Q. Duh

Prognostic Scoring Systems in Patients with Follicular Thyroid Cancer: A Comparison of Different Staging Systems in Predicting the Patient Outcome

BACKGROUND The use of prognostic scoring systems is important for predicting the survival of individuals with thyroid carcinoma. Relatively few studies have addressed this issue for patients with follicular thyroid cancer. The goal of this retrospective study was to establish the best and most pertinent prognostic scoring system to predict survival in patients with follicular thyroid cancer. METHODS We selected 86 patients with follicular thyroid cancer treated at University of California, San Francisco (UCSF) hospitals from January 1954 to April 1998. The mean follow-up time was 11.5 years. There were 60 women (70%) and 26 men (30%), with a mean age if 48.6 years. Prognostic scoring systems included tumor, node, metastases (TNM), European Organization for Research and Treatment of Cancer (EORTC), Age, Grade, Extent, Size (AGES), Age, Metastases, Extent, Size (AMES), and the Metastases, Age, Completeness of resection, Invasion, Size (MACIS). Survival time was calculated using the Kaplan-Meier method. Using Cox proportional hazards analysis, the relative importance of each scoring method was determined by calculating the proportion of variation in survival time explained (PVE). RESULTS Kaplan-Meier analysis indicated that all scoring systems were significant predictors of survival time (p < 0.0001). The PVE associated with each system was (from highest to lowest) 0.48 for MACIS, 0.46 for AGES, 0.44 for EORTC, 0.40 for AMES, and 0.33 for TNM. These results indicate that the MACIS scoring system accounted for a great proportion of explained variance in survival and is a more precise predictor of survival compared to the other scoring systems. CONCLUSIONS TNM, EORTC, AGES, AMES, and MACIS, all provided useful prognostic information about the survival in our 86 patients with follicular thyroid cancers. The MACIS classification, however, was the most accurate predictor using PVE as a method of evaluation. Future scoring systems considering additional prognostic factors, may obtain a higher PVE.

Laparoscopic bilateral adrenalectomy: results for 30 consecutive cases

BackgroundMost patients requiring bilateral adrenalectomy have adrenocorticotropin hormone (ACTH)-dependent Cushing’s syndrome. Some of these patients are severely debilitated from the chronic effects of cortisol overproduction. This study aimed to analyze the indications, safety, efficacy, and outcomes for laparoscopic bilateral adrenalectomy from the authors’ experience.MethodsA retrospective review was conducted at a university tertiary referral center. Between March 1996 and August 2006, 30 consecutive patients underwent simultaneous laparoscopic bilateral adrenalectomy. The patient records were analyzed to obtain patient demographics, disease etiology, surgical approach, operating room information, postoperative complications (30 days), hospital length of stay (LOS), and follow-up information.ResultsThe 30 participants (22 women and 8 men) had a mean age of 44 years. The indications for bilateral adrenalectomy were refractory Cushing’s disease (n = 16), occult ectopic ACTH syndrome (n = 9), and bilateral pheochromocytoma (n = 5). A mean of 53 months elapsed between onset of symptoms and adrenalectomy. Laparoscopic bilateral adrenalectomy was completed for all the patients with no intraoperative complications. Four patients (13%) experienced six complications. The mean postoperative LOS was 3.5 days (range, 1–12 days). Seven patients required a preoperative LOS, for a mean of 7.1 days (range, 1–20 days), and a postoperative LOS, for a mean of 5 days (range, 2–12 days). The 23 patients who did not require preoperative hospitalization had a mean postoperative LOS of 3 days (range, 1–7 days). All the patients received postoperative steroid replacement and appropriate follow-up assessment with an endocrinologist. At this writing, the patients with Cushing’s syndrome available for follow-up evaluation continue to receive steroid replacement, and all the pheochromocytoma patients have experienced a documented postoperative biochemical cure.ConclusionsLaparoscopic bilateral adrenalectomy is safe and effective for this high-risk patient population. Although patients should be monitored closely in the postoperative period, most are discharged with glucocorticoid and mineralocorticoid replacement in a short time without complications.

Molecular and cytogenetic characterization of a t(1;10;21) translocation in the human papillary thyroid cancer cell line TPC-1 expressing the ret/H4 chimeric transcript

BACKGROUND Activation of the ret proto-oncogene by three different chromosomal rearrangements occurs in up to 25% of papillary thyroid carcinomas. We developed a rapid screening technique to detect ret rearrangements in human interphase and metaphase cells on the basis of multicolor fluorescence in situ hybridization (FISH) of locus-specific DNA probes. METHODS DNA from individual clones representing the respective ends of a yeast artificial chromosome (YAC) contig spanning the entire ret gene locus were labeled with either digoxigenin (visualized in red) or biotin (green) and hybridized to normal human lymphocytes and the papillary thyroid cancer cell line TPC-1 expressing the ret/H4 chimeric transcript. Further detailed analysis was performed with whole chromosome painting probes and locus-specific probes (YACs, P1s, DNA repeat probes) on tumor metaphase spreads. RESULTS Hybridization of the YACs to unrearranged ret loci in normal human lymphocyte interphase nuclei showed two yellow domains because of probe overlap. Hybridization to TPC-1 interphase nuclei showed one yellow domain, and 1 red and 1 green domain separated by a large physical distance. Further analysis of metaphase spreads revealed a complex translocation t(1;10;21)(1pter > 1q31::21q22.1 > 21qter; 10q11.2 > 10pter::1q31 > 1qter; 21pter > 21q22.1;;10q21.2 > 10q11.2::10q21.2 > 10qter) and loss of the H4 gene locus on the nontranslocated chromosome 10. CONCLUSIONS Break point spanning probes can reliably detect ret rearrangements in interphase nuclei. Locus-specific and whole chromosome painting probes can be used to further characterize complex rearrangements by fluorescence in situ hybridization to metaphase spreads. The papillary thyroid cancer cell line TPC-1 carries the paracentric inversion 10q, inv(10)(q11.2q21) and a complex t(1; 10; 21) translocation. Deletion of the H4 gene on the chromosome 10 not involved in the t(1; 10; 21) translocation suggests lack of normal H4 expression in the TPC-1 cell line. Further studies will have to address the role of the H4 gene product in tumor genesis and progression.

Urinary Parameters as Predictors of Primary Hyperparathyroidism in Patients With Nephrolithiasis

PURPOSE Serum calcium and parathyroid hormone levels are the primary means of evaluating patients for hyperparathyroidism. Whether there are differences in urinary parameters between stone formers with and those without hyperparathyroidism is controversial. In this study we identify urinary parameters that predict primary hyperparathyroidism. MATERIALS AND METHODS From 2001 to 2010 a total of 1,190 adult, noncystine stone forming patients underwent urinary metabolic stone evaluation. Of these patients 34 (3%) underwent parathyroidectomy for primary hyperparathyroidism. Urinary parameters were evaluated as predictors of primary hyperparathyroidism. The most accurate combination of serum and urinary tests and their cutoffs were determined. RESULTS Stone forming patients with primary hyperparathyroidism were more likely to be women and had higher urinary calcium excretion. Hypercalciuria (aOR 4.38), supersaturation calcium oxalate greater than 10 (aOR 4.27), supersaturation calcium phosphate greater than 2 (aOR 3.64), calcium per kg greater than 4 mg/kg (aOR 8.03) and calcium-to-creatinine ratio greater than 150 mg/gm (aOR 7.07) were significant predictors of primary hyperparathyroidism in separate multivariate models after adjustment. The best accuracy was determined using serum calcium and parathyroid hormone levels with our laboratory cutoffs (AUC 0.984) with a sensitivity of 87%, specificity of 99%, positive predictive value of 79% and negative predictive value of 99.5%. No other factor(s) improved diagnostic accuracy or could replace parathyroid hormone level. CONCLUSIONS Greater urinary calcium excretion predicted primary hyperparathyroidism. Serum calcium with parathyroid hormone level was the most accurate test for primary hyperparathyroidism. No other serum or urinary parameter improved diagnostic accuracy or could replace parathyroid hormone. There were no obvious cutoffs for any of the urinary parameters that reliably differentiated cases of hyperparathyroidism.

Heterologous Desensitization in Neoplastic Thyroid Cells: Influence of the Phospholipase C Signal Transduction System on the Thyrotropin–adenylate Cyclase Signal Transduction System

Abstract. Desensitization is defined as a decreased functional response after continuous or repetitive stimulation of a receptor with its agonist. Thyrotropin (TSH) increases cAMP levels in normal and neoplastic thyroid tissue. The tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate (TPA) activates protein kinase C (PKC). The aim was to determine whether TPA induces heterologous desensitization of the TSH–adenylate cyclase (AC) signal transduction system. Three human thyroid neoplasms in culture for 6 months or longer (one papillary carcinoma, one Hurthle cell carcinoma, one follicular adenoma) were incubated with TSH (10 mU/ml) and TPA (1.6 × 10 \-8 M) separately and together for various time periods (from 10 minutes to 24 hours). The mixture was subsequently incubated for 30 minutes with TSH. TPA alone had no effect on cAMP levels, but co-incubation of TPA and TSH caused a significant reduction in cAMP response when compared to the cAMP response that resulted after stimulation with only TSH (p < 0.001). cAMP levels in response to TSH decreased by 31%, 44%, and 57% after preincubation with TSH for 10 minutes, 4 hours, and 24 hours, respectively. cAMP levels in response to TSH decreased by 44%, 33%, and 29% after preincubation with TPA for 10 minutes, 4 hours, and 24 hours, respectively (p < 0.01; ANOVA). Co-incubation of cells with TPA and staurosporine (10 ng/ml), a PKC inhibitor, prevented the effect of TPA on desensitization at 10 minutes and blunted the effect at 4 hours. This is the first demonstration in human neoplastic thyroid cells that TPA induced heterologous desensitization of the cAMP response to TSH. This TPA-induced effect appears to involve PKC activation, as it can be blocked by staurosporine.

The peroxisome proliferator-activated receptor gamma agonist rosiglitazone inhibits growth and downregulates Bcl-2 gene expression in human follicular thyroid cancer cells

S: POSTER PRESENTATIONS P66 Clinico-pathologie and Radiopharmacokinetic Factors Affecting Gamma Probe guided Parathyroidectomy O. Ugur, l F.M. Bozkurt 1 E. Hamaloglu, l C. Sokrnensuer, ~ I. Etikan, 1 I. Sayek, l S.A. Gulec. 2. 1. Hacettepe University Medical Center, Ankara, Turkey; 2. John Wayne Cancer Institute, Santa Monica, CA. Introduction: Mechanisms involved in Tc-99m sestamibi (mibi) kinetics in primary hyperparathyroidism are complex. The aim of this study was to evaluate the factors determining the mibi kinetics and their impact on the success of the gamma probe guided parathyroidectomy. Methods: 31 patients with primary hyperparathyroidism ( 27/31 (87%) with solitary parathyroid adenoma and 4/31 ( 13 %) with multiglandular hyperplasia) underwent dynamic mibi imaging preoperatively. Maximum mibi activity (Amax) and activity elimination half-life (T1/2) in the abnormal parathyroid glands and thyroid glands were measured, and the maximum parathyroid-to-thyroid uptake ratio (URmax) was calculated. All patients underwent gamma probe guided parathyroidectomy and cervical exploration receiving a second mibi injection on the day of surgery. Timing of surgery after mibi injection was individualized based on the previously determined optimal time-to-surgery (time to URmax). Mibi kinetics were correlated with the gland size, oxyphil cell content, P-glycoprotein (P-gp) expression and serum PTH levels. Results: Probe localization of abnormal glands at URmax was successful in all patients. The size of the parathyroid lesion ranged from 0.03 to 9.8 ml (median: 0.7 ml). Parathyroid Amax correlated with the size of the gland (r=0.412, p=0.02 l) and serum PTH level (r=0.495, p=0.005). No correlation between Amax and oxyphil cell content or P-gp expression could be demonstrated. Parathyroid T1/2 inversely correlated with P-gp (r=-0.430, p=0.04). URmax showed correlation with Amax (r=0.369, p=0.04), hence correlated with gland size and serum PTH level. URmax ranged from 30min to 180min (mean: 124min). In 5 cases (16%) URmax was under one half of the mean. In 1 case high P-gp expression was associated with a URmax of 30 min. Conclusion: Size of the parathyroid gland and serum PTH levels are the major determinants of mibi uptake in primary hyperparathyroidism. Gamma probe localization of abnormal gland(s) is most successful if surgery is performed close to URmax. High P-gp expression increases mibi parathyroid clearance rate and may significantly alter the optimal time to surgery. P67 The Peroxisome Proliferator-Activated Receptor Gamma Agonist Rosiglitazone Inhibits Growth and Downregulates Bcl-2 Gene Expression in Human Follicular Thyroid Cancer Cells W.T. Shen,* T.S. Wong, M.G. Wong, E. Kebebew, Q.Y. Duh, O.H. Clark. Surgery, University of California, San Francisco, San Francisco, CA. INTRODUCTION Ligands ofperoxisome proliferator-activated receptor gamma (PPAR-gamma) demonstrate antiproliferative andpro-apoptotic effects in a variety of cancer cell lines. Rosiglitazone is a widely used antidiabetic drug that functions as a PPAR-gamma agonist; its antineoplastic properties are currently being evaluated in laboratory and clinical trials. We studied the effects ofrosiglitazone on cell growth and apoptosis in human follicular thyroid cancer cells. METHODS We used a well-characterized follicular thyroid cancer cell line (FTC133) to evaluate the antineoplastic effects of rosiglitazone. Cells were treated with luM and 5uM doses of rosiglitazone; these doses were determined by previous studies in other cell lines to inhibit cell growth with minimal toxicity. A control group of cells received no treatment. The cells were harvested on days l, 2, and 3 after treatment and their RNA extracted. The Cyquant cell proliferation assay was used to measure cell growth. Real-time quantitative PCR was performed to determine gene expression levels of Bcl-2, a pro-survival gene that plays an important role in the regulation of apoptosis. RESULTS Treatment of FTC-133 cells with rosiglitazone at concentrations of luM and 5uM resulted in time-dependent and dose-dependent growth inhibition over the course of 3 days when compared to untreated controls (see figure). On the first day after treatment, Bcl-2 gene expression was decreased by 22% and 21% in cells treated with luM and 5uM doses of rosglitazone when compared to untreated controls; by the third day of treatment, Bcl-2 gene expression was decreased by 74% and 56%. CONCLUSIONS Rosiglitazone inhibits growth and downregulates Bcl-2 gene expression in human follicular thyroid cancer cells. Downregulation of Bcl2 gene expression suggests that rosiglitazone induces apoptosis by inhibiting the Bcl-2 pro-survival pathway. Rosiglitazone may be an important therapeutic option in patients with follicular thyroid cancer that is refractory to conventional treatment modalities such as surgery and radioiodine ablation. P68 Partial Median Sternotomy: An Attractive Approach to Mediastihal Parathyroid Disease J.S. Gold,* P.L Donovan, R. Udelsman. Yale University School of Medicine, New Haven, CT. Introduction: The vast majority of mediastinal parathyroid adenomas can be resected employing a cervical approach. A subset of these lesions, however, requires transsternal exploration. The technique of partial median sternotomy is underappreciated and particularly attractive. Methods: All parathyroid explorations performed by a single endocrine surgeon over a 13-year period were reviewed from a prospective database. Results: Partial (n-7) or complete (n=3) median sternotomy was employed in 10 cases out of 908 consecutive parathyroid explorations between 1990-2003 (1.1% of cases). Eight cases were remedial having previously failed cervical (n=7) or transsternal (nl ) explorations. Preoperative localization with sestamibi correctly identified a mediastinal parathyroid adenoma in only 3 patients. The technique of partial median sternotomy in which the sternum is transected to the level of the second intercostal space was attempted in all cases. The exposure was successful in 70% of patients, as 3 cases required enhanced exposure obtained by conversion to conventional complete sternotomy. All 7 patients who underwent partial median sternotomy achieved a cure as evidenced by normalization of calcium and parathyroid hormone levels. In 5 cases a parathyroid adenoma was resected from the mediastinum. In 1 case a parathyroid adenoma was ultimately identified in the left carotid sheath. In 1 case despite the absence of pathological material, the patient was unequivocally cured. The mediastinal parathyroid glands were located retroesophageal in the posterior mediastinum, posterior to the aortic arch, and in the inferior thymus. The mean length of stay was 2.6 days after partial sternotomy and 4.0 days for complete sternotomy. One patient sustained a recurrent laryngeal nerve injury after a repeat cervical exploration and partial sternotomy. Conclusions: Median sternotomy is rarely necessary during parathyroid extirpation, but is most often employed during remedial exploration for persistent primary parathyroidism. When required, adequate mediastinal exploration can be accomplished through a partial sternotomy, which is associated with minimal morbidity and a short length of stay. P69 Different operative protocols for minimally invasive radioguided parathyroidectomy. A randomized prospective study E Lumachi, ~* l 2 2 2 2 M. Iacopone, M.C. Marzola, E Zucchetta, D. Cecchin, E Bui, G. Favia. 1 1. Endocrinesurgery, University of Padua, Padova, Italy, 2. Nuclear Medicine, University of Padua, Padova, Italy. Aim: The aim of this study was to establish the optimal interval between radiofarmaceutical administration and the beginning of surgical exploration in patients undergoing minimally-invasive radioguided parathyroidectomy (MIRP). Patients and Methods: Forty-three consecutive patients (35 women SSO 57TH ANNUAL CANCER SYMPOSIUM

Reoperative thyroid surgery

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