Publications by authors named "Caroline Truntzer"

43 Publications

Seroprevalence of SARS-CoV-2 among the staff and patients of a French cancer centre after first lockdown: The canSEROcov study.

Eur J Cancer 2021 Feb 27;148:359-370. Epub 2021 Feb 27.

Department of Medical Oncology, Centre Georges François Leclerc, Dijon, France; Research Platform in Biological Oncology, Georges François Leclerc Cancer Center, Dijon, France; Centre de Recherche INSERM LNC-UMR1231, Dijon, France; University of Burgundy-Franche Comté, France.

Background: In view of the potential gravity of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection for patients with cancer, epidemiological data are vital to assess virus circulation among patients and staff of cancer centres. We performed a prospective study to investigate seroprevalence of SARS-CoV-2 antibodies among staff and patients with cancer at a large cancer centre, at the end of the period of first national lockdown in France and to determine factors associated with the risk of SARS-CoV-2 infection.

Methods: After the first lockdown, all medical and non-medical staff, as well as all patients attending the medical oncology department were invited to undergo serological testing for SARS-CoV-2 between 11 May and 30 June 2020. All participants were also invited to complete a questionnaire collecting data about their living and working conditions, and for patients, medical management during lockdown.

Findings: A total of 1,674 subjects (663 staff members, 1011 patients) were included. Seroprevalence was low in both staff (1.8%) and patients (1.7%), despite more features of high risk for severe forms among patients. None of the risk factors tested in our analysis (working or living conditions, comorbidities, management characteristics during lockdown) was found to be statistically associated with seroprevalence in either staff or patients. There was no significant difference in the proportion of symptomatic and asymptomatic subjects between staff and patients. Only fever, loss of smell, and loss of taste were significantly more frequent among seropositive patients, in both staff and patients.

Interpretation: We report very low seroprevalence of antibodies against SARS-CoV-2 in the staff (caregiving and non-caregiving) and patients of a large cancer care centre in which strict hygiene, personal protection, and social distancing measures were implemented.
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http://dx.doi.org/10.1016/j.ejca.2021.02.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914029PMC
February 2021

Angiotensin-converting enzyme (ACE) inhibitor prescription affects non-small-cell lung cancer (NSCLC) patients response to PD-1/PD-L1 immune checkpoint blockers.

Oncoimmunology 2020 10 27;9(1):1836766. Epub 2020 Oct 27.

Department of Medical Oncology, GF Leclerc Centre, Dijon, France.

Angiotensin-converting enzyme (ACE) inhibitors are frequently used to treat hypertension and congestive heart failure. Preclinical data show that ACE plays a role on both innate and adaptive immune responses. Since interactions between ACE inhibitors and immune checkpoint inhibitors (ICIs) have not been reported, the aim of this study is to investigate the influence of ACE inhibitors on non-small cell lung cancer (NSCLC) patients treated with programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitors. We conducted a retrospective cohort analysis of NSCLC patients treated with PD-1/PD-L1 inhibitors. Clinical and co-medication data as well as tumor biopsies were collected. Groups were defined according to patients' co-medications at the time of ICI initiation. Among the 178 patients included, 22 (13.1%) received ACE inhibitors. While baseline characteristics were similar in both groups, ACE inhibitors group had a shorter median PFS (Progression-Free Survival) compared to the control group: 1.97 vs. 2.56 months, = .01 (HR = 1.8 CI95% 1.1-2.8). Using CIBERSORT, RNA sequencing suggested that tumors from the ACE inhibitors group had less M1 macrophages, activated mast cells, NK cells and memory activated T cells, thus suggesting an immunosuppressed state. , the ACE inhibitor, captopril, induced M2 marker at the cell surface of monocytes engaged into M1 differentiation. Thus, ACE inhibitors prescription concomitant to PD-1/PD-L1 inhibitors treatment seems to be associated with impaired outcome and with a tumor immunosuppressed state in patients with advanced NSCLC. These results should be validated in larger prospective cohorts.
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http://dx.doi.org/10.1080/2162402X.2020.1836766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595630PMC
October 2020

Tumor Infiltrating Lymphocytes Signature as a New Pan-Cancer Predictive Biomarker of Anti PD-1/PD-L1 Efficacy.

Cancers (Basel) 2020 Aug 26;12(9). Epub 2020 Aug 26.

Cancer Biology Transfer Platform, Georges-François Leclerc Cancer Center, 1 rue du Professeur Marion, F-21000 Dijon, France.

Tumor immune infiltrates are associated with tumor prognosis in many cancer types. However, their capacity to predict the efficacy of checkpoint inhibitors is poorly documented. We generate three signatures that evaluate in different ways these infiltrates: lymphoid- and myeloid-alone signatures, and a combined signature of both named the TIL (tumor-infiltrating lymphocyte) transcriptomic signature. We evaluate these signatures in The Cancer Genome Atlas Program (TCGA) Pan-Cancer cohort and four cohorts comprising patients with melanoma, lung, and head and neck cancer treated with anti-PD-1 or anti-CTLA-4 therapies. We observe using TCGA Pan-Cancer cohort that this TIL or lymphoid-alone signature accurately estimates prognosis in most cancer types and outperforms histological TIL evaluation or myeloid signature alone. Both TIL and lymphoid signatures are correlated with response rate to immunotherapy. Combining lymphoid signature or TIL with tumor mutational burden generates a score that is highly efficient in predicting response to immunotherapy. In different series of patients treated with checkpoint inhibitors for non-small cell lung cancer, head and neck cancer, and melanoma, we observed that TIL or lymphoid signature were associated with outcome. These data demonstrate that a simple TIL or lymphoid signature could be used as a Pan-Cancer prognostic and predictive biomarker to estimate patient survival under checkpoint inhibitors.
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http://dx.doi.org/10.3390/cancers12092418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564481PMC
August 2020

Precision medicine phase II study evaluating the efficacy of a double immunotherapy by durvalumab and tremelimumab combined with olaparib in patients with solid cancers and carriers of homologous recombination repair genes mutation in response or stable after olaparib treatment.

BMC Cancer 2020 Aug 10;20(1):748. Epub 2020 Aug 10.

Department of Medical Oncology, Center GF Leclerc, 1 rue du Professeur Marion, 21000, Dijon, France.

Background: Tumors with deficient homologous repair are sensitive to PARP inhibitors such as olaparib which is known to have immunogenic properties. Durvalumab (D) is a human monoclonal antibody (mAb) which inhibits binding of programmed cell death ligand 1 (PD-L1) to its receptor. Tremelimumab (T) is a mAb directed against the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). This study is designed to evaluate the efficacy of combination of olaparib, durvalumab and tremelimumab in patients with a solid tumors with a mutation in homologous gene repair.

Methods: This phase II study will assess the efficacy and safety of olaparib/D/T association in patients (n = 213) with several types of solid cancers (breast cancer, ovarian cancer, pancreatic cancer, endometrial cancer, prostate cancer and others) with at least one mutation in homologous repair genes (BRCA1, BRCA2, PALB2, ATM, FANCA, FANCB, FANCC, FANCE, FANCF, CHEK2, RAD51, BARD1, MRE11, RAD50, NBS1, HDAC2), LKB1/STK11, INPP4B, STAG2, ERG, CHEK1, BLM, LIG4, ATR, ATRX, CDK12). Good performance status patients and corresponding to specific inclusion criteria of each cohort will be eligible. STEP1: Patients will receive olaparib 300 mg BID. In absence of progression after 6 weeks of olaparib, they will follow STEP 2 with olaparib and immunotherapy by durvalumab (1500 mg Q4W) + tremelimumab (75 mg IV Q4W) during 4 months and will further pursue durvalumab alone until disease progression, death, intolerable toxicity, or patient/investigator decision to stop (for a maximum duration of 24 months, and 36 months for ovarian cohort). Primary endpoint is safety and efficacy according to progression-free survival (PFS) of olaparib + immunotherapy (durvalumab + tremelimumab) during 4 months followed by durvalumab alone as maintenance in patients with solid cancers and in response or stable, after prior molecular target therapy by olaparib; secondary endpoints include overall survival (OS), disease control rate (DCR), response rate after 6 weeks of olaparib, safety of olaparib/durvalumab/tremelimumab association. Blood, plasma and tumor tissue will be collected for potential prognostic and predictive biomarkers.

Discussion: This study is the first trial to test the combination of olaparib and double immunotherapy based on molecular screening.

Trial Registration: NCT04169841 , date of registration November 20, 2019.
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http://dx.doi.org/10.1186/s12885-020-07253-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418426PMC
August 2020

Role of pleural and peritoneal metastasis in immune checkpoint inhibitors efficacy patients with non-small cell lung cancer: real-world data from a large cohort in France.

J Cancer Res Clin Oncol 2020 Oct 30;146(10):2699-2707. Epub 2020 May 30.

Department of Medical Oncology, Center Georges François Leclerc, 1 rue du Professeur Marion, 21000, Dijon, France.

Background: Checkpoint inhibitors (CKI) targeting PD-1 or PD-L1 are major therapies for the treatment of non-small cell lung cancer (NSCLC). Despite numerous studies of biological biomarkers, we currently lack a marker to predict CKI primary resistance. The aim of this study was to isolate clinical markers associated with the absence of efficacy of CKI used as monotherapy in NSCLC.

Methods: We conducted a retrospective analysis of 172 patients treated with anti-PD1 or anti-PDL1 monoclonal antibodies (mAb) for advanced NSCLC at the Dijon Cancer Center. Baseline characteristics were compared using the Chi squared test between responders and non-responders. Survival curves were estimated by the Kaplan-Meier method and compared with the Log-rank test for univariate analysis. Cox regression models were used to determine hazard ratios and 95% confidence intervals for progression-free survival (PFS) and overall survival (OS).

Results: Among 172 patients included, 149 (86.5%) received CKI after platinum chemotherapy. Response rate (RR) was 16%, median progression-free survival (PFS) was 2.5 months (95% CI 0.7-30 months) and median overall survival (OS) was 10 months (95% CI 0.7-46.8 months). By univariate analysis, WHO performance status ≥ 1, presence of bone, liver and pleuroperitoneal metastasis were associated with poor PFS and OS. Multivariate analysis showed that only pleuroperitoneal metastasis was independently associated with PFS and OS. Patients with pleuroperitoneal metastasis and WHO performance status ≥ 1 had a < 10% chance of yielding a benefit from CKI.

Conclusions: Our data support the hypothesis that pleuroperitoneal metastasis is a major predictive factor affecting CKI efficacy in NSCLC patients and may be used to avoid CKI monotherapy for such patients.
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http://dx.doi.org/10.1007/s00432-020-03262-2DOI Listing
October 2020

Tumour mutational burden as a biomarker for immunotherapy: Current data and emerging concepts.

Eur J Cancer 2020 05 9;131:40-50. Epub 2020 Apr 9.

Department of Medical Oncology, Center GF Leclerc, Dijon, France; Research Platform in Biological Oncology, Dijon, France; GIMI Genetic and Immunology Medical Institute, Dijon, France; University of Burgundy-Franche Comté, Dijon, France; UMR INSERM 1231, Dijon, France. Electronic address:

Treatment with immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) or its ligand (PD-L1) can generate durable responses in various cancer types, but only in a subset of patients. The use of predictive biomarkers for response to PD-1/PD-L1 inhibitors is critical for patient selection. Expression of PD-L1 has demonstrated utility in patient selection. Tumour mutational burden (TMB) is an emerging biomarker for response to PD-1/PD-L1 inhibitors. The evaluation of this biomarker is based on the hypothesis that a high number of mutations in somatic exonic regions will lead to an increase in neoantigen production, which could then be recognised by CD8 T cells, resulting in improved immune responses. In this review, we will discuss rationale and implementation of TMB usage in patients, development of different methods to assess it, current limitations and technical issues to use this biomarker as a diagnostic test and propose future perspectives beyond TMB.
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http://dx.doi.org/10.1016/j.ejca.2020.02.038DOI Listing
May 2020

Implementation and use of whole exome sequencing for metastatic solid cancer.

EBioMedicine 2020 Jan 7;51:102624. Epub 2020 Jan 7.

Department of Medical Oncology, Georges François Leclerc Cancer Center - UNICANCER, 1 rue Professeur Marion, Dijon 21000, France; Platform of Transfer in Cancer Biology, Georges François Leclerc Cancer Center - UNICANCER, Dijon, France; Université Bourgogne Franche-Comté, Dijon, France; Genomic and Immunotherapy Medical Institute, Dijon, France; INSERM U1231, Dijon, France. Electronic address:

Background: Genomically-guided clinical trials are performed across different tumor types sharing genetic mutations, but trial organization remains complex. Here we address the feasibility and utility of routine somatic and constitutional exome analysis in metastatic cancer patients.

Methods: Exoma trial (NCT02840604) is a multicenter, prospective clinical trial. Eligible patients presented a metastatic cancer progressing after at least one line of systemic therapy. Constitutional genetics testing required geneticist consultation. Somatic and germline exome analysis was restricted to 317 genes. Variants were classified and molecular tumor board made therapeutic recommendations based on ESMO guidelines. Primary endpoint was the feasibility of the approach evaluated by the proportion of patient that received a therapeutic proposal.

Findings: Between May 2016 and October 2018, 506 patients were included. Median time required for tumor sample reception was 8 days. Median time from sample reception to results was 52 days. Somatic analysis was performed for 456 patients (90.1%). Both somatic and constitutional analyses were successfully performed for 386 patients (76.3%). In total, 342 patients (75%) received a therapeutic proposal. Genetic susceptibility to cancer was found in 35 (9%) patients. Only, 79 patients (23.1%) were treated with NGS matched therapy mainly PI3K/AKT/mTOR inhibitors 22 (27.8%), followed by PARP inhibitors 19 (24.1%), antiangiogenics 17 (21.5%), MEK inhibitors 7 (8.9%) and immunotherapy 5 (6.3%). Matched treatment was finally stopped because of disease progression 50 (63%), treatment toxicity 18 (23%), patients' death 4 (5%). PFS2/PFS1 ratio was > 1,3 for 23,5% of patients treated with the NGS matched therapy and 23,7% of patients treated with standard therapy.

Interpretation: Study shows that exome analysis is feasible in cancer routine care. This strategy improves detection of genetic predispositions and enhances access to target therapies. However, no differences were observed between PFS ratios of patients treated with matched therapy versus standard therapy.

Funding: This work was funding by the centre Georges Francois Leclerc.
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http://dx.doi.org/10.1016/j.ebiom.2019.102624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000332PMC
January 2020

Solid-type adenoid cystic carcinoma of the breast, a distinct molecular entity enriched in NOTCH and CREBBP mutations.

Mod Pathol 2020 06 19;33(6):1041-1055. Epub 2019 Dec 19.

Department of Biopathology, Institut Bergonié, Comprehensive Cancer Centre, F-33076, Bordeaux, France.

Adenoid cystic carcinoma (ACC) of the breast with a predominant solid pattern is difficult to diagnose with certainty and differentiate from more common triple-negative breast cancers (TNBCs) of basal-phenotype. To better characterize solid ACC, we performed a clinical, morphological, immunohistochemical, and molecular comparative analysis of 33 ACCs of the breast comprising 17 solid variant ACCs and 16 conventional ACCs. Solid ACCs displayed basaloid morphology with an exclusive or predominant epithelial cell population associated with decreased myoepithelial differentiation, while demonstrating MYB protein overexpression similar to the more common type of ACC. Strong and diffuse MYB expression by immunochemistry was observed in 14/17 (82%) of solid ACCs while MYB rearrangements were detected by break apart fluorescence in situ hybridization (FISH) in only 3/16 (19%) of solid ACCs. Conversely, weak MYB immunohistochemical expression was observed in only 7/204 (3%) of TNBC. Solid ACCs displayed a transcriptomic profile distinct from conventional ACCs with 549 genes showing a highly significant differential expression between conventional and solid ACC [false discovery rate (FDR) < 0.01; log2FC > |1|]. EnrichR and Kegg Pathway analyses identified PI3K-Akt and focal adhesion signaling pathways as significantly overexpressed in conventional ACCs compared with solid ACCs which significantly overexpressed the nitrogen metabolism pathway. CREBBP mutations and NOTCH activating gene mutations were only present in solid ACCs, concerning 5/16 (31%) of cases for each gene. Tumors with NOTCH activating mutations displayed a strong diffuse nuclear NICD1 staining, an established marker of Notch pathway activation. Solid ACCs also differed from basal-type TNBC, with fewer TP53 mutations and a more stable genomic profile on array comparative genomic hybridization (CGH). In summary, solid-type ACC of the breast is a distinct molecular entity within the ACC family and is different from common basal-type TNBC. MYB is a diagnostically useful biomarker of solid ACC and NOTCH could be a novel potential therapeutic target in 30% of cases.
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http://dx.doi.org/10.1038/s41379-019-0425-3DOI Listing
June 2020

Prognostic value of transcriptomic determination of tumour-infiltrating lymphocytes in localised breast cancer.

Eur J Cancer 2019 10 6;120:97-106. Epub 2019 Sep 6.

Platform of Transfer in Biology of Cancer, Georges Francois Leclerc Cancer Center, 1 Rue Du Professeur Marion, 21000 Dijon, France; GIMI Genetic and Immunology Medical Institute, 21000 Dijon, France; Department of Medical Oncology, Georges Francois Leclerc Cancer Center, 1 Rue Du Professeur Marion, 21000 Dijon, France; INSERM U1231, Dijon, France; Univ. Bourgogne Franche-Comté, Dijon, France. Electronic address:

Purpose: Tumour-infiltrating lymphocyte (TIL) detection by histology is associated with outcomes in breast cancer; nevertheless, analysis standardisation is difficult. We determined whether transcriptomic data could generate a genomic signature that estimated TIL infiltrates and determined patient prognosis in localised breast cancer.

Experimental Design: Using 1928 transcriptomic profiles of pure cells, we generated a genetic signature specific to lymphocyte, myeloid, stromal and cancer cells. We then computed a score based on this signature and tested the association between the score and the TILs estimated for patients in an adjuvant setting from public and private data sets. We tested the capacity of the transcriptomic RNA TIL score to predict disease-free survival (DFS) or overall survival (OS) through multivariate Cox models adjusted for classical clinical variables and PAM50 molecular classification in two public data sets (Carte d'Identité des Tumeurs [CIT], n = 530; Metabric, n = 1832).

Results: A high RNA TIL score was significantly associated with the presence of a high level of TILs as assessed by histology. The score was also associated with DFS and OS in multivariate Cox models adjusted for molecular and clinical variables (CIT: OS hazard ratio [HR] = 0.15 [0.04, 0.61], p-value = 0.007; DFS: 0.27 [0.08, 0.8] p-value = 0.02; Metabric: OS HR = 0.87 [0.77, 0.97], p-value = 0.01). The association between the RNA TIL score and survival was tested by univariate analysis in each molecular subgroup; the RNA TIL score was associated with survival only in basal-like tumours.

Conclusions: Determination of the TIL rate using a transcriptomic signature is feasible and has a high prognostic value in patients with basal-like tumours in an adjuvant setting.
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http://dx.doi.org/10.1016/j.ejca.2019.07.020DOI Listing
October 2019

Tim-3/galectin-9 pathway and mMDSC control primary and secondary resistances to PD-1 blockade in lung cancer patients.

Oncoimmunology 2019;8(4):e1564505. Epub 2019 Jan 22.

Platform of Transfer in Cancer Biology, Centre Georges-François Leclerc, Dijon, France.

Nivolumab, a monoclonal antibody targeting PD-1, is currently approved for metastatic non-small cell lung cancer (mNSCLC) treatment after failure of first-line chemotherapy. However, only a quarter of patients benefit from this therapy with objective clinical response. In this context, there is an unmet need for improved understanding of resistance mechanisms. Thus, we studied a prospective cohort of mNSCLC (n = 61) treated in second or third-line with nivolumab. We analyzed various blood myeloid and lymphoid markers by flow cytometry (176 variables) at baseline, and after 15 and 30 days of therapy. By attempting to link the evolution of peripheral lymphoid, myeloid cells and anti-PD-1 response, we observed that accumulation of lymphoid cells and monocytic MDSC (mMDSC) expressing, respectively, Tim-3 and galectin-9 is implicated in resistance to PD-1 blockade both for patients with primary or acquired secondary resistance to anti-PD-1. In vitro, anti-Tim-3 blocking antibody reverses resistance to anti-PD-1 in PBMC from lung cancer patients and high levels of blood mMDSC negatively impact on anti-PD-1 efficacy. Together, these data underline that the galectin-9/Tim-3 pathway and mMDSC are key mechanisms of primary or secondary resistance to anti-PD-1 and could be a new target for immunotherapy drug combinations.
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http://dx.doi.org/10.1080/2162402X.2018.1564505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422400PMC
January 2019

Cell lines and immune classification of glioblastoma define patient's prognosis.

Br J Cancer 2019 04 22;120(8):806-814. Epub 2019 Mar 22.

Research Platform in Biological Oncology, Dijon, France.

Background: Prognostic markers for glioblastoma are lacking. Both intrinsic tumour characteristics and microenvironment could influence cancer prognostic. The aim of our study was to generate a pure glioblastoma cell lines and immune classification in order to decipher the respective role of glioblastoma cell and microenvironment on prognosis.

Methods: We worked on two large cohorts of patients suffering from glioblastoma (TCGA, n = 481 and Rembrandt, n = 180) for which clinical data, transcriptomic profiles and outcome were recorded. Transcriptomic profiles of 129 pure glioblastoma cell lines were clustered to generate a glioblastoma cell lines classification. Presence of subtypes of glioblastoma cell lines and immune cells was determined using deconvolution.

Results: Glioblastoma cell lines classification defined three new molecular groups called oncogenic, metabolic and neuronal communication enriched. Neuronal communication-enriched tumours were associated with poor prognosis in both cohorts. Immune cell infiltrate was more frequent in mesenchymal classical classification subgroup and metabolic-enriched tumours. A combination of age, glioblastoma cell lines classification and immune classification could be used to determine patient's outcome in both cohorts.

Conclusions: Our study shows that glioblastoma-bearing patients can be classified based on their age, glioblastoma cell lines classification and immune classification. The combination of these information improves the capacity to address prognosis.
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http://dx.doi.org/10.1038/s41416-019-0404-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474266PMC
April 2019

Genomic biomarker of checkpoint efficacy, highways for precision medicine in lung cancer.

Oncotarget 2018 Nov 27;9(93):36547-36548. Epub 2018 Nov 27.

Francois Ghiringhelli: Platform of Transfer in Cancer Biology, Georges François Leclerc Cancer Center, UNICANCER, Dijon, France; Univ. Bourgogne Franche-Comté, Dijon, France; Georges François Leclerc Cancer Center - UNICANCER, Dijon, France; INSERM U1231, Dijon, France; Genetic and Immunology Medical Institute, Dijon, France.

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http://dx.doi.org/10.18632/oncotarget.26389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6290964PMC
November 2018

RAS status and neoadjuvant chemotherapy impact CD8+ cells and tumor HLA class I expression in liver metastatic colorectal cancer.

J Immunother Cancer 2018 11 19;6(1):123. Epub 2018 Nov 19.

Cancer Biology Research Platform, Centre Georges-François Leclerc, Dijon, France.

Background: T lymphocytes and HLA expression on tumor cell both influence prognostic of localized colorectal cancer, but their role following chemotherapy in patients with liver metastatic colorectal cancer (mCRC) was not addressed.

Methods: One hundred fourteen patients treated in curative intend of liver mCRC were included in this retrospective study. Patients were either untreated or treated with neoadjuvant therapy containing an anti-EGFR, bevacizumab or oxaliplatin. Immune densities were quantified in the tumor core and in invasive margin of metastases, using Qupath software or a pathologist's quantification. CD8, NKp46, Foxp3, CD163, HLA, PD-L1 were analyzed and were correlated with progression free survival (PFS) and overall survival (OS) using multivariable Cox proportional hazards models.

Results: In the whole cohort only a high CD8+ cells infiltrate, a high HLA-I expression and wild-type RAS/RAF status were associated with a better overall survival in both univariate and multivariate model. Moreover, CD8+ cells immune infiltrate at invasive margin combined to HLA expression in cancer cell could increase patient's outcome prediction. RAS status but not immune cell infiltrate was associated with HLA expression on tumor cells. In comparison to untreated patients, neoadjuvant chemotherapy induced CD8+ cells recruitment and increased PD-L1 staining in immune infiltrates only for WT RAS patients. In this context, anti-EGFR and oxaliplatin based chemotherapy are the most powerful to induce CD8+ cells mobilization within the metastatic site.

Conclusions: While CD8 infiltrate and HLA expression appear to be prognostic for mCRC, CD8 and PD-L1 infiltrate are enhanced by neoadjuvant chemotherapy in mCRC under RAS status dependence.
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http://dx.doi.org/10.1186/s40425-018-0438-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6245855PMC
November 2018

Prognostic and predictive role of CD8 and PD-L1 determination in lung tumor tissue of patients under anti-PD-1 therapy.

Br J Cancer 2018 10 15;119(8):950-960. Epub 2018 Oct 15.

Department of Medical Oncology, Center GF Leclerc, Dijon, France.

Background: No study has evaluated the predictive and prognostic role of CD8 and PD-L1 coexpression in non-small-cell lung cancer (NSCLC).

Methods: We analyzed RNA sequencing and/or immunohistochemistry staining in NSCLC patients from The Cancer Genome Atlas (n = 1016), and 34 metastatic NSCLC samples not treated by immunotherapy as prognostic cohorts. As predictive aspect of CD8 and PD-L1, we used 85 NSCLC patients treated with anti-PD-1. Two validation cohorts were used including 44 NSCLC patients treated with anti-PD-1 and an external cohort with different tumor types.

Results: In prognostic cohorts, high CD8A expression was associated with longer OS (p = 0.02), while high CD274 mRNA was associated with poor prognosis (p = 0.05). In predictive cohort, high CD8 expression and CD8A mRNA were associated with longer progression-free survival (PFS) (p = 0.0002). There was no significant association between PD-L1 expression and PFS while high CD274 mRNA was associated with longer PFS (p = 0.009). A combination of CD8A and CD274 was highly predictive of outcome. These results were confirmed in the validation cohorts. This two-genes signature demonstrated similar results compared to gold standard signatures.

Conclusion: CD8 represents both a prognostic and predictive factor of outcomes, while PD-L1 share different prognostic and predictive roles.
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http://dx.doi.org/10.1038/s41416-018-0220-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203820PMC
October 2018

Exome Analysis Reveals Genomic Markers Associated with Better Efficacy of Nivolumab in Lung Cancer Patients.

Clin Cancer Res 2019 02 28;25(3):957-966. Epub 2018 Aug 28.

Platform of Transfer in Cancer Biology, France.

Purpose: Immune checkpoint inhibitors revolutionized the treatment of non-small cell lung cancer (NSCLC). However, only one-quarter of patients benefit from these new therapies. PD-L1 assessment and tumor mutational burden (TMB) are available tools to optimize use of checkpoint inhibitors but novel tools are needed. Exome sequencing could generate many variables but their role in identifying predictors of response is unknown.

Experimental Design: We performed somatic and constitutional exome analyses for 77 patients with NSCLC treated with nivolumab. We studied: one-tumor-related characteristics: aneuploidy, CNA clonality, mutational signatures, TMB, mutations in WNT, AKT, MAPK, and DNA repair pathways, and two-immunologic characteristics: number of intratumoral TCR clones, HLA types, and number of neoantigens; and six clinical parameters.

Results: A high TMB per Mb, a high number of neoantigens, mutational signatures 1A and 1B, mutations in DNA repair pathways, and a low number of TCR clones are associated with greater PFS. Using a LASSO method, we established an exome-based model with nine exome parameters that could discriminate patients with good or poor PFS ( < 0.0001) and overall survival ( = 0.002). This model shows better ability to predict outcomes compared with a PD-L1 clinical model with or without TMB. It was externally validated on two cohorts of patients with NSCLC treated with pembrolizumab or with nivolumab and ipilimumab as well as in urothelial tumors treated with atezolizumab.

Conclusions: Altogether, these data provide a validated biomarker that predicts the efficacy of nivolumab or pembrolizumab in patients with NSCLC. Our biomarker seems to be superior to PD-L1 labeling and TMB models.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1940DOI Listing
February 2019

Baseline splenic volume as a surrogate marker of FOLFIRINOX efficacy in advanced pancreatic carcinoma.

Oncotarget 2018 May 22;9(39):25617-25629. Epub 2018 May 22.

Department of Medical Oncology, Center Georges Francois Leclerc, Dijon, France.

Background: The FOLFIRINOX regimen is the standard first-line treatment for advanced pancreatic adenocarcinoma (aPDAC). However, because of its potential toxicity, predictive biomarkers could help clinical decision-making.

Methods: A cohort of 97 aPDAC patients treated with first-line FOLFIRINOX were studied. The association between splenic volume and progression-free survival (PFS) and overall survival (OS) was evaluated using univariate and multivariable Cox analyses. The external validation cohort was composed of 117 patients treated with Gemcitabine and 52 patients treated with FOLFIRINOX.

Results: In the training cohort, the splenic volume of 97 patients was measured at baseline and at the end of therapy. The spleen size increased in 81% of patients, with at least a 50% increase in 27% of patients. Baseline splenomegaly predicted PFS (HR 1.812, 95% CI = [1.036-3.169]; = 0.03) and OS (HR 1.983, 95% CI = [1.085-3.624]; = 0.02) in the training cohort. These results were then validated in an external cohort of patients who were treated with FOLFIRINOX excluding those in the control cohort who were treated with gemcitabine. In a multivariate model based on the CoxBoost method, the following were selected as predictive markers of FOLFIRINOX efficacy (AUC = 0.81): performance status, liver metastasis, baseline Ca199 and CEA levels and baseline splenomegaly. The predictive ability of the model was validated in the external cohort that was also treated with FOLFIRINOX.

Conclusions: Baseline splenomegaly is a predictive marker of a poor response to FOLFIRINOX in aPDAC and remained predictive when associated with other clinical variables.
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http://dx.doi.org/10.18632/oncotarget.25424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986639PMC
May 2018

Solid papillary carcinoma with reverse polarity of the breast harbors specific morphologic, immunohistochemical and molecular profile in comparison with other benign or malignant papillary lesions of the breast: a comparative study of 9 additional cases.

Mod Pathol 2018 09 21;31(9):1367-1380. Epub 2018 May 21.

Département de Biologie et Pathologie des Tumeurs, Centre Georges-François Leclerc - Unicancer, 1 rue Professeur Marion, 21000, Dijon, France.

Solid papillary carcinoma with reverse polarity is a rare breast cancer of favorable prognosis that can be difficult to diagnose. We report here nine additional cases of this tumor, and we describe its morphologic, immunohistochemical and molecular profile in comparison to other types of papillary and micropapillary lesions of the breast that are intraductal papilloma with usual ductal hyperplasia, encapsulated papillary carcinoma, solid papillary carcinoma and invasive micropapillary carcinoma. We studied nine cases of this special papillary tumor and six of each other types mentioned above. We found that solid papillary carcinoma with reverse polarity harbor specific morphologic features as cuboid or tall cells with abundant eosinophilic cytoplasms located at the basal pole giving the impression of reverse nuclear polarity. Nuclei were sometimes grooved. Immunohistochemistry demonstrated the lack of myoepithelial cells, as in encapsulated papillary carcinoma and solid papillary carcinoma, questioning their invasive nature. Seven of nine solid papillary carcinoma with reverse polarity showed a low Ki67 proliferative index (Ki67 <5%). They showed expression of CK5/6 as in intraductal papilloma with usual ductal hyperplasia. They showed expression of calretinin and a low or lack of hormonal receptor (HR) expression that were not observed in other breast tumors studied. By whole-exome analysis, seven of nine solid papillary carcinomas with reverse polarity (78%) harbored a hotspot mutation in IDH2 (R172) that was totally absent in other groups. Six of nine tumors (67%) also harbored PRUNE2 mutation, including the two IDH2 wild-type cases. We also demonstrated for the first time in this breast tumor, immunostaining with a specific antibody IDH1/2 mutant R132/R172 (7/9) that can highlight IDH2 mutation. Moreover, transcriptomic analysis showed that proteoglycan pathway was significantly enriched. Our findings support the fact that solid papillary carcinoma with reverse polarity is a singular breast neoplasm that can be distinguished from other papillary breast tumors.
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http://dx.doi.org/10.1038/s41379-018-0047-1DOI Listing
September 2018

Linear MALDI-ToF simultaneous spectrum deconvolution and baseline removal.

BMC Bioinformatics 2018 04 5;19(1):123. Epub 2018 Apr 5.

Service de Biostatistique, Hospices Civils de Lyon, Lyon, 69000, France.

Background: Thanks to a reasonable cost and simple sample preparation procedure, linear MALDI-ToF spectrometry is a growing technology for clinical microbiology. With appropriate spectrum databases, this technology can be used for early identification of pathogens in body fluids. However, due to the low resolution of linear MALDI-ToF instruments, robust and accurate peak picking remains a challenging task. In this context we propose a new peak extraction algorithm from raw spectrum. With this method the spectrum baseline and spectrum peaks are processed jointly. The approach relies on an additive model constituted by a smooth baseline part plus a sparse peak list convolved with a known peak shape. The model is then fitted under a Gaussian noise model. The proposed method is well suited to process low resolution spectra with important baseline and unresolved peaks.

Results: We developed a new peak deconvolution procedure. The paper describes the method derivation and discusses some of its interpretations. The algorithm is then described in a pseudo-code form where the required optimization procedure is detailed. For synthetic data the method is compared to a more conventional approach. The new method reduces artifacts caused by the usual two-steps procedure, baseline removal then peak extraction. Finally some results on real linear MALDI-ToF spectra are provided.

Conclusions: We introduced a new method for peak picking, where peak deconvolution and baseline computation are performed jointly. On simulated data we showed that this global approach performs better than a classical one where baseline and peaks are processed sequentially. A dedicated experiment has been conducted on real spectra. In this study a collection of spectra of spiked proteins were acquired and then analyzed. Better performances of the proposed method, in term of accuracy and reproductibility, have been observed and validated by an extended statistical analysis.
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http://dx.doi.org/10.1186/s12859-018-2116-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5887234PMC
April 2018

Variance component analysis to assess protein quantification in biomarker discovery. Application to MALDI-TOF mass spectrometry.

Biom J 2018 03 12;60(2):262-274. Epub 2017 Dec 12.

Service de Biostatistique-Bioinformatique, Hospices Civils de Lyon, Lyon, France.

Controlling the technological variability on an analytical chain is critical for biomarker discovery. The sources of technological variability should be modeled, which calls for specific experimental design, signal processing, and statistical analysis. Furthermore, with unbalanced data, the various components of variability cannot be estimated with the sequential or adjusted sums of squares of usual software programs. We propose a novel approach to variance component analysis with application to the matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) technology and use this approach for protein quantification by a classical signal processing algorithm and two more recent ones (BHI-PRO 1 and 2). Given the high technological variability, the quantification failed to restitute the known quantities of five out of nine proteins present in a controlled solution. There was a linear relationship between protein quantities and peak intensities for four out of nine peaks with all algorithms. The biological component of the variance was higher with BHI-PRO than with the classical algorithm (80-95% with BHI-PRO 1, 79-95% with BHI-PRO 2 vs. 56-90%); thus, BHI-PRO were more efficient in protein quantification. The technological component of the variance was higher with the classical algorithm than with BHI-PRO (6-25% vs. 2.5-9.6% with BHI-PRO 1 and 3.5-11.9% with BHI-PRO 2). The chemical component was also higher with the classical algorithm (3.6-18.7% vs. < 3.5%). Thus, BHI-PRO were better in removing noise from signal when the expected peaks are detected. Overall, either BHI-PRO algorithm may reduce the technological variance from 25 to 10% and thus improve protein quantification and biomarker validation.
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http://dx.doi.org/10.1002/bimj.201600198DOI Listing
March 2018

Cholesterol trafficking and raft-like membrane domain composition mediate scavenger receptor class B type 1-dependent lipid sensing in intestinal epithelial cells.

Biochim Biophys Acta Mol Cell Biol Lipids 2018 Feb 2;1863(2):199-211. Epub 2017 Dec 2.

Centre de Recherche des Cordeliers, INSERM, UMPC Université Paris 6, Université Paris Descartes Paris 5, CNRS, F-75006 Paris, France. Electronic address:

Scavenger receptor Class B type 1 (SR-B1) is a lipid transporter and sensor. In intestinal epithelial cells, SR-B1-dependent lipid sensing is associated with SR-B1 recruitment in raft-like/ detergent-resistant membrane domains and interaction of its C-terminal transmembrane domain with plasma membrane cholesterol. To clarify the initiating events occurring during lipid sensing by SR-B1, we analyzed cholesterol trafficking and raft-like domain composition in intestinal epithelial cells expressing wild-type SR-B1 or the mutated form SR-B1-Q445A, defective in membrane cholesterol binding and signal initiation. These features of SR-B1 were found to influence both apical cholesterol efflux and intracellular cholesterol trafficking from plasma membrane to lipid droplets, and the lipid composition of raft-like domains. Lipidomic analysis revealed likely participation of d18:0/16:0 sphingomyelin and 16:0/0:0 lysophosphatidylethanolamine in lipid sensing by SR-B1. Proteomic analysis identified proteins, whose abundance changed in raft-like domains during lipid sensing, and these included molecules linked to lipid raft dynamics and signal transduction. These findings provide new insights into the role of SR-B1 in cellular cholesterol homeostasis and suggest molecular links between SR-B1-dependent lipid sensing and cell cholesterol and lipid droplet dynamics.
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http://dx.doi.org/10.1016/j.bbalip.2017.11.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5742559PMC
February 2018

Bayesian inference for biomarker discovery in proteomics: an analytic solution.

EURASIP J Bioinform Syst Biol 2017 Dec 14;2017(1). Epub 2017 Jul 14.

Service de Biostatistique - Bioinformatique, Hospices Civils de Lyon, Lyon, France.

This paper addresses the question of biomarker discovery in proteomics. Given clinical data regarding a list of proteins for a set of individuals, the tackled problem is to extract a short subset of proteins the concentrations of which are an indicator of the biological status (healthy or pathological). In this paper, it is formulated as a specific instance of variable selection. The originality is that the proteins are not investigated one after the other but the best partition between discriminant and non-discriminant proteins is directly sought. In this way, correlations between the proteins are intrinsically taken into account in the decision. The developed strategy is derived in a Bayesian setting, and the decision is optimal in the sense that it minimizes a global mean error. It is finally based on the posterior probabilities of the partitions. The main difficulty is to calculate these probabilities since they are based on the so-called evidence that require marginalization of all the unknown model parameters. Two models are presented that relate the status to the protein concentrations, depending whether the latter are biomarkers or not. The first model accounts for biological variabilities by assuming that the concentrations are Gaussian distributed with a mean and a covariance matrix that depend on the status only for the biomarkers. The second one is an extension that also takes into account the technical variabilities that may significantly impact the observed concentrations. The main contributions of the paper are: (1) a new Bayesian formulation of the biomarker selection problem, (2) the closed-form expression of the posterior probabilities in the noiseless case, and (3) a suitable approximated solution in the noisy case. The methods are numerically assessed and compared to the state-of-the-art methods (t test, LASSO, Battacharyya distance, FOHSIC) on synthetic and real data from proteins quantified in human serum by mass spectrometry in selected reaction monitoring mode.
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http://dx.doi.org/10.1186/s13637-017-0062-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5511129PMC
December 2017

Immune classifications with cytotoxic CD8 and Th17 infiltrates are predictors of clinical prognosis in glioblastoma.

Oncoimmunology 2017;6(6):e1321186. Epub 2017 Apr 28.

Department of Medical Oncology, Georges Francois Leclerc Cancer Center, Dijon, France.

Background: Interest is growing on immune cells involvement in central nervous system tumors such as glioblastoma. Even if a few reports highlighted that immune classifications could have a prognostic value, no paradigm has been clearly yet established on large and homogeneous cohorts. The aim of our study was to analyze the prognostic role of the in situ immune response of cytotoxic T cells (i.e., CD8), Foxp3 cells, Th17 and tumor-associated macrophages in glioblastoma on two independent large and homogeneous cohorts.

Methods: We worked on two large homogenous cohorts of patients having glioblastoma who underwent standard radiochemotherapy. The first cohort of 186 patients was analyzed using IHC procedures (CD8, IL-17A, FoxP3 and CD163) of surgery pieces. We next worked with transcriptomic data available online and used metagene strategy analysis for the second cohort of 525 patients.

Results: Cytotoxic CD8 lymphocytes and Foxp3 cells were associated with a good prognosis, while Th17 were associated with a poor clinical outcome. These data were confirmed with transcriptomic analysis. Moreover, we showed for the first time a strong link between angiogenesis and Th17 metagenes expressions in glioblastoma.

Conclusions: Our study shows that glioblastoma bearing patients can be classified on the immune infiltrate aspects. Beyond this prognostic role of immune biomarkers, subsequent classifications could definitely help clinicians to handle targeted therapy administration and immunotherapeutic interventions.
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http://dx.doi.org/10.1080/2162402X.2017.1321186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486170PMC
April 2017

Cholesterol metabolism and glaucoma: Modulation of Muller cell membrane organization by 24S-hydroxycholesterol.

Chem Phys Lipids 2017 10 4;207(Pt B):179-191. Epub 2017 Jun 4.

Centre des Sciences du GoÛt et de l'Alimentation, AgroSup Dijon, CNRS, INRA, Université Bourgogne Franche-Comté, Dijon, France.

Glaucoma is a progressive and irreversible blinding neuropathy that is characterized by the loss of retinal ganglion cells (RGCs). Muller Glial Cell (MGC) activation is induced in retinal gliosis. MGCs are the most numerous glial cells in the retina and one of their roles is to sustain cholesterol homeostasis. 24S-hydroxycholesterol (24S-OHC) is one of the form of cholesterol elimination from the retina and is overexpressed during glaucoma. The objective of this study was to determine whether 24S-OHC triggers MGC membrane dynamics involving lipid rafts and contributes to gliosis at early and late time points. A proteomic analysis was carried out by nanoLC-MS/MS in raft and non-raft fractions from MGCs after treatment with 24S-OHC (10μM). The expression of structural and functional proteins was further analyzed by Western-blotting, as well as the levels of GM3 ganglioside by LC-MS. Cholesterol, sphingomyelin, saturated fatty acids and ganglioside GM3 are enriched in the rafts fractions in MGCs. Caveolin-1, flotillin-1, connexin-30 and -43 are localized in the MGCs rafts. Proteins implicated in adhesion or oxidative stress pathways in raft fractions were up and down-regulated by the treatment. Our data showed that 24S-OHC induced early changes in protein distribution in raft microdomains; however, further studies are needed to better characterize the surrounded mechanisms.
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http://dx.doi.org/10.1016/j.chemphyslip.2017.05.007DOI Listing
October 2017

Peroxisomal ATP-binding cassette transporters form mainly tetramers.

J Biol Chem 2017 04 3;292(17):6965-6977. Epub 2017 Mar 3.

From the Laboratoire Bio-PeroxIL EA7270 and

ABCD1 and its homolog ABCD2 are peroxisomal ATP-binding cassette (ABC) half-transporters of fatty acyl-CoAs with both distinct and overlapping substrate specificities. Although it is established that ABC half-transporters have at least to dimerize to generate a functional unit, functional equivalents of tetramers ( dimers of full-length transporters) have also been reported. However, oligomerization of peroxisomal ABCD transporters is incompletely understood but is of potential significance because more complex oligomerization might lead to differences in substrate specificity. In this work, we have characterized the quaternary structure of the ABCD1 and ABCD2 proteins in the peroxisomal membrane. Using various biochemical approaches, we clearly demonstrate that both transporters exist as both homo- and heterotetramers, with a predominance of homotetramers. In addition to tetramers, some larger molecular ABCD assemblies were also found but represented only a minor fraction. By using quantitative co-immunoprecipitation assays coupled with tandem mass spectrometry, we identified potential binding partners of ABCD2 involved in polyunsaturated fatty-acid metabolism. Interestingly, we identified calcium ATPases as ABCD2-binding partners, suggesting a role of ABCD2 in calcium signaling. In conclusion, we have shown here that ABCD1 and its homolog ABCD2 exist mainly as homotetramers in the peroxisomal membrane.
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http://dx.doi.org/10.1074/jbc.M116.772806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5409465PMC
April 2017

Associations between food consumption patterns and saliva composition: Specificities of eating difficulties children.

Physiol Behav 2017 05 6;173:116-123. Epub 2017 Feb 6.

Centre des Sciences du Goût et de l'Alimentation, CNRS, INRA, Université de Bourgogne Franche-Comté, F-21000 Dijon, France.

Identifying objective markers of diet would be beneficial to research fields such as nutritional epidemiology. As a preliminary study on the validity of using saliva for this purpose, and in order to explore the relationship between saliva and diet, we focused on clearly contrasted groups of children: children with eating difficulties (ED) receiving at least 50% of their energy intake through artificial nutrition vs healthy controls (C). Saliva of ED and C children was analyzed by various methods (targeted biochemical analyses, 2-D electrophoresis coupled to MS, H NMR) and their diet was characterized using food frequency questionnaires, considering 148 food items grouped into 13 categories. Complete datasets were obtained for 16 ED and 16 C subjects (median age 4.7y and 5.0y, respectively) and the statistical link between salivary and dietary characteristics was studied by Multiple Factor Analysis (MFA). Overall, ED children showed as expected lower consumption frequency scores and higher food selectivity. The two groups of children differed in "diet/saliva" associations. Some distinctive salivary variables were common to both groups of children. For example, carbonic anhydrase 6 and the consumption frequency of biscuits & sweets and drinks were positively associated with the MFA axis 1 in C children, but oppositely associated in ED children. Specifically for ED children, abundant salivary proteins (cystatins, amylase, amylase fragments) and some metabolites (amino acids, galactose, lactate) correlated with axis 1, together with the consumption frequency of sauces & seasonings, bread & cereal products, ready-to-eat meals, fish, biscuits & sweets, drinks and potatoes. Specifically for C children, several proteins (serum albumin, haptoglobin, Igκ, apolipoprotein A-1, α-1 antitrypsin) correlated with axis 1, together with the consumption frequency of biscuits & sweets, milk & dairy products, drinks, fruit, meat and vegetables. This study demonstrates that the qualitative aspect of diet is linked to saliva composition, and that the associations between dietary consumption and salivary composition differ between groups of subjects with contrasted diets.
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http://dx.doi.org/10.1016/j.physbeh.2017.02.005DOI Listing
May 2017

Blood baseline neutrophil count predicts bevacizumab efficacy in glioblastoma.

Oncotarget 2016 Oct;7(43):70948-70958

Department of Medical Oncology, Georges Francois Leclerc Cancer Center, Dijon, France.

Bevacizumab is used to treat glioblastoma; however, no current biomarker predicts its efficacy. We used an exploratory cohort of patients treated with the radiochemotherapy then bevacizumab or chemotherapy at recurrence (N = 265). Bevacizumab use increased median overall survival (OS) 18.7 vs 11.3 months, p = 0.0014). In multivariate analysis, age, initial surgery, neutrophil count, Karnofsky status >70% and bevacizumab administration were independent prognostic factors of survival. We found an interaction between bevacizumab use and baseline neutrophil count. The cut-off value for the neutrophil count was set at 6000/mm3. Only patients with a high neutrophil count benefited from the bevacizumab treatment (17.3 vs 8.8 months p < 0.0001). We validated this result using data from the TEMAVIR trial, which tested the efficacy of neoadjuvant bevacizumab plus irinotecan versus radiochemotherapy in the first-line treatment of glioblastoma. Transcriptomic data from TCGA underlined that CSF3 expression, the gene encoding G-CSF, the growth factor for neutrophils, correlated with VEGF-A-dependent angiogenesis. In another independent cohort (BELOB trial), which compared lomustine versus lomustine plus bevacizumab at recurrence, bevacizumab only benefited patients with high CSF3 expression in the tumor. These data suggest that only patients with a high peripheral neutrophil count before bevacizumab treatment benefited from this therapy.
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http://dx.doi.org/10.18632/oncotarget.10898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342600PMC
October 2016

Specific enrichment of 2-arachidonoyl-lysophosphatidylcholine in carotid atheroma plaque from type 2 diabetic patients.

Atherosclerosis 2016 08 4;251:339-347. Epub 2016 May 4.

Centre Hospitalier Universitaire Dijon, Hôpital du Bocage, 21034, Dijon, France; CRB Ferdinand Cabanne BB-0033-00044, France; Centre Hospitalier Louis Pasteur, Colmar, France.

Background And Aims: Diabetic patients are at high risk of stroke and coronary artery disease. Recent data suggest that arachidonic acid metabolism is altered in diabetic conditions and that these alterations contribute to accelerated atherosclerosis. Little is known about how these alterations affect the metabolism and the proportions of different lipid species within the atherosclerotic plaque. The aim of our study was to perform a targeted lipidomic analysis of human atherosclerotic lesions, with a specific focus on PUFA-containing lipid species, to reveal differences in the fatty-acid composition of plaque in diabetic patients compared with non-diabetic controls.

Methods: Carotid atheroma plaque samples were obtained from 31 diabetic and 48 non-diabetic patients undergoing carotid endarterectomy. Targeted lipidomic analysis was then performed to determine the fatty acid composition of major glycerophospholipids and cholesteryl ester species by liquid chromatography-tandem mass spectrometry.

Results: Atheroma plaques from diabetic patients were significantly enriched with 2-arachidonoyl-lysophosphatidylcholine (2-AA-LPC) (2.3 ± 0.8% Vs. 1.8 ± 0.6% p = 0.0002). Multivariable logistic regression showed that an increased 2-AA-LPC level was independently associated with diabetes. Finally, a positive relationship was found between 2-AA-LPC and HbA1c levels. Interestingly, endothelial lipase and calcium independent PLA2 gamma which could account for the production of 2-AA-LPC were detected in carotid plaques by immunohistochemistry.

Conclusions: 2-AA-LPC stands at the crossroads of major metabolic pathways that lead to the synthesis of bioactive molecules such as AA-derived eicosanoids, 2-AA-lysophosphatidic acid and 2-AA-glycerol. 2-AA-LPC therefore appears to be a promising molecule to investigate in the context of diabetes.
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http://dx.doi.org/10.1016/j.atherosclerosis.2016.05.004DOI Listing
August 2016

A measure of the impact of CV incompleteness on prediction error estimation with application to PCA and normalization.

BMC Med Res Methodol 2015 Nov 4;15:95. Epub 2015 Nov 4.

Department of Medical Informatics, Biometry and Epidemiology, University of Munich, Marchioninistr. 15, Munich, D-81377, Germany.

Background: In applications of supervised statistical learning in the biomedical field it is necessary to assess the prediction error of the respective prediction rules. Often, data preparation steps are performed on the dataset-in its entirety-before training/test set based prediction error estimation by cross-validation (CV)-an approach referred to as "incomplete CV". Whether incomplete CV can result in an optimistically biased error estimate depends on the data preparation step under consideration. Several empirical studies have investigated the extent of bias induced by performing preliminary supervised variable selection before CV. To our knowledge, however, the potential bias induced by other data preparation steps has not yet been examined in the literature. In this paper we investigate this bias for two common data preparation steps: normalization and principal component analysis for dimension reduction of the covariate space (PCA). Furthermore we obtain preliminary results for the following steps: optimization of tuning parameters, variable filtering by variance and imputation of missing values.

Methods: We devise the easily interpretable and general measure CVIIM ("CV Incompleteness Impact Measure") to quantify the extent of bias induced by incomplete CV with respect to a data preparation step of interest. This measure can be used to determine whether a specific data preparation step should, as a general rule, be performed in each CV iteration or whether an incomplete CV procedure would be acceptable in practice. We apply CVIIM to large collections of microarray datasets to answer this question for normalization and PCA.

Results: Performing normalization on the entire dataset before CV did not result in a noteworthy optimistic bias in any of the investigated cases. In contrast, when performing PCA before CV, medium to strong underestimates of the prediction error were observed in multiple settings.

Conclusions: While the investigated forms of normalization can be safely performed before CV, PCA has to be performed anew in each CV split to protect against optimistic bias.
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http://dx.doi.org/10.1186/s12874-015-0088-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4634762PMC
November 2015

Multi-omics profiling reveals that eating difficulties developed consecutively to artificial nutrition in the neonatal period are associated to specific saliva composition.

J Proteomics 2015 Oct 29;128:105-12. Epub 2015 Jul 29.

CNRS, UMR6265 Centre des Sciences du Goût et de l'Alimentation, F-21000 Dijon, France; INRA, UMR1324 Centre des Sciences du Goût et de l'Alimentation, F-21000 Dijon, France; Université de Bourgogne, UMR Centre des Sciences du Goût et de l'Alimentation, F-21000 Dijon, France.

Prolonged enteral or parenteral nutrition in neonatal periods sometimes results in eating difficulties persisting for years, with reduced food intake through the oral route and thereby reduced stimulation of the oral cavity. Aiming at describing the consequences on oral physiology, saliva of 21 children with eating difficulties (ED) was compared to that of 23 healthy controls, using various omics and targeted methods. Overall, despite heterogeneity within the groups (age, medication etc.), the three spectral methods (MALDI-TOF, SELDI-TOF, (1)H NMR) allowed discriminating ED and controls, confirming that oral stimulation by food intake plays a role in shaping the composition of saliva. Saliva of ED patients exhibited a lower antioxidant status and lower levels of the salivary protease inhibitors cystatins. Other discriminant features (IgA1, dimethylamine) may relate to modified oral and/or intestinal microbial ecology. Finally, salivary profiles of ED patients were partly comparable to those of subjects with exacerbated gustatory sensitivities, in particular with reduced abundance of cystatin SN and higher abundance of zinc-alpha-2-glycoprotein. Whether this translates taste hypersensitivity and contributes to the eating difficulties deserves further attention.
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http://dx.doi.org/10.1016/j.jprot.2015.07.028DOI Listing
October 2015