Kyunga Kim

Serum gamma-glutamyltransferase within its normal concentration range is related to the presence of diabetes and cardiovascular risk factors.

Aims  Although many studies have reported an association between serum γ‐glutamyltransferase (GGT) and cardiovascular risk factors, the mechanism of this relationship has not been clarified.

Capecitabine monotherapy in patients with anthracycline-and taxane-pretreated metastatic breast cancer

The selection of chemotherapeutic regimens is challenging for metastatic breast cancer (MBC) patients whose diseases have failed to respond to anthracyline and taxane. Capecitabine has advantages of oral administration and favorable toxicity profiles. This study was conducted to evaluate the efficacy of capecitabine and to identify the subgroup of patients who would potentially have benefit from capecitabine monotherapy in patients with anthracycline- and taxane-pretreated MBC. Female patients with MBC who had been previously treated with anthracycline and taxane received oral capecitabine 2500 mg/m2 divided in two doses daily for 2 wk with 1-wk rest period. Between September, 1999, and December, 2002, a total of 38 patients were enrolled. Among the 36 evaluable patients, one patient achieved a complete response (CR), 9 patients had partial responses (PRs), and 13 patients had stable diseases (SDs). Response rate was 26% [95% confidence interval (CI), 12–40%] and the tumor control rate (TCR, CR+PR+SD) was 61% (95% CI, 45–77%). The median follow-up duration was 27.8 mo. The median duration of response was 8.9 mo, the median time to progression was 4.6 mo, and the median overall survival was 18.1 mo. The major toxicities were hand-foot syndrome, diarrhea, and emesis. There was no treatment-related death. The predictors of better overall survival were positivity of hormone receptor, disease-free survival longer than 1 yr, non-refractoriness to anthracycline, and fewer number (≤3) of involved organs. Capecitabine monotherapy is effective and well tolerated for MBC patients who had previously been treated with anthracycline and taxane. The TCR could predict overall survival as well as the objective respose in this study, suggesting a possible role of TCR as a surrogate marker for survival in MBC patients on salvage chemotherapy. The patients who have relatively slow growing tumor and less tumor burden could have benefit from capecitabine monotherapy following anthracycline- and taxane-based chemotherapy.

Co‐Transplantation of Bone Marrow‐Derived Endothelial Progenitor Cells Improves Revascularization and Organization in Islet Grafts

Bone marrow‐derived early endothelial progenitor cells (BM‐EPCs) are a clinical tool for enhancing revascularization. However, the therapeutic efficacy of co‐transplantation of BM‐EPC with islets has not been investigated. In this study, marginal mass islets were co‐transplanted with or without BM‐EPCs under the kidney capsules of syngeneic streptozotocin‐induced diabetic mice. Using green fluorescent protein transgenic (GFP‐Tg) mice as BM‐EPC and islet donors or recipients, the role of EPCs in revascularization was assessed for graft morphology, vascular density and fate of EPCs by immunohistochemistry. Islet‐EPC co‐transplantation improved the outcome of islet transplantation as measured by glucose tolerance, serum insulin level and diabetes reversal rate, compared with transplantation of islets alone. Between groups, the morphology of islet grafts showed significant differences in size and composition of grafted endocrine tissues. Significantly more vessel density derived from donors and recipients was detected with islet‐EPC co‐transplantation. Abundant GFP‐Tg mice‐derived BM‐EPCs (GFP‐EPCs) were observed in or around islet grafts and incorporated into CD31‐positive capillaries. Remaining GFP‐EPCs expressed VEGF. In conclusion, co‐transplantation of islets with BM‐EPCs could improve the outcome of marginal mass islet transplantation by promoting revascularization and preserving islet morphology.

IFNγ/TNFα synergism in MHC class II induction: effect of nicotinamide on MHC class II expression but not on islet-cell apoptosis

Abstract.Aims/hypothesis: Interferon-γ (IFNγ) and TNFα synergistically induce pancreatic beta-cell apoptosis. Apart from their direct effect, we studied the possible indirect immunological role of IFNγ/TNFα synergism on pancreatic beta-cell death by investigating MHC class II induction by cytokines. The effect of nicotinamide on the cytokine-induced MHC class II expression and pancreatic beta-cell death was also studied. Methods: Immunocytochemistry, flow cytometry and RNase protection assay were used to study MHC class II expression. Immunoblotting was done to study downstream signals of IFNγ. The effects of nicotinamide on islet-cell apoptosis and diabetes mellitus were examined using MTT assay and adoptive transfer model. Results: IFNγ alone induced MHC class II expression on a small number of insulinoma cells. TNFα alone did not induce MHC class II expression, but enhanced IFNγ-induced MHC class II expression. MHC class II expression by cytokine(s) was due to the induction of class II transactivator (CIITA). Nicotinamide reduced MHC class II expression by cytokine(s) but did not protect insulinoma-cell apoptosis by IFNγ and TNFα in combination or protect against the development of diabetes mellitus after adoptive transfer of diabetogenic lymphocytes. Conclusion/interpretation: IFNγ and TNFα synergistically induced MHC class II expression on insulinoma cells through the induction of CIITA; nicotinamide reduced the expression of cytokine-induced MHC class II expression on insulinoma cells through its effect on CIITA expression; and the preventive effect of nicotimamide on Type I (insulin-dependent) diabetes mellitus is probably due to its effect of MHC class II expression rather than that on islet cell apoptosis. [Diabetologia (2002) 45: 385–393]

Small Hypervascular Hepatocellular Carcinoma: Limited Value of Portal and Delayed Phases on Dynamic Magnetic Resonance Imaging

Background: Characterization of small nodules in the cirrhotic liver is always challenging in clinical practice. In the differential diagnosis of small hypervascular lesions, it has been reported that portal venous or delayed hypointensity is a useful sign to characterize hepatocellular carcinomas (HCCs) during dynamic magnetic resonance (MR) imaging. However, few studies have assessed the diagnostic value of this sign. Purpose: To determine the diagnostic value of portal-phase (PP) and delayed-phase (DP) images for the diagnosis of small hypervascular HCCs during intravenous (IV) contrast-enhanced dynamic MR imaging of cirrhotic liver. Material and Methods: A total of 69 small (6–20 mm) hypervascular HCCs in 53 cirrhotic patients were subjected to a retrospective analysis of the signal intensities (hypo-, iso-, or hyperintense) and rim enhancement on PP and 5-min DP images from three-phased dynamic MR imaging according to the pre-contrast T1- and T2-weighted imaging features. After exclusion of 33 subcapsular wedge-shaped pseudolesions and three hemangiomas by typical imaging features, 74 centrally located small hypervascular benign or pseudolesions were used as a control group for comparative analyses. Results: The sensitivities of PP hypointensity, DP hypointensity, and rim enhancement in the diagnosis were 11%, 29%, and 18%, respectively, for 6–10-mm hypervascular HCCs, and 42%, 63%, and 58%, respectively, for 16–20-mm lesions. After exclusion of the 48 lesions showing T2-weighted hyperintensity (HCCs, n=39; benign lesions, n=9), the overall sensitivity for diagnosis of small hypervascular HCCs decreased (8.3%, 25.0%, and 8.3%, respectively). Conclusion: Although DP provides a better sensitivity than PP, both PP and DP have very limited diagnostic value for diagnosis of small hypervascular HCCs during dynamic MR imaging of the cirrhotic liver.

TERT promoter mutations and long-term survival in patients with thyroid cancer

TERT promoter mutations are emerging prognostic biomarkers in multiple cancers and are found in highly aggressive thyroid cancer. Our aim is to investigate the prognostic value of these mutations for the outcome of thyroid cancer-related mortality in a large cohort of thyroid cancer patients. This was a retrospective study of 409 patients (393 with differentiated thyroid cancer) with a median age of 44 years (range 16-81 years) and median follow-up of 13 years (interquartile range 11-16 years). Analyses of associations between mutational status and various clinicopathological variables were performed. TERT promoter mutations were identified in 32 (9.8%) papillary, 11 (16.7%) follicular and seven (43.8%) poorly differentiated/anaplastic thyroid cancer patients. The presence of TERT promoter mutations was associated with factors such as increased age (P < 0.001), extrathyroidal invasion (P = 0.01), increased stage at diagnosis (P < 0.001) and dedifferentiated histological type (P = 0.001). A TERT promoter mutation was independently associated with poorer overall survival in patients with differentiated thyroid cancer (10-year survival rate, 66.2% vs 98.3% for wild type; adjusted HR, 7.18; 95% CI: 2.77-18.59) and in patients with papillary cancer (74.2% vs 99.3%; 14.20; 3.03-66.68). Concomitant TERT and BRAF mutations worsened the survival rate of patients with papillary cancer (82.6% vs 99.4% for exclusively BRAF mutation alone; 5.62; 1.85-17.09). In conclusion, the presence of TERT promoter mutations is independently associated with increased mortality in patients with differentiated thyroid cancer. The results suggest that inclusion of TERT promoter mutation analysis with conventional clinicopathological evaluation can lead to better prognostication and management for individual patients.

Prognostic value of the eighth edition AJCC TNM classification for differentiated thyroid carcinoma

BACKGROUND The prognostic value of the proposed eighth edition of the American Joint Committee on Cancer (AJCC) tumor, node, and metastasis (TNM) classification is currently unclear. The aim of the study was to evaluate the prognostic value of the eighth edition of the AJCC TNM classification. METHODS We retrospectively assessed 3176 patients with differentiated thyroid carcinoma (DTC) who underwent thyroidectomy at a tertiary Korean hospital from 1996 to 2005. Cancer-specific survival (CSS) was analyzed using the Kaplan-Meier method and compared using the log-rank test. Performance of the eighth edition TNM with respect to prediction of CSS was assessed against the current seventh edition. RESULTS Upon reclassification according to the eighth edition, 37.6% of patients were down-staged. The proportions of stage I and II tumors increased from 61.9% to 81.1% and from 1.7% to 16.0%, respectively, whereas those of stage III and IVB (formerly IVC in the seventh edition) decreased from 27.6% to 2.3% and 0.8% to 0.5%, respectively. The proportions of variance explained (PVEs) for the ability of the eighth and the seventh edition to predict CSS were 3.9% and 2.9%, respectively. The C-index values were 0.765 (95% confidence interval 0.764-0.766) for the eighth edition and 0.736 (0.735-0.737) for the seventh edition. CONCLUSION Our results demonstrate that the eighth edition TNM more accurately predicts CSS for patients with DTC than does the seventh edition.

Helicobacter pylori infection is an independent risk factor of early and advanced colorectal neoplasm.

The role of Helicobacter pylori (H. pylori) in the development of colorectal neoplasm remains controversial. We examined the association between H. pylori infection and colorectal neoplasm in a large sample of healthy participants who underwent screening colonoscopy.

Counting Small Hypointense Spots Confounds the Quantification of Functional Islet Mass Based on Islet MRI

Iron‐containing fragmented islets or free iron released from dying cells could confound the interpretation of MRI of iron nanoparticle‐labeled islets. Exclusion of small hypointense spots could be a useful strategy to avoid such artifact. We investigated whether this strategy could improve the estimation of functioning islet mass after islet transplantation. Using a rat syngeneic intraportal islet transplantation model, we quantitatively assessed the relationships between total area, number of hypointense spots on MRI that belong to each size quartile and glycemic control of the recipients. The total area of hypointense spots on MRI was greater in the recipients that achieved diabetes reversal (p = 0.002), whereas the total number of hypointense spots was not different (p = 0.757). Exclusion of small hypointense spots improved the association between the number of hypointense spots and the blood glucose level of the recipients (p < 0.001). Ex‐vivo imaging and histologic study confirmed that some small hypointense spots represent the phagocytosed free iron. Exclusion of small hypointense spots improved the quantification of the functional islet mass based on islet MRI. This would be a useful principle in the development of an algorithm to estimate functioning islet mass based on islet MRI.

Effect of PK11195, a peripheral benzodiazepine receptor agonist, on insulinoma cell death and insulin secretion

Functional role of peripheral benzodiazepine receptor on mitochondrial membrane in apoptosis and insulin secretion from insulinoma cells was studied. A prototypic peripheral benzodiazepine receptor agonist PK11195 induced insulinoma cell apoptosis, while a central benzodiazepine receptor agonist did not. Death of insulinoma cells by PK11195 was inhibited by cyclosporin A,{ a blocker of mitochondrial permeability transition pore}. Caspase inhibitors further inhibited MIN6N8 cell death. PK11195 induced dissipation of mitochondrial potential and cytochrome c translocation to cytoplasm. PK11195 induced an increase in cytoplasmic [Ca2 +], which was reversed by cyclosporin A. Rhod-2 staining showed decreased mitochondrial [Ca2 +] after PK11195 treatment. PK11195 potentiated glucose-induced insulin secretion probably due to the increased cytoplasmic [Ca2 +]. Calpain was activated following Ca2 + release, and calpain inhibitors attenuated death of insulinoma cells by PK11195. These results suggest that PK11195 induces mitochondrial potential loss, cytochrome c translocation, increased insulin secretion in conjunction with an increase in cytoplasmic [Ca2 +] and calpain activation, which collectively leads to apoptosis of insulinoma cells.