Response of tumors to therapy studied by 31P magnetic resonance spectroscopy

Magnetic resonance (MR) methods have been used to study the metabolic and vascular response of model tumors to tumor necrosis factor (TNF). Magnetic resonance measurements demonstrated acute reductions in tumor blood flow, measured from tumor uptake of D2O, and in tumor adenosine triphosphate (ATP), measured by 31P magnetic resonance spectroscopy (MRS) following administration of TNF. The decrease in ATP generally followed reduction in tumor blood flow, and therefore was probably due to ischemia caused by damage to tumor vasculature. Superficial human tumors have been studied by MRS to characterize their 31P spectra, and to measure metabolic changes during therapy. The ratio of the intensities of the phosphomonoester (PME) and ATP resonances (PME/ATP) was much higher in tumors than in the normal tissue displaced by the tumors. During therapy, decreases in PME/ATP were detected that paralleled, but did not anticipate, decreases in tumor size. In some cases, a transient increase in PME/ATP was detected during therapy, which did not correlate with changes in tumor size, and which may reflect stimulation of cell growth in some tumor zones.     

Clinical application of 31P MRS to malignant liver tumors--with an emphasis on evaluation of response to therapy]

Malignant liver tumors in 19 cases (13 hepatomas and 6 metastatic tumors) were studied by 31P magnetic resonance (MR) spectroscopy. Five healthy volunteers were also studied. Volume localization was performed using the ISIS sequence. Compared with normal liver, the MR spectra of malignant tumors showed an elevated phosphomonoester (PME) peak relative to beta ATP (p less than 0.005), and tumors were slightly alkaline (pH 7.32 +/- 0.08) before therapy. Nine cases of hepatomas responding to chemoembolization showed extremely reduced signal intensity of spectra. Tumor pH was compared before and after therapy in four cases that showed good response to therapy, and was elevated in all of them. Three metastatic tumors with good response showed reductions in PME and ATP after therapy. MR spectroscopy with adequate localization technique is useful in demonstrating the response of malignant tumors to therapy.     

P-31 MR spectroscopy in assessing testicular torsion: rat model

To develop phosphorus-31 magnetic resonance (MR) spectroscopy as an indicator of testicular viability, unilateral 720 degrees torsion of the spermatic cord was performed in 11 Copenhagen rats. In six of 11 rats, detorsion was done 1 hour later. The authors used special surface coils to obtain P-31 MR spectra (at 2 T) from both tests, then correlated MR findings with those from gross morphologic and histologic examination. In the normal testis, P-31 MR spectra had prominent phosphomonoester (PME) and adenosinetriphosphate (ATP) peaks. Testicular torsion dramatically reduced ATP to almost undetectable levels and significantly decreased the PME/Pi at 1 hour (1.18 +/- 0.22) in nine rats. In two rats, however, no spectral changes were present. Of the six rats in which detorsion was performed, three showed immediate regeneration of ATP and a normal PME/Pi (2.87 +/- 0.06) 3 hours later; testicles in the other three rats did not recover (PME/Pi = 0.72 +/- 0.01). Because gross morphologic observations and histologic findings prior to detorsion were unable to differentiate viable from nonviable tests, these preliminary data suggest P-31 MR spectroscopy may help clinicians diagnose testicular torsion and assess testicular viability.     

Androgen sensitivity of rat prostate carcinoma studied by 31P NMR spectroscopy, 1H MR imaging, and 23Na MR imaging

31P NMR spectroscopy, 1H magnetic resonance (MR) imaging, and 23Na MR imaging were used to study the biochemical difference between nine hormone-sensitive and six hormone-resistant rat prostate cancers and to follow bioenergetic and morphologic changes subsequent to androgen deprivation in the hormone-sensitive model. Neither 1H nor 23Na MR image characteristics were useful in distinguishing androgen-sensitive from androgen-resistant prostate cancer nor in identifying androgen deprivation. 31P NMR spectroscopy did detect bioenergetic differences between the hormone-sensitive and hormone-resistant tumors. Baseline spectra showed a significantly higher PCr/ATP ratio (mean 0.86 +/- 0.09 SEM) for hormone-sensitive tumors than for hormone-resistant tumors (mean 0.26 +/- 0.07 SEM). By 3 days after androgen deprivation (orchiectomy (castration], PCr/ATP ratios had decreased noticeably; by 1 week, the decrease was statistically significant and remained so for the rest of the study (3 weeks). It appears that 31P NMR spectroscopy is useful in detecting androgen sensitivity of prostatic carcinoma.     

31P NMR spectra of extremity sarcomas: diversity of metabolic profiles and changes in response to chemotherapy

We have used 31P NMR spectroscopy to study 22 patients with suspected sarcomas prior to any treatment. The spectra are characterized by the same peaks noted in murine tumors. The mean pH was 7.14 +/- 0.08 and PCr/Pi was 1.18 +/- 0.83. Comparison of pH and PCr/Pi ratios in human and a murine tumor with a low hypoxic cell fraction revealed no significant differences. Six patients subsequently received chemotherapy and three responded to therapy (based on pathologic examination and/or tumor reduction greater than 50%). The three responding patients were noted to have significantly lower PDE/PME in their pretreatment spectra than the three nonresponding patients. The three responding patients with sarcomas also showed a rise of greater than 100% in PDE/PME during the first cycle of therapy. Two of the responding patients had an increase of 0.37 pH units during this interval, which was not detected in the nonresponding patients. These data suggest that 31P NMR spectroscopy may be a useful prognostic indicator in conjunction with other clinical parameters.     

Hepatic cancers and their response to chemoembolization therapy. Quantitative image-guided 31P magnetic resonance spectroscopy.

RATIONALE AND OBJECTIVES. Hepatic embolization combined with intra-arterial administration of cytostatic drugs (chemoembolization) is frequently used to treat primary and metastatic cancers to the liver. Quantitative phosphorus-31 magnetic resonance spectroscopy (31P MRS) was used to assess the metabolic state of hepatic cancers and their metabolic response to chemoembolization. METHODS. Fifteen localized 31P MRS studies were performed on five patients with liver tumors. Thirteen healthy volunteers served as controls. Metabolite ratios and molar metabolite concentrations were calculated. RESULTS. Untreated hepatic tumors, relative to normal controls, showed elevated phosphomonoester/adenosine triphosphate (PME/ATP) ratios, reduced concentrations of ATP and inorganic phosphate (Pi), and normal phosphodiester (PDE) concentrations. As an acute response to chemoembolization, ATP, PME, and/or PDE concentrations diminished, whereas Pi concentrations increased or stayed relatively constant. Long-term follow-up after chemoembolization showed decreased PME/ATP and increased ATP concentrations in the absence of changes on standard magnetic resonance and computed tomographic images. CONCLUSIONS. These preliminary spectroscopic data suggest that quantitative 31P MRS can be successfully used to monitor directly metabolic response to hepatic chemoembolization.     

Serial P-31 MR spectroscopy after fructose infusion in patients with chronic hepatitis.

Serial changes in phosphorus metabolites after intravenous administration of fructose were compared between five healthy volunteers and five patients with chronic hepatitis by means of phosphorus-31 magnetic resonance (MR) spectroscopy. P-31 spectra were obtained every 5 minutes after intravenous drip infusion of 20% fructose at a dose of 0.5 g/kg of body weight. In the healthy volunteers, phosphomonoesters (PME) increased to 338% +/- 76% of the preadministration value at 15-20 minutes. Inorganic phosphate (Pi) was depleted in the first 15 minutes, then rebounded to 260% +/- 67% of the initial value. beta-adenosine triphosphate decreased to less than 50% of its initial value and then gradually recovered. In patients with chronic hepatitis, the increase of PME at 15-20 minutes (151% +/- 49% of the preadministration value) was significantly less than that in healthy volunteers (P less than .05). In addition, the rebound of Pi at 35-40 minutes (126% +/- 42%) was significantly less than that in healthy volunteers (P less than .05). In conclusion, P-31 MR spectroscopy with fructose administration is valuable in the functional evaluation of diffuse liver diseases.     

1990 ARRS Executive Council Award. Renal transplant rejection: diagnosis with 31P MR spectroscopy

We evaluated the role of 31P MR spectroscopy in the diagnosis of renal transplant allograft dysfunction. Thirty-six 31P MR spectroscopy examinations were prospectively performed in 35 patients with renal allografts. The study was performed in two phases. In the first phase, 12 transplant recipients with normal graft function were studied as normal controls. During phase two, 24 31P MR spectroscopy studies were performed in patients at the time of renal transplant biopsy for allograft dysfunction. Twenty-one of these studies were technically adequate. Pathologic analysis of the biopsy specimens showed evidence of allograft rejection in 14 and no rejection in seven. Various phosphorus metabolite ratios were calculated for each patient, including phosphodiesters/phosphomonoesters (PDE/PME), phosphomonoesters/inorganic phosphate (PME/Pi), and inorganic phosphate/adenosine triphosphate (Pi/ATP). The PDE/PME and Pi/ATP ratios in the allografts with rejection differed significantly from the corresponding metabolite ratios in patients without rejection (p = .017 and p = .024, respectively). A PDE/PME ratio exceeding 0.8 had a sensitivity of 100% and specificity of 86% for predicting rejection. A Pi/ATP ratio greater than 0.6 had a sensitivity of 72% and a specificity of 86% for predicting rejection. We conclude that 31P MR spectroscopy may be useful as a noninvasive method for evaluating renal metabolism during episodes of transplant allograft dysfunction.     

Metabolism of tumor regression from angiogenesis inhibition: 31P magnetic resonance spectroscopy

31P NMR spectroscopy was used to analyzed the in vivo metabolism of reticulum cell sarcoma of mice. The ratio of high- to low-energy phosphates ATPB/(Pi + PME) was measured to reflect the relative metabolic state in the tumor. Of the 34 mice studied, 26 were treated with an antiangiogenesis regimen of heparin and cortisone. Eighty-two percent of the tumors treated eventually decreased in volume (P less than 0.01). Volumes and spectroscopic information of 20 tumors were analyzed. Although the average untreated volume was similar to the volume after 3 days of treatment, the average ATPB/(Pi + PME) ratio rose from 0.34 +/- 0.10 to 0.47 +/- 0.07 (P = 0.02). However, after 6 days of treatment, the volume significantly decreased (P less than 0.0001) but the ratio did not significantly rise further (P = 0.06). The rise in the high-energy phosphate preceded a significant decrease in volume of the tumors. In addition, the replenishment of high-energy stores with tumor regression coincided with the histologic findings of a decrease in the number of tumor cells, a decrease of the mitotic index, and a decrease of the number of necrotic cells present with ongoing treatment. Our data suggest that noninvasive methods of assessing early biochemical response of tumor regression may be possible.     

Combined MR imaging and spectroscopy of bone and soft tissue tumors

Twenty-three patients with bone and soft tissue tumors were studied with combined magnetic resonance (MR) imaging and spectroscopy. The MR examinations were utilized to determine the size, internal characteristics, and relationships of the tumor to the surrounding tissues. They also determined the optimal placement of the surface coil. The surface coil profile was the localization technique utilized. Four patients were also studied with one-dimensional chemical shift localization. Tumors were grouped according to histologic type, degree of muscle contamination, size, and extent of necrosis. Quantitative comparison among the groups was carried out by comparing the mean ratios of the low-energy phosphate portion of the spectra [phosphomonoester (PME), Pi, phosphodiester (PDE)] to beta-nucleotide triphosphate (NTP). Tumor spectra typically showed a relative elevation in PME, Pi, and PDE and a relative decrease in phosphocreatinine. No characteristic spectra were observed for individual tumor types. Contamination of the tumor spectra from surrounding muscle impaired interpretation of the spectral data. Tumor size and extent of necrosis were important determinants of the relative degree of abnormally elevated metabolite peaks (PME, Pi, PDE). A trend toward a higher mean PME/beta-NTP ratio was observed among high-grade lesions. Combined MR imaging and spectroscopy is a useful way to study tumor metabolism. Muscle contamination is a significant problem in analysis of the spectra. Better localization techniques are required.     

兔Vx2肿瘤对表阿霉素骨水泥介入治疗反应的^31P磁共振频谱监测

目的：用３１Ｐ ＭＲＳ监测表阿霉素骨水泥介入兔Ｖｘ２ 肿瘤的治疗反应。　方法：对５ 个皮下Ｖｘ２ 实体瘤作表阿霉素骨水泥经皮介入治疗;对另５ 个肿瘤仅作单纯骨水泥注入以作对照。对二组肿瘤均作治疗前后３１Ｐ ＭＲＳ检查。　结果：表阿霉素骨水泥治疗早期出现ＰＯＥ和Ｐｉ峰值升高,ＰＭＥ和ＡＴＰ信号峰减低的改变,提示良好的治疗反应。　结论：表阿霉素骨水泥可从骨水泥中释放并具有抗肿瘤效应;３１ＰＭＲＳ具有早期监测肿瘤化疗反应的作用。     

Clinical magnetic resonance spectroscopy of human breast disease.

Using image-guided volume-selection techniques, in vivo phosphorus-31 magnetic resonance (MR) spectroscopic profiles were obtained from 12 patients with malignant breast tumors, six patients with benign breast tumors, and nine volunteers with no underlying pathologic condition. Phosphatic metabolites identified in the spectral profiles included the phosphomonoesters (PME), inorganic phosphate (Pi), phosphodiesters (PDE), phosphorylated glycans (PG), phosphocreatine (PCr) and adenosine triphosphate (ATP). Based on the results of previous high-resolution ex vivo 31P MR spectroscopic analyses of breast tissues, the resonance of PG was identified in malignant and benign breast tumors. Malignant tumors were found to have a significantly (P less than .05) lower concentration of (PME + Pi) than normal breast parenchyma, and were distinguishable from both benign tumors and normal breast parenchymal tissue by significantly (P less than .01) elevated levels of (PDE + PG). 31P MR spectroscopy is the first technique potentially capable of differentiating among malignant breast tumors, benign breast tumors, and normal breast parenchymal tissues based on their in vivo phosphatic metabolic profiles.     

Human breast cancer in vivo: H-1 and P-31 MR spectroscopy at 1.5 T

To assess the potential of in vivo magnetic resonance (MR) spectroscopy for breast cancer, hydrogen-1 and phosphorus-31 MR spectra of five malignant human breast tumors were compared with those of unaffected breast tissue. The water-to-fat ratio was high in the tumors (average, 2.2) but low in the unaffected tissue (average, 0.3). The P-31 spectrum of normal breast tissue showed low levels of phosphomonoesters (PMEs), inorganic phosphate, phosphodiesters (PDEs), and ATP. In addition, an intense phosphocreatine (PCr) signal was observed in breast tissue of young women: The relative intensities of the PCr and ATP signals had a mean value of 1.9. The tumor spectrum showed elevated levels of PMEs, Pi, and PDEs, while no PCr was seen (PCr/ATP less than 0.2). In two breast cancers treated with radiation therapy, resulting in a decrease of tumor volume of more than 50%, a similar change in the tumor P-31 spectrum was observed: An intense PCr signal developed (PCr/ATP = 1.1). Control experiments indicated that the appearance of PCr after radiation therapy was the result of a radiation-induced metabolic change in the tumor itself.     

磁共振动态磷谱对正常人骨骼肌运动状态功能的定量研究

目的用磁共振动态磷谱技术(31P-MRS)无创性在体评价骨骼肌的功能。资料与方法对10名成年人和6名青少年受试者骨骼肌进行动态31P-MRS分析,对磷酸单酯(PME)、无机磷(Pi)、磷酸二酯(PDE)、磷酸肌酸(CP)、γ-ATP、α-ATP和β-ATP进行半绝对定量分析,同时计算二磷酸腺苷(ADP)和线粒体内氧化磷酸化潜能(PP)以及细胞内镁离子的浓度。分析在静息期、运动期和恢复期两组受试者能量代谢特点及肌肉做功效率。结果肌肉运动时CP和PP含量明显降低,Pi、Pi/CP和ADP升高,而ATP维持恒定。青少年肌细胞内ATP明显高于成人,而CP和PP含量相似,动态变化趋势相同。成人做功较多,但肌肉的效率与青少年组相同。结论动态磷谱技术可以无创性定量评价骨骼肌不同运动状态能量代谢特点,为肌肉的功能影像学提供客观信息。     

Monitoring human tumor response to therapy by means of P-31 MR spectroscopy

Tumors in 23 patients were studied by means of in vivo phosphorus-31 magnetic resonance (MR) spectroscopy. In five patients, the response to chemotherapy and radiation therapy was monitored in a long-term follow-up study. In one patient, the P-31 MR spectra were recorded during the infusion of chemotherapeutic drugs. In comparison with healthy muscle tissue of patients, the tumors showed elevated inorganic phosphate, phosphomonoester, and phosphodiester peaks and reduced creatine phosphate peaks, whereas the nucleoside 5'-triphosphate levels remained nearly unchanged. Tumor treatment resulted in changes in the ratio of the signal intensity value of creatine phosphate to that of inorganic phosphate and in the sum of these values. In an osteosarcoma, an initial response followed by renewed tumor growth was clearly indicated by changes in these parameters. In the short-term follow-up examination, slight spectral changes were observed during the infusion of chemotherapeutic drugs. Changes in the concentrations of phosphorus metabolites during therapy can therefore be monitored in human tumors by means of P-31 MR spectroscopy.     

31P MRS as an early prognostic indicator of patient response to chemotherapy.

In this study 31P spectral changes were closely monitored following the initial administration of cytotoxic drugs and related to five parameters of patient response. Pre- and postchemotherapy 31P MRS examinations were performed on 16 patients with large, malignant tumors. These included four tumor types: (i) lymphoma (n = 7), (ii) breast carcinoma (n = 4), (iii) musculoskeletal tumors (n = 4), and (iv) adenocarcinoma (n = 1). A mean of 5 spectra/patient (range 2-10) was performed following the initial chemotherapy. The spectral trends exhibited by 14 of 16 patients reached "points of maximum change," after which they began to revert toward prechemotherapy values. In 2 of 16 patients that did not respond to the initial chemotherapy regimen, no spectral trends were observed. The degree of change of certain spectral parameters, namely, decreases in PME, PME/PDE, PME/PCr, PME/NTP, PDE/PCr, and tumor pH, as well as increases in the ratios Pi/PME and Pi/PDE, were associated with good patient response and separated responders from nonresponders. Pi/PME appears the most promising for discriminating partial from complete responders.     

Characterization of tumor hypoxia by 31P MR spectroscopy.

Tumor hypoxia is of considerable importance to the oncologist in selecting and optimizing cancer therapy, because hypoxia can determine the effectiveness of various therapies. The relationship between tumor hypoxia and tumor bioenergetics, assessed by 31P MR spectroscopy, is examined to determine whether 31P MR spectroscopy can be clinically useful to measure or characterize tumor hypoxia. Work with experimental tumors has suggested that several different types of hypoxia may exist and that 31P MR spectroscopy cannot be used to characterize all types. Metabolic hypoxia is the level of hypoxia that results in mitochondrial impairment in cells, and it is associated with declining cellular bioenergetic status, which can be measured by enzymatic assay of adenosine triphosphate (ATP). Because 31P MR spectroscopy is sensitive to levels of ATP, it is potentially sensitive to metabolic hypoxia in vivo and may provide a rapid and noninvasive technique for characterizing metabolic hypoxia in tumors. Radiobiologic hypoxia is the level of hypoxia that results in attenuated cell death due to radiation, because radiotoxicity is directly related to tissue levels of oxygen. Radiobiologic hypoxia of tumors thus has more impact on choice of therapy, yet the relationship between metabolic hypoxia and radiobiologic hypoxia remains to be elucidated. An analysis of published data suggests that 31P MR spectroscopy is directly sensitive to metabolic hypoxia in tumors, but it is only indirectly sensitive to radiobiologic hypoxia in tumors. Therefore, 31P MR spectroscopy may be unable to quantify the cell fraction of a tumor that has radiobiologic hypoxia. However, preliminary data suggest that MR spectroscopy may prove useful for determining the effectiveness of therapeutic interventions designed to manipulate radiobiologic hypoxia in tumors or for monitoring the kinetics of tumor reoxygenation after treatment.     

Assessment of Blood Flow in Solid Tumors Using PET

OBJECTIVE: To develop a technique for the evaluation of tumor perfusion prior to and during chemo- and radiation therapy.METHODS: Using the [(15)O]water autoradiographic technique and positron emission tomography (PET), perfusion in solid cervical tumors was investigated in a series of women prior to and during radiation therapy for cervical cancer. A 60-second summed image was used with the arterial blood curve to create a parametric image. The parametric images were registered to sagittal magnetic resonance (MR) images. Regions drawn on the MR images encompassing the tumor were transferred to the corresponding co-registered PET images.RESULTS: All tumors were easily visualized by both imaging modalities and tissue heterogeneity could be evaluated. Mean pre- and during therapy flow values averaged 41.5 +/- 11.9 and 48.2 +/- 7.2 mL/min/100 g tumor, respectively.CONCLUSIONS: Perfusion status of solid tumors, an assumed predictor of response potential, can be assessed using PET and the [(15)O]water technique.     

Exertional heatstroke and muscle metabolism: an in vivo 31P-MRS study.

An impairment of muscle energy metabolism has been suggested as a predisposing factor for, as well as a consequence of exertional heatstroke (EHS). Thirteen young men were investigated 6 months after a well-documented EHS using 31Phosphorus Magnetic Resonance Spectroscopy (31P-MRS). The relative concentrations of ATP, phosphocreatine (PCr), inorganic phosphate (Pi), phosphomonoesters (PME), and the intracellular pH (pHi) were determined at rest, during a graded standardized exercise protocol (360 active plantar flexions) and during recovery. Also the leg tissue blood flow was determined by venous occlusion plethysmography during the MRS procedure. Sixteen age-matched healthy male volunteers served as control group. In resting muscle, there were no significant differences between the groups as regards pHi, Pi/PCr, and ATP/PCr+Pi+PME ratios. During steady state exercise conditions, effective power outputs were similar for both groups at each level of exercise: 20, 35, and 50% of maximal voluntary contraction (MVC) of the calf muscle. No significant differences were shown between the two groups in Pi/PCr, pHi, or changes of leg blood flow at each level of exercise. At 50% MVC, Pi/PCr was 0.48 +/- 0.08 vs 0.47 +/- 0.05 (P = 0.96), pHi was 6.94 +/- 0.03 vs 6.99 +/- 0.02, respectively (P = 0.13). Finally, the rate of PCr resynthesis during recovery was not significantly different between the two groups: t1/2 PCr = 0.58 +/- 0.07 vs 0.50 +/- 0.05 min, respectively (P = 0.35). Therefore, no evidence of an impairment of muscle energy metabolism was shown in the EHS group during a standardized submaximal exercise using 31P-MRS performed 6 months after an EHS.     

Intracranial germinomas: correlation of imaging findings with tumor response to radiation therapy

OBJECTIVE: The purpose of this study was to correlate imaging characteristics of intracranial germinomas with response to radiation therapy. MATERIALS AND METHODS: Using tumor size at the completion of irradiation, we classified 23 patients with histologically proven germinomas in the pineal gland (n = 6), the suprasellar region (n = 7), and the basal ganglia (n = 10) into two groups: excellent response group (n = 14) and good response group (n = 9). Excellent response was defined as complete resolution or residual tumor less than 1.0 cm in diameter, and good response was defined as residual tumor of 1.0-3.0 cm in diameter. CT (n = 53) and MR (n = 32) images obtained before, during, and after radiation therapy were retrospectively analyzed with particular attention to the location, size, presence of cystic change, and CSF seeding of the tumors. RESULTS: In all 23 patients, the tumors decreased 85-100% in size at the completion of irradiation with 40-56 Gy. A significant factor in the different responses to irradiation between patients in the excellent and good response groups was cystic change of the tumor. Tumors with cystic components responded more slowly and had larger residual lesions than did tumors without cystic components (p < .01). In eight of 12 cystic tumors, the cystic portion of the tumor responded more slowly than did the solid portion and remained visible on imaging 6-12 months after irradiation. We found no significant differences between the two groups in location, size, and CSF seeding of tumors. In 12 patients with residual lesions at the completion of irradiation, the tumors proceeded to resolve after completion of treatment. CONCLUSION: In our study, tumor response to radiation therapy correlated negatively with the presence of a cystic region.