Publications by authors named "Neeta Pandit-Taskar"

118 Publications

A Phase II, Nonrandomized Open Trial Assessing Pain Efficacy with Radium-223 in Symptomatic Metastatic Castration-resistant Prostate Cancer.

Clin Genitourin Cancer 2021 Apr 19. Epub 2021 Apr 19.

Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Genitourinary Oncology Service, Weill Cornell Medicine, New York, NY.

Background: Prostate Cancer Working Group 3 and FDA guidelines recommend a standardized approach to pain assessment in preapproval trials. No prior trial has examined pain palliation of Radium-223 using standard dosing and contemporary PRO pain-assessment tools.

Methods: In this multicenter phase II trial, patients with Brief Pain Inventory (BPI) ≥3 were eligible for Radium-223 per its label. Primary endpoint was a 30% decrease in BPI Worst Pain from baseline to Week 8, sustained at Week 12 without escalation of medication on the World Health Organization (WHO) analgesic ladder. Secondary endpoints included changes in Brief Fatigue Inventory (BFI) Worst fatigue and BPI pain interference. If six of 27 subjects (22%) met the primary endpoint, the trial would expand by another 36 subjects.

Results: Twenty-nine subjects were accrued. Nine of 29 (31%) subjects met the primary endpoint, with 21 (72%) evaluable for the primary endpoint. Among responders: median worst pain declined 62% (range 36-100) at Week 8 and 63% (range 38-100) at Week 12; median reduction of pain interference with general activity and sleep at Week 12 was 62% (range 18-100) and 53% (range 8-100) respectively; median reduction in worst fatigue of 45% (range 10-85) at Week 12.

Conclusions: In the first prospective trial using standard Ra-223 doses, contemporary pain endpoints and PRO collection tools, Ra-223 palliated pain, reduced fatigue, and improved pain interference. The pain response rate easily exceeded the requirements for expansion to the second phase, but the trial was closed due to slow accrual.
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http://dx.doi.org/10.1016/j.clgc.2021.04.005DOI Listing
April 2021

Evaluation of a patient-specific algorithm for predicting distribution for convection-enhanced drug delivery into the brainstem of patients with diffuse intrinsic pontine glioma.

J Neurosurg Pediatr 2021 May 14:1-9. Epub 2021 May 14.

2Department of Neurological Surgery, Weill Medical College of Cornell University, New York, New York.

Objective: With increasing use of convection-enhanced delivery (CED) of drugs, the need for software that can predict infusion distribution has grown. In the context of a phase I clinical trial for pediatric diffuse intrinsic pontine glioma (DIPG), CED was used to administer an anti-B7H3 radiolabeled monoclonal antibody, iodine-124-labeled omburtamab. In this study, the authors retrospectively evaluated a software algorithm (iPlan Flow) for the estimation of infusate distribution based on the planned catheter trajectory, infusion parameters, and patient-specific MRI. The actual infusate distribution, as determined on MRI and PET imaging, was compared to the distribution estimated by the software algorithm. Similarity metrics were used to quantify the agreement between predicted and actual distributions.

Methods: Ten pediatric patients treated at the same dose level in the NCT01502917 trial conducted at Memorial Sloan Kettering Cancer Center were considered for this retrospective analysis. T2-weighted MRI in combination with PET imaging was used to determine the distribution of infusate in this study. The software algorithm was applied for the generation of estimated fluid distribution maps. Similarity measures included object volumes, intersection volume, union volume, Dice coefficient, volume difference, and the center and average surface distances. Acceptable similarity was defined as a simulated distribution volume (Vd Sim) object that had a Dice coefficient higher than or equal to 0.7, a false-negative rate (FNR) lower than 50%, and a positive predictive value (PPV) higher than 50% compared to the actual Vd (Vd PET).

Results: Data for 10 patients with a mean infusion volume of 4.29 ml (range 3.84-4.48 ml) were available for software evaluation. The mean Vd Sim found to be covered by the actual PET distribution (PPV) was 77% ± 8%. The mean percentage of PET volume found to be outside the simulated volume (FNR) was 34% ± 10%. The mean Dice coefficient was 0.7 ± 0.05. In 8 out of 10 patients, the simulation algorithm fulfilled the combined acceptance criteria for similarity.

Conclusions: iPlan Flow software can be useful to support planning of trajectories that produce intraparenchymal convection. The simulation algorithm is able to model the likely infusate distribution for a CED treatment in DIPG patients. The combination of trajectory planning guidelines and infusion simulation in the software can be used prospectively to optimize personalized CED treatment.
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http://dx.doi.org/10.3171/2020.11.PEDS20571DOI Listing
May 2021

High-Specific-Activity-I-MIBG versus Lu-DOTATATE Targeted Radionuclide Therapy for Metastatic Pheochromocytoma and Paraganglioma.

Clin Cancer Res 2021 Jun 8;27(11):2989-2995. Epub 2021 Mar 8.

Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland.

Targeted radionuclide therapies (TRT) using I-metaiodobenzylguanidine (I-MIBG) and peptide receptor radionuclide therapy (Lu or Y) represent several of the therapeutic options in the management of metastatic/inoperable pheochromocytoma/paraganglioma. Recently, high-specific-activity-I-MIBG therapy was approved by the FDA and both Lu-DOTATATE and I-MIBG therapy were recommended by the National Comprehensive Cancer Network guidelines for the treatment of metastatic pheochromocytoma/paraganglioma. However, a clinical dilemma often arises in the selection of TRT, especially when a patient can be treated with either type of therapy based on eligibility by MIBG and somatostatin receptor imaging. To address this problem, we assembled a group of international experts, including oncologists, endocrinologists, and nuclear medicine physicians, with substantial experience in treating neuroendocrine tumors with TRTs to develop consensus and provide expert recommendations and perspectives on how to select between these two therapeutic options for metastatic/inoperable pheochromocytoma/paraganglioma. This article aims to summarize the survival outcomes of the available TRTs; discuss personalized treatment strategies based on functional imaging scans; address practical issues, including regulatory approvals; and compare toxicities and risk factors across treatments. Furthermore, it discusses the emerging TRTs.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172462PMC
June 2021

A simple strategy to reduce the salivary gland and kidney uptake of PSMA-targeting small molecule radiopharmaceuticals.

Eur J Nucl Med Mol Imaging 2021 07 25;48(8):2642-2651. Epub 2021 Jan 25.

Department of Radiology, Memorial Sloan Kettering Cancer Center, MSKCC Zuckerman Building, 417 E 68th St, New York, NY, 10065, USA.

Purpose: Peptide-based prostate-specific membrane antigen (PSMA) targeted radionuclide therapy (TRT) agent [Lu]-PSMA-617 has emerged as leading TRT candidate for treatment of castration-resistant prostate cancer (mCRPC). [Lu]-PSMA-617 and other small molecule-based PSMA ligands have shown efficacy in reducing the tumor burden in mCRPC patients but irradiation to the salivary gland and kidneys is a concern and dose-limiting factor. Therefore, methods to reduce non-target organ toxicity are needed to safely treat patients and preserve their quality of life. Herein, we report that addition of cold PSMA ligand PSMA-11 can aid in reducing the uptake of [Lu]-PSMA-617 in the salivary glands and kidneys.

Methods: Groups of athymic nude mice (n = 4) bearing PC3-PIP (PSMA+) tumor xenografts were administered with [Lu]-PSMA-617 along with 0, 5, 100, 500, 1000, and 2000 pmoles of PSMA-11 and biodistribution studies were performed at 1 h.

Results: Biodistribution studies at 1 h post-administration revealed that [Lu]-PSMA-617 uptake in PC3-PIP tumors was 21.71 ± 6.13, 18.7 ± 2.03, 26.44 ± 2.94, 16.21 ± 3.5, 13.52 ± 3.68, and 12.03 ± 1.96 %ID/g when 0, 5, 100, 500, 1000, and 2000 pmoles of PSMA-11 were added, respectively. Corresponding uptake values in kidney were 123.14 ± 52.52, 132.31 ± 47.4, 84.29 ± 78.25, 2.12 ± 1.88, 1.16 ± 0.36, and 0.64 ± 0.23 %ID/g, respectively. Corresponding salivary gland uptake values were 0.48 ± 0.11, 0.45 ± 0.15, 0.38 ± 0.3, 0.08 ± 0.03, 0.09 ± 0.07, and 0.05 ± 0.02 % ID/g, respectively.

Conclusion: The uptake of [Lu]-PSMA-617 in the salivary gland and kidney can be substantially reduced without significantly impacting tumor uptake by adding cold PSMA-11.
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http://dx.doi.org/10.1007/s00259-020-05150-wDOI Listing
July 2021

Imaging Tumor-Infiltrating Lymphocytes in Brain Tumors with [Cu]Cu-NOTA-anti-CD8 PET.

Clin Cancer Res 2021 Apr 25;27(7):1958-1966. Epub 2021 Jan 25.

Department of Pharmacology, Weill Cornell Medical College, New York, New York.

Purpose: Glioblastoma (GBM) is the most common malignant brain tumor in adults. Various immunotherapeutic approaches to improve patient survival are being developed, but the molecular mechanisms of immunotherapy resistance are currently unknown. Here, we explored the ability of a humanized radiolabeled CD8-targeted minibody to noninvasively quantify tumor-infiltrating CD8-positive (CD8) T cells using PET.

Experimental Design: We generated a peripheral blood mononuclear cell (PBMC) humanized immune system (HIS) mouse model and quantified the absolute number of CD8 T cells by flow cytometry relative to the [Cu]Cu-NOTA-anti-CD8 PET signal. To evaluate a patient-derived orthotopic GBM HIS model, we intracranially injected cells into NOG mice, humanized cohorts with multiple HLA-matched PBMC donors, and quantified CD8 tumor-infiltrating lymphocytes by IHC. To determine whether [Cu]Cu-NOTA-anti-CD8 images brain parenchymal T-cell infiltrate in GBM tumors, we performed PET and autoradiography and subsequently stained serial sections of brain tumor tissue by IHC for CD8 T cells.

Results: Nontumor-bearing NOG mice injected with human PBMCs showed prominent [Cu]Cu-NOTA-anti-CD8 uptake in the spleen and minimal radiotracer localization to the normal brain. NOG mice harboring intracranial human GBMs yielded high-resolution PET images of tumor-infiltrating CD8 T cells. Radiotracer retention correlated with CD8 T-cell numbers in spleen and tumor tissue. Our study demonstrates the ability of [Cu]Cu-NOTA-anti-CD8 PET to quantify peripheral and tumor-infiltrating CD8 T cells in brain tumors.

Conclusions: Human CD8 T cells infiltrate an orthotopic GBM in a donor-dependent manner. Furthermore, [Cu]Cu-NOTA-anti-CD8 quantitatively images both peripheral and brain parenchymal human CD8 T cells.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026513PMC
April 2021

SNMMI Procedure Standard/EANM Practice Guideline on Pediatric F-FDG PET/CT for Oncology 1.0.

J Nucl Med 2021 01;62(1):99-110

Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts

PREAMBLEThe Society of Nuclear Medicine and Molecular Imaging (SNMMI) is an international scientific and professional organization founded in 1954 to promote the science, technology, and practical application of nuclear medicine. The European Association of Nuclear Medicine (EANM) is a professional nonprofit medical association founded in 1985 to facilitate communication worldwide among individuals pursuing clinical and academic excellence in nuclear medicine. SNMMI and EANM members are physicians, technologists, and scientists specializing in the research and practice of nuclear medicine.The SNMMI and EANM will periodically put forth new standards/guidelines for nuclear medicine practice to help advance the science of nuclear medicine and improve service to patients. Existing standards/guidelines will be reviewed for revision or renewal, as appropriate, on their fifth anniversary or sooner, if indicated. Each standard/guideline, representing a policy statement by the SNMMI/EANM, has undergone a thorough consensus process, entailing extensive review. The SNMMI and EANM recognize that the safe and effective use of diagnostic nuclear medicine imaging requires particular training and skills, as described in each document. These standards/guidelines are educational tools designed to assist practitioners in providing appropriate and effective nuclear medicine care for patients. These guidelines are consensus documents, and are not inflexible rules or requirements of practice. They are not intended, nor should they be used, to establish a legal standard of care. For these reasons and those set forth below, the SNMMI and the EANM cautions against the use of these standards/guidelines in litigation in which the clinical decisions of a practitioner are called into question.The ultimate judgment regarding the propriety of any specific procedure or course of action must be made by medical professionals taking into account the unique circumstances of each case. Thus, there is no implication that action differing from what is laid out in the standards/guidelines, standing alone, is below standard of care. To the contrary, a conscientious practitioner may responsibly adopt a course of action different from that set forth in the standards/guidelines when, in the reasonable judgment of the practitioner, such course of action is indicated by the condition of the patient, limitations of available resources, or advances in knowledge or technology subsequent to publication of the standards/guidelines.The practice of medicine involves not only the science, but also the art of dealing with the prevention, diagnosis, alleviation, and treatment of disease. The variety and complexity of human conditions make it impossible for general guidelines to consistently allow for an accurate diagnosis to be reached or a particular treatment response to be predicted. Therefore, it should be recognized that adherence to these standards/guidelines will not ensure a successful outcome. All that should be expected is that the practitioner follows a reasonable course of action, based on their level of training, the current knowledge, the available resources, and the needs/context of the particular patient being treated.PET and computerized tomography (CT) have been widely used in oncology. F-FDG is the most common radiotracer used for PET imaging. The purpose of this document is to provide imaging specialists and clinicians guidelines for recommending, performing, and interpreting F-FDG PET/CT in pediatric patients in oncology. There is not a high level of evidence for all recommendations suggested in this paper. These recommendations represent the expert opinions of experienced leaders in this field. Further studies are needed to have evidence-based recommendations for the application of F-FDG PET/CT in pediatric oncology. These recommendations should be viewed in the context of good practice of nuclear medicine and are not intended to be a substitute for national and international legal or regulatory provisions.
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http://dx.doi.org/10.2967/jnumed.120.254110DOI Listing
January 2021

A Framework for Patient-Centered Pathways of Care for Radiopharmaceutical Therapy: An ASTRO Consensus Document.

Int J Radiat Oncol Biol Phys 2021 03 26;109(4):913-922. Epub 2020 Nov 26.

Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, New York.

Radiopharmaceutical therapy (RPT) is an area of projected growth and importance with several agents in clinical use, new agents in late-phase clinical trials, and many others under testing and development. This article proposes a framework for developing pathways of care that can be broadly applied to all RPTs, representing the current status of RPT. It suggests foundational elements for many pathways of care for patients with cancer and concludes with areas in active development and the future horizon for RPT treatment centers. Developing a framework for patient-centered pathways of care is a critical step in establishing RPT as standard therapy for patients with a diverse spectrum of cancers. This expected increase in RPT treatment options will affect a much larger population of patients with complex cancer. It will also require enhanced coordination and collaboration among appropriately qualified personnel with diverse expertise in image acquisition, image interpretation, quantitative imaging, dosimetry calculation, radiation quality assurance and safety as well as oncology care and RPT-induced sequelae and response assessment. The essential role of this evolving RPT care team within multidisciplinary oncology care is a cornerstone of this framework for a patient-centered pathway of care for RPT. Given the status of current RPT practice and the horizon for future applications, this patient-centered pathway of care guidance is timely and should help inform future clinical RPT practice paradigms. A task force was recruited from the Theranostic Working Group of the American Society for Radiation Oncology (ASTRO) in May 2019 with equal representation from the nuclear medicine community. The task force expanded on a framework that was originally conceived by the Working Group for patient-centered care. This framework was developed to incorporate the strengths of both radiation oncologists and nuclear medicine physicians. The manuscript was then developed by the task force and posted on the ASTRO website for a 6-week public comment period ending in July 2020. Comments were adjudicated, and the draft was sent to external organizations for potential endorsement. This document was sent to the ASTRO Board of Directors in October 2020 for approval.
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http://dx.doi.org/10.1016/j.ijrobp.2020.11.048DOI Listing
March 2021

Novel Agents and Future Perspectives on Theranostics.

Semin Radiat Oncol 2021 Jan;31(1):83-92

Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY.; Department of Radiology, Weill Cornell Medical College, New York, NY.. Electronic address:

In the current era of precision medicine, there is renewed interest in radiopharmaceutical therapy and theranostics. The approval of somatostatin receceptor directed therapy and norepinephrine transporter targeted I-MIBG therapies by the FDA and the rapid progress of highly promising beta and alpha emitter tagged PSMA directed therapy of prostate cancer have stimulated clinically impactful changes in practice. Many novel strategies are being explored and novel radiopharmaceutical therapeutic agents including peptide based ligands as well as antibodies or antibody fragments are being developed preclinically or are in early phase clinical trials. While beta particle emitters have most commonly been used for targeted radiotherapy and radioimmunotargeting, there is an emerging interest in alpha emitters that cause greater density of ionization events leading to increased double-strand DNA damage and cluster breaks because of the high-energy particles within a shorter tissue range of penetration and thereby lower toxicity to adjacent normal tissues.
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http://dx.doi.org/10.1016/j.semradonc.2020.07.010DOI Listing
January 2021

B7H3-Directed Intraperitoneal Radioimmunotherapy With Radioiodinated Omburtamab for Desmoplastic Small Round Cell Tumor and Other Peritoneal Tumors: Results of a Phase I Study.

J Clin Oncol 2020 12 29;38(36):4283-4291. Epub 2020 Oct 29.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY.

Purpose: Desmoplastic small round cell tumor (DSRCT), a rare sarcoma of adolescents/young adults primarily involving the peritoneum, has a long-term survival of < 20% despite aggressive multimodality treatment. B7H3 is expressed on DSRCT cell surface, providing a target for antibody-based immunotherapy.

Patients And Methods: In this phase I study, we evaluated the safety, pharmacokinetics, and biodistribution of intraperitoneal (IP) radioimmunotherapy (RIT) with the anti-B7H3 murine monoclonal antibody I-omburtamab in patients with DSRCT or other B7H3-expressing tumors involving the peritoneum. After thyroid blockade, patients received I-omburtamab as a single IP injection at escalated activities from 1.11 to 3.33/GBq/m. A prior tracer dose of IP 74 MBqI-omburtamab was used for radioimmuno-positron emission tomography imaging. Each injection was followed by IP saline infusion.

Results: Fifty-two patients (48, three, and one with DSRCT, peritoneal rhabdomyosarcoma, and Ewing sarcoma, respectively) received IP I-omburtamab administered on an outpatient basis. Maximum tolerated dose was not reached; there were no dose-limiting toxicities. Major related adverse events were transient: grade 4 neutropenia (n = 2 patients) and thrombocytopenia (n = 1), and grade 1 (10%) and grade 2 (52%) pain lasting < 2 hours related to saline infusion. Hypothyroidism was not observed, and antidrug antibody was elicited in 5%. Mean (± SD) projected peritoneal residence time was 22.4 ± 7.9 hours. Mean projected absorbed doses for I-omburtamab based on I-omburtamab dosimetry to normal organs were low and well within tolerable limits. More than 80% I remained protein bound in blood 66 hours after RIT. On the basis of peritoneal dose and feasibility for outpatient administration, the recommended phase II activity was established at 2.96 GBq/m. Patients with DSRCT receiving standard whole-abdominal radiotherapy after RIT did not experience unexpected toxicity.

Conclusion: IP RIT I-omburtamab was well tolerated with minimal toxicities. Radiation exposure to normal organs was low, making combination therapy with other anticancer therapies feasible.
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http://dx.doi.org/10.1200/JCO.20.01974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768336PMC
December 2020

Immune-Directed Molecular Imaging Biomarkers.

Semin Nucl Med 2020 Nov 15;50(6):584-603. Epub 2020 Jul 15.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Imaging has played a critical role in the management of patients with cancer. Novel therapies are emerging rapidly; however, they are effective only in some patients. With the advent of new targeted therapeutics and immunotherapy, the limitations of conventional imaging methods are becoming more evident. FDG-PET imaging is restricted to the optimal assessment of immune therapies. There is a critical unmet need for pharmacodynamic and prognostic imaging biomarkers. Radiolabeled antibodies or small molecules can allow for specific assessment of targets in expression and concentration. Several such imaging agents have been under preclinical development. Early human studies with radiolabeled monoclonal antibodies or small molecules targeted to the epidermal growth factor receptor pathway have shown potential; targeted imaging of CA19.9 and CA-IX and are being further explored. Immune-directed imaging agents are highly desirable as biomarkers and preliminary studies with radiolabeled antibodies targeting immune mechanisms appear promising. While novel agents are being developed, larger well-designed studies are needed to validate the role of these agents as biomarkers in the clinical management of patients.
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http://dx.doi.org/10.1053/j.semnuclmed.2020.06.005DOI Listing
November 2020

IntraOmmaya compartmental radioimmunotherapy using I-omburtamab-pharmacokinetic modeling to optimize therapeutic index.

Eur J Nucl Med Mol Imaging 2021 04 13;48(4):1166-1177. Epub 2020 Oct 13.

Department of Pediatrics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.

Purpose: Radioimmunotherapy (RIT) delivered through the cerebrospinal fluid (CSF) has been shown to be a safe and promising treatment for leptomeningeal metastases. Pharmacokinetic models for intraOmmaya antiGD2 monoclonal antibody I-3F8 have been proposed to improve therapeutic effect while minimizing radiation toxicity. In this study, we now apply pharmacokinetic modeling to intraOmmaya I-omburtamab (8H9), an antiB7-H3 antibody which has shown promise in RIT of leptomeningeal metastases.

Methods: Serial CSF samples were collected and radioassayed from 61 patients undergoing a total of 177 intraOmmaya administrations of I-omburtamab for leptomeningeal malignancy. A two-compartment pharmacokinetic model with 12 differential equations was constructed and fitted to the radioactivity measurements of CSF samples collected from patients. The model was used to improve anti-tumor dose while reducing off-target toxicity. Mathematical endpoints were (a) the area under the concentration curve (AUC) of the tumor-bound antibody, AUC [C(t)], (b) the AUC of the unbound "harmful" antibody, AUC [C(t)], and (c) the therapeutic index, AUC [C(t)] ÷ AUC [C(t)].

Results: The model fit CSF radioactivity data well (mean R = 96.4%). The median immunoreactivity of I-omburtamab matched literature values at 69.1%. Off-target toxicity (AUC [C(t)]) was predicted to increase more quickly than AUC [C(t)] as a function of I-omburtamab dose, but the balance of therapeutic index and AUC [C(t)] remained favorable over a broad range of administered doses (0.48-1.40 mg or 881-2592 MBq). While antitumor dose and therapeutic index increased with antigen density, the optimal administered dose did not. Dose fractionization into two separate injections increased therapeutic index by 38%, and splitting into 5 injections by 82%. Increasing antibody immunoreactivity to 100% only increased therapeutic index by 17.5%.

Conclusion: The 2-compartmental pharmacokinetic model when applied to intraOmmaya I-omburtamab yielded both intuitive and nonintuitive therapeutic predictions. The potential advantage of further dose fractionization warrants clinical validation.

Clinical Trial Registration: ClinicalTrials.gov , NCT00089245.
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http://dx.doi.org/10.1007/s00259-020-05050-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279045PMC
April 2021

Proceedings of the ASTRO-RSNA Oligometastatic Disease Research Workshop.

Int J Radiat Oncol Biol Phys 2020 11 17;108(3):539-545. Epub 2020 May 17.

Department of Radiation Oncology, MD Anderson Cancer Center, Houston, Texas.

Purpose: On June 13 to 14, 2019, the American Society for Radiation Oncology and the Radiological Society of North America convened a workshop on the treatment of oligometastatic disease in Washington, DC. The workshop was initiated for several reasons. First, oligometastatic disease is of increasing academic and community interest and has been identified by the American Society for Radiation Oncology membership as a top research priority. Second, emerging imaging and diagnostic technologies are more readily defining and detecting oligometastatic disease, making contemporary discussion of oligometastatic disease especially relevant. Third, radiosurgery and radiation in general are theorized to be ideal noninvasive therapy for the treatment of oligometastatic disease. Finally, innovations in targeted therapy and immune therapy have the potential to reverse widely disseminating disease into an oligometastatic state.

Methods And Materials: The workshop was organized into 2 keynote addresses, 6 scientific sessions, and 3 group discussions during an end-of-workshop breakout session. New scientific work was presented in the form of 4 oral presentations and a poster session. Workshop participants were charged with attempting to answer 3 critical questions: (1) Can we refine the clinical and biological definitions of oligometastatic disease; (2) how can we better treat oligometastatic disease; and (3) what clinical trials are needed?

Results: Here, we present the proceedings of the workshop.

Conclusions: The clinical implications of improved treatment of oligometastatic disease are enormous and immediate. Radiation oncology and diagnostic radiology should rightly be at the forefront of the characterization and treatment of oligometastatic disease. Focused effort is required so that we can translate current efforts of large numbers of studies with few patients to larger studies of larger impact.
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http://dx.doi.org/10.1016/j.ijrobp.2020.05.018DOI Listing
November 2020

Comparison of Ga-DOTA-JR11 PET/CT with dosimetric Lu-satoreotide tetraxetan (Lu-DOTA-JR11) SPECT/CT in patients with metastatic neuroendocrine tumors undergoing peptide receptor radionuclide therapy.

Eur J Nucl Med Mol Imaging 2020 12 6;47(13):3047-3057. Epub 2020 May 6.

Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.

Purpose: Paired imaging/therapy with radiolabeled somatostatin receptor (SSTR) antagonists is a novel approach in neuroendocrine tumors (NETs). The aim of this study was to compare tumor uptake of Ga-DOTA-JR11 and Lu-satoreotide tetraxetan (Lu-DOTA-JR11) in patients with NETs.

Methods: As part of a prospective clinical trial, 20 patients with metastatic NETs underwent Ga-DOTA-JR11 PET/CT and serial imaging with Lu-satoreotide tetraxetan. PET/CT and SPECT/CT parameters for lesion uptake and absorbed dose of Lu-satoreotide tetraxetan in lesions were compared using linear regression analysis and Pearson correlation.

Results: A total of 95 lesions were analyzed on Ga-DOTA-JR11 PET/CT and Lu-satoreotide tetraxetan SPECT/CT. SUVs and tumor-to-normal-tissue ratios on PET/CT and SPECT/CT were significantly correlated (p < 0.01), but the degree of correlation was modest with Pearson correlation coefficients ranging from 0.3 to 0.7. Variation in intrapatient lesional correlation was observed. Nevertheless, in all patients, the lesion SUVpeak uptake ratio for Lu-satoreotide tetraxetan vs. Ga-DOTA-JR11 was high; even in those with low uptake on Ga-DOTA-JR11 PET/CT (SUVpeak ≤ 10), a ratio of 8.0 ± 5.2 was noted. Correlation of SUVpeak of Ga-DOTA-JR11 with projected Lu-satoreotide tetratexan-absorbed dose (n = 42) was modest (r = 0.5, p < 0.01), while excellent correlation of SUVpeak of Lu-satoreotide tetraxetan with projected Lu-satoreotide tetraxetan-absorbed dose was noted (r = 0.9, p < 0.0001).

Conclusion: Our study shows that Ga-DOTA-JR11 PET can be used for patient selection and PRRT and that low tumor uptake on PET should not preclude patients from treatment with Lu-satoreotide tetraxetan. The ability to use single time-point SPECT/CT for absorbed dose calculations could facilitate dosimetry regimens, save costs, and improve patient convenience.
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http://dx.doi.org/10.1007/s00259-020-04832-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644587PMC
December 2020

Assessing Cerebrospinal Fluid Flow Dynamics in Pediatric Patients with Central Nervous System Tumors Treated with Intraventricular Radioimmunotherapy.

J Nucl Med 2020 05 31;61(5):662-664. Epub 2020 Jan 31.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.

The incidence of abnormal cerebrospinal fluid (CSF) flow dynamics in children with central nervous system (CNS) tumors before intraventricular therapy has not been described. We performed a single-institution, retrospective review of patients with primary or metastatic CNS tumors treated between 2003 and 2018 (15 y). Patients underwent In-diethylenetriaminepentaacetic acid injection into the CSF intraventricular space followed by nuclear medicine imaging at 90 min, 4 h, 24 h, and 48 h (if required). CSF flow was classified as normal, delayed, asymmetric, or obstructed. In total, 278 CSF flow studies were performed on 224 patients, 202 of whom (90%) were less than 18 y old. Of these, 116 patients (52%) had metastatic CNS neuroblastoma, 57 (25%) had medulloblastoma, and 51 (23%) had other histologic types of CNS tumors. Of the 278 studies, 237 (85%) were normal, 9 (3%) required neurosurgical intervention, 25 (9%) were delayed, and 7 (3%) were asymmetric. Abnormal CSF flow and the necessity for neurosurgical intervention must be considered when attempting to ensure appropriate intraventricular therapy in the pediatric population.
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http://dx.doi.org/10.2967/jnumed.119.232678DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198389PMC
May 2020

Patient-adapted organ absorbed dose and effective dose estimates in pediatric 18F-FDG positron emission tomography/computed tomography studies.

BMC Med Imaging 2020 01 29;20(1). Epub 2020 Jan 29.

Department of Medical Physics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA.

Background: Organ absorbed doses and effective doses can be used to compare radiation exposure among medical imaging procedures, compare alternative imaging options, and guide dose optimization efforts. Individual dose estimates are important for relatively radiosensitive patient populations such as children and for radiosensitive organs such as the eye lens. Software-based dose calculation methods conveniently calculate organ dose using patient-adjusted and examination-specific inputs.

Methods: Organ absorbed doses and effective doses were calculated for 429 pediatric 18F-FDG PET-CT patients. Patient-adjusted and scan-specific information was extracted from the electronic medical record and scanner dose-monitoring software. The VirtualDose and OLINDA/EXM (version 2.0) programs, respectively, were used to calculate the CT and the radiopharmaceutical organ absorbed doses and effective doses. Patients were grouped according to age at the time of the scan as follows: less than 1 year old, 1 to 5 years old, 6 to 10 years old, 11 to 15 years old, and 16 to 17 years old.

Results: The mean (+/- standard deviation, range) total PET plus CT effective dose was 14.5 (1.9, 11.2-22.3) mSv. The mean (+/- standard deviation, range) PET effective dose was 8.1 (1.2, 5.7-16.5) mSv. The mean (+/- standard deviation, range) CT effective dose was 6.4 (1.8, 2.9-14.7) mSv. The five organs with highest PET dose were: Urinary bladder, heart, liver, lungs, and brain. The five organs with highest CT dose were: Thymus, thyroid, kidneys, eye lens, and gonads.

Conclusions: Organ and effective dose for both the CT and PET components can be estimated with actual patient and scan data using commercial software. Doses calculated using software generally agree with those calculated using dose conversion factors, although some organ doses were found to be appreciably different. Software-based dose calculation methods allow patient-adjusted dose factors. The effort to gather the needed patient data is justified by the resulting value of the characterization of patient-adjusted dosimetry.
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http://dx.doi.org/10.1186/s12880-020-0415-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988339PMC
January 2020

Positron Lymphography via Intracervical F-FDG Injection for Presurgical Lymphatic Mapping in Cervical and Endometrial Malignancies.

J Nucl Med 2020 08 10;61(8):1123-1130. Epub 2020 Jan 10.

Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York

The presence of metastasis in local lymph nodes (LNs) is a key factor influencing choice of therapy and prognosis in cervical and endometrial cancers; therefore, the exploration of sentinel LNs (SLNs) is highly important. Currently, however, SLN mapping requires LN biopsy for pathologic evaluation, since there are no clinical imaging approaches that can identify tumor-positive LNs in early stages. Staging lymphadenectomy poses risks, such as leg lymphedema or lymphocyst formation. Furthermore, in 80%-90% of patients, the explored LNs are ultimately tumor-free, meaning most patients are unnecessarily subjected to lymphadenectomy. Current lymphoscintigraphy methods identify only the anatomic location of the SLNs and do not provide information on their tumor status. There are no noninvasive methods to reliably identify metastases in LNs before surgery. We have developed positron lymphography (PLG), a method to detect tumor-positive LNs, in which F-FDG is injected interstitially into the uterine cervix on the day of surgery, and its rapid transport through the lymphatic vessels to the SLN is then visualized with dynamic PET/CT. We previously showed that PLG was able to identify metastatic LNs in animal models. Here, we present the first results from our pilot clinical trial (clinical trials identifier NCT02285192) in 23 patients with uterine or cervical cancer. On the morning of surgery, F-FDG was injected into the cervix, followed by an immediate dynamic PET/CT scan of the pelvis and a delayed 1-h whole-body scan. There were 3 (15%) node-positive cases on final pathologic analysis, and all of these LNs (including 1 with a focus of only 80 tumor cells) were identified by PLG. There were 2 (10%) false-positive cases with PLG, in which the final pathology of the corresponding SLNs was negative for tumor. This first-in-humans study of PLG in women with uterine and cervical cancer demonstrates its feasibility and its ability to identify patients with nodal metastases and warrants further evaluation in additional studies.
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http://dx.doi.org/10.2967/jnumed.119.230714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413230PMC
August 2020

First-in-Humans Imaging with Zr-Df-IAB22M2C Anti-CD8 Minibody in Patients with Solid Malignancies: Preliminary Pharmacokinetics, Biodistribution, and Lesion Targeting.

J Nucl Med 2020 04 4;61(4):512-519. Epub 2019 Oct 4.

Department of Medicine, Weill Cornell Medical College, New York, New York.

Immunotherapy is becoming the mainstay for treatment of a variety of malignancies, but only a subset of patients responds to treatment. Tumor-infiltrating CD8-positive (CD8+) T lymphocytes play a central role in antitumor immune responses. Noninvasive imaging of CD8+ T cells may provide new insights into the mechanisms of immunotherapy and potentially predict treatment response. We are studying the safety and utility of Zr-IAB22M2C, a radiolabeled minibody against CD8+ T cells, for targeted imaging of CD8+ T cells in patients with cancer. The initial dose escalation phase of this first-in-humans prospective study included 6 patients (melanoma, 1; lung, 4; hepatocellular carcinoma, 1). Patients received approximately 111 MBq (3 mCi) of Zr-IAB22M2C (at minibody mass doses of 0.2, 0.5, 1.0, 1.5, 5, or 10 mg) as a single dose, followed by PET/CT scans at approximately 1-2, 6-8, 24, 48, and 96-144 h after injection. Biodistribution in normal organs, lymph nodes, and lesions was evaluated. In addition, serum samples were obtained at approximately 5, 30, and 60 min and later at the times of imaging. Patients were monitored for safety during infusion and up to the last imaging time point. Zr-IAB22M2C infusion was well tolerated, with no immediate or delayed side effects observed after injection. Serum clearance was typically biexponential and dependent on the mass of minibody administered. Areas under the serum time-activity curve, normalized to administered activity, ranged from 1.3 h/L for 0.2 mg to 8.9 h/L for 10 mg. Biodistribution was dependent on the minibody mass administered. The highest uptake was always in spleen, followed by bone marrow. Liver uptake was more pronounced with higher minibody masses. Kidney uptake was typically low. Prominent uptake was seen in multiple normal lymph nodes as early as 2 h after injection, peaking by 24-48 h after injection. Uptake in tumor lesions was seen on imaging as early as 2 h after injection, with most Zr-IAB22M2C-positive lesions detectable by 24 h. Lesions were visualized early in patients receiving treatment, with SUV ranging from 5.85 to 22.8 in 6 target lesions. Zr-IAB22M2C imaging is safe and has favorable kinetics for early imaging. Biodistribution suggests successful targeting of CD8+ T-cell-rich tissues. The observed targeting of tumor lesions suggests this may be informative for CD8+ T-cell accumulation within tumors. Further evaluation is under way.
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http://dx.doi.org/10.2967/jnumed.119.229781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198374PMC
April 2020

Restaging [F] fludeoxyglucose positron emission tomography/computed tomography scan in recurrent cutaneous squamous cell carcinoma: Diagnostic performance and prognostic significance.

J Am Acad Dermatol 2020 Apr 25;82(4):878-886. Epub 2019 Sep 25.

Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address:

Background: There are no specific recommendations for [F] fludeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in assessing recurrent cutaneous squamous cell carcinoma (cSCC).

Objective: To evaluate FDG-PET/CT in recurrent cSCC.

Methods: FDG-PET/CT scans were retrospectively reviewed. Sites of abnormal uptake were noted and correlated with biopsy/histopathology studies, where available, and with follow-up imaging or clinical data in others. Comparison with available CT/magnetic resonance imaging was performed. The prognostic significance of PET/CT parameters was evaluated, and PET/CT-based change in management was recorded.

Results: A total of 115 FDG-PET/CT scans were analyzed in 100 consecutive patients with cSCC. Of these, 96 (84%) scans were positive for recurrence, and 25 showed distant metastases. PET/CT detected unsuspected disease sites in 39 of 115 scans (34%), locoregional disease in 14, distant metastases in 11, both locoregional disease and distant metastases in 8, additional local cutaneous disease in 5, and second malignancy in 1. Comparison of 78 PET/CT scans with available CT/magnetic resonance imaging showed 37 additional abnormalities on 23 PET/CT scans, predominantly including skin/subcutaneous lesions and nodes. PET/CT led to change in management in 28% of patients. On univariate/multivariate analysis, increased number of FDG-positive lesions and lung metastases on PET/CT was associated with increased risk of death/disease progression.

Limitations: Retrospective study.

Conclusions: FDG-PET/CT was sensitive in detecting recurrent disease in cSCC, led to change in management for 28% of patients, and proved to be of prognostic value.
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http://dx.doi.org/10.1016/j.jaad.2019.09.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549433PMC
April 2020

Retooling a Blood-Based Biomarker: Phase I Assessment of the High-Affinity CA19-9 Antibody HuMab-5B1 for Immuno-PET Imaging of Pancreatic Cancer.

Clin Cancer Res 2019 12 20;25(23):7014-7023. Epub 2019 Sep 20.

Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: In patients with cancer who have an abnormal biomarker finding, the source of the biomarker in the bloodstream must be located for confirmation of diagnosis, staging, and therapy planning. We evaluated if immuno-PET with the radiolabeled high-affinity antibody HuMab-5B1 (MVT-2163), binding to the cancer antigen CA19-9, can identify the source of elevated biomarkers in patients with pancreatic cancer.

Patients And Methods: In this phase I dose-escalating study, 12 patients with CA19-9-positive metastatic malignancies were injected with MVT-2163. Within 7 days, all patients underwent a total of four whole-body PET/CT scans. A diagnostic CT scan was performed prior to injection of MVT-2163 to correlate findings on MVT-2163 PET/CT.

Results: Immuno-PET with MVT-2163 was safe and visualized known primary tumors and metastases with high contrast. In addition, radiotracer uptake was not only observed in metastases known from conventional CT, but also seen in subcentimeter lymph nodes located in typical metastatic sites of pancreatic cancer, which were not abnormal on routine clinical imaging studies. A significant fraction of the patients demonstrated very high and, over time, increased uptake of MVT-2163 in tumor tissue, suggesting that HuMab-5B1 labeled with beta-emitting radioisotopes may have the potential to deliver therapeutic doses of radiation to cancer cells.

Conclusions: Our study shows that the tumor antigen CA19-9 secreted to the circulation can be used for sensitive detection of primary tumors and metastatic disease by immuno-PET. This significantly broadens the number of molecular targets that can be used for PET imaging and offers new opportunities for noninvasive characterization of tumors in patients.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052809PMC
December 2019

Targeted Radioimmunotherapy and Theranostics with Alpha Emitters.

J Med Imaging Radiat Sci 2019 12 23;50(4 Suppl 1):S41-S44. Epub 2019 Aug 23.

Department of Radiology, Molecular Imaging and Therapy Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA. Electronic address:

Radiolabeled antibodies allow for selective targeting of the cancer cells within a tumor. Both beta- and alpha-emitting radioisotopes can be linked to the antibodies for delivery of radiation to the cells. The choice of the radionuclide would depend on the biological characteristics of the antibody including its biodistribution and biological half-life. Alpha-emitting isotopes deliver high energy to target sites within short range and therefore less radiation to adjacent normal tissues. Whole antibodies have long biological clearance times that may be limiting due to radiation levels to blood and marrow. Novel strategies, such as development of smaller antibody fragments such as minibodies and diabodies, which have faster biological clearance, engineered bispecific antibodies, and multistep targeting that uses pretargeting and bioorthogonal click chemistry methods, appear promising. Several novel targets are being investigated in early-phase studies. This review provides a brief summary and current status of radioimmunotargeted agents in oncology.
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http://dx.doi.org/10.1016/j.jmir.2019.07.006DOI Listing
December 2019

Phase I Trial of Well-Differentiated Neuroendocrine Tumors (NETs) with Radiolabeled Somatostatin Antagonist Lu-Satoreotide Tetraxetan.

Clin Cancer Res 2019 12 22;25(23):6939-6947. Epub 2019 Aug 22.

Molecular Imaging and Therapy Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: Radiolabeled somatostatin receptor 2 (SSTR2) antagonists have shown higher tumor uptake and tumor-to-organ ratios than somatostatin agonists in preclinical models of neuroendocrine tumors (NETs). We performed a phase I study to evaluate the safety and efficacy of SSTR2 antagonist Lu-satoreotide tetraxetan.

Patients And Methods: Twenty patients with advanced SSTR2-positive NETs were treated with Lu-satoreotide tetraxetan. Patients first underwent a dosimetry study with Lu-satoreotide tetraxetan to determine the therapeutic activity that could be safely administered. This activity was split into two equal cycles to be delivered 3 months apart. The maximum activity was 7.4 GBq per cycle.

Results: Of 20 patients with NETs (one lung, seven small bowel, nine pancreatic, one gastric, one rectal, one kidney; mean prior treatments: three), six received one cycle of Lu- satoreotide tetraxetan and 14 received two cycles. Hematologic toxicity after cycle 1 was mild-moderate and reversed before cycle 2. However, grade 4 hematologic toxicity occurred in four of seven (57%) patients after cycle 2 of Lu-satoreotide tetraxetan. The study was suspended, and the protocol modified to limit the cumulative absorbed bone marrow dose to 1 Gy and to reduce prescribed activity for cycle 2 by 50%. The best overall response rate was 45% [5% complete response (1/20), 40% partial response (8/20)]; with 40% stable disease (8/20) and 15% progression of disease (3/20). Median progression-free survival (PFS) was 21.0 months (95% CI, 13.6-NR).

Conclusions: In this trial of heavily treated NETs, preliminary data are promising for the use of Lu-satoreotide tetraxetan. Additional studies are ongoing to determine optimal therapeutic dose/schedule.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-1026DOI Listing
December 2019

Biodistribution and Dosimetry of Intraventricularly Administered I-Omburtamab in Patients with Metastatic Leptomeningeal Tumors.

J Nucl Med 2019 12 12;60(12):1794-1801. Epub 2019 Aug 12.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.

Radiation dose estimations are key for optimizing therapies. We studied the role of I-omburtamab (8H9) given intraventricularly in assessing the distribution and radiation doses before I-omburtamab therapy in patients with metastatic leptomeningeal disease and compared it with the estimates from cerebrospinal fluid (CSF) sampling. Patients with histologically proven malignancy and metastatic disease to the central nervous system or leptomeninges who met eligibility criteria for I-omburtamab therapy underwent immuno-PET imaging with I-8H9 followed by I-8H9 antibody therapy. Patients were imaged with approximately 74 MBq of intraventricular I-omburtamab via an Ommaya reservoir. Whole-body PET images were acquired at approximately 4, 24, and 48 h after administration and analyzed for dosimetry calculations. Peripheral blood and CSF samples were obtained at multiple time points for dosimetry estimation. Forty-two patients with complete dosimetry and therapy data were analyzed. I-omburtamab PET-based radiation dosimetry estimations revealed mean (±SD) absorbed dose to the CSF for I-8H9 of 0.62 ± 0.40 cGy/MBq, compared with 2.22 ± 2.19 cGy/MBq based on I-omburtamab CSF samples and 1.53 ± 1.37 cGy/MBq based on I-omburtamab CSF samples. The mean absorbed dose to the blood was 0.051 ± 0.11 cGy/MBq for I-omburtamab samples and 0.07 ± 0.04 cGy/MBq for I-omburtamab samples. The effective whole-body radiation dose for I-omburtamab was 0.49 ± 0.27 mSv/MBq. The mean whole-body clearance half-time was 44.98 ± 16.29 h. PET imaging with I-omburtamab antibody administered intraventricularly allows for noninvasive estimation of dose to CSF and normal organs. High CSF-to-blood absorbed-dose ratios are noted, allowing for an improved therapeutic index to leptomeningeal disease and reduced systemic doses. PET imaging-based estimates were less variable and more reliable than CSF sample-based dosimetry.
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http://dx.doi.org/10.2967/jnumed.118.219576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894373PMC
December 2019

European Association of Nuclear Medicine Practice Guideline/Society of Nuclear Medicine and Molecular Imaging Procedure Standard 2019 for radionuclide imaging of phaeochromocytoma and paraganglioma.

Eur J Nucl Med Mol Imaging 2019 Sep 29;46(10):2112-2137. Epub 2019 Jun 29.

Eunice Kennedy Shriver National Institutes of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

Purpose: Diverse radionuclide imaging techniques are available for the diagnosis, staging, and follow-up of phaeochromocytoma and paraganglioma (PPGL). Beyond their ability to detect and localise the disease, these imaging approaches variably characterise these tumours at the cellular and molecular levels and can guide therapy. Here we present updated guidelines jointly approved by the EANM and SNMMI for assisting nuclear medicine practitioners in not only the selection and performance of currently available single-photon emission computed tomography and positron emission tomography procedures, but also the interpretation and reporting of the results.

Methods: Guidelines from related fields and relevant literature have been considered in consultation with leading experts involved in the management of PPGL. The provided information should be applied according to local laws and regulations as well as the availability of various radiopharmaceuticals.

Conclusion: Since the European Association of Nuclear Medicine 2012 guidelines, the excellent results obtained with gallium-68 (Ga)-labelled somatostatin analogues (SSAs) in recent years have simplified the imaging approach for PPGL patients that can also be used for selecting patients for peptide receptor radionuclide therapy as a potential alternative or complement to the traditional theranostic approach with iodine-123 (I)/iodine-131 (I)-labelled meta-iodobenzylguanidine. Genomic characterisation of subgroups with differing risk of lesion development and subsequent metastatic spread is refining the use of molecular imaging in the personalised approach to hereditary PPGL patients for detection, staging, and follow-up surveillance.
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http://dx.doi.org/10.1007/s00259-019-04398-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446938PMC
September 2019

Zr-Immuno-PET: Toward a Noninvasive Clinical Tool to Measure Target Engagement of Therapeutic Antibodies In Vivo.

J Nucl Med 2019 12 30;60(12):1825-1832. Epub 2019 May 30.

Department of Radiology and Nuclear Medicine, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Zr-immuno-PET is a promising noninvasive clinical tool that measures target engagement of monoclonal antibodies (mAbs) to predict toxicity in normal tissues and efficacy in tumors. Quantification of Zr-immuno-PET will need to move beyond SUVs, since total uptake may contain a significant non-target-specific contribution. Nonspecific uptake is reversible (e.g., blood volume) or irreversible (due to Zr-residualization after mAb degradation). The aim of this study was to assess nonspecific uptake in normal tissues as a first critical step toward quantification of target engagement in normal tissues and tumors using Zr-immuno-PET. Data from clinical studies with 4 Zr-labeled intact IgG1 antibodies were collected, resulting in a total of 128 PET scans (1-7 d after injection from 36 patients: Zr-obinutuzumab [ = 9], Zr-cetuximab [ = 7], Zr-huJ591 [ = 10], and Zr-trastuzumab [ = 10] [denoted as Zr-anti-CD20, Zr-anti-EGFR, Zr-anti-PSMA and Zr-anti-HER2, respectively]). Nonspecific uptake was defined as uptake measured in tissues without known target expression. Patlak graphical evaluation of transfer constants was used to estimate the reversible ( ) and irreversible ( ) contributions to the total measured uptake for the kidney, liver, lung, and spleen. Baseline values were calculated per tissue combining all mAbs without target expression (kidney: Zr-anti-CD20, Zr-anti-EGFR, and Zr-anti-HER2; liver: Zr-anti-CD20; lung: Zr-anti-CD20, Zr-anti-EGFR, and Zr-anti-PSMA; spleen: Zr-anti-EGFR and Zr-anti-HER2). For the kidney, liver, lung, and spleen, baseline was 0.20, 0.24, 0.09, and 0.24 mL⋅cm, respectively, and baseline was 0.7, 1.1, 0.2 and 0.5 μL⋅g⋅h, respectively. For Zr-anti-PSMA, a 4-fold higher was observed for the kidney, indicating target engagement. In this case, nonspecific uptake accounted for 66%, 34%, and 22% of the total signal in the kidney at 1, 3, and 7 d after injection, respectively. This study shows that nonspecific uptake of mAbs for tissues without target expression can be quantified using Zr-immuno-PET at multiple time points. These results form a crucial base for measurement of target engagement by therapeutic antibodies in vivo with Zr-immuno-PET. For future studies, a pilot phase including at least 3 scans at 1 or more days after injection is required to assess nonspecific uptake as a function of time, to optimize study design for detection of target engagement.
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http://dx.doi.org/10.2967/jnumed.118.224568DOI Listing
December 2019

Pharmacokinetics and Biodistribution of a [Zr]Zr-DFO-MSTP2109A Anti-STEAP1 Antibody in Metastatic Castration-Resistant Prostate Cancer Patients.

Mol Pharm 2019 07 31;16(7):3083-3090. Epub 2019 May 31.

Department of Radiology , Joan and Sanford I. Weill Cornell Medical Center , New York , New York 10065 , United States.

A six-transmembrane epithelial antigen of prostate-1 (STEAP1) is a newly identified target in prostate cancer. The use of radio-labeled STEAP1-targeting antibodies with positron emission tomography (PET) may allow for detection of sites of metastatic prostate cancer and may refine patient selection for antigen-directed therapies. This was a prospective study in seven patients with metastatic castration-resistant prostate cancer who had at least one archival biopsy that was STEAP1-positive by immunohistochemistry. Patients received intravenous injections of ∼185 MBq and 10 mg of [Zr]Zr-DFO-MSTP2109A, a humanized IgG1 monoclonal antibody directed against STEAP1. PET/CT images, blood samples, and whole-body counts were monitored longitudinally in six patients. Here, we report on safety, biodistribution, pharmacokinetics, dose estimates to normal tissues, and initial tumor targeting for this group of patients. There was no significant acute or subacute toxicity. Favorable biodistribution and enhanced lesion uptake (in both bone and soft tissue) were observed on imaging using a mass of 10 mg of DFO-MSTP2109A. The best lesion discrimination was seen at the latest imaging time, a median of 6 days postadministration. Pharmacokinetics showed a median serum T β of 198 h, volume of central compartment of 3.54 L (similar to plasma volume), and clearance of 19.7 mL/h. The median biologic T for whole-body retention was 469 h. The highest mean absorbed doses to normal organs (mGy/MBq) were 1.18, 1.11, 0.78, 0.73, and 0.71 for liver, heart wall, lung, kidney, and spleen, respectively. Excellent targeting of metastatic prostate sites in both bone and soft tissue was observed, with an optimal imaging time of 6 days postadministration. The liver and heart were the normal organs that experienced the highest absorbed doses. The pharmacokinetics were similar to other antibodies without major cross-reactivity with normal tissues. A more detailed analysis of lesion targeting in a larger patient population with correlation to immunohistology and standard imaging modalities has been reported.
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http://dx.doi.org/10.1021/acs.molpharmaceut.9b00326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176438PMC
July 2019

Clinical value of 18F-FDG-PET/CT in staging cutaneous squamous cell carcinoma.

Nucl Med Commun 2019 Jul;40(7):744-751

Departments of Radiology.

Background: Cutaneous squamous cell carcinoma (cSCC) is the second most common skin malignancy. Computed tomography (CT) and/or MRI are commonly used for staging, however, the role of fluorine-18-fluorodeoxyglucose (F-FDG)-PET is not clearly established. In this study, we evaluated F-FDG-PET/CT imaging for initial staging of cSCC.

Patients And Methods: F-FDG-PET/CT scans performed in patients with newly diagnosed cSCC were reviewed retrospectively. Images were visually assessed for lesions and F-FDG uptake [standardized uptake value (SUV)] in primary and secondary sites was measured. Suspected lesions on F-FDG-PET/CT were correlated with histopathology when available, follow-up imaging or clinical data in others.

Results: Twenty-three cSCC patients who underwent F-FDG-PET/CT at diagnosis were evaluated. Primary sites were in head/neck (n=21), chest (n=1), and foot (n=1). All patients had F-FDG-positive scans with a total of 51 F-FDG-positive lesions. All primary lesions (n=24) were F-FDG-positive (SUV: 2.3-22.8; mean 10.2), and additional 27 F-FDG-positive lesions, including 21 nodes, four cutaneous, one osseous and one lung lesion, were noted in 13 patients. Mean size of F-FDG-positive nodes was 0.9 cm (range: 0.4-2.5 cm), predominantly clinically impalpable. Pathology was available for 40/51 lesions; 31 sites positive for malignancy. SUV (mean±SD) was 9.2±6.2 for malignant and 2.7±1.2 for benign lesions. Sensitivity, positive predictive value, and accuracy of F-FDG-PET/CT scan were 100, 77.5, and 77.5%, respectively. F-FDG detected seven additional lesions in three patients, compared to CT/MRI. Overall, staging F-FDG-PET/CT detected nine prior unknown lesions in five patients that were proven metastatic disease by histopathology or follow-up; F-FDG-PET/CT modified management in 5/23 (21.7%) patients.

Conclusion: F-FDG-PET/CT has high sensitivity in the detection of cSCC lesions, including small cutaneous and nodal disease, and has a potential role in initial staging and management.
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http://dx.doi.org/10.1097/MNM.0000000000001029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7518232PMC
July 2019

Radium-223 in combination with docetaxel in patients with castration-resistant prostate cancer and bone metastases: a phase 1 dose escalation/randomised phase 2a trial.

Eur J Cancer 2019 06 11;114:107-116. Epub 2019 May 11.

Department of Medicine, University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

Purpose: Radium 223 dichloride (radium-223) is an alpha particle-emitting bone-directed therapy that prolongs overall survival in men with bone-predominant metastatic castration-resistant prostate cancer (mCRPC). Docetaxel is an antimicrotubule cytotoxic agent that improves survival in mCRPC. We investigated whether combining these potentially cross-sensitising agents to dually target tumour and bone would be safe and effective.

Patients And Methods: Phase 1 was a dose escalation study to define a recommended phase 2 dose (RP2D) of docetaxel and radium-223. In phase 2a, patients were randomised 2:1 to the recommended combination regimen or docetaxel at a dose of 75 mg/m every 3 weeks (q3w). Patients with bone-predominant mCRPC were eligible. End-points were safety, efficacy and treatment-related changes in serum and imaging biomarkers.

Results: Twenty patients were enrolled in phase 1; 53 patients were randomised in phase 2a: 36 to combination treatment and 17 to docetaxel alone. The RP2D for the combination was radium-223 55 kBq/kg every six weeks × 5 doses, plus docetaxel 60 mg/m q3w × 10 doses. Febrile neutropenia was dose limiting. A higher rate of febrile neutropenia was seen in the docetaxel monotherapy arm (15% vs 0%); the safety profile of the treatment groups was otherwise similar. The combination arm had more durable suppression of prostate-specific antigen (median time to progression, 6.6 vs 4.8 months, respectively), alkaline phosphatase (9 vs 7 months) and osteoblastic bone deposition markers.

Conclusions: Radium-223 in combination with docetaxel at the RP2D was well tolerated. Exploratory efficacy data suggested enhanced antitumour activity for the combination relative to docetaxel alone. Comparative studies with end-points of clinical benefit are warranted. ClinicalTrials.gov number: NCT01106352.
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http://dx.doi.org/10.1016/j.ejca.2019.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474951PMC
June 2019

Imaging Patients with Metastatic Castration-Resistant Prostate Cancer Using Zr-DFO-MSTP2109A Anti-STEAP1 Antibody.

J Nucl Med 2019 11 3;60(11):1517-1523. Epub 2019 May 3.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Six-transmembrane epithelial antigen of prostate-1 (STEAP1) is a relatively newly identified target in prostate cancer. We evaluated the ability of PET/CT with Zr-DFO-MSTP2109A, an antibody that recognizes STEAP1, to detect lesions in patients with metastatic castration-resistant prostate cancer (mCRPC). Nineteen mCRPC patients were prospectively imaged using approximately 185 MBq/10 mg of Zr-DFO-MSTP2109A. Zr-DFO-MSTP2109A PET/CT images obtained 4-7 d after injection were compared with bone and CT scans. Uptake in lesions was measured. Fifteen patients were treated with an antibody-drug conjugate (ADC) based on MSTP2109A; ADC treatment-related data were correlated with tumor uptake by PET imaging. Bone or soft-tissue biopsy samples were evaluated. No significant toxicity occurred. Excellent uptake was observed in bone and soft-tissue disease. Median SUV was 20.6 in bone and 16.8 in soft tissue. Sixteen of 17 lesions biopsied were positive on Zr-DFO-MSTP2109A, and all sites were histologically positive (1 on repeat biopsy). Bayesian analysis resulted in a best estimate of 86% of histologically positive lesions being true-positive on imaging (95% confidence interval, 75%-100%). There was no correlation between SUV tumor uptake and STEAP1 immunohistochemistry, survival after ADC treatment, number of ADC treatment cycles, or change in prostate-specific antigen level. Zr-DFO-MSTP2109A is well tolerated and shows localization in mCRPC sites in bone and soft tissue. Given the high SUV in tumor and localization of a large number of lesions, this reagent warrants further exploration as a companion diagnostic in patients undergoing STEAP1-directed therapy.
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http://dx.doi.org/10.2967/jnumed.118.222844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836860PMC
November 2019

Targeted radioimmunotherapy for embryonal tumor with multilayered rosettes.

J Neurooncol 2019 May 16;143(1):101-106. Epub 2019 Mar 16.

Department of Pediatrics, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY, 10065, USA.

Purpose: We explored the use of intraventricular I-Omburtamab targeting B7-H3 in patients with ETMR.

Methods: Patients were enrolled in an IRB approved, phase 1, 3 + 3 dose escalation trial. Patients with CNS disease expressing the antibody target antigen B7-H3 were eligible. We report on a cohort of three patients with ETMR who were enrolled on the study. Three symptomatic children (ages 14 months, 3 and 3.5 years) had large parietal masses confirmed to be B7-H3-reactive ETMR. Patients received 2 mCi I-Omburtamab as a tracer followed by one or two therapeutic I-Omburtamab injections. Dosimetry was based on serial CSF, blood samplings and region of interest (ROI) on nuclear scans. Brain and spine MRIs and CSF cytology were done at baseline, 5 weeks after I-Omburtamab, and approximately every 3 months thereafter. Acute toxicities and survival were noted.

Results: Patients received surgery, focal radiation, and high dose chemotherapy. Patients 1 and 2 received I-Omburtamab (80 and 53 mCi, respectively). Patient 3 had a local recurrence prior to I-Omburtamab treated with surgery, external beam radiation, chemotherapy, then I-Omburtamab (36 mCi). I-Omburtamab was well-tolerated. Mean dose delivered by I-Omburtamab was 68.4 cGy/mCi to CSF and 1.95 cGy/mCi to blood. Mean ROI doses were 230.4 (ventricular) and 58.2 (spinal) cGy/mCi. Patients 1 and 2 remain in remission 6.8 years and 2.3 years after diagnosis, respectively; patient 3 died of progressive disease 7 months after therapy (2 years after diagnosis).

Conclusions: I-Omburtamab appears safe with favorable dosimetry therapeutic index. When used as consolidation following surgery and chemoradiation therapy, I-Omburtamab may have therapeutic benefit for patients with ETMR.
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http://dx.doi.org/10.1007/s11060-019-03139-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7416633PMC
May 2019

and Amplifications Determine Response to HER2 Inhibition in -Amplified Esophagogastric Cancer.

Cancer Discov 2019 02 21;9(2):199-209. Epub 2018 Nov 21.

Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, New York.

The anti-HER2 antibody trastuzumab is standard care for advanced esophagogastric (EG) cancer with (HER2) amplification or overexpression, but intrinsic and acquired resistance are common. We conducted a phase II study of afatinib, an irreversible pan-HER kinase inhibitor, in trastuzumab-resistant EG cancer. We analyzed pretreatment tumor biopsies and, in select cases, performed comprehensive characterization of postmortem metastatic specimens following acquisition of drug resistance. Afatinib response was associated with coamplification of and . Heterogeneous Zr-trastuzumab PET uptake was associated with genomic heterogeneity and mixed clinical response to afatinib. Resistance to afatinib was associated with selection for tumor cells lacking amplification or with acquisition of amplification, which could be detected in plasma cell-free DNA. The combination of afatinib and a MET inhibitor induced complete tumor regression in and coamplified patient-derived xenograft models established from a metastatic lesion progressing on afatinib. Collectively, differential intrapatient and interpatient expression of HER2, EGFR, and MET may determine clinical response to HER kinase inhibitors in -amplified EG cancer. SIGNIFICANCE: Analysis of patients with -amplified, trastuzumab-resistant EG cancer who were treated with the HER kinase inhibitor afatinib revealed that sensitivity and resistance to therapy were associated with / coamplification and amplification, respectively. HER2-directed PET imaging and cell-free DNA sequencing could help guide strategies to overcome the emergence of resistant clones...
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http://dx.doi.org/10.1158/2159-8290.CD-18-0598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368868PMC
February 2019
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