Volkan Beylergil

A Phase I/II Study for Analytic Validation of 89Zr-J591 ImmunoPET as a Molecular Imaging Agent for Metastatic Prostate Cancer

Purpose: Standard imaging for assessing osseous metastases in advanced prostate cancer remains focused on altered bone metabolism and is inadequate for diagnostic, prognostic, or predictive purposes. We performed a first-in-human phase I/II study of 89Zr-DFO-huJ591 (89Zr-J591) PET/CT immunoscintigraphy to assess performance characteristics for detecting metastases compared with conventional imaging modalities (CIM) and pathology. Experimental Design: Fifty patients with progressive metastatic castration-resistant prostate cancers were injected with 5 mCi of 89Zr-J591. Whole-body PET/CT scans were obtained, and images were analyzed for tumor visualization. Comparison was made to contemporaneously obtained bone scintigraphy and cross-sectional imaging on a lesion-by-lesion basis and with biopsies of metastatic sites. Results: Median standardized uptake value for 89Zr-J591–positive bone lesions (n = 491) was 8.9 and for soft-tissue lesions (n = 90), it was 4.8 (P < 0.00003). 89Zr-J591 detected 491 osseous sites compared with 339 by MDP and 90 soft-tissue lesions compared with 124 by computed tomography (CT). Compared with all CIMs combined, 89Zr-J591 detected an additional 99 osseous sites. Forty-six lesions (21 bone and 25 soft tissue) were biopsied in 34 patients; 18 of 19 89Zr-J591–positive osseous sites and 14 of 16 89Zr-J591–positive soft tissue sites were positive for prostate cancer. The overall accuracy of 89Zr-J591 was 95.2% (20 of 21) for osseous lesions and 60% (15 of 25) for soft-tissue lesions. Conclusions: 89Zr-J591 imaging demonstrated superior targeting of bone lesions relative to CIMs. Targeting soft-tissue lesions was less optimal, although 89Zr-J591 had similar accuracy as individual CIMs. This study will provide benchmark data for comparing performance of proposed prostate-specific membrane antigen (PSMA) targeting agents for prostate cancer. Clin Cancer Res; 21(23); 5277–85. ©2015 AACR.

Pilot study of 68Ga-DOTA-F(ab′)2-trastuzumab in patients with breast cancer

Objective68Ga-1,4,7,10-Tetraazacyclododecane-N,N′,N′′,N′′′-tetraacetic acid (DOTA)-F(ab′)2-trastuzumab [68Ga-DOTA-F(ab′)2-trastuzumab] has been developed at our institution as a positron imaging reagent for assessing human epidermal growth factor receptor 2 (HER2) expression status by in-vivo imaging. Initial studies on animals demonstrated promising results in the monitoring of treatment response to heat shock protein 90-targeted drugs that inhibit the client protein HER2. We report here our initial clinical experience in the assessment of the toxicity, pharmacokinetics, biodistribution, and dosimetry profile of 68Ga-DOTA-F(ab′)2-trastuzumab with PET/computed tomography using a mean of 236 MBq/5 mg administered intravenously. Materials and methodsA group of 16 women with breast cancer were enrolled in this study. The one patient who did not receive 68Ga-DOTA-F(ab′)2-trastuzumab was excluded from analysis. Both HER2-negative (n=7) and HER2-positive (n=8) cases were studied. Among the latter, seven had undergone trastuzumab treatment previously and one had not. ResultsIt was determined that 68Ga-DOTA-F(ab′)2-trastuzumab was well tolerated, with a T½ of ∼3.6±0.9 h; the critical organ was the kidney, with a mean dose of 0.383 cGy/37 MBq; and tumor targeting was seen in 4/8 patients with HER2-positive disease. ConclusionThe reagent is safe, and assessments through additional studies in a better-defined group of patients, using larger administered masses of antibodies, with a better immunoreactive fraction are needed.

False impression of positive Meckel's scintigraphy caused by ectopic cross-fused kidneys.

A 3-year-old boy with a history of intermittent rectal bleeding was referred to our department for evaluation of a Meckels diverticulum. Three foci of increased uptake were noted in the midlower abdominal region during early dynamic acquisition, but they faded in the following hour. When the patient data were reviewed retrospectively, the authors noted that Tc-99m DTPA and Tc-99m DMSA renal scintigraphic studies had been performed previously for recurrent urinary tract infections, which revealed ectopically located cross-fused kidney. The observed activity was judged to be a result of the calyces of the ectopic kidneys and therefore negative for Meckels diverticulum.

FDG PET/CT findings in a rare case of giant fibrovascular polyp of the esophagus harboring atypical lipomatous tumor/well-differentiated liposarcoma.

A 70-year-old man with a history of chronic lymphocytic leukemia (CLL) underwent FDG PET/CT scan, which revealed a large polypoid soft tissue lesion in the esophagus with peripheral FDG avidity. An endoscopic biopsy revealed inflammatory changes with scattered CLL cells. The final histopathology demonstrated an 18-cm long and 4-cm wide giant fibrovascular polyp that was removed in 2 pieces. The polyp was composed of atypical adipose tissue with scattered giant cells and spindle-shaped cells as well as foci of CLL. Mouse double minute 2 homolog amplification was noted by fluorescence in situ hybridization diffusely in the giant polyp consistent with well-differentiated liposarcoma in a giant fibrovascular polyp.

Pharmacokinetics, biodistribution, and radiation dosimetry for 89Zr-trastuzumab in patients with esophagogastric cancer

Trastuzumab with chemotherapy improves clinical outcomes in patients with human epidermal growth factor receptor 2 (HER2)–positive esophagogastric adenocarcinoma (EGA). Despite the therapeutic benefit, responses are rarely complete, and most patients develop progression. To our knowledge, this is the first report evaluating 89Zr-trastuzumab in HER2-positive EGA; here, we evaluate the safety, pharmacokinetics, biodistribution, and dosimetry 89Zr-trastuzumab. Methods: Trastuzumab was conjugated with deferoxamine and radiolabeled with 89Zr. A mean activity of 184 MBq was administered to 10 patients with metastatic HER2-positive EGA. PET imaging, whole-body probe counts, and blood draws were performed to assess pharmacokinetics, biodistribution, and dosimetry. Results: No clinically significant toxicities were observed. At the end of infusion, the estimated 89Zr-trastuzumab in plasma volume was a median 102% (range, 78%–113%) of the injected dose. The median biologic half-life T1/2β was 111 h (range, 78–193 h). The median biologic whole-body retention half-life was 370 h (range, 257–578 h). PET images showed optimal tumor visualization at 5–8 d after injection. The maximum tumor SUV ranged from no to minimal uptake in 3 patients to a median of 6.8 (range, 2.9–22.7) for 20 lesions in 7 patients. Dosimetry estimates from OLINDA showed that the organs receiving the highest absorbed doses were the liver and heart wall, with median values of 1.37 and 1.12 mGy/MBq, respectively. Conclusion: 89Zr-trastuzumab imaging tracer is safe and provides high-quality images in patients with HER2-positive EGA, with an optimal imaging time of 5–8 d after injection.

Extrahepatic visualization in the distribution of falciform artery in posttreatment Bremsstrahlung images after radioembolization with 90Y microspheres

We report the case of a 39-year-old female with metastatic colorectal cancer. Pretreatment SPECT/CT imaging revealed extrahepatic tracer accumulation along the falciform artery distribution. Prior to the administration of (90)Y microspheres, hepatic arterial anatomy was evaluated angiographically. It was not possible to identify the hepatic falciform artery so that no coil-embolization was performed. The patient tolerated the treatment well with only mild pain around the umbilicus during the procedure that spontaneously abated. As far as we know, this is the first report of Bremsstrahlung SPECT/CT images that has clearly shown that the microspheres accumulation in the anterior abdominal wall corresponds to hepatic falciform artery distribution on CT.

Schwannomatosis/neurofibromatosis type 2 associated multiple schwannomas visualized on FDG-PET/CT.

We present a patient with neurocutaneous syndrome, status prior resections for cervical schwannomas and median as well as radial nerve schwannomas. This is a 57-year-old female with neurocutaneous syndrome presenting at 42 years of age with unilateral vestibular schwannoma. Genetic testing was negative but on clinical criteria neurofibromatosis-2 (NF-2) or schwannomatosis were considered.1 She underwent FDG PET/CT 85 min after intravenous injection of 11.3 mCi (418.1 MBq) FDG, for recent onset of severe left back pain with suspected cauda equina compression. Whole-body FDG PET/CT showed multiple FDG avid soft tissue foci overlying the sciatic nerve, consistent with multiple schwannomas (Fig. 1). It also demonstrated heterogenous uptake corresponding to multiple lesions visualized on MRI (Fig. 2).

Molecular imaging and therapy of merkel cell carcinoma.

Several molecular imaging modalities have been evaluated in the management of Merkel cell carcinoma (MCC), a rare and aggressive tumor with a high tendency to metastasize. Continuous progress in the field of molecular imaging might improve management in these patients. The authors review the current modalities and their impact on MCC in this brief review article.

A Historical Perspective on the Use of Radionuclides for Therapy

At present, standard of care for targeted therapy with radionuclides include; 131I for therapy of well-differentiated thyroid cancer; 89Sr chloride, and 153Sm-EDTMP for bone pain; radionuclide microembolization with either resin or glass microspheres; radiolabeled antibodies in lymphoma; metaiodobenzylguanidine for pheochromocytoma; radio peptide therapy for carcinoid, and other endocrine tumors. Growth in this sector of nuclear medicine has been modest. Recent advances in targeted radiotherapy are predicted to set the stage for a phase of rapid growth of the therapeutic aspects of nuclear medicine, as the most unique and potentially most distinctive utilitarian feature of our specialty. A plethora of targeting agents, ranging from small molecules to large nanoparticles offers many alternatives for pharmaceutical carrier of the radioactivity. In particular, major improvement in efficient production of a range of biologicals such as peptides, nanobodies, affibodies, and antibodies has occurred in the recent past and this has led to serious consideration of these agents as carriers of radioactivity after parenteral injection. In this brief overview, we highlight selected advances that have occurred in quantitative imaging, cancer biology, and radiobiology/radiochemistry which are likely to have significant short-term impact on radionuclide therapy. In regard to imaging improvements, there is now widespread availability of the potential for truly quantitative images, especially fusion images based on PET-CT, PET MRI, and SPECT-CT that have the ability to permit internal dosimetry as a guide to optimize therapeutic radionuclide dosing for better management of individual patients. Such imaging improvements, are leading to opportunities for use of theranostic radiotracers, whereby the same drug with minor changes is used for both diagnosis at tracer levels and therapy at tumoricidal levels. From a cancer biology point of view, targeted therapy of specific oncoproteins can restore some cancer cells to a more, nearly normal or differentiated state and this may have special relevance to thyroid cancers and other cancers (Pacak et al. 2012). Thus, non-iodine avid thyroid cancers can be differentiated to concentrate therapeutic levels of radioactive iodine or MIBG, by treatment with a short course of drugs that overcome the effects of specific oncogenic proteins. In regard to radiobiology/radiochemistry improvements, practical methods for accessing alpha emitters as therapeutic radionuclides have been developed.

Alternating increased unilateral vocal cord uptake in a patient with metastatic breast cancer

We present a 58 year old female with stage IV breast cancer, status bilateral mastectomies that underwent FDG PET/CT for evaluation of extent of disease. The PET scan shows increased uptake in the left vocal cord (SUV max 3.9), consistent with right vocal cord paralysis presumably from a hypermetabolic right paratracheal node involving the recurrent laryngeal. Clinically hoarseness was confirmed and intermittent aspiration of liquids led to treatment with injection of CAHA in the right vocal cord. A follow up restaging scan performed a year after the initial scan showed FDG uptake in the injected vocal cord overlying the area of dense material in the injected side (SUVmax 9.2) and resolution of previously noted hypermetabolic metastasis in the paratracheal region and bone metastasis(data not shown). Correspondence to: Volkan Beylergil, The Metrohealth Campus of Case Western Reserve University, Department of Radiology, 2500 Metrohealth Drive Cleveland, OH 44108; E-mail: vbeylergil@metrohealth.org Received: March 10, 2016; Accepted: April 04, 2016; Published: April 08, 2016 Introduction Vocal cord paralysis(VCP) is a fairly common and usually a harbinger of an underlying significant illness. Unilateral increased FDG uptake in the unaffected cord is a common pitfall and have sometimes been misinterpreted as primary or secondary malignancy especially in the pre-PET/CT era. Additionally, local injection therapies for VCP can cause pitfalls and complicate the interpretation. Case report We present a 58 year old female with stage IV breast cancer, status bilateral mastectomies who underwent FDG PET/CT for follow up. The PET scan showed increased uptake in the left vocal cord (SUV max 3.9), consistent with right vocal cord paralysis presumably from a hypermetabolic right paratracheal node involving the recurrent laryngeal nerve (Figure 1A). Post-treatment axial PET, CT and fused PET/CT images showed focal intense FDG uptake in the right vocal cord at the CAHA injection site(SUV 9.2) (Figure 1B). Baseline FDG PET/CT scan showed a hypermetabolic right paratracheal adenopathy, the possible culprit for recurrent laryngeal nerve palsy. Literature review and discussion In a retrospective study, Chen et al have reported neoplastic disease as the second most common cause of VCP [1], with the traumatic causes being the most common cause. The unilateral increased FDG uptake in the unaffected, non-paralyzed vocal cord has been well demonstrated [2] and attributed to compensatory increased workload of the normal vocal cord. To improve symptoms, medialization of the vocal cord is often performed using a variety of materials including teflon, fat, collagen, hyaluronic acid, calcium hydroxyapatite gel(CAHA), and polydimethylsiloxane gel. Some of these injections have been associated with increased FDG uptake in the ipsilateral injected vocal cord [3,4] (Figure 2). Blodgett et al. [5] have summarized common physiologic variants and pitfalls of combined PET/CT in the head and neck in an excellent review. It is important to distinguish unilateral vocal cord uptake from vocal cord neoplasms. This patient illustrates both the physiologic contralateral normal vocal cord uptake during vocal cord paralysis as well as the ipsilateral uptake due to inflammatory changes associated with vocal cord injections. Vocal cord injection is a valuable procedure for the treatment of VCP. Materials for augmentation Figure 1. (A) The PET scan showing increased uptake in the left vocal cord (SUV max 3.9), consistent with right vocal cord paralysis. (B) Post-treatment axial PET, CT and fused PET/CT images showing focal intense FDG uptake in the right vocal cord at the CAHA injection site(SUV 9.2). Beylergil V (2016) Alternating increased unilateral vocal cord uptake in a patient with metastatic breast cancer Volume 1(1): 1-2 Nucl Med Biomed Imaging, 2016 doi: 10.15761/NMBI.1000101 are usually classified as either temporary or permanent/long lasting. Long lasting or permanent materials include autologous fat, CAHA, particulate silicone and Teflon. Examples for temporary materials include bovine gelatin, collagen based products, hyaluronic acid and carboxymethylcellulose [6]. Some of the materials can cause substantial immunologic reaction at the injection material [7]. Several case reports have been published, illustrating increased FDG uptake associated with Teflon injection [4,8]. Increased FDG uptake in the injected vocal cord is probably due to a granulomatous reaction and may mimic laryngeal cancer [9]. CAHA used as a volumizing filler is known commercially as Radiesse® (Bioform Inc, San Mateo, Calif), although canine models have failed to show foreign body reaction to CAHA, Tanna et al. and others have reported serious foreign body reaction which required partial removal of the CAHA material [10]. A few case reports have described focal intense FDG uptake in the paralyzed vocal cord due to previous injection of CAHA [11-13]. Our case is unique in that it demonstrates two important pitfalls in the same patient and supports the fact that CAHA injection may cause paradoxical focal intense FDG uptake in the paralyzed cord.