Infrared analysis of benign tumors
11513112 · 2022-11-29
Inventors
Cpc classification
International classification
Abstract
A method including identifying a subject as possibly having a benign tumor in ovarian tissue and obtaining an infrared spectrum of a PBMC sample of the subject and assessing a characteristic of the sample at at least one wavenumber selected from the group consisting of: 754.0±4 cm-1, 1103.6±4 cm-1, 1121.4±4 cm-1, 1346.1±4 cm-1, 1376.9±4 cm-1, 753.50±4 cm-1, 850.5±4 cm-1, 918.9±4 cm-1, 1058.7±4 cm-1, 1187.9±4 cm-1 and 1651.7±4 cm-1. Using a processor comparing, at the at least one wavenumber, the infrared spectrum to an infrared spectrum obtained from a PBMC sample from a person without a benign tumor, to detect a difference between the infrared spectrum of the PBMC sample of the subject and the infrared spectrum obtained from the PBMC sample from the person without a benign tumor. Other applications are also described.
Claims
1. A method comprising: depositing a biological sample from a subject on a slide; drying the slide at 26-34° C. for about 0.5 hour; and subsequently to the drying, analyzing the sample by infrared spectroscopy.
2. The method according to claim 1, wherein drying the slide comprises drying the slide at 30-34° C.
3. The method according to claim 1, wherein the method further comprises isolating, using a gradient, a blood plasma sample from a peripheral blood sample taken from the subject, and wherein depositing the biological sample on the slide comprises depositing the isolated blood plasma sample on the slide.
4. The method according to claim 1, wherein the method further comprises isolating, using a gradient, a Peripheral Blood Mononuclear Cells (PBMC) sample from a peripheral blood sample taken from the subject, and wherein depositing the biological sample on the slide comprises depositing the isolated Peripheral Blood Mononuclear Cells (PBMC) sample on the slide.
5. The method according to claim 1, wherein the slide is a zinc selenide (ZnSe) slide, and wherein depositing the biological sample on the slide comprises depositing the biological sample on the zinc selenide (ZnSe) slide.
6. The method according to claim 1, for improving infrared (IR) spectrum analysis of the sample.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
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DETAILED DESCRIPTION OF THE EMBODIMENTS
(17) Some applications of the present invention comprise apparatus and methods for performing differential diagnosis of benign and malignant solid tumors by FTIR microspectroscopy (MSP) techniques. In accordance with some applications of the present invention, FTIR microspectroscopy is used to differentially diagnose a solid tumor and a benign tumor based on biochemical properties of a blood and/or plasma sample of a subject. Some applications of the present invention comprise obtaining a blood sample from a subject and analyzing PBMC and/or plasma from the sample by FTIR-MSP techniques for the detection of a malignant or a benign solid tumor. Typically, blood plasma and/or a PBMC sample of a patient having a benign solid tumor is identified as exhibiting FTIR spectra that are different from FTIR spectra produced by blood plasma/PBMC from a subject who has a malignant solid tumor. Additionally, blood plasma and/or a PBMC sample of a patient suffering from a benign solid tumor is identified as exhibiting FTIR spectra that are different from FTIR spectra produced by blood plasma/PBMC from a subject who does not suffer from a malignant or benign solid tumor (for some applications the control group may include subjects suffering from a pathology that is not a solid tumor). Accordingly, some applications of the present invention provide a useful method for diagnosing a cancer patient and distinguishing between a cancer patient and a subject with a benign tumor.
METHODS USED IN SOME EMBODIMENTS OF THE PRESENT INVENTION
(18) A series of protocols are described hereinbelow which may be used separately or in combination, as appropriate, in accordance with applications of the present invention. It is to be appreciated that numerical values are provided by way of illustration and not limitation. Typically, but not necessarily, each value shown is an example selected from a range of values that is within 20% of the value shown. Similarly, although certain steps are described with a high level of specificity, a person of ordinary skill in the art will appreciate that other steps may be performed, mutatis mutandis.
(19) In accordance with some applications of the present invention, the following methods were applied:
(20) Obtaining Patient and Control Populations
(21) All studies were approved by the local Ethics Committee of the Edith Wolfson Medical Center, Holon, Israel, and Beilinson Hospital, Israel. Studies were conducted in accordance with the Declaration of Helsinki. Qualified personnel obtained informed consent from each individual participating in this study.
(22) A first patient population included subjects diagnosed with solid tumors in breast and gastrointestinal tissue as set forth in the following Table A:
(23) TABLE-US-00001 TABLE A Gastrointestinal tissue Breast tissue (colorectal) Control Benign Cancer Control Benign Cancer Number of 15 15 29 15 14 35 subjects. Mean age ± SD 42 ± 14 46 ± 21 60 ± 13 55 ± 16 71 ± 10 67 ± 14 Gender Male — — — 8 7 19 Female 15 15 29 7 7 16 Disease stage Pre-malignant — — 0 — — 6 I — — 11 — — 6 II — — 13 — — 13 III — — 2 — — 8 IV — — 0 — — 2
(24) The diagnosis of cancer was determined by clinical, surgical, histological, and pathologic diagnosis. The pathologic stage of the tumor was determined according to tumor-node-metastasis (TNM) classification, as described in “TNM Classification of Malignant Tumours”, by Sobin LH. et al., 7th Edition, New York: John Wiley, 2009. Clinical details for breast and colorectal cancer patient is presented in
(25) A control group (n=15) included healthy volunteers.
(26) A second patient population included subjects diagnosed with solid tumors in gynecological tissue as set forth in the following Table B:
(27) TABLE-US-00002 TABLE B Control Breast Gastrointestinal Lung Other Mean 52 ± 14 59 ± 12 66 ± 13 59 ± 8 47 ± 15 age ± SD Gender Male 18 0 27 9 3 Female 37 42 24 2 2 Disease Pre 0 0 6 0 0 stage I 0 11 3 0 1 II 0 17 13 1 0 III 0 4 11 3 1 IV 0 1 8 7 0
(28) The diagnosis of cancer was determined by clinical, surgical, histological, and pathologic diagnosis. The pathologic stage of the tumor was determined according to tumor-node-metastasis (TNM) classification, as described in “TNM Classification of Malignant Tumours”, by Sobin LH. et al., 7th Edition, New York: John Wiley, 2009.
(29) A control group (n=28) included healthy volunteers.
(30) An additional control group consisted of pregnant women (n=11).
(31) Collection of Blood Samples
(32) 1-2 ml of peripheral blood was collected in 5 ml EDTA blood collection tubes (BD Vacutainer® Tubes, BD Vacutainer, Toronto) from patients and controls using standardized phlebotomy procedures. Samples were processed within two hours of collection.
(33) Extraction of Peripheral Blood Mononuclear Cells (PBMC)
(34) Platelet-depleted residual leukocytes obtained from cancer patients and healthy controls were applied to Histopaque 1077 gradients (Sigma Chemical Co., St. Louis, Mo., USA) following manufacturer's protocol to obtain PBMC.
(35) The cells were aspirated from the interface, washed twice with isotonic saline (0.9% NaCl solution) at 500 g for 7 minutes, and resuspended in 10 ul fresh isotonic saline. The cells were diluted with saline to different concentrations (respectively, by 1×, 2×, 3×, 5× and 6×), and 0.4 ul from each concentration was deposited on zinc selenide (ZnSe) slides to form a uniform layer of dried cells. It is noted that any other suitable slide may be used, e.g., reflection measurements may be carried out using a gold slide. The slides were then air dried for 0.5 h under laminar flow at a temperature of 30±4 C to remove water. The dried cells were then assessed by FTIR microscopy.
(36) Isolation of Plasma from Peripheral Blood Samples
(37) Blood from cancer patients and healthy controls was diluted 1:1 in isotonic saline (0.9% NaCl solution). The diluted blood was applied carefully to Histopaque 1077 gradients (Sigma Chemical Co., St. Louis, Mo., USA) in 15 ml collection tubes, and centrifuged at 400 g for 30 min.
(38) To discard platelets and cell debris, the plasma was transferred to 1.5 ml eppendorf tubes and centrifuged at 6000 g for 10 min. Then, 500 ul of the mid section of the plasma was transferred to a new eppendorf tube, and 0.8 ul of plasma was deposited on a zinc selenide (ZnSe) slide. It is noted that any other suitable slide may be used, e.g., reflection measurements may be carried out using a gold slide. The slide was air dried for 0.5 h under laminar flow at a temperature of 30±4 C to remove water. The dried plasma was then subjected to FTIR microscopy.
(39) FTIR-Microspectroscoy
(40) Fourier Transform Infrared Microspectroscopy (FTIR-MSP) and Data Acquisition Measurements were performed using the FTIR microscope Nicolet Centaurus with a liquid-nitrogen-cooled mercury-cadmium-telluride (MCT) detector, coupled to the FTIR spectrometer Nicolet iS10, using OMNIC software (Nicolet, Madison, Wis.). To achieve high signal-to-noise ratio (SNR), 128 coadded scans were collected in each measurement in the wavenumber region 700 to 4000 cm-1. The measurement site was circular, with a diameter of 100 um and spectral resolution of 4 cm-1 (0.482 cm-1 data spacing). To reduce plasma sample thickness variation and achieve proper comparison between different samples, the following procedures were adopted:
(41) 1. Each sample was measured at least five times at different spots.
(42) 2. Analog to Digital Converter (ADC) rates were empirically chosen between 2000 to 3000 counts/sec (providing measurement areas with similar material density).
(43) 3. The obtained spectra were baseline corrected using the rubber band method, with 64 consecutive points, and normalized using vector normalization in OPUS software as described in an article entitled “Early spectral changes of cellular malignant transformation using Fourier transformation infrared microspectroscopy”, by Bogomolny et al., 2007. J Biomed Opt. 12:024003.
(44) In order to obtain precise absorption values at a given wavenumber with minimal background interference, the second derivative spectra were used to determine concentrations of bio-molecules of interest. This method is susceptible to changes in FWHM (full width at half maximum) of the IR bands. However, in the case of biological samples, all samples (plasma) from the same type are composed of similar basic components, which give relatively broad bands. Thus, it is possible to generally neglect the changes in band FWHM, as described in an article entitled “Selenium alters the lipid content and protein profile of rat heart: An FTIR microspectroscopy study”, by Toyran et al., Arch. Biochem. Biophys. 2007 458:184-193.
(45) Spectra Processing and Statistical Analysis
(46) The IR spectrum reflects biochemical data of the measured sample. To distinguish between cancer and control groups, specific sections from the selected interval of the spectra were selected as determined by the T-test. The differences were considered significant at P<0.05. Data reduction was implemented by Principal Component Analysis (PCA). If each one of the wave numbers is considered as a direction, then the PCA technique searched for new directions in the data that have largest variance and subsequently projected the data onto a new multi-dimensional space. Following the PCA, Fisher's Linear Discriminant Analysis (FLDA) was performed to classify between the cancer and control groups. Leave-One-Out Cross-Validation (LOOCV), which is a common method in FTIR spectral analysis, was used to evaluate the classifier performance. The data were verified by additional unsupervised analytical methods such as cluster analysis using Ward's method and Euclidean distances to further verify the analysis (STATISTICA, StatSoft, Tulsa, Okla.).
Experimental Data
(47) The experiments described hereinbelow were performed by the inventors in accordance with applications of the present invention and using the techniques described hereinabove.
(48) The experiments presented hereinbelow with reference to Examples 1-4 demonstrate that in accordance with some applications of the present invention, analysis of PBMC samples and/or plasma samples by FTIR-MSP techniques can be used for differential diagnosis of benign and malignant solid tumors based on the FTIR-MSP spectral pattern at selected wavenumbers.
Example 1
(49) In a set of experiments, differential diagnosis of benign breast tumors and malignant breast tumors was performed based on a FTIR-MSP spectral pattern at selected wavenumbers of PBMC samples.
(50) In accordance with applications of the present invention, PBMC samples from 15 healthy controls were analyzed by FTIR-MSP, and a typical FTIR-MSP spectral pattern was established for control PBMC. Additionally, PBMC samples from 29 breast cancer patients were subjected to FTIR-MSP analysis and compared to the control FTIR-MSP spectral pattern. Additionally, PBMC samples from 15 subjects with a benign tumor in breast tissue were subjected to FTIR-MSP analysis and compared to the control FTIR-MSP spectral pattern and to the breast cancer FTIR-MSP spectral pattern. The PBMC samples were obtained by preliminary processing of the peripheral blood in accordance with the protocols described hereinabove with reference to extraction of peripheral blood mononuclear cells (PBMC). The PBMC samples were then analyzed by FTIR-MSP, in accordance with the protocols described hereinabove with reference to FTIR-MSP.
(51) Reference is made to
(52)
(53) Table C represents some of the main IR absorption bands for PBMC cells, and their corresponding molecular functional groups:
(54) TABLE-US-00003 TABLE C Wavenumber (cm − 1 ± 4) Assignment 2958 ν.sub.as CH.sub.3, mostly proteins, lipids 2922 ν.sub.as CH.sub.2, mostly lipids, proteins 2873 ν.sub.s CH.sub.3, mostly proteins, lipids 2854 ν.sub.s CH.sub.2, mostly lipids, proteins ~1,656 Amide I ν C═O (80%), ν C—N (10%), δ N—H ~1,546 Amide II δ N—H (60%), ν C—N (40%) 1400 ν COO—, δ s CH3 lipids, proteins 1313 Amide III band components of proteins 1240 ν.sub.as PO.sub.2.sup.−, phosphodiester groups of nucleic acids 1170 C—O bands from glycomaterials and proteins 1155 νC—O of proteins and carbohydrates 1085 νs PO2— of nucleic acids, phospholipids, proteins 1053 ν C—O & δ C—O of carbohydrates 996 C—C & C—O of ribose of RNA 967 C—C & C—O of deoxyribose skeletal motions of DNA 780 sugar-phosphate Z conformation of DNA 740 ν N═H of Thymine
(55) Reference is made to
(56) The mean±standard error of the mean SEM for each of the data sets (healthy, benign, breast cancer) is represented by the thickness of the graph lines representing the healthy, benign, and breast cancer groups, in accordance with the figure legend, as shown in
(57) Reference is made to
(58) Table D lists wavenumbers that were identified in this set of experiments as presented in
(59) TABLE-US-00004 TABLE D Healthy Healthy control vs. control vs. Benign vs. Benign Cancer Cancer Wavenumber Wavenumber Wavenumber (cm−1 ± 4) (cm−1 ± 4) (cm−1 ± 4) 712.1 711.6 729.0 725.6 838.9 753.1 745.8 946.9 758.9 758.9 1010.5 847.1 773.8 1082.4 870.2 784.9 1100.7 882.8 793.6 1115.1 1003.8 798.4 1140.7 1011.0 803.7 1176.8 1023.5 837.4 1213.0 1034.1 845.2 1254.0 1047.2 862.5 1278.6 1071.7 871.2 1366.3 1080.9 882.3 1437.2 1128.2 897.7 1443.0 1141.7 903.5 1453.1 1158.0 928.6 1459.4 1173.0 945.9 1465.2 1181.7 963.3 1473.3 1197.6 1027.9 1498.4 1253.5 1077.5 1501.8 1341.7 1116.1 1507.1 1372.1 1129.6 1512.4 1423.2 1182.6 1524.9 1437.2 1196.6 1528.3 1449.2 1213.0 1532.2 1466.1 1238.6 1535.5 1475.3 1271.8 1542.8 1498.9 1278.1 1548.1 1502.3 1292.6 1551.9 1509.0 1320.0 1559.6 1524.9 1332.6 1568.8 1536.0 1537.5 1608.3 1542.3 1544.2 1616.1 1548.1 1612.7 1618.9 1559.2 1632.9 1626.2 1576.5 1644.0 1635.3 1602.1 1702.4 1641.1 1612.7 1712.0 1645.5 1627.1 1778.5 1647.9 1637.3 1653.2 1642.1 1658.5 1654.1 1674.4 1659.9 1684.5 1667.6 1693.2 1678.7 1698.5 1709.6 1701.4 1730.8 1762.1
(60) For some applications, one, two, three, or more of the following wavenumbers selected from Table Dare used to differentiate between the absence of a tumor and a malignant breast tumor; 1140.7±±4 cm-1, 1254.0±4 cm-1, 1473.3±4 cm-1, 1551.9±4 cm-1, 1635.3±4 cm-1, and 1658.5±4 cm-1.
(61) For some applications, one, two, three, or more of the following wavenumbers selected from Table D are used to differentiate between the absence of a tumor and a benign breast tumor: 837.4±4 cm-1, 1027.9±4 cm-1, 1182.6±4 cm-1, 1213.0±4 cm-1, 1278.1±4 cm-1, 1544.2±4 cm-1.
(62) For some applications, one, two, three, or more of the following wavenumbers selected from Table D are used to differentiate between a malignant breast tumor and a benign breast tumor: 1011.0±4 cm-1, 1071.7, 1141.7±4 cm-1, 1158.0±4 cm-1, 1181.7±4 cm-1, 1502.3±4 cm-1.
Example 2
(63) In a set of experiments, differential diagnosis of benign breast tumors and malignant breast tumors was performed based on a FTIR-MSP spectral pattern of plasma samples at selected wavenumbers
(64) In accordance with applications of the present invention, plasma samples from 15 healthy controls were analyzed by FTIR-MSP, and a typical FTIR-MSP spectral pattern was established for control plasma. Additionally, plasma samples from 29 breast cancer patients were subjected to FTIR-MSP analysis and compared to the control FTIR-MSP spectral pattern. Additionally, plasma samples from 15 subjects with a benign tumor in breast tissue were subjected to FTIR-MSP analysis and compared to the control FTIR-MSP spectral pattern and to the breast cancer FTIR-MSP spectral pattern. The plasma samples were obtained by preliminary processing of the peripheral blood in accordance with the protocols described hereinabove with reference to isolation of plasma from peripheral blood samples. The blood plasma samples were then analyzed by FTIR-MSP, in accordance with the protocols described hereinabove with reference to FTIR-MSP.
(65) Reference is made to
(66)
(67) Reference is made to
(68) The mean SEM for each of the data sets (healthy, benign, breast cancer) is represented by the thickness of the graph lines representing the healthy, benign, and breast cancer groups, in accordance with the figure legend, as shown in
(69) Reference is made to
(70) Table E1 lists wavenumbers that were identified in this set of experiments as presented in
(71) TABLE-US-00005 TABLE E1 Healthy control vs. Healthy control vs. Benign vs. Benign Cancer Cancer Wavenumber Wavenumber Wavenumber (cm−1 ± 4) (cm−1 ± 4) (cm−1 ± 4) 724.1 723.7 713.5 761.3 728.0 726.5 768.5 746.8 740.5 897.7 752.6 756.0 924.7 769.9 761.7 943.5 840.8 772.8 959.9 883.2 867.8 980.6 916.5 1020.2 989.3 925.7 1200.5 1013.4 943.0 1249.2 1032.7 958.9 1267.0 1049.1 965.2 1330.6 1054.9 980.6 1355.2 1089.6 990.7 1378.9 1117.5 1021.6 1427.1 1134.4 1033.7 1437.7 1146.0 1081.4 1443.9 1152.3 1088.6 1467.6 1169.6 1094.9 1474.3 1255.4 1101.6 1479.6 1266.5 1118.0 1494.6 1279.1 1146.5 1502.3 1286.3 1153.2 1512.4 1300.3 1180.7 1525.4 1310.9 1200.5 1528.8 1325.3 1232.8 1532.2 1343.7 1250.6 1535.1 1349.0 1279.1 1542.3 1388.0 1288.2 1547.1 1396.2 1305.1 1552.9 1402.5 1312.8 1560.1 1411.2 1326.8 1565.9 1425.6 1342.2 1569.8 1453.6 1350.9 1612.2 1466.6 1386.6 1616.1 1581.3 1406.8 1619.4 1587.1 1424.2 1626.7 1731.3 1429.5 1634.9 1741.9 1453.6 1641.1 1752.0 1480.1 1645.9 1757.3 1498.4 1647.9 1768.9 1502.3 1653.2 1779.5 1512.4 1659.4 1524.9 1667.6 1528.3 1674.9 1532.2 1698.5 1534.6 1736.1 1542.3 1748.6 1547.1 1754.4 1551.9 1758.8 1559.6 1765.5 1584.2 1770.8 1612.2 1776.1 1619.4 1780.5 1626.7 1785.8 1635.8 1790.6 1637.3 1645.9 1652.7 1659.9 1667.6 1673.9 1699.0 1741.9 1756.8 1767.9
(72) For some applications, one, two, three, or more of the following wavenumbers selected from Table E1 are used to differentiate between the absence of a tumor and a benign breast tumor: 761.3±4 cm-1, 1117.5±4 cm-1, 1152.3±4 cm-1, 1310.9±4 cm-1, 1388.0±4 cm-1, and 1453.6±4 cm-1.
(73) For some applications, one, two, three, or more of the following wavenumbers selected from Table E1 are used to differentiate between the absence of a tumor and a malignant breast tumor: 925.7±4 cm-1, 1153.2±4 cm-1, 1200.5±4 cm-1, 1350.9±4 cm-1, 1453.6±4 cm-1, 1637.3±4 cm-1.
(74) For some applications, one, two, three, or more of the following wavenumbers selected from Table E1 are used to differentiate between a malignant breast tumor and a benign breast tumor: 761.7±4 cm-1, 1020.2±4 cm-1, 1249.2±4 cm-1, 1560.1±4 cm-1, 1647.9±4 cm-1, 1736.1±4 cm-1.
(75) Reference is now made to
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(80) Table E2 represents the data corresponding to the numbers in
(81) TABLE-US-00006 TABLE E2 1 CANCER23 2 CANCER22 3 CANCER21 4 CANCER13 5 BEN6 6 CANCER17 7 CANCER14 8 CANCER24 9 H6 10 CANCER11 11 CANCER20 12 H5 13 CANCER27 14 CANCER19 15 CANCER25 16 CANCER18 17 CANCER15 18 CANCER6 19 BEN7 20 BEN5 21 CANCER9 22 CANCER16 23 CANCER5 24 CANCER7 25 CANCER1 26 CANCER3 27 H7 28 CANCER12 29 CANCER10 30 HGDISP 31 H4 32 H14 33 BEN8 34 H13 35 BEN12 36 BEN14 37 H12 38 H10 39 H9 40 CANCER28 41 H11 42 H8 43 BEN13 44 BEN11 45 BEN1 46 CANCER2 47 BEN9 48 BEN3 49 BEN15 50 BEN2 51 BEN10 52 CANCER8 53 H3 54 CANCER26 55 BEN4 56 H2 57 CANCER4 58 H1
(82) Reference is now made to
(83) Table E3 is a table representing clinical data for 23 female breast cancer patients who took part in the studies described herein. In Table E3:
(84) “Location at main organ” column: “R” represents Right breast and “L” represents Left breast
(85) Pathology column: “M” represents Malignant and “U” represents Undetermined
(86) Malignancy type column: “IDC” represents Infiltrating Ductal Carcinoma, and “ILC” represents Infiltrating Lobular Carcinoma.
(87) “LN” means lymph node
(88) “MS” means “mass size” (in mm)
(89) “#m” means “number of masses”
(90) TABLE-US-00007 TABLE E3 Location at # Stage main # # Positive Vascular S Malignancy Age Organ MS m LN LN Margin Invasion Pathology T N M No S Sub type 39 L 20 8 14 2 R1 Y M 1 1 0 2 a IDC 51 L 75 1 3 0 R0 No M 3 0 0 2 b ILC 62 L 21 2 4 0 R0 No M 2 0 0 2 a IDC 55 R 15 1 9 2 R0 No M 1 1 0 2 a IDC 71 R 8 1 3 0 R0 NA M 1 0 0 1 a IDC 77 R 25 1 2 0 R0 NA M 2 0 0 2 a ILC 68 L 20 2 4 0 R0 NA M 1 0 0 1 a Mucinous Carcinoma (Colloid) 69 L 18 1 3 0 R0 Y M 1 0 0 1 a IDC 62 R 10 1 6 0 R0 NA M 1 0 0 1 a IDC 42 L 25 NA 21 13 R0 No M 2 3 0 3 c IDC + ILC 69 R NA 1 8 0 R0 No U Ductal Carcinoma In- Situ (DCIS) 29 R 10 1 3 0 R0 No M 1 0 0 1 a IDC 51 L 28 1 34 6 R0 Y M 2 2 0 3 a IDC 70 L 7 2 5 0 R0 NA M 1 0 0 1 a ILC + Mucinous 57 L NR NR 11 0 NR NR M 2 0 0 2 a IDC 47 R 33 1 10 0 R0 Y M 2 0 0 2 a IDC 51 L 9 1 4 0 R0 NA M 1 0 0 1 a IDC 60 L 45 1 NA NA R0 NA M 2 0 0 2 a IDC 67 R 13 1 3 0 R0 No M 1 0 0 1 a IDC 71 R 10 1 9 0 R0 No M 1 0 0 1 a ILC 58 R 5 1 1 0 R0 NA M 1 0 0 1 a ILC 63 L 20 1 9 1 R0 NA M 1 1 0 2 a IDC 66 R 18 2 2 0 R0 Y M 1 0 0 1 a IDC
(91)
(92) Table F lists wavenumbers that were identified in the set of experiments as presented in
(93) TABLE-US-00008 TABLE F Num. of Num. Size of Malignancy Vascular Positive of Mass type Stage Invasion LN Masses (mm) 729.9 717.4 712.6 717.4 734.3 746.3 737.2 794.0 810.9 761.3 752.6 753.5 750.7 801.3 892.9 777.7 769.0 803.2 774.8 817.7 1261.2 825.9 807.5 818.2 785.4 823.9 1306.1 832.1 884.7 824.9 848.0 830.7 1317.1 885.2 899.1 831.7 855.8 920.8 1324.9 1097.3 911.7 864.0 865.4 925.7 1377.9 1136.3 929.0 881.3 870.7 931.4 1410.2 1168.7 1001.8 919.9 892.9 940.6 1449.7 1277.1 1022.1 958.4 902.0 996.1 1461.3 1286.8 1106.9 1058.7 908.3 1033.7 1489.7 1293.0 1172.5 1136.3 912.2 1064.5 1499.4 1319.6 1250.1 1231.3 928.1 1122.9 1503.7 1324.9 1259.3 1246.3 957.5 1139.7 1510.0 1360.5 1292.6 1281.0 963.8 1161.9 1549.5 1368.7 1344.6 1394.8 1012.9 1185.0 1648.4 1382.2 1353.3 1020.2 1218.8 1753.0 1397.7 1376.9 1058.7 1288.2 1762.6 1417.9 1392.4 1080.4 1323.9 1769.4 1422.7 1409.2 1098.3 1363.4 1780.5 1430.4 1450.2 1148.9 1405.4 1785.3 1484.4 1456.0 1152.3 1502.3 1791.1 1520.6 1461.8 1168.7 1508.5 1725.5 1473.8 1192.3 1593.4 1745.7 1534.6 1241.9 1539.9 1247.7 1560.1 1270.4 1565.9 1307.0 1596.3 1318.6 1632.0 1326.3 1654.6 1337.9 1660.9 1343.2 1763.1 1353.8 1393.8 1398.6 1441.5 1451.7 1458.4 1484.4 1494.6 1529.3 1548.6 1597.3 1604.0 1614.6 1649.3 1663.3 1709.6 1725.5 1729.8 1745.7 1751.5 1762.6 1775.2 1780.5 1785.8
(94) For some applications, one, two, three, or more of the following wavenumbers selected from Table F are used to identify in PBMC samples a distinct spectral pattern caused by the malignancy type of the breast tumor: 785.4±4 cm-1, 848.0±4 cm-1, 1012.9±4 cm-1, 1080.4±4 cm-1, 1148.9±4 cm-1, and 1451.7±4 cm-1.
(95) For some applications, one, two, three, or more of the following wavenumbers selected from Table F are used to distinguish between stage 1 and stage 2 of malignant breast tumors: 717.4±4 cm-1, 801.3±4 cm-1, 823.9±4 cm-1, 920.8±4 cm-1, and 1405.4±4 cm-1.
(96) For some applications, one, two, three, or more of the following wavenumbers selected from Table F are used to identify in PBMC samples a distinct spectral pattern caused by vascular invasion of a breast tumor: 1306.1±4 cm-1, 1489.74 cm-1, 1503.7±4 cm-1, 1648.4±4 cm-1, 1762.6±4 cm-1.
(97) For some applications, one, two, three, or more of the following wavenumbers selected from Table F are used to identify in PBMC samples a distinct spectral pattern caused by the number of positive lymph nodes of a breast cancer patient: 717.4±4 cm-1, 825.9±4 cm-1, 1097.3±4 cm-1, 1293.0±4 cm-1, 1417.9±4 cm-1, and 1520.6±4 cm-1.
(98) For some applications, one, two, three, or more of the following wavenumbers selected from Table F are used to identify in PBMC samples a distinct spectral pattern caused by the number of masses of a breast cancer patient: 752.6 cm-1, 769.0±4 cm-1, 899.1±4 cm-1, 911.7±4 cm-1, 1353.3±4 cm-1, and 1450.2±4 cm-1.
(99) For some applications, one, two, three, or more of the following wavenumbers selected from Table F are used to identify in PBMC samples a distinct spectral pattern caused by the size of the mass (mm) of the breast tumor: 746.3 cm-1, 818.2±4 cm-1, 919.9±4 cm-1, 1136.3±4 cm-1, and 1394.8±4 cm-1.
(100)
(101) Table G lists wavenumbers that were identified in this set of experiments as presented in
(102) TABLE-US-00009 TABLE G Num. of Size of Malignancy Vascular Positive Num. of Mass type Stage Invasion LN Masses (mm) 775.7 729.4 712.6 726.5 766.1 753.1 790.7 757.9 813.3 746.3 792.1 757.9 830.2 763.7 836.5 892.4 837.0 781.5 866.8 780.5 843.2 927.1 856.7 799.3 897.7 797.9 850.9 1023.5 893.4 814.3 922.8 803.2 876.5 1174.9 915.1 890.5 951.2 809.0 902.0 1202.4 931.0 914.1 1070.8 815.7 913.6 1212.5 949.3 922.8 1116.6 825.4 932.4 991.7 946.9 1166.7 831.7 945.4 1021.1 1055.8 1211.6 852.9 1014.9 1043.3 1072.7 1266.5 883.2 1089.1 1073.7 1117.5 1317.6 889.5 1105.0 1102.1 1147.9 1447.3 890.0 1120.4 1116.6 1180.7 1466.6 907.8 1129.1 1156.1 1206.3 1561.6 954.6 1138.3 1173.0 1226.0 1569.3 961.8 1145.5 1179.7 1397.2 1692.7 968.6 1150.8 1206.3 1608.8 1699.5 979.2 1173.0 1235.7 1626.2 1712.0 985.0 1211.1 1266.5 1717.8 997.0 1237.6 1292.1 1736.6 1012.9 1244.8 1317.1 1740.9 1024.0 1266.5 1328.2 1761.2 1040.4 1280.5 1387.5 1057.8 1291.1 1414.0 1077.5 1316.2 1430.9 1095.4 1328.2 1453.1 1110.8 1332.6 1459.4 1134.9 1380.3 1491.7 1147.0 1412.1 1497.0 1190.8 1424.2 1499.9 1201.0 1430.9 1504.7 1224.1 1445.9 1527.3 1255.0 1529.8 1567.4 1264.6 1578.9 1579.4 1271.8 1611.2 1589.1 1282.9 1621.4 1608.3 1344.1 1642.6 1613.6 1355.2 1653.2 1639.2 1366.3 1678.2 1373.6 1737.1 1427.1 1438.6 1512.9 1546.6 1553.9 1560.6 1572.7 1609.3 1616.5 1662.3
(103) For some applications, one, two, three, or more of the following wavenumbers selected from Table G are used to identify in plasma samples a distinct spectral pattern caused by a malignancy type of the breast tumor: 775.7±4 cm-1, 897.7±4 cm-1, 922.8±4 cm-1, 1070.8±4 cm-1, 1447.3±4 cm-1, and 1569.3±4 cm-1.
(104) For some applications, one, two, three, or more of the following wavenumbers selected from Table G are used to distinguish between stage 1 and stage 2 of malignant breast tumors: 763.7±4 cm-1, 809.0±4 cm-1, 889.5±4 cm-1, 961.8±4 cm-1, 1255.0±4 cm-1, and 1190.8±4 cm-1.
(105) For some applications, one, two, three, or more of the following wavenumbers selected from Table G are used to identify in plasma samples a distinct spectral pattern caused by vascular invasion of a breast tumor: 843.24 cm-1, 876.5±4 cm-1, 1145.5±4 cm-1, 1316.2±4 cm-1, 1328.2±4 cm-1, 1412.1±4 cm-1, and 1578.9±4 cm-1.
(106) For some applications, one, two, three, or more of the following wavenumbers selected from Table G are used to identify in plasma samples a distinct spectral pattern caused by the number of positive lymph nodes of a breast cancer patient: 746.3±4 cm-1, 892.4±4 cm-1, 927.1±4 cm-1, 1023.5±4 cm-1, and 1174.9±4 cm-1.
(107) For some applications, one, two, three, or more of the following wavenumbers selected from Table G are used to identify in plasma samples a distinct spectral pattern caused by the number of masses of a breast cancer patient: 856.7 cm-1, 1043.3±4 cm-1, 1116.6±4 cm-1, 1235.7±4 cm-1, 1387.5±4 cm-1, 1504.7±4 cm-1, and 1608.3±4 cm-1.
(108) For some applications, one, two, three, or more of the following wavenumbers selected from Table G are used to identify in plasma samples a distinct spectral pattern caused by the size of the mass (mm) of the breast tumor: 781.5 cm-1, 922.8±4 cm-1, 946.9±4 cm-1, 1072.7±4 cm-1, 1147.9±4 cm-1 and 1206.3±4 cm-1.
Example 3
(109) In a set of experiments, differential diagnosis of benign gastrointestinal (specifically colorectal) tumors and malignant and pre-malignant gastrointestinal tumors was performed based on a FTIR-MSP spectral pattern at a range of wavenumbers of PBMC samples.
(110) In accordance with applications of the present invention, PBMC samples from 15 healthy controls were analyzed by FTIR-MSP, and a typical FTIR-MSP spectral pattern was established for control PBMC. Additionally, PBMC samples from 36 colorectal cancer patients were subjected to FTIR-MSP analysis and compared to the control FTIR-MSP spectral pattern. Additionally, PBMC samples from 14 subjects with a benign tumor in colorectal tissue were subjected to FTIR-MSP analysis and compared to the control FTIR-MSP spectral pattern and to the colorectal cancer FTIR-MSP spectral pattern. The PBMC samples were obtained by preliminary processing of the peripheral blood in accordance with the protocols described hereinabove with reference to extraction of peripheral blood mononuclear cells (PBMC). The PBMC samples were then analyzed by FTIR-MSP, in accordance with the protocols described hereinabove with reference to FTIR-MSP.
(111) For the purpose of the gastrointestinal set of experiments, the 36 colorectal cancer patients included patients with pre-malignant conditions, typically, high-grade dysplasia. As shown hereinbelow, some applications of the present invention allow distinguishing between patients with a gastrointestinal pre-malignant condition (e.g., a tumor exhibiting high dysplasia) and patients with a malignant tumor in gastrointestinal tissue.
(112) Reference is made to
(113)
(114) Reference is made to
(115) The mean±SEM for each of the data sets (healthy, benign, colorectal cancer) is represented by the thickness of the graph lines representing the healthy, benign, and colorectal cancer groups, in accordance with the figure legend, as shown in
(116) Reference is made to
(117) Table H lists wavenumbers that were used in this set of experiments as presented in
(118) TABLE-US-00010 TABLE H Healthy Healthy control vs. control vs. Benign vs. Benign Cancer Cancer Wavenumber Wavenumber Wavenumber (cm−1 ± 4) (cm−1 ± 4) (cm−1 ± 4) 707.3 707.3 712.6 785.4 724.1 724.1 811.9 741.0 760.8 879.9 811.9 785.9 1253.0 1033.7 831.7 1485.4 1060.2 870.7 1509.0 1141.7 920.8 1576.9 1253.0 999.9 1662.8 1285.3 1020.2 1378.4 1104.0 1428.0 1175.4 1460.8 1265.1 1475.3 1365.8 1526.9 1371.1 1565.0 1378.4 1613.6 1430.9 1627.6 1460.3 1638.7 1485.9 1695.6 1491.2 1796.8 1499.9 1509.5 1526.9 1543.7 1569.3 1608.8 1619.9 1627.1 1638.7 1649.8 1662.8 1680.7 1699.0 1751.5 1795.9
(119) For some applications, one, two, three, or more of the following wavenumbers selected from Table H are used to differentiate between the absence of a tumor and a benign colorectal tumor: 785.44 cm-1, 811.9±4 cm-1, 879.9±4 cm-1, 1253.0±4 cm-1, 1485.4±4 cm-1, and 1526.9±4 cm-1.
(120) For some applications, one, two, three, or more of the following wavenumbers selected from Table H are used to differentiate between the absence of a tumor and a malignant colorectal tumor: 724.1±4 cm-1, 741.0±4 cm-1, 1141.7±4 cm-1, 1475.3±4 cm-1, 1627.6±4 cm-1, 1695.6±4 cm-1.
(121) For some applications, one, two, three, or more of the following wavenumbers selected from Table H are used to differentiate between a malignant colorectal tumor and a benign colorectal tumor: 760.8±4 cm-1, 870.7±4 cm-1, 1371.1±4 cm-1, 1485.9±4 cm-1, 1526.9±4 cm-1, 1627.1±4 cm-1.
Example 4
(122) In a set of experiments, differential diagnosis of benign gastrointestinal (specifically colorectal) tumors and malignant and pre-malignant gastrointestinal tumors was performed based on a FTIR-MSP spectral pattern at selected wavenumbers of plasma samples.
(123) In accordance with applications of the present invention, plasma samples from 15 healthy controls were analyzed by FTIR-MSP, and a typical FTIR-MSP spectral pattern was established for control plasma. Additionally, plasma samples from 36 colorectal cancer patients were subjected to FTIR-MSP analysis and compared to the control FTIR-MSP spectral pattern. Additionally, plasma samples from 14 subjects with a benign tumor in colorectal tissue were subjected to FTIR-MSP analysis and compared to the control FTIR-MSP spectral pattern and to the colorectal cancer FTIR-MSP spectral pattern. The plasma samples were obtained by preliminary processing of the peripheral blood in accordance with the protocols described hereinabove with reference to isolation of plasma from peripheral blood samples. The plasma samples were then analyzed by FTIR-MSP, in accordance with the protocols described hereinabove with reference to FTIR-MSP.
(124) Reference is made to
(125)
(126) Reference is made to
(127) The mean±SEM for each of the data sets (healthy, benign, colorectal cancer) is represented by the thickness of the graph lines representing the healthy, benign, and colorectal cancer groups, in accordance with the figure legend, as shown in
(128) Reference is made to
(129) Table I lists wavenumbers that were used in this set of experiments as presented in
(130) TABLE-US-00011 TABLE I Healthy Healthy control vs. control vs. Benign vs. Benign Cancer Cancer Wavenumber Wavenumber Wavenumber (cm−1 ± 4) (cm−1 ± 4) (cm−1 ± 4) 780.1 713.5 713.1 841.3 720.8 718.8 872.6 780.1 735.2 1043.8 816.2 774.3 1061.1 822.0 790.2 1142.1 829.2 817.2 1378.9 840.8 830.2 1383.2 846.6 839.8 1399.6 859.1 846.1 1622.8 904.5 872.1 922.8 877.5 947.4 904.9 1007.6 921.8 1035.6 948.3 1052.0 964.2 1061.6 992.7 1074.6 1034.6 1088.6 1049.1 1104.5 1053.4 1109.8 1075.6 1126.2 1080.9 1135.9 1089.1 1144.5 1104.0 1154.7 1110.3 1175.4 1127.2 1199.0 1133.9 1228.0 1153.2 1278.6 1174.0 1289.2 1187.5 1313.3 1200.0 1322.9 1277.1 1331.1 1321.0 1342.2 1332.1 1352.8 1340.3 1378.9 1355.2 1399.1 1378.4 1419.8 1404.9 1430.4 1420.8 1447.3 1430.0 1464.2 1460.8 1481.1 1480.1 1584.2 1510.5 1609.3 1612.7 1613.2 1627.1 1620.4 1662.3 1626.7 1729.8 1662.3 1744.3 1697.1 1757.8 1768.9 1775.6 1780.9 1789.6
(131) For some applications, one, two, three, or more of the following wavenumbers selected from Table I are used to differentiate between the absence of a tumor and a benign colorectal tumor: 780.1±4 cm-1, 872.6±4 cm-1, 1142.1±4 cm-1, 1378.9±4 cm-1, 1399.6±4 cm-1, and 1622.8±4 cm-1.
(132) For some applications, one, two, three, or more of the following wavenumbers selected from Table I are used to differentiate between the absence of a tumor and a malignant colorectal tumor: 840.8±4 cm-1, 922.8±4 cm-1, 1035.6±4 cm-1, 1154.7±4 cm-1, 1352.8±4 cm-1, 1378.9±4 cm-1.
(133) For some applications, one, two, three, or more of the following wavenumbers selected from Table I are used to differentiate between a malignant colorectal tumor and a benign colorectal tumor: 948.3±4 cm-1, 1034.6±4 cm-1, 1110.3±4 cm-1, 1153.2±4 cm-1, 1340.3±4 cm-1, 1378.4±4 cm-1.
(134) Reference is now made to
(135)
(136)
(137)
(138)
(139) Reference is now made to
(140) Table J1 is a table representing clinical data for 23 colorectal cancer patients who took part in the studies described herein. In Tale J1:
(141) Gender column: “M” represents Male and “F” represents Female
(142) Main organ column: “R” represents Rectum and “C” represents Colon
(143) Location at main organ column: “Re” represents Rectum. “Rt” represents Right, “L” represents Left, “C” represents Colon, “A” represents Ascending,
(144) Pathology column: “M” represents Malignant and “PM” represents Pre-Malignant
(145) Malignancy type column: AC represents Adenocarcinoma.
(146) “#M” represents number of masses
(147) “MS” represents mass size (in mm)
(148) “LN” represents number of lymph nodes
(149) TABLE-US-00012 TABLE J1 Location at # Stage Main main # Positive Vascular S S Malignancy Gender Age Organ Organ MS M LN LN Margin Invasion Pathology T N M No Sub type M 80 R Re NA NA 10 2 R0 NA M 3 1 0 3 b AC M 66 R Re 15 1 18 0 R0 No PM sessile villous adenoma HGD M 72 C A 90 1 11 0 R0 NA M 3 0 0 2 a Mucinous AC M 61 C Rt 18 1 16 0 R0 No PM TVA HGD M 56 C Rt 70 1 16 12 R0 NA M 3 2 0 3 c AC F 74 C L NA 1 20 0 R0 NA M 3 0 0 2 a AC F 37 C C NA 1 NA NA R0 No M 1 0 0 1 — AC F 83 C L 55 1 15 0 R0 No M 3 0 0 2 a AC F 82 C Rt NA 1 20 0 R0 NA M 3 0 0 2 a Mucinous AC M 69 C Rt 6 1 14 0 R0 No M 3 0 0 2 a AC M 59 C Rt 9 1 10 1 R0 Yes M 3 1 0 3 b Mucinous AC M 88 C Rt 33 1 18 0 R0 No M 3 0 0 2 a AC M 72 C Rt NA 1 20 0 R0 No U TVA HGD F 69 C L NA 1 4 0 R0 No M 2 0 0 1 — AC F 68 C Rt NA 1 11 4 R1 Yes M 3 2 0 3 b AC F 88 C L 46 1 27 0 R0 NA M 3 0 0 2 a AC F 54 C Rt NA 1 19 0 R0 No M 3 0 0 2 a AC F 84 C Rt 60 1 15 0 R0 Yes M 3 0 0 2 a AC M 81 C Rt 22 1 23 0 R0 NA M 3 0 0 2 a AC F 69 C L 25 1 4 0 R0 No M 2 0 0 1 — AC M 45 R Re 50 1 11 3 R0 No M 3 1 0 3 b AC M 93 C C NA NA 4 0 NA NA U TVA HGD F 78 C L NA 1 16 13 R0 Yes M 3 2 0 3 c AC
(150)
(151) Table J2 lists wavenumbers that were identified in this set of experiments as presented in
(152) TABLE-US-00013 TABLE J2 Malignancy Number Num. of Size of Type Stage of masses Positive LN Mass (mm) Wave- Wave- Wave- Wave- Wave- number number number number number (cm−1 ± 4) (cm−1 ± 4) (cm−1 ± 4) (cm−1 ± 4) (cm−1 ± 4) 746.3 705.3 713.5 704.9 756.4 753.1 716.9 734.3 716.4 1019.2 809.5 767.0 759.8 755.0 1201.0 815.3 789.7 766.1 766.6 1516.3 829.2 804.7 769.9 770.9 1632.9 856.7 810.0 836.5 789.7 1645.0 868.8 815.7 860.1 796.0 880.8 837.9 893.8 837.9 892.9 846.6 909.3 846.6 957.5 861.1 932.9 847.1 1033.2 895.8 946.9 861.1 1049.1 992.2 981.6 895.3 1061.1 1007.6 992.2 945.9 1104.0 1076.6 1006.2 991.2 1118.5 1266.5 1031.2 1007.1 1129.6 1274.7 1039.4 1076.6 1145.0 1798.3 1050.1 1183.6 1186.5 1329.2 1063.5 1232.3 1201.9 1351.9 1075.6 1266.5 1229.4 1371.1 1163.3 1292.6 1235.7 1446.4 1183.1 1329.7 1251.6 1497.9 1213.0 1351.9 1293.0 1507.6 1224.1 1371.1 1364.9 1574.6 1267.5 1438.2 1418.4 1605.4 1274.7 1445.9 1626.7 1657.5 1298.8 1488.3 1665.7 1715.9 1310.4 1550.0 1690.3 1727.9 1379.2 1575.1 1739.0 1370.7 1605.9 1761.2 1371.1 1657.5 1773.7 1425.6 1707.2 1535.5 1707.7 1540.4 1717.3 1546.1 1727.9 1558.7 1738.0 1590.5 1742.9 1673.9 1773.7 1718.3 1727.9 1740.4
(153) For some applications, one, two, three, or more of the following wavenumbers selected from Table J2 are used to identify in PBMC samples a distinct spectral pattern caused by a malignancy type of the colorectal tumor: 868.8±4 cm-1, 957.5±4 cm-1, 1145.0±4 cm-1, 1251.6±4 cm-1, and 1364.9±4 cm-1.
(154) For some applications, one, two, three, or more of the following wavenumbers selected from Table J2 are used to distinguish between stage 1 and 2 and stage 3 of colorectal tumor: 815.7±4 cm-1, 837.9±4 cm-1, 895.8±4 cm-1, 992.2±4 cm-1, 1371.1±4 cm-1, 1574.6±4 cm-1 and 1657.5±4 cm-1.
(155) For some applications, one, two, three, or more of the following wavenumbers selected from Table J2 are used to identify in PBMC samples a distinct spectral pattern caused by the number of masses of a colorectal tumor: 734.3±4 cm-1, 759.8±4 cm-1, 893.8±4 cm-1, 932.9±4 cm-1, 1370.7±4 cm-1, 1412.1±4 cm-1, and 1578.9±4 cm-1.
(156) For some applications, one, two, three, or more of the following wavenumbers selected from Table J2 are used to identify in PBMC samples a distinct spectral pattern caused by the number of positive lymph nodes of a colorectal cancer patient: 837.94 cm-1, 895.3±4 cm-1, 1292.6±4 cm-1, 1371.1±4 cm-1, 1550.0±4 cm-1, and 1575.1±4 cm-1.
(157) For some applications, one, two, three, or more of the following wavenumbers selected from Table J2 are used to identify in PBMC samples a distinct spectral pattern caused by the size of the mass (mm) of the colorectal tumor: 756.4 cm-1, 1019.2±4 cm-1, 1201.0±4 cm-1, and 1516.3±4 cm-1.
(158)
(159) Table K lists wavenumbers that were identified in this set of experiments as presented in
(160) TABLE-US-00014 TABLE K Vascular Num. of Size of Invasion Stage Positive LN Mass (mm) Wave- Wave- Wave- Wave- number number number number (cm−1 ± 4) (cm−1 ± 4) (cm−1 ± 4) (cm−1 ± 4) 729.4 709.7 710.2 740.5 746.3 756.4 756.4 832.1 751.1 806.6 807.1 844.7 775.7 813.3 813.3 992.7 793.1 819.1 818.6 1051.0 808.0 826.3 826.8 1155.2 814.8 861.1 833.6 1377.4 833.6 872.6 861.1 1426.1 857.7 945.9 872.1 1578.0 870.7 952.2 910.2 1669.6 905.4 971.9 945.9 1712.5 912.6 988.3 952.2 1718.3 946.4 1018.7 1013.4 1728.9 958.0 1043.8 1019.2 1740.4 976.3 1165.3 1043.8 1751.0 998.0 1196.1 1052.9 1756.8 1007.6 1216.9 1164.8 1767.9 1019.2 1245.8 1172.5 1773.2 1028.4 1267.5 1195.6 1778.0 1040.4 1279.1 1356.7 1046.2 1288.7 1664.3 1052.9 1664.3 1725.5 1074.6 1738.0 1746.2 1143.6 1763.6 1157.1 1168.2 1177.3 1192.3 1216.9 1222.2 1229.9 1251.1 1264.6 1269.9 1282.4 1356.7 1531.7 1546.1 1559.2 1568.8 1572.2 1621.4 1635.3 1643.1 1663.8 1692.7 1738.0
(161) For some applications, one, two, three, or more of the following wavenumbers selected from Table K are used to identify in plasma samples a distinct spectral pattern caused by vascular invasion of a colorectal tumor: 976.3±4 cm-1, 1052.9±4 cm-1, 1143.6±4 cm-1, 1177.3±4 cm-1, 1229.9±4 cm-1, and 1356.7±4 cm-1.
(162) For some applications, one, two, three, or more of the following wavenumbers selected from Table K are used to distinguish between stage 1 and 2 and stage 3 of colorectal tumor: 756.4±4 cm-1, 806.6±4 cm-1, 945.9±4 cm-1, 1165.3±4 cm-1, 1196.1±4 cm-1, 1288.7±4 cm-1 and 1657.5±4 cm-1.
(163) For some applications, one, two, three, or more of the following wavenumbers selected from Table K are used to identify in plasma samples a distinct spectral pattern caused by the number of positive lymph nodes of a colorectal cancer patient: 756.4±4 cm-1, 807.1±4 cm-1, 861.1±4 cm-1, 872.1±4 cm-1, 945.9±4 cm-1, and 1164.8±4 cm-1.
(164) For some applications, one, two, three, or more of the following wavenumbers selected from Table K are used to identify in plasma samples a distinct spectral pattern caused by the size of the mass (mm) of the colorectal tumor: 740.54 cm-1, 844.7±4 cm-1, 1051.0±4 cm-1, and 1377.4±4 cm-1, 1751.0±4 cm-1, 1778.0±4 cm-1.
(165) Reference is made to
(166) As shown in
(167) As shown in
Example 5
(168) In a set of experiments, differential diagnosis of various types of malignant tumors in gynecological tissue was performed based on a FTIR-MSP spectral pattern at selected wavenumbers of PBMC samples. Additionally, differential diagnosis of malignant ovarian tumors and benign ovarian tumors was performed based on a FTIR-MSP spectral pattern at selected wavenumbers of PBMC samples. Patient data is presented hereinabove in Table B. As mentioned hereinabove, an additional control group for this set of experiments consisted of pregnant women (n=11). (Pregnancy may trigger a false positive cancer diagnosis due to physiological changes and the presence of blood markers. Therefore, pregnancy acts as an appropriate control for gynecological tumors and for the effectiveness of some applications of the present invention to differentiate between cancer and other non-cancerous conditions, e.g., pregnancy.)
(169) In accordance with applications of the present invention, PBMC samples from 28 healthy controls were analyzed by FTIR-MSP, and a typical FTIR-MSP spectral pattern was established for control PBMC. Additionally, PBMC samples from 11 ovarian cancer patients, 15 endometrial cancer patients, 6 gynecological sarcoma patients, 7 cervical cancer patients, 4 vulvar cancer patients and 3 patients diagnosed with a borderline ovarian tumor (BOT) were subjected to FTIR-MSP analysis and compared to the control FTIR-MSP spectral pattern. Additionally, PBMC samples from 8 subjects with a benign tumor in ovarian tissue were subjected to FTIR-MSP analysis and compared to the control FTIR-MSP spectral pattern and to the cancer FTIR-MSP spectral pattern. Further additionally, PBMC samples from 11 pregnant women were subjected to FTIR-MSP analysis and compared to the control FTIR-MSP spectral pattern, to the cancer FTIR-MSP spectral pattern and to the benign FTIR-MSP spectral pattern.
(170) The PBMC samples were obtained by preliminary processing of the peripheral blood in accordance with the protocols described hereinabove with reference to extraction of peripheral blood mononuclear cells (PBMC). The PBMC samples were then analyzed by FTIR-MSP, in accordance with the protocols described hereinabove with reference to FTIR-MSP.
(171) Results are presented in
(172)
(173) Reference is made to
(174) Reference is made to
(175)
(176) Table L lists wavenumbers that were identified in the set of experiments as presented in
(177) TABLE-US-00015 TABLE L Healthy Control vs. Cancer CS (pregnant) vs. Cancer Wavenumber Wavenumber (cm−1 ± 4) (cm−1 ± 4) 706.3 750.2 752.6 755.5 767.5 789.2 776.7 795.0 784.9 806.6 798.4 811.9 804.2 820.6 877.5 828.8 883.2 843.2 920.4 848.5 927.6 891.0 955.6 900.1 985.4 919.4 998.5 935.8 1008.6 994.6 1030.3 1000.9 1036.6 1006.2 1058.2 1034.1 1067.9 1048.6 1081.9 1061.1 1095.9 1139.2 1102.6 1167.7 1117.1 1178.8 1134.9 1185.0 1161.4 1221.7 1170.1 1240.0 1186.5 1261.7 1201.0 1328.7 1219.3 1385.6 1228.4 1403.4 1237.1 1436.2 1247.7 1486.8 1265.6 1497.9 1274.7 1501.3 1305.6 1506.6 1348.5 1512.4 1365.4 1527.3 1370.7 1533.1 1384.2 1538.9 1389.5 1544.7 1414.0 1558.2 1452.1 1564.0 1458.4 1595.3 1464.2 1605.4 1496.5 1610.8 1523.0 1615.1 1535.1 1629.1 1558.7 1634.4 1564.0 1645.0 1574.6 1653.2 1605.4 1684.5 1618.0 1690.8 1624.3 1783.4 1632.4 1789.1 1638.7 1647.9 1653.7 1669.6 1678.2 1684.5 1728.9 1783.4
(178) For some applications, one, two, three, or more of the following wavenumbers selected from Table L are used to differentiate between the healthy controls and gynecological cancer patients: 1030.34 cm-1, 1067.94 cm-1, 1134.94 cm-1, 1161.4±4 cm-1, 1186.5±4 cm-1, and 1389.5±4 cm-1.
(179) For some applications, one, two, three, or more of the following wavenumbers selected from Table L are used to differentiate between the pregnant women and gynecological cancer patients: 750.2±4 cm-1, 843.2±4 cm-1, 1034.1±4 cm-1, 1048.6±4 cm-1, 1185.0±4 cm-1, 1506.6±4 cm-1.
(180)
(181) Table M lists wavenumbers that were identified in the set of experiments as presented in
(182) TABLE-US-00016 TABLE M Healthy control vs. Healthy control vs. Benign vs. Cancer Benign Cancer Wavenumber Wavenumber Wavenumber (cm−1 ± 4) (cm−1 ± 4) (cm−1 ± 4) 745.4 702.9 733.3 752.1 733.8 740.0 776.2 740.5 747.3 783.4 754.0 753.5 788.7 840.8 840.8 797.9 850.5 850.5 804.2 868.3 887.1 829.2 880.3 909.8 919.9 909.8 918.9 929.5 1002.8 1058.7 946.9 1008.6 1073.7 956.5 1066.4 1127.7 985.4 1103.6 1146.5 992.2 1121.4 1187.9 1007.1 1128.2 1237.1 1029.8 1135.4 1252.1 1057.8 1146.0 1266.5 1068.4 1173.5 1329.7 1080.4 1199.5 1347.5 1096.3 1228.0 1408.3 1133.0 1303.6 1445.9 1162.4 1333.5 1523.5 1171.5 1338.8 1540.4 1188.4 1346.1 1551.9 1200.5 1376.9 1574.1 1219.8 1391.9 1582.8 1238.6 1407.8 1588.6 1330.6 1440.1 1595.8 1348.5 1445.9 1618.0 1354.7 1456.0 1629.1 1384.6 1489.3 1635.8 1389.5 1514.3 1641.1 1418.4 1524.0 1651.7 1468.5 1532.2 1657.5 1476.2 1535.5 1728.4 1497.0 1540.8 1761.7 1522.0 1546.6 1773.2 1532.6 1552.4 1778.5 1536.0 1558.2 1558.2 1563.5 1564.0 1575.6 1574.1 1582.3 1604.5 1588.6 1618.0 1630.0 1653.2 1635.8 1666.7 1642.1 1728.9 1651.7 1740.9 1666.7 1751.0 1678.2 1685.0 1694.2 1747.7 1753.5 1771.8 1778.5 1794.4
(183) For some applications, one, two, three, or more of the following wavenumbers selected from Table M are used to differentiate between the healthy controls and ovarian cancer patients: 752.1±4 cm-1, 956.5±4 cm-1, 1029.8±4 cm-1, 1057.8±4 cm-1, 1162.4±4 cm-1, 1389.5±4 cm-1, and 1476.2±4 cm-1.
(184) For some applications, one, two, three, or more of the following wavenumbers selected from Table M are used to differentiate between the healthy controls and subjects with a benign ovarian tumor: 754.0±4 cm-1, 1103.6±4 cm-1, 1121.4±4 cm-1, 1346.1±4 cm-1, and 1376.9±4 cm-1.
(185) For some applications, one, two, three, or more of the following wavenumbers selected from Table M are used to differentiate between the subjects with a benign ovarian tumor and the ovarian cancer patients: 753.50±4 cm-1, 850.5±4 cm-1, 918.9±4 cm-1, 1058.7±4 cm-1, 1187.9±4 cm-1 and 1651.7±4 cm-1.
Example 6
(186) In a set of experiments, differential diagnosis of various types of malignant tumors in gynecological tissue was performed based on a FTIR-MSP spectral pattern at selected wavenumbers of plasma samples. Additionally, differential diagnosis of malignant ovarian tumors and benign ovarian tumors was performed based on a FTIR-MSP spectral pattern at selected wavenumbers of plasma samples. Patient data is presented hereinabove in Table B. As mentioned hereinabove, an additional control group for this set of experiments consisted of pregnant women (n=11). Pregnancy may trigger a false positive cancer diagnosis due to physiological changes, thus acting as an appropriate control for gynecological tumors.
(187) In accordance with applications of the present invention, plasma samples from 28 healthy controls were analyzed by FTIR-MSP, and a typical FTIR-MSP spectral pattern was established for control plasma. Additionally, plasma samples from 11 ovarian cancer patients, 15 endometrial cancer patients, 6 gynecological sarcoma patients, 7 cervical cancer patients, 4 vulvar cancer patients and 3 patients diagnosed with a borderline ovarian tumor (BOT) were subjected to FTIR-MSP analysis and compared to the control FTIR-MSP spectral pattern. Additionally, plasma samples from 8 subjects with a benign tumor in ovarian tissue were subjected to FTIR-MSP analysis and compared to the control FTIR-MSP spectral pattern and to the cancer FTIR-MSP spectral pattern. Further additionally, plasma samples from 11 pregnant women were subjected to FTIR-MSP analysis and compared to the control FTIR-MSP spectral pattern, to the cancer FTIR-MSP spectral pattern and to the benign FTIR-MSP spectral pattern.
(188) The plasma samples were obtained by preliminary processing of the peripheral blood in accordance with the protocols described hereinabove with reference to extraction of plasma. The plasma samples were then analyzed by FTIR-MSP, in accordance with the protocols described hereinabove with reference to FTIR-MSP.
(189) Results are presented in
(190)
(191) Reference is made to
(192) Reference is made to
(193)
(194) Table N lists wavenumbers that were identified in the set of experiments as presented in
(195) TABLE-US-00017 TABLE N Healthy Control vs. Cancer CS (pregnant) vs. Cancer Wavenumber Wavenumber (cm−1 ± 4) (cm−1 ± 4) 745.4 729.4 752.6 740.0 781.5 749.2 821.5 760.8 830.2 800.8 836.5 846.1 846.6 859.1 856.7 864.9 870.2 926.6 898.2 938.2 906.4 951.2 919.4 971.0 928.6 992.2 971.5 1012.0 980.1 1019.7 989.8 1030.3 1007.6 1049.6 1015.3 1064.5 1038.0 1071.7 1055.4 1079.5 1066.4 1091.0 1100.2 1101.2 1112.7 1115.1 1130.1 1181.2 1137.8 1205.8 1145.5 1217.3 1156.1 1237.1 1171.5 1246.8 1199.0 1281.5 1233.7 1291.1 1266.0 1329.7 1279.5 1350.9 1287.7 1362.0 1294.5 1378.4 1304.1 1399.1 1313.8 1427.5 1324.9 1436.2 1336.4 1453.6 1349.9 1466.1 1378.9 1475.3 1388.0 1496.5 1401.5 1501.3 1413.6 1506.6 1421.8 1512.4 1435.7 1519.6 1449.2 1131.5 1460.3 1147.4 1475.3 1160.0 1519.2 1168.2 1529.3 1523.5 1544.7 1530.2 1564.0 1545.7 1578.5 1557.2 1585.2 1564.0 1620.4 1610.3 1642.1 1621.4 1647.4 1634.4 1653.7 1644.5 1669.6 1652.7 1676.3 1658.5 1684.0 1669.1 1691.7 1676.8 1699.9 1683.1 1689.3 1714.9 1725.5 1730.8 1739.0 1764.1
(196) For some applications, one, two, three, or more of the following wavenumbers selected from Table N are used to differentiate between the healthy controls and gynecological cancer patients: 980.14 cm-1, 1007.6±4 cm-1, 1038.0±4 cm-1, 1055.4±4 cm-1, 1171.5±4 cm-1, and 1279.5±4 cm-1.
(197) For some applications, one, two, three, or more of the following wavenumbers selected from Table N are used to differentiate between the pregnant women and gynecological cancer patients: 740.04 cm-1, 971.04 cm-1, 1019.7±4 cm-1, 1064.5±4 cm-1, 1291.1±4 cm-1, 1378.4±4 cm-1.
(198)
(199) Table O lists wavenumbers that were identified in the set of experiments as presented in
(200) TABLE-US-00018 TABLE O Healthy control vs. Healthy control vs. Benign vs. Cancer Benign Cancer Wavenumber Wavenumber Wavenumber (cm−1 ± 4) (cm−1 ± 4) (cm−1 ± 4) 717.9 732.3 705.3 724.1 763.7 731.9 746.3 771.9 777.2 751.6 777.2 787.3 764.2 830.7 809.5 786.3 838.4 846.6 792.6 849.0 900.6 809.0 979.2 967.1 818.2 1007.6 975.8 832.1 1026.9 984.5 839.8 1045.7 1028.4 846.6 1134.4 1039.4 856.7 1153.2 1052.5 873.1 1174.4 1114.2 904.0 1218.3 1156.1 919.4 1259.8 1197.1 981.1 1276.6 1218.3 1001.4 1290.1 1234.2 1007.1 1320.5 1258.8 1036.6 1337.4 1274.7 1056.8 1351.4 1293.5 1072.2 1391.4 1318.6 1113.7 1398.6 1333.1 1146.5 1432.9 1339.3 1156.6 1450.7 1357.6 1172.5 1456.0 1369.2 1198.1 1461.8 1391.4 1233.3 1488.8 1456.5 1269.9 1537.0 1490.2 1281.0 1543.3 1522.5 1288.2 1557.2 1549.0 1312.8 1576.0 1618.9 1323.9 1633.9 1634.4 1348.0 1651.7 1658.5 1379.8 1666.7 1666.7 1386.1 1671.0 1673.4 1400.1 1676.8 1688.4 1448.8 1716.3 1696.6 1467.1 1722.1 1710.6 1522.0 1730.8 1731.3 1529.8 1748.6 1743.3 1544.7 1754.9 1755.4 1550.5 1765.5 1767.4 1563.5 1771.8 1771.8 1584.7 1781.9 1781.9 1618.0 1786.2 1642.1 1653.2 1675.4 1692.2 1700.4 1724.5 1761.2
(201) For some applications, one, two, three, or more of the following wavenumbers selected from Table O are used to differentiate between the healthy controls and ovarian cancer patients: 846.6±4 cm-1, 1056.8±4 cm-1, 1146.5±4 cm-1, 1156.6±4 cm-1, 1172.5±4 cm-1, 1198.1±4 cm-1.
(202) For some applications, one, two, three, or more of the following wavenumbers selected from Table O are used to differentiate between the healthy controls and subjects with a benign ovarian tumor: 830.7±4 cm-1, 1007.6±4 cm-1, 1290.1±4 cm-1, 1676.8±4 cm-1, 1716.3±4 cm-1, and 1754.9±4 cm-1.
(203) For some applications, one, two, three, or more of the following wavenumbers selected from Table O are used to differentiate between the subjects with a benign ovarian tumor and the ovarian cancer patients: 777.2±4 cm-1, 1039.4±4 cm-1, 1052.5±4 cm-1, 1156.1±4 cm-1, 1218.3±4 cm-1 and 1369.2±4 cm-1.
(204) Reference is made to Examples 1-6 and to
(205)
(206) Table P lists wavenumbers that were identified in the set of experiments as presented in
(207) TABLE-US-00019 TABLE P Breast vs. Colorectal Breast vs. Wavenumber Gynecological Colorectal vs. Gynecological (cm−1 ± 4) Wavenumber (cm−1 ± 4) Wavenumber (cm−1 ± 4) 704.9 731.4 707.7 753.1 737.6 736.7 879.9 753.5 764.6 939.2 767.5 776.7 956.0 784.9 783.9 990.7 805.1 788.7 1008.1 928.1 806.1 1035.1 955.6 812.8 1049.6 999.4 820.1 1066.0 1030.3 836.5 1072.7 1039.0 850.0 1102.6 1067.4 864.0 1172.5 1126.2 870.2 1221.2 1162.9 880.3 1401.5 1170.1 887.1 1568.8 1178.3 898.2 1186.0 920.4 1202.9 927.6 1219.8 939.6 1251.1 946.4 1264.6 954.1 1309.4 986.9 1365.4 999.4 1371.1 1008.1 1378.4 1028.4 1384.6 1037.0 1405.9 1051.5 1414.0 1067.9 1427.1 1083.3 1437.2 1128.2 1452.6 1153.2 1458.9 1161.4 1465.6 1170.1 1474.3 1179.3 1501.8 1186.5 1506.1 1202.9 1511.9 1252.1 1528.3 1262.7 1532.2 1275.7 1540.8 1299.8 1546.6 1303.6 1552.4 1313.8 1559.6 1365.8 1568.3 1371.6 1574.6 1377.4 1589.1 1384.6 1605.4 1403.9 1615.6 1414.0 1631.0 1425.6 1637.3 1435.7 1642.1 1443.5 1645.5 1453.1 1648.4 1459.8 1654.6 1467.1 1660.9 1474.8 1664.7 1498.4 1694.6 1501.8 1698.5 1507.1 1512.4 1516.7 1528.3 1534.6 1541.3 1546.6 1551.9 1568.3 1574.1 1578.5 1590.0 1605.0 1611.7 1626.7 1642.1 1648.4 1660.4 1673.9 1693.7 1700.9 1728.4 1734.7
(208) For some applications, one, two, three, or more of the following wavenumbers selected from Table P are used to differentiate between breast cancer patients and colorectal cancer patients: 879.9±4 cm-1, 939.2±4 cm-1, 1035.1±4 cm-1, 1066.0±4 cm-1, 1172.5±4 cm-1, 1568.8±4 cm-1.
(209) For some applications, one, two, three, or more of the following wavenumbers selected from Table P are used to differentiate between breast cancer patients and gynecological cancer patients: 1162.94 cm-1, 1186.014 cm-1, 1251.1±4 cm-1, 1365.4±4 cm-1, 1465.6±4 cm-1, 1528.3±4 cm-1 and 1648.4±4 cm-1.
(210) For some applications, one, two, three, or more of the following wavenumbers selected from Table P are used to differentiate between colorectal cancer patients and gynecological cancer patients: 954.1±4 cm-1, 1037.0±4 cm-1, 1067.9±4 cm-1, 1170.1±4 cm-1, 1365.8±4 cm-1 and 1384.6±4 cm-1.
(211)
(212) Table Q lists wave numbers that were identified in the set of experiments as presented in
(213) TABLE-US-00020 TABLE Q Breast vs. Breast vs. Colorectal vs. Colorectal Gynecological Gynecological Wavenumber Wavenumber Wavenumber (cm−1 ± 4) (cm−1 ± 4) (cm−1 ± 4) 716.9 715.0 739.1 728.5 728.0 773.3 742.0 756.0 795.0 796.5 762.2 823.0 823.0 821.5 833.6 831.2 829.2 847.1 883.2 836.5 856.7 904.5 846.6 876.0 948.3 856.7 940.6 955.6 876.0 955.1 975.3 882.3 962.3 1003.8 904.9 976.8 1010.5 919.4 987.9 1030.8 927.1 998.5 1039.0 937.7 1009.6 1050.1 948.3 1017.3 1070.8 961.3 1028.4 1080.4 980.1 1047.6 1090.5 1005.2 1056.8 1099.7 1018.7 1062.1 1106.0 1039.9 1071.3 1115.1 1055.8 1082.8 1142.1 1144.1 1098.7 1156.1 1157.1 1107.4 1174.4 1164.8 1116.1 1199.5 1171.1 1138.3 1249.6 1177.3 1175.9 1271.3 1193.7 1193.2 1282.4 1204.8 1201.9 1370.7 1217.3 1241.9 1379.8 1229.9 1257.8 1464.7 1238.1 1271.8 1573.1 1315.2 1284.8 1609.3 1335.9 1295.9 1634.4 1388.5 1304.1 1661.9 1412.6 1322.9 1666.2 1421.3 1336.4 1740.4 1436.7 1360.1 1745.3 1448.8 1389.5 1751.0 1459.4 1412.1 1790.1 1467.1 1426.6 1473.8 1437.2 1479.6 1448.8 1497.0 1458.9 1501.3 1466.1 1506.1 1473.3 1511.9 1479.6 1521.1 1484.9 1528.3 1496.5 1534.6 1501.3 1552.4 1511.4 1565.9 1519.6 1579.4 1528.3 1587.6 1535.5 1591.5 1542.3 1610.8 1552.4 1615.1 1565.9 1630.5 1578.0 1641.1 1587.6 1647.9 1615.1 1653.7 1626.7 1660.9 1631.0 1667.6 1635.3 1694.2 1642.1 1701.9 1647.9 1735.1 1654.1 1748.2 1659.9 1756.8 1667.2 1778.0 1678.7 1783.4 1685.0 1693.7 1701.9 1712.0 1719.7 1734.7 1740.9 1749.1 1756.4 1767.4
(214) For some applications, one, two, three, or more of the following wavenumbers selected from Table Q are used to differentiate between breast cancer patients and colorectal cancer patients: 823.04 cm-1, 904.5±4 cm-1, 955.6±4 cm-1, 1003.8±4 cm-1, 1039.0±4 cm-1, 1099.7±4 cm-1, and 1174.4±4 cm-1.
(215) For some applications, one, two, three, or more of the following wavenumbers selected from Table Q are used to differentiate between breast cancer patients and gynecological cancer patients: 961.3±4 cm-1, 1005.2±4 cm-1, 1039.9±4 cm-1, 1055.8±4 cm-1, 1528.3±4 cm-1, and 1647.9±4 cm-1.
(216) For some applications, one, two, three, or more of the following wavenumbers selected from Table Q are used to differentiate between colorectal cancer patients and gynecological cancer patients: 955.1±4 cm-1, 1028.4±4 cm-1, 1047.6±4 cm-1, 1098.7±4 cm-1, 1175.9±4 cm-1 1535.5±4 cm-1, and 1647.9±4 cm-1.
(217) Reference is made to
(218) Table R lists wavenumbers that were identified for diagnosis of cancer using PBMC samples with reference to the set of experiments as presented in
(219) TABLE-US-00021 TABLE R Wavenumber (cm−1 ± 4) 706.3 742.9 749.7 841.8 900.1 910.7 942.5 956.5 977.7 993.6 1034.1 1048.1 1059.7 1071.3 1079.0 1094.9 1110.3 1117.1 1134.9 1146.5 1162.4 1188.4 1200.5 1220.7 1228.1 1276.6 1285.3 1292.1 1298.8 1321.0 1369.2 1382.2 1389.5 1403.9 1420.8 1431.4 1437.2 1453.6 1470.9 1476.7 1485.4 1496.0 1499.4 1504.2 1510.0 1514.3 1523.0 1529.8 1538.0 1544.2 1555.8 1562.5 1566.9 1569.3 1579.4 1587.1 1598.7 1613.6 1623.3 1628.1 1643.1 1649.8 1663.3 1669.6 1675.8 1681.6 1699.5 1709.6
(220) For some applications, one, two, three, or more of the following wavenumbers selected from Table R are used to diagnose cancer using PBMC samples: 749.70±4 cm-1, 841.8±4 cm-1, 993.6±4 cm-1, 1034.1±4 cm-1, 1117.1±4 cm-1, 1146.5±4 cm-1, 1228.1±4 cm-1 and 1276.6±4 cm-1.
(221) Table S lists wavenumbers that were identified for diagnosis of cancer using plasma samples with reference to the set of experiments as presented in
(222) TABLE-US-00022 TABLE S 733.3 748.2 753.5 771.4 779.1 799.3 821.5 821.5 827.8 840.3 846.6 858.6 870.2 889.0 897.2 913.6 923.7 938.7 948.3 959.4 963.8 971.9 979.7 989.8 994.6 1008.1 1014.4 1038.0 1054.9 1066.9 1074.6 1088.6 1111.3 1128.6 1136.8 1146.0 1153.7 1160.9 1174.0 1180.7 1199.5 1217.3 1227.5 1233.7 1263.6 1278.1 1289.7 1295.0 1307.5 1321.5 1331.6 1339.8 1352.3 1364.4 1378.9 1384.6 1392.4 1399.1 1414.5 1421.3 1429.5 1448.8 1454.1 1460.8 1484.9 1490.7 1499.4 1504.2 1510.0 1515.3 1519.2 1523.0 1529.8 1537.5 1544.2 1555.8 1562.5 1577.5 1584.2 1601.6 1627.1 1643.1 1651.3 1666.2 1675.8 1681.6 1687.4 1694.2 1707.2 1717.8 1733.2 1739.5 1758.3 1769.4
(223) For some applications, one, two, three, or more of the following wavenumbers selected from Table S are used to diagnose cancer using plasma samples: 846.6±4 cm-1, 1008.1±4 cm-1, 1038.0±4 cm-1, 1111.3±4 cm-1, 1153.7±4 cm-1, 1278.1±4 cm-1, and 1289.7±4 cm-1.
(224)
(225)
(226) It is noted that the scope of the present invention includes the use of only one wavenumber biomarker for differential diagnosis of benign and malignant solid tumors, as well as the use of two, three, four, or more wavenumbers.
(227) Embodiments of the present invention described herein can take the form of an entirely hardware embodiment, an entirely software embodiment or an embodiment including both hardware and software elements. In an embodiment, the invention is implemented in software, which includes but is not limited to firmware, resident software, microcode, etc.
(228) Furthermore, the embodiments of the invention can take the form of a computer program product accessible from a computer-usable or computer-readable medium providing program code for use by or in connection with a computer or any instruction execution system. For the purposes of this description, a computer-usable or computer readable medium can be any apparatus that can comprise, store, communicate, propagate, or transport the program for use by or in connection with the instruction execution system, apparatus, or device. The medium can be an electronic, magnetic, optical, electromagnetic, infrared, or semiconductor system (or apparatus or device) or a propagation medium.
(229) Examples of a computer-readable medium include a semiconductor or solid state memory, magnetic tape, a removable computer diskette, a random access memory (RAM), a read-only memory (ROM), a rigid magnetic disk and an optical disk. Current examples of optical disks include compact disk-read only memory (CD-ROM), compact disk-read/write (CD-R/W) and DVD.
(230) Reference is made to
(231) A data processing system suitable for storing and/or executing program code will include at least one processor coupled directly or indirectly to memory elements through a system bus. The memory elements can include local memory employed during actual execution of the program code, bulk storage, and cache memories which provide temporary storage of at least some program code in order to reduce the number of times code must be retrieved from bulk storage during execution. The system can read the inventive instructions on the program storage devices and follow these instructions to execute the methodology of the embodiments of the invention.
(232) Input/output (I/O) devices (including but not limited to keyboards, displays, pointing devices, etc.) can be coupled to the system either directly or through intervening I/O controllers. Network adapters may also be coupled to the system to enable the data processing system to become coupled to other data processing systems or remote printers or storage devices through intervening private or public networks. Modems, cable modem and Ethernet cards are just a few of the currently available types of network adapters.
(233) Computer program code for carrying out operations of the present invention may be written in any combination of one or more programming languages, including an object oriented programming language such as Java, Smalltalk, C++ or the like and conventional procedural programming languages, such as the C programming language or similar programming languages.
(234) It will be understood that the operations described herein can be implemented by computer program instructions. These computer program instructions may be provided to a processor (e.g., processor 22) of a general purpose computer, special purpose computer, or other programmable data processing apparatus to produce a machine, such that the instructions, which execute via the processor of the computer or other programmable data processing apparatus, create means for implementing the functions/acts described herein. These computer program instructions may also be stored in a computer-readable medium that can direct a computer or other programmable data processing apparatus to function in a particular manner, such that the instructions stored in the computer-readable medium produce an article of manufacture including instruction means which implement the functions/acts described herein. The computer program instructions may also be loaded onto a computer or other programmable data processing apparatus to cause a series of operational steps to be performed on the computer or other programmable apparatus to produce a computer implemented process such that the instructions which execute on the computer or other programmable apparatus provide processes for implementing the functions/acts described herein.
(235) It will be appreciated by persons skilled in the art that the present invention is not limited to what has been particularly shown and described hereinabove. Rather, the scope of the present invention includes both combinations and subcombinations of the various features described hereinabove, as well as variations and modifications thereof that are not in the prior art, which would occur to persons skilled in the art upon reading the foregoing description.