National needs assessment of patients treated at the United States Federally-Funded Hemophilia Treatment Centers.

AIM: The National Hemophilia Program Coordinating Center, with the U.S. Regional Hemophilia Network conducted a national needs assessment of U.S. Hemophilia Treatment Center (HTC) patients. The objectives were to determine: (i) To what extent do patients report that they receive needed services and education; (ii) How well do the services provided meet their needs; and (iii) What are the patients' perspectives about their care. METHODS: A survey was mailed to active patients of 129 HTCs. Respondents completed the anonymous surveys on line or returned them by mail. Questions focused on management and information, access and barriers to care, coping, resources, and transition. RESULTS: Of 24 308 questionnaires mailed, 4004 (16.5%) were returned. Most respondents reported very few gaps in needed services or information and reported that services and information met their needs. Over 90% agreed or strongly agreed that care was patient-centred and rated HTC care as important or very important. Identified gaps included dietary advice, genetic testing, information on ageing, sexual health and basic needs resources. Minority respondents reported more barriers. CONCLUSION: This survey is the largest assessment of the HTC population. Respondents reported that the services and information provided by the HTCs met their needs. Quality improvement opportunities include transition and services related to ageing and sexual health. Further investigation of barriers to care for minorities is underway. Results will help develop national priorities to better serve all patients in the US. HTCs.

Nanoencapsulation of ABT-737 and camptothecin enhances their clinical potential through synergistic antitumor effects and reduction of systemic toxicity.

The simultaneous delivery of multiple cancer drugs in combination therapies to achieve optimal therapeutic effects in patients can be challenging. This study investigated whether co-encapsulation of the BH3-mimetic ABT-737 and the topoisomerase I inhibitor camptothecin (CPT) in PEGylated polymeric nanoparticles (NPs) was a viable strategy for overcoming their clinical limitations and to deliver both compounds at optimal ratios. We found that thrombocytopenia induced by exposure to ABT-737 was diminished through its encapsulation in NPs. Similarly, CPT-associated leukopenia and gastrointestinal toxicity were reduced compared with the administration of free CPT. In addition to the reduction of dose-limiting side effects, the co-encapsulation of both anticancer compounds in a single NP produced synergistic induction of apoptosis in both in vitro and in vivo colorectal cancer models. This strategy may widen the therapeutic window of these and other drugs and may enhance the clinical efficacy of synergistic drug combinations.

Identification of an acetylation-dependant Ku70/FLIP complex that regulates FLIP expression and HDAC inhibitor-induced apoptosis.

FLIP is a potential anti-cancer therapeutic target that inhibits apoptosis by blocking caspase 8 activation by death receptors. We report a novel interaction between FLIP and the DNA repair protein Ku70 that regulates FLIP protein stability by inhibiting its polyubiquitination. Furthermore, we found that the histone deacetylase (HDAC) inhibitor Vorinostat (SAHA) enhances the acetylation of Ku70, thereby disrupting the FLIP/Ku70 complex and triggering FLIP polyubiquitination and degradation by the proteasome. Using in vitro and in vivo colorectal cancer models, we further demonstrated that SAHA-induced apoptosis is dependant on FLIP downregulation and caspase 8 activation. In addition, an HDAC6-specific inhibitor Tubacin recapitulated the effects of SAHA, suggesting that HDAC6 is a key regulator of Ku70 acetylation and FLIP protein stability. Thus, HDAC inhibitors with anti-HDAC6 activity act as efficient post-transcriptional suppressors of FLIP expression and may, therefore, effectively act as 'FLIP inhibitors'.

Ward-based non-invasive ventilation for hypercapnic exacerbations of COPD: a 'real-life' perspective.

BACKGROUND: Non-invasive ventilation (NIV) has revolutionized the management of hypercapnic exacerbations of chronic obstructive pulmonary disease (COPD). However, most published data have evaluated highly selected patients within the context of randomized controlled trials. OBJECTIVE: We wished to evaluate the outcomes of ward-based NIV in 'real-life' patients admitted to hospital with a hypercapnic exacerbation of COPD. METHODS: Retrospective data (gender, age, baseline pH, PaCO(2) and values after 1 and 4 h of NIV, and outcomes) were evaluated for all patients receiving NIV in the respiratory unit of Aberdeen Royal Infirmary from January 2006 to December 2009. Data were analysed in three groups: as a whole, in those with baseline pH >or=7.25 and baseline pH <7.25. RESULTS: Data were available for all 392 patients commenced on ward-based NIV [45% male, mean age (range) 71 years (42-89)] with mean baseline pH of 7.24 and PaCO(2) of 10.1 kPa; respective values improved significantly (P <0.0001) following 1 and 4 h of NIV and treatment was considered successful in 66%. In those with baseline pH <7.25 and >or=7.25, the success rates of NIV were 58 and 72%, respectively. CONCLUSION: In hypercapnic exacerbations of COPD, ward-based NIV is useful in the 'real-life' setting with physiological parameters improving after only a short treatment period, while two-thirds of all patients were discharged from hospital. Further data are required to help determine factors other than pH which influence the outcome of NIV.

Procaspase 8 overexpression in non-small-cell lung cancer promotes apoptosis induced by FLIP silencing.

We found that procaspase 8 was overexpressed in non-small-cell lung cancers (NSCLCs) compared with matched normal tissues. The caspase 8 inhibitor FLICE-inhibitory protein (FLIP) was also overexpressed in the majority of NSCLCs. Silencing FLIP induced caspase 8 activation and apoptosis in NSCLC cell lines, but not in normal lung cell lines. Apoptosis induced by FLIP silencing was mediated by the TRAIL death receptors DR4 and DR5, but was not dependent on ligation of the receptors by TRAIL. Furthermore, the apoptosis induced by FLIP silencing was dependent on the overexpression of procaspase 8 in NSCLC cells. Moreover, in NSCLC cells, but not in normal cells, FLIP silencing induced co-localization of DR5 and ceramide, and disruption of this co-localization abrogated apoptosis. FLIP silencing supra-additively increased TRAIL-induced apoptosis of NSCLC cells; however, normal lung cells were resistant to TRAIL, even when FLIP was silenced. Importantly, FLIP silencing sensitized NSCLC cells but not normal cells to chemotherapy in vitro, and silencing FLIP in vivo retarded NSCLC xenograft growth and enhanced the anti-tumour effects of cisplatin. Collectively, our results suggest that due to frequent procaspase 8 overexpression, NSCLCs may be particularly sensitive to FLIP-targeted therapies.

Restricting cadaveric kidney transplantation based on age: the impact on efficiency and equity.

BACKGROUND: Caring for patients with end-stage renal disease (ESRD) is resource intense, and health care costs for this small segment of the population continue to rise. When compared to long-term dialysis as a therapy for ESRD, kidney transplantation increases survival, improves quality of life, and is cost saving. METHODS: We used decision analytic techniques to determine if cadaveric kidney transplantation is cost-effective in all age groups. We then looked at the impact of a strategy of restricting access to transplantation to those under 60 years of age to determine the impact on overall clinical outcomes and costs, as well as the outcomes and costs within each age group. RESULTS: Equal access to cadaveric kidney transplantation resulted in an increase in expected life years (7.4 vs 6.7 years) and a significant cost savings ($376,577 vs $568,670 per patient) compared to a strategy of long-term dialysis therapy over a 25-year time horizon. This pattern was seen for the overall cohort, and for all four age groups individually. Restricting access to transplantation to patients under the age of 60 resulted in only a very small improvement in expected life years and small cost savings under base-case assumptions. As expected, older patients were adversely impacted by this strategy. CONCLUSION: We have shown that transplantation is cost-effective for all age groups. A strategy of restricting access to transplantation to younger patients does not result in large cost savings and provides only small improvements in expected life-years at the expense of significantly worse outcomes in older patients.