction of c-Met in KM12SM cells abolished liver metastases when cells were injected intrasplenically in an experimental metastasis assay. However, c-Met downregulation in theses clones was unstable. Three stable KM20 clones with a 25–35% reduction in c-Met protein levels but 60–90% reduction in basal c-Met autophosphorylation and kinase activity were obtained. While HGF increased c-Met kinase activity in the clones with reduced c-Met, the activity was less than that observed in parental or control transfected cells. Correlating with the reduction in c-Met kinase activity, subclones with reduced c-Met expression had significantly reduced in vitro growth rates, soft-agar colony forming abilities, and increased apoptosis. HGF/SF treatment did not affect anchorage-dependent growth or soft-agar colony forming abilities. Further, c-Met downregulation significantly impaired the ability of HGF/SF to induce migration. To examine the effects of reduced c-Met on tumor formation, parental and c-Met reduced KM20 cells were grown subcutaneously and intrahepatically in nude mice. c-Met downregulation delayed, but did not abolish growth at the subcutaneous site. When these cells were injected intrahepatically, both tumor incidences and size were significantly reduced. To further understand the molecular basis of c-Met in promoting tumor growth, the activation of several signaling intermediates that have been implicated in c-Met mediated growth, survival and migration were compared between KM20 parental cells and subclones with reduced c-Met expression levels. The expression and activity (as determined by phosphorylation) of AKT and Erk1/2 were unaltered. In contrast, Src kinase activity, as measured by immune complex kinase assay, was reduced 2–5 fold following c-Met downregulation. As Src has been implicated in growth, survival and migration, Src activation in c-Met overexpressing lines is likely contributing to the tumorigenic and metastatic capabilities of colon tumor cell lines that overexpress c-Met. Collectively, these results suggest that c-Met overexpression plays a causal role in the development of CRC liver metastases, and that c-Src and c-Met inhibitors may be of potential therapeutic benefit for late-stage colon cancer. ^

Identification of a biomarker panel for colorectal cancer diagnosis

Background Malignancies arising in the large bowel cause the second largest number of deaths from cancer in the Western World. Despite progresses made during the last decades, colorectal cancer remains one of the most frequent and deadly neoplasias in the western countries. Methods A genomic study of human colorectal cancer has been carried out on a total of 31 tumoral samples, corresponding to different stages of the disease, and 33 non-tumoral samples. The study was carried out by hybridisation of the tumour samples against a reference pool of non-tumoral samples using Agilent Human 1A 60-mer oligo microarrays. The results obtained were validated by qRT-PCR. In the subsequent bioinformatics analysis, gene networks by means of Bayesian classifiers, variable selection and bootstrap resampling were built. The consensus among all the induced models produced a hierarchy of dependences and, thus, of variables. Results After an exhaustive process of pre-processing to ensure data quality--lost values imputation, probes quality, data smoothing and intraclass variability filtering--the final dataset comprised a total of 8, 104 probes. Next, a supervised classification approach and data analysis was carried out to obtain the most relevant genes. Two of them are directly involved in cancer progression and in particular in colorectal cancer. Finally, a supervised classifier was induced to classify new unseen samples. Conclusions We have developed a tentative model for the diagnosis of colorectal cancer based on a biomarker panel. Our results indicate that the gene profile described herein can discriminate between non-cancerous and cancerous samples with 94.45% accuracy using different supervised classifiers (AUC values in the range of 0.997 and 0.955)

Identification of a biomarker panel for colorectal cancer diagnosis

Background:Malignancies arising in the large bowel cause the second largest number of deaths from cancer in the Western World. Despite progresses made during the last decades, colorectal cancer remains one of the most frequent and deadly neoplasias in the western countries. Methods: A genomic study of human colorectal cancer has been carried out on a total of 31 tumoral samples, corresponding to different stages of the disease, and 33 non-tumoral samples. The study was carried out by hybridisation of the tumour samples against a reference pool of non-tumoral samples using Agilent Human 1A 60-mer oligo microarrays. The results obtained were validated by qRT-PCR. In the subsequent bioinformatics analysis, gene networks by means of Bayesian classifiers, variable selection and bootstrap resampling were built. The consensus among all the induced models produced a hierarchy of dependences and, thus, of variables. Results: After an exhaustive process of pre-processing to ensure data quality--lost values imputation, probes quality, data smoothing and intraclass variability filtering--the final dataset comprised a total of 8, 104 probes. Next, a supervised classification approach and data analysis was carried out to obtain the most relevant genes. Two of them are directly involved in cancer progression and in particular in colorectal cancer. Finally, a supervised classifier was induced to classify new unseen samples. Conclusions: We have developed a tentative model for the diagnosis of colorectal cancer based on a biomarker panel. Our results indicate that the gene profile described herein can discriminate between non-cancerous and cancerous samples with 94.45% accuracy using different supervised classifiers (AUC values in the range of 0.997 and 0.955).

On-line breath analysis of volatile organic compounds as a method for colorectal cancer detection

Background: Analysis of exhaled volatile organic compounds (VOCs) in breath is an emerging approach for cancer diagnosis, but little is known about its potential use as a biomarker for colorectal cancer (CRC). We investigated whether a combination of VOCs could distinct CRC patients from healthy volunteers. Methods: In a pilot study, we prospectively analyzed breath exhalations of 38 CRC patient and 43 healthy controls all scheduled for colonoscopy, older than 50 in the average-risk category. The samples were ionized and analyzed using a Secondary ElectroSpray Ionization (SESI) coupled with a Time-of-Flight Mass Spectrometer (SESI-MS). After a minimum of 2 hours fasting, volunteers deeply exhaled into the system. Each test requires three soft exhalations and takes less than ten minutes. No breath condensate or collection are required and VOCs masses are detected in real time, also allowing for a spirometric profile to be analyzed along with the VOCs. A new sampling system precludes ambient air from entering the system, so background contamination is reduced by an overall factor of ten. Potential confounding variables from the patient or the environment that could interfere with results were analyzed. Results: 255 VOCs, with masses ranging from 30 to 431 Dalton have been identified in the exhaled breath. Using a classification technique based on the ROC curve for each VOC, a set of 9 biomarkers discriminating the presence of CRC from healthy volunteers was obtained, showing an average recognition rate of 81.94%, a sensitivity of 87.04% and specificity of 76.85%. Conclusions: A combination of cualitative and cuantitative analysis of VOCs in the exhaled breath could be a powerful diagnostic tool for average-risk CRC population. These results should be taken with precaution, as many endogenous or exogenous contaminants could interfere as confounding variables. On-line analysis with SESI-MS is less time-consuming and doesn’t need sample preparation. We are recruiting in a new pilot study including breath cleaning procedures and spirometric analysis incorporated into the postprocessing algorithms, to better control for confounding variables.