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Colon cancer stemness as a reversible epigenetic state:Implications for anticancer therapies

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World Journal of Stem Cells 2019年第11期11卷 920-936页

作者： Audrey Vincent Aicha Ouelkdite-Oumouchal Mouloud Souidi julie leclerc Bernadette Neve Isabelle Van Seuningen Lille University Institut National de la Sante et de la Recherche MédicaleCHU LilleUMR-S 1172-Jean-Pierre Aubert Research CenterLille F-59000France Department of Biochemistry and Molecular Biology Lille University HospitalLille F-59000France

The recent discovery of cancer cell plasticity,*** ability to reprogram into cancer stem cells(CSCs)either naturally or under chemotherapy and/or radiotherapy,has changed,once again,the way we consider cancer *** cancer stemness is a reversible epigenetic state rather than a genetic identity,opportunities will arise for therapeutic strategies that remodel epigenetic landscapes of ***,the systematic use of DNA methyltransferase and histone deacetylase inhibitors,alone or in combination,in advanced solid tumors including colorectal cancers,regardless of their molecular subtypes,does not seem to be the best *** this review,we first summarize the knowledge researchers have gathered on the epigenetic signatures of CSCs with the difficulty of isolating rare populations of *** raise questions about the relevant use of currently available epigenetic inhibitors(epidrugs)while the expression of numerous cancer stem cell markers are often repressed by epigenetic *** markers include the three cluster of differentiation CD133,CD44 and CD166 that have been extensively used for the isolation of colon ***,we describe current treatment strategies using epidrugs,and we hypothesize that,using correlation tools comparing associations of relevant CSC markers with chromatin modifier expression,we could identify better candidates for epienzyme targeting.

关键词： Cancer stem cells Colon cancer Epigenetics Chromatin modifying enzymes CD44 CD133 CD166

EGFR amplification induces sensitivity to antiEGFR therapy in pancreatic acinar cell carcinoma

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World Journal of Gastrointestinal Oncology 2018年第4期10卷 103-107页

作者： Corentin Richard julie Niogret Romain Boidot Francois Ghiringhelli Platform of Transfer in Oncology Center GF LeclercDijon 21000France INSERM U1231 Dijon 21000France University of Bourgogne Franche Comte Dijon 21000France Department of Medical Oncology Georges Francois Leclerc Cancer CenterDijon 21000France

Pancreatic acinar cell carcinoma(PACC) is a rare cancer. When the tumor is metastatic, few therapeutic options are available. Precision medicine using next-generation sequencing is defined by the administration of drugs based on the tumor genetic mutations. The usage of precision medicine for finding new therapeutic options for rare cancers is an emerging field. We have reported here the case of a patient bearing a multitreated metastatic PACC. This patient underwent somatic and constitutional exome analyses. The analyses revealed in the liver metastasis an amplification of the EGFR gene. Accordingly, the patient was treated with off-label usage of panitumumab. We observed rapid response with necrosis of the liver metastasis, while no efficacy was observed in the primary tumor. An exome analysis of the primary tumor revealed amplification of HER2 and MET with EGFR amplification. Such amplifications are known as a resistance mechanism to anti EGFR therapy. Our results suggest that exome analysis may be helpful to highlight targets in rare cancers, such as PACC. EGFR amplification in this pathology should be determined and could be used as a biomarker to propose anti EGFR therapy.

关键词： Pancreatic cancer Acinar cell carcinoma Exome Genetic mutations Precision medicine

Prognostic value of chemotherapy-induced hematological toxicity in metastatic colorectal cancer patients

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World Journal of Gastroenterology 2014年第6期20卷 1565-1573页

作者： Laurie Rambach Aurelie Bertaut julie Vincent Veronique Lorgis Sylvain Ladoire Francois Ghiringhelli Department of Medical Oncology Centre Georges-Fran ois Leclerc Biostatistics and Epidemiological Unit EA4184 Centre Georges-Fran ois Leclerc Institut National de la Santé et de la Recherche Médicale (INSERM) CRI-866 Faculty of Medicine School of Medicine University of Burgundy

AIM: To establish whether chemotherapy-induced neutropenia is predictive of better outcome in patients with metastatic colorectal cancer (mCRC).

关键词： Colorectal cancer Metastasis Prognostic factor Neutropenia Chemotherapy

FOLFIRI plus bevacizumab as a second-line therapy for metastatic intrahepatic cholangiocarcinoma

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World Journal of Gastroenterology 2015年第7期21卷 2096-2101页

作者： Jean-Florian Guion-Dusserre Veronique Lorgis julie Vincent Leila Bengrine Francois Ghiringhelli Department of Medical Oncology Centre Georges-Fran?ois Leclerc Institut National de la Santé et de la Recherche Médicale University of Burgundy

AIM:To evaluate the efficacy and tolerance of FOLFIRI plus bevacizumab treatment outcome as second-line treatment for metastatic intrahepatic ***:Thirteen consecutive patients with metastatic intrahepatic cholangiocarcinoma who were refractory tofirst-line therapy consisting of gemcitabine plus oxaliplatinbased first-line chemotherapy given intravenously via intra-arterial infusion were treated with FOLFIRI[irinotecan(180 mg/m2 *** 90 min)concurrently with folinic acid(400 mg/m2 *** 120 min)followed by fluorouracil(400 mg/m2 ***)then fluorouracil 2400 mg/m2 intravenous infusion over 46 h]and bevacizumab(5mg/kg)every 2 *** response was evaluated by computed tomography scan every 4 ***:The best tumor responses using response evaluation criteria in solid tumor criteria were:complete response for 1 patient,partial response for 4 patients,and stable disease for 6 patients after 6 mo of *** response rate was 38.4%(95%CI:12.5-89)and the disease control rate was 84.5%(95%CI:42-100).Seven deaths occurred at the time of analysis,progression free survival was 8 mo(95%CI:7-16),and median overall survival was 20 mo(95%CI:8-48).No grade 4toxic events were *** grade 3 hematological toxicities and one grade 3 digestive toxicity *** adaptive reduction in chemotherapy dosage was required in 2 patients due to hematological toxicity,and a delay in chemotherapy cycles was required for 3 ***:FOLFIRI plus bevacizumab combination treatment showed promising efficacy and safety as second-line treatment for metastatic intrahepatic cholangiocarcinoma after failure of the first-line treatment of gemcitabine plus oxaliplatin chemotherapy.

关键词： Biliary tract cancer Intrahepatic cholangiocarcino

Influence of primary tumor location and resection on survival in metastatic colorectal cancer

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World Journal of Gastrointestinal Oncology 2020年第11期12卷 1296-1310页

作者： ZoéTharin julie Blanc Ikram Charifi Alaoui Aurélie Bertaut François Ghiringhelli Department of Medical Oncology Centre Georges-François LeclercDijon 21000France Department of Bioastatistics Centre Georges-François LeclercDijon 21000France

BACKGROUND Patients with right sided colorectal cancer are known to have a poorer prognosis than patients with left sided colorectal cancer, whatever the cancer stage. To this day, primary tumor resection(PTR) is still controversial in a metastatic, non resectable *** To explore the survival impact of PTR in patients with metastatic colorectal cancer(mCRC) depending on *** We retrospectively collected data from all consecutive patients treated for mCRC at the Centre Georges Francois leclerc Hospital. Univariate and multivariate Cox proportional hazard regression models were used to assess the influence of PTR on survival. We then evaluated the association between PTL and overall survival among patients who previously underwent or did not undergo PTR. A propensity score was performed to match *** Four hundred and sixty-six patients were included. A total of 153(32.8%) patients had unresected synchronous mCRC and 313(67.2%) patients had resected synchronous mCRC. The number of patients with right colic cancer, left colic cancer and rectal cancer was respectively 174(37.3%), 203(43.6%) and 89(19.1%). In the multivariate analysis only PTL, PTR, resection of hepatic and or pulmonary metastases and the use of oxaliplatin, EGFR inhibitors or bevacizumab throughout treatment were associated to higher overall survival rates. Survival evaluation depending on PTR and PTL found that PTR improved the prognosis of both left and right sided mCRC. Results were confirmed by using a weighted propensity *** In mCRC, PTR seems to confer a higher survival rate to patients whatever the PTL.

关键词： Colorectal cancer Metastatic Primary tumor resection Chemotherapy Primary tumor location Synchronous

Safety and efficacy of a docetaxel-5FU-oxaliplatin regimen with or without trastuzumab in neoadjuvant treatment of localized gastric or gastroesophageal junction cancer: A retrospective study

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World Journal of Gastrointestinal Oncology 2019年第8期11卷 634-641页

作者： Valeria Basso David Orry Jean Fraisse julie Vincent Audrey Hennequin Leila Bengrine Francois Ghiringhelli Department of Surgery Centre Georges Francois LeclercDijon 21000France Department of Medical Oncology Centre Georges Francois LeclercDijon 21000France

BACKGROUND Triplet chemotherapy,with docetaxel-5FU-oxaliplatin FLOT regimen recently became the standard perioperative treatment for localized gastric cancer(GC).An adapted regimen called TeFOX was recently tested in metastatic setting and gave promising *** To determine safety and efficacy of TeFOX perioperative *** This monocentric retrospective study aims to test efficacy and safety of the perioperative TeFOX regimen given alone or in combination with trastuzumab in patients with localized *** consist in docetaxel(50 mg/m^2)with oxaliplatin 85 mg/m^2 and and leucovorin(400mg/m^2^)5 FU bolus(400mg/m^2)on day 1,followed by continuous infusion of 5FU for 46h(2400mg/m^2)every 2 *** Thirty-three consecutive patients were included in this retrospective *** patients have a gastroesophageal junction cancer and 11 have a *** follow-up of surviving patients was 32 mo.R0 resection was obtained in 30(91)*** patients(36)had a pathological complete response and 8(24)patients a nearly complete pathological *** OS and PFS were not reached at data base *** have observed 6 metastatic relapses and 1 localized *** relapse was observed in patients with pathological complete *** most common grade 3-4 adverse events were peripheral neuropathy(21)and asthenia(20).CONCLUSION TeFOX regimen could be safely administrated in perioperative treatment of localized *** and the FLOT regimen have comparable efficacy and safety profiles.

关键词： Gastric cancer Neoadjuvant chemotherapy TeFOX Retrospective study

Folfirinox in elderly patients with pancreatic or colorectal cancer-tolerance and efficacy

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World Journal of Gastroenterology 2016年第42期22卷 9378-9386页

作者： Jean-Florian Guion-Dusserre Aurélie Bertaut Fran?ois Ghiringhelli julie Vincent Valérie Quipourt Sophie Marilier Zoé Tharin Leila Bengrine-Lefevre Department of Medical Oncology Centre Georges-Fran?ois Leclerc Institut National de la Santé et de la Recherche Médicale University of Burgundy

AIM To study the tolerance and the efficiency of FOLFIRINOX in elderly patients diagnosed with colorectal or pancreatic *** This retrospective study included elderly patients aged over 70 years of age treated at Georges-Francois leclerc Center by FOLFIRINOX for histological proved colorectal or pancreatic cancer between January 2009 and January 2015. Chemotheapy regimen consisted of oxaliplatin(85 mg/m2 in over 120 min) followed by leucovorin(400 mg/m2 in over 120 min), with the addition, after 30 min of irinotecan(180 mg/m2 in over 90 min) then 5 fluorouracil(5FU)(400 mg/m2 administred intravenous bolus), followed by 5FU(2400 mg/m2 intraveinous infusion over 46 h) repeated every 2 wk. Geriatric parameters were recorded at the beginning. Toxicities were evaluated with the Common Terminology Criteria for Adverse Events 4.03. Tumor response was evaluated by CT scan. Treatment continued until disease progression, unacceptable toxicities or patient *** Fifty-two patients aged from 70 to 87 years were treated by FOLFIRINOX, 34 had colorectal cancer and 18 had pancreatic cancer. Most of them were in good general condition, 82.7% had a 0-1 performance status and 61.5% had a Charlson Comorbidity Index < 10. The most frequent severe toxicities were neutropenia(17 patients, n = 32.7%) and diarrhea(35 patients n = 67.3%); 10 of the case of neutropenia and 5 of diarrhea registered a grade 4 toxicity. Thirty-nine patients(75%) initially received an adapted dose of chemotherapy. The dosage was adjusted for 26% of patients during the course of treatment. Tumor response evaluated by RECIST criteria showed a controlled disease for 25 patients(48.1%), a stable disease for 13 and a partial response for 12 patients. Time under treatment was higher for colorectal cancer with a median time of 2.44 mo(95%CI: 1.61-3.25). Overall survival was 43.88 mo for colorectal cancer and 12.51 mo for pancreatic cancer. In univariate or multivariate analysis, none of geriatric pa

关键词： Elderly patients Feasibility treatment Pancreatic cancer Colorectal cancer FOLFIRINOX

Retrospective evaluation of FOLFIRI3 alone or in combination with bevacizumab or aflibercept in metastatic colorectal cancer

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World Journal of Clinical Oncology 2019年第2期10卷 75-85页

作者： Madeline Devaux Laura Gerard Corentin Richard Leila Bengrine-Lefevre julie Vincent Antonin Schmitt Fran?ois Ghiringhelli Department of Medical Oncology Centre George Fran?ois Leclerc Platform of Transfer in Biological Oncology Centre George Fran?ois Leclerc

BACKGROUND The treatment of metastatic colorectal cancer(mCRC) relies of chemotherapy. The efficacy of the standard FOLFIRI-therapy could be improved by a modification of the regimen by splitting the dose of irinotecan on day 1 and day 3 in the FOLFIRI3 *** To determine safety and efficacy of FOLFIRI3 *** This is a monocentric retrospective study evaluating the efficacy and safety of the FOLFIRI3 regimen given alone or in combination with bevacizumab or aflibercept in patients with previously treated *** One hundred and fifty-three consecutive patients were included(18 treated with FOLFIRI3, 99 with FOLFIRI3 plus bevacizumab and 36 with FOLFIRI3 plus aflibercept). The overall response rate(ORR) and disease control rate were 51%and 62%, respectively. Similar ORRs were observed in all 3 cohorts. Median progression-free survival(PFS) and overall survival(OS) were 3.9 mo(95%CI:3.2-4.9) and 9.4 mo(95%CI: 6.6-12), respectively. Median PFS and OS values were improved in the FOLFIRI3 plus aflibercept group. The most common grade 3-4 adverse events were diarrhoea(21.6%) and neutropenia(11.8%), and these toxicities were more frequent in the FOLFIRI3 plus aflibercept group. According to the multivariate Cox proportional model, previous surgery of metastasis andaflibercept were associated with *** The modification of the FOLFIRI regimen impacted treatment response of mCRC patients. The addition of an antiangiogenic agent, in particular aflibercept,enhanced the clinical benefit and improved survival.

关键词： Colorectal cancer Chemotherapy Irinotecan Second-line Aflibercept