TW201625945A - Method for predicting hepatocellular carcinoma occurrence in liver cirrhotic patients - Google Patents
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本揭示內容是關於預斷癌症的領域。更具體來說，本揭示內容是關於一種用以預斷肝硬化病患是否會罹患肝癌的方法。 The present disclosure is directed to the field of pre-cancerous cancer. More specifically, the present disclosure relates to a method for predicting whether a liver cirrhosis patient will develop liver cancer.
肝癌高居全球好發性固態惡性腫瘤第五位，且為癌症相關死因第三位。約70%-90%的肝癌病患具有慢性肝臟疾病及肝硬化的病史，其中肝硬化肇因於傷疤組織修復受損的肝臟細胞而形成。導致肝硬化的主要危險因子包含B型肝炎病毒或C型肝炎病毒的慢性感染、酒精性肝臟疾病(alcoholic liver disease)及非酒精性脂肪肝(non-alcoholic fatty liver disease,NAFLD)。其餘會導致肝癌的致癌因子尚包含攝取遭受黃麴毒素污染的食物、糖尿病、肥胖、血色素沉著病(hemochromatosis)等遺傳性疾病及代謝失調。 Liver cancer ranks fifth in the world for solid malignant tumors and is the third leading cause of cancer. About 70%-90% of liver cancer patients have a history of chronic liver disease and cirrhosis, in which cirrhosis is formed by repairing damaged liver cells by scar tissue. The main risk factors for cirrhosis include chronic infection with hepatitis B virus or hepatitis C virus, alcoholic liver disease, and non-alcoholic fatty liver disease (NAFLD). The remaining carcinogenic factors that cause liver cancer include the ingestion of foods contaminated with safrole, diabetes, obesity, hemochromatosis and other genetic diseases and metabolic disorders.
有鑑於肝硬化及肝癌之間具有密切的關連性，肝硬化病患每年應接受一或多種諸如電腦斷層攝影 (computed tomography,CT)、核磁共振成像(magnetic resonance imaging,MRI)或超音波(ultrasound,US)等檢測，以定期追蹤防治。早期確診之肝癌病患通常擁有較多的治療選擇。舉例來說，罹患早期肝癌的病患可接受肝臟移植、手術切除及消融治療等較具治癒性的療法；而罹患晚期肝癌的病患則缺乏有效的治療方法。治療的功效往往反應在病患的存活率上。已知多數罹患早期肝癌的病患可存活超過5年，而罹患晚期肝癌之病患的平均存活率則少於1年。然而，傳統的檢測方法多受限於僅能偵測大於2公分的肝臟結節(liver nodules)。依據之前的報導，在偵測小於2公分的肝臟結節時，超音波、電腦斷層攝影及核磁共振成像的敏感度分別只有21%、40%及47%。此外，可得性與診斷儀器的高成本價位更進一步限定了核磁共振成像及電腦斷層攝影的應用。 In view of the close relationship between cirrhosis and liver cancer, patients with cirrhosis should receive one or more such as computed tomography each year. (computed tomography, CT), magnetic resonance imaging (MRI) or ultrasound (US), etc., to track and control regularly. Early diagnosis of liver cancer patients usually have more treatment options. For example, patients with early liver cancer can receive more curative treatments such as liver transplantation, surgical resection, and ablation. Patients with advanced liver cancer lack effective treatment. The efficacy of treatment often reflects the survival rate of patients. It is known that most patients with early stage liver cancer can survive for more than 5 years, while those with advanced liver cancer have an average survival rate of less than 1 year. However, traditional detection methods are mostly limited to detecting liver nodules larger than 2 cm. According to previous reports, the sensitivity of ultrasound, computed tomography and magnetic resonance imaging was only 21%, 40% and 47%, respectively, when detecting liver nodules less than 2 cm. In addition, the high cost price of availability and diagnostic instruments further defines the application of MRI and computed tomography.
有鑑於此，相關技術領域一直亟需一種可有效預斷肝癌發生風險的方法；相較於傳統的核磁共振成像及/或電腦斷層攝影，本預斷方法將更準確且不需搭配使用任何昂貴的儀器設備；藉此，病患可即時接受適當的治療。 In view of this, there is a need in the related art for a method for effectively predicting the risk of liver cancer; compared with conventional MRI and/or computed tomography, the pre-break method will be more accurate and does not need to be used with any expensive instrument. Equipment; thereby, patients can receive appropriate treatment immediately.
發明內容旨在提供本揭示內容的簡化摘要，以使閱讀者對本揭示內容具備基本的理解。此發明內容並非本揭示內容的完整概述，且其用意並非在指出本發 明實施方式的重要/關鍵元件或界定本發明的範圍。發明內容旨在提供本揭示內容的簡化摘要，以使閱讀者對本揭示內容具備基本的理解。 SUMMARY OF THE INVENTION The Summary of the Disclosure is intended to provide a basic understanding of the present disclosure. This summary is not an extensive overview of the disclosure, and is not intended to The important/critical elements of the embodiments are defined or defined. SUMMARY OF THE INVENTION The Summary of the Disclosure is intended to provide a basic understanding of the present disclosure.
本揭示內容是關於一種預斷癌症的方法，其係利用肝硬化病患的血液檢體來預斷該名病患罹患肝癌的風險高低。該方法包含：(1)由該血液檢體測量空腹血糖(mg/dL)、胰島素(μIU/mL)及高密度脂蛋白(mg/dL)的濃度、血小板的數量(number/μL)及淋巴球與嗜中性白血球的百分比；(2)利用以下一公式來計算一風險指數：
依據本揭示內容的實施方式，該血液檢體是一全血檢體。 According to an embodiment of the present disclosure, the blood sample is a whole blood sample.
一般來說，肝硬化是由一慢性肝臟疾病所導致，該慢性肝臟疾病是選自由酒精性肝臟疾病、非酒精性脂肪肝、B型肝炎及C型肝炎所組成的群組。 Generally, cirrhosis is caused by a chronic liver disease selected from the group consisting of alcoholic liver disease, nonalcoholic fatty liver disease, hepatitis B, and hepatitis C.
空腹血糖、胰島素、高密度脂蛋白、血小板、淋巴球及嗜中性白血球的數值可由相關領域習知技藝人士所熟知的任何生化或血液檢測方法來取得。依據本揭示內容的實施方式，空腹血糖的濃度是利用一酵素、一芳香胺或一連續流動分析(continuous flow analysis)來進行測量。適用於測量空腹血糖濃度的酵素包含，但不限於，葡萄糖氧化酶(glucose oxidase)、葡萄糖去氫酶(glucose dehydrogenase)及己醣激酶(hexokinase)。適用於測量空腹血糖濃度之芳香胺可以是苯胺(aniline)、聯苯胺(benzidine)、2-胺基聯苯(2-aminobiphenyl)或鄰甲苯胺(o-toluidine)。 The values of fasting blood glucose, insulin, high density lipoprotein, platelets, lymphocytes, and neutrophils can be obtained by any biochemical or blood testing method well known to those skilled in the relevant art. In accordance with an embodiment of the present disclosure, the concentration of fasting blood glucose is measured using an enzyme, an aromatic amine, or a continuous flow analysis. Enzymes suitable for measuring fasting blood glucose concentrations include, but are not limited to, glucose oxidase, glucose dehydrogenase, and hexokinase. The aromatic amine suitable for measuring the fasting blood glucose concentration may be aniline, benzidine, 2-aminobiphenyl or o-toluidine.
依據本揭示內容的實施方式，胰島素的濃度是利用一抗體來進行測量，其中該抗體對於胰島素的A鏈或B鏈具有專一性。 In accordance with an embodiment of the present disclosure, the concentration of insulin is measured using an antibody wherein the antibody is specific for the A or B chain of insulin.
在本揭示內容的某些實施方式中，高密度脂蛋白的濃度可利用一酵素、一電泳分析(electrophoresis assay)、一連續流動分析或一核磁共振分析(nuclear magnetic resonance assay)來進行測量。用以測量高密度脂蛋白之酵素包含，但不限於，膽固醇氧化酶(cholesterol oxidase)。 In certain embodiments of the present disclosure, the concentration of high density lipoprotein can be measured using an enzyme, an electrophoresis assay, a continuous flow assay, or a nuclear magnetic resonance assay. The enzyme used to measure high density lipoproteins includes, but is not limited to, cholesterol oxidase.
依據本揭示內容的實施方式，血小板的數量、淋巴球的百分比及嗜中性白血球的百分比是分別以 一血球計、一血液分析儀及一抗體來進行測量。為測量血小板的數量，使用的抗體對血小板的表面標記具有專一性，其中該表面標記是選自由CD41、CD42、CD49、CD61、CD62及CD109所組成的群組。在測量淋巴球的百分比時，使用的抗體對淋巴球的表面標記具有專一性，其中該表面標記是選自由CD3、CD4、CD25、CD40、CD62L、CD80及CD152所組成的群組。而使用於測量嗜中性白血球之百分比的抗體，則是對嗜中性白血球的標記具有專一性，其中該標記是選自由CD66、CD177、Ly6G及嗜中性白血球彈性蛋白酶(neutrophil elastase)所組成的群組。非必要性地，使用於本揭示內容之抗體係與一螢光染料接合，便於偵測與抗體結合的細胞。 According to an embodiment of the present disclosure, the number of platelets, the percentage of lymphocytes, and the percentage of neutrophils are A blood cell meter, a blood analyzer, and an antibody are used for measurement. To measure the amount of platelets, the antibodies used are specific for the surface label of the platelets, wherein the surface markers are selected from the group consisting of CD41, CD42, CD49, CD61, CD62 and CD109. The antibody used is specific for the surface label of the lymphocytes when measuring the percentage of lymphocytes, wherein the surface marker is selected from the group consisting of CD3, CD4, CD25, CD40, CD62L, CD80 and CD152. The antibody used to measure the percentage of neutrophils is specific for the label of neutrophils, which is selected from the group consisting of CD66, CD177, Ly6G and neutrophil elastase. Group. Optionally, the anti-system used in the present disclosure is conjugated to a fluorescent dye to facilitate detection of cells that bind to the antibody.
在參閱下文實施方式後，本發明所屬技術領域中具有通常知識者當可輕易瞭解本發明之基本精神及其他發明目的，以及本發明所採用之技術手段與實施態樣。 The basic spirit and other objects of the present invention, as well as the technical means and implementations of the present invention, will be readily apparent to those skilled in the art of the invention.
為讓本發明的上述與其他目的、特徵、優點與實施例能更明顯易懂，所附圖式之說明如下：第1圖為一累積風險曲線(cumulative hazard curve)，用以闡述183名肝硬化病患於1.5年內罹患肝癌的風險，其中該些肝硬化病患是依本揭示內容之風險指數分為低度、中度或高度風險族群；以及 第2圖為一累積風險曲線，用以闡述344名肝硬化病患於1.5年內罹患肝癌的風險，其中該些肝硬化病患是依本揭示內容之風險指數分為低度、中度或高度風險族群。 To make the above and other objects, features, advantages and embodiments of the present invention more apparent, the description of the drawings is as follows: Figure 1 is a cumulative hazard curve for 183 livers The risk of liver cancer in a sclerosing patient within 1.5 years, wherein the cirrhotic patients are classified into low, moderate or high risk groups according to the risk index of this disclosure; Figure 2 is a cumulative risk curve to illustrate the risk of liver cancer in 344 patients with cirrhosis, which are classified as low, moderate or based on the risk index of this disclosure. Highly risky ethnic group.
依照慣用作法，不同敍述之特色/元件並非描繪範圍，而是用以描繪與本發明相關之最佳說明具體特色/元件。另外，在不同圖例的相似標記和命名用於表示相似的元件/部件。 The features/components of the different descriptions are not to be construed as a limitation of the invention. In addition, similar reference numerals and designations in the different drawings are used to indicate similar elements/components.
為了使本揭示內容的敘述更加詳盡與完備，下文針對了本發明的實施態樣與具體實施例提出了說明性的描述；但這並非實施或運用本發明具體實施例的唯一形式。實施方式中涵蓋了多個具體實施例的特徵以及用以建構與操作這些具體實施例的方法步驟與其順序。然而，亦可利用其他具體實施例來達成相同或均等的功能與步驟順序。 The description of the embodiments of the present invention is intended to be illustrative and not restrictive. The features of various specific embodiments, as well as the method steps and sequences thereof, are constructed and manipulated in the embodiments. However, other specific embodiments may be utilized to achieve the same or equivalent function and sequence of steps.
為求方便，此處將本說明書、實施例與附隨申請專利範圍中所用的某些詞彙整理餘下。除非本說明書另有定義，此處所用的科學與技術詞彙之含義與本發明所屬技術領域中具有通常知識者慣用者相同。此外，除非本說明書另有定義，此處所用的單數名詞涵蓋該名詞的複數型；而所用的複數名詞時亦涵蓋該名詞的單數型。具體來說，除非另外指明，否則在本文及附隨之請求項範圍中所述及之單數型式詞，「一(“a“及“an”)」均 涵蓋其複數形式。此外，本文及附隨之請求項範圍中所述及之「至少一(“at least one“)」及「一或多(“one or more“)」等詞具有相同意義，且包含一、二、三或更多。 For the sake of convenience, some of the words used in the specification, examples, and accompanying claims are hereby incorporated herein. Unless otherwise defined in the specification, the scientific and technical terms used herein have the same meaning as those of ordinary skill in the art to which the invention pertains. Moreover, the singular noun used herein encompasses the plural of the noun, unless the specification is otherwise defined, and the singular of the noun is used in the plural. Specifically, unless otherwise stated, the singular type "s" ("a" and "an")" Covers its plural form. In addition, the words "at least one" and "one or more" in the context of this article and the accompanying claims have the same meaning and include one or two. Three or more.
雖然用以界定本發明較廣範圍的數值範圍與參數界是約略的數值，此處已盡可能精確地呈現具體實施方式的相關數值。然而，任何數值本質上不可避免地含有因個別測試方法所致的標準偏差。在此處，「約」通常係指實際數值在一特定數值或範圍的正負10%、5%、1%或0.5%之內。或者是，「約」一詞代表實際數值落在平均值的可接受標準差之內，視本發明所屬技術領域中具有通常知識者的考量而定。除了實驗例之外，或除非另有明確的說明，當可理解此處所用的所有範圍、數量、數值與百分比(例如用以描述材料用量、時間長短、溫度、操作條件、數量比例及其他相似者)均經過「約」的修飾。因此，除非另有相反的說明，本說明書與附隨申請專利範圍所揭示的數值參數皆為約略的數值，且可視需求而更動。至少應將這些數值參數理解為所指出的有效位數與套用一般進位法所得到的數值。 Although numerical ranges and parameter boundaries are used to define a broad range of the present invention, the relevant values of the specific embodiments are presented as precisely as possible. However, any numerical value inherently inevitably contains standard deviations due to individual test methods. As used herein, "about" generally means that the actual value is within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range. Alternatively, the term "about" means that the actual value falls within the acceptable standard deviation of the average, depending on the considerations of those of ordinary skill in the art to which the invention pertains. Except for the experimental examples, or unless otherwise explicitly stated, all ranges, quantities, values, and percentages used herein are understood (eg, to describe the amount of material used, the length of time, the temperature, the operating conditions, the quantity ratio, and the like. Are all modified by "about". Therefore, unless otherwise indicated to the contrary, the numerical parameters disclosed in the specification and the appended claims are intended to be At a minimum, these numerical parameters should be understood as the number of significant digits indicated and the values obtained by applying the general carry method.
「接受者操作特徵曲線」(receiver operating characteristic curve,ROC curve)一詞於本文中是指一利用真陽性率(true positive rate)與偽陽性率(false positive rate)繪出的曲線，用以決定一預斷試驗之切點(cut-off point)。ROC曲線通常將(1-專一性)定義為x軸，將敏感度定義為y軸。一高敏感度的數值表示低偽陽性率。同理，一高專一性的數值亦表 示低偽陽性率。「切點」(cut-off point)一詞於此處是指一由ROC曲線所得的數值，用以表示該預斷試驗之敏度感及專一性達到平衡。一切點範圍可以包含數個切點實施方式，其中各切點分別代表不同的敏感度及其專一性間的平衡。 The term "receiver operating characteristic curve" (ROC curve) is used herein to refer to a curve drawn using the true positive rate and the false positive rate. A cut-off point of a pre-break test. The ROC curve typically defines (1-specificity) as the x-axis and sensitivity as the y-axis. A high sensitivity value indicates a low false positive rate. Similarly, the value of a high specificity is also Show low false positive rate. The term "cut-off point" as used herein refers to a value obtained from the ROC curve to indicate that the sensitivity and specificity of the pre-break test are balanced. All point ranges can include several tangent point implementations, where each tangent point represents a balance between different sensitivities and their specificity.
在本文中，「曲線下面積」(area under the curve,AUC)為相關領域習知技藝人士所慣用的名詞，且定義為ROC曲線下的面積。一AUC數值通常介於0.5-1.0之間，用以代表一預斷試驗的準確度；其中，AUC的數值愈高，表示該預斷試驗的預斷效果愈佳。AUC數值通常會伴隨95%信賴區間(confidence interval,CI)，其係指一具有特定概率的統計範圍，以使一設定參數可落於該範圍內。 In this context, "area under the curve" (AUC) is a term that is customary to those skilled in the relevant art and is defined as the area under the ROC curve. An AUC value is usually between 0.5 and 1.0 to represent the accuracy of a pre-break test; wherein the higher the AUC value, the better the pre-breaking effect of the pre-break test. The AUC value is usually accompanied by a 95% confidence interval (CI), which refers to a statistical range with a specific probability such that a set parameter can fall within the range.
「風險」(risk)一詞於此是指一項可能會產生不良結果的可能性，例如，肝癌的發生、進展或復發。依據一個體、其檢體或其相關事件的分析結果，該名個體可被歸類至「高度風險」(high risk)、「中度風險」(intermediate risk)或「低度風險」(low risk)群族。至於本揭示內容所述之風險指數是指，當一病患的風險指數>75th百分比(即，一介於0.65至1的數值)時，該名病患是為「高度風險」族群；亦即，他/她五年內罹患肝癌的可能性高於分析族群中，其餘四分之三的病患。當一病患的風險指數<50th百分比(即，一介於0至0.5的數值)時，該名病患是為「低度風險」族群；亦即，他/她五年內罹患肝癌的可能性低於分析族群 中，其餘二分之一的病患。據此，若一病患的風險指數之百分比介於50th及75th之間(即，一介於0.5至0.65的數值)時，則該名病患是為「中度風險」族群。 The term "risk" here refers to a possibility that may result in undesirable outcomes, such as the occurrence, progression or recurrence of liver cancer. According to the analysis of a body, its specimen or its related events, the individual can be classified as "high risk", "intermediate risk" or "low risk" (low risk) ) group of people. As to the risk index of the present disclosure means that, when a patient's risk index> 75 th percentage (i.e., a value of between 0.65 to 1), the patient name is "high risk"groups; i.e. He/she is more likely to develop liver cancer within five years than the analysis group, and the remaining three-quarters of patients. When a patient's risk index th percentage <50 (ie, a value of between 0 to 0.5), the name of the patient is "low risk"groups; that is, he / she may be suffering from liver cancer within five years The sex is lower than the analysis of the remaining one-half of the patients. Accordingly, if the patient's risk index is between 50 th and 75 th (ie, a value between 0.5 and 0.65), the patient is a "moderate risk" group.
有鑑於相關領域亟需一種可準確且有效預斷肝硬化病患罹患肝癌之機率的方法，並藉此投予病患適當的治療，本揭示內容的主要目的是提供一組與肝癌發生率相關的臨床參數。一旦確認，該組臨床參數可用以計算出一風險指數，再依據該風險指數來預斷一肝硬化病患是否具有罹患肝癌的風險，使醫療人員可依據該預斷結果給予病患適當的治療。 In view of the urgent need for an accurate and effective method for predicting the risk of liver cancer in patients with cirrhosis, and to give appropriate treatment to patients, the main purpose of this disclosure is to provide a group related to the incidence of liver cancer. Clinical parameters. Once confirmed, the clinical parameters of the group can be used to calculate a risk index, and then according to the risk index to predict whether a liver cirrhosis patient has the risk of developing liver cancer, so that the medical staff can give appropriate treatment to the patient according to the pre-breaking result.
參與本發明之肝硬化病患會先接受健康檢查，以評估其肝臟的狀況(例如，肝硬化或肝癌)，且接受個人健康諮詢，例如身高、體重、年齡、種族、病史及過去的手術經歷(若有)。 Patients with cirrhosis who are involved in the present invention will undergo a health check to assess their liver status (eg, cirrhosis or liver cancer) and receive personal health counseling such as height, weight, age, race, medical history, and past surgical experience. (if any).
適用於診斷肝硬化的方法包含，但不限於，肝臟組織切片、內視鏡、血液檢驗、影像檢驗及其組合。一般來說，肝硬化病患由於肝功能不足，白蛋白(albumin)、鹼性磷酸酶(alkaline phosphatase)、膽紅素(bilirubin)及肌酸酐(creatinine)等肝臟酵素會異常表現於體內，而該異常可利用血液檢驗準確地定量及評估，其中該血液檢驗可以是任何相關領域習知技藝人士所熟知的傳統方法。若病患具有較嚴重的肝硬化，則可利用影像檢驗來檢測其肝臟的不規則表面、胃底靜脈曲張(gastric varices)及脾臟腫大(splenomegaly)等病徵，其中該影像檢驗包含超音波、電腦斷層攝影、核 磁共振成像及彈性影像(elastography)。依據一實施方式，參與本揭示內容之病患是利用肝臟組織切片、內視鏡及影像檢驗來診斷其肝硬化；其中，該影像檢驗是超音波或彈性影像。 Methods suitable for diagnosing cirrhosis include, but are not limited to, liver tissue sections, endoscopy, blood tests, image examinations, and combinations thereof. In general, liver cirrhosis patients with liver function deficiency, albumin (albumin), alkaline phosphatase (alkaline phosphatase), bilirubin (bilirubin) and creatinine (creatinine) and other liver enzymes will be abnormal in the body, and The abnormality can be accurately quantified and evaluated using a blood test, which can be a conventional method well known to those skilled in the relevant art. If the patient has severe cirrhosis, an imaging test can be used to detect irregularities in the liver, gastric varices, and splenomegaly. The image test contains ultrasound, Computer tomography, nuclear Magnetic resonance imaging and elastography. According to one embodiment, a patient participating in the present disclosure diagnoses cirrhosis using liver tissue sections, endoscopy, and imaging tests; wherein the image test is an ultrasound or an elastic image.
至於肝癌，適用於診斷肝癌的方法包含，但不限於，肝臟組織切片、血液檢驗及影像檢驗。一般來說，肝癌病患會高量表現諸如甲型胎兒蛋白(alpha-fetoprotein,AFP)等生長相關的致癌蛋白，而利用血液檢驗可準確測量並呈現該些致癌蛋白的表現量。在偵檢腫瘤結節時，可利用超音波、電腦斷層攝影、核磁共振成像或血管造影術(angiography)來進行。本揭示內容之一實施方式是利用肝臟組織切片、血液檢驗及影像檢驗來評估肝硬化病患是否罹患肝癌，其中該影像檢驗是電腦斷層攝影或血管造影術。 As for liver cancer, methods suitable for diagnosing liver cancer include, but are not limited to, liver tissue sectioning, blood testing, and imaging testing. In general, liver cancer patients will exhibit high levels of growth-related oncogenic proteins such as alpha-fetoprotein (AFP), and blood tests can accurately measure and present the expression of these oncogenic proteins. When detecting tumor nodules, ultrasound, computed tomography, magnetic resonance imaging, or angiography can be used. One embodiment of the present disclosure is to use liver tissue sections, blood tests, and imaging tests to assess whether a liver cirrhosis patient has liver cancer, wherein the imaging test is computed tomography or angiography.
依據健康檢查之結果，肝硬化病患可分為二群：(1)從未罹患肝癌的肝硬化病患；及(2)曾罹患早期肝癌，但接受治療後已完全緩解之肝硬化病患。第二群病患是用以模擬相較於第一群病患，較易罹患肝癌的族群。由於伴隨肝癌出現的癌細胞因子應被視為肝癌的診斷因子，而非預斷因子，故第二群病患之肝癌的完全緩解可以防止該些癌細胞因子干擾本發明之測量及評估結果。 According to the results of the health check, patients with cirrhosis can be divided into two groups: (1) patients with liver cirrhosis who have never had liver cancer; and (2) patients with liver cirrhosis who have suffered from early liver cancer but have been completely relieved after treatment. . The second group of patients was used to simulate a population that was more likely to develop liver cancer than the first group of patients. Since cancer cell factors accompanying the development of liver cancer should be regarded as a diagnostic factor for liver cancer, rather than a pre-break factor, complete remission of liver cancer of the second group of patients can prevent the cancer cell factors from interfering with the measurement and evaluation results of the present invention.
先抽取每名病患的血液檢體，以篩選出該些於第一及第二群肝硬化病患中具有不同表現量的臨床參數。一般來說，血液檢體是指病患周邊血液的全血檢 體。本揭示內容分析的臨床參數包含：(1)天門冬胺酸轉胺酶(aspartate transaminase,AST)、丙胺酸轉胺酶(alanine transaminase,ALT)、膽紅素、甲型胎兒蛋白、血紅素結合素(haptoglobin)、空腹血糖、醣化血紅素(glycohemoglobin)、甲狀腺促素(thyrotropin)、游離甲狀腺素(free thyroxin,T4)、總蛋白、白蛋白、α 1-球蛋白(alphal-globulin)、α 2-球蛋白、β-球蛋白、γ-球蛋白、脂蛋白元-A1(apolipoprotein-A1,Apo-A1)、尿酸(uric acid,UA)、高密度脂蛋白、低密度脂蛋白(low density lipoprotein,LDL)、極低密度脂蛋白(very low density lipoprotein,VLDL)、膽固醇(cholesterol)、三酸甘油脂(triglyceride)、胰島素、鐵蛋白(ferritin)、血漿銅藍蛋白(ceruloplasmin)、鐵、總鐵結合能力(total iron binding capacity,TIBC)、不飽合鐵結合能力(unsaturated iron binding capacity,UIBC)、補體成分3(complement component 3,C3)、補體成分4(complement component 4,C4)、血脲氮(blood urea nitrogen,BUN)、肌酸酐及衡定模式評估之胰島素抗性(homeostasis model assessment-estimated insulin resistance,HOMA-IR)的濃度；(2)白蛋白/球蛋白、胰島素/空腹血糖、膽固醇/高密度脂蛋白及低密度脂蛋白/高密度脂蛋白的比值；(3)白血球、血紅素及血小板的數量；(4)嗜中性白血球、淋巴球及單核球於白血球中的百分比；以及(5)凝血酶原時間(prothrombin time,PT)。 Blood samples from each patient were first drawn to screen out clinical parameters with different performance in the first and second groups of patients with cirrhosis. In general, a blood sample refers to a whole blood test of the blood surrounding the patient. body. The clinical parameters analyzed in this disclosure include: (1) aspartate transaminase (AST), alanine transaminase (ALT), bilirubin, alpha-fetoprotein, heme binding Haptoglobin, fasting blood glucose, glycohemoglobin, thyrotropin, free thyroxin (T4), total protein, albumin, alpha 1-globulin, alpha 2-globulin, β-globulin, γ-globulin, lipoprotein-A1 (apo-A1), uric acid (UA), high-density lipoprotein, low-density lipoprotein (low density) Lipoprotein, LDL), very low density lipoprotein (VLDL), cholesterol (cholesterol), triglyceride, insulin, ferritin, ceruloplasmin, iron, Total iron binding capacity (TIBC), unsaturated iron binding capacity (UIBC), complement component 3 (C3), complement component 4 (C4), Blood urea nitrogen Nitrogen, BUN), creatinine and concentration of homeostasis model assessment-estimated insulin resistance (HOMA-IR); (2) albumin/globulin, insulin/fasting blood glucose, cholesterol/high density The ratio of lipoprotein to low density lipoprotein/high density lipoprotein; (3) the number of white blood cells, heme and platelets; (4) the percentage of neutrophils, lymphocytes and mononuclear cells in white blood cells; and (5) ) Prothrombin time (PT).
依據所得之臨床參數來評估肝硬化病患罹患肝癌的風險。具體來說，先篩選出在二群病患間具有不同表現量之臨床參數，再利用運算操作來結合該些臨床參數，該運算操作可以是指數運算、代數運算、對數運算或其組合。不同臨床參數之結合可產生不同的演算法，並以風險指數表示，風險指數可進一步作為肝癌發生率指標；再依據各演算法的AUC數值來評估該演算法的準確度。利用不同的運算操作及調整使用的臨床參數，直到取得一具有最高AUC數值的演算法。再依據最終所得之演算法來計算風險指數，將肝硬化病患分為具有低度、中度或高度罹患肝癌風險的族群。 The risk of liver cancer in patients with cirrhosis is assessed based on the clinical parameters obtained. Specifically, the clinical parameters having different performance amounts between the two groups of patients are first screened, and the operation parameters are used to combine the clinical parameters, and the operation operations may be exponential operations, algebraic operations, logarithmic operations, or a combination thereof. The combination of different clinical parameters can produce different algorithms, and is represented by risk index. The risk index can be further used as an indicator of liver cancer incidence rate; then the accuracy of the algorithm is evaluated according to the AUC value of each algorithm. Use different arithmetic operations and adjust the clinical parameters used until an algorithm with the highest AUC value is obtained. According to the final algorithm, the risk index is calculated, and the patients with cirrhosis are divided into groups with low, moderate or high risk of liver cancer.
據此，本揭示內容提供一種準確的預斷方法，其係利用肝硬化病患的血液檢體來預斷該名病患是否會罹患肝癌。大致而言，本方法包含：(1)由該血液檢體測量空腹血糖、胰島素及高密度脂蛋白的濃度、血小板的數量及淋巴球與嗜中性白血球的百分比；(2)利用一公式來計算一風險指數：
依據本揭示內容的實施方式，血液檢體是一全血檢體。肝硬化病患是患有一慢性肝臟疾病，而該慢性肝臟疾病可以是酒精性肝臟疾病、非酒精性脂肪肝、B型肝炎或C型肝炎。在一較佳實施方式中，肝硬化病患是患有B型肝炎。 According to an embodiment of the present disclosure, the blood sample is a whole blood sample. A patient with cirrhosis is suffering from a chronic liver disease, which may be alcoholic liver disease, nonalcoholic fatty liver disease, hepatitis B or hepatitis C. In a preferred embodiment, the cirrhotic patient is suffering from hepatitis B.
在步驟(1)中，空腹血糖的濃度是以mg/dL(每分升之毫克)表示；胰島素的濃度是以μIU/mL(每毫升之微-國際單位)表示；高密度脂蛋白的濃度是以mg/dL(每分升之毫克)表示；血小板的數量是以數量/μL(每微升之血小板數量)；而淋巴球及嗜中性白血球的百分比則是分別以白血球總數作為基準值所分析出的數值。 In step (1), the concentration of fasting blood glucose is expressed in mg/dL (mg per deciliter); the concentration of insulin is expressed in μIU/mL (micro-international units per ml); the concentration of high-density lipoprotein It is expressed in mg/dL (mg per deciliter); the number of platelets is in number/μL (number of platelets per microliter); and the percentage of lymphocytes and neutrophils is based on the total number of white blood cells, respectively. The value analyzed.
依據本揭示內容的實施方式，適用於分析空腹血糖濃度的方法包含，但不限於，酵素、芳香胺或連續流動分析。依據本領域實驗室或臨床所熟知之技術，該酵素是選自由葡萄糖氧化酶、葡萄糖去氫酶及己醣激酶所組成的群組；而芳香胺則可以是苯胺、聯苯胺、2-胺基聯苯或鄰甲苯胺。 Methods for analyzing fasting blood glucose concentrations according to embodiments of the present disclosure include, but are not limited to, enzymes, aromatic amines, or continuous flow analysis. The enzyme is selected from the group consisting of glucose oxidase, glucose dehydrogenase and hexokinase according to techniques well known in the laboratory or clinically in the art; and the aromatic amine may be aniline, benzidine or 2-amino group. Biphenyl or o-toluidine.
依據本揭示內容某些實施方式，用以分析胰 島素濃度的非限定實施方式包含利用抗體進行的試驗，其中該抗體對於胰島素的A鏈或B鏈具有專一性。 According to some embodiments of the present disclosure, for analyzing pancreas A non-limiting embodiment of an island concentration comprises an assay using an antibody wherein the antibody is specific for the A or B chain of insulin.
在本揭示內容的實施方式中，高密度脂蛋白的濃度可利用酵素、電泳分析、連續流動分析或核磁共振分析來進行測量。依據相關領域習知技藝人士所熟知的試驗，用以測量高密度脂蛋白濃度的酵素是膽固醇氧化酶。 In embodiments of the present disclosure, the concentration of high density lipoprotein can be measured using enzymes, electrophoretic analysis, continuous flow analysis, or nuclear magnetic resonance analysis. The enzyme used to measure the high density lipoprotein concentration is cholesterol oxidase, according to tests well known to those skilled in the relevant art.
依據本揭示內容的實施方式，適用於分析血小板數量、淋巴球百分比及嗜中性白血球百分比的試驗包含，但不限於，血球計、血液分析儀及抗體。在本揭示內容中，用於分析血小板數量的抗體對於血小板的表面標記具有專一性，其中該表面標記是選自由CD41、CD42、CD49、CD61、CD62及CD109所組成的群組。用於測量淋巴球百分比的抗體對於淋巴球的表面標記具有專一性，其中該表面標記包含，但不限於，CD3、CD4、CD25、CD40、CD62L、CD80及CD152。相似地，用以測量嗜中性白血球百分比的抗體對於嗜中性白血球的標記具有專一性，其中該標記是選自由CD66、CD177、Ly6G及嗜中性白血球彈性蛋白酶所組成的群組。此外，本揭示內容所使用的抗體是與一螢光染料接合，便於偵測與抗體結合的細胞。 In accordance with embodiments of the present disclosure, assays suitable for analyzing platelet count, lymphocyte percentage, and neutrophil percentage include, but are not limited to, hemocytometers, blood analyzers, and antibodies. In the present disclosure, an antibody for analyzing the number of platelets is specific for a surface marker of platelets, wherein the surface marker is selected from the group consisting of CD41, CD42, CD49, CD61, CD62, and CD109. Antibodies for measuring the percentage of lymphocytes are specific for surface labeling of lymphocytes, including, but not limited to, CD3, CD4, CD25, CD40, CD62L, CD80, and CD152. Similarly, antibodies used to measure the percentage of neutrophils are specific for markers of neutrophils, wherein the markers are selected from the group consisting of CD66, CD177, Ly6G, and neutrophil elastase. In addition, the antibodies used in the present disclosure are conjugated to a fluorescent dye to facilitate detection of cells that bind to the antibody.
在步驟(2)中，利用本揭示內容之公式，並佐以步驟(1)所得之血小板數量、高密度脂蛋白濃度、空腹血糖濃度與胰島素濃度的比值，以及淋巴球百分比與嗜中性白血球百分比的比值來計算風險指數。 In step (2), using the formula of the present disclosure, and taking the number of platelets obtained in step (1), high-density lipoprotein concentration, ratio of fasting blood glucose concentration to insulin concentration, and percentage of lymphocytes and neutrophils The ratio of percentages is used to calculate the risk index.
在步驟(3)中，依據步驟(2)計算的風險指數將病患分為具有低度、中度或高度罹患肝癌風險的族群。依據本揭示內容之一實施方式，相較於低度或中度風險族群的病患，高度風險族群的病患較易罹患肝癌。 In step (3), the risk index calculated according to step (2) divides the patient into a group with low, moderate or high risk of developing liver cancer. According to one embodiment of the present disclosure, patients of a high risk group are more susceptible to liver cancer than patients with a low or moderate risk group.
下文舉出多種實施例來闡明本發明之部分態樣，以使本發明所屬技術領域中具有通常知識者能藉以實踐本發明。因此不應將這些實施例視為對本發明範圍之限制。本發明所屬技術領域中具有通常知識者基於此處提的說明，當可在不需過度推衍的情形下運用本發明。此處提及的所有文獻，皆視為已完全引用而成為本說明書的一部份。 Various embodiments are set forth below to clarify some aspects of the present invention so that those skilled in the art can practice the invention. Therefore, these examples should not be construed as limiting the scope of the invention. The present invention is based on the description herein, and can be applied without excessive derivation. All documents mentioned herein are considered to be fully incorporated into this specification.
實施例1 建立風險指數Example 1 Establishing a risk index
醫療人員依據健康檢查結果將193名參與本發明試驗的肝硬化病患分為二個群組。第一群組包含161名病患，該些病患患有B型肝炎，且從未罹患過肝癌(標記為「非肝癌群組」)。第二群組包含32名病患，該些病患患有B型肝炎，且曾經罹患早期肝癌，而後接受臨床治療後已治癒(標記為「肝癌群組」)。然而，在分群後一年內，5名原屬非肝癌群組的病患陸續罹患肝癌。將該5名病患重新分群後，肝癌群組包含37名病患，而非肝癌群組則包含156名病患。依據表1所示的基線人口統計資料，肝癌群組與非肝癌群組間並沒有顯著的差異存在。 According to the results of the health check, the medical staff divided 193 patients with liver cirrhosis who participated in the test of the present invention into two groups. The first group consisted of 161 patients with hepatitis B who had never had liver cancer (labeled "non-hepatoma group"). The second group consisted of 32 patients with hepatitis B who had developed early liver cancer and were cured after clinical treatment (labeled "Hepatoma Group"). However, within one year after grouping, five patients who were originally in the non-hepatoma group were suffering from liver cancer. After regrouping the five patients, the liver cancer group contained 37 patients, while the non-hepatoma group contained 156 patients. According to the baseline demographic data shown in Table 1, there was no significant difference between the liver cancer group and the non-hepatoma group.
表1 基線人口統計資料
將由肝癌群組及非肝癌群組之病患所抽取的血液檢體(在抽血前空腹12個小時)利用連續流動分析或血液分析儀來進行相關的生化或血液分析。表2總結44個所得的臨床參數值。 Blood samples taken from patients with liver cancer and non-hepatoma groups (12 hours on fasting before blood draw) were subjected to relevant biochemical or blood analysis using a continuous flow analysis or blood analyzer. Table 2 summarizes the 44 obtained clinical parameter values.
如表2所示，在44個臨床參數中，有4個參數在肝癌群組及非肝癌群組間具有顯著不同的表現量：(1)高密度脂蛋白的濃度(AUC=0.405，p-值=0.074)；(2)空腹血糖濃度與胰島素濃度的比值(AUC=0.354，p-值=0.006)；(3)血小板的數量(AUC=0.317，p-值=0.001)；以及(4)淋巴球百分比與嗜中性白血球百分比的比值(AUC=0.373，p-值=0.017)。 As shown in Table 2, among the 44 clinical parameters, 4 parameters have significantly different expressions between the HCC group and the non-hepatoma group: (1) High-density lipoprotein concentration (AUC=0.405, p - Value = 0.074); (2) ratio of fasting blood glucose concentration to insulin concentration (AUC = 0.354, p - value = 0.006); (3) number of platelets (AUC = 0.317, p - value = 0.001); and (4) The ratio of the percentage of lymphocytes to the percentage of neutrophils (AUC = 0.373, p - value = 0.017).
為使評估的準確度最佳化，利用運算操作將上述4個具有高可信度及高辨別度的臨床參數合併運算。經過數次篩選及修正，可得到一最終公式，其係具
有最佳的分群準確度(AUC=0.78)，且可表示為：
依據該風險指數，可將肝硬化病患分為三族群：(1)低度風險：指數介於0至0.5的病患；(2)中度風險：指數介於0.5至0.65的病患；以及(3)高度風險：指數介於0.65至1的病患。 According to the risk index, patients with cirrhosis can be divided into three groups: (1) low risk: patients with an index between 0 and 0.5; (2) moderate risk: patients with an index between 0.5 and 0.65; And (3) high risk: patients with an index between 0.65 and 1.
據此，若-病患的血小板數量為每微升140個，高密度脂蛋白為每分升45毫克，空腹血糖為每分升100毫克，胰島素為每毫升8微-國際單位，淋巴球佔總白血球數量的30%，而嗜中性白血球佔總白血球數量的60%，則該名病患的風險指數為0.535，將分群至中等風險族群。 Accordingly, if the patient's platelet count is 140 per microliter, high-density lipoprotein is 45 mg per deciliter, fasting blood glucose is 100 mg per deciliter, insulin is 8 micro-international units per ml, and lymphocytes account for For 30% of the total white blood cells, and neutrophils account for 60% of the total white blood cells, the patient's risk index is 0.535, which will be grouped to moderate risk groups.
實施例2 驗證實施例1之風險指數Example 2 Verification of the risk index of Example 1
利用實施例1所建立的公式計算183名肝硬 化病患的風險指數，並依其風險指數進行分群；其中85名病患是為低度風險族群，38名病患是為中度風險族群，而60名病患是為高度風險族群。持續追蹤觀察該些病患1.5年。在這段觀察期間，低度風險族群中，沒有人罹患肝癌；而中度及高度風險族群則分別有3名及7名病患被診斷罹患肝癌。依據第1圖所示之累積風險曲線，相較於低度或中度風險族群的病患，高度風險族群的病患較易罹患肝癌，且具有顯著的差異(p=0.0213)。 Using the formula established in Example 1, the risk index of 183 patients with liver cirrhosis was calculated and grouped according to their risk index; among them, 85 patients were low-risk groups and 38 patients were moderate risk groups. The 60 patients were highly at risk. Continue to follow up on these patients for 1.5 years. During this observation period, no one in the low-risk group had liver cancer; in the moderate and high-risk group, 3 and 7 patients were diagnosed with liver cancer. According to the cumulative risk curve shown in Figure 1, patients with high-risk groups were more likely to have liver cancer than patients with low or moderate risk groups, with significant differences ( p = 0.0213).
為進一步確認本揭示內容方法的準確度，利用實施例1之公式分別評估共344名病患(包含161名建立實施例1公式的病患及183名第1圖所分析的病患)的風險指數，並進行分群；其中167名病患是為低度風險族群，76名病患是為中度風險族群，而101名病患是為高度風險族群。在1.5年的觀察期中，低度風險族群中，沒有人罹患肝癌；而中度及高度風險族群則分別有3名及12名病患被診斷罹患肝癌。因此，若以預斷之日起算，高度風險族群的病患較低度或中度風險族群的病患更快罹患肝癌，且具有顯著的差異(p=0.0001，第2圖)。 To further confirm the accuracy of the method of the present disclosure, the risk of a total of 344 patients (including 161 patients who established the formula of Example 1 and 183 patients analyzed in Figure 1) was evaluated using the formula of Example 1. The index was divided into groups; 167 patients were of low risk group, 76 patients were moderate risk groups, and 101 patients were highly risky. In the 1.5-year observation period, no one in the low-risk group had liver cancer; in the moderate and high-risk group, 3 and 12 patients were diagnosed with liver cancer. Therefore, patients with low- or moderate-risk groups of patients at high risk groups were more likely to have liver cancer at the onset of pre-breaking, with significant differences ( p = 0.0001, Figure 2).
總結上述，本揭示內容提供一種預斷方法，其係用以預斷一肝硬化病患未來罹患肝癌的風險。本方法包含一利用空腹血糖、胰島素、高密度脂蛋白、血小板、淋巴球及嗜中性白血球之數值進行計算的公式。依據公式計算出的風險指數，可將該名肝硬化病患分群至具有低度、中度或高度罹患肝癌風險的族群。相較於傳 統的影像檢驗，本揭示內容提供一種更為準確及有效的肝癌預斷方法；藉此，醫療人員可提供病患適當且及時的治療。 In summary, the present disclosure provides a pre-breaking method for pre-diagnosing the risk of liver cancer in a patient with cirrhosis. The method comprises a formula for calculating the values of fasting blood glucose, insulin, high density lipoprotein, platelets, lymphocytes and neutrophils. According to the risk index calculated by the formula, the cirrhosis patient can be grouped into a group with low, moderate or high risk of liver cancer. Compared with Based on the imaging test, the present disclosure provides a more accurate and effective method for predicting liver cancer; thereby, medical personnel can provide appropriate and timely treatment for patients.
當可理解上述實施方式與實施例僅為例示，且熟習此技藝者可對齊進行各種修飾。上文提出之說明書、實施例與資料的目的在於使本說明書的結構完備，並作為實作本發明之例示。雖然本揭示內容已以實施方式揭露如上，然其並非用以限定本揭示內容，任何熟習此技藝者，在不脫離本揭示內容之精神和範圍內，當可作各種之更動與潤飾，因此本揭示內容之保護範圍當視後附之申請專利範圍所界定者為準。 It will be understood that the above-described embodiments and examples are merely illustrative, and that those skilled in the art can align various modifications. The description, examples, and materials set forth above are intended to be illustrative of the present invention and are illustrative of the invention. The present disclosure has been disclosed in the above embodiments, but it is not intended to limit the disclosure, and any person skilled in the art can make various changes and refinements without departing from the spirit and scope of the disclosure. The scope of protection of the disclosure is subject to the definition of the scope of the patent application.
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