Exome sequencing of tumors: relevance in copy-number alteration (CNA) analysis and fixed tissue samples.
Wenric, Stéphane ; JOSSE, Claire ; Fasquelle, Corinne et al
Poster (2013, March 15)
Genomic DNA has been extracted from both cryopreserved and formalin-fixed paraffin-embedded forms of 2 different tumor samples (triple negative, and Her2+). Exome sequencing has been performed on all 4 ... [more ▼]
Genomic DNA has been extracted from both cryopreserved and formalin-fixed paraffin-embedded forms of 2 different tumor samples (triple negative, and Her2+). Exome sequencing has been performed on all 4 forms, as well as SNP and CNA detection. A comparison of the various metrics and results related to the sequencing, mapping, and variants detection has been done, outlining what can, and can’t be done with exome data sequenced from cryopreserved and FFPE tissue. [less ▲]Detailed reference viewed: 18 (3 ULg)
The 2006 adjuvant Trastuzumab convention in Belgium: 5 years later
; ; et al
Poster (2013, March)Detailed reference viewed: 10 (1 ULg)
Everolimus Plus Exemestane Versus Everolimus or Capecitabine Monotherapy in Breast Cancer : BOLERO-6
; JERUSALEM, Guy ; et al
Poster (2013, March)
The data from this trial will provide insight into the safety and efficacy of the combination of EVE and EXE versus EVE or capecitabine monotherapy in women with ER+, HER2- ABC progressing on/after prior ... [more ▼]
The data from this trial will provide insight into the safety and efficacy of the combination of EVE and EXE versus EVE or capecitabine monotherapy in women with ER+, HER2- ABC progressing on/after prior LET or ANA. [less ▲]Detailed reference viewed: 55 (1 ULg)
Le cas clinique du mois. Metastase musculaire en presence d'un cancer de l'ovaire.
; Jerusalem, Guy ; GENNIGENS, Christine
in Revue medicale de Liege (2013), 68(11), 557-61
We report the case of a patient with a sero-papillary ovarian cancer and a pectoral muscle metastasis. Muscular metastases are more common than previously suspected; any physician could encounter this ... [more ▼]
We report the case of a patient with a sero-papillary ovarian cancer and a pectoral muscle metastasis. Muscular metastases are more common than previously suspected; any physician could encounter this type of case in his daily practice. This paper summarizes the literature on the subject. [less ▲]Detailed reference viewed: 23 (4 ULg)
Cancer risk in immune-mediated inflammatory diseases (IMID).
; ; et al
in Molecular cancer (2013), 12(1), 98
Inflammation and cancer have a profound yet ambiguous relationship. Inflammation - especially chronic inflammation - has protumorigenic effects, but inflammatory cells also mediate an immune response ... [more ▼]
Inflammation and cancer have a profound yet ambiguous relationship. Inflammation - especially chronic inflammation - has protumorigenic effects, but inflammatory cells also mediate an immune response against the tumor and immunosuppression is known to increase the risk for certain tumors.This article reviews current literature on the role of inflammation in cancer and the cancer risk in immune-mediated inflammatory diseases (IMIDs). We discuss the effect on cancer risk of different drug classes used in the treatment of IMIDs treatment, including biologicals such as tumor necrosis factor (TNF) inhibitors.Overall cancer incidence and mortality risk are similar to the general population in inflammatory bowel disease (IBD), and slightly increased for rheumatoid arthritis and psoriasis, with risk profiles differing for different tumor types. Increased risk for non-melanoma skin cancer is associated with thiopurine treatment in IBD, with the combination of anti-TNF and methotrexate in rheumatoid arthritis and with PUVA, cyclosporine and anti-TNF treatment in psoriasis. Data on the safety of using biologic or immunosuppressant therapy in IMID patients with a history of cancer are scarce.This review provides clinicians with a solid background to help them in making decisions about treatment of immune-mediated diseases in patients with a tumor history.This article is related to another review article in Molecular Cancer: http://www.molecular-cancer.com/content/12/1/86. [less ▲]Detailed reference viewed: 38 (7 ULg)
Comparative efficacy of everolimus plus exemestane versus fulvestrant for hormone-receptor-positive advanced breast cancer following progression/recurrence after endocrine therapy: a network meta-analysis.
; ; et al
in Breast cancer research and treatment (2013)
Postmenopausal women with advanced breast cancer recurring/progressing on or after initial (adjuvant or first-line) endocrine therapy may be treated multiple times with one of several endocrine or ... [more ▼]
Postmenopausal women with advanced breast cancer recurring/progressing on or after initial (adjuvant or first-line) endocrine therapy may be treated multiple times with one of several endocrine or combinatorial targeted treatment options before initiating chemotherapy. In the absence of direct head-to-head comparisons of these treatment options, an indirect comparison can inform treatment choice. This network meta-analysis compared the efficacy of everolimus plus exemestane with that of fulvestrant 250 and 500 mg in the advanced breast cancer setting following adjuvant or first-line endocrine therapy. The reported hazard ratios (HRs) for progression-free survival (PFS) or time to progression from six studies that formed a network to compare everolimus plus exemestane (BOLERO-2 trial) with fulvestrant were analyzed by means of a Bayesian network meta-analysis. In the primary comparison (PFS analysis based on the local review of disease progression from BOLERO-2 with the data from the other studies), everolimus plus exemestane appeared to be more efficacious than both fulvestrant 250 mg (HR = 0.47; 95 % credible interval [CrI] 0.38-0.58) and 500 mg (HR = 0.59; 95 % CrI 0.45-0.77). Similar results were obtained in an alternate comparison based on central review of disease progression from BOLERO-2 with the data from the other studies (HR = 0.40; 95 % CrI 0.31-0.51 and HR = 0.50; 95 % CrI 0.37-0.67, respectively), and in a subgroup analysis of patients who had received prior aromatase inhibitor therapy (HR = 0.47; 95 % CrI 0.38-0.58 and HR = 0.55; 95 % CrI 0.40-0.76, respectively). These results suggest that everolimus plus exemestane may be more efficacious than fulvestrant in patients with advanced breast cancer who progress on or after adjuvant or first-line therapy with a nonsteroidal aromatase inhibitor. [less ▲]Detailed reference viewed: 16 (1 ULg)
Attitudes of young patients with breast cancer toward fertility loss related to adjuvant systemic therapies. EORTC study 10002 BIG 3-98.
; ; et al
in Psycho-oncology (2013)
OBJECTIVE: Infertility due to anticancer treatments is a major source of distress for young patients with cancer. A survey was performed among breast cancer patients younger than 35 years, to evaluate the ... [more ▼]
OBJECTIVE: Infertility due to anticancer treatments is a major source of distress for young patients with cancer. A survey was performed among breast cancer patients younger than 35 years, to evaluate the acceptance of chemotherapy in the context of infertility risk. METHODS: After obtaining written informed consent, we asked 400 premenopausal, early stage breast cancer patients aged </=35 years to complete a short, previously pilot-tested questionnaire. Three hundred and eighty-nine patients were evaluable. The association between the explanatory variables and the outcome variables was assessed using logistic regression. RESULTS: Two hundred and twenty-eight (59%) participants wanted to have (more) children in the future, whereas 158 (41%) did not. Fifty-seven (36%) of the latter did not want additional children because of fear of cancer recurrence. Thirty-two women (8%) stated they would not accept chemotherapy should it reduce their fertility. This was dependent upon already having children, the wish to have (further) children, geographical area, disease stage, and already planned chemotherapy. One hundred and seventy-one women who would agree to chemotherapy (48%) would accept a risk of infertility of 76-100%. This acceptance was dependent on already having children and the wish to have (more) children. Of the 355 participants (91%) accepting chemotherapy, 48 would accept it only for >/=20% gain in cure. CONCLUSION: For the majority of young patients with breast cancer, cure remains their first priority; for this, they are willing to accept a considerable decrease in future fertility, and only less than 10% will forego chances of cure to preserve fertility. Copyright (c) 2013 John Wiley & Sons, Ltd. [less ▲]Detailed reference viewed: 20 (0 ULg)
Two schedules of etirinotecan pegol (NKTR-102) in patients with previously treated metastatic breast cancer: a randomised phase 2 study.
; ; et al
in The lancet oncology (2013)
BACKGROUND: New therapeutic options are needed for patients with heavily pretreated breast cancer. Etirinotecan pegol is a long-acting topoisomerase-I inhibitor designed to provide prolonged tumour-cell ... [more ▼]
BACKGROUND: New therapeutic options are needed for patients with heavily pretreated breast cancer. Etirinotecan pegol is a long-acting topoisomerase-I inhibitor designed to provide prolonged tumour-cell exposure to SN38, the active metabolite. We aimed to assess the efficacy and safety of two etirinotecan pegol dosing schedules in patients with previously treated metastatic breast cancer to determine an optimum dosing schedule for phase 3 trials. METHODS: In this randomised, two-stage, open-label phase 2 trial, we recruited patients aged 18 years or older who had received taxane therapy and undergone two or fewer previous chemotherapy regimens for metastatic breast cancer, with an Eastern Cooperative Oncology Group performance status of 0 or 1, from 18 sites in three countries. Eligible patients were randomly assigned (1:1) to etirinotecan pegol 145 mg/m2 every 14 days or every 21 days. The primary endpoint was the proportion of patients with a confirmed objective response as defined by Response Evaluation Criteria in Solid Tumors version 1.0, analysed by intention to treat. Safety was assessed in all patients who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT00802945. FINDINGS: 70 patients (35 in each group) were randomly assigned to treatment between Feb 17, 2009 and April 13, 2010. Of the 70 patients, 20 (29%; 95% CI 18.4-40.6) achieved an objective response (two [3%] had a complete response and 18 [26%] had a partial response). Ten patients on the 14-day schedule achieved an objective response (29%; 95% CI 14.6-46.3; eight partial responses, two complete responses) as did ten on the 21-day schedule (29%; 95% CI 14.6-46.3; all partial responses). The most common grade 3 or worse adverse events were delayed diarrhoea (seven [20%] of 35 patients on the 14-day schedule vs eight [23%] of 35 patients on the 21-day schedule), fatigue (five [14%] vs three [9%]), neutropenia (four [11%] vs four [11%]), and dehydration (three [9%] vs four [11%]); 14 [20%] patients discontinued treatment because of drug-related toxicity. There were two possible drug-related deaths (acute renal failure and septic shock) in the 14-day group; other drug-related serious adverse events reported by more than one patient included ten [14%] patients with diarrhoea (six [17%] patients on the 14-day schedule vs four [11%] on the 21-day schedule), six [9%] with dehydration (two [6%] vs four [11%]), two [3%] with nausea (two [6%] vs none), and two [3%] with vomiting (two [6%] vs none). INTERPRETATION: On the basis of the overall clinical data, pharmacokinetics, and tolerability profile, etirinotecan pegol 145 mg/m2 every 21 days has been selected for a phase 3 trial against treatment of physician's choice in patients with advanced breast cancer. FUNDING: Nektar Therapeutics. [less ▲]Detailed reference viewed: 18 (5 ULg)
Comparing duration of response and duration of clinical benefit between fulvestrant treatment groups in the CONFIRM trial: application of new methodology.
; ; JERUSALEM, Guy et al
in Breast Cancer Research and Treatment (2013), 138(1), 149-55
Comparisons of duration of response (DoR) and duration of clinical benefit (DoCB) within clinical trials are prone to biases. To address these biases, we used new methodology to prospectively analyze ... [more ▼]
Comparisons of duration of response (DoR) and duration of clinical benefit (DoCB) within clinical trials are prone to biases. To address these biases, we used new methodology to prospectively analyze expected DoR and expected DoCB. Objective response rate and clinical benefit rate were calculated for fulvestrant 500 and 250 mg, and used to calculate expected DoR and expected DoCB for each dose group. The ratios for expected DoR and expected DoCB (expected DoR500/expected DoR250 and expected DoCB500/expected DoCB250) were then calculated, thereby allowing statistical comparisons of these endpoints between each arm of the COmparisoN of Faslodex In Recurrent or Metastatic breast cancer (CONFIRM) trial. Expected DoRs for fulvestrant 500 and 250 mg were 3.2 and 3.6 months, respectively. The expected DoR ratio between fulvestrant 500 and 250 mg was not statistically significant (0.89; 95 % CI, 0.48-1.67, P = 0.724). The expected DoCBs for fulvestrant 500 and 250 mg were 9.8 and 7.2 months, respectively. The expected DoCB ratio showed that the expected DoCB for fulvestrant 500 mg was significantly improved compared with the expected DoCB for fulvestrant 250 mg (1.36; 95 % CI, 1.07-1.73, P = 0.013). Analysis of the expected DoR and expected DoCB showed fulvestrant 500 mg significantly increased expected DoCB compared with fulvestrant 250 mg in the CONFIRM trial. [less ▲]Detailed reference viewed: 14 (2 ULg)
Final analysis of overall survival for the Phase III CONFIRM trial: fulvestrant 500 mg versus 250 mg
; JERUSALEM, Guy ; et al
in Cancer Research. Supplement (2012, December 15), 72(24), 1-4Detailed reference viewed: 22 (10 ULg)
The 2006 Adjuvant Trastuzumab Convention in Belgium: 5 years later
; ; et al
Poster (2012, December)Detailed reference viewed: 17 (2 ULg)
Carcinomatose péritonéale d'origine indéterminée
Marchal, Nathalie ; GENNIGENS, Christine ; JERUSALEM, Guy
in Revue Médicale de Liège (2012), 67(11), 582-586
La carcinomatose péritonéale est définie comme l'envahissement néoplasique secondaire du péritoine. Cette entité peut amener de nombreuses difficultés, à la fois sur le plan de son diagnostic, de sa mise ... [more ▼]
La carcinomatose péritonéale est définie comme l'envahissement néoplasique secondaire du péritoine. Cette entité peut amener de nombreuses difficultés, à la fois sur le plan de son diagnostic, de sa mise au point et de la recherche de son origine ainsi que pour son traitement. Le cas clinique que nous relatons illustre les difficultés pouvant être rencontrées par l'équipe soignante face à une carcinomatose péritonéale et décrit l'importance d'une approche multidisciplinaire pour sa prise en charge. Lorsque son origine n'est pas déterminée avant l'instauration du traitement, la carcinomatose péritonéale entre dans le cadre des carcinomes de primitif inconnu (CAPI). Chez une femme, une telle présentation de CAPI en fait une entité particulière, facteur de meilleur pronostic, pour laquelle un traitement plus spécifique doit être instauré en première intention. [less ▲]Detailed reference viewed: 69 (2 ULg)
Patterns of Clinical Management and Resource Utilisation for Postmenopausal Hormone-Receptor-Positive HER2-Negative (HR+ HER2-) Advanced Breast Cancer (BC) in Europe
; ; et al
in Value in Health (2012, November), 15(7), 419Detailed reference viewed: 26 (4 ULg)
Ph Ib/II study of BKM120 plus trastuzumab in patients with trastuzumab-resistant HER2+ advanced breast cancer
; ; et al
in Annals of Oncology (2012), 23(supplément 9), 116Detailed reference viewed: 42 (7 ULg)
European inter-institutional impact study of MammaPrint
CUSUMANO, Giuseppe ; ; et al
Poster (2012)Detailed reference viewed: 29 (1 ULg)
Clinical Management and Resource Utilisation for Postmenopausal Hormone-Receptor-Positive HER2-Negative (HR+ HER2-) Advanced Breast Cancer (BC) in Europe
JERUSALEM, Guy ; ; et al
Objective: To understand treatment patterns and quantify resource utilisation of HR+ HER2– Advanced BC, with the overall aim of comparing costs and disease burden as patients progress from hormonal ... [more ▼]
Objective: To understand treatment patterns and quantify resource utilisation of HR+ HER2– Advanced BC, with the overall aim of comparing costs and disease burden as patients progress from hormonal therapy (HT) to chemotherapy (CT). Methods: We conducted a chart audit in France, Germany, The Netherlands, Belgium, and Sweden of 399 living and deceased postmenopausal female patients (target, 75 per country) diagnosed with HR+ HER2– advanced BC in the past 4 years. Patients were required to have progressed on ≥ 1 line of prior HT either in the adjuvant or advanced setting and to have completed ≥ 1 line of CT (minimum 2 full cycles) in the advanced BC setting. The chart audit was completed online using a standardised form developed with the assistance of European academic physicians, pharmacy directors, and hospital administrators. Participation was sought from 25 oncologists per country, except in Germany (15 oncologists and 10 gynecologists to reflect local clinical practice). Study was compliant with European and country market research regulations. Results: Our report details the patient care pathway, CT side effects, and resource utilisation in the inpatient and outpatient settings throughout the continuum of advanced BC care. In the study sample 55% of HR+ HER2– advanced BC patients are first treated with HT and switch to CT after an average of 1.5 lines of HT. This switch is primarily influenced by the extent (56%) and progression rate (36%) of metastases. The switch from HT to CT is associated with increased resource utilisation of treating advanced BC. Conclusions: Our results highlight the increased resource utilisation for postmenopausal HR+ HER2– advanced BC patients treated with CT versus HT. [less ▲]Detailed reference viewed: 53 (2 ULg)
Pazopanib (Votrient) dans le traitement du cancer du rein et des sarcomes des tissus mous.
GENNIGENS, Christine ; JERUSALEM, Guy
in Revue Médicale de Liège (2012), 67(7-8), 437-42
Renal cell carcinoma accounts for 3% of all malignant tumors. Until a few years ago, immunotherapy (Interferon and/or Interleukin-2) was the only approved systemic treatment in the metastatic setting ... [more ▼]
Renal cell carcinoma accounts for 3% of all malignant tumors. Until a few years ago, immunotherapy (Interferon and/or Interleukin-2) was the only approved systemic treatment in the metastatic setting. Better knowledge of renal cell cancer biology drew attention on the fundamental role of angiogenesis. Several strategies targeting angiogenesis have been developed including VEGF and VEGFR inhibitors. They are now the standard treatment in first and second line. Pazopanib, a VEGFR tyrosine kinase inhibitor, is one of the treatment options recommended for patients with metastatic renal cell carcinoma, in first line and after cytokines failure. Since more recently, pazopanib is also approved in the treatment of metastatic soft tissue sarcoma, after failure of at least one line of chemoterapy. In this paper, we will review the mechanism of action and the clinical results of pazopanib in renal cell carcinoma and sarcoma. [less ▲]Detailed reference viewed: 51 (4 ULg)
Les traitements cibles remplaceront-ils la chimiotherapie?
COLLIGNON, Joëlle ; JERUSALEM, Guy
in Revue Médicale de Liège (2012), 67 Spec No
The oncologist dream is to provide more benefit with lower toxicity. The increasing knowledge of molecular mechanism for survival and proliferation of cancer cells leads to the development of targeted ... [more ▼]
The oncologist dream is to provide more benefit with lower toxicity. The increasing knowledge of molecular mechanism for survival and proliferation of cancer cells leads to the development of targeted therapies with impressive results for some cancers even if not associated with chemotherapy. These targeted treatments could be monoclonal antibodies or tyrosine kinase inhibitors. Inactivation of only one oncogene can lead to the regression of tumours as well as the inhibition of only one pathway with one or more inhibitors. This result is related to the oncogenic addiction of these tumours. Examples are imatinib in CML and GIST, trastuzumab in HER2 positive breast cancer, gefitinib in mutated EGFR, crizotinib in EML4-ALK positive lung cancer and, also, vemurafenib in BRAF 600E mutated metastatic melanoma. We shall specifically discuss HER2 positive breast cancer, which represent some 15-20% of breast cancers and the recent targeted and bi-targeted therapies. Trastuzumab, an anti-HER2 monoclonal antibody has changed the prognosis of the disease improving survival in the metastatic and adjuvant setting. Lapatinib, a dual tyrosine kinase inhibitor of EGFR and HER2 is approved with capecitabine in trastuzumab resistant patients and in combination with letrozole in first line. Unfortunately, 20% of patients receiving adjuvant trastuzumab relapse and metastatic patients only transienly respond to trastuzumab or lapatinib combined with chemotherapy. New HER2 targeted drugs are currently in development like pertuzumab, T-DMI or mTOR and PI3K inhibitors. New strategies combining these drugs with or without chemotherapy showed interesting results in metastatic and neoadjuvant trials. The selection of patients who will most benefit from these combinations is still a challenge. Currently, chemotherapy in association with anti-HER2 therapy remains the most effective treatment option. [less ▲]Detailed reference viewed: 98 (7 ULg)
Immediate Administration of Zoledronic Acid Reduces Aromatase Inhibitor-Associated Bone Loss in Postmenopausal Women With Early Breast Cancer: 12-month analysis of the E-ZO-FAST trial.
; ; et al
in Clinical Breast Cancer (2012), 12(1), 40-8
BACKGROUND: Letrozole is a proven and effective adjuvant therapy in postmenopausal women with hormone receptor-positive (HR(+)) early breast cancer (EBC). As with other aromatase inhibitors (AIs), long ... [more ▼]
BACKGROUND: Letrozole is a proven and effective adjuvant therapy in postmenopausal women with hormone receptor-positive (HR(+)) early breast cancer (EBC). As with other aromatase inhibitors (AIs), long-term letrozole administration is associated with decreased bone mineral density (BMD) and increased fracture risk. This study compared potential bone-protecting effects of immediate vs. delayed administration of zoledronic acid (ZOL) in patients with EBC receiving adjuvant letrozole. PATIENTS AND METHODS: Patients with HR(+) EBC in whom adjuvant letrozole treatment was initiated (2.5 mg/day for 5 years) were randomized to immediate ZOL treatment (immediate ZOL) or delayed ZOL treatment (delayed ZOL) (both at 4 mg every 6 months). Patients in the delayed ZOL group received ZOL only for a BMD T-score that decreased to < -2.0 (lumbar spine [LS] or total hip [TH]) or for fracture. The primary endpoint was percentage change in the LS BMD at month 12. Patients were stratified by established or recent postmenopausal status, baseline T-scores, and adjuvant chemotherapy history. RESULTS: At 12 months, the LS BMD increased in the immediate ZOL group (+2.72%) but decreased in the delayed ZOL group (-2.71%); the absolute difference between groups was significant (5.43%; P < .0001). Across all subgroups, patients receiving immediate ZOL had significantly increased LS and TH BMD vs. those who received delayed ZOL (P < .0001). Differences in fracture incidence or disease recurrence could not be ascertained because of early data cutoff and low incidence of events. Adverse events were generally mild, transient, and consistent with the known safety profiles of both agents. CONCLUSION: Immediate ZOL administration effectively prevented BMD loss and increased BMD in postmenopausal women with HR(+) EBC receiving adjuvant letrozole, regardless of BMD status at baseline. [less ▲]Detailed reference viewed: 16 (2 ULg)
Extended Benefit from Sequential Administration of Docetaxel after Standard Fluorouracil, Epirubicin, and Cyclophosphamide Regimen for Node-Positive Breast Cancer: The 8-Year Follow-Up Results of the UNICANCER-PACS01 Trial.
; ; et al
in Oncologist (2012), 17(7), 900-909
Purpose. The initial report from the Programme Action Concertee Sein (PACS) PACS01 trial demonstrated a benefit at 5 years for disease-free survival (DFS) and overall survival (OS) rates with the ... [more ▼]
Purpose. The initial report from the Programme Action Concertee Sein (PACS) PACS01 trial demonstrated a benefit at 5 years for disease-free survival (DFS) and overall survival (OS) rates with the sequential administration of docetaxel after FEC100 (fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2), and cyclophosphamide 500 mg/m(2)) for patients with node-positive, operable breast cancer. We evaluate here the impact of this regimen at 8 years. Patients and Methods. Between June 1997 and March 2000, a total of 1,999 patients (age <65) with localized, resectable, non-pretreated, unilateral breast cancer were randomly assigned to receive either standard FEC100 for 6 cycles or 3 cycles of FEC100 followed by 3 cycles of 100 mg/m(2) docetaxel (FEC-D), both given every 21 days. Radiotherapy was mandatory after conservative surgery and tamoxifen was given for 5 years to hormone receptor (HR)-positive patients. Five-year DFS was the trial's main endpoint. Updated 8-year survival data are presented. Results. With a median follow-up of 92.8 months, 639 patients experienced at least one event. A total number of 383 deaths were registered. Eight-year DFS rates were 65.8% with FEC alone and 70.2% with FEC-D. OS rates at 8 years were 78% with FEC alone and 83.2% with FEC-D. Cox regression analysis adjusted for age and number of positive nodes showed a 15% reduction in the relative risk of relapse and a 25% reduction in the relative risk of death in favor of FEC-D. Significant relative risk reductions were observed in the HR-positive, HER2-positive, and Ki67 >/=20% subpopulations. Conclusion. Benefits for DFS and OS rates with the sequential FEC-D regimen are fully confirmed at 8 years. [less ▲]Detailed reference viewed: 52 (2 ULg)