Hyperthermia induces T1 relaxation and blood flow changes in tumors. A MRI thermometry study in vivo

Regional hyperthermia in combination with chemotherapy and/or radiotherapy has proven to be an effective treatment concept for locally advanced deep-seated tumors. Simultaneous MR-imaging could be a promising approach for therapy optimization. Purpose of this study was the in vivo investigation of temperature induced longitudinal relaxation time (T(1)) and blood flow changes in a tumor model. Using a 1.5 Tesla MR system, the T(1) sensitivity on temperature and the onset of tissue changes at temperatures >44 degrees C were investigated in muscle samples. Also, fourteen Syrian Golden Hamsters with amelanotic melanoma A-MEL-3 were examined during heating of the tumors. Temperature induced blood flow and T(1) changes were determined continuously during hyperthermia. Changes of T(1) correlated linearly with temperature over a wide range (27-44 degrees C) in the tissue sample. Tissue changes became notable above 44 degrees C. In the tumor model, relative changes of T(1) (unlike blood flow) showed linear correlation with temperature over the entire range of hyperthermia relevant temperatures (32-44 degrees C). For a low thermal dose, T(1) allows the assessment of temperature changes in tumors in vivo. At higher thermal doses, in addition to temperature changes, T(1) also shows tissue changes. Both temperature and tissue changes supply important information for hyperthermia.     

Magnetic nanoparticle-induced hyperthermia treatment under magnetic resonance imaging

Super paramagnetic iron oxide Fe₃O₄ nanoparticles prepared via photochemical reaction in pure form were used for inducing hyperthermia to treat subcutaneous Ehrlich carcinoma implanted in female mice. Our results indicate that the mean temperature profiles at the rectum, periphery of the tumor surface and at the center of the tumor during hyperthermia treatment increased gradually. The maximum temperature achieved in the tumor center was 47±1°C after 20 min with radiofrequency exposures at 25 kW. The acquired magnetic resonance images identified apoptotic cells in the center of the tumor which were exposed to magnetic resonance hyperthermia (MRH). Apoptotic cells presented as dark signal intensity in the T₁-weighted images which were further confirmed by pathological examinations. Also, the results revealed that the tumor size in the all mice exposed to MRH is still as the same as before the treatment, but the rate of tumor growth was very slow by comparing with the growth rate of the control group.     

Effects of hepatic impairment on the metabolism of fructose and 5-fluorouracil, as studied in fatty liver models using in vivo 31P-MRS and 19F-MRS

The purpose of this study was to observe the effects of hepatic impairment on the metabolism of fructose and 5-fluorouracil (5-FU) in fatty liver models using in vivo 31P-MRS and 19F-MRS and to compare the results. In addition, we compared the results to those of other conventional tests such as laboratory examinations, imaging and pathology. Male SIc:Wistar rats were examined on BEM170/200 (4.7 T, Otsuka Electronics, USA) with 17-mm diameter surface coil. Fatty liver was induced by a choline deficient diet (CD diet) for 2 weeks. 31P-MRS were obtained for 90 min after intravenous (i.v.) injection of 1 g/kg of fructose and 19F-MRS were measured for 100 min after i.v. injection of 100 mg/kg of 5-FU. 1H-MRS and 1H-MRI were also performed. On 31P-MRS, there was no statistical difference in the time course of phosphomonoester (PME), adenosine triphosphate (ATP), and inorganic phosphate (Pi) between CD diet group and control group. On 19F-MRS, we detected high peak of fluoronucleotide (Fnct) and suppressed peak of alpha-fluoro-beta-alanine (FBAL) in CD diet group. We showed the metabolism of fructose and 5-FU by 31P-MRS and 19F-MRS, respectively. There was no difference in fructose metabolism but we observed increased fluoronucleotide and decreased a-fluoro-b-alanine in 5-FU metabolism of fatty liver. We speculate that the effects of hepatic impairment in fatty liver may be more severe on 5-FU metabolism and the increased fluoronucleotide may reflect cell proliferation.     

Focusing cross-fire applicator for ultrasonic hyperthermia of tumors

An improved concept for ultrasonic hyperthermia of tumors is presented. This concept is based on past experience of a German government supported project , which ended in 1984. It offers a low cost alternative to common RF- and microwave methods for hyperthermia of tumors with volumes between 1 and 40 ml at treatment times between 30 and 60 min. Our new version of the system considerably improves the temperature suppression in the healthy tissue around the target area and enables the adjustment of the beam width to the actual tumor size and the field geometry to the depth and shape of the tumor. The applicator can be used for moderate hyperthermia with tissue overheating up to 10K or for ablation therapy with short high temperature pulses. Its central area is free for the integration of a commercial ultrasonic diagnostic sector scanner or a Doppler flow sensor in order to support the adjustment of the transducer and to monitor the whole area during the therapy.     

Loss of moisture from harvested rice seeds on MRI

The drying of rough rice seeds was visualized with the single point mapping imaging (SPI) technique by magnetic resonance imaging (MRI) at various temperatures, and the results were compared with those of the oven-drying method. Most of the water was present in the embryo and endosperm. The water reduction rate was larger on the outside than in the central position of the rice seeds at 50 degrees C, although this discrepancy was not obvious at 40 degrees C. Water reduction was brought about with time according to the kinetics of the multiple components, for both MR imaging and the ventilated-oven method. Images were continuously measured (10 min per image for 100 min). The reduction rate of water from rice kernels increased rapidly with temperature (up) to near 60 degrees C then rose slowly above 60 degrees C. Latent heat was calculated as 15 kcal/mol. deg from the changes of drying rate at temperatures below 60 degrees C.     

Synergistic Effect of Thermo‐Radiotherapy Using Au@FeS Core–Shell Nanoparticles as Multifunctional Therapeutic Nanoagents

Imaging guided combined therapy has attracted great attention in recent years. This study develops core–shell Au@FeS nanoparticles with polyethylene glycol (PEG) coating as multifunctional nanotheranostic agent for tumor imaging and combined photothermal therapy (PTT) and radiotherapy (RT). In this Au@FeS nanostructure, the gold core can act as a radiosensitizer for enhanced RT, while FeS shell offers contrast for T2‐weighted magnetic resonance imaging and endows the nanoparticles with strong high near‐infrared (NIR) for photoacoustic imaging and PTT. As demonstrated by both in vitro and in vivo experiments, Au@FeS‐PEG can act as excellent therapeutic agent for cancer synergistic treatment. More importantly, mild PTT boosts the blood flow into tumor and increases oxygenation to overcome the tumor hypoxia microenvironment, further enhancing the efficacy of RT. Moreover, Au@FeS‐PEG induces on obvious toxicity at a high dose (20 mg kg^?1) to the treated mice as evidenced by blood biochemistry. Therefore, this study brings an excellent strategy for cancer enhanced RT through NIR‐triggered mild PTT to overcome hypoxia‐associated radioresistance.     

Pre-transplantation 31P-magnetic resonance spectroscopy for quality assessment of human pancreatic grafts – A feasibility study

ObjectiveTo investigate the feasibility of using ³¹P-MRS for objective non-invasive quality assessment of human pancreas grafts prior to transplantation or islet isolation.Materials and methodsPancreata from 5 human donors, 3 males and 2 females, aged 49–78 years, with body mass index (BMI) 22–31 kg/m², were included. Pancreata were perfused with histidine-tryptophan-ketoglutarate solution during procurement and stored in hypothermic condition (4 °C) for 21–44 h. During the period of hypothermic storage repeated spectra were obtained for each graft by ³¹P-MRS (1.5 Tesla) to measure the cold ischemia time (CIT) dependent changes of the phosphorous metabolites adenosine triphosphate (ATP), phosphomonoesters (PME), phosphodiesters (PDE) and inorganic phosphate (Pi), in the grafts. Graft temperature was measured immediately before and after MR-examination. Reference spectrum for non-viable tissue was obtained after graft exposure to room temperature.ResultsPME/Pi, PDE/Pi and ATP/Pi spectral intensities ratios decreased with increasing CIT, reflecting the decreased viability of the grafts. PME/Pi ratio was the most discriminatory variable at prolonged CIT. ³¹P-MRS could be performed without significantly increasing graft temperature.Conclusions³¹P-MRS may provide quantitative parameters for evaluating graft viability ex vivo, and is a promising tool for objective non-invasive assessment of the quality of human pancreas grafts prior to transplantation or islet isolation.     

Radiation-induced changes in phosphorus T1values in human melanoma xenografts studied by P-MRS

³¹P-magnetic resonance spectroscopy (MRS) has been shown to be a promising method for monitoring tumor response to radiation therapy. The purpose of the work reported here was to investigate whether the usefulness of ³¹P-MRS might be enhanced by measurement of spin-lattice relaxation times (T₁s) in addition to resonance ratios. The work was based on the hypothesis that tumors having a high probability of being controlled locally would show shortened T₁s during the treatment course due to reoxygenation and development of necrosis. BEX-t human melanoma xenografts, which show efficient reoxygenation and development of necrosis following single dose irradiation, were used as tumor models. Tumors were treated with single doses of 5.0 or 15.0 Gy and the T₁s of the inorganic phosphate and nucleoside triphosphate β resonances were measured as a function of time after irradiation by using the superfast inversion recovery method. Fractional tumor water content was determined by drying excised tumors at 50°C until a constant weight was reached. The T₁s in irradiated tumors were either longer than or not significantly different from those in unirradiated control tumors. The increase in the T₁s following irradiation coincided in time with a radiation-induced increase in tumor water content, suggesting a causal relationship. The effects of reoxygenation and development of necrosis on T₁s were probably overshadowed by the effects of tumor water content. Consequently, the usefulness of ³¹P-MRS in monitoring tumor response to radiation therapy might not be significantly enhanced by measurement of T₁s.     

Magnetohydrodynamic thermochemotherapy and MRI of mouse tumors

A dextran-ferrite magnetic fluid was successfully tested as magnetic resonance imaging (MRI) contrast agent. The same magnetic fluid was then combined with Melphalan, a chemotherapeutic drug, and used for magnetohydrodynamic thermochemotherapy of different tumors. The placement of the tumors in an AC magnetic field led to hyperthermia at 46 °C for 30 min. In combination with tumor slime aspiration, a 30% regression of ∼130 mm³ non-metastatic P388 tumors in BDF₁ mice was reached, together with a life span increase of 290%. The same procedure associated with cyclophosphamide treatment of ∼500 mm³ metastases tumor increased the animal's life span by 180%.     

A magnetic resonance imaging based method for measurement of tissue iron concentration in liver arterially embolized with ferrimagnetic particles designed for magnetic hyperthermia treatment of tumors

Rabbit liver was loaded with ferrimagnetic particles of gamma -Fe2 O3 (designed for magnetic hyperthermia treatment of liver tumors) by injecting various doses of a suspension of the particles into the hepatic artery in vivo. Proton transverse relaxation rate (R(2)) images of the livers in vivo, excised, and dissected were generated from a series of single spin-echo images. Mean R(2) values for samples of ferrimagnetic-particle-loaded liver dissected into approximate 1 cm cubes were found to linearly correlate with tissue iron concentration over the range from approximately 0.1 to at least 2.7 mg Fe/g dry tissue when measured at room temperature. Changing the temperature of ferrimagnetic-particle-loaded samples of liver from 1 degrees C to 37 degrees C had no observable effect on tissue R(2) values. However, a small but significant decrease in R(2) was found for control samples containing no ferrimagnetic material on raising the temperature from 1 degrees C to 37 degrees C. Both chemically measured iron concentrations and mean R(2) values for rabbit livers with implanted tumors tended to be higher than those measured for tumor-free liver. This study indicates that tissue R(2) measurement and imaging by nuclear magnetic resonance may have a useful role in magnetic hyperthermia therapy protocols for the treatment of liver cancer.     

鼠S180肉瘤的体内31P MRS研究

利用表面线圈³¹P NMR研究了小鼠S180肉瘤生长过程中能量代谢和磷脂类变化的特点.结果发现:随着肿瘤体积的增大,(1)Pi和PME升高;(2)PCr降低,在肿瘤体积较大时常检测不到;(3)β-NTP(通常用来表示ATP的量)变化较小;(4)PDE波动性较大;(5)PCr/Pi和β-NTP/Pi比值均下降,且PCr/Pi比β-NTP/Pi下降得快;(6)PME/β-NTP比值升高;(7)肿瘤pH下降,且与PCr/Pi、β-NTP/Pi或(PCr+β-NTP)/Pi比值有相关性.讨论了与这些参数变化相关联的生物学意义.     

Silica-modified Fe-doped calcium sulfide nanoparticles for in vitro and in vivo cancer hyperthermia

In this study, sulfide-based magnetic Fe-doped CaS nanoparticles modified with a silica layer were investigated for cancer hyperthermia. A polyvinyl pyrrolidone polymer was used as the coupling agent. The developed nanoparticles contained 11.6 wt% iron concentration, and their X-ray diffraction pattern was similar to those of CaS and Fe–CaS nanoparticles. The average particle size was approximately 47.5 nm and homogeneously dispersed in aqueous solutions. The major absorption bands of silica were observed from the FTIR spectrum. The magnetic properties and heating efficiency were also examined. The specific absorption ratio of nanoparticles at a concentration of 10 mg/mL at 37 °C in an ethanol carrier fluid was 37.92 W/g, and the nanoparticles would raise the temperature to over 45 °C within 15 min. A cytotoxicity analysis revealed that the nanoparticles had good biocompatibility, which indicated that the nanoparticles did not affect cell viability. The therapeutic effects of the nanoparticles were investigated using in vitro and animal studies. Cells seeded with nanoparticles and treated under an AC magnetic field revealed a percentage of cytotoxicity (60%) that was significantly higher from that in other groups. In the animal study, during a hyperthermia period of 15 days, tumor-bearing Balb/c mice that were subcutaneously injected with nanoparticles and exposed to an AC magnetic field manifested a reduction in tumor volume. The newly developed silica-modified Fe–CaS nanoparticles can thus be considered a promising and attractive hyperthermia thermoseed.     

Partial cerebral ischemia assessed by "in vivo" 31P NMR spectroscopy in rats.

31P NMR spectroscopy was used to assess the cerebral ischemia status in rats by measuring the relative levels of phosphate metabolites. Partial cerebral ischemia was induced in 49 rats by reversible occlusion of the carotid arteries. Rats were intubated and mechanically ventilated on a hypoxic gas mixture. Physiological parameters such as temperature and arterial pressure were strictly controlled during the experiments. 31P spectra were acquired at 7 T during basal observation, for 15-20 min after the induction of ischemia, and for 1 hr after reperfusion. Depletion and increase in PCr and Pi levels, respectively, were already observable in the collected spectra within few minutes after the onset of ischemia. No appreciable changes were found in the ATP levels.     

磷酸-氨水蒸沉γ晶型聚酰胺6的热行为研究

尼龙6是一种多晶型的半结晶高聚物。实验采用蒸沉法制备出尼龙6,首先通过XRD和FTIR的手段进行表征,与采用沸水处理的尼龙6样品表征结果对比,确定其为γ晶型,然后在130～211℃的温度范围内进行热处理,通过DSC研究其在低于熔点热处理时的整个热行为变化过程,并运用FTIR观察其在不同条件下热处理发生的晶型变化。发现蒸沉法制备的γ晶型尼龙6随着热处理温度的升高,整体结晶完善度以及晶片厚度随着处理温度的升高而增加。而且在这个过程中,样品厚度不同的晶片在不同温度下发生了γ晶型向α晶型的转化,最终在接近熔点(211℃)热处理时,样品变为以α晶型为主。     

Magnetic resonance of brain tumors: considerations of imaging contrast on the basis of relaxation measurements

Proton spin-lattice and spin-spin relaxation times have been measured in surgically-removed normal CNS tissues and a variety of tumors of the brain. All measurements were made at 20 MHz and 37 degrees C. Between grey and white matter from autopsy human or canine specimens significant differences in T1 or T2 were observed, with greater differences seen in T1. Such discrimination was reduced in samples obtained from live brain-tumor patients due to lengthening in T1 and T2 of white matter near tumorous lesions. Edematous white matter showed T1 and T2 values higher than those of autopsy disease-free white matter. Compared to normal CNS tissues, most brain tumors examined in this study demonstrated elevated T1 and T2 values. Exceptions, however, did exist. No definitive correlation was indicated on a T1 or T2 basis which allowed a distinction to be made between benign and malignant states. Furthermore, considerable variation in relaxation times occurred from tumor to tumor of the same type, suggesting that within a tumor type there are important differences in physiology, biology, and/or pathologic state. Such variation caused partial overlap in relaxation times among certain tumor types and hence may limit the capability of magnetic resonance imaging (MR) alone for the diagnosis of specific disease. Nonetheless, this study predicts that on the basis of T1 or T2 differences most brain tumors are readily detectable by MR via saturation recovery or inversion recovery with appropriate selections of pulse-spacing parameters. In general, tumors can be discriminated against white matter better than grey matter and contrast between glioma and grey matter is usually superior to that between meningioma and grey matter. This work did not consider tissue-associated proton density which should be addressed together with T1 and T2 for a complete treatment of MR contrast.     

急性低氧大鼠脑31P核磁共振波谱研究

³¹P磁共振波谱是目前唯一可以用作在体无损伤的检测细胞水平能量代谢变化的非侵入性技术,可测得脑内多种能量代谢产物.目的：急性低氧大鼠脑组织的³¹P MRS检测.方法：(1)20只成年SD大鼠分为4组：低氧0min(对照),5min,10min,15min后,迅速液氮冷冻;(2)将脑组织研碎后,加入高氯酸(PCA),冷冻干燥;(3)将提取物用0.5mL D\-2O溶解后进行MRS检测.结果：(1)急性低氧早期即引起³¹P MRS中PCr和ATP峰降低,ADP和Pi峰增高,PCr/Pi和ATP/Pi降低,而ADP/ATP增高.可交换磷池(EPP)中PCr的正常值为42.4%,低氧5min后降到28.9%, ATP从33.8%降到19.2%,Pi从17.7%升到42.0%.(2)急性低氧时³¹P MRS中脑内磷酯分解代谢产物GPC、GPE含量增加,说明低氧早期脑内即有膜磷酯的分解增加.结论：³¹P磁共振波谱可用于脑低氧性疾病的诊断,我们波谱中最敏感的指标是PCr/Pi和ATP/Pi,尤其早期降低更为显著.     

The study of heat stress in tomato fruits by NMR microimaging.

The ripening of the tomato fruit was delayed for several days (average 5 days) by a 1-day heat treatment at 42 degrees C. Ethylene production increased during the first 3 h, but, after 6 h inhibition was almost total in tomato fruit incubated at 42 degrees C. However, recovery of ethylene production was rapid if fruits were returned to a temperature of 25 degrees C after heating. In NMR microimaging, three imaging pulse sequences with different repetition and echo times at 42 degrees C were used to obtain the proton density (TR = 6000 ms, TE = 15 ms), the T1 weighted image (TR = 1000 ms, TE = 15 ms) and the T2-weighted image (TR = 6000 ms, TE = 120 ms). After 12 h heating, the water in locular tissues began to show shorter T1 and T2 values. Though the tomatos were returned to 25 degrees C and preserved one more day, the water having a shorter T2 value in locular tissues, did not change. These results show that tomato fruit do not fully recover from heating even after one day, although ethylene production is recovered almost immediately. For this reason, we suggest that some denaturation event inside the tomato, which goes on after the end of heating, is the cause of the delay in tomato ripening.     

人淋巴瘤白血病细胞系Molt-4的31P核磁共振研究

用³¹P核磁共振(NMR)观察了人淋巴瘤白血病细胞系Molt-4的³¹P谱.NMR测试温度为37℃、20℃和4℃时,随着测试时间增长,细胞³¹P谱中ATP峰降低,无机磷峰升高,细胞³¹P谱的变化随测试温度降低依次减缓.实验温度为4℃,从收集细胞至开始NMR累加在30min内,NMR累加在60min内,获得活细胞的稳定的³¹P谱.根据细胞内无机磷的化学位移数值,对细胞内pH值进行了测定.     

In vivo MR spectroscopy and MR imaging on non-anaesthetized marine fish: techniques and first results

In vivo Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS) experiments were carried out in non-anaesthetized marine fish with a maximum body length of 40 cm using a 4.7 T horizontal magnet. In flow-through animal chambers long-term investigations could be carried out for several days in a sessile benthic zoarcid species, the eelpout Zoarces viviparus, as well as in a pelagic gadid species, the cod Gadus morhua. Sea water adapted probes and optimised excitation and refocusing pulse shapes reduced the negative effects of the highly conductive medium. In both species, in vivo 31P-NMR spectra were collected within 5 minutes with a reasonable signal to noise ratio (PCr/Pi ratio > 40 in cod) and typical line widths in the range of 20 to max. 40 Hz. Magnetic resonance images were recorded in the sessile species without movement artefacts. In these fish it was even possible to measure the blood flow of different vessels with a flow compensated gradient echo sequence and to carry out localized in vivo 1H-NMR spectroscopy in different organs.     

Dynamic contrast-enhanced MRI of Implanted VX2 tumors in rabbit muscle: comparison of Gd-DTPA and NMS60

We studied the dynamics of injected contrast enhancement in implanted VX2 tumors in rabbit thigh muscle. We compared two contrast agents Gd-DTPA and NMS60, a novel gadolinium containing trimer of molecular weight 2.1 kd. T1-weighted spin echo images were acquired preinjection and at 5-60 min after i.v. injection of 0.1 mmol/kg of agent. Dynamic T1-weighted SPGR images (1.9 s/image) were acquired during the bolus injection. Male NZW rabbits (n = 13) were implanted with approximately 2 x 10(6) VX2 tumor cells and grew tumors of 28+/-27 mL over 12 to 21 days. NMS60 showed significantly greater peak enhancement in muscle, tumor rim, and core compared to DTPA in both T1-weighted and SPGR images. NMS60 also showed delayed peak enhancement in the dynamic scans (compared to Gd-DTPA) and significantly reduced leakage rate constant into the extravascular space for tumor rim (K21 = 5.1 min(-1) vs. 11.5 min(-1) based on a 2 compartment kinetic model). The intermediate weight contrast agent NMS60 offers greater tumor enhancement than Gd-DTPA and may offer improved regional differentiation on the basis of vascular permeability in tumors.