Concurrent chemoradiation strategies in the management of unresectable stage III non-small-cell lung cancer

Locally advanced or unresectable stage III non-small-cell lung cancer (NSCLC) patients treated with combined-modality therapy with chemotherapy plus thoracic radiation have improved survival compared to those treated with radiotherapy alone. Furthermore, recent studies in good performance status, stage III patients have shown that concurrent chemoradiotherapy improves survival compared to sequential chemoradiotherapy. However, the optimal chemoradiation approach continues to evolve and is the subject of this review. Since the majority of patients completing chemoradiotherapy will succumb to distant metastatic disease, active systemic agents targeting this tumor compartment are required. Recent data suggest that full-dose chemotherapy designed to eradicate distant micrometastases given either as induction or consolidation has the potential to yield improved patient outcomes. Many of these chemotherapeutic agents are also potent radiosensitizers, hence providing enhanced local control. The integration of these chemotherapeutic agents into chemoradiotherapy programs in stage III NSCLC is the focus of current trials. Ongoing research with novel therapeutic agents with activity against distant micrometastases, refined radiation techniques, and enhanced imaging methodologies to aid in accurate staging are being pursued and should lead to improved survival and toxicity outcomes in this disease.     

Phase I pharmacodynamic study of time and sequence dependency of hydroxyurea in combination with gemcitabine: a California Cancer Consortium Trial

Preclinical studies in our laboratory have demonstrated that prior exposure to hydroxyurea increases the percentage of cells in S phase, enhancing the cytotoxicity of subsequent gemcitabine treatment in human oropharyngeal KB cells. To evaluate the clinical implications of this time- and sequence-dependent potentiation, we performed a phase I trial of hydroxyurea given over 24 h followed by a 30-min infusion of gemcitabine in weeks 1 and 2 of a 3-week cycle. The dose of hydroxyurea was fixed at 500 mg orally every 6 h for four doses starting 24 h before each dose of gemcitabine. The initial dose level of gemcitabine was 250 mg/m(2) on days 2 and 9, and this was escalated stepwise to 1000 mg/m(2) on days 2 and 9. Gemcitabine pharmacokinetics were determined on days 2 and 9 of the first cycle. Of 27 patients enrolled (12 female, 15 male), 24 were evaluable for response and 23 were evaluable for toxicity. Their median age was 56 years (range 27-76 years). Tumor types included lung, head and neck, pancreas, breast, colon, prostate, stomach, ovary, esophagus, germ cell, thyroid, gallbladder, and unknown primary. A total of 80 cycles of treatment were completed. One patient (unknown primary) had an objective partial response lasting 21 months, and 12 patients had stable disease. All observed dose-limiting toxicities were related to myelosuppression. The gemcitabine maximum tolerated dose was established at 750 mg/m(2) on days 2 and 9. Hydroxyurea had no effect on the plasma pharmacokinetics of gemcitabine. These results suggest that hydroxyurea followed by gemcitabine can be safely administered and has activity on this schedule. We are presently developing a phase II trial of this regimen for patients with platinum-resistant head and neck cancer.     

A randomized phase II trial of the matrix metalloproteinase inhibitor BMS-275291 in hormone-refractory prostate cancer patients with bone metastases.

BACKGROUND: BMS-275291 is a selective matrix metalloproteinase inhibitor (MMPI) that does not inhibit sheddases implicated in the dose-limiting arthritis of older MMPIs. We conducted a randomized phase II trial of two doses of BMS-275291 (1,200 versus 2,400 mg) in hormone-refractory prostate cancer (HRPC) patients with bone metastases to probe for a dose-response relationship and to assess differential toxicities. Serial serum and urine specimens were collected to assess for markers of bone metabolism. METHODS: The primary end point was 4-month progression-free survival (PFS). Eligibility criteria included documentation of androgen-independent disease (including anti-androgen withdrawal), skeletal metastasis, adequate end-organ function and performance status, and no more than one prior chemotherapy regimen. Patients were randomized to 1,200 mg orally once daily (arm A) or 1,200 mg orally twice daily (arm B). Response was assessed every 56 days. RESULTS: Eighty patients were enrolled: 39 in arm A and 41 in arm B. There were no responders by prostate-specific antigen or measurable disease to treatment. Stable disease was noted at 8 weeks in 39% of patients in arm A and in 17% of patients in arm B. Progression of disease at 8 weeks was seen in 61% of patients in arm A versus 83% of patients in arm B. Median survival time was 21.6 months (95% confidence interval, 17.5; not reached), whereas median PFS time was 1.8 months (95% confidence interval 1.74; 2) for all patients. Patients in arm A had a median survival time that was not reached, whereas patients on arm B has a median survival time of 21 months (P = 0.2). PFS at 4 months favored arm A: 22% versus 10% (log-rank, P = 0.008). Grade 3 toxicities occurred in 5 (13%) patients in arm A and in 9 (22%) patients in arm B. Grade 4 toxicities were uncommon (only 4% of patients): one each of thrombosis, fatigue, and motor neuropathy was seen in the arm B. Bone marker studies showed that baseline serum levels of N-telopeptide, osteocalcin, procollagen I NH2-terminal propeptide, and PICP had prognostic significance for PFS and/or overall survival. CONCLUSIONS: Regardless of dose schedule, BMS-275291 was well tolerated in HRPC patients and had no dose-limiting arthritis. Toxicities differed modestly according to the dose schedule employed. As overall survival and PFS favored the once daily schedule, this dose schedule is recommended for future studies. Baseline markers of bone metabolism may have prognostic value in HRPC patients with bone metastases.     

听性稳态反应应用于婴幼儿听力评估的现状

刺激速率为70～110 Hz的听性稳态反应(auditory steady-state response, ASSR)(亦称为80 Hz)最近倍受听力学工作者特别是小儿听力学工作者的关注,设备制造商也正在推销其产品.本文回顾了ASSR的技术、应用基础,并总结了其应用于婴幼儿听力评估的现状.文中斜体字为基本原则.详细的ASSR方法学、正常值以及一些ASSR研究结果请参阅Picton(2003)的综述.ASSR并不是一个新发现的听觉反应,1960年Geisler就从人类头颅上记录到了该反应;以后研究者又记录到了短声、正弦调制波以及方波调制波所诱发的反应.Galambos等在1981年发表的有关40 Hz事件相关电位将ASSR引入听力领域.不同刺激速率的ASSR的产生部位是不同的,40 Hz的ASSR产生于皮层和脑干,而80 Hz的ASSR主要来源于脑干,而且很有可能它就是ABR的波Ⅴ,只是与ABR的刺激和记录方法不同而已.ASSR的重要特征之一就是在频域内分析的方法,通过计算位相相关性或刺激速率值处的信噪比,再根据统计学分析来判定反应的引出与否,这种客观性使ASSR显著优于ABR.ASSR的刺激信号最早是象ABR一样的短纯音信号,以后主要用调幅调制声,有时也加入10%～20%的调频调制,目前大多数设备都采用这一信号,最近一种新ASSR设备的缺省设置是5～8 ms的短音.ASSR的另一个重要特征是能够同时记录多个刺激声信号所产生的反应,这种多频刺激的方法能够同时记录双耳八个频率(每耳四个频率)的反应.研究证明只要各个信号的频率相距一个倍频程以上,强度在75 dB SPL以下,多个刺激声之间的干扰就很小或没有.不对称型的听力图、不同频率所产生的反应幅度的不同以及多频刺激方式所导致的各个频率反应幅度整体的下降延长了这种方法的测试时间,使其不如理想中的那么省时,但仍比单一刺激方式快2～3倍.80 Hz ASSR通常采用的是正弦调幅调制纯音,因为其特有的频率特异性而被认为是优于短纯音ABR的一个方面,但是声信号的频率特异性只是其中的一方面,还应考虑到耳蜗基底膜的部位特异性以及神经反应的特异性.研究证明ASSR的频率特异性与短纯音ABR是非常接近的.ASSR技术以飞快的速度发展,十年前还没有商用的设备,五年前只有两家,而目前至少有六种不同的设备.随着设备的增加,各个设备之间标准化的问题突显出来.有些设备有很浑厚的研究背景,而有些则没有,使用者应该根据设备的性能及临床资料而加以选择.关于80 Hz ASSR与行为听力测试相关性的研究很多,多为感音神经性聋成人或较大儿童,结果表明至少在该人群中ASSR的阈值能够很好地预测行为听力阈值.许多ABR与ASSR的比较研究声称ASSR比ABR能够更好地评估残余听力,也就是当受试者听力损失很重、ABR不能引出时,仍能够引出ASSR.尽管这一现象客观存在,但是还有一些其他需要考虑的影响因素,如:①所比较的信号在某一特定频率上的能量是不相等的,众所周知短声的能量分布频率范围很宽,其最大输出强度较ASSR信号小;②ASSR在高强度会有伪迹或非听性反应;③ASSR的长时强声刺激会导致耳蜗损害.因此需慎重对待这一问题.目前还没有关于传导性聋或混合性聋气导ASSR的研究,模拟传导性聋的研究表明气导ASSR阈值远高于行为听阈,而且ASSR骨气导差过大.骨导ASSR的研究显示听力正常婴幼儿各个频率的ASSR的阈值与成人显著不同.正常听力婴幼儿的短纯音ABR阈值以及诊断标准已经确立,而ASSR在这一方面的研究则显得不足,而且不同研究所采用的刺激(单频与多频)及记录(不同信噪比、噪声标准以及记录时间)方法不同,使这一形势更加恶化.综合不同调幅调制纯音ASSR的研究结果,正常听力婴幼儿在500、1 000、2 000及4 000 Hz的平均阈值分别为41、43、35和32 dB HL,如果转换为dB SPL则与短纯音ABR非常相似.如果以均值的90%～95%为可信区间,取二倍标准差,则诊断标准在500 Hz为60 dB HL,1 000、2 000及4 000 Hz为50 dB HL.关于感音神经性聋儿童ASSR的研究有很多,这种研究比较理想的方法应该将婴幼儿的ASSR阈值与行为听阈或短纯音ABR阈值相比较.遗憾的是多数研究都是短声ABR与ASSR的比较.总结以上工作发现,首先样本数量还很少,其次多数有方法学的缺陷,加之不同研究所采用的刺激和记录方法不同,临床资料就更加减少.最后还没有不同类型听力损失的婴幼儿ASSR的研究.总而言之,尽管ASSR在婴幼儿听力评估方面很有前途,但目前单独以此作为听力诊断的电生理方法还为时过早,还必须结合短纯音ABR,因为只有短纯音ABR才具有充足的基础、临床研究和明确的诊断标准,因而也是目前婴幼儿听力诊断电生理方法的金标准.根据上述回顾,ASSR在婴幼儿听力诊断的现状总结如下:①新的刺激及记录方法通常都没有经过同行审阅的临床科研为依据,特别是缺乏听力障碍婴幼儿的数据;②不同设备采用不同的刺激和记录方法,且缺少专业人员的评估;③不同的方法或设备层出不穷,缺乏标准化;④刺激声信号的校准问题以及ASSR与行为听力之间的关系问题还没有解决,各种设备采用不同的刺激和记录方法更加恶化了这一状况;⑤极重度聋者的ABR和ASSR的关系还有待于进一步研究;⑥听力损失儿童的ASSR与行为听力测试的关系的研究还很少,而且现有的大多数研究没有能够将ASSR与听力诊断的金标准--行为听力和/或短纯音ABR进行比较;⑦六个月以下婴幼儿的ASSR 研究还很少;⑧传导性聋或混合性聋成人和婴幼儿的研究还很少;⑨成人的骨导ASSR研究很少,还没有婴幼儿骨导ASSR的研究报道,也没有病理状态下成人或婴幼儿的骨导ASSR研究(极重度聋除外).如果上述问题得不到解决,ASSR技术就不能称为成熟.因为对于一个结果,无法准确地判定该阈值是正常还是升高.短纯音ABR的研究虽然尚需完善,但它已有非常多的研究背景和临床数据,能够提供气导和骨导听阈,是当前婴幼儿(特别是6个月以下儿童)听阈确定的首选方法.因此目前ASSR还需与短纯音ABR或行为听力测试结合使用. 80 Hz ASSR除了用于阈值的评估外,也可以用于阈上功能的评估,如单词识别或助听器效果的预估.结果 表明在正常或异常听力成人以言语调制声为信号,其识别阈与ASSR有显著相关性,它反映了较低水平的听觉处理能力.     

Timing of supplementation of selenium and isoflavones determines prostate cancer risk factor reduction in rats

Drug-drug interactions have become an important issue in health care. It is now realized that many drug-drug interactions can be explained by alterations in the metabolic enzymes that are present in the liver and other extra-hepatic tissues. Many of the major pharmacokinetic interactions between drugs are due to hepatic cytochrome P450 (P450 or CYP) enzymes being affected by previous administration of other drugs. After coadministration, some drugs act as potent enzyme inducers, whereas others are inhibitors. However, reports of enzyme inhibition are very much more common. Understanding these mechanisms of enzyme inhibition or induction is extremely important in order to give appropriate multiple-drug therapies. In future, it may help to identify individuals at greatest risk of drug interactions and adverse events.     

Antibodies to tumor necrosis factor alpha prevent increases in cell replication in liver due to the potent peroxisome proliferator, WY- 14,643

Several structurally dissimilar hypolipidemic drugs, plasticizers and halogenated hydrocarbons induce peroxisomes in hepatocytes, and cause hepatocellular adenoma and carcinoma in rats and mice. The mechanism by which these agents act is unknown, although recent studies have suggested a link between increased cell proliferation and hepatic cancer caused by peroxisome proliferators. Here, we demonstrate that neutralizing antibodies to tumor necrosis factor alpha (TNF alpha) block increases in protein kinase C and cell proliferation due to [4- chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (WY-14,643), a hypolipidemic drug and potent peroxisome proliferator that causes tumors. WY-14,643 moderately elevated the level of TNF alpha mRNA in the liver. TNF alpha was detected immunohistochemically exclusively in Kupffer cells. These results demonstrate that WY-14,643 acts as an indirect mitogen on hepatocytes via TNF alpha. We propose that the Kupffer cell, a major source of TNF alpha in the liver, is involved in the mechanism of the mitogenic effect of WY-14,643.      

Computer-assisted image analysis of bronchioloalveolar carcinoma

In clinical trials, response rate is an important endpoint for assessing the efficacy of an anticancer drug. The Response Evaluation Criteria for Solid Tumors (RECIST) has been widely used as a standard method to assess response. The RECIST requires only 1-dimensional measurement of tumor size. However, bronchioloalveolar carcinoma (BAC), which commonly presents as infiltrative or micronodular lesions, is not always readily assessable by RECIST. During the past 2 years, we have been developing computer-based programs to more accurately measure tumor size on chest computed tomography (CT) scans. In a first-generation computer-assisted image analysis (CAIA) system, we were able to capture and quantify lesions on CT scans by linking the software programs of eFilm, HyperSnap, and Scion. We have applied this CAIA approach to measuring BAC response to gefitinib in the Southwest Oncology Group (S0126) trial. However, this first-generation CAIA system involves multiple manual steps and is therefore labor intensive. We are now developing a fully automated CAIA program based on a versatile software platform, ImageJ, created at the National Institutes of Health. Taking theoretical and physical considerations into account, Java plug-in programs for ImageJ are created to automatically analyze CT scans in the Digital Imaging and Communications in Medicine format. We have demonstrated the feasibility of an ImageJ-based automated CAIA program for measuring BAC bidimensionally on CT scans. This automated CAIA system will be applied in a prospective clinical trial of the GVAX vaccine in patients with BAC.