Inpatient morbidity and cost of cytoreductive radical prostatectomy in the United States

INTRODUCTION AND OBJECTIVES: Clinical trials are currently examining the role of local therapy in metastatic prostate cancer (mPCa). While the safety of RP in localized disease is proven, few studies have looked at perioperative complications and cost of cytoreductive RP (cRP). We used the National Inpatient Sample (NIS) to study the inpatient morbidity, and cost of cRP in the United States (US). METHODS: Analyzing the NIS dataset from 2008-2014, we identified 90,662 patients (weighted estimate 449,025 in the US) who underwent RP for non-metastatic disease, and 1,173 patients (weighted estimate 5,835) who underwent cRP for mPCa (see Fig. 1). Outcomes of interest were inpatient complications, individual complications, hospital stay, and total cost. Covariates included age, race, Charlson Comorbidity score, insurance status, rural/semi-urban/urban location, income, hospital location (rural/urban), teaching status, geographical location of hospital, and hospital volume. Multivariable logistic regression was used to evaluate the effect of metastatic disease on morbidity after adjusting for covariates. RESULTS: Inpatient complication rates were 14.9% (13,688/91,835) overall, 14.9% (13,464/90,662) in the non-metastatic group, and 19.1% (224/1,173) in the cRP group (p = 0.01). On multivariable analysis, metastasis was an independent predictor of inpatient complications (OR 1.329; 95% CI: 1.077-1.640; p = 0.01). The cRP group also had higher rates of blood transfusion (6.9% [82/1,173] vs 4.3% [3,869/90,662]; p \u3c 0.001), longer hospital stay (median 1.25 vs 0.97 days; p \u3c 0.001), and higher cost (median $14,123 vs$11,591; p \u3c 0.001) compared to the non-metastatic group (see table 1). Majority of cRP was performed in urban teaching hospitals. CONCLUSIONS: cRP is associated with higher inpatient morbidity, longer hospital stay, and higher cost compared to RP for non-metastatic disease. This information may be valuable for informed decision-making in practice and before recruiting patients in clinical trials on this subject. Source of Funding: Nonehttps://scholarlycommons.henryford.com/merf2019hvc/1006/thumbnail.jp

Downregulation of Mcl-1 has anti-inflammatory pro-resolution effects and enhances bacterial clearance from the lung

Phagocytes not only coordinate acute inflammation and host defense at mucosal sites, but also contribute to tissue damage. Respiratory infection causes a globally significant disease burden and frequently progresses to acute respiratory distress syndrome, a devastating inflammatory condition characterized by neutrophil recruitment and accumulation of protein-rich edema fluid causing impaired lung function. We hypothesized that targeting the intracellular protein myeloid cell leukemia 1 (Mcl-1) by a cyclin-dependent kinase inhibitor (AT7519) or a flavone (wogonin) would accelerate neutrophil apoptosis and resolution of established inflammation, but without detriment to bacterial clearance. Mcl-1 loss induced human neutrophil apoptosis, but did not induce macrophage apoptosis nor impair phagocytosis of apoptotic neutrophils. Neutrophil-dominant inflammation was modelled in mice by either endotoxin or bacteria (Escherichia coli). Downregulating inflammatory cell Mcl-1 had anti-inflammatory, pro-resolution effects, shortening the resolution interval (R(i)) from 19 to 7 h and improved organ dysfunction with enhanced alveolar–capillary barrier integrity. Conversely, attenuating drug-induced Mcl-1 downregulation inhibited neutrophil apoptosis and delayed resolution of endotoxin-mediated lung inflammation. Importantly, manipulating lung inflammatory cell Mcl-1 also accelerated resolution of bacterial infection (R(i); 50 to 16 h) concurrent with enhanced bacterial clearance. Therefore, manipulating inflammatory cell Mcl-1 accelerates inflammation resolution without detriment to host defense against bacteria, and represents a target for treating infection-associated inflammation

Proteomics identifies neddylation as a potential therapy target in small intestinal neuroendocrine tumors.

Patients with small intestinal neuroendocrine tumors (SI-NETs) frequently develop spread disease; however, the underlying molecular mechanisms of disease progression are not known and effective preventive treatment strategies are lacking. Here, protein expression profiling was performed by HiRIEF-LC-MS in 14 primary SI-NETs from patients with and without liver metastases detected at the time of surgery and initial treatment. Among differentially expressed proteins, overexpression of the ubiquitin-like protein NEDD8 was identified in samples from patients with liver metastasis. Further, NEDD8 correlation analysis indicated co-expression with RBX1, a key component in cullin-RING ubiquitin ligases (CRLs). In vitro inhibition of neddylation with the therapeutic agent pevonedistat (MLN4924) resulted in a dramatic decrease of proliferation in SI-NET cell lines. Subsequent mass spectrometry-based proteomics analysis of pevonedistat effects and effects of the proteasome inhibitor bortezomib revealed stabilization of multiple targets of CRLs including p27, an established tumor suppressor in SI-NET. Silencing of NEDD8 and RBX1 using siRNA resulted in a stabilization of p27, suggesting that the cellular levels of NEDD8 and RBX1 affect CRL activity. Inhibition of CRL activity, by either NEDD8/RBX1 silencing or pevonedistat treatment of cells resulted in induction of apoptosis that could be partially rescued by siRNA-based silencing of p27. Differential expression of both p27 and NEDD8 was confirmed in a second cohort of SI-NET using immunohistochemistry. Collectively, these findings suggest a role for CRLs and the ubiquitin proteasome system in suppression of p27 in SI-NET, and inhibition of neddylation as a putative therapeutic strategy in SI-NET

The role of the carotenoids, lutein and zeaxanthin, in protecting against age-related macular degeneration: A review based on controversial evidence

PURPOSE: A review of the role of the carotenoids, lutein and zeaxanthin, and their function in altering the pathogenesis of age-related macular degeneration (AMD). METHODS: Medline and Embase search. RESULTS: Recent evidence introduces the possibility that lutein and zeaxanthin, carotenoids found in a variety of fruits and vegetables may protect against the common eye disease of macular degeneration. This potential and the lack to slow the progression of macular degeneration, has fueled high public interest in the health benefits of these carotenoids and prompted their inclusion in various supplements. The body of evidence supporting a role in this disease ranges from basic studies in experimental animals to various other clinical and epidemiological studies. Whilst some epidemiological studies suggest a beneficial role for carotenoids in the prevention of AMD, others are found to be unrelated to it. Results of some clinical studies indicate that the risk for AMD is reduced when levels of the carotenoids are elevated in the serum or diet, but this correlation is not observed in other studies. Published data concerning the toxicity of the carotenoids or the optimum dosage of these supplements is lacking. CONCLUSION: An intake of dietary supplied nutrients rich in the carotenoids, lutein and zeaxanthin, appears to be beneficial in protecting retinal tissues, but this is not proven. Until scientifically sound knowledge is available we recommend for patients judged to be at risk for AMD to: alter their diet to more dark green leafy vegetables, wear UV protective lenses and a hat when outdoors. Future investigations on the role of nutrition, light exposure, genetics, and combinations of photodynamic therapy with intravitreal steroid (triamcinolone-acetonide) injections hold potential for future treatment possibilities

Immunomodulatory properties of quercetin-3-O-α-L-rhamnopyranoside from Rapanea melanophloeos against influenza a virus

Abstract Background Influenza infection is a major public health threat. The role of influenza A virus-induced inflammatory response in severe cases of this disease is widely recognized. Drug resistance and side effects of chemical treatments have been observed, resulting in increased interest in alternative use of herbal medications for prophylaxis against this infection. The South African medicinal plant, Rapanea melanophloeos (RM) (L.) Mez of the family Myrsinaceae was selected owing to its traditional use for the treatment of several diseases such as respiratory ailments and also previous preliminary studies of anti-influenza activity of its methanolic extract. The aim of this study was to investigate the immunomodulatory properties of a glycoside flavone isolated from RM against influenza A virus. Methods The non-cytotoxic concentration of the quercetin-3-O-α-L-rhamnopyranoside (Q3R) was determined by MTT assay and tested for activity against influenza A virus (IAV) in simultaneous, pre-penetration and post-penetration combination treatments over 1 h incubation on MDCK cells. The virus titer and viral load targeting NP and M2 viral genes were determined using HA and qPCR, respectively. TNF-α and IL-27 as pro- and anti-inflammatory cytokines were measured at RNA and protein levels by qPCR and ELISA, respectively. Results Quercetin-3-O-α-L-rhamnopyranoside at 150 μg/ml decreased the viral titer by 6 logs (p < 0.01) in the simultaneous procedure. The NP and M2 genes copy numbers as viral target genes, calculated based on the Ct values and standard formula, significantly decreased in simultaneous treatment (p < 0.01). The expression of cytokines was also considerably affected by the compound treatment. Conclusions This is the first report of quercetin-3-O-α-L-rhamnopyranoside from RM and its immunomodulatory properties against influenza A virus. Further research will focus on detecting the specific mechanism of virus-host interactions

Pseudo-ductility and reduced notch sensitivity in multi-directional all-carbon/epoxy thin-ply hybrid composites

Un-notched and notched tensile response and damage accumulation of quasi-isotropic carbon/epoxy hybrid laminates made of ultra-high modulus and intermediate modulus carbon fibre/epoxy thin-ply prepregs were studied. It was confirmed that the ply fragmentation demonstrated previously in unidirectional hybrids as a successful pseudo-ductility mechanism can be transferred to multi-directional laminates. Furthermore, reduced notch sensitivity was demonstrated in quasi-isotropic specimens for both open holes and sharp notches as a result of local ply fragmentation around the notch

The changing face of surgically treated low-risk prostate cancer (PCa): A national cancer database (NCDB) analysis

Introduction & Objectives: The last decade witnessed an increasing adoption of active surveillance (AS)as a treatment option in low-risk PCa patients. However, low-risk patients who don\u27t fulfill the AS criteria still receive some form of local treatment, such as radical prostatectomy (RP)or radiotherapy. We tested the hypothesis that these individuals harbor a higher burden of tumor in comparison to their historic counterparts. Materials & Methods: We identified 164215 clinically low-risk PCa patients (PSA ≤10 ng/ml, biopsy Gleason score ≤6, and clinical T1-T2a stage)who were treated with RP, radiotherapy, or Observation, between 2010 and 2015, within the NCDB. Patients were stratified based on treatment type, and regression analysis was used to evaluate changes in PSA values, percentage of positive cores (%PCores), and life expectancy (LE)overtime. To analyze pathological data, we focused on RP patients and used regression analysis to test changes in the rate of upgrading (pathological Gleason ≥3+4), upstaging (pathological ≥T3a stage), and positive surgical margins overtime, after adjusting to all available covariates. Results: Median (Interquartile range [IQR])PSA, %PCores, and LE were 5.25 (4.1-6.4)ng/mL, 25% (12.5-41.67%), and, 20.75 (15.68-24.63)years respectively. Among these, the %PCores changed significantly overtime among the different treatment groups. Specifically, between 2010 and 2015, mean %PCores increased from 31.33 to 32.44% in RP, 29.25 to 30.70% in radiotherapy, and decreased from 24.78 to 20.41% in AS patients (p\u3c0.0001). On pathological data analysis, more contemporary RP patients (year 2015)showed higher rates of upgrading (54.45% vs 41.62%, P\u3c.0001), upstaging (11.62% vs 9.03%, P\u3c.0001), and positive surgical margins (18.08% vs 15.67%, P\u3c.0001)than their more historic counterparts (year 2010). These findings were confirmed on multivariable analysis. Conclusions: Our findings show that contemporary low-risk PCa patients treated surgically harbor more aggressive disease than historic patients. This is an important observation that should be considered when planning surgery in these individuals, and when using pre-operative prediction models based on historic data. Several factors could have resulted in these changes, such as the increased utilization of AS, and the recommendation against PSA screening, among others