Genomic biomarkers in prostate cancer.

Prostate cancer is the most common non-cutaneous cancer among men in the United States. In the last decade there has been a rapid expansion in the field of biomarker assays for diagnosis, prognosis, and treatment prediction in prostate cancer. The evidence base for these assays is rapidly evolving. With several commercial assays available at each stage of the disease, deciding which genomic assays are appropriate for which patients can be nuanced for physicians. In an effort to help guide these decisions in clinical practice, we aim to give an update on the current status of the biomarker field of prostate cancer

Reading Acquisition in Morocco

While interest in reading and writing has always been important to researchers and educational policy-makers, multidisciplinary investigations of the acquisition of literacy are a relatively new enterprise. In the Arabic-speaking wrold, in particular, there have been relatively few efforts to discover what kinds of literacy abilities the child brings to the classroom, and what kinds of home, preschool, and language environments lead to various levels of literacy both in and out of school. The research described here presents data collected during the first three years of the Morocco Literacy Project, whose general aim has been to investigate the process of literacy acquisition and retention in Morocco. The present paper will consider the effects of preschool experience and language background on a sample of primary school children living in contrastin rural and urban environments in Morocco

Comparison of joint modeling and landmarking for dynamic prediction under an illness‐death model

Dynamic prediction incorporates time‐dependent marker information accrued during follow‐up to improve personalized survival prediction probabilities. At any follow‐up, or “landmark”, time, the residual time distribution for an individual, conditional on their updated marker values, can be used to produce a dynamic prediction. To satisfy a consistency condition that links dynamic predictions at different time points, the residual time distribution must follow from a prediction function that models the joint distribution of the marker process and time to failure, such as a joint model. To circumvent the assumptions and computational burden associated with a joint model, approximate methods for dynamic prediction have been proposed. One such method is landmarking, which fits a Cox model at a sequence of landmark times, and thus is not a comprehensive probability model of the marker process and the event time. Considering an illness‐death model, we derive the residual time distribution and demonstrate that the structure of the Cox model baseline hazard and covariate effects under the landmarking approach do not have simple form. We suggest some extensions of the landmark Cox model that should provide a better approximation. We compare the performance of the landmark models with joint models using simulation studies and cognitive aging data from the PAQUID study. We examine the predicted probabilities produced under both methods using data from a prostate cancer study, where metastatic clinical failure is a time‐dependent covariate for predicting death following radiation therapy.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/140034/1/bimj1778.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/140034/2/bimj1778_am.pd

Spine Patient Optimal Radiosurgery Treatment for Symptomatic Metastatic Neoplasms (SPORTSMEN): a randomized phase II study protocol

Background: Approximately 40% of patients with metastatic cancer will have spinal metastatic disease. Historically treated with external beam radiation therapy (EBRT) with limited durability in pain control, the increased lifespan of this patient population has necessitated more durable treatment results via spine radiosurgery/stereotactic body radiation therapy (SBRT). The goal of this study is to assess three-month pain freedom rates via the Spine Patient Optimal Radiosurgery Treatment for Symptomatic Metastatic Neoplasms (SPORTSMEN) randomized trial. Materials and methods: This study is a prospective randomized three-arm phase II trial which will recruit patients with symptomatic spine metastases. All patients will be randomized to standard-of care SBRT (24 Gy in 2 fractions), single-fraction SBRT (19 Gy in 1 fraction), or EBRT (8 Gy in 1 fraction), with the primary endpoint of three-month pain freedom (using the Brief Pain Inventory). We expect that SPORTSMEN will help definitively answer the efficacy of spine SBRT versus EBRT for achieving pain freedom, while defining the safety and efficacy of 19 Gy single-fraction spine SBRT. Local control will be defined according to Spine Response Assessment in Neuro-Oncology (SPINO) criteria. Discussion: This is the first phase II trial to objectively assess optimal spine SBRT dosing in the treatment of symptomatic spine metastatic disease, while assessing spine SBRT versus EBRT. Findings should allow for better determination of the efficacy of two-fraction spine SBRT versus EBRT in the United States, as well as for the novel single-fraction 19 Gy spine SBRT regimen in patients with symptomatic spine metastases. Trial Registration: Clinicaltrials.gov identifier: NCT05617716 (registration date: November 14, 2022)

Adverse events in radiation oncology: A case series from wake up safe, the pediatric anesthesia quality improvement initiative

BackgroundRadiation therapy in pediatric patients often requires anesthesia and poses environmental challenges. Monitoring must be done remotely to limit radiation exposure to the provider. Airway access can be limited by masks or frames. Care is often delivered in relatively inaccessible locations in the hospital. While individual institutions have reported their outcomes, this case series aims to review a multicenter registry of significant adverse events and make recommendations for improved care.MethodsWake Up Safe: The Pediatric Quality Improvement Initiative maintains a multisite, voluntary registry of pediatric perianesthetic significant adverse events. This was queried for reports from radiation oncology from January 1, 2010 to May 10, 2018. The database contained 3,379 significant adverse events from approximately 3.3 million anesthetics. All 33 institutions submitted data on a standardized form to a central data repository (Axio Research, Seattle Washington). Prior to each significant adverse events case submission, three anesthesiologists who were not involved in the event analyzed the event using a standardized root cause analysis method to identify the causal or contributing factor(s).ResultsSix significant adverse events were identified. In three, incorrect programming of a propofol infusion resulted in overdose. In case one, the 3â yearâ old female became hypotensive, requiring vasopressors and volume resuscitation. In the second, the 2â yearâ old female experienced airway obstruction and apnea requiring chin lift. In case three, the child suffered no consequences despite a noted overdose of propofol infusion. In case four, a 2â yearâ old female with recent respiratory infection suffered laryngospasm during an unmonitored transport to the recovery area. She developed profound oxygen desaturation with bradycardia treated with succinylcholine and chest compressions. In case five, a 6â yearâ old former premature child suffered laryngospasm at the conclusion of mask creation under general anesthesia with a laryngeal mask airway. The radiation mask delayed recognition of copious secretions. Finally, in case six, a 6â yearâ old undergoing stereotactic radiosurgery in a head halo suffered bronchospasm and unintended extubation during therapy which required multiple attempts at reintubation by multiple providers ultimately requiring cancellation of the treatment and transport to the intensive care unit.ConclusionThere were few radiation oncology significant adverse events, but analysis has led to the identification of several specific opportunities for improvement in pediatric anesthesia for radiation oncology.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148238/1/pan13567_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148238/2/pan13567.pd

Androgen receptor as a mediator and biomarker of radioresistance in triple-negative breast cancer.

Increased rates of locoregional recurrence have been observed in triple-negative breast cancer despite chemotherapy and radiation therapy. Thus, approaches that combine therapies for radiosensitization in triple-negative breast cancer are critically needed. We characterized the radiation therapy response of 21 breast cancer cell lines and paired this radiation response data with high-throughput drug screen data to identify androgen receptor as a top target for radiosensitization. Our radiosensitizer screen nominated bicalutamide as the drug most effective in treating radiation therapy-resistant breast cancer cell lines. We subsequently evaluated the expression of androgen receptor in >2100 human breast tumor samples and 51 breast cancer cell lines and found significant heterogeneity in androgen receptor expression with enrichment at the protein and RNA level in triple-negative breast cancer. There was a strong correlation between androgen receptor RNA and protein expression across all breast cancer subtypes (R2 = 0.72, p < 0.01). In patients with triple-negative breast cancer, expression of androgen receptor above the median was associated with increased risk of locoregional recurrence after radiation therapy (hazard ratio for locoregional recurrence 2.9-3.2)) in two independent data sets, but there was no difference in locoregional recurrence in triple-negative breast cancer patients not treated with radiation therapy when stratified by androgen receptor expression. In multivariable analysis, androgen receptor expression was most significantly associated with worse local recurrence-free survival after radiation therapy (hazard ratio of 3.58) suggesting that androgen receptor expression may be a biomarker of radiation response in triple-negative breast cancer. Inhibition of androgen receptor with MDV3100 (enzalutamide) induced radiation sensitivity (enhancement ratios of 1.22-1.60) in androgen receptor-positive triple-negative breast cancer lines, but did not affect androgen receptor-negative triple-negative breast cancer or estrogen-receptor-positive, androgen receptor-negative breast cancer cell lines. androgen receptor inhibition with MDV3100 significantly radiosensitized triple-negative breast cancer xenografts in mouse models and markedly delayed tumor doubling/tripling time and tumor weight. Radiosensitization was at least partially dependent on impaired dsDNA break repair mediated by DNA protein kinase catalytic subunit. Our results implicate androgen receptor as a mediator of radioresistance in breast cancer and identify androgen receptor inhibition as a potentially effective strategy for the treatment of androgen receptor-positive radioresistant tumors

Correlation between cribriform/intraductal prostatic adenocarcinoma and percent Gleason pattern 4 to a 22‐gene genomic classifier

BackgroundThe Decipher test measures expression of 22 RNA biomarkers associated with aggressive prostate cancer used to improve risk stratification of patients to help guide management. To date, Decipher’s genomic classification has not been extensively correlated with specific histologic growth patterns in prostatic adenocarcinoma. With a growing understanding of the clinical aggressiveness associated with cribriform growth pattern (CF), intraductal carcinoma (IDC), and percent Gleason pattern 4 (G4%), we sought to determine if their presence was associated with an increased genomic risk as measured by the Decipher assay.DesignClinical use of the Decipher assay was performed on the highest Gleason score (GS) tumor nodule of prostatectomy specimens from a prospective cohort of 48 patients, with GS varying from 7 through 9 to help guide clinical risk stratification. The tumors were reviewed for CF, IDC, and G4%, which were then compared to the Decipher score (0‐1) and risk stratification (high vs not high).ResultsThe presence of CF/IDC was significantly associated with Decipher risk score (P = .007), with a high‐risk Decipher score in 22% vs 56% of patients without or with CF/IDC. On binary logistic regression analysis, G4% (odds ratio [OR] 1.04 per percent increase [95% confidence interval [CI], 1.02‐1.06]; P = .0004) and CF predominant (OR, 9.60 [95%CI, 1.48‐62.16]; P = .02) were significantly associated with a high‐risk GC score. IDC did not reach significance (OR, 1.92 [95%CI, 0.65‐5.67]; P = .24).ConclusionsOur findings add to an expanding knowledge base that supports G4% and CF/IDC as molecularly unique and clinically relevant features in prostatic adenocarcinoma. These histologic features should be standardly reported as they are associated with more aggressive prostate cancer. Future work should determine the independent information of these histologic findings that are relative to genomic assessment on long‐term outcomes.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153011/1/pros23926.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153011/2/pros23926_am.pd

Changes in prostate‐specific antigen at the time of prostate cancer diagnosis after Medicaid expansion in young men

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155914/1/cncr32930_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155914/2/cncr32930.pd

Impact of the SPOP Mutant Subtype on the Interpretation of Clinical Parameters in Prostate Cancer.

Purpose: Molecular characterization of prostate cancer, including The Cancer Genome Atlas, has revealed distinct subtypes with underlying genomic alterations. One of these core subtypes, SPOP (speckle-type POZ protein) mutant prostate cancer, has previously only been identifiable via DNA sequencing, which has made the impact on prognosis and routinely used risk stratification parameters unclear. Methods: We have developed a novel gene expression signature, classifier (Subclass Predictor Based on Transcriptional Data), and decision tree to predict the SPOP mutant subclass from RNA gene expression data and classify common prostate cancer molecular subtypes. We then validated and further interrogated the association of prostate cancer molecular subtypes with pathologic and clinical outcomes in retrospective and prospective cohorts of 8,158 patients. Results: The subclass predictor based on transcriptional data model showed high sensitivity and specificity in multiple cohorts across both RNA sequencing and microarray gene expression platforms. We predicted approximately 8% to 9% of cases to be SPOP mutant from both retrospective and prospective cohorts. We found that the SPOP mutant subclass was associated with lower frequency of positive margins, extraprostatic extension, and seminal vesicle invasion at prostatectomy; however, SPOP mutant cancers were associated with higher pretreatment serum prostate-specific antigen (PSA). The association between SPOP mutant status and higher PSA level was validated in three independent cohorts. Despite high pretreatment PSA, the SPOP mutant subtype was associated with a favorable prognosis with improved metastasis-free survival, particularly in patients with high-risk preoperative PSA levels. Conclusion: Using a novel gene expression model and a decision tree algorithm to define prostate cancer molecular subclasses, we found that the SPOP mutant subclass is associated with higher preoperative PSA, less adverse pathologic features, and favorable prognosis. These findings suggest a paradigm in which the interpretation of common risk stratification parameters, particularly PSA, may be influenced by the underlying molecular subtype of prostate cancer