EP4260067A1 - Biomarqueurs prédictifs du risque de cancer de la vessie chez des patients atteints de diabète - Google Patents

Biomarqueurs prédictifs du risque de cancer de la vessie chez des patients atteints de diabète

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Publication number
EP4260067A1
EP4260067A1 EP21839081.3A EP21839081A EP4260067A1 EP 4260067 A1 EP4260067 A1 EP 4260067A1 EP 21839081 A EP21839081 A EP 21839081A EP 4260067 A1 EP4260067 A1 EP 4260067A1
Authority
EP
European Patent Office
Prior art keywords
patients
t2dm
patient
vegf
mcp
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP21839081.3A
Other languages
German (de)
English (en)
Inventor
Chris Watson
Stephen Peter Fitzgerald
John Lamont
Mark RUDDOCK
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Randox Laboratories Ltd
Original Assignee
Randox Laboratories Ltd
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Filing date
Publication date
Application filed by Randox Laboratories Ltd filed Critical Randox Laboratories Ltd
Publication of EP4260067A1 publication Critical patent/EP4260067A1/fr
Pending legal-status Critical Current

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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
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
    • G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
    • G01N2333/4701—Details
    • G01N2333/4742—Keratin; Cytokeratin
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/475—Assays involving growth factors
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/52—Assays involving cytokines
    • G01N2333/521—Chemokines
    • G01N2333/523—Beta-chemokines, e.g. RANTES, I-309/TCA-3, MIP-1alpha, MIP-1beta/ACT-2/LD78/SCIF, MCP-1/MCAF, MCP-2, MCP-3, LDCF-1or LDCF-2
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/52—Assays involving cytokines
    • G01N2333/54—Interleukins [IL]
    • G01N2333/5412—IL-6
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/50—Determining the risk of developing a disease
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • T2DM Type 2 diabetes mellitus
  • the current epidemic has been attributed to population aging, urbanization, and the increased prevalence of obesity and physical inactivity (3).
  • T2DM has been linked to an increased risk of cancer including breast (4), colon (5) and bladder (6), and has a weak negative association with prostate cancer (7).
  • BC bladder cancer
  • BC is the most common malignancy of the urinary system and a leading cause of cancer-related death (11). BC occurs more commonly in men than in women and tobacco smoke is an important risk factor, accounting for amongst 50% of all cases (12).
  • Other risk factors for BC include; age, past exposure to chemicals, drinking water contaminants (e.g. arsenic, cadmium), phenacetin-containing analgesics and some aspects of diet (13).
  • Diabetic medications have also been associated with BC risk, with longterm insulin use being linked to increased risk of developing invasive BC (14), whereas there have been conflicting reports as to whether metformin and pioglitazone increase or decrease risk for BC (15-18).
  • haematuria blood in urine (19).
  • Haematuria that is observed by a patient is referred to as 'macroscopic' haematuria
  • haematuria that is detected by performing a urinalysis test for blood is referred to as 'microscopic' haematuria (19).
  • NDRD non-diabetic renal disease
  • management of DM includes regular check-ups at designated diabetes clinics to monitor how the condition is being managed and to pre-empt possible future health problems.
  • a simple blood or urine test to monitor risk of other associated diseases could feasibly be introduced to these nurse- led clinics.
  • the current invention provides a novel biomarker combination for early diagnosis of BC in T2DM patients who present with haematuria.
  • the combination of serum MCP-l and VEGF, and urinary IL-6, CK8 and CK18 had an AUC of 0.84 for the detection of bladder carcinomas in T2DM patients, with a positive predictive value (PPV) of 63.64% and a negative predictive value (NPV) of 91.07%.
  • a second aspect of the current invention is a method for detecting BC in an ex vivo sample taken from a T2DM patient, wherein the sample is contacted with a solid- state device onto which has been immobilized probes specific to each of the biomarkers.
  • a third aspect of the invention is a solid-state device comprising a substrate having an activated surface onto which is immobilized probes to MCP-l, VEGF, IL-6, and CK8/CK18 in discrete areas of said activated surface.
  • This solid-state device not only has potential in diagnosis, but also in monitoring the progression of BC.
  • a fourth aspect of the invention is a method of determining the efficacy of a drug treatment for BC comprising determining the levels of MCP-l, VEGF, IL-6 and CK8/CK18 in a sample from a T2DM patient treated with the drug and comparing levels with those from a healthy control, or with levels from the same patient before treatment with the drug, wherein dependent on the biomarker, either an increase or decrease in level indicates the effectiveness of the treatment.
  • A) shows that urine IL-6 levels (pg/ml) were significantly increased in BC patients without diabetes but not those with T2DM.
  • B) shows that urine CK8/CK18 levels (ng/ml) were significantly increased in all BC patients.
  • C) shows that serum MCP-l levels (pg/ml) were significantly decreased in BC patients with T2DM and that they showed the opposite direction of change in BC patients without diabetes (although this increase was not found to be significant).
  • D) shows that serum VEGF levels (pg/ml) significantly increased in all BC patients.
  • the present invention describes a biomarker-based method to aid in the early diagnosis of BC in T2DM patients who present with haematuria. Specifically, it relates to the measurement of relative levels or concentrations of biomarkers in ex vivo samples obtained from patients.
  • the utility for diagnosing BC has been used as way of an example. However, it is further envisaged that the invention may also be used for monitoring the progression or recurrence of BC, or to determine the effectiveness of any treatment strategy which has been implemented.
  • the current invention can also be used to determine T2DM patients with haematuria at risk of developing BC.
  • patient refers to any mammal to be the recipient of the diagnosis, preferably a human.
  • the patients of the current invention are patients with diabetes and haematuria. More preferably, the patients of the current invention are T2DM patients with haematuria.
  • the patient may be a person presenting for routine screening for disease or they may present with symptoms suggestive of cancer.
  • the patient may also be an individual deemed at high risk for BC, due to smoking history for example.
  • the patient could be an individual who has received treatment for BC and they are screened to monitor progress or detect possible recurrence.
  • biomarker in the context of the current invention, refers to a molecule present in a biological sample of a patient, the levels of which may be indicative of BC. Such molecules may include peptides/proteins or nucleic acids and derivatives thereof.
  • the preferred biomarker combination of the current invention for the detection of BC comprises monocyte chemotactic protein 1 (MCP-1), vascular endothelial growth factor (VEGF), interleukin 6 (IL- 6) and cytokeratin 8 (CK8)/cytokeratin 18 (CK18).
  • MCP-1 monocyte chemotactic protein 1
  • VEGF vascular endothelial growth factor
  • IL-6 interleukin 6
  • CK8/cytokeratin 18 CK18
  • TGFpi transforming growth factor beta 1
  • MMP9TIMP1 matrix metallopeptidase 9/TIMP metallopeptidase inhibitor 1 complex
  • ACR albumin/creatinine ratio
  • BTA bladder tumour antigen
  • cystatin B D-dimer
  • Fas receptor interleukin 13 (IL-13), interleukin 1 beta (IL-lb), neuron-specific enolase (NSE) and plasminogen activator inhibitor-l/tissue plasminogen activator complex (PAI-l/tPA).
  • MCP-1 Monocyte chemotactic protein 1, also known as C-C motif chemokine 2 (UniProt: P13500).
  • VEGF Vascular endothelial growth factor A, also known as Vascular permeability factor (UniProt: P15692).
  • IL-6 refers to interleukin 6, also known as B-cell stimulatory factor 2 and Interferon beta-2 (UniProt: P05231).
  • CK18 refers to cytokeratin 18, also known as keratin type I cytoskeletal 18, keratin 18 and Cell proliferation-inducing gene 46 protein (UniProt: P05783), or fragments thereof.
  • CK8 refers to cytokeratin 8, also known as keratin type II cytoskeletal 8 and keratin 8 (UniProt: P05787), or fragments thereof.
  • CK8/CK18 refers to CK8 and/or CK18 or fragments thereof. This includes soluble oligomer complexes formed between CK8 and CK18, for example dimers.
  • CK8 and CK18 can be detected separately by antibodies with specificity for CK8 and CK18, or fragments thereof, or they can be detected by antibodies which have specificity for a shared epitope of CK8 and CK18.
  • Combinations of antibodies can be used, for example, in a sandwich enzyme-linked immunosorbent assay (ELISA)-based detection method with specific capture antibodies used to initially bind CK8 and CK18 then a generic (specific to a shared epitope of CK8 and CK18) labelled detection antibody added to generate a detectable signal.
  • ELISA enzyme-linked immunosorbent assay
  • a deviation from a control value for a biomarker may be an indication that the patient suffers from bladder cancer. Dependent on the individual biomarker this deviation may be an increase or a decrease from a control value.
  • levels of MCP-l were lower in BC patients with T2DM when compared to those in healthy controls and controls with T2DM ( Figure 1C).
  • Levels of VEGF, IL-6 and CK8/CK18 were higher in BC patients than in controls ( Figure 1A, B, and D).
  • the current invention provides an early stage biomarker combination (MCP-l, VEGF, IL-6 and CK8/CK18), which allows the detection of neoplastic disease at an early and still benign stage and/or early tumour stages. Early detection and removal of a BC is critical and can dramatically increase the patients' chances of survival. Additionally, the biomarker combination of the current invention allows the monitoring of BC development within an individual through serial testing of serum and urine from said individual over an extended period. For example, routine determination of the levels of the biomarkers of the preferred combination (MCP-l, VEGF, IL-6 and CK8/CK18) could detect the changes from healthy control values, which are indicative of the development of BC. A further change in levels could then be indicative of the progression of the disease to a later stage.
  • MCP-l, VEGF, IL-6 and CK8/CK18 early stage biomarker combination
  • a further aspect of the present invention is a method of determining the efficacy of a treatment for BC comprising determining the levels of MCP-l, VEGF, IL-6 and CK8/CK18 in a sample from a patient who has had treatment for BC and, comparing levels with those from a healthy control or with levels from the same patient taken before the treatment, wherein dependent on the biomarker, either an increase or decrease in level indicates the effectiveness of the treatment.
  • the treatment can be for example, a drug treatment, a radiotherapy-based treatment or a surgical intervention.
  • the method of determining the efficacy of the drug treatment for BC would comprise determining the levels of biomarkers, for example MCP-l, VEGF, IL-6 and CK8/CK18 in a sample from a patient treated with the drug, and comparing biomarker levels with those from a healthy control or with levels from the same patient before treatment with the drug, wherein, dependent on the biomarker, either an increase or decrease in level indicates the effectiveness of the drug treatment.
  • a "control value" is understood to be the level of a particular biomarker, such as MCP-l, VEGF, IL-6 or CK8/CK18 typically found in healthy individuals.
  • the control level of a biomarker may be determined by analysis of a sample isolated from a healthy individual or may be the level of the biomarker understood by the skilled person to be typical for a healthy individual.
  • the control value may be a range of values considered by the skilled person to be a normal level for the biomarker in a healthy individual.
  • control values for a biomarker may be calculated by the user analysing the level of the biomarker in a sample from a healthy individual or by reference to typical values provided by the manufacturer of the assay used to determine the level of biomarker in the sample.
  • the “sample” of the current invention can be any ex vivo biological sample from which the levels of biomarkers can be determined.
  • the sample isolated from the patient is a serum or urine sample.
  • the sample could be selected from, for example, whole blood, plasma, saliva or sputum.
  • the determination of the level of biomarkers may be carried out on one or more samples obtained from the patient.
  • one or more biomarkers could be measured in a serum sample and these results combined with those for one or more biomarkers which are measured in a urine sample from the same patient.
  • IL-6 and CK8/CK18 are measured in urine samples and MCP-l and VEGF are measured in serum samples.
  • the sample may be obtained from the patient by methods routinely used in the art.
  • the determination of the level of biomarkers in the sample may be determined by immunological methods such as an ELISA-based assay.
  • the methods of the current invention preferably comprise the following steps; the biomarkers binding to a probe(s), adding a detector probe(s) and detecting and measuring the biomarker/probe complex signal(s), placing these values into a machine algorithm and analysing the output value, said value indicating whether the patient has or is at risk of having BC.
  • the methods of the present invention use a solid-state device for determining the level of biomarkers in the sample isolated from the patient.
  • the solid-state device comprises a substrate having a probe or multiple different probes immobilised upon it that bind specifically to a biomarker.
  • the interactions between a biomarker and its respective probe can be monitored and quantified using various techniques that are well-known in the art.
  • the term "probe” refers to a molecule that is capable of specifically binding to a target molecule such that the target molecule can be detected as a consequence of said specific binding.
  • Probes that can be used in the present invention include, for example, antibodies, aptamers, phages and oligonucleotides. In a preferred embodiment of the current invention the probe is an antibody.
  • the "level" of a biomarker refers to the amount, expression level or concentration of the biomarker within the sample. This level can be a relative level in comparison to another biomarker or a previous sample.
  • antibody refers to an immunoglobulin which specifically recognises an epitope on a target as determined by the binding characteristics of the immunoglobulin variable domains of the heavy and light chains (VHS and VLS), more specifically the complementarity-determining regions (CDRs).
  • VHS and VLS immunoglobulin variable domains of the heavy and light chains
  • CDRs complementarity-determining regions
  • antibodies may include, but are not limited to, a plurality of intact monoclonal antibodies or polyclonal mixtures comprising intact monoclonal antibodies, antibody fragments (for example Fab, Fab', and Fv fragments, linear antibodies single chain antibodies and multi-specific antibodies comprising antibody fragments), single-chain variable fragments (scFvs), multi-specific antibodies, chimeric antibodies, humanised antibodies and fusion proteins comprising the domains necessary for the recognition of a given epitope on a target.
  • references to antibodies in the context of the present invention refer to polyclonal or monoclonal antibodies.
  • Antibodies may also be conjugated to various reporter moieties for a diagnostic effect, including but not limited to radionuclides, fluorophores, dyes or enzymes including, for example, horse-radish peroxidase and alkaline phosphatase.
  • Such antibodies may be immobilised at discrete areas of an activated surface of the substrate.
  • the solid-state device may perform multi-analyte assays such that the level of a biomarker in a sample isolated from the patient may be determined simultaneously with the level of a further biomarker of interest in the sample.
  • the solid-state device has a multiplicity of discrete reaction sites each bearing a desired antibody covalently bound to the substrate, and in which the surface of the substrate between the reaction sites is inert with respect to the target biomarker.
  • the solid-state, multi-analyte device may therefore exhibit little or no non-specific binding.
  • the combination of biomarkers may also be referred to as a panel of biomarkers.
  • the substrate can be any surface able to support one or more probes but is preferably a biochip.
  • a biochip is a planar substrate that may be, for example, mineral or polymer based, but is preferably ceramic.
  • identifying the various biomarkers/proteins of the invention it will be apparent to the skilled person that as well as identifying the full-length protein, the identification of a fragment or several fragments of a protein is possible, provided this allows accurate identification of the protein.
  • a preferred probe of the invention is a polyclonal or monoclonal antibody, other probes such as aptamers, molecular imprinted polymers, phages, short chain antibody fragments and other antibody-based probes may be used.
  • a solid-state device that may be used in the invention may be prepared by activating the surface of a suitable substrate and applying an array of antibodies on to the discrete sites on the surface. If desired, the other active areas may be blocked.
  • the ligands may be bound to the substrate via a linker.
  • it is preferred that the activated surface is reacted successively with an organosilane, a bifunctional linker and the antibody.
  • the solid-state device used in the methods of the present invention may be manufactured according to the method disclosed in, for example, GB-A-2324866 the contents of which are incorporated herein in its entirety.
  • the solid-state device can be any substrate to which probes of the current invention can be attached for example a microtitre plate or beads.
  • the solid-state device used in the methods of the present invention is a biochip.
  • the biochip may be a biochip which is incorporated into the Biochip Array Technology System (BAT) available from Randox Laboratories Limited (Crumlin, UK).
  • BAT Biochip Array Technology System
  • a solid-state device may be used to determine the levels of MCP-l, VEGF, IL-6 and CK8/CK18 in the sample isolated from the patient.
  • the solid-state device comprises a substrate having an activated surface on to which is applied antibodies specific to each of the two or more biomarkers to discrete areas of the activated surface. Therefore, the solid-state device may perform multi-analyte assays such that the levels of biomarkers, for example MCP-l, VEGF, IL-6, and CK8/CK18 in a sample may be determined simultaneously.
  • the solid- state device has a multiplicity of discrete reaction sites each bearing a desired antibody covalently bound to the substrate, and in which the surface of the substrate between the reaction sites is inert with respect to the target biomarkers.
  • Each probe whether individually or in multiplex, is specific to one target analyte. For example, a probe to MCP-l will only show specific binding to this analyte and will have no significant cross-reactivity with VEGF, IL-6, CK8/CK18 or indeed any other potentially interfering substance which could compromise the assay.
  • the solid-state device of the invention can consist of two identical solid-state devices with the same antibodies to the same biomarkers or it may consist of two separate solid-state devices, one for each sample type, comprising the antibodies specific to the biomarkers which are to be determined in each sample type.
  • the solid- state device could be four separate devices each comprising antibodies specific to a different target biomarker.
  • the solid-state device could be one device with probes to VEGF, MCP-l, CK8/CK18 and IL-6 or it could be two separate devices, one with probes to VEGF and MCP-l and another with probes to CK8/CK18 and IL-6.
  • the solid- state device not only has potential in diagnosis but also in monitoring the progression and recurrence of BC as well as determining the success of any treatments.
  • each of the biomarker concentration values is inputted into a statistical methodology to produce an output value that correlates with the chances that the patient has or is at risk of developing BC.
  • the statistical methodology used is logistic regression, decision trees, support vector machines, neural networks, random forest or another machine-learning algorithm.
  • ROC receiver operating characteristics
  • the ROC curve addresses both the sensitivity (the number of true positives) and the specificity (the number of true negatives) of the test. Therefore, sensitivity and specificity values for a given combination of biomarkers are an indication of the performance of the test. For example, if a biomarker combination has a sensitivity and specificity value of 80%, out of 100 patients, 80 will be correctly identified from the determination of the presence of the particular combination of biomarkers as positive for the disease, while out of 100 patients who do not have the disease 80 will accurately test negative for the disease.
  • a suitable statistical classification model such as logistic regression
  • the logistic regression equation can be extended to include other (clinical) variables such as age and gender of the patient as well.
  • the ROC curve can be used to access the performance of the discrimination between patients and controls by the logistic regression model. Therefore, the logistic regression equation can be used apart or combined with other clinical characteristics to aid clinical decision making.
  • a logistic regression equation is a common statistical procedure used in such cases and is preferred in the context of the current invention, other mathematical/statistical, decision trees or machine learning procedures can also be used.
  • the two different conditions can be whether a patient has or does not have cancer.
  • Haematuria Biomarker Study is a three-way collaboration between Queen's University Harbor, Randox Laboratories Ltd and hospitals in Northern Ireland, conducted to identify panels of serum/urine biomarkers for biochip development for cancer risk stratification in patients with haematuria (http://www.qub.ac.uk/sites/habio). Following ethical approval (ORECNI ll/NI/0164). A total of 675 patients were recruited between 17 October 2012 and 28 June 2016. A detailed description of the HaBio study methodology has been published online, and includes extensive information on study population, recruitment, clinical and biochemical measurements, biomarker analysis, and outcomes. Trial registration: http://www.isrctn.com/ISRCTN25823942. Specific to this diabetes sub-analysis of the HaBio study, all 109 T2DM patients and 218 age and sex matched nondiabetic patients were selected for analysis.
  • Urine samples ( ⁇ 50 ml) and serum samples ( ⁇ 10 ml) were collected from all patients in sterile containers. Unfiltered and uncentrifuged urine samples were immediately aliquoted and frozen at - 80°C until analyses. Urine samples were thawed on ice and then centrifuged (1200 x g, 10 minutes, 4°C) to remove any particulate matter prior to analysis. All patient samples were run in triplicate and the results are expressed as mean ⁇ SD. Biochip Array Technology (Randox Clinical Laboratory Services, Crumlin, Northern Ireland, UK) was used for the simultaneous detection of multiple analytes from a single patient sample (e.g. urine).
  • the technology is based on the Randox Biochip, a 9mm 2 solid substrate supporting an array of discrete test regions with immobilized, antigen-specific antibodies. Following antibody activation with assay buffer, standards and samples were added and incubated at 37°C for 60 minutes, then placed in a thermo-shaker at 370 rpm for 60 minutes. Antibody conjugates (HRP) were added and incubated in the thermo-shaker at 370 rpm for 60 minutes. The chemiluminescent signals formed after the addition of luminol (1:1 ratio with conjugate) were detected and measured using digital imaging technology and compared with that from a calibration curve to calculate concentration of the analytes in the samples.
  • HRP Antibody conjugates
  • T2DM patients were matched with non-diabetic controls based on age and BC diagnosis in a 2:1 ratio.
  • Smoking and drinking habits between T2DM and non-T2DM patients were similar, however, T2DM patients had higher BMI than non-diabetic patients (31.8 ⁇ 6.5 vs. 28.4 ⁇ 4.5, p ⁇ 0.001).
  • One of the main risk factors for BC is exposure to occupational hazards such as dyes, leather, chemicals etc.
  • the T2DM group had significantly increased incidence of hypertension reported in their medical history (69.7% vs. 44.0%, p ⁇ 0.001) compared to patients without T2DM.
  • a significantly greater proportion of T2DM patients had uncontrolled blood pressure and were on blood pressure medications (86.2% vs.
  • a panel of 66 candidate biomarkers were measured in either serum, urine, or both, from all patients. Urine levels of CK18 and CK8 were also measured using the UBC® assay (IDL), which specifically measures soluble fragments of cytokeratin 8 and cytokeratin 18 in urine samples.
  • IDL UBC® assay
  • Table la Demographic, clinical, and biochemical profile of patients with and without diabetes
  • Table lb Demographic, clinical, and biochemical profile of patients with and without diabetes (matched)
  • BMI body mass index
  • dx disease/disorder
  • hx history
  • BP blood pressure
  • meds medications
  • BC bladder cancer
  • BPE/BPH benign prostate enlargement/benign prostate hyperplasia
  • neg negative
  • CIS cancer in situ
  • ONS office for national statistics
  • path pathology
  • BCH Harbor City Hospital
  • CAH Craigavon area hospital
  • UHD Ulster Hospital Dundonald

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Abstract

Nous avons identifié une signature de protéine qui est facilement mesurée dans le sang et l'urine et hautement prédictive du risque de cancer de la vessie chez les patients atteints de diabète sucré de type 2 (T2DM). Ce modèle de biomarqueur pourrait être appliqué pour cribler des patients atteints de T2DM présentant une hématurie, en relation avec le cancer de la vessie, dans des cliniques de traitement du diabète sucré. L'orientation urologique précoce de patients atteints de T2DM permet d'améliorer les résultats pour ces patients.
EP21839081.3A 2020-12-14 2021-12-13 Biomarqueurs prédictifs du risque de cancer de la vessie chez des patients atteints de diabète Pending EP4260067A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB2019663.0A GB202019663D0 (en) 2020-12-14 2020-12-14 Predictive biomarkers for risk of bladder cancer in diabetes patients
PCT/EP2021/085424 WO2022128881A1 (fr) 2020-12-14 2021-12-13 Biomarqueurs prédictifs du risque de cancer de la vessie chez des patients atteints de diabète

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EP4260067A1 true EP4260067A1 (fr) 2023-10-18

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Publication number Priority date Publication date Assignee Title
CZ297165B6 (cs) 1997-04-21 2006-09-13 Randox Laboratories Ltd. A British Company Of Ardmore Zpusob výroby zarízení s pevnou fází k provádení multianalytních rozboru

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