No prior trial has compared hypofractionated postprostatectomy radiotherapy (HYPORT) to conventionally fractionated postprostatectomy (COPORT) in patients primarily treated with prostatectomy.
To ...determine if HYPORT is noninferior to COPORT for patient-reported genitourinary (GU) and gastrointestinal (GI) symptoms at 2 years.
In this phase 3 randomized clinical trial, patients with a detectable prostate-specific antigen (PSA; ≥0.1 ng/mL) postprostatectomy with pT2/3pNX/0 disease or an undetectable PSA (<0.1 ng/mL) with either pT3 disease or pT2 disease with a positive surgical margin were recruited from 93 academic, community-based, and tertiary medical sites in the US and Canada. Between June 2017 and July 2018, a total of 296 patients were randomized. Data were analyzed in December 2020, with additional analyses occurring after as needed.
Patients were randomized to receive 62.5 Gy in 25 fractions (HYPORT) or 66.6 Gy in 37 fractions (COPORT).
The coprimary end points were the 2-year change in score from baseline for the bowel and urinary domains of the Expanded Prostate Cancer Composite Index questionnaire. Secondary objectives were to compare between arms freedom from biochemical failure, time to progression, local failure, regional failure, salvage therapy, distant metastasis, prostate cancer-specific survival, overall survival, and adverse events.
Of the 296 patients randomized (median range age, 65 44-81 years; 100% male), 144 received HYPORT and 152 received COPORT. At the end of RT, the mean GU change scores among those in the HYPORT and COPORT arms were neither clinically significant nor different in statistical significance and remained so at 6 and 12 months. The mean (SD) GI change scores for HYPORT and COPORT were both clinically significant and different in statistical significance at the end of RT (-15.52 18.43 and -7.06 12.78, respectively; P < .001). However, the clinically and statistically significant differences in HYPORT and COPORT mean GI change scores were resolved at 6 and 12 months. The 24-month differences in mean GU and GI change scores for HYPORT were noninferior to COPORT using noninferiority margins of -5 and -6, respectively, rejecting the null hypothesis of inferiority (mean SD GU score: HYPORT, -5.01 15.10 and COPORT, -4.07 14.67; P = .005; mean SD GI score: HYPORT, -4.17 10.97 and COPORT, -1.41 8.32; P = .02). With a median follow-up for censored patients of 2.1 years, there was no difference between HYPORT vs COPORT for biochemical failure, defined as a PSA of 0.4 ng/mL or higher and rising (2-year rate, 12% vs 8%; P = .28).
In this randomized clinical trial, HYPORT was associated with greater patient-reported GI toxic effects compared with COPORT at the completion of RT, but both groups recovered to baseline levels within 6 months. At 2 years, HYPORT was noninferior to COPORT in terms of patient-reported GU or GI toxic effects. HYPORT is a new acceptable practice standard for patients receiving postprostatectomy radiotherapy.
ClinicalTrials.gov Identifier: NCT03274687.
Abstract Introduction When expressed as a percentage of the average result in young adults, bone mineral content lags behind bone length before puberty. Even though this observation has led to ...speculation about bone fragility in children, such relationships could simply be due to scaling effects when measures with different geometrical dimensions are compared. Methods The study population comprised 145 healthy subjects (6–25 years, 94 females). Magnetic resonance imaging and dual-energy X-ray absorptiometry were used to determine femur length, bone mineral content, cortical bone mineral density, cross-sectional bone geometry (bone diameter; cortical thickness; total, cortical and medullary areas; cross-sectional and polar moments of area; bone strength index) and muscle area at the proximal one-third site of the femur. Results were dimensionally scaled by raising two-, three- and four-dimensional variables to the power of 1/2, 1/3 and 1/4, respectively. Sex-differences were also assessed before and after functionally adjusting variables for femur length and weight or muscle size. Results In prepubertal children, unscaled results expressed as percentages of adult values were lowest for variables with the highest dimensions (e.g., moments of area < bone mineral content < cross-sectional areas < femur length). However, when dimensionally scaled, results in children represented similar percentages of the respective average adult values, even after functional adjustments. Before puberty, there was no sex-difference in adjusted bone or muscle variables. After puberty, males had greater total and cortical bone area, bone diameter, moments of area, bone strength index and muscle area than women, both in absolute terms as well as adjusted for femur length and weight. The largest sex-difference was found for muscle area. When compared relative to muscle size, young adult women attained greater total and cortical bone area than men. Conclusions Growth in femoral length, diameter, mass and strength appears well coordinated before puberty. Postpubertal females have narrower femora, less bone strength and muscle size than males. However, when muscle size is taken into account, females have a larger femoral bone cross-section and more cortical bone. These sex-differences likely result from a combination of mechanical and hormonal effects occurring during puberty.
The rs1076560 polymorphism of DRD2 (encoding dopamine receptor D2) is associated with alternative splicing and cognitive functioning; however, a mechanistic relationship to schizophrenia has not been ...shown. Here, we demonstrate that rs1076560(T) imparts a small but reliable risk for schizophrenia in a sample of 616 affected families and five independent replication samples totaling 4017 affected and 4704 unaffected individuals (odds ratio=1.1; P=0.004). rs1076560(T) was associated with impaired verbal fluency and comprehension in schizophrenia but improved performance among healthy comparison subjects. rs1076560(T) also associated with lower D2 short isoform expression in postmortem brain. rs1076560(T) disrupted a binding site for the splicing factor ZRANB2, diminished binding affinity between DRD2 pre-mRNA and ZRANB2 and abolished the ability of ZRANB2 to modulate short:long isoform-expression ratios of DRD2 minigenes in cell culture. Collectively, this work implicates rs1076560(T) as one possible risk factor for schizophrenia in the Han Chinese population, and suggests molecular mechanisms by which it may exert such influence.
Background
Bulimic behaviors (i.e., binge eating and compensatory behaviors) and substance use frequently co‐occur. However, the etiology underlying this association is poorly understood. This study ...evaluated the association between bulimic behaviors and early substance use, controlling for genetic and shared environmental factors.
Methods
Participants were 3,540 young adult women from the Missouri Adolescent Female Twin Study. A telephone adaptation of the Semi‐Structured Assessment for the Genetics of Alcoholism interview assessed DSM‐IV bulimic behaviors, substance use, and other psychological characteristics. Lifetime bulimic behaviors were examined in twin pairs concordant and discordant for early substance use. Logistic regressions were adjusted for the nonindependence of twin data, zygosity, age, body mass index, early menarche (onset before age 12), and early sex (first consensual sexual intercourse before age 15).
Results
In the entire study population, women who reported early use of alcohol or nicotine were more likely to engage in bulimic behaviors after adjusting for covariates. In 53 pairs of monozygotic twins discordant for alcohol experimentation before age 15, the twin who reported early alcohol experimentation had 3.21 (95% confidence interval = 1.54 to 6.67) times higher odds of reporting bulimic behaviors than the cotwin who did not report early alcohol experimentation, even after adjustment for covariates.
Conclusions
Findings suggest that early alcohol experimentation may contribute to the development of bulimic behaviors via mechanisms extending beyond shared vulnerability, including individual‐specific environmental experiences or causal pathways.
Background:
Nicotine dependence is associated with considerable morbidity and mortality. Two predominant classification systems, the Diagnostic and Statistical Manual (DSM-IV) and Fagerström Test for ...Nicotine Dependence (FTND), have been used to measure liability to nicotine dependence, yet few studies have attempted to simultaneously examine both sets of criteria.
Methods:
Using a sample of 624 regular smoking individuals who are offspring of Vietnam Era Twin fathers ascertained for an offspring of twin study, we applied latent class analysis to the 7 DSM-IV and the 6 FTND criteria to classify individuals by their nicotine dependence symptom profiles. Post-hoc across-class comparisons were conducted using a variety of smoking-related variables and aspects of psychopathology. Whether a single class identified offspring at high genetic and environmental vulnerability was also investigated.
Results:
The cross-diagnosis kappa was .30. A 4-class solution fit these data best. The classes included a low DSM-low FTND class and a high DSM-high FTND class; a moderate DSM-moderate FTND class, which was distinguished by moderate levels of smoking and intermediate levels of comorbid psychopathology; and a light smoking-moderate FTND class consisting primarily of lighter smokers with a more recent onset of regular smoking. High genetic and environmental vulnerability to nicotine dependence was noted in all classes with no statistically significant across-class differences.
Conclusions:
In general, the DSM-IV and FTND criteria performed similarly to define a continuum of risk for nicotine dependence. The emerging class of light smokers should be further investigated to assess whether they transition to another class or remain as such.
Abstract Objective The aim of the current study was to determine whether the higher rates of childhood sexual abuse (CSA) but lower rates of cigarette smoking in African-American vs. ...European-American women can be explained in part by a lower magnitude of association between CSA and smoking in African-American women. Methods Data were drawn from a same-sex female twin study of substance use (n = 3521; 14.3% African-American). Cox proportional hazards regression analyses using CSA to predict smoking initiation and progression to regular smoking were conducted separately by race/ethnicity. Co-twin status on the smoking outcome was used to adjust for familial influences on smoking (which may overlap with family-level influences on CSA exposure). Results After adjusting for co-twin status, CSA was associated with smoking initiation in European Americans (hazard ratio (HR) = 1.43, 95% confidence intervals (CI): 1.26–1.62) and with smoking initiation ≤ 16 in African Americans (HR = 1.70, CI: 1.26–2.29). CSA was associated with regular smoking onset ≤ 15 in European Americans (HR = 1.63, CI: 1.21–2.18), with no change in HR after adjusting for co-twin status. In the African-American subsample, the HR for CSA was reduced to non-significance after adjusting for co-twin status (from HR = 3.30, CI: 1.23–8.89 to HR = 1.16, CI: 0.71–1.92 for regular smoking ≤ 15). Conclusions CSA is associated with moderate elevation in risk for initiating smoking among African-American and European-American women. By contrast, CSA is associated with elevated risk for (adolescent onset) regular smoking only in European-American women. Furthermore, there is significant overlap between risk conferred by CSA and familial influences on regular smoking in African-American but not European-American women.
Rates of alcohol dependence are elevated in women with eating disorders who engage in binge eating or compensatory behaviors compared with women with eating disorders who do not report binge eating ...or compensatory behaviors and with healthy controls. Alcohol dependence, binge eating, and compensatory behaviors are heritable; however, it is unclear whether a shared genetic liability contributes to the phenotypic association among these traits, and little information exists regarding this shared liability in men. We investigated genetic and environmental correlations among alcohol dependence, binge eating, and compensatory behaviors in male and female twins.
Participants included 5,993 same- and opposite-sex twins from the Australian Twin Registry who completed a modified version of the Semi-Structured Assessment for the Genetics of Alcoholism that assessed lifetime alcohol dependence and binge eating as defined in the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised. Compensatory behaviors were assessed via a general health questionnaire in women only. Biometrical twin models estimated genetic and environmental influences on alcohol dependence, binge eating, and compensatory behaviors.
In women, the multivariate twin model suggested that additive genetic and nonshared environmental effects influenced alcohol dependence, binge eating, and compensatory behaviors, with heritability estimates ranging from 38% to 53%. The best-fitting sex-limitation model was a common effects model that equated all genetic and nonshared environmental influences in men and women. The heritability estimates were 50% and 38% for alcohol dependence and binge eating, respectively. Overall, there were significant genetic correlations between alcohol dependence and binge eating, alcohol dependence and compensatory behaviors, and binge eating and compensatory behaviors.
These findings indicate that common genetic factors may underlie the vulnerability to alcohol dependence and the liability to binge eating and compensatory behaviors.
Highlights • Alcohol use disorder (AUD) and bulimic behaviors co-occur, yet it is unknown why. • Few studies have included African American women in genetic research. • We examined their shared ...etiology in European American and African American women. • Common genetic and environmental factors underlie liability to these behaviors. • There were no significant differences between racial/ethnic groups.
The current investigation assessed for moderating effects of childhood trauma on genetic and environmental contributions to timing of alcohol use initiation and alcohol use disorder in African ...American (AA) and European American (EA) women. Data were drawn from diagnostic telephone interviews conducted with 3786 participants (14.6% AA) in a longitudinal female twin study. Childhood trauma was defined alternately as child maltreatment and more broadly to include other events (e.g., witnessing violence). Phenotypic associations between childhood trauma and alcohol outcomes were estimated using logistic regression analyses. Twin modeling was conducted to test for moderating effects of childhood trauma on the contributions of genetic and environmental factors to timing of initiation and alcohol use disorder. Under both definitions, childhood trauma was associated with early initiation (relative risk ratios: 1.90, 1.72) and alcohol use disorder (odds ratios: 1.92, 1.76). Yet gene by environment effects were observed only for child maltreatment and timing of initiation in EA women, with heritable influences less prominent in those who had experienced child maltreatment (0.35, 95% CI: 0.05–0.66 vs. 0.52, 95% CI: 0.30–0.73). We found more similarities than differences in the association of childhood trauma with alcohol outcomes across racial/ethnic groups, trauma type, and stages of alcohol use. However, findings suggest that the relative contribution of genetic factors to alcohol outcomes differs by childhood maltreatment history in EA women specifically in the earliest stage of alcohol use.
Abstract Purpose We examined timing of first voluntary sexual intercourse as a joint function of parental separation during childhood and parental history of alcoholism. Methods Data were drawn from ...a birth cohort of female like-sex twins (n = 569 African ancestry AA; n = 3,415 European or other ancestry EA). Cox proportional hazards regression was conducted predicting age at first sex from dummy variables coding for parental separation and parental alcoholism. Propensity score analysis was also employed to compare intact and separated families, stratified by predicted probability of separation. Results Earlier sex was reported by EA twins from separated and alcoholic families, compared to EA twins from intact nonalcoholic families, with effects most pronounced through the age of 14 years. Among AA twins, effects of parental separation and parental alcoholism were largely nonsignificant. Results of propensity score analyses confirmed unique risks from parental separation in EA families, where consistent effects of parental separation were observed across predicted probability of separation. For AA families, there was poor matching on risk factors presumed to predate separation, which limited interpretability of survival-analytic findings. Conclusions In European American families, parental separation during childhood is an important predictor of early-onset sex, beyond parental alcoholism and other correlated risk factors. To characterize risk for African Americans associated with parental separation, additional research is needed where matching on confounders can be achieved.
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