Publications by authors named "John M Buatti"

130 Publications

Temporal Relationship Between Visual Field, Retinal and Microvascular Pathology Following 125I-Plaque Brachytherapy for Uveal Melanoma.

Invest Ophthalmol Vis Sci 2021 Jan;62(1)

Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, Iowa, United States.

Purpose: To define the temporal relationship of vascular versus neuronal abnormalities in radiation retinopathy.

Methods: Twenty-five patients with uveal melanoma treated with brachytherapy and sixteen controls were tested. Functional outcome measures included visual acuity and threshold perimetry (HVF 10-2), while structural outcomes included retinal thickness by OCT and vascular measures by OCT angiography and digital fundus photography. The degree of structural abnormality was determined by intereye asymmetry compared with normal subject asymmetry. Diagnostic sensitivity and specificity of each measure were determined using receiver operating characteristic curves. The relationships between the outcome measures were quantified by Spearman correlation. The effect of time from brachytherapy on visual function, retinal layer thickness, and capillary density was also determined.

Results: Within the first 2 years of brachytherapy, outcome measures revealed visual field loss and microvascular abnormalities in 38% and 31% of subjects, respectively. After 2 years, they became more prevalent, increasing to 67% and 67%, respectively, as did retinal thinning (50%). Visual field loss, loss of capillary density, and inner retinal thickness were highly correlated with one another. Diagnostic sensitivity and specificity were highest for abnormalities in digital fundus photography, visual field loss within the central 10°, and decrease in vessel density.

Conclusions: Using quantitative approaches, radiation microvasculopathy and visual field defects were detected earlier than loss of inner retinal structure after brachytherapy. Strong correlations eventually developed between vascular pathology, change in retinal thickness, neuronal dysfunction, and radiation dose. Radiation-induced ischemia seems to be a primary early manifestation of radiation retinopathy preceding visual loss.
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http://dx.doi.org/10.1167/iovs.62.1.3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794259PMC
January 2021

Assessment of Gadobutrol Safety in Combination with Ionizing Radiation Using a Preclinical MRI-Guided Radiotherapy Model.

Radiat Res 2020 Dec 21. Epub 2020 Dec 21.

Department of Radiation Oncology, University of Iowa, Iowa City, Iowa.

MR-linac technology enhances the precision of therapeutic radiation by clarifying the tumor-normal tissue interface and provides the potential for adaptive treatment planning. Accurate delineation of tumors on diagnostic magnetic resonance imaging (MRI) frequently requires gadolinium-based contrast agents (GBCAs). Despite generally being considered safe, previous literature suggests that GBCAs are capable of contrast-induced acute kidney injury (AKI). It is unclear if the risk for AKI is enhanced when GBCAs are administered concurrently with ionizing radiotherapy. During irradiation, gadolinium may be liberated from its chelator which may induce AKI. The goal of this work was to determine if radiation combined with GBCAs increased the incidence of AKI. Using a preclinical MRI-guided irradiation system, where MRI acquisitions and radiation delivery are performed in rapid succession, tumor-bearing mice with normal kidney function were injected with GBCA and treated with 2, 8 or 18 Gy irradiation. Renal function was assessed on days three and seven postirradiation to assess for AKI. No clinically relevant changes in blood urea nitrogen and creatinine were observed in any combination of GBCA and radiation dose. From these data, we conclude that GBCA in combination with radiation does not increase the risk for AKI in mice. Additional investigation of multiple doses of GBCA administered concurrently with irradiation is warranted to evaluate the risk of chronic kidney injury.
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http://dx.doi.org/10.1667/RADE-20-00199.1DOI Listing
December 2020

Magnetic resonance imaging (MRI) of pharmacological ascorbate-induced iron redox state as a biomarker in subjects undergoing radio-chemotherapy.

Redox Biol 2021 Jan 19;38:101804. Epub 2020 Nov 19.

Department of Radiology, Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, USA. Electronic address:

Pharmacological ascorbate (P-AscH) combined with standard of care (SOC) radiation and temozolomide is being evaluated in a phase 2 clinical trial (NCT02344355) in the treatment of glioblastoma (GBM). Previously published data demonstrated that paramagnetic iron (Fe) catalyzes ascorbate's oxidation to form diamagnetic iron (Fe). Because paramagnetic Fe may influence relaxation times observed in MR imaging, quantitative MR imaging of P-AscH-induced changes in redox-active Fe was assessed as a biomarker for therapy response. Gel phantoms containing either Fe or Fe were imaged with T2* and quantitative susceptibility mapping (QSM). Fifteen subjects receiving P-AscH plus SOC underwent T2* and QSM imaging four weeks into treatment. Subjects were scanned: pre-P-AscH infusion, post-P-AscH infusion, and post-radiation (3-4 h between scans). Changes in T2* and QSM relaxation times in tumor and normal tissue were calculated and compared to changes in Fe and Fe gel phantoms. A GBM mouse model was used to study the relationship between the imaging findings and the labile iron pool. Phantoms containing Fe demonstrated detectable changes in T2* and QSM relaxation times relative to Fe phantoms. Compared to pre-P-AscH, GBM T2* and QSM imaging were significantly changed post-P-AscH infusion consistent with conversion of Fe to Fe. No significant changes in T2* or QSM were observed in normal brain tissue. There was moderate concordance between T2* and QSM changes in both progression free survival and overall survival. The GBM mouse model showed similar results with P-AscH inducing greater changes in tumor labile iron pools compared to the normal tissue. CONCLUSIONS: T2* and QSM MR-imaging responses are consistent with P-AscH reducing Fe to Fe, selectively in GBM tumor volumes and represent a potential biomarker of response. This study is the first application using MR imaging in humans to measure P-AscH-induced changes in redox-active iron.
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http://dx.doi.org/10.1016/j.redox.2020.101804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708874PMC
January 2021

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

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

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

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

The Rapid Evolution of Theranostics in Radiation Oncology.

Semin Radiat Oncol 2021 Jan;31(1):1-2

Johns Hopkins University, Department of Radiation Oncology and Molecular Radiation Sciences, Baltimore, Maryland.

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http://dx.doi.org/10.1016/j.semradonc.2020.07.001DOI Listing
January 2021

Stereotactic radiotherapy of appropriately selected meningiomas and metastatic brain tumor beds with gamma knife icon versus volumetric modulated arc therapy.

J Appl Clin Med Phys 2020 Dec 18;21(12):246-252. Epub 2020 Nov 18.

Department of Radiation Oncology, University of Iowa Hospital and Clinics, 200 Hawkins Drive, Iowa City, IA, 52242, USA.

Purpose: To determine if the gamma knife icon (GKI) can provide superior stereotactic radiotherapy (SRT) dose distributions for appropriately selected meningioma and post-resection brain tumor bed treatments to volumetric modulated arc therapy (VMAT).

Materials And Methods: Appropriately selected targets were not proximal to great vessels, did not have sensitive soft tissue including organs-at-risk (OARs) within the planning target volume (PTV), and did not have concave tumors containing excessive normal brain tissue. Four of fourteen candidate meningioma patients and six of six candidate patients with brain tumor cavities were considered for this treatment planning comparison study. PTVs were generated for GKI and VMAT by adding 1 mm and 3 mm margins, respectively, to the GTVs. Identical PTV V -values were obtained for the GKI and VMAT plans for each patient. Meningioma and tumor bed prescription doses were 52.7-54.0 in 1.7-1.8 Gy fractions and 25 Gy in 5 Gy fractions, respectively. GKI dose rate was 3.735 Gy/min for 16 mm collimators.

Results: PTV radical dose homogeneity index was 3.03 ± 0.35 for GKI and 1.27 ± 0.19 for VMAT. Normal brain D , D , and D were lower for GKI than VMAT by 45.8 ± 10.9%, 38.9 ± 11.5%, and 35.4 ± 16.5% respectively. All OARs considered received lower maximum doses for GKI than VMAT. GKI and VMAT treatment times for meningioma plans were 12.1 ± 4.13 min and 6.2 ± 0.32 min, respectively, and, for tumor cavities, were 18.1 ± 5.1 min and 11.0 ± 0.56 min, respectively.

Conclusions: Appropriately selected meningioma and brain tumor bed patients may benefit from GKI-based SRT due to the decreased normal brain and OAR doses relative to VMAT enabled by smaller margins. Care must be taken in meningioma patient selection for SRT with the GKI, even if they are clinically appropriate for VMAT.
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http://dx.doi.org/10.1002/acm2.13100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769414PMC
December 2020

Survival in Patients With Brain Metastases: Summary Report on the Updated Diagnosis-Specific Graded Prognostic Assessment and Definition of the Eligibility Quotient.

J Clin Oncol 2020 11 15;38(32):3773-3784. Epub 2020 Sep 15.

Miami Cancer Institute, Miami, FL.

Purpose: Conventional wisdom has rendered patients with brain metastases ineligible for clinical trials for fear that poor survival could mask the benefit of otherwise promising treatments. Our group previously published the diagnosis-specific Graded Prognostic Assessment (GPA). Updates with larger contemporary cohorts using molecular markers and newly identified prognostic factors have been published. The purposes of this work are to present all the updated indices in a single report to guide treatment choice, stratify research, and define an eligibility quotient to expand eligibility.

Methods: A multi-institutional database of 6,984 patients with newly diagnosed brain metastases underwent multivariable analyses of prognostic factors and treatments associated with survival for each primary site. Significant factors were used to define the updated GPA. GPAs of 4.0 and 0.0 correlate with the best and worst prognoses, respectively.

Results: Significant prognostic factors varied by diagnosis and new prognostic factors were identified. Those factors were incorporated into the updated GPA with robust separation ( < .01) between subgroups. Survival has improved, but varies widely by GPA for patients with non-small-cell lung, breast, melanoma, GI, and renal cancer with brain metastases from 7-47 months, 3-36 months, 5-34 months, 3-17 months, and 4-35 months, respectively.

Conclusion: Median survival varies widely and our ability to estimate survival for patients with brain metastases has improved. The updated GPA (available free at brainmetgpa.com) provides an accurate tool with which to estimate survival, individualize treatment, and stratify clinical trials. Instead of excluding patients with brain metastases, enrollment should be encouraged and those trials should be stratified by the GPA to ensure those trials make appropriate comparisons. Furthermore, we recommend the expansion of eligibility to allow for the enrollment of patients with previously treated brain metastases who have a 50% or greater probability of an additional year of survival (eligibility quotient > 0.50).
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http://dx.doi.org/10.1200/JCO.20.01255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655019PMC
November 2020

Radioresistance in Glioblastoma and the Development of Radiosensitizers.

Cancers (Basel) 2020 Sep 3;12(9). Epub 2020 Sep 3.

Free Radical & Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA.

Ionizing radiation is a common and effective therapeutic option for the treatment of glioblastoma (GBM). Unfortunately, some GBMs are relatively radioresistant and patients have worse outcomes after radiation treatment. The mechanisms underlying intrinsic radioresistance in GBM has been rigorously investigated over the past several years, but the complex interaction of the cellular molecules and signaling pathways involved in radioresistance remains incompletely defined. A clinically effective radiosensitizer that overcomes radioresistance has yet to be identified. In this review, we discuss the current status of radiation treatment in GBM, including advances in imaging techniques that have facilitated more accurate diagnosis, and the identified mechanisms of GBM radioresistance. In addition, we provide a summary of the candidate GBM radiosensitizers being investigated, including an update of subjects enrolled in clinical trials. Overall, this review highlights the importance of understanding the mechanisms of GBM radioresistance to facilitate the development of effective radiosensitizers.
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http://dx.doi.org/10.3390/cancers12092511DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564557PMC
September 2020

The Effect of Concurrent Stereotactic Body Radiation and Anti-PD-1 Therapy for Recurrent Metastatic Sarcoma.

Radiat Res 2020 08;194(2):124-132

Department of Radiation Oncology.

Patients diagnosed with metastatic sarcoma have limited options for achieving both local and distant tumor control. While SBRT can achieve local control, distant response rates remain low. There is limited evidence demonstrating the safety and efficacy for combining SBRT with concurrent PD-1 checkpoint blockade in metastatic sarcoma. In this prospective case-series, we examined five patients with metastatic sarcoma on pembrolizumab treated concurrently with SBRT from July 1, 2016-October 30, 2018. Acute and chronic toxicity were recorded using Common Terminology Criteria for Adverse Events (CTCAE, version 5.0). SBRT-treated tumor control was assessed using Response Evaluation Criteria in Solid Tumors (RECIST version 1.1). With median follow-up of 14.9 months, three patients with undifferentiated pleomorphic sarcoma, one with intimal, and one with chondroblastic osteosarcoma received SBRT with concurrent pembrolizumab to 10 sites of metastatic disease. No grade 5 toxicities were observed. There was a single incidence of transient grade 4 lymphopenia which resolved without intervention. Grade 3 toxicities included anemia, thrombocytopenia, lymphopenia and colitis. One tumor demonstrated local progression after SBRT, and all others remained stable or with response. In conclusion, combining SBRT with PD-1 inhibition appeared to be safe in this patient population. Expected high rates of treated-tumor local control after SBRT were observed. Two of five patients demonstrated either enhanced local tumor regression, or possible abscopal effect.
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http://dx.doi.org/10.1667/RADE-20-00017DOI Listing
August 2020

Multisite Technical and Clinical Performance Evaluation of Quantitative Imaging Biomarkers from 3D FDG PET Segmentations of Head and Neck Cancer Images.

Tomography 2020 06;6(2):65-76

Electrical and Computer Engineering.

Quantitative imaging biomarkers (QIBs) provide medical image-derived intensity, texture, shape, and size features that may help characterize cancerous tumors and predict clinical outcomes. Successful clinical translation of QIBs depends on the robustness of their measurements. Biomarkers derived from positron emission tomography images are prone to measurement errors owing to differences in image processing factors such as the tumor segmentation method used to define volumes of interest over which to calculate QIBs. We illustrate a new Bayesian statistical approach to characterize the robustness of QIBs to different processing factors. Study data consist of 22 QIBs measured on 47 head and neck tumors in 10 positron emission tomography/computed tomography scans segmented manually and with semiautomated methods used by 7 institutional members of the NCI Quantitative Imaging Network. QIB performance is estimated and compared across institutions with respect to measurement errors and power to recover statistical associations with clinical outcomes. Analysis findings summarize the performance impact of different segmentation methods used by Quantitative Imaging Network members. Robustness of some advanced biomarkers was found to be similar to conventional markers, such as maximum standardized uptake value. Such similarities support current pursuits to better characterize disease and predict outcomes by developing QIBs that use more imaging information and are robust to different processing factors. Nevertheless, to ensure reproducibility of QIB measurements and measures of association with clinical outcomes, errors owing to segmentation methods need to be reduced.
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http://dx.doi.org/10.18383/j.tom.2020.00004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289247PMC
June 2020

Clinical Trial Design and Development Work Group Within the Quantitative Imaging Network.

Tomography 2020 06;6(2):60-64

Irving Medical Center, Columbia University, New York Presbyterian Hospital, New York, NY.

The Clinical Trial Design and Development Working Group within the Quantitative Imaging Network focuses on providing support for the development, validation, and harmonization of quantitative imaging (QI) methods and tools for use in cancer clinical trials. In the past 10 years, the Group has been working in several areas to identify challenges and opportunities in clinical trials involving QI and radiation oncology. The Group has been working with Quantitative Imaging Network members and the Quantitative Imaging Biomarkers Alliance leadership to develop guidelines for standardizing the reporting of quantitative imaging. As a validation platform, the Group led a multireader study to test a semi-automated positron emission tomography quantification software. Clinical translation of QI tools cannot be possible without a continuing dialogue with clinical users. This article also highlights the outreach activities extended to cooperative groups and other organizations that promote the use of QI tools to support clinical decisions.
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http://dx.doi.org/10.18383/j.tom.2019.00022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289239PMC
June 2020

Long-term outcome comparison for standard fractionation (>59 Gy) versus hyperfractionated (>45 Gy) radiotherapy plus concurrent chemotherapy for limited-stage small-cell lung cancer.

Rep Pract Oncol Radiother 2020 Jul-Aug;25(4):489-493. Epub 2020 Apr 27.

Department of Radiation Oncology, University of Iowa, Iowa City, Iowa, US.

Background: Concurrent chemoradiotherapy (CCRT) is commonly employed in limited-stage small-cell lung cancer (LS-SCLC); however, the optimal radiotherapy regimen is still unknown. This 3-institution analysis compares long-term disease control and survival outcomes for once- (QD) versus twice-daily (BID) radiotherapy at contemporary doses.

Methods And Materials: Data were collected for LS-SCLC patients treated with platinum-based CCRT and planned RT doses of >5940 cGy at >180 cGy QD or >4500 cGy at 150 cGy BID. Comparative outcome analyses were performed for treatment groups.

Results: From 2005 through 2014, 132 patients met inclusion criteria for analysis (80 QD, 52 BID). Treatment groups were well-balanced, excepting higher rate of advanced mediastinal staging, longer interval from biopsy to treatment initiation, and lower rate of prophylactic cranial irradiation for the QD group, as well as institutional practice variation. At median survivor follow-up of 33.5 months (range, 4.6-105.8), 80 patients experienced disease failure (44 QD, 36 BID), and 106 died (62 QD, 44 BID). No differences in disease control or survival were demonstrated between treatment groups.

Conclusion: The present analysis did not detect a difference in disease control or survival outcomes for contemporary dose QD versus BID CCRT in LS-SCLC.
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http://dx.doi.org/10.1016/j.rpor.2020.03.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251533PMC
April 2020

Beyond an Updated Graded Prognostic Assessment (Breast GPA): A Prognostic Index and Trends in Treatment and Survival in Breast Cancer Brain Metastases From 1985 to Today.

Int J Radiat Oncol Biol Phys 2020 06 19;107(2):334-343. Epub 2020 Feb 19.

Miami Cancer Institute, Miami, Florida.

Purpose: Brain metastases are a common sequelae of breast cancer. Survival varies widely based on diagnosis-specific prognostic factors (PF). We previously published a prognostic index (Graded Prognostic Assessment [GPA]) for patients with breast cancer with brain metastases (BCBM), based on cohort A (1985-2007, n = 642), then updated it, reporting the effect of tumor subtype in cohort B (1993-2010, n = 400). The purpose of this study is to update the Breast GPA with a larger contemporary cohort (C) and compare treatment and survival across the 3 cohorts.

Methods And Materials: A multi-institutional (19), multinational (3), retrospective database of 2473 patients with breast cancer with newly diagnosed brain metastases (BCBM) diagnosed from January 1, 2006, to December 31, 2017, was created and compared with prior cohorts. Associations of PF and treatment with survival were analyzed. Kaplan-Meier survival estimates were compared with log-rank tests. PF were weighted and the Breast GPA was updated such that a GPA of 0 and 4.0 correlate with the worst and best prognoses, respectively.

Results: Median survival (MS) for cohorts A, B, and C improved over time (from 11, to 14 to 16 months, respectively; P < .01), despite the subtype distribution becoming less favorable. PF significant for survival were tumor subtype, Karnofsky Performance Status, age, number of BCBMs, and extracranial metastases (all P < .01). MS for GPA 0 to 1.0, 1.5-2.0, 2.5-3.0, and 3.5-4.0 was 6, 13, 24, and 36 months, respectively. Between cohorts B and C, the proportion of human epidermal receptor 2 + subtype decreased from 31% to 18% (P < .01) and MS in this subtype increased from 18 to 25 months (P < .01).

Conclusions: MS has improved modestly but varies widely by diagnosis-specific PF. New PF are identified and incorporated into an updated Breast GPA (free online calculator available at brainmetgpa.com). The Breast GPA facilitates clinical decision-making and will be useful for stratification of future clinical trials. Furthermore, these data suggest human epidermal receptor 2-targeted therapies improve clinical outcomes in some patients with BCBM.
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http://dx.doi.org/10.1016/j.ijrobp.2020.01.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276246PMC
June 2020

Estrogen/progesterone receptor and HER2 discordance between primary tumor and brain metastases in breast cancer and its effect on treatment and survival.

Neuro Oncol 2020 09;22(9):1359-1367

Miami Cancer Institute, Miami, Florida, USA.

Background: Breast cancer treatment is based on estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth factor receptor 2 (HER2). At the time of metastasis, receptor status can be discordant from that at initial diagnosis. The purpose of this study was to determine the incidence of discordance and its effect on survival and subsequent treatment in patients with breast cancer brain metastases (BCBM).

Methods: A retrospective database of 316 patients who underwent craniotomy for BCBM between 2006 and 2017 was created. Discordance was considered present if the ER, PR, or HER2 status differed between the primary tumor and the BCBM.

Results: The overall receptor discordance rate was 132/316 (42%), and the subtype discordance rate was 100/316 (32%). Hormone receptors (HR, either ER or PR) were gained in 40/160 (25%) patients with HR-negative primary tumors. HER2 was gained in 22/173 (13%) patients with HER2-negative primary tumors. Subsequent treatment was not adjusted for most patients who gained receptors-nonetheless, median survival (MS) improved but did not reach statistical significance (HR, 17-28 mo, P = 0.12; HER2, 15-19 mo, P = 0.39). MS for patients who lost receptors was worse (HR, 27-18 mo, P = 0.02; HER2, 30-18 mo, P = 0.08).

Conclusions: Receptor discordance between primary tumor and BCBM is common, adversely affects survival if receptors are lost, and represents a missed opportunity for use of effective treatments if receptors are gained. Receptor analysis of BCBM is indicated when clinically appropriate. Treatment should be adjusted accordingly.

Key Points: 1. Receptor discordance alters subtype in 32% of BCBM patients.2. The frequency of receptor gain for HR and HER2 was 25% and 13%, respectively.3. If receptors are lost, survival suffers. If receptors are gained, consider targeted treatment.
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http://dx.doi.org/10.1093/neuonc/noaa025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523450PMC
September 2020

A 3D deep convolutional neural network approach for the automated measurement of cerebellum tracer uptake in FDG PET-CT scans.

Med Phys 2020 Mar 6;47(3):1058-1066. Epub 2020 Jan 6.

Department of Electrical and Computer Engineering, The University of Iowa, Iowa City, IA, 52242, USA.

Purpose: The purpose of this work was to assess the potential of deep convolutional neural networks in automated measurement of cerebellum tracer uptake in F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) scans.

Methods: Three different three-dimensional (3D) convolutional neural network architectures (U-Net, V-Net, and modified U-Net) were implemented and compared regarding their performance in 3D cerebellum segmentation in FDG PET scans. For network training and testing, 134 PET scans with corresponding manual volumetric segmentations were utilized. For segmentation performance assessment, a fivefold cross-validation was used, and the Dice coefficient as well as signed and unsigned distance errors were calculated. In addition, standardized uptake value (SUV) uptake measurement performance was assessed by means of a statistical comparison to an independent reference standard. Furthermore, a comparison to a previously reported active-shape-model-based approach was performed.

Results: Out of the three convolutional neural networks investigated, the modified U-Net showed significantly better segmentation performance. It achieved a Dice coefficient of 0.911 ± 0.026, a signed distance error of 0.220 ± 0.103 mm, and an unsigned distance error of 1.048 ± 0.340 mm. When compared to the independent reference standard, SUV uptake measurements produced with the modified U-Net showed no significant error in slope and intercept. The estimated reduction in total SUV measurement error was 95.1%.

Conclusions: The presented work demonstrates the potential of deep convolutional neural networks in automated SUV measurement of reference regions. While it focuses on the cerebellum, utilized methods can be generalized to other reference regions like the liver or aortic arch. Future work will focus on combining lesion and reference region analysis into one approach.
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http://dx.doi.org/10.1002/mp.13970DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067677PMC
March 2020

Deep segmentation networks predict survival of non-small cell lung cancer.

Sci Rep 2019 11 21;9(1):17286. Epub 2019 Nov 21.

University of Iowa, Department of Radiation Oncology, Iowa City, IA, 52242, United States.

Non-small-cell lung cancer (NSCLC) represents approximately 80-85% of lung cancer diagnoses and is the leading cause of cancer-related death worldwide. Recent studies indicate that image-based radiomics features from positron emission tomography/computed tomography (PET/CT) images have predictive power for NSCLC outcomes. To this end, easily calculated functional features such as the maximum and the mean of standard uptake value (SUV) and total lesion glycolysis (TLG) are most commonly used for NSCLC prognostication, but their prognostic value remains controversial. Meanwhile, convolutional neural networks (CNN) are rapidly emerging as a new method for cancer image analysis, with significantly enhanced predictive power compared to hand-crafted radiomics features. Here we show that CNNs trained to perform the tumor segmentation task, with no other information than physician contours, identify a rich set of survival-related image features with remarkable prognostic value. In a retrospective study on pre-treatment PET-CT images of 96 NSCLC patients before stereotactic-body radiotherapy (SBRT), we found that the CNN segmentation algorithm (U-Net) trained for tumor segmentation in PET and CT images, contained features having strong correlation with 2- and 5-year overall and disease-specific survivals. The U-Net algorithm has not seen any other clinical information (e.g. survival, age, smoking history, etc.) than the images and the corresponding tumor contours provided by physicians. In addition, we observed the same trend by validating the U-Net features against an extramural data set provided by Stanford Cancer Institute. Furthermore, through visualization of the U-Net, we also found convincing evidence that the regions of metastasis and recurrence appear to match with the regions where the U-Net features identified patterns that predicted higher likelihoods of death. We anticipate our findings will be a starting point for more sophisticated non-intrusive patient specific cancer prognosis determination. For example, the deep learned PET/CT features can not only predict survival but also visualize high-risk regions within or adjacent to the primary tumor and hence potentially impact therapeutic outcomes by optimal selection of therapeutic strategy or first-line therapy adjustment.
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http://dx.doi.org/10.1038/s41598-019-53461-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6872742PMC
November 2019

Phase IIb, Randomized, Double-Blind Trial of GC4419 Versus Placebo to Reduce Severe Oral Mucositis Due to Concurrent Radiotherapy and Cisplatin For Head and Neck Cancer.

J Clin Oncol 2019 12 16;37(34):3256-3265. Epub 2019 Oct 16.

University of Iowa Hospitals and Clinics, Iowa City, IA.

Purpose: Oral mucositis (OM) remains a common, debilitating toxicity of radiation therapy (RT) for head and neck cancer. The goal of this phase IIb, multi-institutional, randomized, double-blind trial was to compare the efficacy and safety of GC4419, a superoxide dismutase mimetic, with placebo to reduce the duration, incidence, and severity of severe OM (SOM).

Patients And Methods: A total of 223 patients (from 44 institutions) with locally advanced oral cavity or oropharynx cancer planned to be treated with definitive or postoperative intensity-modulated RT (IMRT; 60 to 72 Gy [≥ 50 Gy to two or more oral sites]) plus cisplatin (weekly or every 3 weeks) were randomly assigned to receive 30 mg (n = 73) or 90 mg (n = 76) of GC4419 or to receive placebo (n = 74) by 60-minute intravenous administration before each IMRT fraction. WHO grade of OM was assessed biweekly during IMRT and then weekly for up to 8 weeks after IMRT. The primary endpoint was duration of SOM tested for each active dose level versus placebo (intent-to-treat population, two-sided α of .05). The National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03, was used for adverse event grading.

Results: Baseline patient and tumor characteristics as well as treatment delivery were balanced. With 90 mg GC4419 versus placebo, SOM duration was significantly reduced ( = .024; median, 1.5 19 days). SOM incidence (43% 65%; = .009) and severity (grade 4 incidence, 16% 30%; = .045) also were improved. Intermediate improvements were seen with the 30-mg dose. Safety was comparable across arms, with no significant GC4419-specific toxicity nor increase of known toxicities of IMRT plus cisplatin. The 2-year follow-up for tumor outcomes is ongoing.

Conclusion: GC4419 at a dose of 90 mg produced a significant, clinically meaningful reduction of SOM duration, incidence, and severity with acceptable safety. A phase III trial (ROMAN; ClinicalTrials.gov identifier: NCT03689712) has begun.
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http://dx.doi.org/10.1200/JCO.19.01507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6881100PMC
December 2019

First-in-Human Phase I Clinical Trial of Pharmacologic Ascorbate Combined with Radiation and Temozolomide for Newly Diagnosed Glioblastoma.

Clin Cancer Res 2019 11 19;25(22):6590-6597. Epub 2019 Aug 19.

Department of Radiation Oncology, University of Iowa Hospitals & Clinics, Iowa City, Iowa.

Purpose: Standard treatment for glioblastoma (GBM) includes surgery, radiation therapy (RT), and temozolomide (TMZ), yielding a median overall survival (OS) of approximately 14 months. Preclinical models suggest that pharmacologic ascorbate (P-AscH) enhances RT/TMZ antitumor effect in GBM. We evaluated the safety of adding P-AscH to standard RT/TMZ therapy.

Patients And Methods: This first-in-human trial was divided into an RT phase (concurrent RT/TMZ/P-AscH) and an adjuvant (ADJ) phase (post RT/TMZ/P-AscH phase). Eight P-AscH dose cohorts were evaluated in the RT phase until targeted plasma ascorbate levels were achieved (≥20 mmol/L). In the ADJ phase, P-AscH doses were escalated in each subject at each cycle until plasma concentrations were ≥20 mmol/L. P-AscH was infused 3 times weekly during the RT phase and 2 times weekly during the ADJ phase continuing for six cycles or until disease progression. Adverse events were quantified by CTCAE (v4.03).

Results: Eleven subjects were evaluable. No dose-limiting toxicities occurred. Observed toxicities were consistent with historical controls. Adverse events related to study drug were dry mouth and chills. Targeted ascorbate plasma levels of 20 mmol/L were achieved in the 87.5 g cohort; diminishing returns were realized in higher dose cohorts. Median progression-free survival (PFS) was 9.4 months and median OS was 18 months. In subjects with undetectable promoter methylation (), median PFS was 10 months and median OS was 23 months.

Conclusions: P-AscH/RT/TMZ is safe with promising clinical outcomes warranting further investigation.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-0594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858950PMC
November 2019

Estimating survival in patients with gastrointestinal cancers and brain metastases: An update of the graded prognostic assessment for gastrointestinal cancers (GI-GPA).

Clin Transl Radiat Oncol 2019 Sep 27;18:39-45. Epub 2019 Jun 27.

Miami Cancer Institute, USA.

Background: Patients with gastrointestinal cancers and brain metastases (BM) represent a unique and heterogeneous population. Our group previously published the Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) for patients with GI cancers (GI-GPA) (1985-2007, n = 209). The purpose of this study is to update the GI-GPA based on a larger contemporary database.

Methods: An IRB-approved consortium database analysis was performed using a multi-institutional (18), multi-national (3) cohort of 792 patients with gastrointestinal (GI) cancers, with newly-diagnosed BM diagnosed between 1/1/2006 and 12/31/2017. Survival was measured from date of first treatment for BM. Multiple Cox regression was used to select and weight prognostic factors in proportion to their hazard ratios. These factors were incorporated into the updated GI-GPA.

Results: Median survival (MS) varied widely by primary site and other prognostic factors. Four significant factors (KPS, age, extracranial metastases and number of BM) were used to formulate the updated GI-GPA. Overall MS for this cohort remains poor; 8 months. MS by GPA was 3, 7, 11 and 17 months for GPA 0-1, 1.5-2, 2.5-3.0 and 3.5-4.0, respectively. >30% present in the worst prognostic group (GI-GPA of ≤1.0).

Conclusions: Brain metastases are not uncommon in GI cancer patients and MS varies widely among them. This updated GI-GPA index improves our ability to estimate survival for these patients and will be useful for therapy selection, end-of-life decision-making and stratification for future clinical trials. A user-friendly, free, on-line app to calculate the GPA score and estimate survival for an individual patient is available at brainmetgpa.com.
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http://dx.doi.org/10.1016/j.ctro.2019.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6612649PMC
September 2019

Machine learning with the TCGA-HNSC dataset: improving usability by addressing inconsistency, sparsity, and high-dimensionality.

BMC Bioinformatics 2019 Jun 17;20(1):339. Epub 2019 Jun 17.

Department of Electrical and Computer Engineering, Center for Bioinformatics and Computational Biology, University of Iowa, 5017 Seamans Center, Iowa City, IA, 52242, USA.

Background: In the era of precision oncology and publicly available datasets, the amount of information available for each patient case has dramatically increased. From clinical variables and PET-CT radiomics measures to DNA-variant and RNA expression profiles, such a wide variety of data presents a multitude of challenges. Large clinical datasets are subject to sparsely and/or inconsistently populated fields. Corresponding sequencing profiles can suffer from the problem of high-dimensionality, where making useful inferences can be difficult without correspondingly large numbers of instances. In this paper we report a novel deployment of machine learning techniques to handle data sparsity and high dimensionality, while evaluating potential biomarkers in the form of unsupervised transformations of RNA data. We apply preprocessing, MICE imputation, and sparse principal component analysis (SPCA) to improve the usability of more than 500 patient cases from the TCGA-HNSC dataset for enhancing future oncological decision support for Head and Neck Squamous Cell Carcinoma (HNSCC).

Results: Imputation was shown to improve prognostic ability of sparse clinical treatment variables. SPCA transformation of RNA expression variables reduced runtime for RNA-based models, though changes to classifier performance were not significant. Gene ontology enrichment analysis of gene sets associated with individual sparse principal components (SPCs) are also reported, showing that both high- and low-importance SPCs were associated with cell death pathways, though the high-importance gene sets were found to be associated with a wider variety of cancer-related biological processes.

Conclusions: MICE imputation allowed us to impute missing values for clinically informative features, improving their overall importance for predicting two-year recurrence-free survival by incorporating variance from other clinical variables. Dimensionality reduction of RNA expression profiles via SPCA reduced both computation cost and model training/evaluation time without affecting classifier performance, allowing researchers to obtain experimental results much more quickly. SPCA simultaneously provided a convenient avenue for consideration of biological context via gene ontology enrichment analysis.
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http://dx.doi.org/10.1186/s12859-019-2929-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580485PMC
June 2019

FDG PET based prediction of response in head and neck cancer treatment: Assessment of new quantitative imaging features.

PLoS One 2019 19;14(4):e0215465. Epub 2019 Apr 19.

Department of Radiation Oncology, The University of Iowa, Iowa City, United States of America.

Introduction: 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) is now a standard diagnostic imaging test performed in patients with head and neck cancer for staging, re-staging, radiotherapy planning, and outcome assessment. Currently, quantitative analysis of FDG PET scans is limited to simple metrics like maximum standardized uptake value, metabolic tumor volume, or total lesion glycolysis, which have limited predictive value. The goal of this work was to assess the predictive potential of new (i.e., nonstandard) quantitative imaging features on head and neck cancer outcome.

Methods: This retrospective study analyzed fifty-eight pre- and post-treatment FDG PET scans of patients with head and neck squamous cell cancer to calculate five standard and seventeen new features at baseline and post-treatment. Cox survival regression was used to assess the predictive potential of each quantitative imaging feature on disease-free survival.

Results: Analysis showed that the post-treatment change of the average tracer uptake in the rim background region immediately adjacent to the tumor normalized by uptake in the liver represents a novel PET feature that is associated with disease-free survival (HR 1.95; 95% CI 1.27, 2.99) and has good discriminative performance (c index 0.791).

Conclusion: The reported findings define a promising new direction for quantitative imaging biomarker research in head and neck squamous cell cancer and highlight the potential role of new radiomics features in oncology decision making as part of precision medicine.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215465PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474600PMC
January 2020

Training Requirements for Theranostics: A Unique Opportunity for Collaboration.

J Nucl Med 2019 Sep 6;60(9):1205-1206. Epub 2019 Apr 6.

Department of Radiation Oncology, University of Iowa, Iowa City, Iowa.

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http://dx.doi.org/10.2967/jnumed.119.228940DOI Listing
September 2019

Survival and prognostic factors in patients with gastrointestinal cancers and brain metastases: have we made progress?

Transl Res 2019 06 27;208:63-72. Epub 2019 Feb 27.

Miami Cancer Institute.

The literature describing the prognosis of patients with gastrointestinal (GI) cancers and brain metastases (BM) is sparse. Our group previously published a prognostic index, the Graded Prognostic Assessment (GPA) for GI cancer patients with BM, based on 209 patients diagnosed from 1985-2005. The purpose of this analysis is to identify prognostic factors for GI cancer patients with newly diagnosed BM in a larger contemporary cohort. A multi-institutional retrospective IRB-approved database of 792 GI cancer patients with new BM diagnosed from 1/1/2006 to 12/31/2016 was created. Demographic data, clinical parameters, and treatment were correlated with survival and time from primary diagnosis to BM (TPDBM). Kaplan-Meier median survival (MS) estimates were calculated and compared with log-rank tests. The MS from time of first treatment for BM for the prior and current cohorts were 5 and 8 months, respectively (P < 0.001). Eight prognostic factors (age, stage, primary site, resection of primary tumor, Karnofsky Performance Status (KPS), extracranial metastases, number of BM and Hgb were found to be significant for survival, in contrast to only one (KPS) in the prior cohort. In this cohort, the most common primary sites were rectum (24%) and esophagus (23%). Median TPDBM was 22 months. Notably, 37% (267/716) presented with poor prognosis (GPA 0-1.0). Although little improvement in overall survival in this cohort has been achieved in recent decades, survival varies widely and multiple new prognostic factors were identified. Future work will translate these factors into a prognostic index to facilitate clinical decision-making and stratification of future clinical trials.
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http://dx.doi.org/10.1016/j.trsl.2019.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527460PMC
June 2019

FLT PET Radiomics for Response Prediction to Chemoradiation Therapy in Head and Neck Squamous Cell Cancer.

Tomography 2019 03;5(1):161-169

Departments of Electrical and Computer Engineering.

Radiomics is an image analysis approach for extracting large amounts of quantitative information from medical images using a variety of computational methods. Our goal was to evaluate the utility of radiomic feature analysis from F-fluorothymidine positron emission tomography (FLT PET) obtained at baseline in prediction of treatment response in patients with head and neck cancer. Thirty patients with advanced-stage oropharyngeal or laryngeal cancer, treated with definitive chemoradiation therapy, underwent FLT PET imaging before treatment. In total, 377 radiomic features of FLT uptake and feature variants were extracted from volumes of interest; these features variants were defined by either the primary tumor or the total lesion burden, which consisted of the primary tumor and all FLT-avid nodes. Feature variants included normalized measurements of uptake, which were calculated by dividing lesion uptake values by the mean uptake value in the bone marrow. Feature reduction was performed using clustering to remove redundancy, leaving 172 representative features. Effects of these features on progression-free survival were modeled with Cox regression and -values corrected for multiple comparisons. In total, 9 features were considered significant. Our results suggest that smaller, more homogenous lesions at baseline were associated with better prognosis. In addition, features extracted from total lesion burden had a higher concordance index than primary tumor features for 8 of the 9 significant features. Furthermore, total lesion burden features showed lower interobserver variability.
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http://dx.doi.org/10.18383/j.tom.2018.00038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6403029PMC
March 2019

Estimating survival for renal cell carcinoma patients with brain metastases: an update of the Renal Graded Prognostic Assessment tool.

Neuro Oncol 2018 11;20(12):1652-1660

Miami Cancer Institute, Department of Radiation Oncology, Miami, Florida.

Background: Brain metastases are a common complication of renal cell carcinoma (RCC). Our group previously published the Renal Graded Prognostic Assessment (GPA) tool. In our prior RCC study (n = 286, 1985-2005), we found marked heterogeneity and variation in outcomes. In our recent update in a larger, more contemporary cohort, we identified additional significant prognostic factors. The purpose of this study is to update the original Renal-GPA based on the newly identified prognostic factors.

Methods: A multi-institutional retrospective institutional review board-approved database of 711 RCC patients with new brain metastases diagnosed from January 1, 2006 to December 31, 2015 was created. Clinical parameters and treatment were correlated with survival. A revised Renal GPA index was designed by weighting the most significant factors in proportion to their hazard ratios and assigning scores such that the patients with the best and worst prognoses would have a GPA of 4.0 and 0.0, respectively.

Results: The 4 most significant factors were Karnofsky performance status, number of brain metastases, extracranial metastases, and hemoglobin. The overall median survival was 12 months. Median survival for GPA groups 0-1.0, 1.5-2.0, 2.5-3, and 3.5-4.0 (% n = 25, 27, 30 and 17) was 4, 12, 17, and 35 months, respectively.

Conclusion: The updated Renal GPA is a user-friendly tool that will help clinicians and patients better understand prognosis, individualize clinical decision making and treatment selection, provide a means to compare retrospective literature, and provide more robust stratification of future clinical trials in this heterogeneous population. To simplify use of this tool in daily practice, a free online application is available at brainmetgpa.com.
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http://dx.doi.org/10.1093/neuonc/noy099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6231200PMC
November 2018

Pharmacologic Ascorbate Reduces Radiation-Induced Normal Tissue Toxicity and Enhances Tumor Radiosensitization in Pancreatic Cancer.

Cancer Res 2018 12 25;78(24):6838-6851. Epub 2018 Sep 25.

Department of Surgery, University of Iowa Hospitals and Clinics, Iowa City, Iowa.

: Chemoradiation therapy is the mainstay for treatment of locally advanced, borderline resectable pancreatic cancer. Pharmacologic ascorbate (P-AscH, i.e., intravenous infusions of ascorbic acid, vitamin C), but not oral ascorbate, produces high plasma concentrations capable of selective cytotoxicity to tumor cells. In doses achievable in humans, P-AscH decreases the viability and proliferative capacity of pancreatic cancer via a hydrogen peroxide (HO)-mediated mechanism. In this study, we demonstrate that P-AscH radiosensitizes pancreatic cancer cells but inhibits radiation-induced damage to normal cells. Specifically, radiation-induced decreases in clonogenic survival and double-stranded DNA breaks in tumor cells, but not in normal cells, were enhanced by P-AscH, while radiation-induced intestinal damage, collagen deposition, and oxidative stress were also reduced with P-AscH in normal tissue. We also report on our first-in-human phase I trial that infused P-AscH during the radiotherapy "beam on." Specifically, treatment with P-AscH increased median overall survival compared with our institutional average (21.7 vs. 12.7 months, = 0.08) and the E4201 trial (21.7 vs. 11.1 months). Progression-free survival in P-AscH-treated subjects was also greater than our institutional average (13.7 vs. 4.6 months, < 0.05) and the E4201 trial (6.0 months). Results indicated that P-AscH in combination with gemcitabine and radiotherapy for locally advanced pancreatic adenocarcinoma is safe and well tolerated with suggestions of efficacy. Because of the potential effect size and minimal toxicity, our findings suggest that investigation of P-AscH efficacy is warranted in a phase II clinical trial. SIGNIFICANCE: These findings demonstrate that pharmacologic ascorbate enhances pancreatic tumor cell radiation cytotoxicity in addition to offering potential protection from radiation damage in normal surrounding tissue, making it an optimal agent for improving treatment of locally advanced pancreatic adenocarcinoma.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-1680DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6295907PMC
December 2018

Using Smaller-Than-Standard Radiation Treatment Margins Does Not Change Survival Outcomes in Patients with High-Grade Gliomas.

Pract Radiat Oncol 2019 Jan 5;9(1):16-23. Epub 2018 Jun 5.

Department of Radiation Oncology, University of Iowa Hospitals and Clinics, Iowa City, Iowa. Electronic address:

Purpose: The number of studies that evaluate treatment margins for high grade gliomas (HGG) are limited. We hypothesize that patients with HGG who are treated with a gross tumor volume (GTV) to planning tumor volume (PTV) expansion of ≤1 cm will have progression-free survival (PFS) and overall survival (OS) rates similar to those treated in accordance with standard protocols by the Radiation Therapy Oncology Group or European Organisation for Research and Treatment of Cancer. Furthermore, the PFS and OS of subgroups within the study population will have equivalent survival outcomes with GTV1-to-PTV1 margins of 1.0 cm and 0.4 cm.

Methods And Materials: Treatment plans and outcomes for patients with pathologically confirmed HGG were analyzed (n = 267). Survival (PFS and OS) was calculated from the time of the first radiation treatment and a χ test or Fisher exact test was used to calculate the associations between margin size and patient characteristics. Survival was estimated using Kaplan-Meier and compared using the log-rank test. All analyses were performed on the univariate level.

Results: The median PFS and OS times were 10.6 and 19.1 months, respectively. By disease, the median PFS and OS times were 8.6 and 16.1 months for glioblastoma and 26.7 and 52.5 months for anaplastic glioma. The median follow-up time was 18.3 months. The treatment margin had no effect on outcome and the 1.0 cm GTV1-PTV1 margin subgroup (n = 212) showed median PFS and OS times of 10.7 and 19.1 months, respectively, and the 0.4 cm margin subgroup (n = 55) 10.2 and 19.3 months, respectively. In comparison with the standard treatment with 2 cm to 3 cm margins, there was not a significant difference in outcomes.

Conclusions: There is no apparent difference in survival when utilizing smaller versus larger margins as defined by the guidelines of the Radiation Therapy Oncology Group and European Organisation for Research and Treatment of Cancer. Although there remains no class I evidence that outcomes after treatment with smaller margins are identical to those after treatment with larger margins, this large series with long-term follow up suggests that a reduction of the margins is safe and further investigation is warranted.
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http://dx.doi.org/10.1016/j.prro.2018.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6487873PMC
January 2019

Effect of Targeted Therapies on Prognostic Factors, Patterns of Care, and Survival in Patients With Renal Cell Carcinoma and Brain Metastases.

Int J Radiat Oncol Biol Phys 2018 07 12;101(4):845-853. Epub 2018 Apr 12.

Miami Cancer Institute, Miami, Florida.

Purpose: To identify prognostic factors, define evolving patterns of care, and the effect of targeted therapies in a larger contemporary cohort of renal cell carcinoma (RCC) patients with new brain metastases (BM).

Methods And Materials: A multi-institutional retrospective institutional review board-approved database of 711 RCC patients with new BM diagnosed from January 1, 2006, to December 31, 2015, was created. Clinical parameters and treatment were correlated with median survival and time from primary diagnosis to BM. Multivariable analyses were performed.

Results: The median survival for the prior/present cohorts was 9.6/12 months, respectively (P < .01). Four prognostic factors (Karnofsky performance status, extracranial metastases, number of BM, and hemoglobin b) were significant for survival after the diagnosis of BM. Of the 6 drug types studied, only cytokine use after BM was associated with improved survival. The use of whole-brain radiation therapy declined from 50% to 22%, and the use of stereotactic radiosurgery alone increased from 46% to 58%. Nonneurologic causes of death were twice as common as neurologic causes.

Conclusions: Additional prognostic factors refine prognostication in this larger contemporary cohort. Patterns of care have changed, and survival of RCC patients with BM has improved over time. The reasons for this improvement in survival remain unknown but may relate to more aggressive use of local brain metastasis therapy and a wider array of systemic treatment options for those patients with progressive extracranial tumor.
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http://dx.doi.org/10.1016/j.ijrobp.2018.04.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925530PMC
July 2018

The Use of Quantitative Imaging in Radiation Oncology: A Quantitative Imaging Network (QIN) Perspective.

Int J Radiat Oncol Biol Phys 2018 11 30;102(4):1219-1235. Epub 2018 Jun 30.

Department of Radiation Oncology, University of Iowa, Iowa City, Iowa.

Modern radiation therapy is delivered with great precision, in part by relying on high-resolution multidimensional anatomic imaging to define targets in space and time. The development of quantitative imaging (QI) modalities capable of monitoring biologic parameters could provide deeper insight into tumor biology and facilitate more personalized clinical decision-making. The Quantitative Imaging Network (QIN) was established by the National Cancer Institute to advance and validate these QI modalities in the context of oncology clinical trials. In particular, the QIN has significant interest in the application of QI to widen the therapeutic window of radiation therapy. QI modalities have great promise in radiation oncology and will help address significant clinical needs, including finer prognostication, more specific target delineation, reduction of normal tissue toxicity, identification of radioresistant disease, and clearer interpretation of treatment response. Patient-specific QI is being incorporated into radiation treatment design in ways such as dose escalation and adaptive replanning, with the intent of improving outcomes while lessening treatment morbidities. This review discusses the current vision of the QIN, current areas of investigation, and how the QIN hopes to enhance the integration of QI into the practice of radiation oncology.
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http://dx.doi.org/10.1016/j.ijrobp.2018.06.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348006PMC
November 2018

SBRT to adrenal metastases provides high local control with minimal toxicity.

Adv Radiat Oncol 2017 Oct-Dec;2(4):581-587. Epub 2017 Aug 4.

Department of Radiation Oncology, University of Iowa, Iowa City, Iowa.

Purpose: The adrenal glands are a common site of metastases because of their rich blood supply. Previously, adrenal metastases were treated with systemic chemotherapy or, more rarely, with surgical resection or palliative radiation therapy. Stereotactic body radiation therapy (SBRT) has recently emerged as an attractive noninvasive approach to definitively treat these lesions. We present our experience in treating adrenal metastases using SBRT and review the current literature.

Methods And Materials: This is a single-institution retrospective review of patients who received SBRT to adrenal metastases originating from various primary malignancies. Patients who were eligible for SBRT included those with limited metastatic disease (≤5 sites) with otherwise controlled metastatic disease and uncontrolled adrenal metastases.

Results: Ten patients met the study's inclusion criteria and received SBRT doses of 30 to 48 Gy in 3 to 5 fractions. Acute sequelae of SBRT treatment included 4 patients with grades 1 or 2 nausea, 3 patients with grade 1 fatigue, and 1 with grade 1 diarrhea. The median follow-up was 6 months with a median overall survival of 9.9 months. One patient demonstrated progressive adrenal gland disease 18.8 months after SBRT treatment. Seven patients developed new distant metastases after treatment, with a median progression-free survival of 3.4 months. Three months after SBRT to the adrenal gland, 1 patient developed a gastrointestinal bleed.

Conclusions: These results complement the limited existing body of literature by demonstrating that SBRT provides good control of treated adrenal gland metastasis; however, high-grade late toxicities may occur. More stringent dose constraint limits may prevent associated serious adverse events.
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http://dx.doi.org/10.1016/j.adro.2017.07.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707423PMC
August 2017