RAS-expanded Mutations and HER2 Expression in Metastatic Colorectal Cancer: A New Step of Precision Medicine.

Cetuximab and panitumumab monoclonal antibodies are a milestone in the history of treatment of metastatic colorectal cancer (mCRC) and point toward future directions for personalized treatment. Recent studies have shown that broader RAS testing is needed to select patients for targeted therapy. The objectives of our study were to identify the prevalence of RAS mutations and evaluate human epidermal growth factor receptor 2 (HER2) expression in KRAS exon 2 wild-type (WT) mCRC patients, correlating the findings with objective response rate, progression-free survival, and overall survival. In total, 29 mCRC patients undergoing treatment with cetuximab therapy were enrolled in this study. By pyrosequencing, mutations were found in 17% of nonresponder patients, in KRAS codon 146 and NRAS codon 12. HER2 positivity was limited to only 1 responder carcinoma specimen. There was no correlation between RAS mutation, HER2/neu expression, and clinicopathologic findings. We highlighted significantly the differences between objective response rate and RAS gene status. The overall survival and progression-free survival of RAS WT patients were higher compared with those with RAS-mutated disease. Clinical response to cetuximab therapy is impaired in the presence of RAS-expanded mutations. In fact, our finding of 5 mutations in RAS-expanded genes allowed us to understand the resistance to cetuximab in 33% of KRAS WT exon 2 nonresponder patients. HER2 does not seem to be a potential biomarker for cetuximab-targeted therapy. These analyses suggest that the assessment of other biomarkers is needed to determine the best treatment for patients with mCRC, to maximize benefit and minimize harm.

Small bowel capsule endoscopy revealing neuromuscular and vascular hamartoma of the jejunum: A case report.

RATIONALE: Digestive hemorrhage is a life-threatening and represents for both clinicians and patient a challenger problematic condition with the urgencies to discover the origin for correct the cause and safe the life of patient. PATIENT CONCERNS: We report the case of a 58 -year-old man with extremely rare hamartomatous neurovascular lesion. Following recurrent episode of intestinal hemorrhage the patient underwent small bowel capsule endoscopy. DIAGNOSES: Diagnosed with small intestine neoplasia. INTERVENTIONS: The patient underwent curative small bowel resection. Histologic diagnosis was neuromuscular and vascular hamartoma (NMVH). In the small intestine, neoplastic lesions are very rare (2%) and mostly malformative while the more frequent cause of cryptic digestive hemorrhage remains angiodysplasia (50%) . The preexisting NMVH was exacerbated by the use of non-steroidal anti-inflammatory drugs, causing hemorrhage due to diffuse ulceration. OUTCOMES: The patient stay healthy after treatment. LESSONS: This is an hemorrhagic lesion with macroscopic "neoplastic" patterns due to abnormal mixing of normal indigenous tissue components. It poses a diagnostic challenge for clinicians and pathologists, but diagnosis is facilitated by capsule endoscopy and surgical treatment should provide definitive resolution.

Characterization of a rare variant (c.2635-2A>G) of the MSH2 gene in a family with Lynch syndrome.

INTRODUCTION: Lynch syndrome is caused by germline mutations in one of the mismatch repair genes ( MLH1, MSH2, MSH6, and PMS2) or in the EPCAM gene. Lynch syndrome is defined on the basis of clinical, pathological, and genetic findings. Accordingly, the identification of predisposing genes allows for accurate risk assessment and tailored screening protocols. CASE DESCRIPTION: Here, we report a family case with three family members manifesting the Lynch syndrome phenotype, all of which harbor the rare variant c.2635-2A>G affecting the splice site consensus sequence of intron 15 of the MSH2 gene. This mutation was previously described only in one family with Lynch syndrome, in which mismatch repair protein expression in tumor tissues was not assessed. In this study, we report for the first time the molecular characterization of the MSH2 c.2635-2A>G variant through in silico prediction analysis, microsatellite instability, and mismatch repair protein expression experiments on tumor tissues of Lynch syndrome patients. The potential effect of the splice site variant was revealed by three splicing prediction bioinformatics tools, which suggested the generation of a new cryptic splicing site. The potential pathogenic role of this variant was also revealed by the presence of microsatellite instability and the absence of MSH2/MSH6 heterodimer protein expression in the tumor cells of cancer tissues of the affected family members. CONCLUSIONS: We provide compelling evidence in favor of the pathogenic role of the MSH2 variant c.2635-2A>G, which could induce an alteration of the canonical splice site and consequently an aberrant form of the protein product (MSH2).

Chemotherapeutic agents for colorectal cancer with a defective mismatch repair system: the state of the art.

Mismatch repair (MMR) proteins are capable of recognizing and processing not only single base-pair mismatches and insertion-deletion loops that occur during DNA replication, but also adducts in DNA resulting from treatment with cancer chemotherapy agents. MMR deficiency leads to microsatellite instability (MSI) and results in resistance to antimetabolites, alkylating and platinating agents, DNA minor groove binders, and inhibitors of topoisomerases. Therefore, anticancer agents that can be recommended for use in MMR deficient colorectal cancers are those that exert their cytotoxicity regardless of the MMR status. These include some alkylating drugs, brostacillin, gemcytabine, photodynamic therapy, taxanes. An approach that is currently receiving much attention is the use of agents such as 5-azacytidine, an inhibitor of the DNA methyltransferases, in combination with inhibitors of histone de-acetylation, to restore the MMR function. A strong anti-proliferative efficacy with a relatively low direct cytotoxicity, obtainable with oloumicine and roscovitine (selective cyclin-dependent kinases inhibitors) can represent a new expedient for the therapeutic treatment of MMR deficient colorectal cancers. The question of how MMR defects modulate the response to chemotherapeutics deserves further investigation, to enable a more aware choice of cancer treatment.