Clinical utility of plasma KRAS, NRAS and BRAF mutational analysis with real time PCR in metastatic colorectal cancer patients -The importance of tissue/plasma discordant cases

Background: Tumor tissue (T) mutational analysis represents the standard for metastatic colorectal cancer (mCRC); however, circulating tumor DNA (ctDNA) detected by liquid biopsy in plasma (PL) can better represent tumor heterogeneity. Methods: mCRC patients undergoing standard first-line chemotherapy with known T-KRAS/NRAS/BRAF status were enrolled in the present prospective study. PL mutations were assessed within 2 weeks before chemotherapy start with real time PCR and correlated with T status and Progression free survival (PFS). Clinical and biochemical variables including also total number of tumor lesions (TNL) and the sum of maximum diameter (SMD) of all lesions were assessed as potential predictors of T/PL discordance. RESULTS: Among 45 enrolled patients, all BRAF mutations were concordant between T and PL and there were 20% of patients RAS discordant: 9% wild type in T and mutated in PL and 11% mutated in T and wild type in PL. T mutations were significantly associated to median PFS (mPFS of 4.5, 8.3 and 22.9 months for T-BRAF mutated, T-RAS mutated, and T-wild type patients, respectively, p for trend 0.00014). PL mutations further refined prognosis: RAS wild type in T and mutated in PL had significantly shorter PFS than concordant RAS wild type in T and PL: mPFS 9.6 vs. 23.3 months, respectively, p = 0.02. Patients RAS mutated in T and wild type in PL had longer PFS than concordant RAS mutated in T and PL: 24.4 vs. 7.8 months, respectively, p = 0.008. At a multivariate cox regression analysis for PFS, PL mutations were independent prognostic factor superior to T analysis (HR 0.13, p = 0.0008). At multivariate logistic regression analysis TNL and SMD were significant predictors of discordant cases. Conclusions: PL mutational analysis allows a better prognostication than T analysis alone and could help in mCRC treatment management

Single nucleotide polymorphisms of ABCC5 and ABCG1 transporter genes correlate to irinotecan-associated gastrointestinal toxicity in colorectal cancer patients: a DMET microarray profiling study.

Abstract Recent findings have disclosed the role of UDP-glucuronosyltransferase (UGT) 1A1*28 on the haematological toxicity induced by irinotecan (CPT-11), a drug commonly used in the treatment of metastatic colorectal cancer (mCRC). We investigated the pharmacogenomic profile of irinotecan-induced gastrointestinal (GI) toxicity by the novel drug-metabolizing enzyme and transporter (DMET) microarray genotyping platform. Twenty-six mCRC patients who had undergone to irinotecan-based chemotherapy were enrolled in a case (patients experiencing > grade 3 gastrointestinal, (GI) toxicity) - control (matched patients without GI toxicity) study. A statistically significant difference of SNP genotype distribution was found in the case versus control group. The homozygous genotype C/C in the (rs562) ABCC5 gene occurred in 6/9 patients with GI toxicity versus 1/17 patients without GI toxicity (P=0.0022). The homozygous genotype G/G in the (rs425215) ABCG1 was found in 7/9 patients with GI toxicity versus 4/17 patients without GI toxicity (P=0.0135). The heterozygous genotype G/A in the 388G>A (rs2306283) OATP1B1/SLCO1B1 was found in 3/9 patients with grade > 3 GI toxicity versus 14/17 patients without GI toxicity (P=0.0277). DNA extracted from peripheral blood cells was genotyped by DMET Plus chip on Affymetrix array system. Genotype association was calculated by Fisher's exact test (two tailed) and relevant SNPs were further analyzed by direct sequencing. We have identified 3 SNPs mapping in ABCG1, ABCC5 and OATP1B1/SLCO1B1 transporter genes associated with GI toxicity induced by irinotecan in mCRC patients expanding the available knowledge of irinogenomics. The DMET microarray platform is an emerging technology for easy identification of new genetic variants for personalized medicine

Lipid Oxidation Assessed by Indirect Calorimetry Predicts Metabolic Syndrome and Type 2 Diabetes

Purpose: Diabetes has been linked to an impaired ability to oxidize fatty acids. Fat oxidation can be assessed clinically by a respiratory quotient measurement during fasting. We hypothesized that a respiratory quotient might predict metabolic syndrome and type 2 diabetes onset.Methods: In this longitudinal study we used an existing database of 233 individuals who had complete nutritional and biochemical data at baseline and after 12-month follow-up. All participants underwent an indirect calorimetry to measure the respiratory quotient. We excluded participants with diabetes, metabolic syndrome, chronic diseases, and those who had changed food habits in the previous 3 months. Only 88 subjects met the inclusion criteria.Results: Two individuals developed type 2 diabetes and 10 metabolic syndrome after 1 year. Participants in the high respiratory quotient group (>0.91) had a higher incidence of metabolic syndrome/diabetes than those in the low quotient group (25 vs. 8% p = 0.04). In this group, mean basal respiratory quotient was 0.97 ± 0.04. In the high respiratory quotient group, Kaplan-Meier curves showed a greater probability of having metabolic syndrome/diabetes than those in the low respiratoryquotient group (log Rank χ2-test = 8.44; p = 0.004). A multivariable Cox proportional hazards model demonstrated that energy expenditure and weight increase did not predict metabolic syndrome/diabetes [HR (95% CI) = 1 (0.996–1.005), p = 0.86 and 3.9 (0.407–38.061), p = 0.23, respectively).Conclusions: A greater probability of metabolic syndrome/diabetes was found in individuals with a basal respiratory quotient of >0.91 than in those with a respiratoryquotient of ≤ 0.91 after 1 year. In the short-term anthropometric measurements and their variation overtime were not correlated with metabolic syndrome/diabetes

Enacted Stigma in Inflammatory Bowel Disease: An Italian Phenomenological Study

Inflammatory bowel disease (IBD) is a chronic disease of the gastrointestinal tract that has a profound impact on the quality of life of those afflicted with it. The scientific literature shows how the quality of life of people with IBD influences and is influenced by the clinical manifestations of the disease. Strongly connected with excretory functions, which have always been taboo in society, these clinical manifestations can lead to stigmatizing behaviours. The purpose of this study was to understand the lived experiences of the enacted stigma of people with IBD through Cohen’s phenomenological method. Two main themes (stigma in the workplace and stigma in social life) and one subtheme (stigma in love life) emerged from the data analysis. The data analysis revealed that stigma is associated with a multitude of negative health outcomes for the people targeted by it and can add to the already complex physical, psychological and social burdens endured by people with IBD. Having a better understanding of the stigma attached to IBD will facilitate the development of care and training interventions that can improve the quality of life of people suffering from IBD

Enacted Stigma in Inflammatory Bowel Disease: An Italian Phenomenological Study

Inflammatory bowel disease (IBD) is a chronic disease of the gastrointestinal tract that has a profound impact on the quality of life of those afflicted with it. The scientific literature shows how the quality of life of people with IBD influences and is influenced by the clinical manifestations of the disease. Strongly connected with excretory functions, which have always been taboo in society, these clinical manifestations can lead to stigmatizing behaviours. The purpose of this study was to understand the lived experiences of the enacted stigma of people with IBD through Cohen’s phenomenological method. Two main themes (stigma in the workplace and stigma in social life) and one subtheme (stigma in love life) emerged from the data analysis. The data analysis revealed that stigma is associated with a multitude of negative health outcomes for the people targeted by it and can add to the already complex physical, psychological and social burdens endured by people with IBD. Having a better understanding of the stigma attached to IBD will facilitate the development of care and training interventions that can improve the quality of life of people suffering from IBD

Gastrointestinal Symptoms of and Psychosocial Changes in Inflammatory Bowel Disease: A Nursing-Led Cross-Sectional Study of Patients in Clinical Remission

Background and Objectives: Nursing management in Inflammatory Bowel Disease (IBD) is focused on global patient care. Starting from basic knowledge of diagnostic and therapeutic management, nurses can assess the impact of IBD on patients’ quality of life not only at the physical level, but also at the psychological, social, and emotional levels. The aim of this study was to evaluate the impact of gastrointestinal symptoms on psychosocial changes in IBD patients in remission through nursing-led Patient-Reported Outcomes. Materials and Methods: We performed a cross-sectional study of 109 IBD patients in clinical and endoscopic remission. Specialist nurses invited patients to complete questionnaires on gastrointestinal symptoms and quality of life through the Patient-Reported Outcomes Measurement Information System (PROMIS). Results: We found that the gastrointestinal symptoms that the patients reported had a significant impact on the analyzed aspects of health. More specifically, belly pain, diarrhea, and bloating were associated with depressive symptoms (p < 0.001), anxiety (p < 0.001), fatigue (p < 0.001), and sleep disturbances (p < 0.001). Moreover, these symptoms also significantly affected patients’ social dimension in terms of satisfaction with participation in social roles (p < 0.001, p < 0.05, and p < 0.001 for belly pain, diarrhea, and bloating, respectively) and physical functions (p < 0.001). The results were virtually the same in a multivariable analysis adjusted by age, gender, body mass index (BMI), and disease duration. Conclusions: Even during remission, gastrointestinal symptoms are the main factors that influence quality of life in IBD patients. This exploratory study highlights the need to adopt validated questionnaires in clinical practice, and demonstrates that PROMIS is a valid, objective, and standardized instrument that can help nursing staff to better define the consequences of the disease in a patient’s daily life

Weight Gain and Liver Steatosis in Patients with Inflammatory Bowel Diseases

Background and Aim: Most studies focused on the benefits of weight loss on hepatic steatosis and no studies have been specifically designed to assess the role of weight gain on the development of liver steatosis in patients affected by inflammatory bowel diseases. The aim of this study was to analyse the relation between weight change over time and liver steatosis in patients with inflammatory bowel diseases. Methods: We retrospectively evaluated a population of 89 ambulatory patients in clinical remission or affected by mild disease, as determined from disease activity indices, with at least one follow-up visit. Transient elastography was used to quantify liver steatosis. Results: A total of 49 individuals (55%) were overweight/obese at baseline. A significant difference in weight change was found between participants that improved, were stable and worsened, over a mean follow-up of four years. (−1.0 kg ± 4; 2.5 kg ± 6; and 5.4 kg ± 5; respectively, p = 0.009). We found a greater probability of worsening in the hepatic fat content in individuals who gained more than 6% of body weight than in those gaining less than this value (log⁻rank (Mantel⁻Cox) χ2 test = 9.85; df = 1; p = 0.002). Conclusions: A body weight gain of 6% increases the probability of deterioration in liver steatosis over a period of four years in patients with inflammatory bowel diseases. Weight gain prevention with lifestyle interventions may be the cornerstone treatment of these patients