Enteropathy-associated T-cell lymphoma: clinical and histological findings from the international peripheral T-cell lymphoma project

Few large, international series of enteropathy-associated T-cell lymphoma (EATL) have been reported. We studied a cohort of 62 patients with EATL among 1153 patients with peripheral T-cell or natural killer (NK)-cell lymphoma from 22 centers worldwide. The diagnosis was made by a consensus panel of 4 expert hematopathologists using World Health Organization (WHO) criteria. Clinical correlations and survival analyses were performed. EATL comprised 5.4% of all lymphomas in the study and was most common in Europe (9.1%), followed by North America (5.8%) and Asia (1.9%). EATL type 1 was more common (66%) than type 2 (34%), and was especially frequent in Europe (79%). A clinical diagnosis of celiac sprue was made in 32.2% of the patients and was associated with both EATL type 1 and type 2. The median overall survival was only 10 months, and the median failure-free survival was only 6 months. The International Prognostic Index (IPI) was not as good a predictor of survival as the Prognostic Index for Peripheral T-Cell Lymphoma (PIT). Clinical sprue predicted for adverse survival independently of the PIT. Neither EATL subtype nor other biologic parameters accurately predicted survival. Our study confirms the poor prognosis of patients with EATL and the need for improved treatment options.     

Peripheral T-cell lymphoma, not otherwise specified: a report of 340 cases from the International Peripheral T-cell Lymphoma Project

The International Peripheral T-cell Lymphoma Project is a collaborative effort to better understand peripheral T-cell lymphoma (PTCL). A total of 22 institutions submitted clinical and pathologic material on 1314 cases. One objective was to analyze the clinical and pathologic features of 340 cases of PTCL, not otherwise specified. The median age of the patients was 60 years, and the majority (69%) presented with advanced stage disease. Most patients (87%) presented with nodal disease, but extranodal disease was present in 62%. The 5-year overall survival was 32%, and the 5-year failure-free survival was only 20%. The majority of patients (80%) were treated with combination chemotherapy that included an anthracycline, but there was no survival advantage. The International Prognostic Index (IPI) was predictive of both overall survival and failure-free survival (P < .001). Multivariate analysis of clinical and pathologic prognostic factors, respectively, when controlling for the IPI, identified bulky disease (≥ 10 cm), thrombocytopenia (< 150 × 10(9)/L), and a high number of transformed tumor cells (> 70%) as adverse predictors of survival, but only the latter was significant in final analysis. Thus, the IPI and a single pathologic feature could be used to stratify patients with PTCL-not otherwise specified for novel and risk-adapted therapies.     

模拟后路椎间盘镜下腰椎间盘摘除术与传统术式治疗腰椎间盘突出症对腰椎生物力学稳定性的影响

目的探讨后路椎间盘镜下腰椎间盘摘除术(MED)及传统开放腰椎间盘摘除术对腰椎生物力学稳定性的影响。方法选用6具新鲜尸体脊柱标本,模拟后路腰椎间盘摘除的不同术式,依次对标本腰3～4间隙进行处理,共设计5种减压情况:MED、半椎板切除、半椎板切除并下关节突1/2切除、半椎板切除并下关节突全部切除和全椎板切除髓核摘除术。在力学实验机上分别对实验标本进行前屈/后伸、左/右侧屈及左/右轴向旋转运动,测量不同运动的最大范围。结果模拟MED手术脊柱标本向各个方向的运动与正常对照组比较差异无统计学意义(P>0.05);半椎板切除术、半椎板切除并下关节突1/2切除后,标本向各个方向的运动除半椎板切除并下关节突1/2切除后右侧旋转外与正常对照组差异无统计学意义(P>0.05),半椎板切除并下关节突全部切除后,标本向各个方向运动与正常对照组比较差异均有统计学意义(P<0.05,右侧旋转P<0.01);模拟全椎板切除标本向各个方向的运动与正常对照组比较差异均有统计学意义(P<0.01)。结论MED手术对脊柱破坏性较小,对稳定性无影响,而半椎板并小关节切除则破坏了稳定性。     

Interaction between anandamide and sphingosine-1-phosphate in mediating vasorelaxation in rat coronary artery

Background and purpose:

This study establishes a pharmacokinetic/pharmacodynamic (PK/PD) model to describe the time course and in vivo mechanisms of action of the antinociceptive effects of lumiracoxib, evaluated by the thermal hyperalgesia test in rats.

Experimental approach:

Female Wistar fasted rats were injected s.c. with saline or carrageenan in the right hind paw, followed by either 0, 1, 3, 10 or 30 mg·kg⁻¹ of oral lumiracoxib at the time of carrageenan injection (experiment I), or 0, 10 or 30 mg·kg⁻¹ oral lumiracoxib at 4 h after carrageenan injection (experiment II). Antihyperalgesic responses were measured as latency time (LT) to a thermal stimulus. PK/PD modelling of the antinociceptive response was performed using the population approach with NONMEM VI.

Results:

A two-compartment model described the plasma disposition. A first-order model, including lag time and decreased relative bioavailability as a function of the dose, described the absorption process. The response model was: LT=LT₀/(1 +MED). LT₀ is the baseline response, and MED represents the level of inflammatory mediators. The time course of MED was assumed to be equivalent to the predicted profile of COX-2 activity and was modelled according to an indirect response model with a time variant synthesis rate. Drug effects were described as a reversible inhibition of the COX-2 activity. The in vivo estimate of the dissociation equilibrium constant of the COX-2-lumiracoxib complex was 0.24 µg·mL⁻¹.

Conclusions:

The model developed appropriately described the time course of pharmacological responses to lumiracoxib, in terms of its mechanism of action and pharmacokinetics.     

Density-dependent decay in HIV-1 dynamics

The decay of HIV-1-infected cell populations after treatment with antiretroviral therapy has been measured using simple exponential decay models. These models are unlikely to be realistic over periods longer than a few months, however, because the population dynamics of HIV are complex. We considered an alternate model developed by Perelson and colleagues that extends the standard model for biphasic viral load decline and allows for nonlinear log decay of infected cell populations. Using data from 6 children on highly active antiretroviral therapy (HAART) and a single parameter in the new model, the assumption of log linear decay of infected cell populations is tested. Our analysis indicates that the short-lived and long-lived infected cell populations do not decay according to a simple exponential model. Furthermore, the resulting estimates of time to eradication of infected cell compartments are dramatically longer than those previously reported (eg, decades vs. years for long-lived infected cell populations and years vs. weeks for short-lived infected cell populations). Furthermore, estimates of the second-phase decay rates are significantly different than 0 for most children when obtained using the Perelson biphasic decay model. In contrast, this rate is not significantly different than 0 when the density-dependent decay model is used for parameter estimation and inference. Thus, the density-dependent decay model but not the simple exponential decay model is consistent with recent data showing that even under consistent HAART-mediated suppression of viral replication, decay rates of infected cell reservoirs decay little over several years. This suggests that conclusions about long-term viral dynamics of HIV infection based on simple exponential decay models should be carefully re-evaluated.     

Androgens and estrogens in relation to hot flushes during the menopausal transition.

In this paper, the association of hormones to vasomotor complaints during the menopausal transition is discussed. Fifty-seven regularly menstruating women without history of hormone replacement therapy (HRT) were selected for a longitudinal, prospective study around the menopausal transition. The mean age at the start of the study was 51.3 (+/-2.0) years. At intervals of 12 months all women went through a semi-structured interview and filled in questionnaires. Venous blood samples were collected every 12-month for analyses of estradiol (E2), testosterone, androstendione, dehydroepiandrosterone-sulphate (DHEA-S), follicle stimulating hormone (FSH), thyrotropin (TSH), and luteinizing hormone (LH). Vasomotor complaints were tested using questions about hot flushes and bouts of sweating in terms of occurrence, frequency and degree of distress. Forty-six percent of the subjects reported hot flushes and bouts of sweating before menopause, increasing to 67% during the first year after menopause and 49% in the second year postmenopause. Low levels of estradiol and high levels of FSH were associated with vasomotor complaints before menopause. During menopause high levels of TSH were related to vasomotor complaints. The first year after menopause, women, who at this point achieved hot flushes, were characterised by high levels of E2, but declining and low levels of FSH, but increasing. Postmenopausal, high levels of testosterone and DHEA-S seemed to protect against vasomotor symptoms. Our most important finding was, that among women who achieved hot flushes at the first assessment postmenopause, the high androgen levels was a significant predictor of recovery from hot flushes at the last assessment, 1 year later.