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

• Colorectal cancer is one of the most common cancers in the U.S.A. and Canada accounting for approximately 146,000 new cases in 1999. The lifetime risk that an individual in North America will develop colorectal cancer is about 5 - 6 %. Symptoms associated with colorectal cancer, including blood in the stool, anemia, abdominal pain and alteration of bowel habits often become apparent only when the disease has advanced significantly. It is well known that prognosis for a patient depends largely on the stage of the disease at the time of diagnosis. In fact, whereas the five-year survival for a patient whose colorectal cancer is detected at an early stage is 92%, survival decreases to about 60% in patients with regional spread, and to about 6% in those with distant metastasises. Accordingly, it is important to detect the precursor adenomas and cancer as early as possible to increase the chances of successful therapeutic intervention.
• Colorectal cancer meets these requirements and, thus, is an ideal candidate for such a program.
• the natural history of colorectal cancer namely the progression from adenoma to adenocarcinoma occurring over a number of years (5 - 15), also makes it a suitable target.
• the cost benefit analysis for the early detection of colorectal cancer has also been shown to be favourable (Bolin, TD. Cost benefit of early diagnosis of colorectal cancer. Scand J Gastroenterol 1996; 31 Suppl 220:142-146).
• the screening technique itself also has to meet a series of criteria, such as, high sensitivity and specificity, low cost, safety and simplicity.
• digital rectal examination DRE
• fecal occult blood test FBT
• barium enema fecal occult blood test
• direct colon visualization sigmoidoscopy and colonoscopy
• DRE involves examining the rectum using a finger. This method detects cancers that can be palpated and are within reach of the finger. A negative DRE provides little reassurance that a patient is free of cancer, because fewer than 10% of colorectal cancers can be palpated by the examining finger.
• FOBT detects hidden blood in the stool by chemical means on the assumption that all colorectal cancers bleed.
• the FOBT method has low sensitivity, moderate specificity and is usually not good for early detection.
• a major drawback of this technique is that more than half of the cancers discovered by this method followed by x-ray or endoscopy are usually beyond the limit of early staging.
• a false positive rate of 10-12% is expected when the patients tested are on an unrestricted diet.
• Estimates of the positive predictive value range from 2.2 to 50%.
• the guaiac tests have a very low sensitivity, generally around 50% (Ransohoff DF, Lang CA., Screening for colorectal cancer with the fecal occult blood test; a background paper. Ann Intern Med 1997; 126:811-822).
• the use of FOBT is based on the assumption that colorectal cancers are associated with bleeding. However, some colorectal cancers bleed intermittently and others not at all.
• a barium enema involves an x-ray of the bowel using a contrast agent.
• the enema can be a single or double contrast.
• the main radiologic signs of malignancy include muscosal distraction, abrupt cut-off and shouldering and localized lesions with sharp demarcations from uninvolved areas.
• the estimated sensitivity of double contrast barium enema for cancer and large polyps is only about 65-75% and even lower for small adenomas.
• double contrast barium enema has a false-negative rate of 2-18%.
• the method involves exposure to radiation, the repeated use of which may not be safe. Perforation from barium enema is extremely uncommon, but when it happens it is frequently fatal or leads to serious long term problems as a result of barium spillage into the abdominal cavity.
• Endoscopes A variety of instruments (collectively called endoscopes) are used for examining the bowel. Endoscopes can be rigid or flexible with varying lengths. Rigid sigmoidoscopes are usually 25 cm long while flexible sigmoidoscopes are 35 or 60 cm long.
• a colonoscope is a 130 - 160 cm flexible viewing instrument for examining the entire colon. Biopsies are taken from suspicious looking areas while viewing the colon through the endoscope. The flexible sigmoidoscopy examination is limited to the left side of the colon and rectum. Approximately 1/3 of neoplastic tumors occur in areas proximal to the splenic flexure that are inaccessible by sigmoidoscopy.
• MRS Magnetic resonance spectroscopy
• United States Patent No. 5,318,031 issued to Mountford et al on June 7, 1997 describes a method for determining chemical states of living animal or human tissue using NMR and 2D-COSY (two-dimensional correlation) NMR spectroscopy, and comparing measured values to reference measurements of normal, abnormal and transitions state tissue.
• NMR and 2D-COSY two-dimensional correlation
• the object of the present invention is to provide a relatively simple, non-invasive method of detecting colorectal adenomas and cancer which meets the above defined criteria of high sensitivity and specificity, low cost and safety.
• the invention relates to a method of detecting the presence of colorectal adenomas and colorectal cancer in a patient comprising the steps of subjecting a liquid suspension of a stool sample from the patient to magnetic resonance spectroscopy; and comparing the resulting spectrum with the magnetic resonance spectra of stool from non-cancerous subjects, with observed differences in spectra being indicative of cancer.
• the performing of spectral analysis on human stool offers a significant advantage over other methods, because the collection of the specimen is non- invasive and presents no risk to the patient. Moreover, no special processing of the sample is required prior to analysis.
• the use of 2D-COSY spectroscopy is preferred, because while one- dimensional 1 D MRS can give information on the nature and relative intensities of biochemical species present in a given sample, it does not always allow an exclusive and unambiguous identification of some of the species.
• Two dimensional MRS can be defined as a series of 1 D MR spectra acquired with varying pulse delays, and subsequently Fourier-transformed along two axes (the acquisition time and the delay time).
• Figure 1 is a 360 MHz 1 H MR symmetrized COSY spectrum of human stool from a subject with a normal colon;
• Figure 2 is a 360MHz 1 H MR symmetrized COSY spectrum of human stool from a subject with adenomatous polyps (1 cm and 3 mm tubular adenomas in ascending colon);
• Figure 3 is a 360 MHZ 1 H MR symmetrized COSY spectrum of human stool from a subject with colorectal cancer (adenocarcinoma in the right colon, stage TisNOMX, with residual villus adenoma).
• the subjects were instructed to collect the first bowel movement after the start of their colonic preparation for colonoscopy or surgery scheduled for the following day.
• the stool samples were collected at the University of Texas M.D. Anderson Cancer Center.
• the samples were kept frozen in the patients' refrigerators for an average of 24-48 hours prior to their delivery to the hospital in small ice chests (mailers). They were then stored in a -70 °C freezer until being shipped to the National Research Council Institute for Biodiagnostics, Winnipeg,
• Teflon (trademark for polytetrafluoroethylene) plug. This was then put in a standard
• Colonoscopy was the standard to which the results were compared. Information such as the exact location of the neoplasia (tumor or polyp), the stage of the cancer, the histological type of polyps (i.e. tubular, villus, or tubulovillous), and the size and number of polyps was provided for each patient, where applicable. Results
• the reported sensitivity of FOBT for a single test for colorectal carcinoma ranges between 30% to 50%, while its specificity is estimated to be about 90%. These values are lower for adenomatous polyps.
• Table 3 the sensitivity and positive predictive value of the method of the present invention is excellent, at least in this small sample. The diagnostic accuracy improves when all the subjects with some sort of abnormality from the analysis are excluded (compare row 3 vs. row 4 in Table 3). Although the sensitivity stays the same, both the specificity and the positive predictive value decrease considerably with the inclusion of such subjects. The last row, however, is the one that reflects the true clinical picture.
• the true specificity and positive predictive value of the analysis could actually be higher than set out herein.
• the MRS method is to be of any use in the screening of asymptomatic subjects, it has to be able to identify those subjects with adenomatous polyps. A large percentage (70%) of these subjects gave positive MRS results.
• the malignant potential of polyps depends on their size, histological type, and number of polyps. It is known that polyps less than 1 cm in size are less likely to become malignant, and 2/3 of those subjects who gave negative MRS results had polyps 1 cm or less in size. However, neither the histological type nor the number of polyps showed any correlation with the (accuracy of) MRS diagnosis.
• the use of the method of the present invention makes it possible to make better decisions as to whether to perform full colonoscopy on a patient.

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• Physics & Mathematics (AREA)
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• Life Sciences & Earth Sciences (AREA)
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• 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)

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• 2000
  • 2000-05-16 CA CA002373598A patent/CA2373598C/en not_active Expired - Fee Related
  • 2000-05-16 AU AU48511/00A patent/AU772906B2/en not_active Ceased
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  • 2000-05-16 EP EP00930747A patent/EP1188045A4/en not_active Withdrawn
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