Repeat Transarterial Chemoembolization (TACE) for Progressive Hepatic Carcinoid Metastases Provides Results Similar to First TACE

Background Transarterial chemoemobolization (TACE) is commonly used to treat metastatic carcinoid tumors; however, the management of progressive disease is less clear. We sought to determine if patients with disease progression after TACE would benefit from repeat TACE. Methods The records of 27 patients undergoing repeat TACE for radiologic or symptomatic progression after TACE for metastatic carcinoid were reviewed and compared to 122 undergoing first TACE. Overall and progression-free survivals were estimated by the Kaplan–Meier method. Results Mean disease-free interval after first TACE was 11.8 months. Radiologic response was observed in 61% compared to 82% after first TACE (p = 0.058); hormone response in 64% compared to 80% (p = 0.159); and symptomatic response in 77% compared to 92% (p = 0.053). The complication rate after repeat TACE was lower than after first TACE (p = 0.03). Median overall survival was similar after repeat (28.1 months) and first TACE (33.3 months) (p = 0.53). Progression-free survival was shorter after repeat TACE but not significantly so. No factor examined could predict survival after repeat TACE. Conclusion Repeat TACE for patients with hepatic carcinoid metastases failing first TACE or having evidence of disease progression is safe and offers a viable treatment option. Presented at the 48th Annual Meeting of The Society for Surgery of the Alimentary Tract, Washington, DC, May, 2007.     

Simultaneous versus sequential optimal design for pharmacokinetic-pharmacodynamic models with FO and FOCE considerations

We consider nested multiple response models which are used extensively in the area of pharmacometrics. Given the conditional nature of such models, differences in predicted responses are a consequence of different assumptions about how the models interact. As such, sequential versus simultaneous and First Order (FO) versus First Order Conditional Estimation (FOCE) techniques have been explored in the literature where it was found that the sequential and FO approaches can produce biased results. It is therefore of interest to determine any design consequences between the various methods and approximations. As optimal design for nonlinear mixed effects models is dependent upon initial parameter estimates and an approximation to the expected Fisher information matrix, it is necessary to incorporate any influence of nonlinearity (or parameter-effects curvature) into our exploration. Hence, sequential versus simultaneous design with FO and FOCE considerations are compared under low, typical and high degrees of nonlinearity. Additionally, predicted standard errors of parameters are also compared to empirical estimates formed via a simulation/estimation study in NONMEM. Initially, design theory for nested multiple response models is developed and approaches mentioned above are investigated by considering a pharmacokinetic–pharmacodynamic model found in the literature. We consider design for situations where all responses are continuous and extend this methodology to the case where a response may be a discrete random variable. In particular, for a binary response pharmacodynamic model, it is conjectured that such responses will offer little information about all parameters and hence a sequential optimization, in the form of product design optimality, may yield near optimal designs.     

Parental alcohol use and brain volumes in early- and late-onset alcoholics.

BACKGROUND: Studies have shown that alcoholics have smaller brain volumes than non-alcoholic cohorts, but an effect of family history (FH) of heavy drinking on brain volume has not been demonstrated. We examined the relationship between an FH of heavy drinking and both brain shrinkage as measured by the ratio of brain volumes to intracranial volume (ICV) as well as maximal brain growth as measured by ICV in early-onset and late-onset alcoholics. METHODS: With T1-weighted resonance imaging, we measured ICV, brain volume, and white and gray matter volume in adult treatment-seeking late-onset and early-onset alcoholics with either a positive or a negative FH of heavy alcohol use, and in healthy control subjects. We also calculated brain shrinkage using a ratio of soft tissue volumes to ICV. RESULTS: The FH positive alcoholic patients had significantly smaller ICVs than FH negative patients, suggesting smaller premorbid brain growth. Brain shrinkage did not correlate with FH. Late-onset alcoholics showed a greater difference in ICV between FH positive and FH negative patients than early-onset alcoholics. Late-onset FH positive patients also had significantly lower IQ scores than late-onset FH negative patients, and IQ scores were correlated with ICV. CONCLUSIONS: These data provide evidence that parental alcohol use might increase risk for alcoholism in offspring in part by a genetic and/or environmental effect that might be related to reduced brain growth.     

CT导引经皮穿刺注射无水乙醇治疗溶骨性骨转移瘤

目的探讨CT导引下经皮穿刺注射无水乙醇（CT～PEI）治疗溶骨性骨转移瘤的价值及安全性。方法对17例骨转移瘤患者（25个病灶）采用CT—PEI治疗，使用无水乙醇和超化碘油10：1的混合剂，用CT精确定位、准确穿刺瘤灶并密切监控无水乙醇弥散情况及用量，以减少并发症。对接近椎管及椎间孔的病灶，采用利多卡因实验性治疗以避免严重并发症。术前及术后定期CT检查，3例病人行同位素骨扫描检查，与治疗前检查进行对照研究。对患者随访3～30个月观察其临床疗效。结果所有患者经1次CT—PEI治疗后，疼痛即明显减轻，经2～3次CT-PEI治疗后疼痛完全缓解（CR）16例（24处病灶），疼痛部分缓解（PR）1例。术后随访3个月时，23处病灶内肿瘤组织均发生坏死，被高密度碘油混合液均匀浸润。其中，9处病灶体积缩小。随访3～30个月，除1例因周边出现新的肿瘤浸润灶而再次出现疼痛，其余病例转移瘤处止痛效果无反复。所有病例无严重并发症。结论CT—PEI是一种治疗骨转移瘤有效、微创、安全、简便的方法，使骨转移瘤内肿瘤组织坏死，最大限度的杀灭肿瘤细胞，从而达到满意的止痛效果，明显改善恶性肿瘤溶骨性转移病人的生活质量。     

血管内皮生长因子在高原脑水肿形成中作用的实验研究

目的:探讨血管内皮生长因子(VEGF)在高原脑水肿形成中的作用。方法:建立大鼠模拟高原模型,应用脑干湿重比率法定量脑水肿情况、应用荧光素钠透过率测定BBB通透性、应用实时荧光定量RT-PCR法检测脑组织VEGF mRNA含量以及应用蛋白印迹法半定量脑组织VEGF含量。结果:大鼠在高原24 h后脑组织含水率明显增高(P<0.05),荧光素钠透过率显著增加(P<0.01);VEGF mRNA转录及其表达显著增高(P<0.001)。结论:VEGF表达在高原脑水肿形成中起重要作用。     

Deep Brain Stimulation——A new treatment for tinnitus

Intractable tinnitus can lead to serious consequences. Study evidence indicates that the central nervous system is involved in generation and maintenance of chronic tinnitus and that tinnitus and other neurologic symptoms such as chronic pain may share similar mechanisms. Brain ablation and stimulation are used to treat chronic pain with success. Recent studies showed that ablation and stimulation in non-auditory areas resulted in tinnitus improvement. Deep brain stimulation (DBS) may be an alternative treatment for intractable tinnitus and deserves further study.     

内镜下鼻胆管引流治疗急性梗阻性化脓性胆管炎(附25例报告)

目的探讨急性梗阻性化脓性胆管炎伴多器官衰竭的治疗方法。方法对25例急性梗阻性化脓性胆管炎伴多器官衰竭的患者采取以内镜下鼻胆管引流术、经鼻胆管冲洗及灌注抗生素为主的非手术综合治疗,观察患者治疗前后的血清总胆红素水平、B超下胆总管内径变化,并对患者临床资料进行回顾性分析。结果本组25例患者除2例需转外科急诊手术治疗外,其余23例内镜下胰胆管造影、内镜下鼻胆管引流术成功,胆汁引流通畅,多器官衰竭得以纠正,急性梗阻性化脓性胆管炎伴多器官衰竭治愈率为92.0%。结论对急性梗阻性化脓性胆管炎伴多器官衰竭患者采取内镜下鼻胆管引流术、静脉应用和经鼻胆管冲洗及灌注抗生素为主的综合治疗是有效、安全的。     

早期脑室置管行颅内压监护对中型颅脑损伤患者的预后影响

目的　探讨早期脑室置管行颅内压 (ICP)和脑灌注压 (CPP)监护在中型颅脑损伤中的临床应用价值。方法　将 12 5例伤后 2 4h入院无手术指征的中型颅脑损伤 (GCS 9～ 12分 )患者 ,随机分为ICP监护组 :入院后即经恻脑室内穿刺置管行ICP与CPP连续监测 ,根据颅内压变化调整治疗方案 ;对照组 :入院后不做ICP监测 ,依据临床观察的意识及生命体征变化 ,进行治疗。结果　颅内压监护组脱水剂剂量、应用时间均低于对照组 ,疗效优于对照组 ,两组差异有显著意义 (P <0 0 5 )。结论　中型颅脑损伤病情极不稳定 ,早期行ICP监护能及早发现病情变化 ,对及时采取有效治疗措施 ,降低死残率 ,改善预后有重要意义。     

Fisher information matrix for nonlinear mixed effects multiple response models: Evaluation of the appropriateness of the first order linearization using a pharmacokinetic/pharmacodynamic model

We focus on the Fisher information matrix used for design evaluation and optimization in nonlinear mixed effects multiple response models. We evaluate the appropriateness of its expression computed by linearization as proposed for a single response model. Using a pharmacokinetic–pharmacodynamic (PKPD) example, we first compare the computation of the Fisher information matrix with approximation to one derived from the observed matrix on a large simulation using the stochastic approximation expectation–maximization algorithm (SAEM). The expression of the Fisher information matrix for multiple responses is also evaluated by comparison with the empirical information obtained through a replicated simulation study using the first‐order linearization estimation methods implemented in the NONMEM software (first‐order (FO), first‐order conditional estimate (FOCE)) and the SAEM algorithm in the MONOLIX software. The predicted errors given by the approximated information matrix are close to those given by the information matrix obtained without linearization using SAEM and to the empirical ones obtained with FOCE and SAEM. The simulation study also illustrates the accuracy of both FOCE and SAEM estimation algorithms when jointly modelling multiple responses and the major limitations of the FO method. This study highlights the appropriateness of the approximated Fisher information matrix for multiple responses, which is implemented in PFIM 3.0, an extension of the R function PFIM dedicated to design evaluation and optimization. It also emphasizes the use of this computing tool for designing population multiple response studies, as for instance in PKPD studies or in PK studies including the modelling of the PK of a drug and its active metabolite. Copyright © 2009 John Wiley & Sons, Ltd.