Low paramagnetic-ion content in cancer cells: its significance in cancer detection by magnetic resonance imaging.

In previous publications, one of us demonstrated that variation in paramagnetic-ion contents is a major contributing factor to the different NMR relaxation times, T1 and T2, of water protons among normal mouse tissues; and between normal tissues and cancer cells. The nature of the paramagnetic ions involved was not determined. In the present communication, we report results of analysis of the contents of three biologically prominent paramagnetic ions (manganese, iron and copper) in 9 normal mouse tissues (brain, heart, small intestine, kidney, liver, lung, voluntary muscle, spleen and stomach); one strain of rat cancer cells (As-30, rat hepatoma); and 6 strains of mouse cancer cells (Ehrlich mammary adenocarcinoma, LSA lymphoma, Krebs carcinoma of the inguinal region; sarcoma 180; Klein TA3 mammary adenocarcinoma; P815 mast cell leukemia). Our data indicate that manganese and iron are by far the two most important paramagnetic ions contributing to the diversity of NMR relaxation times. The average manganese content of all the normal mouse tissues studied (29.6 +/- 4.99 mu mole/kg) is 24 times higher than the average manganese contents of all the cancer cells studied (1.22 +/- 0.27 mu moles/kg) and there is essentially no overlap between the two groups of data. The average iron content of the normal mouse tissues (281.6 +/- 51.2 mumoles/kg) is 4 times the average in cancer cells (66.7 +/- 7.74 mumoles/kg) but there is some overlap here. The observed differences in both the manganese and iron contents are statistically highly significant, with P's below 0.0001. The copper contents of the cancer cells is lower than the average of normal mouse tissues but only by some 20%. The difference is statistically insignificant at the 0.05 level but significant at the 0.2 level.

Improved discrimination of normal and malignant tissue using 1H NMR relaxation time measurements at 2.18 MHz.

The 1H NMR spin-lattice relaxation time (T1), spin-spin relaxation time (T2), and spin-lattice relaxation time in the rotating frame (T1rho) were determined for Novikoff hepatoma, Walker-256 Carcinosarcoma, Sarcoma-180 and Ehrlich Ascites tumor as well as for 7 normal tissues in the rat at 2.18 MHz. T1 values yielded improved discrimination of normal and malignant tissue compared to previous results at higher frequencies.

23Na NMR maps of head sized phantoms and a low resolution 23Na map of the live human head.

An NMR system capable of obtaining 23Na NMR signals and scans from large objects containing biological concentrations of sodium in a 411 gauss magnetic field in less than one hour was developed. Scans were carried out on 6"-8" diameter phantoms containing 150 mM NaCl and the first low resolution 23Na NMR map of a live human head was obtained.

Field focusing n.m.r. (FONAR) and the formation of chemical images in man.

The first proposals for n.m.r. scanning in medical diagnosis was made by Damadian (1971a; 1972) and were followed by Lauterbur (1973). Damadian's method of scanning used the principle that the forced precessions of a nuclear magnetization under radio frequency (r.f.) driving field specify the conditions for obtaining spatial resolution of the signal producing domains of a nuclear resonance sample. Sufficient coupling of the nuclear spins to the radiation field to produce a signal detectable by r.f. spectroscopy requires that the stringent Bohr frequency condition, hv = microH0/I, be met. It became possible to construct, with the aid of direct current auxiliary coils, a small volume, called the resonance aperture, inside the applied static field of the magnetic resonance experiment. The correct value of H0 for the applied frequency is restricted to this aperture. The technique (Damadian 1972) was developed to provide a method for non-surgically detecting chemical abnormalities in the diseased organs of patients (Damadian 1971a). The first n.m.r. scans of normal patients and of those with malignant disease are discussed.

Pulsed nuclear magnetic resonance of potassium (39K) of whole body live and dead newborn mice. Double oscillation frequencies in T1 decay curves.

Pulsed nuclear magnetic resonance relaxation curves (T2 and T1) of potassium (39K) have been measured in detail on whole body newborn mice when alive, and on the same mice after death. The T2 curves are simple exponential with respect to time, but are shorter than for 39K in simple solutions. The T1 curves are not exponential decays, but show large oscillations that may be described approximately as the sum of two separate sine waves of different frequencies. Large T1 oscillations of complex waveform were previously observed by us with 39K in cancer tissues. Gyroscopic motion of adsorbed magnetoelectric dipoles is proposed as a possible physical mechanism accounting for the experimental observations.

NMR in cancer, XIII: application of the NMR malignancy index to human mammary tumours.

One hundred and nineteen specimens of human mammary tissue taken from 112 individuals, were inspected by pulsed proton magnetic-resonance techniques (at 22.5 MH2). The purpose of the study was to evaluate the diagnostic capabilities of the nuclear magnetic resonance (NMR) technique with regard to the recognition of malignancy. The combination of two NMR parameters (spin lattice (T1) and spin-spin(T2) relaxation times) into a malignancy index produced better than 95% discrimination between the 2 populations of tissue on a case-by-case basis. The mean and standard deviations obtained were 2.002 +/- 0.351 for normal tissue, and 3.137 +/- 0.667 for malignant specimens. The probability that this difference is not significant is considerably less than 0.01. In addition, specimens of fibrocystic disease and fibrous mastopathy had indices of 2.263 +/- 0.503 and 2.151 +/- 0.505 respectively. Both groups yielded P values less than 0.01 when compared to the malignant specimens.

Field-focusing nuclear nuclear magnetic resonance (fomar).

A technique, field-focusing NMR (FONAR), is described for doing NMR scans in large samples. The method utilizes a shaped D.C. magnetic field that confines the NMR-signal-producing region of the sample to a small volume called the resonance aperture. The aperture contains the required values of the Ho field to fully bracket the band of the r.f. pulse. The magnet system and r.f. pick-up coil that achieved the first human NMR can is discussed.

Whole-body nuclear magnetic resonance scanning: n.m.r. studies of tumour cells.

A technique, field-foxusing nuclear magnetic resonance (n.m.r.) spectroscopy (FONAR), is described for doing n.m.r. scans in large samples. The method utilizes a shaped d.c. magnetic field that confines the n.m.r. signal-producing region of the sample to a small volume called the resonance aperture. The aperture contains the required values of the Ho field to fully bracket the band of the r.f. pulse. The magnet system and r.f. pick-up coil that achieved the first human n.m.r. scan are discussed.

NMR in cancer. X. A malignancy index to discriminate normal and cancerous tissue.

Proton nuclear magnetic resonance relaxation parameters (T1, T2, T1p) were measured on 84 normal and malignant samples of colon, lung and breast tissue at 22.5 MHz. The purpose of this study was to evaluate the ability of NMR measurements to discriminate between normal and malignant tissue. By combining T1 and T2 into a normalized NMR malignancy index, it was possible to discriminate malignant and normal tissue in all 36 colon samples, 22 out of 23 breast samples, and 26 out of 29 lung cases. Furthermore, histologically normal tissue adjacent to malignant colonic tissue was found to have an elevated NMR malignancy index comparable to that of malignant colon.

NMR in cancer. XI. Application of the NMR malignancy index to human gastro-intestinal tumors.

One hundred two specimens of human gastro-intestinal tissue taken from eighty-seven individuals were inspected by proton magnetic resonance techniques (at 22.5 Megahertz). The purpose of the study was to evaluate the diagnostic capabilities of the nuclear magnetic resonance (NMR) technique with regard to the diagnosis of malignancy. The combination of two NMR parameters (spin-lattice ((T1) and spin-spin ((T2)) relaxation times) into a malignancy index yielded complete discrimination between the two populations of tissue. The mean and standard deviations obtained were 2.004 +/- 0.342 for normal tissue, and 3.266 +/- 0.642 for malignant specimens. In addition, the NMR technique indicated that histologically normal tissue taken adjacent to the malignancy was pathologically "involved". Analysis of the electrolyte and water content of such tissues confirms this abnormality.

Nuclear magnetic resonance in cancer, XII: Application of NMR malignancy index to human lung tumours.

Sixty specimens of human lung tissue from 52 individuals were inspected at 22.5 MHz by proton magnetic resonance techniques. The purpose of the study was to evaluate the diagnostic capabilities of the nuclear magnetic resonance (NMR) technique for the diagnosis of malignancy. The combination of two NMR parameters (spin-lattice (T1) and spin-spin (T2) relaxation times) into a malignancy index yielded 3 cases of overlap between the two populations of tissue. The mean and standard deviations obtained were 1.966 +/- 0.262 for normal tissue, and 2.925 +/- 0.864 for malignant specimens. In addition, analysis of the electrolyte and water content of the tissues confirm that factors other than specimen water content influence the relaxation time.

NMR in cancer: XVII. dewar for a 53-inch superconducting NMR magnet.

A giant nitrogen-jacketed liquid-helium metal dewar built in this laboratory is described for housing 53-inch superconducting magnet used in the human FONAR experiments. This dewar is 10 feet tall, 6 feet wide, 18 inches deep, and weighs 1 1/2 tons. It consists of the main magnet hoop connected through a demountable gooseneck to a liquid helium reservoir tank.

NMR in cancer: XVIII. A superconductive NMR magnet for a human sample.

A 53-inch superconducting magnet built in our laboratory for human-size NMR is described. It was made from .026 inches superconducting wire laid on a 2.5-inch piece of channel bar that had been rolled into a 53-inch diameter circle and butt-welded at the ends.

NMR in cancer: XVI. FONAR image of the live human body.

The FONAR technique that achieved the first chemical image of the live human being is described. Color and black-and-white video images of a cross-section through the chest at the level of the eighth thoracic vertebra were generated. The imaging showed the heart and mediastinum in the midline between the left and right lungs with the heart encroaching on the left lung space as it does at this level. Also seen was the descending aorta just left and anterior to the vertebral body.