Diagnostic method for selecting BCG intravesical infusion therapy

Abstract

To provide a method capable of determining the selection of a BCG intravesical injection therapy and total cystectomy with less burden on patients.SOLUTION: 2-ethylhydracrylic acid-2, arabinonic acid-2, carnitines, lauric acids, myristic acids, octanoylcarnitines, paraxanthine, S-methylcysteine, S-methylcysteine-S-oxide, SDMA, theobromine, indole-3-acetic acids, pentanoic acids, 1-methyl-4-imidazoleacetic acids, ADMA, alanine, argininosuccinic acids, choline, citrulline, creatinine, guanidoacetic acids, lysine, methionine sulfoxide, myristic acids, N - (1-deoxy-1-fructosyl) leucine, N-acetylneuraminic acids, N6, N6, N6 trimethyllysine, propionylcarnitines, threonine, gamma-glutamyl-glycine, gamma-glutamyl-tyrosine, the method comprises measuring gamma-glutamyl-valine.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a decision method for selecting intravesical BCG therapy. [Background technology]

[0002] Bladder cancer is a general term for cancer that develops in the bladder, and most cases are urothelial carcinomas that develop in the urothelium that lines the inside of the bladder. Bladder cancer is divided into "non-muscle-invasive cancer" and "muscle-invasive cancer" depending on whether or not it has invaded the muscle layer. When treating bladder cancer, a treatment plan is decided based on a comprehensive assessment of factors such as the stage of progression, but surgery is often used to remove the cancer. Endoscopic resection of bladder cancer is called transurethral resection of bladder tumor (TURBT), and involves inserting a surgical endoscope through the urethra under spinal or general anesthesia and performing resection with a scalpel.

[0003] In bladder cancer, even if the tumor is successfully removed by surgery, the tumor often recurs in the bladder. Therefore, to prevent the recurrence of tumors in the bladder, intravesical BCG therapy is performed, in which BCG (attenuated bovine tuberculosis vaccine) is administered into the bladder.

[0004] However, intravesical BCG therapy has severe side effects. Specifically, it often causes sleep disturbances, pain, frequent urination, and discomfort, significantly reducing quality of life. Furthermore, although intravesical BCG therapy itself is an effective preventive method, there are many cases of tumor recurrence in the bladder after treatment. According to the Bladder Cancer Clinical Practice Guidelines (2019), "In cases where early recurrence occurs despite adequate intravesical BCG therapy or where reintroduction of intravesical BCG therapy is considered ineffective, radical cystectomy is indicated. The EAU and NCCN guidelines cite cases in which a T1 high-grade tumor recurs after one or two courses of intravesical BCG therapy as cases in which early radical cystectomy is recommended. Among high-risk cases, there are "ultra-high-risk" cases, which are considered to be at even higher risk of progression, and in these cases, immediate radical cystectomy is recommended rather than intravesical BCG therapy." In other words, there are cases where patients undergo endoscopic resection and then intravesical BCG therapy, but ultimately end up having to undergo radical cystectomy again. This situation places a heavy burden on patients and is undesirable from the perspective of early treatment and prevention. Summary of the Invention [Problem to be solved by the invention]

[0005] Therefore, the main object of the present invention is to provide a method for determining whether or not to select radical cystectomy instead of intravesical BCG therapy, i.e., a method for determining with less burden on patients when considering and selecting a treatment method. In other words, the present invention aims to provide a method for determining whether or not to select intravesical BCG therapy for bladder cancer patients, a method for determining whether or not to select radical cystectomy for bladder cancer patients, a method for determining the possibility of bladder cancer recurrence after intravesical BCG therapy, and a method for determining the risk of bladder cancer after intravesical BCG therapy. [Means for solving the problem]

[0006] In order to solve the above problems, the method of the present invention is directed to determining the amount of 2-ethylhydracrylic acid-2, arabinonic acid-2, carnitine, lauric acid, myristic acid, octanoylcarnitine, paraxanthine, S-methylcysteine, S-methylcysteine-S-oxide, SDMA, theobromine, 2-ethylhydracrylic acid-2, arabinonic acid-2, carnitine, lauric acid, myristic acid, octanoylcarnitine, paraxanthine, S-methylcysteine, S-methylcysteine-S-oxide, SDMA, theobromine, 2-ethylhydracrylic acid-2, arabinonic acid-2, carnitine, lauric acid, myristic acid, octanoylcarnitine, paraxanthine, S-methylcysteine, S-methylcysteine-S-oxide, SDMA, theobromine, 2-methyl-2-hydroxybenzoate ... The method comprises measuring at least one of indole-3-acetic acid, pentanoic acid, 1-methyl-4-imidazoleacetic acid, ADMA, alanine, argininosuccinic acid, choline, citrulline, creatinine, guanidoacetic acid, lysine, methionine sulfoxide, myristic acid, N-(1-deoxy-1-fructosyl)leucine, N-acetylneuraminic acid, N6,N6,N6-trimethyllysine, propionylcarnitine, threonine, gamma-glutamyl-glycine, gamma-glutamyl-tyrosine, and gamma-glutamyl-valine. Measurement includes measuring at least one compound, but multiple compounds may be measured for determination. Furthermore, the term "determination" in this application encompasses concepts such as diagnosis, prediction, determination, and decision.

[0007] Furthermore, it is preferable that the measurement compound includes at least one of 2-ethylhydracrylic acid-2, arabinonic acid-2, carnitine, lauric acid, myristic acid, octanoylcarnitine, paraxanthine, S-methylcysteine, S-methylcysteine-S-oxide, SDMA, theobromine, indole-3-acetic acid, and pentanoic acid, and it is further preferable that two or more compounds are measured.

[0008] It is also preferable to measure at least one of 2-ethylhydracrylic acid-2, carnitine, octanoylcarnitine, paraxanthine, S-methylcysteine-S-oxide, theobromine, indole-3-acetic acid, and pentanoic acid.

[0009] Furthermore, it is preferable that the composition contains at least one of carnitine, indole-3-acetic acid, and pentanoic acid.

[0010] Furthermore, it is preferable to measure a plurality of compounds, assign a score to each compound, and make a judgment based on the total score. It is also preferable that the measurement is performed by liquid chromatography mass spectrometry. Furthermore, the present invention comprises an agent or kit characterized by comprising a reagent for measuring the concentration of the above compound in blood, serum, or plasma.

[0011] The system or program further comprises a means for comparing an input value relating to the content of at least one of the above compounds contained in blood, serum, or plasma with a predetermined threshold value and determining whether the content is higher or lower than the predetermined threshold value, the predetermined value being a value applicable to determining the selection of intravesical BCG therapy, the selection of radical cystectomy for bladder cancer patients, the possibility of bladder cancer recurrence after intravesical BCG therapy, the risk of bladder cancer after intravesical BCG therapy, or the policy for bladder cancer treatment. It is also preferable that the system or program comprises a means for determining the possibility in stages using multiple threshold values.

[0012] The system or program further comprises a means for comparing input values ​​relating to the amounts of at least two of the above compounds contained in blood, serum, or plasma with a predetermined threshold value to determine whether the amounts are higher or lower than the predetermined threshold value, and a means for adding up scores set for each compound if the amounts are higher or lower than the threshold value, comparing the added value, i.e., the total value, with a predetermined threshold value to determine whether the amounts are higher or lower than the predetermined threshold value, wherein the predetermined threshold value or predetermined score value is a value applicable to selecting intravesical BCG therapy, selecting radical cystectomy for bladder cancer patients, the possibility of bladder cancer recurrence after intravesical BCG therapy, the risk of bladder cancer after intravesical BCG therapy, or determining the course of bladder cancer treatment. Preferably, the system or program comprises a means for determining the possibility in stages using multiple predetermined threshold values.

[0013] Each compound is explained below. 2-Ethylhydracrylic acid-2 is a type of organic acid with an ethyl group and a carboxyl group on its carbon skeleton. Chemical name: 2-ethyl-2-hydracrylic acid, molecular formula: C5H10O3, structure: 2-hydracrylic acid with the ethyl group attached to the second position. It is sometimes used as an intermediate in organic synthesis, and plays an important role in the production of pharmaceuticals and polymeric materials, for example.

[0014] Arabinonic acid-2 is a type of carboxylic acid formed when the aldehyde group of arabinose (C5H10O5) is oxidized to a carboxyl group. Its molecular formula is C5H10O6 and it is also known as D-arabinonic acid (the D form is more common in nature).

[0015] Carnitine, with the molecular formula C7H15NO3, is a type of beta-hydroxy acid that plays an important role in fatty acid metabolism. The chemical structure of carnitine contains a carboxyl group, a hydroxyl group, and an amino group.

[0016] Lauric acid is a saturated fatty acid with the IUPAC name dodecanoic acid and molecular formula C12H24O2. It is a linear saturated fatty acid with 12 carbon atoms and a carboxyl group at the end of the carbon chain, giving it acidic properties.

[0017] Myristic acid is a saturated fatty acid with the IUPAC name: tetradecanoic acid and molecular formula: C14H28O2. It is a saturated fatty acid with 14 carbon atoms arranged in a straight chain. Because the carboxyl group is located at the end, it has the stability and physical properties unique to saturated fatty acids.

[0018] Octanoylcarnitine, with the molecular formula C15H29NO4, is a compound formed by esterifying carnitine with octanoic acid. It is produced during the metabolism of medium-chain fatty acids and is believed to be involved in certain metabolic pathways. While both octanoylcarnitine and carnitine play important roles in fatty acid metabolism, they differ in structure and function, and are believed to play different roles in specific metabolic processes and medical applications.

[0019] Paraxanthine has the molecular formula C7H8N4O2 and is also known as 1,7-dimethylxanthine because two methyl groups are located at positions 1 and 7 on the xanthine ring. It is said to have physiological effects similar to those of caffeine.

[0020] S-Methylcysteine ​​has the molecular formula C4H9NO2S and is a compound in which a methyl group is bound to the amino acid cysteine. It is one of the major sulfur-containing compounds found in garlic.

[0021] S-Methylcysteine ​​S-oxide, IUPAC name: 2-amino-3-(methylsulfinyl)propanoic acid, molecular formula: C4H9NO3S, is an oxidized derivative of S-methylcysteine. It has a structure in which the thioether group of S-methylcysteine ​​is oxidized to a sulfoxide group.

[0022] SDMA (Symmetric Dimethylarginine) has the chemical formula C8H18N4O2 and is a methylated derivative of arginine. It is sometimes used as a biomarker for assessing renal function and for several pathological conditions. It has a structure in which two methyl groups are symmetrically attached to the termini of the guanidino group of arginine, and is produced by methylation of arginine residues in proteins by the enzyme protein arginine methyltransferase.

[0023] Theobromine, chemically known as 3,7-dimethylxanthine and with the molecular formula C7H8N4O2, is a xanthine derivative with methyl groups attached to the 3rd and 7th positions. It is an alkaloid compound found in cacao and chocolate, and is said to have properties that act on the central nervous system similar to caffeine.

[0024] 1-Methyl-4-imidazoleacetic acid has the molecular formula C6H8N2O2 and has a structure in which a methyl group is attached to the 1-position of the imidazole ring and an acetate group is attached to the 4-position. It can be produced in the body as a metabolic product of histamine and histidine, and is known to be produced as a by-product of histamine production by histidine decarboxylase.

[0025] ADMA (Asymmetric Dimethylarginine) is a methylated derivative of arginine and is considered an important compound, particularly as a biomarker for cardiovascular and renal diseases. Chemical name: N,N-Dimethylarginine, molecular formula: C8H18N4O2, it has a structure in which two methyl groups are asymmetrically bound to one of the two nitrogen atoms in the guanidino group of arginine. It is produced when arginine residues in proteins are methylated by protein methyltransferases (PRMTs) and then degraded by proteases.

[0026] Alanine has the structural formula CH3-CH(NH2)-COOH and is a type of amino acid. It exists in two optical isomers: L and D.

[0027] Argininosuccinic acid is a compound formed by the combination of arginine and succinic acid, with the molecular formula: C10H16N4O6. It is an intermediate in the urea cycle (ornithine cycle) and plays a role in detoxifying ammonia in the body.

[0028] Choline, with its IUPAC name of 2-hydroxyethyl-N,N,N-trimethylammonium and molecular formula of C10H16N4O6, is a quaternary ammonium compound with a structure consisting of an alcohol group (-OH), an ethyl group, and a trimethylammonium group. As a component of cell membranes, it is believed to be involved in the synthesis of neurotransmitters and the metabolism of fats.

[0029] Citrulline, with the molecular formula C6H13N3O3, is a compound containing an amino group, a carboxyl group, and a ureido group. It is a non-essential amino acid and is thought to be involved in the urea cycle and nitric oxide (NO) production.

[0030] Creatinine, with the IUPAC name 2-amino-1-methyl-5H-imidazol-4-one and molecular formula C4H7N3O, has a ring structure with two nitrogen atoms and one carbonyl group. Creatinine is produced when creatine phosphate in muscles is broken down for energy.

[0031] Guanidinoacetic acid, with the molecular formula C3H7N3O2, is a precursor for creatine synthesis and is a compound containing a guanidino group and an acetate group.

[0032] Lysine is an amino acid. It is an α-amino acid, with an amino group and a carboxyl group attached to the alpha carbon, and another amino group at the end of the carbon chain.

[0033] Methionine sulfoxide, whose IUPAC name is 2-amino-4-(methylsulfinyl)butanoic acid and molecular formula is C5H11NO3S, is a derivative of methionine that is oxidized and is thought to be related to oxidative stress in the body.

[0034] Myristic acid, with its IUPAC name of tetradecanoic acid and molecular formula of C14H28O2, is a type of saturated fatty acid with a linear chain of 14 carbon atoms, each with a carboxyl group attached to its end. It is found in large amounts in vegetable oils and animal fats.

[0035] N-(1-Deoxy-1-fructosyl)leucine, with the molecular formula C12H23NO6, is a compound formed by the combination of the amino acids leucine and fructose. It is known as a product of glycation.

[0036] N-acetylneuraminic acid (Neu5Ac) is a member of the group of compounds known as sialic acids. Its IUPAC name is 5-(acetylamino)-3,5-dideoxy-D-glycero-α-D-galacto-nonono-2-urono-1,4-lactone, and its molecular formula is C11H19NO9. It is a monosaccharide found at the end of sugar chains and is widely found on the surface of animal cells, in glycoproteins, and glycolipids.

[0037] N6,N6,N6-Trimethyllysine (TML) has the IUPAC name 2,6-bis(methylamino)-6-oxohexanoic acid and the molecular formula C9H20N2O2. It is a compound in which the amino acid lysine is modified with three methyl groups, and exists in the body as a precursor for carnitine synthesis.

[0038] Propionyl-L-carnitine, with the molecular formula C10H19[N+]O3[O-], is a derivative of carnitine, a compound formed by combining propionic acid and carnitine. It has been implicated in energy metabolism and cardiovascular health.

[0039] Threonine, with the molecular formula C4H9NO3, is a type of amino acid. It cannot be synthesized in the body and must be obtained through diet.

[0040] γ-Glu-Gly (γ-Glutamyl-glycine) has the molecular formula C7H12N2O5 and is a dipeptide consisting of glutamic acid and glycine linked by a peptide bond. It is an intermediate in the degradation pathway of glutathione (GSH) and is involved in antioxidant and detoxification effects.

[0041] γ-Glu-Tyr (γ-Glutamyl-tyrosine) has the molecular formula C14H18N2O6 and is a dipeptide formed by the peptide bond between the amino acids glutamic acid and tyrosine. It is believed to function as an intermediate in enzymatic reactions involved in amino acid metabolism.

[0042] γ-Glu-Val (γ-Glutamyl-valine) has the molecular formula C10H18N2O5 and is a dipeptide formed by the amino acids glutamic acid and valine linked together via a peptide bond. It functions as an intermediate in amino acid metabolism and is thought to be involved in the metabolism of glutamic acid and valine.

[0043] Indole-3-acetic acid (IAA) is a plant hormone also known as auxin. Its IUPAC name is 1H-Indole-3-acetic acid and its molecular formula is C10H9NO2. It has a structure consisting of an indole ring and an acetate group.

[0044] Pentanoic acid, also known as valeric acid, is an organic compound and a type of carboxylic acid. Its molecular formula is C5H10O2, and it is a colorless liquid with a pungent odor. Its structure consists of a carboxyl group (-COOH) bonded to pentane (an alkane with five carbon atoms bonded in a straight chain). [Brief explanation of the drawings]

[0045] [Figure 1] These are the results of comprehensive analysis using metabolome measurements of samples taken before BCG treatment. [Figure 2] These are the results of a comprehensive analysis of metabolome measurements of samples taken after BCG treatment. [Figure 3] These are the results of comprehensive analysis using metabolome measurements of samples taken before BCG treatment. [Figure 4] This is an example of a prediction model for the rate of recurrence of bladder abscess using a Kaplan-Meier curve. [Figure 5] 5 is a graph showing the results of the Discovery set in the model of FIG. 4. [Figure 6] The Kaplan-Meier curve of the no-bladder recurrence rate for the validation set in the model in Figure 4. [Figure 7] 10 is another example of a prediction model for the rate of recurrence of bladder abscess using a Kaplan-Meier curve. [Figure 8] 8 is a graph showing the results of the Discovery set in the model of FIG. 7. [Figure 9] 8 is a graph showing the results of the validation set for the model of FIG. 7. DETAILED DESCRIPTION OF THE INVENTION

[0046] In order to discover biomarkers for assessing the risk of bladder cancer recurrence after intravesical BCG therapy, the inventors collected blood samples before BCG therapy from 23 bladder cancer patients (Discovery set) who had received intravesical BCG therapy, and then collected blood samples from the same 23 patients after BCG therapy after 6-8 BCG administrations. By comparing patients who responded to intravesical BCG therapy (who did not experience bladder recurrence during follow-up) with patients who did not respond to intravesical BCG therapy (who experienced bladder recurrence during follow-up), the inventors succeeded in identifying metabolites thought to be related to bladder recurrence from the metabolites in the analysis data 1100.

[0047] Blood sample analysis method: 50 μL of serum was added to 200 μL of methanol solution containing a 20 μM internal standard and vortexed. 150 μL of Milli-Q water was added and vortexed, then transferred to an ultrafiltration tube (Ultrafree MC PLHCC, HMT, centrifugal filter unit 5 kDa). The tube was centrifuged (9,100 x g, 4°C, 120 minutes) and ultrafiltered. The filtrate was dried and redissolved in Milli-Q water. Comprehensive metabolomic analysis was performed using capillary electrophoresis-time-of-flight mass spectrometry (CE-TOFMS). Figure 1 shows the results for the pre-BCG treatment sample, and Figure 2 shows the results for the post-BCG treatment sample (P values ​​less than 0.05 for both). The hazard ratio (HR) in the figure is calculated by dividing the recurrence rate in the high-concentration group by the recurrence rate in the low-concentration group. For example, for myristic acid, a group with a high concentration has a high HR and a high recurrence rate, while a group with an HR below 1 has the opposite evaluation (lower HR means more recurrences), and it is highly likely that a sufficiently large or small number is a clear indicator.

[0048] Furthermore, among the markers whose absolute values ​​could be measured in the pre-BCG treatment samples, the markers that were useful for determining the risk of recurrence in the 23 cases in the Discovery set (P value less than 0.05) were found to be carnitine, indole-3-acetic acid, and pentanoic acid, as shown in Figure 3.

[0049] Of these, the markers explored for use before BCG treatment are suitable for the purpose of selecting and deciding whether or not to perform intravesical BCG therapy. Furthermore, cartinine, indole-3-acetic acid, and pentanoic acid are suitable from the perspective of quantitative measurement. Furthermore, cartinine appears to be suitable from the perspective of both HR values ​​and other indicators. Furthermore, reliability can be improved by measuring multiple markers and making a decision.

[0050] Furthermore, the inventors prepared a validation set of 40 bladder cancer cases, separate from the 23 cases mentioned above. They obtained blood samples from patients before BCG treatment, which was considered more effective and efficient for the purpose of this invention (determining whether to administer BCG therapy). They then performed comprehensive metabolomic analysis and verified which combination of candidate markers was most effective. Specifically, using PRISM ver. 10 software, the 40 validation cases were divided into two groups, high and low, for each marker, using the markers and their corresponding cutoff values ​​selected from the discovery set of 23 cases. The recurrence risk was compared (log-rank test). Significant differences, i.e., P values ​​less than 0.05, were narrowed down to six (see Figure 4). Therefore, the measurement of 2-ethylhydracrylic acid-2, carnitine, octanoylcarnitine, paraxanthine, S-methylcysteine-S-oxide, and theobromine was found to be suitable.

[0051] Hazard scores were set for these six identified compounds based on HR values, P values, etc., and a prediction model for the rate of recurrence without bladder using Kaplan-Meier curves was created (see Figures 4 to 6). This was then verified in both the discovery set and the validation set. As a result, clear differences in risk stages were observed (see Figures 4 to 6). Furthermore, a prediction model for the rate of recurrence without bladder using Kaplan-Meier curves was similarly created for the three compounds for which absolute values ​​are currently known (carnitine, indole-3-acetic acid, and pentanoic acid) (see Figures 7 to 9). This was then verified in both the discovery set and the validation set. As a result, clear differences in risk stages were observed (see Figures 7 to 9). Therefore, it was found that all of the above markers discovered in the present invention are useful, and furthermore, it is effective to set a hazard score for each compound and make a comprehensive judgment.

[0052] The present invention can be configured as a system or a program for causing a computer to function that uses the above-mentioned compounds or indicators as criteria for judgment. Specifically, the present invention can be configured as a system or a program for causing a computer to function that, when a value (at least one type) obtained from the content of the above-mentioned compounds in blood, serum, or plasma is input, compares the input value with a predetermined threshold value for the compound and determines whether the input value is higher or lower than the predetermined threshold value. The predetermined value can be used to determine whether the value is higher or lower than the predetermined threshold value for selecting intravesical BCG therapy, selecting radical cystectomy for bladder cancer patients, or determining the likelihood of bladder cancer recurrence after intravesical BCG therapy. Furthermore, the present invention can be configured as a system or a program for causing a computer to function that uses the amount of each target compound as an input value, compares the input value with a predetermined threshold value, and, if the input value is higher or lower than the predetermined threshold value, adds up the hazard scores assigned to each compound, compares the sum with a predetermined hazard assessment threshold value, and outputs a graded assessment (e.g., a multi-level assessment from low risk to high risk).

[0053] The system can utilize known hardware configurations, such as a computing device such as a CPU, a database storing thresholds and hazard scores for each compound, thresholds and scores for graded evaluation, and / or a memory storing programs, RAM, etc., and can be constructed as a cloud-based system via a server or as a standalone system.

[0054] The measurement is not limited to the above-mentioned search method as long as it can measure the above compounds. However, measurement by chromatography-mass spectrometry, particularly liquid chromatography-mass spectrometry, is preferred for its simplicity and practicality. Chromatography-mass spectrometry is an analytical method that uses a gas, liquid, or supercritical fluid as the mobile phase to separate and detect mixtures through the interaction of the substance with a stationary phase held in a column. It separates each component in a sample and determines its content and content ratio. Gas chromatography-mass spectrometry, which uses a gas as the mobile phase, targets volatile substances, while liquid chromatography-mass spectrometry can target substances ranging from volatile to refractory. Among liquid chromatography-mass spectrometry methods, high-performance liquid chromatography-mass spectrometry is characterized by using a highly pressurized liquid as the mobile phase. By forcibly applying high pressure, the mobile phase solvent is passed through the column at a high flow rate, thereby shortening the time the analyte remains in the stationary phase and improving separation ability and detection sensitivity. Detection can be performed by appropriately selecting from these chromatographic analyses depending on the target substance.

[0055] Furthermore, if a diagnostic agent containing a concentration measurement reagent using a specific receptor for the above substance is provided, it can be provided as a kit effective for diagnosis.

[0056] There have been no prior disclosures focusing on blood components and biomarkers for determining whether intravesical BCG therapy should be administered. In other words, none of the above-mentioned compounds have been mentioned as indicators for the administration of intravesical BCG therapy or as indicators of the risk of bladder cancer recurrence after intravesical BCG therapy. Furthermore, if high-risk patients could undergo immediate radical cystectomy without intravesical BCG therapy, they would not suffer from the side effects of intravesical BCG therapy and would be able to receive early, appropriate bladder cancer treatment, thereby not only reducing the risk of recurrence but also enabling early treatment.

[0057] Furthermore, the present invention provides a method and indicator for diagnosis that can be easily collected, is highly versatile for routine clinical use, and is independent of the patient's symptoms, thereby enabling objective diagnosis and facilitating the diagnosis itself. Furthermore, diagnosis can be made from serum or plasma.

Claims

1. For the purpose of determining the selection of intravesical BCG therapy, the following substances in blood, serum, or plasma may be detected: 2-ethylhydracrylic acid-2, arabinonic acid-2, carnitine, lauric acid, myristic acid, octanoylcarnitine, paraxanthine, S-methylcysteine, S-methylcysteine-S-oxide, SDMA, theobromine, indole-3-acetic acid, pentanoic acid, 1-methyl-4-imidazoleacetic acid, ADMA, alanine, argininosuccinic acid, A method for measuring at least one of choline, citrulline, creatinine, guanidoacetic acid, lysine, methionine sulfoxide, myristic acid, N-(1-deoxy-1-fructosyl)leucine, N-acetylneuraminic acid, N6,N6,N6-trimethyllysine, propionylcarnitine, threonine, gamma-glutamyl-glycine, gamma-glutamyl-tyrosine, and gamma-glutamyl-valine.

2. The method according to claim 1, wherein the measurement compound comprises at least one of 2-ethylhydracrylic acid-2, arabinonic acid-2, carnitine, lauric acid, myristic acid, octanoylcarnitine, paraxanthine, S-methylcysteine, S-methylcysteine-S-oxide, SDMA, theobromine, indole-3-acetic acid, and pentanoic acid.

3. 2. The method according to claim 1, wherein the measurement compound comprises at least one of 2-ethylhydracrylic acid-2, carnitine, octanoylcarnitine, paraxanthine, S-methylcysteine-S-oxide, theobromine, indole-3-acetic acid, and pentanoic acid.

4. 4. The method according to claim 1, wherein a plurality of compounds are measured and evaluated.

5. 5. The method according to claim 4, wherein a score is assigned to each compound and a judgment is made based on a total score.

6. The method according to any one of claims 1 to 5, wherein the measurement is performed by chromatography-mass spectrometry.

7. For the purpose of deciding whether to perform radical cystectomy for bladder cancer patients, deciding on the possibility of bladder cancer recurrence after intravesical BCG therapy, deciding on the risk of bladder cancer after intravesical BCG therapy, or deciding on a bladder cancer treatment policy, The method for measuring at least one of 2-ethylhydracrylic acid-2, arabinonic acid-2, carnitine, lauric acid, myristic acid, octanoylcarnitine, paraxanthine, S-methylcysteine, S-methylcysteine-S-oxide, SDMA, theobromine, indole-3-acetic acid, pentanoic acid, 1-methyl-4-imidazoleacetic acid, ADMA, alanine, argininosuccinic acid, choline, citrulline, creatinine, guanidoacetic acid, lysine, methionine sulfoxide, myristic acid, N-(1-deoxy-1-fructosyl)leucine, N-acetylneuraminic acid, N6,N6,N6-trimethyllysine, propionylcarnitine, threonine, gamma-glutamyl-glycine, gamma-glutamyl-tyrosine, and gamma-glutamyl-valine.

8. The method according to claim 7, wherein the measurement compound comprises at least one of 2-ethylhydracrylic acid-2, arabinonic acid-2, carnitine, lauric acid, myristic acid, octanoylcarnitine, paraxanthine, S-methylcysteine, S-methylcysteine-S-oxide, SDMA, theobromine, indole-3-acetic acid, and pentanoic acid.

9. The method according to claim 8, wherein the measurement compound comprises at least one of 2-ethylhydracrylic acid-2, carnitine, octanoylcarnitine, paraxanthine, S-methylcysteine-S-oxide, theobromine, indole-3-acetic acid, and pentanoic acid.

10. 10. The method according to claim 7, wherein a plurality of compounds are measured and evaluated.

11. The method according to claim 10, wherein a score is assigned to each compound and a judgment is made based on a total score.

12. The method according to any one of claims 7 to 11, wherein the measurement is performed by chromatography-mass spectrometry.

13. 2-Ethylhydracrylic acid-2, arabinonic acid-2, carnitine, lauric acid, myristic acid, octanoylcarnitine, paraxanthine, S-methylcysteine, S-methylcysteine-S-oxide, SDMA, theobromine, indole-3-acetic acid, pentanoic acid, 1-methyl-4-imidazoleacetic acid, ADMA, alanine, argininosuccinic acid, choline, citrulline, creatinine, guanidoacetic acid, lysine, methionine sulfoxide, myristic acid, N-(1-deoxy-1-fructosyl) methylpropional, methylparaben ... A measuring agent or kit for determining whether to use intravesical BCG therapy, whether to use radical cystectomy for bladder cancer patients, whether to use intravesical BCG therapy, whether to use intravesical BCG therapy, whether to use bladder cancer risk after intravesical BCG therapy, or whether to use bladder cancer treatment guidelines, characterized by containing at least one measuring reagent selected from the group consisting of isin, N-acetylneuraminic acid, N6,N6,N6-trimethyllysine, propionylcarnitine, threonine, gamma-glutamyl-glycine, gamma-glutamyl-tyrosine, and gamma-glutamyl-valine.

14. The measuring agent or kit according to claim 13, characterized in that the measuring reagent is any one of 2-ethylhydracrylic acid-2, carnitine, octanoylcarnitine, paraxanthine, S-methylcysteine-S-oxide, theobromine, indole-3-acetic acid, and pentanoic acid.

15. 2-Ethylhydracrylic acid-2, arabinonic acid-2, carnitine, lauric acid, myristic acid, octanoylcarnitine, paraxanthine, S-methylcysteine, S-methylcysteine-S-oxide, SDMA, theobromine, indole-3-acetic acid, pentanoic acid, 1-methyl-4-imidazoleacetic acid, ADMA, alanine, argininosuccinic acid, choline, citrulline, creatinine, guanidoacetic acid, lysine, methionine sulfoxide, myristic acid, N-(1-deoxy-1-fructosyl)leucine, N-acetylneuraminic acid, N6, The system is characterized by comprising a means for comparing an input value relating to the content of at least one of N6,N6-trimethyllysine, propionylcarnitine, threonine, gamma-glutamyl-glycine, gamma-glutamyl-tyrosine, and gamma-glutamyl-valine with a predetermined threshold value and determining whether the content is higher or lower than the predetermined threshold value, wherein the predetermined value is a value applicable to selecting BCG intravesical instillation therapy, selecting radical cystectomy for bladder cancer patients, the possibility of bladder cancer recurrence after BCG intravesical instillation therapy, the risk of bladder cancer after BCG intravesical instillation therapy, or determining a bladder cancer treatment policy.

16. The system according to claim 15, further comprising a means for determining in stages, the means having a plurality of thresholds.

17. 2-Ethylhydracrylic acid-2, arabinonic acid-2, carnitine, lauric acid, myristic acid, octanoylcarnitine, paraxanthine, S-methylcysteine, S-methylcysteine-S-oxide, SDMA, theobromine, indole-3-acetic acid, pentanoic acid, 1-methyl-4-imidazoleacetic acid, ADMA, alanine, argininosuccinic acid, choline, citrulline, creatinine, guanidoacetic acid, contained in blood, serum or plasma means for comparing input values ​​relating to the contents of at least two of lysine, methionine sulfoxide, myristic acid, N-(1-deoxy-1-fructosyl)leucine, N-acetylneuraminic acid, N6,N6,N6-trimethyllysine, propionylcarnitine, threonine, gamma-glutamyl-glycine, gamma-glutamyl-tyrosine, and gamma-glutamyl-valine with a predetermined threshold value and determining whether the input values ​​are higher or lower than the predetermined threshold value; a means for adding up the score values ​​set for each compound when the score is higher or lower than the threshold, comparing the total value with a predetermined score threshold, and determining whether the total value is higher or lower than the predetermined score threshold; The system is characterized in that the specified threshold or specified score value is a value that can be applied to selecting BCG intravesical instillation therapy, selecting radical cystectomy for bladder cancer patients, determining the possibility of bladder cancer recurrence after BCG intravesical instillation therapy, or the risk of bladder cancer after BCG intravesical instillation therapy, or determining the course of bladder cancer treatment.

18. 18. The system according to claim 17, further comprising a means for determining a plurality of predetermined score values ​​in a stepwise manner.

19. Computer, 2-Ethylhydracrylic acid-2, arabinonic acid-2, carnitine, lauric acid, myristic acid, octanoylcarnitine, paraxanthine, S-methylcysteine, S-methylcysteine-S-oxide, SDMA, theobromine, indole-3-acetic acid, pentanoic acid, 1-methyl-4-imidazoleacetic acid, ADMA, alanine, argininosuccinic acid, choline, citrulline, creatinine, guanidoacetic acid, lysine, methionine contained in blood, serum, or plasma a program for functioning as a means for comparing an input value relating to the content of at least one of sulfoxide, myristic acid, N-(1-deoxy-1-fructosyl)leucine, N-acetylneuraminic acid, N6,N6,N6-trimethyllysine, propionylcarnitine, threonine, gamma-glutamyl-glycine, gamma-glutamyl-tyrosine, and gamma-glutamyl-valine with a predetermined threshold value, and determining whether the input value is higher or lower than the predetermined threshold value, The program is characterized in that the predetermined value is a value applicable to selecting BCG intravesical instillation therapy, selecting radical cystectomy for bladder cancer patients, the possibility of bladder cancer recurrence after BCG intravesical instillation therapy, or the risk of bladder cancer after BCG intravesical instillation therapy, or determining a bladder cancer treatment policy.

20. Computer, 2-Ethylhydracrylic acid-2, arabinonic acid-2, carnitine, lauric acid, myristic acid, octanoylcarnitine, paraxanthine, S-methylcysteine, S-methylcysteine-S-oxide, SDMA, theobromine, indole-3-acetic acid, pentanoic acid, 1-methyl-4-imidazoleacetic acid, ADMA, alanine, argininosuccinic acid, choline, citrulline, creatinine, guanidoacetic acid, contained in blood, serum or plasma means for comparing input values ​​relating to the contents of at least two of lysine, methionine sulfoxide, myristic acid, N-(1-deoxy-1-fructosyl)leucine, N-acetylneuraminic acid, N6,N6,N6-trimethyllysine, propionylcarnitine, threonine, gamma-glutamyl-glycine, gamma-glutamyl-tyrosine, and gamma-glutamyl-valine with a predetermined threshold value and determining whether the input values ​​are higher or lower than the predetermined threshold value; a program for functioning as a means for adding up score values ​​set for each compound when the score is higher or lower than a threshold, comparing the added value with a predetermined score threshold, and determining whether the score is higher or lower than the predetermined score threshold, The program is characterized in that the specified threshold or specified score value is a value applicable to selecting BCG intravesical instillation therapy, selecting radical cystectomy for bladder cancer patients, the possibility of bladder cancer recurrence after BCG intravesical instillation therapy, or the risk of bladder cancer after BCG intravesical instillation therapy, or determining the course of bladder cancer treatment.

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