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A Novel Multivariate Index for Pancreatic Cancer Detection Based On the Plasma Free Amino Acid Profile.

Fukutake N, Ueno M, Hiraoka N, Shimada K, Shiraishi K, Saruki N, Ito T, Yamakado M, Ono N, Imaizumi A, Kikuchi S, Yamamoto H, Katayama K - PLoS ONE (2015)

Bottom Line: Several amino acid concentrations in plasma were significantly altered in PC.The area under curve (AUC) based on receiver operating characteristic (ROC) curve analysis of the resulting index to discriminate PC from HC were 0.89 [95% confidence interval (CI), 0.86-0.93] in the training set.These findings suggest that the PFAA profile of PC was significantly different from that of HC.

View Article: PubMed Central - PubMed

Affiliation: Department of Hepatobiliary and Pancreatic Oncology, Osaka Medical Center of Cancer and Cardiovascular Diseases, Osaka, Japan.

ABSTRACT

Background: The incidence of pancreatic cancer (PC) continues to increase in the world, while most patients are diagnosed with advanced stages and survive <12 months. This poor prognosis is attributable to difficulty of early detection. Here we developed and evaluated a multivariate index composed of plasma free amino acids (PFAAs) for early detection of PC.

Methods: We conducted a cross-sectional study in multi-institutions in Japan. Fasting plasma samples from PC patients (n = 360), chronic pancreatitis (CP) patients (n = 28), and healthy control (HC) subjects (n = 8372) without apparent cancers who were undergoing comprehensive medical examinations were collected. Concentrations of 19 PFAAs were measured by liquid chromatography-mass spectrometry. We generated an index consisting of the following six PFAAs: serine, asparagine, isoleucine, alanine, histidine, and tryptophan as variables for discrimination in a training set (120 PC and matching 600 HC) and evaluation in a validation set (240 PC, 28 CP, and 7772 HC).

Results: Several amino acid concentrations in plasma were significantly altered in PC. Plasma tryptophan and histidine concentrations in PC were particularly low, while serine was particularly higher than that of HC. The area under curve (AUC) based on receiver operating characteristic (ROC) curve analysis of the resulting index to discriminate PC from HC were 0.89 [95% confidence interval (CI), 0.86-0.93] in the training set. In the validation set, AUCs based on ROC curve analysis of the PFAA index were 0.86 (95% CI, 0.84-0.89) for all PC patients versus HC subjects, 0.81 (95% CI, 0.75-0.86) for PC patients from stage IIA to IIB versus HC subjects, and 0.87 (95% CI, 0.80-0.93) for all PC patients versus CP patients.

Conclusions: These findings suggest that the PFAA profile of PC was significantly different from that of HC. The PFAA index is a promising biomarker for screening and diagnosis of PC.

No MeSH data available.


Related in: MedlinePlus

ROC curves of the PFAA index with different tumor stages, sizes, and locations.(A) ROC curves of the PFAA index in stage IIA (red), stage IIB (pink), stage III (orange), and stage IV (yellow–green), respectively. (B) ROC curves in TS1 (red), TS2 (pink), TS3 (orange), and TS4 (yellow–green), respectively. TS1 ≤ 2.0 cm, 2.0 cm < TS2 ≤ 4.0 cm, 4.0 cm < TS3 ≤ 6.0 cm, and TS4 > 6.0 cm. (C) ROC curves in the pancreatic head (red), body (pink), and tail (orange), respectively.
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pone.0132223.g004: ROC curves of the PFAA index with different tumor stages, sizes, and locations.(A) ROC curves of the PFAA index in stage IIA (red), stage IIB (pink), stage III (orange), and stage IV (yellow–green), respectively. (B) ROC curves in TS1 (red), TS2 (pink), TS3 (orange), and TS4 (yellow–green), respectively. TS1 ≤ 2.0 cm, 2.0 cm < TS2 ≤ 4.0 cm, 4.0 cm < TS3 ≤ 6.0 cm, and TS4 > 6.0 cm. (C) ROC curves in the pancreatic head (red), body (pink), and tail (orange), respectively.

Mentions: Furthermore, subgroup analysis was performed for tumor stage, size, and location in the pancreas. The AUC of the PFAA index according to tumor stage was as follows: 0.79 (95% CI, 0.72–0.86) for stage IIA, 0.85 (95% CI, 0.77–0.92) for stage IIB, 0.88 (95% CI, 0.83–0.94) for stage III, and 0.91 (95% CI, 0.88–0.94) for stage IV (Fig 4A). The AUC of the PFAA index according to tumor size was as follows: 0.76 (95% CI, 0.66–0.86) for TS1, 0.87 (95% CI, 0.83–0.90) for TS2, 0.91 (95% CI, 0.86–0.95) for TS3, and 0.97 (95% CI, 0.95–1.00) for TS4 (Fig 4B). The AUC of the PFAA index according to tumor location was as follows: 0.86 (95% CI, 0.82–0.90) for the pancreatic head, 0.88 (95% CI, 0.83–0.93) for the pancreatic body, and 0.90 (95% CI, 0.83–0.96) for the pancreatic tail (Fig 4C). In addition, we evaluated the correlations between PFAA index values and other biomarkers (i.e., CA19-9, CEA, and elastase-1) because the combinatorial use of multiple independent tumor markers is effective to detect PC. There were no significant correlations between the PFAA indices and levels of CA19-9 (r = 0.075, p = 0.247), CEA (r = −0.005, p = 0.957), or elastase-1 (r = 0.009, p = 0.351) in PC (Fig 5, S2 Table).


A Novel Multivariate Index for Pancreatic Cancer Detection Based On the Plasma Free Amino Acid Profile.

Fukutake N, Ueno M, Hiraoka N, Shimada K, Shiraishi K, Saruki N, Ito T, Yamakado M, Ono N, Imaizumi A, Kikuchi S, Yamamoto H, Katayama K - PLoS ONE (2015)

ROC curves of the PFAA index with different tumor stages, sizes, and locations.(A) ROC curves of the PFAA index in stage IIA (red), stage IIB (pink), stage III (orange), and stage IV (yellow–green), respectively. (B) ROC curves in TS1 (red), TS2 (pink), TS3 (orange), and TS4 (yellow–green), respectively. TS1 ≤ 2.0 cm, 2.0 cm < TS2 ≤ 4.0 cm, 4.0 cm < TS3 ≤ 6.0 cm, and TS4 > 6.0 cm. (C) ROC curves in the pancreatic head (red), body (pink), and tail (orange), respectively.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4489861&req=5

pone.0132223.g004: ROC curves of the PFAA index with different tumor stages, sizes, and locations.(A) ROC curves of the PFAA index in stage IIA (red), stage IIB (pink), stage III (orange), and stage IV (yellow–green), respectively. (B) ROC curves in TS1 (red), TS2 (pink), TS3 (orange), and TS4 (yellow–green), respectively. TS1 ≤ 2.0 cm, 2.0 cm < TS2 ≤ 4.0 cm, 4.0 cm < TS3 ≤ 6.0 cm, and TS4 > 6.0 cm. (C) ROC curves in the pancreatic head (red), body (pink), and tail (orange), respectively.
Mentions: Furthermore, subgroup analysis was performed for tumor stage, size, and location in the pancreas. The AUC of the PFAA index according to tumor stage was as follows: 0.79 (95% CI, 0.72–0.86) for stage IIA, 0.85 (95% CI, 0.77–0.92) for stage IIB, 0.88 (95% CI, 0.83–0.94) for stage III, and 0.91 (95% CI, 0.88–0.94) for stage IV (Fig 4A). The AUC of the PFAA index according to tumor size was as follows: 0.76 (95% CI, 0.66–0.86) for TS1, 0.87 (95% CI, 0.83–0.90) for TS2, 0.91 (95% CI, 0.86–0.95) for TS3, and 0.97 (95% CI, 0.95–1.00) for TS4 (Fig 4B). The AUC of the PFAA index according to tumor location was as follows: 0.86 (95% CI, 0.82–0.90) for the pancreatic head, 0.88 (95% CI, 0.83–0.93) for the pancreatic body, and 0.90 (95% CI, 0.83–0.96) for the pancreatic tail (Fig 4C). In addition, we evaluated the correlations between PFAA index values and other biomarkers (i.e., CA19-9, CEA, and elastase-1) because the combinatorial use of multiple independent tumor markers is effective to detect PC. There were no significant correlations between the PFAA indices and levels of CA19-9 (r = 0.075, p = 0.247), CEA (r = −0.005, p = 0.957), or elastase-1 (r = 0.009, p = 0.351) in PC (Fig 5, S2 Table).

Bottom Line: Several amino acid concentrations in plasma were significantly altered in PC.The area under curve (AUC) based on receiver operating characteristic (ROC) curve analysis of the resulting index to discriminate PC from HC were 0.89 [95% confidence interval (CI), 0.86-0.93] in the training set.These findings suggest that the PFAA profile of PC was significantly different from that of HC.

View Article: PubMed Central - PubMed

Affiliation: Department of Hepatobiliary and Pancreatic Oncology, Osaka Medical Center of Cancer and Cardiovascular Diseases, Osaka, Japan.

ABSTRACT

Background: The incidence of pancreatic cancer (PC) continues to increase in the world, while most patients are diagnosed with advanced stages and survive <12 months. This poor prognosis is attributable to difficulty of early detection. Here we developed and evaluated a multivariate index composed of plasma free amino acids (PFAAs) for early detection of PC.

Methods: We conducted a cross-sectional study in multi-institutions in Japan. Fasting plasma samples from PC patients (n = 360), chronic pancreatitis (CP) patients (n = 28), and healthy control (HC) subjects (n = 8372) without apparent cancers who were undergoing comprehensive medical examinations were collected. Concentrations of 19 PFAAs were measured by liquid chromatography-mass spectrometry. We generated an index consisting of the following six PFAAs: serine, asparagine, isoleucine, alanine, histidine, and tryptophan as variables for discrimination in a training set (120 PC and matching 600 HC) and evaluation in a validation set (240 PC, 28 CP, and 7772 HC).

Results: Several amino acid concentrations in plasma were significantly altered in PC. Plasma tryptophan and histidine concentrations in PC were particularly low, while serine was particularly higher than that of HC. The area under curve (AUC) based on receiver operating characteristic (ROC) curve analysis of the resulting index to discriminate PC from HC were 0.89 [95% confidence interval (CI), 0.86-0.93] in the training set. In the validation set, AUCs based on ROC curve analysis of the PFAA index were 0.86 (95% CI, 0.84-0.89) for all PC patients versus HC subjects, 0.81 (95% CI, 0.75-0.86) for PC patients from stage IIA to IIB versus HC subjects, and 0.87 (95% CI, 0.80-0.93) for all PC patients versus CP patients.

Conclusions: These findings suggest that the PFAA profile of PC was significantly different from that of HC. The PFAA index is a promising biomarker for screening and diagnosis of PC.

No MeSH data available.


Related in: MedlinePlus