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Obesity is a risk factor for intrahepatic cholangiocarcinoma progression associated with alterations of metabolic activity and immune status.

ABSTRACT: Body mass index (BMI) is well known to be associated with poor prognosis in several cancers. The relationship between BMI and the long-term outcomes of patients with intrahepatic cholangiocarcinoma (ICC) is incompletely understood. This study investigated the relationships of BMI with clinicopathological characteristics and patient outcomes, focusing on metabolic activity and immune status. The relationship between BMI and the maximum standardized uptake value (SUVmax) on fluorine-18 fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography/computed tomography (PET/CT) was analyzed. In addition, immunohistochemistry was performed for programmed cell death-ligand 1 (PD-L1), cluster of differentiation 8 (CD8), and forkhead box protein P3 (Foxp3). Seventy-four patients with ICC were classified into normal weight (BMI?2, n?=?48) and obesity groups (BMI???25.0 kg/m², n?=?26), respectively. Serum carbohydrate antigen 19-9 levels were higher in the obesity group than in the normal weight group. Tumor size and the intrahepatic metastasis rate were significantly larger in the obesity group. Patients in the obesity group had significantly worse prognoses than those in the normal weight group. Moreover, BMI displayed a positive correlation with SUVmax on ¹⁸F-FDG PET/CT (n?=?46, r?=?0.5152). Patients with high ¹⁸F-FDG uptake had a significantly higher rate of PD-L1 expression, lower CD8?+?tumor-infiltrating lymphocyte (TIL) counts, and higher Foxp3?+?TIL counts. The elevated BMI might predict the outcomes of patients with ICC. Obesity might be associated with ICC progression, possibly through alterations in metabolic activity and the immune status.

SUBMITTER: Yugawa K

PROVIDER: S-EPMC7955092 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Obesity is a risk factor for intrahepatic cholangiocarcinoma progression associated with alterations of metabolic activity and immune status.

Yugawa Kyohei K Itoh Shinji S Iseda Norifumi N Kurihara Takeshi T Kitamura Yoshiyuki Y Toshima Takeo T Harada Noboru N Kohashi Kenichi K Baba Shingo S Ishigami Kousei K Oda Yoshinao Y Yoshizumi Tomoharu T Mori Masaki M

Scientific reports 20210312 1

Body mass index (BMI) is well known to be associated with poor prognosis in several cancers. The relationship between BMI and the long-term outcomes of patients with intrahepatic cholangiocarcinoma (ICC) is incompletely understood. This study investigated the relationships of BMI with clinicopathological characteristics and patient outcomes, focusing on metabolic activity and immune status. The relationship between BMI and the maximum standardized uptake value (SUVmax) on fluorine-18 fluorodeoxy ...[more]

PMID: 33712681

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Project description:Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer arising from the bile ducts with a need for earlier diagnosis and a greater range of treatment options. KRAS/NRAS mutations are common in ICC tumours and 6-32% of patients also have isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) gene mutations associated with metabolic changes. This feasibility study investigated sequencing circulating tumour DNA (ctDNA) combined with metabolite profiling of plasma as a method for biomarker discovery in ICC patients. Plasma was collected from four ICC patients receiving radio-embolisation and healthy controls at multiple time points. ctDNA was sequenced using Ampliseq cancer hotspot panel-v2 on Ion Torrent PGM for single nucleotide variants (SNV) detection and with Illumina whole genome sequencing for copy number variants (CNV) and further targeted examination for SNVs. Untargeted analysis of metabolites from patient and control plasma was performed using liquid chromatography coupled with high-resolution tandem mass spectrometry (LC-MS/MS). Metabolite identification was performed using multi-parameter comparisons with analysis of authentic standards, and univariate statistical analysis was performed to identify differences in metabolite abundance between patient and control samples. Recurrent somatic SNVs and CNVs were identified in ctDNA from three out of four patients that included both NRAS and IDH1 mutations linked to ICC. Plasma metabolite analysis revealed biomarker metabolites associated with ICC and in particular 2-hydroxyglutarate (2-HG) levels were elevated in both samples from the only patient showing a variant allele in IDH1. A reduction in the number of CNVs was observed with treatment. This study demonstrates that ctDNA and metabolite levels can be identified and correlated in ICC patient blood samples and differentiated from healthy controls. We conclude that combining genomic and metabolic analysis of plasma offers an effective approach to biomarker identification with potential for disease stratification and early detection studies.

Project description:BackgroundLymph node metastasis (LNM) is a well-established prognostic factor for intrahepatic cholangiocarcinoma (ICC), but there are still some controversies relating to the evaluation of nodal status. Therefore, we investigated the role of lymph node dissection (LND), compared the prognostic performances of different nodal staging systems, and then developed and validated a nomogram to predict cancer-specific survival (CSS) of ICC patients.MethodsThe study cohort was taken from the Surveillance, Epidemiology, and End Results database. Akaike information criterion, Bayesian information criterion, Harrell's C-index and area under the receiver operating characteristic curves were calculated to evaluate the different staging models. The nomogram for the CSS was constructed based on Cox regression models and validated by calibration curves. Decision curve analysis was introduced to examine the clinical value of the models.ResultsA total of 664 patients were enrolled, and 331 (51.4%) patients underwent LND. An increasing number of lymph nodes retrieved showed no oncologic benefit (P=0.876). LNM was identified in 103 (31.1%) patients, which was the cause of their poor prognoses (5-yr CSS 13.1% versus 44.9%, P<0.001). Patients without LNM could not benefit from adjuvant therapy after propensity score matching (P=0.140). Based on the Youden index, 4 or more lymph nodes retrieved might be adequate for accurate staging. The lymph node ratio (LNR) classification, with an optimal cut-off value of 0.15, displayed the best prognostic performance. Age, size, tumor number, T Stage, grade and the LNR classification were independent predictive factors for the CSS in ICC patients. The nomogram for predicting the CSS of ICC patients according to the independent factors was well calibrated and it showed better discrimination power and higher net benefits than the American Joint Committee on Cancer (8th edition) staging system.ConclusionsLNM is an independent prognostic factor in ICC. Although it shows no oncologic benefits, LND should still be considered as a method of stratifying patients, with 4 or more lymph nodes retrieved potentially enough to do so. LNR appears to be a promising and easy-to-use prognosticator for nodal staging. The constructed nomogram could serve as an effective tool to predict the CSS probabilities of ICC patients.

Dataset Information

Obesity is a risk factor for intrahepatic cholangiocarcinoma progression associated with alterations of metabolic activity and immune status.

Publications

Obesity is a risk factor for intrahepatic cholangiocarcinoma progression associated with alterations of metabolic activity and immune status.

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