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.     

A Priori Subcell Limiting Approach for the FR/CPR Method on Unstructured Meshes

A priori subcell limiting approach is developed for high-order flux reconstruction/correction procedure via reconstruction (FR/CPR) methods on two-dimensional unstructured quadrilateral meshes. Firstly, a modified indicator based on modal energy coefficients is proposed to detect troubled cells, where discontinuities exist. Then, troubled cells are decomposed into nonuniform subcells and each subcell has one solution point. A second-order finite difference shock-capturing scheme based on nonuniform nonlinear weighted (NNW) interpolation is constructed to perform the calculation on troubled cells while smooth cells are calculated by the CPR method. Numerical investigations show that the proposed subcell limiting strategy on unstructured quadrilateral meshes is robust in shock-capturing.     

Development of an IgG-Fc fusion COVID-19 subunit vaccine,AKS-452

AKS-452 is a biologically-engineered vaccine comprising an Fc fusion protein of the SARS-CoV-2 viral spike protein receptor binding domain antigen (Ag) and human IgG1 Fc (SP/RBD-Fc) in clinical development for the induction and augmentation of neutralizing IgG titers against SARS-CoV-2 viral infection to address the COVID-19 pandemic. The Fc moiety is designed to enhance immunogenicity by increasing uptake via Fc-receptors (FcγR) on Ag-presenting cells (APCs) and prolonging exposure due to neonatal Fc receptor (FcRn) recycling. AKS-452 induced approximately 20-fold greater neutralizing IgG titers in mice relative to those induced by SP/RBD without the Fc moiety and induced comparable long-term neutralizing titers with a single dose vs. two doses. To further enhance immunogenicity, AKS-452 was evaluated in formulations containing a panel of adjuvants in which the water-in-oil adjuvant, Montanide™ ISA 720, enhanced neutralizing IgG titers by approximately 7-fold after one and two doses in mice, including the neutralization of live SARS-CoV-2 virus infection of VERO-E6 cells. Furthermore, ISA 720-adjuvanted AKS-452 was immunogenic in rabbits and non-human primates (NHPs) and protected from infection and clinical symptoms with live SARS-CoV-2 virus in NHPs (USA-WA1/2020 viral strain) and the K18 human ACE2-trangenic (K18-huACE2-Tg) mouse (South African B.1.351 viral variant). These preclinical studies support the initiation of Phase I clinical studies with adjuvanted AKS-452 with the expectation that this room-temperature stable, Fc-fusion subunit vaccine can be rapidly and inexpensively manufactured to provide billions of doses per year especially in regions where the cold-chain is difficult to maintain.     

玻璃体切割联合内界膜剥除治疗糖尿病性黄斑水肿

评估玻璃体切割联合内界膜剥除对糖尿病性黄斑水肿（DME）的疗效。方法：回顾性病例对照研究。2014年6月至2017年1月间因糖尿病视网膜病变合并玻璃体积血或增殖病变于温州医科大学附属眼视光医院杭州院区行玻璃体切割手术治疗，且术前或术中经光学相干断层扫描（OCT）检查确诊合并DME的患者31例（33眼）纳入研究。16例（18眼）术中联合内界膜剥除作为剥膜组，15例（15眼）仅接受玻璃体切割手术治疗者作为对照组。所有手术均由同一医师主刀完成。术后1、3个月随访时复查OCT，对比观察黄斑中心厚度（CMT）和视力的术后变化情况。随访中CMT和最佳矫正视力（BCVA）比较采用重复测量方差分析，组间CMT和BCVA比较采用独立样本t检验。结果：手术前，手术后1、3个月2组间比较LogMAR视力总体差异有统计学意义（F=15.93，P<0.001）。术后 1个月时剥膜组BCVA高于对照组（t=2.55，P=0.02），但术后3个月时2组间差异无统计学意义（t=0.82， P=0.42）。手术前，手术后1、3个月CMT总体差异无统计学意义（F=2.85，P=0.065）。术后1、3个月时，剥膜组的CMT均低于对照组，2组间差异均有统计学意义（t=2.24，P=0.03；t=3.79，P=0.001）。术后1个月时，剥膜组有效（与术前比CMT减少20%以上）、无效（变化不超过20%）及恶化（增厚超过 20%）的例数分别为8、6、4例，术后3个月时则分别为11、5、2例，与对照组相比，术后1个月时组间差异无统计学意义（Z=-1.687，P=0.092），术后3个月时剥膜组DME改善有效比例明显高于对照组，组间差异有统计学意义（Z=-2.177，P=0.029）。结论：对于非牵拉性DME，内界膜剥除有助于术后早期DME消退。     

慢性肺心病哮喘持续状态218例临床分析

目的探索治疗慢性肺心病哮喘持续状态的方法。方法回顾性分析1983年10月～2005年3月收治的218例慢性肺心病哮喘持续状态患者的临床资料。结果哮喘持续状态在48h以内被控制的62例（28．4％）；在72h以内控制的56例（25．7％）；在120h以内控制的25例（11．5％）；在168h以内控制的34例（15．6％）；痊愈出院177例（81．2％）；死亡41例（18．8％）。结论（1）治疗慢性肺心病哮喘持续状态．根据患者的病理变化．综合治疗．效果显著。（2）在治疗过程中．要恰当选择抗生素和平喘药；对那些血液黏滞度增高的患者．要加用血液稀释疗法。（3）测定血液黏滞度和氧饱和度．可以指导治疗、估计预后．应当列为常规检查。     

Longitudinal study of the frequency of cytotoxic T cell precursors in kidney allograft recipients

Clonal deletion or inactivation of donor-specific alloreactive cells are important mechanisms that are believed to account for acquired immune tolerance in allograft recipients. Serial assessment of precursor cytotoxic T lymphocyte frequencies (CTLpf) by limiting dilution analysis (LDA) provides information at the clonal level on changes in the alloimmune response of graft recipients. We performed a longitudinal study of 15 cadaveric kidney recipients before and every 3 months throughout the first year after transplantation (Tx). Pre-Tx values of donor CTLpf showed high interindividual variability without a predictive value for the clinical outcome. All patients with well functioning kidneys had decreased CTLpf at 3 months post-Tx in comparison with pre-Tx values. This decrease was donor-specific in four patients and was permanent in two cases throughout the study. Most patients presented decreased anti-donor CTLpf values from 6 to 9 months, whereas a partial recovery of donor CTLpf was observed in three patients. Reversible acute rejection was diagnosed in three patients, and it was associated with a marked increase in anti-donor CTLpf, returning to pre-Tx values by 9 months post-Tx. In addition, one patient with chronic rejection displayed a transient increase in CTLpf 6 months after Tx. The results of this sequential study indicate the establishment of a state of either hyporesponsiveness or functional clonal inactivation, transient or permanent, which could facilitate allograft acceptance.     

分泌巨噬细胞激活因子的淋巴细胞前体细胞的定量检测研究

巨噬细胞激活因子(MAF),是致敏T淋巴细胞在抗原刺激下产生的一种淋巴因子,它能激活巨噬细胞,是参与细胞免疫效应的一种重要免疫分子。因此,当机体接受抗原刺激后,若测定淋巴组织或淋巴细胞群中该种抗原特异的分泌MAF的淋巴细胞前体细胞(MAF-P)的数目,可在一定程度上反映机体的免疫反应能力。本文试图应用     

人体β-胡萝卜素的肠转化和吸收后转化的研究

目的 :为了解部分中国人体内 β 胡萝卜素 ( β carotene ,以下简称 β C)转化维生素A (vitaminA ,以下简称VA)的效率 ,开展了本研究。方法 :使用稳定同位素稀释法对 15名 5 0 60岁健康农村志愿者 (男 9,女6)进行β C人体代谢实验。 2周适应期和 5 6天实验期内 ,志愿者接受常规膳食 ,避免大量VA和 β C摄入以及烟、酒和营养补充剂。实验第 1天 ,给受试者含 6mg氘标记 β C( 2 H8β C)玉米油胶丸 ,随半流质早餐 (脂肪热能比 2 5 % )一起摄入。实验第 4天 ,受试者以同样方法摄入含 3mg氘标记醋酸视黄醇 ( 2 H8RAC)油剂胶丸。实验第 1天和第 4天摄入标记物后 0 ,3 ,5 ,7,9,11,13h时 ,实验第 2 ,3 ,5 ,6,7,8,9,10 ,14,2 1,2 8,3 5 ,42 ,49,5 6天晨空腹时 ,采静脉血。用高效液相色谱仪 (HPLC)分离血清 β C和VA组分 ,再分别使用气相质谱仪(GC MS)和液相质谱仪 (LC MS)测定VA和 β C组分的同位素丰度。根据VA和 β C的浓度和同位素丰度 ,描述标记VA和β C在体内应答的血液动力学曲线。 结果 :所有 15名受试者对2 H8RAC应答明显 ;但是在对2 H8β C的应答方面 ,只有 11名受试者2 H4视黄醇应答曲线明显 ,有 4名受试者血清2 H4视黄醇应答曲线非常微弱。经过对备份血清样品进行的多次重复GC MS测定 ,我们目前初步?     

Subclinical pulmonary oedema and intermittent haemodialysis

It has been postulated that patients with chronic renal failure,even in the absence of cardiopulmonary symptoms, accumulateinterstitial pulmonary fluid, which is removed by haemodialysis.To test this hypothesis we used the indocyanine green (ICG)-heavywater double indicator dilution method to measure lung water,cardiac output, and central blood volume in relation to haemodialysis.Ten uraemic patients, without cardiopulmonary symptoms, wereinvestigated at the beginning and end, and 2 h after, a regulardialysis session. A group of 18 surgical patients about to undergoelective abdominal surgery served as controls. Despite normalgas exchange, central blood volume, and cardiac output at thestart of dialysis the mean (SD) lung water was significantlyhigher than in the control group [4.8 (0.9) compared with 3.6(0.7) ml/kg, P<0.001]. There was no correlation between weightgain between sessions of dialysis and the magnitude of lungwater at the start of dialysis. Lung water decreased (P <0.001)to the level of the control group in response to dialysis. Therewas no correlation between weight loss and reduction in lungwater induced by dialysis. In conclusion, we have verified thepresence of subclinical pulmonary oedema which was removed bydialysis in a group of patients with established renal failure.The variations in lung water cannot be explained by hydrostaticmechanisms alone.