WO2013046760A1 - Procédé d'inspection du cancer de l'estomac et trousse d'inspection - Google Patents

Procédé d'inspection du cancer de l'estomac et trousse d'inspection Download PDF

Info

Publication number
WO2013046760A1
WO2013046760A1 PCT/JP2012/058088 JP2012058088W WO2013046760A1 WO 2013046760 A1 WO2013046760 A1 WO 2013046760A1 JP 2012058088 W JP2012058088 W JP 2012058088W WO 2013046760 A1 WO2013046760 A1 WO 2013046760A1
Authority
WO
WIPO (PCT)
Prior art keywords
serum
tff
gastric cancer
antibody
tff3
Prior art date
Application number
PCT/JP2012/058088
Other languages
English (en)
Japanese (ja)
Inventor
幸世 野村
満 貝瀬
Original Assignee
国立大学法人東京大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 国立大学法人東京大学 filed Critical 国立大学法人東京大学
Publication of WO2013046760A1 publication Critical patent/WO2013046760A1/fr

Links

Images

Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56911—Bacteria
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57446—Specifically defined cancers of stomach or intestine

Definitions

  • the present invention relates to a method for examining gastric cancer including a step of measuring the amount of trefoil factor family (TFF) protein in the serum of a subject.
  • TNF trefoil factor family
  • gastric cancer screening is performed by gastric fluoroscopy or gastroscopy with barium.
  • screening by barium or gastroscopy is obligatory for those over 40 years old, but the consultation rate is still low.
  • One cause of this is the complexity and pain of inspection techniques and physical burden.
  • there is a pepsinogen method as a gastric cancer screening method using blood Non-Patent Document 1
  • the pepsinogen method measures the ratio of pepsinogen I and pepsinogen II in serum, and the cost increases because two factors must be measured.
  • Gastric cancer is still the fourth leading cause of cancer death worldwide.
  • the possibility of cure depends on the stage of gastric cancer, and early detection is the most effective means of reducing mortality from gastric cancer. Therefore, there is a need for a method for examining gastric cancer that is simpler and more sensitive and specific.
  • the present invention [1] A method for examining gastric cancer or Helicobacter pylori infection, which comprises a step of measuring a trefoil factor family (TFF) level in the serum of a subject; [2] A method for examining gastric cancer, wherein the TFF is TFF1 or TFF3; [3] A method for testing Helicobacter pylori infection, wherein the TFF is TFF1; [4] The method according to any one of [1] to [3] above, wherein the step of measuring the serum TFF level is performed by immunoassay using an anti-TFF protein antibody; [5] The method according to any one of [1] to [4] above, wherein the method for examining gastric cancer has a cutoff value of serum TFF1 level of 0.1 ng / mL to 10 ng / mL; [6] A method for examining gastric cancer according to any one of [1] to [5] above, wherein the serum TFF3 level has a cutoff
  • gastric cancer with high sensitivity and specificity can be tested by a simple and painless method of measuring the TFF concentration in serum prepared from the blood of a subject.
  • TFF1 and TFF3 are used, the sensitivity and specificity are significantly higher than those of the conventional pepsinogen method, and the cost can be reduced as compared with the pepsinogen method that measures the amount of two types of markers.
  • Such a test is considered to increase the consultation rate, leading to early detection of gastric cancer, and possibly reducing the mortality from gastric cancer.
  • FIG. 1 shows the results of measuring the serum TFF1, TFF2, and TFF3 levels of gastric cancer patient group and control group (positive or negative for H pylori infection) by ELISA.
  • FIG. 2 shows the results of ROC analysis based on the measurement results of FIG.
  • FIG. 2A is an ROC curve for serum TFF levels for determining the presence or absence of H pylori infection.
  • FIG. 2B is an ROC curve for serum TFF levels to distinguish gastric cancer patients from non-gastric cancer patients.
  • FIG. 2C is an ROC curve for serum TFF levels for discriminating H pylori infection negative gastric cancer patients from H pylori infection negative non-gastric cancer patients.
  • FIG. 1 shows the results of measuring the serum TFF1, TFF2, and TFF3 levels of gastric cancer patient group and control group (positive or negative for H pylori infection) by ELISA.
  • FIG. 2 shows the results of ROC analysis based on the measurement results of FIG.
  • FIG. 2D is an ROC curve for serum TFF levels for distinguishing H pylori positive gastric cancer patients from H pylori positive non-gastric cancer patients.
  • FIG. 3 shows the results of determining the sensitivity, specificity, and odds ratio of the gastric cancer test method using serum TFF1-3 levels, pepsinogen I / II, and anti-H pylori IgG as indices.
  • FIG. 4 shows the results of comparing the serum TFF3 level with the age-matched control group for the second cohort (30s-60s) of gastric cancer patients.
  • FIG. 5 is an ROC curve for each of the pepsinogen method, serum TFF3 level, and a combination of these methods for discriminating gastric cancer patients.
  • FIG. 6A shows the results of measuring serum TFF1 levels in differentiated gastric cancer patients and undifferentiated gastric cancer patients.
  • FIG. 6B shows the results of measuring serum TFF2 levels in differentiated gastric cancer patients and undifferentiated gastric cancer patients.
  • FIG. 6C shows the results of measuring serum TFF3 levels in differentiated gastric cancer patients and undifferentiated gastric cancer patients.
  • FIG. 7 shows the results of measurement of serum TFF levels before and after one week from gastrectomy in gastric cancer patients.
  • FIG. 8 shows the results of measuring the serum TFF level after 3 months or more have passed since gastrectomy in a stomach cancer patient.
  • TFF Teest method for gastric cancer and Helicobacter pylori infection
  • One aspect of the method for examining gastric cancer according to the present invention includes a step of measuring the amount of TFF protein in the serum of a subject.
  • TFF is a family consisting of three stable proteins, TFF1, TFF2, and TFF3, each of 12 kDa to 22 kDa, and is known to be secreted from the digestive tract of mammals (Non-Patent Documents 2 to 5). .
  • TFF was named after the three loop structures that TFF1-3 have in common. This loop structure makes TFF extremely stable against proteolysis and has excellent acid resistance and heat resistance.
  • TFF1-3 are widely expressed in a tissue-specific manner in the gastrointestinal tract.
  • TFF1 is expressed in the surface mucous cells of the gastric mucosa
  • TFF2 is expressed in mucus neck cells, deep antral gland cells, and Brunner's gland in the duodenum
  • TFF3 is expressed in goblet cells of the small and large intestines .
  • Gastric cancer follows chronic atrophic gastritis caused by chronic Helicobacter pylori infection.
  • Mucosal histological changes in chronic atrophic gastritis include foveolar hyperplasia, Spasmolytic polypeptide (TFF2) -expressing metaplasia (SPEM), and secreted atrophy with intestinal metaplasia.
  • Foveolar hyperplasia is an extension of a gastric pit consisting of pit surface mucus cells that originally express TFF1.
  • SPEM is an antral phenotype lineage characterized by TFF2-positive cells in the stomach fundus. SPEM is common in the gastric mucosa surrounding gastric cancer, and TFF2 is positive in 58% of early gastric cancer.
  • Intestinal metaplasia is characterized by intestinal phenotype cells that occur in the gastric mucosa and is considered to be a precancerous lesion of intestinal gastric cancer.
  • TFF3 is also expressed in the intestinal metaplasia of the stomach in addition to the aforementioned goblet cells of the small and large intestines.
  • serum TFF1 levels tend to be significantly higher in the positive group than in the Helicobacter pylori infection negative group, and higher in the gastric cancer patient group than in the non-gastric cancer patient group. It was seen. Thus, serum TFF1 levels are thought to be particularly useful for testing for Helicobacter pylori infection.
  • the test for Helicobacter pylori is generally carried out by a method using an anti-Helicobacter pylori antibody. However, Helicobacter pylori dies when atrophic gastritis worsens and cannot be detected by this method. If detected by the serum TFF1 level, it is possible to detect the presence or absence of infection even after such Helicobacter pylori dies. TFF1 exhibits high sensitivity, specificity, and odds ratio in discrimination between Helicobacter pylori infection negative groups and gastric cancer patients, and is also useful for gastric cancer testing.
  • Serum TFF2 and serum TFF3 were significantly higher in the positive group than in the Helicobacter pylori infection negative group, and significantly higher in the gastric cancer patient group than in the non-gastric cancer patient group.
  • TFF3 shows high sensitivity, specificity, and odds ratio in discrimination between non-gastric cancer patients and gastric cancer patients regardless of the presence or absence of Helicobacter pylori infection, and is useful for gastric cancer testing.
  • serum used in the test according to the present invention one prepared from blood collected from a subject according to a conventional method can be used.
  • the step of measuring TFF in serum can be performed using any method for detecting and measuring a specific protein in a liquid.
  • immunoassay including agglutination and turbidimetry), Western blotting , Surface plasmon resonance (SPR) method and the like, but are not limited thereto.
  • An immunoassay that measures the amount of TFF using an antigen-antibody reaction between an anti-TFF antibody and TFF is particularly simple and preferred.
  • the immunoassay uses a detectably labeled anti-TFF antibody and / or an antibody (secondary antibody) against the detectably labeled anti-TFF antibody.
  • enzyme immunoassay EIA or ELISA
  • radioimmunoassay RIA
  • fluorescent immunoassay FPIA
  • fluorescence polarization immunoassay FPIA
  • chemiluminescent immunoassay CLIA
  • fluorescent enzyme immunoassay FLEIA
  • chemiluminescent enzymessay chemiluminescent enzyme immunoassay
  • enzymes such as peroxidase and alkaline phosphatase
  • radioactive substances such as 125 I, 131 I, 35 S and 3 H
  • Fluorescent substances such as isothiocyanate and near-infrared fluorescent materials, and CLIA methods use antibodies labeled with luminescent substances such as luciferase, luciferin, and aequorin.
  • antibodies labeled with nanoparticles such as colloidal gold and quantum dots can also be detected.
  • anti-TFF antibody can be detected by labeling with biotin and binding avidin or streptavidin labeled with an enzyme or the like.
  • the ELISA method using an enzyme label is preferable because it can easily and rapidly measure an antigen.
  • the ELISA method includes a competitive method and a sandwich method.
  • an anti-TFF antibody is immobilized on a solid phase carrier such as a microplate, and a serum sample and enzyme-labeled TFF are added to cause an antigen-antibody reaction. Once washed, it reacts with the enzyme substrate, develops color, and the absorbance is measured. If the serum sample has a large amount of TFF, the color development becomes weak. If the serum sample has a small amount of TFF, the color development becomes strong. Therefore, the TFF level can be obtained using a calibration curve.
  • an anti-TFF antibody is immobilized on a solid phase carrier, a serum sample is added and reacted, and then an anti-TFF antibody that recognizes another epitope labeled with an enzyme is further added and reacted. After washing, the amount of TFF can be determined by reacting with the enzyme substrate, causing color development, and measuring the absorbance.
  • an antibody immobilized on a solid phase carrier is reacted with TFF in a serum sample, an unlabeled antibody (primary antibody) is added, and an antibody against the unlabeled antibody (secondary antibody) is enzyme-labeled. Further, it may be added.
  • DAB 3,3'-diaminobenzidine
  • TMB 3,3'5,5'-tetramethylbenzidine
  • OPD o-phenylenediamine
  • NPP p-nitropheny phosphate
  • the “solid phase carrier” is not particularly limited as long as it can immobilize the antibody, and is made of a microtiter plate made of glass, metal, resin, etc., substrate, beads, nitrocellulose membrane, nylon membrane, PVDF Examples include a membrane, and the target substance can be immobilized on these solid phase carriers according to a known method.
  • an agglutination method is also preferable as a method for easily detecting a trace amount of protein.
  • the aggregation method include a latex aggregation method in which latex particles are bound to an antibody.
  • TFF serum-binding protein
  • the concentration of the antigen can be determined by irradiating the sample with near-infrared light and quantifying the aggregate by measuring the absorbance (turbidimetric method) or the scattered light (Hipple method).
  • Anti-TFF antibodies can be prepared according to known methods for both monoclonal antibodies and polyclonal antibodies.
  • the monoclonal antibody is, for example, an antibody-producing cell isolated from a non-human mammal immunized with each of TFF1 to 3 or a fragment thereof, and this is fused with a myeloma cell to produce a hybridoma, and the antibody produced by this hybridoma Can be obtained by purification.
  • Polyclonal antibodies can also be obtained from the sera of animals immunized with each of TFF1-3 or fragments thereof. An existing antibody may be used as the anti-TFF antibody.
  • gastric cancer is used in the usual sense, and includes gastric cancer in any state regardless of pathological classification, morphology, depth of advance, stage indicated by progression, and the like.
  • inspection means to examine a sample collected from a subject in order to obtain information necessary for diagnosis, and the inspection method of the present invention can be performed by, for example, an inspection company.
  • One aspect of the test method of the present invention is a gastric cancer test method comprising a step of measuring serum TFF1 level, wherein the cutoff value of serum TFF1 level is 0.1 ng / mL to 10 ng / mL, 0.3 ng / mL to 8 ng / mL, 0.5 ng / mL to 5 ng / mL, 0.8 ng / mL to 1.2 ng / mL, and the like.
  • the cut-off value within this range, it is possible to make a test with sufficiently high sensitivity, specificity, and odds ratio.
  • One aspect of the test method of the present invention is a gastric cancer test method comprising a step of measuring serum TFF3 level, wherein the cutoff value of serum TFF3 level is 1 ng / mL to 15 ng / mL, 2 ng / mL to 10 ng / mL 3 ng / mL to 5 ng / mL, 3.4 ng / mL to 3.8 ng / mL, and the like.
  • the cut-off value of serum TFF3 level is 1 ng / mL to 15 ng / mL, 2 ng / mL to 10 ng / mL 3 ng / mL to 5 ng / mL, 3.4 ng / mL to 3.8 ng / mL, and the like.
  • the inspection method according to the present invention may be combined with a conventionally used pepsinogen method.
  • the pepsinogen method is a method for measuring pepsinogen I and II in serum using an anti-pepsinogen antibody, and is positive when the serum pepsinogen I level is less than 70 ng / mL and the serum pepsinogen I / II ratio is less than 3. Determined.
  • sensitivity and specificity can be further increased by combining the method for measuring serum TFF3 level and the pepsinogen method.
  • this invention also includes the diagnostic method of gastric cancer or Helicobacter pylori infection including the process of measuring the trefoil factor family (TFF) level in the serum of a subject.
  • diagnostic means that the medical practitioner determines whether the subject suffers from a specific disease based on the test result or the like.
  • diagnosis means that the medical practitioner determines whether the subject suffers from a specific disease based on the test result or the like.
  • the terms used for diagnosing gastric cancer and Helicobacter pylori infection according to the present invention are synonymous with them, and the description thereof is omitted here.
  • the test kit for gastric cancer according to the present invention is a kit for performing a test for gastric cancer using the test method described above, and includes at least one of an anti-TFF1 antibody, an anti-TFF2 antibody, and an anti-TFF3 antibody.
  • the test kit of the present invention includes reagents and devices necessary for measuring serum TFF levels by immunoassay using an antigen-antibody reaction between an anti-TFF antibody and TFF.
  • test kit is for measuring TFF by the sandwich method; a microtiter plate; an anti-TFF antibody for capture; an anti-TFF antibody labeled with alkaline phosphatase or peroxidase; and an alkaline phosphatase substrate (NPP Or a substrate of peroxidase (DAB, TMB, OPD, etc.).
  • the capture antibody and the labeled antibody recognize different epitopes.
  • a capture antibody is immobilized on a microtiter plate, a serum sample is appropriately diluted and added thereto, and then incubated, and the sample is removed and washed.
  • the labeled antibody is added and then incubated, and the substrate is added to cause color development.
  • the TFF level can be determined by measuring the color development using a microtiter plate reader or the like.
  • test kit is for measuring TFF by a sandwich method using a secondary antibody; a microtiter plate; an anti-TFF antibody for capture; an anti-TFF antibody as a primary antibody; a secondary
  • the antibody includes an anti-TFF antibody labeled with alkaline phosphatase or peroxidase; and an alkaline phosphatase (NPP or the like) or a substrate of peroxidase (DAB, TMB, OPD or the like).
  • NPP alkaline phosphatase
  • DAB alkaline phosphatase
  • TMB peroxidase
  • OPD peroxidase
  • the capture antibody and the primary antibody recognize different epitopes.
  • a capture antibody is immobilized on a microtiter plate, a serum sample is appropriately diluted and added thereto, and then incubated, and the sample is removed and washed.
  • the primary antibody is added to incubate and wash, and the enzyme-labeled secondary antibody is further added and incubated, and then the substrate is added to cause color development.
  • the TFF level can be determined by measuring the color development using a microtiter plate reader or the like.
  • the reaction is amplified and the detection sensitivity can be increased.
  • test kit includes a microtiter plate; an anti-TFF antibody as a primary antibody; an anti-TFF antibody labeled with alkaline phosphatase or peroxidase; and an alkaline phosphatase or peroxidase substrate.
  • a microtiter plate is coated with a sample diluted to an appropriate concentration, and a primary antibody is added. After incubation and washing, an enzyme-labeled secondary antibody is added, incubation and washing are performed, and a substrate is added to cause color development.
  • the TFF level can be determined by measuring the color development using a microtiter plate reader or the like.
  • each test kit further contains necessary buffer solution, enzyme reaction stop solution, microplate reader and the like.
  • Labeled antibodies are not limited to enzyme-labeled antibodies, but include radioactive substances ( 25 I, 131 I, 35 S, 3 H, etc.), fluorescent substances (fluorescein isothiocyanate, rhodamine, dansyl chloride, phycoerythrin, tetramethylrhodamine isothiocyanate, Near-infrared fluorescent materials, etc.), luminescent substances (luciferase, luciferin, aequorin, etc.), nanoparticles (gold colloid, quantum dots), etc.
  • a biotinylated antibody can be used as a labeled antibody, and labeled avidin or streptavidin can be added to the kit.
  • test kit of the present invention includes one for measuring the TFF level by the latex agglutination method.
  • This kit contains anti-TFF antibody-sensitized latex, a serum sample and anti-TFF antibody are mixed, and the clump is quantified by an optical method. It is also preferable that an agglutination reaction plate for visualizing the agglutination reaction is included in the kit.
  • Example 1 ⁇ Subject> The subjects were 183 patients with gastric cancer who were treated from February 2006 to September 2008 in gastroesophageal surgery at the University of Tokyo Hospital. Blood samples were taken before treatment. Patients were categorized by early or advanced cancer, histology (differentiated, undifferentiated), number, depth, tumor size, lymph node metastasis, and clinical stage. The control group consisted of 280 healthy male and female donors who had undergone a medical examination at NTT Kanto Central Hospital from September to November 2006. The characteristics of patients and donors are shown in the table below.
  • FIG. 1 shows the serum TFF1, TFF2, and TFF3 levels of the stomach cancer patient group and the control group (H pylori infection positive group and negative group). H pylori infection was determined by serum anti-H pylori IgG levels.
  • TFF1 ( Figure 1 left) In the control group negative for H pylori infection, the serum TFF1 level was 0.57 ⁇ 0.29 (median 0.51, range 0.18-3.10) ng / mL. In the control group positive for H pylori infection, the serum TFF1 level was 2.51 ⁇ 1.52 (median 2.43, range 0.36-6.94) ng / mL, which was significantly higher than the H pylori negative control group. The serum TFF1 level in the gastric cancer patient group was 3.35 ⁇ 3.06 (median 2.37, range 0.31-19.1) ng / mL, which was significantly higher than the H pylori negative control group. Compared with the H pylori positive control group, the serum TFF1 level of the gastric cancer patient group tended to be higher, but no significant difference was obtained.
  • TFF2 (in Fig. 1)
  • the serum TFF2 level was 2.88 ⁇ 1.04 (median 2.7, range 0.53-7.2) ng / mL.
  • the serum TFF2 level was 5.15 ⁇ 2.41 (median 4.83, range 1.51-14.5) ng / mL, which was significantly higher than the H pylori negative control group.
  • the serum TFF2 level in the gastric cancer patient group was 8.79 ⁇ 16.2 (median 6.36, range 0.78-210) ng / mL, which was significantly higher than any of the control groups.
  • TFF3 (right in Fig. 1)
  • the serum TFF3 level was 2.72 ⁇ 0.80 (median 2.56, range 1.22-5.30) ng / mL.
  • the serum TFF3 level was 3.05 ⁇ 1.10 (median 2.79, range 1.40-6.25) ng / mL, which was significantly higher than the H pylori negative control group.
  • the serum TFF1 level in the gastric cancer patient group was 6.44 ⁇ 6.19 (median 5.02, range 1.85-74.4) ng / mL, which was significantly higher than any of the control groups. There were no significant differences in serum TFF3 levels between the 7 patients who developed the second cancer during the follow-up period and other patients.
  • FIG. 2A shows the ROC curve of the serum TFF level when comparing the H pylori infection positive group and the H pylori infection negative group determined by the serum anti-H pylori IgG level.
  • the areas under the curves for TFF1, TFF2, and TFF3 were 0.952, 0.811, and 0.587, respectively.
  • the area under the ROC curve for TFF1 was 0.95.
  • Serum TFF levels as a predictor of gastric cancer ROC analysis was performed to examine the accuracy of gastric cancer diagnosis using serum TFF levels and pepsinogen I / II ratio.
  • positive is determined when the serum pepsinogen I level is less than 70 ng / mL and the serum pepsinogen I / II ratio is less than 3.
  • FIG. 2B is an ROC curve showing the discrimination ability of gastric cancer patients by serum TFF level and pepsinogen I / II ratio.
  • the areas under the ROC curves for TFF3, TFF1, pepsinogen I / II ratio, and TFF2 were 0.89, 0.84, 0.76, and 0.74, respectively.
  • TFF1, TFF2, TFF3, and pepsinogen I / II ratio were 0.65, 0.67, 0.71, and 0.61, respectively, and the negative predictive values were 0.92, 0.81, 0.90, and 0.87, respectively.
  • the results of the ROC analysis show that TFF3 and TFF1 are more accurate indicators than the pepsinogen I / II ratio.
  • FIG. 2C shows the results of ROC analysis when a group of H pylori-negative gastric cancer patients is compared with a non-gastric cancer patient who is H pylori-negative.
  • the area under the curve increased in all curves, but in particular, TFF3 and TFF1 were recognized as better markers than TFF2 and pepsinogen I / II.
  • the positive predictive values for TFF1, TFF2, TFF3, and pepsinogen I / II ratio were 0.92, 0.84, 0.78, and 0.81, and the negative predictive values were 0.93, 0.87, 0.94, and 0.89, respectively.
  • 2D shows the results of ROC analysis when comparing H pylori positive gastric cancer patient groups with H pylori positive non-gastric cancer patients.
  • the area under the curve of TFF1 and pepsinogen I / II was small, suggesting that it is not a powerful gastric cancer marker when H pylori infection is positive.
  • the area under the curve for TFF2 was also small.
  • the area under the curve of TFF3 was large, indicating that TFF3 can be a useful marker for detecting gastric cancer regardless of the presence or absence of H pylori infection.
  • the positive predictive values for TFF1, TFF2, TFF3, and pepsinogen I / II ratio were 0.62, 0.81, 0.78, and 0.61, respectively, and the negative predictive values were 0.68, 0.59, 0.81, and 0.51.
  • FIG. 3 shows sensitivity, specificity, and odds ratio for TFF, pepsinogen method, and anti-H pylori IgG. Cut-off values were 1.0 ng / mL for serum TFF1, 4.0 ng / mL for serum TFF2, and 3.6 ng / mL for serum TFF3.
  • the odds ratio of serum TFF1 level was 18.1 (10.5-31.0), sensitivity was 89.6%, and specificity was 67.7%.
  • the odds ratio of serum TFF3 level was 18.1 (11.2-29.2), sensitivity was 80.9%, and specificity was 81.0%. TFF1 and TFF3 showed significantly higher odds ratios than the pepsinogen method.
  • Serum TFF levels before and after gastrectomy To investigate the cause of elevated serum TFF levels, serum TFF levels before and after gastric cancer resection were compared. Forty-six patients were measured for serum TFF1, TFF2, and TFF3 levels before and one week after surgery. Nine patients underwent total gastrectomy, 32 underwent pyloric gastrectomy, and 5 underwent cardiotomy. FIG. 7 shows the distribution of serum TFF levels before and after gastrectomy. Serum TFF1 and serum TFF2 levels were less than half a week after surgery. On the other hand, there was no significant change in serum TFF3 level.
  • TFF3 levels were measured for more than 3 months thereafter, confirming that TFF1 and TFF2 levels remained low and TFF3 levels remained high (FIG. 8).
  • TFF3 level was measured. Serum TFF3 levels were 7.13 ⁇ 8.18 ng / mL before surgery and 5.32 ⁇ 2.04 ng / mL after surgery. The patient showed higher TFF3 levels compared to the healthy control group, but no post-upregulation was seen.
  • Example 2 From October 2007 to December 2009, patients with gastric cancer who underwent endoscopy before surgery at Toshiba Hospital were included. Those with other cancers or serious illnesses were excluded from the subjects.
  • the control group consisted of healthy men and women who underwent a medical examination at the Health Medical Center of Nomura Hospital from December 2008 to December 2009.
  • the ratio of the patient group and the control group was 1: 3
  • the age was matched within 3 years in the patient group and the control group
  • the sex was completely matched.
  • the serum TFF1 to 3 levels of the patient group and the control group measured by the same method as in Example 1 are as shown in the table below.
  • the P values are both less than 0.0001, and there is a significant difference between the patient group and the control group. It was.
  • the area under the curve was 0.812.
  • the sensitivity and specificity were determined for TFF3 with a cutoff value of 7 ng / mL, which was 66.1% (63.6-68.6%) and 91.7% (90.1% -93.1%), respectively.
  • the sensitivity and specificity of the pepsinogen I / II ratio for this patient group and the control group were 67.2% (64.7-69.6%) and 81.7% (79.6-83.6%).
  • the TFF3 method was about 10% more specific and about 25% more positive than the pepsinogen method.
  • the sensitivity of the gastric cancer patient group was determined by dividing the cancer progression into the cancer progression and tissue type. The results are shown in the table below.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Urology & Nephrology (AREA)
  • Hematology (AREA)
  • Biomedical Technology (AREA)
  • Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Medicinal Chemistry (AREA)
  • Biochemistry (AREA)
  • Cell Biology (AREA)
  • Pathology (AREA)
  • Biotechnology (AREA)
  • Food Science & Technology (AREA)
  • General Physics & Mathematics (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Microbiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Oncology (AREA)
  • Hospice & Palliative Care (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Virology (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention a pour but de proposer un procédé d'inspection du cancer de l'estomac qui est plus commode et a une sensibilité et une spécificité élevées. La présente invention concerne un procédé d'inspection du cancer de l'estomac ou d'une infection bactérienne à Helicobacter pylori comprenant une étape pour mesurer des niveaux de la famille du facteur en feuille de trèfle (TFF) dans le sérum de sang d'un sujet.
PCT/JP2012/058088 2011-09-30 2012-03-28 Procédé d'inspection du cancer de l'estomac et trousse d'inspection WO2013046760A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2011-217263 2011-09-30
JP2011217263A JP2014238264A (ja) 2011-09-30 2011-09-30 胃癌の検査方法及び検査キット

Publications (1)

Publication Number Publication Date
WO2013046760A1 true WO2013046760A1 (fr) 2013-04-04

Family

ID=47994830

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2012/058088 WO2013046760A1 (fr) 2011-09-30 2012-03-28 Procédé d'inspection du cancer de l'estomac et trousse d'inspection

Country Status (2)

Country Link
JP (1) JP2014238264A (fr)
WO (1) WO2013046760A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013083556A (ja) * 2011-10-11 2013-05-09 Univ Of Tokyo 膵臓癌の検査方法及び検査キット

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP6300324B2 (ja) * 2015-03-26 2018-03-28 株式会社大一商会 遊技機

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KAISE M. ET AL.: "The combination of serum trefoil factor3 and pepsinogen testing is a valid non-endoscopic biomarker for predicting the presence of gastric cancer a new marker for gastric cancer risk", J. GASTROENTEROL, vol. 46, no. 6, 4 July 2011 (2011-07-04), pages 736 - 745, XP019917557, DOI: doi:10.1007/s00535-011-0396-8 *
MITSURU KAISE ET AL.: "Kessei trefoil factor3 to Pepsinogen-ho no Kumiawase wa Koritsuteki na Igan Risk Biomarker to Naru", JAPANESE JOURNAL OF GASTROENTEROLOGY, vol. 108, 15 September 2011 (2011-09-15), pages A459 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013083556A (ja) * 2011-10-11 2013-05-09 Univ Of Tokyo 膵臓癌の検査方法及び検査キット

Also Published As

Publication number Publication date
JP2014238264A (ja) 2014-12-18

Similar Documents

Publication Publication Date Title
JP5744385B2 (ja) Ｃｖｄ分析
CN112362871B (zh) 食管癌的生物标志物及其应用
TWI704228B (zh) 肝癌的檢查方法
US20070178443A1 (en) Method for diagnosing liver fibrosis
WO2017022315A1 (fr) Procédé de dépistage de maladie rénale
US20190376975A1 (en) Antibody assay
CN110361547B (zh) 一种化学发光定量检测粪便潜血的试剂及其检测方法和其在检测下消化道健康的用途
US20070178442A1 (en) Method for diagnosing liver fibrosis
Yu et al. Distinction between bacterial and viral infections by serum measurement of human neutrophil lipocalin (HNL) and the impact of antibody selection
JP2018136122A (ja) 膵がんを診断するための血漿バイオマーカーパネル
WO2013046760A1 (fr) Procédé d'inspection du cancer de l'estomac et trousse d'inspection
WO2020158858A1 (fr) Procédé d'analyse immunologique d'un aim libre dans un échantillon biologique, et procédé de détection de la nash chez un sujet
Kraemer et al. Automated Fecal Biomarker Profiling-a Convenient Procedure to Support Diagnosis for Patients with Inflammatory Bowel Diseases.
JP5754844B2 (ja) 泌尿器科がんの検査方法及び検査用キット
CN115372616A (zh) 胃癌相关的生物标志物及其应用
JPWO2017204295A1 (ja) 消化器癌の判定方法
US20100047830A1 (en) Compositions and methods for detecting cancers in a subject
KR102018209B1 (ko) 위암 진단용 조성물 및 상기 조성물을 이용한 위암 진단 방법
US8697368B2 (en) Diagnostic marker for lung cancer comprising HPαR as active ingredient
US11242408B2 (en) Monoclonal antibody specific for gamma-glutamyl-l-epsilon-lysine for the monitoring of apoptosis
JP2013083556A (ja) 膵臓癌の検査方法及び検査キット
CN114167059A (zh) 一种用于食管鳞癌诊断的生物标志物及检测试剂盒
ES2494845T3 (es) Diagnosis de enteritis aguda por determinación en sangre de la proteína intestinal de unión a ácidos grasos
JP4907399B2 (ja) 血中腸型脂肪酸結合蛋白測定による急性腸炎の検出方法
JP2024521881A (ja) 非アルコール性脂肪性肝疾患のための線維症バイオマーカー

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12837587

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12837587

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP