Genomic Characterization of Upper-Tract Urothelial Carcinoma in Patients With Lynch Syndrome.

PURPOSE: Patients with Lynch syndrome (LS) have a significantly increased risk of developing upper-tract urothelial carcinoma (UTUC). Here, we sought to identify differences in the patterns of mutational changes in LS-associated versus sporadic UTUCs. PATIENTS AND METHODS: We performed targeted sequencing of 17 UTUCs from patients with documented LS-associated germline mutations (LS-UTUCs) using the Memorial Sloan Kettering Integrated Molecular Profiling of Actionable Cancer Targets targeted exon capture assay and compared the results with those from a recently characterized cohort of 82 patients with sporadic UTUC. RESULTS: Patients with LS-UTUC were significantly younger, had had less exposure to tobacco, and more often presented with a ureteral primary site compared with patients with sporadic UTUC. The median number of mutations per tumor was significantly greater in LS-UTUC tumors than in tumors from the sporadic cohort (58; interquartile range [IQR], 47-101 v 6; IQR, 4-10; P < .001), as was the MSIsensor score (median, 25.1; IQR, 17.9-31.2 v 0.03; IQR, 0-0.44; P < .001). Differences in the genetic landscape were observed between sporadic and LS-associated tumors. Alterations in KMT2D, CREBBP, or ARID1A or in DNA damage response and repair genes were present at a significantly higher frequency in LS-UTUC. CIC, NOTCH1, NOTCH3, RB1, and CDKN1B alterations were almost exclusive to LS-UTUC. Although FGFR3 mutations were identified in both cohorts, the R248C hotspot mutation was highly enriched in LS-UTUC. CONCLUSION: LSand sporadic UTUCs have overlapping but distinct genetic signatures. LS-UTUC is associated with hypermutation and a significantly higher prevalence of FGFR3 R248C mutation. Prospective molecular characterization of patients to identify those with LS-UTUC may help guide treatment.

Improved clinical outcomes with high-dose image guided radiotherapy compared with non-IGRT for the treatment of clinically localized prostate cancer.

PURPOSE: To compare toxicity profiles and biochemical tumor control outcomes between patients treated with high-dose image-guided radiotherapy (IGRT) and high-dose intensity-modulated radiotherapy (IMRT) for clinically localized prostate cancer. MATERIALS AND METHODS: Between 2008 and 2009, 186 patients with prostate cancer were treated with IGRT to a dose of 86.4 Gy with daily correction of the target position based on kilovoltage imaging of implanted prostatic fiducial markers. This group of patients was retrospectively compared with a similar cohort of 190 patients who were treated between 2006 and 2007 with IMRT to the same prescription dose without, however, implanted fiducial markers in place (non-IGRT). The median follow-up time was 2.8 years (range, 2-6 years). RESULTS: A significant reduction in late urinary toxicity was observed for IGRT patients compared with the non-IGRT patients. The 3-year likelihood of grade 2 and higher urinary toxicity for the IGRT and non-IGRT cohorts were 10.4% and 20.0%, respectively (p = 0.02). Multivariate analysis identifying predictors for grade 2 or higher late urinary toxicity demonstrated that, in addition to the baseline Internatinoal Prostate Symptom Score, IGRT was associated with significantly less late urinary toxicity compared with non-IGRT. The incidence of grade 2 and higher rectal toxicity was low for both treatment groups (1.0% and 1.6%, respectively; p = 0.81). No differences in prostate-specific antigen relapse-free survival outcomes were observed for low- and intermediate-risk patients when treated with IGRT and non-IGRT. For high-risk patients, a significant improvement was observed at 3 years for patients treated with IGRT compared with non-IGRT. CONCLUSIONS: IGRT is associated with an improvement in biochemical tumor control among high-risk patients and a lower rate of late urinary toxicity compared with high-dose IMRT. These data suggest that, for definitive radiotherapy, the placement of fiducial markers and daily tracking of target positioning may represent the preferred mode of external-beam radiotherapy delivery for the treatment of prostate cancer.

Dose escalation for prostate cancer radiotherapy: predictors of long-term biochemical tumor control and distant metastases-free survival outcomes.

BACKGROUND: Higher radiation dose levels have been shown to be associated with improved tumor-control outcomes in localized prostate cancer (PCa) patients. OBJECTIVE: Identify predictors of biochemical tumor control and distant metastases-free survival (DMFS) outcomes for patients with clinically localized PCa treated with conformal external-beam radiotherapy (RT) as well as present an updated nomogram predicting long-term biochemical tumor control after RT. DESIGN, SETTING, AND PARTICIPANTS: This retrospective analysis comprised 2551 patients with clinical stages T1-T3 PCa. Median follow-up was 8 yr, extending >20 yr. INTERVENTION: Prescription doses ranged from 64.8 to 86.4 Gy. A total of 1249 patients (49%) were treated with neoadjuvant and concurrent androgen-deprivation therapy (ADT); median duration of ADT was 6 mo. MEASUREMENTS: A proportional hazards regression model predicting the probability of biochemical relapse and distant metastases after RT included pretreatment prostate-specific antigen (PSA) level, clinical stage, biopsy Gleason sum, ADT use, and radiation dose. A nomogram predicting the probability of biochemical relapse after RT was developed. RESULTS AND LIMITATIONS: Radiation dose was one of the important predictors of long-term biochemical tumor control. Dose levels < 70.2 Gy and 70.2-79.2 Gy were associated with 2.3- and 1.3-fold increased risks of PSA relapse compared with higher doses. Improved PSA relapse-free survival (PSA-RFS) outcomes with higher doses were observed for all risk groups. Use of ADT, especially for intermediate- and high-risk patients, was associated with significantly improved biochemical tumor-control outcomes. A nomogram predicting PSA-RFS was generated and was associated with a concordance index of 0.67. T stage, Gleason score, pretreatment PSA, ADT use, and higher radiation doses were also noted to be significant predictors of improved DMFS outcomes. CONCLUSIONS: Higher radiation dose levels were consistently associated with improved biochemical control outcomes and reduction in distant metastases. The use of short-course ADT in conjunction with RT improved long-term PSA-RFS and DMFS in intermediate- and high-risk patients; however, an overall survival advantage was not observed.

Incremental value of diffusion weighted and dynamic contrast enhanced MRI in the detection of locally recurrent prostate cancer after radiation treatment: preliminary results.

OBJECTIVES: To assess the incremental value of diffusion-weighted (DW-MRI) and dynamic contrast-enhanced MRI (DCE-MRI) to T2-weighted MRI (T2WI) in detecting locally recurrent prostate cancer after radiotherapy. METHODS: Twenty-four patients (median age, 70 years) with a history of radiotherapy-treated prostate cancer underwent multi-parametric MRI (MP-MRI) and transrectal prostate biopsy. Two readers independently scored the likelihood of cancer on a 1-5 scale, using T2WI alone and then adding DW-MRI and DCE-MRI. Areas under receiver operating characteristic curves (AUCs) were estimated at the patient and prostate-side levels. The apparent diffusion coefficient (ADC) from DW-MRI and the K(trans), k(ep), v(e), AUGC90 and AUGC180 from DCE-MRI were recorded. RESULTS: Biopsy was positive in 16/24 (67%) and negative in 8/24 (33%) patients. AUCs for readers 1 and 2 increased from 0.64 and 0.53 to 0.95 and 0.86 with MP-MRI, at the patient level, and from 0.73 and 0.66 to 0.90 and 0.79 with MP-MRI, at the prostate-side level (p values < 0.05). Biopsy-positive and biopsy-negative prostate sides differed significantly in median ADC [1.44 vs. 1.68 (×10(-3) mm(2)/s)], median K(trans) [1.07 vs. 0.34 (1/min)], and k(ep) [2.06 vs 1.0 (1/min)] (p values < 0.05). CONCLUSIONS: MP-MRI was significantly more accurate than T2WI alone in detecting locally recurrent prostate cancer after radiotherapy.

Depressed patients with co-occurring alcohol use disorders: a unique patient population.

OBJECTIVE: Alcohol use and depressive disorders are frequently comorbid. Few studies have assessed the impact of comorbid alcohol use disorders (AUDs) on clinical aspects of major depression. We compared depressed subjects with and without co-occurring AUDs with respect to demographic and clinical parameters. METHOD: 505 individuals participated. 318 subjects had DSM-IV major depressive disorder (MDD) without a history of any alcohol or substance abuse/dependence (MDD only), and 187 individuals had MDD and a history of alcohol abuse/dependence (MDD/AUD). Demographic, clinical, and psychiatric history measures of patients in the 2 groups were examined and compared. The study was conducted from January 1990 to June 2005. RESULTS: MDD/AUD patients were younger at their first psychiatric hospitalization (p = .014), their first major depressive episode (p = .041), and their first suicide attempt (p = .001). They reported more previous major depressive episodes (p = .001), suicide attempts (p = .001), and recent life events (p = .001); and had higher lifetime aggression (p < .001), impulsivity (p < .001), and hostility (p < .001) scores. MDD/AUD patients were also more likely to report tobacco smoking (p < .001), a lifetime history of abuse (p = .004), and a history of AUD among first-degree relatives (p < .001) compared to MDD only patients. MDD/AUD individuals also had higher childhood (p < .001), adolescent (p < .001), and adult (p < .001) aggression scores and reported more behavioral problems during their childhood compared to their counterparts. Logistic regression analysis demonstrates that the number of previous depressive episodes, lifetime aggression, and smoking drive the difference between the groups. CONCLUSIONS: Our findings suggest that comorbid MDD/AUD may result from worse antecedents and lead to early onset, more comorbidity, and a more severe course of illness.

Triggers for suicidal behavior in depressed older adolescents and young adults: do alcohol use disorders make a difference?

UNLABELLED: Adolescent suicide is a major social and medical problem. Alcohol use disorders with comorbid major depression represent an especially high-risk profile for suicidal behavior, repeated suicidal behavior and completed suicide. We compared demographic and clinical characteristics, prevalence of interpersonal triggers and the number of triggers for suicidal behavior in depressed late adolescents and young adults with or without comorbid alcohol use disorders. METHODS: 18-26-year-old subjects were recruited through advertising and referrals and participated in mood disorders research in a university hospital. Thirty-eight depressed suicide attempters without a history of any alcohol or substance abuse/dependence and 29 depressed suicide attempters with comorbid alcohol abuse or dependence participated in the study. Demographic and clinical parameters including parameters related to suicidal behavior were examined and recorded. RESULTS: There was no difference with regard to demographic parameters between the two groups. Depressed suicide attempters with comorbid alcohol use disorders had higher aggression and impulsivity scale scores and were more likely to be tobacco smokers compared to their counterparts without alcohol use disorders. Additionally, there was a trend towards higher lethality of suicide attempts in subjects with alcohol use disorders compared to the other group. We found no difference in the prevalence of interpersonal triggers or in the number of triggers for suicidal behavior between the two groups. CONCLUSION: It appears that among 18-26-year-old depressed suicide attempters, individuals with comorbid alcohol use disorders are more impaired with regard to aggressiveness and impulsivity compared to persons without comorbid alcohol abuse/dependence.

Psychological autopsy studies: the role of alcohol use in adolescent and young adult suicides.

UNLABELLED: Alcohol abusers seem to be prone to both suicide attempts and completions. The relationship between alcohol abuse and suicide in adolescence is complex. OBJECTIVES: To examine the role of alcohol abuse and dependence in adolescent suicide in psychological autopsy studies. METHOD: A search in the National Library of Medicine (NLM) PubMed database using "adolescents" and "all child: 0-18 years" as the search terms for age and "psychological autopsy" as the search term for title or abstract. RESULTS: Forty articles met the selection criteria and each one is described. There was a high prevalence of alcohol abuse detected in the studies (range 21.42% to 43.47% in samples aged under 20 years). Alcohol misuse was present in suicides in the form of chronic abuse, acute abuse and dependence. CONCLUSIONS: Alcohol abuse and dependence is highly prevalent among adolescent suicides. In many studies, alcohol consumption is analyzed in combination with drug abuse. Further studies are necessary to clarify the prevalence of chronic and acute alcohol abuse in order to identify specific high-risk population groups and design antisuicidal interventions for them. Both acute and chronic alcohol use should be evaluated when assessing suicide risk in adolescents.