Publications by authors named "Jerry Froelich"

33 Publications

First Multimodal, Three-Dimensional, Image-Guided Total Marrow Irradiation Model for Preclinical Bone Marrow Transplantation Studies.

Int J Radiat Oncol Biol Phys 2021 Jun 11. Epub 2021 Jun 11.

Department of Radiation Oncology, City of Hope Medical Center, Duarte, California; Beckman Research Institute of City of Hope, Duarte, California; Department of Radiation Oncology, University of Minnesota, Minneapolis, Minnesota. Electronic address:

Purpose: Total marrow irradiation (TMI) has significantly advanced radiation conditioning for hematopoietic cell transplantation in hematologic malignancies by reducing conditioning-induced toxicities and improving survival outcomes in relapsed/refractory patients. However, the relapse rate remains high, and the lack of a preclinical TMI model has hindered scientific advancements. To accelerate TMI translation to the clinic, we developed a TMI delivery system in preclinical models.

Methods And Materials: A Precision X-RAD SmART irradiator was used for TMI model development. Images acquired with whole-body contrast-enhanced computed tomography (CT) were used to reconstruct and delineate targets and vital organs for each mouse. Multiple beam and CT-guided Monte Carlo-based plans were performed to optimize doses to the targets and to vary doses to the vital organs. Long-term engraftment and reconstitution potential were evaluated by a congenic bone marrow transplantation (BMT) model and serial secondary BMT, respectively. Donor cell engraftment was measured using noninvasive bioluminescence imaging and flow cytometry.

Results: Multimodal imaging enabled identification of targets (skeleton and spleen) and vital organs (eg, lungs, gut, liver). In contrast to total body irradiation (TBI), TMI treatment allowed variation of radiation dose exposure to organs relative to the target dose. Dose reduction mirrored that in clinical TMI studies. Similar to TBI, mice treated with different TMI regimens showed full long-term donor engraftment in primary BMT and second serial BMT. The TBI-treated mice showed acute gut damage, which was minimized in mice treated with TMI.

Conclusions: A novel multimodal image guided preclinical TMI model is reported here. TMI conditioning maintained long-term engraftment with reconstitution potential and reduced organ damage. Therefore, this TMI model provides a unique opportunity to study the therapeutic benefit of reduced organ damage and BM dose escalation to optimize treatment regimens in BMT and hematologic malignancies.
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http://dx.doi.org/10.1016/j.ijrobp.2021.06.001DOI Listing
June 2021

A bicentric retrospective analysis of clinical utility of F-fluciclovine PET in biochemically recurrent prostate cancer following primary radiation therapy: is it helpful in patients with a PSA rise less than the Phoenix criteria?

Eur J Nucl Med Mol Imaging 2021 Jun 6. Epub 2021 Jun 6.

Department of Radiology, University of Minnesota, Minneapolis, MN, USA.

Purpose: F-Fluciclovine PET imaging has been increasingly used in the restaging of prostate cancer patients with biochemical recurrence (BCR); however, its clinical utility in patients with low prostate-specific antigen (PSA) levels following primary radiation therapy has not been well-studied. This study aims to determine the detection rate and diagnostic accuracy of F-fluciclovine PET and the patterns of prostate cancer recurrence in patients with rising PSA after initial radiation therapy, particularly in patients with PSA levels below the accepted Phoenix definition of BCR (PSA nadir +2 ng/mL).

Methods: This retrospective study included patients from two tertiary institutions who underwent F-fluciclovine PET scans for elevated PSA level following initial external beam radiation therapy, brachytherapy, and/or proton therapy. Logistic regression and receiver operating characteristic (ROC) curve analyses were performed to determine the diagnostic accuracy of F-fluciclovine PET and associations of PSA kinetic parameters with F-fluciclovine PET outcome.

Results: One hundred patients were included in this study. The overall detection rate on a patient-level was 79% (79/100). F-Fluciclovine PET was positive in 62% (23/37) of cases with PSA below the Phoenix criteria. The positive predictive value of F-fluciclovine PET was 89% (95% CI: 80-94%). In patients with PSA below the Phoenix criteria, the PSA velocity had the highest predictive value of F-fluciclovine PET outcome. PSA doubling time (PSADT) and PSA velocity were associated with the presence of extra-pelvic metastatic disease.

Conclusion: F-Fluciclovine PET can identify recurrent disease at low PSA level and PSA rise below accepted Phoenix criteria in patients with suspected BCR after primary radiation therapy, particularly in patients with low PSADT or high PSA velocity. In patients with low PSADT or high PSA velocity, there is an increased probability of extra-pelvic metastases. Therefore, these patients are more likely to benefit from PET/CT or PET/MRI than pelvic MRI alone.
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http://dx.doi.org/10.1007/s00259-021-05415-yDOI Listing
June 2021

COMPARISON OF THE EFFECT OF THREE DIFFERENT DIETARY MODIFICATIONS ON MYOCARDIAL SUPPRESSION IN F-FDG PET/CT EVALUATION OF PATIENTS FOR SUSPECTED CARDIAC SARCOIDOSIS.

J Nucl Med 2021 Mar 26. Epub 2021 Mar 26.

University of Minnesota, United States.

A definitive dietary preparation recommendation is not possible based on literature in achievement of myocardial suppression for diagnosis of cardiac sarcoidosis (CS) with F-FDG PET/CT. Our goal is to compare three different dietary preparations in achievement of the best myocardial suppression and CS diagnosis. We retrospectively reviewed and compared three dietary preparations used at our institution. Three different diets were applied from 03/2014 to 12/2019. 24-h ketogenic diet with overnight fasting ( = 94); 18h-fasting ( = 44); 72-h daytime ketogenic diet with 3-day overnight fasting ( = 98). The interpretation of initial reports was recorded, and an independent radiologist (observer) retrospectively re-evaluated each case regarding CS diagnosis (Negative, Positive, Indeterminant) and myocardial suppression (Complete, Failed, Partial). Interobserver agreement was analyzed. We measured MaxSUV from bloodpool, liver, and the most suppressed normal myocardium. We identified superior myocardial suppression with the 72-h preparation indicated by a higher bloodpool/myocardium and liver/myocardium ratios (P<0.001). Myocardial suppression rates for 72-h ketogenic diet, 24-h ketogenic diet and 18-h fasting preparations are as follows; Complete myocardial suppression: 96.9%/68.1%/52.3%, Failed myocardial suppression: 0%/23.4%/25%, Partial myocardial suppression: 3.1%/8.5%/22.7%) (P<0.001). The 72-hour preparation had significantly fewer "indeterminant" and "positive" exams. CS diagnosis rates for 72-h ketogenic diet, 24-h ketogenic diet and 18-h fasting preparations are as follows; Negative: 82.7%/52.1%/27.3%, Indeterminant: 2.0%/24.5%/40.9%, Positive: 15.3%/23.4%/31.8% (P<0.001). High agreement was present with the observer and the report (κ=0.88) A 72-h daytime ketogenic diet with 3-day overnight fasting, achieved substantially superior myocardial suppression versus 24-h ketogenic diet with overnight fasting and 18h-fasting using F-FDG PET/CT. This 72-h preparation results in significantly fewer "indeterminant" and potentially "false positive" CS results.
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http://dx.doi.org/10.2967/jnumed.121.261981DOI Listing
March 2021

Biophysical Characterization of the Leukemic Bone Marrow Vasculature Reveals Benefits of Neoadjuvant Low-Dose Radiation Therapy.

Int J Radiat Oncol Biol Phys 2021 01 22;109(1):60-72. Epub 2020 Aug 22.

Department of Radiation Oncology, City of Hope, Duarte, California; Beckman Research Institute of City of Hope, Duarte, California. Electronic address:

Purpose: Although vascular alterations in solid tumor malignancies are known to decrease therapeutic delivery, the effects of leukemia-induced bone marrow vasculature (BMV) alterations on therapeutic delivery are not well known. Additionally, functional quantitative measurements of the leukemic BMV during chemotherapy and radiation therapy are limited, largely due to a lack of high-resolution imaging techniques available preclinically. This study develops a murine model using compartmental modeling for quantitative multiphoton microscopy (QMPM) to characterize the malignant BMV before and during treatment.

Methods And Materials: Using QMPM, live time-lapsed images of dextran leakage from the local BMV to the surrounding bone marrow of mice bearing acute lymphoblastic leukemia (ALL) were taken and fit to a 2-compartment model to measure the transfer rate (K), fractional extracellular extravascular space (ν), and vascular permeability parameters, as well as functional single-vessel characteristics. In response to leukemia-induced BMV alterations, the effects of 2 to 4 Gy low-dose radiation therapy (LDRT) on the BMV, drug delivery, and mouse survival were assessed post-treatment to determine whether neoadjuvant LDRT before chemotherapy improves treatment outcome.

Results: Mice bearing ALL had significantly altered K, increased ν, and increased permeability compared with healthy mice. Angiogenesis, decreased single-vessel perfusion, and decreased vessel diameter were observed. BMV alterations resulted in disease-dependent reductions in cellular uptake of Hoechst dye. LDRT to mice bearing ALL dilated BMV, increased single-vessel perfusion, and increased daunorubicin uptake by ALL cells. Consequently, LDRT administered to mice before receiving nilotinib significantly increased survival compared with mice receiving LDRT after nilotinib, demonstrating the importance of LDRT conditioning before therapeutic administration.

Conclusion: The developed QMPM enables single-platform assessments of the pharmacokinetics of fluorescent agents and characterization of the BMV. Initial results suggest BMV alterations after neoadjuvant LDRT may contribute to enhanced drug delivery and increased treatment efficacy for ALL. The developed QMPM enables observations of the BMV for use in ALL treatment optimization.
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http://dx.doi.org/10.1016/j.ijrobp.2020.08.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736317PMC
January 2021

Automated in vivo Assessment of Vascular Response to Radiation using a Hybrid Theranostic X-ray Irradiator/Fluorescence Molecular Imaging System.

IEEE Access 2020 15;8:93663-93670. Epub 2020 May 15.

Department of Radiation Oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010 USA.

Hypofractionated stereotactic body radiotherapy treatments (SBRT) have demonstrated impressive results for the treatment of a variety of solid tumors. The role of tumor supporting vasculature damage in treatment outcome for SBRT has been intensely debated and studied. Fast, non-invasive, longitudinal assessments of tumor vasculature would allow for thorough investigations of vascular changes correlated with SBRT treatment response. In this paper, we present a novel theranostic system which incorporates a fluorescence molecular imager into a commercial, preclinical, microCT-guided, irradiator and was designed to quantify tumor vascular response (TVR) to targeted radiotherapy. This system overcomes the limitations of single-timepoint imaging modalities by longitudinally assessing spatiotemporal differences in intravenously-injected ICG kinetics in tumors before and after high-dose radiation. Changes in ICG kinetics were rapidly quantified by principle component (PC) analysis before and two days after 10 Gy targeted tumor irradiation. A classifier algorithm based on PC data clustering identified pixels with TVR. Results show that two days after treatment, a significant delay in ICG clearance as measured by exponential decay (40.5±16.1% P=0.0405 Paired t-test n=4) was observed. Changes in the mean normalized first and second PC feature pixel values (PC1 & PC2) were found (P=0.0559, 0.0432 paired t-test), suggesting PC based analysis accurately detects changes in ICG kinetics. The PC based classification algorithm yielded spatially-resolved TVR maps. Our first-of-its-kind theranostic system, allowing automated assessment of TVR to SBRT, will be used to better understand the role of tumor perfusion in metastasis and local control.
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http://dx.doi.org/10.1109/access.2020.2994943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295127PMC
May 2020

Changing Insulinoma Management Due to Incidentally Discovered Metastasis: A Case Report.

Am J Case Rep 2020 Jun 14;21:e923356. Epub 2020 Jun 14.

Department of Diabetes, Endocrinology and Metabolism, University of Minnesota Medical Center, Minneapolis, MN, USA.

BACKGROUND Hypoglycemia is rare in individuals without drug-treated diabetes mellitus. In a seemingly well individual, the differential diagnosis of hypoglycemia narrows to 2 major categories: 1) accidental, surreptitious, or intentional hypoglycemia, or 2) endogenous hyperinsulinism (EHH). Insulinomas are the most common cause of EHH. Localization of insulinomas can be challenging, as most tumors are less than 2 cm in size and may be present in any part of the pancreas. In fact, almost 30% of neuroendocrine tumors (NET) cannot be located preoperatively by traditional imaging techniques such as computerized tomography (CT) or magnetic resonance imaging (MRI). CASE REPORT This report describes a case of metastatic insulinoma in a patient with a complex medical history. CT with contrast of the abdomen identified 1 lesion located in the pancreas body. Endoscopic ultrasound (EUS) identified an additional 3 to 4 hypoechoic lesions in the pancreatic neck and body. 68-Gallium Dotatate scanning identified 3 distinct lesions within the pancreas and a right posterior rib sclerotic lesion. CONCLUSIONS Reliance upon traditional imaging techniques (CT/MRI) for tumor localization would not have identified the multifocal pancreatic lesions and the metastatic bone lesion. Accurate identification of multifocal, metastatic insulinomas requires multiple imaging modalities, including first-line non-invasive imaging (CT or MRI) followed by second-line imaging (EUS or nuclear imaging).
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http://dx.doi.org/10.12659/AJCR.923356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310576PMC
June 2020

Solitary Penile Metastasis of Prostate Cancer on 18F-Fluciclovine PET/CT Imaging in a Patient With PSA of 1 ng/mL.

Clin Nucl Med 2020 May;45(5):389-391

From the Department of Radiology, University of Minnesota, Minneapolis, MN.

An 85-year-old asymptomatic man with suspected biochemical recurrence of prostate cancer underwent an F-fluciclovine PET/CT scan, which revealed a solitary suspicious tracer uptake in the dorsal right corporal body of the proximal pendulous penis. The patient underwent ultrasound-guided fine-needle aspiration of the penile lesion, which revealed metastatic prostate cancer. The patient had definitive external beam radiation therapy 3 years before the examination. At the time of scan, the prostatic-specific antigen (PSA) was only 1.0 ng/mL, although the PSA doubling time was 2.6 months. It is unusual to detect a solitary penile metastasis in a patient with a low level of PSA.
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http://dx.doi.org/10.1097/RLU.0000000000002987DOI Listing
May 2020

Artificial Intelligence in PET/CT Is about to Make Whole-Body Tumor Burden Measurements a Clinical Reality.

Radiology 2020 Feb 10;294(2):453-454. Epub 2019 Dec 10.

From the Department of Radiology, University of Minnesota, 420 Delaware St SE, Mayo Bldg, MMC 292, Minneapolis, MN 55455.

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http://dx.doi.org/10.1148/radiol.2019192425DOI Listing
February 2020

Safety Considerations of 7-T MRI in Clinical Practice.

Radiology 2019 09 16;292(3):509-518. Epub 2019 Jul 16.

From the Department of Radiology, University of Washington, 1959 NE Pacific St, Seattle, WA 98195-7117 (M.N.H.); Department of Radiology, University of Minnesota, Minneapolis, Minn (A.M., J.F.); Department of Clinical Physical Therapy, University of Southern California, Los Angeles, Calif (F.G.S.); Department of Radiology, University of Utah Health Sciences Center, Salt Lake City, Utah (U.R.); RADIOLOGY-Planning, Kansas City, Mo (T.G.); Department of Radiology, Mayo Clinic, Rochester, Minn (R.E.W.); G3 Global Group, Boulder, Colo, Mo (T.D.G.); and Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pa (E.K.).

Although 7-T MRI has recently received approval for use in clinical patient care, there are distinct safety issues associated with this relatively high magnetic field. Forces on metallic implants and radiofrequency power deposition and heating are safety considerations at 7 T. Patient bioeffects such as vertigo, dizziness, false feelings of motion, nausea, nystagmus, magnetophosphenes, and electrogustatory effects are more common and potentially more pronounced at 7 T than at lower field strengths. Herein the authors review safety issues associated with 7-T MRI. The rationale for safety concerns at this field strength are discussed as well as potential approaches to mitigate risk to patients and health care professionals.
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http://dx.doi.org/10.1148/radiol.2019182742DOI Listing
September 2019

An unusual altered biodistribution of F-FDG on PET/CT: diffuse perimuscular uptake in the setting of acute adrenal crisis.

Eur J Nucl Med Mol Imaging 2019 Apr 7;46(4):1037-1038. Epub 2019 Jan 7.

Department of Radiology, Nuclear Medicine Section, University of Minnesota, Minneapolis, MN, USA.

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http://dx.doi.org/10.1007/s00259-018-4247-1DOI Listing
April 2019

FDG-PET/CT for Assessing the Response to Neoadjuvant Chemotherapy in Bladder Cancer Patients.

Clin Genitourin Cancer 2018 10 31;16(5):360-364. Epub 2018 May 31.

Department of Urology, University of Minnesota, Minneapolis, MN.

Purpose: To determine the accuracy of F-fluorodeoxyglucose with positron emission tomography and computed tomography (FDG-PET/CT) scans in assessing the response to neoadjuvant chemotherapy (NAC) in patients with bladder cancer scheduled to undergo radical cystectomy (RC).

Patients And Methods: All patients treated at our center for muscle-invasive bladder cancer (MIBC) were counseled and offered NAC before RC. FDG-PET/CT scans were performed before the initiation of chemotherapy and after completion of the regimen. Patients with disease with complete response to NAC were those who had (pT0) or residual carcinoma-in-situ (pTis) on final pathology. Those who were downstaged from MIBC to non-MIBC were considered to have a chemosensitive tumor. We used percentage reduction in standardized maximum uptake value (SUV) from PET/CT scans as our measure to correlate with the final pathology after cystectomy.

Results: Thirty-seven patients with MIBC who underwent NAC followed by RC were included in the final analysis. FDG-PET/CT had 75% sensitivity (89.66% specificity) in identifying those with complete pathologic response with a 100% change in SUV, and 83% sensitivity (94% specificity) for the detection of chemosensitive tumors.

Conclusion: FDG-PET/CT can help determine the response of primary tumor to NAC in patients with MIBC and thus can more accurately predict the prognosis of the patients, or potentially the appropriate time for cystectomy.
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http://dx.doi.org/10.1016/j.clgc.2018.05.008DOI Listing
October 2018

Whole-Body Distribution of Leukemia and Functional Total Marrow Irradiation Based on FLT-PET and Dual-Energy CT.

Mol Imaging 2017 Jan-Dec;16:1536012117732203

2 Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.

This report describes a multimodal whole-body 3'-deoxy-3'[(18)F]-fluorothymidine positron emission tomography (FLT-PET) and dual-energy computed tomography (DECT) method to identify leukemia distribution within the bone marrow environment (BME) and to develop disease- and/or BME-specific radiation strategies. A control participant and a newly diagnosed patient with acute myeloid leukemia prior to induction chemotherapy were scanned with FLT-PET and DECT. The red marrow (RM) and yellow marrow (YM) of the BME were segmented from DECT using a basis material decomposition method. Functional total marrow irradiation (fTMI) treatment planning simulations were performed combining FLT-PET and DECT imaging to differentially target irradiation to the leukemia niche and the rest of the skeleton. Leukemia colonized both RM and YM regions, adheres to the cortical bone in the spine, and has enhanced activity in the proximal/distal femur, suggesting a potential association of leukemia with the BME. The planning target volume was reduced significantly in fTMI compared with conventional TMI. The dose to active disease (standardized uptake value >4) was increased by 2-fold, while maintaining doses to critical organs similar to those in conventional TMI. In conclusion, a hybrid system of functional-anatomical-physiological imaging can identify the spatial distribution of leukemia and will be useful to both help understand the leukemia niche and develop targeted radiation strategies.
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http://dx.doi.org/10.1177/1536012117732203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5624344PMC
July 2018

Positron Emission Tomography-Based Assessment of Metabolic Tumor Volume Predicts Survival after Autologous Hematopoietic Cell Transplantation for Hodgkin Lymphoma.

Biol Blood Marrow Transplant 2018 01 20;24(1):64-70. Epub 2017 Sep 20.

Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota. Electronic address:

Autologous hematopoietic cell transplantation (AHCT) is curative for 60% of patients with relapsed or refractory Hodgkin lymphoma (R/R HL). A more precise assessment of the depth of remission before AHCT may help to identify patients likely to benefit from AHCT. We aimed to determine whether positron emission tomography (PET)-based quantitative parameters of total metabolic tumor volume (TMTV), total lesion glycolysis (TLG), and maximal standardized uptake volume (SUV) measured before AHCT predict progression-free survival (PFS) after transplant. Pretransplant PET/computed tomography images of 96 consecutive patients with R/R HL were analyzed. Median TMTV, TLG, and SUV were 7.97 cm (range, 1.3 to 102.1), 23.7 (range, 4.0 to 813.1), and 5.23 (range, 2.7 to 23.2). Two-year PFS in patients with high TMTV (TMTVhigh; more than median; n = 17) was only 12% (95% CI, 1% to 38%) compared with 53% (95% CI, 28% to 73%; P = .05) in patients with TMTVlow (lower or equal to median; n = 17) and 63% (95% CI, 50% to 74%) in 61 patients with no metabolically active tumor (TMTV0; P > .01). In concordance, high TLG (>19) and SUV (>4.9) predicted inferior 2-year PFS. In multivariate analysis patients with TMTVhigh had a 3.5-fold higher risk of treatment failure compared with TMTV0/TMTVlow (HR, 3.49; 95% CI, 1.75 to 6.93; P < .01). Deauville (D)-scores of 4 to 5 before AHCT predicted worse PFS compared with D-scores of 1 to 3 (HR, 3.7; 95% CI, 1.92 to 7.28; P < .01). Yet, TMTV and D-scores were disconcordant in 12 subjects; 9 patients in the D4 group with TMTVlow had 2-year PFS of 44% (95% CI, 14% to 72%), which was 2-fold higher than predicted by D4 score. In conclusion, in patients with R/R HL and PET-positive residual disease, TMTVhigh can identify very poor AHCT responders. Patients with TMTVlow, TLG, and SUV before AHCT have similar outcomes to those without metabolically active disease.
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http://dx.doi.org/10.1016/j.bbmt.2017.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6431258PMC
January 2018

Evaluation of 18-F-fluoro-2-deoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) as a staging and monitoring tool for dogs with stage-2 splenic hemangiosarcoma - A pilot study.

PLoS One 2017 21;12(2):e0172651. Epub 2017 Feb 21.

Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, United States of America.

Positron Emission Tomography-Computed Tomography (PET-CT) is routinely used for staging and monitoring of human cancer patients and is becoming increasingly available in veterinary medicine. In this study, 18-fluorodeoxyglucose (18FDG)-PET-CT was used in dogs with naturally occurring splenic hemangiosarcoma (HSA) to assess its utility as a staging and monitoring modality as compared to standard radiography and ultrasonography. Nine dogs with stage-2 HSA underwent 18FDG-PET-CT following splenectomy and prior to commencement of chemotherapy. Routine staging (thoracic radiography and abdominal ultrasonography) was performed prior to 18FDG-PET-CT in all dogs. When abnormalities not identified on routine tests were noted on 18FDG-PET-CT, owners were given the option to repeat a PET-CT following treatment with eBAT. A PET-CT scan was repeated on Day 21 in three dogs. Abnormalities not observed on conventional staging tools, and most consistent with malignant disease based on location, appearance, and outcome, were detected in two dogs and included a right atrial mass and a hepatic nodule, respectively. These lesions were larger and had higher metabolic activity on the second scans. 18FDG-PET-CT has potential to provide important prognostic information and influence treatment recommendations for dogs with stage-2 HSA. Additional studies will be needed to precisely define the value of this imaging tool for staging and therapy monitoring in dogs with this and other cancers.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0172651PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5319762PMC
August 2017

Safe and Effective Sarcoma Therapy through Bispecific Targeting of EGFR and uPAR.

Mol Cancer Ther 2017 05 13;16(5):956-965. Epub 2017 Feb 13.

Animal Cancer Care and Research (ACCR) Program, University of Minnesota, St. Paul, Minnesota.

Sarcomas differ from carcinomas in their mesenchymal origin. Therapeutic advancements have come slowly, so alternative drugs and models are urgently needed. These studies report a new drug for sarcomas that simultaneously targets both tumor and tumor neovasculature. eBAT is a bispecific angiotoxin consisting of truncated, deimmunized exotoxin fused to EGF and the amino terminal fragment of urokinase. Here, we study the drug in an "ontarget" companion dog trial as eBAT effectively kills canine hemangiosarcoma and human sarcoma cells We reasoned the model has value due to the common occurrence of spontaneous sarcomas in dogs and a limited lifespan allowing for rapid accrual and data collection. Splenectomized dogs with minimal residual disease were given one cycle of eBAT followed by adjuvant doxorubicin in an adaptive dose-finding, phase I-II study of 23 dogs with spontaneous, stage I-II, splenic hemangiosarcoma. eBAT improved 6-month survival from <40% in a comparison population to approximately 70% in dogs treated at a biologically active dose (50 μg/kg). Six dogs were long-term survivors, living >450 days. eBAT abated expected toxicity associated with EGFR targeting, a finding supported by mouse studies. Urokinase plasminogen activator receptor and EGFR are targets for human sarcomas, so thorough evaluation is crucial for validation of the dog model. Thus, we validated these markers for human sarcoma targeting in the study of 212 human and 97 canine sarcoma samples. Our results support further translation of eBAT for human patients with sarcomas and perhaps other EGFR-expressing malignancies. .
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http://dx.doi.org/10.1158/1535-7163.MCT-16-0637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418099PMC
May 2017

Use of dual-energy computed tomography to measure skeletal-wide marrow composition and cancellous bone mineral density.

J Bone Miner Metab 2017 Jul 9;35(4):428-436. Epub 2016 Dec 9.

Department of Radiation Oncology, University of Minnesota, Minneapolis, MN, USA.

Temporal and spatial variations in bone marrow adipose tissue (MAT) can be indicative of several pathologies and confound current methods of assessing immediate changes in bone mineral remodeling. We present a novel dual-energy computed tomography (DECT) method to monitor MAT and marrow-corrected volumetric BMD (mcvBMD) throughout the body. Twenty-three cancellous skeletal sites in 20 adult female cadavers aged 40-80 years old were measured using DECT (80 and 140 kVp). vBMD was simultaneous recorded using QCT. MAT was further sampled using MRI. Thirteen lumbar vertebrae were then excised from the MRI-imaged donors and examined by microCT. After MAT correction throughout the skeleton, significant differences (p < 0.05) were found between QCT-derived vBMD and DECT-derived mcvBMD results. McvBMD was highly heterogeneous with a maximum at the posterior skull and minimum in the proximal humerus (574 and 0.7 mg/cc, respectively). BV/TV and BMC have a nearly significant correlation with mcvBMD (r = 0.545, p = 0.057 and r = 0.539, p = 0.061, respectively). MAT assessed by DECT showed a significant correlation with MRI MAT results (r = 0.881, p < 0.0001). Both DECT- and MRI-derived MAT had a significant influence on uncorrected vBMD (r = -0.86 and r = -0.818, p ≤ 0.0001, respectively). Conversely, mcvBMD had no correlation with DECT- or MRI-derived MAT (r = 0.261 and r = 0.067). DECT can be used to assess MAT while simultaneously collecting mcvBMD values at each skeletal site. MAT is heterogeneous throughout the skeleton, highly variable, and should be accounted for in longitudinal mcvBMD studies. McvBMD accurately reflects the calcified tissue in cancellous bone.
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http://dx.doi.org/10.1007/s00774-016-0796-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5689468PMC
July 2017

Evaluation of Functional Marrow Irradiation Based on Skeletal Marrow Composition Obtained Using Dual-Energy Computed Tomography.

Int J Radiat Oncol Biol Phys 2016 11 6;96(3):679-87. Epub 2016 Jul 6.

Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota; Department of Therapeutic Radiology, University of Minnesota, Minneapolis, Minnesota; Department of Radiation Oncology, Beckman Research Institute, City of Hope, Duarte, California. Electronic address:

Purpose: To develop an imaging method to characterize and map marrow composition in the entire skeletal system, and to simulate differential targeted marrow irradiation based on marrow composition.

Methods And Materials: Whole-body dual energy computed tomography (DECT) images of cadavers and leukemia patients were acquired, segmented to separate bone marrow components, namely, bone, red marrow (RM), and yellow marrow (YM). DECT-derived marrow fat fraction was validated using histology of lumbar vertebrae obtained from cadavers. The fractions of RM (RMF = RM/total marrow) and YMF were calculated in each skeletal region to assess the correlation of marrow composition with sites and ages. Treatment planning was simulated to target irradiation differentially at a higher dose (18 Gy) to either RM or YM and a lower dose (12 Gy) to the rest of the skeleton.

Results: A significant correlation between fat fractions obtained from DECT and cadaver histology samples was observed (r=0.861, P<.0001, Pearson). The RMF decreased in the head, neck, and chest was significantly inversely correlated with age but did not show any significant age-related changes in the abdomen and pelvis regions. Conformity of radiation to targets (RM, YM) was significantly dependent on skeletal sites. The radiation exposure was significantly reduced (P<.05, t test) to organs at risk (OARs) in RM and YM irradiation compared with standard total marrow irradiation (TMI).

Conclusions: Whole-body DECT offers a new imaging technique to visualize and measure skeletal-wide marrow composition. The DECT-based treatment planning offers volumetric and site-specific precise radiation dosimetry of RM and YM, which varies with aging. Our proposed method could be used as a functional compartment of TMI for further targeted radiation to specific bone marrow environment, dose escalation, reduction of doses to OARs, or a combination of these factors.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5081224PMC
http://dx.doi.org/10.1016/j.ijrobp.2016.06.2459DOI Listing
November 2016

Longitudinal FDG-PET Revealed Regional Functional Heterogeneity of Bone Marrow, Site-Dependent Response to Treatment and Correlation with Hematological Parameters.

J Cancer 2015 15;6(6):531-7. Epub 2015 Apr 15.

1. Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA ; 4. Department of Therapeutic Radiology, Medical School, University of Minnesota, Minneapolis, MN, USA.

Purpose: The purposes of this study were: 1) to show bone marrow (BM) functional heterogeneity, 2) to demonstrate site-dependent responses of BM to cancer treatment utilizing whole body FDG-PET/CT and 3) to identify correlations between FDG uptake in different bone sites and long term complete blood count (CBC).

Methods: Thirty two patients who had pre- and post-treatment FDG-PET/CT scans were selected retrospectively. Each patient received either head and neck radiation for cancer of the tongue, or pelvic radiation for rectal or cervical cancer with chemotherapy. Patients had FDG-PET/CT performed prior to the first radiation therapy session and at least one FDG-PET/CT after completion of the prescribed radiation therapy.

Results: FDG uptake before radiotherapy was significantly different among bone regions (p < 0.01). This heterogeneity was felt to reflect site-dependent amounts of BM contents possibly due to structural and functional requirements. FDG uptake in the irradiated regions was significantly decreased on the first and second follow-ups after radiation. Feasibly, this could be due to a reduction in the number of active BM cells following intensive radiation in addition to concurrent chemotherapy. Overall, CBC significantly decreased after treatment. Correlation values of each hematological parameter with FDG uptake varied among skeletal regions and scan time points. FDG uptake in sacrum and lumbar regions had better correlation with white blood cells and neutrophils.

Conclusions: Longitudinal FDG-PET revealed a regional functional heterogeneity of the BM site-dependent response to treatment. Patients experienced immediate and prolonged marrow metabolic damage that correlates with hematological parameters. FDG-PET/CT may provide additional capabilities to assess BM health.
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http://dx.doi.org/10.7150/jca.11348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4439938PMC
May 2015

A phase I feasibility study of multi-modality imaging assessing rapid expansion of marrow fat and decreased bone mineral density in cancer patients.

Bone 2015 Apr 20;73:90-7. Epub 2014 Dec 20.

Masonic Cancer Center, University of Minnesota, MN, USA; Department of Medicine, University of Minnesota, MN, USA.

Purpose: Cancer survivors are at an increased risk for fractures, but lack of effective and economical biomarkers limits quantitative assessments of marrow fat (MF), bone mineral density (BMD) and their relation in response to cytotoxic cancer treatment. We report dual energy CT (DECT) imaging, commonly used for cancer diagnosis, treatment and surveillance, as a novel biomarker of MF and BMD.

Methods: We validated DECT in pre-clinical and phase I clinical trials and verified with water-fat MRI (WF-MRI), quantitative CT (QCT) and dual-energy X-ray absorptiometry (DXA). Basis material composition framework was validated using water and small-chain alcohols simulating different components of bone marrow. Histologic validation was achieved by measuring percent adipocyte in the cadaver vertebrae and compared with DECT and WF-MRI. For a phase I trial, sixteen patients with gynecologic malignancies (treated with oophorectomy, radiotherapy or chemotherapy) underwent DECT, QCT, WF-MRI and DXA before and 12months after treatment. BMD and MF percent and distribution were quantified in the lumbar vertebrae and the right femoral neck.

Results: Measured precision (3mg/cm(3)) was sufficient to distinguish test solutions. Adiposity in cadaver bone histology was highly correlated with MF measured using DECT and WF-MRI (r=0.80 and 0.77, respectively). In the clinical trial, DECT showed high overall correlation (r=0.77, 95% CI: 0.69, 0.83) with WF-MRI. MF increased significantly after treatment (p<0.002). Chemotherapy and radiation caused greater increases in MF than oophorectomy (p<0.032). L4 BMD decreased 14% by DECT, 20% by QCT, but only 5% by DXA (p<0.002 for all). At baseline, we observed a statistically significant inverse association between MF and BMD which was dramatically attenuated after treatment.

Conclusion: Our study demonstrated that DECT, similar to WF-MRI, can accurately measure marrow adiposity. Both imaging modalities show rapid increase in MF following cancer treatment. Our results suggest that MF and BMD cannot be used interchangeably to monitor skeletal health following cancer therapy.
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http://dx.doi.org/10.1016/j.bone.2014.12.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336831PMC
April 2015

Standardized MR terminology and reporting of implants and devices as recommended by the American College of Radiology Subcommittee on MR Safety.

Radiology 2015 Mar 20;274(3):866-70. Epub 2014 Oct 20.

From the Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pa (E.K., E.S.); Department of Radiology, University of Minnesota, 420 Delaware St, SE MMC 292, Minneapolis, MN 55455 (J.F.); Department of Radiology and Biomedical Imaging, University of California at San Francisco and UCSF-Benioff Children's Hospital, San Francisco, Calif (A.J.B.); Department of Radiology, University of Colorado, Denver, Colo (J.B.); Department of Radiology, University of California San Diego Medical Center, San Diego, Calif (W.B.); Cardiology Associates of East Tennessee, Knoxville, Tenn (J.R.G.); Office of Clinical Affairs, University of Michigan Health System and Red Forest Consulting LLC, Ann Arbor, Mich (J.G.); Proscan International, Cincinnati, Ohio (T.G.); Department of Medical Physics, University of Wisconsin-Madison, Madison, Wis (E.J.); Radiology Associates of Fox Valley, Neenah, Wis (P.L.); Durham Radiology Associates, Durham, NC (J.L.); Keck School of Medicine, University of Southern California, Los Angeles, Calif (F.G.S.); Department of Radiology, Yale School of Medicine, New Haven, Conn (J.W.); Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio (B.L.W.); and Department of Quality and Safety, American College of Radiology, Reston, Va (D.H.).

Considerable confusion exists among the magnetic resonance (MR) imaging user community as to how to determine whether a patient with a metal implanted device can be safely imaged in an MR imaging unit. Although there has been progress by the device manufacturers in specifying device behavior in a magnetic field, and some MR imaging manufacturers provide maps of the "spatial gradients," there remains significant confusion because of the lack of standardized terminology and reporting guidelines. The American College of Radiology, through its Subcommittee on MR Safety, has proposed standardized terminology that will contribute to greater safety and understanding for screening metal implants and/or devices prior to MR imaging.
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http://dx.doi.org/10.1148/radiol.14141645DOI Listing
March 2015

Evaluation of dose modulation software through the assessment of body mass index, radiation dose and image noise.

J Comput Assist Tomogr 2013 Jul-Aug;37(4):547-50

Department of Radiology, University of Minnesota, Minneapolis, MN 55455, USA.

Purpose: This study attempts to establish a quantitative link between a patient's body mass index (BMI), the delivered radiation dose, and the image noise.

Methods: The CARE Dose4D computed tomography (CT) acquisitions from 206 patients undergoing "eyes-to-thighs" contrast-enhanced positron emission tomography/CT studies were retrospectively examined. Computed tomography dose index volume (CTDIVOL), mAs, and dose-length product were recorded from the dose report card. The image noise was quantified by evaluating the SD of regions of interest placed over the contrast enhanced aorta.

Results: The multivariate regressions f(BMI, mAs) and f(BMI, CTDIVOL) had R values of 0.4840 and 0.4802, respectively. Unpaired t tests demonstrate that statistically significant difference in image noise required more than 12.17 kg/m of separation between the average BMI values for the groups compared.

Conclusions: The evaluation of image noise with BMI and CTDIVOL or mAs is a means to evaluate the consistency of dose modulation software. There is considerable variability in the radiation dose generated by the CARE Dose4D software.
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http://dx.doi.org/10.1097/RCT.0b013e318293d507DOI Listing
September 2013

Water-fat MRI for assessing changes in bone marrow composition due to radiation and chemotherapy in gynecologic cancer patients.

J Magn Reson Imaging 2013 Dec 28;38(6):1578-84. Epub 2013 Feb 28.

Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota, Minneapolis, Minnesota, USA.

Purpose: To assess the feasibility of using fat-fraction imaging for measuring marrow composition changes over large regions in patients undergoing cancer therapy.

Materials And Methods: Thirteen women with gynecologic malignancies who were to receive radiation and/or chemotherapy were recruited for this study. Subjects were imaged on a 3T magnetic resonance (MR) scanner at baseline (after surgery but before radiation or chemotherapy), 6 months, and 12 months after treatment. Water-fat imaging was used to generate high-resolution, 3D signal fat fraction (sFF) maps extending from mid-femur to L3. Treatment changes were assessed by measuring marrow sFF in the L4 vertebra, femoral necks, and control tissues.

Results: Pretreatment and 6-month scans were compared in nine women. sFF increased significantly in both the L4 vertebral marrow (P = 0.04) and the femoral necks (P = 0.03), while no significant change was observed in control regions. Qualitatively, chemotherapy changes were more uniform in space, whereas the radiation-induced changes were largest in marrow regions inside and close to the target radiation field.

Conclusion: Water-fat MRI is sensitive to changes in red/yellow marrow composition, and can be used for quantitative and qualitative assessment of treatment-induced marrow damage.
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http://dx.doi.org/10.1002/jmri.24071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3690168PMC
December 2013

ACR guidance document on MR safe practices: 2013.

J Magn Reson Imaging 2013 Mar 23;37(3):501-30. Epub 2013 Jan 23.

Department of Radiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213, USA.

Because there are many potential risks in the MR environment and reports of adverse incidents involving patients, equipment and personnel, the need for a guidance document on MR safe practices emerged. Initially published in 2002, the ACR MR Safe Practices Guidelines established de facto industry standards for safe and responsible practices in clinical and research MR environments. As the MR industry changes the document is reviewed, modified and updated. The most recent version will reflect these changes.
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http://dx.doi.org/10.1002/jmri.24011DOI Listing
March 2013

Assessing the clinical utility of quantitative computed tomography with a routinely used diagnostic computed tomography scanner in a cancer center.

J Clin Densitom 2011 Jan-Mar;14(1):41-6

Department of Therapeutic Radiology, University of Minnesota, Minneapolis, MN 55455, USA.

The purpose of this study was to characterize quantitative computed tomography (QCT) in our multi-detector computed tomography (MDCT) scanner with regard to the influence of the QCT phantom on dose and the influence of varying mA and CIRS phantom size on bone mineral density (BMD) measurements. We accomplish this by scanning a commercially available QCT phantom and a corresponding quality assurance phantom. To assess the feasibility of having the QCT phantom in place while patients are being scanned, we measured radiation dose difference in a CT body phantom with and without the QCT phantom on the CT table and also, with and without the use of dose modulation programs. We also analyzed reconstructed QCT phantom images with the manufacturer's software to measure BMD. Although patient characteristics may be different, leading to different mA values, the influence of the QCT phantom on the dose to patients was minimal when compared with doses measured without the phantom in place. Average BMD measurements were not significantly affected by varying mA, for a fixed-size phantom. The average BMD exhibited a weak dependence on computerized imaging reference systems (CIRS) torso phantom size, with a propensity for decreasing BMD with increasing size. Measurement precision was unaffected by varying CIRS size. Having the ability to measure bone density as part of the routine management of cancer patients, with no added cost, time, or radiation dose, will allow for the prospective evaluation of bone mineral changes. We believe that this ability will facilitate the detection of abnormal bone loss and will lead to better management of this loss and, thus, reduce the complications and associated morbidity in these cancer survivors.
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http://dx.doi.org/10.1016/j.jocd.2010.02.004DOI Listing
April 2011

Longitudinal assessment of bone loss from diagnostic computed tomography scans in gynecologic cancer patients treated with chemotherapy and radiation.

Am J Obstet Gynecol 2010 Oct 3;203(4):353.e1-7. Epub 2010 Aug 3.

Department of Therapeutic Radiology, University of Minnesota School of Medicine, Minneapolis, MN 55455, USA.

Objective: The objective of the study was to measure the volumetric bone mineral density (vBMD) using diagnostic computed tomography scans in gynecologic oncology patients.

Study Design: In a retrospective study, spine and femoral neck (FN) vBMD was measured for 1 year in 40 patients receiving chemotherapy or radiation.

Results: There is significant bone loss after chemotherapy, radiation, and a combination of radiation and chemotherapy (P = .0211). In 1 year, the percent reduction in vBMD (±SE) at L1-L2 spine and the FN was a 15.9% (±5.67) and 10.4% (±4.06) in chemotherapy; 11% (±5.68) and 15.8% (±2.56) in radiation; and 21.0% (±7.03) and 3.6% (±3.3.7) in the combined therapy group. Bone loss was evident immediately after treatment and persisted or worsened in most women.

Conclusion: Gynecologic cancer patients treated with chemotherapy or radiation experience immediate and prolonged bone loss; thus, pre- and posttreatment monitoring of bone loss is important in these patients.
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http://dx.doi.org/10.1016/j.ajog.2010.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2947567PMC
October 2010

Positron emission tomography scanning in the setting of post-transplant lymphoproliferative disorders.

Clin Transplant 2009 Nov-Dec;23(6):794-9

Division of Hematology/Oncology/Transplantation, Department of Medicine, University of Minnesota, Medicine, 420 Delaware Street, S.E., MMC 480, Minneapolis, MN, USA.

Background: Post-transplant lymphoproliferative disorder (PTLD) is a serious complication of transplantation. We examined the role of positron emission tomography (PET) scanning in PTLD.

Methods: All patients treated for PTLD from 2001-2006 who also underwent PET scans were reviewed.

Results: Nineteen PTLD patients were included. Seventeen patients had PET scans for staging at diagnosis. Of these, two patients with primary central nervous system lymphoma and one patient with only bone marrow involvement after complete surgical resection of a bowel lesion had no abnormalities on CT or PET scan. The remaining patients had measurable, extracranial disease by CT scan and PET scan. The median maximum standard uptake value was 8.2 (range 3-30). Thirteen patients had a PET scan following treatment. Eleven of 13 patients had a complete response (CR). Two of 13 patients had persistent disease following therapy; in one of these patients, relapsed disease was documented by PET scan alone. Of the 11 patients with CR, three patients relapsed shortly thereafter. In each case, at the time of relapse, the PET scan confirmed recurrent disease regardless of histopathologic subtype.

Conclusions: PET scans may have a role in the staging and follow-up of patients with PTLD. Additional prospective studies are warranted.
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http://dx.doi.org/10.1111/j.1399-0012.2008.00938.xDOI Listing
September 2010

Multimodality image guided total marrow irradiation and verification of the dose delivered to the lung, PTV, and thoracic bone in a patient: a case study.

Technol Cancer Res Treat 2009 Feb;8(1):23-8

Department of Therapeutic Radiology, Division of Hematology, Oncology and Bone Marrow Transplantation, University of Minnesota, 420 Delaware St SE, MMC 494, Minneapolis, MN 55455, USA.

This work reports our initial experience using multimodality image guidance to improve total marrow irradiation (TMI) using helical tomotherapy. We also monitored the details of the treatment delivery to glean information necessary for the implementation of future adaptive processes. A patient with metastatic Ewing's sarcoma underwent MRI, and bone scan imaging prior to TMI. A whole body kilovoltage CT (kVCT) scan was obtained for intensity modulated TMI treatment planning, including a boost treatment to areas of bony involvement. The delivered dose was estimated by using MVCT images from the helical tomotherapy treatment unit, compared to the expected dose distributions mapped onto the kVCT images. Clinical concerns regarding patient treatment and dosimetric uncertainties were also evaluated. A small fraction of thoracic bone volume received lower radiation dose than the prescribed dose. Reconstructed planned treatment volume (PTV) and the dose delivered to the lung were identical to planned dose. Bone scan imaging had a higher sensitivity for detecting skeletal metastasis compared to MR imaging. However the bone scan lacked sufficient specificity in three dimensions to be useful for planning conformal radiation boost treatments. Inclusion of appropriate imaging modalities improves detection of metastases, which allows the possibility of a radiation dose boost to metastases during TMI. Conformal intensity modulated radiation therapy via helical tomotherapy permitted radiation delivery to metastases in the skull with reduced dose to brain in conjunction with TMI. While TMI reduces irradiation to the lungs, onboard megavoltage computed tomography (MVCT) to verify accurate volumetric dose coverage to marrow-containing thoracic bones may be essential for successful conformal TMI treatment.
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http://dx.doi.org/10.1177/153303460900800104DOI Listing
February 2009

ACR MRI accreditation: yesterday, today, and tomorrow.

J Am Coll Radiol 2005 Jun;2(6):494-503

Department of Radiology, Yale University School of Medicine, New Haven, Connecticut, USA.

The ACR's Magnetic Resonance Imaging (MRI) Accreditation Program has generated controversy and debate since the Committee on MRI Accreditation began the development of the program in the early 1990s. This article discusses the motivation and development process for the program. It also presents outcomes from the MRI Accreditation Program, including passing and failing statistics by field strength and body part. The on-site survey process and outcomes are presented, and a case study is described.
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http://dx.doi.org/10.1016/j.jacr.2004.11.004DOI Listing
June 2005
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