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To date, several papers have been published about prostate-specific membrane antigen (PSMA)-based radioligand diagnostic and therapeutic approaches. This paper mainly provides information for nuclear medicine physicians that are clinically engaged in the diagnosis and treatment of prostate cancer patients. It aims to present the utility of PSMA imaging and therapy in a step-by-step practical approach; thus, it does not discuss radiochemistry and the molecular basics of PSMA.

Background Monocentric and retrospective studies indicate effectiveness of peptide receptor radionuclide therapy targeting somatostatin receptors of neuroendocrine neoplasms. We assessed overall and progression-free survival and adverse events of peptide receptor radionuclide therapy by a multi-institutional, board certified registry with prospective follow-up in five centres in Germany. Methods A total of 450 patients were included and followed for a mean of 24.4 months. Most patients had progressive low- or intermediate grade neuroendocrine neoplasms and 73% were pretreated with at least one therapy. Primary neuroendocrine neoplasms were mainly derived of pancreas (38%), small bowel (30%), unknown primary (19%) or bronchial system (4%). Patients were treated with Lutetium-177 in 54%, with Yttrium-90 in 17% and with both radionuclides in 29%. Overall and progression-free survival was determined with Kaplan–Meier curves and uni-variate log rank test Cox models. Findings Median overall survival of all patients was 59 (95% confidence interval [CI] 49–68.9) months. Overall survival was significantly inferior in the patients treated with Yttrium-90 solely (hazard ratio, 3.22; 95% CI, 1.83–5.64) compared to any peptide receptor radionuclide therapy with Lutetium-177. Grade II (hazard ratio, 2.06; 95% CI, 0.79–5.32) and grade III (hazard ratio, 4.22; 95% CI, 1.41–12.06) neuroendocrine neoplasms had significantly worse overall survival than grade I neuroendocrine neoplasms. Patients with small neuroendocrine neoplasms of small bowel had significantly increased survival (hazard ratio, 0.39; 95% CI, 0.18–0.87) compared to neuroendocrine neoplasms of other locations. Median progression-free survival was 41 (35.9–46.1) months and significantly inferior in patients treated with Yttrium solely (hazard ratio, 2.7; 95% CI, 1.71–4.55). Complete remission was observed in 5.6% of patients, 22.4% had a partial remission, 47.3% were stable and 4% were progressive as best response. Adverse events of bone marrow and kidney function higher than grade III occurred in 0.2–1.5% of patients. Interpretation These results indicate that peptide receptor radionuclide therapy is a highly effective therapy for patients with low to intermediate grade neuroendocrine neoplasms with minor adverse events.

Increasing evidence supports the value of peptide receptor radionuclide therapy (PRRT) in patients with metastatic neuroendocrine tumours (NET), but there are limited data on its specific efficacy in NET of small intestinal (midgut) origin. This study aims to define the benefit of PRRT with 177Lu-octreotate for this circumscribed entity derived by a uniformly treated patient cohort. A total of 61 consecutive patients with unresectable, advanced small intestinal NET G1–2 stage IV treated with 177Lu-octreotate (4 intended cycles at 3-month intervals, mean activity per cycle 7.9 GBq) were analysed. Sufficient tumour uptake on baseline receptor imaging and either documented tumour progression (n = 46) or uncontrolled symptoms (n = 15) were prerequisites for treatment. Response was evaluated according to modified Southwest Oncology Group (SWOG) criteria and additionally with Response Criteria in Solid Tumors (RECIST) 1.1. Assessment of survival was performed using Kaplan-Meier curves and Cox proportional hazards model for uni- and multivariate analyses. Toxicity was assessed according to standardized follow-up laboratory work-up including blood counts, liver and renal function, supplemented with serial 99mTc-diethylenetriaminepentaacetic acid (DTPA) clearance measurements. The median follow-up period was 62 months. Reversible haematotoxicity (≥ grade 3) occurred in five patients (8.2 %). No significant nephrotoxicity (≥ grade 3) was observed. Treatment response according to modified SWOG criteria consisted of partial response in 8 (13.1 %), minor response in 19 (31.1 %), stable disease in 29 (47.5 %) and progressive disease in 5 (8.2 %) patients. The disease control rate was 91.8 %. Median progression-free survival (PFS) and overall survival (OS) was 33 [95 % confidence interval (CI) 25–41] and 61 months (95 % CI NA), respectively. Objective response was associated with longer survival (p = 0.005). Independent predictors of shorter PFS were functionality [hazard ratio (HR) 2.1, 95 % CI 1.0–4.5, p = 0.05] and high plasma chromogranin A (CgA) levels > 600 ng/ml (HR 2.9, 95 % CI 1.5–5.5, p

The tumor proliferation marker, Ki-67 index, is a well-established prognostic marker in gastroenteropancreatic neuroendocrine neoplasms (NENs). Noninvasive molecular imaging allows whole-body metabolic characterization of metastatic disease. We investigated the prognostic impact of 18F-FDG PET in inoperable multifocal disease. Methods: Retrospective, dual-center analysis was performed on 89 patients with histologically confirmed, inoperable metastatic gastroenteropancreatic NENs undergoing 18F-FDG PET/CT within the staging routine. Metabolic (PET-based) grading was in accordance with the most prominent 18F-FDG uptake (reference tumor lesion): mG1, tumor-to-liver ratio of maximum standardized uptake value ≤ 1.0; mG2, 1.0–2.3; mG3, >2.3. Other potential variables influencing overall survival, including age, tumor origin, performance status, tumor burden, plasma chromogranin A (≥600 μg/L), neuron-specific enolase (≥25 μg/L), and classic grading (Ki-67–based) underwent univariate (log-rank test) and multivariate analysis (Cox proportional hazards model), with a P value of less than 0.05 considered significant. Results: The median follow-up period was 38 mo (95% confidence interval [CI], 27–49 mo); median overall survival of the 89 patients left for multivariate analysis was 29 mo (95% CI, 21–37 mo). According to metabolic grading, 9 patients (10.2%) had mG1 tumors, 22 (25.0%) mG2, and 57 (64.8%) mG3. On multivariate analysis, markedly elevated plasma neuron-specific enolase (P = 0.016; hazard ratio, 2.9; 95% CI, 1.2–7.0) and high metabolic grade (P = 0.015; hazard ratio, 4.7; 95% CI, 1.2–7.0) were independent predictors of survival. Conclusion: This study demonstrated the feasibility of prognostic 3-grade stratification of metastatic gastroenteropancreatic NENs by whole-body molecular imaging using 18F-FDG PET.

Outcome analyses for patients with gastroenteropancreatic neuroendocrine tumors (GEP NET) after peptide receptor radionuclide therapy (PRRT) are still limited, especially with regard to the impact of the Ki-67 index. Using a single-center analysis, we aimed to establish predictors of survival.We retrospectively analyzed a consecutive cohort of 74 patients who had metastatic GEP NET and underwent PRRT with (177)Lu-octreotate (mean activity of 7.9 GBq per cycle, aimed at 4 treatment cycles at standard intervals of 3 mo). Patients (33 with pancreatic NET and 41 with nonpancreatic GEP NET) had unresectable metastatic disease graded as G1 or G2 (G1/G2) and documented morphologic or clinical progression within less than 12 mo or uncontrolled disease under somatostatin analog treatment. Responses were evaluated according to modified Southwest Oncology Group criteria. Potential predictors of survival were analyzed with the Kaplan-Meier curve method (log-rank test) and multivariate analysis (P0.05).The response rates were 36.5% partial response, 17.6% minor response, 35.1% stable disease, and 10.8% progressive disease for the entire cohort; 54.5% partial response, 18.2% minor response, 18.2% stable disease, and 9.1% progressive disease for pancreatic NET; and 22.0% partial response, 17.1% minor response, 48.8% stable disease, and 12.2% progressive disease for nonpancreatic GEP NET. The median progression-free survival and overall survival were 26 mo (95% confidence interval, 18.3-33.7) and 55 mo (95% confidence interval, 48.8-61.2), respectively. Besides the Ki-67 index, a Karnofsky performance score of less than or equal to 70%, a hepatic tumor burden of greater than or equal to 25%, and a baseline plasma level of neuron-specific enolase of greater than 15 ng/mL independently predicted shorter overall survival (hazard ratio, 2.1-3.1). Patients with a Ki-67 index of greater than 10% still had median progression-free survival and overall survival of 19 and 34 mo, respectively.The results of this study demonstrated the favorable response and long-term outcome of patients with G1/G2 GEP NET after PRRT. Independent predictors of survival were the Ki-67 index, the patient's performance status (Karnofsky performance scale score), the tumor burden, and the baseline neuron-specific enolase level. Even patients with a Ki-67 index of greater than 10% seemed to benefit from PRRT, with a good response and a notable long-term outcome. We present the first evidence, to our knowledge, that even in patients with metastatic disease the distinction between G1 and G2-in particular, between G1 (Ki-67 index of 1%-2%) and low-range G2 (Ki-67 index of 3%-10%)-provides prognostic stratification.

Renal radiation during peptide receptor radionuclide therapy (PRRT) may result in glomerular damage, a potential reduction of glomerular filtration rate (GFR) and ultimately lead to renal failure. While reported PRRT nephrotoxicity is limited to data derived from serum creatinine-allowing only approximate estimates of GFR-the aim of this study is to accurately determine PRRT-induced long-term changes of renal function and associated risk factors according to state-of-the-art GFR measurement.Nephrotoxicity was analysed using (99m)Tc-diethylenetriaminepentaacetic acid (DTPA) clearance data of 74 consecutive patients with gastroenteropancreatic neuroendocrine tumours (GEP NET) undergoing PRRT with (177)Lu-octreotate. The mean follow-up period was 21 months (range 12-50) with a median of five GFR measurements per patient. The change of GFR was analysed by linear curve fit. Potential risk factors including diabetes mellitus, arterial hypertension, previous chemotherapy, renal impairment at baseline and cumulative administered activity were analysed regarding potential impact on renal function loss. In addition, Common Terminology Criteria for Adverse Events (CTCAE) v3.0 were used to compare nephrotoxicity determined by (99m)Tc-DTPA clearance versus serum creatinine.The alteration in GFR differed widely among the patients (mean -2.1 ± 13.1 ml/min/m(2) per year, relative yearly reduction -1.8 ± 18.9%). Fifteen patients (21%) experienced a mild (2-10 ml/min/m(2) per year) and 16 patients (22%) a significant (10 ml/min/m(2) per year) decline of GFR following PRRT. However, 11 patients (15%) showed an increase of10 ml/min/m(2) per year. Relevant nephrotoxicity according to CTCAE (grade ≥3) was observed in one patient (1.3%) with arterial hypertension and history of chemotherapy. Nephrotoxicity according to serum creatinine was discordant to that defined by GFR in 15% of the assessments and led to underestimation in 12% of patients. None of the investigated factors including cumulative administered activity contributed to the decline of renal function.Serious nephrotoxicity after PRRT with (177)Lu-octreotate is rare (1.3%). However, slight renal impairment (GFR loss2 ml/min/m(2) per year) can frequently (43%) be detected by (99m)Tc-DTPA clearance assessments. Cumulative administered activity of (177)Lu-octreotate is not a major determinant of renal impairment in our study.

Reported experience with systemic (131)I-metaiodobenzylguanidine ((131)I-MIBG) therapy of neuroendocrine tumors comprises different dosing schemes. The aim of this study was to assess the long-term outcome and toxicity of treatment with 11.1 GBq (300 mCi) of (131)I-MIBG per cycle.We performed a retrospective review of 31 patients with advanced metastatic neuroendocrine tumors (20 with carcinoid tumors and 11 with other tumors) treated with (131)I-MIBG. Treatment outcome was analyzed for patients with carcinoid tumors (the most common tumors in this study), and toxicity was analyzed for the entire patient cohort (n = 31). Treatment comprised 11.1 GBq (300 mCi) per course and minimum intervals of 3 mo. The radiographic response was classified according to modified Response Evaluation Criteria in Solid Tumors. Toxicity was determined according to Common Terminology Criteria for Adverse Events (version 3.0) for all laboratory data at regular follow-up visits and during outpatient care, including complete blood counts and hepatic and renal function tests. Survival analysis was performed with the Kaplan-Meier curve method (log rank test; P0.05).The radiographic responses in patients with carcinoid tumors comprised a minor response in 2 patients (10%), stable disease in 16 patients (80%; median time to progression, 34 mo), and progressive disease in 2 patients (10%). The symptomatic responses in patients with functioning carcinoid tumors comprised complete resolution in 3 of the 11 evaluable symptomatic patients (27%), partial resolution in 6 patients (55%), and no significant change in 11 patients. The median overall survival in patients with carcinoid tumors was 47 mo (95% confidence interval, 32-62), and the median progression-free survival was 34 mo (95% confidence interval, 13-55). Relevant treatment toxicities were confined to transient myelosuppression of grade 3 or 4 in 15.3% (leukopenia) and 7.6% (thrombocytopenia) of applied cycles and a suspected late adverse event (3% of patients), myelodysplastic syndrome, after a cumulative administered activity of 66.6 GBq. The most frequent nonhematologic side effect was mild nausea (grade 1 or 2), which was observed in 28% of administered cycles. No hepatic or renal toxicities were noted.Dose-intensified treatment with (131)I-MIBG at a fixed dose of 11.1 GBq (300 mCi) per cycle is safe and offers effective palliation of symptoms and disease stabilization in patients with advanced carcinoid tumors. The favorable survival and limited toxicity suggest that high cycle activities are suitable and that this modality may be used for targeted carcinoid treatment--either as an alternative or as an adjunct to other existing therapeutic options.

Distant metastasis has a negative impact on survival in differentiated thyroid carcinoma (DTC). The timing of this manifestation, however, is of unknown prognostic relevance. The aim of this retrospective study was to investigate the potential significance of discriminating synchronous versus metachronous distant metastases (SDM vs. MDM) for the outcome of patients with DTC.We retrospectively analyzed a consecutive cohort of n = 89 patients with distant metastases of DTC (43 with follicular, 46 with papillary DTC histology; mean age 52.6 ± 17.7 years) undergoing radioiodine treatment at our institution. All patients were treated with the same protocol consisting of ablative radioiodine therapy (RIT, 3.7 GBq) and one post-ablation treatment after 3 months (3.7-11.1 GBq). Further cycles of RIT were administered for recurrent, progressive or newly developed metastatic disease. We distinguished 2 types of distant metastases according to the time of manifestation: SDM (within ≤12 months after DTC diagnosis) and MDM (occurring12 months after diagnosis). Tumor-related survival was analyzed using the Kaplan-Meier method. Uni- and multivariate analyses including the Cox proportional hazards model were performed with a significance level of p 0.05.The mean follow-up period was 13.8 ± 1.2 years. SDM were present in 49 (55.1 %), MDM in 40 (44.9 %) patients. MDM were associated with shorter tumor-related survival (p = 0.002). 5-year and 10-year survival rates were 68.5 % and 34.8 % for MDM, and 84.3 % and 66.9 % for SDM, respectively. Within both age subgroups of45 and ≥45 years, SDM were also linked with longer survival. No effect on tumor-related survival was found for the co-variables sex, lymph node metastases and histologic type.Distinguishing synchronous from metachronous manifestation of distant metastases may add an important prognostic feature to risk stratification in DTC, as proven metachronous appearance is associated with impaired survival.

Lobar radioembolization (RE) of the liver can result in reduction in volume of the ipsilateral lobe as well as hypertrophy of the contralateral lobe. Theoretically, hypertrophy of the contralateral liver lobe after RE could increase the chance of a successful liver resection, especially in patients with limited liver function reserve. The aim of this preliminary study was to evaluate the early effects of RE with resin microspheres on the volumes of the liver lobes and spleen. We retrospectively investigated 24 patients (12 women, 44–78 years old) with different types of cancer and liver-dominant metastatic disease who had undergone RE of the liver with resin microspheres. Changes in the volumes of the liver lobes and spleen were quantified by CT before and about 4 to 8 weeks after treatment. Of the 24 patients, 17 suffered from metastases in both liver lobes (group A) and 7 had metastases only in the right liver lobe (group B). The patients in the group A underwent sequential treatment starting with the right liver lobe. The median administered dose was 1.75 GBq. RE was associated with a median increase in volume of the left liver lobe of 34 % (P

Previous radiation therapy of the liver is a contraindication for performing (90)Y microsphere radioembolization, and its safety after internal radiation exposure through peptide receptor radionuclide therapy (PRRT) has not yet been investigated.We retrospectively assessed a consecutive cohort of 23 neuroendocrine tumor (NET) patients with liver-dominant metastatic disease undergoing radioembolization with (90)Y microspheres as a salvage therapy after failed PRRT. Toxicity was recorded throughout follow-up and reported according to Common Terminology Criteria for Adverse Events (version 3). Radiologic (response evaluation criteria in solid tumors), biochemical, and symptomatic responses were investigated at 3 mo after treatment, and survival analyses were performed with the Kaplan-Meier method (log-rank test, P0.05).The median follow-up period after radioembolization was 38 mo (95% confidence interval, 18-58 mo). The mean previous cumulative activity of (177)Lu-DOTA-octreotate was 31.8 GBq. The mean cumulative treatment activity of (90)Y microspheres was 3.4 ± 2.1 GBq, administered to the whole liver in a single session (n = 8 patients), in a sequential lobar fashion (n = 10 patients), or to only 1 liver lobe (n = 5 patients). Only transient, mostly minor liver toxicity (no grade 4) was recorded. One patient (4.3%) developed a gastroduodenal ulcer (grade 2). The overall response rates for radiologic, biochemical, and symptomatic responses were 30.4%, 53.8%, and 80%, respectively. The median overall survival was 29 mo (95% confidence interval, 4-54 mo) from the first radioembolization session and 54 mo (95% confidence interval, 47-61 mo) from the first PRRT cycle. A tumor proliferation index Ki-67 greater than 5% predicted shorter survival (P = 0.007).Radioembolization is a safe and effective salvage treatment option in advanced NET patients with liver-dominant tumor burden who failed or reprogressed after PRRT. The lack of relevant liver toxicity despite high applied (90)Y activities and considerable previous cumulative activities of (177)Lu-octreotate is noteworthy and disputes internal radiation exposure by PRRT as a toxicity risk factor in subsequent radioembolization.

Selection of candidates for peptide receptor radionuclide therapy (PRRT) is increasingly based on receptor positron emission tomography (PET) imaging, including the common tracer 68Ga DOTATOC. However, no studies have yet compared standardized uptake values (SUVs) and absorbed doses in this field.We retrospectively analyzed a consecutive cohort of 21 patients with 61 evaluable tumor lesions undergoing both pretherapeutic 68Ga DOTATOC-PET/CT (Biograph Duo [Siemens Medical Solutions, Erlangen, Germany]; PET acquisition, 75.3 ± 15.4 minutes postinjection; 117.3 ± 33.9 MBq 68Ga DOTATOC) and PRRT with Lu octreotate (7.47 ± 1.39 GBq; intratherapeutic tumor dosimetry with serial whole-body scans; 1, 2, and 4 days postinjection) at our institution. SUVs were compared with the tumor-absorbed doses per injected activity (D/A0) of the subsequent first treatment cycle.The correlation of SUV and D/A0 was r = 0.72 (SUVmean) and r = 0.71 (SUVmax), both P0.001. Pancreatic origin and hepatic localization were associated with higher D/A0, and chromogranin A level and Ki-67 index had no influence on SUV or D/A0. High-SUV lesions (SUVmean15; SUVmax25) resulted in high D/A0 (10 Gy/GBq) in 66.7% to 70.8% and low D/A0 (5 Gy/GBq) in only 8.3% to 12.5% on subsequent PRRT. The mentioned low D/A0 range, on the other hand, was achieved by all lesions with SUVmean7 or SUVmax9.Somatostatin receptor PET imaging may predict tumor-absorbed doses. The ability to indicate insufficient target irradiation by a low SUV could aid in selection of appropriate candidates for PRRT. However, larger series are needed to confirm and validate these initial findings.

Sentinel lymph node biopsy (SLNB) is a widely accepted procedure to accurately stage melanomas with a thickness ≥1 mm. The value of SLNB in thin melanomas is still controversial, especially because long-term observations of these patients are rare. The purpose of the current study was to identify the positive sentinel lymph node (SLN) ratio in low-risk patients with cutaneous melanoma (CM) of thickness less than 1 mm and its possible prognostic value, focusing on long-term follow-up data.In a retrospective single-centre study performed at the Department of Dermatology and Allergy, University of Bonn, 121 patients who had received SLNB were identified out of 621 patients with a diagnosis of CM of1.00 mm thickness presenting between September 2000 and February 2009 (mean follow-up time, 50.9 months).Of the 121 patients, 5 (4.1%) had a positive SLN. All positive SLNs were found in patients with a tumour thickness between 0.90 mm and 1.00 mm. There were no significant differences in the presence of positive SLNs according to Clark level and ulceration status (Clark levels II and III and no ulceration vs. Clark levels IV and V or ulceration), regression, gender or age. Disease-free survival was 100% in the SLN-positive patients. On the other hand, five SLN-negative patients (4.1%) developed disease progression. One of these five progressive patients showed recurrence in the former negative SLN basin (16.7% false-negative rate).A positive SLN in thin melanomas is uncommon with a prevalence of 4.1% in our study population. We could not identify reliable clinicopathological risk factors which could predict results of SLNB in thin melanomas. Based on our results, SLNB may be considered in patients with a melanoma of thickness in the range 0.90-0.99 mm, because all SLN-positive patients belonged to this subgroup.

Purpose Unwanted deposition of 90Y microspheres in organs other than the liver during radioembolization of liver tumours may cause severe side effects such as duodenal ulcer. The aim of this study was to evaluate the significance of posttherapy bremsstrahlung (BS) SPECT/CT images of the liver in comparison to planar and SPECT images in the prediction of radioembolization-induced extrahepatic side effects.Methods A total of 188 radioembolization procedures were performed in 123 patients (50 women, 73 men) over a 2-year period. Planar, whole-body and BS SPECT/CT imaging were performed 24 h after treatment as a part of therapy work-up.Any focally increased extrahepatic accumulation was evaluated as suspicious. Clinical follow-up and gastroduodenoscopy served as reference standards. The studies were reviewed to evaluate whether BS SPECT/CT imaging was of benefit.Results In the light of anatomic data obtained from SPECT/CT, apparent extrahepatic BS in 43% of planar and in 52% of SPECT images proved to be in the liver and hence false positive.The results of planar scintigraphy could not be analysed further since 12 images were not assessable due to high scatter artefacts. On the basis of the gastrointestinal (GI)complications and the results of gastroduodenoscopy, true positive,true-negative, false-positive and false-negative results of BS SPECT and SPECT/CT imaging in the prediction of GI ulcers were determined. The sensitivity, specificity, positive and negative predictive values and the accuracy of SPECT and SPECT/CT in the prediction of GI ulcers were 13%, 88%, 8%,92% and 82%, and 87%, 100%, 100%, 99% and 99%,respectively.Conclusion Despite the low quality of BS images, BSSPECT/CT can be used as a reliable method to confirm the safe distribution of 90Y microspheres and in the prediction of GI side effects.

An angiographic evaluation combined with (99m)Tc-macroaggregated albumin (Tc-MAA) scanning should precede the treatment of any selected candidates for radioembolization (RE) of the liver. If the tumours in one liver lobe have not been targeted in the test angiogram, it should be repeated. However, in a few cases treatment of one liver lobe or at least some segments is safe and feasible and performing a repeated test angiogram with Tc-MAA (Re-MAA) in a separate session leads to more radiation exposure and could be time consuming. Our aim was to evaluate the feasibility of concurrent RE of a part of the liver and therapy planning for another region by simultaneous injection of the Tc-MAA and (90)Y-microspheres in two different locations in the therapy session. Tc-MAA and bremsstrahlung (BS) single photon emission computed tomography (SPECT)/CT were performed separately in an effort to distinguish between the distributions of these two different radiopharmaceuticals.RE was combined with a simultaneous second test angiogram of another lobe or segments in the same session in six patients [44-70 years; five women (83%)]. Five patients suffered from colorectal carcinoma (CRC) and one from ovarian cancer. Tc-MAA and BS SPECT/CT were performed for all cases.Post-therapeutic Tc-MAA SPECT/CT showed in all patients only the distribution of Tc-MAA without any detectable BS. Evaluation of (90)Y-microsphere distribution was not always possible in the post-therapeutic BS scan performed 24 h later due to remaining Tc-MAA radiation. However, scans performed at 48 h post-intervention no longer showed any Tc-MAA "contamination".Combining RE and Re-MAA is feasible in appropriately selected patients.

A 24-year-old man with extraosseous Ewing sarcoma in the pelvis underwent a triphasic bone scintigraphy to rule out bone metastases and local bone infiltration before chemotherapy. The bone scintigraphy showed tracer uptake in the tumor in all 3 phases.

Tc-MAA uptake in the portal vein tumor thrombus may be a predictor of a favorable response to radioembolization. We report here 2 patients with hepatocellular carcinoma and massive intrahepatic and extrahepatic tumor thrombus that showed Tc-MAA uptake in SPECT/CT, who underwent radioembolization with Y resin microspheres. The patients did not experience any adverse effects.

Selective internal radiation therapy (SIRT), a catheter-based liver-directed modality for treating primary and metastatic liver cancer, requires appropriate planning to maximize its therapeutic response and minimize its side effects. 99mTc-macroaggregated albumin (MAA) scanning should precede the therapy to detect any extrahepatic shunting to the lung or gastrointestinal tract. Our aim was to compare the ability of SPECT/CT with that of planar imaging and SPECT in the detection and localization of extrahepatic 99mTc-MAA accumulation and to evaluate the impact of SPECT/CT on SIRT treatment planning and its added value to angiography in this setting. Methods: Ninety diagnostic hepatic angiograms with 99mTc-MAA were obtained for 76 patients with different types of cancer. All images were reviewed retrospectively for extrahepatic MAA deposition in the following order: planar, non–attenuation-corrected SPECT, and SPECT/CT. Review of angiograms and follow-up of patients with abdominal shunting served as reference standards. Results: Extrahepatic accumulation was detected by planar imaging, SPECT, and SPECT/CT in 12%, 17%, and 42% of examinations, respectively. The sensitivity for detecting extrahepatic shunting with planar imaging, SPECT, and SPECT/CT was 32%, 41%, and 100%, respectively; specificity was 98%, 98%, and 93%, respectively. The respective positive predictive values were 92%, 93%, and 89%, and the respective negative predictive values were 71%, 73%, and 100%. The therapy plan was changed according to the results of planar imaging, SPECT, and SPECT/CT in 7.8%, 8.9%, and 29% of patients, respectively. Conclusion: In pre-SIRT planning, 99mTc-MAA SPECT/CT is valuable for identifying extrahepatic visceral sites at risk for postradioembolization complications.

The diagnostic accuracy of 18F-FDG-PET (fluoro-2-deoxyglucose-positron emission tomography) remains questionable for primary hepatocellular carcinoma (HCC) but seems to be more promising for restaging and therapy control. Yet, there are no data on FDG-PET in 131I-lipiodol treatment for primary liver cancer. The aim of this study was to relate baseline FDG-PET findings to histologic data and to assess, for the first time, the role of repetitive FDG-PET imaging for follow-up of 131I-lipiodol treatment. Eighteen (18) patients (16 HCC, 2 cholangiocellular carcinoma; CCC) with 36 treatment courses (up to four per patient) had 35 PET exams, including 18 post-treatment follow-up scans in 10 patients (up to three per patient, one without baseline PET; n = 17). Histopathologic results were available in 15 patients. PET results were retrospectively related to histopathologic type, grading, presence of cirrhosis, and tumor size at baseline and compared with computed tomography (CT) during follow-up. Prior to 131I-lipiodol treatment, 8 patients were PET positive and 9 PET negative. Most of the large HCCs were PET positive and most small tumors PET negative (p0.05), despite an overlap below 11 cm. There was no identifiable correlation between PET results and degree of tumor differentiation. Overall, 9 of 10 patients with 17 of 18 follow-up scans showed concordant results with CT. The one discrepant case became PET negative after the first treatment course, despite CT-proven tumor growth (false negative). Patient management was not changed due to PET results. In conclusion, large HCCs were significantly more often PET positive, but there was no correlation with the degree of differentiation. Follow-up PET may be useful if the tumor is first demonstrated to be FDG positive.

There is a lack (1.) of a single criterion for the definitive differentiation between immunogenic (IH) and non-immunogenic hyperthyroidism (NIH), and (2.) also a lack of an unequivocal prognostic predictor for the individual course of patients with immunogenic hyperthyroidism. In 152 patients scheduled for iodine-131 therapy, serum neopterin concentrations were measured using a commercially available RIA, and the neopterin concentrations of IH (n = 84) and NIH (n = 42) patients were compared. Of these patients, 83 and 26 per cent respectively were treated with antithyroid drugs which did not have a significant impact on neopterin levels. In patients with IH and NIH, the concentrations [mean +/- SD] of neopterin were 1.89 +/- 0.79 milligrams and 1.98 +/- 0.9 milligrams, respectively (p = 0.4). After therapy with iodine-131, 28% of the IH-patients were euthyroid, 32% hyperthyroid, and 40% hypothyroid. In finally euthyroid patients, pretherapeutic neopterin concentrations were higher (3.1 +/- 2.8 milligrams) than in finally hyperthyroid (1.8 +/- 0.7 milligrams), or hypothyroid (1.6 +/- 0.7 milligrams) patients. These results argue against a relevant clinical role of neopterin concentrations for the differential diagnosis of IH versus NIH in these patients. However, a prognostic significance of neopterin concentrations in patients with IH is suggested.

The aim of the present study was to evaluate the prognostic value of hemodynamic variables during ergometric stress testing for (99m)Tc-sestamibi myocardial perfusion scintigraphy (MPS) as compared to several patient-related variables and MPS results with regard to referral to early coronary angiography (3 months after MPS; CA) as well as cardiac event (CE) free survival in a study population agedor =70 years. About 90 patients agedor =70 years (74.5 +/- 3.6 years) who underwent ergometric stress/rest MPS were included in this study. About 19 hemodynamic variables during stress testing were assessed. Semiquantitative visual interpretation of MPS images were performed and Summed-Stress-(SSS), Summed-Difference-, and Summed-Rest-Scores were calculated. Emerging CE comprised myocardial revascularization and -infarction as well as cardiac-related death. Multivariate logistic regression analyses were performed for evaluation of independent prognostic impact of hemodynamic-, MPS- and clinical-variables with regard to referral to early catheterization as well as emerging CE. Kaplan-Meier survival- and log rank analyses were calculated for assessment of CE free survival. History of CAD (Odds ratio; OR: 99.3), low rest heart rate (OR: 14.9) and low peak systolic blood pressure (OR: 15.4) during ergometric stress testing as well as pathological SSS (OR: 48.4) were significantly associated with referral to CA. History of ischemic ECG (OR: 4.7) and pathological SSS (OR: 3.7) independently predicted emerging CE and were associated with a lower CE free survival. In patients agedor =70 years, CA is independently predicted by clinical variables, pathological results of MPS and hemodynamic variables. In contrast, hemodynamic response to stress testing failed to show any predictive impact on emerging CE.

The objective of this study was to evaluate the role of preoperative 18F-fluorodeoxyglucose-positron emission tomography/computed tomography scanning, preoperative lymphoscintigraphy (LS), and sentinel lymph node biopsy in patients with malignant melanoma. Fifty-two patients (36 men: 16 women; mean age 55.0+/-13.0 years; median age 61 years; range 17-76 years) with malignant melanoma were selected. According to the latest version of the American Joint Committee on Cancer staging system, the disease in the study patients was initially classified as either stage I or II. The other primary tumor characteristics were mean Breslow depth=2.87 mm and median=2 mm; range 1-12.0 mm and Clarks levels III-V. None of the study patients had clinical or radiological evidence of regional lymph node metastatic disease. At least one sentinel node was identified in all patients. Preoperative LS detected a total of 111 sentinel lymph nodes (average 2.13 sentinel lymph node per patient) and demonstrated a single nodal draining basin in 38 (73%) patients and multiple (2-3 draining basins) in the remaining 14 (27%) patients. Fourteen out of the 52 patients (27%) had at least one involved sentinel node. Positron emission tomography was true positive in two patients with a sentinel node greater than 1 cm and false positive in two other patients. In this study, the detection of sentinel lymph node by LS and gamma probe had a sensitivity of 100%. In contrast, 18F-FDG-PET imaging demonstrated very low sensitivity (14.3%; 95% CI, 2.5 to 44%) and positive predictive value (50%; 95% CI, 9 to 90%) for localizing the subclinical nodal metastases. The specificity, net present value, and diagnostic accuracy were 94.7, 75, and 73%, respectively. Preoperative fluorodeoxyglucose-positron emission tomography/computed tomography imaging is not able to substitute LS/sentinel lymph node biopsy in patients at stage I or II.

Positron-emission tomography (PET) employing fluorodeoxyglucose (FDG) has proven to be a highly sensitive and specific diagnostic method in the staging and restaging of various neoplasms, including melanoma, complementing morphologic imaging. FDG uptake has been correlated with proliferation rate, and thus, the degree of malignancy of a given tumor (i.e., grading). Consecutively, a relationship of survival prognosis and the extent of tumor burden as well as degree of FDG accumulation--determined by FDG-PET--has been suggested in various tumors. The aim of this study was to assess the potential of fluor-18-FDG-PET in order to evaluate the survival prognosis in melanoma. Patient data (n=95) were retrospectively analyzed, and the results of functional FDG-PET staging was correlated with survival data. Time of staging (diagnosis of primary versus recurrence) had no statistically significant effect on survival prognosis when patients were matched for pertaining node metastasis (NM) stages. Differences in survival were owing to the presence of metastatic disease rather than time of staging. Tumor (T)-stage (T1-T4) alone had no effect on survival prognosis when patients were matched for NM stages. Differences in survival were also due to higher rates of lymph node (LN) and organ metastases in higher T-stages. Detection of LN metastases (N1M0) had a statistically significant and predominant impact on 5-year survival (N0M0 80% versus N1M0 45%; p0.01). Additional presence of distant metastases in LN-positive patients (N1M1) had only a statistically insignificant further impact on survival (5-year survival in N1M0 45% versus N1M1 29%; p0.05). Exclusive presence of organ metastases (N0M1) showed a statistically significant drop of survival with a 5-year survival of 61% in N0M1 versus 80% in N0M0, respectively (p0.03). Further, the combined presence of LN and distant metastases had the worst prognosis (5-year survival in N1M1 29% versus N0M1 61%; p0.02). Based on a qualitative 4-point scoring system, patients with malignancy-typical FDG uptake showed an overall 5-year survival of 38%, as compared to patients with malignancy-suspicious lesions (71%; por= 0.02) or patients without evidence of disease (80%; p0.001). When PET and computed tomography (CT) findings were compared, survival was best in patients with both studies (CT and PET) being negative (5-year survival, 83%), worst when PET and CT were positive (5-year survival, 61%; p0.02), and showed an intermediate survival when PET was positive, but with CT still negative (5-year survival, 73%). In patients staged by FDG-PET, significant risk factors--as identified by univariate und multivariate analyses--were (i) malignancy-typical FDG uptake, (ii) detection of LN, and (iii) organ metastases. In conclusion, FDG-PET offers valid prognostic information, demonstrating a good relationship of functional TNM-stage and actual survival prognosis. The results obtained in one PET study seem to be as suitable as the combined results of conventional staging, including clinical and morphologic (e.g., CT) methods and clinical follow-up. FDG-PET was more accurate in tumor detection and seemed to detect tumor spread earlier, as compared to CT.

The aim of this study was to evaluate the efficacy of a systemic application of rhenium-186 hydroxyethylidenediphosphonate (Re HEDP) for pain treatment in patients with hemophilic arthropathies.Twelve patients with hemophilic arthropathy with at least 3 involved joints with persistent pain were included in this prospective study. A single dose of 15 mCi (555 MBq) Re HEDP was administered intravenously. Before and 12 weeks after treatment, pain assessment was performed using the visual analog scale (VAS). The pain status assessment included the general status, pain of all joints affected, and pain of the 3 mostly involved joints. Furthermore, quality of life was assessed.With regard to the 3 most involved joints, an improvement of the pain symptoms in 25 of 36 (69.4%) joints was observed. With regard to all involved joints a median of 3 joints per patient improved after Re HEDP therapy. General pain status after treatment was 2.0 VAS points lower as compared with pretreatment. The total number of involved joints remained unchanged in 7 patients, increased in 1 patient, and decreased in the remaining 4 patients.The results of this study show an improvement of the pain symptoms of the involved joints 12 weeks after therapy with Re HEDP in patients with hemophilic arthropathy. The only moderate success regarding a reduction of the total number of involved joints is by the fact that despite this improvement most affected joints remained still painful on a lower level after the therapy or due to newly affected joints not painful before initiation of the radionuclide therapy.

SummaryAim: Dosimetry in 131I-lipiodol therapy for hepatocellular carcinoma (HCC) in the hitherto largest existing patient cohort. Patients, methods: 38 courses of intra-arterial 131I-lipiodol therapy with a total activity up to 6.7 GBq were performed in 18 patients with HCC. Liver and tumour volume were measured by computed tomography (CT) and 131I activity by scintigraphy on day 3, 6, 14, 28 and 42 after injection. Lipiodol deposition in tumour nodules as shown by CT rendered definite attachment to scintigraphic data possible. The radiation dose in tumour nodules, liver and lungs was calculated according to the MIRD concept and the tumour dose related to pre-therapeutic tumour volume, response and survival. Results: Mean tumour dose was 23.6 ± 3.6 Gy (14.2 ± 2.1 mGy/MBq) with maximal 162 Gy (90.1 mGy/MBq) after one and 274 Gy after three courses. The dose to nontumourous liver was 1.9 ± 0.2 Gy (1.2 ± 0.1 mGy/MBq) and the mean dose ratio of tumour / nontumourous liver 11.1 ± 1.7 (max. 82). The pulmonary dose was 25.9 ± 1.8 mGy (16.3 ± 1.2 μGy/MBq) and therefore much lower. There was a reciprocal relation between tumour dose and pretherapeutic tumour volume. Tumour dose had no effect on response or survival. Conclusion: High radiation doses are particularly in small tumour nodes achievable but not necessarily related to tumour response. The dose of non-tumourous liver and lungs is much lower.

99mTc-tetrofosmin and 99mTc-sestamibi are approved tracers for myocardial perfusion studies. Recently, a 99mTc-MIBI preparation from a different manufacturer (99mTc-cardiospect-MIBI) has been introduced to the market. Therefore, the aim of this study was the evaluation of 99mTc-tetrofosmin as well as of two different 99mTc-labeled MIBI tracers with regard to differences in imaging quality under resting conditions.Sixty patients (mean age 63.8 years +/- 1.25) with known or suspected coronary artery disease but without evidence of rest-ischemia were included. Twenty patients in each group were examined by a two-day-rest-stress protocol using the three 99mTc-labeled tracers. Visual analysis of all images was performed by two experienced physicians blinded with regard to the applied tracer. Regions of interest (ROI) were defined over the heart, lung and whole body only in the rest imaging in order to calculate heart-to-lung, lung-to-whole body-, and heart-to-whole body-ratios.The heart-to-lung ratio was statistically significant higher for 99mTc-cardiospect-MIBI as compared to 99mTc-sestamibi as well as to 99mTc-tetrofosmin. Furthermore, a significantly higher heart-to-lung ratio was found for 99mTc-sestamibi as compared to 99mTc-tetrofosmin. The heart-to-whole body-ratio and the lung-to-whole body-ratio were equivalent between all tracers. Visual analysis revealed only slight differences regarding image quality between all tracers.ROI analysis surprisingly revealed a significant higher myocardial uptake and consequently a higher heart-to-lung ratio for 99mTc-cardiospect-MIBI. Whether this leads to a better visual image quality has to be evaluated in future studies with larger study populations as well as semiquantitative segmental analysis of the myocardial perfusion images.

Unlike hyperthyroidism, few data exist regarding the impact of hypothyroidism on systemic anticoagulation with coumarin derivates. Therefore, we evaluated a potential impact of short-term hypothyroid conditions on systemic anticoagulation with coumarin derivates in patients after complete thyroidectomy for treatment of thyroid cancer. Fifteen patients with differentiated thyroid cancers and continued international normalized ratio (INR)-adjusted therapy with coumarin derivates were included in this retrospective analysis. A total of 88 laboratory tests was analyzed. INR values were compared between thyroid-stimulating hormone (TSH) values greater than 10 and 10 mU/L or less. An INR value of less than 2.0 was defined as being out of the therapeutic range. Analysis of significant differences between categorized TSH and INR values were performed by using X(2) analysis, correlation of continuous TSH and INR values by using the Pearson's analysis. When TSH was greater than 10 mU/L (n = 50) the INR value was less than 2.0 in 76.0% (n = 38) cases. In contrast, the INR value was less than 2.0 in only 21.1% (n = 8; p < 0.0001) of patients with TSH of 10 mU/L or less (n = 38). Correlation between continuous TSH and INR values was r = -0.589 (p < 0.0001). Based on the results of the present study, it seems to be necessary to monitor the anticoagulation parameters more often in patients with hypothyroidism and either to correct the hypothyroid state, or in cases of desired hypothyroid conditions, to adjust the therapy with coumarin derivates in order to ensure a sufficient anticoagulation.

Abnormalities in regional cerebral blood flow (rCBF) have been reported to characterize depressive episodes; they are at least partly reversed by antidepressant treatment. Treatment-specific as well as response-related changes in rCBF have been reported. We explored the changes in rCBF induced by vagus nerve stimulation (VNS), a recently proposed antidepressant strategy, by application of single photon emission-computed tomography with (99m)Tc-hexamethyl-propylene amine oxime in otherwise treatment-refractory patients. Both region-of-interest (ROI) and statistical parametric mapping (SPM) analytic approaches were used. Decreases of rCBF in the amygdala, left hippocampus, left subgenual cingulate cortex, left and right ventral anterior cingulum, right thalamus and brain stem were observed; the only increase of rCBF was found by SPM analysis in the middle frontal gyrus. This pattern shares features with changes of rCBF previously associated with the administration of selective serotonin reuptake inhibitors. Similarities to other brain-stimulation strategies in antidepressant treatment were less pronounced.

The aim of this study was to evaluate the predictive value of early metabolic response 4 weeks post-treatment using (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT in patients with unresectable hepatic metastases of colorectal cancer (CRC) undergoing radioembolization (RE) with (90)Y-labelled microspheres.A total of 51 consecutive patients with liver-dominant metastases of CRC were treated with RE and underwent (18)F-FDG PET/CT at baseline and 4 weeks after RE. In each patient, three hepatic metastases with the highest maximum standardized uptake value (SUVmax) were selected as target lesions. Metabolic response was defined as50 % reduction of tumour to liver ratios. Survival analyses using Kaplan-Meier and multivariate analyses were performed to identify prognostic factors for overall survival (OS). Investigated baseline characteristics included age (60 years), performance status (Eastern Cooperative Oncology Group1), bilirubin (1.0 mg/dl), hepatic tumour burden (25 %) and presence of extrahepatic disease.The median OS after RE was 7 months [95 % confidence interval (CI) 5-8]; early metabolic responders (n = 33) survived longer than non-responders (p 0.001) with a median OS of 10 months (95 % CI 3-16) versus 4 months (95 % CI 2-6). Hepatic tumour burden also had significant impact on treatment outcome (p 0.001) with a median OS of 5 months (95 % CI, 3-7) for patients with25 % metastatic liver replacement vs 14 months (95 % CI 6-22) for the less advanced patients. Both factors (early metabolic response and low hepatic tumour burden) remained as independent predictors of improved survival on multivariate analysis.These are the first findings to show that molecular response assessment in CRC using (18)F-FDG PET/CT appears feasible as early as 4 weeks post-RE, allowing risk stratification and potentially facilitating early response-adapted treatment strategies.

Eight patients (77 joints) with polyarthritis were treated systemically with 570 MBq (15.4 mCi) of rhenium 186 ((186)Re) hydroxyethylidenediphosphonate (HEDP). Pain and disease activity were assessed monthly. In six (75%) of eight patients, a single injection of (186)Re HEDP led to an improvement in disease activity. Systemic low-dose treatment with (186)Re HEDP can reduce pain and disease activity in patients with polyarthritis.

The aim of this study was to determine the maximum tolerated dose of rhenium-188 hydroxyethylidene diphosphonate (HEDP) in prostate cancer patients with osseous metastases who are suffering from bone pain. Twenty-two patients received a single injection of escalating doses of carrier-added 188Re-HEDP [1.3 GBq (35 mCi), 2.6 GBq (70 mCi), 3.3 GBq (90 mCi) and 4.4 GBq (120 mCi)]. Blood counts and biochemical parameters were measured weekly over a period of 8 weeks. Haematological toxicity (WHO grading) of grade 3 or 4 was considered unacceptable. Clinical follow-up studies including methods of pain documentation (medication, pain diary) were performed for 6 months after treatment. In the 1.3-GBq group, no haematological toxicity was observed. First haematotoxic results were noted in those patients with a dose of 2.6 GBq 188Re-HEDP. In the 3.3-GBq group, one patient showed a reversible thrombopenia of grade 1, one a reversible thrombopenia of grade 2 and three a reversible leukopenia of grade 1. In the 4.4-GBq group, thrombopenia of grades 3 and 4 was observed in one and two patients (baseline thrombocyte count200x10(9)/l), respectively, and leukopenia of grade 3 was documented in one patient. The overall nadir of thrombopenia was at week 4. The individual, maximum percentage decrease in thrombocytes in the 1.3-, 2.6-, 3.3- and 4.4-GBq groups was 17%, 40%, 60% and 86%, respectively. In two patients, a transient increase in serum creatinine was observed (max. 1.6 mg/dl). Pain palliation was reported by 64% of patients, with a mean duration of 7.5 weeks. The response rate seemed to increase with higher doses, reaching 75% in the 4.4-GBq group. It is concluded that in prostate cancer patients, the maximum tolerated dose of 188Re-HEDP is 3.3 GBq if the baseline thrombocyte count is below 200x10(9)/l. In patients with thrombocyte counts significantly above 200x10(9)/l, a dose of 4.4 GBq might be tolerable. Thrombo- and leukopenia are the most important side-effects. Pain palliation can be achieved in 60%-75% of patients receiving a dose of 2.6 GBq or more of 188Re-HEDP. Studies in a larger patient population are warranted to evaluate further the palliative effect of 188Re-HEDP.

Malignant fibrous histiocytomas are rare soft-tissue sarcomas of uncertain histogenesis but represent the most common soft-tissue sarcomas in adults. In this report of a 70-year-old male patient suffering from this rare malignant disease, we describe the diagnostic benefits of combined functional and morphological imaging as realized in positron emission tomography and computed tomography, helping to avoid invasive diagnostic methods and, most importantly, harmful and quality-of-life-reducing, oncologically ineffective therapies.

Nonresectable colorectal cancer metastases in the liver respond to chemotherapy in 20-25% only. Early identification of nonresponders might allow the use of other regimens. In a limited feasibility study, it should be determined whether (a) a single high-dose chemotherapy application has an early effect on glucose-utilization, detectable and quantitatable by noninvasive positron emission tomography using [18F]-Fluoro-deoxyglucose (FDG-PET) and (b) assess its value as a predictor of the final therapeutic outcome. A total of 10 patients with documented nonresectable liver metastases of a colorectal cancer were studied by FDG-PET, prior and 72 h after a single infusion of 5-Fluorouracil and Folinic acid (5-FU/FA). Glucose utilization was quantitated by determination of standard-uptake values and correlated with final therapy outcome following completion of the anticipated therapy cycle. Patients were followed up for at least 6 months. All metastases responding to therapy (n = 6) exerted a statistically significant decrease of FDG uptake (-22+/-10%), metastases (n = 2) showing a short-term effect (duration of tumor reduction

The clinical benefit of peptide receptor radionuclide therapy (PRRT) in patients with pancreatic neuroendocrine tumours (pNET) has not yet been well described and defined in its full extent due to limited data in this tumour subgroup. This study was intended to obtain robust, comparative data on the outcome and toxicity of standardized PRRT with (177)Lu-octreotate in a well-characterized population of patients with advanced pNET of grade 1/2 (G1/2).We retrospectively analysed a cohort of 68 pNET patients with inoperable metastatic disease consecutively treated with (177)Lu-octreotate (four intended cycles at 3-monthly intervals; mean activity per cycle 8.0 GBq). Of these 68 patients, 46 (67.6 %) had documented morphological tumour progression during the 12 months before initiation of treatment, and PRRT was the first-line systemic therapy in 35 patients (51.5 %). Response was evaluated according to modified Southwest Oncology Group (SWOG) criteria and additionally with Response Criteria in Solid Tumors (RECIST) 1.1. Survival was analysed using Kaplan-Meier curves and Cox proportional hazards model for univariate and multivariate analyses. Toxicity was assessed by standard follow-up laboratory work-up including blood count, and liver and renal function, supplemented with serial (99m)Tc-DTPA clearance measurements.The median follow-up period was 58 months (range 4 - 112). Reversible haematotoxicity (grade 3 or more) occurred in four patients (5.9 %). No significant nephrotoxicity (grade 3 or more) was observed. Treatment responses (SWOG criteria) consisted of a partial response in 41 patients (60.3 %), a minor response in 8 (11.8 %), stable disease in 9 (13.2 %), and progressive disease in 10 (14.7 %). Median progression-free survival (PFS) and overall survival (OS) were 34 (95 % CI 26 - 42) and 53 months (95 % CI 46 - 60), respectively. A G1 proliferation status was associated with longer PFS (p = 0.04) and OS (p = 0.044) in the multivariate analysis. Variables linked to impaired OS, on the other hand, were a reduced performance status (Karnofsky score ≤ 70 %, p = 0.007), a high hepatic tumour burden (≥ 25 % liver volume, p = 0.017), and an elevated plasma level of neuron-specific enolase (NSE15 ng/ml, p = 0.035).The outstanding response rates and survival outcomes suggest that PRRT is highly effective in advanced G1/2 pNET when compared to data of other treatment modalities. Independent predictors of survival are the tumour proliferation index, the patient's performance status, tumour burden and baseline plasma NSE level.

We assessed the outcome and toxicity of salvage therapy (repeat treatment) with (177)Lu-octreotate and high cumulative activities in patients with metastatic gastroenteropancreatic neuroendocrine tumours (GEP-NET).We retrospectively analysed a consecutive cohort of 33 patients with metastatic GEP-NET who underwent salvage peptide receptor radionuclide therapy (PRRT) in our institution. All patients had progressive NET prior to salvage treatment and had shown an initial response to PRRT. The mean cumulative activity was 44.3 GBq (30.0-83.7 GBq). Radiographic response was assessed using CT and/or MRI according to modified SWOG criteria. Toxicity was evaluated using laboratory data, including complete blood counts and renal function tests using CTCAE 3.0. Survival analysis was performed with the Kaplan-Meier curve method and a significance level at p 0.05.Radiographic responses consisted of complete response in 1 patient (3.0%), partial response in 6 patients (18.2%), minor response in 1 patient (3.0%), stable disease in 14 patients (42.4%), and progressive disease in 11 patients (33.3%). Median progression-free survival (PFS) from the start of salvage therapy was 13 months (95% CI 9-18) and patients with a history of a durable PFS after initial PRRT tended to have long-lasting PFS after salvage treatment (p = 0.04). None of the patients developed severe nephrotoxicity (grade 3/4) or a myelodysplastic syndrome during follow-up. Relevant albeit reversible haematotoxicity (grade 3/4) occurred in 7 patients (21.2%). The cumulative administered activity was not associated with an increased incidence of haematotoxicity.PRRT with (177)Lu-octreotate in the re-treatment setting is safe and effective in patients with metastatic GEP-NET.

This study was designed to assess the additional value of SPECT/CT of the trunk used in conjunction with conventional nuclear imaging and its effects on patient management in a large patient series. In 353 patients, whole-body scintigraphy (WBS), SPECT, and SPECT/CT were prospectively performed for staging and restaging. SPECT/CT of the trunk was performed in all patients. In the 308 evaluable patients (211 with breast cancer, 97 with prostate cancer), clinical follow-up was used as the gold standard. Bone metastases were confirmed in 72 patients and excluded in 236. Multistep analyses per lesion and per patient were performed. Clinical relevance was expressed in terms of downstaging and upstaging rates on a per-patient basis. In the total patient group, sensitivities, specificities, and negative and positive predictive values on a per-patient basis were 93 %, 78 %, 95 % and 59 % for WBS, 94 %, 71 %, 97 % and 53 % for SPECT, and 97 %, 94 %, 97 % and 88 % for SPECT/CT, respectively. In all subgroups, specificity and positive predictive value were significantly (p

A 76-year-old man with bone metastases of prostate cancer diagnosed a year ago was admitted for relief of bone pain (visual analogue scale: 90%) most markedly in cervical spine and upper extremities due to skeletal metastases. His serum prostate specific antigen level was markedly increased (351 ng/ml). After documentation of sufficient tracer uptake in multiple bone metastases on whole-body 99mTc-MDP bone scan, we treated him with a single intravenous injection of 2.4 GBq 188Re-HEDP. Quality control of 188Re-HEDP was performed with TLC within 30 min prior to injection, radiochemical purity was >95%, free rhenium and colloid ratios were less than 3%. For pain, he was taking Novalgin 30 drops t.i.d. and used Fentanyl patch 50 g/72 h. Fig. 1 shows increased activity localization in multiple bone metastases and the liver lesion after treatment with 188Re-HEDP, as well as on the whole-body scans obtained a week prior to treatment. This metastatic liver lesion was diagnosed on a conventional CT scan 6 months before treatment. The SPECT/CT study (obtained at 24 h after injection) shows tracer accumulation in the liver lesion, in abdominal lymph nodes (in the hepatoduodenal ligament) and in stomach (Fig. 2A and B). An abdominal section of the SPECT/CT study shows that the area of activity localization on right side of abdomen on whole body image corresponds to intestinal contents (Fig. 2C). Liver metastases of various malignant tumors such as breast cancer have been reported to show accumulation on bone scintigraphy with 99mTc-MDP. Limouris and Skukla reported 186Re-HEDP uptake in the stomach in two patients with osseous metastases because of prostate and breast cancer1; however, we could not find any reports on visualization of lymph node metastases on posttherapy scan after administration of 188Re-HEDP. Accumulation of

INTRODUCTION: 3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is a recreational club drug with supposed neurotoxic effects selectively on the serotonin system. MDMA users consistently exhibit memory dysfunction but there is an ongoing debate if these deficits are induced mainly by alterations in the prefrontal or mediotemporal cortex, especially the hippocampus. Thus, we investigated the relation of verbal memory deficits with alterations of regional cerebral brain glucose metabolism (rMRGlu) in recreational MDMA users. METHODS: Brain glucose metabolism in rest was assessed using 2-deoxy-2-((18)F)fluoro-D-glucose positron emission tomography ((18)FDG PET) in 19 male recreational users of MDMA and 19 male drug-naïve controls. (18)FDG PET data were correlated with memory performance assessed with a German version of the Rey Auditory Verbal Learning Test. RESULTS: As previously shown, MDMA users showed significant impairment in verbal declarative memory performance. PET scans revealed significantly decreased rMRGlu in the bilateral dorsolateral prefrontal and inferior parietal cortex, bilateral thalamus, right hippocampus, right precuneus, right cerebellum, and pons (at the level of raphe nuclei) of MDMA users. Among MDMA users, learning and recall were positively correlated with rMRGlu predominantly in bilateral frontal and parietal brain regions, while recognition was additionally related to rMRGlu in the right mediotemporal and bihemispheric lateral temporal cortex. Moreover, cumulative lifetime dose of MDMA was negatively correlated with rMRGlu in the left dorsolateral and bilateral orbital and medial PFC, left inferior parietal and right lateral temporal cortex. CONCLUSIONS: Verbal learning and recall deficits of recreational MDMA users are correlated with glucose hypometabolism in prefrontal and parietal cortex, while word recognition was additionally correlated with mediotemporal hypometabolism. We conclude that memory deficits of MDMA users arise from combined fronto-parieto-mediotemporal dysfunction.

Peptide receptor radionuclide therapy is an effective treatment option for patients with well-differentiated somatostatin receptor-expressing neuroendocrine tumors. However, published data result mainly from retrospective monocentric studies. We initiated a multi-institutional, prospective, board-reviewed registry for patients treated with peptide receptor radionuclide therapy in Germany in 2009. In five centers, 297 patients were registered. Primary tumors were mainly derived from pancreas (117/297) and small intestine (80/297), whereas 56 were of unknown primary. Most tumors were well differentiated with median Ki67 proliferation rate of 5% (range 0.9-70%). Peptide receptor radionuclide therapy was performed using mainly yttrium-90 and/or lutetium-177 as radionuclides in 1-8 cycles. Mean overall survival was estimated at 213 months with follow-up between 1 and 230 months after initial diagnosis, and 87 months with follow-up between 1 and 92 months after start of peptide receptor radionuclide therapy. Median overall survival was not yet reached. Subgroup analysis demonstrated that best results were obtained in neuroendocrine tumors with proliferation rate below 20%. Our results indicate that peptide receptor radionuclide therapy is an effective treatment for well- and moderately differentiated neuroendocrine tumors irrespective of previous therapies and should be regarded as one of the primary treatment options for patients with somatostatin receptor-expressing neuroendocrine tumors.

Peptide receptor radionuclide therapy (PRRT) is an efficient treatment for gastroenteropancreatic neuroendocrine tumors (GEP NETs), with outstanding overall response rates and survival. However, little is known about the particular efficacy regarding bone metastasis (BM). Methods: We retrospectively analyzed a consecutive subgroup of 42 patients with BM of GEP NETs treated with PRRT (177Lu-octreotate, 4 intended cycles at 3 monthly intervals [10–14 wk]; mean activity per cycle, 8.1 GBq). Availability of restaging and outcome data was required for patient inclusion. Baseline characteristics, including age, tumor origin, performance score, Ki-67 index, tumor load, tumor uptake, plasma chromogranin A, and neuron-specific enolase, were analyzed regarding impact on tumor regression (modified M.D. Anderson criteria) and time to progression. Survival analyses were performed using Kaplan–Meier curves, log-rank test at a significance level of P less than 0.05, and Cox proportional hazards model for uni- and multivariate analyses. Results: Median follow-up was 32 mo. The observed response of BMs consisted of complete remission in 2 (4.8%), partial remission in 14 (33.3%), minor response in 5 (11.9%), stable disease in 16 (38.1%), and progressive disease in 5 (11.9%) patients. Median progression-free survival and overall survival (OS) were 35 mo (26–44, 95% confidence interval) and 51 mo (37–65, 95% confidence interval), respectively. Patients with responding BMs (complete remission, partial remission, or minor response) exhibited a trend toward better OS (median OS not reached after 53 mo) when compared to nonresponding patients (39 mo, P = 0.076). Only Ki-67 index (>10%) and chromogranin A level (>600 ng/mL) contributed to regression analysis. Conclusion: BM of GEP NETs is effectively controlled by PRRT, with long progression-free survival and OS. Poor patient condition and multifocality of BMs do not clearly affect treatment efficacy, possibly encouraging the use of PRRT in advanced bone metastatic disease. Larger studies are needed to assess predictors of treatment outcome in these patients.

While influx of chemoembolic agents into the hepatic falciform artery (HFA) from the hepatic artery can cause supraumbilical skin rash, epigastric pain and even skin necrosis, the significance of a patent HFA in patients undergoing radioembolization is not completely clear. Furthermore, the presence of tracer in the anterior abdominal wall seen in (99m)Tc-macroaggregated albumin ((99m)Tc-MAA) images, which is generally performed prior to radioembolization, has been described as a sign of a patent HFA. The aim of this retrospective study was to evaluate the incidence and consequences of (99m)Tc-MAA accumulation in the anterior abdominal wall, indicating a patent HFA, in patients undergoing radioembolization of liver tumours.A total of 224 diagnostic hepatic angiograms combined with (99m)Tc-MAA SPECT/CT were acquired in 192 patients with different types of cancer, of whom 142 were treated with a total of 214 radioembolization procedures. All patients received a whole-body scan, and planar and SPECT/CT scans of the abdomen. Only patients with extrahepatic (99m)Tc-MAA accumulation in the anterior abdominal wall were included in this study. Posttreatment bremsstrahlung SPECT/CT and follow-up results for at least 3 months served as reference standards.Tracer accumulation in the anterior abdominal wall was present in pretreatment (99m)Tc-MAA SPECT/CT images of 18 patients (9.3%). The HFA was found and embolized by radiologists before treatment in one patient. In the remaining patients radioembolization was performed without any modification in the treatment plan despite the previously mentioned extrahepatic accumulation. Only one patient experienced abdominal muscle pain above the navel, which started 24 h after treatment and lasted for 48 h without any skin changes. The remaining patients did not experience any relevant side effects during the follow-up period.Side effects after radioembolization in patients with tracer accumulation in the anterior abdominal wall on (99m)Tc-MAA scans indicating a patent HFA are neither common nor severe. Thus, there is no absolute need for prophylactic embolization of the HFA or modification of the treatment plan if the HFA is not detectable on angiography.

The role of the Ki-67 tumour proliferation index (PI) in predicting the efficacy of peptide receptor radionuclide therapy (PRRT) in gastroenteropancreatic tumours (GEP-NET) remains undetermined. This single-centre analysis focused on the potential therapeutic impact of this immunohistochemical parameter.A total of 81 consecutive GEP-NET patients treated with (177)Lu-DOTA-octreotate (mean activity of 7.9 GBq per cycle, usually four treatment cycles at standard intervals of 3 months) were retrospectively analysed. Both an evaluable PI and tumour response (modified SWOG criteria) were required for patient inclusion.Response of tumours with a PI of ≤20% (partial response 40%, minor response 15%, stable disease 34%, progressive disease 11%) was comparable in all PI subsets, including those with a PI of 20%. However, G3 tumours (PI 20%) showed progression in 71% of patients.Response to PRRT is consistent over the PI range of ≤20% (G1 + G2). Contrary to preliminary previous suggestions, a PI of 15% or 20% should not preclude candidates from somatostatin receptor-targeted radiotherapy.

Ziel der vorliegenden Studie war, einen moglichen Einfluss des weiblichen Geschlechts auf das Ausmas moglicher myokardialer Perfusionsdefekte in der 99mTc-sestamibi-Myokardperfusions-Szintigraphie (MPS) und auf neu auftretende kardiale Ereignisse (KE) bei Patienten mit einem Alter ≥ 70 Jahre zu erfassen. 86 Patienten ≥ 70 Jahre (74,4 ± 3,2 Jahre; Frauen: n = 46; 53,5%) mit Verdacht auf oder bekannter KHK, die mit einer MPS untersucht wurden, wurden in die Studie eingeschlossen. Eine semiquantitative Analyse der MPS wurde durchgefuhrt und die Summed Stress (SSS), Summed Difference (SDS) und Summed Rest Scores (SRS) berechnet. Kardiale Ereignisse umfassten Myokardrevaskularisation und -infarkt und Herztod. Eine multivariate Regressionanalyse wurde durchgefuhrt, um einen moglichen unabhangigen Einfluss verschiedener patientenbezogener Variablen auf die Ergebnisse der MPS zu ermitteln. Kaplan-Meier- und Log-rank- Analysen wurden berechnet, um das KE-freie Uberleben in Relation zum Geschlecht zu erfassen. Normale SSS (87,0% vs. 27,5%; p < 0,0001), SDS (80,4% vs. 27,5%; p < 0,0001) und SRS (97,8% vs. 82,5%; p = 0,023) wurden signifikant haufiger bei Frauen gefunden, wahrend die Inzidenz mild und ausgepragt pathologischer SSS (6,5% vs. 35%; p = 0,001 bzw. 2,2% vs. 25%; p = 0,002) und SDS (15,2% vs. 52,5%; p < 0,0001 bzw. 2,2% vs. 17,5%; p = 0,023) signifikant hoher fur Manner war. Die multivariate Regressionsanalyse zeigte weibliches Geschlecht als unabhangigen Pradiktor fur normale SSS- (Odds ratio/OR: 17,6) und SDS-Werte (OR: 53,3). Im Vergleich zu Mannern war das weibliche Geschlecht mit einem signifikant hoheren Herztod-freien Uberleben assoziiert (p = 0,031). Weibliches Geschlecht zeigt eine unabhangige Assoziation mit einem signifikant niedrigeren Ausmas pathologischer MPS-Ergebnisse und einem hoheren Herztod-freien Uberleben bei alteren Patienten.

In this case we show the significance of dual time point PET in determining the nature of an abdominal process in a 67-year-old man with a newly diagnosed adenocarcinoma of the esophagus. Whole body PET/CT detected abnormal uptake in the distal part of the esophagus. In addition, focally increased FDG uptake was detected in the right abdomen. The late PET images of the abdomen showed an increase in the SUV resulting in this lesion being evaluated as malignant. The final pathology of the abdominal mass revealed a follicular B-Cell non-Hodgkin lymphoma grade I.

Medulloblastoma (MB) is a primitive neuroectodermal tumour constituting a grade IV brain malignancy. Early and correct detection of recurrence or metastasis is desirable for follow-up of patients in this entity. Frequent expression of somatostatin receptors by MB lesions facilitates functional tumour imaging by somatostatin receptor scintigraphy (SRS). To investigate the value of SRS in the follow-up of MB, the results of ten consecutive patients (seven children and three adults) undergoing additional imaging with 111In-pentetreotide were reviewed. Four, 24 and 48 h p.i. planar and whole body images as well as a SPECT study at 4 h p.i. were acquired after intravenous injection of 109 +/- 35 MBq 111In-pentetreotide (Octreoscan). SRS yielded 11 positive and ten negative imaging results, compared to 17 positive and four negative in magnetic resonance imaging (MRI). The lesion-by-lesion analysis with a total of 44 lesions revealed a sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 42%, 83%, 94%, 18% for SRS and 89.5%, 50%, 92%, 43% for MRI. Based on a per-patient analysis, considering the patient as to be either tumour-free or tumour-positive by one imaging modality, the following values for sensitivity, specificity, PPV and NPV were obtained: 61%, 100%, 100%, 30% for SRS and 94%, 67%, 94%, 67% for MRI. MRI remains the first step imaging technique in medulloblastoma patients before and after surgery and during the follow-up providing the highest sensitivity. However, to improve specificity and contribute to correct diagnosis in MB 111In-pentetreotide scintigraphy should be considered as a confirmatory second step imaging tool, especially in case of equivocal MRI results. Moreover, a positive SRS scan might serve as a reference before and after somatostatin receptor targeted radiotherapy.

Diagnosis of prostate cancer (PC) still remains critical as non-invasive screening with prostate specific-antigen (PSA) lacks to indicate malignancy of the prostate in some cases. Recent research has shown that clinically meaningful PC can develop in patients with a PSA value4 ng/ml, frequently defined as upper limit of normal serum PSA levels. Furthermore, both morphological (computed tomography (CT), magnetic resonance imaging, transrectal ultrasound) and functional imaging with (18)fluorodeoxyglucose positron emission tomography (FDG-PET) are associated with several limitations for primary diagnosis of PC. We report a case of an incidentally diagnosed PSA-negative PC by (18)FDG PET/CT in a patient with a previous diagnosis of a hypopharyngeal cancer.

A 61-year-old man presented with spontaneous pneumothorax. After diagnosis of emphysemic bullae, the patient underwent talc pleurodesis and had no further complaints. Five years later a routine chest X-ray showed suspicious pleural lesions in addition to the emphysema, which was deemed compatible with the known history of talc pleurodesis. Subsequent chest CT, however, revealed one lesion in the right lung that appeared not typical for this condition in addition to multiple lesions in pleural proximity. FDG-PET/CT demonstrated high glucose uptake in all the lesions. Subsequent needle biopsy of the suspicious intrapulmonary and also of one mediastinal lesion yielded the histopathological diagnosis of talcum granuloma with long-standing calculous fibrotic changes and no evidence of malignancy. This report on PET/CT after talc pleurodesis addresses the potential pitfalls caused by this condition, as chronic granulomatous reactions, like other inflammatory lesions, may account for highly increased FDG uptake which should be interpreted with caution and not simply read as a sign of malignancy. PET/CT offers the opportunity to exactly localize the areas of increased FDG uptake within regions of pleural thickening caused by talc deposition, however, the dilemma of misleading FDG accumulation cannot be solved by this hybrid imaging modality.

Background As single-head data acquisition for thallium-201 myocardial SPECT is a frequently used method mainly in the outpatient medical care as well as in smaller hospitals, comparison to dual-head data collection is a still discussed issue mainly with regard to quality control and -assurance. Methods A total of 1334 patients undergoing thallium-201 myocardial SPECT for diagnosis of myocardial ischemia and/or viability have been retrospectively analyzed. In 554 patients, a single-head gamma camera (360° rotation) has been applied, whereas a dual-head gamma camera (180° rotation) has been used in 780 patients. Four hundred twenty-six patients received both myocardial SPECT as well as coronary angiography. The diagnostic value of both applied acquisition techniques has been analyzed. Results Regarding myocardial viability, positive predictive value for the diagnosis of myocardial scar tissue was significantly higher for dual-head- as compared to single-head acquisition. Among the 426 patients undergoing diagnosis of myocardial ischemia, significant differences have only been found with regard to specificity being higher in the single-head acquisition. Diagnosis of myocardial ischemia related to a distinct myocardial perfusion region showed a significantly higher sensitivity of dual-head acquisition for the left anterior descending perfusion area, whereas specificity was significantly higher for single-head acquisition. Conclusions Our results indicate a beneficial effect of dual-head data collection with regard to sensitivity of the diagnosis of myocardial ischemia. In contrast, single-head data acquisition was superior with regard to specificity. However, it is justified to preferably apply dual-head data collection in clinical routine due to the shorter acquisition time leading to an evident time benefit of this acquisition technique.

Radiolabeled octreotide analogs (Oct) and metaiodobenzylguanidine (MIBG) offer 2 different approaches for imaging and targeting metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NET). Despite successful establishment of the revised World Health Organization (WHO) classification, which distinguishes between low- and high-grade malignant GEP-NET, there is a lack of scintigraphic studies comparing uptake behavior on the basis of this categorization. This study aims to define predisposing factors of tracer uptake for both imaging principles implementing the updated tumor criteria of the current WHO classification.Fifty-seven consecutive patients with histologically confirmed metastatic GEP-NET evaluated with both 111In-pentetreotide and 123I/131I-MIBG scintigraphy were included in this study. Intensity of tracer uptake was graded according to the different metastatic regions. Patients were classified as overall positive when avid uptake in the clinically relevant tumor lesions was present. Correlation was tested between the proportion of positive patients and tumor origin, function, and malignancy.Overall, 52 patients (91.2%) were Oct positive and 28 patients (49.1%) were MIBG positive. The proportion of tracer-positive patients was significantly higher (P0.05) in low-grade malignant tumors for both tracers and in functioning as well as in gastroenteral NET for MIBG. Five patients were negative for both tracers. None of the Oct-negative patients proved to be MIBG positive.Oct affinity is observed with high frequency throughout the subgroups of metastatic GEP-NET, whereas corresponding MIBG uptake is overall less prevalent and more group dependent. Tumor differentiation significantly impacts both Oct and MIBG uptake, whereas functionality predisposes only for MIBG accumulation. Though clearly inferior to Oct-based radioimaging in most GEP-NET, MIBG achieves a remarkable rate of radioligand accumulation in functioning midgut enterochromaffin cell metastases (80% of patients positive). These results may have implications for patient management and potentially for selection and performance of targeted therapy.

Nicotinic acetylcholine receptors mediate the parasympathetic autonomic control of cardiac function. Aim of this study was the assessment of cardiac nicotinic acetylcholine receptor distribution with a novel (alpha4beta2) nicotinic acetylcholine receptor PET ligand (2-deoxy-2- [18F]fluoro-D-glucose-A85380) in humans. Five healthy volunteers without cardiac disease and six patients with either Parkinson's disease or multiple system atrophy without additional overt cardiac disease were evaluated with 2-deoxy-2-[18F]fluoro-D-glucose-A85380 PET-imaging to assess the cardiac parasympathetic innervation and the putative impact of both disorders. 2-deoxy-2- [18F]fluoro-D-glucose-A85380 whole body PET-scans were performed on a Siemens PET/CT biograph(TM) 75.4 min +/- 6.7 after i.v. injection of 371.2 +/- 58.1 MBq. Average count rate density of left ventricle ROI's and a standard ROI in the right lung were measured within three consecutive slices of 10.0 mm thickness. Heart-to-lung ratios were calculated in each volunteer and patient. Tracer uptake in the left ventricle could be measured in all of the five volunteers and the six patients. Heart-to-lung ratios in the volunteer group were not different from patients suffering from Parkinson's disease or MSA (3.2 +/- 0.5 vs 3.2 +/- 0.8 and 2.96+/-0.7, mean +/- SD), respectively. Human cardiac nicotinic acetylcholine receptors can be visualized and measured by 2-deoxy-2- [18F]fluoro-D-glucose-A85380 PET scans both in cardiac-healthy subjects and patients suffering from Parkinson's disease or multiple system atrophy. The heart- as well as the lung-tracer uptake was almost constant throughout all subjects leading to a good target-to-background ratio. These first results suggest no impact of either PD or MSA on cardiac nicotinic acetylcholine receptors.