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PDF file - 117K, Supplemental Figure 1A: PSA waterfall plots by dose received. Each individual subjects best PSA response on study. The top figure depicts those subjects who received 65 mCi/m2 and the bottom figure depicts those who received 70 mCi/m2 (the phase I maximum tolerated dose). Supplemental Figure 1B: Circulating Tumor Cell Count waterfall plot Each individual subjects % change in CTC count from baseline to 4-6 weeks following therapy with 70 mCi/m2 of 177Lu-J591. Using the 5 CTC/7.5 mL cutoff, 6 began and remained favorable, 3 converted from unfavorable to favorable (7-->3, 18-->0, 34-->0), and 3 had decline in counts, but remained unfavorable (161-->118, 228-->110, 60-->16). Three subjects had 0 CTCs per 7.5 mL blood at baseline and remained with 0 at follow up. Supplemental Figure 1C: Change in measurable disease Each individual subject with measurable disease is depicted with % change in sum of unidimensional measurements (RECIST). Dose of 177Lu-J591 received is indicted by color.

CCR Translation for This Article from Phase II Study of Lutetium-177–Labeled Anti-Prostate-Specific Membrane Antigen Monoclonal Antibody J591 for Metastatic Castration-Resistant Prostate Cancer

Purpose: To assess the efficacy of a single infusion of radiolabeled anti-prostate-specific membrane antigen (PSMA) monoclonal antibody J591 (lutetium-177; 177Lu) by prostate-specific antigen (PSA) decline, measurable disease response, and survival.Experimental Design: In this dual-center phase II study, two cohorts with progressive metastatic castration-resistant prostate cancer received one dose of 177Lu-J591 (15 patients at 65 mCi/m2, 17 at 70 mCi/m2) with radionuclide imaging. Expansion cohort (n = 15) received 70 mCi/m2 to verify response rate and examine biomarkers.Results: Forty-seven patients who progressed after hormonal therapies (55.3% also received prior chemotherapy) received 177Lu-J591. A total of 10.6% experienced ≥50% decline in PSA, 36.2% experienced ≥30% decline, and 59.6% experienced any PSA decline following their single treatment. One of 12 with measurable disease experienced a partial radiographic response (8 with stable disease). Sites of prostate cancer metastases were targeted in 44 of 47 (93.6%) as determined by planar imaging. All experienced reversible hematologic toxicity, with grade 4 thrombocytopenia occurring in 46.8% (29.8% received platelet transfusions) without significant hemorrhage. A total of 25.5% experienced grade 4 neutropenia, with one episode of febrile neutropenia. The phase I maximum tolerated dose (70 mCi/m2) resulted in more 30% PSA declines (46.9% vs. 13.3%, P = 0.048) and longer survival (21.8 vs. 11.9 months, P = 0.03), but also more grade 4 hematologic toxicity and platelet transfusions. No serious nonhematologic toxicity occurred. Those with poor PSMA imaging were less likely to respond.Conclusion: A single dose of 177Lu-J591 was well tolerated with reversible myelosuppression. Accurate tumor targeting and PSA responses were seen with evidence of dose response. Imaging biomarkers seem promising. Clin Cancer Res; 19(18); 5182–91. ©2013 AACR.

Background Prostate cancer is radiosensitive. Prostate-specific membrane antigen (PSMA) is selectively overexpressed on advanced, castration-resistant tumors. Lutetium-177-labeled anti-PSMA monoclonal antibody J591 (177 Lu-J591) targets prostate cancer with efficacy and dose-response/toxicity data when delivered as a single dose. Dose fractionation may allow higher doses to be administered safely. Method Men with metastatic castration-resistant prostate cancer refractory to or refusing standard treatment options with normal neutrophil and platelet counts were enrolled in initial phase 1b dose-escalation cohorts followed by phase 2a cohorts treated at recommended phase 2 doses (RP2Ds) comprising 2 fractionated doses of 177 Lu-J591 2 weeks apart. 177 Lu-J591 imaging was performed after treatment, but no selection for PSMA expression was performed before enrollment. Phase 2 patients had circulating tumor cell (CTC) counts assessed before and after treatment. Results Forty-nine men received fractionated doses of 177 Lu-J591 ranging from 20 to 45 mCi/m2 ×2 two weeks apart. The dose-limiting toxicity in phase 1 was neutropenia. The RP2Ds were 40 mCi/m2 and 45 mCi/m2 ×2. At the highest RP2D (45 mCi/m2 ×2), 35.3% of patients had reversible grade 4 neutropenia, and 58.8% of patients had thrombocytopenia. This dose showed a greater decrease in prostate-specific antigen (PSA) levels and longer survival (87.5% with any PSA decrease, 58.8% with >30% decrease, 29.4% with >50% decrease; median survival, 42.3 months [95% confidence interval, 19.9-64.7]). Fourteen of 17 (82%) patients with detectable CTCs experienced a decrease in CTC count. Overall, 79.6% of patients had positive PSMA imaging; those with less intense PSMA imaging tended to have poorer responses. Conclusion Fractionated administration of 177 Lu-J591 allowed higher cumulative radiation dosing. The frequency and depth of PSA decrease, overall survival, and toxicity (dose-limiting myelosuppression) increased with higher doses.

Context No therapies are approved for the treatment of metastatic and/or recurrent pheochromocytoma or paraganglioma (PPGL) in the United States. Objective To determine the maximum tolerated dose (MTD) of high-specific-activity I-131 meta-iodobenzylguanidine (MIBG) for the treatment of metastatic and/or recurrent PPGL. Design Phase 1, dose-escalating study to determine the MTD via a standard 3 + 3 design, escalating by 37 MBq/kg starting at 222 MBq/kg. Setting Three centers. Patients Twenty-one patients were eligible, received study drug, and were evaluable for MTD, response, and toxicity. Intervention Open-label use of high-specific-activity I-131 MIBG therapy. Main Outcome Measures Dose-limiting toxicities, adverse events, radiation absorbed dose estimates, radiographic tumor response, biochemical response, and survival. Results The MTD was determined to be 296 MBq/kg on the basis of two observed dose-limiting toxicities at the next dose level. The highest mean radiation absorbed dose estimates were in the thyroid and lower large intestinal wall (each 1.2 mGy/MBq). Response was evaluated by total administered activity: four patients (19%), all of whom received >18.5 GBq of study drug, had radiographic tumor responses of partial response by Response Evaluation Criteria in Solid Tumors. Best biochemical responses (complete or partial response) for serum chromogranin A and total metanephrines were observed in 80% and 64% of patients, respectively. Overall survival was 85.7% at 1 year and 61.9% at 2 years after treatment. The majority (84%) of adverse events were considered mild or moderate in severity. Conclusions These findings support further development of high-specific-activity I-131 MIBG for the treatment of metastatic and/or recurrent PPGL at an MTD of 296 MBq/kg.

This review traces the development of targeted radionuclide therapy (TRT) (the Magic Bullet) from the discovery of radioactivity in nature and the subsequent discovery of artificial radioactivity (the production of radioactive isotopes of stable elements) to the current status of TRT in the medical literature and clinical practice. With the availability of radioisotopes of iodine, initially to study thyroidal iodine kinetics, it was soon observed that sufficient amounts of radiation could control thyroid hyperfunction. Shortly thereafter, when radioiodine was administered to a patient with differentiated thyroid carcinoma whose hypermetabolism was secondary to excess thyroid hormone production, it was observed that radioiodine also had an antitumor effect. The concept of the Magic Bullet has since been extended to other disease states such as (1) 131I-meta-iodobenzylguanidine (131I-MIBG) to treat malignant and metastatic pheochromocytomas and paragangliomas; (2) 131I-tositumomab, a radioiodinated anti-CD20 IgG to treat CD20 expressing non-Hodgkins lymphoma. In recent years, other β-emitting radionuclides, Yttrium-90 (90Y) and Lutetium-177 (177Lu), have been added to this list. These radiometals have different physical properties that were thought to be possibly more effective than radioiodine. 90Y was initially used to radio-label somatostatin analogues to treat metastatic neuroendocrine tumors but has virtually been replaced by 177Lu since the physical characteristics of the latter appear to be better suited to effectively irradiate the micrometastases of neuroendocrine tumors. A similar evolution is taking place in the development of a targeted radionuclide therapeutic that recognizes prostate-specific membrane antigen (PSMA), an epitope expressed in increased amounts in prostate carcinoma. Both an anti-PSMA immunoglobulin (J591) and a small molecule glutamase ligand are currently being evaluated as targeted radionuclide therapy agents. Radionuclides that have affinity for the calcium hydroxyapatite in bone have been used to relieve bone pain due to tumor metastases based on increased deposition of the bone seeking radiometals at the osteoblastic interface of the tumor metastases and boney matrix. Most of these trials have been in patients with metastatic prostate cancer since there are few other options. In this regard, targeted radionuclide therapy has come full circles as the most recent addition to this anti-tumor arsenal is a radioisotope of Radium, 223Ra, an alpha emitter which has a greater radiobiologic effect but limited range in tissue thus adding an element of safety when treating marrow metastases. Other alpha emitting radiometals are currently being evaluated as alternative radiometals in place of 90Y and 177Lu to label targeting molecules.

Radioactive iodine [RAI] has been used in the management of patients with differentiated thyroid cancer for over 70 years. During this period, the role of RAI has evolved from treatment of metastatic disease only to include ablation of thyroid remnant tissue following total or near-total thyroidectomy. Along the way, it became apparent that patients who received RAI ablation had fewer recurrences than patients managed with thyroid hormone replacement therapy only, assigning an additional role to RAI, i.e., administration as adjuvant therapy. Currently, based on the long-term outcome experience in patients receiving ablative doses of RAI, physicians involved in the utilization of RAI are reexamining its role as an adjuvant therapy. Thus, at the present time, the decision as to ablate or not to ablate remnant tissue (and hence to forgo an adjuvant role) in patients with minimal disease and few risk factors is undergoing revision. In addition, advances in imaging instrumentation (gamma camera, SPECT, SPECT/CT, and PET/CT) and radionuclide production (I-123, I-124, F-18 FDG), available pharmacologic agents (recombinant human TSH and tyrosine kinase inhibitors), and laboratory testing (serum TSH and thyroglobulin) provide many options in terms of management. Hence, the role and utilization of RAI have become increasingly complex. This review presents the highlights of the present knowledge and understanding of the role of RAI in differentiated thyroid cancer. The reader is encouraged to investigate the many references provided as well as chapters in this compendium dealing with some aspects in more detail.

Prostate cancer is radiosensitive. Prostate-specific membrane antigen (PSMA) is selectively overexpressed on advanced, castration-resistant tumors. Lutetium-177-labeled anti-PSMA monoclonal antibody J591 (Men with metastatic castration-resistant prostate cancer refractory to or refusing standard treatment options with normal neutrophil and platelet counts were enrolled in initial phase 1b dose-escalation cohorts followed by phase 2a cohorts treated at recommended phase 2 doses (RP2Ds) comprising 2 fractionated doses ofForty-nine men received fractionated doses ofFractionated administration of

Prostate specific membrane antigen (PSMA) is the single most well-validated prostate cancer (PCa)-specific cell membrane antigen known. It is present in high levels in 95% of PCa, and is an ideal target to develop radiopharmaceuticals for imaging studies and radionuclide therapy. Humanized J591 monoclonal antibody (mAb) binds specifically with nanomolar affinity to the extracellular domain of PSMA. After binding, the PSMA-antibody complex is rapidly internalized, increasing the potential utility of PSMA as a target for the delivery of mAb-conjugated radionuclides or cytotoxins. J591 mAb was labeled with 177Lu at a high specific activity (10-30 mCi/mg) using DOTA as the bifunctional chelate. The preclinical data in PSMA positive xenografts, strongly suggested that 177;Lu-J591 mAb is an ideal radiopharmaceutical for RIT of metastatic PCa. Since October 2000, five clinical studies (phase I and II) were performed in subjects with metastatic castration-resistant prostate cancer (CRPC) using 177Lu-J591. The methodology and the results of these clinical studies are briefly reviewed in this article. The maximum tolerated dose (MTD) as a single dose was 70 mCi2. Based on dose fractionation (DF), MTD was 90 mCi/m2(2 doses of 45 mCi/m2, 2 wks apart). Phase II study in patients with progressive metastatic CRPC, at a dose of 65- 70 mCi/m2 resulted in significant PSA declines in 60% of the patients. While myelosuppression was the dose limiting toxicity, DF alone or in combination with docetaxel also resulted in significant PSA declines with much less toxicity. 177Lu imaging studies demonstrated accurate targeting of known metastatic sites in >90% of patients and those with stronger PSMA expression by semi-quantitative imaging had more PSA declines. These clinical studies clearly documented the potential therapeutic value of radioimmunotherapy (RIT) in metastatic PCa.

To reconstruct reliable nuclear medicine-related occupational radiation doses or doses received as patients from radiopharmaceuticals over the last five decades, the authors assessed which radiopharmaceuticals were used in different time periods, their relative frequency of use, and typical values of the administered activity. This paper presents data on the changing patterns of clinical use of radiopharmaceuticals and documents the range of activity administered to adult patients undergoing diagnostic nuclear medicine procedures in the U.S. between 1960 and 2010. Data are presented for 15 diagnostic imaging procedures that include thyroid scan and thyroid uptake; brain scan; brain blood flow; lung perfusion and ventilation; bone, liver, hepatobiliary, bone marrow, pancreas, and kidney scans; cardiac imaging procedures; tumor localization studies; localization of gastrointestinal bleeding; and non-imaging studies of blood volume and iron metabolism. Data on the relative use of radiopharmaceuticals were collected using key informant interviews and comprehensive literature reviews of typical administered activities of these diagnostic nuclear medicine studies. Responses of key informants on relative use of radiopharmaceuticals are in agreement with published literature. Results of this study will be used for retrospective reconstruction of occupational and personal medical radiation doses from diagnostic radiopharmaceuticals to members of the U.S. radiologic technologists' cohort and in reconstructing radiation doses from occupational or patient radiation exposures to other U.S. workers or patient populations.

In 2006, a multidisciplinary thyroid conference (MDTC) was implemented to better plan management of thyroid cancer patients at our institution. This study assessed the clinical impact of a MDTC on radioactive iodine (RAI) treatment patterns. A prospective database (2003–2014) collected patient and tumor characteristics, RAI doses, and tumor recurrences. Patients treated with total thyroidectomy for differentiated thyroid carcinoma ≥1 cm were stratified based on American Thyroid Association (ATA) risk classification. RAI regimens were compared before initiation of MDTC (2003–2005, n = 88), after establishment of MDTC (2007–2009, n = 95), and after the release of 2009 ATA guidelines (2011–2014, n = 181). RAI doses were defined as low (≤75 mCi), intermediate (76–150 mCi), and high (>150 mCi). There was a significant decrease in the number of patients who received high-dose RAI after implementation of MDTC compared to before initiation of MDTC in the intermediate and high-risk patient groups (p = 0.04 and p

Radioimmunotherapy (RIT) is effective treatment for indolent non-Hodgkin lymphomas (NHLs), but response durations are usually limited, especially in aggressive NHL. We hypothesized that administration of bortezomib as a radiosensitizer with RIT would be tolerable and improve efficacy in NHL. This phase 1 dose-escalation study evaluated escalating doses of bortezomib combined with 131I-tositumomab in patients with relapsed/refractory NHL. Twenty-five patients were treated. Treatment was well tolerated, with primarily hematologic toxicity. The maximum tolerated dose (MTD) was determined to be 0.9 mg/m2 bortezomib, in combination with a standard dose of 75 cGy 131I-tositumomab. Sixteen patients responded (64%), including 44% complete responses (CRs), with 82% CR in patients with follicular lymphoma (FL). At a median follow-up of 7 months, median progression-free survival was 7 months, and seven of 11 patients with FL remained in remission at a median of 22 months. In conclusion, bortezomib can be safely administered in combination with 131I-tositumomab with promising response rates.

In hematological malignancies, multidrag resistance (MDR) has been associated with the drag efflux pumps: one is the classical Mr 170,000 P-glycoprotein (Pgp) and the other Mr 190,000 multidrag resistance-associated protein (MRP). In addition, the overexpression of a recently identified protein, lung resistance protein (LRP), is also associated with reduced intracellular drag accumulation and retention. Currently available detection methods may provide variable results among laboratories, as there is no single set of standards for detection techniques at the mRNA or protein level. Moreover, these methods may not be informative about the in vivo function of Pgp, MRP or LRP. Single-photon emission tomography (SPECT) and positron emission tomography (PET) have been evaluated for the non-invasive determination of Pgp- and MRP- mediated transport systems. Tc-99m-hexaxis-2-methoxyisobutyl isonitrile (Tc-99m-Sestamibi), an agent used in myocardial perfusion and tumor imaging, is a substrate for Pgp and MRP, and has been used for tumor imaging, and to visualize Pgp expression. Tc-99m-Tetrofosmin and several Tc-99m-Q complexes, are also recognized as substrates by Pgp pump mechanism. Moreover, radiopharmaceuticals including carbon-11-labeled colchicine, verapamil and daunorabicin have been used for the assessment of Pgp-mediated transport functions in vivo using PET technology. The results suggest that the potential exists for nuclear medicine imaging using either Tc-99m-labeled compounds and SPECT or carbon-11-labeled compounds and PET to detect MDR in tumors prior to or after exposure to chemotherapeutic agents.

INTRODUCTION AND TECHNICAL ASPECTS. Physics and History of SPECT/CT. CLINICAL APPLICATIONS OF SPECT/CT IN TUMOR IMAGING. 99mTc-Sestamibi SPECT/CT for Parathyroid Imaging. 131Iodine SPECT/CT for Thyroid Cancer Imaging. 123Iodine MIBG SPECT/CT for Tumor Imaging. 111Indium Octreotide SPECT/CT for Neuroendocrine Tumor Imaging. Bone SPECT/CT in Oncology. 67Gallium SPECT/CT in Imaging of Lymphoma. Sentinal Node Scintigraphic Mapping Using SPECT/CT. SPECT/CT Imaging for Prostate Cancer. SPECT/CT for Dosimetry Calculations. ADDITIONAL AND FUTURE APPLICATIONS OF SPECT/CT. SPECT/CT Attenuation Compensation in Nuclear Cardiology. SPECT/CT in the Evaluation of Infection. SPECT/CT Imaging of Small Animals

It has been demonstrated that the humanized clivatuzumab tetraxetan (hPAM4) antibody targets pancreatic ductal carcinoma selectively. After a trial of radioimmunotherapy that determined the maximum tolerated dose of single-dose yttrium-90-labeled hPAM4 ((90) Y-hPAM4) and produced objective responses in patients with advanced pancreatic ductal carcinoma, the authors studied fractionated radioimmunotherapy combined with low-dose gemcitabine in this disease.Thirty-eight previously untreated patients (33 patients with stage IV disease and 5 patients with stage III disease) received gemcitabine 200 mg/m(2) weekly for 4 weeks with (90) Y-hPAM4 given weekly in Weeks 2, 3, and 4 (cycle 1), and the same cycle was repeated in 13 patients (cycles 2-4). In the first part of the study, 19 patients received escalating weekly (90) Y doses of 6.5 mCi/m(2) , 9.0 mCi/m(2) , 12.0 mCi/m(2) , and 15.0 mCi/m(2) . In the second portion, 19 additional patients received weekly doses of 9.0 mCi/m(2) or 12.0 mCi/m(2) .Grade 3/4 thrombocytopenia or neutropenia (according to version 3.0 of the National Cancer Institute's Common Terminology Criteria for Adverse Events) developed in 28 of 38 patients after cycle 1 and in all retreated patients; no grade3 nonhematologic toxicities occurred. Fractionated dosing of cycle 1 allowed almost twice the radiation dose compared with single-dose radioimmunotherapy. The maximum tolerated dose of (90) Y-hPAM4 was 12.0 mCi/m(2) weekly for 3 weeks for cycle 1, with ≤9.0 mCi/m(2) weekly for 3 weeks for subsequent cycles, and that dose will be used in future trials. Six patients (16%) had partial responses according to computed tomography-based Response Evaluation Criteria in Solid Tumors, and 16 patients (42%) had stabilization as their best response (58% disease control). The median overall survival was 7.7 months for all 38 patients, including 11.8 months for those who received repeated cycles (46% [6 of 13 patients] ≥1 year), with improved efficacy at the higher radioimmunotherapy doses.Fractionated radioimmunotherapy with (90) Y-hPAM4 and low-dose gemcitabine demonstrated promising therapeutic activity and manageable myelosuppression in patients with advanced pancreatic ductal carcinoma.

Ablation of residual thyroid tissue after total or near-total thyroidectomy is widely accepted by many practitioners and endorsed by relevant professional societies in the United States and the international community for patients with defined risk factors, including age greater than 45 years, large tumors; tumors with undesirable histopathology; lymph node involvement; positive surgical margins; gross and possibly microscopic extrathyroidal extension; and, of course, evidence or suspicion of distal metastases, including mediastinal lymphadenopathy, pulmonary or osseous metastases or involvement of other organs. (131)I therapy doses of 3.7-5.5 GBq (100-150 mCi) should be used, and additional activity should be used in the event there are additional findings on pretreatment whole-body scans. Depending upon the patient's age, general medical condition, and renal function, nuclear medicine practitioners should be prepared to perform whole body (blood or bone marrow) dosimetry in the event doses >5.5 GBq (150 mCi) are being considered to assure patient safety. Still unresolved is the role of (131)I ablation in the so-called "low risk" patient--particularly in a patient who has undergone a near-total thyroidectomy in the hands of a skilled surgeon. If an ablative dose is to be administered, 0.9-1.8 MBq (25-50 mCi) appears to be sufficient to eliminate most if not all thyroid tissue. The problem is defining the "low-risk" patient. After review of the extensive literature on this subject, it appears that the thoughtful and informed practitioner must make a patient specific decision in this setting on the basis of his/her experience and review of the details in each case and continue to review the evidence on this subject as it becomes available.

The presence of isolated splenic metastasis in rectal carcinoma is uncommon and usually presents as an asymptomatic mass, noted incidentally on imaging. Splenectomy is usually performed with the goal of curing metastatic disease. It is unclear if adjuvant chemotherapy affords any benefit, and the prognosis is unknown. The case of a young woman is reported, in whom an isolated metastatic lesion in the spleen was discovered 9 months after adjuvant chemotherapy for stage III rectal adenocarcinoma. The patient has remained disease-free for nearly 5 years following splenectomy and chemotherapy. To our knowledge, this is the fourth reported case in the English literature of an isolated splenic metastatic lesion from rectal cancer. We discuss the unique presentation, the importance of post-treatment surveillance, and the implementation of multi-modality treatment strategies in this young patient.

VOICE Credit: This activity has been approved for 1.0 VOICE (Category A) credit. For CE credit, participants can access this activity on page 325 or on the SNM Web site (http://www.snm.org/ce_online) through December 31, 2013. You must answer 80% or the questions correctly to receive 1.0 CEH (Continuing Education Hour) credit.

Purpose The efficacy and safety of cyclophosphamide, vincristine, and prednisone (CVP) followed by tositumomab and iodine-131 (131I) –tositumomab therapy were evaluated in a multicenter phase II study in patients with untreated low-grade follicular lymphoma. Patients and Methods Patients received six cycles of CVP followed by one cycle of tositumomab and 131I-tositumomab (one dosimetric dose and one therapeutic dose). The treatment was evaluated for efficacy and safety. Results All 30 patients enrolled completed CVP as well as tositumomab and 131I-tositumomab therapy. The overall response rate after completion of therapy was 100%, with 28 patients (93%) achieving a complete response (CR) and two patients achieving a partial response. Of the 17 patients with bone marrow involvement at enrollment, 15 achieved a confirmed CR. Fourteen of 15 patients with bulky disease (≥ 5 cm) had a CR after treatment completion. After a median follow-up of 8.4 years, the median response duration had not been reached (range, 3 to 111+ months). Five-year progression-free and overall survival rates were 56% and 83%, respectively. The most common grade ≥ 3 hematologic adverse events were neutropenia (87%) and thrombocytopenia (37%). Nineteen patients received growth factor support, and three required blood product transfusions. No patients developed human antimurine antibodies. Two patients developed myelodysplastic syndrome/acute myeloid leukemia. Conclusion These mature data demonstrate that sequential therapy with a non-anthracycline–containing regimen comprising CVP followed by one cycle of tositumomab and 131I-tositumomab produced high response rates with adequate safety and durable remissions and that this regimen represents a highly active treatment for first-line therapy of follicular non-Hodgkin's lymphoma.

Radioimmunotherapy is a form of targeted radionuclide therapy that uses a monoclonal antibody to deliver localized radiation. It is most appropriate for treatment of multiple tumor sites that cannot be readily excised surgically or irradiated using external beam radiation or brachytherapy. At present, 2 products, Bexxar ((131)I-tositumomab and unlabeled tositumomab, GlaxoSmithKline, Triangle Park, NC) and Zevalin ((90)Y-ibritumomab tiuxetan and unlabeled rituximab, Spectrum Pharmaceuticals, Irvine, CA and Cell Therapeutics, Seattle, WA) are approved for treatment of non-Hodgkin's lymphoma in certain clinical situations in the United States and Canada. Zevalin is available also in Europe, and there are plans to make both agents more widely available. The therapeutic dose to be used depends upon a number of patient-specific variables. Both regimen achieve a complete response or partial response in approximately 3 of 4 patients, with a duration of remission lasting many years in some cases. This article reviews the basis for dose selection, the nuclear medicine procedures involved, the results obtained to date, and issues related to patient and staff safety.

Here we report the first PET imaging studies of leptin's systemic biodistribution in vivo. PET imaging using 18F and 68Ga labeled leptin revealed that in mouse the hormone was rapidly taken up by megalin (gp330/LRP2), a multiligand endocytic receptor localized in renal tubules. In addition, in rhesus monkeys 15% of labeled leptin localized to red bone marrow which was consistent with hormone uptake in rodent tissues. These data confirm a megalin-dependent mechanism for renal uptake in vivo. The significant binding to immune cells and blood cell precursors in bone marrow is also consistent with prior evidence showing that leptin modulates immune function. These experiments set the stage for similar studies in humans to assess the extent to which alterations of leptin's biodistribution might contribute to obesity and also provide a novel and general chemical strategy for 18F labeling of proteins for PET imaging of other polypeptide hormones.

The role of the base in the synthesis of 3′-deoxy-3′-[18F]fluorothymidine, [18F]FLT, via nucleophilic substitution of the nosyl group with [18F]fluoride was investigated. The rate of 18F-incorporation into the molecule dramatically changed as a function of the precursor-to-base ratio. In the presence of excess base, the precursor was consumed by elimination before substitution was complete. When the precursor-to-base ratio was optimal, an overall [18F]FLT yield of 30–40% was achieved even if the precursor amount was as small as 8–13 mg.

Radioimmunotherapy (RIT) with tositumomab and iodine 131 tositumomab can produce durable and complete responses in relapsed/refractory low-grade Non-Hodgkin's lymphoma. Patients with bone marrow involvement (BMI) with tumor25% of the intertrabecular space are generally excluded from RIT because of risk of excessive hematologic toxicity. The authors conducted a dose-escalation study of tositumomab and iodine 131 tositumomab to determine whether RIT is feasible in this population. Patients had baseline BMI of25% and platelet count ofor=150,000/mm3. In contrast to the usual 75 cGy total body dose of radiation, dose escalation of Iodine I 131 tositumomab began at a total body dose of 45 cGy, and increased to 55 cGy in a second cohort. Dose-limiting toxicity (DLT) was defined as absolute neutrophil count500 cells/mm3 or platelets25,000/mm3 for17 days, or absolute neutrophil count750/mm3 or platelets50,000/mm3 for24 days. Eleven subjects were enrolled (8 at 45 cGy and 3 at 55 cGy). Estimated BMI ranged from 30 to 65% (median approximately 40%). Patients had received a median of three prior chemotherapies (range 1 - 6). One of the six evaluable patients treated at 45 cGy experienced DLT. Three patients received 55 cGy, one had hematologic DLT concurrent with lymphoma progression and extensive BMI at relapse. Three of 11 (27%) patients received hematologic supportive care. Two patients had objective responses of 1 and 42.4+ months, respectively. RIT with attenuated dose iodine 131 tositumomab for patients with25% BMI has acceptable toxicity and can result in lymphoma responses.

To reconstruct reliable nuclear medicine-related occupational radiation doses or doses received as patients from radiopharmaceuticals over the last five decades, the authors assessed which radiopharmaceuticals were used in different time periods, their relative frequency of use, and typical values of the administered activity. This paper presents data on the changing patterns of clinical use of radiopharmaceuticals and documents the range of activity administered to adult patients undergoing diagnostic nuclear medicine procedures in the U.S. between 1960 and 2010. Data are presented for 15 diagnostic imaging procedures that include thyroid scan and thyroid uptake; brain scan; brain blood flow; lung perfusion and ventilation; bone, liver, hepatobiliary, bone marrow, pancreas, and kidney scans; cardiac imaging procedures; tumor localization studies; localization of gastrointestinal bleeding; and non-imaging studies of blood volume and iron metabolism. Data on the relative use of radiopharmaceuticals were collected using key informant interviews and comprehensive literature reviews of typical administered activities of these diagnostic nuclear medicine studies. Responses of key informants on relative use of radiopharmaceuticals are in agreement with published literature. Results of this study will be used for retrospective reconstruction of occupational and personal medical radiation doses from diagnostic radiopharmaceuticals to members of the U.S. radiologic technologists' cohort and in reconstructing radiation doses from occupational or patient radiation exposures to other U.S. workers or patient populations.

Milatuzumab (hLL1), a humanized anti-CD74 monoclonal antibody, has activity in preclinical non-Hodgkin lymphoma (NHL) models. We conducted a phase 1 trial in previously treated B-cell malignancies. Dose escalation included four planned dose levels (1.5, 4, 6 and 8 mg/kg) with milatuzumab given twice weekly for 6 weeks. After dose level 1, the schedule was changed to daily (Monday-Friday) for 10 days. Twenty-two patients were treated. The most common possibly related toxicities were infusion reaction, anemia, lymphopenia, neutropenia and thrombocytopenia. Three patients experienced dose-limiting toxicity (neutropenia, neutropenia, rash) at dose levels 1, 2 and 4, respectively. Eight patients had stable disease, with no objective responses. The serum half-life of milatuzumab was ∼2 h. In seven patients, In-111 imaging showed no clear evidence of tumor targeting. The short half-life may reflect CD74 rapid internalization and presence on extratumoral tissues; this antigen sink must be overcome to capitalize on the promising preclinical activity of the drug.

Prostate cancer represents an ideal target for radioimmunotherapy based on the pattern of spread, including bone marrow and lymph nodes, sites that typically receive high levels of circulating antibody, and the small volume of disease, ideally suited for antibody delivery and antigen access. This review explores possible antibody targets in prostate cancer and focuses on the potential role for radioimmunotherapy by highlighting several clinical trials involving radiolabeled anti-prostate-specific membrane antigen monoclonal antibody J591. Prostate-specific membrane antigen, a highly prostate-restricted transmembrane glycoprotein with increased expression in high-grade, metastatic, and hormone-refractory disease, represents an ideal target for monoclonal antibody therapy in prostate cancer. Radiolabeled anti-prostate-specific membrane antigen monoclonal antibody J591 trials using the radiometals yttrium-90 and lutetium-177 have demonstrated manageable myelotoxicity, no significant nonhematologic toxicity, excellent targeting of soft-tissue and bone metastases, and preliminary efficacy including prostate-specific antigen and measurable disease responses. Additional studies are under way to better define the activity of radiolabeled antibody therapy as well as the role for fractionated therapy and combination approaches with taxane-based chemotherapy.

Determination of the immunoreactive fraction (IF) of radiolabeled monoclonal antibodies (MAb) is essential to the understanding of the effects of radiolabeling and subsequent target-specific tumor localization. There has been generally no accepted method of determining the IF of MAbs. The conventional method is based on a radioimmunoassay technique in which the fraction of radiolabeled MAb bound to antigen under conditions of "antigen excess" is determined. Lindmo et al. introduced a modified method in which the IF is determined by extrapolation to conditions representing "infinite antigen excess." Although the Lindmo method, in principle, is insensitive to experimental parameters, it does not always provide a reliable estimate of IF. We, therefore, evaluated an alternate method in which percent cell bound fraction is measured under conditions of fixed antigen concentration and various dilutions of radiolabeled MAb. We developed a mathematical equation to estimate immunoreactivity. J591 MAb specific for prostate-specific membrane antigen was radiolabeled with (111)In, (90)Y and (177)Lu to specific activities of 1-20 mCi/mg. We compared the effect of several experimental conditions on the determination of IF using all three different methods. The Lindmo method requires careful optimization of experimental conditions for each radiolabeled MAb. The alternate method, based on a fixed antigen concentration, appears to be practical and may provide a more reliable measure of immunoreactivity.

Interpretation of positron emission tomographic (PET) scans in the absence of correlative anatomic information can be challenging. PET-computed tomography (CT) fusion imaging is a novel multimodality technology that allows the correlation of findings from two concurrent imaging modalities in a comprehensive examination. CT demonstrates exquisite anatomic detail but does not provide functional information, whereas 2-[fluorine 18]fluoro-2-deoxy-D-glucose (FDG) PET reveals aspects of tumor function and allows metabolic measurements. Subtle findings at FDG PET that might otherwise be disregarded or interpreted as physiologic variants may lead to detection of a malignant process after being correlated with simultaneously acquired CT findings. Alternatively, equivocal CT findings, which could represent malignant tumor, reactive changes, or fibrosis, can be clarified with the help of the additional metabolic information provided by concurrent FDG PET. Accurate interpretation of FDG PET scans requires a thorough knowledge of the normal physiologic distribution of FDG and of normal variants that may reduce the accuracy of PET studies, thereby significantly affecting patient treatment. Although in rare instances PET-CT cannot help resolve the diagnostic dilemma, it is enjoying widespread acceptance in the medical imaging community, usually allowing differentiation of physiologic variants from juxtaposed or mimetic neoplastic lesions and more accurate tumor localization.

Purpose To determine the maximum-tolerated dose (MTD), toxicity, human antihuman antibody (HAHA) response, pharmacokinetics, organ dosimetry, targeting, and preliminary efficacy of yttrium-90–labeled anti–prostate-specific membrane antigen monoclonal antibody J591 (90Y-J591) in patients with androgen-independent prostate cancer (PC). Patients and Methods Patients with androgen-independent PC and evidence of disease progression received indium-111–J591 for pharmacokinetic and biodistribution determinations followed 1 week later by 90Y-J591 at five dose levels: 5, 10, 15, 17.5, and 20 mCi/m2. Patients were eligible for up to three re-treatments if platelet and neutrophil recovery was satisfactory. Results Twenty-nine patients with androgen-independent PC received 90Y-J591, four of whom were re-treated. Dose limiting toxicity (DLT) was seen at 20 mCi/m2, with two patients experiencing thrombocytopenia with non–life-threatening bleeding episodes requiring platelet transfusions. The 17.5-mCi/m2 dose level was determined to be the MTD. No re-treated patients experienced DLT. Nonhematologic toxicity was not dose limiting. Targeting of known sites of bone and soft tissue metastases was seen in the majority of patients. No HAHA response was seen. Antitumor activity was seen, with two patients experiencing 85% and 70% declines in prostate-specific antigen (PSA) levels lasting 8 and 8.6 months, respectively, before returning to baseline. Both patients had objective measurable disease responses. An additional six patients (21%) experienced PSA stabilization. Conclusion The recommended dose for 90Y-J591 is 17.5 mCi/m2. Acceptable toxicity, excellent targeting of known sites of PC metastases, and biologic activity in patients with androgen-independent PC warrant further investigation of 90Y-J591 in the treatment of patients with PC.

We performed an interim analysis of imaging data collected in 2 phase I radioimmunotherapy trials to determine the ability of monoclonal antibody (mAb) J591 directed to the extracellular domain of prostate specific membrane antigen (PSMA) to target sites of known metastatic prostate cancer accurately.Patients with progressing hormone independent prostate cancer were entered in 2 phase I dose finding trials with radiolabeled mAb J591. J591 is the first mAb targeting the extracellular domain of PSMA as well as the first de-immunized (humanized) mAb to PSMA to be tested in humans. These trials were primarily designed to assess dose limiting toxicity, maximum tolerated dose, pharmacokinetics and organ dosimetry. Planar gamma camera imaging studies obtained on the first 53 patients were reviewed and compared to sites of metastatic prostate cancer visualized on conventional imaging studies including bone scan, computerized tomography and/or magnetic resonance imaging. In 1 trial 29 patients received 111indium-J591 for imaging followed by 90yttrium-J591 for therapy. In the parallel trial 24 patients were treated with 177lutetium-J591, an isotope that can be imaged directly.Of 53 patients reviewed 46 (87%) had evidence of metastatic disease on conventional scans. Overall, of the 43 evaluable patients J591 accurately targeted bone and/or soft tissue lesions in 42 (98%). J591 accurately targeted bone lesions in 32 of 34 (94%) and soft tissue lesions in 13 of 18 (72%) evaluable patients.Radiolabeled J591 accurately targets bone and soft tissue metastatic prostate cancer sites, and may be useful for targeting therapeutic and/or diagnostic imaging agents.

For the last 60 years, hormonal therapy has been the cornerstone of treatment of metastatic prostate cancer. Unfortunately, hormonal therapy is purely palliative and improved systemic therapies are necessary. Monoclonal antibodies (mAbs) have proven valuable in the treatment of several diseases including cancer. mAbs act by focusing an immune response on or by targeting delivery of highly cytotoxic agents to the cancer cells without targeting normal cells. Prostate-specific membrane antigen (PSMA) has been identified as an ideal antigenic target in prostate cancer. PSMA is the most well-established, highly restricted prostate cancer cell surface antigen. It is expressed at high density on the cell membrane of all prostate cancers, and after antibody binding, the PSMA-antibody complex is rapidly internalized along with any payload carried by the antibody. J591 is the first IgG mAb developed to target the extracellular domain of PSMA, and it has been deimmunized (humanized) to allow repeated dosing in patients. Three phase I studies are in progress, two using the β-emitting radiometals yttrium 90 and lutetium 177, and a third using a cytotoxin (DM1) linked to J591. Imaging of patients after they have received radiolabeled J591 demonstrates excellent tumor targeting.

Radioimmunotherapy (RIT) is a promising new treatment option for patients with relapsed/refractory non-Hodgkin's lymphoma. Clinical trials have demonstrated that both iodine-131 (131I) and yttrium-90 (90Y) are suitable radionuclides for RIT. Iodine-131 and 90Y differ markedly in their physical properties including half-life, path length, type of energy emissions, intracellular stability, and the organs targeted by the free radionuclide. Both radionuclides can be safely administered in the outpatient setting under current Nuclear Regulatory Commission guidelines. Potential advantages of 131I for RIT include availability, stable chemistry, longer half-life, and an emission spectrum that allows for dosimetric studies and therapy with the same immunoconjugate. By contrast, 90Y has a longer path length and superior intracellular stability compared with 131I. Yttrium-90 may therefore be preferable to 131I for patients with bulky disease, poorly vascularized solid tumors, or when targeting internalized antigens. Although 90Y emits no gamma photon, dosimetry studies for 90Y RIT can be performed using a surrogate radionuclide such as indium-111. Both 131I- and 90Y-labeled anti-CD20 antibodies have demonstrated efficacy in treating relapsed/refractory non-Hodgkin's lymphoma. Further studies are needed, however, to determine if the differences in the pharmacology of 131I and 90Y are clinically relevant.

BACKGROUND The accuracy of fluorodeoxyglucose positron emission tomography (FDG-PET; dual-head camera with attenuation correction) and Ga-67 scintigraphy was compared to identify disease sites in patients with Hodgkin disease (HD) and intermediate and high-grade non-Hodgkin lymphoma (NHL) at initial diagnosis or clinical recurrence. METHODS Fifty-one contemporaneous FDG-PET and Ga-67 scintigraphies were performed on patients with NHL (35 intermediate grade, 3 high grade) or HD (13 patients). Sites of disease were correlated on a site-by-site basis on FDG-PET and Ga-67 images. Tumor-to-background (T/B) ratios were obtained for both techniques. Discordant FDG-PET and Ga-67 findings were correlated with computed tomography findings or clinical evaluation including repeat FDG-PET scans obtained after therapy. RESULTS Fluorodeoxyglucose positron emission tomography was positive at all 158 sites in 51 patients compared with 113 sites in 41 positive studies with Ga-67 scintigraphy (single positron emission computed tomography [SPECT] and/or planar images). In 44 patients who had complete Ga-67 SPECT data on all tumor sites, FDG-PET was positive at 126 sites and Ga-67 SPECT was positive at 81 sites. Ga-67 SPECT failed to demonstrate disease at 45 sites (35.7%). In 10 of 44 patients, Ga-67 SPECT completely failed to detect any disease at 22 of 45 sites (17.5%) and partially identified disease sites at 23 of 45 sites (18.2%) in 11 patients regardless of the tumor site and histology. In these patients, the lesions measured between 0.6 and 14.0 cm by CT. Fluorodeoxyglucose positron emission tomography revealed higher stage disease in 13 patients compared with Ga-67 imaging. Tumor-to-background ratios were statistically different between the two techniques with higher ratios obtained with FDG-PET (P < 0.0001). CONCLUSIONS In imaging aggressive lymphoma and HD before therapy, FDG-PET has significantly higher site and patient sensitivity than Ga-67 scintigraphy (100% vs. 71.5% and 100% vs. 80.3%, respectively). The change in disease stage by FDG-PET may result in a change in therapy strategy. Cancer 2002;94:879–88. © 2002 American Cancer Society. DOI 10.1002/cncr.10336

TPS5093 Background: PC is a radiosensitive disease. PSMA is selectively overexpressed in advanced PC with upregulation by androgen receptor (AR) pathway dysregulation; limited expression exists in other organs. A series of sequential studies of radiolabeled anti-PSMA antibody J591 revealed 1) targeting and safety [Bander 2003]; 2) safety and prelim efficacy [Milowsky 2004, Bander 2005]; 3) efficacy and initial dose-response [Tagawa 2013]; 4) dose-fractionation allows higher doses, ability to combine with docetaxel, confirmation of dose-response (PSA and overall survival) [ASCO 2010, 2014, 2016]; 5) predictable, reversible myelosuppression is dose-limiting [Tagawa 2013]. Small molecule PSMA inhibitor ligands can be successfully radiolabeled and are widely used for imaging and treatment in Europe. 177Lu-PSMA-617 is the most commonly used, but experience is mostly anecdotal/retrospective and no formal dose-escalation studies have been performed. Methods: Men with progressive mCRPC following at least 1 potent AR-targeted agent (e.g. abi/enza) and docetaxel (or unfit/refuse chemo) without limit of # prior therapies provided adequate organ function will undergo imaging with 68Ga-PSMA-HBED-CC PET/CT followed by escalating fractionated doses of 177Lu-PSMA-617. Cohort 1 = 3.7 GBq x2 two weeks apart up to 11.1 GBq x2 in a 3+3 dose-escalation study. Dose-limiting toxicity (DLT) is defined as attributable grade 4 heme toxicity or grade 3/4 non-heme toxicity. Planned cohort expansion will occur at recommended phase 2 dose (RP2D) in a 2-stage design. The primary endpoint is determination of DLT and RP2D. Secondary endpoints include toxicity, PSA decline rate, RECIST response, PFS, rPFS, OS. Correlatives include baseline/follow up PSMA imaging, whole body distribution of 177Lu-PSMA-617, CTC count (CellSearch) changes, tissue and circulating genomic assessment of DNA repair pathways, patient reported outcomes (FACT-P and BPI-SF). Clinical trial information: NCT03042468.

BACKGROUND AND PURPOSE Evidence from animal models and examination of human epilepsy surgery specimens indicates that inflammation plays an important role in epilepsy. Positron emission tomography (PET) using [C11]PK11195, a marker of activated microglia, provides a means to visualize neuroinflammation in vivo in humans. We hypothesize that in patients with active epilepsy, [C11]PK11195 PET (PK-PET) may be able to identify areas of focally increased inflammation corresponding to the seizure onset zone. METHODS A young woman with intractable epilepsy underwent PK-PET as part of an approved research study. PK-PET results were compared with results from other clinical studies. RESULTS PK-PET revealed an area of focally increased radiotracer uptake in the right frontal lobe corresponding to this patient’s seizure focus as identified by ictal and interictal 18Ffluorodeoxyglucose (FDG)-PET and EEG. Routine brain magnetic resonance imaging (MRI) was initially considered normal, though high-resolution studies showed possible subtle dysplasia of the right frontal lobe. The patient underwent a right frontal lobe resection, and pathological evaluation showed focal cortical dysplasia with activated microglia. CONCLUSIONS PK-PET can identify neuroinflammation associated with subtle focal cortical dysplasia, and may therefore have a clinical role in guiding epilepsy surgery for patients with difficult-to-localize seizure foci.

Multiple myeloma (MM) is a relatively rare hematologic disorder characterized by proliferation of plasma cells, primarily involving the bone marrow. Extramedullary involvement also occurs with poor prognosis. Asymptomatic plasma cell disorders, monoclonal gammopathy of uncertain significance, and smoldering MM, which do not require therapy, should be distinguished from symptomatic MM, which requires treatment. MM may present with CRAB , elevated C alcium levels, R enal insufficiency, A nemia, and B one lesions (including lytic lesions and osteopenia), as well as elevated levels of serum M protein or urine M protein or both. Nonsecretory myeloma in which serum and urine M proteins are absent occurs rarely, accounting for 1%-5% of patients with myeloma, but low levels of abnormal immunoglobulins are often present. Staging of patients with MM is done according to the Durie and Salmon criteria based on laboratory testing (determination of hemoglobin, serum calcium, and serum and urine M proteins) and conventional radiography. A variety of diagnostic imaging procedures have been employed to assess the extent of disease in MM and to evaluate the response to treatment as well as provide surveillance for the detection of recurrent disease. These include whole-body x-ray, which despite its limitations is regularly used to detect lytic bone lesions; CT radiography; MRI; and a variety of radionuclide imaging procedures, with 18 F-FDG-PET/CT emerging as the radionuclide procedure of choice. Recently, the Durie-Salmon criteria have been upgrade to the Durie-Salmon PLUS system, which includes 18 F-FDG-PET/CT and MRI of the spine and pelvis.

Prostate specific membrane antigen (PSMA) is the single most well-validated prostate cancer (PCa)-specific cell membrane antigen known. It is present in high levels in 95% of PCa, and is an ideal target to develop radiopharmaceuticals for imaging studies and radionuclide therapy. Humanized J591 monoclonal antibody (mAb) binds specifically with nanomolar affinity to the extracellular domain of PSMA. After binding, the PSMA-antibody complex is rapidly internalized, increasing the potential utility of PSMA as a target for the delivery of mAb-conjugated radionuclides or cytotoxins. J591 mAb was labeled with 177Lu at a high specific activity (10-30 mCi/mg) using DOTA as the bifunctional chelate. The preclinical data in PSMA positive xenografts, strongly suggested that 177;Lu-J591 mAb is an ideal radiopharmaceutical for RIT of metastatic PCa. Since October 2000, five clinical studies (phase I and II) were performed in subjects with metastatic castration-resistant prostate cancer (CRPC) using 177Lu-J591. The methodology and the results of these clinical studies are briefly reviewed in this article. The maximum tolerated dose (MTD) as a single dose was 70 mCi2. Based on dose fractionation (DF), MTD was 90 mCi/m2(2 doses of 45 mCi/m2, 2 wks apart). Phase II study in patients with progressive metastatic CRPC, at a dose of 65- 70 mCi/m2 resulted in significant PSA declines in 60% of the patients. While myelosuppression was the dose limiting toxicity, DF alone or in combination with docetaxel also resulted in significant PSA declines with much less toxicity. 177Lu imaging studies demonstrated accurate targeting of known metastatic sites in90% of patients and those with stronger PSMA expression by semi-quantitative imaging had more PSA declines. These clinical studies clearly documented the potential therapeutic value of radioimmunotherapy (RIT) in metastatic PCa.

Prostate-specific membrane antigen (PSMA) is a well-established target for developing radiopharmaceuticals for imaging and therapy of prostate cancer (PCa). We have recently reported that novel 99m Tc-labeled small-molecule PSMA inhibitors bind with high affinity to PSMA-positive tumor cells in vitro and localize in PCa xenografts. This study reports the first, to our knowledge, human data in men with metastatic PCa and in healthy male subjects. Methods: Under an exploratory investigational new drug, using a cross-over design, we compared the pharmacokinetics, biodistribution, and tumor uptake of 99m Tc-MIP-1404 and 99m Tc-MIP-1405 in 6 healthy men and 6 men with radiographic evidence of metastatic PCa. Wholebody images were obtained at 10 min and 1, 2, 4, and 24 h. SPECT was performed between 3 and 4 h after injection. Results: Both agents cleared the blood rapidly, with MIP-1404 demonstrating significantly lower urinary activity (7%) than MIP-1405 (26%). Both agents showed persistent uptake in the salivary, lacrimal, and parotid glands. Uptake in the liver and kidney was acceptable for imaging at 1–2 h. In men with PCa, both agents rapidly localized in bone and lymph node lesions as early as 1 h. SPECT demonstrated excellent lesion contrast. Good correlation was seen with bone scanning; however, more lesions were demonstrated with 99mTc-MIP-1404 and 99mTc-MIP-1405. The high-contrast images exhibited tumor-tobackground ratios from 3:1 to 9:1 at 4 and 20 h. Conclusion: Compared with the standard-of-care bone scanning, 99mTc-MIP1404 and 99mTc-MIP-1405 identified most bone metastatic lesions and rapidly detected soft-tissue PCa lesions including subcentimeter lymph nodes. Because 99mTc-MIP-1404 has minimal activity in the bladder, further work is planned to correlate imaging findings with histopathology in patients with high-risk metastatic PCa.

Data on occupational radiation exposure from nuclear medicine procedures for the time period of the 1950s through the 1970s is important for retrospective health risk studies of medical personnel who conducted those activities. However, limited information is available on occupational exposure received by physicians and technologists who performed nuclear medicine procedures during those years. To better understand and characterize historical radiation exposures to technologists, the authors collected information on nuclear medicine practices in the 1950s, 1960s, and 1970s. To collect historical data needed to reconstruct doses to technologists, a focus group interview was held with experts who began using radioisotopes in medicine in the 1950s and the 1960s. Typical protocols and descriptions of clinical practices of diagnostic radioisotope procedures were defined by the focus group and were used to estimate occupational doses received by personnel, per nuclear medicine procedure, conducted in the 1950s to 1960s using radiopharmaceuticals available at that time. The radionuclide activities in the organs of the reference patient were calculated using the biokinetic models described in ICRP Publication 53. Air kerma rates as a function of distance from a reference patient were calculated by Monte Carlo radiation transport calculations using a hybrid computational phantom. Estimates of occupational doses to nuclear medicine technologists per procedure were found to vary from less than 0.01 μSv (thyroid scan with 1.85 MBq of administered I-iodide) to 0.4 μSv (brain scan with 26 MBq of Hg-chlormerodin). Occupational doses for the same diagnostic procedures starting in the mid-1960s but using Tc were also estimated. The doses estimated in this study show that the introduction of Tc resulted in an increase in occupational doses per procedure.

Both radiolabeled ligands to specific receptors on cell surfaces and radiolabeled antibodies to specific cell surface epitopes provide new opportunities to scintigraphically identify tumors. Both radiolabeled ligands and antibodies are characterized by high orders of affinity for their respective binding sites and offer greater specificity over the agents previously used for tumor imaging including gallium 67, thallium 201, technetium 99m MIBI, and flourine-18-labeled deoxyglucose. The two classes of tumor-binding tracers differ primarily based on molecular weight although the nonspecific portion of the immunoglobulins are also antigenic. Increased molecular weight results in prolonged plasma survival, which increases the interval available for tumor permeation but also produces increased nonspecific background activity, which impairs image contrast. At the present time, encouraging clinical results have been obtained with both agent types, but further development is necessary. Receptor-ligand tracers provide better contrast than antibodies or antibody fragments. Receptor-ligand imaging technology awaits further developments in an understanding of the biology of receptor expression in normal tissue and tumors and improved radio-chemical techniques and pharmacology to define the radioligands of choice. Radiolabeled antibodies will probably evolve in the direction of increased use of antibody fragments and possibly the identification and polymerization of epitope-recognition units in order to provide high-affinity, nonantigenic, small molecular weight tracers that will be more permeable in tumors and clear more rapidly from background tissue. Rather than compete or complement each other, the techniques will likely produce a hybrid technology, radiolabeled molecular recognition units, with the better features of both technologies including high binding affinity (low dissociation constant) for surface membrane epitopes, including receptor sites.