One-year mortality in patients with bone and soft tissue sarcomas as an indicator of delay in presentation

IntroductionFor many cancers, one-year mortality following diagnosis is a reflection of either advanced stage at diagnosis, multiple co-morbidities and/or complications of treatment. One-year mortality has not been reported for soft tissue or bone sarcomas. This study reports 1-year sarcoma mortality data over a 25-year period, investigates prognostic factors and considers whether a delay in presentation affects 1-year mortality.MethodsA total of 4,945 newly diagnosed bone sarcoma and soft tissue sarcoma patients were identified from a prospectively maintained, single institution oncology database. Of these, 595 (12%) died within 1 year of diagnosis. Both patient factors and tumour characteristics available at diagnosis were analysed for effect.ResultsThere was significant variation in one-year mortality between different histological subtypes. There has been no significant change in mortality rate during the last 25 years (mean: 11.7%, standard deviation: 2.8 percentage points). Soft tissue sarcoma patients who survived over one year reported a longer duration of symptoms preceding diagnosis than those who died (median: 26 vs 20 weeks, p<0.001). Prognostic factors identified in both bone and soft tissue sarcomas mirrored those for mid to long-term survival, with high tumour stage, large tumour size, metastases at diagnosis and increasing age having the greatest predictive effect.ConclusionsOne-year mortality in bone and soft tissue sarcoma patients is easy to measure, and could be a proxy for late presentation and therefore a potential performance indicator, similar to other cancers. It is possible to predict the risk of one-year mortality using factors available at diagnosis. Death within one year does not correlate with a long history but is associated with advanced disease at diagnosis.     

Characterization of megakaryocyte spleen colony-forming units by response to 5-fluorouracil and by unit gravity sedimentation

Properties of megakaryocyte progenitor cells in mouse bone marrow have been examined using an in vivo assay system. Perturbation with 5- fluorouracil (5-FU) and separation by unit gravity sedimentation was used to characterize the cells. Bone marrow was assayed for the presence of megakaryocyte colony-forming cells (MK CFU-S) by transplantation into lethally irradiated mice and examining spleen sections 10 days later. Donor mice were untreated or injected intravenously with 5-FU (150 mg/kg), 1 (FU-1) or 7 (FU-7) days beforehand. There was a lack of correlation between the numbers of MK CFU-S and cells giving rise to macroscopic spleen surface colonies (CFU- S10). The sedimentation profile of MK CFU-S in normal marrow was similar (modal velocity 4.16 +/- 0.05 mm/hr) to that of CFU-S10. In FU- 1 marrow, MK CFU-S exhibited a bimodal sedimentation profile, with peaks at 3.26 +/- 0.06 mm/hr and 4.53 +/- 0.07 mm/hr. The marrow content of CFU-S10 was reduced to 5% of normal, while MK CFU-S numbers were only reduced to 60%. In FU-7 marrow, the sedimentation profile of MK CFU-S (modal velocity 4.86 +/- 0.16 mm/hr) differed from that of CFU- S10 (5.5 +/- 0.16 mm/hr). It was concluded MK CFU-S and CFU-S10 are different entities. The MK colonies formed from FU-1 marrow contained on average 3.8-fold more cells than those formed from normal marrow. The enhanced megakaryocyte production may be accounted for on the basis of the generation-age model for cell proliferation. It is proposed that MK CFU-S are a heterogeneous population with regard to proliferation potential and that the FU-1 marrow contains cells that survive 5-FU and have a high proliferative potential. These cells may be equivalent among megakaryocytic progenitors to the high proliferative potential colony-forming cells of the granulocyte/macrophage series. They may be responsible for the enhanced megakaryocytopoiesis seen in the marrow of mice 7 days after the injection of 5-FU.     

The sequential analysis of T lymphocyte subsets and interleukin-6 in polymyalgia rheumatica patients as predictors of disease remission and steroid withdrawal

CD4 and CD8 T lymphocyte subsets, the late T cell activation marker, HLA-DR, and serum interleukin-6 (IL-6) levels of 57 polymyalgia rheumatica (PMR) patients were followed over 2 yr to investigate whether they could be used to predict the safe withdrawal of steroid therapy. Cell phenotypes were studied by flow cytometry and IL-6 levels by ELISA. %CD8 cells were reduced below the normal range in PMR patients prior to steroid therapy. In 56% of patients, the %CD8 T lymphocytes failed to return to normal levels when quiescent disease allowed cessation of steroid therapy. Activated CD8 T cells, as detected by HLA-DR positivity, were above the normal range at the initiation of therapy and showed a negative correlation with %CD8 T cells. The serum concentration of IL-6 fluctuated over 24 months, and the correlation between IL-6 and erythrocyte sedimentation rate (ESR) seen prior to treatment was not seen at later intervals. The %CD8 T cell and serum IL-6 levels are not a good indicator of disease activity in PMR and are, therefore, unable to predict the safe withdrawal of steroids.      

High prevalence of nonsense, frame shift, and splice-site mutations in 16 patients with full-blown Wiskott-Aldrich syndrome

Wiskott-Aldrich syndrome (WAS) is a fully penetrant X-linked recessive disorder characterized by immunodeficiency, thrombocytopenia, and severe eczema. WAS is a life-threatening disease, with a poor quality of life and high mortality rate in childhood. The gene responsible for the disease has been localized to the proximal short arm of the X- chromosome and recently isolated through positional cloning and named WAS protein (WASP). We have characterized 17 WAS families. We have developed a rapid, nonradioactive screening protocol for identifying WASP gene alterations in genomic DNA. Our method allows simultaneous evaluation of single strand confirmation polymorphism and heteroduplex formation. We have identified 15 novel mutations that involve single basepair changes, or small insertions or deletions, all of which result in premature stop cordon, frame shift with secondary premature stop codon, or splice site defect. These studies document the considerable heterogeneity of the location of mutations in the WASP gene causing full-blown WAS and show the efficiency and rapidity of a screening approach for mutation identification in WAS that will be useful for carrier detection and prenatal diagnosis.     

成人脑死亡判定的循证医学指南更新——美国神经病学会质量标准分会报告

目的就如下问题对美国神经病学会1995年脑死亡判定实践标准进行更新：①符合脑死亡临床判定标准的患者神经功能能恢复吗？②确定患者神经功能永久性停止的恰当观察时间是多长？③有时可能观察到脑死亡患者的复合肢体运动,这是否错误地提示仍然保留脑功能？④何种技术手段判断呼吸停止是相对安全的？⑤是否存在新的辅助检测能准确判断患者脑死亡？方法系统回顾MEDLINE及EMBASE数据库1996年1月-2009年5月收录的文献,其研究仅限于成年人（≥18岁）。结果及建议对成年人,按照美国神经病学会于1995年确定的脑死亡判定实践标准,目前尚无判定为脑死亡患者出现神经功能恢复的报告。脑死亡患者可以存在复合的自发运动及假阳性触发呼吸机。目前还无足够的证据用以确定神经功能不可逆性停止的最短观察时间。通过氧扩散来确定呼吸停止是安全的,但目前还无足够证据确定呼吸停止检测技术的相对安全性。目前还无足够的证据确定新型辅助检测能否准确判断患者全脑功能已经停止。     

Endothelin-converting enzyme 1 promotes re-sensitization of neurokinin 1 receptor-dependent neurogenic inflammation

Background and purpose:

The metalloendopeptidase endothelin-converting enzyme 1 (ECE-1) is prominently expressed in the endothelium where it converts big endothelin to endothelin-1, a vasoconstrictor peptide. Although ECE-1 is found in endosomes in endothelial cells, the role of endosomal ECE-1 is unclear. ECE-1 degrades the pro-inflammatory neuropeptide substance P (SP) in endosomes to promote recycling and re-sensitization of its neurokinin 1 (NK₁) receptor. We investigated whether ECE-1 regulates NK₁ receptor re-sensitization and the pro-inflammatory effects of SP in the endothelium.

Experimental approach:

We examined ECE-1 expression, SP trafficking and NK₁ receptor re-sensitization in human microvascular endothelial cells (HMEC-1), and investigated re-sensitization of SP-induced plasma extravasation in rats.

Key results:

HMEC-1 expressed all four ECE-1 isoforms (a-d), and fluorescent SP trafficked to early endosomes containing ECE-1b/d. The ECE-1 inhibitor SM-19712 prevented re-sensitization of SP-induced Ca²⁺ signals in HMEC-1 cells. Immunoreactive ECE-1 and NK₁ receptors co-localized in microvascular endothelial cells in the rat. SP-induced extravasation of Evans blue in the urinary bladder, skin and ears of the rat desensitized when the interval between two SP injections was 10 min, and re-sensitized after 480 min. SM-19712 inhibited this re-sensitization.

Conclusions and implications:

By degrading endocytosed SP, ECE-1 promotes the recycling and re-sensitization of NK₁ receptors in endothelial cells, and thereby induces re-sensitization of the pro-inflammatory effects of SP. Thus, ECE-1 inhibitors may ameliorate the pro-inflammatory actions of SP.