Publications by authors named "Emilie Soularue"

12 Publications

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Local treatment of pancreatic cancer metastases: A multicenter French study of the AGEO group.

Clin Res Hepatol Gastroenterol 2021 Mar 1;45(6):101607. Epub 2021 Mar 1.

Department of Oncology, Institute Mutualiste Montsouris, 42 Boulevard Jourdan, 75014 Paris, France.

Objective: This study reports the efficacy and safety of local treatment of metastases of pancreatic ductal adenocarcinoma (PDAC), with a curative intent.

Methods: We retrospectively included patients with histologically proven PDAC, who underwent a local treatment for metastases between January 1, 2000 and December 31, 2017, from 11 French hospitals. Complications of local treatment were reported. Univariate Cox models were performed to identify prognosis factors associated with overall survival (OS) and disease-free survival (DFS).

Results: We included 52 patients treated for 68 metastases; 33 (64%) of whom had metachronous metastases. Metastatic sites treated were: 39 (57%) hepatic, 18 (27%) pulmonary and 11 (16%) others. Metastases treatments were: 45 (66%) surgery, 9 (13%) radiofrequency and 14 (21%) other procedures. The rates of severe complications and mortality were respectively 10% and 4%. The median OS and DFS after local treatment were 36.5 months and 12.7 months, respectively. Prognosis factors associated with a shorter OS were: liver metastases when compared with lung metastases (HR 4.04; 95%CI: 1.18-13.81), N2 status of primary pancreatic tumor when compared to N0-N1 (HR 9.43; 95%CI: 2.44-36.36) and synchronous metastases when compared to metachronous metastases (HR 2.34; 95%CI: 1.05-5.23). N2 status of primary pancreatic tumor was associated with a shorter DFS when compared to N0-N1 (HR 2.82; 95%CI: 1.05-7.58).

Conclusion: In this series of highly selected patients, local treatment of metastases from PDAC is associated with prolonged survival. The rate of severe complications was low. Factors associated with shorter OS were liver metastases, N2 status and synchronous metastases.
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http://dx.doi.org/10.1016/j.clinre.2020.101607DOI Listing
March 2021

Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer.

Nat Commun 2020 05 1;11(1):2168. Epub 2020 May 1.

Université Paris-Saclay, Institut Gustave Roussy, Inserm, CNRS, Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse, Laboratoire d'Immunomonitoring en Oncologie, F-94805, Villejuif, France.

Gut microbiota composition influences the clinical benefit of immune checkpoints in patients with advanced cancer but mechanisms underlying this relationship remain unclear. Molecular mechanism whereby gut microbiota influences immune responses is mainly assigned to gut microbial metabolites. Short-chain fatty acids (SCFA) are produced in large amounts in the colon through bacterial fermentation of dietary fiber. We evaluate in mice and in patients treated with anti-CTLA-4 blocking mAbs whether SCFA levels is related to clinical outcome. High blood butyrate and propionate levels are associated with resistance to CTLA-4 blockade and higher proportion of Treg cells. In mice, butyrate restrains anti-CTLA-4-induced up-regulation of CD80/CD86 on dendritic cells and ICOS on T cells, accumulation of tumor-specific T cells and memory T cells. In patients, high blood butyrate levels moderate ipilimumab-induced accumulation of memory and ICOS + CD4 + T cells and IL-2 impregnation. Altogether, these results suggest that SCFA limits anti-CTLA-4 activity.
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http://dx.doi.org/10.1038/s41467-020-16079-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195489PMC
May 2020

Withholding the Introduction of Anti-Epidermal Growth Factor Receptor: Impact on Outcomes in RAS Wild-Type Metastatic Colorectal Tumors: A Multicenter AGEO Study (the WAIT or ACT Study).

Oncologist 2020 02 2;25(2):e266-e275. Epub 2019 Oct 2.

Department of Gastroenterology, Cochin Hospital, Paris, France.

Background: Patients with RAS wild-type (WT) nonresectable metastatic colorectal cancer (mCRC) may receive either bevacizumab or an anti-epidermal growth factor receptor (EGFR) combined with first-line, 5-fluorouracil-based chemotherapy. Without the RAS status information, the oncologist can either start chemotherapy with bevacizumab or wait for the introduction of the anti-EGFR. Our objective was to compare both strategies in a routine practice setting.

Materials And Methods: This multicenter, retrospective, propensity score-weighted study included patients with a RAS WT nonresectable mCRC, treated between 2013 and 2016 by a 5-FU-based chemotherapy, with either delayed anti-EGFR or immediate anti-vascular endothelial growth factor (VEGF). Primary criterion was overall survival (OS). Secondary criteria were progression-free survival (PFS) and objective response rate (ORR).

Results: A total of 262 patients (129 in the anti-VEGF group and 133 in the anti-EGFR group) were included. Patients receiving an anti-VEGF were more often men (68% vs. 56%), with more metastatic sites (>2 sites: 15% vs. 9%). The median delay to obtain the RAS status was 19 days (interquartile range: 13-26). Median OS was not significantly different in the two groups (29 vs. 30.5 months, p = .299), even after weighting on the propensity score (hazard ratio [HR] = 0.86, 95% confidence interval [CI], 0.69-1.08, p = .2024). The delayed introduction of anti-EGFR was associated with better median PFS (13.8 vs. 11.0 months, p = .0244), even after weighting on the propensity score (HR = 0.74, 95% CI, 0.61-0.90, p = .0024). ORR was significantly higher in the anti-EGFR group (66.7% vs. 45.6%, p = .0007).

Conclusion: Delayed introduction of anti-EGFR had no deleterious effect on OS, PFS, and ORR, compared with doublet chemotherapy with anti-VEGF.

Implications For Practice: For RAS/RAF wild-type metastatic colorectal cancer, patients may receive 5-fluorouracil-based chemotherapy plus either bevacizumab or an anti-epidermal growth factor receptor (EGFR). In daily practice, the time to obtain the RAS status might be long enough to consider two options: to start the chemotherapy with bevacizumab, or to start without a targeted therapy and to add the anti-EGFR at reception of the RAS status. This study found no deleterious effect of the delayed introduction of an anti-EGFR on survival, compared with the introduction of an anti-vascular endothelial growth factor from cycle 1. It is possible to wait one or two cycles to introduce the anti-EGFR while waiting for RAS status.
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http://dx.doi.org/10.1634/theoncologist.2019-0328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011620PMC
February 2020

Management of Patients With Immune Checkpoint Inhibitor-Induced Enterocolitis: A Systematic Review.

Clin Gastroenterol Hepatol 2020 May 31;18(6):1393-1403.e1. Epub 2020 Jan 31.

Department of Gastroenterology, Kremlin Bicêtre Hospital, Assistance Publique-Hopitaux de Paris, Le Kremlin Bicêtre, France; Paris Saclay University, Le Kremlin Bicêtre, France; INSERM 1018, UPS, UVSQ Institut Gustave Roussy, Villejuif Cedex, France. Electronic address:

Immune checkpoint inhibitors (ICIs) have improved the treatment of several cancers. These drugs increase T-cell activity and the antitumor immune response but also have immune-related adverse effects that can affect the gastrointestinal (GI) tract. These adverse effects have been observed in 7% to 30% of patients treated with ICIs. As the number of diseases treated with ICIs increases, gastroenterologists will see more patients with ICI-induced GI adverse events. We performed a systematic review of the incidence, risk factors, clinical manifestations, and management of the adverse effects of ICIs on the GI tract. Treatment with anti-cytotoxic T-lymphocyte-associated antigen-4 often causes severe enterocolitis, whereas treatment with inhibitors of programmed cell death 1 have less frequent and more diverse adverse effects. Management of patients with GI adverse effects of ICIs should involve first ruling out other disorders, followed by assessment of severity, treatment with corticosteroids, and rapid introduction of infliximab therapy for nonresponders.
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http://dx.doi.org/10.1016/j.cgh.2020.01.033DOI Listing
May 2020

Three fluoropyrimidine-based regimens in routine clinical practice after nab-paclitaxel plus gemcitabine for metastatic pancreatic cancer: An AGEO multicenter study.

Clin Res Hepatol Gastroenterol 2020 06 10;44(3):295-301. Epub 2019 Oct 10.

Department of Gastroenterology and Digestive Oncology, Georges-Pompidou European Hospital, Assistance publique-Hôpitaux de Paris (AP-HP), Sorbonne Paris Cité Paris Descartes University, Paris, France.

Background: A combination of nab-paclitaxel plus gemcitabine (N+G) has recently become a standard first-line treatment in patients with metastatic pancreatic adenocarcinoma (MPA), but there are currently no published data concerning second-line treatment after N+G. The aim of this study was to evaluate the survival outcomes and tolerability of three usual fluoropyrimidine-based regimens FOLFOX, FOLFIRI and FOLFIRINOX after N+G failure in MPA patients.

Methods: Patients receiving N+G as first-line regimen were prospectively identified in 11 French centers between January 2014 and January 2017. After disease progression or unacceptable toxicity, patients eligible for second-line therapy were enrolled in the study. The primary endpoint was overall survival following the second-line regimen. Secondary endpoints were objective response, progression-free survival and safety.

Results: Out of 137 patients treated with N+G as first-line regimen, 61 (44.5%) received second-line chemotherapy, including FOLFOX (39.4%), FOLFIRI (34.4%) or FOLFIRINOX (26.2%). Baseline characteristics were not different between the 3 groups. In particular, median age was 71.7 years, sex ratio was 1/1, and performance status (PS) was 0 in 11.5% of case. Main grade 3 toxicities were neutropenia (4.9%) and nausea (3.3%), without major differences between the groups. No toxic death was observed. Median second-line progression-free survival (PFS) and overall survival (OS) were 2.95 (95% CI: 2.3-5.4) and 5.97 months (95% CI: 4.0-8.0), respectively, with no difference between the 3 groups. Median OS from the start of first-line chemotherapy was 12.7 months (10.4-15.1) and was significantly better in patients receiving FOLFIRI after N+G failure, 18.4 months (95% CI: 11.7-24.1, P<0.05), as compared with FOLFOX or FOLFIRINOX (10.4 and 12.3 months, respectively).

Conclusion: This study suggests that second-line fluoropyrimidine-based regimens after N+G failure are feasible, have a manageable toxicity profile in selected patients with MPA, and are associated with promising clinical outcomes, in particular when combined with irinotecan. Randomized phase 3 trials are needed to confirm this trend.
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http://dx.doi.org/10.1016/j.clinre.2019.08.009DOI Listing
June 2020

Evolution and recurrence of gastrointestinal immune-related adverse events induced by immune checkpoint inhibitors.

Eur J Cancer 2019 01 23;106:106-114. Epub 2018 Nov 23.

Department of Gastroenterology, Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), 94270, Le Kremlin-Bicêtre, France; University Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, 94276, France. Electronic address:

Background: Immune checkpoint inhibitors (ICIs), such as anti-CTLA-4 and anti-PD-1 antibodies, are effective against several malignancies. They are associated with gastrointestinal immune-related adverse events (GI-IrAEs), which may be severe and lead to ICI discontinuation. We assessed the risk of evolution of GI-IrAEs to chronic GI inflammation and the risk of recurrence after a second line of ICI.

Patients And Methods: This was a single-centre study. Included patients had a GI-IrAE due to ICIs between September 2010 and July 2017. We assessed the persistence of symptoms, endoscopic and/or histological inflammation, and the risk of recurrent GI-IrAEs after the second line of ICIs.

Results: Eighty patients were included. The median follow-up was 8.4 months (0.36-72.3). The median duration of GI symptoms was 1.5 months (5 days-10.3 months): 1.4 months (7 days-4.9 months) with anti-CTLA-4, 2.0 months (5 days-10.3 months) with anti-PD-1 and 1.0 month (8 days-3.4 months) with combination therapy (log-rank test: p = 0.02). Three and 6 months after the beginning of GI-IrAEs, 22% (95% confidence interval: 14%-33%) and 5.4% (2.0%-14.7%) of patients had persistent symptoms, respectively. After a median of 6 months, 20/27 patients had endoscopic and/or histological inflammation, of whom, seven were symptom free. After the first episode, 6/26 patients relapsed after receiving another course of ICIs. Among these 26, 89% (77%-100%) had no recurrence after 3 months, 71% or 95% if the second line was anti-CTLA-4 or anti-PD-1, respectively.

Conclusion: GI-IrAEs seem to be acute or subacute, not chronic. Reintroduction of ICIs is possible in patients who had GI-IrAE.
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http://dx.doi.org/10.1016/j.ejca.2018.10.006DOI Listing
January 2019

Enterocolitis due to immune checkpoint inhibitors: a systematic review.

Gut 2018 11 21;67(11):2056-2067. Epub 2018 Aug 21.

Department of Gastroenterology, Kremlin Bicêtre Hospital, Assistance Publique- Hôpitaux de Paris (AP-HP), Le Kremlin Bicêtre, France.

Immune checkpoint inhibitors targeting cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and programmed death-1 (PD-1)/ligand are increasingly used to treat several types of cancer. These drugs enhance antitumour T-cell activity and therefore induce immune-related adverse effects (irAE), of which gastrointestinal (GI) irAE are among the most frequent and severe. This systematic literature review summarises the clinical manifestations, management and pathophysiology of GI irAE due to immune checkpoint inhibitors. GI irAE induced by anti-CTLA-4 are frequent, potentially severe and resemble IBD, whereas those induced by PD-1 blockade seem to be less frequent and clinically more diverse. Baseline symbiotic gut microbiota is associated with an enhanced antitumour response to immune checkpoint inhibitors and an increased susceptibility to developing enterocolitis, in patients treated with anti-CTLA-4. These findings open new perspectives for possible manipulation of the gut microbiota in order to better identify responders to immune checkpoint inhibitors and to increase their efficacy and safety.
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http://dx.doi.org/10.1136/gutjnl-2018-316948DOI Listing
November 2018

Trastuzumab beyond progression in patients with HER2-positive advanced gastric adenocarcinoma: a multicenter AGEO study.

Oncotarget 2017 Nov 8;8(60):101383-101393. Epub 2017 Sep 8.

Department of Gastroenterology and Digestive Oncology, European Georges Pompidou Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.

Introduction: Trastuzumab in combination with platinum-based chemotherapy is the standard first-line regimen in HER2-positive advanced gastric cancer. However, there are very few data concerning efficacy of continuing trastuzumab beyond first-line progression.

Methods: This retrospective multicenter study included all consecutive patients with HER2-positive advanced gastric or gastro-esophageal junction (GEJ) adenocarcinoma who received a second-line of chemotherapy with or without trastuzumab after progression on platinum-based chemotherapy plus trastuzumab. Progression-free survival (PFS) and overall survival (OS) were estimated from the start of second-line chemotherapy using the Kaplan-Meier method and compared using log-rank test. The prognostic variables with values ≤ 0.05 in univariate analysis were eligible for the Cox multivariable regression model.

Results: From May 2010 to December 2015, 104 patients were included (median age, 60.8 years; male, 78.8%; ECOG performance status [PS] 0-1, 71.2%). The continuation (n=39) versus discontinuation (n=65) of trastuzumab beyond progression was significantly associated with an improvement of median PFS (4.4 versus 2.3 months; =0.002) and OS (12.6 versus 6.1 months; =0.001. In the multivariate analysis including the ECOG PS, number of metastatic sites and measurable disease, the continuation of trastuzumab beyond progression remained significantly associated with longer PFS (HR, 0.56; 95% CI, 0.35-0.89; =0.01) and OS (HR, 0.47; 95% CI, 0.28-0.79; =0.004).

Conclusion: This study suggests that continuation of trastuzumab beyond progression has clinical benefit in patients with HER2-positive advanced gastric cancer. These results deserve a prospective randomized validation.
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http://dx.doi.org/10.18632/oncotarget.20711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731882PMC
November 2017

Trastuzumab in Combination with FOLFIRI in Patients with Advanced HER2-Positive Gastro-Esophageal Adenocarcinoma: A Retrospective Multicenter AGEO Study.

Target Oncol 2018 02;13(1):107-112

Department of Gastroenterology and Digestive Oncology, European Georges Pompidou Hospital, Assistance Publique-Hôpitaux de Paris, 20 rue Leblanc, 75015, Paris, France.

Background: Trastuzumab with fluoropyrimidine and cisplatin is the standard first-line treatment in patients with HER2-positive advanced gastro-esophageal adenocarcinoma. However, there are no safety and efficacy data of trastuzumab with FOLFIRI.

Objective: To evaluate safety and efficacy of FOLFIRI plus trastuzumab in patients with HER2-positive advanced gastro-esophageal adenocarcinoma.

Patients And Methods: This retrospective multicenter study included all consecutive patients with HER2-positive advanced gastro-esophageal adenocarcinoma treated with FOLFIRI plus trastuzumab between 2012 and 2015.

Results: A total of 33 patients (median age, 60.3; performance status 0-1, 78.8%) with HER2-positive advanced gastro-esophageal adenocarcinoma treated with FOLFIRI plus trastuzumab in first (n = 3), second (n = 20) or third (n = 10) line of chemotherapy were included. There was one case of a severe non-hematological adverse event corresponding to a left ventricular systolic dysfunction. The most common hematological grade 3 or 4 adverse events were neutropenia (12.9%) and thrombocytopenia (6.4%). There was no febrile neutropenia. For patients treated with FOLFIRI plus trastuzumab in second-line chemotherapy, the median overall survival was 9.5 months.

Conclusions: This is the first western population-based study of FOLFIRI plus trastuzumab reporting a satisfactory safety profile and a potential efficacy in advanced HER2-positive gastric cancer.
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http://dx.doi.org/10.1007/s11523-017-0531-4DOI Listing
February 2018

Colon Immune-Related Adverse Events: Anti-CTLA-4 and Anti-PD-1 Blockade Induce Distinct Immunopathological Entities.

J Crohns Colitis 2017 Oct;11(10):1238-1246

Gustave Roussy, Laboratory d'Immunomonitoring en Oncologie, CNRS-UMS 3655 and INSERM-US23, Villejuif F-94805, France.

Background And Aim: Immune checkpoint inhibitors targeting CTLA-4 and PD-1 improve survival in cancer patients but may induce immune-related adverse events, including colitis. The immunological characteristics of anti-CTLA-4 [αCTLA-4]- and anti-PD-1 [αPD-1]-related colitis have been poorly described. The aim of the present study was to compare the immunological and histological characteristics of αCTLA-4-induced colitis and αPD-1-induced colitis.

Methods: Colonic biopsies from patients with αCTLA-4-induced colitis, αPD-1-induced colitis, and inflammatory bowel disease [IBD] were analysed by immunohistochemistry and flow cytometry. Tumour necrosis factor alpha [TNFα] concentration was assessed in biopsy supernatants.

Results: CD8+ T cells were found in the lamina propria and epithelium in αPD-1-induced colitis, whereas CD4+ T cells were found in the lamina propria in αCTLA-4-induced colitis. No or low intraepithelial lymphocytes were observed in αCTLA-4-induced colitis. No difference in numbers of mucosal regulatory T cells was observed between αCTLA-4- or αPD-1-induced colitis and IBD patients. Higher numbers of activated ICOS+ conventional CD4+ T cells were observed in αCTLA-4-induced colitis compared with patients with IBD. Among ICOS+CD4+ T cells, conventional CD4+ T cells were the main T cell population in patents with αCTLA-4-induced colitis, whereas Treg cells were predominant in IBD or αPD-1-induced colitis. High mucosal TNFα concentrations were observed in αCTLA-4-induced colitis. Low mucosal TNFα concentrations were associated with steroid sensitivity.

Conclusions: These observations show that αCTLA-4- and αPD-1-induced colitis have distinct immunological characteristics. Mucosal TNFα concentration might detect patients at risk of developing corticosteroid resistance after CTLA-4 blockade.
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http://dx.doi.org/10.1093/ecco-jcc/jjx081DOI Listing
October 2017

Inflammatory bowel disease and cancer response due to anti-CTLA-4: is it in the flora?

Semin Immunopathol 2017 04 16;39(3):327-331. Epub 2017 Jan 16.

Gustave Roussy, Département de Médecine, Service de Dermatologie, et Université Paris-Sud Villejuif, Villejuif, F-94805, France.

Checkpoint inhibitors blocking CTLA-4 (ipilimumab) and PD-1 (nivolumab, pembrolizumab) have transfigured our cancer treatment paradigm. However, these drugs can induce immune-related adverse events that share clinical and pathological characteristics with immune-mediated diseases. One of the most severe immune-related adverse event observed with anti-CTLA-4 is an enterocolitis that mirrors naturally occurring inflammatory bowel disease. This paper reviews the clinical, immunological, and microbiota data associated with the immune-related enterocolitis induced by the cancer immunotherapy blocking CTLA-4, ipilimumab. A parallel analysis of the mechanisms underlying inflammatory bowel diseases on the one hand, and anti-CTLA-4-induced colitis on the other hand, stresses the crucial role of the gut microbiota and of resident T in the genesis of both iatrogenic and spontaneous inflammatory bowel diseases.
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http://dx.doi.org/10.1007/s00281-016-0613-xDOI Listing
April 2017

Efficacy and safety of trastuzumab in combination with oxaliplatin and fluorouracil-based chemotherapy for patients with HER2-positive metastatic gastric and gastro-oesophageal junction adenocarcinoma patients: a retrospective study.

Bull Cancer 2015 Apr 3;102(4):324-31. Epub 2015 Mar 3.

Hôpital Saint-Antoine, 75012 Paris, France. Electronic address:

Background: Trastuzumab with 5-fluorouracil (5-FU) and cisplatin offers prolonged survival in patients with HER2-overexpressing advanced gastric cancer (AGC) and advanced gastro-oesophageal junction cancer (AGOJ). Oxaliplatin in combination with intravenous 5-FU plus leucovorin (LV; modified [m]FOLFOX6) or capecitabine (XELOX) improves tolerability compared with 5-FU/cisplatin regimen. There are few data available on the efficacy and safety of trastuzumab-oxaliplatin-based chemotherapy in previously untreated HER2-positive AGC and AGOJ patients.

Methods: Clinical data were retrospectively analysed in patients receiving trastuzumab plus mFOLFOX6 or XELOX as first-line therapy between July 2009 and December 2012. Eligible patients had histologically proven AGC or AGOJ, HER2 overexpression, and no prior chemotherapy for metastatic disease.

Results: Thirty-four patients met the eligibility criteria. Median age was 63 years, 79% of patients had ECOG PS score of 0-1, and all had metastatic disease. Median duration of treatment was 7.5 months. Overall response rate was 41% (95% CI: 25-56). Median progression-free survival and overall survival were 9.0 months (95% CI: 5.6-12) and 17.3 months (95% CI: 13.5-32.3), respectively. Tolerability was acceptable. The most frequent grade 3-4 toxicities were neutropenia (8.8%) and neuropathy (17.6%).

Conclusion: mFOLFOX6-trastuzumab combination is an efficient regimen with an acceptable safety profile for AGC and AGOJ patients. These results warrant further prospective study.
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http://dx.doi.org/10.1016/j.bulcan.2014.08.001DOI Listing
April 2015