Genetic and molecular evaluation of gastric caner

Hereditary diffuse gastric cancer (HDGC) is an inherited form of diffuse-type gastric cancer. Germline pathogenic and likely pathogenic variants of the E-cadherin (CDH1) gene, located on chromosome 16q22.1, have been identified in approximately 15 to 50 percent of affected kindreds with HDGC worldwide.●HDGC is inherited as an autosomal dominant trait with high penetrance. The lifetime cumulative risk for advanced gastric cancer in individuals with a germline CDH1 pathogenic or likely pathogenic variant is up to 70 percent in men and up to 56 percent in women. Affected patients generally develop gastric cancer at an average age of 38 years●Women in HDGC families are also at high risk of developing lobular breast cancer (estimated lifetime risk approximately 42 percent).●Updated consensus-based criteria are available from the International Gastric Cancer Linkage Consortium (IGCLC) to identify which patients with diffuse gastric cancer or a family history of gastric cancer should be referred for genetic testing●Clinical genetic testing is usually accomplished by sequencing and large deletion analysis if sequencing is unrevealing when families meet HDGC criteria. More recently, CDH1 has been commonly included on commercial next-generation sequencing germline multiplex gene panel tests for breast cancer susceptibility●Prophylactic total gastrectomy is the recommended approach in patients who are carriers of a germline CDH1 pathogenic or likely pathogenic variant. The appropriate age at which to perform gastrectomy is debated, but it may in part be dependent on the pattern of penetrance within the kindred. Most guidelines suggest prophylactic gastrectomy between age 20 and 30. (See ●Annual surveillance endoscopy with random biopsies may be considered for patients who are diagnosed as carriers before age 20, and for individuals over the age of 20 who receive a recommendation for prophylactic gastrectomy but who decide to postpone (or refuse) the procedure. Another scenario in which endoscopic surveillance may be considered is in individuals with genetic variants of unknown significance and in those in whom a pathogenic or likely pathogenic variant cannot be identified in the index case. However, in all cases, patients should be counseled as to the focal nature of these endoscopically invisible lesions and the possibility that they will not be detected by the surveillance procedure●Management guidelines for CDH1 pathogenic or likely pathogenic variant carriers are based upon data generated from high-penetrant HDGC families and therefore may not reflect the risk for individuals with a CDH1 pathogenic or likely pathogenic variant without a personal or family history of diffuse gastric cancer or lobular breast cancer. There is no consensus on how to best manage such patients. Referral to centers with experience in this setting is critical for cases such as these where current guidelines are not easily applied Females who carry a CDH1 pathogenic or likely pathogenic variant should be managed similar to other high-risk conditions for breast cancer and ideally should be referred to a high-risk breast cancer clinic. Current guidelines for breast cancer surveillance suggest annual breast magnetic resonance imaging (MRI; which can be combined with mammography) starting at age 30 . In addition, for affected kindreds with a history of colorectal cancer, updated guidelines from the IGCLC suggest surveillance with colonoscopy starting at age 40 or 10 years younger than the youngest diagnosis of colon cancer, whichever is younger, to be repeated every three to five yearsTargeted Therapy in AML Acute myeloid leukemia (AML) is a heterogenous and complex disease characterized by rapid cellular proliferation, an aggressive clinical course, and generally high mortality Acute myeloid leukemia (AML) remains a challenge to both patients and clinicians. treatment has changed minimally and outcomes remain poor for the majority of patients Within the last decade, there have been an increasing number of potential targets and pathways identified for development in AML Recently, rapid movement of potentially useful agents from bench to bedside has translated into new therapies either recently approved or in clinical trials. These therapies include improved chemotherapies, mutationally targeted inhibitors, pro-apoptotic agents, microenvironment targeting molecules, cell cycle checkpoint inhibitors, and epigenetic regulators. Furthermore, advances in immunotherapy employ monoclonal and bispecific antibodies, chimeric antigen receptor (CAR) T cells, checkpoint inhibitors, and vaccines provide an alternative pathway for AML treatment Venetoclax, a BCL-2 inhibitor is a promising agent, as BCL-2 overexpression is present in 84% of acute myeloid leukemia patients at diagnosis and 95% of patients at relapse and has been associated with leukemia cell survival, chemotherapy resistance and poor prognosis. FLT3 inhibitors are classified as first- or second-generation based on their selectivity for FLT3, a receptor tyrosine kinase that promotes proliferation and survival of hematopoietic cells.5 Gemtuzumab ozogamicin a monoclonal antibody The antibody attaches to a protein called CD33, which is found on most AML cells. The antibody acts like a homing signal, bringing the chemo drug to the leukemia cells, where it enters the cells and kills them when they try to divide into new cells