JP6256986B2 - Evaluation method of esophageal cancer - Google Patents
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- JP6256986B2 JP6256986B2 JP2014068064A JP2014068064A JP6256986B2 JP 6256986 B2 JP6256986 B2 JP 6256986B2 JP 2014068064 A JP2014068064 A JP 2014068064A JP 2014068064 A JP2014068064 A JP 2014068064A JP 6256986 B2 JP6256986 B2 JP 6256986B2
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- 208000000461 Esophageal Neoplasms Diseases 0.000 title claims description 32
- 206010030155 Oesophageal carcinoma Diseases 0.000 title claims description 32
- 201000004101 esophageal cancer Diseases 0.000 title claims description 32
- 238000011156 evaluation Methods 0.000 title 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 42
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 38
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 10
- 208000036765 Squamous cell carcinoma of the esophagus Diseases 0.000 claims description 7
- 208000007276 esophageal squamous cell carcinoma Diseases 0.000 claims description 7
- 206010061534 Oesophageal squamous cell carcinoma Diseases 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 39
- 239000000835 fiber Substances 0.000 description 12
- 238000002470 solid-phase micro-extraction Methods 0.000 description 12
- 238000004817 gas chromatography Methods 0.000 description 8
- 239000012855 volatile organic compound Substances 0.000 description 6
- 201000011510 cancer Diseases 0.000 description 5
- 238000005070 sampling Methods 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 4
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- 238000001514 detection method Methods 0.000 description 3
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- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
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- 208000020816 lung neoplasm Diseases 0.000 description 2
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- CXQXSVUQTKDNFP-UHFFFAOYSA-N octamethyltrisiloxane Chemical compound C[Si](C)(C)O[Si](C)(C)O[Si](C)(C)C CXQXSVUQTKDNFP-UHFFFAOYSA-N 0.000 description 2
- 238000004987 plasma desorption mass spectroscopy Methods 0.000 description 2
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 2
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- 241000282472 Canis lupus familiaris Species 0.000 description 1
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
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- 239000002156 adsorbate Substances 0.000 description 1
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- 238000001839 endoscopy Methods 0.000 description 1
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- 238000000605 extraction Methods 0.000 description 1
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- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
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- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000002414 normal-phase solid-phase extraction Methods 0.000 description 1
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Description
本発明は、食道癌の判定方法及び食道癌診断装置に関する。 The present invention relates to an esophageal cancer determination method and an esophageal cancer diagnostic apparatus.
食道癌は無症候性に進行するため、診断時には進行癌で発見される症例が多い。他の消化器癌と比較し進行が早く予後不良であるため早期発見が重要である。従来の食道癌の診断は主に、上部消化管造影検査および上部消化管内視鏡検査が用いられるが、食道癌の早期発見は未だ困難である。血液検査において腫瘍マーカーも測定されるが、感度・特異度ともに低く、必ずしも食道癌の早期診断に有用とは言えないのが現状である。 Since esophageal cancer progresses asymptomatically, there are many cases of advanced cancer detected at the time of diagnosis. Early detection is important because it progresses faster and has a poorer prognosis than other gastrointestinal cancers. Conventional diagnosis of esophageal cancer mainly uses upper gastrointestinal angiography and upper gastrointestinal endoscopy, but early detection of esophageal cancer is still difficult. Tumor markers are also measured in blood tests, but both sensitivity and specificity are low, and it is not always useful for early diagnosis of esophageal cancer.
近年動物などを使った臭気物質の測定の様々な研究が行われており（非特許文献１）、また一部の感染症や悪性腫瘍の存在は患者の代謝化合物の変化によって同定されている。癌の臭気物質である揮発性有機化合物（ＶＯＣ）を感知する機器の開発も行われている（非特許文献２、３）。 ＭｃＣｕｌｌｏｃｈらは犬による実験で肺癌、乳癌患者の呼気の識別が高い確率で行われたと報告している（非特許文献４）。さらにガスクロマトグラフィーを用いた呼気測定でいくつかの肺癌、乳癌に特異的な揮発性有機化合物が同定されている（非特許文献５〜７）。食道扁平上皮癌に関しては、アルコールを摂取した後、呼気中のアセトアルデヒド濃度の経時変化を測定することによる簡易判定方法（特許文献１、２）が報告されている。 In recent years, various studies on the measurement of odorous substances using animals and the like have been conducted (Non-patent Document 1), and the presence of some infectious diseases and malignant tumors has been identified by changes in metabolic compounds of patients. Devices that sense volatile organic compounds (VOC), which are cancer odor substances, have also been developed (Non-Patent Documents 2 and 3). McCulloch et al. Reported that lung cancer and breast cancer patients were identified with high probability in experiments with dogs (Non-patent Document 4). Furthermore, several breathable organic compounds specific to lung cancer and breast cancer have been identified by breath measurement using gas chromatography (Non-Patent Documents 5 to 7). With regard to esophageal squamous cell carcinoma, a simple determination method (Patent Documents 1 and 2) by measuring the time-dependent change of acetaldehyde concentration in exhaled breath after alcohol is reported.
本発明の課題は、食道癌を早期発見するための非侵襲的で感度、特異度の高い早期診断法を提供することにある。 An object of the present invention is to provide a noninvasive, sensitive and highly specific early diagnosis method for early detection of esophageal cancer.
そこで本発明者は、食道癌患者と健常者の呼気中の揮発性成分を測定し、患者群と健常者群とを対比したところ、アセトニトリル、酢酸、アセトン及び２−ブタノンの濃度が食道癌患者群で有意に高く、当該成分が食道癌の非侵襲的な早期診断マーカーとして有用であることを見出し、本発明を完成した。 Therefore, the present inventor measured the volatile components in the breath of esophageal cancer patients and healthy subjects, and compared the patient groups with the healthy subject groups. It was significantly higher in the group, and it was found that this component was useful as a noninvasive early diagnostic marker for esophageal cancer, and the present invention was completed.
すなわち、本発明は、次の〔１〕〜〔４〕を提供するものである。 That is, the present invention provides the following [1] to [4].
〔１〕呼気中のアセトニトリル、酢酸、アセトン及び２−ブタノンから選ばれる成分の濃度を測定することを特徴とする食道癌の判定方法。
〔２〕食道癌が、食道扁平上皮癌である〔１〕記載の判定方法。
〔３〕呼気中のアセトニトリル、酢酸、アセトン及び２−ブタノンから選ばれる成分の濃度の測定装置からなる食道癌診断装置。
〔４〕固相マイクロ抽出ファイバー及びガスクロマトグラフィーを有する〔３〕記載の食道癌診断装置。
[1] A method for determining esophageal cancer, comprising measuring the concentration of a component selected from acetonitrile, acetic acid, acetone and 2-butanone in exhaled breath.
[2] The determination method according to [1], wherein the esophageal cancer is squamous cell carcinoma of the esophagus.
[3] An esophageal cancer diagnostic device comprising a device for measuring the concentration of a component selected from acetonitrile, acetic acid, acetone and 2-butanone in exhaled breath.
[4] The esophageal cancer diagnostic apparatus according to [3], comprising a solid-phase microextraction fiber and gas chromatography.
本発明の判定方法によれば、対象者の呼気を採取するだけで非侵襲的、かつ早期に食道癌の診断が可能となる。 According to the determination method of the present invention, esophageal cancer can be diagnosed non-invasively and early by simply collecting the breath of the subject.
本発明の食道癌の判定方法は、呼気中のアセトニトリル、酢酸、アセトン及び２−ブタノンから選ばれる成分の濃度を測定することを特徴とする。すなわち、本発明は、食道癌を診断する目的で、呼気中のアセトニトリル、酢酸、アセトン及び２−ブタノンから選ばれる成分の濃度を測定する方法でもある。 The esophageal cancer determination method of the present invention is characterized by measuring the concentration of a component selected from acetonitrile, acetic acid, acetone and 2-butanone in exhaled breath. That is, the present invention is also a method for measuring the concentration of a component selected from acetonitrile, acetic acid, acetone and 2-butanone in exhaled breath for the purpose of diagnosing esophageal cancer.
対象者は、食道癌が疑われる患者であるが、前述のように食道癌は早期の段階ではほとんど無症状であるため、食道癌が疑われる患者に限らず、健康診断者も対象とするのが望ましい。対象者は、食道扁平上皮癌が疑われる患者がより好ましい。 The subject is a patient suspected of esophageal cancer, but as mentioned above, esophageal cancer is almost asymptomatic at an early stage, so not only patients with suspected esophageal cancer but also health checkers Is desirable. The subject is more preferably a patient suspected of having esophageal squamous cell carcinoma.
呼気の収集は、対象者に５００mL〜１Ｌのサンプリングバッグ等の容器に呼気を排出してもらえばよい。 The collection of exhalation may be performed by having the subject discharge the exhalation into a container such as a 500 mL to 1 L sampling bag.
呼気中のアセトニトリル、酢酸、アセトン及び２−ブタノンから選ばれる成分の濃度の測定は、これらの成分を測定可能な手段であれば特に限定されないが、ガスクロマトグラフィーによるのが簡便かつ正確である。ガスクロマトグラフィーとしては、前記成分を定量する点から、ガスクロマトグラフィー質量分析法（ＧＳ／ＭＳ）を採用するのが好ましい。
また、呼気中の前記成分を抽出するため、固相マイクロ抽出ファイバー（ＳＰＭＥファイバー）を用いて、呼気中の成分を一晩吸着して、ガスクロマトグラフィーに供するのが好ましい。ＳＰＭＥファイバーとしては、シグマアルドリッチ社等から販売されているもの（例えば、商品名：ｃａｍｂｏｘｅｎ／ＰＤＭＳ）を使用できる。
従って、呼気中の前記４成分濃度の測定装置、例えば固相マイクロ抽出ファイバー及びガスクロマトグラフィーの組み合わせは、食道癌診断装置として有用である。
The concentration of components selected from acetonitrile, acetic acid, acetone, and 2-butanone in exhaled breath is not particularly limited as long as it is a means capable of measuring these components, but gas chromatography is simple and accurate. As the gas chromatography, it is preferable to employ gas chromatography mass spectrometry (GS / MS) from the viewpoint of quantifying the components.
Moreover, in order to extract the said component in exhalation, it is preferable to adsorb | suck the component in exhalation overnight using a solid-phase micro extraction fiber (SPME fiber), and to use for gas chromatography. As the SPME fiber, those sold by Sigma-Aldrich Corporation (for example, trade name: camboxen / PDMS) can be used.
Therefore, a device for measuring the concentration of the four components in exhaled breath, for example, a combination of solid-phase microextraction fiber and gas chromatography is useful as an esophageal cancer diagnostic device.
後記実施例に示すように、呼気中のアセトニトリル、酢酸、アセトン及び２−ブタノン濃度は、食道癌患者、特に食道扁平上皮癌患者において、健常者に比べて有意に高い。従って、呼気中のこれらの成分は、食道癌診断マーカーとして有用である。より具体的には、呼気中のアセトニトリル、酢酸、アセトン及び２−ブタノンから選ばれる成分の濃度が健常者のそれに比べて高い場合に、当該呼気を有する対象者が食道癌と診断できる。 As shown in Examples below, the concentrations of acetonitrile, acetic acid, acetone, and 2-butanone in exhaled breath are significantly higher in esophageal cancer patients, particularly in patients with esophageal squamous cell carcinoma, compared to healthy individuals. Therefore, these components in exhaled breath are useful as esophageal cancer diagnostic markers. More specifically, when the concentration of a component selected from acetonitrile, acetic acid, acetone, and 2-butanone in exhaled air is higher than that in a healthy person, a subject having the exhaled breath can diagnose esophageal cancer.
次に実施例を挙げて本発明を詳細に説明する。 EXAMPLES Next, an Example is given and this invention is demonstrated in detail.
実施例１
Ａ．方法
（１）対象
２０１３年５月から２０１３年１１月に順天堂大学医学部附属順天堂医院食道胃外科で食道癌と診断され治療中の食道扁平上皮癌患者１７名および癌の既往のない健常者９名の呼気中の揮発性有機化合物を測定した。患者群と健常者群にはそれぞれ問診を行い、加療中の疾患、内服の有無、喫煙の有無、家族歴を確認した。患者群は病理学的に食道扁平上皮癌の診断がついており、代謝に変化を与える可能性のある放射線、化学療法を既に施行されている患者は除外した。本研究は順天堂大学倫理委員会の承認に基づき行われた。
Example 1
A. Method (1) Subjects 17 patients with squamous cell carcinoma of the esophagus who were diagnosed with esophageal cancer at Juntendo University School of Medicine, Juntendo University School of Medicine from May 2013 to November 2013, and 9 healthy subjects with no history of cancer Volatile organic compounds in the exhaled breath were measured. The patient group and the healthy group were interviewed to confirm the disease being treated, the presence of internal use, the presence of smoking, and family history. The patient group was pathologically diagnosed with squamous cell carcinoma of the esophagus, and patients who had already undergone radiation or chemotherapy that could change the metabolism were excluded. This study was conducted with the approval of Juntendo University Ethics Committee.
（２）呼気捕集
患者群、健常者群それぞれの呼気は薬剤等の影響がない環境下で、１Ｌのガスサンプリングバッグ（シグマアルドリッチ社）を用いて収集した。収集前のサンプリングバッグはより他の影響を少なくするため、窒素にて予備洗浄を行った。収集したサンプルは全て低温室に保管し、３日以内に処理を行った。
(2) Exhalation collection The exhalation of each of the patient group and the healthy person group was collected using a 1 L gas sampling bag (Sigma Aldrich) in an environment free from the influence of drugs and the like. The sampling bag before collection was pre-cleaned with nitrogen to reduce other effects. All collected samples were stored in a cold room and processed within 3 days.
（３）揮発性有機化合物の抽出と解析
サンプルの解析にはマイクロ固相出（ＳＰＭＥ）ファイバー（シグマアルドリッチ社）、およびガスクロマトグラフィー（ＧＣ／ＭＳ）を用いた。サンプリングバッグに収集した呼気をＳＰＭＥファイバーで濃縮し吸着した。ＳＰＭＥファイバーで１６時間（ｏｖｅｒｎｉｇｈｔ）かけて呼気を吸着した。またＳＰＭＥファイバーには８５μｍ ｃａｒｂｏｘｅｎ／ＰＤＭＳ(シグマアルドリッチ社：ガス状および低分子化合物 (分子量：３０−２２５)の吸着に優れる。）を用いて検討を行った。抽出した揮発性有機化合物は２５０℃のインジェクターを用いて離脱させ、ＧＣ／ＭＳで測定した。
(3) Extraction and analysis of volatile organic compounds Micro solid phase extraction (SPME) fiber (Sigma Aldrich) and gas chromatography (GC / MS) were used for the analysis of samples. The exhaled breath collected in the sampling bag was condensed with SPME fiber and adsorbed. Exhaled air was adsorbed with SPME fiber for 16 hours (overnight). The SPME fiber was examined using 85 μm carboxen / PDMS (Sigma-Aldrich: excellent in adsorption of gaseous and low molecular compounds (molecular weight: 30-225)). The extracted volatile organic compound was removed using a 250 ° C. injector and measured by GC / MS.
（４）統計解析
それぞれのサンプリングバッグから抽出した揮発性有機化合物をガスクロマトグラフィーで分析し、得られた種々の物質のピークを差異解析ソフト（ＳＩＥＶＥ）を用いて解析し、フィッシャー比から有意なピークを抽出し第１〜第５主成分を求めて主成分分析を行い、それぞれのサンプルの分布を図表化した（図１）。患者群と健常者群の分離の検討には、選択された物質のＲＯＣ曲線を作成し検討した。主成分分析はＳＰＳＳ（統計ソフト）を用いて行った。
(4) Statistical analysis The volatile organic compounds extracted from each sampling bag are analyzed by gas chromatography, and the peaks of various substances obtained are analyzed using difference analysis software (SIEVE). Peaks were extracted, the first to fifth principal components were obtained, principal component analysis was performed, and the distribution of each sample was graphed (FIG. 1). In order to examine the separation of the patient group and the healthy group, an ROC curve of the selected substance was created and examined. The principal component analysis was performed using SPSS (statistical software).
Ｂ．結果
ＳＰＭＥファイバーでｏｖｅｒｎｉｇｈｔ吸着をしたものの主成分分析で比較すると、患者群と健常者群の分離が良好であった。
ＳＰＭＥファイバーでｏｖｅｒｎｉｇｈｔ吸着し分析したピークを患者群と健常者群で比較したところ、アセトニトリル、酢酸、アセトン、２−ブタノンの４成分において差があることが示され（図２、３）、統計学的にも有意差を認めた（図４：アセトニトリルＰ＝０．００３７、酢酸Ｐ＝０．００２４、アセトンＰ＝０．００２４、２−ブタノンＰ＝０．００３７）。
アセトニトリル、酢酸、アセトン、２−ブタノンのＲＯＣ曲線（図５）を作成したところＡＵＣ（ａｒｅａ ｕｎｄｅｒ ｔｈｅ ｃｕｒｖｅ）：０．９３と高い確率で食道癌患者の分離が可能となることが示された。
B. Results The comparison of the principal component analysis of the overlight adsorbed with the SPME fiber showed good separation between the patient group and the healthy group.
Comparison of the peaks that were absorbed and analyzed with SPME fibers over the patient group and the healthy group showed that there were differences in the four components of acetonitrile, acetic acid, acetone, and 2-butanone (Figs. 2 and 3). (Fig. 4: Acetonitrile P = 0.0037, acetic acid P = 0.024, acetone P = 0.024, 2-butanone P = 0.0003).
When ROC curves (FIG. 5) of acetonitrile, acetic acid, acetone, and 2-butanone were created, it was shown that esophageal cancer patients can be separated with a high probability of AUC (area under the curve): 0.93.
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