JP5936181B2 - Method for measuring bladder cancer or determining prognosis after cancer treatment - Google Patents
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Description
本発明は、尿中の揮発性成分を指標として、被験者について癌、特に膀胱癌の罹患の有無を測定する方法、または癌患者、特に膀胱癌患者について癌治療後の予後を判定する方法に関する。 The present invention relates to a method for measuring the presence or absence of cancer, particularly bladder cancer, in a subject using a volatile component in urine as an index, or a method for determining a prognosis after cancer treatment for a cancer patient, particularly a bladder cancer patient.
わが国において、現在、膀胱癌は、毎年1万6千人の罹患を認める。膀胱癌の約70%は、癌浸潤が筋層にまでは至らない表在性がんである。その標準療法である経尿道的膀胱腫瘍切除術により、膀胱温存が可能で生命予後も良好であるが、術後早期に、膀胱内再発が高い割合で発生する。また、浸潤性がんが発見された場合には、標準療法として膀胱全摘術およびそれに伴う尿路変更が余儀なくされるため、QOLの低下が重要な問題となる。 In Japan, bladder cancer currently affects 16,000 people each year. About 70% of bladder cancers are superficial cancers where cancer invasion does not reach the muscle layer. The standard therapy, transurethral excision of the bladder tumor, can preserve the bladder and has a good life prognosis, but a high rate of intravesical recurrence occurs early in the procedure. In addition, when invasive cancer is discovered, the reduction of QOL becomes an important issue because total cystectomy and urinary tract change accompanying it are unavoidable as standard therapy.
そのため、他のがんと同様に膀胱癌においても、早期発見が重要である。特に、膀胱癌は、上記するように治療後早期に膀胱内再発を来すため、膀胱内再発を念頭に置いた定期的な検査が必要であり、患者にとって身体的、精神的、及び経済的負担が大きいことが問題であった。このため、従来から、患者に負担のない方法で膀胱癌を検査・診断する方法が求められている。 Therefore, early detection is important in bladder cancer as well as other cancers. In particular, bladder cancer causes intravesical recurrence early after treatment, as described above, and therefore requires periodic examinations with intravesical recurrence in mind, which is physical, mental, and economical for patients. The problem was the heavy burden. For this reason, there is a need for a method for examining and diagnosing bladder cancer in a manner that does not burden the patient.
従来、膀胱癌の非侵襲的な検査・診断方法(膀胱癌スクリーニング)として、犬の嗅覚を利用した尿臭気分析により膀胱癌が識別出来る可能性があることが報告されている(非特許文献1)。また、同様に、犬の鋭敏な嗅覚を癌のスクリーニングに利用し、患者の呼気の臭気より乳癌や肺癌が識別できるという報告もある(非特許文献2)。 Conventionally, as a noninvasive examination / diagnosis method (bladder cancer screening) of bladder cancer, it has been reported that bladder cancer may be identified by urine odor analysis using the olfactory sense of dogs (Non-patent Document 1). ). Similarly, there is a report that a dog's sensitive olfaction can be used for cancer screening, and breast cancer and lung cancer can be distinguished from the breath odor of the patient (Non-patent Document 2).
しかしながら、尿中の臭気物質に基づく癌の判定方法は科学的根拠が乏しいのが現状である。 However, the current situation is that the method of determining cancer based on odorous substances in urine has a poor scientific basis.
本発明は、被験者について、非侵襲的に癌、特に膀胱癌の罹患の有無を測定する方法を提供することを目的とする。また、本発明は、癌患者、特に膀胱癌の患者について、非侵襲的に癌治療後の再発の危険性(再発リスク)を予測又は判定する方法、言い換えれば癌(膀胱癌)の予後を予測又は判定する方法を提供することを目的とする。 An object of the present invention is to provide a method for non-invasively measuring the presence or absence of cancer, particularly bladder cancer, in a subject. The present invention also provides a method for predicting or determining the risk of recurrence after cancer treatment (recurrence risk) non-invasively for cancer patients, particularly bladder cancer patients, in other words, predicting the prognosis of cancer (bladder cancer). Alternatively, an object is to provide a method for determination.
本発明者らは、上記課題を解決すべく、膀胱癌や前立腺癌などの癌患者について、腫瘍を摘出する外科的手術前後の尿、及び健常者の尿を対象として、尿中の揮発性化合物をメタボノミクス(Metabonomics)解析(「メタボロミクス解析」ともいう)をしたところ、癌患者と健常者では、尿に含まれる特定の揮発性化合物の量に明らかな違いがあること、また当該化合物の量は、同一の癌患者の癌摘出手術前と後で有意に異なり、手術で癌腫瘍部を摘出することによって、健常者の値に近づくことを見いだした。 In order to solve the above-mentioned problems, the present inventors have developed volatile compounds in urine for cancer patients such as bladder cancer and prostate cancer for urine before and after surgical operation to remove the tumor and urine of healthy subjects. Metabonomics analysis (also referred to as “metabolomics analysis”) shows that there is a clear difference in the amount of certain volatile compounds in urine between cancer patients and healthy volunteers, and the amount of such compounds Found that it was significantly different from before and after cancer removal surgery for the same cancer patient, and that it was close to that of healthy individuals by removing the cancerous tumor part by surgery.
これらの知見に基づいて、さらなる検討を重ねた結果、尿に含まれるこれらの揮発性化合物を同定することに成功し、尿中に含まれるこれらの揮発性化合物を指標とすることで、癌、特に膀胱癌の罹患の有無が診断できること、また癌治療後の再発の可能性、つまり癌治療後の予後を判定することができることを確信した。 Based on these findings, as a result of further studies, we succeeded in identifying these volatile compounds contained in urine, and by using these volatile compounds contained in urine as an index, In particular, I was convinced that I could diagnose the presence or absence of bladder cancer, and determine the possibility of recurrence after cancer treatment, that is, the prognosis after cancer treatment.
本発明は、かかる知見に基づいて完成したものであり、下記の実施形態を有するものである。 The present invention has been completed based on this finding, and has the following embodiments.
即ち、本発明は以下の発明に関する。
(I)癌罹患の測定方法
(I-1)下記の工程を有する、被験者について癌罹患を測定する方法:
(A)被験者の尿中に含まれる下記の揮発性化合物からなる群から選択される少なくとも1つの量を測定する工程、
(1)(S)-2-ヒドロキシプロパン酸((S)-2-Hydroxypropanoic acid)、
(2)ヘプチルヒドロペルオキシド(Heptyl hydroperoxide)、
(3)2, 3-ジヒドロキシプロパナール(2, 3-Dihydroxypropanal)、
(4)塩化ノナノイル(Nonanoyl chloride)、
(5)ドデカナール(Dodecanal)、
(6)(Z)-2-ノネナール((Z)-2-Nonenal)、
(7)4, 5-ジメチル-3(2H)-イソキサゾロン(4, 5-Dimethyl-3(2H)-isoxazolone)、
(8)(Z)-2-デセナール ((Z)-2-Decenal)、
(9)トリクロロ酸3 - トリデシルエステル(Trichloroacetic acid 3-tridecyl ester)、
(10)レボグルコサン(Levoglucosan)、
(11)4-(ジメチルアミノ)-3-メチル-2-ブタノン(4-(Dimethylamino)-3-methyl-2-butanone)、
(12)4-メチル-1-ブテン-1-イルペンタン酸エステル(Pentanoic acid 4-methyl-1-buten-1-yl ester)、
(13)ジエチルフタル酸(Diethyl phthalate)、
(14)1-クロロ-8-ヘプタデセン(1-Chloro-8-heptadecene)、
(15)ペンタデカン酸(Pentadecanoic acid)、
(16)1, 2-ベンゼンジカルボン酸ブチルデシルエステル(1, 2-Benzenedicarboxylic acid butyldecyl ester)、
(B)上記測定値(以下、「被験値」という)と、健常者の尿中に含まれる上記に対応する揮発性組成物の量(以下、「基準値」という)とを比較し、被験値と基準値との乖離度を求める工程、
(C)有意水準5%として、上記乖離度に有意差がある場合に、被験者について癌罹患の疑いがあると決定するか、または上記乖離度に有意差がない場合に、被験者について癌罹患の疑いがないと決定する工程。
(I-2)前記癌が、膀胱癌、前立腺癌、腎臓癌、及び子宮頸癌からなる群から選択される少なくとも一つの固形癌である(I-1)に記載する癌罹患の測定方法。
(I-3)前記癌が、膀胱癌である(I-1)に記載する癌罹患の測定方法。
That is, the present invention relates to the following inventions.
(I) Method for measuring cancer incidence (I-1) A method for measuring cancer incidence for a subject having the following steps:
(A) measuring at least one amount selected from the group consisting of the following volatile compounds contained in the urine of a subject;
(1) (S) -2-hydroxypropanoic acid ((S) -2-Hydroxypropanoic acid),
(2) Heptyl hydroperoxide,
(3) 2,3-Dihydroxypropanal,
(4) Nonanoyl chloride,
(5) Dodecanal,
(6) (Z) -2-Nonenal ((Z) -2-Nonenal),
(7) 4,5-dimethyl-3 (2H) -isoxazolone (4,5-Dimethyl-3 (2H) -isoxazolone),
(8) (Z) -2-Decenal ((Z) -2-Decenal),
(9) Trichloroacetic acid 3-tridecyl ester,
(10) Levoglucosan,
(11) 4- (Dimethylamino) -3-methyl-2-butanone (4- (Dimethylamino) -3-methyl-2-butanone),
(12) 4-methyl-1-buten-1-ylpentanoic acid ester (Pentanoic acid 4-methyl-1-buten-1-yl ester),
(13) Diethyl phthalate,
(14) 1-Chloro-8-heptadecene,
(15) Pentadecanoic acid,
(16) 1,2-Benzenedicarboxylic acid butyldecyl ester,
(B) The measured value (hereinafter referred to as “test value”) is compared with the amount of the volatile composition corresponding to the above (hereinafter referred to as “reference value”) contained in the urine of a healthy person. A process for calculating the degree of divergence between the value and the reference value,
(C) As a significance level of 5%, if there is a significant difference in the degree of divergence, it is determined that the subject is suspected of having cancer, or if there is no significant difference in the degree of divergence, The process of determining that there is no doubt.
(I-2) The method for measuring cancer incidence according to (I-1), wherein the cancer is at least one solid cancer selected from the group consisting of bladder cancer, prostate cancer, kidney cancer, and cervical cancer.
(I-3) The method for measuring cancer incidence according to (I-1), wherein the cancer is bladder cancer.
(II)癌患者の癌治療後の予後を判定する方法
(II-1)下記の工程を有する、癌患者について癌治療後の予後を判定する方法:
(a)癌患者の癌治療前と後の尿を被験試料として、当該尿中に含まれる下記の揮発性化合物からなる群から選択される少なくとも1つの量を測定する工程、
(1)(S)-2-ヒドロキシプロパン酸((S)-2-Hydroxypropanoic acid)、
(2)ヘプチルヒドロペルオキシド(Heptyl hydroperoxide)、
(3)2, 3-ジヒドロキシプロパナール(2, 3-Dihydroxypropanal)、
(4)塩化ノナノイル(Nonanoyl chloride)、
(5)ドデカナール(Dodecanal)、
(6)(Z)-2-ノネナール((Z)-2-Nonenal)、
(7)4, 5-ジメチル-3(2H)-イソキサゾロン(4, 5-Dimethyl-3(2H)-isoxazolone)、
(8)(Z)-2-デセナール ((Z)-2-Decenal)、
(9)トリクロロ酸3 - トリデシルエステル(Trichloroacetic acid 3-tridecyl ester)、
(10)レボグルコサン(Levoglucosan)、
(11)4-(ジメチルアミノ)-3-メチル-2-ブタノン(4-(Dimethylamino)-3-methyl-2-butanone)、
(12)4-メチル-1-ブテン-1-イルペンタン酸エステル(Pentanoic acid 4-methyl-1-buten-1-yl ester)、
(13)ジエチルフタル酸(Diethyl phthalate)、
(14)1-クロロ-8-ヘプタデセン(1-Chloro-8-heptadecene)、
(15)ペンタデカン酸(Pentadecanoic acid)、
(16)1, 2-ベンゼンジカルボン酸ブチルデシルエステル(1, 2-Benzenedicarboxylic acid butyldecyl ester)、
(b)上記で得られる治療前の値(以下、「治療前値」という)、治療後の値(以下、「治療後値」という)、及び健常者の尿中に含まれる上記に対応する揮発性組成物の量(以下、「基準値」という)をそれぞれ比較し、治療前値と基準値との乖離度、及び治療後値と基準値との乖離度を求める工程、
(c)治療後値と基準値との乖離度が治療前値と基準値との乖離度よりも小さく、且つ、有意水準5%として、治療後値と基準値との乖離度に有意差がない場合に、当該癌患者は癌治療後の予後が良好と判定する工程。
(II-2)前記癌患者が、膀胱癌、前立腺癌、腎臓癌、及び子宮頸癌からなる群から選択される少なくとも一つの癌に罹患した患者である(II-1)に記載する予後判定方法。
(II-3)前記癌患者が、膀胱癌の患者である(II-1)に記載する予後判定方法。
(II) Method for determining the prognosis after cancer treatment of a cancer patient (II-1) Method for determining the prognosis after cancer treatment for a cancer patient having the following steps:
(A) measuring at least one amount selected from the group consisting of the following volatile compounds contained in the urine using urine before and after cancer treatment of a cancer patient as a test sample;
(1) (S) -2-hydroxypropanoic acid ((S) -2-Hydroxypropanoic acid),
(2) Heptyl hydroperoxide,
(3) 2,3-Dihydroxypropanal,
(4) Nonanoyl chloride,
(5) Dodecanal,
(6) (Z) -2-Nonenal ((Z) -2-Nonenal),
(7) 4,5-dimethyl-3 (2H) -isoxazolone (4,5-Dimethyl-3 (2H) -isoxazolone),
(8) (Z) -2-Decenal ((Z) -2-Decenal),
(9) Trichloroacetic acid 3-tridecyl ester,
(10) Levoglucosan,
(11) 4- (Dimethylamino) -3-methyl-2-butanone (4- (Dimethylamino) -3-methyl-2-butanone),
(12) 4-methyl-1-buten-1-ylpentanoic acid ester (Pentanoic acid 4-methyl-1-buten-1-yl ester),
(13) Diethyl phthalate,
(14) 1-Chloro-8-heptadecene,
(15) Pentadecanoic acid,
(16) 1,2-Benzenedicarboxylic acid butyldecyl ester,
(B) Corresponding to the above-mentioned values contained in the urine of healthy subjects, the values obtained before treatment (hereinafter referred to as “pre-treatment values”), the values after treatment (hereinafter referred to as “post-treatment values”). A step of comparing the amounts of volatile compositions (hereinafter referred to as “reference values”) to determine the divergence between the pre-treatment value and the reference value and the divergence between the post-treatment value and the reference value,
(C) The difference between the post-treatment value and the reference value is smaller than the difference between the pre-treatment value and the reference value, and the significance level is 5%. If not, the step of determining that the cancer patient has a good prognosis after cancer treatment.
(II-2) The prognosis determination described in (II-1), wherein the cancer patient is a patient suffering from at least one cancer selected from the group consisting of bladder cancer, prostate cancer, kidney cancer, and cervical cancer Method.
(II-3) The prognosis determination method according to (II-1), wherein the cancer patient is a bladder cancer patient.
本発明によれば、検体として尿を利用するため、被験者について、非侵襲的に癌、特に膀胱癌の罹患の有無を測定する方法、並びに癌患者、特に膀胱癌の患者について、癌治療後の再発リスクの有無、つまり膀胱癌の予後を非侵襲的に判定する方法を提供することができる。 According to the present invention, in order to use urine as a specimen, a method for non-invasively measuring the presence or absence of cancer, particularly bladder cancer, for a subject, and cancer patients, particularly bladder cancer patients, after cancer treatment It is possible to provide a method for non-invasively determining the presence or absence of recurrence risk, that is, the prognosis of bladder cancer.
本発明は、癌の診断、または癌治療後の予後の判定に機器や器具を、皮膚または身体開口部を通じて挿入する必要が無いので、従来の生検などの侵襲的な方法と比較して、被験者にとって肉体的苦痛、精神的苦痛などの負担が少ない。よって、本発明は、年齢や身体状態(疾患の程度)に関わらず、適用することができるので、臨床検査方法として好ましい。 The present invention eliminates the need to insert a device or instrument through the skin or body opening for diagnosis of cancer or determination of prognosis after cancer treatment, compared to invasive methods such as conventional biopsy, There is little burden on the subject such as physical pain and mental pain. Therefore, the present invention can be applied regardless of age or physical condition (degree of disease), and thus is preferable as a clinical examination method.
本発明は、腫瘍摘出手術前後に採取した尿を検体とすることで、残存腫瘍又はリンパ管転移など、腫瘍摘出の成功率又は術後の癌の予後(癌再発の可能性)の判定、並びに癌の再発の予防のためのモニタリングなどに広く利用することができる。 The present invention uses a sample of urine collected before and after tumor excision surgery to determine the success rate of tumor removal, such as residual tumor or lymphatic metastasis, or the prognosis of cancer after surgery (possibility of cancer recurrence), and It can be widely used for monitoring for preventing recurrence of cancer.
乖離度合解析工程では、前記揮発性組成物測定工程によって得られるクロマトグラムから被験者由来の測定値と健常者由来の基準値の乖離度合を解析する工程である。測定値および基準値は、主成分得点として示される。 The divergence degree analysis step is a step of analyzing the divergence degree between the measured value derived from the subject and the reference value derived from the healthy person from the chromatogram obtained by the volatile composition measuring step. The measured value and the reference value are shown as principal component scores.
<本発明が対象とする癌>
本発明が対象とする癌には、膀胱癌、前立腺癌、子宮頸癌、及び腎臓癌等の固形癌が含まれる。好ましくは膀胱癌である。
<Cancer targeted by the present invention>
The cancers targeted by the present invention include solid cancers such as bladder cancer, prostate cancer, cervical cancer, and kidney cancer. Bladder cancer is preferred.
<本発明が検出対象とする揮発性化合物>
本発明が検出対象とする揮発性化合物は、下記に記載の化合物である。(1)(S)-2-ヒドロキシプロパン酸((S)-2-Hydroxypropanoic acid)、
(2)ヘプチルヒドロペルオキシド(Heptyl hydroperoxide)、
(3)2, 3-ジヒドロキシプロパナール(2, 3-Dihydroxypropanal)、
(4)塩化ノナノイル(Nonanoyl chloride)、
(5)ドデカナール(Dodecanal)、
(6)(Z)-2-ノネナール((Z)-2-Nonenal)、
(7)4, 5-ジメチル-3(2H)-イソキサゾロン(4, 5-Dimethyl-3(2H)-isoxazolone)、
(8)(Z)-2-デセナール ((Z)-2-Decenal)、
(9)トリクロロ酸3 - トリデシルエステル(Trichloroacetic acid 3-tridecyl ester)、
(10)レボグルコサン(Levoglucosan)、
(11)4-(ジメチルアミノ)-3-メチル-2-ブタノン(4-(Dimethylamino)-3-methyl-2-butanone)、
(12)4-メチル-1-ブテン-1-イルペンタン酸エステル(Pentanoic acid 4-methyl-1-buten-1-yl ester)、
(13)ジエチルフタル酸(Diethyl phthalate)、
(14)1-クロロ-8-ヘプタデセン(1-Chloro-8-heptadecene)、
(15)ペンタデカン酸(Pentadecanoic acid)、
(16)1, 2-ベンゼンジカルボン酸ブチルデシルエステル(1, 2-Benzenedicarboxylic acid butyldecyl ester)。
<Volatile compounds to be detected by the present invention>
The volatile compounds to be detected by the present invention are the compounds described below. (1) (S) -2-hydroxypropanoic acid ((S) -2-Hydroxypropanoic acid),
(2) Heptyl hydroperoxide,
(3) 2,3-Dihydroxypropanal,
(4) Nonanoyl chloride,
(5) Dodecanal,
(6) (Z) -2-Nonenal ((Z) -2-Nonenal),
(7) 4,5-dimethyl-3 (2H) -isoxazolone (4,5-Dimethyl-3 (2H) -isoxazolone),
(8) (Z) -2-Decenal ((Z) -2-Decenal),
(9) Trichloroacetic acid 3-tridecyl ester,
(10) Levoglucosan,
(11) 4- (Dimethylamino) -3-methyl-2-butanone (4- (Dimethylamino) -3-methyl-2-butanone),
(12) 4-methyl-1-buten-1-ylpentanoic acid ester (Pentanoic acid 4-methyl-1-buten-1-yl ester),
(13) Diethyl phthalate,
(14) 1-Chloro-8-heptadecene,
(15) Pentadecanoic acid,
(16) 1,2-Benzenedicarboxylic acid butyldecyl ester.
本発明は、上記に記載する16種類の揮発性化合物のうち、少なくとも1つを検出対象とすることができる。具体的には、本発明では、被験試料とする尿に、上記の化合物群から選択されるいずれか少なくとも1個の化合物が含まれているか、またその含有量を測定することを特徴とする。好ましくは、上記化合物群のうち、任意に選択される少なくとも4個の化合物、更に好ましくは12個の化合物、最も好ましくは16個の全ての化合物を対象として、被験者の尿中にこれらの化合物が含まれているか、またその含有量を測定することが好ましい。 The present invention can detect at least one of the 16 types of volatile compounds described above. Specifically, the present invention is characterized in that the urine used as a test sample contains at least one compound selected from the above compound group and the content thereof is measured. Preferably, at least 4 compounds selected from the above group of compounds, more preferably 12 compounds, and most preferably all 16 compounds are targeted in the subject's urine. It is preferable to measure whether or not it is contained.
本発明は、後述するように、被験者(癌罹患者を含む)の尿中に含まれる上記の揮発性化合物を測定し、健常者の尿に含まれる対応の化合物の量と対比解析する工程を含むが、この工程を、メタボノミクス解析により行ってもよい。 As described later, the present invention includes a step of measuring the volatile compound contained in the urine of a subject (including a cancer-affected person) and comparing and analyzing the amount of the corresponding compound contained in the urine of a healthy person. This step may be performed by metabonomic analysis.
メタボノミクス解析(または「メタボロミクス解析」ともいう。以下「メタボノミクス解析」という用語を使用する)は、生命活動によって生じる特異的な内因性代謝物を網羅的に検出・解析し、生体内のメカニズムを調べる解析手法である。メタボノミクス解析は、従来から、特定の疾患や病態等と尿中代謝物との相関関係を解析するためにも使用されている。尚、メタボノミクス解析については、メタボロミクス:その解析技術と臨床・創薬応用研究の最前線(遺伝子医学MOOK16号)(メディカルドゥ社;田口良編集)にも記載されている。 Metabonomic analysis (or “metabolomics analysis”, hereinafter referred to as “metabonomics analysis”) is a comprehensive detection and analysis of specific endogenous metabolites generated by life activities, This is an analysis method to investigate. Metabonomic analysis has been conventionally used to analyze the correlation between a specific disease or disease state and urinary metabolites. Metabonomics analysis is also described in Metabolomics: its analysis technology and the forefront of clinical and drug discovery application research (gene medicine MOOK16) (Medical Do, edited by Ryo Taguchi).
以下、本発明の方法について説明する。
(I)癌罹患の測定方法
本発明の癌罹患の測定方法は、被験者の尿に含まれる特定の揮発性化合物を指標として癌罹患の有無(癌罹患の疑いの有無)を測定する方法であり、下記の工程(A)〜(C)を含む。
(A)被験者の尿に含まれる、上記揮発性化合物(1)〜(16)からなる群から選択される少なくとも1つの揮発性化合物の量を測定する工程(揮発性化合物測定工程)、
(B)上記被験者の測定値と、健常者の尿中に含まれる上記測定値に対応する揮発性化合物の量(以下、これを「基準値」という)の量を比較し、その乖離度を求める工程(乖離度測定工程)、及び
(C)上記乖離度に有意差がある場合に、被験者について癌罹患の疑いがあると判定するか、または乖離度に有意差がない場合に、被験者について癌罹患の疑いがないと判定する工程(判定工程)。
Hereinafter, the method of the present invention will be described.
(I) Method for Measuring Cancer Incidence The method for measuring cancer incidence according to the present invention is a method of measuring the presence or absence of cancer (presence of suspected cancer) using a specific volatile compound contained in the urine of a subject as an index. The following steps (A) to (C) are included.
(A) A step of measuring the amount of at least one volatile compound selected from the group consisting of the volatile compounds (1) to (16) contained in the urine of the subject (volatile compound measurement step),
(B) The measured value of the subject is compared with the amount of volatile compound corresponding to the measured value contained in the urine of a healthy person (hereinafter referred to as “reference value”), and the degree of divergence is calculated. Step of obtaining (difference degree measuring step), and (C) If there is a significant difference in the above divergence degree, it is determined that the subject is suspected of having cancer, or if there is no significant difference in the divergence degree, A step of determining that there is no suspicion of having cancer (determination step).
(A)尿中の揮発性化合物を測定する工程(揮発性化合物測定工程)
当該揮発性化合物測定工程は、尿に含まれる測定対象となる揮発性化合物を定量分析する工程である。上記の揮発性化合物(1)〜(16)のいずれか少なくとも1つ、好ましくは4つ以上、より好ましくは12つ以上分析できる方法であればよいが、好ましくはこれらの化合物が網羅的に分析できる方法が使用される。
(A) A step of measuring volatile compounds in urine (volatile compound measuring step)
The volatile compound measurement step is a step of quantitatively analyzing a volatile compound to be measured contained in urine. Any method can be used as long as it can analyze at least one of the above volatile compounds (1) to (16), preferably 4 or more, more preferably 12 or more, but preferably these compounds are comprehensively analyzed. A possible method is used.
なお、当該分析に供する試料は、予め特定量の尿からガス収集器を用いて回収した尿中の揮発性脂肪酸画分であることが好ましい。 In addition, it is preferable that the sample to be subjected to the analysis is a volatile fatty acid fraction in urine collected in advance from a specific amount of urine using a gas collector.
当該分析方法には、尿に含まれる揮発性画分、好ましくは揮発性脂肪酸画分から上記の揮発性化合物(1)〜(16)を分離する方法(分離方法)と、当該分離後に揮発性化合物(1)〜(16)の量を測定する方法(定量方法)の両方が含まれる。 The analysis method includes a method (separation method) for separating the volatile compounds (1) to (16) from a volatile fraction contained in urine, preferably a volatile fatty acid fraction, and a volatile compound after the separation. Both methods (quantitative methods) for measuring the amounts of (1) to (16) are included.
ここで分離方法としては、クロマトグラフィー法又はキャピラリ・電気泳動(CE)法を用いることができる。クロマトグラフィーとしては、揮発性成分を分析するガスクロマトグラフィー(GC)法を挙げることができる。 Here, as a separation method, a chromatography method or a capillary electrophoresis (CE) method can be used. An example of chromatography is a gas chromatography (GC) method for analyzing volatile components.
また定量方法としては、クロマトグラフィー法を用いることができる。具体的には、上記分離方法によって分離された揮発性化合物(1)〜(16)からなる群から選択される少なくとも1つの化合物の強度あるいは量を、クロマトグラフィー法を用いて測定する。尿試料に含まれる揮発性化合物のクロマトグラムを作成する工程である。特に、質量分析測定(MS)法が好ましい。 As a quantitative method, a chromatographic method can be used. Specifically, the intensity or amount of at least one compound selected from the group consisting of volatile compounds (1) to (16) separated by the separation method is measured using a chromatography method. This is a step of creating a chromatogram of volatile compounds contained in a urine sample. In particular, a mass spectrometry (MS) method is preferable.
本発明では、クロマトグラフィー法によって得られるクロマトグラムから、検出時間と検出強度との関係を表すクロマトグラムにおけるピークを選択し、選択されたピークの強度および質量に基づいて、評価対象の揮発性化合物を同定する方法が特に好ましい。 In the present invention, from the chromatogram obtained by the chromatography method, a peak in the chromatogram representing the relationship between the detection time and the detection intensity is selected, and the volatile compound to be evaluated is selected based on the intensity and mass of the selected peak. The method of identifying is particularly preferred.
この場合、連続的に低質量から高質量までのイオン強度を表す複数のピークを逐次選択していき、生データとして記憶しておいてもよい。 In this case, a plurality of peaks representing ionic strengths from low mass to high mass may be successively selected and stored as raw data.
上述の工程によって、尿に含まれる評価対象の揮発性化合物の強度あるいは量を測定することができ、2次元プロファイルを得ることができる。 Through the above-described steps, the strength or amount of the volatile compound to be evaluated contained in urine can be measured, and a two-dimensional profile can be obtained.
ここで2次元プロファイルは、評価対象となる揮発性化合物のいずれかを比較しているのではなく、揮発性化合物測定工程によって得られた評価対象の揮発性化合物の測定結果のデータセットから評価対象化合物の強度あるいは量を変数として、揮発性化合物測定を行った結果得られる2次元のマッピングである。すなわち、被験者および健常者由来の強度あるいは濃度のばらつき方を手がかりとした計算によって、それぞれが直交するように新たに引かれた軸(主成分)によって示される平面図である。 Here, the two-dimensional profile does not compare any of the volatile compounds to be evaluated, but from the data set of the measurement results of the volatile compounds to be evaluated obtained by the volatile compound measurement process. It is a two-dimensional mapping obtained as a result of measuring a volatile compound using the intensity or amount of the compound as a variable. That is, it is a plan view indicated by axes (principal components) newly drawn so as to be orthogonal to each other by calculation based on variations in intensity or concentration derived from subjects and healthy subjects.
(B)被験者の測定値と基準値との乖離度を求める工程(乖離度測定工程)
乖離度測定工程は、前記(A)の揮発性化合物測定工程によって得られる2次元プロファイルから被験者由来の測定値と健常者由来の基準値の乖離度を求める工程である。2次元プロファイルでは、被験者の尿に関するクロマトグラムにおける評価対象の揮発性化合物の強度の標準偏差の値が1になるように、又基準値の平均値が0になるように2次元的にマッピングされている。
(B) A step of obtaining the degree of divergence between the measured value and the reference value of the subject (deviation degree measuring step)
The divergence degree measuring step is a step of obtaining a divergence degree between the measured value derived from the subject and the reference value derived from the healthy person from the two-dimensional profile obtained by the volatile compound measuring step (A). The two-dimensional profile is two-dimensionally mapped so that the standard deviation value of the intensity of the volatile compound to be evaluated is 1 in the chromatogram of the subject's urine and the average value of the reference value is 0. ing.
乖離度は、被験者由来の測定値と健常者由来の基準値における有意水準(P)の値であり、算出される乖離度は、分散分析に基づき、5%以下が有意となる(95%以上の確率で健常者である範囲を超えた範囲に被験者のデータが存在する時に有意となる)。したがって、有意水準が5%未満となる場合は乖離が存在していることになる。乖離度合は、揮発性化合物測定の結果示された二次元プロファイルにおける健常者由来の基準値と被験者由来の測定値の距離に反比例する。 The degree of divergence is a value of the significance level (P) in the measured value derived from the subject and the reference value derived from the healthy person, and the calculated degree of divergence becomes significant 5% or less based on analysis of variance (95% or more This is significant when the subject's data exists in a range that exceeds the range of healthy individuals with a probability of. Therefore, a divergence exists when the significance level is less than 5%. The degree of divergence is inversely proportional to the distance between the reference value derived from a healthy person and the measured value derived from the subject in the two-dimensional profile indicated as a result of the volatile compound measurement.
つまり、下記の(C)工程において、被験者由来の測定値と健常者由来の基準値との「乖離度に有意差がある」とは、分散分析に基づいて算出される有意水準(P)が5%以下であることを意味し、「乖離度に有意差がない」とは、分散分析に基づいて算出される有意水準(P)が5%より大きいことを意味する。 That is, in the following step (C), “there is a significant difference in the degree of divergence” between the measurement value derived from the subject and the reference value derived from the healthy person means that the significance level (P) calculated based on analysis of variance is It means 5% or less, and “there is no significant difference in divergence” means that the significance level (P) calculated based on analysis of variance is greater than 5%.
(C)癌罹患の有無を判定する工程(判定工程)
当該判定工程は、上記(B)の乖離度測定工程で測定した乖離度について、有意差の有無を指標として癌罹患(の疑い)の有無を判定する工程である。
(C) A step of determining the presence or absence of cancer (determination step)
The determination step is a step of determining the presence or absence of cancer (suspicion) using the presence or absence of a significant difference as an index for the degree of deviation measured in the degree of deviation measurement step (B).
具体的には、(C)工程では、上記(B)で測定した乖離度に有意差がある場合、つまり分散分析に基づいて算出した有意水準(P)が5%以下である場合に、被験者について癌罹患の疑いがあると判定される。または、上記(B)で測定した乖離度に有意差がない場合、つまり分散分析に基づいて算出した有意水準(P)が5%より大きい場合に、被験者について癌罹患の疑いがないと判定される。 Specifically, in step (C), when there is a significant difference in the degree of divergence measured in (B) above, that is, when the significance level (P) calculated based on analysis of variance is 5% or less, Is suspected of having cancer. Alternatively, when there is no significant difference in the degree of divergence measured in (B) above, that is, when the significance level (P) calculated based on analysis of variance is greater than 5%, it is determined that the subject is not suspected of having cancer. The
以上、これら(A)〜(C)の工程を行うことにより、被験者について癌罹患の有無(癌罹患の疑いの有無)を測定することができる。本発明の方法で、癌罹患の疑いがあると診断された被験者は、さらに他の精密検査等による確定判断を受けることができる。その結果、癌の罹患が確定した場合は、癌治療を受けることになる。 As described above, by performing the steps (A) to (C), it is possible to measure the presence or absence of cancer in the subject (presence of suspected cancer). A subject who is diagnosed as suspected of having cancer by the method of the present invention can further receive a definite determination by other work-up. As a result, if cancer is confirmed, the patient will receive cancer treatment.
つまり、本発明の方法は、侵襲的な診断方法である精密検査を行う前に、予備的また網羅的に行う診断方法として有用である。
(II)癌患者の癌治療後の予後を判定する方法(予後判定方法)
本発明の予後判定方法は、癌患者の尿に含まれる特定の揮発性化合物を指標として、
癌患者について癌治療後の予後を判定する方法であり、下記の工程(a)〜(c)を含む。
That is, the method of the present invention is useful as a diagnostic method that is performed in a preliminary and exhaustive manner before conducting a detailed examination that is an invasive diagnostic method.
(II) Method for determining the prognosis of cancer patients after cancer treatment (Prognosis determination method)
The prognosis determination method of the present invention uses a specific volatile compound contained in the urine of a cancer patient as an index,
A method for determining the prognosis after cancer treatment for a cancer patient, comprising the following steps (a) to (c).
(a)癌患者の癌治療前と癌治療後の尿を被験試料として、当該尿中に含まれる前述する揮発性化合物(1)〜(16)からなる群から選択される少なくとも1つの量を測定する工程(揮発性化合物測定工程)、
(b)上記で得られる治療前の値(以下、「治療前値」という)、治療後の値(以下、「治療後値」という)、及び健常者の尿中に含まれる上記に対応する揮発性組成物の量あるいは強度(以下、「基準値」という)をそれぞれ比較し、治療前値と基準値との乖離度、及び治療後値と基準値との乖離度を求める工程(乖離度測定工程)、及び
(c)治療後値と基準値との乖離度が治療前値と基準値との乖離度よりも小さく、且つ、有意水準5%として、治療後値と基準値との乖離度に有意差がない場合に、当該癌患者は癌治療後の予後が良好と判定する工程(判定工程)。
(A) Using at least one amount selected from the group consisting of the above-mentioned volatile compounds (1) to (16) contained in urine, using urine before and after cancer treatment of a cancer patient as a test sample. Measuring process (volatile compound measuring process),
(B) Corresponding to the above-mentioned values contained in the urine of healthy subjects, the values obtained before treatment (hereinafter referred to as “pre-treatment values”), the values after treatment (hereinafter referred to as “post-treatment values”). A step of comparing the amount or intensity of the volatile composition (hereinafter referred to as “reference value”) to obtain the degree of divergence between the pre-treatment value and the reference value and the degree of divergence between the post-treatment value and the reference value (degree of divergence) Measurement step), and (c) the difference between the post-treatment value and the reference value is smaller than the pre-treatment value and the reference value, and the significance level is 5%, and the difference between the post-treatment value and the reference value If there is no significant difference in the degree, the cancer patient determines that the prognosis after cancer treatment is good (determination step).
なお、ここで「癌治療」とは、膀胱癌、前立腺癌、腎臓癌、及び子宮頸癌等の固形癌、好ましくは膀胱癌に適用される癌治療を広く意味するものであり、癌腫瘍部の切除等の外科的治療、抗がん剤の投与などの化学的療法、免疫療法、及び放射線照射療法などを例示することができる。 As used herein, the term “cancer treatment” broadly means cancer treatment applied to solid cancers such as bladder cancer, prostate cancer, kidney cancer, and cervical cancer, preferably bladder cancer, Examples include surgical treatment such as excision, chemotherapy such as administration of an anticancer agent, immunotherapy, and radiation therapy.
また、本発明において「癌治療後の予後」とは、癌治療の結果、癌疾患が回復治癒する見込み(または癌再発や転移などの癌疾患の悪化、及びそれを理由として死亡する見込み)を意味する。具体的には、「癌治療後の予後が良好」とは、癌治療の結果、5年以内に再発や転移がないか、又はその可能性が低いことを意味する。逆に「癌治療後の予後が不良」とは、癌治療の結果、5年以内に再発や転移をするか、又はその可能性が高いことを意味する。 Further, in the present invention, “prognosis after cancer treatment” refers to the possibility of recovery from cancer treatment as a result of cancer treatment (or deterioration of cancer disease such as cancer recurrence and metastasis, and death due to that). means. Specifically, “good prognosis after cancer treatment” means that as a result of cancer treatment, there is no recurrence or metastasis within 5 years, or the possibility is low. Conversely, "poor prognosis after cancer treatment" means that cancer treatment results in recurrence or metastasis within 5 years, or is highly likely.
(a)尿中の揮発性化合物を測定する工程(揮発性化合物測定工程)
当該工程は、癌患者の治療前後の尿に含まれる測定対象となる揮発性化合物を定量分析する工程である。前述する揮発性化合物(1)〜(16)のいずれか少なくとも1つ、好ましくは4つ以上、より好ましくは12つ以上分析できる方法であればよいが、好ましくはこれらの化合物が網羅的に分析できる方法が使用される。当該分析に供する試料は、予め特定量の尿からガス収集器を用いて回収した尿中の揮発性脂肪酸画分であることが好ましい。
(A) Step of measuring volatile compounds in urine (volatile compound measuring step)
This step is a step of quantitatively analyzing a volatile compound to be measured contained in urine before and after treatment of a cancer patient. Any method can be used as long as it can analyze at least one of the volatile compounds (1) to (16) described above, preferably 4 or more, and more preferably 12 or more. Preferably, these compounds are comprehensively analyzed. A possible method is used. It is preferable that the sample to be subjected to the analysis is a volatile fatty acid fraction in urine collected in advance using a gas collector from a specific amount of urine.
本工程は、被験試料として、癌患者の癌治療前の尿と癌治療後の尿を使用する以外、「(I)癌罹患の測定方法」における「(A)工程」と同様の方法を使用することができる。 This step uses the same method as “Step (A)” in “(I) Method for measuring cancer incidence”, except that urine before cancer treatment and urine after cancer treatment are used as test samples. can do.
(b)治療前値と基準値との乖離度、及び治療後値と基準値との乖離度を求める工程(乖離度測定工程)
乖離度測定工程は、前記(a)の揮発性化合物測定工程によって得られる2次元プロファイルから癌患者の癌治療前の測定値(治療前値)と健常者由来の基準値の乖離度、及び癌患者の癌治療後の測定値(治療後値)と健常者由来の基準値の乖離度を求める工程である。
(B) Step of obtaining the degree of deviation between the pre-treatment value and the reference value and the degree of deviation between the post-treatment value and the reference value (deviation degree measuring step)
The divergence degree measurement step includes a divergence degree between a measured value before cancer treatment (pretreatment value) of a cancer patient and a reference value derived from a healthy person, and a cancer from the two-dimensional profile obtained by the volatile compound measurement step (a) This is a step of obtaining a degree of divergence between a measured value after cancer treatment (post-treatment value) of a patient and a reference value derived from a healthy person.
なお、ここで治療前値と基準値との乖離度、及び治療後値と基準値との乖離度との間に差異があり、治療後値と基準値との乖離度が治療前値と基準値との乖離度よりも小さい場合に、癌治療効果があると判断することができる。 Here, there is a difference between the divergence between the pre-treatment value and the reference value, and the divergence between the post-treatment value and the reference value, and the divergence between the post-treatment value and the reference value is the pre-treatment value and the reference value. When the degree of deviation from the value is smaller, it can be determined that there is a cancer therapeutic effect.
この場合、後述するように、治療後値と基準値との乖離度に有意差があるか否かで癌治療後の予後を判断することができる。 In this case, as will be described later, the prognosis after cancer treatment can be determined based on whether or not there is a significant difference in the difference between the post-treatment value and the reference value.
治療後値と基準値との乖離度は、治療後値と基準値における有意水準(P)の値であり、算出される乖離度は、分散分析に基づき、5%以下が有意となる(95%以上の確率で健常者である範囲を超えた範囲に癌患者のデータが存在する時に有意となる)。したがって、有意水準が5%未満となる場合は乖離が存在していることになる。乖離度合は、揮発性化合物測定の結果示された二次元プロファイルにおける健常者由来の基準値と癌治療後の癌患者由来の測定値の距離に反比例する。 The degree of divergence between the post-treatment value and the reference value is a value of the significance level (P) between the post-treatment value and the reference value, and the calculated degree of divergence becomes significant at 5% or less based on analysis of variance (95 % Is significant when cancer patient data exists outside the range of healthy individuals with a probability of% or more). Therefore, a divergence exists when the significance level is less than 5%. The degree of divergence is inversely proportional to the distance between a reference value derived from a healthy person and a measured value derived from a cancer patient after cancer treatment in a two-dimensional profile indicated as a result of volatile compound measurement.
つまり、下記の(c)工程において、被験者由来の測定と健常者由来の基準値との「乖離度に有意差がある」とは、分散分析に基づいて算出される有意水準(P)が5%以下であることを意味し、また「乖離度に有意差がない」とは、分散分析に基づいて算出される有意水準(P)が5%より大きいことを意味する。 That is, in the following step (c), “there is a significant difference in the degree of divergence” between the measurement derived from the subject and the reference value derived from the healthy person means that the significance level (P) calculated based on the analysis of variance is 5 % Means that the significance level (P) calculated based on analysis of variance is greater than 5%.
(c)癌治療後の予後を判定する工程(判定工程)
当該判定工程は、上記(b)の乖離度測定工程で測定した乖離度のうち、特に治療後値と基準値との乖離度に有意差が有るか無いかを指標として、癌治療後の予後を判定する工程であり、下記の基準に基づいて、癌治療後の予後が良好であると判断することができる。
(i)治療後値と基準値との乖離度が治療前値と基準値との乖離度よりも小さいこと、
(ii)治療後値と基準値との乖離度に有意差がないこと。
(C) A step of determining the prognosis after cancer treatment (determination step)
The determination step includes, as an index, whether or not there is a significant difference in the divergence degree between the post-treatment value and the reference value among the divergence degrees measured in the divergence degree measurement step (b) above, and the prognosis after cancer treatment It can be determined that the prognosis after cancer treatment is good based on the following criteria.
(I) The degree of deviation between the post-treatment value and the reference value is smaller than the degree of deviation between the pre-treatment value and the reference value,
(Ii) There is no significant difference in the difference between the post-treatment value and the reference value.
(ii)は、治療後値が基準値を母集団とする95%信頼区間に当てはまる場合であり、分散分析に基づいて算出した有意水準(P)が5%より大きいことを意味する。 (Ii) is a case where the post-treatment value falls within the 95% confidence interval with the reference value as the population, and means that the significance level (P) calculated based on analysis of variance is greater than 5%.
癌治療を受けた癌患者がかかる(i)と(ii)の要件を充足する場合に、当該癌患者は、癌治療後の予後が良好であると判断することができる。(i)と(ii)の要件を充足しない場合は、予後不良または追加の治療が必要であると判断することが出来る。 When a cancer patient who has undergone cancer treatment satisfies the requirements (i) and (ii), the cancer patient can determine that the prognosis after cancer treatment is good. If the requirements of (i) and (ii) are not met, it can be determined that the prognosis is poor or additional treatment is required.
以上、これら(a)〜(c)の工程を行うことにより、癌治療を受けた癌患者について、癌治療後の予後(予後が良好か否か)を判定することができる。 As described above, by performing these steps (a) to (c), the prognosis after cancer treatment (whether the prognosis is good) can be determined for cancer patients who have undergone cancer treatment.
本発明の方法で、予後良好と判定されなかった癌患者は、さらに精密検査を受けて癌の転移が発見された場合は適切な処置を受けるか、または定期的に癌検診を受けることで早期に再発を発見することに努めることができる。 Cancer patients who have not been judged to have a good prognosis by the method of the present invention can receive early treatment by receiving appropriate treatment if cancer metastasis is found through further workup or regular cancer screening. You can try to find a recurrence.
つまり、本発明の方法は、癌治療後の予後を判定することで、癌治療後の患者に自分の疾患に対して正しい認識を持ってもらうことで、その後の治療計画、定期的健診を含む生活習慣、並びに人生設計をたてるうえで有用である。 In other words, the method of the present invention determines the prognosis after cancer treatment, and allows the patient after cancer treatment to have correct recognition of his / her disease, so that subsequent treatment plans and periodic medical examinations can be conducted. It is useful for life style including life planning.
以下、本発明を更に詳しく説明するため実施例及び比較例を挙げる。しかし、本発明はこれら実施例等になんら限定されるものではない。尚、下記の実験は、高知大学医学部倫理委委員会の承認を得て行った。 Examples and comparative examples will be given below to explain the present invention in more detail. However, the present invention is not limited to these examples. The following experiment was conducted with the approval of the Kochi University School of Medicine Ethics Committee.
実施例1
(1)膀胱癌の判定方法
膀胱の全摘出の手術を受ける膀胱癌の患者3名(癌患者1〜3)及び健常者を被験者とした。各被験者の年齢、性別、膀胱癌のステージ、及び膀胱癌以外に併発している癌の有無を表1に示す。膀胱癌のステージは、多くの固形癌において癌の進展の程度を示す方法をとして採用されているTNM分類方法に従って分類した。
Example 1
(1) Determination method of bladder cancer Three bladder cancer patients (cancer patients 1 to 3) undergoing surgery for total removal of the bladder and healthy subjects were subjects. Table 1 shows the age, sex, bladder cancer stage of each subject, and the presence or absence of cancers other than bladder cancer. The stage of bladder cancer was classified according to the TNM classification method adopted as a method showing the degree of cancer progression in many solid cancers.
Tは癌の広がりの程度を示し、Nはリンパ節への転移の有無及びその程度を示し、Mは遠隔組織への転移の有無及びその程度を示す。各値が大きいほど重度のステージであることを示す。 T indicates the extent of cancer spread, N indicates the presence / absence of metastasis to lymph nodes, and M indicates the presence / absence of metastasis to distant tissue. A larger value indicates a more severe stage.
癌患者1〜3について、膀胱の腫瘍部の摘出手術前と手術後の尿を被験試料としてメタボノミクス解析を行った。 For cancer patients 1 to 3, metabonomic analysis was performed using urine before and after surgery for removing the tumor part of the bladder as a test sample.
術前及び術後に自己採尿により早朝の尿を20ml採取した。術後の尿は、肉眼で血尿が認められなくなった後に採取を行った。採取した尿20mlのガス成分の中から、北川式ガス収集器を用いて、脂肪酸画分を回収し、回収した脂肪酸画分のガス(揮発成分)を濃縮した。次いで、濃縮されたガスをガスクロマトグラフ質量分析計(GC/MS)に供した。 20 ml of early morning urine was collected by self-collection before and after surgery. Postoperative urine was collected after no hematuria was observed with the naked eye. The fatty acid fraction was collected from the collected gas component of 20 ml of urine using a Kitagawa gas collector, and the collected fatty acid fraction gas (volatile component) was concentrated. The concentrated gas was then subjected to a gas chromatograph mass spectrometer (GC / MS).
また、対照コントロールとして、7人の健常者から自己採尿により早朝の尿200mlを得て、上記と同様に、それから回収した脂肪酸画分のガス(揮発性成分)をガスクロマトグラフ質量分析計(GC/MS)に供した。 In addition, as a control, 200 ml of early morning urine was obtained from 7 healthy individuals by self-collection, and the gas (volatile component) collected from the fatty acid fraction was collected from a gas chromatograph mass spectrometer (GC / GC) as described above. MS).
具体的には、各尿から採取した脂肪酸画分のガスサンプルを、溶融石英ガラスのキャピラリーカラム(DB-1 Column 60 m x 0.32 mm; film thickness 0.1 μm)を用いて、サンプルの流速を1として移動層(ここではヘリウムガス)の流速を15に設定したスプリッド注入式のGC/MS(Model QP5050A, GC/MS 島津製作所)に供した。オーブンの温度は、試料注入の当初は40℃に設定し、注入2分後から280℃まで毎分8℃ずつ上昇するようにし、280℃に達した後、その温度条件を33分間維持した。他のパラメータは、次の通りである。
Electron energy:70EV、
Ion Source Temperature: 250℃、
Injector Temperature:250℃、
Carrier Gas:ヘリウム、
Column Flow Rate:2.4ml/min、
Dwell Time:100ms。
Specifically, a gas sample of the fatty acid fraction collected from each urine was transferred to a moving bed using a fused silica glass capillary column (DB-1 Column 60 mx 0.32 mm; film thickness 0.1 μm) with a sample flow rate of 1. The sample was supplied to a split injection type GC / MS (Model QP5050A, GC / MS Shimadzu Corporation) in which the flow rate of helium gas (here, helium gas) was set to 15. The temperature of the oven was set to 40 ° C. at the beginning of the sample injection, and increased by 8 ° C. per minute from 2 minutes after injection to 280 ° C. After reaching 280 ° C., the temperature condition was maintained for 33 minutes. Other parameters are as follows.
Electron energy: 70EV,
Ion Source Temperature: 250 ° C
Injector Temperature: 250 ° C
Carrier Gas: Helium
Column Flow Rate: 2.4 ml / min,
Dwell Time: 100 ms.
全ての測定結果をフルスキャンモード(40-500m/z)で記録した。 All measurement results were recorded in full scan mode (40-500 m / z).
結果を図1に示す。図1は、3名の癌患者の手術前後の尿由来のサンプル及び7名の健常者の尿由来のサンプルのGC/MS TIC クロマトグラムを表している。最初の保持時間10分まではいずれのサンプルもピークが観察されなかったので、保持時間が10分から38分についてのみ示した。 The results are shown in FIG. FIG. 1 shows GC / MS TIC chromatograms of urine-derived samples before and after surgery for 3 cancer patients and urine samples of 7 healthy subjects. Since no peak was observed in any of the samples until the first retention time of 10 minutes, only retention times of 10 to 38 minutes are shown.
図1において、3名の癌患者について特異的に観察されたピークは、癌患者の尿中に特有に存在する揮発性物質を示す化学指紋である。そこで癌患者のサンプルで特異的に観察されたピークの物質を、NISTデータベースとの照合することで同定した。その結果、これらは下記に挙げる化合物であることがわかった(表2)。 In FIG. 1, the peaks specifically observed for the three cancer patients are chemical fingerprints indicating volatile substances that are uniquely present in the urine of the cancer patients. Therefore, we identified the peak substances specifically observed in cancer patient samples by collating them with the NIST database. As a result, it was found that these are the compounds listed below (Table 2).
次に、GC/MSによる分析データを、MATLABを用いて処理した。尚、MOTLABについては、MATLAB 数値解析(オーム社;G. J. Borse著)に記載されている。処理されたデータを、アルゴリズム主成分分析法(PCA)によって解析した。尚、アルゴリズム主成分分析法(PCA)については、丘本正(1991):多変量解析の諸方法のモデル再現性に関する数値実験(行動計量学、Vol.18、No.2、P.47-56)に記載されている。解析は、二次元のマッピング法の二次元スコアプロットを用い、多変量空間におけるサンプル分布を平均化することによって行った。斯くして、癌患者の術前と術後の尿及び健常者の尿に含まれている上記揮発性物質に関してプロファイルを得た。結果を図2に示す。 Next, the analysis data by GC / MS was processed using MATLAB. MOTLAB is described in MATLAB numerical analysis (Ohm Co .; G. J. Borse). The processed data was analyzed by Algorithm Principal Component Analysis (PCA). For algorithm principal component analysis (PCA), Masaru Okamoto (1991): Numerical experiments on model reproducibility of various methods of multivariate analysis (Behaviometrics, Vol.18, No.2, P.47-56) It is described in. The analysis was performed by averaging the sample distribution in the multivariate space using a two-dimensional score plot of a two-dimensional mapping method. Thus, a profile was obtained regarding the volatile substances contained in urine before and after surgery of cancer patients and in urine of healthy subjects. The results are shown in FIG.
(2)判定結果
図2に示すように、全ての膀胱癌患者(3名)の尿に含まれる特定揮発性物質のプロファイルは、健常者の尿に含まれる特定揮発性物質のプロファイルと明らかな乖離が存在した。
(2) Determination Results As shown in FIG. 2, the profiles of specific volatile substances contained in the urine of all bladder cancer patients (3 patients) are clearly the profiles of specific volatile substances contained in the urine of healthy individuals There was a divergence.
前述するように、癌患者1は、術前、前立腺まで癌が浸潤しており、癌ステージは、「T4aN0M0, ly0, v0」であった。癌患者1の術後の測定値は、術前の測定値から有意に変化したが、それでも健常者由来の測定値(これを「基準値」とする)から、明らかな乖離が存在することが認められた(P=0.00079)。 As described above, cancer patient 1 had cancer infiltrated to the prostate before surgery and the cancer stage was “T4aN0M0, ly0, v0”. Although the post-operative measurement values of cancer patient 1 changed significantly from the pre-operative measurement values, there may still be a clear divergence from the measurement values derived from healthy subjects (this is referred to as “reference value”). Admitted (P = 0.00079).
また、癌患者2は、術前、肉眼で膀胱周囲組織に浸潤が確認され、更に、リンパ節転移、リンパ管浸潤、及び血管浸潤が見受けられ、その癌ステージは、「T3bN2M0, ly1, v1」であった。癌患者2の術前の測定値と術後の測定値について、健常者由来の基準値との乖離度を比較したところ、術後の測定値の方が術前の測定値よりも乖離度が顕著に小さくなった。しかし、依然として健常者の基準値よりも乖離が認められた(P=0.0035)。この結果から、癌患者2の場合、重度のステージであった癌は殆ど切除されたが、未だ他に癌が残っている可能性があると判定することができる。
In addition, before surgery,
癌患者3は、術前、筋層まで至らない表在性の癌が広範囲にあり、リンパ管浸潤が見られ、その癌ステージは、「T1N0M0, ly1, v0」であった。癌患者3のプロファイルによると、術後の測定値の方が術前の測定値よりも、若干であるものの健常者の基準値との乖離度が小さくなった。しかし、依然として健常者の基準値よりも乖離が認められた(P=0.04)。この結果から、癌患者3では、軽度のステージである膀胱癌を切除したが、他の癌が残っている可能性があると判定することができる。 Cancer patient 3 had a wide range of superficial cancers that did not reach the muscle layer before surgery, lymphatic invasion was observed, and the cancer stage was “T1N0M0, ly1, v0”. According to the profile of the cancer patient 3, the measured value after the operation is slightly smaller than the measured value before the operation, but the degree of deviation from the reference value of the healthy person is small. However, there was still a discrepancy from the standard value for healthy subjects (P = 0.04). From this result, in cancer patient 3, it was determined that bladder cancer, which is a mild stage, was excised, but other cancers may remain.
以上の結果、術前の測定値(治療前値)と健常者由来の基準値との乖離度と、術後の測定値(治療後値)と健常者由来の基準値との乖離度とには、顕著または有意に差が見られ、術後のほうが術前に比べて、基準値との乖離度が明らかに減少することが確認された。このことは、膀胱の腫瘍部が手術により切除されたことによるものである。しかしながら、癌患者1〜3の術後の測定値と健常者由来の基準値との間には依然として乖離度が存在し、P値が0.05より高くなることはなかった。これは、膀胱癌の患者がいずれも多臓器への浸潤または泌尿器癌を併発していたことが影響したものである。仮に、他に併発する癌疾病が存在せず、膀胱癌のみであれば、完全にそれを切除することにより、治療後値と健常者由来の基準値との間に乖離度(有意差)がなくなる、即ち、P値が0.05以上になると考えられる。また、この場合は、治療後に癌が再発するリスクは低く、癌治療後の予後は良好であると判断される。 As a result of the above, the degree of divergence between the pre-operative measurement value (pre-treatment value) and the reference value derived from the healthy person, and the divergence degree between the post-operation measurement value (post-treatment value) and the reference value derived from the healthy person Was significantly or significantly different, and it was confirmed that the degree of deviation from the reference value was clearly reduced after surgery compared to before surgery. This is because the tumor part of the bladder was removed by surgery. However, the degree of divergence still exists between the post-operative measurement values of cancer patients 1 to 3 and the reference values derived from healthy subjects, and the P value never became higher than 0.05. This was due to the fact that all patients with bladder cancer had multiple organ invasion or urinary cancer. If there is no other concurrent cancer disease and it is only bladder cancer, the degree of divergence (significant difference) between the post-treatment value and the reference value derived from a healthy person can be obtained by completely removing it. It is considered that the P value is 0.05 or more. In this case, the risk of cancer recurrence after treatment is low, and the prognosis after cancer treatment is judged to be good.
Claims (4)
(A)被験者の尿中に含まれる下記の揮発性化合物の量を測定する工程、
(1)(S)-2-ヒドロキシプロパン酸((S)-2-Hydroxypropanoic acid)、
(2)ヘプチルヒドロペルオキシド(Heptyl hydroperoxide)、
(3)2, 3-ジヒドロキシプロパナール(2, 3-Dihydroxypropanal)、
(4)塩化ノナノイル(Nonanoyl chloride)、
(5)ドデカナール(Dodecanal)、
(6)(Z)-2-ノネナール((Z)-2-Nonenal)、
(7)4, 5-ジメチル-3(2H)-イソキサゾロン(4, 5-Dimethyl-3(2H)-isoxazolone)、
(8)(Z)-2-デセナール ((Z)-2-Decenal)、
(9)トリクロロ酸3 - トリデシルエステル(Trichloroacetic acid 3-tridecyl ester)、
(10)レボグルコサン(Levoglucosan)、
(11)4-(ジメチルアミノ)-3-メチル-2-ブタノン(4-(Dimethylamino)-3-methyl-2-butanone)、
(12)4-メチル-1-ブテン-1-イルペンタン酸エステル(Pentanoic acid 4-methyl-1-buten-1-yl ester)、
(13)ジエチルフタル酸(Diethyl phthalate)、
(14)1-クロロ-8-ヘプタデセン(1-Chloro-8-heptadecene)、
(15)ペンタデカン酸(Pentadecanoic acid)、
(16)1, 2-ベンゼンジカルボン酸ブチルデシルエステル(1, 2-Benzenedicarboxylic acid butyldecyl ester)、
(B)上記測定値と、健常者の尿中に含まれる上記に対応する揮発性組成物の基準値とを比較し、その乖離度を求める工程、および
(C)有意水準5%として、上記乖離度に有意差がある場合に、被験者について癌罹患の疑いがあると判定するか、または上記乖離度に有意差がない場合に、被験者について癌罹患の疑いがないと判定する工程。 A method for measuring cancer incidence in a subject having the following steps:
(A) a step of measuring the amount of the following volatile compound contained in the urine of the subject,
(1) (S) -2-hydroxypropanoic acid ((S) -2-Hydroxypropanoic acid),
(2) Heptyl hydroperoxide,
(3) 2,3-Dihydroxypropanal,
(4) Nonanoyl chloride,
(5) Dodecanal,
(6) (Z) -2-Nonenal ((Z) -2-Nonenal),
(7) 4,5-dimethyl-3 (2H) -isoxazolone (4,5-Dimethyl-3 (2H) -isoxazolone),
(8) (Z) -2-Decenal ((Z) -2-Decenal),
(9) Trichloroacetic acid 3-tridecyl ester,
(10) Levoglucosan,
(11) 4- (Dimethylamino) -3-methyl-2-butanone (4- (Dimethylamino) -3-methyl-2-butanone),
(12) 4-methyl-1-buten-1-ylpentanoic acid ester (Pentanoic acid 4-methyl-1-buten-1-yl ester),
(13) Diethyl phthalate,
(14) 1-Chloro-8-heptadecene,
(15) Pentadecanoic acid,
(16) 1,2-Benzenedicarboxylic acid butyldecyl ester,
(B) and the measured value is compared with standard values of the volatile composition corresponding to the contained in the urine of a healthy person, step obtains the deviation degree, and (C) as a significance level of 5% A step of determining that the subject is suspected of having cancer when the degree of divergence is significant, or determining that the subject is not suspected of having cancer when the degree of divergence is not significant.
(a)癌患者の癌治療前と癌治療後の尿を被験試料として、当該尿中に含まれる下記の揮発性化合物の量を測定する工程、
(1)(S)-2-ヒドロキシプロパン酸((S)-2-Hydroxypropanoic acid)、
(2)ヘプチルヒドロペルオキシド(Heptyl hydroperoxide)、
(3)2, 3-ジヒドロキシプロパナール(2, 3-Dihydroxypropanal)、
(4)塩化ノナノイル(Nonanoyl chloride)、
(5)ドデカナール(Dodecanal)、
(6)(Z)-2-ノネナール((Z)-2-Nonenal)、
(7)4, 5-ジメチル-3(2H)-イソキサゾロン(4, 5-Dimethyl-3(2H)-isoxazolone)、
(8)(Z)-2-デセナール ((Z)-2-Decenal)、
(9)トリクロロ酸3 - トリデシルエステル(Trichloroacetic acid 3-tridecyl ester)、
(10)レボグルコサン(Levoglucosan)、
(11)4-(ジメチルアミノ)-3-メチル-2-ブタノン(4-(Dimethylamino)-3-methyl-2-butanone)、
(12)4-メチル-1-ブテン-1-イルペンタン酸エステル(Pentanoic acid 4-methyl-1-buten-1-yl ester)、
(13)ジエチルフタル酸(Diethyl phthalate)、
(14)1-クロロ-8-ヘプタデセン(1-Chloro-8-heptadecene)、
(15)ペンタデカン酸(Pentadecanoic acid)、
(16)1, 2-ベンゼンジカルボン酸ブチルデシルエステル(1, 2-Benzenedicarboxylic acid butyldecyl ester)、
(b)上記で得られる治療前値、治療後値、及び健常者の尿中に含まれる上記に対応する揮発性組成物の基準値をそれぞれ比較し、治療前値と基準値との乖離度、及び治療後値と基準値との乖離度を求める工程、
(c)治療後値と基準値との乖離度が治療前値と基準値との乖離度よりも小さく、且つ、有意水準5%として、治療後値と基準値との乖離度に有意差がない場合に、当該癌患者は癌治療後の予後が良好と判定する工程。 A method for determining a prognosis after cancer treatment for a cancer patient having the following steps:
(A) measuring the amount of the following volatile compound contained in the urine, using urine before and after cancer treatment of a cancer patient as a test sample;
(1) (S) -2-hydroxypropanoic acid ((S) -2-Hydroxypropanoic acid),
(2) Heptyl hydroperoxide,
(3) 2,3-Dihydroxypropanal,
(4) Nonanoyl chloride,
(5) Dodecanal,
(6) (Z) -2-Nonenal ((Z) -2-Nonenal),
(7) 4,5-dimethyl-3 (2H) -isoxazolone (4,5-Dimethyl-3 (2H) -isoxazolone),
(8) (Z) -2-Decenal ((Z) -2-Decenal),
(9) Trichloroacetic acid 3-tridecyl ester,
(10) Levoglucosan,
(11) 4- (Dimethylamino) -3-methyl-2-butanone (4- (Dimethylamino) -3-methyl-2-butanone),
(12) 4-methyl-1-buten-1-ylpentanoic acid ester (Pentanoic acid 4-methyl-1-buten-1-yl ester),
(13) Diethyl phthalate,
(14) 1-Chloro-8-heptadecene,
(15) Pentadecanoic acid,
(16) 1,2-Benzenedicarboxylic acid butyldecyl ester,
(B) the obtained Ru Osamu療前value, the post-treatment values, and standard values of the volatile composition corresponding to the contained in the urine of healthy subjects compared respectively with pre-treatment value and the reference value A step of obtaining the degree of divergence and the degree of divergence between the post-treatment value and the reference value,
(C) The difference between the post-treatment value and the reference value is smaller than the difference between the pre-treatment value and the reference value, and the significance level is 5%. If not, the step of determining that the cancer patient has a good prognosis after cancer treatment.
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