Prognostic role of ERCC1 protein expression in upper tract urothelial carcinoma following radical nephroureterectomy with curative intent

Background

Excision repair cross-complementing 1 (ERCC1) has been associated with outcomes of urothelial carcinoma of the bladder, but was not yet studied in upper tract urothelial carcinoma (UTUC). The aim of this study was to assess the prognostic role of ERCC1 expression in a large international cohort of UTUC patients.

Methods

Immunohistochemical ERCC1 expression was evaluated in 716 UTUC patients who underwent radical nephroureterectomy with curative intent. ERCC1 was considered positive when the H-score was >1.0. Associations with overall survival and cancer-specific survival were assessed using univariable and multivariable Cox models.

Results

ERCC1 was expressed in 303 tumors (42.3 %) and linked with the presence of tumor necrosis (16.2 vs. 10.4 %, p = 0.023), but not with any other clinical or pathological variable. ERCC1 status did not predict cancer-specific survival and overall survival on both univariable (p = 0.70 and 0.32, respectively) and multivariable analyses (p = 0.48 and 0.33, respectively).

Conclusions

ERCC1 is expressed in a significant proportion of UTUC and is linked with tumor necrosis, but its expression appears not to be associated with prognosis following radical nephroureterectomy.

     

The hypothalamic–pituitary–gonadal axis and prostate cancer: implications for androgen deprivation therapy

Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) may play important roles in prostate cancer (PCa) progression. Specifically, LH expression in PCa tissues has been associated with metastatic disease with a poor prognosis, while FSH has been shown to stimulate prostate cell growth in hormone-refractory PCa cell lines. Gonadotropin-realizing hormone (GnRH) analogues are common agents used for achieving androgen deprivation in the treatment for PCa. GnRH analogues include LH-releasing hormone (LHRH) agonists and GnRH antagonists, both of which exhibit distinct mechanisms of action that may be crucial in terms of their overall clinical efficacy. LHRH agonists are typically used as the primary therapy for most patients and function via a negative-feedback mechanism. This mechanism involves an initial surge in testosterone levels, which may worsen clinical symptoms of PCa. GnRH antagonists provide rapid and consistent hormonal suppression without the initial surge in testosterone levels associated with LHRH agonists, thus representing an important therapeutic alternative for patients with PCa. The concentrations of testosterone and dihydrotestosterone are significantly reduced after treatment with both LHRH agonists and GnRH antagonists. This reduction in testosterone concentrations to castrate levels results in significant, rapid, and consistent reductions in prostatic-specific antigen, a key biomarker for PCa. Evidence suggests that careful maintenance of testosterone levels during androgen deprivation therapy provides a clinical benefit to patients with PCa, emphasizing the need for constant monitoring of testosterone concentrations throughout the course of therapy.     

Temporal delimitation of the healing phases via monitoring of fracture callus stiffness in rats

The healing process consists of at least three phases: inflammatory, repair, and remodeling phase. Because callus stiffness correlates with the healing phases, it is suitable for evaluating the fracture healing process. Our aim was to develop a method which allows determination of callus stiffness in vivo, the healing time and the duration of the repair phase. The right femurs of 16 Wistar rats were osteotomized and stabilized with either more rigid or more flexible external fixation. Fixator deformation was measured using strain gauges during gait analysis. The strains were recalculated as the callus stiffness over the time course of healing, and the healing phases were identified based on stiffness thresholds. Our hypothesis was that stabilization with more flexible external fixation prolongs the repair phase, therefore resulting in an extended healing time. Confirming our hypothesis, the duration of the repair phase (rigid: approximately 15 days, flexible: approximately 41 days) and the healing time (rigid: approximately 27 days, flexible: approximately 62 days) were significantly longer for more flexible external fixation. Our method allows the quantitative detection of differences in the healing time and duration of the repair phase without multiple time‐point sacrifices, which reduces the number of animals in experimental studies. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:1589–1595, 2014.     

Blood- and tissue-based biomarkers for prediction of outcomes in urothelial carcinoma of the bladder

ObjectivesUrothelial carcinoma of the bladder (UCB) is a highly heterogeneous malignancy that causes significant morbidity and mortality. Standard pathologic features (stage, grade, and nodal status) are insufficient to predict accurately a patient's outcome. Biomarkers could help clinicians provide individualized prognostications and allow risk-stratified clinical decision making regarding surgical and medical treatment. This review summarizes the existing tissue- and blood-based biomarkers in UCB.Material and methodsA PubMed/Medline search was conducted to identify original articles regarding molecular biomarkers and UCB. Searches were limited to papers published in English. Keywords included urothelial carcinoma, bladder cancer, transitional cell, biomarker, marker, staining, cystectomy, recurrence or progression, survival, prediction, and prognosis.ResultsThe articles with the highest level of evidence were selected and reviewed, with the consensus of all the authors of this paper.ConclusionsThere is no doubt that a panel of biomarkers would eventually improve our clinical decision making regarding treatment and follow-up. However, to date, no biomarker panel is yet validated for daily clinical practice.     

Use of a Learning Collaborative to Support Implementation of Integrated Care for Smoking Cessation for Veterans With Posttraumatic Stress Disorder

Objectives. We evaluated the feasibility of incorporating integrated care (IC) for smoking cessation into routine treatment for posttraumatic stress disorder (PTSD) at Department of Veterans Affairs (VA) Medical Centers and the utility of the Learning Collaborative (LC) model in facilitating implementation.Methods. We conducted 2 LCs aimed at implementing IC for smoking cessation using multidisciplinary teams comprising 70 staff members from 12 VA PTSD clinics. Using questionnaires, we evaluated providers’ perceptions of the LC methodology and the effectiveness and feasibility of routine IC delivery. We assessed number of providers delivering and patients receiving IC using medical record data.Results. More than 85% of participating VA staff considered the LC to be an effective training and implementation platform. The majority thought IC effectively addressed an important need and could be delivered in routine PTSD care. All LC participants who planned to deliver IC did so (n = 52). Within 12 months of initial training, an additional 46 locally trained providers delivered IC and 395 veterans received IC.Conclusions. The LC model effectively facilitated rapid and broad implementation of IC. Facilitators and barriers to sustained use of IC are unknown and should be identified to understand how best to promote ongoing access to evidence-based treatment for smoking cessation in mental health populations.Despite gains in reducing tobacco use among the general public, nicotine dependence continues to disproportionately affect individuals with mental illness, including those with posttraumatic stress disorder (PTSD), a prevalent mental health disorder1 associated with heavy cigarette consumption and low cessation rates.2 One in 10 current US smokers have had PTSD at some point in their lives.2 Tobacco dependence likely contributes to the high mortality,3 morbidity,4 and health care costs5 of persons with PTSD. Recent epidemiological studies, although unable to elucidate causal pathways unequivocally, strongly suggest that smoking cessation reduces risk for suicidal ideation,6 depression,7,8 and anxiety,9 emphasizing the critical importance for cessation among those with PTSD and other mental health conditions. Thus, effective cessation treatment interventions and delivery systems are needed to reach this population.To address this need within the Veterans Health Administration, McFall et al.10 developed integrated care (IC) for smoking cessation, which incorporates guideline-based cessation treatment into mental health care for veterans with PTSD. IC is delivered by veterans’ PTSD providers, capitalizing on the existing therapeutic relationship between provider and patient. A randomized trial at 10 Department of Veterans Affairs (VA) Medical Centers, VA Cooperative Study No. 519 (CSP 519), found that, compared with referral to specialized smoking cessation clinics, IC improved cessation outcomes among veterans with PTSD without detracting from mental health treatment.10Although providers who participated in CSP 519 held positive views of IC and supported delivering cessation treatment in mental health care,11 most did not continue delivering IC at the study’s conclusion (C. Wallace, PhD, unpublished data, August 2011). Such a finding is unsurprising given that the use of evidence-based treatments in mental health remains sparse and inconsistent outside of academic settings.12,13 The challenge of making best practice usual practice has been identified as a major public health priority.12,14 Information dissemination and training remain 2 of the most widely used strategies for attempting to spread new practices13,15 but are insufficient for ensuring broad and sustained use of evidence-based treatments; longer-term multilevel implementation strategies are necessary to overcome numerous and complex barriers to adoption.15–17Quality collaboratives are one methodology used to support health care system change and improve quality of care.18–21 The Breakthrough Series is a quality collaborative model that brings together multidisciplinary teams from different organizations with recognized experts to work in a structured way to accelerate spread of best practices.22 The National Center for Child Traumatic Stress’s Learning Collaborative (LC) Model, an adaptation of the Breakthrough Series, supports rapid delivery and sustained use of effective treatments in community settings23 by melding best practices in training and consultation with quality improvement methods.In 2010, the VA partnered with the Duke Evidence-Based Practice Implementation Center to conduct an LC to implement IC in 6 Veterans Affairs PTSD clinics, followed by a second LC with 6 additional Veterans Affairs PTSD clinics in 2012. The objective of this project evaluation was to assess the feasibility of delivering IC as part of routine PTSD care and the utility of the LC model in facilitating IC implementation. Specifically, we examined whether (1) VA staff actively participated in the collaborative and considered LC methodology useful in supporting IC implementation; (2) collaborative participation resulted in rapid delivery of IC (i.e., delivery within 3 months of training) and continued use of the intervention after LC completion; and (3) VA providers viewed IC as compatible with current clinical practices and feasible to deliver as part of routine mental health care for veterans with PTSD. Because troops newly returning from deployment have higher rates of smoking than the general population24,25 and high rates of PTSD,26 it is imperative than an evidence-based treatment such as IC be widely implemented to preserve the physical and mental health of our returning service members.     

Fatty acid ethanolamide levels are altered in borderline personality and complex posttraumatic stress disorders

Borderline personality (BPD) and complex posttraumatic stress disorders (PTSD) are both powerfully associated with the experience of interpersonal violence during childhood and adolescence. The disorders frequently co-occur and often result in pervasive problems in, e.g., emotion regulation and altered pain perception, where the endocannabinoid system is deeply involved. We hypothesize an endocannabinoid role in both disorders. We investigated serum levels of the endocannabinoids anandamide and 2-arachidonoylglycerol and related fatty acid ethanolamides (FAEs) in BPD, PTSD, and controls. Significant alterations were found for both endocannabinoids in BPD and for the FAE oleoylethanolamide in PTSD suggesting a respective link to both disorders.