Publications by authors named "Minh-Phuong Huynh-Le"

36 Publications

Performance of African-ancestry-specific polygenic hazard score varies according to local ancestry in 8q24.

Prostate Cancer Prostatic Dis 2021 Jun 14. Epub 2021 Jun 14.

School of Public Health, Louisiana State University Health Sciences Center, New Orleans, LA, USA.

Background: We previously developed an African-ancestry-specific polygenic hazard score (PHS46+African) that substantially improved prostate cancer risk stratification in men with African ancestry. The model consists of 46 SNPs identified in Europeans and 3 SNPs from 8q24 shown to improve model performance in Africans. Herein, we used principal component (PC) analysis to uncover subpopulations of men with African ancestry for whom the utility of PHS46+African may differ.

Materials And Methods: Genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Genetic variation in a window spanning 3 African-specific 8q24 SNPs was estimated using 93 PCs. A Cox proportional hazards framework was used to identify the pair of PCs most strongly associated with the performance of PHS46+African. A calibration factor (CF) was formulated using Cox coefficients to quantify the extent to which the performance of PHS46+African varies with PC.

Results: CF of PHS46+African was strongly associated with the first and twentieth PCs. Predicted CF ranged from 0.41 to 2.94, suggesting that PHS46+African may be up to 7 times more beneficial to some African men than others. The explained relative risk for PHS46+African varied from 3.6% to 9.9% for individuals with low and high CF values, respectively. By cross-referencing our data set with 1000 Genomes, we identified significant associations between continental and calibration groupings.

Conclusion: We identified PCs within 8q24 that were strongly associated with the performance of PHS46+African. Further research to improve the clinical utility of polygenic risk scores (or models) is needed to improve health outcomes for men of African ancestry.
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http://dx.doi.org/10.1038/s41391-021-00403-7DOI Listing
June 2021

Quality of Life Is Independently Associated With Neurocognitive Function in Patients With Brain Tumors: Analysis of a Prospective Clinical Trial.

Int J Radiat Oncol Biol Phys 2021 Nov 6;111(3):754-763. Epub 2021 Jun 6.

Department of Radiation Medicine and Applied Sciences, University of California San Diego, San Diego, California. Electronic address:

Purpose: We conducted the first prospective longitudinal study examining the independent association between patient-reported health-related quality of life (hrQoL) (physical, social/family, emotional, functional, and brain cancer-specific) and neurocognitive function (NCF), while controlling for mood symptoms in patients with primary brain tumors.

Methods And Materials: Patients with primary brain tumors (n = 59) receiving brain radiation therapy underwent hrQOL (Functional Assessment of Cancer Therapy-Brain), mood (Beck Depression and Anxiety Inventories), and neurocognitive evaluation at baseline and 3, 6, and 12 months postradiation therapy in a prospective clinical trial. Neurocognitive assessments measured attention/processing speed, memory, and executive function, including the Delis-Kaplan Executive Function System Verbal Fluency, Hopkins Verbal Learning Test Revised (HVLT-R), and Brief Visuospatial Memory Test. Subjects underwent neurocognitive, mood, and hrQoL assessments in the same testing session. Multivariable linear mixed-effects models assessed associations between hrQOL and NCF over time, controlling for patient, tumor, and treatment characteristics as well as timepoint-specific patient-reported mood (ie, anxiety and depression symptoms). P values were adjusted for multiple comparisons.

Results: Higher physical hrQoL was associated with better verbal memory (HVLT-R Total Recall, P = .047), and higher functional hrQoL was associated with better executive function (Delis-Kaplan Executive Function System Verbal Fluency Switching Total, P = .009) and verbal memory (HVLT-R Delayed Recall, P = .006). Higher brain tumor-specific hrQoL was associated with better verbal and nonverbal memory (HVLT-R Total, P = .004 and Delayed Recall, P = .030; Brief Visuospatial Memory Test Total, P = .049 and Delayed Recall, P = .049). There was no association between social/family or emotional hrQoL and NCF after controlling for mood.

Conclusions: Higher physical, functional, and brain tumor-specific hrQoL were associated with better executive function and memory among patients with primary brain tumors. Physical and functional impairments are correlated with cognitive performance. Interventions to maximize quality of life after treatment may influence neurocognition and vice versa.
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http://dx.doi.org/10.1016/j.ijrobp.2021.05.134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8463493PMC
November 2021

In Reply to Schultheiss.

Int J Radiat Oncol Biol Phys 2021 08 18;110(5):1541-1543. Epub 2021 May 18.

Department of Machine Learning, Moffitt Cancer Center, Tampa, Florida.

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http://dx.doi.org/10.1016/j.ijrobp.2021.03.019DOI Listing
August 2021

In Reply to Bunevicius et al.

Int J Radiat Oncol Biol Phys 2021 06;110(2):612

Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California.

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http://dx.doi.org/10.1016/j.ijrobp.2020.12.058DOI Listing
June 2021

Trends in inpatient palliative care use for primary brain malignancies.

Support Care Cancer 2021 Nov 4;29(11):6625-6632. Epub 2021 May 4.

George Washington University School of Medicine and Health Sciences, 2150 Pennsylvania Avenue, NW, DC Level, Washington, DC, 20037, USA.

Introduction: Primary brain malignancies (PBMs) pose significant morbidity and poor prognosis. Despite NCCN recommendations that palliative care should be integrated into general oncologic care plans, it has been historically underused in patients with PBM. We sought to examine trends and factors associated with inpatient palliative care use in patients with PBM.

Methods: Data from the 2007-2016 National (Nationwide) Inpatient Sample was analyzed for descriptive statistics and trends. Multivariable logistic regression was used to identify factors associated with inpatient palliative care in patients with PBMs.

Results: Of the 510,238 observed hospitalizations of adults with PBM in a 10-year period, 37,365 (7.3%) had an associated inpatient palliative care consult. Rates of inpatient palliative care have increased significantly over the 10-year period, from 2.3 in 2007 to 11.9% in 2011. Patients receiving inpatient palliative care were less likely to receive inpatient oncologic treatment such as brain surgery, chemotherapy, or radiation compared to those without palliative care (14.6% with palliative care vs. 42.4% without, p < 0.001). They were more likely to receive life-sustaining treatments such as intubation, mechanical ventilation, tracheostomy, nutritional support, hemodialysis, or CPR (21.0% with palliative care vs. 10.4% without, p < 0.001). Palliative care was associated with decreased cost of admission ($18,602 with palliative care vs. $20,077 without). In a multiple variable logistic regression, age, non-elective admission, comorbidities, history of chemotherapy and radiation, and mechanical ventilation were associated with significantly increased odds of receiving palliative care.

Conclusions: Inpatient palliative care utilization for patients hospitalized with PBM significantly increased between 2007 and 2016, though the service is still underutilized in the context of the severe symptoms and poor prognosis associated with PBM.
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http://dx.doi.org/10.1007/s00520-021-06255-0DOI Listing
November 2021

Common genetic and clinical risk factors: association with fatal prostate cancer in the Cohort of Swedish Men.

Prostate Cancer Prostatic Dis 2021 09 15;24(3):845-851. Epub 2021 Mar 15.

Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, USA.

Background: Clinical variables-age, family history, genetics-are used for prostate cancer risk stratification. Recently, polygenic hazard scores (PHS46, PHS166) were validated as associated with age at prostate cancer diagnosis. While polygenic scores are associated with all prostate cancer (not specific for fatal cancers), PHS46 was also associated with age at prostate cancer death. We evaluated if adding PHS to clinical variables improves associations with prostate cancer death.

Methods: Genotype/phenotype data were obtained from a nested case-control Cohort of Swedish Men (n = 3279; 2163 with prostate cancer, 278 prostate cancer deaths). PHS and clinical variables (family history, alcohol intake, smoking, heart disease, hypertension, diabetes, body mass index) were tested via univariable Cox proportional hazards models for association with age at prostate cancer death. Multivariable Cox models with/without PHS were compared with log-likelihood tests.

Results: Median age at last follow-up/prostate cancer death was 78.0 (IQR: 72.3-84.1) and 81.4 (75.4-86.3) years, respectively. On univariable analysis, PHS46 (HR 3.41 [95% CI 2.78-4.17]), family history (HR 1.72 [1.46-2.03]), alcohol (HR 1.74 [1.40-2.15]), diabetes (HR 0.53 [0.37-0.75]) were each associated with prostate cancer death. On multivariable analysis, PHS46 (HR 2.45 [1.99-2.97]), family history (HR 1.73 [1.48-2.03]), alcohol (HR 1.45 [1.19-1.76]), diabetes (HR 0.62 [0.42-0.90]) all remained associated with fatal disease. Including PHS46 or PHS166 improved multivariable models for fatal prostate cancer (p < 10).

Conclusions: PHS had the most robust association with fatal prostate cancer in a multivariable model with common risk factors, including family history. Adding PHS to clinical variables may improve prostate cancer risk stratification strategies.
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http://dx.doi.org/10.1038/s41391-021-00341-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387332PMC
September 2021

Polygenic hazard score is associated with prostate cancer in multi-ethnic populations.

Nat Commun 2021 02 23;12(1):1236. Epub 2021 Feb 23.

Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Radiotherapy Related Research, The Christie Hospital NHS Foundation Trust, Manchester, UK.

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS (PHS, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p < 10). Comparing the 80/20 PHS percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset.
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http://dx.doi.org/10.1038/s41467-021-21287-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902617PMC
February 2021

Longitudinal change in fine motor skills after brain radiotherapy and in vivo imaging biomarkers associated with decline.

Neuro Oncol 2021 08;23(8):1393-1403

Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California, USA.

Background: We explored fine motor skills (FMS) before and after brain radiotherapy (RT), analyzing associations between longitudinal FMS and imaging biomarkers of cortical and white matter (WM) integrity in motor regions of interest (ROIs).

Methods: On a prospective trial, 52 primary brain tumor patients receiving fractionated brain RT underwent volumetric brain MRI, diffusion tensor imaging, and FMS assessments (Delis-Kaplan Executive Function System Trail Making Test Motor Speed [DKEFS-MS], Grooved Pegboard Dominant Hands [PDH], and Grooved Pegboard Nondominant Hands [PNDH]) at baseline and 3-, 6-, and 12-month post-RT. Motor ROIs autosegmented included: sensorimotor cortices and superficial WM, corticospinal tracts, cerebellar cortices and WM, and basal ganglia. Volume (cc) was measured in all ROIs at each timepoint. Diffusion biomarkers (FA [fractional anisotropy] and MD [mean diffusivity]) were additionally measured in WM ROIs. Linear mixed-effects models assessed biomarkers as predictors of FMS scores. P values were corrected for multiple comparisons.

Results: Higher RT dose was associated with right paracentral cortical thinning (β = -2.42 Gy/(month × mm), P = .03) and higher right precentral WM MD (β = 0.69 Gy/(month × µm2/ms), P = .04). Higher left (β = 38.7 points/(month × µm2/ms), P = .004) and right (β = 42.4 points/(month × µm2/ms), P = .01) cerebellar WM MD, left precentral cortical atrophy (β = -8.67 points/(month × mm), P = .02), and reduced right cerebral peduncle FA (β = -0.50 points/month, P = .01) were associated with worse DKEFS-MS performance. Left precentral cortex thinning was associated with worse PDH scores (β = -17.3 points/(month × mm), P = .02). Left (β = -0.87 points/(month × cm3), P = .001) and right (β = -0.64 points/(month × cm3), P = .02) cerebellar cortex, left pons (β = -19.8 points/(month × cm3), P = .02), and right pallidum (β = -10.8 points/(month × cm3), P = .02) atrophy and reduced right internal capsule FA (β = -1.02 points/month, P = .03) were associated with worse PNDH performance.

Conclusions: Biomarkers of microstructural injury in motor-associated brain regions were associated with worse FMS. Dose avoidance in these areas may preserve FMS.
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http://dx.doi.org/10.1093/neuonc/noab017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328007PMC
August 2021

Additional SNPs improve risk stratification of a polygenic hazard score for prostate cancer.

Prostate Cancer Prostatic Dis 2021 06 8;24(2):532-541. Epub 2021 Jan 8.

Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA.

Background: Polygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46).

Materials And Method: 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy.

Results: 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer.

Conclusions: Incorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.
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http://dx.doi.org/10.1038/s41391-020-00311-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157993PMC
June 2021

Microstructural Injury to Corpus Callosum and Intrahemispheric White Matter Tracts Correlate With Attention and Processing Speed Decline After Brain Radiation.

Int J Radiat Oncol Biol Phys 2021 06 4;110(2):337-347. Epub 2021 Jan 4.

Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California; Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, California. Electronic address:

Purpose: The corpus callosum (CC) and intrahemispheric white matter tracts (IHWM) subserve critical aspects of attention and processing speed. We analyzed imaging biomarkers of microstructural injury within these regions and association with attention and processing speed performance before and after radiation therapy in primary brain tumor patients.

Methods And Materials: In a prospective clinical trial, 44 primary brain tumor patients underwent cognitive testing and magnetic resonance imaging/diffusion-weighted imaging at baseline (pre-radiation therapy) and 3-, 6-, and 12-months post-radiation therapy. CC (subregions, total) and IHWM tracts (left/right without CC, total) were autosegmented; tumor, tumor bed, and edema were censored. Biomarkers included volume changes (cm), mean diffusivity ([MD]; higher values indicate white matter injury), fractional anisotropy ([FA]; lower values indicate white matter injury). Reliable-change indices measured changes in attention (Weschler Adult Intelligence Scale [WAIS-IV] digits-forward; Delis-Kaplan Executive Function System Trail Making [D-KEFS-TM] visual-scanning), and processing speed (WAIS-IV coding; D-KEFS-TM number-sequencing, letter-sequencing), accounting for practice effects. Linear mixed-effects models evaluated associations between mean radiation dose and biomarkers (volume, MD, FA) and imaging biomarkers and neurocognitive performance. Statistics were corrected for multiple comparisons.

Results: Processing speed declined at 6 months following radiation therapy (number sequencing, letter sequencing; P < .04). Seizures and antiepileptic drug therapy were associated with lower visual-scanning attention reliable-change indices at 6 months (P = .039). Higher radiation dose correlated with smaller midanterior CC volume (P = .023); lower FA in posterior CC, anterior CC, and total CC (all P < .03); and higher MD in anterior CC (P = .012). Smaller midanterior CC and left IHWM volume correlated with worse processing speed (coding, letter-sequencing, number-sequencing; all P < .03). Higher FA in right, left, and total IHWM correlated with better coding scores (all P < .01). Lower FA in total IHWM (P = .009) was associated with worse visual-scanning attention scores. Higher FA in midposterior CC (P = .029) correlated with better digits-forward attention scores.

Conclusions: The CC demonstrated radiation dose-dependent atrophy and WM injury. Microstructural injury within the CC and IHWM was associated with attention and processing speed decline after radiation therapy. These areas represent possible avoidance regions for preservation of attention and processing speed.
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http://dx.doi.org/10.1016/j.ijrobp.2020.12.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162991PMC
June 2021

A Primer on Dose-Response Data Modeling in Radiation Therapy.

Int J Radiat Oncol Biol Phys 2021 05 23;110(1):11-20. Epub 2020 Dec 23.

Department of Machine Learning, Moffitt Cancer Center, Tampa, Florida.

An overview of common approaches used to assess a dose response for radiation therapy-associated endpoints is presented, using lung toxicity data sets analyzed as a part of the High Dose per Fraction, Hypofractionated Treatment Effects in the Clinic effort as an example. Each component presented (eg, data-driven analysis, dose-response analysis, and calculating uncertainties on model prediction) is addressed using established approaches. Specifically, the maximum likelihood method was used to calculate best parameter values of the commonly used logistic model, the profile-likelihood to calculate confidence intervals on model parameters, and the likelihood ratio to determine whether the observed data fit is statistically significant. The bootstrap method was used to calculate confidence intervals for model predictions. Correlated behavior of model parameters and implication for interpreting dose response are discussed.
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http://dx.doi.org/10.1016/j.ijrobp.2020.11.020DOI Listing
May 2021

Dose-Volume Predictors of Radiation Pneumonitis After Lung Stereotactic Body Radiation Therapy (SBRT): Implications for Practice and Trial Design.

Cureus 2020 Oct 5;12(10):e10808. Epub 2020 Oct 5.

Radiation Medicine and Applied Sciences, University of California San Diego Moores Cancer Center, La Jolla, USA.

Background and purpose Recently published HyTEC report summarized lung toxicity data and proposed guidelines of mean lung dose (MLD) <8 Gy and normal lung receiving at least 20 Gy, V<10-15% to avoid lung toxicity. Support for preferred use of a particular dosimetric parameter has been limited. We performed a detailed dose-volume analysis of data on radiation pneumonitis (RP) following lung stereotactic body radiation therapy (SBRT) to search for parameters showing the strongest correlation with RP. Materials and methods Two patient cohorts (primary and metastatic lung tumor patients) from previously reported studies were analyzed. Total number of patients was 96, and incidence of grade ≥2 RP was 13.5% (13/96). Fitting to the logistic function was performed to investigate correlation between incidence of RP and reported dosimetric and volumetric parameters. Another independent cohort was used to explore correlation between dosimetric parameters. Results Among normal lung parameters (MLD and reported V), only MLD consistently showed significant correlation with incidence of RP. Gross tumor volume (GTV), internal target volume, planning target volume (PTV), and minimum dose covering 95% of GTV or PTV did not show statistical significance. A significant correlation between reported V and MLD was observed in all cohorts. Conclusions In considering tumor- and target-specific (e.g., GTV, PTV) and normal lung-specific (e.g., MLD, V) metrics, MLD was the only parameter that consistently correlated with incidence of RP across both cohorts. Because SBRT planning constraints allow small normal lung volumes to receive high doses, utility of MLD is not obvious. The parallel structure of lung is one possible explanation, but correlation between dosimetric parameters obscures elucidation of the preferred or mechanistically based parameter to guide radiotherapy planning.
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http://dx.doi.org/10.7759/cureus.10808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641492PMC
October 2020

African-specific improvement of a polygenic hazard score for age at diagnosis of prostate cancer.

Int J Cancer 2021 01 24;148(1):99-105. Epub 2020 Sep 24.

UMR Inserm 1134 Biologie Intégrée du Globule Rouge, INSERM/Université Paris Diderot-Université Sorbonne Paris Cité/INTS/Université des Antilles, Paris, France.

Polygenic hazard score (PHS) models are associated with age at diagnosis of prostate cancer. Our model developed in Europeans (PHS46) showed reduced performance in men with African genetic ancestry. We used a cross-validated search to identify single nucleotide polymorphisms (SNPs) that might improve performance in this population. Anonymized genotypic data were obtained from the PRACTICAL consortium for 6253 men with African genetic ancestry. Ten iterations of a 10-fold cross-validation search were conducted to select SNPs that would be included in the final PHS46+African model. The coefficients of PHS46+African were estimated in a Cox proportional hazards framework using age at diagnosis as the dependent variable and PHS46, and selected SNPs as predictors. The performance of PHS46 and PHS46+African was compared using the same cross-validated approach. Three SNPs (rs76229939, rs74421890 and rs5013678) were selected for inclusion in PHS46+African. All three SNPs are located on chromosome 8q24. PHS46+African showed substantial improvements in all performance metrics measured, including a 75% increase in the relative hazard of those in the upper 20% compared to the bottom 20% (2.47-4.34) and a 20% reduction in the relative hazard of those in the bottom 20% compared to the middle 40% (0.65-0.53). In conclusion, we identified three SNPs that substantially improved the association of PHS46 with age at diagnosis of prostate cancer in men with African genetic ancestry to levels comparable to Europeans.
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http://dx.doi.org/10.1002/ijc.33282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135907PMC
January 2021

Comparison of Hematologic Toxicity and Bone Marrow Compensatory Response in Head and Neck vs. Cervical Cancer Patients Undergoing Chemoradiotherapy.

Front Oncol 2020 21;10:1179. Epub 2020 Jul 21.

Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, CA, United States.

Hematologic toxicity is a critical problem limiting treatment delivery in cancer patients undergoing concurrent chemoradiotherapy. However, the extent to which anatomic variations in radiation dose limit chemotherapy delivery is poorly understood. A unique natural experiment arises in patients with head and neck and cervical cancer, who frequently undergo identical chemotherapy but receive radiation to different regions of the body. Comparing these cohorts can help elucidate to what extent hematologic toxicity is attributable to marrow radiation as opposed to chemotherapy. In this longitudinal cohort study, we compared hematologic toxicity and bone marrow compensatory response in 148 patients (90 cervix, 58 head/neck) undergoing chemoradiotherapy with concurrent weekly cisplatin 40 mg/m. We used linear mixed effect models to compare baseline and time-varying peripheral cell counts and hemoglobin levels between cohorts. To assess bone marrow compensatory response, we measured the change in metabolically active bone marrow (ABM) volume on F-fluorodeoxyglucose positron emission tomography/computed tomography. We observed greater reductions in log-transformed lymphocyte, platelet, and absolute neutrophil counts (ANC) for cervix compared to head/neck cancer patients (fixed effects for time-cohort interaction [95% CI]: lymphocytes, -0.06 [-0.09, -0.031]; platelets,-0.028 [-0.051, -0.0047]; ANC, -0.043 [-0.075, -0.011]). Mean ANC nadirs were also lower for cervical vs. head/neck cancer cohorts (2.20 vs. 2.85 × 10 per μL, < 0.01). Both cohorts exhibited reductions in ABM volume within the radiation field, and increases in ABM volume in out-of-field areas, indicating varying compensatory response to radiation injury. Cervical cancer patients had faster decreases in ANC, lymphocyte, and platelet counts, and lower ANC nadirs, indicating a significant effect of pelvic irradiation on acute peripheral blood cell counts. Both cohorts exhibited a compensatory response with increased out-of-field bone marrow activity.
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http://dx.doi.org/10.3389/fonc.2020.01179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385402PMC
July 2020

Microstructural Injury to Left-Sided Perisylvian White Matter Predicts Language Decline After Brain Radiation Therapy.

Int J Radiat Oncol Biol Phys 2020 12 23;108(5):1218-1228. Epub 2020 Jul 23.

Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California; Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, California. Electronic address:

Purpose: Our purpose was to investigate the association between imaging biomarkers of radiation-induced white matter (WM) injury within perisylvian regions and longitudinal language decline in patients with brain tumors.

Methods And Materials: Patients with primary brain tumors (n = 44) on a prospective trial underwent brain magnetic resonance imaging, diffusion-weighted imaging, and language assessments of naming (Boston Naming Test [BNT]) and fluency (Delis-Kaplan Executive Function System Category Fluency [DKEFS-CF]) at baseline and 3, 6, and 12 months after fractionated radiation therapy (RT). Reliable change indices of language function (0-6 months), accounting for practice effects (RCI-PE), evaluated decline. Bilateral perisylvian WM regions (superficial WM subadjacent to Broca's area and the superior temporal gyrus [STG], inferior longitudinal fasciculus [ILF], inferior fronto-occipital fasciculus [IFOF], and arcuate fasciculus) were autosegmented. We quantified volume and diffusion measures of WM microstructure: fractional anisotropy (FA; lower values indicate disruption) and mean diffusivity (MD; higher values indicate injury). Linear mixed-effects models assessed mean dose as predictor of imaging biomarker change and imaging biomarkers as longitudinal predictors of language scores.

Results: DKEFS-CF scores declined at 6 months post-RT (RCI-PE, -0.483; P = .01), whereas BNT scores improved (RCI-PE, 0.262; P = .04). Higher mean dose to left and right regions was predictive of decreased volume (left-STG, P = .02; right-ILF and IFOF, P = .03), decreased FA (left-WM tracts, all P < .01; right-STG and IFOF, P < .02), and increased MD of left-WM tracts (all P < .03). Volume loss within left-Broca's area (P = .01), left-ILF (P = .01), left-IFOF (P = .01), and left-arcuate fasciculus (P = .04) was associated with lower BNT scores. Lower FA correlated with poorer DKEFS-CF and BNT scores within left-ILF (P = .02, not significant), left-IFOF (P = .02, .04), and left-arcuate fasciculus (P = .01, .01), respectively. Poorer DKEFS-CF scores correlated with increased MD values within the left-arcuate fasciculus (P = .03). Right-sided biomarkers did not correlate with language scores.

Conclusions: Patients with primary brain tumors experience language fluency decline post-RT. Poorer fluency and naming function may be explained by microstructural injury to left-sided perisylvian WM, representing potential dose-avoidance targets for language preservation.
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http://dx.doi.org/10.1016/j.ijrobp.2020.07.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680351PMC
December 2020

Longitudinal Analysis of Depression and Anxiety Symptoms as Independent Predictors of Neurocognitive Function in Primary Brain Tumor Patients.

Int J Radiat Oncol Biol Phys 2020 12 4;108(5):1229-1239. Epub 2020 Jul 4.

Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California. Electronic address:

Purpose: Primary brain tumor patients are vulnerable to depression and anxiety symptoms, which may affect their neurocognitive functioning. We performed a prospective longitudinal analysis to examine the association between depression and anxiety symptoms and domain-specific neurocognitive functioning in primary brain tumor patients receiving radiation therapy (RT).

Methods And Materials: On a prospective trial, 54 primary brain tumor patients receiving RT underwent comprehensive neurocognitive evaluation at baseline (pre-RT), and 3, 6, and 12 months post-RT. Neurocognitive assessments measured attention/processing speed, verbal and visuospatial memory, and executive functioning, including Delis-Kaplan Executive Function System Trail-Making Test (DKEFS-TMT), DKEFS Verbal Fluency, and Brief Visuospatial Memory Test-Revised. Depression and anxiety symptoms were also assessed at each time point with Beck Depression and Anxiety Inventories (BDI-II and BAI), respectively. Higher scores reflect more numerous or severe depression or anxiety symptoms. Univariable and multivariable linear mixed-effects models assessed associations between BDI-II and BAI scores and domain-specific neurocognitive scores over time, controlling for pre-existing depression or anxiety disorders and other patient, tumor, and treatment characteristics.

Results: Higher BAI scores were associated with worse attention and processing speed in univariable analyses: DKEFS-TMT visual scanning (P = .003), number sequencing (P = .011), and letter sequencing (P <.001). On multivariable analyses, these associations remained significant (all P ≤ .01). Higher BDI-II scores were also associated with poorer attention/processing speed (DKEFS-TMT Letter Sequencing) in univariable (P = .002) and multivariable (P = .013) models. Higher BAI scores were associated with worse visuospatial memory (Brief Visuospatial Memory Test-Revised Delayed Recall) on univariable (P = .012) but not multivariable analyses (P = .383). Similarly, higher BDI-II scores were associated with poorer executive functioning (DKEFS Verbal Fluency Category Switching) on univariable (P = .031) but not multivariable analyses (P = .198).

Conclusions: Among primary brain tumor patients receiving RT, increased depression and anxiety were independently associated with worsened neurocognition, particularly in attention/processing speed. Depression and anxiety symptoms should be controlled for in prospective clinical trials and managed in the clinical setting to optimize neurocognitive functioning.
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http://dx.doi.org/10.1016/j.ijrobp.2020.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680441PMC
December 2020

A Genetic Risk Score to Personalize Prostate Cancer Screening, Applied to Population Data.

Cancer Epidemiol Biomarkers Prev 2020 09 24;29(9):1731-1738. Epub 2020 Jun 24.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.

Background: A polygenic hazard score (PHS), the weighted sum of 54 SNP genotypes, was previously validated for association with clinically significant prostate cancer and for improved prostate cancer screening accuracy. Here, we assess the potential impact of PHS-informed screening.

Methods: United Kingdom population incidence data (Cancer Research United Kingdom) and data from the Cluster Randomized Trial of PSA Testing for Prostate Cancer were combined to estimate age-specific clinically significant prostate cancer incidence (Gleason score ≥7, stage T3-T4, PSA ≥10, or nodal/distant metastases). Using HRs estimated from the ProtecT prostate cancer trial, age-specific incidence rates were calculated for various PHS risk percentiles. Risk-equivalent age, when someone with a given PHS percentile has prostate cancer risk equivalent to an average 50-year-old man (50-year-standard risk), was derived from PHS and incidence data. Positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was calculated using PHS-adjusted age groups.

Results: The expected age at diagnosis of clinically significant prostate cancer differs by 19 years between the 1st and 99th PHS percentiles: men with PHS in the 1st and 99th percentiles reach the 50-year-standard risk level at ages 60 and 41, respectively. PPV of PSA was higher for men with higher PHS-adjusted age.

Conclusions: PHS provides individualized estimates of risk-equivalent age for clinically significant prostate cancer. Screening initiation could be adjusted by a man's PHS.

Impact: Personalized genetic risk assessments could inform prostate cancer screening decisions.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483627PMC
September 2020

The effect of sample size on polygenic hazard models for prostate cancer.

Eur J Hum Genet 2020 10 8;28(10):1467-1475. Epub 2020 Jun 8.

Humangenetik Tuebingen, Paul-Ehrlich-Str 23, D-72076, Tuebingen, Germany.

We determined the effect of sample size on performance of polygenic hazard score (PHS) models in prostate cancer. Age and genotypes were obtained for 40,861 men from the PRACTICAL consortium. The dataset included 201,590 SNPs per subject, and was split into training and testing sets. Established-SNP models considered 65 SNPs that had been previously associated with prostate cancer. Discovery-SNP models used stepwise selection to identify new SNPs. The performance of each PHS model was calculated for random sizes of the training set. The performance of a representative Established-SNP model was estimated for random sizes of the testing set. Mean HR (hazard ratio of top 2% to average in test set) of the Established-SNP model increased from 1.73 [95% CI: 1.69-1.77] to 2.41 [2.40-2.43] when the number of training samples was increased from 1 thousand to 30 thousand. Corresponding HR of the Discovery-SNP model increased from 1.05 [0.93-1.18] to 2.19 [2.16-2.23]. HR of a representative Established-SNP model using testing set sample sizes of 0.6 thousand and 6 thousand observations were 1.78 [1.70-1.85] and 1.73 [1.71-1.76], respectively. We estimate that a study population of 20 thousand men is required to develop Discovery-SNP PHS models while 10 thousand men should be sufficient for Established-SNP models.
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http://dx.doi.org/10.1038/s41431-020-0664-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608255PMC
October 2020

Reply to The 5-year relative survival of older patients with prostate cancer is insignificantly different from the 5-year survival of all men of a similar age.

Cancer 2020 06 19;126(11):2718-2719. Epub 2020 Feb 19.

Department of Radiation Medicine and Applied Sciences, University of California at San Diego, La Jolla, California.

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http://dx.doi.org/10.1002/cncr.32791DOI Listing
June 2020

Implementation of peer-review quality rounds for gynecologic brachytherapy in a high-volume academic center.

Brachytherapy 2020 Nov - Dec;19(6):881-888. Epub 2020 Jan 6.

Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA. Electronic address:

Purpose: While peer review is critical for quality and safety in radiotherapy, there are neither formal guidelines nor format examples for brachytherapy (BT) peer review. We report on a gynecologic BT peer-review method implemented at a high-volume academic center.

Methods And Materials: We analyzed discussions at bimonthly gynecologic BT peer-review rounds between July and December 2018. Rounds consisted of 2-5 attending physicians with gynecologic BT expertise, 1-2 BT physicists, and trainees. Peer-review targets included clinical case review, contours, implant technique, dose/fractionation, and target/organ-at-risk (OAR) dosimetry. The projected/final target and OAR dosimetry were analyzed.

Results: 55 separate implants from 44 patients were reviewed. Implants were mostly reviewed after the first BT fraction (n = 16, 29%) or at another time point during BT (n = 20, 36%). One (2%) implant was presented prospectively. The applicator type and BT technique were reviewed for all implants. Dose/fractionation was evaluated for 46 implants (84%); contours were discussed for 21 (38%). Target and OAR dosimetry were reviewed for 54 (98%) and 28 implants (51%), respectively. Six cases (11%) underwent minor changes to the applicator type to improve target and/or OAR dosimetry. One case (2%) had a major change recommended to the dose/fractionation.

Conclusions: Gynecologic BT peer review may enhance BT quality by allowing for implant optimization and formal review of challenging cases, ultimately improving medical decision-making and team communication. Peer review should be implemented in centers offering gynecologic BT.
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http://dx.doi.org/10.1016/j.brachy.2019.11.010DOI Listing
June 2021

Adverse Events Associated With Radium-223 in Metastatic Prostate Cancer: Disproportionality Analysis of FDA Data Reflecting Worldwide Utilization.

Clin Genitourin Cancer 2020 06 5;18(3):192-200.e2. Epub 2019 Dec 5.

Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA. Electronic address:

Background: Radionuclide radium-223 improves survival in men with metastatic castrate-resistant prostate cancer. The United States (US) Food and Drug Administration Adverse Events Reporting System (FAERS) is a post-market pharmacovigilance database valuable for adverse event (AE) assessments. We analyzed FAERS to identify disproportionate AE signals related to radium-223, and to explore radium-223's international utilization.

Materials And Methods: We identified 2182 radium-223 cases associated with AE(s) from 2013 to 2018. The duration of radium-223 therapy was calculated. Reporting odds ratio (ROR) and proportional reporting ratio (PRR), with 95% confidence intervals (CIs), were calculated for AEs of interest. ROR shows disproportionate signals if the lower limit of the 95% CI > 1. PRR shows disproportionate signals if PRR ≥ 2, χ statistic ≥ 4, and ≥ 3 AEs were reported. We identified any US Food and Drug Administration enforcement actions for radium-223.

Results: A majority (60.8%) of events occurred outside the US. Among patients with radium-223-associated AEs, the median therapy duration was only 56 days (corresponding to 2-3 treatment cycles). Disproportionate signals were detected for general health deterioration (ROR, 5.03; 95% CI, 4.23-5.98 and PRR, 4.94; 95% CI, 4.16-5.87), bone pain (ROR, 4.53; 95% CI, 3.67-5.59 and PRR, 4.48; 95% CI, 3.63-5.53), and hematologic AEs including anemia (ROR, 2.89; 95% CI, 2.55-3.27 and PRR, 2.80; 95% CI, 2.48-3.17), thrombocytopenia (ROR, 3.22; 95% CI, 2.77-3.74 and PRR, 3.16; 95% CI, 2.72-3.67), and pancytopenia/bone marrow failure (ROR, 4.83; 95% CI, 4.11-5.67 and PRR, 4.73; 95% CI, 4.03-5.55). There were no enforcement actions for radium-223.

Conclusions: Patients with metastatic castrate-resistant prostate cancer experiencing AEs are only receiving one-half the prescription dose of radium-223 required for survival benefit. Radium-223 is associated with health deterioration, bone pain, and hematologic AEs. Real-world analyses are important for ongoing radium-223 risk-benefit assessments.
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http://dx.doi.org/10.1016/j.clgc.2019.11.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272257PMC
June 2020

Age dependence of modern clinical risk groups for localized prostate cancer-A population-based study.

Cancer 2020 04 3;126(8):1691-1699. Epub 2020 Jan 3.

Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California.

Background: Optimal prostate cancer (PCa) screening strategies will focus on men likely to have potentially lethal disease. Age-specific incidence rates (ASIRs) by modern clinical risk groups could inform risk stratification efforts for screening.

Methods: This cross-sectional population study identified all men diagnosed with PCa in Norway from 2014 to 2017 (n = 20,356). Age, Gleason score (primary plus secondary), and clinical stage were extracted. Patients were assigned to clinical risk groups: low, favorable intermediate, unfavorable intermediate, high, regional, and metastatic. Chi-square tests analyzed the independence of Gleason scores and modern PCa risk groups with age. ASIRs for each risk group were calculated as the product of Norwegian ASIRs for all PCa and the proportions observed for each risk category.

Results: Older age was significantly associated with a higher Gleason score and more advanced disease. The percentages of men with Gleason 8 to 10 disease among men aged 55 to 59, 65 to 69, 75 to 79, and 85 to 89 years were 16.5%, 23.4%, 37.2%, and 59.9%, respectively (P < .001); the percentages of men in the same age groups with at least high-risk disease were 29.3%, 39.1%, 60.4%, and 90.6%, respectively (P < .001). The maximum ASIRs (per 100,000 men) for low-risk, favorable intermediate-risk, unfavorable intermediate-risk, high-risk, regional, and metastatic disease were 157.1 for those aged 65 to 69 years, 183.8 for those aged 65 to 69 years, 194.8 for those aged 70 to 74 years, 408.3 for those aged 75 to 79 years, 159.7 for those aged ≥85 years, and 314.0 for those aged ≥85 years, respectively. At the ages of 75 to 79 years, the ASIR of high-risk disease was approximately 6 times greater than the ASIR at 55 to 59 years.

Conclusions: The risk of clinically significant localized PCa increases with age. Healthy older men may benefit from screening.
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http://dx.doi.org/10.1002/cncr.32702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103486PMC
April 2020

Multi-domain neurocognitive classification of primary brain tumor patients prior to radiotherapy on a prospective clinical trial.

J Neurooncol 2020 Jan 23;146(1):131-138. Epub 2019 Nov 23.

Department of Radiation Medicine and Applied Sciences, University of California San Diego, 3960 Health Sciences Dr, Mail Code 0865, La Jolla, CA, USA.

Introduction: We investigated multi-domain baseline neurocognition of primary brain tumor patients prior to radiotherapy (RT), including clinical predictors of function and association between pre-RT and post-RT impairment on a prospective trial.

Methods: A multi-domain neuropsychological battery (memory, executive functioning, language, attention, processing) was performed on 37 patients, pre-RT and 3-(n = 21), 6-(n = 22) and 12-(n = 14) months post-RT. Impairment rate was the proportion of patients with standardized T-scores ≤ 1.5 standard deviations below normative means. Per-patient impairment across all domains was calculated using a global deficit score (GDS; higher value indicates more impairment). Associations between baseline GDS and clinical variables were tested. Global GDS impairment rate at each time point was the fraction of patients with GDS scores > 0.5.

Results: Statistically significant baseline neurocognitive impairments were identified on 4 memory (all p ≤ 0.03) and 2 out of 3 (p = 0.01, p = 0.027) executive functioning tests. Per-patient baseline GDS was significantly associated with tumor volume (p = 0.048), tumor type (p = 0.043), seizure history (p = 0.007), and use of anti-epileptics (p = 0.009). The percentage of patients with the same impairment status at 3-, 6-, and 12-months as at baseline were 88%, 85%, and 85% respectively.

Conclusions: Memory and executive functioning impairment were the most common cognitive deficits prior to RT. Patients with larger tumors, more aggressive histology, and use of anti-epileptics had higher baseline GDS values. GDS is a promising tool to encompass multi-domain neurocognitive function, and baseline GDS can identify those at risk of cognitive impairment.
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http://dx.doi.org/10.1007/s11060-019-03353-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025809PMC
January 2020

Quantitative Imaging Biomarkers of Damage to Critical Memory Regions Are Associated With Post-Radiation Therapy Memory Performance in Brain Tumor Patients.

Int J Radiat Oncol Biol Phys 2019 11 10;105(4):773-783. Epub 2019 Aug 10.

Department of Radiation Medicine and Applied Sciences; Center for Multimodal Imaging and Genetics. Electronic address:

Purpose: We used quantitative magnetic resonance imaging to prospectively analyze the association between microstructural damage to memory-associated structures within the medial temporal lobe and longitudinal memory performance after brain radiation therapy (RT).

Methods And Materials: Patients with a primary brain tumor receiving fractionated brain RT were enrolled on a prospective trial (n = 27). Patients underwent high-resolution volumetric brain magnetic resonance imaging, diffusion-weighted imaging, and neurocognitive testing before and 3, 6, and 12 months post-RT. Medial temporal lobe regions (hippocampus; entorhinal, parahippocampal, and temporal pole white matter [WM]) were autosegmented, quantifying volume and diffusion biomarkers of WM integrity (mean diffusivity [MD]; fractional anisotropy [FA]). Reliable change indices measured changes in verbal (Hopkins Verbal Learning Test-Revised) and visuospatial (Brief Visuospatial Memory Test-Revised [BVMT-R]) memory. Linear mixed-effects models assessed longitudinal associations between imaging parameters and memory.

Results: Visuospatial memory significantly declined at 6 months post-RT (mean reliable change indices, -1.3; P = .012). Concurrent chemotherapy and seizures trended toward a significant association with greater decline in visuospatial memory (P = .053 and P = .054, respectively). Higher mean dose to the left temporal pole WM was significantly associated with decreased FA (r = -0.667; P = .002). Over all time points, smaller right hippocampal volume (P = .021), lower right entorhinal FA (P = .023), greater right entorhinal MD (P = .047), and greater temporal pole MD (BVMT-R total recall, P = .003; BVMT-R delayed recall, P = .042) were associated with worse visuospatial memory. The interaction between right entorhinal MD (BVMT-R total recall, P = .021; BVMT-R delayed recall, P = .004) and temporal pole FA (BVMT-R delayed recall, P = .024) significantly predicted visuospatial memory performance.

Conclusions: Brain tumor patients exhibited visuospatial memory decline post-RT. Microstructural damage to critical memory regions, including the hippocampus and medial temporal lobe WM, were associated with post-RT memory decline. The integrity of medial temporal lobe structures is critical to memory performance post-RT, representing possible avoidance targets for memory preservation.
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http://dx.doi.org/10.1016/j.ijrobp.2019.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876859PMC
November 2019

Impact of marital status on receipt of brachytherapy and survival outcomes in locally advanced cervical cancer.

Brachytherapy 2019 Sep - Oct;18(5):612-619. Epub 2019 May 29.

Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA. Electronic address:

Purpose: Marriage has been associated with enhanced survival among cancer patients, but conflicting correlations have been suggested in cervical cancer. We assessed the impact of marital status on receipt of brachytherapy and survival in women with locally advanced cervical cancer.

Methods And Materials: Three thousand, eight hundred and twelve patients with Stage IB2-IVA cervical cancer diagnosed from 2006 to 2015 treated with external beam radiotherapy were identified from the California Cancer Registry. Chi-square tests were used to compare patient characteristics by marital status and boost type. The association of marital status with brachytherapy (BT) receipt was assessed using multiple logistic regression. Fine and Gray competing risks and Cox proportional hazards regressions were used to estimate cervical cancer-specific survival (CCSS) and overall survival (OS), respectively.

Results: Most women were unmarried (58.8%). Half (50.4%) received BT, while 33.1% received no boost; most (86.3%) received chemotherapy. Unmarried women had similar odds of receiving BT as married women (OR = 1.07, 95% CI: 0.90-1.28, p = 0.4370) but were less likely to receive chemotherapy (84.3% vs. 89.1%, p < 0.0001). Singlehood was significantly associated with worse CCSS (subdistribution hazard ratio = 1.21, 95% CI: 1.03-1.42, p < 0.0174) and OS (hazard ratio = 1.18, 95% CI: 1.03-1.36, p < 0.0153). Not receiving a radiation boost was also significantly associated with worse CCSS (subdistribution hazard ratio = 1.21, 95% CI: 1.02-1.43, p = 0.0317) and OS (hazard ratio = 1.21, 95% CI: 1.05-1.40, p = 0.0100).

Conclusions: There were no differences in BT receipt in married vs. unmarried patients. However, unmarried patients had worse CCSS and OS and were less likely to receive chemotherapy. Interventions targeting social factors are needed to improve outcomes in this vulnerable population.
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http://dx.doi.org/10.1016/j.brachy.2019.04.273DOI Listing
February 2020

Dose-dependent atrophy of the amygdala after radiotherapy.

Radiother Oncol 2019 07 6;136:44-49. Epub 2019 Apr 6.

Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, United States; Department of Bioengineering, University of California San Diego, La Jolla, CA, United States. Electronic address:

Background And Purpose: The amygdalae are deep brain nuclei critical to emotional processing and the creation and storage of memory. It is not known whether the amygdalae are affected by brain radiotherapy (RT). We sought to quantify dose-dependent amygdala change one year after brain RT.

Materials And Methods: 52 patients with primary brain tumors were retrospectively identified. Study patients underwent high-resolution, volumetric magnetic resonance imaging before RT and 1 year afterward. Images were processed using FDA-cleared software for automated segmentation of amygdala volume. Tumor, surgical changes, and segmentation errors were manually censored. Mean amygdala RT dose was tested for correlation with amygdala volume change 1 year after RT via the Pearson correlation coefficient. A linear mixed-effects model was constructed to evaluate potential predictors of amygdala volume change, including age, tumor hemisphere, sex, seizure history, and bevacizumab treatment during the study period. As 51 of 52 patients received chemotherapy, possible chemotherapy effects could not be studied. A two-tailed p-value <0.05 was considered statistically significant.

Results: Mean amygdala RT dose (r = -0.28, p = 0.01) was significantly correlated with volume loss. On multivariable analysis, the only significant predictor of amygdala atrophy was radiation dose. The final linear mixed-effects model estimated amygdala volume loss of 0.17% for every 1 Gy increase in mean amygdala RT dose (p = 0.008).

Conclusions: The amygdala demonstrates dose-dependent atrophy one year after radiotherapy for brain tumors. Amygdala atrophy may mediate neuropsychological effects seen after brain RT.
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http://dx.doi.org/10.1016/j.radonc.2019.03.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041546PMC
July 2019

The role of cancer in marijuana and prescription opioid use in the United States: A population-based analysis from 2005 to 2014.

Cancer 2019 07 22;125(13):2242-2251. Epub 2019 Apr 22.

Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California.

Background: For patients with cancer, marijuana may be an alternative to prescription opioid analgesics. This study analyzed self-reported marijuana and prescription opioid use among people with cancer over a 10-year time period.

Methods: Population-based data sets from the US National Health and Nutrition Examination Survey between 2005 and 2014 were compiled for respondents aged 20 to 60 years. Respondents with cancer and respondents without cancer were propensity score-matched (1:2) by demographics to compare substance use. Outcomes included current marijuana and prescription opioid use (ie, within the past 30 days). Pearson chi-square tests and logistic regressions were performed; a 2-tailed P value < .05 was significant.

Results: There were 19,604 respondents, and 826 people with cancer were matched to 1652 controls. Among the respondents with cancer, 40.3% used marijuana within the past year, and 8.7% used it currently. Respondents with cancer were significantly more likely to use prescription opioids (odds ratio [OR], 2.43; 95% CI, 1.68-3.57; P < .001). Cancer was not associated with current marijuana use in a multivariable conditional logistic regression but was associated with current opioid use (OR, 1.82; 95% CI, 1.17-2.82; P = .008). Among all survey respondents, the odds of marijuana use significantly increased over time (OR, 1.05; 95% CI, 1.01-1.10; P = .012), whereas the odds of opioid use did not significantly change. There were no significant differences in the longitudinal odds of marijuana or opioid use over time between respondents with a cancer diagnosis and those without one.

Conclusions: This population-based analysis revealed a considerable proportion of respondents with cancer self-reporting marijuana use (40.3%) and a significantly higher prevalence of opioid use among respondents with cancer. In the midst of an opioid epidemic, an evolving political landscape, and new developments in oncology, quantifying the prevalence of opioid and marijuana use in the US population, especially among patients with cancer, is particularly relevant. Although opioid use did not significantly change from 2005 to 2014 among all respondents, marijuana use did increase, likely reflecting increased availability and legislative changes. A cancer diagnosis did not significantly affect longitudinal opioid or marijuana use.
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http://dx.doi.org/10.1002/cncr.32059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6810711PMC
July 2019

Intensity Modulated Radiation Therapy Versus Conventional Radiation for Anal Cancer in the Veterans Affairs System.

Int J Radiat Oncol Biol Phys 2018 09 23;102(1):109-115. Epub 2018 May 23.

Department of Radiation Medicine and Applied Sciences, School of Medicine, University of California, San Diego, La Jolla, California; Center for Translational Radiation Medicine and Imaging, School of Medicine, University of California, San Diego, La Jolla, California. Electronic address:

Purpose: Compared with conventional radiation therapy, intensity modulated radiation therapy (IMRT) may reduce acute toxicity from anal cancer treatment, potentially leading to improved long-term outcomes. We analyze the effect of IMRT on short- and long-term outcomes among a large sample of US veterans.

Methods And Materials: From a national Veterans Affairs database, we identified 779 patients (n = 403 conventional radiation therapy, n = 376 IMRT) with locally advanced anal squamous cell carcinoma diagnosed between 2000 and 2015 and treated with concurrent chemoradiation therapy. Radiation treatment planning and dosimetric constraints were not standardized across patients. We analyzed the effect of IMRT on short-term outcomes (acute toxicity, treatment breaks, and incomplete chemotherapy) and long-term outcomes (survival and ostomy placement) in multivariable logistic regression, Fine-Gray, and frailty models, adjusting for potential confounders.

Results: IMRT was associated with decreased radiation treatment breaks ≥5 days (odds ratio [OR] 0.58; 95% confidence interval [CI] 0.37-0.91; P = .02), increased rates of receiving 2 cycles of mitomycin C chemotherapy (OR 2.04; 95% CI 1.22-3.45; P = .007), increased rates of receiving 2 cycles of any chemotherapy (OR 3.45; 95% CI 1.82-6.25; P < .001), and decreased risk of ostomy related to tumor recurrence or progression (subdistribution hazard ratio 0.60; 95% CI 0.37-0.99; P = .045). IMRT was not associated with a decrease in grade 3 to 4 hematologic toxicity (P = .79), hospitalization for gastrointestinal toxicity (P = .59), or cancer-specific survival (P = 0.18).

Conclusions: Among a large sample of US veterans with anal cancer, IMRT was associated with higher rates of receiving 2 chemotherapy cycles, decreased radiation treatment breaks, and decreased rates of ostomy placement. IMRT appears to offer substantial benefits over conventional radiation therapy for patients undergoing concurrent chemoradiation therapy for anal cancer.
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http://dx.doi.org/10.1016/j.ijrobp.2018.05.044DOI Listing
September 2018

Effect of CD4 Count on Treatment Toxicity and Tumor Recurrence in Human Immunodeficiency Virus-Positive Patients With Anal Cancer.

Int J Radiat Oncol Biol Phys 2018 02 22;100(2):478-485. Epub 2017 Sep 22.

Department of Radiation Medicine and Applied Sciences, University of California, San Diego, La Jolla, California; Clinical and Translational Research Institute, University of California, San Diego, La Jolla, California. Electronic address:

Purpose: To study the effects of immunosuppression on treatment toxicity, long-term cancer recurrence risk, and survival among human immunodeficiency virus (HIV)-positive anal cancer patients.

Methods And Materials: From a nationwide retrospective cohort of veterans with anal cancer we identified 142 HIV-positive patients with stage I-III disease, diagnosed between 2000 and 2015 and treated with definitive-intent chemotherapy and radiation. We used regression models to study the impact of pretreatment CD4 counts and longitudinal posttreatment CD4 counts on outcomes including acute toxicity, long-term ostomy rates, cancer recurrence, cancer-specific survival, and overall survival. All models were adjusted for potential confounders.

Results: The median pretreatment CD4 count was 375 cells/mm, which dropped to 157 cells/mm after treatment. Each 100-cell/mm decrease in pretreatment CD4 count was associated with an increased risk of acute hematologic toxicity (odds ratio 1.19, 95% confidence interval [CI] 1.01-1.42, P=.04) and hospitalization for hematologic toxicity (odds ratio 1.24, 95% CI 1.00-1.54, P=.049) but not gastrointestinal toxicity, tumor recurrence, or cancer-specific mortality (P>.05). Each 100-cells/mm decrease in posttreatment CD4 count increased the risk of recurrence by 54% (hazard ratio 1.54, 95% CI 1.09-2.17, P=.01) and cancer mortality by 46% at a trend level (hazard ratio 1.46, 95% CI 0.99-2.14, P=.06). Neither pre- nor posttreatment CD4 count influenced long-term ostomy rates or overall survival (all P>.05).

Conclusions: Lower pretreatment CD4 counts were associated with acute hematologic toxicity, and lower posttreatment CD4 count levels were associated with an increased risk of tumor recurrence. These results suggest that immune surveillance may play an important role in long-term disease control in anal cancer.
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http://dx.doi.org/10.1016/j.ijrobp.2017.09.034DOI Listing
February 2018
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