RESIRT: A Phase 1 Study of Selective Internal Radiation Therapy Using Yttrium-90 Resin Microspheres in Patients With Primary Renal Cell Carcinoma

IntroductionSelective internal radiation therapy (SIRT) is a potential treatment of primary renal cell carcinoma (RCC) deemed unsuitable for conventional therapy. RESIRT is the first-in-human study to evaluate safety and feasibility of SIRT for primary RCC.Patients and MethodsPatients with RCC, unsuitable for, or who declined conventional therapy, were eligible. A single transfemoral micro-catheter administration of yttrium-90 (Y-90) resin microspheres (SIR-Spheres) was delivered super selectively via the renal artery to the tumour at intended radiation doses of 75, 100, 150, 200, 300 Gy and a final cohort with a procedural endpoint of “imminent stasis,” in a dose-escalation design. Post-SIRT follow-up was 12 months. Study endpoints included safety and toxicity 30-days and 12-months post-SIRT and tumour response (RECIST v1.1).ResultsIn total, 21 patients were enrolled, mean (SD) age was 75 (9.3) years, WHO performance status was 0 in 81%, 12 (57%) had stage 3 chronic kidney disease, and 7 (33%) had prior contralateral nephrectomy. Overall, 71% of patients completed 12 months of follow-up. Intended doses were delivered without any dose-limiting toxicity. Seventeen out of 21 (81%) patients experienced an adverse event (AE) from any cause within 30 days post-SIRT; all SIRT-related AEs were grade 1 to 2. Best overall tumour responses were partial response 1/21 (4.8%), stable disease 19/21 (90.5%) and progressive disease 1/21 (4.8%).ConclusionThis study demonstrated good tolerability of SIRT at all dose levels including “imminent stasis” in treating primary tumours in RCC patients otherwise unsuitable for conventional therapy. SIRT with Y-90 resin microspheres may be a feasible treatment option for RCC.     

Pharmacokinetics,safety and metabolite profiling of minesapride,a novel 5-HT4 receptor partial agonist,in healthy elderly and young subjects

Minesapride is a novel 5-hydroxytryptamine 4 (5-HT₄) receptor partial agonist that is expected to show efficacy in patients with irritable bowel syndrome with predominant constipation and functional constipation. An open-label study was conducted to evaluate pharmacokinetics (PK) and safety of minesapride. Japanese subjects, 12 elderly and 12 young, received a single oral dose of minesapride 40 mg/day in the fasted state. Metabolite profiles were also investigated in this clinical study and in an in vitro study using cryopreserved hepatocytes. Clinical results showed that minesapride was rapidly absorbed (C_max: 2302.1 ng/mL in the elderly group, 2117.5 ng/mL in the young group), and the plasma concentration then decreased with half-life of approximately 7 h. There were no notable PK differences between elderly and young groups. No serious adverse events (AEs) were observed. The only AE that occurred in 2 or more subjects was diarrhea. Metabolite profiles in plasma and urine were similar between elderly and young groups. No major metabolites exceeded 10% of unchanged minesapride, and results of the in vitro study suggested that there were no human-specific metabolites. From the viewpoints of PK and metabolite profiling, no dose adjustment of minesapride is warranted in elderly population without renal or hepatic impairment.     

Adverse events due to unnecessary radiation exposure in medical imaging reported in Finland

IntroductionAdverse events in radiology are quite rare, but they do occur. Radiation safety regulations and the law obligate organizations to report certain adverse events, harm and near misses, especially events related to patients' health and safety. The aim of this study was to describe and analyse incidents related to radiation safety issues reported in Finland.MethodsThe data were collected from incident reports documented by radiology personnel concerning notifications of abnormal events in medical imaging made to the Radiation and Nuclear Safety Authority between 2010 and 2017. During these eight years, 312 reports were submitted. Only events reported from radiology departments were included; nuclear medicine, radiotherapy and animal radiology cases were excluded. The final number of reports was 293 (94%).ResultsThe majority of the 293 approved reports were related to computed tomography (CT, 68.3%) and to X-ray examinations (27.6%). Altogether 82.9% of those irradiated were adults, most of whom were exposed to unnecessary radiation through CT (86.5%), 5.5% were children, and 4.4% pregnant women. The most common effective dose of unnecessary radiation was 1 mSv or less (89.7% of all examinations). The highest effective doses were reported in CT (from under 1 mSv–20 mSv and above). The reasons for the adverse events were incorrect identification (32%), incorrect procedure, site or side (30%); and human errors or errors of knowledge (20%).ConclusionAdverse events occurred especially in CT examinations. It is important to collect and analyse incident data, assess the harmful events, learn from them and aim to reduce adverse events.Implications for practiceThis study emphasizes the need for radiological personnel to obtain evidence-based information on adverse events and focus on training to improve patient safety.     

The bioavailability and nonlinear pharmacokinetics of MK-679 in humans

MK-679 (R(?)-3-((3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)(3-(dimethylamino)-3-oxopropyl)thio)methyl)thio(propanoic acid) is a potent and specific LTD₄-receptor antagonist. The disposition of MK-679 was investigated in a three-way crossover study in 12 healthy males receiving single intravenous doses of 75, 250, and 500 mg of MK-679. A greater than proportional increase in the area under the plasma concentration—time curve of MK-679 was observed with increase in dose. The plasma concentration data for each subject fitted well to the differential equations for a two-compartment model with linear tissue distribution and Michaelis-Menten elimination from the central compartment, indicating that the elimination of MK-679 in humans is saturable. In a previous study, the disposition of MK-679 in humans was also dose-dependent when given together with its S(+)-isomer, L-668,018. Thus, the disposition of MK-679 in humans is dose-dependent regardless of the presence of its stereoisomer. Also, the bioavailability of MK-679 was determined in six healthy males receiving simultaneously an oral dose of 250 mg of MK-679 and intravenous infusion of 1 mg ¹⁴C-MK-679. Results of this study indicate that the oral bioavailability of MK-679 is nearly quantitative.     

Foetal radiation dose in radiotherapy for breast cancer

Management of breast cancer during pregnancy is complicated by the high risks of abortion and foetal malformation from the use of radio therapy and chemotherapy. A case of breast cancer during pregnancy, treated with radiotherapy, and the estimated foetal dose is reported.     

Specific statistical considerations relevantto the design and analysis of gingivitis trials demonstrating

Simulation studies were conducted to address specific statistical issues which arise in the design and analysis of gingivitis studies whose principal aim is the demonstration of superiority or equivalence of one product to another. The effects of measurement scale, using differences or ratios of group means, particular statistical test produces and specific rules demonstrating superiority or equivalence were investigated. An alternative concept to equivalence—denoted “least as good”—was also defined and evaluated. For a wide class of possible distributions of gingivitis scores, characterized by specific gamma distributions, the student-t test applied to means of subject GI gingivitis scores proved to be the most powerful of the test produces considered, having statistical properties quite similar to the randomization or permutation test procedure. Transformations of subject GI mean gingivitis scores did not produce an advantage in demonstrating either superiority or equivalence, and in some cases made it more difficult. Little difference was observed in test results when using the difference in group means as compared with using the ratio of group means for demonstrating either equivalence or superiority. The clinically significant rule produced the lowest false-positive rates for products slightly better than the active control, and similar false-positive and -negative rates as the statistically significant rule for products clearly superior to the active control. Demonstration of product equivalence will require more subjects per group than demonstrating product superiority, the size of this difference being a function of the definition of superiority that is accepted. Showing that the 90% confidence interval for 100*R is completely contained within the [90%, 110%] interval is the preferred method of demonstrating equivalence today, although much more research needs to be done to improve methods for demonstrating product equivalence. The “least as good” alternative to “equivalence” makes it easier to demonstrate “equivalence” for products slightly better than the active control product, but both experience great difficulty in demonstrating equivalence for lest products not quite as good as the active control.     

阳江高本底地区居民健康流行病学调查数据库与统计分析方法

目的 研究应用计算机数据库技术及先进统计分析方法,对阳江高本底地区10多万人20余年的健康随访研究资料和剂量学调查资料进行储存、管理和分析。方法 通过调研和比较分析,确定采用Foxbase系列数据库管理系统按专题建立数据库,借助于ID号实现记录连接；一般统计分析由SAS完成；交叉分组人年列表由Epicure中的Datab完成；癌症相对危险分析用AMFIT程序。结果 建立了40MB的各专题研究库,主要包括：10余万人的人口学数据库(1979～1995)、1.2万人的死因数据库(1979～1995)和526个村庄6783户、5273人的剂量数据库。提出了动态群组研究资料(1979～1986)与固定群组研究资料(1987～1995)的合并方法：首选方法是建立假想的基于记录连接的以1979年为起点的(固定)群组。另一方法是将不同阶段群组研究的人年表分层直接相加。计算了每个成员基于卧室内、起居室内、室外村平均剂量率与性别-年龄别居留因子的累积剂量。完成了以性别、atainedage、随访年代及剂量交叉分组的人年列表,对癌症死亡资料(1979～1990)进行了危险分析。结论 应用计算机数据库管理系统与统计分析技术使阳江高本底地区研