Christian Uprimny

68Ga-DOTA-Tyr3-Octreotide PET in Neuroendocrine Tumors: Comparison with Somatostatin Receptor Scintigraphy and CT

The aim of this study was to evaluate the diagnostic value of a new somatostatin analog, 68Ga-labeled 1,4,7,10-tetraazacyclododecane-N,N′,N″,N″′-tetraacetic acid-d-Phe1-Tyr3-octreotide (68Ga-DOTA-TOC), for PET in patients with known or suspected neuroendocrine tumors. PET was compared with conventional scintigraphy and dedicated CT. Methods: Eighty-four patients (48 men, 36 women; age range, 28–79 y; mean age ± SD, 58.2 ± 12.2 y) were prospectively studied. For analysis, patients were divided into 3 groups: detection of unknown primary tumor in the presence of clinical or biochemical suspicion of neuroendocrine malignancy (n = 13 patients), initial tumor staging (n = 36 patients), and follow-up after therapy (n = 35 patients). Each patient received 100–150 MBq 68Ga-DOTA-TOC. Imaging results of PET were compared with 99mTc-labeled hydrazinonicotinyl-Tyr3-octreotide (99mTc-HYNIC-TOC) and 111In-DOTA-TOC. CT was also performed on every patient using a multidetector scanner. Each imaging modality was interpreted separately by observers who were unaware of imaging findings before comparison with PET. The gold standard for defining true-positive (TP), true-negative (TN), false-positive (FP), and false-negative (FN) results was based on all available histologic, imaging, and follow-up findings. Results: PET was TP in 69 patients, TN in 12 patients, FP in 1 patient, and FN in 2 patients, indicating a sensitivity of 97%, a specificity of 92%, and an accuracy of 96%. The FP finding was caused by enhanced tracer accumulation in the pancreatic head, and the FN results were obtained in patients with a tumor of the gastrointestinal tract displaying liver metastases. 68Ga-DOTA-TOC showed higher diagnostic efficacy compared with SPECT (TP in 37 patients, TN in 12 patients, FP in 1 patient, and FN in 34 patients) and diagnostic CT (TP in 41 patients, TN in 12 patients, FP in 5 patients, and FN in 26 patients). This difference was of statistical significance (P < 0.001). However, the combined use of PET and CT showed the highest overall accuracy. Conclusion: 68Ga-DOTA-TOC PET shows a significantly higher detection rate compared with conventional somatostatin receptor scintigraphy and diagnostic CT with clinical impact in a considerable number of patients.

Bone Metastases in Patients with Neuroendocrine Tumor: 68Ga-DOTA-Tyr3-Octreotide PET in Comparison to CT and Bone Scintigraphy

Somatostatin receptor scintigraphy is an accurate imaging modality for the diagnosis of neuroendocrine tumor. Because detection of distant metastases has a major impact on treatment, early diagnosis of metastatic spread is of great importance. So far, no standard procedure has become established for the early diagnosis of bone metastases from neuroendocrine tumor. We compared the diagnostic value of CT with that of the novel somatostatin analog 68Ga-1,4,7,10-tetraazacyclododecane-N,N′,N″,N′′′-tetraacetic acid-d-Phe1-Tyr3-octreotide (68Ga-DOTATOC) in the detection of such metastases. Methods: Fifty-one patients (22 women and 29 men; age range, 32–87 y) with histologically verified neuroendocrine tumor were included in this study. PET scans were fused with CT scans using a vacuum fixation device. 18F-NaF or 99mTc-dicarboxypropane diphosphonate bone scans or clinical follow-up served as the reference standard. Results: Twelve of the 51 patients had no evidence of bone metastases on any of the available imaging modalities, and 37 patients had 68Ga-DOTATOC PET results true-positive for bone metastases. 68Ga-DOTATOC PET results were true-negative for 12 patients, false-positive for one, and false-negative for another, resulting in a sensitivity of 97% and a specificity of 92%. 68Ga-DOTATOC PET detected bone metastases at a significantly higher rate than did CT (P < 0.001). Furthermore, conventional bone scans confirmed the results of somatostatin receptor PET but did not reveal additional tumors in any patients. Conclusion: 68Ga-DOTATOC PET is a reliable, novel method for the early detection of bone metastases in patients with neuroendocrine tumor. Our results show that CT and conventional bone scintigraphy are less accurate than 68Ga-DOTATOC PET in the primary staging or restaging of neuroendocrine tumor.

68Ga-DOTA-Tyr3-Octreotide PET for Assessing Response to Somatostatin-Receptor–Mediated Radionuclide Therapy

68Ga-labeled 1,4,7,10-tetraazacyclododecane-N,N′,N′′,N′′′-tetraacetic acid-d-Phe1-Tyr3-octreotide (DOTA-TOC) PET has proven its usefulness in the diagnosis of patients with neuroendocrine tumors. Radionuclide therapy (90Y-DOTA-TOC or 177Lu-DOTA-octreotate) is a choice of treatment that also requires an accurate diagnostic modality for early evaluation of treatment response. Our study compared 68Ga-DOTA-TOC PET with CT or MRI using the Response Evaluation Criteria in Solid Tumors. Furthermore, standardized uptake values (SUVs) were calculated and compared with treatment outcome. Methods: Forty-six patients (29 men, 17 women; age range, 34–84 y) with advanced neuroendocrine tumors were investigated before and after 2–7 cycles of radionuclide therapy. Long-acting somatostatin analogs were not applied for at least 6 wk preceding the follow-up. Data were acquired with a dedicated PET scanner. Emission image sets were acquired at 90–100 min after injection. 68Ga-DOTA-TOC PET images were visually interpreted by 2 experienced nuclear medicine physicians. For comparison, multislice helical CT scans and 1.5-T MRI scans were obtained. Attenuation-corrected PET images were used to determine SUVs. Repeated CT evaluation and other imaging modalities, for example, 18F-FDG, were used as the reference standard. Results: According to the reference standard, 68Ga-DOTA-TOC PET and CT showed a concordant result in 32 patients (70%). In the remaining 14 patients (30%), discrepancies were observed, with a final outcome of progressive disease in 9 patients and remission in 5 patients. 68Ga-DOTA-TOC PET was correct in 10 patients (21.7%), including 5 patients with progressive disease. In these patients, metastatic spread was detected with the follow-up whole-body PET but was missed when concomitant CT was used. On the other hand, CT confirmed small pulmonary metastases not detected on 68Ga-DOTA-TOC in 1 patient and progressive liver disease not detected on 68Ga-DOTA-TOC in 3 patients. Quantitative SUV analysis of individual tumor lesions showed a large range of variability. Conclusion: 68Ga-DOTA-TOC PET shows no advantage over conventional anatomic imaging for assessing response to therapy when all CT information obtained during follow-up is compared. Only the development of new metastases during therapy was detected earlier in some cases when whole-body PET was used. SUV analysis of individual lesions is of no additional value in predicting individual responses to therapy.

Functional imaging in phaeochromocytoma and neuroblastoma with 68Ga-DOTA-Tyr3-octreotide positron emission tomography and 123I-metaiodobenzylguanidine: a clarification

Purpose 68Ga-DOTA-Tyr3-octreotide positron emission tomography (68Ga-DOTA-TOC PET) has proven to be superior to 111In-DTPA-D-Phe1-octreotide (111In-octreotide) planar scintigraphy and SPECT imaging in neuroendocrine tumours (NETs). Because of these promising results, we compared the accuracy of 123I-metaiodobenzylguanidine (123I-MIBG) imaging with PET in the diagnosis and staging of metastatic phaeochromocytoma and neuroblastoma, referring to radiological imaging as reference standard.

68 Ga-PSMA ligand PET versus 18 F-NaF PET: evaluation of response to 223 Ra therapy in a prostate cancer patient

Recent reports suggest that Ra prolongs survival in prostate cancer patients [1]. Bone scintigraphy is considered the gold standard in the assessment of osseous metastatic disease in prostate cancer [2]. Ga-labelled prostate-specific membrane antigen (PSMA) ligand is a novel, highly specific tracer for the detection of metastatic lesions of prostate cancer [3]. We present the case of a 69-year-old prostate cancer patient with extensive metastases to the bone (adenocarcinoma, Gleason score 8, PSA 1,239 μg/l, at initial diagnosis) who underwent both Ga-PSMA PET and F-NaF PET for the evaluation of response to therapy with Ra. F-NaF PET and a Ga-PSMA PET performed prior to

68Ga-PSMA-PET/CT-Guided Salvage Retroperitoneal Lymph Node Dissection for Disease Relapse After Radical Prostatectomy for Prostate Cancer

Approximately 30% of patients submitted to radical therapy for prostate cancer will develop local or distant relapse within 10 years from primary treatment, thus receiving second-line treatment within 5 years. The efficacy of salvage lymph node dissection for prostate cancer relapse has been established. However, there is a lack of PET radiopharmaceuticals that might be considered a valid tool to identify nodal metastases. Ga-PSMA-PET/CT (Ga-labeled prostate-specific membrane antigen ligand HBED-CC positron emission tomography/positron emission tomography) showed higher performance compared to choline PET/CT, in particular during the early phase of biochemical relapse, with low prostate-specific antigen levels. We report a case of a patient with biochemical relapse who underwent salvage retroperitoneal lymph node dissection according to the results obtained by GaPSMA-PET/CT. The patient exhibited a complete biochemical response after surgery (prostate-specific antigen < 0.2 ng/mL) at short-term follow-up.

Development of standardized image interpretation for 68Ga-PSMA PET/CT to detect prostate cancer recurrent lesions

MethodsAfter primary treatment, biochemical relapse (BCR) occurs in a substantial number of patients with prostate cancer (PCa). PET/CT imaging with prostate-specific membrane antigen based tracers (68Ga-PSMA) has shown promising results for BCR patients. However, a standardized image interpretation methodology has yet to be properly agreed. The aim of this study, which was promoted and funded by European Association of Nuclear Medicine (EANM), is to define standardized image interpretation criteria for 68Ga-PSMA PET/CT to detect recurrent PCa lesions in patients treated with primary curative intent therapy (radical prostatectomy or radiotherapy) who presented a biochemical recurrence. In the first phase inter-rater agreement between seven readers from seven international centers was calculated on the reading of 68Ga-PSMA PET/CT images of 49 patients with BCR. Each reader evaluated findings in five different sites of recurrence (local, loco-regional lymph nodes, distant lymph nodes, bone, and other). In the second phase the re-analysis was limited to cases with poor, slight, fair, or moderate agreement [Krippendorff’s (K) alpha<0.61]. Finally, on the basis of the consensus readings, we sought to define a list of revised consensus criteria for 68Ga-PSMA PET/CT interpretation.ResultsBetween-reader agreement for the presence of anomalous findings in any of the five sites was only moderate (K’s alpha: 0.47). The agreement improved and became substantial when readers had to judge whether the anomalous findings were suggestive for a pathologic, uncertain, or non-pathologic image (K’s alpha: 0.64). K’s alpha calculations for each of the five sites of recurrence were also performed and evaluated. First Delphi round was thus conducted. A more detailed definition of the criteria was proposed by the project coordinator, which was then discussed and finally agreed by the seven readers. After the second Delphi round only four cases of disagreement still remained. These were evaluated for a final round, allowing a final agreement table to be written.ConclusionWe hope that by developing these consensus guidelines on the interpretation of 68Ga-PSMA PET/CT, clinicians reporting these studies will be able to provide more consistent clinical reports and that within clinical trials, abnormality classifications will be harmonized, allowing more robust assessment of its diagnostic performance.

Detection of bioprosthetic valve infection by image fusion of (18)fluorodeoxyglucose-positron emission tomography and computed tomography.

A 63-year old male with prior bioprosthetic mitral valve replacement and coronary artery bypass graft surgery presented with dyspnea. C-reactive protein and white blood cells were elevated and serial blood cultures were negative. Transesophageal echocardiography showed a paravalvular leak and a thickened anterior leaflet of unclear either infective or degenerative origin. For differential diagnosis, cardiac 128-dual source computed tomography (CT) was performed. The CT image showed a thickened anterior leaflet and further revealed that the paravalvular leak was draining into a large wall thickened pseudoaneurysm with dense tissue adjacent suggestive for an abscess. Therefore, (18)fluorodeoxyglucose-positron emission tomography ((18)FDG-PET) was appended and fused with the CT images. There was no tracer-uptake surrounding the leak excluding an abscess. However, an increased (18)FDG-tracer uptake at the thickened anterior leaflet indicated active inflammation. During the subsequent cardiac surgery, vegetations were identified on the anterior cusp of the bioprosthetic valve. Intraoperative biopsy was taken and the cell culture was positive for Staphylococcus aureus. The pseudoaneurysm was repaired and the valve was replaced with a bioprosthesis. The patient was discharged uneventfully from hospital on day 12 and antibiotic treatment was continued for 4 weeks. In conclusion, our case indicates that (18)FDG-PET with cardiac CT image fusion may be a useful tool in patients with unclear focus of inflammation and possible bioprosthesis infection.

First experience with proteasome inhibitor treatment of radioiodine nonavid thyroid cancer using bortezomib.

PURPOSE Radioiodine nonavid thyroid cancer (TC) is a rare disease entity with a poor prognosis. Despite a multimodal therapeutic approach including surgery, chemotherapy, and external beam radiation, radioiodine nonavid TC accounts for a high number of TC-associated deaths. The aim of this investigation was to evaluate the response rate of progressive TC patients to treatment with the proteasome inhibitor bortezomib. MATERIALS AND METHODS Seven patients with inoperable, metastasized progressive TC proven to be radioiodine nonavid were included into this pilot study. Patients received bortezomib intravenously with a standardized dose of 1.3 mg/m on days 1, 4, 8, and 11. All patients underwent 3 therapeutic cycles with an interval of 10 days. [F]2-deoxy-2-fluoro-D-glucose positron emission tomography (F-FDG PET) and measurements of thyroglobulin levels were performed before, during, and after therapy, with a 6-week interval to post-therapeutic follow-up. RESULTS Stable disease was seen after proteasome inhibitor therapy in 4 of the 7 patients. Two of the 7 patients showed decrease of maximum standardized uptake value in both post-therapeutic follow-up investigations, and one of these cases also had decreasing thyroglobulin levels. Two patients experienced stable disease during the posttherapeutic follow-up. Two patients showing a mixed response had an improvement in their clinical situation. One patient had rapidly progressive disease, and died 3 months after the last therapeutic cycle. Adverse events included mild polyneuropathy in 2 patients and alterations of the blood count up to WHO (World Health Organization) grade 2 in 5 patients. CONCLUSION Proteasome inhibitor treatment with bortezomib is a promising therapeutic approach in TC patients without an established treatment alternative. The development of a specific therapeutic regimen for the treatment of radioiodine nonavid TC is warranted.

Pelvic Lymph Node Staging by Combined 18 F-FDG-PET/CT Imaging in Bladder Cancer Prior to Radical Cystectomy

Micro‐Abstract Lymph node (LN) metastases are important predictors for poor oncologic outcome. Therefore, accurate LN staging in bladder cancer before radical cystectomy is essential. Most studies used a 10 mm cutoff in detecting LN spread. We identified the “best” cutoff for detecting pelvic LN metastases at 8 mm. Using this cutoff, additional 18F‐fluorodeoxyglucose positron emission tomography is not recommended in preoperative staging. Background: Accurate lymph node (LN) staging in bladder cancer before radical cystectomy is essential as LN metastases have an independent prognostic value. Most studies used a cutoff of > 10 mm in detecting pelvic LN spread. The aim of this study was to evaluate the diagnostic accuracy of contrast‐enhanced computed tomography (CT) and 18F‐fluorodeoxyglucose (18F‐FDG) positron emission tomography (PET) alone, or combined for preoperative pelvic LN staging. Patients and Methods: We retrospectively analyzed the data of 70 bladder cancer patients that were staged with 18F‐FDG‐PET/CT before radical cystectomy between 2012 and 2015. 18F‐FDG‐PET images were analyzed visually and semi‐quantitatively by calculating the maximum standardized uptake value. CT scans were reviewed using different cutoffs of pelvic LNs, with the best cutoff at 8 mm (area under the curve = 0.684). Results: Metastatic LNs were confirmed in 53 (2.8%) of 1906 resected LNs in 11 (15.7%) patients. Sensitivity, specificity, and accuracy were 54.5%, 89.8%, and 84.3% for 18F‐FDG‐PET alone; 45.5%, 91.5%, and 84.3% for CT (LNs > 8 mm) alone; and 27.3%, 96.6%, and 85.7% for CT (LNs > 10 mm) alone, respectively. Combined 18F‐FDG‐PET/CT resulted in a nonsignificant increase of diagnostic accuracy using a cutoff > 8 mm for LN evaluation (63.6%, 86.4%, and 82.9%, respectively). A significant improvement of sensitivity to 63.6% was achieved only when LNs > 10 mm were considered suspicious (P = .046), but this reduced specificity to 88.1% (P = .025). Conclusions: Combined 18F‐FDG‐PET/CT does not seem to be justified in preoperative staging if the threshold of pelvic LNs is set > 8 mm.