Publications by authors named "Daniel Pryma"

93 Publications

Incremental prognostic value of visually estimated coronary artery calcium in patients undergoing positron emission tomography imaging.

Open Heart 2021 May;8(1)

Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA

Objective: Visually estimated coronary artery calcium (VECAC) from chest CT or attenuation correction (AC)/CT obtained during positron emission tomography (PET)-myocardial perfusion imaging (MPI) is feasible. Our aim was to determine the prognostic value of VECAC beyond conventional risk factors and PET imaging parameters, including coronary flow reserve (CFR).

Methods: We analysed 608 patients without known coronary artery disease who underwent PET-MPI between 2012 and 2016 and had AC/CT and/or chest CT images. We used Cox regression to estimate the association of VECAC categories (≤10, 11-400, >400 Agatston units (AU)) with the primary outcome of all-cause death, acute coronary syndrome or stroke (mean follow-up 4.3±1.8 years). C-statistics assessed the relationship between PET parameters and VECAC with the primary outcome.

Results: Mean age was 58±11 years, 65% were women and 67% were black. VECAC ≤10, 11-400 and >400 AU was observed in 68%, 12% and 20% of subjects, respectively. Compared with VECAC ≤10, VECAC categories 11-400 (HR 2.25, 95% CI 1.24 to 4.08) and >400 AU (HR 3.05, 95% CI 1.87 to 4.98) were associated with the primary outcome after adjusting for traditional risk factors, MPI findings and CFR. Adding VECAC to a model that included PET-MPI, CFR and clinical risk factors improved the prognostic value for the primary outcomes (c-statistic 0.71 to 0.75 with VECAC, p=0.01).

Conclusions: VECAC is a potent predictor of events beyond traditional risk factors and PET imaging markers, including CFR. These data further support the importance for routine VECAC implementation.
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http://dx.doi.org/10.1136/openhrt-2021-001648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108688PMC
May 2021

The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Management of Metastatic and/or Unresectable Pheochromocytoma and Paraganglioma.

Pancreas 2021 Apr;50(4):469-493

Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX.

Abstract: This manuscript is the result of the North American Neuroendocrine Tumor Society consensus conference on the medical management and surveillance of metastatic and unresectable pheochromocytoma and paraganglioma held on October 2 and 3, 2019. The panelists consisted of endocrinologists, medical oncologists, surgeons, radiologists/nuclear medicine physicians, nephrologists, pathologists, and radiation oncologists. The panelists performed a literature review on a series of questions regarding the medical management of metastatic and unresectable pheochromocytoma and paraganglioma as well as questions regarding surveillance after resection. The panelists voted on controversial topics, and final recommendations were sent to all panel members for final approval.
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http://dx.doi.org/10.1097/MPA.0000000000001792DOI Listing
April 2021

In vivo visualization of PARP inhibitor pharmacodynamics.

JCI Insight 2021 Apr 22;6(8). Epub 2021 Apr 22.

Division of Nuclear Medicine Imaging and Therapy, Department of Radiology, and.

BACKGROUND[18F]FluorThanatrace ([18F]FTT) is a radiolabeled poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi) that enables noninvasive quantification of PARP with potential to serve as a biomarker for patient selection for PARPi therapy. Here we report for the first time to our knowledge noninvasive in vivo visualization of drug-target engagement during PARPi treatment.METHODSTwo single-arm, prospective, nonrandomized clinical trials were conducted at the University of Pennsylvania from May 2017 to March 2020. PARP expression in breast cancer was assessed in vivo via [18F]FTT PET before and after initiation of PARPi treatment and in vitro via [125I]KX1 (an analog of [18F]FTT) binding to surgically removed breast cancer.RESULTSThirteen patients had baseline [18F]FTT PET. Nine of these then had resection and in vitro evaluation of [18F]FTT uptake with an analog and uptake was blocked with PARPi. Of the other 4 patients, 3 had [18F]FTT PET uptake, and all had uptake blocked with treatment with a therapeutic PARPi. Initial in vivo [18F]FTT tumor uptake ranged from undetectable to robust. Following initiation of PARPi therapy, [18F]FTT uptake was not detectable above background in all cases. In vitro tumor treatment with a PARPi resulted in 82% reduction in [125I]KX1 binding.CONCLUSION[18F]FTT noninvasively quantifies PARP-1 expression. Early results indicate ability to visualize PARPi drug-target engagement in vivo and suggest the utility of further study to test [18F]FTT PET as a predictive and pharmacodynamic biomarker.TRIAL REGISTRATIONClinicalTrials.gov identifiers NCT03083288 and NCT03846167.FUNDINGMetavivor Translational Research Award, Susan G. Komen for the Cure (CCR 16376362), Department of Defense BC190315, and Abramson Cancer Center Breakthrough Bike Challenge.
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http://dx.doi.org/10.1172/jci.insight.146592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119179PMC
April 2021

Kinetic and static analysis of poly-(adenosine diphosphate-ribose) polymerase-1 (PARP-1) targeted F-FluorThanatrace (F-FTT) PET images of ovarian cancer.

J Nucl Med 2021 Apr 16. Epub 2021 Apr 16.

University of Pennsylvania, United States.

The poly-(adenosine diphosphate-ribose) polymerase (PARP) family of proteins participates in numerous functions, most notably the DNA damage response. Cancer vulnerability to DNA damage has led to development of several PARP inhibitors (PARPi). This class of drugs has demonstrated therapeutic efficacy in ovarian, breast, and prostate cancers, but with variable response. Consequently, clinics need to select patients likely to benefit from these targeted therapies. In vivo imaging of F-FluorThanatrace (F-FTT) uptake has been shown to correspond to PARP-1 expression in tissue. This study characterizes the pharmacokinetics of F-FTT and tests kinetic and static models to guide metric selection in future studies assessing F-FTT as a biomarker of response to PARPi therapy. Fourteen prospectively enrolled ovarian cancer patients were injected with F-FTT and imaged dynamically for 60-minutes post-injection followed by up to two whole-body scans, with venous blood activity and metabolite measurements. Maximum and peak standardized uptake values (SUV and SUVpeak) were extracted from dynamic images and whole-body scans. Kinetic parameter estimates and SUVs were assessed for correlations with tissue PARP-1 immunofluorescence ( = 7). Simulations of population kinetic parameters enabled estimation of measurement bias and precision in parameter estimates. F-FTT blood clearance was variable, but labeled metabolite profiles were similar across patients, supporting use of a population parent fraction curve. Total distribution volume (VT) from a reversible two-tissue compartment model and Logan reference tissue distribution volume ratio (Logan DVR) from the first hour of PET acquisition correlated with tumor PARP-1 expression by immunofluorescence (r=0.76 and 0.83 respectively, p<0.05). DVR bias and precision estimates were 6.4% and 29.1%, respectively. SUV and SUVpeak acquired from images with midpoints of 57.5, 110±3, and 199±4 min highly correlated with PARP-1 expression (mean±standard deviation, r≥0.79, p<0.05). Tumor SUV and SUVpeak at 55-60 minutes post-injection and later and DVR from ≥ 60-minutes appear to be robust non-invasive measures of PARP-1 binding. F-FTT uptake in ovarian cancer was best described by models of reversible binding. However, pharmacokinetic patterns of tracer uptake were somewhat variable, especially at later time points.
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http://dx.doi.org/10.2967/jnumed.121.261894DOI Listing
April 2021

Laboratory, Clinical, and Survival Outcomes Associated With Peptide Receptor Radionuclide Therapy in Patients With Gastroenteropancreatic Neuroendocrine Tumors.

JAMA Netw Open 2021 03 1;4(3):e212274. Epub 2021 Mar 1.

Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

Importance: Peptide receptor radionuclide therapy (PRRT) is approved in the US for treatment of gastroenteropancreatic neuroendocrine tumors (NETs), but data on PRRT outcomes within US populations remain scarce.

Objective: To analyze the first 2 years of PRRT implementation at a US-based NET referral center.

Design, Setting, And Participants: This cohort study was conducted using medical records of patients with metastatic NET receiving PRRT from 2018 through 2020 in a NET program at a tertiary referral center. Included patients were those at the center with metastatic NETs who received at least 1 dose of PRRT over the study period. Laboratory toxic effects were assessed using Common Terminology Criteria for Adverse Events version 5.0. Tumor response was determined using Response Evaluation Criteria in Solid Tumors 1.1. Survival analysis was conducted to identify factors associated with progression-free survival (PFS) and overall survival. Data were analyzed from August 2018 through August 2020.

Exposures: Receiving 4 cycles of lutetium-177-dotatate infusion, separated by 8-week intervals targeted to 7.4 GBq (200 mCi) per dose.

Main Outcomes And Measures: Data were compared from before and after PRRT to determine hematologic, liver, and kidney toxic effects and to assess tumor progression and patient survival.

Results: Among 78 patients receiving at least 1 dose of PRRT, median (interquartile range) age at PRRT initiation was 59.8 (53.5-69.2) years and 39 (50.0%) were men. The most common primary NET sites included small bowel, occurring in 34 patients (43.6%), and pancreas, occurring in 22 patients (28.2%). World Health Organization grade 1 or 2 tumors occurred in 62 patients (79.5%). Among all patients, 56 patients underwent pretreatment with tumor resection (71.8%), 49 patients received nonsomatostatin analogue systemic therapy (62.8%), and 49 patients received liver-directed therapy (62.8%). At least 1 grade 2 or greater toxic effect was found in 47 patients (60.3%). Median PFS was 21.6 months for the study group, was not reached by 22 months for patients with small bowel primary tumors, and was 13.3 months for patients with pancreatic primary tumors. Having a small bowel primary tumor was associated with a lower rate of progression compared with having a pancreatic primary tumor (hazard ratio, 0.19; 95% CI, 0.07-0.55; P = .01). Median overall survival was not reached.

Conclusions And Relevance: This cohort study of patients with metastatic NETs found that PRRT was associated with laboratory-measured toxic effects during treatment for most patients and an overall median PFS of 21.6 months. Patients with small bowel NETs had longer PFS after PRRT compared with patients with pancreatic NETs.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.2274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7988364PMC
March 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 stratified phase I dose escalation trial of hypofractionated radiotherapy followed by ipilimumab in metastatic melanoma: long-term follow-up and final outcomes.

Oncoimmunology 2021 01 31;10(1):1863631. Epub 2021 Jan 31.

Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

We conducted a phase I dose-escalation trial of radiation with ipilimumab in patients with melanoma with ≥2 metastatic lesions. Here, we report the final full clinical analysis. Patients received RT (6 or 8 Gy x 2 or 3 doses) to a single lesion followed by 4 cycles of ipilimumab. The primary endpoint was maximum tolerated dose of RT, and secondary endpoint was response at non-radiated sites. Twenty-two patients with treatment-naïve (n = 11) or treatment-refractory (n = 11) Stage IV melanoma were enrolled. There were 31 treatment-related adverse events (AEs), of which 16 were deemed immune-related. Eleven patients had grade 3 AEs (no grade 4/5). There were no dose-limiting toxicities related to the radiation/ipilimumab combination. Five of 22 patients (22.7%, 95% CI 7.8-45.4%) had partial response as best response and three (13.6%) had stable disease. Median overall survival was 10.7 months (95% CI, 4.9 months to not-estimable) and median progression-free survival 3.6 months (95% CI, 2.9 months to 7.8 months). Seven patients were still alive at the time of last follow-up (median follow-up 89.2 months), most of whom received pembrolizumab after progression. Radiotherapy followed by ipilimumab was well tolerated and yielded a response rate that compares favorably to the objective response rate with ipilimumab alone. Furthermore, 32% of patients are long-term survivors, most of whom received pembrolizumab. Based on these results, the recommended dose that was used in subsequent Phase 2 trials was 8 Gy x 3 doses. Clinical Trial Registration: NCT01497808 (www.clinicaltrials.gov).
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http://dx.doi.org/10.1080/2162402X.2020.1863631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7872096PMC
January 2021

PARP Targeted Alpha-Particle Therapy Enhances Response to PD-1 Immune-Checkpoint Blockade in a Syngeneic Mouse Model of Glioblastoma.

ACS Pharmacol Transl Sci 2021 Feb 26;4(1):344-351. Epub 2021 Jan 26.

Division of Nuclear Medicine and Clinical Molecular Imaging, Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, United States.

We have previously demonstrated potent antitumor effects of PARP targeted alpha-therapy with astatine-211-MM4 ([At]MM4) in neuroblastoma preclinical models, although differential sensitivity suggests it is unlikely to be curative as a single-agent in all tumor types. Alpha-particle induced DNA damage can elicit an immune response that results in T-cell activation against tumor cells; however, tumor cells can evade immune surveillance through expression of programmed death ligand 1 (PD-L1). Therefore, we investigated the effects of α particle therapy in combination with immune-checkpoint blockade using astatine-211-MM4 and anti-programmed death receptor 1 (anti-PD-1) immunotherapy in a syngeneic mouse model of glioblastoma. We characterized the sensitivity of four human glioblastoma cell lines to [At]MM4 . To evaluate [At]MM4 treatment effects on hematological tissues, complete blood counts were performed after a single dose at 12, 24, or 36 MBq/kg. In vivo efficacy was evaluated in a syngeneic mouse model of glioblastoma using GL26 glioblastoma cells in CB57BL/6J mice treated with either 36 MBq/kg [At]MM4, anti-PD-1 antibody, or a combination of the two. Following a single dose of [At]MM4, lymphocytes are significantly decreased compared to control at both 72 h and 1 week following treatment followed by recovery of counts by 2 weeks. However, neutrophils showed an increase with all dose levels of [At]MM4 exhibiting higher levels than control. The average best tumor responses for combination, anti-PD-1, and [At]MM4 were 100%, 83.6%, and 58.2% decrease in tumor volume, respectively. Average progression free intervals for combination, anti-PD-1, [At]MM4, and control groups was 65, 36.4, 23.2, and 3 days, respectively. The percentages of disease-free mice at the end of the study for combination and anti-PD-1 were 100% and 60%, while [At]MM4 and control groups were both 0%. In summary, combination therapy was more effective than either single agent in all response categories analyzed, highlighting the potential for PARP targeted alpha-therapy to enhance PD-1 immune-checkpoint blockade.
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http://dx.doi.org/10.1021/acsptsci.0c00206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887847PMC
February 2021

Integration of Risk Survival Measures Estimated From Pre- and Posttreatment Computed Tomography Scans Improves Stratification of Patients With Early-Stage Non-small Cell Lung Cancer Treated With Stereotactic Body Radiation Therapy.

Int J Radiat Oncol Biol Phys 2021 Apr 19;109(5):1647-1656. Epub 2021 Jan 19.

Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

Purpose: To predict overall survival of patients receiving stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer (ES-NSCLC), we developed a radiomic model that integrates risk of death estimates and changes based on pre- and posttreatment computed tomography (CT) scans. We hypothesize this innovation will improve our ability to stratify patients into various oncologic outcomes with greater accuracy.

Methods And Materials: Two cohorts of patients with ES-NSCLC uniformly treated with SBRT (a median dose of 50 Gy in 4-5 fractions) were studied. Prediction models were built on a discovery cohort of 100 patients with treatment planning CT scans, and then were applied to a separate validation cohort of 60 patients with pre- and posttreatment CT scans for evaluating their performance.

Results: Prediction models achieved a c-index up to 0.734 in predicting survival outcomes of the validation cohort. The integration of the pretreatment risk of survival measures (risk-high vs risk-low) and changes (risk-increase vs risk-decrease) in risk of survival measures between the pretreatment and posttreatment scans further stratified the patients into 4 subgroups (risk: high, increase; risk: high, decrease; risk: low, increase; risk: low, decrease) with significant difference (χ = 18.549, P = .0003, log-rank test). There was also a significant difference between the risk-increase and risk-decrease groups (χ = 6.80, P = .0091, log-rank test). In addition, a significant difference (χ = 7.493, P = .0062, log-rank test) was observed between the risk-high and risk-low groups obtained based on the pretreatment risk of survival measures.

Conclusion: The integration of risk of survival measures estimated from pre- and posttreatment CT scans can help differentiate patients with good expected survival from those who will do more poorly following SBRT. The analysis of these radiomics-based longitudinal risk measures may help identify patients with early-stage NSCLC who will benefit from adjuvant treatment after lung SBRT, such as immunotherapy.
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http://dx.doi.org/10.1016/j.ijrobp.2020.12.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7965338PMC
April 2021

A Mighty Oak Forest from a Single, Well-Planted Acorn.

J Nucl Med 2020 12;61(Suppl 2):83S-84S

Division of Nuclear Medicine and Clinical Molecular Imaging, Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

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http://dx.doi.org/10.2967/jnumed.120.251389DOI Listing
December 2020

Overview of the First NRG-NCI Workshop on Dosimetry of Systemic Radiopharmaceutical Therapy (RPT).

J Nucl Med 2020 12 4. Epub 2020 Dec 4.

McMaster University.

In 2018, the National Cancer Institute (NCI) and the NRG Oncology partnered for the first time to host a joint Workshop on Systemic Radiopharmaceutical Therapy (RPT) to specifically address issues and strategies of dosimetry for future clinical trials. The workshop focused on (1) current dosimetric approaches for clinical trials, (2) strategies under development that would provide optimal dose reporting, and (3) future desired/optimized approaches for the new and novel emerging radionuclides and carriers in development. In this proceedings, we review the main approaches that are applied clinically to calculate the absorbed dose: These include absorbed doses calculated over a variety of spatial scales including organ, suborgan, and voxel, all achievable within the Medical Internal Radiation Dose (MIRD) schema (S-value) can be calculated with analytic methods or Monte Carlo methods, the latter in most circumstances. This proceeding will also contrast currently available methods and tools with those used in the past, to propose a pathway whereby dosimetry helps the field by optimizing the biological effect of the treatment and trial design in the drug approval process to reduce financial and logistical costs. We will also discuss the dosimetric equivalent of biomarkers to help bring a precision medicine approach to RPT implementation-when merited by evidence collected during early-phase trial investigations. Advances in the methodology and related tools have made dosimetry the optimum biomarker for RPT.
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http://dx.doi.org/10.2967/jnumed.120.255547DOI Listing
December 2020

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

Int J Radiat Oncol Biol Phys 2021 Mar 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

Radiopharmaceutical Chemistry and Drug Development-What's Changed?

Semin Radiat Oncol 2021 Jan;31(1):3-11

Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA.

Radiation oncologists and nuclear medicine physicians have seen a resurgence in the clinical use of radiopharmaceuticals for the curative or palliative treatment of cancer. To enable the discovery and the development of new targeted radiopharmaceutical treatments, the United States National Cancer Institute has adapted its clinical trial enterprise to accommodate the requirements of a development program with investigational agents that have a radioactive isotope as part of the studied drug product. One change in perspective has been the consideration of investigational radiopharmaceuticals as drugs, with maximum tolerable doses determined by normal organ toxicity frequency like in drug clinical trials. Other changes include new clinical trial enterprise elements for biospecimen handling, adverse event reporting, regulatory conduct, writing services, drug master files, and reporting of patient outcomes. Arising from this enterprise, the study and clinical use of alpha-particle and beta-particle emitters have emerged as an important approach to cancer treatment. Resources allocated to this enterprise have brought forward biomarkers of molecular pathophysiology now used to select treatment or to evaluate clinical performance of radiopharmaceuticals. The clinical use of diagnostic and therapeutic radionuclide pairs is anticipated to accelerate radiopharmaceutical clinical development.
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http://dx.doi.org/10.1016/j.semradonc.2020.07.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7703672PMC
January 2021

Prospective Study of Systemic Yttrium-90 Elution during Radioembolization of Hepatic Metastases.

J Vasc Interv Radiol 2020 12 2;31(12):2007-2013.e1. Epub 2020 Nov 2.

Department of Radiology, Hospital of the University of Pennsylvania, 3400 Spruce St., 1 Founders, MRI Education Center, Philadelphia, PA 19104.

Purpose: To evaluate total blood radioactivity (BR) after SIR-Spheres yttrium-90 (Y) radioembolization and differences in BR based on delivery method.

Materials And Methods: Twenty participants with hepatic metastases undergoing first radioembolization were prospectively enrolled from December 2017 to June 2018. Blood samples were drawn at baseline and 0, 10, 20, 60, and 120 minutes after Y administration. BR was measured with a γ-counter and scaled by estimated blood volume. Percentage of instilled radioactivity in the bloodstream was calculated as area under the fitted curve, and differences between delivery methods were examined with nonparametric statistical tests.

Results: In 10 participants, resin microspheres were instilled with 50% Isovue 300 diluted in saline solution in the D line, and 10 others were treated with dextrose 5% in water (D5W) in the D line. Median administered activities were 944 MBq (range, 746-1,993 MBq) and 1,213 MBq (range, 519-2,066 MBq), respectively. Fraction of Y in blood was significantly higher with dilute contrast agent than with D5W (median, 0.5% of injected activity vs 0.2%; P = .001). Among all participants, the maximum activity delivered was 2,066 MBq, and a maximum of 1% of administered radioactivity was measured as free Y in blood. Assuming these highest-case values and complete decay of all free Y in bone, a dose to red marrow of 132.3 mGy was calculated by Organ Level INternal Dose Assessment/EXponential Modeling.

Conclusions: Blood sampling after radioembolization allowed for estimation of the time-activity curve and BR. Delivery with 50% contrast agent in saline solution resulted in a significant increase in BR vs D5W, even though the total BR for both groups was nominal.
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http://dx.doi.org/10.1016/j.jvir.2020.08.011DOI Listing
December 2020

Ga-DOTATATE Positron Emission Tomography-Computed Tomography Quantification Predicts Response to Somatostatin Analog Therapy in Gastroenteropancreatic Neuroendocrine Tumors.

Oncologist 2021 01 17;26(1):21-29. Epub 2020 Sep 17.

Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

Background: Somatostatin analogs (SSAs) are the frontline antitumor therapy in advanced well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs). A subset of patients demonstrate early disease progression on SSA therapy, yet the currently known predictors for treatment failure lack specificity to affect therapeutic decision. SSAs target tumor somatostatin receptors, the level of which can be quantitatively assessed with Ga-DOTATATE positron emission tomography-computed tomography (PET/CT). We investigated the ability of Ga-DOTATATE PET/CT to predict response to SSA therapy.

Materials And Methods: The records of 108 consecutive patients with well-differentiated grade 1-2 GEP-NETs on SSA monotherapy who received Ga-DOTATATE PET/CT scans were retrospectively reviewed to obtain baseline characteristics, Ga-DOTATATE maximum standardized uptake value (SUVmax), and progression-free survival (PFS) data. The optimal SUVmax cutoff for patient stratification was obtained with receiver operating characteristic curve analysis. PFS in the high versus low SUVmax groups was compared with Kaplan-Meier survival analysis. The effects of baseline characteristics and SUVmax on PFS were examined with univariate and multivariate Cox regression.

Results: Ga-DOTATATE SUVmax predicted therapeutic failure with sensitivity and specificity of 39% and 98%, respectively. SUVmax of <18.35 was associated with shorter PFS, which was reproduced in the subgroup analysis of SSA-naïve patients. Low SUVmax was the only predictor of early treatment failure (hazard ratio, 6.85) in multivariate analysis, as well as in the subgroup analysis of grade 2 GEP-NETs.

Conclusion: Low SUVmax on Ga-DOTATATE PET/CT independently predicts early failure on SSA monotherapy in patients with well-differentiated grade 1-2 GEP-NET. Patients with lack of expected benefit from SSA therapy can be readily identified using routine Ga-DOTATATE PET/CT with very high specificity.

Implications For Practice: Based on Ga-DOTATATE positron emission tomography-computed tomography imaging, clinicians can better inform patients on the expected benefit of somatostatin analog therapy for gastroenteropancreatic neuroendocrine tumors, especially when access to the therapy is difficult, and offer proactive discussion on alternative management options.
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http://dx.doi.org/10.1634/theoncologist.2020-0165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794177PMC
January 2021

Pathological response in children and adults with large unresected intermediate-grade or high-grade soft tissue sarcoma receiving preoperative chemoradiotherapy with or without pazopanib (ARST1321): a multicentre, randomised, open-label, phase 2 trial.

Lancet Oncol 2020 08 20;21(8):1110-1122. Epub 2020 Jul 20.

Department of Radiology and Medical Imaging, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

Background: Outcomes for children and adults with advanced soft tissue sarcoma are poor with traditional therapy. We investigated whether the addition of pazopanib to preoperative chemoradiotherapy would improve pathological near complete response rate compared with chemoradiotherapy alone.

Methods: In this joint Children's Oncology Group and NRG Oncology multicentre, randomised, open-label, phase 2 trial, we enrolled eligible adults (aged ≥18 years) and children (aged between 2 and <18 years) from 57 hospitals in the USA and Canada with unresected, newly diagnosed trunk or extremity chemotherapy-sensitive soft tissue sarcoma, which were larger than 5 cm in diameter and of intermediate or high grade. Eligible patients had Lansky (if aged ≤16 years) or Karnofsky (if aged >16 years) performance status score of at least 70. Patients received ifosfamide (2·5 g/m per dose intravenously on days 1-3 with mesna) and doxorubicin (37·5 mg/m per dose intravenously on days 1-2) with 45 Gy preoperative radiotherapy, followed by surgical resection at week 13. Patients were randomly assigned (1:1) using a web-based system, in an unmasked manner, to receive oral pazopanib (if patients <18 years 350 mg/m once daily; if patients ≥18 years 600 mg once daily) or not (control group), with pazopanib not given immediately before or after surgery at week 13. The study projected 100 randomly assigned patients were needed to show an improvement in the number of participants with a 90% or higher pathological response at week 13 from 40% to 60%. Analysis was done per protocol. This study has completed accrual and is registered with ClinicalTrials.gov, NCT02180867.

Findings: Between July 7, 2014, and Oct 1, 2018, 81 eligible patients were enrolled and randomly assigned to the pazopanib group (n=42) or the control group (n=39). At the planned second interim analysis with 42 evaluable patients and a median follow-up of 0·8 years (IQR 0·3-1·6) in the pazopanib group and 1 year (0·3-1·6) in the control group, the number of patients with a 90% pathological response or higher was 14 (58%) of 24 patients in the pazopanib group and four (22%) of 18 patients in the control group, with a between-group difference in the number of 90% or higher pathological response of 36·1% (83·8% CI 16·5-55·8). On the basis of an interim analysis significance level of 0·081 (overall one-sided significance level of 0·20, power of 0·80, and O'Brien-Fleming-type cumulative error spending function), the 83·8% CI for response difference was between 16·5% and 55·8% and thus excluded 0. The improvement in pathological response rate with the addition of pazopanib crossed the predetermined boundary and enrolment was stopped. The most common grade 3-4 adverse events were leukopenia (16 [43%] of 37 patients), neutropenia (15 [41%]), and febrile neutropenia (15 [41%]) in the pazopanib group, and neutropenia (three [9%] of 35 patients) and febrile neutropenia (three [9%]) in the control group. 22 (59%) of 37 patients in the pazopanib group had a pazopanib-related serious adverse event. Paediatric and adult patients had a similar number of grade 3 and 4 toxicity. There were seven deaths (three in the pazopanib group and four in the control group), none of which were treatment related.

Interpretation: In this presumed first prospective trial of soft tissue sarcoma spanning nearly the entire age spectrum, adding pazopanib to neoadjuvant chemoradiotherapy improved the rate of pathological near complete response, suggesting that this is a highly active and feasible combination in children and adults with advanced soft tissue sarcoma. The comparison of survival outcomes requires longer follow-up.

Funding: National Institutes of Health, St Baldrick's Foundation, Seattle Children's Foundation.
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http://dx.doi.org/10.1016/S1470-2045(20)30325-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745646PMC
August 2020

Flare Phenomenon in -(2-[F]-Fluoroethyl)-L-Tyrosine PET After Resection of Gliomas: Potential Contribution from Postoperative Ischemia.

J Nucl Med 2020 12 9;61(12):1851-1852. Epub 2020 Jul 9.

Perelman School of Medicine of the University of Pennsylvania 3400 Spruce St. Philadelphia, PA 19104 E-mail:

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http://dx.doi.org/10.2967/jnumed.120.251116DOI Listing
December 2020

ACR-ACNM-ASTRO-SNMMI Practice Parameter for the Performance of Therapy With Radium-223.

Am J Clin Oncol 2020 08;43(8):539-544

University of Michigan, Ann Arbor, MI.

Aim/objectives/background: The goal of therapy with unsealed radiopharmaceutical sources is to provide either cure or significant prolongation of disease-specific survival, and effective reduction and/or prevention of adverse disease-related symptoms or untoward events while minimizing treatment-associated side effects and complications. Radium-223 dichloride (radium-223) is an alpha particle-emitting isotope used for targeted bone therapy. This practice parameter is intended to guide appropriately trained and licensed physicians performing therapy with radium-223. Such therapy requires close cooperation and communication between the physicians who are responsible for the clinical management of the patient and those who administer radiopharmaceutical therapy and manage the attendant side effects. Adherence to this parameter should help to maximize the efficacious use of radium-223, maintain safe conditions, and ensure compliance with applicable regulations.

Methods: This practice parameter was developed according to the process described on the American College of Radiology (ACR) website ("The Process for Developing ACR Practice Parameters and Technical Standards," www.acr.org/ClinicalResources/Practice-Parameters-and-Technical-Standards) by the Committee on Practice Parameters of the ACR Commission on Radiation Oncology in collaboration with the American College of Nuclear Medicine (ACNM), the American Society for Radiation Oncology (ASTRO), and the Society of Nuclear Medicine and Molecular Imaging (SNMMI). All these societies contributed to the development of the practice parameter and approved the final document.

Results: This practice parameter addresses the many factors which contribute to appropriate, safe, and effective clinical use of radium-223. Topics addressed include qualifications and responsibilities of personnel, specifications of patient examination and treatment; documentation, radiation safety, quality control/improvement, infection control, and patient education.

Conclusions: This practice parameter is intended as a tool to guide clinical use of radium-223 with the goal of facilitating safe and effective medical care based on current knowledge, available resources and patient needs. The sole purpose of this document is to assist practitioners in achieving this objective.
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http://dx.doi.org/10.1097/COC.0000000000000702DOI Listing
August 2020

Biodistribution, dosimetry, and temporal signal-to-noise ratio analyses of normal and cancer uptake of [Ga]Ga-P15-041, a gallium-68 labeled bisphosphonate, from first-in-human studies.

Nucl Med Biol 2020 Jul - Aug;86-87:1-8. Epub 2020 Apr 20.

Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, United States of America.

Introduction: [Ga]Ga-P15-041 ([Ga]Ga-HBED-CC-BP) is a novel bone-seeking PET radiotracer that can be generator-produced. We undertook a Phase 0/I clinical trial to assess its potential for imaging bone metastases in prostate cancer including assessment of radiotracer biodistribution and dosimetry.

Methods: Subjects with prostate cancer and known or suspected osseous metastatic disease were enrolled into one of two arms: dosimetry or dynamic. Dosimetry was performed with 6 whole body PET acquisitions and urine collection spanning 3 h; normal organ dosimetry was calculated using OLINDA/EXM. Dynamic imaging included a 60 min acquisition over a site of known or suspected disease followed by two whole body scans. Bootstrapping and subsampling of the acquired list-mode data were conducted to recommend image acquisition parameters for future clinical trials.

Results: Up to 233 MBq (6.3 mCi) of [Ga]Ga-P15-041 was injected into 12 enrolled volunteers, 8 in dosimetry and 4 in dynamic cohorts. Radiotracer accumulated in known bone lesions and cleared rapidly from blood and soft tissue. The highest individual organ dose was 0.135 mSv/MBq in the urinary bladder wall. The average effective dose was 0.0173 ± 0.0036 mSv/MBq. An average injected activity of 166.5 MBq (4.5 mCi) resulted in absorbed dose estimates of 22.5 mSv to the urinary bladder wall, 8.2 mSv to the kidneys, and an effective dose of 2.9 mSv. Lesion signal to noise ratios on images generated from subsampled data were significantly higher for injected activities above 74 MBq (2 mCi) and were also significantly higher for imaging at 90 min than at 180 min post-injection.

Conclusions: Dosimetry estimates are acceptable and [Ga]Ga-P15-041 uptake characteristics in patients with confirmed bone metastases support its continued development.

Advances In Knowledge And Implications For Patient Care: Use of [Ga]Ga-P15-041 would not require cyclotron infrastructure for manufacturing and distribution, allowing for improved patient access to a promising PET bone imaging agent.
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http://dx.doi.org/10.1016/j.nucmedbio.2020.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311273PMC
April 2020

Machine learning highlights the deficiency of conventional dosimetric constraints for prevention of high-grade radiation esophagitis in non-small cell lung cancer treated with chemoradiation.

Clin Transl Radiat Oncol 2020 May 24;22:69-75. Epub 2020 Mar 24.

Department of Radiation Oncology, University of Pennsylvania, Perelman Center for Advanced Medicine, 3400 Civic Center Blvd, Philadelphia, PA 19104, United States.

Background And Purpose: Radiation esophagitis is a clinically important toxicity seen with treatment for locally-advanced non-small cell lung cancer. There is considerable disagreement among prior studies in identifying predictors of radiation esophagitis. We apply machine learning algorithms to identify factors contributing to the development of radiation esophagitis to uncover previously unidentified criteria and more robust dosimetric factors.

Materials And Methods: We used machine learning approaches to identify predictors of grade ≥ 3 radiation esophagitis in a cohort of 202 consecutive locally-advanced non-small cell lung cancer patients treated with definitive chemoradiation from 2008 to 2016. We evaluated 35 clinical features per patient grouped into risk factors, comorbidities, imaging, stage, histology, radiotherapy, chemotherapy and dosimetry. Univariate and multivariate analyses were performed using a panel of 11 machine learning algorithms combined with predictive power assessments.

Results: All patients were treated to a median dose of 66.6 Gy at 1.8 Gy per fraction using photon (89.6%) and proton (10.4%) beam therapy, most often with concurrent chemotherapy (86.6%). 11.4% of patients developed grade ≥ 3 radiation esophagitis. On univariate analysis, no individual feature was found to predict radiation esophagitis (AUC range 0.45-0.55, p ≥ 0.07). In multivariate analysis, all machine learning algorithms exhibited poor predictive performance (AUC range 0.46-0.56, p ≥ 0.07).

Conclusions: Contemporary machine learning algorithms applied to our modern, relatively large institutional cohort could not identify any reliable predictors of grade ≥ 3 radiation esophagitis. Additional patients are needed, and novel patient-specific and treatment characteristics should be investigated to develop clinically meaningful methods to mitigate this survival altering toxicity.
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http://dx.doi.org/10.1016/j.ctro.2020.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7132156PMC
May 2020

Abnormal Pretreatment Liver Function Tests Are Associated with Discontinuation of Peptide Receptor Radionuclide Therapy in a U.S.-Based Neuroendocrine Tumor Cohort.

Oncologist 2020 07 6;25(7):572-578. Epub 2020 Mar 6.

Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Background: Peptide receptor radionuclide therapy (PRRT) is effective for treating midgut neuroendocrine tumors (NETs); however, incorporation of PRRT into routine practice in the U.S. is not well studied. Herein we analyze the first year of PRRT implementation to determine tolerance of PRRT and factors that increase risk of PRRT discontinuation.

Materials And Methods: Medical records were reviewed and data were abstracted on all patients with NETs scheduled for PRRT during the first year of PRRT implementation at a U.S. NET referral center (August 2018 through July 2019). Logistic regression was used to identify factors associated with PRRT discontinuation.

Results: Fifty-five patients (56% male) were scheduled for PRRT over the study period. The most common primary NET location was small bowel (47%), followed by pancreas (26%), and 84% of the NETs were World Health Organization grade 1 or 2. The cohort was heavily pretreated with somatostatin analog (SSA) therapy (98%), non-SSA systemic therapy (64%), primary tumor resection (73%), and liver-directed therapy (55%). At the time of analysis, 52 patients completed at least one PRRT treatment. Toxicities including bone marrow suppression and liver function test (LFT) abnormalities were comparable to prior publications. Eleven patients (21%) prematurely discontinued PRRT because of toxicity or an adverse event. Pretreatment LFT abnormality was associated with increased risk of PRRT cancellation (odds ratio: 12; 95% confidence interval: 2.59-55.54; p < .001).

Conclusion: PRRT can be administered to a diverse NET population at a U.S. NET referral center. Baseline liver function test abnormality increases the likelihood of PRRT discontinuation.

Implications For Practice: Peptide receptor radionuclide therapy (PRRT) can be successfully implemented at a U.S. neuroendocrine tumor (NET) referral center in a NET population that is diverse in tumor location, grade, and prior treatment history. Toxicity and adverse effects of PRRT are comparable to prior reports; however, 21% of individuals prematurely discontinued PRRT. Patients with baseline liver function test abnormalities were more likely to discontinue PRRT than patients with normal liver function tests, which should be taken into consideration when selecting treatment options for NETs.
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http://dx.doi.org/10.1634/theoncologist.2019-0743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356755PMC
July 2020

The role of resting myocardial blood flow and myocardial blood flow reserve as a predictor of major adverse cardiovascular outcomes.

PLoS One 2020 13;15(2):e0228931. Epub 2020 Feb 13.

Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

Cardiac perfusion PET is increasingly used to assess ischemia and cardiovascular risk and can also provide quantitative myocardial blood flow (MBF) and flow reserve (MBFR) values. These have been shown to be prognostic biomarkers of adverse outcomes, yet MBF and MBFR quantification remains underutilized in clinical settings. We compare MBFR to traditional cardiovascular risk factors in a large and diverse clinical population (60% African-American, 35.3% Caucasian) to rank its relative contribution to cardiovascular outcomes. Major adverse cardiovascular events (MACE), including unstable angina, non-ST and ST-elevation myocardial infarction, stroke, and death, were assessed for consecutive patients who underwent rest-dipyridamole stress 82Rb PET cardiac imaging from 2012-2015 at the Hospital of the University of Pennsylvania (n = 1283, mean follow-up 2.3 years). Resting MBF (1.1 ± 0.4 ml/min/g) was associated with adverse cardiovascular outcomes. MBFR (2.1 ± 0.8) was independently and inversely associated with MACE. Furthermore, MBFR was more strongly associated with MACE than both traditional cardiovascular risk factors and the presence of perfusion defects in regression analysis. Decision tree analysis identified MBFR as superior to established cardiovascular risk factors in predicting outcomes. Incorporating resting MBF and MBFR in CAD assessment may improve clinical decision making.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0228931PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018061PMC
June 2020

Breast Cancer F-ISO-1 Uptake as a Marker of Proliferation Status.

J Nucl Med 2020 05 13;61(5):665-670. Epub 2019 Dec 13.

Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

The σ receptor is a potential in vivo target for measuring proliferative status in cancer. The feasibility of using -(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1)-yl)butyl)-2-(2-F-fluoroethoxy)-5-methylbenzamide (F-ISO-1) to image solid tumors in lymphoma, breast cancer, and head and neck cancer has been previously established. Here, we report the results of the first dedicated clinical trial of F-ISO-1 in women with primary breast cancer. Our study objective was to determine whether F-ISO-1 PET could provide an in vivo measure of tumor proliferative status, and we hypothesized that uptake would correlate with a tissue-based assay of proliferation, namely Ki-67 expression. Twenty-eight women with 29 primary invasive breast cancers were prospectively enrolled in a clinical trial (NCT02284919) between March 2015 and January 2017. Each received an injection of 278-527 MBq of F-ISO-1 and then underwent PET/CT imaging of the breasts 50-55 min later. In vivo uptake of F-ISO-1 was quantitated by SUV and distribution volume ratios and was compared with ex vivo immunohistochemistry for Ki-67. Wilcoxon rank-sum tests assessed uptake differences across Ki-67 thresholds, and Spearman correlation tested associations between uptake and Ki-67. Tumor SUV (median, 2.0 g/mL; range, 1.3-3.3 g/mL), partial-volume-corrected SUV, and SUV ratios were tested against Ki-67. Tumors stratified into the high-Ki-67 (≥20%) group had SUV greater than the low-Ki-67 (<20%) group ( = 0.02). SUV exhibited a positive correlation with Ki-67 across all breast cancer subtypes (ρ = 0.46, = 0.01, = 29). Partial-volume-corrected SUV was positively correlated with Ki-67 for invasive ductal carcinoma (ρ = 0.51, = 0.02, = 21). Tumor-to-normal-tissue ratios and tumor distribution volume ratio did not correlate with Ki-67 ( > 0.05). F-ISO-1 uptake in breast cancer modestly correlates with an in vitro assay of proliferation.
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http://dx.doi.org/10.2967/jnumed.119.232363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7198384PMC
May 2020

Optimized CT Attenuation and SUV Prediction Thresholds for Differentiating Enostoses From Untreated and Treated Metastases on Attenuation-Corrected 18F-FDG PET/CT.

Clin Nucl Med 2020 Jan;45(1):32-37

From the Departments of Radiology.

Purpose: The objective of this study was to evaluate the accuracy of using CT attenuation and SUVs to differentiate enostoses from untreated and treated osteoblastic metastases on the attenuation-correction CT component of F-FDG PET/CTs.

Methods: We retrospectively reviewed F-FDG PET/CT studies of 117 patients (169 lesions), of which 65 had imaging of enostoses, and 52 had imaging showing the transition of lesions from untreated to treated osteoblastic metastases. We measured the mean CT attenuations and the SUVmax and SUVmean of each lesion. Receiver operating characteristic curve analyses were used to evaluate the accuracy of each metric in distinguishing enostoses from untreated and treated osteoblastic metastases.

Results: For differentiating enostoses from untreated osteoblastic metastases, mean CT attenuation achieved an area under the receiver operating characteristic curve (AUC) of 90.8%, with an optimized threshold of 795 HU. SUVmax achieved an AUC of 94.9%, with an optimized threshold of 2.2. For differentiating enostoses from treated osteoblastic metastases, the AUCs for every metric decreased, with mean CT attenuation being the best at 82.7%. A joint predictive model combining both CT attenuation and SUV increased the AUC to 88.3%, and performance was significantly better than SUVmax or SUVmean alone (P = 0.029 and P = 0.049, respectively).

Conclusions: CT attenuation and SUV can reliably distinguish between enostoses and metastases on F-FDG PET/CT. However, the accuracy of these metrics decreases when used to differentiate enostoses from treated metastases. A joint prediction model combining CT attenuation with SUV can improve accuracy.
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http://dx.doi.org/10.1097/RLU.0000000000002808DOI Listing
January 2020

PARP-1-Targeted Auger Emitters Display High-LET Cytotoxic Properties In Vitro but Show Limited Therapeutic Utility in Solid Tumor Models of Human Neuroblastoma.

J Nucl Med 2020 06 1;61(6):850-856. Epub 2019 Nov 1.

Department of Radiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania; and

The currently available therapeutic radiopharmaceutical for high-risk neuroblastoma, I-metaiodobenzylguanidine, is ineffective at targeting micrometastases because of the low-linear-energy-transfer (LET) properties of high-energy β-particles. In contrast, Auger radiation has high-LET properties with nanometer ranges in tissue, efficiently causing DNA damage when emitted near DNA. The aim of this study was to evaluate the cytotoxicity of targeted Auger therapy in preclinical models of high-risk neuroblastoma. We used a radiolabled poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor called I-KX1 to deliver Auger radiation to PARP-1, a chromatin-binding enzyme overexpressed in neuroblastoma. The in vitro cytotoxicity of I-KX1 was assessed in 19 neuroblastoma cell lines, followed by in-depth pharmacologic analysis in a sensitive and resistant pair of cell lines. Immunofluorescence microscopy was used to characterize I-KX1-induced DNA damage. Finally, in vitro and in vivo microdosimetry was modeled from experimentally derived pharmacologic variables. I-KX1 was highly cytotoxic in vitro across a panel of neuroblastoma cell lines, directly causing double-strand DNA breaks. On the basis of subcellular dosimetry, I-KX1 was approximately twice as effective as I-KX1, whereas cytoplasmic I-metaiodobenzylguanidine demonstrated low biological effectiveness. Despite the ability to deliver a focused radiation dose to the cell nuclei, I-KX1 remained less effective than its α-emitting analog At-MM4 and required significantly higher activity for equivalent in vivo efficacy based on tumor microdosimetry. Chromatin-targeted Auger therapy is lethal to high-risk neuroblastoma cells and has the potential to be used in micrometastatic disease. This study provides the first evidence for cellular lethality from a PARP-1-targeted Auger emitter, calling for further investigation into targeted Auger therapy.
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http://dx.doi.org/10.2967/jnumed.119.233965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7262217PMC
June 2020

PennPET Explorer: Human Imaging on a Whole-Body Imager.

J Nucl Med 2020 01 27;61(1):144-151. Epub 2019 Sep 27.

Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania

The PennPET Explorer, a prototype whole-body imager currently operating with a 64-cm axial field of view, can image the major body organs simultaneously with higher sensitivity than that of commercial devices. We report here the initial human imaging studies on the PennPET Explorer, with each study designed to test specific capabilities of the device. Healthy subjects were imaged with FDG on the PennPET Explorer. Subsequently, clinical subjects with disease were imaged with F-FDG and Ga-DOTATATE, and research subjects were imaged with experimental radiotracers. We demonstrated the ability to scan for a shorter duration or, alternatively, with less activity, without a compromise in image quality. Delayed images, up to 10 half-lives with F-FDG, revealed biologic insight and supported the ability to track biologic processes over time. In a clinical subject, the PennPET Explorer better delineated the extent of F-FDG-avid disease. In a second clinical study with Ga-DOTATATE, we demonstrated comparable diagnostic image quality between the PennPET scan and the clinical scan, but with one fifth the activity. Dynamic imaging studies captured relatively noise-free input functions for kinetic modeling approaches. Additional studies with experimental research radiotracers illustrated the benefits from the combination of large axial coverage and high sensitivity. These studies provided a proof of concept for many proposed applications for a PET scanner with a long axial field of view.
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http://dx.doi.org/10.2967/jnumed.119.231845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954463PMC
January 2020

Clinical Outcomes of the HIV Protease Inhibitor Nelfinavir With Concurrent Chemoradiotherapy for Unresectable Stage IIIA/IIIB Non-Small Cell Lung Cancer: A Phase 1/2 Trial.

JAMA Oncol 2019 Oct;5(10):1464-1472

Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia.

Importance: Local failure after chemoradiotherapy (CT-RT) significantly contributes to mortality in patients with locally advanced non-small cell lung cancer (LA-NSCLC). One approach to improve local control is through targeted radiosensitization of the tumor.

Objective: To evaluate the dose-limiting toxic effects, maximally tolerated dose, and recommended phase 2 dose of the protease inhibitor nelfinavir mesylate, administered concurrently with CT-RT in patients with LA-NSCLC, and, in the phase 2 portion of the study, to estimate the objective response rate, local and distant failure rates, and overall survival.

Design, Setting, And Participants: This prospective, open-label, single-group, single-institution phase 1/2 trial tested the oral protease inhibitor nelfinavir in combination with concurrent CT-RT in 35 patients aged 18 to 89 years with biopsy-confirmed unresectable stage IIIA/IIIB LA-NSCLC and a minimum Karnofsky performance status from June 29, 2007, to February 22, 2012, with an analysis date of May 9, 2017. Median follow-up for all patients was 6.8 years, with a minimum 5 years of follow-up for all survivors.

Interventions: Oral nelfinavir mesylate, 625 mg, twice daily or 1250 mg, twice daily was administered for 7 to 14 days before and during concurrent CT-RT.

Main Outcomes And Measures: Graded toxic effects, overall survival, local failure, distant failure, objective response rate, and progression-free survival as measured by Response Evaluation Criteria in Solid Tumors, version 1.1.

Results: Thirty-five patients (16 women and 19 men; median age, 60 years [range, 39-79 years]) enrolled and met protocol-specified criteria for adherence, with 5 at a dose of 625 mg twice daily and 30 at a dose of 1250 mg twice daily. No dose-limiting toxic effects were observed. No grade 4 or higher nonhematologic toxic effects were observed. Thirty-three of the 35 patients had evaluable posttreatment computed tomographic scans, with an objective response rate of 94% (31 of 33; 95% CI, 86%-100%). The cumulative incidence of local failure was 39% (95% CI, 30.5%-47.5%). Median progression-free survival was 11.7 months (95% CI, 6.2-17.1 months). Median overall survival for all patients was 41.1 months (95% CI, 19.0-63.1 months); the 5-year mean (SE) overall survival rate was 37.1% (8.2%).

Conclusions And Relevance: This study suggests that nelfinavir administered with concurrent CT-RT is associated with acceptable toxic effects and a promising objective response rate, local failure, progression-free survival, and overall survival in unresectable LA-NSCLC. These data suggest that nelfinavir may enhance the efficacy of standard CT-RT in this disease. Additional testing in the randomized phase 3 setting should be conducted to establish the improvement associated with nelfinavir with concurrent CT-RT.

Trial Registration: ClinicalTrials.gov identifier: NCT00589056.
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http://dx.doi.org/10.1001/jamaoncol.2019.2095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707020PMC
October 2019

NANETS/SNMMI Procedure Standard for Somatostatin Receptor-Based Peptide Receptor Radionuclide Therapy with Lu-DOTATATE.

J Nucl Med 2019 07;60(7):937-943

Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, Florida.

With the recent approval of Lu-DOTATATE for use in gastroenteropancreatic neuroendocrine tumors, access to peptide receptor radionuclide therapy is increasing. Representatives from the North American Neuroendocrine Tumor Society and the Society of Nuclear Medicine and Molecular Imaging collaborated to develop a practical consensus guideline for the administration of Lu-DOTATATE. In this paper, we discuss patient screening, maintenance somatostatin analog therapy requirements, treatment location and room preparation, drug administration, and patient release as well as strategies for radiation safety, toxicity monitoring, management of potential complications, and follow-up. Controversies regarding the role of radiation dosimetry are discussed as well. This document is designed to provide practical guidance on how to safely treat patients with this therapy.
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http://dx.doi.org/10.2967/jnumed.118.230607DOI Listing
July 2019