Bone marrow phospho-STAT5 expression in non-CML chronic myeloproliferative disorders correlates with JAK2 V617F mutation and provides evidence of in vivo JAK2 activation

The recently described JAK2 V617F mutation, present in a substantial proportion of nonchronic myelogenous leukemia chronic myeloproliferative disorders (non-CML CMPDs), is changing the way we conceptualize and diagnose these diseases. We hypothesized that the activation of this tyrosine kinase might result in activation of downstream mediators such as STAT5, which would be detectable in bone marrow biopsies. We examined the expression of activated STAT5 (nuclear phospho-STAT5) in 73 bone marrow biopsies from patients with CMPDs [20 essential thrombocythemia (ET), 26 chronic idiopathic myelofibrosis (CIMF), and 27 polycythemia vera] and 39 controls. We compared the results with the JAK2 mutational status and clinical parameters. The frequency of the JAK2 V617F was 73% (85% in PV, 65% in ET, and 65% in CIMF). All patients with the JAK2 V617F showed abnormal nuclear megakaryocytic phospho-STAT5 (nMEG pSTAT5) expression. In the JAK2 wild-type group, nMEG pSTAT5 was observed in 2/7 ET, and 3/9 CIMF patients. nMEG pSTAT5 staining was 100% sensitive and 88% specific for JAK2 V617F. Clinically, nMEG pSTAT5+ patients seemed to require cytoreductive therapy more often than those without nMEG p-STAT expression. pSTAT5 immunohistochemistry is a useful diagnostic test in bone marrow biopsies from suspected non-CML CMPD patients. It identifies most of the patients with the JAK2 V617F but also other JAK2 wild-type CMPD patients. The presence of nMEG pSTAT5 in a subset of CMPD patients lacking the mutation suggests that alternate tyrosine kinase/phosphatase pathways may be involved and warrant further investigation. Phosphoprotein detection represents a new area for diagnostic pathology that exploits specific functional characteristics of cells within the context of a tissue section.     

Critical Appraisal on the Role and Outcome of Emergency Colectomy for Uncomplicated Right-sided Colonic Diverticulitis

Background Emergency colectomy is well accepted for treating complicated right-sided colonic diverticulitis. However, the role of colectomy for uncomplicated diverticulitis is not well defined. The aim of this study was to evaluate the short-term and long-term surgical outcome of uncomplicated right-sided diverticulitis in our locality. Patients and Methods Retrospective chart review of patients operated for right-sided diverticulitis over a 20-year period was conducted. Recurrent attacks of right-sided diverticulitis, re-operation rate and re-hospitalisation rate were the long-term parameters of interest. An updated telephone interview was carried out for all surviving patients. Results Seventy-four patients (35 males and 39 females), median age 35.5 (range 16–70) years, were operated for uncomplicated diverticulitis. Thirty patients underwent colectomy, whereas the others underwent appendectomy with diverticulectomy (n = 8) or appendectomy alone (n = 36). All short-term parameters were less favourable for the colectomy group, including higher complication rate, slower return of gastrointestinal function, higher requirement of parenteral analgesic and longer hospital stay. Without colectomy, only 2 patients developed recurrent diverticulitis necessitating hospitalisation, both of whom resolved on conservative treatment. On the other hand, 1 patient required re-operation after colectomy because of intestinal obstruction. The overall re-hospitalisation rate was comparable between the colectomy and the non-colectomy group (16.7% vs. 13.6%). Conclusions Emergency colectomy can eradicate suspicious lesions and eliminate risk of recurrent diverticulitis but at the expense of higher morbidity rates. As the natural course of uncomplicated right-sided colonic diverticulitis is usually benign, conservative treatment with minimal surgery may be a better therapeutic option.     

Biologic predictors in follicular lymphoma: importance of markers of immune response

We sought to identify biologic indicators of prognosis in a series of 94 follicular lymphoma (FL) patients, focusing on markers of the host immune response as well as of B-cell maturation. Immune response was assessed with immunostains for CD68 (for lymphoma-associated macrophages, LAMs) and FOXP3 (regulatory T-cells). Lymphoma cells were evaluated for expression of bcl-2, CD10, and MUM-1. Clinical data were obtained for FLIPI, presence of bulky disease, presence of B-symptoms, treatment, and overall survival (OS). For the 69 initially treated patients, extrafollicular CD68+ cells (ef-CD68) and follicular FOXP3+ cells (f-FOXP3) were associated with shorter OS, while receipt of rituximab was associated with longer OS. Multivariable analysis showed ef-CD68 was the only independent factor associated with shorter OS. In subset analysis, ef-CD68 remained statistically significant in rituximab-na?ve but not rituximab-treated patients. We confirm the importance of LAMs and f-FOXP3 as predictors of OS in FL.     

Anti-HCV therapies in chimeric scid-Alb/uPA mice parallel outcomes in human clinical application

Compounds with in vitro anti-hepatitis C virus (HCV) activity are often advanced directly into clinical trials with limited or no in vivo efficacy data. This limits prediction of clinical efficacy of compounds in the HCV drug pipeline, and may expose human subjects to unnecessary treatment effects. The scid-Alb-uPA mouse supports proliferation of transplanted human hepatocytes and subsequent HCV infection. Cohorts of genotype 1a HCV-infected mice were treated with interferon alpha-2b(IFN-alpha), BILN-2061 (anti-NS3 protease), or HCV371 (anti-NS5B polymerase). Mice treated with 1350 IU/g/day IFN-alpha intramuscularly for 10 to 28 days demonstrated reduced viral titers compared with controls in all five experiments (P < .05, t test); viral titers rebounded after treatment withdrawal. A more pronounced antiviral effect with IFN-alpha was seen in genotype 3a-infected mice. Pilot studies with BILN2061 confirmed exposure to 10X replicon EC50 at trough and reduced viral titer over 2 log at 4 days. In a second 7-day study, mean HCV RNA titers dropped 1.1 log in BILN2061-treated animals, 0.6 log in IFN-treated mice, and rose 0.2 log in controls (P = .013, ANOVA). Pre-existing mutants with partial resistance to BILN2061 were identified by sequencing both the human inoculum and sera from treated mice. The polymerase inhibitor HCV371 yielded a decline in HCV titers of 0.3 log relative to vehicle-treated controls (P = NS). Performance of all three antiviral regimens in the chimeric mouse model paralleled responses in humans. In conclusion, this system may help selection of lead compounds for advancement into human trials with an increased likelihood of clinical success while broadening the tools available for study of the biology of HCV infection.     

地西泮-聚羟基丁酸酯-羟基戊酸酯共聚物缓释微球制备与性质

目的 :探索以新型生物可降解材料聚羟基丁酸酯 羟基戊酸酯共聚物 (PHBV)为载体的地西泮药物中长期缓释微球制备工艺 ;方法 :以溶剂蒸发法制备微球 ,用扫描电镜SEM观察微球表面及内部横断面形态结构 ;结果 :微球的平均粒径为 3 0 .5μm ,平均载药量 (1 8.66± 0 .2 3 ) % ,包封率 (80 .85± 1 .0 1 ) %。体外释放第一天呈突释效应 ,而后药物释放基本符合零级动力学过程 .其释放曲线方程为 Q =2 0 .55 2 .3 99t,r=0 .9569;结论 :开发与研制PHBV为载体的中长期缓释微球具有较好应用前景。     

Low circulating adiponectin and resistin, but not leptin, levels are associated with multiple myeloma risk: a case–control study

Accumulating evidence supports a role for obesity in the etiology of multiple myeloma (MM). The distinct possibility exists that obesity may be linked to MM through altered adipokine secretion and circulating levels, one of which, adiponectin, has a protective role in several malignancies, including leukemia. In this case–control study, we investigated the role of serum adiponectin, resistin, and leptin levels in the etiopathogenesis of MM and we explored their association with several established prognostic factors. Seventy three patients with incident, histologically confirmed MM and 73 controls matched on gender and age were studied between 2001 and 2007, and blood samples were collected. Serum adiponectin, leptin, resistin, as well as MM prognostic parameters were determined. Statistical analysis of the data was performed using univariate and multivariate analyses. Lower serum adiponectin and resistin levels were associated with higher risk of MM by bivariate analysis and after adjusting for age, gender, BMI, and serum levels of leptin (p < 0.0001). Adiponectin may have a protective role in MM, whereas leptin was not associated with risk for MM at a comparable level of significance and resistin levels may be decreased via a compensatory mechanism. Further studies are needed to confirm these associations and to explore the mechanisms underlying adiponectin’s role in MM and plasma cell dyscrasias.