The prognostic and predictive value of sstr2-immunohistochemistry and sstr2-targeted imaging in neuroendocrine tumors.

PURPOSE: Our aim was to assess the prognostic and predictive value of somatostatin receptor 2 (sstr2) in neuroendocrine tumors (NETs). METHODS: We established a tissue microarray and imaging database from NET patients that received sstr2-targeted radiopeptide therapy with yttrium-90-DOTATOC, lutetium-177-DOTATOC or alternative treatment. We used univariate and multivariate analyses to identify prognostic and predictive markers for overall survival, including sstr2-imaging and sstr2-immunohistochemistry. RESULTS: We included a total of 279 patients. In these patients, sstr2-immunohistochemistry was an independent prognostic marker for overall survival (HR: 0.82, 95 % CI: 0.67 - 0.99, n = 279, p = 0.037). In DOTATOC patients, sstr2-expression on immunohistochemistry correlated with tumor uptake on sstr2-imaging (n = 170, p < 0.001); however, sstr2-imaging showed a higher prognostic accuracy (positive predictive value: +27 %, 95 % CI: 3 - 56 %, p = 0.025). Sstr2-expression did not predict a benefit of DOTATOC over alternative treatment (p = 0.93). CONCLUSIONS: Our results suggest sstr2 as an independent prognostic marker in NETs. Sstr2-immunohistochemistry correlates with sstr2-imaging; however, sstr2-imaging is more accurate for determining the individual prognosis.

Towards tailored radiopeptide therapy.

PURPOSE: Somatostatin receptor-targeted radiopeptide therapy is commonly performed using single radioisotopes. We evaluated the benefits and harms of combining radioisotopes in radiopeptide therapy in patients with neuroendocrine tumor. METHODS: Using multivariable-adjusted survival analyses and competing risk analyses we evaluated outcomes in patients with neuroendocrine tumor receiving (90)Y-DOTATOC, (177)Lu-DOTATOC or their combination. RESULTS: (90)Y-DOTATOC plus (177)Lu-DOTATOC treatment was associated with longer survival than (90)Y-DOTATOC (66.1 vs. 47.5 months; n = 1,358; p < 0.001) or (177)Lu-DOTATOC alone (66.1 vs. 45.5 months; n = 390; p < 0.001). (177)Lu-DOTATOC was associated with longer survival than (90)Y-DOTATOC in patients with solitary lesions (HR 0.3, range 0.1 - 0.7; n = 153; p = 0.005), extrahepatic metastases (HR 0.5, range 0.3 - 0.9; n = 256; p = 0.029) and metastases with low uptake (HR 0.1, range 0.05 - 0.4; n = 113; p = 0.001). (90)Y-DOTATOC induced higher hematotoxicity rates than combined treatment (9.5% vs. 4.0%, p = 0.005) or (177)Lu-DOTATOC (9.5 vs. 1.4%, p = 0.002). Renal toxicity was similar among the treatments. CONCLUSIONS: Using (90)Y and (177)Lu might facilitate tailoring radiopeptide therapy and improve survival in patients with neuroendocrine tumors.

Somatostatin-based radiotherapy with [90Y-DOTA]-TOC in neuroendocrine tumors: long-term outcome of a phase I dose escalation study.

BACKGROUND: We describe the long-term outcome after clinical introduction and dose escalation of somatostatin receptor targeted therapy with [90Y-DOTA]-TOC in patients with metastasized neuroendocrine tumors. METHODS: In a clinical phase I dose escalation study we treated patients with increasing [90Y-DOTA]-TOC activities. Multivariable Cox regression and competing risk regression were used to compare efficacy and toxicities of the different dosage protocols. RESULTS: Overall, 359 patients were recruited; 60 patients were enrolled for low dose (median: 2.4 GBq/cycle, range 0.9-7.8 GBq/cycle), 77 patients were enrolled for intermediate dose (median: 3.3 GBq/cycle, range: 2.0-7.4 GBq/cycle) and 222 patients were enrolled for high dose (median: 6.7 GBq/cycle, range: 3.7-8.1 GBq/cycle) [90Y-DOTA]-TOC treatment. The incidences of hematotoxicities grade 1-4 were 65.0%, 64.9% and 74.8%; the incidences of grade 4/5 kidney toxicities were 8.4%, 6.5% and 14.0%, and the median survival was 39 (range: 1-158) months, 34 (range: 1-118) months and 29 (range: 1-113) months. The high dose protocol was associated with an increased risk of kidney toxicity (Hazard Ratio: 3.12 (1.13-8.59) vs. intermediate dose, p = 0.03) and a shorter overall survival (Hazard Ratio: 2.50 (1.08-5.79) vs. low dose, p = 0.03). CONCLUSIONS: Increasing [90Y-DOTA]-TOC activities may be associated with increasing hematological toxicities. The dose related hematotoxicity profile of [90Y-DOTA]-TOC could facilitate tailoring [90Y-DOTA]-TOC in patients with preexisting hematotoxicities. The results of the long-term outcome suggest that fractionated [90Y-DOTA]-TOC treatment might allow to reduce renal toxicity and to improve overall survival. (ClinicalTrials.gov number NCT00978211).

The impact of 18F-FDG PET on the management of patients with suspected large vessel vasculitis.

PURPOSE: We aimed to assess the impact of (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) on the management of patients with suspected large vessel vasculitis. METHODS: An international expert panel determined diagnoses and clinical management in patients with suspected large vessel vasculitis, with and without the results of (18)F-FDG PET, respectively. The accuracy of the clinical diagnosis and the resulting clinical management with and without the (18)F-FDG PET results were compared using logistic regression models. RESULTS: The analysis included 30 patients referred to a tertiary care centre with large vessel vasculitis and 31 controls. (18)F-FDG PET had an overall sensitivity of 73.3% [95% confidence interval (CI) 54.1-87.7%], a specificity of 83.9% (95% CI 66.3-94.5%), a positive predictive value of 81.5% (95% CI 61.9-93.7%) and a negative predictive value of 76.5% (95% CI 58.8-89.3%). The diagnostic accuracy of (18)F-FDG PET was higher in patients not receiving immunosuppressive drugs (93.3 vs 64.5%, p = 0.006). Taken in context with other available diagnostic modalities, the addition of (18)F-FDG PET increased the clinical diagnostic accuracy from 54.1 to 70.5% (p = 0.04). The addition of (18)F-FDG PET increased the number of indicated biopsies from 22 of 61 patients (36.1%) to 25 of 61 patients (41.0%) and changed the treatment recommendation in 8 of 30 patients (26.7%) not receiving immunosuppressive medication and in 7 of 31 patients (22.6%) receiving immunosuppressive medication. CONCLUSION: (18)F-FDG PET is a sensitive and specific imaging tool for large vessel vasculitis, especially when performed in patients not receiving immunosuppressive drugs. It increases the overall diagnostic accuracy and has an impact on the clinical management in a significant proportion of patients.

Peptide receptor radionuclide therapy with Y-DOTATOC and (177)Lu-DOTATOC in advanced neuroendocrine tumors: results from a Danish cohort treated in Switzerland.

AIM: Limited therapeutic options have highlighted the demand for new treatment modalities for patients with advanced neuroendocrine tumors (NET). Promising results of initial studies have warranted the implementation of peptide receptor radionuclide therapy (PRRT) in clinical practice. However, this treatment option still needs clinical evaluation. METHODS: In this study, we evaluated the PRRT treatment response of 69 Danish patients with NET mainly originating from the gastroenteropancreatic system. Fifty-six patients (81%) were referred for PRRT to the Department of Nuclear Medicine, University Hospital Basel, Switzerland, between 2004 and 2008 due to progression assessed by the referring physicians. However, when retrospectively evaluated, only 42 of the 69 patients (61%) had progression according to RECIST (Response Evaluation Criteria in Solid Tumors). Most patients were treated with 9°Y-DOTATOC. RESULTS: Based on RECIST, a complete response was observed in 5 patients (7.4%), a partial response in 11 patients (16.2%) and stable disease in 42 patients (61.8%). Progressive disease after completed therapy was observed in 10 patients (14.7%). The median progression-free survival was 29 months (95% CI: 22-36 months). Pancreatic NET seemed to respond better to PRRT than small intestinal carcinoid tumors (p = 0.03). The overall frequency of serious adverse events was low. CONCLUSION: Implementation of PRRT in clinical routine has provided a valuable new therapeutic option for the treatment of advanced NET. We suggest that PRRT may advance from second- or third-line to first- or second-line therapy in inoperable/unresectable NET patients.

Predictors of impaired heart rate recovery: a myocardial perfusion SPECT study.

BACKGROUND: Heart rate recovery (HRR) is an established prognostic predictor. However, a number of methodological issues have not been fully explored, including differences in HRR 1 versus 2 min after exercise termination, absolute versus relative HRR, and the impact of beta-blockers. DESIGN: Cross-sectional study. METHODS: Predictors of impaired absolute and relative HRR 1 (HRR-1, HRR-1%) and 2 min after exercise termination (HRR-2, HRR-2%), defined as their lowest quartiles, were assessed in 1667 patients undergoing cycle exercise myocardial perfusion single photon emission computed tomography, and measures of HRR were compared between patients undergoing myocardial perfusion single photon emission computed tomography with continued, discontinued, and without beta-blockers. RESULTS: Higher resting heart rate was an independent predictor of all measures of impaired HRR (P<0.001 for all). Lower peak heart rate was independently associated with impaired HRR-1, HRR-2, and HRR-2% (P<0.001 for all) but not HRR-1%. Higher summed rest score as a marker of scar and in part left ventricular dysfunction was an independent predictor of impaired HRR-1 (P = 0.010) and HRR-1% (P = 0.025) but not HRR-2 and HRR-2%, whereas lower stroke volume index was an independent predictor of slow HRR-2 (P = 0.004) and HRR-2% (P = 0.02) but not HRR-1 and HRR-1%. HRR-1 (P = 0.98) and HRR-2 (P = 0.86) were similar in patients with continued, discontinued, and without beta-blocker therapy. In contrast, HRR-1% (P = 0.01) and HRR-2% (P = 0.001) were faster in patients on beta-blockers than in the other groups. CONCLUSION: HRR-1 and HRR-2 as well as HRR-1% and HRR-2% reflect different pathophysiological processes. Relative but not absolute measures of HRR seem to be enhanced under beta-blockers.

Neoadjuvant targeting of glioblastoma multiforme with radiolabeled DOTAGA-substance P--results from a phase I study.

Complete surgical resection beyond tumor margins cannot be achieved in glioblastoma multiforme (GBM) because of infiltrative nature. In several cancers, neoadjuvant treatment has been implemented to reduce the risk of tumor cell spreading during resection. In GBM, the objective of a neoadjuvant approach is reduction of tumor cells within the main tumor mass and beyond in the infiltration zone. Such an approach can only be performed if elevated intracranial pressure can be medically controlled. In a previous study with recurrent gliomas, we showed that local intratumoral injection of radiolabeled DOTAGA-substance P substantially inhibited further growth and led to radionecrotic transformation of the tumor (CCR 2006). We have now examined this modality as neoadjuvant treatment for GBM, primarily assessing feasibility, toxicity, the extent of resection, and functional outcome. After diagnosis of GBM, 17 patients were included in a prospective phase I study. Repetitive intratumoral injections of radiolabeled DOTAGA-substance P were performed, followed by surgical resection. Chemical synthesis, radiolabeling, and local injection of the peptidic vector [90Yttrium]-DOTAGA-substance P were described previously. Neoadjuvant injection of [90Y]-DOTAGA-substance P was feasible without decompensation of intracranial pressure. Prolonged application of corticosteroids was identified as the main risk factor for side effects. Fifteen patients stabilized or improved their functional status. The mean extent of resection in subsequent surgery was 96%. Neoadjuvant therapy of GBM using locally injected radiolabeled DOTAGA-substance P was feasible and of low toxicity. The high extent of resection and concomitant irradiation of tumor cells in the infiltration zone may be prognostically relevant.

Interrelation of ST-segment depression during bicycle ergometry and extent of myocardial ischaemia by myocardial perfusion SPECT.

PURPOSE: The aim of this study was to compare ST-segment depression (STD) during bicycle ergometry and extent of myocardial ischaemia assessed by myocardial perfusion SPECT (MPS) in a large patient cohort. METHODS: Consecutive patients (n = 955) referred for MPS with bicycle ergometry and interpretable stress ECG were evaluated with respect to ECG and MPS findings of ischaemia. The maximal STD was recorded and exercise ECG was considered ischaemic if STD was horizontal or downsloping (>or=1 mm). MPS was interpreted using a 20-segment model with a scale of 0 to 4. A summed stress (SSS), summed rest (SRS) and summed difference score (SDS = SSS-SRS, e.g. extent of ischaemia) were derived. Ischaemia was defined as an SDS >or= 2. RESULTS: An exercise-induced STD was present in 215 patients (22%) and myocardial ischaemia on MPS was present in 366 patients (38%). The extent of ST-segment depression and the number of ECG leads with significant STD were each strongly and significantly associated with increasing severity of ischaemia and the number of coronary territories involved (p < 0.01 for all correlations). CONCLUSION: These data demonstrate a strong correlation between the extent of STD, number of ischaemic leads and severity of myocardial ischaemia as assessed by MPS during bicycle ergometry.

In vitro characterization of (177)Lu-radiolabelled chimeric anti-CD20 monoclonal antibody and a preliminary dosimetry study.

PURPOSE: (131)I- and (90)Y-labelled anti-CD20 antibodies have been shown to be effective in the treatment of low-grade, B-cell non-Hodgkin's lymphoma (NHL). However, the most appropriate radionuclide in terms of high efficiency and low toxicity has not yet been established. In this study we evaluated an immunoconjugate formed by the anti-CD20 antibody rituximab and the chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid). DOTA-rituximab was prepared as a kit formulation and can be labelled in a short time (<20 min) with either (177)Lu or (90)Y. MATERIALS AND METHODS: Immunoconjugates with different numbers of DOTA molecules per rituximab were prepared using p-SCN-Bz-DOTA. In vitro immunoreactivity and stability were tested and preliminary dosimetric results were acquired in two patients. RESULTS: The immunological binding properties of DOTA-rituximab to the CD20 antigen were found to be retained after conjugation with up to four chelators. The labelled product was stable against a 10(5) times excess of diethylenetriaminepentaacetic acid (DTPA, 37 degrees C, 7 days). Two patients with relapsed NHL were treated with 740 MBq/m(2) body surface (177)Lu-DOTA-rituximab. Scintigraphic images showed specific uptake at tumour sites and acceptable dosimetric results. The mean whole-body dose was found to be 314 mGy. The administration of (177)Lu-DOTA-rituximab was tolerated well. CONCLUSION: Our results show that DOTA-rituximab (4:1) can be labelled with (177)Lu with sufficient stability while the immunoconjugate retains its immunoreactivity. (177)Lu-DOTA-rituximab is an interesting, well-tolerated radiolabelled antibody with clinical activity in a low dose range, and provides an approach to the efficient treatment with few side effects for patients with relapsed NHL.

Response to [90Yttrium-DOTA]-TOC treatment is associated with long-term survival benefit in metastasized medullary thyroid cancer: a phase II clinical trial.

PURPOSE: We aimed to explore the efficacy of (90)Yttrium-1,4,7,10-tetra-azacyclododecane N,N',N'',N-'''-tetraacetic acid ((90)Y-DOTA)-Tyr(3)-octreotide (TOC) therapy in advanced medullary thyroid cancer. EXPERIMENTAL DESIGN: In a phase II trial, we investigated the response, survival, and long-term safety profile of systemic [(90)Y-DOTA]-TOC treatment in metastasized medullary thyroid cancer. Adverse events were assessed according to the criteria of the National Cancer Institute. Survival analyses were done using multiple regression models. RESULTS: Thirty-one patients were enrolled. A median cumulative activity of 12.6 GBq (range, 1.7-29.6 GBq) of [(90)Y-DOTA]-TOC was administered. Response was found in nine patients (29.0%). Four patients (12.9%) developed hematologic toxicities and seven patients (22.6%) developed renal toxicities. Response to treatment was associated with longer survival from time of diagnosis (hazard ratio, 0.20; 95% confidence interval, 0.05-0.81; P = 0.02) and from time of first [(90)Y-DOTA]-TOC therapy (hazard ratio, 0.16; 95% confidence interval, 0.04-0.63; P = 0.009). The visual grade of scintigraphic tumor uptake was not associated with treatment response or survival. CONCLUSIONS: Response to [(90)Y-DOTA]-TOC therapy in metastasized medullary thyroid cancer is associated with a long-term survival benefit. Treatment should be considered independently from the result of the pretherapeutic scintigraphy.

The dental safety profile of high-dose radioiodine therapy for thyroid cancer: long-term results of a longitudinal cohort study.

UNLABELLED: The long-term dental safety profile of high-dose radioiodine therapy remained elusive despite more than 6 decades of clinical use. METHODS: In a cohort study, we investigated the incidence of sialadenitis, xerostomia, caries, and tooth extractions after high-dose radioiodine therapy for differentiated thyroid cancer and explored risk factors by multiple regression models. RESULTS: One hundred seventy-six participants were recruited (median follow-up, 6.6 y; range, 1.1-32.6 y; patient-years: 8,472 before and 1,421 after radioiodine therapy). Scintigraphic salivary gland uptake during radioiodine treatment predicted development of sialadenitis (odds ratio: 1.31 [1.05-1.63], P = 0.015) and xerostomia (odds ratio: 1.58 [1.16-2.16], P = 0.004). The caries risk increased by postradioiodine xerostomia (% increase: 98.8 [26.5-212], P = 0.003). The long-term risk for postradioiodine tooth extractions increased with increasing cumulative radioiodine activities (% increase [per gigabequerel]: 8.14 [1.07, 15.7], P = 0.02). CONCLUSION: High-dose radioiodine treatment can impair the long-term dental health, depending on the cumulative radioiodine activity and individual salivary gland radioiodine uptake.

Predictors and prognostic impact of silent coronary artery disease in asymptomatic high-risk patients with diabetes mellitus.

AIMS: Evaluation of predictors of silent coronary artery disease (SCAD) in high-risk asymptomatic diabetic patients and to evaluate their two-year outcome. METHODS AND RESULTS: Four hundred diabetic patients without prior CAD but at high CAD risk underwent myocardial perfusion scintigraphy (MPS) in this prospective multicentre outcome trial. MPS were abnormal in 22% of patients. Male sex (OR 2.223, 1.152-4.290; p=0.017), diabetes duration (OR 1.049,1.015-1.085; p=0·005), peripheral artery disease (OR 2.134, 1·150-3.961; p=0.016), smoking (OR 2.064, 1.109-3.839; p=0·022), systolic blood pressure (OR 1.014, 1.00-1.03, p=0·056), brain natriuretic peptide (OR 1.002, 1.001-1.004, p=0·005) independently predicted an abnormal MPS: if <2 and >3 predictors were present, 3.2% and 47% patients had an abnormal MPS, respectively (p<0·001). Two-year major adverse cardiac event rates increased from 2·9% to 14·6%, cardiac death rates from 0·6% to 4·1% in patients with summed stress scores ≤10 and >10%, respectively (each p<0.045). CONCLUSIONS: Male sex, diabetes duration, peripheral artery disease, smoking, elevated systolic blood pressure and increased brain-natriuretic peptides independently predicted SCAD. In presence of >3 predictors, almost 50% of patients had an abnormal MPS. They may benefit from screening by MPS since the extent of the MPS abnormality discriminated clearly between a favourable compared to a bad 2-year outcome. However, even highest risk patients without objective evidence of CAD had a benign prognosis without need for specific evaluation or therapy. TRIAL REGISTRATION NUMBER: ISRCTN87953632.

Diabetes Mellitus and Its Effects on All-Cause Mortality After Radiopeptide Therapy for Neuroendocrine Tumors.

We aimed to assess the risk of developing diabetes mellitus and its effects on all-cause mortality after radiopeptide therapy for neuroendocrine tumors (NETs). METHODS: NET patients received somatostatin radiopeptide therapy with 90Y-DOTATOC or 177Lu-DOTATOC. The incidence of diabetes mellitus and its mortality were assessed using univariate and multivariate regression. RESULTS: Overall, 1,535 NET patients were enrolled and received 3,807 treatment cycles. After treatment, 72 patients developed diabetes mellitus, including 47 cases after 90Y-DOTATOC and 25 cases after combined treatment. The diabetes mellitus risk was higher before than after DOTATOC (estimate, 0.0032; P < 0.001), and overall survival was similar in patients with and without diabetes mellitus (hazard ratio, 1.13; 95% confidence interval, 0.91-1.39; n = 1,535; P = 0.27). CONCLUSION: Radiopeptide therapy does not appear to increase the risk of developing diabetes mellitus in NET patients, whereas diabetes mellitus does not appear to increase the mortality of NET patients undergoing receptor-targeted radiopeptide therapy.

Peptide Receptor Radionuclide Therapy Outcomes in a North American Cohort With Metastatic Well-Differentiated Neuroendocrine Tumors.

OBJECTIVES: The objective of this study was to describe the outcomes of patients in the University of Iowa Neuroendocrine Tumor (NET) Database treated with peptide receptor radionuclide therapy (PRRT). METHODS: One hundred thirty-five patients from the University of Iowa NET Database who received PRRT were analyzed, their characteristics were described, and survival was calculated. RESULTS: The median age at diagnosis was 51 years, and 64% were men. The primary tumor was located in the small bowel (SBNET) in 37.8%, in the pancreas (PNET) in 26.0%, in the lung in 13.3%, in unknown primary in 9.6%, and in other sites in 13.3%. A radiographic response of any magnitude was observed in 65.8%, 11.1% had a mixed response, and 15.4% showed progression. The overall survival (OS) from the first PRRT was 40 months, and the median time to progression was 23.9 months. Higher pretreatment chromogranin A and pancreastatin levels predicted inferior OS. CONCLUSIONS: Peptide receptor radionuclide therapy resulted in a relatively long OS and time to progression in heavily pretreated North American patients with advanced NETs. Elevated pretreatment chromogranin A and pancreastatin predicted shorter OS after therapy. Peptide receptor radionuclide therapy is a valuable treatment option in patients with advanced NETs, especially SBNETS.

Extraction of high-integrity RNA suitable for microarray gene expression analysis from long-term stored human thyroid tissues.

INTRODUCTION: Isolation of high-quality RNA from fresh-frozen thyroid tissues stored for more than a decade would open novel options for gene expression profiling. Herein, we describe successful extraction of high-integrity RNA from human thyroid tissues that were stored for more than a decade. METHODS: Seventy-nine samples (15 goitres, 20 follicular adenomas, 30 papillary carcinomas, 14 follicular carcinomas) that were shock-frozen in isopentane and stored for a median of 11 years (range 1-16 years) were processed using standard precipitation and column filtration techniques. RNA integrity was assessed by electrophoresis using the RNA integrity number (RIN) algorithm and by gene expression profiling determining the 3'/5' ratio of the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene and the percentage of transcripts detected on the Affymetrix U133 2.0 human genome GeneChip. RESULTS: The median RNA yield was 1.9 microg/mg tissue (papillary carcinoma 2.1 microg/mg, range 0.2-7.2 microg/mg; follicular carcinoma 2.4 microg/mg, range 0.2-3.2 microg/mg; goitre 1.4 microg/mg, range 0.1-5.4 microg/mg; follicular adenoma 1.6 microg/mg, range 0.1-6.2 microg/mg; p = 0.46) with an 8.6 (7.3-9.8) median RIN. The median GAPDH gene 3'/5' ratio was 1.43 (1.34-1.52) and the median percentage of present calls was 48.1% (42.7-52.0%). CONCLUSIONS: Age and entity independent RNA suitable for expression profiling can be extracted from long-term stored fresh-frozen human thyroid tissues.

Survival after somatostatin based radiopeptide therapy with (90)Y-DOTATOC vs. (90)Y-DOTATOC plus (177)Lu-DOTATOC in metastasized gastrinoma.

We aimed to explore the effects of (90)Y-DOTATOC and (90)Y-DOTATOC plus (177)Lu-DOTATOC on survival of patients with metastasized gastrinoma. Patients with progressive metastasized gastrinoma were treated with repeated cycles of (90)Y-DOTATOC or with cycles alternating between (90)Y-DOTATOC and (177)Lu-DOTATOC until tumor progression or permanent toxicity. Multivariable Cox regression analyses were used to study predictors of survival. A total of 36 patients were enrolled; 30 patients received (90)Y-DOTATOC (median activity per patient 11.8GBq; range: 6.1-62.2GBq) and 6 patients received (90)Y-DOTATOC plus (177)Lu-DOTATOC (median activity per patient: 14.8GBq; range: 7.4-14.8GBq). Response was found in 26 patients (72.2%), including morphological (n=12, 33.3%), biochemical (n=14, 38.9%) and/or clinical response (n=6, 16.2%). A total of 21 patients (58.3%) experienced hematotoxicity grade 1/2, while 1 patient (2.8%) experienced hematotoxicity grade 3; no grade 4 hematotoxicity occurred. Furthermore, 2 patients (5.6%) developed grade 4 renal toxicity; no grade 5 renal toxicity occurred. Responders had a significantly longer median survival from time of enrollment than non-responders (45.1 months, range: 37.1-53.1 months vs. 12.6 months, range: 11.0-14.2, hazard ratio: 0.12 (0.027-0.52), p=0.005). Additionally, there was a trend towards longer median survival with (90)Y-DOTATOC plus (177)Lu-DOTATOC as compared to (90)Y-DOTATOC alone (60.2 months, range: 19.8-100.6 months vs. 27.0 months, range: 4.0-50.0, hazard ratio: 0.21 (0.01-3.98), p=0.16). Response to (90)Y-DOTATOC and (90)Y-DOTATOC plus (177)Lu-DOTATOC therapy is associated with a longer survival in patients with metastasized gastrinoma. Both treatment regimens are promising tools for management of progressive gastrinoma.

Somatostatin receptor-targeted radiopeptide therapy with 90Y-DOTATOC and 177Lu-DOTATOC in progressive meningioma: long-term results of a phase II clinical trial.

UNLABELLED: Meningiomas express members of the somatostatin receptor family. The present study assessed the long-term benefits and harm of somatostatin-based radiopeptide therapy in meningioma patients. METHODS: Patients with progressive unresectable meningioma were treated with (90)Y-DOTATOC and (177)Lu-DOTATOC until tumor progression or permanent toxicity occurred. Multivariable Cox regression analyses were used to study predictors of survival. RESULTS: Overall, 74 treatment cycles were performed on 34 patients. Stable disease was achieved in 23 patients. Severe hematotoxicity occurred in 3 patients, and severe renal toxicity in 1 patient. Mean survival was 8.6 y from the time of recruitment. Stable disease after treatment (hazard ratio, 0.017 vs. progressive disease; 95% confidence interval, 0.001-0.35; n = 34; P = 0.01) and high tumor uptake (hazard ratio, 0.046 vs. intermediate or low tumor uptake; 95% confidence interval, 0.004-0.63; n = 34; P = 0.019) were associated with longer survival. CONCLUSION: (90)Y-DOTATOC and (177)Lu-DOTATOC are promising tools for treating progressive unresectable meningioma, especially in cases of high tracer uptake in the tumor.

Evidence for left ventricular remodeling after percutaneous coronary intervention: effect of percutaneous coronary intervention on left ventricular ejection fraction and volumes.

BACKGROUND: Post-stress ejection fraction (EF), end-diastolic (EDV) and end-systolic (ESV) volumes by gated myocardial perfusion SPECT (MPS) are well validated, reproducible and of prognostic significance. However, little is known about the impact of percutaneous coronary intervention (PCI) on left ventricular volumes and remodeling. METHODS: Thirty-eight patients who underwent MPS before and 6 months after PCI were evaluated. MPS were interpreted deriving summed stress (SSS), rest (SRS) and difference (SDS = SSS-SRS; extent of ischemia) scores. EF, EDV and ESV were generated by QGS trade mark. Pre-PCI MPS were compared to post-PCI MPS. RESULTS: Single vessel disease was present in 63% of patients. PCI of one vessel was performed in 82% of patients. After 6 months, SSS (10.6 +/- 6.3 vs. 2.8 +/- 4.3, p < 0.001) and SDS (8.2 +/- 5.6 vs. 1.4 +/- 2.3, p < 0.001) had improved; however, EF did not change significantly (55 +/- 10 vs. 57 +/- 13, p = ns). Still, EDV (105 +/- 25 ml vs. 96 +/- 25 ml, p = 0.006) and ESV (49 +/- 19 ml vs. 41 +/- 18 ml, p = 0.001) were significantly reduced. CONCLUSION: Results of MPS documented the beneficial effect of PCI on symptoms and extent of ischemia. In addition, the findings showed a significant decrease in ESV and EDV after PCI as compared to pre-PCI findings which points to a positive effect on left ventricular remodeling even in the absence of significant changes in EF.

Progression to overt or silent CAD in asymptomatic patients with diabetes mellitus at high coronary risk: main findings of the prospective multicenter BARDOT trial with a pilot randomized treatment substudy.

OBJECTIVES: The purpose of this study was to evaluate prevalence, progression, treatment, and outcome of silent coronary artery disease (CAD) in asymptomatic patients with diabetes (DM) at high coronary risk. BACKGROUND: Despite the close association of diabetes and CAD, general CAD screening in asymptomatic patients with DM is discouraged even though outcome data in patients at high coronary risk are lacking. METHODS: Prospective multicenter outcome study-with a pilot randomized treatment substudy. The study comprised 400 asymptomatic patients with DM (type 2) without history or symptoms of CAD at high CAD risk. They underwent clinical evaluation and myocardial perfusion single-photon emission computed tomography (MPS) at baseline and after 2 years. Patients with normal MPS received usual care; those with abnormal MPS received medical or combined invasive and medical management. RESULTS: An abnormal MPS was found in 87 of 400 patients (22%). In patients with normal MPS, MACE occurred in 2.9% and ischemia or new scar in 3.2%. Patients with abnormal MPS had more MACE (9.8%; hazard ratio: 3.44; 95% confidence interval [CI]: 1.32 to 8.95; p = 0.011) and ischemia or new scar (34.2%; odds ratio: 15.91; 95% CI: 7.24 to 38.03; p < 0.001) despite therapy, resulting in "overt or silent CAD progression" of 35.6% versus 4.6% (odds ratio: 11.53; 95% CI: 5.63 to 24.70; p < 0.001). Patients with abnormal MPS randomized to medical versus invasive-medical strategies had similar event rates (p = 0.215), but more ischemic or new scar findings (54.3% vs. 15.8%; p < 0.001). CONCLUSIONS: High-risk asymptomatic patients with DM and normal MPS (78%) have a low rate of first manifestations of CAD. Patients with abnormal MPS at baseline (22%) have a 7-fold higher rate of progression to "overt or silent CAD," despite therapy. Randomized patients' outcomes suggest that a combined invasive and medical strategy for silent CAD may reduce scintigraphic but not symptomatic CAD progression versus medical therapy alone. (Trial of Invasive versus Medical therapy of Early coronary artery disease in Diabetes Mellitus ISRCTN87953632).