A Phase II Study of Antineoplastons A10 and AS2-1 in Children with High-Grade Glioma. Final Report (Protocol BT-06), and Review of Recent Trials

Standard treatment for high-grade glioma involves surgical resection followed by radiation therapy and temozolomide. Unfortunately, there are no standard treatment recommendations after recurrence and new therapies are needed for patients whose tumor recurs after first-line treatment. This single-arm, two-stage, interventional Phase II study evaluated the efficacy and safety of a combination of antineoplastons A10 and AS2-1. Nineteen patients were enrolled in the study (safety population), but fifteen patients with a median age of 9.4 years who met eligibility criteria were evaluated. The majority of subjects (12/15) were Caucasian and 8/15 (53%) were female. More than half (53%) of patients were diagnosed with glioblastoma and 33% with anaplastic astrocytoma. All patients had failed standard therapy including surgery, radiation, and chemotherapy. Antineoplastons were administered intravenously every four hours (median dose of A10 6.9 g/kg/d and AS2-1 0.30 g/kg/d) until objective response was documented and thereafter for a further 8 months. Clinical evaluations were performed every 8 weeks. All patients enrolled in the study were included in the safety analysis but only patients fulfilling the inclusion criteria were included in the efficacy evaluation. The duration of treatment with antineoplastons ranged from 2 weeks to 120 weeks. A complete response was documented in 2/15 (13%), partial response in 2/15 (13%), stable disease in 3/15 (20%). Progression-free survival at six months was 47% and overall survival (OS) at one year was 33.3%. One patient (6.7%) survived 10 years from treatment start. A small group of patients suffered reversible Grade 3 and 4 toxicities including hypernatremia 2/19 (11%) and decrease of neutrophils 1/19 (5%). There were no chronic toxicities. There was improvement of quality of life in patients who had objective response. It is concluded that antineoplastons show efficacy with an acceptable profile in this cohort of patients with recurrent high-grade glioma.

Safety and efficacy of intraperitoneal perfusion with tumor vesicle-encapsulated methotrexate for the treatment of cancerous ascites - an open, randomized and controlled clinical trial

Background:Cancerous ascites is a common and severe complication that occurs in patients with late-stage malignant tumors.The prognosis of cancerous ascites is poor,clinical treatment is difficult and therapeutic outcome is disappointing.In the present study,tumor cell-derived vesicles were used as drug delivery vehicles that encapsulated a chemotherapeutic agent and were perfused into a patients’abdominal cavity to effectively kill the cancer cells in cancerous ascites.Pre-clinical data has demonstrated that tumor vesicles that carry low-dose chemotherapeutics can efficiently eliminate metastatic tumor cells in the abdominal cavity with minimal toxic or adverse effects.When combined,tumor cell-derived vesicles can sensitize tumor cells,which facilitates the entry of chemotherapeutics into tumor cells,thereby enhancing killing of tumor cells and limiting the risk of drug resistance.In this study,we designed a clinical trial to evaluate the safety and efficacy of intraperitoneal perfusion with tumor vesicle-encapsulated methotrexate for the treatment of cancerous ascites.Methods:Sixty patients with cancerous ascites were enrolled in this open,randomized and controlled clinical trial.Participants were randomly assigned a visit number and,according to their visiting order for which a random numerical table was used,were assigned to the trial group or the control group in a 1:1 ratio.The change in ascetic volume was used as the study outcome and adverse events were monitored during the entire length of the study.Conclusion:In this clinical trial,randomization and electronic case report forms were implemented.The trial indicated that tumor vesicle-encapsulated methotrexate was proposed to be a safe and effective method for treating malignant ascites.Our study may provide at the first time evidence for the clinical application of tumor vesicles in tumor therapy.

Injected spectrum for TeV γ-ray emission from the galactic center

The detection of very high energy γ-ray emission from the Galactic center has been reported by four independent groups. One of these γ-ray sources, the 10 TeV -γ-ray radiation reported by HESS, has been suggested as having a hadronic origin when relativistic protons are injected into and interact with the dense ambient gas. Assuming that such relativistic protons required by the hadronic model come from the tidal disruption of a star by the massive black hole of Sgr A＊, we explore the spectrum of the relativis- tic protons. In the calculations, we investigate cases where different types of stars are tidally disrupted by the black hole of Sgr A＊, and we consider that different diffusion mechanisms are used for the propagation of protons. The initial energy distribution of the injected spectrum of protons is assumed to follow a power-law with an exponential cut-off, and we derive the different indices of the injected spectra for the tidal disruption of different types of stars. For the best fit to the spectrum of photons detected by HESS, the spectral index of the injected relativistic protons is about 2.05 when a red giant is tidally disrupted by the black hole of Sgr A＊ and the diffusion mechanism is the Effective Confinement of Protons.

GRAPHICAL COMPUTING METHOD ON FOUR-BAR LINKAGE(1)——Inflexion Circle,Focal Axis,Ball's Point,Centering-point Curve and Circling-point Curve For Four ISPs,Coupler Curves Based on Ball's Points——

By means of programs GTMPAC based- on generalized triangle method,analysis and synthesis of mechanism design in accordance with absolutely graphicalmethod( absolutely germetrical method) are developed.In this paper,we make aspecial study about centering- point curve and circling- point curve and couplercurves based on Ball’s points.

审判中心内涵再讨论--基于理论、制度及实践视角

国内法学界对于审判中心这一范畴的理论阐释存在理论逻辑不清晰的缺陷,对审判中心内涵的理论阐释既不深入、也不系统,对于审判中心这一范畴的理论内涵的探讨陷入了方法论立场上的实用主义。审判中心在理论层面称为审判中心主义,主要指以居中裁判职能发挥作用为指引的反映刑事诉讼程序纵向结构和横向结构规律的程序结构思想。制度层面的审判中心称为以审判为中心,即保证庭审在查明事实、认定证据、保护诉权、公正裁判中发挥决定性作用。实践层面的审判中心称为庭审实质化,主要是保障判决基础来源于法庭。

审判中心语境下刑事二审的问题研判与路径优化--以Z市中级人民法院近5年二审庭审运行实践为分析样本

作为我国刑事司法改革顶层设计的“审判中心”制度,尽管在内涵界定上尚未形成统一认识,但其通过庭审实质化实现对案件事实与法律适用的精准掌控,从而维护被追诉人合法权利成为学界共识。然而,我国当前较低的二审开庭率相对弱化了被追诉人的辩护权。不少国家已确立了二审开庭原则,这种将法律审与事实审相结合的庭审实质化方式,具有一定的借鉴价值。鉴于此,我国有必要对刑事二审庭审程序进行优化:宏观方面--确立以审判为中心的诉讼原则;中观方面--建立二审“以开庭为原则,以不开庭为例外”的制度;微观方面--制定二审开庭的具体措施。

监察案件中非法证据排除规则适用实证研究--以贪污贿赂和渎职犯罪为视角

通过对136份申请排除非法证据的监察案件刑事裁判文书分析后发现,申请人申请排除的主要是被调查人供述,申请排除被调查人供述的主要原因是被刑讯逼供或采用威胁、引诱、欺骗等非法方式取证,审判机关在监察案件中对“相关线索或者材料”的认定总体上比较严苛,决定排除非法证据的比例较低。非法证据排除规则在监察案件中的适用,存在着非法证据认定标准被不当提升、非法证据排除调查程序启动困难、非法证据排除的庭审程序流于形式等问题。为确保非法证据排除规则在监察案件中的有效适用,应当继续推进以审判为中心的诉讼制度改革,完善监察非法证据的认定标准,并合理设定辩方提供相关线索或者材料要求的内涵。

响应面法优化秸秆发酵产β-葡萄糖苷酶的研究

为了高效利用废弃的农作物秸秆,优化康氏木霉固态发酵秸秆生产β-葡萄糖苷酶的发酵参数,首先利用Plackett-Burman试验,对影响生产β-葡萄糖苷酶的参数麸皮添加量、(NH4)2SO4添加量、培养温度、培养时间、料水比、装料比、浸提液p H值进行了主要影响因子的筛选;然后再利用Center Composite Design响应面分析对产酶参数进行了优化。结果表明:培养温度和培养时间是影响固态发酵生产β-葡萄糖苷酶的主要因素;经CCD优化后,得到产酶最适条件为培养时间6.6 d、培养温度27℃,该条件下β-葡萄糖苷酶活性为77.68 IU/m L。验证试验证实,预测回归方程的预测值与试验值之间具有较高的拟合度。本研究结果可为农业秸秆资源的再利用和纤维素酶的工业化生产提供科学依据。

KCl-KBr∶OH^-混合晶体中的(F_2^+)H心研究

Tunable color center lasers making use of electron trapping defects such as F A and F + 2 like centers in alkali halide crystals can deliver broadly tunable power over the near infrared 0.8—4.0μm range.The tunable range and their impressive feature of narrow linewidth make these solid state lasers important to molecular spectroscopy,pollution detection,fiber optics communication and other scientific research fields.The( F + 2) H center consisting of an F + 2 center and an neibouring O 2- ion,is one of the most important color centers.In this paper,we will study the preparation,absorption and emission spectra of the ( F + 2) H center in mixed crystal KCl KBr∶OH -. Single crystals of KCl,KBr and different compositions of KCl x Br 1-x solid solutions are growtn with 0.1mol%—0.3mol% KOH in the melt by the Czochralski technique in air.

A Phase II Study of Antineoplastons A10 and AS2-1 in Adult Patients with Recurrent Glioblastoma Multiforme: Final Report (Protocol BT-21)

Treatment of recurrent glioblastoma multiforme (RGBM) creates one of the most difficult challenges to neuro-oncology. The purpose of this study is to evaluate the outcome of adults with high-grade glioma with special attention to RGBM patients treated with Antineoplastons (ANP) A10 and AS2-1 injections. The study was conducted according to Protocol BT-21, which accrued patients who failed standard radiation therapy (RT) and chemotherapy. There were 40 candidates registered in the study. Among the intent-to-treat (ITT) population, there were 30 cases of RGBM that progressed during and after prior treatment, 4 patients with anaplastic astrocytoma (AA), 1 with anaplastic mixed glioma (AMG), and 5 with persistent GBM. The aim of this paper is to evaluate the responses, survival and toxicity of all 40 patients, the efficacy in 30 patients with RGBM, and in 24 patients with RGBM who received at least 28 days of ANP (ERGBM). All RGBM patients were treated before with RT and chemotherapy, except one patient who only had surgery (patient refused radiation). In this group, 63% had one recurrence, 30% had two recurrences, and 7% had three recurrences. The median duration of ANP and ITT was 12 weeks and the median dosage of ANP A10 was 6.52 g/kg/d and ANP AS2-1 was 0.23 g/kg/d. Responses were assessed by gadolinium-enhanced magnetic resonance imaging (MRI) repeated every eight weeks. In the ITT population, objective responses (ORs) were determined in 10% of cases (complete response—CR, and partial response—PR in 5% each). Progression-free survival (PFS) in ITT at six months was 17.5%. Overall survival (OS) was 28.3% at one year, 2.6% at two years, five and ten years. In the RGBM population, objective responses (ORs) were determined in 13.3% of cases (CR and PR in 6.7% each). PFS in RGBM at six months was 16.7%. OS was 34.7% at one year, 3.47% at two years, five?and ten years. In the ERGBM population, ORs were determined in 16.7% of cases (CR and PR in?8.3% each). PFS in ERGBM at six months was 20.8%, OS was 39.3% at one year, 4.4% at two years, five and ten years. The treatment was well-tolerated with reversible Grades 3 and 4 toxicity in 17.5% of patients (7 patients who experienced multiple toxicities) and no chronic toxicity. In conclusion, the study reached efficacy endpoint. ANP is well-tolerated and compares favorably to the current treatment for RGBM.

A Phase II Study of Antineoplastons A10 and AS2-1 in Children with Recurrent, Refractory or Progressive Primary Brain Tumors—Final Report (Protocol BT-22)

Primary malignant brain tumors are a leading cause of cancer-related death in children. This Phase II study evaluated the efficacy and safety of Antineoplastons A10 and AS2-1 (ANP) in children who developed progression during standard treatment. A total of 43 children were recruited to the study, but only 41 met eligibility criteria. There were twelve cases of glioblastoma multiforme (GBM), eight anaplastic astrocytomas (AA), twelve diffuse intrinsic pontine gliomas (DIPG), three supertentorial primitive neuroectodermal tumors (sPNET), three cases of medulloblastoma and one case each of anaplastic ependymoma (AE), atypical teratoid rhabdoid tumor (AT/RT), and disseminated pilocytic astrocytoma (PAD). ANP was administered intravenously daily every four hours (median dose of A10 8.74 g/kg/d and AS2-1 0.35 g/kg/d), until objective response (OR) was documented, and then a further eight months. All enrolled patients were included in safety, but only eligible patients in the efficacy evaluation. A total of 12.2% of patients obtained OR;2.4% complete response (CR) and 9.8% partial response (PR). Stable disease (SD) was determined in 17.1% and progressive disease (PD) in 43.9% of cases. There were 26.8% of nonevaluable (NE) cases due to premature discontinuation. Out of five OR cases, four patients were diagnosed with recurrent DIPG and one with recurrent AA. Median progression-free survival (PFS) was 2.5 months. Median overall survival was 4.8 months. OS at 6 months was 46.3%, one year was 12.2%, and 4.8% at two, five, and ten years. The longest survivor is a patient diagnosed with DIPG and gliosarcoma who remains alive more than 15 years. A group of eleven patients reported grade 3 and 4 toxicity including hypernatremia in eight cases, somnolence in two cases, and hypokalemia in one case. There were no chronic toxicities, and the quality of life was very good. The largest group of patients were represented by DIPG, GBM, and AA. The best results were obtained in the DIPG and AA groups. In the DIPG group, CR was in 8.3%, PR was 25%, median PFS was 4.8 months, median OS was 6.1 months, and OS at 6 months was 58.3%, at one year 25%, and 8.3% at two, five, and ten years. In the AA group, PR was 12.5%, median PFS was 3.7 months, median OS was 4.7 months, and OS at 6 months was 37.5%, and 12.5%, at one, two, five, and ten years. In conclusion, antineoplastons showed efficacy and acceptable toxicity in patients with recurrent, refractory or progressive primary brain tumors.

Optimization Design for Fixed Table of Gantry Machining Center Based on Sensitivity and Topology Analyses

In order to decrease the deformation and stress and increase the natural frequency of the fixed table,a method of optimization driven by the sensitivity and topology analyses is proposed.The finite element model of the fixed table is constructed and analyzed by using ANSYS software.Based on the results of static analysis and modal analysis,the maximum deformation,the maximum stress,and natural frequencies are obtained.Then,the sensitivity analysis and topology optimization are carried out to find out the parameters to be optimized.The fixed table is reconstructed according to optimal design scheme.In the comparison of the results between original model and the optimized one,the maximum deformation and stress are decreased by 71.73%and 60.27%respectively.At the same time,the natural frequencies from the first mode to the sixth mode are increased by 30.28%,29.57%,29.51%,31.52%,22.19%,and 21.80%,respectively.The method can provide technology guide for the design and optimization of machining structure.

A Phase II Study of Antineoplastons A10 and AS2-1 in Patients with Brainstem Gliomas. The Report on Non-Diffuse Intrinsic Pontine Glioma (Protocol BT-11)

Inoperable brainstem gliomas (BSG) are among the most difficult to treat malignancies. In the intent-to-treat (ITT) population of the BT-11 study for BSG, forty patients (median age 11.2 years old) were enrolled. Antineoplastons A10 and AS2-1 (ANP) were administered intravenously daily. The median daily dose of A10 was 8.70 g/kg/day and AS2-1 was 0.32 g/kg/day. Efficacy analyses were conducted in two subgroups: recurrent pediatric diffuse intrinsic pontine glioma (RPDIPG, N?= 17) and non-diffuse intrinsic pontine glioma (NDIPG, N?= 11). This paper reports the results of the study of the efficacy and safety of ANP in patients with NDIPG. The results in the RPDIPG group were reported before;complete response (CR) was 6%, partial response (PR) 23.5%, and stable disease (SD) 17.6%. One year overall survival (OS) was 29.4%, 2 years 11.8%, and 5, 10, and 15 years 6%. In the NDIPG group, there were 36% CR and 27.5% SD. OS at 1, 5, 10, and 15 years was 82%, 73%, 62%, and 50% correspondingly. There was only one serious adverse event (9%) reported in NDIPG represented by hypokalemia, Grade 4. The results suggest that ANP shows efficacy and an acceptable tolerability profile in patients with RPDIPG and NDIPG.

Recurrent Glioblastoma Multiforme—A Strategy for Long-Term Survival

Recurrent GBM (RGBM) has a highly unfavorable prognosis with majority of patients dying within 6 months and no standard treatments available. Antineoplaston (ANP) A10 and AS2-1 injections underwent Phase II trials in RGBM patients, which reported a long-term overall survival (OS) in a small percentage of patients. The additional Phase II studies BT-07, and BT-21 with ANP in GBM also revealed cases of a long-term OS. ANP shares active ingredients with metabolites of sodium phenylbutyrate (PB), which was used in private practice setting in combination of targeted and chemotherapeutic agents for the treatment of RGBM. The treatment contributed to cases of rapid complete response (CR) and significant OS. This paper provides case studies of three patients treated with ANP under Phase II protocols and two patients treated with PB in combination with targeted therapy, who obtained CR and long-term OS. Based on these studies and basic research on the effects of ANP and PB on the genome of GBM and review of results of preclinical and clinical research on targeted agents, the authors suggest a new strategy for successful treatment of RGBM. They propose Phase I/II clinical trials with ANP and PB in combination with targeted agents, bevacizumab (BVZ), pazopanib, dasatinib and everolimus in patients with RGBM after failure of standard surgery, radiation therapy (RT) and chemotherapy including temozolomide (TMZ) to be conducted to evaluate survival, response and toxicity in these patients.

知识产权案例指导制度实践样本--北京知识产权法院庭审实质化诉讼改革

最高人民法院在北京知识产权法院设立基地,建立中国特色的知识产权案例指导制度(或称判例制),已经取得较高的学术共识。该制度的建立,需要解决外部社会条件或体制条件,以及司法先例制度本身建设两大基础性问题。北京知识产权法院在审判权运行机制改革基础上,推行以"诉、审、判一致性"为核心的诉讼制度改革,解决了以法官独立审判为核心的司法体制条件问题和判例制度自身建设的审判程序问题,探索了一条以形式正义约束和保障实质正义、矫正司法恣意的中国判例之路。

以审判为中心背景下,认罪认罚从宽制度中控审关系的透析--以余金平案为视角

余金平案引发了诸多争议,在案件的背后是紧张的控审关系。余金平案中检察院与法院对量刑权争夺,检察机关偏离了所具有的中立客观性。立法一方面对适用认罪认罚的案件没有限制适用范围,另一方面规定对于认罪认罚的案件,法院一般应当采纳检察机关的量刑建议,检察机关几乎具备了“准审判”的功能。对于认罪认罚制度中控审关系的优化完善,法院应当实质性行使审判权。一方面无论审判程序如何简化,法官都要进行实质审查;另一方面,无论是否适用速裁程序,法庭都应当开庭审理。鉴于检察官提出确定刑量刑能力有所不足,应当对案件予以区分,将重罪与轻罪区别开以及明确从宽幅度。

A Phase II Study of Antineoplastons A10 and AS2-1 in Children with Low-Grade Astrocytomas—Final Report (Protocol BT-13)

Nonresectable Low-Grade Astrocytomas (LGA) can compromise function and threaten life. For the majority of patients, the most appropriate strategy is initial chemotherapy followed by Radiation Therapy (RT). Since curative treatment is not available for most of these patients, it is reasonable to conduct clinical studies to evaluate new agents. This Phase II study evaluates efficacy and safety of Antineoplastons A10 and AS2-1 (ANP) in LGA. Sixteen children diagnosed with LGA were treated. They included 12 males and 4 females, ages 1.6 - 17.4 years (median 10.6). Efficacy was evaluated in 16 patients. The majority of patients were previously treated, but 1 patient had stereotactic biopsy only. Out of the remaining 15 patients, 6 patients received chemotherapy, and 7 patients had surgery, and 2 patients received RT and chemotherapy after surgery. The patients received treatment with ANP administered daily every 4 hours (median dose of A10 was 7.71 g/kg/d and AS2-1 was 0.26 g/kg/d) until objective response or stable disease was documented and for 8 months thereafter. The duration of ANP IV ranged from 1.4 to 286 weeks with a median of 83 weeks. A complete response was documented in 25.0%, partial response in 12.5%, and stable disease in 37.5%. Overall survival was 67.7% at 5 years, and 54.2% at 10 and 15 years. Progression-free survival was 48.1%, 34.4% and 34.4% at 5, 10, and 15 years respectively. The treatment was associated with grade 3 or grade 4 Adverse Drug Experiences (ADE) in 6 patients. There were two hypernatremias of grade 4 (12%). Grade 3 ADE included urinary frequency (6%), fatigue (6%) and hypernatremia (6%). There were no chronic toxicities, and there was a high quality of survival. ANP shows efficacy with a very good toxicity profile in this cohort of children with low-grade astrocytoma.

关于《刑事诉讼法》第四次修改的几点思考

近日,刑事诉讼法的第四次修改提上日程。学界对本次修改整体上较为积极,也有部分观点对修改存有隐忧。从整体上看,启动第四次刑事诉讼法修改有其必要性和重要的时代价值,应当抓住此次难得时机,同时,也要对实践中重打击轻保护的氛围保持高度警惕,牢牢把握人权保障和正当程序的目标和方向。刑事诉讼法第四次修改应当将刑事诉讼法典实质化作为目标,采取大修的立法模式,立足当下,着眼长远,系统规划,分步实施,迈出刑事诉讼法典实质化的关键一步。刑事诉讼法修改也要设定改革的亮点,这些亮点可以包括但不限于:重塑刑事诉讼法的篇章体例、以技术主义路径推进以审判为中心和庭审实质化、因应轻罪时代扩大附条件不起诉的适用范围、探索构建律师无效辩护制度、重塑强制措施体系、构建相对独立的涉案财物处置程序、完善证据制度等。

A Phase II Study of Antineoplastons A10 and AS2-1 in Adult Patients with Primary Brain Tumors—Final Report (Protocol BT-09)

Antineoplastons A10 and AS2-1 (ANP) are synthetic derivatives of glutamine, isoglutamine, and phenylacetic acid. In 1993, a phase II clinical trial program began according to protocols based on the initial protocol, BT-06, which was transferred from the National Institutes of Health (NIH). Protocol BT-09 was designed for different types of primary brain tumors in adults that were not curable by standard treatment. The study was designed as a single arm, two-stage, phase II trial of ANP as a monotherapy in a high-risk, poor-prognosis population. The total number of registered subjects was 40. The majority of patients were diagnosed with high-grade tumors (N = 33). In this group, 12 patients carried diagnosis of anaplastic astrocytoma (AA) and 11 patients of glioblastoma. In the group of low-grade tumors (N = 7), there were 6 cases of low-grade glioma, and 1 neurocytoma grade 2. A group of 12 patients did not receive any prior treatment, 12 patients had surgical resection only, 5 patients received radiation therapy (RT) only, and 11 patients received both RT and chemotherapy. The median duration of ANP was 16.6 weeks. The median dosage of A10 was 7.16 g/kg/d and AS2-1 was 0.27 g/kg/d. Responses were accessed by gadolinium-enhanced magnetic resonance imaging (MRI). Objective responses (OR) in all patients were 22.5% and in the AA group were 41.7% of patients. The median progression-free survival (PFS) in the AA group was 5.4 months. The median overall survival (OS) was 12.7 months and OS at 1 and 2 years was 54.5% and 45.5% correspondingly. The treatment was well-tolerated with reversible grade 3 and 4 toxicities in 35% of all patients (N = 40). In conclusion, the study reached efficacy endpoint and ANP was well-tolerated and compared favorably to the current treatment of AA.