Publications by authors named "Christopher J Schultz"

54 Publications

BRCA1 Protein Expression Predicts Survival in Glioblastoma Patients from an NRG Oncology RTOG Cohort.

Oncology 2021 May 6:1-9. Epub 2021 May 6.

Department of Radiation Oncology, Weill Cornell Medicine, New York, New York, USA.

Purpose: Glioblastoma, the most common malignant brain tumor, was associated with a median survival of <1 year in the pre-temozolomide (TMZ) era. Despite advances in molecular and genetic profiling studies identifying several predictive biomarkers, none has been translated into routine clinical use. Our aim was to investigate the prognostic significance of a panel of diverse cellular molecular markers of tumor formation and growth in an annotated glioblastoma tissue microarray (TMA).

Methods And Materials: A TMA composed of archived glioblastoma tumors from patients treated with surgery, radiation, and non-TMZ chemother-apy, was provided by RTOG. RAD51, BRCA-1, phosphatase and tensin homolog tumor suppressor gene (PTEN), and miRNA-210 expression levels were assessed using quantitative in situ hybridization and automated quantitative protein analysis. The objectives of this analysis were to determine the association of each biomarker with overall survival (OS), using the Cox proportional hazard model. Event-time distributions were estimated using the Kaplan-Meier method and compared by the log-rank test.

Results: A cohort of 66 patients was included in this study. Among the 4 biomarkers assessed, only BRCA1 expression had a statistically significant correlation with survival. From univariate analysis, patients with low BRCA1 protein expression showed a favorable outcome for OS (p = 0.04; hazard ratio = 0.56) in comparison with high expressors, with a median survival time of 18.9 versus 4.8 months.

Conclusions: BRCA1 protein expression was an important survival predictor in our cohort of glioblastoma patients. This result may imply that low BRCA1 in the tumor and the consequent low level of DNA repair cause vulnerability of the cancer cells to treatment.
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http://dx.doi.org/10.1159/000516168DOI Listing
May 2021

The impact of age on outcome in phase III NRG Oncology/RTOG trials of radiotherapy (XRT) +/- systemic therapy in locally advanced head and neck cancer.

J Geriatr Oncol 2021 Apr 1. Epub 2021 Apr 1.

Stanford University, United States of America.

Purpose: To examine the role age plays in the treatment and prognosis of locally advanced head and neck cancer (LAHNC) treated definitively with radiation alone or combined modality therapy.

Methods: A retrospective analysis was performed of three NRG/RTOG trials examining either radiation alone or combined radiation and systemic therapy for LAHNC. The effect of age (≥70 yrs.) on cause-specific survival (CSS), overall survival (OS), and toxicity was evaluated.

Results: A total of 2688 patients were analyzed, of whom 309 patients (11.5%) were ≥ 70. For all studies combined, the hazard ratio (HR) for CSS for patients age ≥ 70 vs. those <70 was 1.33 (95%CI: 1.14-1.55, p < 0.001). For OS, the HR for patients age ≥ 70 vs. those <70 for all studies combined was 1.55 (95% CI 1.35-1.77, p < 0.001). After adjustment for all covariates, age ≥ 70 was associated with worse OS regardless of adjustment for smoking and p16 status. The survival difference was more pronounced in those receiving combined radiation and systemic therapy. Hematologic and renal toxicities were increased in combined modality trials in patients ≥70 years old.

Conclusions: Patients age ≥ 70 with LAHNC were underrepresented in these clinical trials. Their CSS and OS proved inferior to patients <70 years old.
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http://dx.doi.org/10.1016/j.jgo.2021.03.011DOI Listing
April 2021

In Reply to Peñagarícano.

Int J Radiat Oncol Biol Phys 2021 02;109(2):641

Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin.

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http://dx.doi.org/10.1016/j.ijrobp.2020.08.066DOI Listing
February 2021

Observations of lightning in relation to transitions in volcanic activity during the 3 June 2018 Fuego Eruption.

Sci Rep 2020 Oct 22;10(1):18015. Epub 2020 Oct 22.

Earth System Science Center, The University of Alabama in Huntsville, Huntsville, AL, USA.

Satellite and ground-based remote sensing are combined to characterize lightning occurrence during the 3 June 2018 Volcán de Fuego eruption in Guatemala. The combination of the space-based Geostationary Lightning Mapper (GLM) and ground-based Earth Networks Total Lightning Network observed two distinct periods of lightning during this eruption totaling 75 unique lightning flash occurrences over five hours (57 in cloud, 18 cloud-to-ground). The first period of lightning coincided with the rapid growth of the ash cloud, while the second maxima occurred near the time of a deadly pyroclastic density current (PDC) and thunderstorm. Ninety-one percent of the lightning during the event was observed by only one of the lightning sensors, thus showing the importance of combining lightning datasets across multiple frequencies to characterize electrical activity in volcanic eruptions. GLM flashes during the event had a median total optical energy and flash length of 16 fJ, and 12 km, respectively. These median GLM flash energies and lengths observed in the volcanic plume are on the lower end of the flash spectrum because flashes observed in surrounding thunderstorms on 3 June had larger median total optical energy values (130 fJ) and longer median flash lengths (20 km). All 18 cloud-to-ground flashes were negative polarity, supportive of net negative charge within the plume. Mechanisms for the generation of the secondary lightning maxima are discussed based on the presence and potential interaction between ash plume, thunderstorm, and PDC transport during this secondary period of observed lightning.
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http://dx.doi.org/10.1038/s41598-020-74576-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582158PMC
October 2020

The MOMENTUM Study: An International Registry for the Evidence-Based Introduction of MR-Guided Adaptive Therapy.

Front Oncol 2020 7;10:1328. Epub 2020 Sep 7.

Department of Radiation Oncology, University Medical Center Utrecht, Utrecht, Netherlands.

MR-guided Radiation Therapy (MRgRT) allows for high-precision radiotherapy under real-time MR visualization. This enables margin reduction and subsequent dose escalation which may lead to higher tumor control and less toxicity. The Unity MR-linac (Elekta AB, Stockholm, Sweden) integrates a linear accelerator with a 1.5T diagnostic quality MRI and an online adaptive workflow. A prospective international registry was established to facilitate the evidence-based implementation of the Unity MR-linac into clinical practice, to systemically evaluate long-term outcomes, and to aid further technical development of MR-linac-based MRgRT. In February 2019, the Multi-OutcoMe EvaluatioN of radiation Therapy Using the MR-linac study (MOMENTUM) started within the MR-linac Consortium. The MOMENTUM study is an international academic-industrial partnership between several hospitals and industry partner Elekta. All patients treated on the MR-linac are eligible for inclusion in MOMENTUM. For participants, we collect clinical patient data (e.g., patient, tumor, and treatment characteristics) and technical patient data which is defined as information generated on the MR-linac during treatment. The data are captured, pseudonymized, and stored in an international registry at set time intervals up to two years after treatment. Patients can choose to provide patient-reported outcomes and consent to additional MRI scans acquired on the MR-linac. This registry will serve as a data platform that supports multicenter research investigating the MR-linac. Rules and regulations on data sharing, data access, and intellectual property rights are summarized in an academic-industrial collaboration agreement. Data access rules ensure secure data handling and research integrity for investigators and institutions. Separate data access rules exist for academic and industry partners. This study is registered at ClinicalTrials.gov with ID: NCT04075305 (https://clinicaltrials.gov/ct2/show/NCT04075305). The multi-institutional MOMENTUM study has been set up to collect clinical and technical patient data to advance technical development, and facilitate evidenced-based implementation of MR-linac technology with the ultimate purpose to improve tumor control, survival, and quality of life of patients with cancer.
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http://dx.doi.org/10.3389/fonc.2020.01328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505056PMC
September 2020

Comprehensive Genomic Analysis in NRG Oncology/RTOG 9802: A Phase III Trial of Radiation Versus Radiation Plus Procarbazine, Lomustine (CCNU), and Vincristine in High-Risk Low-Grade Glioma.

J Clin Oncol 2020 10 24;38(29):3407-3417. Epub 2020 Jul 24.

The Ohio State University, Columbus, OH.

Purpose: NRG Oncology/RTOG 9802 (ClinicalTrials.gov Identifier: NCT00003375) is a practice-changing study for patients with WHO low-grade glioma (LGG, grade II), as it was the first to demonstrate a survival benefit of adjuvant chemoradiotherapy over radiotherapy. This post hoc study sought to determine the prognostic and predictive impact of the WHO-defined molecular subgroups and corresponding molecular alterations within NRG Oncology/RTOG 9802.

Methods: mutations were determined by immunohistochemistry and/or deep sequencing. A custom Ion AmpliSeq panel was used for mutation analysis. 1p/19q codeletion and promoter methylation were determined by copy-number arrays and/or Illumina 450K array, respectively. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Hazard ratios (HRs) were calculated using the Cox proportional hazard model and tested using the log-rank test. Multivariable analyses (MVAs) were performed incorporating treatment and common prognostic factors as covariates.

Results: Of the eligible patients successfully profiled for the WHO-defined molecular groups (n = 106/251), 26 (24%) were wild type, 43 (41%) were mutant/non-codeleted, and 37(35%) were mutant/codeleted. MVAs demonstrated that WHO subgroup was a significant predictor of PFS after adjustment for clinical variables and treatment. Notably, treatment with postradiation chemotherapy (PCV; procarbazine, lomustine (CCNU), and vincristine) was associated with longer PFS (HR, 0.32; = .003; HR, 0.13; < .001) and OS (HR, 0.38; = .013; HR, 0.21; = .029) in the mutant/non-codeleted and mutant/codeleted subgroups, respectively. In contrast, no significant difference in either PFS or OS was observed with the addition of PCV in the wild-type subgroup.

Conclusion: This study is the first to report the predictive value of the WHO-defined diagnostic classification in a set of uniformly treated patients with LGG in a clinical trial. Importantly, this post hoc analysis supports the notion that patients with -mutant high-risk LGG regardless of codeletion status receive benefit from the addition of PCV.
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http://dx.doi.org/10.1200/JCO.19.02983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527157PMC
October 2020

Pulsed Reduced Dose Rate Radiotherapy in Conjunction With Bevacizumab or Bevacizumab Alone in Recurrent High-grade Glioma: Survival Outcomes.

Int J Radiat Oncol Biol Phys 2020 11 27;108(4):979-986. Epub 2020 Jun 27.

Department of Radiation Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin.

Purpose: Dismal prognosis and limited treatment options for recurrent high-grade glioma have provoked interest in various forms of reirradiation. Pulsed reduced dose rate radiation therapy (pRDR) is a promising technique that exploits low-dose hyper-radiosensitivity of proliferating tumor cells while sparing adjacent nonproliferating normal brain tissue. Large radiation treatment volumes can thus be used to target both contrast-enhancing and FLAIR abnormalities thought to harbor recurrent gross and microscopic disease, respectively. The aim of this retrospective study was to determine whether the addition of pRDR to bevacizumab improves survival over bevacizumab alone for recurrent high-grade glioma.

Methods And Materials: Eighty patients with recurrent high-grade glioma were included in this study; 47 patients received bevacizumab monotherapy (BEV), and 33 patients received pRDR with bevacizumab (BEV/pRDR). Progression-free survival (PFS) and overall survival were compared between the BEV and BEV/pRDR groups. Regression analysis was performed to identify and control for confounding influences on survival analyses.

Results: Significant (P < .05) advantages in PFS (12 vs 4 months; hazard ratio = 2.37) and OS (16 vs. 9 months; hazard ratio = 1.68) were observed with BEV/pRDR compared with BEV alone.

Conclusions: This retrospective analysis suggests that treatment with pRDR in addition to bevacizumab could significantly prolong PFS and overall survival compared with bevacizumab alone for recurrent high-grade glioma.
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http://dx.doi.org/10.1016/j.ijrobp.2020.06.020DOI Listing
November 2020

The association between BMI and BSA-temozolomide-induced myelosuppression toxicities: a correlative analysis of NRG oncology RTOG 0525.

Neurooncol Pract 2019 Dec 6;6(6):473-478. Epub 2019 Apr 6.

Baptist Hospital of Miami, FL.

Background: Fearing increased myelotoxicity, many practitioners adjust the body surface area (BSA)-calculated doses in obese patients. Regarding temozolomide (TMZ), a prior study suggested men with a BSA >2 m may experience increased toxicity; however, surprisingly, the inverse observation was noted in women, ie, BSA <2 m was associated with higher toxicity. To further clarify this issue, data derived from a large clinical trial were analyzed.

Methods: The incidence of grade 3 and 4 myelotoxicity in a newly diagnosed glioblastoma phase 3 trial (RTOG 0525) was statistically correlated with BMI and separately with BSA. All patients received radiation and TMZ followed by adjuvant standard dose TMZ vs dose-dense TMZ; dosing regimen-associated myelotoxicity and BMI/BSA were analyzed separately. was defined as a BMI ≥30.

Results: There was no statistically significant correlation between gender and BSA and the occurrence of myotoxicities. For the standard arm, surprisingly the incidence of grade 3/4 myotoxicities in patients with a BMI <30 was significantly higher than in patients with a BMI ≥30 (12% vs 1%, odds ratio [OR] 12.5, < .001). There was no significant difference between obese and nonobese patients (BMI "cut-point" of 30) in the dose-dense arm (OR = 0.9, 95% confidence interval: 0.4-1.6). The grade hematological 3/4 toxicity rate was significantly higher in women vs men (14% vs 8%) = .009 in spite of the lack of association between gender and BSA or BMI.

Conclusion: TMZ dosing based on actual BSA is recommended with the caveat that woman are likely at higher toxicity risk.
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http://dx.doi.org/10.1093/nop/npz006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899045PMC
December 2019

The transformation of radiation oncology using real-time magnetic resonance guidance: A review.

Eur J Cancer 2019 11 12;122:42-52. Epub 2019 Oct 12.

Medical College of Wisconsin, Department of Radiation Oncology, USA.

Radiation therapy (RT) is an essential component of effective cancer care and is used across nearly all cancer types. The delivery of RT is becoming more precise through rapid advances in both computing and imaging. The direct integration of magnetic resonance imaging (MRI) with linear accelerators represents an exciting development with the potential to dramatically impact cancer research and treatment. These impacts extend beyond improved imaging and dose deposition. Real-time MRI-guided RT is actively transforming the work flows and capabilities of virtually every aspect of RT. It has the opportunity to change entirely the delivery methods and response assessments of numerous malignancies. This review intends to approach the topic of MRI-based RT guidance from a vendor neutral and international perspective. It also aims to provide an introduction to this topic targeted towards oncologists without a speciality focus in RT. Speciality implications, areas for physician education and research opportunities are identified as they are associated with MRI-guided RT. The uniquely disruptive implications of MRI-guided RT are discussed and placed in context. We further aim to describe and outline important future changes to the speciality of radiation oncology that will occur with MRI-guided RT. The impacts on RT caused by MRI guidance include target identification, RT planning, quality assurance, treatment delivery, training, clinical workflow, tumour response assessment and treatment scheduling. In addition, entirely novel research areas that may be enabled by MRI guidance are identified for future investigation.
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http://dx.doi.org/10.1016/j.ejca.2019.07.021DOI Listing
November 2019

Lymph node yield, depth of invasion, and survival in node-negative oral cavity cancer.

Oral Oncol 2019 11 3;98:125-131. Epub 2019 Oct 3.

Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, Saint Louis, MO, United States.

Objective: To determine the effects of nodal yield on survival in early stage oral cavity squamous cell carcinoma (OCSCC) in the context of primary tumor depth of invasion (DOI).

Materials And Methods: Patients with early-stage clinically node-negative OCSCC who underwent upfront surgery at the primary site were identified using the National Cancer Database between 2004 and 2015.

Results: There were 3384 patients with <4 mm DOI and 1387 patients with ≥4 mm DOI identified. Management of the neck included observation (40%), END with <18 nodes harvested ± postoperative radiation (ND < 18, 16%), and END with ≥18 nodes harvest ± postoperative radiation (ND ≥ 18, 44%). When adjusted for relevant covariates, ND ≥ 18 demonstrated statistically significant improvements in overall survival for both DOI < 4 mm and ≥4 mm (DOI < 4 mm: HR 0.67, 95%CI 0.54-0.85; DOI ≥ 4 mm: HR 0.47, 95%CI 0.34-0.64). However, ND < 18 showed no significant difference from observation of the neck regardless of DOI (DOI < 4 mm: HR 0.82, 95%CI 0.63-1.07; DOI ≥ 4 mm: HR 0.72, 95%CI 0.51-1.03). Of patients undergoing END, the most significant factors associated with obtaining a nodal yield of 18 or more were age less than 40 years (HR 2.58, 95%CI 1.84-3.63) and treatment at an academic facility (HR 2.47, 95%CI 2.06-2.96).

Conclusions: END with 18 or more nodes is associated with improved survival outcomes in patients with early stage OCSCC regardless of DOI. END with less than 18 nodes, however, does not appear significantly different than observation of the neck alone. Achieving a lymph node yield of 18 or more is multifactorial and includes both patient and provider factors.
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http://dx.doi.org/10.1016/j.oraloncology.2019.09.028DOI Listing
November 2019

Intermediate-grade carcinoma of the parotid and the impact of adjuvant radiation.

Am J Otolaryngol 2019 Nov - Dec;40(6):102282. Epub 2019 Sep 6.

Department of Otolaryngology and Communication Sciences, Medical College of Wisconsin, Milwaukee, WI, United States of America. Electronic address:

Purpose: To determine the influence of adjuvant radiotherapy on survival in surgically-managed early stage intermediate-grade mucoepidermoid and acinic cell carcinoma of the parotid.

Materials And Methods: The National Cancer Database was reviewed between 2004 and 2015 to identify patients with intermediate-grade, early T-stage, node-negative parotid carcinoma who underwent parotidectomy ± radiotherapy.

Results: There were 744 patients identified of which 81% had mucoepidermoid carcinoma and 19% had acinic cell carcinoma. Positive surgical margins were identified in 21% and adjuvant radiotherapy was administered in 38% of cases. Of the 159 patients with positive margins, 113 (71%) received adjuvant radiotherapy. Of the 585 patients with negative margins, 173 (30%) underwent adjuvant radiotherapy. In multivariable analysis, age (over 52 years: HR 5.19, 95%CI 2.33-11.57), insurance status (private insurance: HR 0.24 95%CI 0.13-0.43), and extent of parotidectomy (total parotidectomy: HR 2.02 95%CI 1.23-3.31) were significantly associated with overall survival, while adjuvant radiotherapy was not a significant predictive factor (HR 0.81, 95%CI 0.49-1.36). In patients with positive margin resections, however, adjuvant radiation was an independent predictor of improved survival when adjusted for age, insurance status, and extent of parotidectomy (HR 0.34, 95%CI 0.13-0.88). Conversely, in patients with negative margin resections, adjuvant radiation did not influence survival outcomes when adjusted for these covariates (HR 1.02, 95%CI 0.53-1.93).

Conclusions And Relevance: In patients with early stage intermediate-grade parotid carcinoma, adjuvant radiotherapy significantly and independently improves survival in those with post-operative positive margins. Adjuvant therapy, however, does not appear to improve survival outcomes in those with negative margin resections.
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http://dx.doi.org/10.1016/j.amjoto.2019.102282DOI Listing
April 2020

Spatial, Temporal, and Electrical Characteristics of Lightning in Reported Lightning-Initiated Wildfire Events.

Fire (Basel) 2019 Jun 3;2(2). Epub 2019 Apr 3.

Earth System Science Center, University of Alabama in Huntsville, Huntsville, AL.

Analysis was performed to determine if a lightning flash could be associated with every reported lightning-initiated wildfire that grew to at least 4 km. In total, 905 lightning-initiated wildfires within CONUS between 2012 and 2015 were analyzed. Fixed and fire radius search methods showed that 81-88% of wildfires had a corresponding lightning flash within a 14 day period prior to the report date. The two methods showed that 52-60% of lightning-initiated wildfire were reported on the same day as the closest lightning flash. The fire radius method indicated the most promising spatial results, where the median distance between the closest lightning and the wildfire start location was 0.83 km, followed by a 75 percentile of 1.6 km, and a 95 percentile of 5.86 km. Ninety percent of the closest lightning flashes to wildfires were negative polarity. Maximum flash densities were less than 0.41 flashes km2 for the 24 hour period at the fire start location. The majority of lightning-initiated holdover events were observed in the Western CONUS, with a peak density in north-central Idaho. A twelve day holdover event from New Mexico was also discussed; outlining the opportunities and limitations of using lightning data to characterize wildfires.
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http://dx.doi.org/10.3390/fire2020018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662225PMC
June 2019

Serial T2-Weighted Magnetic Resonance Images Acquired on a 1.5 Tesla Magnetic Resonance Linear Accelerator Reveal Radiomic Feature Variation in Organs at Risk: An Exploratory Analysis of Novel Metrics of Tissue Response in Prostate Cancer.

Cureus 2019 Apr 20;11(4):e4510. Epub 2019 Apr 20.

Radiation Oncology, Medical College of Wisconsin, Milwaukee, USA.

"Delta-radiomics" investigates variations in quantitative image metrics over time and can yield important clinical information. We hypothesized that in patients undergoing active radiation therapy (RT) for prostate cancer (PCa), there would exist observable variation in the quantitative metrics that describe the T-weighted (T) intensity histogram in the prostate and surrounding organs at risk (OAR) over time. We investigated the feasibility of acquisition and subsequent analysis of the delta-radiomic profiles of these regions of interest (ROI) in serial T magnetic resonance (MR) images obtained on a 1.5 Tesla (T) Magnetic Resonance Linear Accelerator (MRL). Principally, we sought to illustrate the significance of longitudinal radiomic data acquisition for tissue response monitoring and provide a framework for future hypothesis driven research. Patients with PCa undergoing treatment with RT were compiled from an ongoing prospective observational imaging trial using a 1.5 T MRL (NCT30500081). Contiguous axial slices of prostate parenchyma were contoured and temporally normalized to sections of Sartorius muscle which served as a control. Similarly, contiguous sections of rectal and bladder wall adjacent to the prostate were contoured and temporally normalized to regions of these organs further removed from the planning target volume (PTV). First order statistical descriptors of the T intensity histogram were extracted and evaluated for changes over time using linear mixed effects regression modeling and post-hoc contrasts. Benjamini-Hochberg corrections were employed to reduce the effects of multiple testing and control for the false discovery rate (FDR). Four patients with a median age of 69 comprised this exploratory cohort. One patient had low-risk disease, two had intermediate (one favorable, one unfavorable), and one had high risk disease. Three out of four patients underwent definitive radiation to 75.6 Gray (Gy) in 42 fractions and one received hypofractionated therapy to a total dose of 70 Gy over 28 fractions, and all received treatment on a conventional linear accelerator. The most significant acute toxicity event was grade 2 GU dysfunction observed in two patients. Follow up ranged from 1 month to 10 months post treatment, and no long-term complications were reported in patients who completed treatment at least one month prior. Bladder wall adjacent to the prostate demonstrated significant variation in the mean and median metric values after the first week of treatment. In addition, rectal wall adjacent to the prostate exhibited significant variation in the mean, median, and standard deviation metric values by the second week of treatment. No significant variation in any radiomic feature was observed in the Sartorius control. This exploratory study is one of the earliest examining the delta-radiomic characteristics of the T intensity histogram in OAR extracted from images acquired on a 1.5 T MRL in patients actively being treated with RT for PCa. We demonstrated a feasible approach to longitudinal radiomic data acquisition providing limitless opportunity for future research. Analysis of the delta-radiomic profiles in OAR revealed significant variation in metrics after only one week of RT in bladder and rectal wall adjacent to the prostate. These findings must be further investigated and validated with expanded data sets with long-term follow up and correlation to clinical outcomes including toxicity and tumor control.
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http://dx.doi.org/10.7759/cureus.4510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590865PMC
April 2019

Lymph node yield from neck dissection in HPV-associated oropharyngeal cancer.

Laryngoscope 2020 03 17;130(3):666-671. Epub 2019 Jun 17.

Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, Saint Louis, Missouri, U.S.A.

Objectives: To determine the influence of nodal yield during neck dissection on survival in surgically managed human papillomavirus (HPV)-associated oropharyngeal cancer.

Methods: The National Cancer Database was used to identify patients with HPV-associated tumor T1 to T2 oropharyngeal squamous cell carcinoma who underwent upfront surgery with or without adjuvant therapy. Patients were stratified by lymph node yield (<26 vs. ≥26 nodes). Multivariable Cox proportional hazards regression analysis was used to identify factors associated with overall survival. Models were stratified by pathologically positive node number.

Results: There were 2,554 patients identified with previously untreated T1 to T2 oropharyngeal squamous cell carcinoma who underwent resection of the primary tumor and neck dissection between 2010 and 2015. Fifty-two percent had zero to one pathologically involved lymph node. Among all study patients, lymph node harvest of ≥26 was not associated with survival when adjusted for relevant covariates (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.49-1.00). However, in patients with zero to one pathologically involved node, lymph node harvest of ≥26 was significantly associated with improved overall survival (HR 0.29, 95% CI 0.20-0.78). This survival benefit was lost in patients with two or more positive nodes (2-4 positive nodes: HR 0.89, 95% CI 0.52-1.51; 5 or more positive nodes: HR 1.01, 95% CI 0.47-2.20).

Conclusion: For patients with surgically managed early T-stage HPV-associated oropharyngeal squamous cell carcinoma, lymph node yield was not associated with survival outcomes for patients with multiple positive lymph nodes. Those with a more limited burden of regional metastatic disease, however, may benefit harvest of at least 26 nodes during neck dissection.

Level Of Evidence: 4 Laryngoscope, 130:666-671, 2020.
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http://dx.doi.org/10.1002/lary.28102DOI Listing
March 2020

Salvage of Recurrence after Surgery and Adjuvant Therapy: A Multi-institutional Study.

Otolaryngol Head Neck Surg 2019 07 12;161(1):74-81. Epub 2019 Feb 12.

9 Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, Saint Louis, Missouri, USA.

Objectives: To determine the oncologic outcomes of patients undergoing salvage surgery for recurrent oral cavity squamous cell carcinoma (OCSCC) and oropharyngeal squamous cell carcinoma (OPSCC) after initial treatment with surgery and adjuvant therapy.

Study Design: Retrospective case series with chart review.

Setting: Five academic tertiary care centers.

Subjects And Methods: Patients included those with OCSCC and OPSCC who were initially treated with surgery and adjuvant therapy between 2000 and 2015 and underwent salvage surgery for local and/or regional recurrence.

Results: A total of 102 patients were included (76% OCSCC, 24% OPSCC). Five-year overall survival was 31% (95% CI, 21%-41%) and was significantly improved among patients with human papillomavirus-associated oropharyngeal tumors (hazard ratio [HR], 0.34; 95% CI, 0.11-0.98) and significantly worse for those with postoperative positive margins (HR, 2.65; 95% CI, 1.43-4.93). Adjuvant (chemo)reirradiation was not associated with disease control or survival regardless of margin status. Combined locoregional recurrence was significantly correlated with a positive margin resection (HR, 5.75; 95% CI, 1.94-17.01). Twenty-five patients (25%) underwent a second salvage surgical procedure, of whom 8 achieved long-term disease control.

Conclusion: Patients presenting with resectable recurrence after initial therapy with surgery and adjuvant therapy have a reasonable salvage rate when a negative margin resection can be attained. Patients with postoperative positive margins have poor survival outcomes that are not significantly improved with adjuvant (chemo)reirradiation. Those with combined locoregional recurrence are at particularly high risk for postoperative positive margins. The functional consequences of salvage surgery and its effect on quality of life are critical in decision making and require further investigation.
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http://dx.doi.org/10.1177/0194599819830664DOI Listing
July 2019

Association of MGMT Promoter Methylation Status With Survival Outcomes in Patients With High-Risk Glioma Treated With Radiotherapy and Temozolomide: An Analysis From the NRG Oncology/RTOG 0424 Trial.

JAMA Oncol 2018 10;4(10):1405-1409

Department of Radiation Oncology, The Ohio State University, Columbus.

Importance: The initial report of NRG Oncology/Radiation Therapy Oncology Group (RTOG) 0424 demonstrated a 3-year overall survival benefit with the addition of temozolomide to radiotherapy compared with a historical control. However, an important end point of the trial-evaluation of the association between O6-methylgaunine-DNA-methyltransferase (MGMT) promoter methylation and survival outcomes-was not previously reported.

Objective: To examine the proportion of patients in NRG Oncology/RTOG 0424 with MGMT promoter methylation and its association with survival outcomes.

Design, Setting, And Participants: Specimens collected were analyzed after trial completion to determine MGMT promoter methylation and IDH1/2 status and the association between MGMT status and survival outcomes. A model derived from logistic regression (MGMT-STP27) was used to calculate MGMT promoter methylation status. Univariate and multivariable analyses were performed using the Cox proportional hazards regression model to determine the association of MGMT status with survival outcomes. Patient pretreatment characteristics were included as covariates in multivariable analyses.

Main Outcomes And Measures: Progression-free survival (PFS) and overall survival (OS).

Results: Of all 129 eligible patients in NRG Oncology/RTOG 0424, 75 (58.1%) had MGMT status available (median age, 48 years; age range, 20-76 years; 42 [56.0%] male): 57 (76.0%) methylated and 18 (24.0%) unmethylated. A total of 13 unmethylated patients (72.2%) had astrocytoma as opposed to oligoastrocytoma or oligodendroglioma, whereas 23 methylated patients (40.4%) had astrocytoma. On univariate analyses, an unmethylated MGMT promoter was significantly associated with worse OS (hazard ratio [HR], 3.52; 95% CI, 1.64-7.56; P < .001) and PFS (HR, 3.06; 95% CI, 1.55-6.04; P < .001). The statistical significances were maintained in multimarker multivariable analyses, including IDH1/2 status for both OS (HR, 2.70; 95% CI, 1.02-7.14; P = .045) and PFS (HR, 2.74; 95% CI, 1.19-6.33; P = .02).

Conclusions And Relevance: In this study, MGMT promoter methylation was an independent prognostic biomarker of high-risk, low-grade glioma treated with temozolomide and radiotherapy. This is the first study, to our knowledge, to validate the prognostic importance of MGMT promoter methylation in patients with grade II glioma treated with combined radiotherapy and temozolomide and highlights its potential prognostic value beyond IDH1/2 mutation status.

Trial Registration: ClinicalTrials.gov Identifier: NCT00114140.
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http://dx.doi.org/10.1001/jamaoncol.2018.1977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6117103PMC
October 2018

Characteristics of Lightning within Electrified Snowfall Events using Lightning Mapping Arrays.

J Geophys Res Atmos 2018 Feb 6;123(4):2347-2367. Epub 2018 Feb 6.

Department of Atmospheric Science, the University of Alabama-Huntsville, Huntsville, AL, 35805.

This study examined 34 lightning flashes within four separate thundersnow events derived from lightning mapping arrays (LMAs) in northern Alabama, central Oklahoma, and Washington DC. The goals were to characterize the in-cloud component of each lightning flash, as well as the correspondence between the LMA observations and lightning data taken from national lightning networks like the National Lightning Detection Network (NLDN). Individual flashes were examined in detail to highlight several observations within the dataset. The study results demonstrated that the structures of these flashes were primarily normal polarity. The mean area encompassed by this set of flashes is 375 km, with a maximum flash extent of 2300 km, a minimum of 3 km, and a median of 128 km. An average of 2.29 NLDN flashes were recorded per LMA-derived lightning flash. A maximum of 11 NLDN flashes were recorded in association with a single LMA-derived flash on 10 January 2011. Additionally, seven of the 34 flashes in the study contain zero NLDN identified flashes. Eleven of the 34 flashes initiated from tall human-made objects (e.g., communication towers). In at least six lightning flashes, the NLDN detected a return stroke from the cloud back to the tower and not the initial upward leader. This study also discusses lightning's interaction with the human built environment and provides an example of lightning within heavy snowfall observed by GOES-16's Geostationary Lightning Mapper.
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http://dx.doi.org/10.1002/2017JD027821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999043PMC
February 2018

NRG oncology RTOG 9006: a phase III randomized trial of hyperfractionated radiotherapy (RT) and BCNU versus standard RT and BCNU for malignant glioma patients.

J Neurooncol 2018 Mar 5;137(1):39-47. Epub 2018 Feb 5.

Emory University/Winship Cancer Institute, 1365 Clifton Rd NE, Atlanta, GA, 30322, USA.

From 1990 to 1994, patients with newly diagnosed malignant gliomas were enrolled and randomized between hyperfractionated radiation (HFX) of 72.0 Gy in 60 fractions given twice daily and 60.0 Gy in 30 fractions given once daily. All patients received 80 mg/m of 1,3 bis(2 chloroethyl)-1 nitrosourea on days 1-3 q8 weeks for 1 year. Patients were stratified by age, KPS, and histology. The primary endpoint was overall survival (OS), with secondary endpoints including progression-free survival (PFS) and toxicity. Out of the 712 patients accrued, 694 (97.5%) were analyzable cases (350 HFX, 344 standard arm). There was no significant difference between the arms on overall acute or late treatment-related toxicity. No statistically significant effect for HFX, as compared to standard therapy, was found on either OS, with a median survival time (MST) of 11.3 versus 13.1 months (p = 0.20) or PFS, with a median PFS time of 5.7 versus 6.9 months (p = 0.18). The treatment effect on OS remained insignificant based on the multivariate analysis (hazard ratio 1.16; p = 0.0682). When OS was analyzed by histology subgroup there was also no significant difference between the two arms for patients with glioblastoma multiforme (MST: 10.3 vs. 11.2 months; p = 0.34), anaplastic astrocytoma (MST: 69.8 vs. 50.0 months; p = 0.91) or anaplastic oligodendroglioma (MST: 92.1 vs. 66.5 months; p = 0.33). Though this trial provided many invaluable secondary analyses, there was no trend or indication of a benefit to HFX radiation to 72.0 Gy in any subset of malignant glioma patients.
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http://dx.doi.org/10.1007/s11060-017-2558-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6020014PMC
March 2018

Kinematic and Microphysical Significance of Lightning Jumps versus Non-Jump Increases in Total Flash Rate.

Weather Forecast 2017 Feb 25;32(1):275-288. Epub 2017 Jan 25.

NASA Marshall Space Flight Center, Huntsville, Alabama.

Thirty-nine thunderstorms are examined using multiple-Doppler, polarimetric and total lightning observations to understand the role of mixed phase kinematics and microphysics in the development of lightning jumps. This sample size is larger than those of previous studies on this topic. The principal result of this study is that lightning jumps are a result of mixed phase updraft intensification. Larger increases in intense updraft volume (≥ 10 m s) and larger changes in peak updraft speed are observed prior to lightning jump occurrence when compared to other non-jump increases in total flash rate. Wilcoxon-Mann-Whitney Rank Sum testing yields p-values ≤0.05, indicating statistical independence between lightning jump and non-jump distributions for these two parameters. Similar changes in mixed phase graupel mass magnitude are observed prior to lightning jumps and non-jump increases in total flash rate. The p-value for graupel mass change is p=0.096, so jump and non-jump distributions for graupel mass change are not found statistically independent using the p=0.05 significance level. Timing of updraft volume, speed and graupel mass increases are found to be 4 to 13 minutes in advance of lightning jump occurrence. Also, severe storms without lightning jumps lack robust mixed phase updrafts, demonstrating that mixed phase updrafts are not always a requirement for severe weather occurrence. Therefore, the results of this study show that lightning jump occurrences are coincident with larger increases in intense mixed phase updraft volume and peak updraft speed than smaller non-jump increases in total flash rate.
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http://dx.doi.org/10.1175/WAF-D-15-0175.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5693383PMC
February 2017

Precision Oncology and Genomically Guided Radiation Therapy: A Report From the American Society for Radiation Oncology/American Association of Physicists in Medicine/National Cancer Institute Precision Medicine Conference.

Int J Radiat Oncol Biol Phys 2018 06 9;101(2):274-284. Epub 2017 Jun 9.

Departments of Radiation Oncology, Urology, and Medicine and the Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.

Purpose: To summarize important talking points from a 2016 symposium focusing on real-world challenges to advancing precision medicine in radiation oncology, and to help radiation oncologists navigate the practical challenges of precision, radiation oncology.

Methods And Materials: The American Society for Radiation Oncology, American Association of Physicists in Medicine, and National Cancer Institute cosponsored a meeting on precision medicine in radiation oncology. In June 2016 numerous scientists, clinicians, and physicists convened at the National Institutes of Health to discuss challenges and future directions toward personalized radiation therapy. Various breakout sessions were held to discuss particular components and approaches to the implementation of personalized radiation oncology. This article summarizes the genomically guided radiation therapy breakout session.

Results: A summary of existing genomic data enabling personalized radiation therapy, ongoing clinical trials, current challenges, and future directions was collected. The group attempted to provide both a current overview of data that radiation oncologists could use to personalize therapy, along with data that are anticipated in the coming years. It seems apparent from the provided review that a considerable opportunity exists to truly bring genomically guided radiation therapy into clinical reality.

Conclusions: Genomically guided radiation therapy is a necessity that must be embraced in the coming years. Incorporating these data into treatment recommendations will provide radiation oncologists with a substantial opportunity to improve outcomes for numerous cancer patients. More research focused on this topic is needed to bring genomic signatures into routine standard of care.
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http://dx.doi.org/10.1016/j.ijrobp.2017.05.044DOI Listing
June 2018

Technical Note: Dose effects of 1.5 T transverse magnetic field on tissue interfaces in MRI-guided radiotherapy.

Med Phys 2016 Aug;43(8):4797

Department of Radiation Oncology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226.

Purpose: The integration of MRI with a linear accelerator (MR-linac) offers great potential for high-precision delivery of radiation therapy (RT). However, the electron deflection resulting from the presence of a transverse magnetic field (TMF) can affect the dose distribution, particularly the electron return effect (ERE) at tissue interfaces. The purpose of the study is to investigate the dose effects of ERE at air-tissue and lung-tissue interfaces during intensity-modulated radiation therapy (IMRT) planning.

Methods: IMRT and volumetric modulated arc therapy (VMAT) plans for representative pancreas, lung, breast, and head and neck (HN) cases were generated following commonly used clinical dose volume (DV) criteria. In each case, three types of plans were generated: (1) the original plan generated without a TMF; (2) the reconstructed plan generated by recalculating the original plan with the presence of a TMF of 1.5 T (no optimization); and (3) the optimized plan generated by a full optimization with TMF = 1.5 T. These plans were compared using a variety of DV parameters, including V100%, D95%, DHI [dose heterogeneity index: (D20%-D80%)/Dprescription], Dmax, and D1cc in OARs (organs at risk) and tissue interface. All the optimizations and calculations in this work were performed on static data.

Results: The dose recalculation under TMF showed the presence of the 1.5 T TMF can slightly reduce V100% and D95% for PTV, with the differences being less than 4% for all but one lung case studied. The TMF results in considerable increases in Dmax and D1cc on the skin in all cases, mostly between 10% and 35%. The changes in Dmax and D1cc on air cavity walls are dependent upon site, geometry, and size, with changes ranging up to 15%. The VMAT plans lead to much smaller dose effects from ERE compared to fixed-beam IMRT in pancreas case. When the TMF is considered in the plan optimization, the dose effects of the TMF at tissue interfaces (e.g., air-cavity wall, lung-tissue interfaces, skin) are significantly reduced in most cases.

Conclusions: The doses on tissue interfaces can be significantly changed by the presence of a TMF during MR-guided RT when the magnetic field is not included in plan optimization. These changes can be substantially reduced or even eliminated during VMAT/IMRT optimization that specifically considers the TMF, without deteriorating overall plan quality.
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http://dx.doi.org/10.1118/1.4959534DOI Listing
August 2016

Radiation plus Procarbazine, CCNU, and Vincristine in Low-Grade Glioma.

N Engl J Med 2016 Apr;374(14):1344-55

From the Mayo Clinic, Rochester, MN (J.C.B.); Wake Forest University School of Medicine, Winston-Salem (E.G.S.), and Triangle Neurosurgeons, Raleigh (D. Bullard) - both in North Carolina; NRG Oncology Statistics and Data Management Center, Philadelphia (S.L.P., M.W.); Ohio State University, Columbus (A.C., E.H.B.), and Cleveland Clinic, Cleveland (J.H.S.) - both in Ohio; M.D. Anderson Cancer Center, University of Texas, Houston (M.R.G., P.D.B.); Wayne State University, Detroit (G.R.B., H.K.); Barrow Neurological Institute (S.C.) and Arizona Oncology Services Foundation (D. Brachman) - both in Phoenix; Radiology Imaging Associates, Englewood, CO (P.R.); Mid-Columbia Medical Center, The Dalles, OR (K.S.); Medical College of Wisconsin, Milwaukee (C.J.S.); Centre Hospitalier de l'Université de Montréal, Montreal (J.-P.B.), the London Regional Cancer Program, London, ON (B.J.F.), and the Cross Cancer Institute, Edmonton, AB (A.D.M.) - all in Canada; University of Maryland, Baltimore (M.P.M.); and Emory University, Atlanta (W.J.C.).

Background: Grade 2 gliomas occur most commonly in young adults and cause progressive neurologic deterioration and premature death. Early results of this trial showed that treatment with procarbazine, lomustine (also called CCNU), and vincristine after radiation therapy at the time of initial diagnosis resulted in longer progression-free survival, but not overall survival, than radiation therapy alone. We now report the long-term results.

Methods: We included patients with grade 2 astrocytoma, oligoastrocytoma, or oligodendroglioma who were younger than 40 years of age and had undergone subtotal resection or biopsy or who were 40 years of age or older and had undergone biopsy or resection of any of the tumor. Patients were stratified according to age, histologic findings, Karnofsky performance-status score, and presence or absence of contrast enhancement on preoperative images. Patients were randomly assigned to radiation therapy alone or to radiation therapy followed by six cycles of combination chemotherapy.

Results: A total of 251 eligible patients were enrolled from 1998 through 2002. The median follow-up was 11.9 years; 55% of the patients died. Patients who received radiation therapy plus chemotherapy had longer median overall survival than did those who received radiation therapy alone (13.3 vs. 7.8 years; hazard ratio for death, 0.59; P=0.003). The rate of progression-free survival at 10 years was 51% in the group that received radiation therapy plus chemotherapy versus 21% in the group that received radiation therapy alone; the corresponding rates of overall survival at 10 years were 60% and 40%. A Cox model identified receipt of radiation therapy plus chemotherapy and histologic findings of oligodendroglioma as favorable prognostic variables for both progression-free and overall survival.

Conclusions: In a cohort of patients with grade 2 glioma who were younger than 40 years of age and had undergone subtotal tumor resection or who were 40 years of age or older, progression-free survival and overall survival were longer among those who received combination chemotherapy in addition to radiation therapy than among those who received radiation therapy alone. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00003375.).
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http://dx.doi.org/10.1056/NEJMoa1500925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5170873PMC
April 2016

Phase I and II Study of Induction Chemotherapy With Methotrexate, Rituximab, and Temozolomide, Followed By Whole-Brain Radiotherapy and Postirradiation Temozolomide for Primary CNS Lymphoma: NRG Oncology RTOG 0227.

J Clin Oncol 2016 05 28;34(14):1620-5. Epub 2016 Mar 28.

Jon Glass and Maria Werner-Wasik, Thomas Jefferson University; Minhee Won, NRG Oncology Statistics and Data Management Center, Philadelphia, PA; Christopher J. Schultz and Joseph A. Bovi, Medical College of Wisconsin, Milwaukee, WI; Daniel Brat, Emory University, Atlanta, GA; Nancy L. Bartlett, Washington University School of Medicine, St Louis, MO; John H. Suh, Cleveland Clinic, Cleveland, OH; Barbara Jean Fisher, London Regional Cancer Program, London, Ontario, Canada; Marcia K. Liepman, Kalamazoo CCOP-West Michigan Cancer Center, Kalamazoo, MI; Mark Augspurger, Florida Radiation Oncology Group and Baptist Regional, Jacksonville, FL; Felix Bokstein, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel; Matthew C. Solhjem, Columbia River CCOP, Portland, OR; and Minesh P. Mehta, University of Maryland Medical Systems, Baltimore, MD.

Purpose: This study investigated the treatment of primary CNS lymphoma with methotrexate, temozolomide (TMZ), and rituximab, followed by hyperfractionated whole-brain radiotherapy (hWBRT) and subsequent TMZ. The primary phase I end point was the maximum tolerated dose of TMZ. The primary phase II end point was the 2-year overall survival (OS) rate. Secondary end points were preirradiation response rates, progression-free survival (PFS), neurologic toxicities, and quality of life.

Patients And Methods: The phase I study increased TMZ doses from 100 to 150 to 200 mg/m(2). Patients were treated with rituximab 375 mg/m(2) 3 days before cycle 1; methotrexate 3.5 g/m(2) with leucovorin on weeks 1, 3, 5, 7, and 9; TMZ daily for 5 days on weeks 4 and 8; hWBRT 1.2 Gy twice-daily on weeks 11 to 13 (36 Gy); and TMZ 200 mg/m(2) daily for 5 days every 28 days on weeks 14 to 50.

Results: Thirteen patients (one ineligible) were enrolled in phase I of the study. The maximum tolerated dose of TMZ was 100 mg/m(2). Dose-limiting toxicities were hepatic and renal. In phase II, 53 patients were treated. Median follow-up for living eligible patients was 3.6 years, and 2-year OS and PFS were 80.8% and 63.6%, respectively. Compared with historical controls from RTOG-9310, 2-year OS and PFS were significantly improved (P = .006 and .030, respectively). In phase II, the objective response rate was 85.7%. Among patients, 66% (35 of 53) had grade 3 and 4 toxicities before hWBRT, and 45% (24 of 53) of patients experienced grade 3 and 4 toxicities attributable to post-hWBRT chemotherapy. Cognitive function and quality of life improved or stabilized after hWBRT.

Conclusion: This regimen is safe, with the best 2-year OS and PFS achieved in any Radiation Therapy Oncology Group primary CNS lymphoma trial. Randomized trials that incorporate this regimen are needed to determine its efficacy compared with other strategies.
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http://dx.doi.org/10.1200/JCO.2015.64.8634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872318PMC
May 2016

Automated Storm Tracking and the Lightning Jump Algorithm Using GOES-R Geostationary Lightning Mapper (GLM) Proxy Data.

J Operat Meteorol 2016 28;4(7):92-107. Epub 2016 Jun 28.

USRA, Huntsville, AL.

This study develops a fully automated lightning jump system encompassing objective storm tracking, Geostationary Lightning Mapper proxy data, and the lightning jump algorithm (LJA), which are important elements in the transition of the LJA concept from a research to an operational based algorithm. Storm cluster tracking is based on a product created from the combination of a radar parameter (vertically integrated liquid, VIL), and lightning information (flash rate density). Evaluations showed that the spatial scale of tracked features or storm clusters had a large impact on the lightning jump system performance, where increasing spatial scale size resulted in decreased dynamic range of the system's performance. This framework will also serve as a means to refine the LJA itself to enhance its operational applicability. Parameters within the system are isolated and the system's performance is evaluated with adjustments to parameter sensitivity. The system's performance is evaluated using the probability of detection (POD) and false alarm ratio (FAR) statistics. Of the algorithm parameters tested, sigma-level (metric of lightning jump strength) and flash rate threshold influenced the system's performance the most. Finally, verification methodologies are investigated. It is discovered that minor changes in verification methodology can dramatically impact the evaluation of the lightning jump system.
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http://dx.doi.org/10.15191/nwajom.2016.0407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5749929PMC
June 2016

Predictive value of tumor recurrence using urinary vascular endothelial factor levels in patients receiving radiation therapy for Glioblastoma Multiforme (GBM).

Biomark Res 2013 Oct 31;1(1):29. Epub 2013 Oct 31.

National Cancer Institute/NIH, Bethesda, MD, USA.

Background: Glioblastoma Multiforme (GBM) is the most common primary malignant tumor of the central nervous system. Standard of care includes maximal resection followed by chemoradiotherapy. Tumors need adequate perfusion and neovascularization to maintain oxygenation and for removal of wastes. Vascular endothelial growth factor (VEGF) is a well characterized pro-angiogenic factor. We hypothesized that the increases in urinary VEGF levels would occur early in the course of tumor recurrence or progression. We examine the feasibility of collecting and analyzing urinary VEGF levels in a prospective, multi-institutional trial (Radiation Therapy Oncology Group, RTOG, 0611) as well as the role of VEGF as a marker of tumor recurrence.

Method: We evaluated VEGF levels in urine specimens collected post-operatively, at the conclusion of radiation therapy (RT) and one month following RT. Urinary VEGF levels were correlated with tumor progression at one year. VEGF levels were measured by enzyme-linked immunosorbant assay in urine specimens and normalized to urinary creatinine levels. Sample size was determined based on a 50% 1-year recurrence rate. With a sensitivity and specificity of 80%, the expected 95% confidence interval was (0.69, 0.91) with 100 patients. A failure was defined as documented disease progression, recurrence or death before one year.

Results: 202 patients were enrolled between February-2006 and October-2007. Four patients were ineligible as they did not receive RT. Of the remaining 198 patients, 128 had all three samples collected. In this group, 35 patients (27.3%) did not progress, 89 (69.5%) had progression and 4 (3.1%) died without evidence of progression. Median VEGF levels at baseline were 52.9 pg/mg Cr (range 0.2- 15,034.4); on the last day of RT, 56.6 (range 0-2,377.1); and at one month follow-up, 70.0 (range 0.1-1813.2). In patients without progression at 1-year, both baseline VEGF level and end of RT VEGF level were lower than those of patients who progressed: 40.3 (range 0.2-350.8) vs. 59.7 (range 1.3-15,034.4) and 41.8 (range 0-356.8) vs. 69.7 (range 0-2,377.1), respectively. This did not reach statistical significance. Comparison of the change in VEGF levels between the end of RT and one month following RT, demonstrated no significant difference in the proportions of progressors or non-progressors at 1-year for either the VEGF increased or VEGF decreased groups.

Conclusion: Urine can be collected and analyzed in a prospective, multi-institutional trial. In this study of patients with GBM a change in urinary VEGF levels between the last day of RT and the one month following RT did not predict for tumor progression by one year.
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http://dx.doi.org/10.1186/2050-7771-1-29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4177620PMC
October 2013

Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial.

J Clin Oncol 2013 Nov 7;31(32):4085-91. Epub 2013 Oct 7.

Mark R. Gilbert, Kenneth D. Aldape, Terri S. Armstrong, Jeffrey S. Wefel, Anita Mahajan, and Paul D. Brown, University of Texas MD Anderson Cancer Center; Terri S. Armstrong, University of Texas Health Science Center-School of Nursing, Houston, TX; Meihua Wang and Minhee Won, Radiation Therapy Oncology Group Statistical Center, Philadelphia, PA; Roger Stupp and Monika E. Hegi, Lausanne University Hospitals, Lausanne, Switzerland; Kurt A. Jaeckle, Mayo Clinic Florida, Jacksonville, FL; Deborah T. Blumenthal, Tel Aviv Medical Center, Tel Aviv; Tzahala Tzuk-Shina, Rambam Medical Center, Haifa, Israel; Christopher J. Schultz, Medical College of Wisconsin, Milwaukee, WI; Sara Erridge, University of Edinburgh, Edinburgh, Scotland; Brigitta G. Baumert, Maastricht University Medical Center, Maastricht, the Netherlands; Kristen I. Hopkins, University Hospitals Bristol, Bristol, United Kingdom; Arnab Chakravarti, Arthur G. James Cancer Hospital/Ohio State University Comprehensive Cancer Center, Columbus, OH; Walter J. Curran Jr, Emory University Winship Cancer Center, Atlanta, GA; and Minesh P. Mehta, University of Maryland, Baltimore, MD.

Purpose: Radiotherapy with concomitant and adjuvant temozolomide is the standard of care for newly diagnosed glioblastoma (GBM). O(6)-methylguanine-DNA methyltransferase (MGMT) methylation status may be an important determinant of treatment response. Dose-dense (DD) temozolomide results in prolonged depletion of MGMT in blood mononuclear cells and possibly in tumor. This trial tested whether DD temozolomide improves overall survival (OS) or progression-free survival (PFS) in patients with newly diagnosed GBM.

Patients And Methods: This phase III trial enrolled patients older than age 18 years with a Karnofsky performance score of ≥ 60 with adequate tissue. Stratification included clinical factors and tumor MGMT methylation status. Patients were randomly assigned to standard temozolomide (arm 1) or DD temozolomide (arm 2) for 6 to 12 cycles. The primary end point was OS. Secondary analyses evaluated the impact of MGMT status.

Results: A total of 833 patients were randomly assigned to either arm 1 or arm 2 (1,173 registered). No statistically significant difference was observed between arms for median OS (16.6 v 14.9 months, respectively; hazard ratio [HR], 1.03; P = .63) or median PFS (5.5 v 6.7 months; HR, 0.87; P = .06). Efficacy did not differ by methylation status. MGMT methylation was associated with improved OS (21.2 v 14 months; HR, 1.74; P < .001), PFS (8.7 v 5.7 months; HR, 1.63; P < .001), and response (P = .012). There was increased grade ≥ 3 toxicity in arm 2 (34% v 53%; P < .001), mostly lymphopenia and fatigue.

Conclusion: This study did not demonstrate improved efficacy for DD temozolomide for newly diagnosed GBM, regardless of methylation status. However, it did confirm the prognostic significance of MGMT methylation. Feasibility of large-scale accrual, prospective tumor collection, and molecular stratification was demonstrated.
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http://dx.doi.org/10.1200/JCO.2013.49.6968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3816958PMC
November 2013

The role of pre-treatment white matter abnormalities in developing white matter changes following whole brain radiation: a volumetric study.

J Neurooncol 2013 Sep 30;114(3):291-7. Epub 2013 Jun 30.

Department of Neurology, Medical College of Wisconsin, Milwaukee, WI 53226-3596, USA.

White matter injury is a known complication of whole brain radiation (WBRT). Little is known about the factors that predispose a patient to such injury. The current study used MR volumetrics to examine risk factors, in particular the influence of pre-treatment white matter health, in developing white matter change (WMC) following WBRT. Thirty-four patients with unilateral metastatic disease underwent FLAIR MRI pre-treatment and at several time points following treatment. The volume of abnormal FLAIR signal in the white matter was measured in the hemisphere contralateral to the diseased hemisphere at each time point. Analyses were restricted to the uninvolved hemisphere to allow for the measurement of WBRT effects without the potential confounding effects of the disease on imaging findings. The relationship between select pre-treatment clinical variables and the degree of WMC following treatment was examined using correlational and regression based analyses. Age when treated and volume of abnormal FLAIR prior to treatment were significantly associated with WMC following WBRT; however, pre-treatment FLAIR volume was the strongest predictor of post-treatment WMCs. Age did not add any predictive value once white matter status was considered. No significant relationships were found between biological equivalent dose and select cerebrovascular risk factors (total glucose, blood pressure, BMI) and development of WMCs. The findings from this study identify pre-treatment white matter health as an important risk factor in developing WMC following WBRT. This information can be used to make more informed decisions and counsel patients on their risk for treatment effects.
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http://dx.doi.org/10.1007/s11060-013-1181-8DOI Listing
September 2013

American College of Radiology (ACR) and American Society for Radiation Oncology (ASTRO) Practice Guideline for the Performance of Stereotactic Radiosurgery (SRS).

Am J Clin Oncol 2013 Jun;36(3):310-5

Department of Radiation Oncology, The Oregon Clinic, Portland, OR 97213, USA.

American College of Radiology and American Society for Radiation Oncology Practice Guideline for the Performance of Stereotactic Radiosurgery (SRS). SRS is a safe and efficacious treatment option of a variety of benign and malignant disorders involving intracranial structures and selected extracranial lesions. SRS involves a high dose of ionizing radiation with a high degree of precision and spatial accuracy. A quality SRS program requires a multidisciplinary team involved in the patient management. Organization, appropriate staffing, and careful adherence to detail and to established SRS standards is important to ensure operational efficiency and to improve the likelihood of procedural success. A collaborative effort of the American College of Radiology and American Society for Therapeutic Radiation Oncology has produced a practice guideline for SRS. The guideline defines the qualifications and responsibilities of all the involved personnel, including the radiation oncologist, neurosurgeon, and qualified medical physicist. Quality assurance is essential for safe and accurate delivery of treatment with SRS. Quality assurance issues for the treatment unit, stereotactic accessories, medical imaging, and treatment-planning system are presented and discussed. Adherence to these practice guidelines can be part of ensuring quality and patient safety in a successful SRS program.
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http://dx.doi.org/10.1097/COC.0b013e31826e053dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4285440PMC
June 2013