Targeting PI3K/AKT/mTOR pathway in non small cell lung cancer

While PI3K/AKT/mTOR pathway is altered in a variety of cancers including non small cell lung cancer, abnormalities in this pathway are more common in squamous cell lung carcinoma than in adenocarcinoma of the lung. Moreover, aberrant activation of PI3K/AKT/mTOR pathway is one of the mechanisms of acquired resistance to EGFR-TK inhibitors in patients with adenocarcinoma carrying EGFR activating mutations.     

加味痛泻要方对家兔体外结肠平滑肌的作用

[目的]观察加味痛泻要方对家兔体外结肠平滑肌的作用。[方法]用生理记录仪记录正常及药物致痉孪肠管蠕动曲线,分别加入加味痛泻要方40、80、160 mg/ml,记录用药后兔结肠的蠕动曲线。分别计算给药前、后的抑制率和拮抗率。[结果]加味痛泻要方不仅对正常家兔结肠蠕动呈明显抑制作用,而且对平滑肌兴奋药,包括乙酰胆碱及氯化钡引起的平滑肌痉挛均有明显的对抗作用,具有剂量依赖性。[结论]加味痛泻要方可以很好地改善肠痉挛,对家兔体外结肠平滑肌的非规律性收缩有明显的缓解作用,推测该方可能是通过拮抗乙酰胆碱M受体起作用。     

Phase-I/II study to evaluate dose limiting toxicity, maximum tolerated dose, and tolerability of bendamustine HCl in pre-treated patients with B-chronic lymphocytic leukaemia (Binet stages B and C) requiring therapy

Purpose: Bendamustine hydrochloride, an anti-neoplastic agent with unique mechanism of action, is known to cause impressive remissions in relapsed nonHodgkin’s lymphoma and chronic lymphocytic leukaemia (CLL). Optimal bendamustine dosing for CLL patients had not been finally established and a phase I/II study was conducted to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of bendamustine. Methods: The open-label, single-centre phase I/II study was conducted from March 2001 to September 2002 in Sofia, Bulgaria. The 15 study patients were extendedly pre-treated, but fludarabine-naive (3 female, 12 male, 47–72 years of age, 61 years on average). Bendamustine was given at a starting dose of 100 mg/m² on days 1 and 2 every 3 weeks based on the previous results in lymphoma. Results: Bendamustine was well tolerated in spite of heavy pre-treatment of the study participants. Toxicity corresponded to the known safety profile of bendamustine, with the exception of bilirubin elevation. The level of 110 mg/m² was established as MTD. A bendamustine dose of 100 mg/m² is the recommended dose for further clinical investigations. A 4-week interval is recommended to allow for sufficient recovery. Efficacy results confirmed powerful anti-neoplastic activity of bendamustine even in extendedly pre-treated CLL patients. Based on the remission criteria, nine patients were defined as responders (four CRs, two PR, three NC) and two patients as nonresponders to therapy. Four patients were not evaluable for response, because they had received less than three courses bendamustine. After a follow-up period of 15 months, the four patients with CR were still in remission. One patient with PR had relapsed, the other had ongoing response. Conclusions: Bendamustine is a very active and well-tolerated drug in patients with pre-treated and refractory CLL. Fludarabine-naivity of patients appears to markedly improve their bendamustine tolerability. First-line use of bendamustine is a safe option for CLL-patients requiring treatment, because bendamustine—owing to its unique pharmacodynamics—(1) is highly effective, (2) reasonably safe, and (3) does hardly produce cross-resistance against other anti-neoplastic drugs effective in this indication.     

A learning method for the class imbalance problem with medical data sets

In medical data sets, data are predominately composed of “normal” samples with only a small percentage of “abnormal” ones, leading to the so-called class imbalance problems. In class imbalance problems, inputting all the data into the classifier to build up the learning model will usually lead a learning bias to the majority class. To deal with this, this paper uses a strategy which over-samples the minority class and under-samples the majority one to balance the data sets. For the majority class, this paper builds up the Gaussian type fuzzy membership function and α-cut to reduce the data size; for the minority class, we use the mega-trend diffusion membership function to generate virtual samples for the class.Furthermore, after balancing the data size of classes, this paper extends the data attribute dimension into a higher dimension space using classification related information to enhance the classification accuracy. Two medical data sets, Pima Indians’ diabetes and the BUPA liver disorders, are employed to illustrate the approach presented in this paper. The results indicate that the proposed method has better classification performance than SVM, C4.5 decision tree and two other studies.     

Adaptive dose modification for phase I clinical trials

Most phase I dose‐finding methods in oncology aim to find the maximum‐tolerated dose from a set of prespecified doses. However, in practice, because of a lack of understanding of the true dose–toxicity relationship, it is likely that none of these prespecified doses are equal or reasonably close to the true maximum‐tolerated dose. To handle this issue, we propose an adaptive dose modification (ADM) method that can be coupled with any existing dose‐finding method to adaptively modify the dose, when it is needed, during the course of dose finding. To reflect clinical practice, we divide the toxicity probability into three regions: underdosing, acceptable, and overdosing regions. We adaptively add a new dose whenever the observed data suggest that none of the investigational doses are likely to be located in the acceptable region. The new dose is estimated via a nonparametric dose–toxicity model based on local polynomial regression. The simulation study shows that ADM substantially outperforms the similar existing method. We applied ADM to a phase I cancer trial. Copyright © 2016 John Wiley & Sons, Ltd.     

SBNF肌肉注射和静脉注射给药的急性毒性试验

目的考察SBNF的急性毒性作用。方法测定其单次给药的最大耐受量（MTD）。将6周龄SPF级KM小鼠80只随机分戍4组，雌雄各半，分别按最大浓度（20mg／m1）和最大容积一次性肌肉注射（0．1ml／10g）、静脉注射（0．3ml／10g）SBNF和溶媒。密切观察14d内动物的中毒症状、外观体征和死亡情况，记录体重变化，静脉注射组进行血液常规和血清生化值的测定，所有动物均进行全身器官大体解剖及病变组织病理学检查。结果给药14d后，各组动物均存活；静脉注射SBNF组有2／20只出现上睑下垂，2d后恢复正常，其他各组动物未见任何中毒症状；第l周SBNF静脉注射组体重极显著低于SBNF肌肉注射组和溶媒组（P〈0．01），第2周SBNF静脉注射组体重显著低干SBNF肌肉注射组（P〈0．05），雌性与溶媒组差异不显著，而雄性与溶媒组差异显著；静脉注射SBNF组血红蛋白显著低于溶媒组（P〈0．05），但在正常值范围内，红细胞、白细胞、血小板及白细胞分类计数没有统计性差异；静脉注射SBNF组总蛋白显著低于溶媒组，而尿素氮显著高于溶媒组（P〈0，05），其他生化指标没有统计性差异；全身器官大体解剖均未见肉眼可见变化。结论SBNF一次性肌肉注射给药KM小鼠的最大耐受量（MTD）〉200mg／kg，SBNF一次性静脉注射给药KM小鼠的最大耐受量（MTD）〉600mg／kg；SBNF一次性静脉注射给药600mg／kg对KM小鼠的体重增长有抑制作用，对其血液学和血生化检查指标如血红蛋白、总蛋白和尿素氮也有显著影响。     

A trivariate continual reassessment method for phase I/II trials of toxicity,efficacy, and surrogate efficacy

Recently, many Bayesian methods have been developed for dose finding when simultaneously modeling both toxicity and efficacy outcomes in a blended phase I/II fashion. A further challenge arises when all the true efficacy data cannot be obtained quickly after the treatment so that surrogate markers are instead used (e.g., in cancer trials). We propose a framework to jointly model the probabilities of toxicity, efficacy, and surrogate efficacy given a particular dose. Our trivariate binary model is specified as a composition of two bivariate binary submodels. In particular, we extend the bivariate continual reassessment method (CRM), as well as utilize a particular Gumbel copula. The resulting trivariate algorithm utilizes all the available data at any given time point and can flexibly stop the trial early for either toxicity or efficacy. Our simulation studies demonstrate that our proposed method can successfully improve dosage targeting efficiency and guard against excess toxicity over a variety of true model settings and degrees of surrogacy. Copyright © 2012 John Wiley & Sons, Ltd.     

Old formula, new Rx: the journey of PHY906 as cancer adjuvant therapy

Ethnopharmacological relevance

PHY906, is a decoction of a mixture of the four herbs Scutellaria baicalensis Geori, Glycyrrhiza uralensis Fisch, Paeonia lactiflora Pall, and Ziziphus jujuba Mill. A combination of these four herbs has been in continuous use in traditional Chinese medicine for over 1800 years for treating a variety of gastrointestinal distress such as diarrhea, cramps, nausea, vomiting etc.

Aim of the study

Preclinical and clinical studies to find PHY906 enhances the therapeutic indices of a broad spectrum of anticancer agents.

Materials and methods

Using various mouse tumor xenograft and allograft models, PHY906 has been shown to enhance the chemotherapeutic efficacy of a variety of anticancer agents in various cancers. The PHY906 clinical program consists of five trials in three different types of cancers in both the United States and Taiwan. To date, approximately 150 subjects have received PHY906 in combination with chemotherapy in these five clinical studies.

Results

Preclinical studies have shown that PHY906 enhances the therapeutic indices of a broad spectrum of anticancer agents. These findings have been examined in clinical studies for colorectal, liver, and pancreatic cancers when PHY906 is used as an adjuvant to chemotherapy and the results were promising; i.e. PHY906 could reduce chemotherapy-induced toxicities and/or increase chemotherapeutic efficacy. Furthermore, PHY906 did not affect the pharmacokinetics of the chemotherapeutic agents used. Some information has been obtained regarding the mechanism of action of PHY906 in preclinical studies. A comprehensive platform, PhytomicsQC that integrates chemical and biological fingerprints together with a novel biostatistical methodology has been developed to assess the quality of different batches of PHY906.

Conclusions

Over a ten-year period, the multiplex technology “PhytomicsQC” has been used to show batch-to-batch consistency of PHY906 production. Advanced clinical trials are ongoing to demonstrate the effectiveness of PHY906 as adjuvant therapy for cancer patients undergoing chemotherapy.