Cathepsins B and D drive hepatic stellate cell proliferation and promote their fibrogenic potential

El pdf del artículo es el manuscrito de autor.-- PubMed: PMCID:PMC2670444Cathepsins have been best characterized in tumorigenesis and cell death and implicated in liver fibrosis; however, whether cathepsins directly regulate hepatic stellate cell (HSC) activation and proliferation, hence modulating their fibrogenic potential, is largely unknown. Here, we show that expression of cathepsin B (CtsB) and cathepsin D (CtsD) is negligible in quiescent HSCs but parallels the increase of -smooth muscle actin and transforming growth factor- during in vitro mouse HSC activation. Both cathepsins are necessary for HSC transdifferentiation into myofibroblasts, because their silencing or inhibition decreasedHSC proliferation and the expression of phenotypicmarkers ofHSC activation, with similar results observed with the human HSC cell line LX2. CtsB inhibition blunted AKT phosphorylation in activated HSCs in response to platelet-derived growth factor.Moreover, during in vivo liver fibrogenesis caused by CCl4 administration, CtsB expression increased in HSCs but not in hepatocytes, and its inactivation mitigated CCl4-induced inflammation, HSC activation, and collagen deposition. Conclusion: These findings support a critical role for cathepsins inHSC activation, suggesting that the antagonismof cathepsins inHSCsmay be of relevance for the treatment of liver fibrosis.Financial support: The work was supported by CIBEREHD and grant PI070193 (Instituto de Salud Carlos III); by grant SAF2006-06780 (Plan Nacional de I+D), Spain; and by grant P50-AA-11999 (Research Center for Liver and Pancreatic Diseases, US National Institute on Alcohol Abuse and Alcoholism).Peer reviewe

Multiple partial nephrectomy for multifocal synchronous renal cancer in a solitary kidney

Introduction & Objectives: multifocal synchronous renal cancer on a solitary kidney represent a challenging clinical scenario. The complexity of imperative nephron-sparring surgery in this setting resides in ensuring complete excision of cancer with the maximal preservation of renal function. We aim to present a case of multiple partial nephrectomy (MPN) for multifocal synchronous renal cancer in a patient with a solitary kidney and discuss our experience of imperative partial in this setting. Materials & Methods: We present a case of a 76 years old man with a past medical history of hypertension, chronic obstructive pulmonary disease, peripheral vascular disease, left radical nephrectomy for renal mass (2006) and a right renal artery stent placement for renal artery stenosis. During his surveillance, computerized axial tomography (CAT) scan showed 3 enhancing renal masses (2.2cm, 1.5cm and 1cm, respectively). Biopsy of the largest mass was consistent in clear cell renal cell carcinoma (ccRCC). Preoperative level of creatinine was 1.4mg/dL and estimated glomerular filtration rate (eGFR) 50ml/min/1,73m2. After ablative therapy was deemed unsafe, a MPN was planned

Intermittent hypoxia increases kidney tumor vascularization in a murine model of sleep apnea

We investigate the effects of intermittent hypoxia (IH), a characteristic feature of obstructive sleep apnea (OSA), on renal cancer progression in an animal and cell model. An in vivo mouse model (Balb/c, n = 50) of kidney cancer was used to assess the effect of IH on tumor growth, metastatic capacity, angiogenesis and tumor immune response. An in vitro model tested the effect of IH on RENCA cells, macrophages and endothelial cells. Tumor growth, metastatic capacity, circulating vascular endothelial growth factor (VEGF) and content of endothelial cells, tumor associated macrophages and their phenotype were assessed in the tumor. In vitro, VEGF cell expression was quantified.Although IH did not boost tumor growth, it significantly increased endothelial cells (p = 0.001) and circulating VEGF (p<0.001) in the in vivo model. Macrophages exposed to IH in vitro increased VEGF expression, whereas RENCA cells and endothelial cells did not. These findings are in keeping with previous clinical data suggesting that OSA has no effect on kidney cancer size and that the association observed between OSA and higher Fuhrman grade of renal cell carcinoma may be mediated though a proangiogenic process, with a key role of macrophages

Obstructive sleep apnea and Fuhrman grade in patients with clear cell renal cell carcinoma treated surgically

PURPOSE: To assess the association between obstructive sleep apnea (OSA) and Fuhrman grade in patients with clear cell renal cell carcinoma (ccRCC). As secondary endpoints, we studied its association with tumor size, metastasis-free survival (MFS) and cancer-specific survival (CSS). METHODS: We reviewed the databases of two tertiary care centers, identifying 2579 patients who underwent partial or radical nephrectomy for ccRCC between 1991 and 2014. Descriptive statistics were used to compare pathologic variables between patients with and without OSA. Linear and logistic regression models were used to assess the association of OSA with Fuhrman grade and tumor size. A Cox proportional hazards model was used to determine OSA association with MFS and CSS. A pathway analysis was performed on a cohort with available gene expression data. RESULTS: In total, 172 patients (7 %) had self-reported OSA at diagnosis. More patients with OSA had high Fuhrman grade compared to those without OSA [51 vs. 38 %; 13 % risk difference; 95 % confidence interval (CI), 5-20 %; p = 0.003]. On multivariable analysis, the association remained significant (OR 1.41; 95 % CI 1.00-1.99; p = 0.048). OSA was not associated with tumor size (p > 0.5), MFS (p = 0.5) or CSS (p = 0.4). A trend toward vascular endothelial growth factor pathway enrichment was seen in OSA patients (p = 0.08). CONCLUSIONS: OSA is associated with high Fuhrman grade in patients undergoing surgery for ccRCC. Pending validation of this novel finding in further prospective studies, it could help shape future research to better understand etiological mechanisms associated

Reporting Magnetic Resonance Imaging in Men on Active Surveillance for Prostate Cancer : The PRECISE Recommendations-A Report of a European School of Oncology Task Force

Background: Published data on prostate magnetic resonance imaging (MRI) during follow-up of men on active surveillance are lacking. Current guidelines for prostate MRI reporting concentrate on prostate cancer (PCa) detection and staging. A standardised approach to prostate MRI reporting for active surveillance will facilitate the robust collection of evidence in this newly developing area. Objective: To develop preliminary recommendations for reporting of individual MRI studies in men on active surveillance and for researchers reporting the outcomes of cohorts of men having MRI on active surveillance. Design, setting, and participants: The RAND/UCLA Appropriateness Method was used. Experts in urology, radiology, and radiation oncology developed a set of 394 statements relevant to prostate MRI reporting in men on active surveillance for PCa. Each statement was scored for agreement on a 9-point scale by each panellist prior to a panel meeting. Each statement was discussed and rescored at the meeting. Outcome measurements and statistical analysis: Measures of agreement and consensus were calculated for each statement. The most important statements, derived from both group discussion and scores of agreement and consensus, were used to create the Prostate Cancer Radiological Estimation of Change in Sequential Evaluation (PRECISE) checklist and case report form. Results and limitations: Key recommendations include reporting the index lesion size using absolute values at baseline and at each subsequent MRI. Radiologists should assess the likelihood of true change over time (ie, change in size or change in lesion characteristics on one or more sequences) on a 1-5 scale. A checklist of items for reporting a cohort of men on active surveillance was developed. These items were developed based on expert consensus in many areas in which data are lacking, and they are expected to develop and change as evidence is accrued. Conclusions: The PRECISE recommendations are designed to facilitate the development of a robust evidence database for documenting changes in prostateMRI findings over time ofmen on active surveillance. If used, they will facilitate data collection to distinguish-measurement error and natural variability in MRI appearances from true radiologic progression. Patient summary: Few published reports are available on how to use and interpret magnetic resonance imaging for men on active surveillance for prostate cancer. The PRECISE panel recommends that data should be collected in a standardised manner so that natural variation in the appearance and measurement of cancer over time can be distinguished from changes indicating significant tumour progression. (C) 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.Peer reviewe

Feasibility study of a clinically-integrated randomized trial of modifications to radical prostatectomy

<p>Abstract</p> <p>Background</p> <p>Numerous technical modifications to radical prostatectomy have been proposed. Such modifications are likely to lead to only slight improvements in outcomes. Although small differences would be worthwhile, an appropriately powered randomized trial would need to be very large, and thus of doubtful feasibility given the expense, complexity and regulatory burden of contemporary clinical trials. We have proposed a novel methodology, the clinically-integrated randomized trial, which dramatically streamlines trial procedures in order to reduce the marginal cost of an additional patient towards zero. We aimed to determine the feasibility of implementing such a trial for radical prostatectomy.</p> <p>Methods</p> <p>Patients undergoing radical prostatectomy as initial treatment for prostate cancer were randomized in a factorial design to involvement of the fascia during placement of the anastomotic sutures, urethral irrigation, both or neither. Endpoint data were obtained from routine clinical documentation. Accrual and compliance rates were monitored to determine the feasibility of the trial.</p> <p>Results</p> <p>From a total of 260 eligible patients, 154 (59%) consented; 56 patients declined to participate, 20 were not approached on recommendation of the treating surgeon, and 30 were not approached for logistical reasons. Although recording by surgeons of the procedure used was incomplete (~80%), compliance with randomization was excellent when it was recorded, with only 6% of procedures inconsistent with allocation. Outcomes data was received from 71% of patients at one year. This improved to 83% as the trial progressed.</p> <p>Conclusions</p> <p>A clinically-integrated randomized trial was conducted at low cost, with excellent accrual, and acceptable compliance with treatment allocation and outcomes reporting. This demonstrates the feasibility of the methodology. Improved methods to ensure documentation of surgical procedures would be required before wider implementation.</p> <p>Trial registration</p> <p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT00928850">NCT00928850</a></p

Role of surgery in oligometastatic prostate cancer

Androgen deprivation therapy as single modality therapy was the standard management for oligometastatic prostate cancer (PCa). Current paradigm shifts toward a multimodality therapy approach, targeting all sites of disease, including treatment of the primary in the form of radical prostatectomy or radiation therapy. The objective of this article was to reveiw the literature regarding the role of surgery in oligometastatic PCa. PubMed and MEDLINE electronic databases were queried for English language articles from January 1, 1980 to March 31, 2019. Keywords use included oligometastatic PCa, metastatic prostate cancer (mPCa), radical prostatectomy, and cytoreductive prostatectomy. Preclinical, prospective, and retrospective studies were included. There is no published randomized controlled trials, evaluating the role of surgery in mPCa. Preclinical and retrospective data suggest benefit of primary tumor treatment in mPCa. Current literature supports the concept of cytoreductive surgery as it can prevent late symptomatic local progression, has acceptable complications, and may prolong survival in patients with mPCa. Surgery is a feasible procedure in mPCa which may improve outcome in mPCa. However, there is no Level 1 evidence, yet that support the role of surgery in mPCa. The results from well-organized prospective, randomized controlled trials are awaited before performing radical prostatectomy for mPCa in clinical practice. Keywords: Cytoreductive radical prostatectomy, Metastatic prostate cancer, Oligometastatic prostate cancer, Radical prostatectomy, Surgery in metastatic, Treatment of primary tumo