ABSTRACT
Hereditary diffuse gastric cancer (HDGC) is a rare malignancy characterized by autosomal dominant inheritance of pathological variants of the CDH1 gene encoding E-cadherin, which is involved in cell-cell adhesion, maintenance of epithelial architecture, tumor suppression, and regulation of intracellular signaling pathways. Late-stage recognition of HDGC is typically associated with a poor clinical outcome due to its metastatic potential and risk of lobular breast cancer (LBC) development. The American College of Gastroenterology issued guidelines to evaluate HDGC, test for CDH1 genetic variants, and recommend prophylactic gastrectomy for carriers of CDH1 mutations. If surgery is not pursued, endoscopy is a surveillance alternative, although it carries a limited ability to detect malignant foci. As part of clinical research efforts, novel endoscopy advances are currently studied, and a center of excellence for HDGC was created for a comprehensive multidisciplinary team approach. Within this review, we cover current conventional treatment modalities such as gastrectomy and chemotherapy, as the mainstay treatments, in addition to Pembrolizumab, an immune checkpoint inhibitor, as the last therapeutic resort. We also shed light on novel and promising approaches with emphasis on immunotherapy to treat HDGC. We further break down the therapeutic paradigms to utilize molecular tools, antibodies against checkpoint inhibitors, TGF-ß and tyrosine kinase inhibitors, cell-based adoptive therapies, and oncolytic viral therapies. We aim to expand the understanding on how to modulate the tumor microenvironment to tip the balance towards an anti-tumor phenotype, prevent metastasis of the primary disease, and potentially alter the therapeutic landscape for HDGC.
ABSTRACT
BACKGROUND AND AIM: The incidence and overall mortality of hepatocellular carcinoma (HCC) in the US have been increasing over the past decade. Venous thromboembolism (VTE) is a leading cause of morbidity and mortality in cancer patients. This study aims at examining the epidemiology, risk factors, and short-term outcomes of VTE in hospitalized patients with HCC. METHODS: We utilized the National Inpatient Sample for the years 2008-2013. Using the International Classification of Diseases codes, ninth edition, we identified hospitalized adult patients with a prior diagnosis of HCC who were diagnosed with VTE. Weighted multivariate logistic regression models were used to examine the effect of patients' sociodemographic and clinical characteristics on the occurrence of VTE, and to evaluate the impact of VTE on in-hospital mortality and length of hospital stay. RESULTS: We identified a total of 54,275 hospitalized patients with a prior diagnosis of HCC. The prevalence of VTE in the study cohort was 2.8% (2.5% in 2008 to 3.0% in 2013, a statistically significant increase). Older age, African American ethnicity, history of metastasis, and higher Elixhauser comorbidity index were associated with higher odds of VTE. However, having a prior diagnosis of cirrhosis, hepatitis C, or diabetes mellitus were associated with lower odds of VTE in HCC patients. Furthermore, development of VTE was associated with longer hospital stay and increased in-hospital mortality. CONCLUSION: Our work highlights significant age, racial, and comorbid factors in the development of VTE in hospitalized patients with HCC in the US. These findings can help in stratification of HCC patients according to their VTE risk. Patients at higher risk of VTE may benefit from more aggressive pharmacologic prophylaxis, an area for future investigation.