Racial disparities in prostate cancer outcome among prostate-specific antigen screening eligible populations in the United States.

Background: In 2012, the United States Preventive Services Task Force (USPSTF) recommended against prostate-specific antigen (PSA) screening, despite evidence that Black men are at a higher risk of prostate cancer-specific mortality (PCSM). We evaluated whether Black men of potentially screening-eligible age (55-69 years) are at a disproportionally high risk of poor outcomes. Patients and methods: The SEER database was used to study 390 259 men diagnosed with prostate cancer in the United States between 2004 and 2011. Multivariable logistic regression modeled the association between Black race and stage of presentation, while Fine-Gray competing risks regression modeled the association between Black race and PCSM, both as a function of screening eligibility (age 55-69 years versus not). Results: Black men were more likely to present with metastatic disease (adjusted odds ratio [AOR] 1.65; 1.58-1.72; P < 0.001) and were at a higher risk of PCSM (adjusted hazard ratio [AHR] 1.36; 1.27-1.46; P < 0.001) compared to non-Black men. There were significant interactions between race and PSA-screening eligibility such that Black patients experienced more disproportionate rates of metastatic disease (AOR 1.76; 1.65-1.87 versus 1.55; 1.47-1.65; Pinteraction < 0.001) and PCSM (AHR 1.53; 1.37-1.70 versus 1.25; 1.14-1.37; Pinteraction = 0.01) in the potentially PSA-screening eligible group than in the group not eligible for screening. Conclusions: Racial disparities in prostate cancer outcome among Black men are significantly worse in PSA-screening eligible populations. These results raise the possibility that Black men could be disproportionately impacted by recommendations to end PSA screening in the United States and suggest that Black race should be included in the updated USPSTF PSA screening guidelines.

High PSA anxiety and low health literacy skills: drivers of early use of salvage ADT among men with biochemically recurrent prostate cancer after radiotherapy?

BACKGROUND: Although commonly used, early initiation of salvage androgen deprivation therapy (ADT) has not been proven to enhance survival. We evaluated whether prostate-specific antigen (PSA) anxiety or health literacy are associated with use of early salvage ADT among men with recurrent prostate cancer after radiotherapy. PATIENTS AND METHODS: The prospective Comprehensive, Observational, Multicenter, Prostate Adenocarcinoma Registry was used to study 375 men with biochemically recurrent prostate cancer after external beam radiation or brachytherapy. Multivariable logistic regression was used to determine whether PSA anxiety and health literacy are associated with salvage ADT as initial management after biochemical recurrence. RESULTS: Sixty-eight men (18.1%) received salvage ADT as initial management for PSA recurrence. Men with high PSA anxiety were twice as likely to receive salvage ADT compared with men who did not have high PSA anxiety on both univariable [28.8% versus 13.1%; odds ratio (OR) 2.15; 95% confidence interval (CI) 1.16-4.00; P = 0.015] and multivariable analysis [adjusted OR (AOR) 2.36; 95% CI 1.21-4.62; P = 0.012]. Furthermore, men who had higher levels of health literacy were nearly half as likely to undergo salvage ADT compared with men who had lower levels of health literacy on univariable analysis (15.2% versus 26.3%; OR 0.50; 95% CI 0.29-0.88; P = 0.016), with a trend toward this association on multivariable analysis (AOR 0.58; 95% CI 0.32-1.05; P = 0.07). CONCLUSIONS: Among men with PSA recurrence after radiotherapy, odds of use of salvage ADT were nearly twice as great among men with high PSA anxiety or low health literacy, suggesting that these men are receiving higher rates of unproven treatment. Given that early salvage ADT is costly, worsens quality of life, and has not been shown to improve survival, quality improvement strategies are needed for these individuals.

A refined risk stratification scheme for clinical stage 1 NSGCT based on evaluation of both embryonal predominance and lymphovascular invasion.

BACKGROUND: Active surveillance is an increasingly accepted approach for managing patients with germ-cell tumors (GCTs) after an orchiectomy. Here we investigate a time-to-relapse stratification scheme for clinical stage 1 (CS1) nonseminoma GCT (NSGCT) patients according to factors associated with relapse and identify a group of patients with a lower frequency and longer time-to-relapse who may require an alternative surveillance strategy. PATIENTS AND METHODS: We analyzed 266 CS1 GCT patients from the IRB-approved DFCI GCT database that exclusively underwent surveillance following orchiectomy from 1997 to 2013. We stratified NSGCT patients according to predominance of embryonal carcinoma (EmbP) and lymphovascular invasion (LVI), using a 0, 1, and 2 scoring system. Cox regression and conditional risk analysis were used to compare each NSGCT group to patients in the seminomatous germ-cell tumor (SGCT) category. Median time-to-relapse values were then calculated among those patients who underwent relapse. Relapse-free survival curves were generated using the Kaplan-Meier method. RESULTS: Fifty (37%) NSGCT and 20 (15%) SGCT patients relapsed. The median time-to-relapse was 11.5 versus 6.3 months for the SGCT and NSGCT groups, respectively. For NSGCT patients, relapse rates were higher and median time-to-relapse faster with increasing number of risk factors (RFs). Relapse rates (%) and median time-to-relapse (months) were 25%/8.5 months, 41%/6.8 months and 78%/3.8 months for RF0, RF1 and RF2, respectively. We found a statistically significant difference between SGCT and patients with one or two RFs (P < 0.001) but not between SGCT and NSGCT RF0 (P = 0.108). CONCLUSION: NSGCT patients grouped by a risk score system based on EmbP and LVI yielded three groups with distinct relapse patterns -and patients with neither EmbP nor LVI appear to behave similar to SGCT.

Incidence and determinants of 1-month mortality after cancer-directed surgery.

BACKGROUND: Death within 1 month of surgery is considered treatment related and serves as an important health care quality metric. We sought to identify the incidence of and factors associated with 1-month mortality after cancer-directed surgery. PATIENTS AND METHODS: We used the Surveillance, Epidemiology and End Results Program to study a cohort of 1 110 236 patients diagnosed from 2004 to 2011 with cancers that are among the 10 most common or most fatal who received cancer-directed surgery. Multivariable logistic regression analyses were used to identify factors associated with 1-month mortality after cancer-directed surgery. RESULTS: A total of 53 498 patients (4.8%) died within 1 month of cancer-directed surgery. Patients who were married, insured, or who had a top 50th percentile income or educational status had lower odds of 1-month mortality from cancer-directed surgery {[adjusted odds ratio (AOR) 0.80; 95% confidence interval (CI) 0.79-0.82; P < 0.001], (AOR 0.88; 95% CI 0.82-0.94; P < 0.001), (AOR 0.95; 95% CI 0.93-0.97; P < 0.001), and (AOR 0.98; 95% CI 0.96-0.99; P = 0.043), respectively}. Patients who were non-white minority, male, or older (per year increase), or who had advanced tumor stage 4 disease all had a higher risk of 1-month mortality after cancer-directed surgery, with AORs of 1.13 (95% CI 1.11-1.15), P < 0.001; 1.11 (95% CI 1.08-1.13), P < 0.001; 1.02 (95% 1.02-1.03), P < 0.001; and 1.89 (95% CI 1.82-1.95), P < 0.001 respectively. CONCLUSIONS: Unmarried, uninsured, non-white, male, older, less educated, and poorer patients were all at a significantly higher risk for death within 1 month of cancer-directed surgery. Efforts to reduce 1-month surgical mortality and eliminate sociodemographic disparities in this adverse outcome could significantly improve survival among patients with cancer.

The association between race and treatment regret among men with recurrent prostate cancer.

BACKGROUND: To examine the impact of race on treatment regret among men with recurrent prostate cancer after surgery or radiation. METHODS: The prospective Comprehensive, Observational, Multicenter, Prostate Adenocarcinoma (COMPARE) registry was used to study a cohort of 484 men with biochemically recurrent prostate cancer after radical prostatectomy, external beam radiation or brachytherapy. Multivariable logistic regression was used to model the association between race and treatment regret and to determine whether there was an interaction between race and sexual problems after treatment with regards to treatment regret. RESULTS: Black men (N=78) were significantly more likely to have treatment regret when compared with non-black men (N=406; 21.8% versus 12.6%) on univariable analysis (odds ratio (OR) 1.94; 95% confidence interval 1.05-3.56; P=0.03). On multivariable analysis, black race trended towards but was no longer significantly associated with an increase in treatment regret (adjusted OR (AOR) 1.84 (0.95-3.58); P=0.071). There was an interaction between race and sexual problems after treatment (Pinteraction=0.02) such that among those without sexual problems, black men had more treatment regret than non-black men (26.7% versus 8.4%: AOR 4.68 (1.73-12.63); P=0.002), whereas among those with sexual problems, there was no difference in treatment regret between black and non-black men (18.8% versus 17.3%: AOR 1.04 (0.44-2.46); P=0.93). CONCLUSIONS: Among men with recurrent prostate cancer after surgery or radiation, black men were nearly twice as likely to experience treatment regret. Treating physicians should ensure that patients are fully apprised of the pros and cons of all treatment options to reduce the risk of subsequent regret.

The association between insurance status and prostate cancer outcomes: implications for the Affordable Care Act.

BACKGROUND: The Affordable Care Act (ACA) aims to expand health insurance coverage to over 30 million previously uninsured Americans. To help evaluate the potential impact of the ACA on prostate cancer care, we examined the associations between insurance coverage and prostate cancer outcomes among men <65 years old who are not yet eligible for Medicare. METHODS: The Surveillance, Epidemiology and End Results Program was used to identify 85 203 men aged <65 years diagnosed with prostate cancer from 2007 to 2010. Multivariable logistic regression modeled the association between insurance status and stage at presentation. Among men with high-risk disease, the associations between insurance status and receipt of definitive therapy, prostate cancer-specific mortality (PCSM) and all-cause mortality were determined using multivariable logistic, Fine and Gray competing-risks and Cox regression models, respectively. RESULTS: Uninsured patients were more likely to be non-white and come from regions of rural residence, lower median household income and lower education level (P<0.001 for all cases). Insured men were less likely to present with metastatic disease (adjusted odds ratio (AOR) 0.23; 95% confidence interval (CI) 0.20-0.27; P<0.001). Among men with high-risk disease, insured men were more likely to receive definitive treatment (AOR 2.29; 95% CI 1.81-2.89; P<0.001), and had decreased PCSM (adjusted hazard ratio 0.56; 95% CI 0.31-0.98; P=0.04) and all-cause mortality (adjusted hazard ratio 0.60; 0.39-0.91; P=0.01). CONCLUSIONS: Insured men with prostate cancer are less likely to present with metastatic disease, more likely to be treated if they develop high-risk disease and are more likely to survive their cancer, suggesting that expanding health coverage under the ACA may significantly improve outcomes for men with prostate cancer who are not yet eligible for Medicare.

[3H]-nociceptin ligand-binding and nociceptin opioid receptor mrna expression in the human brain.

Following the cloning of the novel nociceptin opioid receptor (NOP(1)) and the identification of its endogenous ligand orphanin FQ/nociceptin the distribution and functional role of the NOP(1) receptor system have been studied mainly in the rodent CNS. In the present study the regional distribution and splice variant expression of the NOP(1) receptor was investigated in the adult human brain using [(3)H]-nociceptin autoradiography, NOP(1) reverse transcriptase PCR and mRNA in situ hybridization. Ligand binding revealed strong expression of functional NOP(1) receptors in the cerebral cortex and moderate signals in hippocampus and cerebellum. Interestingly, the NOP(1) receptor specific ligand was also strongly bound in the human striatum. A matching pattern of mRNA expression was observed with high amounts of NOP(1) mRNA in the prefrontal and cingulate cortex as well as in the dentate gyrus of the hippocampus. mRNA levels in the Ammon's horn and cerebellar cortex were moderate and low in the striatum. A considerable expression of N-terminal NOP(1) splice variant mRNAs was not detectable in the human brain by means of in situ hybridization. This suggests that functional NOP(1) receptors in the human brain are encoded by N-terminal full length NOP(1) transcripts. The present data on the anatomical distribution of nociceptin binding sites and NOP(1) receptor mRNA contribute to the knowledge about opioid receptor systems in the human brain and may promote the understanding of function and pharmacology of the orphanin FQ/nociceptin receptor system in the human CNS.

The anti-craving compound acamprosate acts as a weak NMDA-receptor antagonist, but modulates NMDA-receptor subunit expression similar to memantine and MK-801.

NMDA-receptor-mediated mechanisms may be crucial in addictive states, e.g. alcoholism, and provide a target for the novel anti-craving compound acamprosate. Here, the pharmacological effects of acamprosate on NMDA-receptors were studied using electrophysiological techniques in different cell lines in vitro. Additionally, a possible modulation of brain NMDA-receptor subunit expression was examined in vivo in rats, and compared to two effective non-competitive NMDA-receptor antagonists, memantine and MK-801. Electrophysiology in cultured hippocampal neurons (IC(50) approx. 5.5mM) and Xenopus oocytes (NR1-1a/NR2A assemblies: IC(50) approx. 350 microM, NR1-1a/NR2B: IC(50) approx. 250 microM) consistently revealed only a weak antagonism of acamprosate on native or recombinant NMDA-receptors. In HEK-293 cells, acamprosate showed almost no effect on NR1-1a/NR2A or NR1-1a/NR2B recombinants (IC(50)s not calculated). Protein blotting demonstrated an up-regulation of NMDA-receptor subunits after acamprosate as well as after memantine or MK-801, in comparison to controls. After acamprosate, protein levels were increased in the cortex (NR1-3/1-4: 190+/-11% of controls) and hippocampus (NR1-1/1-2: 163+/-11%). The up-regulations observed after memantine (cortex, NR2B: 172+/-17%; hippocampus, NR1-1/1-2: 156+/-8%) or MK-801 (cortex, NR2B: 174+/-22%; hippocampus, NR1-1/1-2: 140+/-3%) were almost identical. No changes were detected in the brainstem. The present data indicate an extremely weak antagonism of NMDA-receptors by acamprosate. However, its ability to modulate the expression of NMDA-receptor subunits in specific brain regions - shared with the well established NMDA-antagonists memantine and MK-801 - may be of relevance for its therapeutic profile, especially considering the growing importance of NMDA-receptor plasticity in the research of ethanol addiction.

Effects of chronic alcohol consumption on the expression of different NR1 splice variants in the brain of AA and ANA lines of rats.

Following chronic alcohol treatment alterations in N-methyl-D-aspartate receptor subunit 1 and 2 (NR1 and NR2), mRNA and protein levels have been reported. The NR1 gene undergoes alternative RNA splicing, resulting in eight splice variants, which were shown to differ in their sensitivity to alcohol. Here, we studied mRNA and protein levels of NR1 splice variants in alcohol-preferring (AA) and alcohol-nonpreferring (ANA) rat lines under basal conditions (alcohol-naive), and following chronic alcohol consumption. mRNA levels of three NR1 splice variants (NR1-1, NR1-2, NR1-4), and the protein levels of NR1 (NR1-1/NR1-2), and of NR1 alternative C-terminus (NR1-3/NR1-4) were determined in the hippocampus and nucleus accumbens by competitive RT-PCR and Western blot analysis, respectively. No significant differences in NR1 mRNA, or protein levels were found in the nucleus accumbens between the two rat lines under basal conditions, or following chronic alcohol consumption. In the hippocampus of alcohol-naive rats, the NR1-4 mRNA content was significantly higher in ANA compared to AA rats, however, no significant difference could be detected at the protein level. Following chronic alcohol consumption, the protein level of the NR1 alternative C-terminus (NR1-3/NR1-4) was significantly higher in AA rats compared to the corresponding control. Taken together, these results suggest: (i) brain site-specific alterations in NMDA receptor subunit composition occur following chronic alcohol consumption. (ii) In the hippocampus, NR1 splice variant mRNA levels differ between AA and ANA rats. (iii) The mRNA levels and protein levels of NR1 splice variants are differentially affected by chronic alcohol consumption.

Accurate quantification of the mRNA of NMDAR1 splice variants measured by competitive RT-PCR.

N-methyl-D-aspartate receptors (NMDAR) belong to the subclass of ionotropic glutamate receptors and are widely distributed in the vertebrate brain. Molecular cloning has revealed the existence of six NMDAR subunits: one NMDAR1 (NR1), four different NMDAR2 (NR2A-D) and one NMDAR3A (NR3A). Alternative splicing of the single NR1 gene generates eight isoforms with distinct functional properties [M. Hollmann, J. Boulter, C. Maron, L. Beasley, J. Sullivan, G. Pecht, S. Heinemann, Zinc potentiates agonist-induced currents at certain splice variants of the NMDA receptor, Neuron 10 (1993) 943-954 [8]; R.S. Zukin, M.V.L. Bennett, Alternatively spliced isoforms of the NMDAR1 receptor subunit, TiNS 18 (1995) 306-313 [20]]. Despite the progress made in the functional analysis of NMDARs the molecular architecture of this receptor remains to be elucidated. In situ hybridization studies have already indicated that splicing of the NR1 gene is regionally regulated in the rodent brain, which may contribute to functional diversity of NMDARs in distinct brain areas [D.J. Laurie, P.H. Seeburg, Regional and developmental heterogeneity in splicing of the rat brain NMDAR1 mRNA, J. Neurosci. 14 (1994) 3180-3194 [10]; D.G. Standaert, C.M. Testa, A.B. Young, J.B. Penney Jr., Organization of N-methyl-D-aspartate glutamate receptor gene expression in the basal ganglia of the rat, J. Comp. Neurology 343 (1994) 1-16 [18]; M. Hollmann, S. Heinemann, Cloned glutamate receptors, Ann. Rev. Neurosci. 17 (1994) 31-108 [9]]. Since in situ hybridization techniques do not allow accurate quantification of distinct NR1 splice variants and are also very time-consuming, an accurate and sensitive competitive RT-PCR assay was developed. This method was then used to study the distribution of three NR1 splice variants in the rat brain, and the results are compared with former in situ hybridization studies.

Opioid receptors in the human cerebellum: evidence from [11C]diprenorphine PET, mRNA expression and autoradiography.

Little is known regarding opioid receptors in the human cerebellum. The present [11C]diprenorphine PET study investigated opioid receptor binding in the human cerebellum in vivo, and showed a differential binding level in cerebellar cortex, vermis and dentate nuclei. The additional study in vitro of opioid receptors in human cerebellar cortex and rat brain corroborated the presence of opioidergic mechanisms in the human cerebellum in contrast to the rat. A differential cellular distribution pattern was detected for the three major opioid receptors investigated. For the mu-receptor, and at a lower level for the kappa-receptor, mRNA expression was mainly observed over granule cells. Binding sites were most prominent in the molecular layer. For the delta-receptor no signal was detected. The consideration of cerebellar opioidergic mechanisms and the distribution patterns of the various opioid receptors may promote the understanding of cerebellar function and of opioidergic pharmacology in the human.

Developmental regulation of DEAD box proteins and cloning of putative RNA helicase genes from Dictyostelium discoideum.

RNA secondary structure is essential for RNA function in pre-mRNA splicing, mRNA translation, ribosome assembly and RNA stability. The involvement of DEAD/H RNA helicases in the regulation of these processes has been demonstrated in some cases. To investigate the repertoire of DEAD box proteins expressed in Dictyostelium discoideum, we used PCR techniques to clone two cDNAs coding for DEAD box proteins with high similarity to known yeast proteins: Dictyostelium Hel2A is about 45% identical to Saccharomyces cerevisiae DBP2 and S. pombe dbp2, the yeast homologues of human p68. Dictyostelium Hel2B is about 43% identical to the S. cerevisiae splicing factor PRP28, but has a different domain at the N-terminus, which is unique for Dictyostelium discoideum. Using a polyclonal antibody directed against a DEAD box peptide we show differential expression of three DEAD box proteins during the developmental cycle of Dictyostelium.