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EP0494969A1 - Appareil et procede de detection du cancer par resonance magnetique nucleaire - Google Patents

Appareil et procede de detection du cancer par resonance magnetique nucleaire

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Publication number
EP0494969A1
EP0494969A1 EP90915646A EP90915646A EP0494969A1 EP 0494969 A1 EP0494969 A1 EP 0494969A1 EP 90915646 A EP90915646 A EP 90915646A EP 90915646 A EP90915646 A EP 90915646A EP 0494969 A1 EP0494969 A1 EP 0494969A1
Authority
EP
European Patent Office
Prior art keywords
automatically
cancer
spectrum
ppm
nmr
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP90915646A
Other languages
German (de)
English (en)
Other versions
EP0494969A4 (en
Inventor
Eric T. Fossel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beth Israel Deaconess Medical Center Inc
Original Assignee
Beth Israel Deaconess Medical Center Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Beth Israel Deaconess Medical Center Inc filed Critical Beth Israel Deaconess Medical Center Inc
Publication of EP0494969A1 publication Critical patent/EP0494969A1/fr
Publication of EP0494969A4 publication Critical patent/EP0494969A4/en
Withdrawn legal-status Critical Current

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
    • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
    • G01R33/46—NMR spectroscopy
    • G01R33/465—NMR spectroscopy applied to biological material, e.g. in vitro testing

Definitions

  • the present invention relates to an apparatus and diagnostic method for detecting cancer in a living patient.
  • Prior Art Approaches utilizing the technique of nuclear magnetic resonance (NMR) to aid in arriving at a clinical diagnosis of cancer are well known in the prior art.
  • NMR nuclear magnetic resonance
  • Damadian was the first to propose a medical use for NMR. He suggested it be used for detecting malignancy in tissue. See R. Damadian, "Tumor Detection by Nuclear Magnetic Resonance," Science 171:1151-1153 (1971).
  • U.S. Patent 3,789,832 issued to Damadian covers an apparatus and method for applying nuclear magnetic resonance to surgically removed specimens to measure T 1 and T trash for proton relaxation times, which values, compared to values for healthy tissue, were taken as a means of diagnosing cancer.
  • U.S. Patent Nos. 4,411,270 and 4,354,499 issued to Damadian cover apparatus and method for cancer detection with NMR imaging and scanning of whole-body specimens.
  • a sample of a patient's bodily fluid is subjected to nuclear magnetic resonance spectroscopy to generate a nuclear magnetic resonance spectrum.
  • a resonance line generated by a non-water component of the sample is selected, and the full width of this resonance line at a given height, e.g., at half its height, is measured.
  • the full width so measured has proved to be a statistically reliable measure of the presence or absence of cancer in the patient.
  • the triglyceride level is measured of those patients with a positive result on the proton NMR diagnostic test.
  • a normal triglyceride level confirms the cancer diagnosis; however, the fluid samples of patients with high triglyceride levels are subjected to C-13 NMR.
  • An abnormal result in that test confirms the cancer diagnosis, whereas a normal result indicates that the prior diagnosis a false positive.
  • an apparatus was designed that is an improved nuclear magnetic resonance spectrometer.
  • the present invention automates the process for diagnosing cancer using NMR.
  • the apparatus has a spectrometer component capable of taking water suppressed proton NMR and C-13 NMR readings of a fluid sample. Additionally, the apparatus has computer means for processing the proton and C-13 readings and for obtaining a numerical value corresponding to those readings.
  • the apparatus further comprises memory means for storing a set of standard or normal values.
  • the apparatus also has means for comparing values obtained from the NMR spectra with the set of stored values in the memory means and for classifying the fluid sample on the basis of that comparison.
  • the apparatus has computer programs which direct its function. Additionally, the programs analyze the data and yield a diagnosis with a great degree of accuracy.
  • the sample fluid is blood, spinal fluid, or bone marrow plasma; blood is especially advantageous.
  • the component of interest is lipidic, and is preferably from the methyl and methylene groups of the lipoprotein lipids.
  • an object of the present invention is to provide an apparatus and method of using an apparatus for automatic diagnosis of the presence of cancer in a living patient using NMR spectroscopy.
  • FIG. 1 is a typical 360 MHz NMR spectrum for the non-water components (water-suppressed) of a plasma sample from a healthy control obtained in accordance with the present invention
  • FIG. 2 is an NMR spectrum for the same plasma sample from which the spectrum of FIG. 1 was obtained, using the same equipment and pulse frequency, except without water suppression;
  • FIG. 3 is an expanded view of the methyl and methylene region of the reading of the sample of FIG. 1;
  • FIG. 4 is an expanded view of the methyl and methylene region of an NMR spectrum for a plasma sample for a patient with an untreated malignancy
  • FIGS. 5A and 5B are C-13 NMR spectra of a plasma sample in the olefinic region for a normal control and an untreated cancer patient, respectively, obtained in accordance with the present invention
  • FIGS. 6A and 6B are views of the C-13 NMR spectral region between 10 ppm and 90 ppm, with particular inclusion of the region between 48 ppm and 80 ppm, of the plasma samples shown in FIGS. 5A and 5B for a normal control and an untreated cancer patient, obtained in accordance with the present invention;
  • FIG. 7 schematically illustrates the apparatus of the present invention
  • FIG. 8 shows the results of a study performed using the method of the present invention.
  • FIG. 9 shows a flowchart diagramming the operations of the apparatus of the invention.
  • FIG. 10A shows a flowchart for shimming, a task carried out by the apparatus which ensures reproducible results from water suppressed readings
  • FIG. 10B shows a sample program for shimming, corresponding to the proton spectrum step of the flowchart in FIG. 10A;
  • FIG. IOC shows a sample program for shimming, corresponding to a carbon-13 spectrum
  • FIG. 10D shows a sub-program of step 8, RJ FQSET, of the shimming program shown in FIG. IOC-
  • FIG. 10E shows a sub-program of step 2, RJ TUNE, of the program shown in FIG. 10B;
  • FIG. 10F shows a sub-program of step 6, RJ FQSET, of the program shown in FIG. 10B.
  • the present invention is a method to detect the presence of cancer in a living patient.
  • a sample of a patient's bodily fluid is subjected to proton nuclear magnetic resonance spectroscopy to generate a nuclear magnetic resonance spectrum. Since components of the NMR spectrum which have significant predictive value may be masked by other materials in the sample, the masking is eliminated to produce the NMR spectrum.
  • a resonance line generated by a non-water component of the sample is selected, and the full width of this resonance line at a given height, e.g., at half its height, is measured to provide a reliable measure of the presence or absence of cancer in the patient.
  • a computer component of the apparatus makes the measurement, or measurements in the event that more than one resonance line is selected, and compares the average value obtained to a stored value which is indicative of the normal value; i.e. , for a cancer-free person.
  • SUBSTITUTE SHEET In the event that a positive reading is obtained, this reading may indicate the presence of cancer in the patient, or it may be a false positive reading. It has been discovered that a major source of false positive readings are persons with high levels of plasma triglycerides. Accordingly, if the measured value is greater than the normal value, the program will diagnose the patient as cancer-free. However, if the measured value is less than the stored value, the program will direct the apparatus to obtain a measure of the patient's triglyceride level.
  • the sample tested previously is subjected to C-13 NMR spectroscopy for those who have elevated triglyceride levels.
  • the false positive results due to hypertriglyceridemia and, conversely, the presence of cancer in the patient, can be reliably determined from certain features of the C-13 spectra.
  • proton NMR spectroscopy is performed initially on the sample to be tested.
  • the water suppressed proton NMR spectrum obtained on human blood plasma is dominated by the resonances of the plasma lipoprotein lipids. Without water suppression, these non-water resonances are virtually overwhelmed by the water.
  • Signal averaging allows observation of resonances of some moieties associated with non-water bodily fluid components, at high magnetic fields, even in the presence of the water
  • the apparatus of the present invention operates on any lipid-containing body fluid.
  • Whole blood, serum or plasma may be used. While the test may be performed on any such lipid-containing body fluid, work to date has focused on blood plasma.
  • the lipids, inclusive of cholesterol, triglycerides, and phospholipids are present in the form of lipoproteins.
  • the test for cancer will typically be performed in vitro, preferably on serum or plasma.
  • the selected fluid of a suspect patient or other person to be screened for cancer is exposed to both a magnetic field and radio-frequency energy to generate a nuclear magnetic resonance signal which is then processed by the apparatus which obtains a value for a selected parameter, e.g., W_. /9 , for lipid methyl and/or methylene protons.
  • a selected parameter e.g., W_. /9
  • a relatively broad range of proton frequencies may be employed, e.g., 60 MHz and higher; 360 MHz or above is a preferred frequency. If cost is not a factor, 500 MHz may be the preferred frequency.
  • FIG. 1 shows a water suppressed proton spectrum of a healthy control
  • FIG. 2 shows a proton spectrum of the same sample without water suppression.
  • the truncated resonance line of water is denoted A in FIG.
  • the present invention uses one of a number of conventional water suppression techniques, i.e., techniques for suppression of the water proton NMR signal. Numerous techniques have been devised to suppress the water proton NMR signal in other contexts.
  • the apparatus compares the detected value for the selected parameter with the corresponding parameter for the healthy controls.
  • values for methyl and methylene are averaged and an average value of 33 Hz or less at a proton frequency of 360 MHz (8.45T) or 400 MHz (9.40T) is taken as an indication of malignancy.
  • a second level of testing to confirm the diagnosis is performed.
  • a conventional test commonly called a triglyceride analysis, is performed to determine the triglyceride level of the patient. If the triglyceride level is normal, the positive reading from the water-suppressed proton NMR spectroscopy is a true positive and indicates the presence of cancer in the patient. If the triglyceride level is above normal, in order to differentiate between true and false positive results, the program directs the apparatus to obtain a C-13 NMR spectrum of the patient's plasma sample which is already available because of the earlier proton NMR spectrum.
  • False positive results due to hypertriglyceridemia can be reliably distinguished from true positive results by substantial differences in certain features of C-13 spectra. Accordingly, the plasma sample already obtained from the suspect patient to be screened is exposed to a magnetic field and radio frequency energy to generate a nuclear magnetic signal which is then processed to obtain a value for C-13.
  • the olefinic region, 120-140 ppm, of the spectrum is examined. Two peaks will appear, one at approximately 128-129 ppm and another at approximately 130-131 ppm, about 2 ppm apart.
  • the ratio of the resonance at the general region of 128 ppm to that at 130 ppm is determinative of cancer.
  • the ratio of the height of those two resonances (128/130 ppm) is 0.9 or greater, i.e. the resonance peak at 128 ppm is approximately equal to or taller than that at 130 ppm.
  • the heights of the peaks are measured by computer from the center of the baseline noise to the top of the peak. In readings of plasma from patients with untreated cancer, the ratio of the peak heights is less than 0.86, or the resonance peak at 130 ppm is taller, by at least
  • SUBSTITUTE SHEET 5% than that at 128 ppm. It should be noted that in patients with hypertriglyceridemia, the ratio of the height of the resonances (128/130 ppm) is the same as normal control values. Accordingly, the computer will calculate the ratio of the peak heights already measured, and if the ratio is greater than a stored value will diagnose the patient as healthy, but otherwise will render a diagnosis of cancer. In a preferred embodiment, the stored value is 0.9.
  • FIGS. 5A and 5B show the olefinic regions of spectra taken at 125.76 MHz with broadband proton decoupling from a normal control patient and an untreated cancer patient.
  • the ratio is 1.14 in the normal control patient and in FIG. 5B the ratio is 0.70 in the untreated cancer patient.
  • the ratio ranged from 1.05 to 1.68.
  • the changes in the olefinic region of the spectra of untreated cancer patients can be explained by increases or decreases in polyunsaturated fatty acid chains in the lipids.
  • the levels of oleic acid and linoleic acid are particularly indicative.
  • Oleic acid is a monounsaturated fatty acid and is made by the human body. Linoleic acid is a polyunsaturated fatty acid, having two double bonds, and is not made by the human body, but is obtained by consumption. Dietary fatty acids include polyunsaturated acids, such as linoleic acid.
  • SUBSTITUTE SHEET resonance peak in the general region of 128-129 ppm evidences only linoleic acid in the patient.
  • a resonance peak at the general region of 130-131 ppm evidences both oleic and linoleic acid in the patient.
  • the resonance peak at 130 ppm will be higher, reflecting the decreased linoleic acid in both peaks. If, however, the peak at 128 ppm is not shorter than that at 130 ppm by more than 7%, no depression, or an insignificant depression, of linoleic acid levels has occurred, and the positive result obtained from the proton NMR spectra is confirmed as a false positive. In that case, the apparatus renders a diagnosis of no cancer present.
  • the spectral region between 48 ppm and 80 ppm is far more complex in untreated cancer plasma than in normal control or hypertriglyceridemia plasma.
  • “more complex” is meant that there are more resonance peaks in the region. A resonance peak is counted by the program if its height is at least 50% greater than that of the background noise during a normal testing period. As those skilled in the art will know, the longer data is collected, the more noise lessens and the more clearly peaks show.
  • FIGS. 6A and 6B show this region for normal control and untreated cancer plasma, respectively. These spectra were obtained at 125.76 MHz using a 5 mm sample tube and 14 hour accumulations. C-13 spectra with adequate information can also be obtained at 90.5 MHz in 10 mm or longer sample tubes. Of course, changes to various parameters of the conditions under which the test can be run will be evident to those skilled in the art.
  • SUBSTITUTE SHEET C-13 NMR spectroscopy can be performed initially on a patient as a method to diagnose the presence of cancer, without first performing a proton NMR spectroscopy as described above.
  • the C-13 NMR spectroscopy is time consuming, and therefore expensive to perform. While a proton NMR spectroscopy generally takes 30 seconds to perform, C-13 spectroscopy may take anywhere from one to fifteen hours. This increases costs accordingly. Accordingly, in a preferred embodiment, C-13 spectroscopy is used to verify the positive results obtained from the proton NMR spectra to illuminate statistically and clinically significant differences in a plasma C-13 spectra between true and false positive results from the proton water suppressed NMR spectroscopy test.
  • an NMR spectrometer with a magnet at constant field strength is used and the NMR signal is Fourier transformed, with the full linewidth at half-height for proton resonances of methyl and methylene groups, and then C-13 resonances of linoleic and oleic acid, being the NMR parameters of interest.
  • FIG. 9 shows a flowchart of the operation of the apparatus in which the apparatus first obtains a sample of bodily fluid and then submits it to NMR spectroscopy to obtain a water-suppressed H-l spectrum. The apparatus then selects and measures resonance lines and finds an average linewidth which it compares with the value 33 Hz, a predetermined normal value. If the average linewidth is greater than 33 Hz, the apparatus will yield a negative diagnosis; otherwise, it will
  • SUBSTITUTE SHEET obtain a measure of the triglyceride level in the patient. If the triglyceride level is less than 190 mg/dl then it will render a positive diagnosis; otherwise, it will obtain a C-13 spectrum of the sample. It will then analyze the C-13 spectrum by measuring the ratio of the peak at 128 ppm to the peack at 130 ppm and by counting the number of peaks in the range 48 ppm to 80 ppm. If the ratio is 0.9 or greater, the machine will yield a negative diagnosis; however, if the ratio is less than 0.9 or there is an abnormally high number of peaks in the range 48 ppm to 80 ppm then the apparatus will diagnose the patient as having cancer.
  • FIG. 7 there is illustrated a nuclear magnetic resonance (NMR) spectrometer 2 which in the preferred embodiment is capable of performing proton and C-13 NMR spectroscopy and which is preferably, but not necessarily, of the type that suppresses the NMR signal of water.
  • NMR nuclear magnetic resonance
  • FIG. 10A shows a program (written using the Bruker DISNMR software package) used to automatically perform the procedures depicted in FIG.10A.
  • FIG. IOC shows a sample program for shimming, corresponding to a carbon-13 spectrum.
  • FIG. 10D shows a sub-program of step 8, RJ FQSET, of the shimming program shown in FIG.
  • FIG. 10E shows a sub-program of step 2, RJ TUNE, of the program shown in FIG. 10B; and
  • FIG. 10F shows a sub-program of step 6, RJ FQSET, of the program shown in FIG. 10B.
  • the spectrometer 2 is adapted for examination of a sample 4, which in this example is human blood plasma contained within a test tube 6.
  • the spectrometer 2 contains means 8 for selecting at least one and preferably a plurality such as two NMR resonance lines in the NMR spectrum of the sample 4 and measuring the linewidth of the line or lines so selected.
  • the linewidth is measured at half the height of the line, but this is not necessary and linewidth can be measured at any predetermined fraction of the height of the line in question. Measurement at half of line height is preferred because this is a standard measurement carried out in the field of NMR spectroscopy.
  • Several commercially available computer programs can be used for automatically measuring full linewidths at half height.
  • the means 8 of spectrometer 2 of the invention also measure selected peaks for the examination of the C-13 NMR spectra.
  • the spectrometer 2 also is of conventional construction and includes in addition to all its other structure a means 10 for storing a value or range of values.
  • the spectrometer 2 also includes means 12 for comparing a linewidth which is either measured directly or derived from a plurality of such direct measurements with a value or range of values which represents the value or range of values to be expected from normal patients, i.e. patients who are free of cancer.
  • Means 12 are also used for classifying the measured or derived linewidths, peak heights, and number of peaks as normal (i.e. cancer-free) or abnormal (i.e. cancerous) based upon the stored information. This may be done by comparison, subtraction, or any other appropriate mathematical operation.
  • the selecting and measuring means 8 is pre-adjusted to measure the linewidths of the methyl and methylene groups of the lipoprotein lipids, and the peak heights and number of peaks in the C-13 NMR spectra. This may include suppressing the signal of water from the NMR spectrum of the sample 4, or may alternatively be done directly where the spectrometer 2 is sensitive enough to do so.
  • the linewidths of the methyl and methylene groups are averaged by the measuring means 8 to produce a composite linewidth which is the mathematical mean of the two.
  • This composite linewidth is compared with 33 Hz, the value which is preferably stored in the means 10, by the
  • the method of the present invention was applied to a group of 135 patients undergoing breast biopsy for palpable and non-palpable breast lesions.
  • blood was collected and maintained at 4°C until centrifugation.
  • Blood was collected in non-siliconized vacutainer tubes containing 70 microliters of a solution of 15% Na 2 EDTA.
  • Plasma was separated and stored at 4 C until NMR analysis. Plasma samples were never frozen because freezing destroys lipoprotein lipid structural integrity. Samples which showed any visible sign of hemolysis were excluded.
  • Plasma triglyceride concentrations were measured (Damon Clinical Laboratories, Westwood, Massachusetts) on all fresh plasma samples. All spectra were obtained at 21°C using an improved spectrometer of the present invention operating at 360 MHz for proton (H-l) and 90.5 MHz for carbon (C-13). Additional C-13 spectra were obtained on an 11.8 T Bruker AM spectrometer operating at 125.7 MHz. All studies were carried out in 5 mm OD sample tubes (Wilmad, Vineland, New Jersey; #507PP or #528PP) . Each sample, containing 0.6 ml plasma, was shimmed individually on the area of the proton free induction
  • the sample was spun during shimming of the Z shim coils and during data acquisition.
  • Our H-l spectra were acquired using presaturation to suppress water and an inversion-recovery sequence to null any lactate methyl protons present.
  • the presaturation pulse was 4.0 sec, with a delay of about 0.8 sec between the 180° and 90° pulse.
  • Eight FIDs were signal averaged and then Fourier transformed following multiplication by an exponential resulting in 2 Hz line-broadening.
  • the portion of the spectrum form 0.5 to 1.6 ppm was phased so that the baseline level at the edges of the plot was the same. This resulted in defective phasing of other (non-plotted) portions of the spectra.
  • C-13 spectra were obtained at 8.45 T and 11.5 T signal with broadband proton decoupling by averaging between 2,000 and 28,000 FIDs depending on signal-to-noise level and resolution desired.
  • the sample was identical to the samples for H-l spectra except 100 microliters of D hin0 was added for
  • the patients in the study were a group of otherwise healthy women, outpatients, referred for evaluation because of an abnormality on a routine breast examination or a screening mammogram.
  • the sensitivity and specificity were 93% and 95%, respectively.
  • the predictive value of a positive test was 84%, and the predictive value of a negative

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  • Physics & Mathematics (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Spectroscopy & Molecular Physics (AREA)
  • High Energy & Nuclear Physics (AREA)
  • Condensed Matter Physics & Semiconductors (AREA)
  • General Physics & Mathematics (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Magnetic Resonance Imaging Apparatus (AREA)

Abstract

On a mis au point une technique et un appareil de détection du cancer à l'aide de la résonance magnétique nucléaire (RMN). Spécifiquement, les paramètres RMN des protons de groupes méthyle et/ou méthylène de lipides sont déterminés puis comparés par rapport à une valeur correspondante de patients sains. Selon les modes de réalisation préférés, on utilise un spectromètre de RMN amélioré afin de produire un spectre pour des composants non aqueux du sang, de sérum sanguin ou de plasma sanguin, et l'on mesure automatiquement la largeur des groupes méthyle et/ou méthylène à mi-hauteur, comme détermination de temps (T2) de relaxation de spin-spin, laquelle constitue le paramètre utilisé à des fins de comparaison avec des contrôles de santé. Dans le cas où un affichage positif est obtenu, le niveau de triglycérides du plasma est déterminé, et s'il est élevé, l'échantillon de liquide biologique du patient est à nouveau soumis à une spectroscopie magnétique nucléaire C-13.
EP19900915646 1989-10-06 1990-10-04 Nmr apparatus and method for detecting cancer Withdrawn EP0494969A4 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US41818289A 1989-10-06 1989-10-06
US418182 1989-10-06

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EP0494969A1 true EP0494969A1 (fr) 1992-07-22
EP0494969A4 EP0494969A4 (en) 1992-09-16

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EP (1) EP0494969A4 (fr)
JP (1) JPH05500918A (fr)
AU (1) AU6605290A (fr)
BR (1) BR9007724A (fr)
CA (1) CA2067357A1 (fr)
FI (1) FI921432A0 (fr)
WO (1) WO1991004706A1 (fr)

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GB2366867A (en) * 2000-09-14 2002-03-20 Rolls Royce Plc NMR detection of contaminants or additives in oil
JP2003130937A (ja) * 2001-10-24 2003-05-08 Hitachi Ltd 溶液用核磁気共鳴分析装置

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US4918021A (en) * 1986-02-26 1990-04-17 The Beth Israel Hospital Association Process for the detection of cancer
US4933844A (en) * 1988-09-26 1990-06-12 Otvos James D Measurement of blood lipoprotein constituents by analysis of data acquired from an NMR spectrometer

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JPH05500918A (ja) 1993-02-25
FI921432A7 (fi) 1992-04-01
WO1991004706A1 (fr) 1991-04-18
EP0494969A4 (en) 1992-09-16
AU6605290A (en) 1991-04-28
BR9007724A (pt) 1992-08-18
CA2067357A1 (fr) 1991-04-07
FI921432A0 (fi) 1992-04-01

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