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11503 Background: Adjuvant imatinib improves recurrence-free survival (RFS) when administered after surgery to selected patients with operable gastrointestinal stromal tumor (GIST). It is uncertain whether overall survival (OS) improves, since imatinib improved OS in only one of the 3 large randomized trials conducted, and in this trial (the Scandinavian Sarcoma Group XVIII/German trial; SSGXVIII/AIO; NCT00116935) the statistical significance for OS remained borderline. The objective of the present analysis was to evaluate long-term OS of patients who participated in the SSGXVIII/AIO trial. Methods: SSGXVIII/AIO is an open-label, randomized (1:1), multicenter phase 3 trial. Four hundred patients who underwent macroscopically complete surgery for GIST with a high estimated risk for recurrence according to the modified National Institutes of Health Consensus Criteria were accrued between February 2004 and September 2008. Imatinib was scheduled to be administered 400 mg/day orally for either 12 months or 36 months after surgery. The patients were scheduled to be followed up for 10 years after study entry. Imaging of the abdomen was carried out periodically. The primary end point was RFS; the secondary objectives included OS and treatment safety. Results: The median follow-up time was 119 months. In the Intention-To-Treat Population 194 RFS events and 96 OS events were recorded. In the 36-month group, 5-year and 10-year RFS was 71.4% and 52.5%, and in the 12-month group, 53.0% and 41.8%, respectively (HR 0.66, 95% CI 0.49-0.87; P = .003). In the 36-month group, the 5-year and 10-year OS rates were 92.0% and 79.0%, and in the 12-month group, 85.5% and 65.3%, respectively (HR 0.55, 95% CI 0.37-0.83; P = .004). In the Efficacy Population, from which 15 patients who did not have GIST in central pathology review and 24 patients who had intra-abdominal metastases removed at surgery were excluded, 10-year OS was 81.6% in the 36-month group and 66.8% in the 12-month group (HR, 0.50, 95% CI 0.32-0.80; P = .003). No new safety signals were detected. Conclusions: About 50% of deaths can be avoided during the first decade of follow-up after surgery with 3-year imatinib treatment as compared to 1-year treatment. Clinical trial information: NCT00116935 .

In gastrointestinal stromal tumors (GISTs), KIT exon 11 deletions are associated with poor prognosis. The aim of this study was to determine the gene expression profiles of GISTs carrying KIT exon 11 deletions and to identify genes associated with poor prognosis. Expression profiling was performed on nine tumors with KIT exon 11 deletions and 7 without KIT exon 11 mutations using oligonucleotide microarrays. In addition, gene expression profiles for 35 GISTs were analyzed by meta-analysis. Expression of CD133 (prominin-1) protein was examined by tissue microarray (TMA) analysis of 204 GISTs from a population-based study in western Sweden. Survival analysis was performed on patients subjected to R0 resection (n=180) using the Cox proportional hazards model. Gene expression profiling, meta-analysis, and qPCR showed up regulation of CD133 in GISTs carrying KIT exon 11 deletions. Immunohistochemical analysis on TMA confirmed CD133 expression in 28% of all tumors. CD133 positivity was more frequent in gastric GISTs (48%) than in small intestinal GISTs (4%). CD133 positivity was also more frequent in GISTs with KIT exon 11 mutations (41%) than in tumors with mutations in KIT exon 9, platelet-derived growth factor receptor α (PDGFRA), or wild-type tumors (0-17%). Univariate survival analysis showed a significant correlation between the presence of CD133 protein and shorter overall survival (hazard ratio=2.23, p=0.027). Multivariate analysis showed that CD133 provided additional information on patient survival compared to age, sex, National Institutes of Health (NIH) risk group and mutational status. CD133 is expressed in a subset of predominantly gastric GISTs with KIT exon 11 mutations and poor prognosis.

Adrenocortical carcinoma (ACC) is a rare tumour disease with sinister prognosis also after attempts to radical surgery; better prognosis is seen for low-stage tumours. Adjuvant treatment with the adrenolytic drug mitotane has been attempted, but not proven to prevent from recurrence. The drug may offer survival advantage in case of recurrence. The aim of this single-centre study (1979–2007) of 43 consecutive patients was to evaluate the long-term survival after active surgical treatment combined with monitored mitotane (to reduce side effects of the drug). The series is unique, since all patients were offered a period of mitotane as adjuvant or palliative treatment; six patients refused mitotane. Despite a high proportion of high-stage tumours (67%), the complete resection rate was high (77%). The disease-specific 5-year survival was high (64.1%); very high for patients with low-stage tumours without evident relation to mitotane levels. Patients with high-stage tumours had a clear survival advantage with mitotane levels above a threshold of 14 mg/l in serum. The hazard ratio for patients with high mitotane levels versus all patients indicates a significant effect of the drug. The results indicate that adjuvant mitotane may be the standard of care for patients with high-stage ACC after complete resection.

A key task for health policymakers is to optimise the outcome of health care interventions. The pricing of a new generation of cancer drugs, in combination with limited health care resources, has highlighted the need for improved methodology to estimate outcomes of different treatment options. Here we introduce new general methodology, which for the first time employs continuous hazard functions for analysis of survival data. Access to continuous hazard functions allows more precise estimations of survival outcomes for different treatment options. We illustrate the methodology by calculating outcomes for adjuvant treatment of gastrointestinal stromal tumours with imatinib mesylate, which selectively inhibits the activity of a cancer-causing enzyme and is a hallmark representative for the new generation of cancer drugs. The calculations reveal that optimal drug pricing can generate all win situations that improve drug availability to patients, make the most of public expenditure on drugs and increase pharmaceutical company gross profits. The use of continuous hazard functions for analysis of survival data may reduce uncertainty in health care resource allocation, and the methodology can be used for drug price negotiations and to investigate health care intervention thresholds. Health policy makers, pharmaceutical industry, reimbursement authorities and insurance companies, as well as clinicians and patient organisations, should find the methodology useful.

10505 Background: Three years of adjuvant IM is recommended after surgery for patients (pts) with high-risk GIST with an IM-sensitive mutation. This recommendation is based on the findings from the SSGXVIII/AIO trial that compared 1 year (Arm A) to 3 years (Arm B) duration of administration of adjuvant IM. After a median follow-up of 4.5 yrs, 3 yrs of IM resulted in superior recurrence-free survival (RFS) and overall survival (OS), but the OS benefit was based only on 37 events. Methods: Pts with high-risk GIST according to the modified NIH risk stratification who had GIST resected macroscopically completely were eligible. The pts were randomly assigned 1:1 to Arm A or B, and were scheduled to receive IM 400 mg/day either for 12 or 36 months after surgery. Tumor histology was reviewed centrally after randomization. The study protocol was amended in October 2006 to exclude pts who had completely resected metastatic disease from the study. We now present the second planned analysis of the trial based on a m...

Palliative imatinib treatment has dramatically improved survival in patients with malignant gastrointestinal stromal tumours, particularly in patients with tumours harbouring activating KIT mutations. To evaluate the effectiveness of adjuvant imatinib after radical surgery, a consecutive series of patients with high-risk tumours (n=23) was compared with historic controls (n=48) who were treated with surgery alone. The mean follow-up period was over 3 years in both groups. Only 1 out of 23 patients (4%) in the adjuvant treatment group developed recurrent disease compared to 32 out of 48 patients (67%) in the control group. This preliminary study indicates that 1 year of adjuvant treatment with imatinib dramatically improves recurrence-free survival. Confirmation of these findings awaits the results of ongoing randomised studies.

Background. Gastrointestinal stromal tumors (GISTs) can be effectively treated with tyrosine kinase inhibitors (TKIs). However, some patients with GIST develop drug resistance, and alternative treatment strategies are therefore needed. The aim of this study was to analyze the expression of somatostatin receptors (SSTR) in GIST as a target for peptide receptormediated radiotherapy (PRRT). Material and methods. Expression profi ling of SSTR1 – 5 was performed on biopsies from 34 GISTs (16 gastric tumors, 15 small intestinal tumors, and three rectal tumors). SSTR scintigraphy ( 111 In-octreotide) and measurement of 111 In activity in tumor specimens was performed in seven patients. Uptake and internalization of 177 Luoctreotate was studied in primary cell cultures from two patients. Results. Quantitative PCR analysis showed expression of SSTR1 and SSTR2 in the majority of tumors, while SSTR3 – 5 were expressed at low levels. Immunohistochemical analysis confi rmed the presence of SSTR1 and SSTR2 proteins in all GISTs, and SSTR3 – 5 in a subset of tumors. Diagnostic imaging by SSTR scintigraphy, using 111 In-octreotide, demonstrated tumor uptake of 111 In in three of six GIST patients. Measurement of 111 In activity in excised tumor specimens from fi ve patients gave tumor-to-blood (T/B) activity ratios of between eight and 96. Tumor cells in primary culture (gastric and small intestinal GIST) specifi cally bound and internalized 177 Lu when incubated with the therapeutic compound 177 Lu-octreotate for 4 – 48 hours (p 0.05). Conclusion. Peptide receptor-mediated radiotherapy via SSTR may provide a novel treatment strategy in carefully selected GIST patients with TKI-resistant tumors.

A success rate of about 90% has been achieved after primary operations for hyperparathyroidism, compared with 60% to 80% in most series of secondary operations. The present reoperative series involved 29 patients who underwent venous catheterization with blood sampling for the determination of intact parathyroid hormone before undergoing repeat parathyroid surgery. Blood samples were taken from the internal jugular veins, innominate veins, and superior caval vein. No attempt was made to perform superselective catheterization of the small neck and mediastinal veins. The reoperations were done by four surgeons who did 1, 2, 13, and 13 of the reoperations, respectively. In all patients, distinct step-ups in parathyroid hormone concentrations were found. On average, the gradient between the highest and lowest value was about 5. Close to the location of the step-ups, diseased parathyroid tissue was found in 27 of the patients. In two cases no parathyroid tissue was found, and these patients remained hyperparathyroid postoperatively. They had been treated by the surgeon who did only two of the operations. When the step-up was observed in the left innominate vein, we could not differentiate mediastinal from low cervical adenomas. No patient developed hypoparathyroidism. To avoid this complication, autotransplantation of diseased parathyroid tissue into the abdominal subcutaneous fat was done in nine patients. No case of recurrent laryngeal nerve paralysis occurred. The introduction of reliable assays for the analysis of parathyroid hormone can make selective catheterization unnecessary when localizing remaining parathyroid glands in patients with persistent hyperparathyroidism.

Brown adipose tissue (BAT) has profound effects on body weight and metabolism in rodents. Recent reports show that human adults have significant amounts of BAT. Our aim was to study the gene expression profile of human BAT. Biopsies of adipose tissue with brown-red color and subcutaneous white adipose tissue (WAT) were obtained from 24 patients undergoing surgery in the thyroid region. Intrascapular BAT and epididymal WAT biopsies were obtained from 10 mice. Expression was analyzed by DNA microarray, real-time PCR and immunohistochemistry. Using the expression of the brown adipocyte-specific gene uncoupling protein 1 (UCP1) as a marker, approximately half of the human brown-red adipose tissue biopsies taken in the thyroid region contained BAT, and the presence of cells with brown adipocyte morphology was also verified by histology. Microarray analysis of 9 paired human BAT and WAT samples showed that 17 genes had at least a 4-fold higher expression in BAT compared to WAT and five of them (CKMT1, KCNK3, COBL, HMGCS2, TGM2) were verified using real-time PCR (P

LBA1 Background: Adjuvant IM administered for 12 months (mos) after surgery improves recurrence-free survival (RFS) of patients (pts) diagnosed with operable GIST. We compared 12 vs 36 mos of adjuvant IM as treatment of pts with a high risk for GIST recurrence after surgery. Methods: Pts with histologically diagnosed KIT-positive GIST were entered to this prospective, open-label, multicenter, randomized Phase III study (identifier NCT00116935 ). The risk of recurrence was estimated according to the modified Consensus Criteria. The primary objective was RFS. The secondary objectives included survival (OS) and treatment safety. The key exclusion criteria were ECOG PS >2, metastatic or inoperable GIST, and >12 wks from surgery to the study entry. IM was administered orally 400 mg/d. The sample size (n =200 in each group to obtain ≥110 events) was estimated by simulating log-rank tests assuming an overall hazard ratio (HR) of 0.44, a 20% drop-out rate, 2-sided type-I error rate of .05 and power 0.80. Analysis was based on the intention-to-treat population (ITT). Tumor histology was centrally reviewed. Results: 400 pts were entered to the study from Feb 2004 to Sep 2008. Three pts were excluded due to lack of consent from the ITT, which includes 15 pts who did not have GIST at a central review. The median FU time was 54 mos. RFS was longer in the 36-mo group compared to the 12-mo group (HR 0.46, 95% CI 0.32-0.65; p

10087 Background: The tyrosine kinase inhibitor (TKI) imatinib is the first-line palliative treatment inhibiting mutated KIT. Our aim was to compare the survival of patients only surgically treated...

AN investigation of the spectra mentioned above has been undertaken with a water-cooled hollow cathode of Schuler type with helium filling. The break-off in the CuH-band λ4280 found by Schuler and Gollnow is unique, and does not appear in any of the spectra of the above-mentioned metals. The experimental results show that the interpretation given by Herzberg and Mundie is correct.