Impact of co-existent thyroiditis on clinical outcome in papillary thyroid carcinoma with high preoperative serum antithyroglobulin antibody: a retrospective cohort study.

OBJECTIVES: The aim of this study was to investigate the impact of co-existent chronic lymphocytic thyroiditis (CLT) on changes in serum antithyroglobulin antibody (TgAb) and clinical outcome in papillary thyroid carcinoma (PTC) patients with high preoperative serum TgAb. DESIGN: A retrospective cohort study. SETTING: University teaching hospital. PARTICIPANTS: Thirty-seven PTC patients with high preoperative serum TgAb level (≥100 U/mL) were evaluated. All patients underwent total thyroidectomy followed by high-dose I-131 ablation. MAIN OUTCOME MEASURES: Per cent changes of TgAb between pre-treatment and post-treatment, and disease-free survival were calculated. RESULTS: Twenty-two patients (59.5%) had co-existent CLT, and seven had residual/recurrent tumours. There was a higher proportion of females among the patients with CLT compared to those without CLT (95.5% versus 66.7%; P = 0.0306). There were trends towards more aggressive pathologies, such as tumour size, extrathyroidal extension, surgical margin and lymph node stage, in PTC without CLT than in that with co-existent CLT. Pre-treatment and post-treatment TgAb were all higher in PTC with co-existent CLT. But, per cent changes of TgAb between pre-treatment and post-treatment were no significant difference between PTC with and without CLT (P < 0.05). Patients with co-existent CLT showed a significantly lower residual/recurrent tumour rate than those without CLT (4.5% versus 40%; P = 0.0113). CONCLUSION: Residual/recurrent tumour rate was lower in PTC patients with co-existent CLT than in those without CLT.

A new method for segmentation of FDG PET metabolic tumour volume using the peritumoural halo layer and a 10-step colour scale. A study in patients with papillary thyroid carcinoma.

AIM: We observed a layer between tumour activity and background on FDG PET/CT with the 10-step colour scale and the window level set properly. We named the layer peritumoral halo layer (PHL). We performed this study to establish the reliability of metabolic tumor volume (MTV) segmentation using PHL (MTV(PHL)) in patients with papillary thyroid carcinoma. PATIENTS, METHODS: Of a total of 140 papillary thyroid carcinoma (PTC) patients, 70 (50.0%) had FDG-avid PTC. In these patients, MTV(PHL), MTV segmented according to fixed 50% SUVmax (MTV(50%)), and fixed SUV with 2.5 to 4.0 (MTV(2.5) to MTV(4.0)) were compared with pathologic tumour volume (PTV). The absolute percentage difference between MTV(PHL) and PTV was compared in micropapillary carcinoma (MPTC) and non-micropapillary carcinoma (non-MPTC) subgroups. The % SUVmax and SUV thresholds of MTV(PHL) were compared with tumour SUVmax. RESULTS: Among the MTVs, MTV(50%) was not correlated with PTV (r = -0.16, p = 0.182) and was not reliable according to the Bland-Altman plot. Although MTV(2.5), MTV(3.0), MTV(3.5), and MTV(4.0) correlated with PTV (r = 0.85, 0.86, 0.87, and 0.87, respectively; p < 0.001), these MTVs were not reliable on Bland-Altman analyses. MTV(PHL) was significantly correlated with PTV (r = 0.80, p < 0.001), and the Bland-Altman plot did not show systemic error. The MTV(PHL) was more accurate in non-MPTC than in MPTC (p < 0.001), and the absolute % difference was smaller as PTV became larger (σ = -0.65, p < 0.001). The MTV(PHL) thresholds had correlations with SUVmax (% SUVmax threshold: σ = -0.87, p < 0.001; SUV threshold: r = 0.88, p < 0.001). CONCLUSIONS: MTV(PHL) was more reliable than MTV(%SUVmax) or MTV(SUV). The reliability of MTV(PHL) improved with larger PTVs. The threshold of the MTV(PHL) was naturally altered by PHL according to SUVmax.

Efficient lung orthotopic tumor-growth suppression of oncolytic adenovirus complexed with RGD-targeted bioreducible polymer.

Oncolytic adenoviruses (Ad) have been developed for the eradication of tumors. Although they hold much promise as a cancer therapy, they have a short blood circulation time and high liver toxicity. An effective strategy to overcome these problems has been complexing Ad with shielding materials. However, the therapeutic efficacy of the Ad complexes has also been an issue because passive accumulation does not allow for sufficient delivery of Ad to the cancer cells. To enhance the therapeutic efficacy of the polymer-coated Ads, the attachment of a targeting moiety to polymer-coated Ad vectors is inescapable. Our lab has previously reported the potential use of Arg-Gly-Asp (RGD)-targeted bioreducible polymers with a polyethylene glycol (PEG) linker for delivering oncolytic Ads. We have shown the enhanced in vitro transduction efficiency and increased cancer-killing effect with producing progeny oncolytic Ad particles. In addition, we have shown significant tumor-growth inhibition of the polymer-shielded Ad in an in vivo lung orthotopic tumor model. The shielding effect of the Ad surface with the polymers allowed evasion of host immune responses and reduction of liver toxicity. This data demonstrates that the RGD-conjugated bioreducible polymer for delivering the oncolytic Ad vectors could be utilized for cancer therapy via systemic administration.

Comparison of in vitro developmental competence of cloned caprine embryos using donor karyoplasts from adult bone marrow mesenchymal stem cells vs ear fibroblast cells.

The aim of this study was to produce cloned caprine embryos using either caprine bone marrow-derived mesenchymal stem cells (MSCs) or ear fibroblast cells (EFCs) as donor karyoplasts. Caprine MSCs were isolated from male Boer goats of an average age of 1.5 years. To determine the pluripotency of MSCs, the cells were induced to differentiate into osteocytes, chondrocytes and adipocytes. Subsequently, MSCs were characterized through cell surface antigen profiles using specific markers, prior to their use as donor karyoplasts for nuclear transfer. No significant difference (p > 0.05) in fusion rates was observed between MSCs (87.7%) and EFCs (91.3%) used as donor karyoplasts. The cleavage rate of cloned embryos derived with MSCs (87.0%) was similar (p > 0.05) to those cloned using EFCs (84.4%). However, the in vitro development of MSCs-derived cloned embryos (25.3%) to the blastocyst stage was significantly higher (p < 0.05) than those derived with EFCs (20.6%). In conclusion, MSCs could be reprogrammed by caprine oocytes, and production of cloned caprine embryos with MSCs improved their in vitro developmental competence, but not in their fusion and cleavage rate as compared to cloning using somatic cells such as EFCs.

Monitoring differentiated thyroid cancer patients with negative serum thyroglobulin. Diagnostic implication of TSH-stimulated antithyroglobulin antibody.

AIM: Serum antithyroglobulin antibody (TgAb) has been reported as a surrogate marker for differentiated thyroid cancer (DTC) in some conditions. We investigated changes in serum TgAb levels after stimulation with thyroid-stimulating hormone (TSH) and the clinical implications for monitoring DTC. PATIENTS, METHODS: We retrospectively enrolled 53 DTC patients who had undergone total thyroidectomy and were negative for serum Tg and positive for TgAb. Patients underwent high-dose radioactive iodine treatment, and serum TgAb was measured before (TgAbBAS) and after TSH stimulation (TgAbSTIM). TgAb was followed up 6 to 12 months later (TgAbF/U). The change in TgAb after TSH stimulation (∆TgAbSTIM) was calculated as a percentage of the baseline level. Patient disease status was classified into no residual disease (ND) and residual or recurred disease (RD) by follow-up imaging studies and pathologic data. The characteristics and diagnostic value of serum TgAb levels and ∆ TgAbSTIM were investigated with respect to disease status. RESULTS: 38 patients were in the ND group and 15 were in the RD group. TgAbBAS, TgAbSTIM and TgAbF/U were significantly higher in the RD compared to the ND group (p = 0.0008, 0.0002, and < 0.0001, respectively). ∆TgAbSTIM was also significantly higher in the RD group (p = 0.0009). In the patients who presented with obviously high (≥ 50%) or low (< -50%) ∆ TgAbSTIM, the proportions in the RD group were markedly different at 100% and 7%, respectively. ∆ TgAbSTIM had significant diagnostic value for RD (p < 0.001). CONCLUSION: The change in serum TgAb level after TSH stimulation is different between the RD and ND groups, and thus, it may be used as a surrogate diagnostic marker for DTC when the serum Tg is negative and TgAb is positive.

Clinical implication of (18)F-FDG PET/CT in carcinoma of unknown primary.

The value of (18)F-Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) in the detection of carcinoma of unknown primary (CUP) differs among the studies. This study aimed to evaluate the role of (18)F-FDG PET/CT in CUP. Fifty-one patients (19 women, 32 men) with metastasis confirmed by histopathology from an unknown primary tumor were included in this study. Patients received 370 MBq of (18)F-FDG intravenously, and PET/CT was performed at 60 minutes after injection. Primary tumor sites were detected in 5 of 51 patients (9.6%): in 2 patients with carcinoma of the lung, in 1 patient with carcinoma of the gallbladder, in 1 patient with carcinoma of the esophagus, and in 1 patient with carcinoma of the stomach. No primary tumor was discovered in the remaining 46 patients (90.4%) during the follow-up. The sensitivity, specificity, and accuracy of (18)F-FDG PET/CT were 100%, 80.4%, and 82.4%. The positive and negative predictive values were 35.7 and 100%, respectively. Based on the data presented, (18)F-FDG PET/CT has a clinical implicative value in detecting the primary tumor of CUP. PET/CT can be useful to rule out the possibility of detecting the primary tumor during the follow-up.

MicroRNA signatures associated with immortalization of EBV-transformed lymphoblastoid cell lines and their clinical traits.

OBJECTIVE: MicroRNAs (miRNAs) are negative regulators of gene expression that play important roles in cell processes such as proliferation, development and differentiation. Recently, it has been reported that miRNAs are related to development of carcinogenesis. The aim of this study was to identify miRNAs associated with terminal immortalization of Epstein-Barr virus (EBV)-transformed lymphoblastoid cell line (LCL) and associated clinical traits. MATERIAL AND METHODS: Hence, we performed miRNA microarray approach with early- (p6) and late-passage (p161) LCLs. RESULTS AND CONCLUSION: Microarray data showed that nine miRNAs (miR-20b*, miR-28-5p, miR-99a, miR-125b, miR-151-3p, miR-151:9.1, miR-216a, miR-223* and miR-1296) were differentially expressed in most LCLs during long-term culture. In particular, miR-125b was up-regulated in all the tested late-passage LCLs. miR-99a, miR-125b, miR-216a and miR-1296 were putative negative regulators of RASGRP3, GPR160, PRKCH and XAF1, respectively, which were found to be differentially expressed in LCLs during long-term culture in a previous study. Linear regression analysis showed that miR-200a and miR-296-3p correlated with triglyceride and HbA1C levels, respectively, suggesting that miRNA signatures of LCLs could provide information on the donor's health. In conclusion, our study suggests that expression changes of specific miRNAs may be required for terminal immortalization of LCLs. Thus, differentially expressed miRNAs would be a potential marker for completion of cell immortalization during EBV-mediated tumorigenesis.

Expression phenotype changes of EBV-transformed lymphoblastoid cell lines during long-term subculture and its clinical significance.

OBJECTIVES: The EBV-transformed lymphoblastoid cell line (LCL) is a useful resource for population-based human genetic and pharmacogenetic studies. The principal objective here was to assess expression phenotype changes during long-term subculture of LCLs, and its clinical significance. MATERIALS AND METHODS: We searched for genes that were differentially expressed in 17 LCLs at late (p161) passage compared to early passage (p4) using microarray assay, then validated them by real-time RT-PCR analysis. In addition, we estimated correlations between expression phenotypes of 20 LCL strains at early passage and 23 quantitative clinical traits from blood donors of particular LCL strains. RESULTS: Transcript sequences of 16 genes including nuclear factor-kappaB (NF-kappaB) pathway-related genes (such as PTPN13, HERC5 and miR-146a) and carcinogenesis-related genes (such as XAF1, TCL1A, PTPN13, CD38 and miR-146a) were differentially expressed (>2-fold change) in at least 15 of the 17 LCL strains. In particular, TC2N, FCRL5, CD180, CD38 and miR-146a were downregulated in all 17 of the evaluated LCL strains. In addition, we identified clinical trait-associated expression phenotypes in LCLs. CONCLUSION: Our results showed that LCLs acquired expression phenotype changes involving expression of NF-kappaB pathway- and carcinogenesis-related genes during long-term subculture. These differentially expressed genes can be considered to be a gene signature of LCL immortalization or EBV-induced carcinogenesis. Clinical trait-associated expression phenotypes should prove useful in the discovery of new candidate genes for particular traits.

Detection and prediction of local recurrence of maxillary sinus cancer using F-18 FDG PET/CT.

PURPOSE: The aim of the current study was to investigate the role of F-18 FDG PET/CT in the detection and prediction of local recurrence of maxillary sinus cancer. METHODS: Retrospectively, we analyzed F-18 FDG PET/CT images of maxillary sinus cancer patients for the surveillance after treatment. Twenty-two consecutive patients with maxillary sinus cancer, who underwent maxillectomy followed by adjuvant radiation treatment, were included in the study. F-18 FDG PET/CT images were analyzed visually and quantitatively. RESULTS: The median age of the patients included in the current study population was 54.5 years (range, 35-78). Seven patients (29.1%) had local recurrent diseases. Recurrent diseases show statistically significant higher values in SUV(max) (recurrent: 5.09 +/- 3.3, non-recurrent; 3.05 +/- 0.7, p < 0.05), L/NL (recurrent: 2.95 +/- 0.9, non-recurrent; 1.86 +/- 0.5, p < 0.05), L/Ao (recurrent: 3.37 +/- 2.1: non-recurrent; 1.88 +/- 0.4, p < 0.05), and L/Cbr (recurrent: 1.06 +/- 0.7: non-recurrent; 0.46 +/- 0.1, p < 0.05) than those of non-recurrent disease of maxillary sinus cancer. There were no statistical differences between visual assessment and quantitative indices for the detection of local recurrence. The visual assessment was the potent predictor by logistic regression analysis for prediction of local recurrence. CONCLUSION: The visual assessment of F-18 FDG uptake pattern was potential predictor for local recurrence of maxillary sinus cancer. However, the diagnostic performances were similar between visual assessment and quantitative indices. Further studies are needed to confirm these results and improve statistical accuracy.

Identification of tumor necrosis factor signaling-related proteins during Epstein-Barr virus-induced B cell transformation.

Epstein-Barr virus (EBV) infection in vitro transforms primary B cells into continuously proliferating lymphoblastoid cell lines (LCLs) that have been widely used as a genomic resource for variety of immunological and genetic studies. However, the biochemical and biological characteristics that distinguish LCLs from the B cells have not been thoroughly investigated. Our proteomic approach showed that EBV infection induced changes in the profiles of tumor necrosis factor (TNF) signaling-related proteins in LCLs including heat shock protein family members TNF receptor-associated protein 1 (TRAP-1), heat shock 70-kDa protein 9 (HSPA9)) and superoxide dismutase 2 (SOD2). In addition, our literature co-occurrence study placed TNF at the center of a gene cluster network of differentially expressed proteins in LCLs. This study suggested that deregulation of TNF signaling pathway could contribute to the cellular transformation and immortalization of the EBV-infected B cells.

Outpatient pre-operative assessment in joint replacement surgery.

An anaesthetist-led outpatient pre-operative assessment (OPA) clinic was introduced in our unit in an effort to improve patient care and cost-effectiveness. To assess the efficiency of the clinic, 112 patients who attended the OPA clinic (attendance rate 98%) during the first year were assessed prospectively and compared with 118 patients who did not undergo OPA the year before. There were fewer cancellations among those who attended the OPA clinic (13.6% compared to 3.6%), and the hospital stay was shortened from an average of 10.7 days to 7.0 days. This has resulted in more efficient utilization of operating theatre, reduced hospital costs and improved patient satisfaction. More extensive use of the pre-admission clinic is recommended and should be explored in other clinical settings.