Indium-111 octreotide scintigraphy in patients with bone tumours of the extremities

Radiolabelled somatostatin analogues are of potential value in the imaging of somatostatin receptor-positive tumours. Recently, somatostatin receptors have been demonstrated in the osteoblast precursor cells. In this preliminary study, we evaluated the uptake characteristics of indium-111 octreotide in two benign and two malignant bone tumours. Tracer accumulation was observed in all four cases, and overall lesion to background ratio (mean±SD) was 2.74±0.84 and 2.98±1.49 at 4 h and 24 h, respectively. There was no clear relationship between I¹¹¹In-octreotide accumulation and the benign or malignant nature of the tumour. In one patient, tracer uptake was inhibited by unlabelled octreotide administration. These results suggest that¹¹¹In-octreotide can be taken up by benign and malignant bone tumours. The inhibition of tumour uptake by treatment with cold octreotide supports the concept that specific uptake mechanisms are responsible for¹¹¹In-octreotide deposition by bone tumours.     

Indium-111 pentetreotide in the diagnostic work-up of patients with bronchogenic carcinoma

In a prospective study we examined 38 patients with primary bronchogenic carcinoma to validate the use of indium- I 11 pentetreotide (IPT) as a diagnostic tool. Of these 38 patients, 25 had small cell lung cancer (SCLC) and 13, non-small cell lung cancer (NSCLC). The aim of the study was to investigate whether (a) the disease can be reliably detected, (b) IPT allows differentiation between SCLC and NSCLC and (c) IPT provides further information on metastatic disease. After giving their informed consent the patients were injected and imaged 4 and 24 h later using a planar whole-body technique. In addition single-photon emission tomography of the thorax and, if necessary, other areas of the body was performed at 24 h. In the 25 patients with SCLC 22 sites of primary tumour were correctly identified (true-positive, TP); one was false-negative (FN) and two were true-negative (TN), the patients being in full remission. Metastases were correctly identified in ten instances (lung,bone and brain), while the findings were FN in five cases. An additional six FN findings resulted in the area of the upper abdomen due to the physiological uptake in the liver, spleen and kidneys. In the 13 patients with NSCLC, ten findings were TP and 3 FN with respect to the primary tumour. Two FN_s were squamous cell carcinoma, and one, adenocarcinoma. Metastases were TP in nine cases and FN in one. We therefore conclude: (1) IPT is a highly sensitive method for the detection of primary bronchogenic carcinoma, and in particular for SCLC, (2) differentiation between SCLC and NSCLC cannot be achieved and (3) the method is of limited use in the search for metastatic disease. Compared with the conventional imaging modalities like X-ray, CT and bone scintigraphy, IPT provides only a small amount of additional diagnostic information.     

Myocardial uptake of <Superscript>99m</Superscript>Tc-annexin-V and <Superscript>111</Superscript>In-antimyosin-antibodies after ischemia-reperfusion in rats

Objectives Phosphatidylserin exposure on cell surfaces occurs early during apoptosis and is detected in vivo by using ^99mTc-annexin-V (ANX). Cardiomyocyte membrane disruption is detected in vivo by using ¹¹¹In-antimyosin-antibodies (AM). We aimed to determine if ANX and AM allow evaluation of the time-course of these two distinct cell death events after myocardial ischemia-reperfusion. Methods Coronary tying (20 min) followed by reperfusion (IR) was performed in 31 rats. Twelve of the rats were injected with ANX, 11 with AM, and eight with both tracers. Myocardial uptake of tracers was studied 1–2 h, 4 h, or 24 h after IR by scintigraphy (ANX, n = 14) and autoradiography (all cases), and compared to histology and Apostain staining. Results Scintigraphy was positive in all rats 2 h after IR and in three of five rats at 24 h. On autoradiography, ANX activity was intense in myocardial lesions as early as 1 h post-IR, whereas AM activity was mild at 2 h then increased at 4 h post-IR. ANX and AM uptakes evolved from mid-myocardium to endocardial and epicardial regions from 2 h to 24 h post-IR. Apostain staining was significant in myocardial lesions (p < 10⁶ compared to six sham-operated rats). On histology, myocardial lesion was characterized by interstitial oedema, myocytes necrosis, and dramatic thinning at 24 h. Conclusion These data suggest that ANX and AM allow temporal and regional evaluations of PS exposure and membrane disruption, respectively, during myocytes death after 20-min myocardial ischemia followed by reperfusion. Also, (i) apoptosis starts very early in injured myocardium, (ii) myocyte necrosis occurs later (3–4 h post-reperfusion), and (iii) most dead cells are removed from mid-myocardium between 6 h and 24 h after reperfusion.     

核素分子显像监测胚胎干细胞及诱导性多潜能干细胞移植的研究进展

胚胎干细胞（ESCs）具有分化成多种细胞的能力,而由转录因子转染体细胞获得的诱导性多潜能干细胞（iPSCs）具有与ESCs相似的生物学特性,且不涉及伦理学相关问题,在干细胞治疗领域得到广泛的应用.近年来,干细胞移植治疗的分子影像学监测得到了快速发展,并取得了显著的成果.该文仅就核素分子显像监测ESCs及iPSCs移植的研究进展进行综述.     

大鼠骨髓多能成体祖细胞转化为皮肤组织细胞的在体研究

目的 观察大鼠骨髓多能成体祖细胞(mulipotent adult progenitor cells,MAPCs)是否可在体向皮肤组织细胞分化.方法 采用免疫磁性分选技术(MACS)获取MAPCs;通过皮肤受损的C57BL/6小鼠与免疫缺陷性裸鼠的尾静脉注入MAPCs,免疫组织化学技术检测愈合皮肤中大鼠MHC I类抗原的表达.结果 MHC I抗原在C57BL/6小鼠愈合皮肤处的毛囊皮脂腺周围及毛囊外根鞘与皮脂腺交界处均有阳性表达细胞;裸鼠实验组愈合皮肤内出现毛囊样结构,在表皮基底部及部分毛囊样结构中有MHC I抗原阳性表达的细胞.结论 在皮肤组织损伤的条件下,MAPCs可迁移至受损皮肤表面及皮肤附属器毛囊周围,并通过转化为表皮细胞参与受损皮肤的愈合.     

Real-time in vivo monitoring of viable stem cells implanted on biocompatible scaffolds

Purpose  Three-dimensional fibrous scaffolds provide an environment that enhances transplanted stem cell survival in vivo and facilitates imaging their localization, viability, and growth in vivo. To assess transplanted stem cell viability on biocompatible polymer scaffolds in vivo, we developed in vivo imaging systems for evaluation of implanted viable neural stem cells (NSC) and mesenchymal stem cells (MSC) on scaffolds using luciferase or sodium/iodide symporter (NIS) genes. Methods  Firefly luciferase stably expressing-C6 cell was established (C6-Fluc). The human neural stem cell, F3, was infected with adenoviral vector carrying luciferase gene (F3-Fluc) and MSC expressing NIS controlled by ubiquitin C promoter using lentiviral vector was established by treating blasticidine for 2 weeks (MSC-NIS). Chitosan and poly l-lactic acid (PLLA) scaffolds were used for in vivo image. In vivo expression of luciferase and human NIS was examined by bioluminescence image or ^99mTc-pertechnetate gamma camera image, respectively. The cell/scaffold complex was implanted into subcutaneous or abdominal area of BALB/C nude mouse. For quantitative evaluation of cell viability, regions of interest were drawn on ^99mTc-pertechnetate scintigraphy by manual. Results  The gradual increase of luciferase activity was observed in C6-Fluc seeded with chitosan according to the increase in the number of cells. C6-Fluc/chitosan complex subcutaneously implanted into nude mice showed longitudinal bioluminescence image until 34 days. Luciferase image of abdominal-injected C6-Fluc/PLLA complex was saturated in only 14 days, showing great cell growth due to abundant nutrients. F3 cells showed well-incorporated pattern with fibrous chitosan scaffold using scanning electron microscopy. F3 infected with Ad-Fluc showed >100-fold higher luciferase activity than luciferase activity in F3. Cell-number-dependent increase of luciferase activity was shown in F3-Fluc seeded on chitosan. F3-Fluc incorporation into chitosan after abdominal injection was clearly visible on bioluminescence image up to 11 days. Radionuclide imaging showed higher uptake by MSC-NIS on PLLA scaffolds than by MSC-NIS not seeded on a scaffold. Quantitative data showed significantly better survival of MSC-NIS on PLLA scaffolds than without scaffold at 72 h post-implantation, which concurred with histologic findings. Conclusion  These results suggest that NSC-Fluc and MSC-NIS cells incorporated within polymer scaffolds can be monitored on a long-term basis by serial in vivo imaging. We believe that a biocompatible scaffold-based imaging system could be used to assess stem cell viabilities in a non-invasive way to aid the development of regenerative therapeutics. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. Soonhag Kim and Dong Soo Lee contributed equally to this investigation as corresponding authors and Do Won Hwang and Sung June Jang equally contributed as co-first author.     

Comparison of simultaneous 99mTc-HMPAO and 111In oxine labelled white cell scans in the assessment of inflammatory bowel disease

Forty-seven patients, 29 with chronic inflammatory bowel disease (1131) and 18 with presumed irritable bowel syndrome, including one with uncomplicated diverticular disease, were studied with simultaneous technetium-99m hexamethylpropylene amine oxime and indium-111 oxine labelled leucocyte scans performed at 1, 3 and 24 h. Twenty-seven patients with IBD had active disease as judged by clinical and laboratory criteria and all of these had positive scans with both agents. No false positive studies were obtained. The 1-h ^99mTc-HMPAO WBC scans showed the same distribution to disease as the 3-h ¹¹¹-In WBC scans, with no difference in intensity (P < 0.92); they showed more extensive disease (P < 0.02) and more intense uptake (P < 0.001) than did the 1-h ¹¹¹-In scans. The 3-h ^99mTc-HMPAO WBC scans showed more extensive disease (P < 0.002), with greater intensity (P < 0.0005), than did the 3-h ¹¹¹In WBC scans. Physiological bowel activity on 3-h ^99mTc-HMPAO WBC scans was present in 12 patients but was faint and did not interfere with assessment of disease extent and activity. It is concluded that in terms of isotope availability, radiation dosimetry and image quality, ^99mTc-HMPAO is the agent of choice in detecting active IBD, with localization of disease possible at 1-h after re-injection and optimal resolution and definition of disease extent at 3 h. A negative scan reliably excludes active disease. Correspondence to: R.A. Allan     

自体神经干细胞移植后功能恢复的影像学评价

目的　用1 8F 脱氧葡萄糖 (FDG)PET显像、功能磁共振 (fMRI)和扩展格拉斯哥愈后评分(GOSE)评价成人脑外伤自体神经干细胞移植后功能的恢复。方法　从开放性脑外伤患者中挑选 7例进行神经干细胞移植 ,同时选择 7例年龄相仿、损伤部位及程度一致的患者作为对照。收集暴露于硬膜外的脑组织 ,进行神经干细胞培养 2 5～ 30d后 ,在MRI引导下围绕损伤区将细胞悬液注射于 7个靶点。患者在术后 1周进行1 8F FDGPET、fMRI检查和GOSE ,在接受神经干细胞移植后 1个月进行相同的检查 ,第 1年每 3个月随访 1次 ,第 2年每 6个月随访 1次 ,每次随访都行1 8F FDGPET、fMRI检查和GOSE。对照组同法进行观察。结果应用感兴趣区 (ROI)半定量分析和统计参数地图 (SPM)分析。结果　随访第 3个月时 ,1 8F FDG半定量分析示移植组葡萄糖代谢值由移植前的 (71. 1± 7 .9) %增至移植后的 (15 .7 5± 8. 9) % ,对照组由 (74 . 1± 9. 7) %增至 (91. 6± 17 .6 ) % (P <0 .0 1)。移植组1 8F FDG摄取值在移植后开始升高 ,第 3个月时达平台期 ,对照组1 8F FDG摄取值缓慢上升 ,至 6～ 9个月后达平台期 ;SPM分析结果表明移植组中央前回顶部和前额叶葡萄糖代谢明显增加。fMRI结果示损伤区神经干细胞移植后 3个月出现兴奋信号 ,对照组在随访     

干细胞移植的磁性标记及磁共振成像活体示踪

干细胞移植的临床应用需要解决植入活体内干细胞在体内存活、迁移及分化的监测问题。通过对干细胞进行顺磁性标记,磁共振成像(MRI)能够在活体上显示标记的干细胞,并进行特异性地追踪及定位,是目前干细胞活体示踪极具前景的方法。干细胞进行磁性标记主要利用铁类或钆类对比剂,两者各有优缺点。利用铁类或钆类对比剂标记干细胞并进行MRI活体监测取得了成功。并在心脑缺血损伤的疾病模型中得到应用,但在干细胞磁性标记的载体选用及其标记率、标记的持久性、标记对细胞活力及遗传性状方面尚存在一定的问题。     

肾功能衰竭大鼠超顺磁性氧化铁标记骨髓间充质干细胞肾脏移植MR活体示踪的研究

目的应用磁性氧化铁纳米粒子和多聚左旋赖氨酸（poly-L-lysine，PLL）的偶联物Fe2O3-PLL标记大鼠骨髓间充质干细胞（MSCs），MR活体示踪经肾动脉移植入肾功能衰竭（简称肾衰）大鼠肾脏的标记细胞。方法制备Fe2O3-PLL，分离、纯化并培养大鼠骨髓MSCs，Fe2O3-PLL标记细胞，普鲁士蓝染色显示细胞内铁。肌内注射甘油所致肾衰的大鼠分为2组，分别经左肾动脉移植入标记细胞（6只）和未标记细胞（5只），移植后即刻及第1、3、5、8天应用MRI对移植细胞进行活体示踪，并与肾脏组织切片普鲁士蓝染色和HE染色对照。结果MSCs的Fe2O3-PLL标记率近100％，普鲁士蓝染色显示蓝色铁颗粒位于MSCs胞质内。标记细胞移植后肾衰大鼠肾脏皮质区信号强度明显下降，T2＊WI信号改变最明显，而肾髓质及肾盂信号较细胞移植前无明显变化，信号改变随着时间的延长逐渐减轻一直持续到移植后第8天。组织学分析见绝大多数标记细胞分布于肾皮质肾小球内，与MRI信号改变区域基本一致。未标记细胞移植后未见肾脏信号改变。结论Fe2O3-PLL可以有效标记大鼠骨髓MSCs，临床应用型1．5T磁共振仪可对经肾动脉移植入肾衰大鼠肾脏的标记细胞进行初步活体示踪。     

Monitoring of a new approach of immunotherapy with allogenic <Superscript>111</Superscript>In-labelled NK cells in patients with renal cell carcinoma

The transfusion of allogenic, in vitro expanded natural killer cells (NKC) is a novel therapy option in oncology. To date, however, the biodistribution and kinetics of allogenic NKC have not been investigated. Therefore, in this study three patients with renal cell carcinoma received 3–7×10⁸ NKC labelled with indium-111 oxine with a tenfold excess of unlabelled cells during NKC therapy. Whole-body scintigrams were obtained (0.5–144 h) in the anterior and posterior views. Scintigrams were analysed using a region of interest technique, and single-photon emission tomography (SPET) studies of the abdomen were performed. Results were compared to those obtained with polymerase chain reaction (PCR) of the peripheral blood (determination of foreign DNA, nested PCR, limit of detection 0.01%). Shortly after transfusion of NKC, more than 50% of the activity was accumulated in the lungs. We observed redistribution effects from lungs to liver, spleen and bone marrow. No significant loss of activity could be detected. In two of four large metastases, tracer accumulation could be proven by SPET. As confirmed by scintigrams and PCR, the fraction of circulating transfused cells was low at all times. Long-term activity retention might be caused either by survival of the allogenic cells, as confirmed by PCR (up to 3 days p.i.), or by phagocytosis of labelled cellular fragments. However, PCR data and uptake in metastases indicated long survival of a portion of allogenic NKC. Such long survival and low retention of the cells in the lung are requirements for an effective immunotherapeutic approach.     

MR示踪技术在干细胞治疗心肌梗死中的研究进展

活体细胞MR示踪成像技术能有效在体内实时、准确评价干细胞治疗心肌梗死的效果，可分为MR对比剂标记细胞成像和MR报告基因成像。自体移植干细胞治疗心肌梗死的疗法中，能标记干细胞的MR对比剂主要有以钆剂为主的顺磁性对比剂、化学交换饱和转移成像（CEST）相关对比剂以及氧化铁类对比剂；MR 报告基因导入后能使细胞表达产生MR信号改变的蛋白质，以膜表面蛋白为主，包括铁蛋白受体、膜表面抗原、酶等。目前的MR细胞示踪技术对自体移植干细胞治疗的疗效评价、机制研究有一定的指导作用。     

Multi-tracer small animal PET imaging of the tumour response to the novel pan-Erb-B inhibitor CI-1033

Purpose This study was designed as “proof of concept” for a drug development model utilising multi-tracer serial small animal PET imaging to characterise tumour responses to molecularly targeted therapy. Methods Mice bearing subcutaneous A431 human squamous carcinoma xenografts (n=6–8) were treated with the pan-Erb-B inhibitor CI-1033 or vehicle and imaged serially (days 0, 3 and 6 or 7) with [¹⁸F]fluorodeoxyglucose, [¹⁸F]fluoro-L-thymidine, [¹⁸F]fluoro-azoazomycinarabinoside or [¹⁸F]fluoromisonidazole. Separate cohorts (n=3) were treated identically and tumours were assessed ex vivo for markers of glucose metabolism, proliferation and hypoxia. Results During the study period, mean uptake of all PET tracers generally increased for control tumours compared to baseline. In contrast, tracer uptake into CI-1033-treated tumours decreased by 20–60% during treatment. Expression of the glucose transporter Glut-1 and cell cycle markers was unchanged or increased in control tumours and generally decreased with CI-1033 treatment, compared to baseline. Thymidine kinase activity was reduced in all tumours compared to baseline at day 3 but was sevenfold higher in control versus CI-1033-treated tumours by day 6 of treatment. Uptake of the hypoxia marker pimonidazole was stable in control tumours but was severely reduced following 7 days of CI-1033 treatment. Conclusion CI-1033 treatment significantly affects tumour metabolism, proliferation and hypoxia as determined by PET. The PET findings correlated well with ex vivo biomarkers for each of the cellular processes studied. These results confirm the utility of small animal PET for evaluation of the effectiveness of molecularly targeted therapies and simultaneously definition of specific cellular processes involved in the therapeutic response. The first two authors contributed equally to the results presented in this report.     

间充质干细胞治疗放射性肺纤维化的研究进展

放射性肺纤维化是胸腔肿瘤放疗的一种常见并发症,主要表现为肺间质慢性进行性实变,可导致患者肺部生理功能减退乃至丧失,严重者引起呼吸衰竭而死亡。近年研究发现,间充质干细胞能够通过分化为功能细胞、分泌细胞因子以及调节肺部免疫细胞的活性,在治疗放射性肺纤维化中发挥作用。因此,MSC作为一种细胞治疗手段在RIPF上有着良好的应用...     

血管内皮祖细胞移植防治动脉粥样硬化形成的MRI实验研究

目的通过动物实验，探讨血管内皮祖细胞移植防治动脉粥样硬化形成的可行性。方法分离、鉴定并培养新西兰大白兔外周磁粒子标记血管内皮祖细胞（EPCs），制备氧化铁（Fe2O3）-多聚左旋赖氨酸（PLL）并体外标记EPCs。用2．5F球囊扩张并损伤兔右侧颈动脉血管内皮，对损伤血管进行局部EPCs移植，A组8只，移植Fe：O，-PLL标记的EPCs；B组3只，移植荧光标记的EPCs；C组5只为空白对照，局部注射生理盐水。细胞移植后4d，所有实验兔用1．5TMR仪进行活体颈动脉扫描，并任意选A、B、C组各1只，取受损伤血管做病理组织学检查，并与MRI信号变化进行对比分析，其余所有实验兔继续高脂饲料喂养，15周后对损伤血管做MR及病理组织学检查。结果EPCs的Fe2O3-PLL标记率〉95％，A组标记细胞移植后4d，MR T2·WI显示损伤血管壁呈明显低信号区，而B组和C组无明显异常信号改变；病理学检测显示A组损伤血管内膜有普鲁士蓝染色阳性细胞黏附，B组损伤血管内皮有强荧光表达，C组损伤血管内皮无表达。15周后，A、B组动脉粥样硬化形成（3／9）明显低于C组（4／4）。结论活体MR技术可示踪并检测EPCs在损伤血管内皮的黏附及分布；血管内皮祖细胞局部移植可预防动脉粥样硬化的形成。     

内皮祖细胞治疗脑创伤的研究进展

内皮祖细胞(endothelial progenitor cells,EPCs)可促进创伤性脑损伤患者损伤区血管新生,并保护神经元的再生。近年来,外源性EPCs移植、动员内源性EPCs以及运用EPCs等治疗方法在创伤性脑损伤大鼠的实验研究中证实有很好的疗效,并表明EPCs的水平与脑创伤的恢复程度和预后密切相关。为了详细阐明最新相关研究,笔者就EPCs治疗创伤性脑损伤的作用机制、治疗策略、临床应用、预后作一综述。     

Magnetic targeting of iron-oxide-labeled fluorescent hepatoma cells to the liver

The purpose of this study was to determine whether an external magnet field can induce preferential trafficking of magnetically labeled Huh7 hepatoma cells to the liver following liver cell transplantation. Huh7 hepatoma cells were labeled with anionic magnetic nanoparticles (AMNP) and tagged with a fluorescent membrane marker (PKH67). Iron-uptake was measured by magnetophoresis. Twenty C57Bl6 mice received an intrasplenic injection of 2 × 10⁶ labeled cells. An external magnet (0.29 T; 25 T/m) was placed over the liver of 13 randomly selected animals (magnet group), while the remaining 7 animals served as controls. MRI (1.5 T) and confocal fluorescence microscopy (CFM) were performed 10 days post-transplantation. The presence and location of labeled cells within the livers were compared in the magnet group and controls, and confronted with histological analysis representing the standard of reference. Mean iron content per cell was 6 pg. Based on histology, labeled cells were more frequently present within recipient livers in the magnet group (p < 0.01) where their distribution was preferentially peri-vascular (p < 0.05). MRI and CFM gave similar results for the overall detection of transplanted cells (kappa = 0.828) and for the identification of peri-vascular cells (kappa = 0.78). Application of an external magnet can modify the trafficking of transplanted cells, especially by promoting the formation of perivascular aggregates.     

Demonstration of the dorsal pancreatic artery by CTA to facilitate superselective arterial infusion of stem cells into the pancreas

Purpose

To investigate the diagnostic performance of 64-section CTA in the detection of dorsal pancreatic artery before interventional therapy for patients with diabetes.

Materials and methods

The study was approved by the institutional ethics committee; written informed consent was obtained. Forty-two consecutive patients with diabetes received an experimental treatment of autologous bone marrow-derived stem cell transplantation by means of infusion into the dorsal pancreatic artery. All cases underwent abdominal CTA before angiography of pancreatic arteries in order to locate the origin and course of dorsal pancreatic artery. Angiography of coeliac artery, splenic artery, common hepatic artery and superior mesenteric artery were performed both in CTA and DSA. Superselective catheterization of dorsal pancreatic artery was carried out for the infusion of stem cell. Sensitivity, specificity and accuracy for the detection of dorsal pancreatic artery with CTA were calculated using DSA images as the reference standard.

Results

Thirty-five and thirty-six dorsal pancreatic arteries were detected by CTA and DSA respectively. Dorsal pancreatic artery was not visualized in either CTA or DSA in 5 patients. The sensitivity, specificity and accuracy for CTA were 94.4%, 83.3% and 92.9%.

Conclusion

64-section CTA is accurate for the detection of dorsal pancreatic artery. It may be useful for the facilitation of superselective arterial infusion of stem cells to pancreas.     

骨髓内皮祖细胞在恶性肿瘤血管生成中的作用

新的血管生成是肿瘤发生和发展的重要病理生理过程。人骨髓中含有内皮祖细胞，骨髓内皮祖细胞通过不同的机制动员进入血液循环，并参与肿瘤的血管生成。深入研究骨髓内皮祖细胞参与肿瘤血管生成的机制将为肿瘤治疗提供新的措施。