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1.
Artigo em Inglês | MEDLINE | ID: mdl-33723363

RESUMO

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 < 10-15). 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.

2.
Neuro Oncol ; 2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33543265

RESUMO

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 [PDH] and Non-dominant [PNDH] Hands) at baseline and 3, 6, and 12 months 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 and MD) 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 (ß=-2.42 Gy/(month*mm), p=0.03) and higher right precentral WM MD (ß=0.69 Gy/(month*µm 2/ms), p=0.04). Higher left (ß=38.7 points/(month*µm 2/ms), p=0.004) and right (ß=42.4 points/(month*µm 2/ms), p=0.01) cerebellar WM MD, left precentral cortical atrophy (ß=-8.67 points/(month*mm), p=0.02), and reduced right cerebral peduncle FA (ß=-0.50 points/month, p=0.01) were associated with worse DKEFS-MS performance. Left precentral cortex thinning was associated with worse PDH scores (ß=-17.3 points/(month*mm), p=0.02). Left (ß=-0.87 points/(month*cm 3), p=0.001) and right (ß=-0.64 points/(month*cm 3), p=0.02) cerebellar cortex, left pons (ß=-19.8 points/(month*cm 3), p=0.02), and right pallidum (ß=-10.8 points/(month*cm 3), p=0.02) atrophy and reduced right internal capsule FA (ß=-1.02 points/month, p=0.03, p=0.03) 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.

3.
Nat Commun ; 12(1): 1236, 2021 02 23.
Artigo em Inglês | MEDLINE | ID: mdl-33623038

RESUMO

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 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 < 10-180). Comparing the 80th/20th PHS2 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. PHS2 risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset.


Assuntos
Grupos Étnicos/genética , Herança Multifatorial/genética , Neoplasias da Próstata/genética , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Invasividade Neoplásica , Autorrelato
4.
Artigo em Inglês | MEDLINE | ID: mdl-33412257

RESUMO

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 (cm3), 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.

5.
Artigo em Inglês | MEDLINE | ID: mdl-33420416

RESUMO

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.

6.
Int J Cancer ; 148(1): 99-105, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32930425

RESUMO

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.

7.
Artigo em Inglês | MEDLINE | ID: mdl-33358230

RESUMO

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.

8.
Cureus ; 12(10): e10808, 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-33163312

RESUMO

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, V20Gy<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 Vx), 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 Vx 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, Vx) 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.

9.
Front Oncol ; 10: 1179, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32793487

RESUMO

Background: 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. Methods: 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/m2. 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 18F-fluorodeoxyglucose positron emission tomography/computed tomography. Results: 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 × 103 per µL, p < 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. Conclusions: 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.

10.
Int J Radiat Oncol Biol Phys ; 108(5): 1229-1239, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32634542

RESUMO

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.

11.
Int J Radiat Oncol Biol Phys ; 108(5): 1218-1228, 2020 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-32712255

RESUMO

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.

12.
Cancer Epidemiol Biomarkers Prev ; 29(9): 1731-1738, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32581112

RESUMO

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.

13.
Eur J Hum Genet ; 28(10): 1467-1475, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32514134

RESUMO

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 HR98/50 (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 HR98/50 of the Discovery-SNP model increased from 1.05 [0.93-1.18] to 2.19 [2.16-2.23]. HR98/50 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.

15.
Clin Genitourin Cancer ; 18(3): 192-200.e2, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31902714

RESUMO

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, χ2 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.

16.
Cancer ; 126(8): 1691-1699, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-31899813

RESUMO

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.


Assuntos
Próstata/patologia , Neoplasias da Próstata/patologia , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores/métodos , Noruega , Próstata/metabolismo , Antígeno Prostático Específico/metabolismo , Neoplasias da Próstata/metabolismo , Fatores de Risco
17.
Brachytherapy ; 19(6): 881-888, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31917179

RESUMO

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.

18.
J Neurooncol ; 146(1): 131-138, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31760596

RESUMO

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.


Assuntos
Neoplasias Encefálicas/radioterapia , Função Executiva/efeitos da radiação , Transtornos da Memória/patologia , Transtornos Neurocognitivos/patologia , Radioterapia/efeitos adversos , Adulto , Neoplasias Encefálicas/patologia , Feminino , Seguimentos , Humanos , Masculino , Transtornos da Memória/etiologia , Pessoa de Meia-Idade , Transtornos Neurocognitivos/classificação , Transtornos Neurocognitivos/etiologia , Testes Neuropsicológicos , Prognóstico , Estudos Prospectivos
19.
Int J Radiat Oncol Biol Phys ; 105(4): 773-783, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31408667

RESUMO

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.


Assuntos
Neoplasias Encefálicas/radioterapia , Irradiação Craniana/efeitos adversos , Transtornos da Memória/etiologia , Memória/efeitos da radiação , Lesões por Radiação/complicações , Lobo Temporal/efeitos da radiação , Adulto , Idoso , Agnosia/diagnóstico , Agnosia/etiologia , Anisotropia , Antineoplásicos/efeitos adversos , Neoplasias Encefálicas/tratamento farmacológico , Irradiação Craniana/métodos , Imagem de Difusão por Ressonância Magnética/métodos , Fracionamento da Dose de Radiação , Córtex Entorrinal/diagnóstico por imagem , Córtex Entorrinal/efeitos da radiação , Feminino , Neuroimagem Funcional , Hipocampo/diagnóstico por imagem , Hipocampo/efeitos da radiação , Humanos , Masculino , Transtornos da Memória/diagnóstico , Rememoração Mental/efeitos dos fármacos , Rememoração Mental/efeitos da radiação , Pessoa de Meia-Idade , Testes Neuropsicológicos , Estudos Prospectivos , Convulsões/complicações , Substância Branca/diagnóstico por imagem , Substância Branca/efeitos da radiação , Adulto Jovem
20.
Brachytherapy ; 18(5): 612-619, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31153760

RESUMO

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.


Assuntos
Braquiterapia/estatística & dados numéricos , Estado Civil , Neoplasias do Colo do Útero/mortalidade , Neoplasias do Colo do Útero/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , California/epidemiologia , Feminino , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Sistema de Registros , Taxa de Sobrevida , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia , Adulto Jovem
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