Cost-effectiveness of left ventricular assist devices (LVADs) for patients with advanced heart failure: Analysis of the British NHS bridge to transplant (BTT) program

Background

A previous cost-effectiveness analysis showed that bridge to transplant (BTT) with early design left ventricular assist devices (LVADs) for advanced heart failure was more expensive than medical management while appearing less beneficial.Older LVADs were pulsatile, but current second and third generation LVADs are continuous flow pumps. This study aimed to estimate comparative cost-effectiveness of BTT with durable implantable continuous flow LVADs compared to medical management in the British NHS.

Methods and results

A semi-Markov multi-state economic model was built using NHS costs data and patient data in the British NHS Blood and Transplant Database (BTDB). Quality-adjusted life years (QALYs) and incremental costs per QALY were calculated for patients receiving LVADs compared to those receiving inotrope supported medical management. LVADs cost £80,569 ($127,887) at 2011 prices and delivered greater benefit than medical management. The estimated probabilistic incremental cost-effectiveness ratio (ICER) was £53,527 ($84,963)/QALY (95%CI: £31,802–£94,853; $50,479–$150,560) (over a lifetime horizon). Estimates were sensitive to choice of comparator population, relative likelihood of receiving a heart transplant, time to transplant, and LVAD costs. Reducing the device cost by 15% decreased the ICER to £50,106 ($79,533)/QALY.

Conclusions

Durable implantable continuous flow LVADs deliver greater benefits at higher costs than medical management in Britain. At the current UK threshold of £20,000 to £30,000/QALY LVADs are not cost effective but the ICER now begins to approach that of an intervention for end of life care recently recommended by the British NHS. Cost-effectiveness estimates are hampered by the lack of randomized trials.     

中等收入国家传统医药使用情况调查

大家经常会在文献、官方报告和新闻媒体上听到过这样的说法:80%的亚洲和非洲人民使用传统医药满足医疗需求,但是这项数据事实上来源于世界卫生组织1983年的一项研究,显然早已过时。为知晓传统医药的最新使用情况,践行世界卫生组织的传统医药(2014-2023)战略,特选取35 334名研究对象,进行为期3年的调查研究。该项研究采用单变量和多变量分析法比较传统医药使用者和现代医药使用者在年龄、性别、居住地、收入、教育程度、患病情况等方面的差异。结果表明,印度人民使用传统医药的比例最高,占11.7%;而在中国、加纳、墨西哥、俄罗斯、南非,仅有不到3%的人口将传统医学作为主要医疗途径。单变量研究结果表明,贫困、教育程度不高、农村居住地与传统医药的使用有一定相关性。多变量分析研究结果表明,在中国,农村居住地、自我感觉身体差、关节炎与传统医药的使用有一定相关性,且使用传统医药的人群中糖尿病、高血压、白内障的患病比例较低。在印度和加纳,低收入、抑郁和高血压与传统医药的使用有一定相关性。了解传统医学的实际使用情况有助于世界卫生组织更准确地制定传统医学发展战略。     

Melanoma-Associated Antigen Expression in Lymphangioleiomyomatosis Renders Tumor Cells Susceptible to Cytotoxic T Cells

The antibody HMB45 is used to diagnose lymphangioleiomyomatosis, a hyperproliferative disorder of lung smooth muscle cells with mutations in both alleles of either TSC1 or TSC2. A subset of these tumor cells expresses the melanoma-associated antigens gp100 and melanoma antigen recognized by T cells (MART-1). To explore the feasibility of targeting tumors in lymphangioleiomyomatosis by melanoma immunotherapy, we therefore assessed melanoma target antigen expression and existing immune infiltration of affected tissue compared with normal lung and melanoma as well as the susceptibility of cultured lymphangioleiomyomatosis cells to melanoma reactive cytotoxic T lymphocytes in vitro. Tumors expressed tyrosinase-related proteins 1 and 2 but not tyrosinase, in addition to gp100 and MART-1, and were densely infiltrated by macrophages, but not dendritic cells or T cell subsets. Although CD8⁺ lymphocytes were sparse compared with melanoma, cells cultured from lymphangioleiomyomatosis tissue were susceptible to cytotoxic, gp100 reactive, and major histocompatibility complex class I restricted CD8⁺ T cells in functional assays. Responder T cells selectively clustered and secreted interferon-γ in response to HLA-matched melanocytes and cultured lymphangioleiomyomatosis cells. This reactivity exceeded that based on detectable gp100 expression; thus, tumor cells in lymphangioleiomyomatosis may process melanosomal antigens different from melanocytic cells. Therefore, boosting immune responses to gp100 in lymphangioleiomyomatosis may offer a highly desirable treatment option for this condition.Lymphangioleiomyomatosis (LAM) is a disease that strikes primarily women of child bearing age.¹ Patients with LAM develop cystic lung lesions and present with dyspnea, pneumothoraces, chylous pleural effusions, and progressive loss of lung function, often culminating in lung transplantation.² LAM can occur in patients with hereditary tuberous sclerosis, due to loss of heterozygosity in TSC1 or TSC2 genes.^3,4 The prevalence of tuberous sclerosis complex (TSC)-associated LAM in the United States is approximately 1 in 35,000, or approximately a third of patients with TSC.⁵ Loss of both alleles of either TSC1 or TSC2 in sporadic LAM affects approximately 1 per million individuals.⁶ Thus, diseased cells in the latter are generally clonal, whereas in patients with tuberous sclerosis pleiotropic effects are best explained by separate transformation events.Following the identification of underlying mutations responsible for the symptoms incurred in LAM and intracellular signaling pathways affected by TSC1/TSC2 through the mammalian target of rapamycin complex, proposed disease treatments have been aimed at the hyperproliferative responses observed in mutant cells.⁷ The mammalian target of rapamycin inhibitor rapamycin has been tested in phase 1 trials with mixed results.⁸ As mammalian target of rapamycin inhibition affects primarily cell size and proliferation without inducing cell death in mutant cells, clinical symptoms are not permanently alleviated. Rapamycin may be particularly useful in a prophylactic setting, preventing cyst formation in patients with TSC or patients who have undergone lung transplantation for LAM to prevent recurrence.⁹Patients with LAM are generally not given a diagnosis for several years after the appearance of symptoms, and a lung biopsy is sometimes required.^10,11 HMB45 immunostaining of lung tissue sections has proven a definitive diagnostic marker for lymphangioleiomyomatosis.¹¹ Thus LAM cells express an epitope recognized by antibodies to gp100, which is otherwise expressed exclusively by melanocytic cells and frequently recognized by tumor infiltrating T cells in malignant melanoma.^12,13 These data raised the intriguing question of whether LAM cells have trans-differentiated to express molecules otherwise associated with pigmentation, although melanin synthesis is not commonly observed in LAM tissue.¹⁴Melanosomes are organelles closely related to lysosomes, developing from endosomes after trafficking of melanogenic enzymes by an intricate mechanism that involves several multiprotein complexes including adaptor protein-3 and biogenesis of lysosome-related organelles complex 1 to 3.¹⁵ Tyrosinase is the rate limiting enzyme for melanogenesis, supported by tyrosinase-related proteins (TRPs) 1 and 2; TRP-2 is also known as dopachrome tautomerase and is involved in later steps of melanogenesis. The melanosomal protein MART-1, a melanoma antigen recognized by T cells, has a chaperone-like function that prepares the premelanosome for melanin synthesis, and gp100 is responsible for the striation of early stage melanosomes important for melanin deposition.¹⁶ Skin pigmentation is achieved when ripened melanosomes are transferred to neighboring keratinocytes in a process that is at least in part determined by recipient cells.¹⁷ Melanization thus precedes organelle transfer to neighboring cells.In addition to gp100, expression of MART-1 has been reported in LAM.¹² MART-1 is named for its recognition by tumor infiltrating T cells.¹⁸ Both MART-1 and gp100 are also recognized by T cells that infiltrate the skin of patients with autoimmune vitiligo, further supporting the notion that expression can prime host cells for immune destruction.¹⁹ Vaccines boosting immune responses melanoma-associated antigens have since been developed and tested in clinical trials for the treatment of malignant melanoma.²⁰ Besides adoptive transfer of autologous T cells, identification of T-cell epitopes and reactive T cell receptor (TCR) molecules have enabled additional vaccine strategies including administration of adjuvant-supported antigen preparations or TCR transgenic T cells.²¹ As T cells also mediate autoimmune responses in vitiligo, boosting immune responses directed toward the gp100 and MART-1 antigens may be an effective strategy to eradicate LAM cells.¹⁹However, expression of gp100 as well as MART-1 is observed in only a subset of LAM cells. This prompted a wider investigation of melanoma-associated antigen expression, comparing expression within LAM tissue to normal lung and metastatic melanoma, and in vitro to melanoma cells and smooth muscle cells. Tissue infiltrating leukocytes including macrophages, dendritic cells, and CD4⁺ and CD8⁺ T cells found in LAM lung tissue were also quantified and compared with normal lung tissue and melanoma. The sensitivity of cell cultures derived from LAM lung to relevant T cells was assessed in functional in vitro assays. Techniques used include single and double immunohistochemistry, light and electron microscopy, fluorescence activated cell scanning (FACS) analysis, chromium release assays, and enzyme-linked immunosorbent assay (ELISA). The data are important to evaluate the potential of melanoma immunotherapy for the treatment of LAM.     

The role of K-Ras gene mutation in TRAIL-induced apoptosis in pancreatic and lung cancer cell lines

Purpose

Pancreatic ductal and lung adenocarcinomas are the most common and prevalent types of human neoplasms with a greater than 80% mortality rate. The poor prognosis of both these cancers are likely due to the absence of valid approaches for early detection, the frequency of its metastases at the time of diagnosis, frequent recurrence after surgery, and poor responsiveness to chemotherapy. Most notably, the early development of pancreatic intraepithelial neoplasia and lung lesions is suggested to be the result of a mutation in the K-ras (G12D) oncogene. Tumor necrosis factor-related-apoptosis-inducing-ligand (TRAIL) has been shown to have great potential for the treatment of most human tumor cells, while leaving normal cells unharmed. However, some cancers show resistance to TRAIL treatment, leaving a gap in the understanding of its exact etiology.

Methods

TRAIL-induced resistance to cell death was investigated in pancreatic and lung cancer cell lines. Cell survival was determined by SRB and apoptosis by ELISA-based cell death assay. Activation of bid and caspases were evaluated by Western blotting.

Results

Our study demonstrated that TRAIL significantly suppressed cell survival, by inducing apoptosis in a dose-dependent manner, in the pancreatic cancer BxPC-3 (wild type G12) and lung cancer A549 (G12S) cell lines. In contrast, Panc-1 pancreatic and SK-LU-1 lung cancer cell lines, which have a mutated (G12D) K-ras genotype, were resistant to the actions of TRAIL.

Conclusions

This study demonstrates an association between TRAIL resistance to apoptosis in human pancreatic and lung cancer cell lines and G12D K-ras¹² mutation.     

Levels of vitamin D and cardiometabolic disorders: Systematic review and meta-analysis

Cardiometabolic disorders and vitamin D deficiency are becoming increasingly more prevalent across multiple populations. Different studies have suggested a potential association between abnormal vitamin D levels and multiple pathological conditions including cardiovascular diseases and diabetes.