Publications by authors named "Lisa Bodei"

132 Publications

ACR-ABS-ACNM-ASTRO-SIR-SNMMI practice parameter for selective internal radiation therapy or radioembolization for treatment of liver malignancies.

Brachytherapy 2021 Apr 3. Epub 2021 Apr 3.

Department of Radiology, American Radiology Association, Baylor University Medical Center, Dallas, TX.

Purpose: The American College of Radiology (ACR), American Brachytherapy Society (ABS), American College of Nuclear Medicine (ACNM), American Society for Radiation Oncology (ASTRO), Society of Interventional Radiology (SIR), and Society of Nuclear Medicine and Molecular Imaging (SNMMI) have jointly developed a practice parameter on selective internal radiation therapy (SIRT) or radioembolization for treatment of liver malignancies. Radioembolization is the embolization of the hepatic arterial supply of hepatic primary tumors or metastases with a microsphere yttrium-90 brachytherapy device.

Materials And Methods: The ACR -ABS -ACNM -ASTRO -SIR -SNMMI practice parameter for SIRT or radioembolization for treatment of liver malignancies was revised in accordance with the process described on the ACR website (https://www.acr.org/ClinicalResources/Practice-Parameters-and-Technical-Standards) by the Committee on Practice Parameters-Interventional and Cardiovascular Radiology of the ACR Commission on Interventional and Cardiovascular, Committee on Practice Parameters and Technical Standards-Nuclear Medicine and Molecular Imaging of the ACR Commission on Nuclear Medicine and Molecular Imaging and the Committee on Practice Parameters-Radiation Oncology of the ACR Commission on Radiation Oncology in collaboration with ABS, ACNM, ASTRO, SIR, and SNMMI.

Results: This practice parameter is developed to serve as a tool in the appropriate application of radioembolization in the care of patients with conditions where indicated. It addresses clinical implementation of radioembolization including personnel qualifications, quality assurance standards, indications, and suggested documentation.

Conclusions: This practice parameter is a tool to guide clinical use of radioembolization. It focuses on the best practices and principles to consider when using radioemboliozation effectively. The clinical benefit and medical necessity of the treatment should be tailored to each individual patient.
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http://dx.doi.org/10.1016/j.brachy.2021.01.006DOI Listing
April 2021

Imaging of neuroendocrine tumors: A pictorial review of the clinical value of different imaging modalities.

Rev Endocr Metab Disord 2021 Mar 30. Epub 2021 Mar 30.

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

Neuroendocrine tumors (NETs) are multifaceted tumors occurring in a variety of organs and often present as metastatic at the time of diagnosis. Accurate staging is the most significant factor in therapy planning, but it remains a challenge. Imaging is established as the cornerstone for disease detection/diagnosis, staging, and follow up. To accurately assess and monitor tumor burden in patients with NETs, various imaging techniques have been developed and optimized. Current recommendations for the imaging of patients with NETs include a combination of both morphologic (or anatomic) and molecular imaging, but a final choice can be puzzling for clinicians. Recognizing that there is no uniform sequence consensus on the "best" imaging test, and the heterogeneity of technologic availability at different centers, we hope to provide a pictorial review of the different imaging techniques and their role and utility in management of patients with NETs, aimed to provide a practical guide for all clinicians.
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http://dx.doi.org/10.1007/s11154-021-09631-7DOI Listing
March 2021

Seek and Find: Current Prospective Evidence for Prostate-specific Membrane Antigen Imaging to Detect Recurrent Prostate Cancer.

Eur Urol Focus 2021 Mar 18;7(2):267-278. Epub 2021 Mar 18.

Genitourinary Medical Oncology Service, Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York, NY, USA. Electronic address:

Context: Men with biochemically relapsed prostate cancer face a clinical conundrum. Depending on the detected distribution of disease, treatment goals may range from cure with focal therapy to palliative with systemic therapy to expectant observation. Retrospective studies of prostate-specific membrane antigen (PSMA)-based imaging demonstrate higher disease detection rates than conventional imaging.

Objective: This review focuses on available prospective evidence for diagnostic use of PSMA-based imaging to accurately restage recurrent prostate cancer and explores the potential clinical impact, near future uses, and challenges for PSMA-based imaging in this setting.

Evidence Acquisition: PubMed and EMBASE databases were searched for prospective studies with primary, secondary, or exploratory endpoints evaluating PSMA-based imaging for patients with recurrent prostate cancer published in English in the past 10 yrs.

Evidence Synthesis: We reviewed 48 prospective studies evaluating the role of PSMA positron emission tomography (PET) in recurrent prostate cancer. These studies establish the diagnostic accuracy and safety of PSMA PET using the Ga-PSMA-11 and F-DCFPyL radiotracers even at lower prostate-specific antigen (PSA) levels (0.5 ≤ PSA < 1.0 ng/m: disease detection rate 51-78%). The use of PSMA PET has been shown to result in changes in management in up to two-thirds of patients.

Conclusions: There is now higher-level regulatory-quality prospective evidence for PSMA-based imaging for the detection of recurrent prostate cancer. There is prospective evidence of superiority over cross-sectional imaging and bone scintigraphy, as well as for the alterations in disease management as a result of PSMA-based imaging.

Patient Summary: When the prostate-specific antigen (PSA) level is rising after primary therapy, prostate-specific membrane antigen (PSMA) positron emission tomography (PET) is excellent at detecting and localizing prostate cancer, even at low PSA levels. Those who benefit best from treatment modifications based on PSMA PET findings are yet to be defined.
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http://dx.doi.org/10.1016/j.euf.2021.03.012DOI Listing
March 2021

Treatment of advanced gastroenteropancreatic neuroendocrine neoplasia, are we on the way to personalised medicine?

Gut 2021 Mar 10. Epub 2021 Mar 10.

Department of Gastroenterology, Endocrinology, Metabolism and Infectiology, University Hospital Marburg and Philipps University, Marburg, Germany.

Gastroenteropancreatic neuroendocrine neoplasia (GEPNEN) comprises clinically as well as prognostically diverse tumour entities often diagnosed at late stage. Current classification provides a uniform terminology and a Ki67-based grading system, thereby facilitating management. Advances in the study of genomic and epigenetic landscapes have amplified knowledge of tumour biology and enhanced identification of prognostic and potentially predictive treatment subgroups. Translation of this genomic and mechanistic biology into advanced GEPNEN management is limited. 'Targeted' treatments such as somatostatin analogues, peptide receptor radiotherapy, tyrosine kinase inhibitors and mammalian target of rapamycin inhibitors are treatment options but predictive tools are lacking. The inability to identify clonal heterogeneity and define critical oncoregulatory pathways prior to therapy, restrict therapeutic efficacy as does the inability to monitor disease status in real time. Chemotherapy in the poor prognosis NEN G3 group, though associated with acceptable response rates, only leads to short-term tumour control and their molecular biology requires delineation to provide new and more specific treatment options.The future requires an exploration of the NEN tumour genome, its microenvironment and an identification of critical oncologic checkpoints for precise drug targeting. In the advance to personalised medical treatment of patients with GEPNEN, clinical trials need to be based on mechanistic and multidimensional characterisation of each tumour in order to identify the therapeutic agent effective for the individual tumour.This review surveys advances in NEN research and delineates the current status of translation with a view to laying the basis for a genome-based personalised medicine management of advanced GEPNEN.
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http://dx.doi.org/10.1136/gutjnl-2020-321300DOI Listing
March 2021

Combined use of 177Lu-DOTATATE and metronomic capecitabine (Lu-X) in FDG-positive gastro-entero-pancreatic neuroendocrine tumors.

Eur J Nucl Med Mol Imaging 2021 Feb 18. Epub 2021 Feb 18.

Nuclear Medicine and Radiometabolic Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via P. Maroncelli 40, 47014, Meldola, Italy.

Purpose: FDG-positive neuroendocrine tumors (NETs) have a poorer prognosis and exhibit shorter response duration to peptide receptor radionuclide therapy (PRRT). The aim of this prospective phase II study was to evaluate the efficacy and toxicity of PRRT with Lu-DOTATATE associated with metronomic capecitabine as a radiosensitizer agent in patients with advanced progressive FDG-positive gastro-entero-pancreatic (GEP) NETs.

Patients And Methods: Patients with advanced somatostatin receptor- and FDG-positive G1-G3 GEP-NETs (Ki67 < 55%) were treated with a cumulative activity of 27.5 GBq of Lu-DOTATATE divided in five cycles of 5.5 GBq each every 8 weeks. Capecitabine (1000-1500 mg daily) was administered orally in the inter-cycle period between Lu-DOTATATE treatments. Prior to commencing capecitabine, all patients were triaged with the dihydropyrimidine dehydrogenase (DPD) test. Only DPD-proficient individuals were enrolled. The primary objectives were disease control rate (DCR) and safety. Secondary aims included progression-free (PFS) and overall survival (OS). Treatment response was assessed per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1). Toxicity was assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

Results: From August 2015 to December 2016, 37 subjects were consecutively enrolled. A total of 25 (68%) were affected by pancreatic neuroendocrine tumors (P-NETs), and 12 (32%) had gastrointestinal neuroendocrine tumors (GI-NETs). By grading (WHO 2010 classification), 12 patients (32%) had G1 (Ki67 ≤ 2%), 22 (59%) had G2 (3% < Ki67 ≤ 20%), and 3 patients (9%) had G3 (Ki67 > 20%) NETs. Grade 3 (G3) or 4 (G4) hematological toxicity occurred in 16.2% of patients. Other G3-G4 adverse events were diarrhea in 5.4% of cases and asthenia in 5.4%. No renal toxicity was observed for the duration of follow-up. In 37 patients, 33 were evaluable for response. Objective responses included partial response (PR) in 10 patients (30%) and stable disease (SD) in 18 patients (55%), with a DCR of 85%. The median follow-up was 38 months (range 4.6-51.1 months). The median PFS was 31.4 months (17.6-45.4), and mOS was not reached.

Conclusions: This study demonstrated that the combination of PRRT with Lu-DOTATATE and metronomic capecitabine is active and well tolerated in patients with aggressive FDG-positive G1-G3 GEP-NETs. These data constitute the basis for a randomized study of PPRT alone vs. PRRT plus metronomic capecitabine.
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http://dx.doi.org/10.1007/s00259-021-05236-zDOI Listing
February 2021

Consensus on molecular imaging and theranostics in neuroendocrine neoplasms.

Eur J Cancer 2021 Mar 12;146:56-73. Epub 2021 Feb 12.

Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Nuclear medicine plays an increasingly important role in the management neuroendocrine neoplasms (NEN). Somatostatin analogue (SSA)-based positron emission tomography/computed tomography (PET/CT) and peptide receptor radionuclide therapy (PRRT) have been used in clinical trials and approved by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). European Association of Nuclear Medicine (EANM) Focus 3 performed a multidisciplinary Delphi process to deliver a balanced perspective on molecular imaging and radionuclide therapy in well-differentiated neuroendocrine tumours (NETs). NETs form in cells that interact with the nervous system or in glands that produce hormones. These cells, called neuroendocrine cells, can be found throughout the body, but NETs are most often found in the abdomen, especially in the gastrointestinal tract. These tumours may also be found in the lungs, pancreas and adrenal glands. In addition to being rare, NETs are also complex and may be difficult to diagnose. Most NETs are non-functioning; however, a minority present with symptoms related to hypersecretion of bioactive compounds. NETs often do not cause symptoms early in the disease process. When diagnosed, substantial number of patients are already found to have metastatic disease. Several societies' guidelines address Neuroendocrine neoplasms (NENs) management; however, many issues are still debated, due to both the difficulty in acquiring strong clinical evidence in a rare and heterogeneous disease and the different availability of diagnostic and therapeutic options across countries. EANM Focus 3 reached consensus on employing gallium-labelled somatostatin analogue ([Ga]Ga-DOTA-SSA)-based PET/CT with diagnostic CT or magnetic resonance imaging (MRI) for unknown primary NET detection, metastatic NET, NET staging/restaging, suspected extra-adrenal pheochromocytoma/paraganglioma and suspected paraganglioma. Consensus was reached on employing fluorine-fluoro-2-deoxyglucose ([F]FDG) PET/CT in neuroendocrine carcinoma, G3 NET and in G1-2 NET with mismatched lesions (CT-positive/[Ga]Ga-DOTA-SSA-negative). Peptide receptor radionuclide therapy (PRRT) was recommended for second line treatment for gastrointestinal NET with [Ga]Ga-DOTA-SSA uptake in all lesions, in G1/G2 NET at disease progression, and in a subset of G3 NET provided all lesions are positive at [F]FDG and [Ga]Ga-DOTA-SSA. PRRT rechallenge may be used for in patients with stable disease for at least 1 year after therapy completion. An international consensus is not only a prelude to a more standardised management across countries but also serves as a guide for the direction to follow when designing new research studies.
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http://dx.doi.org/10.1016/j.ejca.2021.01.008DOI Listing
March 2021

Landscape analysis of phase 2/3 clinical trials of targeted radionuclide therapy.

J Nucl Med 2021 Feb 12. Epub 2021 Feb 12.

Memorial Sloan Kettering Cancer Center, United States.

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http://dx.doi.org/10.2967/jnumed.120.258103DOI Listing
February 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 Jan 25. 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
January 2021

Pharmacogenomics in Radionuclide Therapy: Impact on Response to Theranostics.

J Nucl Med 2020 Dec 31. Epub 2020 Dec 31.

Memorial Sloan Kettering Cancer Center.

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http://dx.doi.org/10.2967/jnumed.120.254995DOI Listing
December 2020

Somatostatin Receptor Scintigraphy: Blazing in Indium and Quenching in Gallium.

Authors:
Lisa Bodei

J Nucl Med 2020 12;61(Suppl 2):121S-122S

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

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http://dx.doi.org/10.2967/jnumed.120.251934DOI Listing
December 2020

PET/MRI for neuroendocrine tumors: a match made in heaven or just another hype?

Clin Transl Imaging 2019 Dec 20;7(6):405-413. Epub 2019 Sep 20.

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

Purpose: To evaluate the current literature on technical feasibility and diagnostic value of PET/MRI in management of patients with neuroendocrine tumors (NETs).

Methods: A systematic literature search of the PubMed/MEDLINE database identified studies that evaluated the role of simultaneous PET/MRI for the evaluation of neuroendocrine tumors in human subjects. Exclusion criteria included studies lacking simultaneous PET/MRI, absence of other than attenuation-correction MRI pulse sequences, and case reports. No data-pooling or statistical analysis was performed due to the small number of articles and heterogeneity of the methodologies.

Results: From the 21 identified articles, five were included, which demonstrated successful technical feasibility of simultaneous PET/MRI through various imaging protocols in a total of 105 patients. All articles demonstrated equal or superior detection of liver lesions by PET/MRI over PET/CT. While one study reported superior detection of bone lesions by PET/MRI, two demonstrated favorable detection by PET/CT. Two studies demonstrated superiority of PET/CT in detection of nodal metastases; three studies reported the pitfall of PET/MRI in detection of lung lesion.

Conclusion: The current literature reports successful technical feasibility of PET/MRI for imaging of NETs. While whole-body PET/CT in conjunction with an abdominal MRI may serve as a comprehensive approach for baseline staging, follow up with PET/MRI may be preferred for those with liver-only disease. Another possible role for PET/MRI is to provide a multiparametric approach to follow up of response to treatment. With further advances in MRI imaging acquisitions and post-processing techniques, PET/MRI may become more applicable to a broader group of patients with NETs, and possibly the imaging modality of choice for this patient population.
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http://dx.doi.org/10.1007/s40336-019-00344-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717609PMC
December 2019

The Role of Theranostics in Prostate Cancer.

Semin Radiat Oncol 2021 Jan;31(1):71-82

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

Theranostics in men with metastatic castration-resistant prostate cancer (mCRPC) has been developed to target bone and the tumor itself. Currently, bone-directed targeted alpha therapy with radium-223 (Ra) is the only theranostic agent proven to prolong survival in men with mCRPC who have symptomatic bone metastases and no known visceral metastases. The clinical utility and therapeutic success of Ra has encouraged the development of other tumor-targeting theranostic agents in mCRPC, primarily targeting prostate-specific membrane antigen (PSMA) with radioligand therapy (RLT). There is increasing evidence of promising response rates and a low toxicity profile with Lu-labeled PSMA RLT in patients with mCRPC. A phase III randomized study of Lu-labeled PSMA RLT has completed accrual and is awaiting results as to whether the drug improves radiographic progression-free survival and overall survival in men with mCRPC receiving standard of care treatments. Additional early clinical trials are investigating the role of tumor-directed targeted alpha therapy with radiotracers such as Ac. In this article, we review the current status of theranostics in prostate cancer, discussing the challenges and opportunities of combination therapies with more conventional agents such as androgen receptor inhibitors, cytotoxic chemotherapy, and immunotherapy.
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http://dx.doi.org/10.1016/j.semradonc.2020.07.004DOI Listing
January 2021

Approach to the Treatment of a Patient with an Aggressive Pituitary Tumor.

J Clin Endocrinol Metab 2020 12;105(12)

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

A small subset of pituitary adenomas grows despite maximal treatment with standard therapies; namely, surgery and radiotherapy. These aggressive tumors demonstrate 2 patterns of growth: they may be locally aggressive or metastasize distantly, either hematogenously or through the spinal fluid. Further surgery and radiotherapy may be helpful for palliation of symptoms, but they are rarely definitive in the management of these malignant tumors. The only chemotherapy with established activity in the treatment of pituitary tumors is the alkylating agent temozolomide. At most, 50% of patients exhibit an objective response to temozolomide and the median time to progression is short; thus, there remains a significant unmet need for effective treatments within this patient population. Several targeted agents have reported activity in this tumor type-including small molecule inhibitors, checkpoint inhibitors, and other biologics-but remain investigational at this time.
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http://dx.doi.org/10.1210/clinem/dgaa649DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566322PMC
December 2020

Author Correction: Radiopharmaceutical therapy in cancer: clinical advances and challenges.

Nat Rev Drug Discov 2020 Nov;19(11):819

Johns Hopkins University School of Medicine, Baltimore, MD, USA.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41573-020-0085-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7962575PMC
November 2020

Molecular profiling of neuroendocrine tumours to predict response and toxicity to peptide receptor radionuclide therapy.

Lancet Oncol 2020 09;21(9):e431-e443

Department of Surgery, Yale University School of Medicine, Yale University, New Haven, CT, USA.

Peptide receptor radionuclide therapy (PRRT) is a type of radiotherapy that targets peptide receptors and is typically used for neuroendocrine tumours (NETs). Some of the key challenges in its use are the prediction of efficacy and toxicity, patient selection, and response optimisation. In this Review, we assess current knowledge on the molecular profile of NETs and the strategies and tools used to predict, monitor, and assess the toxicity of PRRT. The few mutations in tumour genes that can be evaluated (eg, ATM and DAXX) are limited to pancreatic NETs and are most likely not informative. Assays that are transcriptomic or based on genes are effective in the prediction of radiotherapy response in other cancers. A blood-based assay for eight genes (the PRRT prediction quotient [PPQ]) has an overall accuracy of 95% for predicting responses to PRRT in NETs. No molecular markers exist that can predict the toxicity of PRRT. Candidate molecular targets include seven single nucleotide polymorphisms (SNPs) that are susceptible to radiation. Transcriptomic evaluations of blood and a combination of gene expression and specific SNPs, assessed by machine learning with algorithms that are tumour-specific, might yield molecular tools to enhance the efficacy and safety of PRRT.
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http://dx.doi.org/10.1016/S1470-2045(20)30323-5DOI Listing
September 2020

γ-Tocotrienol-Loaded Liposomes for Radioprotection from Hematopoietic Side Effects Caused by Radiotherapeutic Drugs.

J Nucl Med 2021 Apr 21;62(4):584-590. Epub 2020 Aug 21.

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

With the successful development and increased use of targeted radionuclide therapy for treating cancer comes the increased risk of radiation injury to bone marrow-both direct suppression and stochastic effects, leading to neoplasia. Herein, we report a novel radioprotector drug, a liposomal formulation of γ-tocotrienol (GT3), or GT3-Nano for short, to mitigate bone marrow radiation damage during targeted radionuclide therapy. GT3 was loaded into liposomes using passive loading. Cu-GT3-Nano and H-GT3-Nano were synthesized to study the in vivo biodistribution profile of the liposome and GT3 individually. The radioprotection efficacy of GT3-Nano was assessed after acute Cs whole-body irradiation at a sublethal (4 Gy), a lethal (9 Gy), or a single high-dose administration of Sm-ethylenediamine--tetrakis(methylene phosphonic acid) (EDTMP). Flow cytometry and fluorescence microscopy were used to analyze hematopoietic cell population dynamics and the cellular site of GT3-Nano localization in the spleen and bone marrow, respectively. Bone marrow uptake and retention (percentage injected dose per gram of tissue) at 24 h was 6.98 ± 2.34 for Cu-GT3-Nano and 7.44 ± 2.52 for H-GT3-Nano. GT3-Nano administered 24 h before or after 4 Gy of total-body irradiation (TBI) promoted rapid and complete hematopoietic recovery, whereas recovery of controls stalled at 60%. GT3-Nano demonstrated dose-dependent radioprotection, achieving 90% survival at 50 mg/kg against lethal 9-Gy TBI. Flow cytometry of the bone marrow indicated that progenitor bone marrow cells MPP2 and CMP were upregulated in GT3-Nano-treated mice. Immunohistochemistry showed that GT3-Nano accumulates in CD105-positive sinusoid epithelial cells. GT3-Nano is highly effective in mitigating the marrow-suppressive effects of sublethal and lethal TBI in mice. GT3-Nano can facilitate rapid recovery of hematopoietic components in mice treated with the endoradiotherapeutic agent Sm-EDTMP.
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http://dx.doi.org/10.2967/jnumed.120.244681DOI Listing
April 2021

Radiopharmaceutical therapy in cancer: clinical advances and challenges.

Nat Rev Drug Discov 2020 09 29;19(9):589-608. Epub 2020 Jul 29.

Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Radiopharmaceutical therapy (RPT) is emerging as a safe and effective targeted approach to treating many types of cancer. In RPT, radiation is systemically or locally delivered using pharmaceuticals that either bind preferentially to cancer cells or accumulate by physiological mechanisms. Almost all radionuclides used in RPT emit photons that can be imaged, enabling non-invasive visualization of the biodistribution of the therapeutic agent. Compared with almost all other systemic cancer treatment options, RPT has shown efficacy with minimal toxicity. With the recent FDA approval of several RPT agents, the remarkable potential of this treatment is now being recognized. This Review covers the fundamental properties, clinical development and associated challenges of RPT.
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http://dx.doi.org/10.1038/s41573-020-0073-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390460PMC
September 2020

Peptide Receptor Radionuclide Therapy During the COVID-19 Pandemic: Are There Any Concerns?

J Nucl Med 2020 Aug 23;61(8):1094-1095. Epub 2020 Jun 23.

Department of Nuclear Medicine, University Hospital Essen, Essen, Germany, and Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, California.

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http://dx.doi.org/10.2967/jnumed.120.249136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413236PMC
August 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

Impact of liver tumour burden, alkaline phosphatase elevation, and target lesion size on treatment outcomes with Lu-Dotatate: an analysis of the NETTER-1 study.

Eur J Nucl Med Mol Imaging 2020 09 2;47(10):2372-2382. Epub 2020 Mar 2.

Department of Nuclear Medicine, Cyclotron Rotterdam BV, Erasmus University Medical Center, Rotterdam, Netherlands.

Purpose: To assess the impact of baseline liver tumour burden, alkaline phosphatase (ALP) elevation, and target lesion size on treatment outcomes with Lu-Dotatate.

Methods: In the phase 3 NETTER-1 trial, patients with advanced, progressive midgut neuroendocrine tumours (NET) were randomised to 177Lu-Dotatate (every 8 weeks, four cycles) plus octreotide long-acting release (LAR) or to octreotide LAR 60 mg. Primary endpoint was progression-free survival (PFS). Analyses of PFS by baseline factors, including liver tumour burden, ALP elevation, and target lesion size, were performed using Kaplan-Meier estimates; hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression.

Results: Significantly prolonged median PFS occurred with Lu-Dotatate versus octreotide LAR 60 mg in patients with low (< 25%), moderate (25-50%), and high (> 50%) liver tumour burden (HR 0.187, 0.216, 0.145), and normal or elevated ALP (HR 0.153, 0.177), and in the presence or absence of a large target lesion (diameter > 30 mm; HR, 0.213, 0.063). Within the Lu-Dotatate arm, no significant difference in PFS was observed amongst patients with low/moderate/high liver tumour burden (P = 0.7225) or with normal/elevated baseline ALP (P = 0.3532), but absence of a large target lesion was associated with improved PFS (P = 0.0222). Grade 3 and 4 liver function abnormalities were rare and did not appear to be associated with high baseline liver tumour burden.

Conclusions: Lu-Dotatate demonstrated significant prolongation in PFS versus high-dose octreotide LAR in patients with advanced, progressive midgut NET, regardless of baseline liver tumour burden, elevated ALP, or the presence of a large target lesion. Clinicaltrials.gov : NCT01578239, EudraCT: 2011-005049-11.
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http://dx.doi.org/10.1007/s00259-020-04709-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396396PMC
September 2020

Lessons from a multicentre retrospective study of peptide receptor radionuclide therapy combined with lanreotide for neuroendocrine tumours: a need for standardised practice.

Eur J Nucl Med Mol Imaging 2020 09 15;47(10):2358-2371. Epub 2020 Feb 15.

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

Purpose: PRELUDE aimed to assess use and effectiveness/safety of lanreotide autogel/depot (LAN) combined with Lu-DOTATOC or Lu-DOTATATE (LAN-peptide receptor radionuclide therapy [PRRT]) in patients with progressive neuroendocrine tumours (NETs).

Methods: International, non-interventional, retrospective, non-comparative analysis of medical records from patients with progressive metastatic or locally advanced grade 1 or 2 gastroenteropancreatic (GEP)- or lung-NETs. The primary endpoint was progression-free survival (PFS) at end of last LAN-PRRT cycle. Secondary endpoints included PFS at last available follow-up, best overall response, objective response rate (ORR), presence and severity of diarrhoea and flushing, and safety. Post-hoc analyses were conducted to determine pre-treatment tumour growth rate (TGR) cutoffs that best predicted the ORR during treatment.

Results: Forty patients were enrolled (GEP-NETs, n = 39; lung-NETs, n = 1). PFS rates were 91.7% at end of last LAN-PRRT cycle and 95.0% at last available follow-up. In the full analysis set, best overall response among patients with GEP-NETs (n = 23) was stable disease (n = 14, 60.9%), partial response (n = 8, 34.8%) and progressive disease (n = 1, 4.3%). The ORR was 27.3% at end of last LAN-PRRT cycle and 36.8% at last available follow-up. Optimal baseline TGR cutoffs for predicting ORR at these time points were 1.18% and 0.33%, respectively. At baseline, 81.0% of patients had diarrhoea or flushing; both remained stable or improved in most cases. No increased adverse drug reactions were reported.

Conclusion: Despite the major recruitment shortfall for the PRELUDE study, effectiveness data were encouraging in this selected population, highlighting the potential usefulness and feasibility of LAN combined with and after PRRT in patients with GEP-NETs. The study also identified challenges associated with evaluating clinical practice in a rare-disease setting and highlighted the need for standardisation of PRRT procedures.

Trial Registration: Trial number: NCT02788578; URL: https://clinicaltrials.gov/ct2/show/NCT02788578.
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http://dx.doi.org/10.1007/s00259-020-04712-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396404PMC
September 2020

Molecular identification of bronchopulmonary neuroendocrine tumours and neuroendocrine genotype in lung neoplasia using the NETest liquid biopsy.

Eur J Cardiothorac Surg 2020 06;57(6):1195-1202

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

Objectives: Diagnosing lung neuroendocrine neoplasia (NEN) requires a biopsy or an operation. We evaluated a 'liquid biopsy' (NETest) as an in vitro diagnostic tool for identifying NEN and compared it to chromogranin A (CgA).

Methods: We identified 4 study cohorts: patients with bronchopulmonary carcinoids (n = 99, including 62 typical and 37 atypical carcinoids), lung cancers [n = 101, including 41 adenocarcinomas, 37 squamous carcinomas (SQC), 16 small-cell lung cancers and 7 large-cell neuroendocrine carcinomas]; benign disease (50 idiopathic pulmonary fibrosis) and healthy controls (n = 102). Transcript levels measured quantitatively (activity scores: 0-100) were compared to CgA (enzyme-linked immunosorbent assay; normal < 109 ng/ml) levels.

Results: The results of the NETest were positive (>20) in 94% of patients with bronchopulmonary carcinoid compared to 8% of the controls (Fisher's exact test; P < 0.001) and were significantly more accurate as a diagnostic test (McNemar's test; P < 0.001, χ2 = 72) than was CgA (positive: 19% bronchopulmonary carcinoid, 15% controls). Small-cell lung cancers (87%), large-cell neuroendocrine carcinomas (86%), adenocarcinoma (42%) and SQC (35%) were also NETest-positive. Increasing the NETest cut-off score to >40 was useful for detecting all NENs and differentiating these tumours from either controls/benign lung diseases (specificity 97%) or adenocarcinoma/SQC (specificity 94%). CgA was positive in 15-44% irrespective of pathology and had no diagnostic value.

Conclusions: A gene-based liquid biopsy is an effective and accurate method for diagnosing lung tumours with neuroendocrine gene expression. CgA has no value. An NETest score >40 provides an accurate (94-97%) rule-in for the diagnosis of NEN and a rule-out for benign and other neoplastic diseases. Because neuroendocrine gene expression is associated with a poor prognosis, NETest levels may have utility both in the diagnosis of and the treatment stratification for lung neoplasia.
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http://dx.doi.org/10.1093/ejcts/ezaa018DOI Listing
June 2020

The clinical applications of a multigene liquid biopsy (NETest) in neuroendocrine tumors.

Adv Med Sci 2020 Mar 13;65(1):18-29. Epub 2019 Dec 13.

Gastroenterological Surgery, Yale University School of Medicine, New Haven, CT, USA.

Purpose: There are few effective biomarkers for neuroendocrine tumors. Precision oncology strategies have provided liquid biopsies for real-time and tailored decision-making. This has led to the development of the first neuroendocrine tumor liquid biopsy (the NETest). The NETest represents a transcriptomic signature of neuroendocrine tumor (NETs) that captures tumor biology and disease activity. The data have direct clinical application in terms of identifying residual disease, disease progress and the efficacy of treatment. In this overview we assess the available published information on the metrics and clinical efficacy of the NETest.

Material And Methods: Published data on the NETest have been collated and analyzed to understand the clinical application of this multianalyte biomarker in NETs.

Results: NETest assay has been validated as a standardized and reproducible clinical laboratory measurement. It is not affected by demographic characteristics, or acid suppressive medication. Clinical utility of the NETest has been documented in gastroenteropancreatic, bronchopulmonary NETs, in paragangliomas and pheochromocytomas. The test facilitates accurate diagnosis of a NET disease, and real-time monitoring of the disease status (stable/progressive disease). It predicts aggressive tumor behavior, identifies operative tumor resection, and efficacy of the medical treatment (e.g. somatostatin analogues), or peptide receptor radionuclide therapy (PRRT). NETest metrics and clinical applications out-perform standard biomarkers like chromogranin A.

Conclusions: The NETest exhibits clinically competent metrics as an effective biomarker for neuroendocrine tumors. Measurement of NET transcripts in blood is a significant advance in neuroendocrine tumor management and demonstrates that blood provides a viable source to identify and monitor tumor status.
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http://dx.doi.org/10.1016/j.advms.2019.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453408PMC
March 2020

PRRT neuroendocrine tumor response monitored using circulating transcript analysis: the NETest.

Eur J Nucl Med Mol Imaging 2020 04 14;47(4):895-906. Epub 2019 Dec 14.

LuGenIum Consortium, Milan, Rotterdam, London, Bad Berka, 54 Portland Place, London, W1B1DY, UK.

Purpose: Peptide receptor radionuclide therapy (PRRT) is effective for metastatic/inoperable neuroendocrine tumors (NETs). Imaging response assessment is usually efficient subsequent to treatment completion. Blood biomarkers such as PRRT Predictive Quotient (PPQ) and NETest are effective in real-time. PPQ predicts PRRT efficacy; NETest monitors disease. We prospectively evaluated: (1) NETest as a surrogate biomarker for RECIST; (2) the correlation of NETest levels with PPQ prediction.

Methods: Three independent Lu-PRRT-treated GEP-NET and lung cohorts (Meldola, Italy: n = 72; Bad-Berka, Germany: n = 44; Rotterdam, Netherlands: n = 41). Treatment response: RECIST1.1 (responder (stable, partial, and complete response) vs non-responder). Blood sampling: pre-PRRT, before each cycle and follow-up (2-12 months). PPQ (positive/negative) and NETest (0-100 score) by PCR. Stable < 40; progressive > 40). CgA (ELISA) as comparator. Samples de-identified, measurement and analyses blinded. Kaplan-Meier survival and standard statistics.

Results: One hundred twenty-two of the 157 were evaluable. RECIST stabilization or response in 67%; 33% progressed. NETest significantly (p < 0.0001) decreased in RECIST "responders" (- 47 ± 3%); in "non-responders," it remained increased (+ 79 ± 19%) (p < 0.0005). NETest monitoring accuracy was 98% (119/122). Follow-up levels > 40 (progressive) vs stable (< 40) significantly correlated with mPFS (not reached vs. 10 months; HR 0.04 (95%CI, 0.02-0.07). PPQ response prediction was accurate in 118 (97%) with a 99% accurate positive and 93% accurate negative prediction. NETest significantly (p < 0.0001) decreased in PPQ-predicted responders (- 46 ± 3%) and remained elevated or increased in PPQ-predicted non-responders (+ 75 ± 19%). Follow-up NETest categories stable vs progressive significantly correlated with PPQ prediction and mPFS (not reached vs. 10 months; HR 0.06 (95%CI, 0.03-0.12). CgA did not reflect PRRT treatment: in RECIST responders decrease in 38% and in non-responders 56% (p = NS).

Conclusions: PPQ predicts PRRT response in 97%. NETest accurately monitors PRRT response and is an effective surrogate marker of PRRT radiological response. NETest decrease identified responders and correlated (> 97%) with the pretreatment PPQ response predictor. CgA was non-informative.
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http://dx.doi.org/10.1007/s00259-019-04601-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515632PMC
April 2020

The Path to the Future: Education of Nuclear Medicine Therapeutic Specialists as Responsible Physicians.

J Nucl Med 2019 12 15;60(12):1663-1664. Epub 2019 Nov 15.

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

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http://dx.doi.org/10.2967/jnumed.119.232454DOI Listing
December 2019

The Use of Deep Learning and Neural Networks in Imaging: Welcome to the New Mathematical Milieu of Medicine.

Neuroendocrinology 2020 7;110(5):322-327. Epub 2019 Nov 7.

Memorial Sloan Kettering Cancer Center, New York, New York, USA.

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http://dx.doi.org/10.1159/000504605DOI Listing
February 2021