Is Surgery Beneficial for MEN1 Patients with Small (≤2 cm), Nonfunctioning Pancreaticoduodenal Endocrine Tumor? An Analysis of 65 Patients from the GTE

Background: The management of small, nonfunctioning pancreaticoduodenal endocrine tumors (NFPET) in multiple endocrine neoplasia type 1 (MEN1) patients is still controversial. We therefore investigated the effect of surgery on survival and tumor progression in MEN1 patients with NFPET ≤2 cm by analyzing data from the Groupe des Tumeurs Endocrines (GTE) registry. Materials and Methods: Among 579 MEN1 patients in the registry, 65 had NFPET ≤ 2 cm. Fifteen (23%) underwent pancreatectomy, 9 at least segmental pancreatectomies and 6 biopsies or enucleations (the surgery group), and 50 (77%) were followed conservatively (the no surgery group). Age at MEN1 and NFPET diagnosis was similar in both groups, as was size of the primary tumor. Seven (10.8%) patients had metastases. Five metastases were synchronous, and 2 (one in each group) were metachronous. Tumor size was similar in patients with or without metastasis. Results: There was no perioperative mortality. The average follow-up time after NFPET diagnosis was 6.7 years in the surgery group and 3.3 years in the no surgery group. Three (4.6%) patients died during follow-up, 2 due to NFPET and 1 due to thymus tumor. The 2 patients who died of NFPET had undergone pancreatic surgery at the time of NFPET diagnosis. The 2 groups did not differ significantly with respect to tumor progression [5/15 (33%) vs 6/38 (16%), P = 0.16]. Overall life expectancy of patients with NFPET ≤2 cm was not different than that of the 229 MEN1 patients in the registry without any pancreaticoduodenal tumor (P = 0.33). Conclusions: This study suggests that surgery may not be beneficial for MEN1 patients with NFPET ≤2 c

RET (Rearranged during transfection)

Review on RET (Rearranged during transfection), with data on DNA, on the protein encoded, and where the gene is implicated

Human Thyroperoxidase Is Largely Retained and Rapidly Degraded in the Endoplasmic Reticulum. Its N-Glycans Are Required for Folding and Intracellular Trafficking

International audienceHuman thyroperoxidase (hTPO), a type I transmembrane heme containing glycoprotein, catalyzes iodide organification and thyroid hormone synthesis and plays a major role in thyroid autoimmunity. Whereas hormonosynthesis occurs at the apical membrane of thyroid cells, TPO localizes mainly in the perinuclear membrane and the endoplasmic reticulum. To establish the intracellular trafficking and the structural characteristics of hTPO in the various cell compartments, hTPO was stably expressed in the Chinese hamster ovary cell line, and its folding was studied with two monoclonal antibodies (mAbs): mAb 47, recognizing a linear epitope; and mAb 15, recognizing a conformational epitope present in the mature protein. The results show that only 15-20% of hTPO molecules were able to acquire a conformation suitable for the recognition by mAb 15. On the other hand, only a part (approximately 15%) of the latter were able to reach the plasma membrane. The hTPO, unable to fold correctly, was more rapidly degraded than that recognized by mAb 15 (half-time, 2 h vs. 7 h). Study of the carbohydrate content of hTPO showed that N-glycans with complex-type structure were found only on hTPO at the cell surface, whereas intracellular hTPO bore high-mannose-type structures. Taken together, these data demonstrate that the intracellular pool of enzyme is formed of newly synthesized molecules and is not caused by recycling of mature hTPO from the cell surface. Complete inhibition of hTPO N-glycosylation with tunicamycin led to a 95% decrease in hTPO at the plasma membrane and, thus, to a decrease in enzymatic activity at the cell surface, emphasizing the role of N-glycans in the intracellular trafficking of hTPO. However, inhibition of formation of complex-type structures with deoxymannojirimycin and of O-glycans with phenyl-alpha-GalNAc did not influence the intracellular trafficking and enzymatic activity of hTPO

Role of Heme in Intracellular Trafficking of Thyroperoxidase and Involvement of H 2 O 2 Generated at the Apical Surface of Thyroid Cells in Autocatalytic Covalent Heme Binding

International audienceThyroperoxidase (TPO) is a glycosylated hemoprotein that plays a key role in thyroid hormone synthesis. We previously showed that in CHO cells expressing human TPO (hTPO) only 2% of synthesized hTPO reaches the cell surface. Herein, we investigated the role of heme moiety insertion in the exit of hTPO from the endoplasmic reticulum. Peroxidase activity at the cell surface and cell surface expression of hTPO were decreased by approximately 30 and approximately 80%, respectively, with succinyl acetone, an inhibitor of heme biosynthesis, and were increased by 20% with holotransferrin and aminolevulinic acid, precursors of heme biosynthesis. Results were similar with holotransferrin plus aminolevulinic acid or hemin, but hemin increased cell surface activity more efficiently (+120%) relative to the control. It had been suggested (DePillis, G., Ozaki, S., Kuo, J. M., Maltby, D. A., and Ortiz de Montellano, P. R. (1997) J. Biol. Chem. 272, 8857-8960) that covalent attachment of heme to mammalian peroxidases could be an H2O2-dependent autocatalytic processing. In our study, heme associated intracellularly with hTPO, and we hypothesized that there was insufficient exposure to H2O2 in Chinese hamster ovary cells before hTPO reached the cell surface. After a 10-min incubation, 10 microM H2O2 led to a 65% increase in cell surface activity. In contrast, in thyroid cells, H2O2 was synthesized at the apical cell surface and allowed covalent attachment of heme. Two-day incubation of primocultures of thyroid cells with catalase led to a 30% decrease in TPO activity at the cell surface. In conclusion, we provide compelling evidence for an essential role of 1) heme incorporation in the intracellular trafficking of hTPO and of 2) H2O2 generated at the apical pole of thyroid cells in the autocatalytic covalent heme binding to the TPO molecule

Can Sporadic Medullary Thyroid Carcinoma Be Biochemically Predicted? Prospective Analysis of 66 Operated Patients with Elevated Serum Calcitonin Levels.

Measuring serum calcitonin (CT) in patients with thyroid diseases allows preoperative diagnoses of sporadic medullary thyroid carcinoma (MTC) and C-cell hyperplasia (CCH). The aim of this prospective study was to distinguish biochemically between CCH and MTC. Basal CT (bCT) was determined in 7276 consecutive patients referred for thyroid disease. Patients with recurrent, persistent, or familial MTC were excluded. When bCT was > 10 pg/ml a pentagastrin-stimulated CT (sCT) assay was performed. Patients were routinely operated on when bCT > 30 pg/ml or sCT > 100 pg/ml or when other indications for surgery were present. An extensive search for CCH or microscopic MTC was conducted by immunochemistry. Pathologic findings were correlated with the bCT and sCT values. In this study 66 patients were included. No morphologic alterations of C-cells were observed in 5 patients; 16 patients presented with CCH and 45 with MTC. Statistical analysis revealed a correlation of sCT and overall bCT with tumor size and staging (p <0.001). Considering cutoff values for bCT of < or = 30 pg/ml and for sCT of < or = 200 pg/ml, the positive predictive value of the test to detect MTC was 100% and the negative predictive value 63%. No patients with MTC at stage 2 to 4 had bCT <30 pg/ml or sCT <200 pg/ml. A bCT value of < or = 30 pg/ml or sCT < or = 200 pg/ml (or both) is highly predictive of MTC, requiring total thyroidectomy with lymph node dissection. Values of bCT <30 pg/ml and sCT <200 pg/ml do not distinguish between CCH and MTC at stage 1. In this case total thyroidectomy at least is recommended, and the role of nodal dissection might be discussed