Vikas Prasad

Molecular Imaging of HER2-Expressing Malignant Tumors in Breast Cancer Patients Using Synthetic 111In- or 68Ga-Labeled Affibody Molecules

The clinical utility of a human epidermal growth factor receptor 2 (HER2)–targeting Affibody molecule for detection and characterization of HER2-positive lesions was investigated in patients with recurrent metastatic breast cancer. Methods: Three patients received 111In- or 68Ga-labeled DOTA0-ZHER2:342-pep2 (ABY-002). γ-Camera, SPECT, or PET/CT images were compared with earlier 18F-FDG PET/CT results. Results: Administration of radiolabeled ABY-002 was well tolerated. Blood kinetics of radiolabeled ABY-002 showed a first half-life of 4–14 min, second half-life of 1–4 h, and third half-life of 12–18 h. Radiolabeled ABY-002 detected 9 of 11 18F-FDG–positive metastases as early as 2–3 h after injection. Conclusion: Molecular imaging using 111In- or 68Ga-labeled ABY-002 has the potential to localize metastatic lesions in vivo, adds qualitative information not available today by conventional imaging techniques, and may allow the HER2 status to be determined for metastases not amenable to biopsy. To our knowledge, this is the first report on clinical imaging data obtained with a non–immunoglobulin-based scaffold protein.

German Multicenter Study Investigating 177Lu-PSMA-617 Radioligand Therapy in Advanced Prostate Cancer Patients

177Lu-labeled PSMA-617 is a promising new therapeutic agent for radioligand therapy (RLT) of patients with metastatic castration-resistant prostate cancer (mCRPC). Initiated by the German Society of Nuclear Medicine, a retrospective multicenter data analysis was started in 2015 to evaluate efficacy and safety of 177Lu-PSMA-617 in a large cohort of patients. Methods: One hundred forty-five patients (median age, 73 y; range, 43–88 y) with mCRPC were treated with 177Lu-PSMA-617 in 12 therapy centers between February 2014 and July 2015 with 1–4 therapy cycles and an activity range of 2–8 GBq per cycle. Toxicity was categorized by the common toxicity criteria for adverse events (version 4.0) on the basis of serial blood tests and the attending physician’s report. The primary endpoint for efficacy was biochemical response as defined by a prostate-specific antigen decline ≥ 50% from baseline to at least 2 wk after the start of RLT. Results: A total of 248 therapy cycles were performed in 145 patients. Data for biochemical response in 99 patients as well as data for physician-reported and laboratory-based toxicity in 145 and 121 patients, respectively, were available. The median follow-up was 16 wk (range, 2–30 wk). Nineteen patients died during the observation period. Grade 3–4 hematotoxicity occurred in 18 patients: 10%, 4%, and 3% of the patients experienced anemia, thrombocytopenia, and leukopenia, respectively. Xerostomia occurred in 8%. The overall biochemical response rate was 45% after all therapy cycles, whereas 40% of patients already responded after a single cycle. Elevated alkaline phosphatase and the presence of visceral metastases were negative predictors and the total number of therapy cycles positive predictors of biochemical response. Conclusion: The present retrospective multicenter study of 177Lu-PSMA-617 RLT demonstrates favorable safety and high efficacy exceeding those of other third-line systemic therapies in mCRPC patients. Future phase II/III studies are warranted to elucidate the survival benefit of this new therapy in patients with mCRPC.

Molecular imaging with 68Ga-SSTR PET/CT and correlation to immunohistochemistry of somatostatin receptors in neuroendocrine tumours

PurposeSomatostatin receptors (SSTR) are known for an overexpression in gastroenteropancreatic neuroendocrine tumours (GEP-NET). The aim of the present study was to find out if the receptor density predicted by the semi-quantitative parameters generated from the static positron emission tomography (PET/CT) correlated with the in vitro immunohistochemistry using a novel rabbit monoclonal anti-SSTR2A antibody (clone UMB-1) for specific SSTR2A immunohistochemistry and polyclonal antibodies for SSTR1 and 3–5.MethodsOverall 14 surgical specimens generated from 34 histologically documented GEP-NET patients were correlated with the preoperative 68Ga-DOTA-NOC PET/CT. Quantitative assessment of the receptor density was done using the immunoreactive score (IRS) of Remmele and Stegner; the additional 4-point IRS classification for immunohistochemistry and standardized uptake values (SUVmax and SUVmean) were used for PET/CT.ResultsThe IRS for SSTR2A and SSTR5 correlated highly significant with the SUVmax on the PET/CT (p < 0.001; p < 0.05) and the IRS for SSTR2A with the SUVmean (p < 0.013). The level of SSTR2A score correlated significantly with chromogranin A staining and indirectly to the tumour grading.ConclusionThe highly significant correlation between SSTR2A and SSTR5 and the SUVmax on the 68Ga-DOTA-NOC PET/CT scans is concordant with the affinity profile of 68Ga-DOTA-NOC to the SSTR subtypes and demonstrates the excellent qualification of somatostatin analogues in the diagnostics of NET. This study correlating somatostatin receptor imaging using 68Ga-DOTA-NOC PET/CT with immunohistochemically analysed SSTR also underlines the approval of therapy using somatostatin analogues, follow-up imaging as well as radionuclide therapy.

PET/CT imaging of osteoblastic bone metastases with 68Ga-bisphosphonates: first human study

Bisphosphonates are well established ligands for Tc for planar and SPECT/CT imaging of osteoblastic metastases. A novelDOTA-based bisphosphonate, (4-{[bis-(phosphonomethyl)) carbamoyl]methyl}-7,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl)acetic acid (BPAMD) [1, 2], was labelled using the Ge/Ga generator-derived positron emitter Ga [3], resulting in the PET tracer [Ga]BPAMD. [Ga]BPAMD was injected i.v. into a patient with known extensive bone metastases of prostate cancer. [Ga]BPAMD [maximum intensity projection (MIP) 50 min post-injection (p.i.), 462 MBq] revealed intense accumulation in multiple osteoblastic lesions in the central skeleton, ribs and proximal extremities: a = coronal PET, b = sagittal PET/CT. For comparison, c shows F-fluoride PET (sagittal, MIP 90 min p.i., 270 MBq). Metastases were detected in the whole skeleton with a maximal standardized uptake value (SUVmax) of 77.1 and 62.1 in the 10th thoracic and L2 vertebra vs 39.1 and 39.2 for F-fluoride, respectively. The advantages of this new bone imaging PET tracer are the very high target to soft tissue ratios and fast clearance, its ease of use and the generator-based availability of Ga which becomes especially important in these days of Tc shortage. While F-fluoride is adsorbed on bone surface and is related to blood flow, the bisphosphonate [Ga]BPAMD is taken up also by osteoclasts reflecting the farnesyl diphosphate synthase enzyme dynamics in the HMG-CoA reductase pathway. Since this pathway is mainly responsible for the osteoclastic bone destruction, [Ga]BPAMD may be superior in osteoclastic lesions. Finally, [Ga]BPAMD seems to be an ideal PET/CT tracer to plan and monitor bisphosphonate therapy in several bone disorders like osteoporosis, osteitis deformans, bone metastases, multiple myeloma, osteogenesis imperfecta, etc. and also to monitor radionuclide therapy for palliation of bone pain.

Receptor PET/CT Imaging of Neuroendocrine Tumors

This chapter is dedicated to Gustav Hor, Professor Emeritus and former Director of the Department of Nuclear Medicine, University of Frankfurt/Main, on the occasion of his 75th birthday.

Peptide receptor radionuclide therapy of Merkel cell carcinoma using 177 lutetium-labeled somatostatin analogs in combination with radiosensitizing chemotherapy: a potential novel treatment based on molecular pathology

Few studies have been published on the safety and feasibility of synchronous use of peptide receptor radionuclide therapy (PRRNT), as source of internal radiation therapy, in combination with chemotherapy. In this study we reported a 53-year-old man with stage IV Merkel cell carcinoma (MCC), who underwent synchronous internal radiation therapy and chemotherapy. Based on presumable poor prognosis with chemotherapy only, functional similarities of MCC with other neuroendocrine tumors and available evidence of effectiveness and safety of synchronous use of external beam radiation therapy and chemotherapy in treatment of high-risk MCC patients, our interdisciplinary neuroendocrine tumor board recommended him to add PRRNT to his ongoing chemotherapy. He received 2 courses of 177Lu-DOTATATE(1, 4, 7, 10-Tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid-1-D-Phe1-Tyr3-Thr8-octreotide) in combination with ongoing 8 cycles of liposomal doxorubicin based on standard protocols. Response to therapy was evaluated by 18F-FDG and 68gallium-somatostatin-receptor PET/CT. There was an impressive improvement of the clinical symptoms. However, follow-up PET/CT studies showed mixed pattern of response. Synchronous use of PRRNT and radiosensitizing chemotherapy seems safe and feasible in high risk MCC patients, however, further prospective studies and clinical trials are warranted to provide reliable evidence of possible pitfalls and effectiveness of PRRNT and 68Ga-somatostatin-receptor PET/CT in the management of MCC.

The Bad Berka Dose Protocol: Comparative Results of Dosimetry in Peptide Receptor Radionuclide Therapy Using 177 Lu-DOTATATE, 177 Lu-DOTANOC, and 177 Lu-DOTATOC

PURPOSE The objective of this study is to analyze the in vivo behavior of the (177)Lu-labeled peptides DOTATATE, DOTANOC, and DOTATOC used for peptide receptor radionuclide therapy (PRRNT) of neuroendocrine tumors (NETs), by measuring organ and tumor kinetics and by performing dosimetric calculations. METHODS Two hundred fifty-three patients (group 1) with metastasized NET who underwent PRRNT were examined. Out of these, 185 patients received (177)Lu-DOTATATE, 9 were treated with (177)Lu-DOTANOC, and 59 with (177)Lu-DOTATOC. Additionally, 25 patients receiving, in consecutive PRRNT cycles, DOTATATE followed by DOTATOC (group 2) and 3 patients receiving DOTATATE and DOTANOC (group 3) were analyzed. Dosimetric calculations (according to MIRD scheme) were performed using OLINDA software. RESULTS In group 1, DOTATOC exhibited the lowest and DOTANOC the highest uptake and therefore mean absorbed dose in normal organs (whole body, kidney, and spleen). In group 2, there was a significant difference between DOTATATE and DOTATOC concerning kinetics and normal organ doses. (177)Lu-DOTATOC had the lowest uptake/dose delivered to normal organs and highest tumor-to-kidney ratio. There were no significant differences between the three peptides concerning tumor kinetics and mean absorbed tumor dose. CONCLUSIONS The study demonstrates a correlation between high affinity of DOTANOC in vitro and high uptake in normal organs/whole body in vivo, resulting in a higher whole-body dose. DOTATOC exhibited the lowest uptake and dose delivered to normal tissues and the best tumor-to-kidney ratio. Due to large interpatient variability, individual dosimetry should be performed for each therapy cycle.

Effect of Peptide Receptor Radionuclide Therapy on Somatostatin Receptor Status and Glucose Metabolism in Neuroendocrine Tumors: Intraindividual Comparison of Ga-68 DOTANOC PET/CT and F-18 FDG PET/CT

The heterogeneous nature of the neuroendocrine tumors (NET) makes it challenging to find one uniformly applicable management protocol which is especially true for diagnosis. The discovery of the overexpression of somatostatin receptors (SMS-R) on neuroendocrine tumor cells lead to the generalized and rapid acceptance of radiolabeled somatostatin receptor analogs for staging and restaging of NET as well as for Peptide Receptor Radionuclide Therapy (PRRNT) using Y-90 and Lu-177 DOTATATE/DOTATOC. In this present work we tried to look in to the effect of PRRNT on the glucose metabolism assessed by F-18 FDG PET/CT and SMS-R density assessed by Ga-68 DOTANOC PET/CT. We observed a complex relationship between the somatostatin receptor expression and glucose metabolism with only 56% (77/138) of the lesions showing match, while the others show mismatch between the receptor status and metabolism. The match between receptor expression and glucose metabolism increases with the grade of NET. In grade 3 NET, there is a concurrence between the changes in glucose metabolism and somatostatin receptor expression. PRRNT was found to be more effective in lesions with higher receptor expression.

A Delphic consensus assessment: imaging and biomarkers in gastroenteropancreatic neuroendocrine tumor disease management

The complexity of the clinical management of neuroendocrine neoplasia (NEN) is exacerbated by limitations in imaging modalities and a paucity of clinically useful biomarkers. Limitations in currently available imaging modalities reflect difficulties in measuring an intrinsically indolent disease, resolution inadequacies and inter-/intra-facility device variability and that RECIST (Response Evaluation Criteria in Solid Tumors) criteria are not optimal for NEN. Limitations of currently used biomarkers are that they are secretory biomarkers (chromogranin A, serotonin, neuron-specific enolase and pancreastatin); monoanalyte measurements; and lack sensitivity, specificity and predictive capacity. None of them meet the NIH metrics for clinical usage. A multinational, multidisciplinary Delphi consensus meeting of NEN experts (n = 33) assessed current imaging strategies and biomarkers in NEN management. Consensus (>75%) was achieved for 78% of the 142 questions. The panel concluded that morphological imaging has a diagnostic value. However, both imaging and current single-analyte biomarkers exhibit substantial limitations in measuring the disease status and predicting the therapeutic efficacy. RECIST remains suboptimal as a metric. A critical unmet need is the development of a clinico-biological tool to provide enhanced information regarding precise disease status and treatment response. The group considered that circulating RNA was better than current general NEN biomarkers and preliminary clinical data were considered promising. It was resolved that circulating multianalyte mRNA (NETest) had clinical utility in both diagnosis and monitoring disease status and therapeutic efficacy. Overall, it was concluded that a combination of tumor spatial and functional imaging with circulating transcripts (mRNA) would represent the future strategy for real-time monitoring of disease progress and therapeutic efficacy.

EDIM - TKTL1 blood test: a noninvasive method to detect upregulated glucose metabolism in patients with malignancies

AIM To determine whether the TKTL1 protein epitope detection in monocytes (EDIM) test allows detection of upregulated glucose metabolism in malignancies. MATERIALS & METHODS The EDIM-TKTL1 blood test was conducted in 240 patients with 17 different confirmed or suspected malignancies. Test scores were compared with (18)F-fluoro-2-deoxy-D-glucose (FDG)-PET/computed tomography (CT) results. RESULTS EDIM-TKTL1 score and FDG-PET results showed a concordance of 90% with a sensitivity of 94% and specificity of 81%. Including CT data, all values were enhanced. A subgroup analysis of non-small-cell lung cancer patients showed a significant correlation between the EDIM-TKTL1 score and the primary tumor size determined by FDG-PET/CT. CONCLUSION EDIM-TKTL1 blood test revealed good concordance with FDG-PET/CT results in patients with malignancies demonstrating its efficacy to detect upregulation of glucose metabolism in primary tumors or metastases.