Reading and spelling profiles of adult poor readers: Phonological, orthographic and morphological considerations.

Reading and spelling skills are important to communicate in today's literate society, however, the underlying processes of spelling skills are under-researched compared to reading skills. Our goals were to (a) study how the component skills of phonological, orthographic and morphological awareness are different in adults with and without reading difficulties, and (b) characterize the relationship between the component skills and reading and spelling performance in both skilled and poor readers. Participants (N = 37, N = 15 with reading impairments and N = 22 skilled readers) took part in the study where they completed several literacy-based measures. We performed a series of mixed ANOVAs to study the between-group differences in performance and the relationship between different literacy outcomes, respectively. We found evidence for poor phonological and morphological awareness in the poor readers compared to the skilled readers. We also found differential relationships between the component skills and reading and spelling behavior. Specifically, sound awareness was significantly related to reading and spelling measures in the skilled readers, whereas morphological and sound awareness played an important role in the same skills in the poor readers. We discuss these findings in the context of potential remediation strategies for adults with persistent literacy impairments.

An investigation of white matter properties as they relate to spelling behaviour in skilled and impaired readers.

RESULTS: While the inferior longitudinal fasciculus was more strongly related to spelling behaviour in skilled adults, the uncinate fasciculus was more strongly related to spelling behaviour in impaired adults. We found strong left lateralization of the arcuate fasciculus and inferior longitudinal fasciculus in both groups. However, lateralization of the inferior frontal occipital fasciculus was more strongly related to spelling response time behaviour in skilled adults, whereas lateralization of the uncinate fasciculus was more strongly related to spelling accuracy behaviour in the impaired adults. CONCLUSION: This study provides some useful information for understanding the underlying white matter pathways that support spelling in skilled and impaired adults and underscore the advantage of adopting multiple spelling tasks and outcomes (i.e., response time and accuracy) to better characterize brain-behaviour relationships in skilled and impaired adults.

Long-term outcomes of prostate radiotherapy for newly-diagnosed metastatic prostate cancer.

BACKGROUND: In patients presenting with metastatic prostate cancer, the role of local therapy is evolving. Two recently reported large-scale randomized trials suggest that radiotherapy (RT) directed at the prostate improves overall survival (OS) in patients with low metastatic burden. We reviewed the experience of prostate RT in this setting at our center. METHODS: The study population consisted of men with newly-diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) referred to a comprehensive cancer center between 2005 and 2015 and treated initially with androgen deprivation therapy. Patients were eligible for inclusion if they received (1) prostate RT with biological effective dose (BED) at least that of a course of 40 Gy in 15 fractions or (2) no prostate RT. The association between receipt of prostate RT and OS was studied. OS was estimated using the Kaplan-Meier method and Cox regression was used to identify factors associated with OS. RESULTS: The cohort consisted of 410 patients, of whom 128 received prostate RT. Median follow-up 61.0 months. On univariate analysis, receipt of prostate RT was associated with improved OS (HR 0.59, 95% CI 0.45-0.77, p = 0.0001). Median OS in those patients receiving prostate RT was 47.4 months versus 26.3 months in those not receiving prostate RT. In a multivariate Cox model, receipt of prostate RT remained associated with improved OS (HR 0.69, 95% CI 0.50-0.94, p = 0.02). In those treated with prostate RT, increasing BED was also associated with improved OS (HR 0.87 per 10 Gy increase, 95% CI 0.76-0.99, p = 0.03). CONCLUSIONS: This cohort represents the largest single-center experience of primary tumor-directed RT in mHSPC reported to date. In this population, receipt of prostate RT was associated with improved OS and the magnitude of the OS benefit was clinically significant. The possibility of an RT dose-response gradient in this setting merits further study.

Patient-Reported Outcomes From a Phase 3 Randomized Controlled Trial Exploring Optimal Sequencing of Short-Term Androgen Deprivation Therapy With Prostate Radiation Therapy in Localized Prostate Cancer.

PURPOSE: Two phase 3 randomized controlled trials (OTT-0101, RTOG-9413) and a meta-analysis have shown an impact of sequencing of androgen deprivation therapy (ADT) and radiation therapy on oncologic outcomes in prostate cancer (PCa). However, the impact of sequencing strategy on health-related quality of life (HR-QoL) is unclear. Here, we present the patient-reported HR-QoL outcomes from the OTT-0101 study. METHODS AND MATERIALS: In this trial, patients with PCa with Gleason score ≤7, clinical stage T1b to T3a, and prostate-specific antigen level <30 ng/mL were randomly assigned to neoadjuvant and concurrent ADT for 6 months, starting 4 months before or concurrent with prostate radiation therapy, or concurrent and adjuvant ADT for 6 months, starting simultaneously with prostate radiation therapy. HR-QoL was assessed using European Organisation for Research and Treatment of Cancer QoL questionnaires. Time until definitive deterioration was defined as time from random allocation to the first deterioration of at least 10 points with no further improvement of ≥10 points or if the patient experienced progression, died, or dropped out after deterioration, resulting in missing data. Stratified log-rank tests were applied for between-group comparisons of time-to-event estimates. RESULTS: Overall, 393 patients (194 and 199 in the 2 arms, respectively) were evaluable, except 214 (101 and 113 in the 2 arms, respectively) for sexual function. Five-year rates of freedom from definitive deterioration of urinary symptoms, bowel symptoms, and sexual activity were 33.5%, 33.1%, and 38.5% in the neoadjuvant group and 34.1%, 35.4%, and 36.7% in the adjuvant group, respectively, with no significant between-group differences. The adjuvant approach was associated with a reduced risk of definitive deterioration of sexual function (hazard ratio, 0.68; 95% confidence interval, 0.49-0.94; P = .02). With respect to clinical relevance, the mean change in score for sexual function showed only a small to moderate difference favoring the adjuvant group at and beyond 3 years. CONCLUSIONS: In this study, no differences were found in the bowel or urinary symptoms between the adjuvant and neoadjuvant approach. Considering a significant likelihood of type I and type II errors and because of a lack of a persistent and clinically meaningful between-group difference in mean score changes over time, our findings do not confer a clear and conclusive picture of the impact of sequencing strategy on sexual function.

Impact of Treating Physician on Radiation Therapy Related Severe Toxicities in Men with Prostate Cancer.

PURPOSE: The impact of treating physician on radiation therapy (RT) related toxicity is unclear. We carried out a secondary analysis of a randomized controlled study to determine whether the risk of RT-related late toxicities in patients with prostate cancer varies depending on the treating radiation oncologist. METHODS AND MATERIALS: This is a secondary analysis of a phase 3 randomized controlled study in which patients with prostate cancer with Gleason score ≤7, clinical stage T1b-T3a, and prostate-specific antigen <30 ng/mL were randomized to receive androgen suppression for 6 months, starting either 4 months before or concurrently with definitive prostate radiation therapy. Incidence of late RT-related toxicity was estimated using Kaplan-Meier methods. We applied multivariable semiparametric shared frailty models with gamma distribution to determine the between-physician variation in the hazard of late RT-related grade ≥3 gastrointestinal, genitourinary, or overall toxicity. Patient level covariables included age, risk group, year of enrollment, and treatment regimen. Frailty variance, a measure of unexplained heterogeneity, was estimated with 95% confidence intervals (CIs). Statistical significance was suggested when the lower limit of the 95% CI for the frailty variance was >0. The Commenges-Andersen test was used for P value estimation. RESULTS: Overall, 426 patients were treated by 9 radiation oncologists. On log-rank test, there was a significant difference in the cumulative incidence of overall grade ≥3 toxicities (P = .001) and grade ≥3 gastrointestinal toxicity (P = .01) among the physician-based clusters. The frailty variance for overall late grade ≥3 toxicity was 0.31 (95% CI, 0.02-1.39; P = .01). The frailty variance for the grade ≥3 gastrointestinal and genitourinary toxicity was 0.84 (95% CI, 0.00-4.20; P = .11) and 0.11 (95% CI, 0.00-1.13; P = .31), respectively. CONCLUSIONS: In our study, the hazard of overall RT-related late grade ≥3 toxicity varied significantly depending on treating radiation oncologist. Further studies are required to explore the underlying processes that lead to such variations in clinical trials involving radiation therapy in prostate cancer.

Prostate Radiotherapy With Adjuvant Androgen Deprivation Therapy (ADT) Improves Metastasis-Free Survival Compared to Neoadjuvant ADT: An Individual Patient Meta-Analysis.

PURPOSE: There remains a lack of clarity regarding the influence of sequencing of androgen deprivation therapy (ADT) and radiotherapy (RT) on outcomes in prostate cancer (PCa). Herein, we evaluate the optimal sequencing of ADT with prostate-directed RT in localized PCa. METHODS: MEDLINE (1966-2018), Embase (1982-2018), ClinicalTrials.gov, and conference proceedings (1990-2018) were searched to identify randomized trials evaluating the sequencing, but not duration, of ADT with RT. Two randomized phase III trials were identified, and individual patient data were obtained: Ottawa 0101 and NRG Oncology's Radiation Therapy Oncology Group 9413. Ottawa 0101 randomly assigned patients to neoadjuvant or concurrent versus concurrent or adjuvant short-term ADT. Radiation Therapy Oncology Group 9413, a 2 × 2 factorial trial, included a random assignment of neoadjuvant or concurrent versus adjuvant short-term ADT. The neoadjuvant or concurrent ADT arms of both trials were combined into the neoadjuvant group, and the arms receiving adjuvant ADT were combined into the adjuvant group. The primary end point of this meta-analysis was progression-free survival (PFS). RESULTS: The median follow-up was 14.9 years. Overall, 1,065 patients were included (531 neoadjuvant and 534 adjuvant). PFS was significantly improved in the adjuvant group (15-year PFS, 29% v 36%, hazard ratio [HR], 1.25 [95% CI, 1.07 to 1.47], P = .01). Biochemical failure (subdistribution HR [sHR], 1.37 [95% CI, 1.12 to 1.68], P = .002), distant metastasis (sHR, 1.40 [95% CI, 1.00 to 1.95], P = .04), and metastasis-free survival (HR, 1.17 [95% CI, 1.00 to 1.37], P = .050) were all significantly improved in the adjuvant group. There were no differences in late grade ≥ 3 gastrointestinal (2% v 3%, P = .33) or genitourinary toxicity (5% v 5%, P = .76) between groups. CONCLUSION: The sequencing of ADT with prostate-directed RT has significant association with long-term PFS and MFS in localized PCa. Our findings favor use of an adjuvant over a neoadjuvant approach, without any increase in long-term toxicity.

Impact of Sequencing of Androgen Suppression and Radiation Therapy on Testosterone Recovery in Localized Prostate Cancer.

PURPOSE: We performed a secondary analysis of a phase 3 randomized trial to determine the influence of sequencing of radiation therapy and androgen deprivation therapy (ADT) on posttreatment testosterone recovery and implications of testosterone recovery on subsequent relapse. METHODS AND MATERIALS: Patients with localized prostate cancer with Gleason score ≤7, clinical stage T1b to T3a, and prostate-specific antigen <30 ng/mL were randomized to neoadjuvant and concurrent ADT for 6 months starting 4 months before prostate radiation therapy (NHT arm) or concurrent and adjuvant ADT for 6 months starting simultaneously with radiation therapy (CAHT arm). Full testosterone recovery (FTR) was defined as recovery of testosterone to >10.5 nmol/L in patients with baseline ≥10.5 nmol/L or to baseline level in patients with baseline <10.5 nmol/L. Restricted mean survival time (RMST) since ADT initiation to supracastrate testosterone level (>1.7 nmol/L), and to FTR was compared between the arms using a truncation time point of 36 months. RESULTS: The adjusted difference in RMST to supracastrate testosterone between the CAHT and NHT arm was 1.5 months (95% confidence interval [CI], 0.5-2.5; P = .005). No difference was noted in RMST to FTR between the arms (18.7 vs 18.5 months, adjusted difference: 0.5; 95% CI, -1.4 to 2.4; P = .61). There was no evidence of heterogeneity of treatment effect (interaction P = .76) on risk of relapse over subgroups stratified by testosterone recovery to supracastrate level at 15 months after start of ADT. Based on a multistate Markov model, no independent effect of time to FTR on risk of subsequent relapse was observed (adjusted hazard ratio: 1.02; 95% CI, 0.96-1.08). CONCLUSIONS: Patients should be counseled that an additional 12 months on average is needed for FTR to occur after treatment with prostate radiation therapy and 6 months of ADT. This is independent of the sequencing of ADT and radiation therapy. Furthermore, recovery of testosterone does not appear to affect the risk of subsequent relapse.

Sequencing of Androgen-Deprivation Therapy With External-Beam Radiotherapy in Localized Prostate Cancer: A Phase III Randomized Controlled Trial.

PURPOSE: Dose-escalated radiotherapy (RT) with androgen-deprivation therapy (ADT) is a standard definitive treatment of localized prostate cancer (LPCa). The optimal sequencing of these therapies is unclear. Our phase III trial compared neoadjuvant versus concurrent initiation of ADT in combination with dose-escalated prostate RT (PRT). PATIENTS AND METHODS: Patients with newly diagnosed LPCa with Gleason score ≤ 7, clinical stage T1b to T3a, and prostate-specific antigen < 30 ng/mL were randomly allocated to neoadjuvant and concurrent ADT for 6 months starting 4 months before RT (neoadjuvant group) or concurrent and adjuvant ADT for 6 months starting simultaneously with RT (concurrent group). The primary end point was biochemical relapse-free survival (bRFS). Stratified log-rank test was used to compare bRFS and overall survival (OS). Incidence of grade ≥ 3 late RT-related toxicities was compared by log-rank test. RESULTS: Overall, 432 patients were randomly assigned to the neoadjuvant (n = 215) or concurrent group (n = 217). At 10 years, bRFS rates for the two groups were 80.5% and 87.4%, respectively. Ten-year OS rates were 76.4% and 73.7%, respectively. There was no significant difference in bRFS (P = .10) or OS (P = .70) between the two groups. Relative to the neoadjuvant group, the hazard ratio for the concurrent group was 0.66 (95% CI, 0.41 to 1.07) for bRFS and 0.94 (95% CI, 0.68 to 1.30) for OS. No significant difference was observed in the 3-year incidence of late RT-related grade ≥ 3 GI (2.5% v 3.9%) or genitourinary toxicity (2.9% v 2.9%). CONCLUSION: In our study, there was no statistically significant difference in bRFS between the two treatment groups. Similarly, no difference was seen in OS or late RT-related toxicities. On the basis of these results, both neoadjuvant and concurrent initiations of short-term ADT with dose-escalated PRT are reasonable standards of care for LPCa.

Epstein-Barr Virus-Associated Acute Liver Failure Present in a 67-Year-Old Immunocompetent Female.

Acute liver failure (ALF) is a rare illness with a high mortality rate. The only favorable management is emergent liver transplantation. About 13% of ALF cases have no clear etiology. Epstein-Barr virus (EBV)-associated ALF accounts for less than 1% of all ALF cases, and is seen mostly in adults younger than 40 years. There are only a few cases of EBV-associated ALF in elderly immunocompromised adults. We report a case of ALF in an immunocompetent 67-year-old woman caused by EBV infection that was treated by orthotopic liver transplantation (OLT). The diagnosis of EBV-associated ALF was established by EBV-DNA polymerase chain reaction (PCR) and EBV-encoded RNA (EBER-RNA) in situ hybridization (EBER-RISH). The patient is currently doing well 6 months after transplantation without any evidence of clinical EBV infection. This case illustrates the importance of early recognition and diagnosis of EBV-associated ALF by detection of EBV from liver biopsy, especially when patients are immunocompetent and other causes are excluded. To the best of our knowledge, this is the first case of EBV-associated ALF present in an immunocompetent elderly female.