Edward J. Kruse

Pancreatic Neoplasms in Pregnancy: Diagnosis, Complications, and Management

BackgroundNeoplasms of the pancreas during pregnancy are rare, with less than 25 cases of benign and malignant tumors reported in the literature.MethodsWe present three unique cases of pancreatic tumors occurring during pregnancy—one mucinous cystic neoplasm and two adenocarcinomas. We review the literature regarding pancreatic neoplasms during pregnancy and discuss the diagnosis, complications, and management of these tumors.ResultsMagnetic resonance imaging and ultrasound are the imaging modalities of choice in pregnancy. In patients with benign or premalignant tumors, surgical resection may be postponed until the second trimester. In symptomatic patients, or if there is a concern for intrauterine growth restriction, urgent surgical intervention should be performed. With malignant tumors, the benefit of delaying surgery must be balanced with the risk of maternal disease progression. Termination of the pregnancy should be discussed when a malignant tumor is diagnosed during the first trimester. Pancreatic tumors diagnosed during the third trimester may be resected after delivery. If malignant, early delivery of the fetus and subsequent maternal operation can be considered at appropriate fetal maturity.ConclusionWhen these tumors occur during pregnancy, they present a diagnostic and treatment dilemma, with variation in treatment based on gestational age and patient preference.

Demographic and clinical factors associated with suicide in gastric cancer in the United States

While increased suicidal tendencies among cancer patients have been well documented, there has been no specific examination of suicide and gastric cancer. The purpose of this study is to characterize suicide incidence among patients diagnosed with gastric cancer from 1973 to 2013 and identify variables associated with higher suicide rates. Patients with gastric cancer were identified in the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute. The study included clinical and demographic data from 1973 to 2013. Standardized mortality ratios (SMRs) and 95% confidence intervals (95% CIs) were calculated. Comparisons with the general US population were based on mortality data collected by the Centers for Disease Control and Preventions National Center for Injury Prevention and Control using the Web-based Injury Statistics Query and Reporting System. Multivariable logistic regression models generated odds ratios (ORs) to assess factors associated with increased suicide in gastric malignancy. There were 210 suicides for patients with gastric cancer (SMR, 3.21; 95% CI: 2.80-3.67). Female gender (SMR 8.54), White race (SMR 4.08), age ≤39 years (SMR 3.06), and age 70-79 years (SMR 2.90), were found to be significant for an increased incidence of suicide compared with the general population. There was not a statistically significant relationship between suicide and marital status, income, mode of radiation therapy, and the role of surgical intervention. Approximately 77% of deaths by suicide occurred within the first year following diagnosis. Female gender, White race, age ≤39 years, and age 70-79 years are factors associated with increased risk of suicide in patients with gastric cancer. These results, coupled with further studies and analyses, will be used to formulate a comprehensive suicide risk factor scoring system for screening all cancer patients.

The antitumor effects of vaccine-activated CD8+ T cells associate with weak TCR signaling and induction of stem-like memory T cells

Vaccine-activated CD8+ T cells that had weaker TCR signaling had stronger antitumor effects. Weak activation halted differentiation at the stem-like memory T-cell stage, generating more Tscm cells, and protected T effectors from antigen-induced exhaustion and apoptosis. To understand why vaccine-activated tumor-specific T cells often fail to generate antitumor effects, we studied two α-fetoprotein–specific CD8+ T cells (Tet499 and Tet212) that had different antitumor effects. We found that Tet499 required high antigen doses for reactivation, but could survive persistent antigen stimulation and maintain their effector functions. In contrast, Tet212 had a low threshold of reactivation, but underwent exhaustion and apoptosis in the presence of persistent antigen. In vivo, Tet499 cells expanded more than Tet212 upon reencountering antigen and generated stronger antitumor effects. The different antigen responsiveness and antitumor effects of Tet212 and Tet499 cells correlated with their activation and differentiation states. Compared with Tet212, the population of Tet499 cells was less activated and contained more stem-like memory T cells (Tscm) that could undergo expansion in vivo. The TCR signaling strength on Tet499 was weaker than Tet212, correlating with more severe Tet499 TCR downregulation. Weak TCR signaling may halt T-cell differentiation at the Tscm stage during immune priming and also explains why Tet499 reactivation requires a high antigen dose. Weak TCR signaling of Tet499 cells in the effector stage will also protect them from exhaustion and apoptosis when they reencounter persistent antigen in tumor lesion, which generates antitumor effects. Further investigation of TCR downregulation and manipulation of TCR signaling strength may help design cancer vaccines to elicit a mix of tumor-specific CD8+ T cells, including Tscm, capable of surviving antigen restimulation to generate antitumor effects. Cancer Immunol Res; 5(10); 908–19. ©2017 AACR.

Identification of α‐fetoprotein‐specific T‐cell receptors for hepatocellular carcinoma immunotherapy

Hepatocellular carcinoma (HCC) is the major form of liver cancer for which there is no effective therapy. Genetic modification with T‐cell receptors (TCRs) specific for HCC‐associated antigens, such as α‐fetoprotein (AFP), can potentially redirect human T cells to specifically recognize and kill HCC tumor cells to achieve antitumor effects. In this study, using lentivector and peptide immunization, we identified a population of cluster of differentiation 8 (CD8) T cells in human leukocyte antigen (HLA)‐A2 transgenic AAD mice that recognized AFP158 epitope on human HCC cells. Adoptive transfer of the AFP158‐specific mouse CD8 T cells eradicated HepG2 tumor xenografts as large as 2 cm in diameter in immunocompromised nonobese diabetic severe combined immunodeficient gamma knockout (NSG) mice. We then established T‐cell hybridoma clones from the AFP158‐specific mouse CD8 T cells and identified three sets of paired TCR genes out of five hybridomas. Expression of the murine TCR genes redirected primary human T cells to bind HLA‐A2/AFP158 tetramer. TCR gene‐engineered human T (TCR‐T) cells also specifically recognized HLA‐A2+AFP+ HepG2 HCC tumor cells and produced effector cytokines. Importantly, the TCR‐T cells could specifically kill HLA‐A2+AFP+ HepG2 tumor cells without significant toxicity to normal primary hepatocytes in vitro. Adoptive transfer of the AFP‐specific TCR‐T cells could eradicate HepG2 tumors in NSG mice. Conclusion: We have identified AFP‐specific murine TCR genes that can redirect human T cells to specifically recognize and kill HCC tumor cells, and those AFP158‐specific TCRs have a great potential to engineer a patients autologous T cells to treat HCC tumors. (Hepatology 2018).