Publications by authors named "Randall Hawkins"

68 Publications

I-MIBG PET/CT to Monitor Metastatic Disease in Children with Relapsed Neuroblastoma.

J Nucl Med 2021 Jan 15;62(1):43-47. Epub 2020 May 15.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California

The metaiodobenzylguanidine (MIBG) scan is one of the most sensitive noninvasive lesion detection modalities for neuroblastoma. Unlike I-MIBG, I-MIBG allows high-resolution PET. We evaluated I-MIBG PET/CT for its diagnostic performance as directly compared with paired I-MIBG scans. Before I-MIBG therapy, standard I-MIBG imaging (5.2 MBq/kg) was performed on 7 patients, including whole-body (anterior-posterior) planar imaging, focused-field-of-view SPECT/CT, and whole-body I-MIBG PET/CT (1.05 MBq/kg). After therapy, 2 of 7 patients also completed I-MIBG PET/CT as well as paired I-MIBG planar imaging and SPECT/CT. One patient underwent I-MIBG PET/CT only after therapy. We evaluated all 8 patients who showed at least 1 I-MIBG-positive lesion with a total of 10 scans. In 8 pairs, I-MIBG and I-MIBG were performed within 1 mo of each other. The locations of identified lesions, the number of total lesions, and the curie scores were recorded for the I-MIBG and I-MIBG scans. Finally, for 5 patients who completed at least 3 PET/CT scans after administration of I-MIBG, we estimated the effective dose of I-MIBG. I-MIBG whole-body planar scans, focused-field-of-view SPECT/CT scans, and whole-body I-MIBG PET scans found 25, 32, and 87 total lesions, respectively. There was a statistically significant difference in lesion detection for I-MIBG PET/CT versus I-MIBG planar imaging ( < 0.0001) and I-MIBG SPECT/CT ( < 0.0001). The curie scores were also higher for I-MIBG PET/CT than for I-MIBG planar imaging and SPECT/CT in 6 of 10 patients. I-MIBG PET/CT demonstrated better detection of lesions throughout the body, including the chest, spine, head and neck, and extremities. The effective dose estimated for patient-specific I-MIBG was approximately 10 times that of I-MIBG; however, given that we administered a very low activity of I-MIBG (1.05 MBq/kg), the effective dose was only approximately twice that of I-MIBG despite the large difference in half-lives (100 vs. 13.2 h). The first-in-humans use of low-dose I-MIBG PET for monitoring disease burden demonstrated tumor detection capability superior to that of I-MIBG planar imaging and SPECT/CT.
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http://dx.doi.org/10.2967/jnumed.120.243139DOI Listing
January 2021

Technical Note: Simplified and practical pretherapy tumor dosimetry - A feasibility study for I-MIBG therapy of neuroblastoma using I-MIBG PET/CT.

Med Phys 2019 May 12;46(5):2477-2486. Epub 2019 Mar 12.

Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.

Purpose: Radiation dose calculated on tumors for radiopharmaceutical therapy varies significantly from tumor to tumor and from patient to patient. Accurate estimation of radiation dose requires multiple time point measurements using radionuclide imaging modalities such as SPECT or PET. In this report, we show our technical development of reducing the number of scans needed for reasonable estimation of tumor and normal organ dose in our pretherapy imaging and dosimetry platform of I-metaiodobenzylguanidine (MIBG) positron emission tomography/computed tomography (PET/CT) for I-MIBG therapy of neuroblastoma.

Methods: We analyzed the simplest kinetic data, areas of two-time point data for five patients with neuroblastoma who underwent 3 or 4 times of I-MIBG PET/CT scan prior to I-MIBG therapy. The data for which we derived areas were percent of injected activity (%IA) and standardized uptake value of tumors. These areas were correlated with time-integrated activity coefficients (TIACs) from full data (3 or 4 time points). TIACs are direct correlates with radiation dose as long as the volume and the radionuclide are known.

Results: The areas of %IAs between data obtained from all the two-time points with time points 1 and 2 (day 0 and day 1), time points 2 and 3 (day 1 and day 2), and time points 1 and 3 (day 0 and day 2) showed reasonable correlation (Pearson's correlation coefficient |r| > 0.5) with not only tumor and organ TIACs but also tumor and organ absorbed doses. The tumor and organ doses calculated using %IA areas of time point 1 and time point 2 were our best fits at about 20% individual percent difference compared to doses calculated using 3 or 4 time points.

Conclusions: We could achieve reasonable accuracy of estimating tumor doses for subsequent radiopharmaceutical therapy using only the two-time point imaging sessions. Images obtained from these time points (within the 48-h after administration of radiopharmaceutical) were also viewed as useful for diagnostic reading. Although our analysis was specific to I-MIBG PET/CT pretherapy imaging data for I-MIBG therapy of neuroblastoma and the number of imaging datasets was not large, this feasible methodology would generally be applicable to other imaging and therapeutic radionuclides with an appropriate data analysis similar to our analysis to other imaging and therapeutic radiopharmaceuticals.
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http://dx.doi.org/10.1002/mp.13446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6510622PMC
May 2019

A Deep Learning Model to Predict a Diagnosis of Alzheimer Disease by Using F-FDG PET of the Brain.

Radiology 2019 02 6;290(2):456-464. Epub 2018 Nov 6.

From the Department of Radiology and Biomedical Imaging (Y.D., J.H.S., H.T., R.H., N.W.J., T.P.C., M.S.A., C.M.A., S.C.B., R.R.F., S.Y.H., Y.S., R.A.H., M.H.P., B.L.F.) and Institute for Computational Health Sciences (J.H.S., M.G.K., H.T., D.L., K.A.Z., D.H.), University of California, San Francisco, 550 Parnassus Ave, San Francisco, CA 94143; Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, Berkeley, Calif (Y.D.); and Department of Radiology, University of California, Davis, Sacramento, Calif (L.N.).

Purpose To develop and validate a deep learning algorithm that predicts the final diagnosis of Alzheimer disease (AD), mild cognitive impairment, or neither at fluorine 18 (F) fluorodeoxyglucose (FDG) PET of the brain and compare its performance to that of radiologic readers. Materials and Methods Prospective F-FDG PET brain images from the Alzheimer's Disease Neuroimaging Initiative (ADNI) (2109 imaging studies from 2005 to 2017, 1002 patients) and retrospective independent test set (40 imaging studies from 2006 to 2016, 40 patients) were collected. Final clinical diagnosis at follow-up was recorded. Convolutional neural network of InceptionV3 architecture was trained on 90% of ADNI data set and tested on the remaining 10%, as well as the independent test set, with performance compared to radiologic readers. Model was analyzed with sensitivity, specificity, receiver operating characteristic (ROC), saliency map, and t-distributed stochastic neighbor embedding. Results The algorithm achieved area under the ROC curve of 0.98 (95% confidence interval: 0.94, 1.00) when evaluated on predicting the final clinical diagnosis of AD in the independent test set (82% specificity at 100% sensitivity), an average of 75.8 months prior to the final diagnosis, which in ROC space outperformed reader performance (57% [four of seven] sensitivity, 91% [30 of 33] specificity; P < .05). Saliency map demonstrated attention to known areas of interest but with focus on the entire brain. Conclusion By using fluorine 18 fluorodeoxyglucose PET of the brain, a deep learning algorithm developed for early prediction of Alzheimer disease achieved 82% specificity at 100% sensitivity, an average of 75.8 months prior to the final diagnosis. © RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Larvie in this issue.
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http://dx.doi.org/10.1148/radiol.2018180958DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358051PMC
February 2019

Phase II Trial of Alisertib in Combination with Irinotecan and Temozolomide for Patients with Relapsed or Refractory Neuroblastoma.

Clin Cancer Res 2018 12 9;24(24):6142-6149. Epub 2018 Aug 9.

Department of Pediatrics, USC Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles, California.

Purpose: In phase I testing, alisertib tablets with irinotecan and temozolomide showed significant antitumor activity in patients with neuroblastoma. This study sought to confirm activity of this regimen; evaluate an alisertib oral solution; and evaluate biomarkers of clinical outcomes.

Patients And Methods: We conducted a two-stage phase II trial of alisertib tablets (60 mg/m/dose × 7 days), irinotecan (50 mg/m/dose i.v. × 5 days), and temozolomide (100 mg/m/dose orally × 5 days) in patients with relapsed or refractory neuroblastoma. The primary endpoint was best objective response. A separate cohort was treated with alisertib at 45 mg/m using oral solution instead of tablets. Exploratory analyses sought to identify predictors of toxicity, response, and progression-free survival (PFS) using pooled data from phase I, phase II, and oral solution cohorts.

Results: Twenty and 12 eligible patients were treated in the phase II and oral solution cohorts, respectively. Hematologic toxicities were the most common adverse events. In phase II, partial responses were observed in 19 evaluable patients (21%). The estimated PFS at 1 year was 34%. In the oral solution cohort, 3 patients (25%) had first cycle dose-limiting toxicity (DLT). Alisertib oral solution at 45 mg/m had significantly higher median and exposure compared with tablets at 60 mg/m. Higher alisertib trough concentration was associated with first cycle DLT, whereas amplification was associated with inferior PFS.

Conclusions: This combination shows antitumor activity, particularly in patients with nonamplified tumors. Data on an alisertib oral solution expand the population able to be treated with this agent.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6295246PMC
December 2018

Predictors of response, progression-free survival, and overall survival using NANT Response Criteria (v1.0) in relapsed and refractory high-risk neuroblastoma.

Pediatr Blood Cancer 2018 05 19;65(5):e26940. Epub 2018 Jan 19.

Department of Pediatrics, University of California San Francisco, San Francisco, California.

Purpose: The New Approaches to Neuroblastoma Therapy Response Criteria (NANTRC) were developed to optimize response assessment in patients with recurrent/refractory neuroblastoma. Response predictors and associations of the NANTRC version 1.0 (NANTRCv1.0) and prognostic factors with outcome were analyzed.

Methods: A retrospective analysis was performed of patients with recurrent/refractory neuroblastoma enrolled from 2000 to 2009 on 13 NANT Phase 1/2 trials. NANTRC overall response integrated CT/MRI (Response Evaluation Criteria in Solid Tumors [RECIST]), metaiodobenzylguanidine (MIBG; Curie scoring), and percent bone marrow (BM) tumor (morphology).

Results: Fourteen (6.9%) complete response (CR) and 14 (6.9%) partial response (PR) occurred among 203 patients evaluable for response. Five-year progression-free survival (PFS) was 16 ± 3%; overall survival (OS) was 27 ± 3%. Disease sites at enrollment included MIBG-avid lesions (100% MIBG trials; 84% non-MIBG trials), measurable CT/MRI lesions (48%), and BM (49%). By multivariable analysis, Curie score of 0 (P < 0.001), lower Curie score (P = 0.003), no measurable CT/MRI lesions (P = 0.044), and treatment on peripheral blood stem cell (PBSC) supported trials (P = 0.005) were associated with achieving CR/PR. Overall response of stable disease (SD) or better was associated with better OS (P < 0.001). In multivariable analysis, MYCN amplification (P = 0.037) was associated with worse PFS; measurable CT/MRI lesions (P = 0.041) were associated with worse OS; prior progressive disease (PD; P < 0.001/P < 0.001), Curie score ≥ 1 (P < 0.001; P = 0.001), higher Curie score (P = 0.048/0.037), and treatment on non-PBSC trials (P = < 0.001/0.003) were associated with worse PFS and OS.

Conclusions: NANTRCv1.0 response of at least SD is associated with better OS in patients with recurrent/refractory neuroblastoma. Patient and tumor characteristics may predict response and outcome. Identifying these variables can optimize Phase 1/2 trial design to select novel agents for further testing.
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http://dx.doi.org/10.1002/pbc.26940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456604PMC
May 2018

Quantitative and Visual Assessments toward Potential Sub-mSv or Ultrafast FDG PET Using High-Sensitivity TOF PET in PET/MRI.

Mol Imaging Biol 2018 06;20(3):492-500

Department of Radiology and Biomedical Imaging, UCSF, 185 Berry Street, Suite 350, San Francisco, CA, 94107, USA.

Purpose: Newer high-performance time-of-flight (TOF) positron emission tomography (PET) systems have the capability to preserve diagnostic image quality with low count density, while maintaining a high raw photon detection sensitivity that would allow for a reduction in injected dose or rapid data acquisition. To assess this, we performed quantitative and visual assessments of the PET images acquired using a highly sensitive (23.3 cps/kBq) large field of view (25-cm axial) silicon photomultiplier (SiPM)-based TOF PET (400-ps timing resolution) integrated with 3 T-MRI in comparison to PET images acquired on non-TOF PET/x-ray computed tomography (CT) systems.

Procedures: Whole-body 2-deoxy-2-[F]fluoro-D-glucose ([F]FDG) PET/CT was acquired for 15 patients followed by whole body PET/magnetic resonance imaging (MRI) with an average injected dose of 325 ± 84 MBq. The PET list mode data from PET/MRI were reconstructed using full datasets (4 min/bed) and reduced datasets (2, 1, 0.5, and 0.25 min/bed). Qualitative assessment between PET/CT and PET/MR images were made. A Likert-type scale between 1 and 5, 1 for non-diagnostic, 3 equivalent to PET/CT, and 5 superior quality, was used. Maximum and mean standardized uptake values (SUV and SUV) of normal tissues and lesions detected were measured and compared.

Results: Mean visual assessment scores were 3.54 ± 0.32, 3.62 ± 0.38, and 3.69 ± 0.35 for the brain and 3.05 ± 0.49, 3.71 ± 0.45, and 4.14 ± 0.44 for the whole-body maximum intensity projections (MIPs) for 1, 2, and 4 min/bed PET/MR images, respectively. The SUV values for normal tissues were lower and statistically significant for images acquired at 4, 2, 1, 0.5, and 0.25 min/bed on the PET/MR, with values of - 18 ± 28 % (p < 0.001), - 16 ± 29 % (p = 0.001), - 16 ± 31 % (p = 0.002), - 14 ± 35 % (p < 0.001), and - 13 ± 34 % (p = 0.002), respectively. SUV and SUV values of all lesions were higher and statistically significant (p < 0.05) for 4, 2, 1, 0.50, and 0.25 min/bed PET/MR datasets.

Conclusion: High-sensitivity TOF PET showed comparable but still better visual image quality even at a much reduced activity in comparison to lower-sensitivity non-TOF PET. Our data translates to a seven times reduction in either injection dose for the same time or total scan time for the same injected dose. This "ultra-sensitivity" PET system provides a path to clinically acceptable extremely low-dose FDG PET studies (e.g., sub 1 mCi injection or sub-mSv effective dose) or PET studies as short as 1 min/bed (e.g., 6 min of total scan time) to cover whole body without compromising diagnostic performance.
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http://dx.doi.org/10.1007/s11307-017-1145-zDOI Listing
June 2018

Effect of Time-of-Flight and Regularized Reconstructions on Quantitative Measurements and Qualitative Assessments in Newly Diagnosed Prostate Cancer With F-Fluorocholine Dual Time Point PET/MRI.

Mol Imaging 2017 Jan-Dec;16:1536012117736703

1 Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, USA.

Recent technical advances in positron emission tomography/magnetic resonance imaging (PET/MRI) technology allow much improved time-of-flight (TOF) and regularized iterative PET reconstruction regularized iterative reconstruction (RIR) algorithms. We evaluated the effect of TOF and RIR on standardized uptake values (maximum and peak SUV [SUV and SUV]) and their metabolic tumor volume dependencies and visual image quality for F-fluorocholine PET/MRI in patients with newly diagnosed prostate cancer. Fourteen patients were administered with 3 MBq/kg of F-fluorocholine and scanned dynamically for 30 minutes. Positron emission tomography images were divided to early and late time points (1-6 minutes summed and 7-30 minutes summed). The values of the different SUVs were documented for dominant PET-avid lesions, and metabolic tumor volume was estimated using a 50% isocontour and SUV threshold of 2.5. Image quality was assessed via visual acuity scoring (VAS). We found that incorporation of TOF or RIR increased lesion SUVs. The lesion to background ratio was not improved by TOF reconstruction, while RIR improved the lesion to background ratio significantly ( P < .05). The values of the different VAS were all significantly higher ( P < .05) for RIR images over TOF, RIR over non-TOF, and TOF over non-TOF. In conclusion, our data indicate that TOF or RIR should be incorporated into current protocols when available.
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http://dx.doi.org/10.1177/1536012117736703DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5703093PMC
October 2018

In Vivo PET Imaging of the Activated Immune Environment in a Small Animal Model of Inflammatory Arthritis.

Mol Imaging 2017 01;16:1536012117712638

1 Department of Radiology and Biomedical Imaging, University of California-San Francisco, San Francisco, CA, USA.

Background: Evolving immune-mediated therapeutic strategies for rheumatoid arthritis (RA) may benefit from an improved understanding of the complex role that T-cell activation plays in RA. This study assessed the potential of fluorine-18-labeled 9-β-d-arabinofuranosylguanine ([F]F-AraG) positron emission tomography (PET) imaging to report immune activation in vivo in an adjuvant-induced arthritis (AIA) small animal model.

Methods: Using positron emission tomography-computed tomography imaging, uptake of [F]F-AraG in the paws of mice affected by arthritis at 6 (acute) and 20 (chronic) days following AIA induction in a single paw was assessed and compared to uptake in contralateral control paws. Fractions of T cells and B cells demonstrating markers of activation at the 2 time points were determined by flow cytometry.

Results: Differential uptake of [F]F-AraG was demonstrated on imaging of the affected joint when compared to control at both acute and chronic time points with corresponding changes in markers of T-cell activation observed on flow cytometry.

Conclusion: [F]F-AraG may serve as an imaging biomarker of T-cell activation in inflammatory arthritis. Further development of this technique is warranted and could offer a tool to explore the temporal link between activated T cells and RA as well as to monitor immune-mediated therapies for RA in clinical trials.
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http://dx.doi.org/10.1177/1536012117712638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5480631PMC
January 2017

A PET Imaging Strategy to Visualize Activated T Cells in Acute Graft-versus-Host Disease Elicited by Allogenic Hematopoietic Cell Transplant.

Cancer Res 2017 06;77(11):2893-2902

Molecular Imaging Program at Stanford, Stanford University, Stanford, California.

A major barrier to successful use of allogeneic hematopoietic cell transplantation is acute graft-versus-host disease (aGVHD), a devastating condition that arises when donor T cells attack host tissues. With current technologies, aGVHD diagnosis is typically made after end-organ injury and often requires invasive tests and tissue biopsies. This affects patient prognosis as treatments are dramatically less effective at late disease stages. Here, we show that a novel PET radiotracer, 2'-deoxy-2'-[18F]fluoro-9-β-D-arabinofuranosylguanine ([18F]F-AraG), targeted toward two salvage kinase pathways preferentially accumulates in activated primary T cells. [18F]F-AraG PET imaging of a murine aGVHD model enabled visualization of secondary lymphoid organs harboring activated donor T cells prior to clinical symptoms. Tracer biodistribution in healthy humans showed favorable kinetics. This new PET strategy has great potential for early aGVHD diagnosis, enabling timely treatments and improved patient outcomes. [18F]F-AraG may be useful for imaging activated T cells in various biomedical applications. .
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http://dx.doi.org/10.1158/0008-5472.CAN-16-2953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5505323PMC
June 2017

Glioma FMISO PET/MR Imaging Concurrent with Antiangiogenic Therapy: Molecular Imaging as a Clinical Tool in the Burgeoning Era of Personalized Medicine.

Biomedicines 2016 Oct 31;4(4). Epub 2016 Oct 31.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, 505 Parnassus Avenue, M-391, San Francisco, CA 94143-0628, USA.

The purpose of this article is to provide a focused overview of the current use of positron emission tomography (PET) molecular imaging in the burgeoning era of personalized medicine in the treatment of patients with glioma. Specifically, we demonstrate the utility of PET imaging as a tool for personalized diagnosis and therapy by highlighting a case series of four patients with recurrent high grade glioma who underwent 18F-fluoromisonidazole (FMISO) PET/MR (magnetic resonance) imaging through the course of antiangiogenic therapy. Three distinct features were observed from this small cohort of patients. First, the presence of pseudoprogression was retrospectively associated with the absence of hypoxia. Second, a subgroup of patients with recurrent high grade glioma undergoing bevacizumab therapy demonstrated disease progression characterized by an enlarging nonenhancing mass with newly developed reduced diffusion, lack of hypoxia, and preserved cerebral blood volume. Finally, a reduction in hypoxic volume was observed concurrent with therapy in all patients with recurrent tumor, and markedly so in two patients that developed a nonenhancing reduced diffusion mass. This case series demonstrates how medical imaging has the potential to influence personalized medicine in several key aspects, especially involving molecular PET imaging for personalized diagnosis, patient specific disease prognosis, and therapeutic monitoring.
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http://dx.doi.org/10.3390/biomedicines4040024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5344267PMC
October 2016

C-L-methyl methionine dynamic PET/CT of skeletal muscle: response to protein supplementation compared to L-[ring C] phenylalanine infusion with serial muscle biopsy.

Ann Nucl Med 2017 May 4;31(4):295-303. Epub 2017 Mar 4.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, Box 0946, San Francisco, CA, 94143-0946, USA.

Objective: The objective of this study was to determine if clinical dynamic PET/CT imaging with C-L-methyl-methionine (C-MET) in healthy older women can provide an estimate of tissue-level post-absorptive and post-prandial skeletal muscle protein synthesis that is consistent with the more traditional method of calculating fractional synthesis rate (FSR) of muscle protein synthesis from skeletal muscle biopsies obtained during an infusion of L-[ring C] phenylalanine (C-Phe).

Methods: Healthy older women (73 ± 5 years) completed both dynamic PET/CT imaging with C-MET and a stable isotope infusion of C-Phe with biopsies to measure the skeletal muscle protein synthetic response to 25 g of a whey protein supplement. Graphical estimation of the Patlak coefficient K from analysis of the dynamic PET/CT images was employed as a measure of incorporation of 11 C-MET in the mid-thigh muscle bundle.

Results: Post-prandial values [mean ± standard error of the mean (SEM)] were higher than post-absorptive values for both K (0.0095 ± 0.001 vs. 0.00785 ± 0.001 min, p < 0.05) and FSR (0.083 ± 0.008 vs. 0.049 ± 0.006%/h, p < 0.001) in response to the whey protein supplement. The percent increase in K and FSR in response to the whey protein supplement was significantly correlated (r = 0.79, p = 0.015).

Conclusions: Dynamic PET/CT imaging with C-MET provides an estimate of the post-prandial anabolic response that is consistent with a traditional, invasive stable isotope, and muscle biopsy approach. These results support the potential future use of C-MET imaging as a non-invasive method for assessing conditions affecting skeletal muscle protein synthesis.
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http://dx.doi.org/10.1007/s12149-017-1157-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5397459PMC
May 2017

Radioembolization with Y glass microspheres for the treatment of unresectable metastatic liver disease from chemotherapy-refractory gastrointestinal cancers: final report of a prospective pilot study.

J Gastrointest Oncol 2016 Dec;7(6):860-874

Department of Medicine, University of California San Francisco, San Francisco, CA, USA.

Background: This prospective pilot single-institution study was undertaken to document the feasibility, safety, and efficacy of radioembolization of liver-dominant metastatic gastrointestinal cancer using Y glass microspheres.

Methods: Between June 2010 and October 2013, 42 adult patients (26 men, 16 women; median age 60 years) with metastatic chemotherapy-refractory unresectable colorectal (n=21), neuroendocrine (n=11), intrahepatic bile duct (n=7), pancreas (n=2), and esophageal (n=1) carcinomas underwent 60 lobar or segmental administrations of Y glass microspheres. Data regarding clinical and laboratory adverse events (AE) were collected prospectively for up to 5.5 years after radioembolization. Radiographic responses were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Time to maximum response, response duration, progression-free survival (PFS) (hepatic and extrahepatic), and overall survival (OS) were measured.

Results: Median target dose and activity were 109.4 Gy and 2.6 GBq per treatment session, respectively. Majority of clinical AE were grade 1 or 2 in severity. Patients with colorectal cancer had hepatic objective response rate (ORR) of 25% and a hepatic disease control rate (DCR) of 80%. Median PFS and OS were 1.0 and 4.4 months, respectively. Patients with neuroendocrine tumors (NET) had hepatic ORR and DCR of 73% and 100%, respectively. Median PFS was 8.9 months for this cohort. DCR and median PFS and OS for patients with cholangiocarcinoma were 86%, 1.1 months, and 6.7 months, respectively.

Conclusions: Y glass microspheres device has a favorable safety profile, and achieved prolonged disease control of hepatic tumor burden in a subset of patients, including all patients enrolled in the neuroendocrine cohort.
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http://dx.doi.org/10.21037/jgo.2016.08.04DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5177572PMC
December 2016

Patterns of Relapse in High-Risk Neuroblastoma Patients Treated With and Without Total Body Irradiation.

Int J Radiat Oncol Biol Phys 2017 02 8;97(2):270-277. Epub 2016 Nov 8.

Harvard Medical School, Boston, Massachusetts; Brigham and Women's Hospital, Boston, Massachusetts; Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts. Electronic address:

Purpose: External beam radiation therapy to initial sites of disease may influence relapse patterns in high-risk neuroblastoma. However, the effect of systemic irradiation by use of total body irradiation (TBI) on anatomic patterns of relapse has not previously been investigated.

Methods And Materials: We retrospectively analyzed patients receiving definitive treatment of high-risk neuroblastoma with subsequent relapse in bony metastatic sites, with a date of relapse between January 1, 1997, and December 31, 2012. Anatomic sites of disease, defined by metaiodobenzylguanidine (MIBG) avidity, were compared at diagnosis and at first relapse. The Fisher exact test was performed to compare relapse in initially involved sites between patients treated with and without TBI.

Results: Seventy-four patients with a median age at diagnosis of 3.5 years (range, 0.3-15.3 years) had relapse in 227 sites of MIBG-avid metastatic disease, with a median time to relapse of 1.8 years. Of the 227 sites of first relapse, 154 sites (68%) were involved at diagnosis. When we compared relapse patterns in patients treated with and without TBI, 12 of 23 patients (52%) treated with TBI had relapse in ≥1 previously MIBG-avid site of disease whereas 40 of 51 patients (78%) treated without TBI had relapse in ≥1 previously MIBG-avid site of disease (P=.03).

Conclusions: Patients treated with systemic irradiation in the form of TBI were significantly less likely to have relapse in prior sites of disease. These findings support further investigation into the role of radiopharmaceutical therapies in curative multimodality therapy.
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http://dx.doi.org/10.1016/j.ijrobp.2016.10.047DOI Listing
February 2017

Ictal lack of binding to brain parenchyma suggests integrity of the blood-brain barrier for 11C-dihydroergotamine during glyceryl trinitrate-induced migraine.

Brain 2016 07 27;139(Pt 7):1994-2001. Epub 2016 May 27.

1 Headache Group, Department of Neurology, University of California San Francisco, San Francisco, CA, USA 4 Headache Group, NIHR-Wellcome Trust, King's Clinical Research Facility, King's College London, London, UK

SEE DREIER DOI 101093/AWW112 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: For many decades a breakdown of the blood-brain barrier has been postulated to occur in migraine. Hypothetically this would facilitate access of medications, such as dihydroergotamine or triptans, to the brain despite physical properties otherwise restricting their entry. We studied the permeability of the blood-brain barrier in six migraineurs and six control subjects at rest and during acute glyceryl trinitrate-induced migraine attacks using positron emission tomography with the novel radioligand (11)C-dihydroergotamine, which is chemically identical to pharmacologically active dihydroergotamine. The influx rate constant Ki, average dynamic image and time activity curve were assessed using arterial blood sampling and served as measures for receptor binding and thus blood-brain barrier penetration. At rest, there was binding of (11)C-dihydroergotamine in the choroid plexus, pituitary gland, and venous sinuses as expected from the pharmacology of dihydroergotamine. However, there was no binding to the brain parenchyma, including the hippocampus, the area with the highest density of the highest-affinity dihydroergotamine receptors, and the raphe nuclei, a postulated brainstem site of action during migraine, suggesting that dihydroergotamine is not able to cross the blood-brain barrier. This binding pattern was identical in migraineurs during glyceryl trinitrate-induced migraine attacks as well as in matched control subjects. We conclude that (11)C-dihydroergotamine is unable to cross the blood-brain barrier interictally or ictally demonstrating that the blood-brain barrier remains tight for dihydroergotamine during acute glyceryl trinitrate-induced migraine attacks.
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http://dx.doi.org/10.1093/brain/aww096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4939703PMC
July 2016

Recovery of Native Renal Function in Patients with Hepatorenal Syndrome Following Combined Liver and Kidney Transplant with Mercaptoacetyltriglycine-3 Renogram: Developing a Methodology.

World J Nucl Med 2016 Jan-Apr;15(1):44-9

Department of Radiology, Division of Nuclear Medicine, University of California, San Francisco (UCSF), San Francisco, California, USA.

Many patients with hepatorenal syndrome (HRS) end up receiving a combined liver and kidney transplant (CKLT) with preservation of native kidneys, specially type 1 HRS since is characterizes by a very rapid deterioration of renal function. Eventually, most of the patients regain renal function, but it is unknown if this is due to the transplanted kidney, the recovery of native renal function, or both. The aim of this study is to evaluate if there is recovery of native renal function in patients with HRS following CKLT. 22 patients (16 men; 6 women) with history of HRS and status post CKLT were studied. Mercapto-acetyltriglycine-3 renograms in the anterior and posterior views with the three kidneys in the field of view were simultaneously acquired. The renograms were analyzed by creating regions of interest around the transplanted and native kidneys. Relative contribution to the renal function, clearance, and effective renal plasma flow for the transplanted and native kidneys were obtained. 1/22 (4.5%) patients presented with a very poor functioning transplanted kidney, in 15/22 (68%) cases the combined native renal function was markedly poorer than the transplanted renal function and in 6/22 (27%) native kidneys showed a contribution to the renal function similar to the transplanted kidney. In conclusion, our series show that around 32% of the HRS patients recovered their native renal function after CKLT. Identification of common factors that affect recovery of native renal function may help to avoid unnecessary renal transplants, significantly reducing morbidity and cost, while facilitating a reallocation of scarce donor resources.
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http://dx.doi.org/10.4103/1450-1147.172140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4729014PMC
February 2016

Phase I Study of the Aurora A Kinase Inhibitor Alisertib in Combination With Irinotecan and Temozolomide for Patients With Relapsed or Refractory Neuroblastoma: A NANT (New Approaches to Neuroblastoma Therapy) Trial.

J Clin Oncol 2016 Apr 16;34(12):1368-75. Epub 2016 Feb 16.

Steven G. DuBois, Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA; Araz Marachelian, Susan Groshen, Jemily Malvar, Hollie Lai, Fariba Goodarzian, Hiroyuki Shimada, Scarlett Czarnecki, and Denice Tsao-Wei, University of Southern California Keck School of Medicine and Children's Hospital Los Angeles, Los Angeles; Randall Hawkins, Jesse Courtier, and Katherine K. Matthay, University of California, San Francisco, School of Medicine and Benioff Children's Hospital, San Francisco, CA; Elizabeth Fox, Rochelle Bagatell, John M. Maris, and Yael P. Mosse, Children's Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Rachel A. Kudgus and Joel M. Reid, Mayo Clinic, Rochester, MN; and Lars Wagner, University of Kentucky College of Medicine, Lexington, KY.

Purpose: Alisertib is an oral Aurora A kinase inhibitor with preclinical activity in neuroblastoma. Irinotecan and temozolomide have activity in patients with advanced neuroblastoma. The goal of this phase I study was to determine the maximum tolerated dose (MTD) of alisertib with irinotecan and temozolomide in this population.

Patients And Methods: Patients age 1 to 30 years with relapsed or refractory neuroblastoma were eligible. Patients received alisertib tablets at dose levels of 45, 60, and 80 mg/m(2) per day on days 1 to 7 along with irinotecan 50 mg/m(2) intravenously and temozolomide 100 mg/m(2) orally on days 1 to 5. Dose escalation of alisertib followed the rolling six design. Samples for pharmacokinetic and pharmacogenomic testing were obtained.

Results: Twenty-three patients enrolled, and 22 were eligible and evaluable for dose escalation. A total of 244 courses were administered. The MTD for alisertib was 60 mg/m(2), with mandatory myeloid growth factor support and cephalosporin prophylaxis for diarrhea. Thrombocytopenia and neutropenia of any grade were seen in the majority of courses (84% and 69%, respectively). Diarrhea in 55% of courses and nausea in 54% of courses were the most common nonhematologic toxicities. The overall response rate was 31.8%, with a 50% response rate observed at the MTD. The median number of courses per patient was eight (range, two to 32). Progression-free survival rate at 2 years was 52.4%. Pharmacokinetic testing did not show evidence of drug-drug interaction between irinotecan and alisertib.

Conclusion: Alisertib 60 mg/m(2) per dose for 7 days is tolerable with a standard irinotecan and temozolomide backbone and has promising response and progression-free survival rates. A phase II trial of this regimen is ongoing.
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http://dx.doi.org/10.1200/JCO.2015.65.4889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872349PMC
April 2016

The utility of radioisotope cisternography in low CSF/volume syndromes compared to myelography.

Cephalalgia 2016 Nov 30;36(13):1291-1295. Epub 2016 Sep 30.

4 Headache Group, Department of Neurology, University of California, San Francisco, USA.

Objective The objective of this report is to compare computed tomography (CT) and magnetic resonance (MR) myelography with radioisotope cisternography (RC) for detection of spinal cerebrospinal (CSF) leaks. Methods We retrospectively reviewed 12 spontaneous intracranial hypotension (SIH) patients; CT and RC were performed simultaneously. Three patients had MR myelography. Results CT and/or MR myelography identified CSF leaks in four of 12 patients. RC detected spinal leaks in all three patients confirmed by CT myelography; RC identified the CSF leak location in two of three cases, and these were due to osteophytic spicules and/or discs. RC showed only enlarged perineural activity. Only intrathecal gadolinium MR myelography clearly identified a slow leak from a perineural cyst. In eight remaining cases, the leak site was unknown; however, two of these showed indirect signs of CSF leak on RC. CSF slow leaks from perineural cysts were the most common presumed etiology; and the cysts were best visualized on myelography. Conclusion RC is comparable to CT myelography but has spatial limitations and should be limited to atypical cases.
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http://dx.doi.org/10.1177/0333102416628467DOI Listing
November 2016

Malignancies with Low Fluorodeoxyglucose Uptake at PET/CT: Pitfalls and Prognostic Importance: Resident and Fellow Education Feature.

Radiographics 2016 Jan-Feb;36(1):293-4

From the Department of Radiology and Biomedical Imaging, University of California-San Francisco, 505 Parnassus Ave, San Francisco, CA 94143.

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http://dx.doi.org/10.1148/rg.2016150073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4801421PMC
October 2016

Extended Sedation With Continuous Midazolam or Dexmedetomidine Infusion for Young Children Receiving 131 I-MIBG Radiopharmaceutical Therapy for Advanced Neuroblastoma.

Pediatr Blood Cancer 2016 Mar 19;63(3):471-8. Epub 2015 Nov 19.

Department of Pediatrics, Division of Critical Care, UCSF Benioff Children's Hospital San Francisco, University of California San Francisco, California.

Background: (131) I-MIBG is increasingly used for treating neuroblastoma; however, administration requires careful adherence to radiation safety guidelines. We describe our experience using continuous sedation to facilitate safe (131) I-MIBG therapy for young children.

Procedure: Patients were included in this case series if they received continuous midazolam or dexmedetomidine infusion for sedation during (131) I-MIBG therapy from November 1, 2012, to October 1, 2014. Key outcomes included adequacy of sedation for both (131) I-MIBG infusion and the duration of radioactive isolation, as well as sedative-related toxicities. Additionally, nuclear medicine scans before and after (131) I-MIBG therapy were assessed using the Curie score. These scores were compared qualitatively between midazolam, dexmedetomidine, and control (no sedative infusion) groups.

Results: Of the 13 patients receiving continuous sedation for (131) I-MIBG therapy, seven achieved adequate sedation with midazolam, five achieved adequate sedation with dexmedetomidine, one patient (1.6 years old) failed to achieve adequate sedation with either medication and did not receive (131) I-MIBG therapy. Sedation was generally well tolerated. Common side effects for dexmedetomidine infusion included hypotension and relative bradycardia. Both treatment and control groups had multiple patients with increased Curie scores post-(131) I-MIBG therapy. However, one patient in the midazolam group and two in the dexmedetomidine group had decreased Curie scores after (131) I-MIBG therapy, while none decreased in the control group.

Conclusions: Although we cannot exclude the possibility of some inhibition of (131) I-MIBG uptake by midazolam or dexmedetomidine, this case series suggests that continuous infusions of either agent can provide effective sedation to allow safe administration of (131) I-MIBG to young patients.
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http://dx.doi.org/10.1002/pbc.25827DOI Listing
March 2016

Impact of Whole-Body Radiation Dose on Response and Toxicity in Patients With Neuroblastoma After Therapy With 131 I-Metaiodobenzylguanidine (MIBG).

Pediatr Blood Cancer 2016 Mar 27;63(3):436-42. Epub 2015 Oct 27.

Department of Pediatrics, UCSF School of Medicine and UCSF Benioff Children's Hospital, University of California San Francisco, San Francisco, California.

Background: (131) I-metaiodobenzylguanidine ((131) I-MIBG) is a targeted radiopharmaceutical for patients with neuroblastoma. Despite its tumor-specific uptake, the treatment with (131) I-MIBG results in whole-body radiation exposure. Our aim was to correlate whole-body radiation dose (WBD) from (131) I-MIBG with tumor response, toxicities, and other clinical factors.

Methods: This retrospective cohort analysis included 213 patients with high-risk neuroblastoma treated with (131) I-MIBG at UCSF Benioff Children's Hospital between 1996 and 2015. WBD was determined from radiation exposure rate measurements. The relationship between WBD ordered tertiles and variables were analyzed using Cochran-Mantel-Haenszel test of trend, Kruskal-Wallis test, and one-way analysis of variance. Correlation between WBD and continuous variables was analyzed using Pearson correlation and Spearman rank correlation.

Results: WBD correlated with (131) I-MIBG administered activity, particularly with (131) I-MIBG per kilogram (P < 0.001). Overall response rate did not differ significantly among the three tertiles of WBD. Correlation between response by relative Curie score and WBD was of borderline significance, with patients receiving a lower WBD showing greater reduction in osteomedullary metastases by Curie score (rs = 0.16, P = 0.049). There were no significant ordered trends among tertiles in any toxicity measures (grade 4 neutropenia, thrombocytopenia < 20,000/μl, and grade > 1 hypothyroidism).

Conclusions: This study showed that (131) I-MIBG activity per kilogram correlates with WBD and suggests that activity per kilogram will predict WBD in most patients. Within the range of activities prescribed, there was no correlation between WBD and either response or toxicity. Future studies should evaluate tumor dosimetry, rather than just WBD, as a tool for predicting response following therapy with (131) I-MIBG.
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http://dx.doi.org/10.1002/pbc.25816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523914PMC
March 2016

Assessing Biological Response to Bevacizumab Using 18F-Fluoromisonidazole PET/MR Imaging in a Patient with Recurrent Anaplastic Astrocytoma.

Case Rep Radiol 2015 22;2015:731361. Epub 2015 Feb 22.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, 505 Parnassus Avenue, M-391, San Francisco, CA 94143-0628, USA ; Department of Neurological Surgery, University of California, San Francisco, 505 Parnassus Avenue, Room 779 M, San Francisco, CA 94143-0112, USA.

We present our initial experience in using single modality fluoromisonidazole (FMISO) PET/MR imaging to noninvasively evaluate the biological effects induced by bevacizumab therapy in a patient treated for recurrent high grade glioma. In this index patient, bevacizumab therapy resulted in the development of nonenhancing tumor characterized by reduced diffusion and markedly decreased FMISO uptake in the setting of maintained CBF and CBV. These observations suggest that the dynamic biological interplay between tissue hypoxia and vascular normalization occurring within treated recurrent high grade glioma can be captured utilizing FMISO PET/MR imaging.
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http://dx.doi.org/10.1155/2015/731361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4352456PMC
March 2015

Phase I Study of Vorinostat as a Radiation Sensitizer with 131I-Metaiodobenzylguanidine (131I-MIBG) for Patients with Relapsed or Refractory Neuroblastoma.

Clin Cancer Res 2015 Jun 18;21(12):2715-21. Epub 2015 Feb 18.

Department of Pediatrics, University of California San Francisco, San Francisco, California.

Purpose: (131)I-metaiodobenzylguanidine (MIBG) is a radiopharmaceutical with activity in neuroblastoma. Vorinostat is a histone deacetylase inhibitor that has radiosensitizing properties. The goal of this phase I study was to determine the MTDs of vorinostat and MIBG in combination.

Experimental Design: Patients ≤ 30 years with relapsed/refractory MIBG-avid neuroblastoma were eligible. Patients received oral vorinostat (dose levels 180 and 230 mg/m(2)) daily days 1 to 14. MIBG (dose levels 8, 12, 15, and 18 mCi/kg) was given on day 3 and peripheral blood stem cells on day 17. Alternating dose escalation of vorinostat and MIBG was performed using a 3+3 design.

Results: Twenty-seven patients enrolled to six dose levels, with 23 evaluable for dose escalation. No dose-limiting toxicities (DLT) were seen in the first three dose levels. At dose level 4 (15 mCi/kg MIBG/230 mg/m(2) vorinostat), 1 of 6 patients had DLT with grade 4 hypokalemia. At dose level 5 (18 mCi/kg MIBG/230 mg/m(2) vorinostat), 2 patients had dose-limiting bleeding (one grade 3 and one grade 5). At dose level 5a (18 mCi/kg MIBG/180 mg/m(2) vorinostat), 0 of 6 patients had DLT. The most common toxicities were neutropenia and thrombocytopenia. The response rate was 12% across all dose levels and 17% at dose level 5a. Histone acetylation increased from baseline in peripheral blood mononuclear cells collected on days 3 and 12 to 14.

Conclusions: Vorinostat at 180 mg/m(2)/dose is tolerable with 18 mCi/kg MIBG. A phase II trial comparing this regimen to single-agent MIBG is ongoing.
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http://dx.doi.org/10.1158/1078-0432.CCR-14-3240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4470833PMC
June 2015

131I-metaiodobenzylguanidine with intensive chemotherapy and autologous stem cell transplantation for high-risk neuroblastoma. A new approaches to neuroblastoma therapy (NANT) phase II study.

Biol Blood Marrow Transplant 2015 Apr 30;21(4):673-81. Epub 2015 Jan 30.

Department of Pediatrics, University of California San Francisco, San Francisco, California.

(131)I-Metaiodobenzylguanidine ((131)I-MIBG) has been used as a single agent or in combination with chemotherapy for the treatment of high-risk neuroblastoma. The activity and toxicity of (131)I-MIBG when combined with carboplatin, etoposide, and melphalan (CEM) and autologous stem cell transplantation (SCT) are now investigated in a phase II multicenter study. Fifty patients with MIBG-avid disease were enrolled into 2 cohorts, stratified by response to induction therapy. The primary study endpoint was response of patients with refractory (n = 27) or progressive disease (n = 15). A second cohort of patients (n = 8) with a partial response (PR) to induction therapy was included to obtain preliminary response data. (131)I-MIBG was administered on day -21 to all patients, with CEM given days -7 to -4, and SCT given on day 0. (131)I-MIBG dosing was determined by pre-therapy glomerular filtration rate (GFR), with 8 mCi/kg given if GFR was 60 to 99 mL/minute/1.73 m(2) (n = 13) and 12 mCi/kg if GFR ≥ 100 mL/minute/1.73 m(2) (n = 37). External beam radiotherapy was delivered to the primary and metastatic sites, beginning approximately 6 weeks after SCT. Responses (complete response + PR) were seen in 4 of 41 (10%) evaluable patients with primary refractory or progressive disease. At 3 years after SCT, the event-free survival (EFS) was 20% ± 7%, with overall survival (OS) 62% ± 8% for this cohort of patients. Responses were noted in 3 of 8 (38%) of patients with a PR to induction, with 3-year EFS 38% ± 17% and OS 75% ± 15%. No statistically significant difference was found comparing EFS or OS based upon pre-therapy GFR or disease cohort. Six of 50 patients had nonhematologic dose-limiting toxicity (DLT); 1 of 13 in the low GFR and 5 of 37 in the normal GFR cohorts. Hepatic sinusoidal obstructive syndrome (SOS) was seen in 6 patients (12%), with 5 events defined as dose-limiting SOS. The median times to neutrophil and platelet engraftment were 10 and 15 days, respectively. Patients received a median 163 cGy (61 to 846 cGy) with (131)I-MIBG administration, with 2 of 3 patients receiving >500 cGy experiencing DLT. The addition of (131)I-MIBG to a myeloablative CEM regimen is tolerable and active therapy for patients with high-risk neuroblastoma.
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http://dx.doi.org/10.1016/j.bbmt.2014.12.008DOI Listing
April 2015

Bone remodeling after MR imaging-guided high-intensity focused ultrasound ablation: evaluation with MR imaging, CT, Na(18)F-PET, and histopathologic examination in a swine model.

Radiology 2015 Feb 8;274(2):387-94. Epub 2014 Oct 8.

From the Department of Radiology and Biomedical Imaging, University of California-San Francisco, 185 Berry St, Suite 350, San Francisco, CA 94107-5705.

Purpose: To serially monitor bone remodeling in the swine femur after magnetic resonance (MR) imaging-guided high-intensity focused ultrasound (HIFU) ablation with MR imaging, computed tomography (CT), sodium fluorine 18 (Na(18)F)-positron emission tomography (PET), and histopathologic examination, as a function of sonication energy.

Materials And Methods: Experimental procedures received approval from the local institutional animal care and use committee. MR imaging-guided HIFU was used to create distal and proximal ablations in the right femurs of eight pigs. The energy used at the distal target was higher (mean, 419 J; range, 390-440 J) than that used at the proximal target (mean, 324 J; range, 300-360 J). Imaging was performed before and after ablation with 3.0-T MR imaging and 64-section CT. Animals were reevaluated at 3 and 6 weeks with MR imaging (n = 8), CT (n = 8), Na(18)F-PET (n = 4), and histopathologic examination (n = 4). Three-dimensional ablation lengths were measured on contrast material-enhanced MR images, and bone remodeling in the cortex was measured on CT images.

Results: Ablation sizes at MR imaging 3 and 6 weeks after MR imaging-guided HIFU ablation were similar between proximal (low-energy) and distal (high-energy) lesions (average, 8.7 × 21.9 × 16.4 mm). However, distal ablation lesions (n = 8) demonstrated evidence of subperiosteal new bone formation at CT, with a subtle focus of new ossification at 3 weeks and a larger focus of ossification at 6 weeks. New bone formation was associated with increased uptake at Na(18)F-PET in three of four animals; this was confirmed at histopathologic examination in four of four animals.

Conclusion: MR imaging-guided HIFU ablation of bone may result in progressive remodeling, with both subcortical necrosis and subperiosteal new bone formation. This may be related to the use of high energies. MR imaging, CT, and PET are suitable noninvasive techniques to monitor bone remodeling after MR imaging-guided HIFU ablation.
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http://dx.doi.org/10.1148/radiol.14132605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4314293PMC
February 2015

Patient-specific dosimetry using pretherapy [¹²⁴I]m-iodobenzylguanidine ([¹²⁴I]mIBG) dynamic PET/CT imaging before [¹³¹I]mIBG targeted radionuclide therapy for neuroblastoma.

Mol Imaging Biol 2015 Apr;17(2):284-94

Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, 94143-0946, USA,

Purpose: Iodine-131-m-iodobenzylguanidine ([(131)I]mIBG)-targeted radionuclide therapy (TRT) is a standard treatment for recurrent or refractory neuroblastoma with response rates of 30-40 %. The aim of this study is to demonstrate patient-specific dosimetry using quantitative [(124)I]mIBG positron emission tomography/X-ray computed tomography (PET/CT) imaging with a GEometry ANd Tracking 4 (Geant4)-based Monte Carlo method for better treatment planning.

Procedures: A Monte Carlo dosimetry method was developed using the Geant4 toolkit with voxelized anatomical geometry and source distribution as input. The presegmented hybrid computational human phantoms developed by the University of Florida and the National Cancer Institute (UF/NCI) were used as a surrogate to characterize the anatomy of a given patient. S values for I-131 were estimated by the phantoms coupled with Geant4 and compared with those estimated by OLINDA|EXM and MCNPX for the newborn model. To obtain patient-specific biodistribution of [(131)I]mIBG, a 10-year-old girl with relapsed neuroblastoma was imaged with [(124)I]mIBG PET/CT at four time points prior to the planned [(131)I]mIBG TRT. The organ- and tumor-absorbed doses of the clinical case were estimated with the Geant4 method using the modified UF/NCI 10-year-old phantom with tumors and the patient-specific residence time.

Results: For the newborn model, the Geant4 S values were consistent with the MCNPX S values. The S value ratio of the Geant4 method to OLINDA|EXM ranged from 0.08 to 6.5 of all major organs. The [(131)I]mIBG residence time quantified from the pretherapy [(124)I]mIBG PET/CT imaging of the 10-year-old patient was mostly comparable to those previously reported. Organ-absorbed dose for the salivary glands was 98.0 Gy, heart wall 36.5 Gy, and liver 34.3 Gy, while tumor-absorbed dose ranged from 143.9 to 1,641.3 Gy in different sites.

Conclusions: Patient-specific dosimetry for [(131)I]mIBG TRT was accomplished using pretherapy [(124)I]mIBG PET/CT imaging and a Geant4-based Monte Carlo dosimetry method. The Geant4 method with quantitative pretherapy imaging can provide dose estimates to normal organs and tumors with more realistic simulation geometry, and thus may improve treatment planning for [(131)I]mIBG TRT.
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http://dx.doi.org/10.1007/s11307-014-0783-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336853PMC
April 2015

Likelihood of bone recurrence in prior sites of metastasis in patients with high-risk neuroblastoma.

Int J Radiat Oncol Biol Phys 2014 Jul 24;89(4):839-45. Epub 2014 May 24.

Department of Radiation Oncology, University of California at San Francisco School of Medicine and UCSF Benioff Children's Hospital, San Francisco, California. Electronic address:

Purpose/objectives: Despite recent improvements in outcomes, 40% of children with high-risk neuroblastoma will experience relapse, facing a guarded prognosis for long-term cure. Whether recurrences are at new sites or sites of original disease may guide decision making during initial therapy.

Methods And Materials: Eligible patients were retrospectively identified from institutional databases at first metastatic relapse of high-risk neuroblastoma. Included patients had disease involving metaiodobenzylguanidine (MIBG)-avid metastatic sites at diagnosis and first relapse, achieved a complete or partial response with no more than one residual MIBG-avid site before first relapse, and received no total body irradiation or therapy with (131)I-MIBG before first relapse. Anatomically defined metastatic sites were tracked from diagnosis through first relapse to determine tendency of disease to recur at previously involved versus uninvolved sites and to assess whether this pattern was influenced by site irradiation.

Results: Of 159 MIBG-avid metastatic sites identified among 43 patients at first relapse, 131 (82.4%) overlapped anatomically with the set of 525 sites present at diagnosis. This distribution was similar for bone sites, but patterns of relapse were more varied for the smaller subset of soft tissue metastases. Among all metastatic sites at diagnosis in our subsequently relapsed patient cohort, only 3 of 19 irradiated sites (15.8%) recurred as compared with 128 of 506 (25.3%) unirradiated sites.

Conclusions: Metastatic bone relapse in neuroblastoma usually occurs at anatomic sites of previous disease. Metastatic sites identified at diagnosis that did not receive radiation during frontline therapy appeared to have a higher risk of involvement at first relapse relative to previously irradiated metastatic sites. These observations support the current paradigm of irradiating metastases that persist after induction chemotherapy in high-risk patients. Furthermore, they raise the hypothesis that metastatic sites appearing to clear with induction chemotherapy may also benefit from radiotherapeutic treatment modalities (external beam radiation or (131)I-MIBG).
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http://dx.doi.org/10.1016/j.ijrobp.2014.04.004DOI Listing
July 2014

90Y glass microspheres for the treatment of unresectable metastatic liver disease from chemotherapy-refractory gastrointestinal cancers: a pilot study.

J Gastrointest Cancer 2014 Jun;45(2):168-80

Department of Radiology, University of California San Francisco, 505 Parnassus Avenue, Room M-361, San Francisco, CA, 94143, USA,

Purpose: This prospective pilot single-institution study was undertaken to document the feasibility, safety, and efficacy of treatment of liver-dominant metastatic gastrointestinal cancer using (90)Y glass microspheres.

Methods: Between June 2010 and November 2012, 30 adult patients (22 men, eight women; median age 61 years) with metastatic chemotherapy-refractory unresectable colorectal (n = 15), neuroendocrine (n = 9), intrahepatic cholangiocarcinoma (n = 3), pancreas (n = 2), and esophageal (n = 1) carcinomas underwent 45 lobar or segmental administrations of (90)Y glass microspheres. Data regarding clinical and laboratory adverse events (AE) were collected prospectively for 6 months after each treatment. Radiographic responses were evaluated using Response Evaluation Criteria in Solid Tumors, version 1.1. Time to maximum response, response duration, progression-free survival (hepatic and extrahepatic), and overall survival were measured.

Results: Median target dose and activity were 111.6 Gy and 2.5 GBq per treatment session, respectively. All but three clinical AE were grade 1 or 2 in severity. Serious AE included an unplanned hospital admission for carcinoid crisis, grade 3 vomiting, and grade 4 gastric ulcer. Patients with colorectal cancer had hepatic objective response rate (ORR) of 27 % and a disease control rate (DCR) of 73 %. Median progression-free and overall survival were 1.0 and 4.9 months, respectively. Patients with neuroendocrine tumors had hepatic ORR and DCR of 78 % and 100 %, respectively. Median progression-free survival was 18.5 months for this cohort.

Conclusions: Y glass microspheres device has a favorable safety profile and achieved prolonged disease control of hepatic tumor burden in a subset of patients, including all patients enrolled in the neuroendocrine cohort.
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http://dx.doi.org/10.1007/s12029-013-9566-7DOI Listing
June 2014

Triple-negative and non-triple-negative invasive breast cancer: association between MR and fluorine 18 fluorodeoxyglucose PET imaging.

Radiology 2013 Nov 22;269(2):354-61. Epub 2013 Jul 22.

Departments of Radiology and Biomedical Imaging, University of California, San Francisco, 1600 Divisadero St, C250, San Francisco, CA 94115.

Purpose: To assess the relationship between parameters measured on dynamic contrast material-enhanced (DCE) magnetic resonance (MR) imaging and fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) in primary invasive breast cancer.

Materials And Methods: This HIPAA-compliant study was a retrospective review of medical records and therefore approved by the institutional review board without the requirement for informed consent. Patients with a diagnosis of invasive breast cancer from January 2005 through December 2009 who underwent both DCE MR imaging and FDG PET/CT before treatment initiation were retrospectively identified. Fractional volumes were measured for ranges of signal enhancement ratio (SER) values from DCE MR imaging data and compared with maximum standardized uptake values (SUVmax) from FDG PET/CT data. Linear regression analysis was performed to clarify the relationship between SER and SUVmax, adjusting for tumor size, pathologic grade, and receptor status.

Results: Analyzed were 117 invasive breast cancers in 117 patients. Overall, a higher percentage of high washout kinetics was positively associated with SUVmax (1.57% increase in SUVmax per 1% increase in high washout; P = .020), and a higher percentage of low plateau kinetics was negatively associated with SUVmax (1.19% decrease in SUVmax per 1% increase in low plateau; P = .003). These relationships were strongest among triple-negative (TN) tumors (4.34% increase in SUVmax per 1% increase in high washout and 2.65% decrease in SUVmax per 1% increase in low plateau; P = .018 and .004, respectively).

Conclusion: In invasive breast carcinoma, there is a positive relationship between the percentage of high washout and SUVmax and a negative relationship between the percentage of low plateau and SUVmax. These results are stronger in TN tumors.

Supplemental Material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13130058/-/DC1.
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http://dx.doi.org/10.1148/radiol.13130058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3807081PMC
November 2013

Acute changes in blood pressure in patients with neuroblastoma treated with ¹³¹I-metaiodobenzylguanidine (MIBG).

Pediatr Blood Cancer 2013 Sep 23;60(9):1424-30. Epub 2013 Apr 23.

Department of Pediatrics, University of California, San Francisco School of Medicine, San Francisco, California 94143-0106, USA.

Background: Iodine-131-metaiodobenzylguanidine ((131)I-MIBG) provides targeted radiotherapy for children with neuroblastoma. The aim of our study was to evaluate systematically the acute effects of (131)I-MIBG on blood pressure in patients with neuroblastoma and to identify possible predictors of hypertension.

Procedure: We conducted a retrospective chart review of neuroblastoma patients who were treated with (131)I-MIBG between January 1, 1999 and June 1, 2012 at the University of California, San Francisco. Clinical data for 172 patients with neuroblastoma, receiving 218 administrations of (131)I-MIBG, were collected. The primary endpoint was development of systolic blood pressure above the 95th percentile for age. Logistic regression with generalized estimating equations to account for multiple administrations in some subjects was used to identify bivariate and multivariate predictors of hypertension.

Results: Of the 218 administrations of (131)I-MIBG, 112 (51.3%) were associated with at least one episode of systolic hypertension during or after the (131)I-MIBG infusion. The majority of these acute elevations in blood pressure resolved within 48 hours of the infusion. Only six administrations in five patients required nifedipine administration to lower blood pressure. Younger age (P = 0.012), lower eGFR (P = 0.047), and elevated blood pressure measurements immediately before infusion began (P = 0.010) were all independently associated with risk of treatment-associated hypertension.

Conclusions: Acute elevations in blood pressure are common after therapeutic doses of (131) I-MIBG. Elevations in blood pressure typically occur only within the first 48 hours after (131)I-MIBG administration. Blood pressure monitoring during this period of risk is recommended.
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http://dx.doi.org/10.1002/pbc.24551DOI Listing
September 2013

131I-MIBG followed by consolidation with busulfan, melphalan and autologous stem cell transplantation for refractory neuroblastoma.

Pediatr Blood Cancer 2013 May 28;60(5):879-84. Epub 2012 Sep 28.

Department of Pediatrics, University of California, San Francisco School of Medicine, San Francisco, California 94143, USA.

Background: (131) I-metaiodobenzylguanidine (MIBG) produces a 37% response rate in relapsed/refractory neuroblastoma, and could be used to improve remission status prior to myeloablative chemotherapy with autologous stem cell transplant (ASCT). The purpose of our report was to evaluate safety and response with MIBG therapy followed by myeloablative busulfan and melphalan (BuMel) with ASCT in patients with refractory neuroblastoma.

Methods: Retrospective chart review was done on patients treated with MIBG (18 mCi/kg) on Day 1 and ASCT on day 14. Six to eight weeks after MIBG, patients without progressive disease received IV busulfan on days -6 to -2 (target Css 700-900), melphalan (140 mg/m2 IV) on day -1, and ASCT on Day 0. Response and toxicity were evaluated after MIBG and again after myeloablative therapy.

Results: Eight patients completed MIBG/ASCT followed by BuMel/ASCT. MIBG was well tolerated, with grade 3 or 4 non-hematologic toxicity limited to one patient with sepsis. Grade 3 mucositis occurred in six patients after BuMel/ASCT. One patient developed sinusoidal obstructive syndrome (SOS) and died 50 days post-ASCT following myeloablative conditioning. All patients engrafted neutrophils (median 16.5 days) and platelets (median 32 days) after BuMel, excluding the patient with SOS. After all therapy, there were three complete, two partial, and one minor response in seven evaluable patients.

Conclusions: MIBG at doses up to 18 mCi/kg can be safely administered 6 weeks prior to a BuMel consolidative regimen for refractory neuroblastoma. Preceding MIBG did not impair engraftment following BuMel. This regimen is being further evaluated in a Children's Oncology Group (COG) trial.
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http://dx.doi.org/10.1002/pbc.24351DOI Listing
May 2013