Colorectal cancer early detection in stool samples tracing CPG islands methylation alterations affecting gene expression

Colorectal cancer (CRC) is a major cause of cancer mortality. Early diagnosis is relevant for its prevention and treatment. Since DNA methylation alterations are early events in tumourigenesis and can be detected in cell-free DNA, they represent promising biomarkers for early CRC diagnosis through non-invasive methods. In our previous work, we identified 74 early altered CpG islands (CGIs) associated with genes involved in cell cross-talking and cell signalling pathways. The aim of this work was to test whether methylation-based biomarkers could be detected in non-invasive matrices. Our results confirmed methylation alterations of GRIA4 and VIPR2 in CRC tissues, using MethyLight, as well as in stool samples, using a much more sensitive technique as droplet digital PCR. Furthermore, we analysed expression levels of selected genes whose promoter CGIs were hypermethylated in CRC, detecting downregulation at mRNA and protein levels in CRC tissue for GRIA4, VIPR2, SPOCK1 and SLC6A3. Most of these genes were already lowly expressed in colon normal tissues supporting the idea that cancer DNA methylation targets genes already barely expressed in the matched normal tissues. Our study suggests GRIA4 and VIPR2 as biomarkers for early CRC diagnosis using stool samples and confirms downregulation of genes hypermethylated in CRC

CD44: A New Prognostic Marker in Colorectal Cancer?

Cluster of differentiation 44 (CD44) is a non-kinase cell surface glycoprotein. It is overexpressed in several cell types, including cancer stem cells (CSCs). Cells overexpressing CD44 exhibit several CSC traits, such as self-renewal, epithelial–mesenchymal transition (EMT) capability, and resistance to chemo- and radiotherapy. The role of CD44 in maintaining stemness and the CSC function in tumor progression is accomplished by binding to its main ligand, hyaluronan (HA). The HA-CD44 complex activates several signaling pathways that lead to cell proliferation, adhesion, migration, and invasion. The CD44 gene regularly undergoes alternative splicing, resulting in the standard (CD44s) and variant (CD44v) isoforms. The different functional roles of CD44s and specific CD44v isoforms still need to be fully understood. The clinicopathological impact of CD44 and its isoforms in promoting tumorigenesis suggests that CD44 could be a molecular target for cancer therapy. Furthermore, the recent association observed between CD44 and KRAS-dependent carcinomas and the potential correlations between CD44 and tumor mutational burden (TMB) and microsatellite instability (MSI) open new research scenarios for developing new strategies in cancer treatment. This review summarises current research regarding the different CD44 isoform structures, their roles, and functions in supporting tumorigenesis and discusses its therapeutic implications

The Role of p53 Expression in Patients with RAS/BRAF Wild-Type Metastatic Colorectal Cancer Receiving Irinotecan and Cetuximab as Later Line Treatment

Background: Preclinical and clinical data indicate that p53 expression might modulate the activity of the epidermal growth factor receptor (EGFR), influencing response/resistance to anti-EGFR monoclonal antibodies. However, the association between p53 status and clinical outcome has not been clarified yet. Objective: In our study, we evaluated the role of p53 expression in patients with RAS/BRAF wild-type metastatic colorectal cancer (mCRC) receiving irinotecan/cetuximab in an exploratory and a validation cohort. Patients and Methods: p53 expression was analysed in patients with RAS/BRAF wild-type mCRC receiving second-line or third-line irinotecan/cetuximab. Survival distribution was assessed by the Kaplan–Meier method, while the log-rank test was used for survival comparison. Results: Among 120 patients with RAS/BRAF wild-type mCRC included in our analysis, 52 (59%) and 19 (59%) patients showed p53 overexpression in the exploratory and validation cohort, respectively. In the exploratory cohort, low p53 expression was correlated with better median progression-free survival (hazard ratio 0.39; p < 0.0001), median overall survival (hazard ratio: 0.23; p < 0.0001) and response rate (p < 0.0001). These results were confirmed by data of the validation cohort where we observed better median progression-free survival (hazard ratio: 0.48; p = 0.0399), median overall survival (hazard ratio: 0.26; p = 0.0027) and response rate (p =0.0007) in patients with p53 normal expression mCRC. Conclusions: In our study, p53 overexpression was associated with anti-EGFR treatment resistance in patients with RAS/BRAF WT mCRC, as confirmed in a validation cohort. Larger studies are needed to validate the role of p53 and investigate EGFR cross-talk in these patients

Molecular-biology-driven treatment for metastatic colorectal cancer

Background: Metastatic CRC (mCRC) is a molecular heterogeneous disease. The aim of this review is to give an overview of molecular-driven treatment of mCRC patients. Methods: A review of clinical trials, retrospective studies and case reports was performed regarding molecular biomarkers with therapeutic implications. Results: RAS wild-type status was confirmed as being crucial for anti-epidermal growth factor receptor (EGFR) monoclonal antibodies and for rechallenge strategy. Antiangiogenic therapies improve survival in first- and second-line settings, irrespective of RAS status, while tyrosine kinase inhibitors (TKIs) remain promising in refractory mCRC. Promising results emerged from anti-HER2 drugs trials in HER2-positive mCRC. Target inhibitors were successful for BRAFV600E mutant mCRC patients, while immunotherapy was successful for microsatellite instability-high/defective mismatch repair (MSI-H/dMMR) or DNA polymerase epsilon catalytic subunit (POLE-1) mutant patients. Data are still lacking on NTRK, RET, MGMT, and TGF-β, which require further research. Conclusion: Several molecular biomarkers have been identified for the tailored treatment of mCRC patients and multiple efforts are currently ongoing to increase the therapeutic options. In the era of precision medicine, molecular-biology-driven treatment is the key to impro patient selection and patient outcomes. Further research and large phase III trials are required to ameliorate the therapeutic management of these patients

Guideline Application in Real world: multi-Institutional Based survey of Adjuvant and first-Line pancreatic Ductal adenocarcinoma treatment in Italy. Primary analysis of the GARIBALDI survey

Background: Information about the adherence to scientific societies guidelines in the ‘real-world’ therapeutic management of oncological patients are lacking. This multicenter, prospective survey was aimed to improve the knowledge relative to 2017-2018 recommendations of the Italian Association of Medical Oncology (AIOM). Patients and methods: Treatment-naive adult patients with pancreatic adenocarcinoma were enrolled. Group A received adjuvant therapy, group B received primary chemotherapy, and group C had metastatic disease. The results on patients accrued until 31 October 2019 with a mature follow-up were presented. Results: Since July 2017, 833 eligible patients of 923 (90%) were enrolled in 44 Italian centers. The median age was 69 years (range 36-89 years; 24% &gt;75 years); 48% were female; 93% had Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 1; group A: 16%, group B: 30%; group C: 54%; 72% Nord, 13% Center, 15% South. In group A, guidelines adherence was 68% [95% confidence interval (CI) 59% to 76%]; 53% of patients received gemcitabine and 15% gemcitabine + capecitabine; median CA19.9 was 29 (range 0-7300; not reported 15%); median survival was 36.4 months (95% CI 27.5-47.3 months). In group B, guidelines adherence was 96% (95% CI 92% to 98%); 55% of patients received nab-paclitaxel + gemcitabine, 27% FOLFIRINOX, 12% gemcitabine, and 3% clinical trial; median CA19.9 was 337 (range 0-20220; not reported 9%); median survival was 18.1 months (95% CI 15.6-19.9 months). In group C, guidelines adherence was 96% (95% CI 94% to 98%); 71% of patients received nab-paclitaxel + gemcitabine, 16% gemcitabine, 8% FOLFIRINOX, and 4% clinical trial; liver and lung metastases were reported in 76% and 23% of patients, respectively; median CA19.9 value was 760 (range 0-1374500; not reported 9%); median survival was 10.0 months (95% CI 9.1-11.1 months). Conclusions: The GARIBALDI survey shows a very high rate of adherence to guidelines and survival outcome in line with the literature. CA19.9 testing should be enhanced; nutritional and psychological counseling represent an unmet need. Enrollment to assess adherence to updated AIOM guidelines is ongoing

Multiple sclerosis: management issues during pregnancy.

Care of pregnant women with multiple sclerosis (MS) is challenging because of the multiple physiological changes associated with pregnancy and the need to consider the impact of any intervention on the foetus. Pregnancy is associated with clinical MS stability or improvement, while the rate of relapse rises significantly during the first three months post-partum before coming back to its level prior to pregnancy. Gestational history has no influence on long-term disability and MS does not seem to influence pregnancy or the child's health. Apart from methotrexate and cyclophosphamide, most drugs used regularly to treat MS can safely be used by pregnant women. Intravenous steroids may be used with relative safety during pregnancy. Maternal use of azathioprine is not associated with an increased risk of congenital malformations, though impaired foetal immunity, intrauterine growth retardation and prematurity are occasionally observed. Cyclosporin is not teratogenic, but may be associated with growth retardation and prematurity. Pregnancy should be avoided in women treated with methotrexate because of its known abortifacient effects and risk of causing typical malformations. Cyclophosphamide is teratogenic in animals, but population studies have not conclusively demonstrated its teratogenicity in humans. Until information is available regarding safety, glatiramer acetate, mitoxantrone, interferon-beta-1a and interferon-beta-1b should be discontinued before an anticipated pregnancy. Women with MS are no more likely to experience delivery complications than are women without MS and the mode of delivery should be decided strictly on obstetrical criteria. Spinal, epidural and general anaesthesia can all be used safely in MS patients. Young women with MS who desire children can be reassured that their infants are not at increased risk of malformations, preterm delivery, low birth weight, or infant death. The progressive nature of the disease may motivate affected women to start or complete their families as soon as possible

Fetal risks related to the treatment of multiple sclerosis during pregnancy and breastfeeding.

In women with multiple sclerosis, pregnancy does not have a long-term adverse effect on lifetime disability; however, there is an increased risk of relapses during the postpartum. Therapies taken during pregnancy may have adverse effects on pregnancy outcome. The small number of pregnancies included in most studies, particularly those evaluating the risks related to the administration of immunomodulating drugs, do not allow firm conclusions to be drawn with regards to their safety. Therefore, until more information regarding safety is available, glatiramer acetate, mitoxantrone and interferon-beta should be discontinued before an anticipated pregnancy. By contrast, glucocorticoids can be used to treat acute relapses during pregnancy