Publications by authors named "Isabelle Bence-Bruckler"

27 Publications

  • Page 1 of 1

Autologous Hematopoietic Stem Cell Transplantation for Liver Transplant Recipients With Recurrent Primary Sclerosing Cholangitis: A Pilot Study.

Transplantation 2021 May 25. Epub 2021 May 25.

Multi Organ Transplant Program, University Health Network, Toronto, ON, Canada. Blood and Marrow Transplant Program, The Ottawa Hospital, Ottawa, ON, Canada. Department of Pathology, University of Pittsburgh, Pittsburgh, PA. Department of Medical Imaging, University Health Network, Toronto, ON, Canada. Ottawa Stem Cell Program, Canadian Blood Services, Ottawa, ON, Canada.

Background: Primary sclerosing cholangitis (PSC) is an indication for liver transplantation, but recurrence after liver transplantation is associated with poor outcomes often requiring repeat transplantation. We investigated whether autologous hematopoietic stem cell transplantation (aHSCT) could be used to stop progression of recurrent PSC and promote operational tolerance.

Methods: Twelve patients with recurrent PSC were fully evaluated and 5 were selected for aHSCT. Autologous hematopoietic stem cells were collected, purified by CD34 immunomagnetic selection and cryopreserved. Immunoablation using busulfan, cyclophosphamide and rabbit anti-thymocyte globulin was followed by aHSCT. The primary endpoint of the study was the establishment of operational tolerance defined as lack of biochemical, histologic and clinical evidence of rejection while off immunosuppression at 2 years post-aHSCT.

Results: Two of the 5 patients achieved operational tolerance with no clinical or histological evidence of PSC progression or allo-rejection. A third patient developed sinusoidal obstruction syndrome following aHSCT requiring repeat liver transplantation but has no evidence of PSC recurrence while on sirolimus monotherapy now more than 3 years after aHSCT. A fourth patient was weaned off immunosuppression but died 212 days after aHSCT from pericardial constriction. A fifth patient died from multiorgan failure. Immunosuppression-free allograft acceptance was associated with deletion of T cell clones, loss of autoantibodies and increases in regulatory T cells, transitional B cells, and programmed cell death protein-1 expressing CD8+ T cells in the 2 long-term survivors.

Conclusions: Although operational tolerance occurred following aHSCT, the high morbidity and mortality observed renders this specific protocol unsuitable for clinical adoption.
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http://dx.doi.org/10.1097/TP.0000000000003829DOI Listing
May 2021

Optimal duration of imatinib treatment/deep molecular response for treatment-free remission after imatinib discontinuation from a Canadian tyrosine kinase inhibitor discontinuation trial.

Br J Haematol 2021 May 20;193(4):779-791. Epub 2021 Apr 20.

Department of Oncology, McMaster University, Hamilton, Canada.

Although total duration of tyrosine kinase inhibitor (TKI) therapy and of molecular response at 4 log reduction or deeper (MR4) correlates with treatment-free remission (TFR) success after TKI discontinuation, the optimal cut-off values of the duration remain unresolved. Thus, 131 patients were enrolled into the Canadian TKI discontinuation study. The molecular relapse-free survival (mRFS) was defined from imatinib discontinuation till molecular recurrence, that is, major molecular response (MMR) loss and/or MR4 loss. We evaluated mRFS at 12 months after imatinib discontinuation, analyzed it according to the imatinib treatment duration and MR4 duration, and calculated P value, positive (PPV) and negative predictive value (NPV) in the yearly cut-off period of time. The shortest cut-off was sought that met the joint criteria of a P value ≤ 0·05, PPV ≥ 60% and NPV ≥ 60%. We propose six years as the shortest imatinib duration cut-off with a P value 0·01, PPV 68% and NPV 62%: The patients treated with imatinib duration ≥ 6 years showed a superior mRFS rate (61·8%) compared to those with less treatment (36·0%). Also, 4·5 years MR4 duration as the shortest cut-off with a P value 0·003, PPV 63% and NPV 61%: those with MR4 duration ≥ 4·5 years showed a higher mRFS rate (64·2%) than those with a shorter MR4 duration (41·9%).
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http://dx.doi.org/10.1111/bjh.17447DOI Listing
May 2021

Renovascular hypertension from the BCR-ABL tyrosine kinase inhibitor ponatinib.

J Clin Hypertens (Greenwich) 2020 04 16;22(4):678-682. Epub 2020 Mar 16.

Division of Nephrology, Department of Medicine, University of Ottawa, Ottawa, ON, Canada.

Drug-induced hypertension is one of the commonest causes of secondary hypertension. In the last few years, secondary hypertension due to tyrosine kinase inhibitors, from the vascular endothelial growth factor class, has been recognized to be an important cause of hypertension, as well as proteinuria, and occasionally kidney dysfunction in some cases. Less well-recognized is that BCR-ABL tyrosine kinase inhibitors also have adverse vascular effects. These manifest as vascular stenoses in large vessels, which may sometimes cause renal artery stenosis and subsequent hypertension. We describe a case report which presented as classical bilateral renal artery stenosis, and responded to revascularization. Increased awareness of these effects, as well as research into the pathogenesis, may provide more insight into vascular biology.
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http://dx.doi.org/10.1111/jch.13843DOI Listing
April 2020

Whole brain radiotherapy improves survival outcomes in primary CNS lymphoma patients ineligible for systemic therapy.

Support Care Cancer 2020 Nov 5;28(11):5363-5369. Epub 2020 Mar 5.

Division of Radiation Oncology, The Ottawa Hospital, 501 Smyth Road, Ottawa, ON, K1H 8L6, Canada.

Purpose: Primary central nervous system lymphoma (PCNSL) is a very rare type of malignancy with a poor prognosis. The role of whole brain radiotherapy (WBRT) in PCNSL has been questioned due to the significant neurotoxicity and lack of convincing data for survival benefit. Even its role in a palliative setting remains to be clearly elucidated. Our study aims to investigate the benefit of WBRT in patients who are ineligible for systemic therapy.

Methods: A single-institution retrospective study was conducted on patients diagnosed with PCNSL between 2002 and 2017. Patients were excluded if they received systemic therapy or focal radiation only. Data on patient demographics and WBRT were collected and correlated with clinical outcomes.

Results: A total of 48 patients were selected for analysis, among which 31 (64.6%) patients received WBRT and 17 (35.4%) patients received supportive care only. Patient baseline characteristics were similar between the two groups. Median overall survival (OS) was 4.3 months among the entire cohort. WBRT was associated with improved median OS (8.0 months, range 1.4-62.3 months) compared with supportive care only (3.3 months, range 0.7-18.3 months) (HR 0.39, 95% CI 0.20-0.75, p = 0.005). Among patients who received WBRT, higher radiation dose to the whole brain was not associated with survival (p = 0.10), but higher radiation dose to the gross tumor was associated with improved survival (p = 0.007).

Conclusion: Patients with PCNSL who are ineligible for systemic therapy may still benefit from WBRT with improvement in survival, compared with the best supportive care. Dose escalation through the addition of a gross tumor boost in these patients was associated with improved overall survival. Further studies in the prospective setting are necessary to confirm the findings from the study.
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http://dx.doi.org/10.1007/s00520-020-05376-2DOI Listing
November 2020

Integration of cell of origin into the clinical CNS International Prognostic Index improves CNS relapse prediction in DLBCL.

Blood 2019 02 7;133(9):919-926. Epub 2019 Jan 7.

1st Department of Medicine, Charles University General Hospital, Prague, Czech Republic.

Central nervous system (CNS) relapse carries a poor prognosis in diffuse large B-cell lymphoma (DLBCL). Integrating biomarkers into the CNS-International Prognostic Index (CNS-IPI) risk model may improve identification of patients at high risk for developing secondary CNS disease. CNS relapse was analyzed in 1418 DLBCL patients treated with obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, prednisone chemotherapy in the phase 3 GOYA study. Cell of origin (COO) was assessed using gene-expression profiling. BCL2 and MYC protein expression was analyzed by immunohistochemistry. The impact of CNS-IPI, COO, and BCL2/MYC dual-expression status on CNS relapse was assessed using a multivariate Cox regression model (data available in n = 1418, n = 933, and n = 688, respectively). High CNS-IPI score (hazard ratio [HR], 4.0; 95% confidence interval [CI], 1.3-12.3; = .02) and activated B-cell‒like (ABC) (HR, 5.2; 95% CI, 2.1-12.9; = .0004) or unclassified COO subtypes (HR, 4.2; 95% CI, 1.5-11.7; = .006) were independently associated with CNS relapse. BCL2/MYC dual-expression status did not impact CNS relapse risk. Three risk subgroups were identified based on the presence of high CNS-IPI score and/or ABC/unclassified COO (CNS-IPI-C model): low risk (no risk factors, n = 450 [48.2%]), intermediate risk (1 factor, n = 408 [43.7%]), and high risk (both factors, n = 75 [8.0%]). Two-year CNS relapse rates were 0.5%, 4.4%, and 15.2% in the respective risk subgroups. Combining high CNS-IPI and ABC/unclassified COO improved CNS relapse prediction and identified a patient subgroup at high risk for developing CNS relapse. The study was registered at www.clinicaltrials.gov as #NCT01287741.
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http://dx.doi.org/10.1182/blood-2018-07-862862DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396175PMC
February 2019

Canadian chronic myeloid leukemia outcomes post-transplant in the tyrosine kinase inhibitor era.

Leuk Res 2018 10 5;73:67-75. Epub 2018 Sep 5.

Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.

The majority of patients with TKI failure respond to HCT. However, the relapse risk remains high. This study has evaluated transplant outcomes in 223 CML patients with TKI failure due to resistance (n = 132) or intolerance (n = 29), as well as those that were TKI naïve/responding with advanced disease (n = 35) or with chronic phase (CP, n = 27). We studied outcomes according to post-transplant BCR-ABL transcript level within 3 months. With respect to transplant outcomes according to the post-transplant BCR/ABLtranscript level within 3 months, the group failing to achieve a 1.3 log reduction (n = 14, 12.4%) showed the highest relapse rate of 78.6% at 5 years, compared to 26.2% and 24.1% in the groups achieving 1.3-4.0 log reduction (n = 45, 39.8%), and ≥4.1 log reduction (n = 54, 47.8%) respectively (p < 0.001). Multivariate analysis confirmed that the group failing to achieve a 1.3 log reduction had a 2.3-fold higher risk of death and 6.6 times higher risk of relapse. Poor overall survival after HCT was associated with advanced disease at diagnosis, but not disease status prior to HCT. Of 61 patients who relapsed after HCT, 47 were treated with post-transplant TKI therapy; those receiving TKI after loss of MR2 or MMR showed higher rates of response and survival compared to those receiving TKI after hematologic relapse (p < 0.001). QPCR log reduction level within 3 months post transplantation is prognostic in this population.
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http://dx.doi.org/10.1016/j.leukres.2018.08.021DOI Listing
October 2018

Health-related quality of life data from a phase 3, international, randomized, open-label, multicenter study in patients with previously treated mantle cell lymphoma treated with ibrutinib versus temsirolimus.

Leuk Lymphoma 2017 12 30;58(12):2824-2832. Epub 2017 May 30.

p Department of Medicine III , Klinikum der Universität München, LMU , Munich , Germany.

Mantle cell lymphoma (MCL) is a rare, aggressive, incurable B-cell malignancy. Ibrutinib has been shown to be highly active for patients with relapsed/refractory (R/R) MCL. The RAY trial (MCL3001) was a phase 3, randomized, open-label, multicenter study that compared ibrutinib with temsirolimus in patients with R/R MCL. Active disease is frequently associated with impaired functional status and reduced well-being. Therefore, the current study employed two patient-reported outcome instruments, the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym) and the EQ-5D-5L, to assess symptoms, well-being, health status, and health-related quality of life of patients on treatment within the RAY trial. We found that patients on ibrutinib had substantial improvement in FACT-Lym subscale and total scores, and had improvement in EQ-5D-5L utility and VAS scores compared with temsirolimus patients, indicating a superior well-being. These improvements in well-being correlated with clinical response, indicating that better health-related quality of life was associated with decreased disease burden.
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http://dx.doi.org/10.1080/10428194.2017.1326034DOI Listing
December 2017

Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial.

Lancet 2016 Aug 9;388(10044):576-85. Epub 2016 Jun 9.

Ottawa Hospital Research Institute, Ottawa, ON, Canada; Department of Medicine, University of Ottawa, Ottawa, ON, Canada; The Ottawa Hospital MS Clinic, Ottawa, ON, Canada.

Background: Strong immunosuppression, including chemotherapy and immune-depleting antibodies followed by autologous haemopoietic stem-cell transplantation (aHSCT), has been used to treat patients with multiple sclerosis, improving control of relapsing disease. We addressed whether near-complete immunoablation followed by immune cell depleted aHSCT would result in long-term control of multiple sclerosis.

Methods: We did this phase 2 single-arm trial at three hospitals in Canada. We enrolled patients with multiple sclerosis, aged 18-50 years with poor prognosis, ongoing disease activity, and an Expanded Disability Status Scale of 3.0-6.0. Autologous CD34 selected haemopoietic stem-cell grafts were collected after mobilisation with cyclophosphamide and filgrastim. Immunoablation with busulfan, cyclophosphamide, and rabbit anti-thymocyte globulin was followed by aHSCT. The primary outcome was multiple sclerosis activity-free survival (events were clinical relapse, appearance of a new or Gd-enhancing lesion on MRI, and sustained progression of Expanded Disability Status Scale score). This study was registered at ClinicalTrials.gov, NCT01099930.

Findings: Between diagnosis and aHSCT, 24 patients had 167 clinical relapses over 140 patient-years with 188 Gd-enhancing lesions on 48 pre-aHSCT MRI scans. Median follow-up was 6.7 years (range 3.9-12.7). The primary outcome, multiple sclerosis activity-free survival at 3 years after transplantation was 69.6% (95% CI 46.6-84.2). With up to 13 years of follow-up after aHSCT, no relapses occurred and no Gd enhancing lesions or new T2 lesions were seen on 314 MRI sequential scans. The rate of brain atrophy decreased to that expected for healthy controls. One of 24 patients died of transplantation-related complications. 35% of patients had a sustained improvement in their Expanded Disability Status Scale score.

Interpretation: We describe the first treatment to fully halt all detectable CNS inflammatory activity in patients with multiple sclerosis for a prolonged period in the absence of any ongoing disease-modifying drugs. Furthermore, many of the patients had substantial recovery of neurological function despite their disease's aggressive nature.

Funding: Multiple Sclerosis Scientific Research Foundation.
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http://dx.doi.org/10.1016/S0140-6736(16)30169-6DOI Listing
August 2016

Myasthenia Gravis Treated With Autologous Hematopoietic Stem Cell Transplantation.

JAMA Neurol 2016 06;73(6):652-8

Division of Hematology, University of Ottawa, Ottawa, Ontario, Canada2The Ottawa Hospital Research Institute, Ottawa, Ontario, Canada3The Bone Marrow Transplant Programme, University of Ottawa, The Ottawa Hospital, Ottawa, Ontario, Canada.

Importance: Some patients with myasthenia gravis (MG) do not respond to conventional treatment and have severe or life-threatening symptoms. Alternate and emerging therapies have not yet proved consistently or durably effective. Autologous hematopoietic stem cell transplant (HSCT) has been effective in treating other severe autoimmune neurologic conditions and may have similar application in MG.

Objective: To report 7 cases of severe MG treated with autologous HSCT in which consistent, durable, symptom-free, and treatment-free remission was achieved.

Design, Setting, And Participants: This retrospective cohort study reports outcomes at The Ottawa Hospital, a large, Canadian, tertiary care referral center with expertise in neurology and HSCT, from January 1, 2001, through December 31, 2014, with a median follow-up of 40 months (range, 29-149 months). Data collection and analysis were performed from February 1 through August 31, 2015. All patients with MG treated with autologous HSCT at The Ottawa Hospital were included. All had persistent severe or life-threatening MG-related symptoms despite continued use of intensive immunosuppressive therapies.

Interventions: Autologous hematopoietic stem cell grafts were mobilized with cyclophosphamide and granulocyte colony-stimulating factor, collected by peripheral blood leukapheresis, and purified away from contaminating lymphocytes using CD34 immunomagnetic selection. Patients were treated with intensive conditioning chemotherapy regimens to destroy the autoreactive immune system followed by graft reinfusion for blood and immune reconstitution.

Main Outcomes And Measures: The primary outcome was MG disease activity after autologous HSCT measured by frequency of emergency department visits and hospitalizations and Myasthenia Gravis Foundation of America (MGFA) clinical classification, MGFA therapy status, and MGFA postintervention status. Safety outcomes included all severe autologous HSCT-related complications.

Results: Seven patients underwent autologous HSCT, 6 for MG and 1 for follicular lymphoma with coincident active MG. Mean (SD) ages at MG diagnosis and at autologous HSCT were 37 (11) and 44 (10) years, respectively. Five patients (71%) had concurrent autoimmune or lymphoproliferative illnesses related to immune dysregulation. All patients had distinct clinical and electromyographic evidence of MG (MGFA clinical classification IIIb-V). All patients achieved durable MGFA complete stable remission with no residual MG symptoms and freedom from any ongoing MG therapy (MGFA postintervention status of complete stable remission). Three patients (43%) experienced transient viral reactivations, and 1 (14%) developed a secondary autoimmune disease after autologous HSCT, all of which resolved or stabilized with treatment. There were no treatment- or MG-related deaths.

Conclusions And Relevance: Autologous HSCT results in long-term symptom- and treatment-free remission in patients with severe MG. The application of autologous HSCT for this and other autoimmune neurologic conditions warrants prospective study.
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http://dx.doi.org/10.1001/jamaneurol.2016.0113DOI Listing
June 2016

Efficacy of Pharmacokinetics-Directed Busulfan, Cyclophosphamide, and Etoposide Conditioning and Autologous Stem Cell Transplantation for Lymphoma: Comparison of a Multicenter Phase II Study and CIBMTR Outcomes.

Biol Blood Marrow Transplant 2016 07 31;22(7):1197-1205. Epub 2016 Mar 31.

Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, New Jersey.

Busulfan, cyclophosphamide, and etoposide (BuCyE) is a commonly used conditioning regimen for autologous stem cell transplantation (ASCT). This multicenter, phase II study examined the safety and efficacy of BuCyE with individually adjusted busulfan based on preconditioning pharmacokinetics. The study initially enrolled Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) patients ages 18 to 80 years but was amended due to high early treatment-related mortality (TRM) in patients > 65 years. BuCyE outcomes were compared with contemporaneous recipients of carmustine, etoposide, cytarabine, and melphalan (BEAM) from the Center for International Blood and Marrow Transplant Research. Two hundred seven subjects with HL (n = 66) or NHL (n = 141) were enrolled from 32 centers in North America, and 203 underwent ASCT. Day 100 TRM for all subjects (n = 203), patients > 65 years (n = 17), and patients ≤ 65 years (n = 186) were 4.5%, 23.5%, and 2.7%, respectively. The estimated rates of 2-year progression-free survival (PFS) were 33% for HL and 58%, 77%, and 43% for diffuse large B cell lymphoma (DLBCL; n = 63), mantle cell lymphoma (MCL; n = 29), and follicular lymphoma (FL; n = 23), respectively. The estimated rates of 2-year overall survival (OS) were 76% for HL and 65%, 89%, and 89% for DLBCL, MCL, and FL, respectively. In the matched analysis rates of 2-year TRM were 3.3% for BuCyE and 3.9% for BEAM, and there were no differences in outcomes for NHL. Patients with HL had lower rates of 2-year PFS with BuCyE, 33% (95% CI, 21% to 46%), than with BEAM, 59% (95% CI, 52% to 66%), with no differences in TRM or OS. BuCyE provided adequate disease control and safety in B cell NHL patients ≤ 65 years but produced worse PFS in HL patients when compared with BEAM.
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http://dx.doi.org/10.1016/j.bbmt.2016.03.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4914052PMC
July 2016

Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study.

Lancet 2016 Feb 7;387(10020):770-8. Epub 2015 Dec 7.

Derriford Hospital, Plymouth, Devon, UK.

Background: Mantle-cell lymphoma is an aggressive B-cell lymphoma with a poor prognosis. Both ibrutinib and temsirolimus have shown single-agent activity in patients with relapsed or refractory mantle-cell lymphoma. We undertook a phase 3 study to assess the efficacy and safety of ibrutinib versus temsirolimus in relapsed or refractory mantle-cell lymphoma.

Methods: This randomised, open-label, multicentre, phase 3 clinical trial enrolled patients with relapsed or refractory mantle-cell lymphoma confirmed by central pathology in 21 countries who had received one or more rituximab-containing treatments. Patients were stratified by previous therapy and simplified mantle-cell lymphoma international prognostic index score, and were randomly assigned with a computer-generated randomisation schedule to receive daily oral ibrutinib 560 mg or intravenous temsirolimus (175 mg on days 1, 8, and 15 of cycle 1; 75 mg on days 1, 8, and 15 of subsequent 21-day cycles). Randomisation was balanced by using randomly permuted blocks. The primary efficacy endpoint was progression-free survival assessed by a masked independent review committee with the primary hypothesis that ibrutinib compared with temsirolimus significantly improves progression-free survival. The analysis followed the intention-to-treat principle. The trial is ongoing and is registered with ClinicalTrials.gov (number NCT01646021) and with the EU Clinical Trials Register, EudraCT (number 2012-000601-74).

Findings: Between Dec 10, 2012, and Nov 26, 2013, 280 patients were randomised to ibrutinib (n=139) or temsirolimus (n=141). Primary efficacy analysis showed significant improvement in progression-free survival (p<0·0001) for patients treated with ibrutinib versus temsirolimus (hazard ratio 0·43 [95% CI 0·32-0·58]; median progression-free survival 14·6 months [95% CI 10·4-not estimable] vs 6·2 months [4·2-7·9], respectively). Ibrutinib was better tolerated than temsirolimus, with grade 3 or higher treatment-emergent adverse events reported for 94 (68%) versus 121 (87%) patients, and fewer discontinuations of study medication due to adverse events for ibrutinib versus temsirolimus (9 [6%] vs 36 [26%]).

Interpretation: Ibrutinib treatment resulted in significant improvement in progression-free survival and better tolerability versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma. These data lend further support to the positive benefit-risk ratio for ibrutinib in relapsed or refractory mantle-cell lymphoma.

Funding: Janssen Research & Development, LLC.
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http://dx.doi.org/10.1016/S0140-6736(15)00667-4DOI Listing
February 2016

Outcomes of both abbreviated hyper-CVAD induction followed by autologous hematopoietic cell transplantation and conventional chemotherapy for mantle cell lymphoma: a 10-year single-centre experience with literature review.

Cancer Med 2015 Dec 3;4(12):1817-27. Epub 2015 Oct 3.

Ottawa Hospital Blood and Marrow Transplant Program, Ottawa, Ontario, Canada.

We retrospectively evaluated consecutive patients diagnosed with Mantle cell lymphoma (MCL) between 01 January 2000 and 31 December 2009. Eighty eight patients with MCL were included in the analysis of whom 46 (52%) received abbreviated Hyper-CVAD (a total of two cycles; with addition of Rituximab since 2005) with an intention of proceeding to autologous hematopoietic cell transplantation (auto-HCT), with a median age of 58 years. Response rate to induction at auto-HCT time was 89% and complete response was 61%. Forty four patients received an auto-HCT with a 5-year progression-free survival (PFS) and overall survival (OS) were 31.2% and 62.5%, respectively. There were 42 nontransplant eligible patients with a median age of 72 years, and 5-year PFS and OS were 0.0% and 39.9%, respectively. The median survival and PFS in the auto-HCT eligible group were 68 and 33 months, compared to 32 and 12 months in nontransplant eligible group, without a plateauing of the survival curves in either group. Treatment-related mortality in the auto-HCT eligible group was 10.9% (n = 5); two patients died during R-Hyper-CVAD and 3 (6.8%) experienced transplant-related mortality. An abbreviated R-Hyper-CVAD-based induction strategy followed by consolidative auto-HCT is feasible and provides moderate potential of long-term survival. Further research to define risk-adapted strategies; to optimize disease control, is required.
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http://dx.doi.org/10.1002/cam4.543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5123787PMC
December 2015

A canadian perspective on the first-line treatment of chronic lymphocytic leukemia.

Clin Lymphoma Myeloma Leuk 2015 Jun 26;15(6):303-13. Epub 2015 Mar 26.

Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.

Despite important advances in the treatment of first-line chronic lymphocytic leukemia (CLL) over the past decade, CLL remains an incurable disease with significant unmet needs. The combination of rituximab with fludarabine and cyclophosphamide (FCR) significantly improved overall survival and progression-free survival compared with fludarabine and cyclophosphamide alone in first-line treatment of CLL. However, because of its high toxicity, FCR is only recommended for younger, fit patients who can tolerate the treatment. This excludes a large fraction of CLL patients who are elderly and/or who have comorbidities. Thus, determining the appropriate treatment choices for this group of patients who are unfit for FCR treatment is a significant challenge in CLL. Current treatment choices in Canadian practice include bendamustine with rituximab, fludarabine with rituximab, and chlorambucil with rituximab. Two novel monoclonal antibodies, ofatumumab and obinutuzumab, have also recently received Health Canada approval for the first-line treatment of CLL patients in combination with chlorambucil. In addition, the Bruton tyrosine kinase inhibitor, ibrutinib, has recently been approved by Health Canada for the first-line treatment of CLL patients with deletion 17p. In the coming years, several other novel agents that are being developed are likely to change the CLL treatment landscape dramatically, however, because these novel agents are currently unavailable, the purpose of this review is to recommend the best treatment approaches in Canada using currently available therapies.
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http://dx.doi.org/10.1016/j.clml.2015.03.002DOI Listing
June 2015

Disseminated histoplasmosis associated with acquired hemophagocytic lymphohistiocytosis.

Clin Case Rep 2015 Mar 4;3(3):195-6. Epub 2014 Dec 4.

Division of Hematopathology, The Ottawa Hospital Ottawa, Ontario, Canada ; Eastern Ontario Regional Laboratory Association Ottawa, Ontario, Canada.

Hemophagocytic lymphohistiocytosis (HLH) is a potentially life-threatening clinical syndrome caused by uncontrolled activation of lymphocytes and histiocytes resulting in high levels of cytokines. Acquired HLH occurs in autoimmune, inflammatory, infectious, and immunosuppressive disorders. Prompt identification and treatment of an underlying triggering cause improves clinical outcome.
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http://dx.doi.org/10.1002/ccr3.179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4377254PMC
March 2015

Autologous stem cell transplantation for stiff person syndrome: two cases from the Ottawa blood and marrow transplant program.

JAMA Neurol 2014 Oct;71(10):1296-9

Ottawa Hospital Blood and Marrow Transplant Program, Ottawa, Ontario, Canada3Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.

Importance: Stiff person syndrome (SPS) is a rare neurological disease causing significant functional disability for patients and presenting a therapeutic challenge for clinicians. Autologous hematopoietic stem cell transplantation (auto-HSCT) has been used successfully to remit autoimmune-mediated neurological diseases. We report 2 cases of severe SPS treated with auto-HSCT, a novel therapy for this disease.

Observations: Two anti-glutamic acid decarboxylase antibody-positive patients with SPS had an autologous hematopoietic stem cell graft collected and stored. Subsequently, the patients underwent auto-HSCT. Both patients achieved clinical remission with sustained, marked improvement in symptoms and a return to premorbid functioning, now more than 2.5 and 4.5 years after the procedure.

Conclusions And Relevance: Stiff person syndrome represents a novel indication for auto-HSCT. The resolution of clinical manifestations of SPS despite the persistence of anti-glutamic acid decarboxylase antibodies following auto-HSCT suggests that the antibody does not play a direct role in pathogenesis of SPS.
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http://dx.doi.org/10.1001/jamaneurol.2014.1297DOI Listing
October 2014

Impact of platelet transfusion on toxicity and mortality after hematopoietic progenitor cell transplantation.

Transfusion 2015 Feb 15;55(2):253-8. Epub 2014 Aug 15.

Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada.

Background: Thrombocytopenia occurs commonly after hematopoietic progenitor cell transplantation (HPCT) and is associated with potential morbidity and mortality. Few studies have examined the impact of platelet (PLT) transfusion on clinical outcomes in HPCT while optimal PLT transfusion strategies after HSCT remain uncertain.

Study Design And Methods: A retrospective single-center cohort study was conducted on 522 patients undergoing HPCT between January 2002 and December 2007. Associations between PLT transfusion events and clinical characteristics with transplant-related outcomes were assessed using univariate and multivariate analysis.

Results: Mean number of PLT transfusion events before Day +60 posttransplant was 7.5 (95% confidence interval, 6.7-8.4) with greater number of events after allogeneic compared with autologous HPCT (p < 0.01). Univariate and multivariate analysis confirmed that the number of PLT transfusion events was associated with increased 100-day nonrelapse mortality (p < 0.01), posttransplant length of hospital stay (p < 0.01), need for intensive care unit admission (p < 0.01), and number of organs affected by severe toxicity (p < 0.01).

Conclusion: HPCT-related toxicity and mortality are associated with increased PLT transfusion events. Alternative strategies to reduce PLT transfusions after HPCT may warrant future study.
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http://dx.doi.org/10.1111/trf.12817DOI Listing
February 2015

PTK2 expression and immunochemotherapy outcome in chronic lymphocytic leukemia.

Blood 2014 Jul 10;124(3):420-5. Epub 2014 Jun 10.

Pharmaceuticals Division, F. Hoffmann-La Roche Ltd., Basel, Switzerland.

Addition of rituximab (R) to fludarabine and cyclophosphamide (FC) has significantly improved patient outcomes in chronic lymphocytic leukemia (CLL). Whether baseline gene expression can identify patients who will benefit from immunochemotherapy over chemotherapy alone has not been determined. We assessed genome-wide expression of 300 pretreatment specimens from a subset of 552 patients in REACH, a study of FC or R-FC in relapsed CLL. An independent test set was derived from 282 pretreatment specimens from CLL8, a study of FC or R-FC in treatment-naïve patients. Genes specific for benefit from R-FC were determined by assessing treatment-gene interactions in Cox proportional hazards models. REACH patients with higher pretreatment protein tyrosine kinase 2 (PTK2) messenger RNA levels derived greater benefit from R-FC, with significant improvements in progression-free survival, independent of known prognostic factors in a multivariate model. Examination of PTK2 gene expression in CLL8 patients yielded similar results. Furthermore, PTK2 inhibition blunted R-dependent cell death in vitro. This retrospective analysis from 2 independent trials revealed that increased PTK2 expression is associated with improved outcomes for CLL patients treated with R-FC vs FC. PTK2 expression may be a useful biomarker for patient selection in future trials. These trials were registered at www.clinicaltrials.gov as #NCT00090051 (REACH) and #NCT00281918 (CLL8).
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http://dx.doi.org/10.1182/blood-2013-12-538975DOI Listing
July 2014

A single-institution analysis of the utility of pre-induction ejection fraction measurement in patients newly diagnosed with acute myeloid leukemia.

Leuk Lymphoma 2015 Jan 17;56(1):135-40. Epub 2014 Jul 17.

The Ottawa Hospital and Department of Medicine, University of Ottawa , Ottawa, ON , Canada.

Anthracyclines, a standard component of induction therapy for acute myeloid leukemia (AML) are known to be cardiotoxic. Existing evidence supporting routine baseline pre-induction cardiac function testing is limited. We conducted a retrospective analysis of 119 consecutive patients diagnosed with AML at our center from 2009 to 2012. In the 76 patients for whom induction chemotherapy was planned, baseline ejection fraction measurements were rarely abnormal (four cases), and in none of these abnormal cases did the result change management decisions. Awaiting LVEF evaluation results led to a delay in chemotherapy administration by a mean of approximately 2 days at significant additional costs to the healthcare system. Routine baseline ejection fraction measurement should be abandoned as it does not change management, results in treatment delay and unnecessary healthcare expenditures. More selective baseline testing, preferentially in patients in whom there is a clinical reason of cardiac disease, should be pursued.
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http://dx.doi.org/10.3109/10428194.2014.883072DOI Listing
January 2015

Results of a prospective phase II trial evaluating interim positron emission tomography-guided high dose therapy for poor prognosis diffuse large B-cell lymphoma.

Leuk Lymphoma 2014 Sep 17;55(9):2064-70. Epub 2014 Feb 17.

Medicine and Oncology, University of Calgary , Calgary , Canada.

Patients with diffuse large B-cell lymphoma (DLBCL) with a poor prognosis based upon advanced stage and elevated serum lactate dehydrogenase achieve a 3-4-year progression-free survival (PFS) of only 55%. The role of interim fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET) to guide use of upfront high dose chemotherapy (HDCT) and autologous stem cell transplant (ASCT) for patients with poor prognosis DLBCL is unproven. A prospective phase II clinical trial was designed to evaluate the outcomes of HDCT/ASCT for patients with poor prognosis DLBCL aged 18-65 years who had unfavorable interim restaging PET scans. Of the 70 eligible patients, 36 had unfavorable and 34 favorable interim PET responses, with 3-year PFS rates of 65.2% and 52.7%, respectively. In conclusion, favorable interim PET response as defined in this study is not associated with improved PFS rates for patients with poor prognosis DLBCL treated with RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). A phase III trial evaluating this PET-guided approach is not warranted.
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http://dx.doi.org/10.3109/10428194.2013.862242DOI Listing
September 2014

Rituximab purging and/or maintenance in patients undergoing autologous transplantation for relapsed follicular lymphoma: a prospective randomized trial from the lymphoma working party of the European group for blood and marrow transplantation.

J Clin Oncol 2013 May 1;31(13):1624-30. Epub 2013 Apr 1.

St George's University of London, Cranmer Terrace, London SW17 0QT, United Kingdom.

Purpose: The objective of this randomized trial was to assess the efficacy and safety of rituximab as in vivo purging before transplantation and as maintenance treatment immediately after high-dose chemotherapy and autologous stem-cell transplantation (HDC-ASCT) in patients with relapsed follicular lymphoma (FL).

Patients And Methods: Patients with relapsed FL who achieved either complete or very good partial remission with salvage chemotherapy were randomly assigned using a factorial design to rituximab purging (P+; 375 mg/m(2) once per week for 4 weeks) or observation (NP) before HDC-ASCT and to maintenance rituximab (M+; 375 mg/m(2) once every 2 months for four infusions) or observation (NM).

Results: From October 1999 to April 2006, 280 patients were enrolled. The median age was 51 years (range, 26 to 70 years), and baseline characteristics were well balanced between groups. On average, patients were 44 months (range, 3 to 464 months) from diagnosis, with 79% having received two lines and 15% three lines of prior therapy. Median follow-up was 8.3 years. In contrast to purging, 10-year progression-free survival (PFS) was 48% for P+ and 42% for NP groups (hazard ratio [HR], 0.80; 95% CI, 0.58 to 1.11; P = .18); maintenance had a significant effect on PFS (10-year PFS, 54% for M+ and 37% for NM; HR, 0.66; 95% CI, 0.47 to 0.91; P = .012). Overall survival (OS) was not improved by either rituximab purging or maintenance.

Conclusion: Rituximab maintenance after HDC-ASCT is safe and significantly prolongs PFS but not OS in patients undergoing transplantation for relapsed FL. Pretransplantation rituximab in vivo purging, even in rituximab-naive patients, failed to improve PFS or OS.
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http://dx.doi.org/10.1200/JCO.2012.47.1862DOI Listing
May 2013

Effect of FCGR2A and FCGR3A variants on CLL outcome.

Blood 2010 Nov 12;116(20):4212-22. Epub 2010 Aug 12.

Molecular Diagnostics and Cancer Cell Biology, Genentech Inc, South San Francisco, CA, USA.

Polymorphisms of activating Fc-γ receptors (FCGRs) on natural killer cells and macrophages result in variable affinity for immunoglobulin G1 monoclonal antibodies and subsequently modulate antibody-dependent cellular cytotoxicity (ADCC) activity. Whether single-nucleotide polymorphisms of FCGRs correlate with survival of chronic lymphocytic leukemia (CLL) patients treated with a monoclonal antibody containing regimen is unclear. We assessed the FCGR3A and FCGR2A genotype of patients enrolled in the REACH trial, where patients received fludarabine and cyclophosphamide (FC) or rituximab plus FC (R-FC). FCGR3A and FCGR2A polymorphisms did not demonstrate prognostic significance in the FC arm (P = .42 and P = .64, respectively) or R-FC arm (P = .41 and P = .88, respectively) with respect to progression free survival. Patients with intermediate affinity genotypes (FV and HR) benefited significantly from addition of rituximab (hazard ratio = 0.55 [0.37-0.8 CI]; P = .0017 and hazard ratio = 0.63 [0.44-0.9 CI]; P = .011, respectively). Similar benefit was suggested for patients with high- affinity VV and HH (hazard ratio = 0.86 [0.4-1.84 CI]; P = .7 and hazard ratio = 0.7 [0.41-1.18 CI]; P = .18, respectively) and low-affinity FF and RR (hazard ratio = 0.85 [0.56-1.29 CI]; P = .44 and hazard ratio = 0.82 [0.47-1.42 CI]; P = .48, respectively). Overall, our results suggest that FCGR2A and FCGR3A polymorphisms do not significantly influence the outcomes of relapsed or refractory CLL patients treated with FC or the monoclonal antibody regimen R-FC.
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http://dx.doi.org/10.1182/blood-2010-03-272765DOI Listing
November 2010

Comparison of favorable early-stage hodgkin's lymphoma treatments: a single-institution review.

Int J Radiat Oncol Biol Phys 2010 Mar 19;76(4):1166-70. Epub 2009 Aug 19.

Division of Radiation Oncology, The Ottawa Hospital Cancer Centre, 501 Smyth Road, Ottawa, ON K1H 8L6, Canada.

Purpose: To compare outcomes of patients receiving combined-modality chemotherapy and radiation (CMT) vs. other approaches for early-stage Hodgkin's lymphoma (HL).

Methods And Materials: A review of patients with nonbulky, early-stage (IA/IIA) HL treated between 1984 and 2002 was performed to determine the treatment approaches used and the outcomes obtained.

Results: There were 173 adult patients with newly diagnosed early-stage HL (49% men, 51% women, median age 33 [range 17-82] years). Treatment was as follows: extended-field radiotherapy alone (EFRT) 49%; chemotherapy alone (CTA) 13%; and CMT 38%. Among CMT patients, 36% received abbreviated doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy (three to four cycles) followed by involved-field radiotherapy. With a median follow-up of 8.3 years, the estimated 10-year relapse-free survival (RFS) and overall survival (OS) rates for the entire cohort were 78% and 85%, respectively. The 10-year RFS and OS rates for the various groups were as follows: 69% and 81% for EFRT; 78% and 84% for CTA; and 87% and 89% for CMT. The 10-year RFS rate was significantly higher (p < 0.01) among CMT patients. The use of EFRT has diminished from approximately 90% in the 1980s to virtually no use at present, whereas the use of CTA and CMT has increased significantly (p < 0.01).

Conclusion: Early-stage HL treatment has changed dramatically over the past 2 decades, and our results support the superiority and continued use of CMT, specifically abbreviated-course chemotherapy and involved-field radiotherapy, as an appropriate treatment approach.
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http://dx.doi.org/10.1016/j.ijrobp.2009.03.070DOI Listing
March 2010

A 15-year analysis of early and late autologous hematopoietic stem cell transplant in relapsed, aggressive, transformed, and nontransformed follicular lymphoma.

Biol Blood Marrow Transplant 2007 Aug;13(8):956-64

The Ottawa Hospital Blood and Marrow Transplant Program, University of Ottawa, Ottawa, Ontario, Canada.

Autologous stem cell transplant (ASCT) has been shown to be an effective treatment for follicular lymphoma (FL). We explored our experience in ASCT for FL among all patients treated over a 15-year period from diagnosis through their entire treatment history including relapse post ASCT. All patients who underwent an unpurged ASCT for relapsed, advanced FL between June 1990 and December 2000 were analyzed. After salvage therapy they received melphalan/etoposide/total body irradiation, BCNU, etoposide, cytarabine, melphalan (BEAM), or cyclophosphamide BCNU etoposide (CBV) as conditioning for the ASCT. One hundred thirty-eight patients with a median age of 48 years and a median follow-up of 7.6 years were analyzed. The majority were of the subtype grade 1, nontransformed (FL-NT), having had 1 prior chemotherapy. The progression-free (PFS) and overall survival (OS) of the FL-NT at 10 years were 46% and 57%, respectively, and at 5 years for the transformed (FL-T) were 25% and 56%, respectively, of which only the PFS was significantly different (P=.007). The median OS from diagnosis was 16 years for the FL-NT. ASCT positively altered the trend of shorter remissions with subsequent chemotherapies, and there was no difference in OS between those who had 1, 2, or >2 chemotherapies prior to ASCT. Salvage therapy for relapse post ASCT was effective (OS>1 year) in a third of patients. Unpurged ASCT is an effective tool in the treatment of relapsed, aggressive FL-NT and FL-T, is superior to retreatment with standard chemotherapy, is effective at various stages of treatment, is likely to have a beneficial influence on the natural history of this disease, and the disease is amenable to salvage therapy post-ASCT relapse.
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http://dx.doi.org/10.1016/j.bbmt.2007.04.009DOI Listing
August 2007

Outpatient autologous hematopoietic stem cell transplantation for patients with relapsed follicular lymphoma.

Ann Hematol 2006 Oct 11;85(10):723-9. Epub 2006 Jul 11.

St. Paul's Hospital and University of British Columbia, 440-1144 Burrard Street, Vancouver, BC, Canada.

Autologous stem cell transplantation (ASCT) has emerged as a viable option for the treatment of relapsed follicular non-Hodgkin's lymphoma. We report on the outpatient experience of 60 patients who underwent ASCT for this condition. The median age was 51 years (30-65). Pre-transplantation conditioning regimens consisted of either etoposide/melphalan/TBI, CBV or BEAM. Patients participated in this transplant program for a median of 20.5 days (14-78), and 58.4% of the total program days were spent in the outpatient setting. Six patients were well enough to be treated solely as outpatients. Ninety percent of patients required at least one inpatient admission (median 7 days), and 70% of first inpatient transfers occurred within the first week following transplant and always before day +12. There were no predictors for prolonged inpatient stays. Febrile neutropenia and gastrointestinal toxicity were the main reasons for inpatient transfers. No outpatient required an urgent admission to the ICU or died in the outpatient setting. The treatment-related mortality at days 30 and 100 was 0 and 1.7%, respectively. The overall and progression-free survivals at 5 years were 65.7 and 56.1%, respectively. Outpatient ASCT with total body irradiation is feasible, safe, and effective for patients with relapsed follicular lymphoma.
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http://dx.doi.org/10.1007/s00277-006-0149-6DOI Listing
October 2006

Lymphoproliferative lesions of the lacrimal gland: clinicopathological, immunohistochemical and molecular genetic analysis.

Can J Ophthalmol 2005 Apr;40(2):151-60

Department of Pathology and Laboratory Medicine, Ottawa Hospital and University of Ottawa, Ont.

Background: Lacrimal gland lymphoproliferative disorders are usually classified as orbital adnexal tumours. Because the lacrimal gland is the only orbital structure with native lymphocytes, we examined cases with primary involvement of the gland.

Methods: The 14 cases were selected from a review of all cases in the surgical pathology files of the Ottawa Hospital between 1992 and 2003. The lesions were categorized according to the latest World Health Organization classification of tumours of lymphoid tissues. We conducted a clinical, histopathological, immunohistochemical, immunophenotypic and molecular genetic analysis of the cases.

Results: The 8 female and 6 male patients, aged 20 to 88 (mean 60) years, were followed for an average of 4 years (range 11 months to 13 years). All presented with supratemporal orbital swelling. The 5 primary lymphomas, of mucosa-associated lymphoid tissue (MALT), were confined to the lacrimal gland (stage IE); 1 tumour transformed to diffuse large B-cell lymphoma, necessitating chemotherapy, and the other 4 were treated with radiation. One of the 5 patients had previously had Sjögren's syndrome. The 6 secondary lymphomas (4 follicular) presented either concurrently with systemic lymphoma or up to 12 years afterwards and were treated in a variety of ways; all the patients had an orbital relapse. At the last follow-up assessment, 6 of the patients with lymphoma had no evidence of disease, 3 were alive with disease, 2 had died (1 of lymphoma, the other with no evidence of disease), and the status of 1 patient was not known. Of the 3 patients with reactive proliferations, 2 had reactive lymphoid hyperplasia (associated with Sjögren's syndrome in 1), and 1 had Rosai-Dorfman disease. All 9 lymphomas that underwent molecular genetic analysis were of B-cell lineage, and 8 had a monoclonal rearrangement in the immunoglobulin heavy-chain gene (IgH); the 9th lymphoma showed an oligoclonal rearrangement. One lymphoma showed the t(14;18) translocation, typical of follicular lymphoma; no lymphoma showed the t(11;18) translocation, commonly found in MALT lymphoma (but only 2 cases were studied). Molecular genetic analysis was performed in 2 of the cases of reactive lymphoid hyperplasia: monoclonal IgH rearrangement was detected in 1 case (the patient with Sjögren's syndrome), oligoclonal rearrangement in the other.

Interpretation: Lacrimal gland lymphomas are B-cell tumours that develop in older adults. Primary tumours, a hIgH proportion of which have MALT characteristics, have a favourable prognosis. Molecular genetic studies may be useful when morphologic and immunophenotypic studies give equivocal results.
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http://dx.doi.org/10.1016/S0008-4182(05)80026-2DOI Listing
April 2005
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