HIGH PREVALENCE OF AGENT ORANGE EXPOSURE AMONG THYROID CANCER PATIENTS IN THE NATIONAL VA HEALTHCARE SYSTEM.

OBJECTIVE: Thyroid cancer is the most common endocrine malignancy and the most rapidly increasing cancer in the U.S. Little is known regarding the epidemiology and characteristics of patients with thyroid cancer within the national Veterans Health Administration (VHA) integrated healthcare system. The aim of this study was to further understand the characteristics of thyroid cancer patients in the VHA population, particularly in relation to Agent Orange exposure. METHODS: This is a descriptive analysis of the VA (Veterans Affairs) Corporate Data Warehouse database from all U.S. VHA healthcare sites from October1, 1999, to December 31, 2013. Information was extracted for all thyroid cancer patients based on International Classification of Diseases-ninth revision diagnosis codes; histologic subtypes of thyroid cancer were not available. RESULTS: There were 19,592 patients (86% men, 76% white, 58% married, 42% Vietnam-era Veteran) in the VHA system with a diagnosis of thyroid cancer within this 14-year study period. The gender-stratified prevalence rates of thyroid cancer among the Veteran population during the study period were 1:1,114 (women) and 1:1,023 (men), which were lower for women but similar for men, when compared to the U.S. general population in 2011 (1:350 for women and 1:1,219 for men). There was a significantly higher proportion of self-reported Agent Orange exposure among thyroid cancer patients (10.0%), compared to the general VHA population (6.2%) (P<.0001). CONCLUSION: Thyroid cancer patients, in this sample, have a higher prevalence of self-reported Agent Orange exposure compared to the overall national VA patient population. ABBREVIATIONS: T4 = thyroxine TCDD = 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin TSH = thyroid-stimulating hormone VA = Veterans Affairs VHA = Veterans Health Administration.

Menin promotes the Wnt signaling pathway in pancreatic endocrine cells.

Menin is a tumor suppressor protein mutated in patients with multiple endocrine neoplasia type 1. We show that menin is essential for canonical Wnt/beta-catenin signaling in cultured rodent islet tumor cells. In these cells, overexpression of menin significantly enhances TCF gene assay reporter activity in response to beta-catenin activation. Contrastingly, inhibition of menin expression with Men1 siRNA decreases TCF reporter gene activity. Likewise, multiple endocrine neoplasia type 1 disease associated missense mutations of menin abrogate the ability to increase TCF reporter gene activity. We show that menin physically interacts with proteins involved in the canonical Wnt signaling pathway, including beta-catenin, TCF3 (TCFL1), and weakly with TCF4 (TCFL2). Menin overexpression increases expression of the Wnt/beta-catenin downstream target gene Axin2, which is associated with increased H3K4 trimethylation of the Axin2 gene promoter. Moreover, inhibition of menin expression by siRNA abrogates H3K4 trimethylation and Axin2 gene expression. Based on these studies, we hypothesized that Wnt signaling could inhibit islet cell proliferation because loss of menin function is thought to increase endocrine tumor cell proliferation. TGP61 rodent islet tumor cells treated with a glycogen synthase kinase 3beta inhibitor that increases Wnt pathway signaling had decreased cell proliferation compared with vehicle-treated cells. Collectively, these data suggest that menin has an essential role in Wnt/beta-catenin signaling through a mechanism that eventually affects histone trimethylation of the downstream target gene Axin2, and activation of Wnt/beta-catenin signaling inhibits islet tumor cell proliferation.

Menin Associates With the Mitotic Spindle and Is Important for Cell Division.

Menin is the protein mutated in patients with multiple endocrine neoplasia type 1 (MEN1) syndrome and their corresponding sporadic tumor counterparts. We have found that menin functions in promoting proper cell division. Here, we show that menin localizes to the mitotic spindle poles and the mitotic spindle during early mitosis and to the intercellular bridge microtubules during cytokinesis in HeLa cells. In our study, menin depletion led to defects in spindle assembly and chromosome congression during early mitosis, lagging chromosomes during anaphase, defective cytokinesis, multinucleated interphase cells, and cell death. In addition, pharmacological inhibition of the menin-MLL1 interaction also led to similar cell division defects. These results indicate that menin and the menin-MLL1 interaction are important for proper cell division. These results highlight a function for menin in cell division and aid our understanding of how mutation and misregulation of menin promotes tumorigenesis.

Localization of deletion to a 300 Kb interval of chromosome 11q13 in cervical cancer.

Previous molecular genetic studies on HeLa cell (a cervical cancer cell line) derived non-tumorigenic and tumorigenic hybrids have localized a tumor suppressor gene to the long arm of chromosome 11. Analysis of cervical cancer cell lines using chromosome 11 specific probes showed deletion and translocation of 11q13 sequences in five out of eight cell lines. Fluorescence in situ hybridization (FISH), using 11q13 specific probes, has shown interstitial deletion of 11q13 sequences in the HeLa cells. In order to determine whether 11q13 deletions occur in primary cervical tumors, we analysed 36 tumors using 20 different microsatellite and RFLP markers. Semi automated fluorescein based allelotyping was performed to identify loss of heterozygosity (LOH) in tumors. The results showed allelic loss in 17 (47%) tumors. Three different regions of loss, one near MEN1, the second near D11S913, and the third near INT2 locus were observed. The smallest region of deletion overlap at the D11S913 locus was localized to a 300 Kb distance between D11S4908 and D11S5023. Fluorescence in situ hybridization (FISH), using 11q13 specific cosmid and BAC (bacterial artificial chromosome) probes, confirmed allelic deletion in the tumors. PCR analysis further identified homozygous deletion of 11q13 sequences in a primary tumor, in HeLa cells and in two HeLa cell derived tumorigenic hybrid cell lines. The homozygous deletion in the cell lines was mapped to a 5.7 kb sequence of 11q13. We hypothesize therefore that a putative cervical cancer tumor suppressor gene exists within the 300 kb of chromosome 11q13.

Frequent deletion of chromosome 3 in malignant sporadic pancreatic endocrine tumors.

Pancreatic endocrine tumors (PETs) arise from neuroendocrine cells in and around the pancreas. As loss of heterozygosity (LOH) of chromosome 3 has been reported in sporadic PETs, we examined 16 sporadic PETs for LOH of 10 polymorphic DNA markers spanning both arms of chromosome 3. LOH was demonstrated in 4 of 8 (50%) sporadic PETs with hepatic metastasis, but in none of 8 sporadic PETs without hepatic involvement. The smallest common-deleted region (SCDR) mapped to 3q27-qter. Analysis of this data with the status of markers on chromosomes 1, 11, and MEN1 mutations in these 16 sporadic PETs revealed that chromosome 3q loss may be a late event in sporadic PET tumorigenesis. These data, combined with reports from other investigators, indicate that chromosome 3q27-qter may contain a tumor suppressor gene that's important in the tumorigenesis of sporadic PETs.

Assessment of routine elimination of postoperative nasogastric decompression after Roux-en-Y gastric bypass.

BACKGROUND: Anastomotic disruption after surgical intervention is an infrequent complication, but may lead to severe morbidity and mortality when it occurs. Of the various gastric procedures, the Roux-en-Y gastric bypass (RYGB) has one of the highest risks for anastomotic leakage. Consequently, a nasogastric tube (NGT) is frequently placed when these operations are performed. Most studies examining the outcomes for patients without postoperative NGTs have been relatively small with groups of patients undergoing a variety of operations. Assessing the incidence of anastomotic leaks by routine elimination of postoperative NGTs requires a large number of patients. In this study, we assessed the safety and efficacy of routine elimination of NGTs in a large cohort of patients undergoing a single operation. METHODS: We reviewed our experience with 1067 patients who underwent RYGB at the UCLA medical center. Fifty-six patients had NGTs routinely placed before the implementation of a standard protocol, which eliminated postoperative NGT decompression. The complication rate for the RYGB patient cohort with and without postoperative NGT was compared. RESULTS: We found no difference in the complication rates between the 2 groups (Fisher exact test; P =.21). CONCLUSIONS: Our findings suggest that routine placement of an NGT after RYGB is unnecessary.

Deletion of chromosome 1, but not mutation of MEN-1, predicts prognosis in sporadic pancreatic endocrine tumors.

Pancreatic endocrine tumors (PETs) may be sporadic or inherited in the multiple endocrine neoplasia type 1 (MEN-1) syndrome. The inherited form is caused by mutations of the MEN-1 gene, which functions as a tumor suppressor gene and maps to chromosome 11q13. These tumors tend to have a better prognosis than their sporadic counterparts, which often have mutations of the MEN-1 gene. Previous molecular analyses of sporadic PETs suggest a high frequency of loss of heterozygosity (LOH) at chromosome 1 as well as mutation of MEN-1. In this study we correlate abnormalities of MEN-1 and chromosome 1 LOH with the biological behavior of sporadic PETs. Loss of heterozygosity for markers at chromosome 11q13 and mutation of MEN-1 were equally frequent in tumors with or without liver metastases. Mutation of MEN-1 is more frequent in gastrinomas than in non-gastrinomas. Loss of heterozygosity for markers on chromosome 1 is more frequent in PETs with liver metastases. These results suggest a molecular tumor model in which there is a dichotomy in the development of benign and malignant PETs.