Late relapses of hepatitis C virus-cured mixed cryoglobulinaemia associated with infection or cancer

Late relapses of hepatitis C virus-cured mixed cryoglobulinaemia associated with infection or cancer Rheumatology key message Infections or tumors may reactivate HCV-cured mixed cryoglobulinaemia, possibly through the formation of immune complexes. Sir, mixed cryoglobulinaemia (MC) secondary to chronic HCV infection regresses in the majority of patients with sustained virologic response (SVR) to antiviral therapy, although disappearance of serum cryoglobulin is seen in only ∼50% of patients [1, 2]. Remarkably, clonally expanded B cells producing cryoglobulin-related RF may persist for at least several months after clearance of HCV [3], possibly explaining the persistence [4] or relapse [5] of vasculitis in some HCV-cured patients. The reason(s) why B cell clones and cryoglobulinaemia persist despite SVR remain unknown, with the exception of a few cases in which a lymphoma was eventually diagnosed [5]. Here we describe five patients with type II MC who had either persistence (one patient) or late relapse (four patients) of vasculitis despite persistently negative HCV RNA in serum and cryoprecipitate. None of these patients had evidence of lymphoma, while in all cases progression or relapse of vasculitis were closely associated with infections or with the diagnosis of a solid tumour. Persistence of MC was seen in a 61-year-old female with HCV genotype 1 b infection presenting with purpura and mild sensory neuropathy. She was treated with ombitasvir/paritaprevir/ritonavir + dasabuvir for 12 weeks but, despite SVR, had a dramatic progression of sensory/motor neuropathy. Six months after therapy she was diagnosed with unresectable lung adenocarcinoma, and died 4 months later of respiratory failure mainly due to overwhelming motor neuropathy. Cryocrit and a large VH1–69+ B cell clone [3] remained substantially unmodified up to her death (cryocrit, 17–24%; B cell clone, 83–74% of B cells). The demographic and clinical characteristics of four patients with relapse of MC vasculitis despite SVR are summarized in Table 1. Patient 1 presented with purpura, peripheral neuropathy, skin ulcers and nephrotic syndrome; she was treated in 2015 with sofosbuvir/ledipasvir for 24 weeks achieving SVR, disappearance of cryoglobulins and waning of vasculitis manifestations. In March 2017, shortly after an upper respiratory infection, she experienced recurrence of serum cryoglobulins, of skin ulcers and of proteinuria. Lymphoma was excluded by negative bone marrow biopsy and PET/CT scan. Patient 2 had a diagnosis of type II MC in 1998 and was treated with pegylated IFN plus ribavirin without achieving SVR. At the beginning of 2015 he was treated with sofosbuvir/simeprevir for 12 weeks, achieving SVR, regression of purpura and normalization of renal function. In December 2016, 5 days after a flu-like syndrome, he complained of diffuse purpura at lower limbs, new-onset paresthesia and worsening of renal function with active urinary sediment (50 red blood cells/μl, proteinuria 600 mg/day). Symptoms and signs of vasculitis gradually subsided and, in August 2017, the patient was in complete clinical remission with absence of cryoglobulins. Patient 3 presented in 2007 with purpura, peripheral neuropathy, glomerulonephritis and skin ulcers, and, because of contraindication to IFN-based therapy, was treated with repeated cycles of rituximab yielding transient responses. In 2015, she was treated with sofosbuvir/simeprevir for 12 weeks achieving SVR, clearance of cryoglobulins and complete response of vasculitis. Twenty-eight months later she presented with fever, pneumonia and pleural effusion of unknown aetiology, together with recurrence of serum cryoglobulins and purpura that subsided after about 2 months. Patient 4 presented in 2001 with purpura and peripheral neuropathy; in 2002 she was treated with pegylated IFN plus ribavirin for 12 months achieving SVR, clearance of cryoglobulins and complete remission of vasculitis for 13 years. In 2016, she had flair of purpura and recurrence of serum cryoglobulins, and a CT scan revealed unresectable lung adenocarcinoma; serum cryoglobulins and purpura persisted up to her death of tumour 17 months later. Table 1 Characteristics of patients Patient Age/sex at diagnosis HCV GT Antiviral therapy Vasculitis at diagnosis Cryocrit at diagnosis (%) Year of relapse (after SVR) Vasculitis at relapse Cryocrit at relapse (%) Disease concomitant to relapse 1 69/F 1b SOF/LED Kidney disease, skin ulcers, neuropathy 3 1.5 Kidney disease, skin ulcers 10 Upper respiratory tract infection 2 52/M 1b SOF/SIM Neuropathy, purpura, arthralgia 4 1.8 Neuropathy, purpura, kidney disease 1 Flu-like syndrome 3 82/F 1b SOF/SIM Neuropathy, purpura, skin ulcers, kidney disease 7 2.5 Purpura 2 Respiratory infection of unknown aetiology 4 38/F 1b PEG-IFN/ RIBA Neuropathy, purpura 3 13 Purpura 2 Unresectable lung adenocarcinoma Patient Age/sex at diagnosis HCV GT Antiviral therapy Vasculitis at diagnosis Cryocrit at diagnosis (%) Year of relapse (after SVR) Vasculitis at relapse Cryocrit at relapse (%) Disease concomitant to relapse 1 69/F 1b SOF/LED Kidney disease, skin ulcers, neuropathy 3 1.5 Kidney disease, skin ulcers 10 Upper respiratory tract infection 2 52/M 1b SOF/SIM Neuropathy, purpura, arthralgia 4 1.8 Neuropathy, purpura, kidney disease 1 Flu-like syndrome 3 82/F 1b SOF/SIM Neuropathy, purpura, skin ulcers, kidney disease 7 2.5 Purpura 2 Respiratory infection of unknown aetiology 4 38/F 1b PEG-IFN/ RIBA Neuropathy, purpura 3 13 Purpura 2 Unresectable lung adenocarcinoma F: female; M: male; GT: genotype; PEG-IFN/RIBA: pegylated interferon + ribavirin; SOF/LED: sofosbuvir + ledipasvir; SOF/SIM: sofosvubir + simeprevir; SVR: sustained virologic response. Table 1 Characteristics of patients Patient Age/sex at diagnosis HCV GT Antiviral therapy Vasculitis at diagnosis Cryocrit at diagnosis (%) Year of relapse (after SVR) Vasculitis at relapse Cryocrit at relapse (%) Disease concomitant to relapse 1 69/F 1b SOF/LED Kidney disease, skin ulcers, neuropathy 3 1.5 Kidney disease, skin ulcers 10 Upper respiratory tract infection 2 52/M 1b SOF/SIM Neuropathy, purpura, arthralgia 4 1.8 Neuropathy, purpura, kidney disease 1 Flu-like syndrome 3 82/F 1b SOF/SIM Neuropathy, purpura, skin ulcers, kidney disease 7 2.5 Purpura 2 Respiratory infection of unknown aetiology 4 38/F 1b PEG-IFN/ RIBA Neuropathy, purpura 3 13 Purpura 2 Unresectable lung adenocarcinoma Patient Age/sex at diagnosis HCV GT Antiviral therapy Vasculitis at diagnosis Cryocrit at diagnosis (%) Year of relapse (after SVR) Vasculitis at relapse Cryocrit at relapse (%) Disease concomitant to relapse 1 69/F 1b SOF/LED Kidney disease, skin ulcers, neuropathy 3 1.5 Kidney disease, skin ulcers 10 Upper respiratory tract infection 2 52/M 1b SOF/SIM Neuropathy, purpura, arthralgia 4 1.8 Neuropathy, purpura, kidney disease 1 Flu-like syndrome 3 82/F 1b SOF/SIM Neuropathy, purpura, skin ulcers, kidney disease 7 2.5 Purpura 2 Respiratory infection of unknown aetiology 4 38/F 1b PEG-IFN/ RIBA Neuropathy, purpura 3 13 Purpura 2 Unresectable lung adenocarcinoma F: female; M: male; GT: genotype; PEG-IFN/RIBA: pegylated interferon + ribavirin; SOF/LED: sofosbuvir + ledipasvir; SOF/SIM: sofosvubir + simeprevir; SVR: sustained virologic response. In all of our patients, a remarkably late (1.5–13 years after antiviral therapy) relapse of HCV-cured cryogloblulinaemic vasculitis occurred in coincidence with infections or with the diagnosis of lung adenocarcinoma, that was in both cases non-mucinous and positive for pneumocyte marker expression (thyroid transcription factor (TTF)-1 and Napsin A). These conditions share an increased production of immune complexes [6], suggesting their role in reactivating MC vasculitis after HCV clearance. B cell clones expressing a B cell receptor (BCR) with both anti-HCV and RF activity are typically found in MC and persist in the peripheral blood of some patients after clearance of virus [3]. Persistence of B cell clones beyond HCV might relay on their RF activity prompting susceptibility to stimulation by immune complexes [7], which may lead, under conditions of abundant production, to their activation and expansion and to disease relapse. We assessed BCR clonality in two patients. In one case we found persistence of a large B cell clone together with MC vasculitis. In another case (number 3) no circulating B cell clones were detected either before antiviral therapy or at relapse, possibly because of exclusive homing to lymphoid tissue, bone marrow or liver [8]. On a practical ground, B cell depletion with rituximab might be effective for preventing or treating relapses in HCV-cured MC patients. Funding: This work was supported in part by the Intramural Research Program of Sapienza University of Rome (C26A15AKF7) and by the Istituto Pasteur Italia- Fondazione Cenci Bolognetti (Prot.76). Disclosure statement: The authors have declared no conflicts of interest. References 1 Gragnani L , Visentini M , Fognani E et al. Prospective study of guideline-tailored therapy with direct-acting antivirals for hepatitis C virus-associated mixed cryoglobulinemia . Hepatology 2016 ; 64 : 1473 – 82 . Google Scholar Crossref Search ADS PubMed 2 Saadoun D , Pol S , Ferfar Y et al. Efficacy and safety of sofosbuvir plus daclatasvir for treatment of HCV-associated cryoglobulinemia vasculitis . Gastroenterology 2017 ; 153 : 49 – 52 . Google Scholar Crossref Search ADS PubMed 3 Del Padre M , Todi L , Mitrevski M et al. Reversion of anergy signatures in clonal CD21low B cells of mixed cryoglobulinemia after clearance of HCV viremia . Blood 2017 ; 130 : 35 – 8 . Google Scholar Crossref Search ADS PubMed 4 Solllma S , Milazzo L , Peri AM et al. Persistent mixed cryoglobulinaemia vasculitis despite hepatitis C virus eradication after interferon-free antiviral therapy . Rheumatology 2016 ; 55 : 2084 – 5 . Google Scholar Crossref Search ADS PubMed 5 Landau DA , Saadoun D , Halfon P et al. Relapse of hepatitis C virus-associated mixed cryoglobulinemia vasculitis in patients with sustained viral response . Arthritis Rheum 2008 ; 58 : 604 – 11 . Google Scholar Crossref Search ADS PubMed 6 Ohyama K , Yoshimi H , Aibara N et al. Immune complexome analysis reveals the specific and frequent presence of immune complex antigens in lung cancer patients: a pilot study . Int J Cancer 2017 ; 140 : 370 – 80 . Google Scholar Crossref Search ADS PubMed 7 Sang A , Niu H , Cullen J et al. Activation of rheumatoid factor-specific B cells is antigen dependent and occurs preferentially outside of germinal centers in the lupus-prone NZM2410 mouse model . J Immunol 2014 ; 193 : 1609 – 21 . Google Scholar Crossref Search ADS PubMed 8 Vallat L , Benhamou Y , Gutierrez M et al. Clonal B cell populations in the blood and liver of patients with chronic hepatitis C virus infection . Arthritis Rheum 2004 ; 50 : 3668 – 78 . Google Scholar Crossref Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Rheumatology Oxford University Press

Late relapses of hepatitis C virus-cured mixed cryoglobulinaemia associated with infection or cancer

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com
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1462-0324
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D.O.I.
10.1093/rheumatology/key157
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Abstract

Rheumatology key message Infections or tumors may reactivate HCV-cured mixed cryoglobulinaemia, possibly through the formation of immune complexes. Sir, mixed cryoglobulinaemia (MC) secondary to chronic HCV infection regresses in the majority of patients with sustained virologic response (SVR) to antiviral therapy, although disappearance of serum cryoglobulin is seen in only ∼50% of patients [1, 2]. Remarkably, clonally expanded B cells producing cryoglobulin-related RF may persist for at least several months after clearance of HCV [3], possibly explaining the persistence [4] or relapse [5] of vasculitis in some HCV-cured patients. The reason(s) why B cell clones and cryoglobulinaemia persist despite SVR remain unknown, with the exception of a few cases in which a lymphoma was eventually diagnosed [5]. Here we describe five patients with type II MC who had either persistence (one patient) or late relapse (four patients) of vasculitis despite persistently negative HCV RNA in serum and cryoprecipitate. None of these patients had evidence of lymphoma, while in all cases progression or relapse of vasculitis were closely associated with infections or with the diagnosis of a solid tumour. Persistence of MC was seen in a 61-year-old female with HCV genotype 1 b infection presenting with purpura and mild sensory neuropathy. She was treated with ombitasvir/paritaprevir/ritonavir + dasabuvir for 12 weeks but, despite SVR, had a dramatic progression of sensory/motor neuropathy. Six months after therapy she was diagnosed with unresectable lung adenocarcinoma, and died 4 months later of respiratory failure mainly due to overwhelming motor neuropathy. Cryocrit and a large VH1–69+ B cell clone [3] remained substantially unmodified up to her death (cryocrit, 17–24%; B cell clone, 83–74% of B cells). The demographic and clinical characteristics of four patients with relapse of MC vasculitis despite SVR are summarized in Table 1. Patient 1 presented with purpura, peripheral neuropathy, skin ulcers and nephrotic syndrome; she was treated in 2015 with sofosbuvir/ledipasvir for 24 weeks achieving SVR, disappearance of cryoglobulins and waning of vasculitis manifestations. In March 2017, shortly after an upper respiratory infection, she experienced recurrence of serum cryoglobulins, of skin ulcers and of proteinuria. Lymphoma was excluded by negative bone marrow biopsy and PET/CT scan. Patient 2 had a diagnosis of type II MC in 1998 and was treated with pegylated IFN plus ribavirin without achieving SVR. At the beginning of 2015 he was treated with sofosbuvir/simeprevir for 12 weeks, achieving SVR, regression of purpura and normalization of renal function. In December 2016, 5 days after a flu-like syndrome, he complained of diffuse purpura at lower limbs, new-onset paresthesia and worsening of renal function with active urinary sediment (50 red blood cells/μl, proteinuria 600 mg/day). Symptoms and signs of vasculitis gradually subsided and, in August 2017, the patient was in complete clinical remission with absence of cryoglobulins. Patient 3 presented in 2007 with purpura, peripheral neuropathy, glomerulonephritis and skin ulcers, and, because of contraindication to IFN-based therapy, was treated with repeated cycles of rituximab yielding transient responses. In 2015, she was treated with sofosbuvir/simeprevir for 12 weeks achieving SVR, clearance of cryoglobulins and complete response of vasculitis. Twenty-eight months later she presented with fever, pneumonia and pleural effusion of unknown aetiology, together with recurrence of serum cryoglobulins and purpura that subsided after about 2 months. Patient 4 presented in 2001 with purpura and peripheral neuropathy; in 2002 she was treated with pegylated IFN plus ribavirin for 12 months achieving SVR, clearance of cryoglobulins and complete remission of vasculitis for 13 years. In 2016, she had flair of purpura and recurrence of serum cryoglobulins, and a CT scan revealed unresectable lung adenocarcinoma; serum cryoglobulins and purpura persisted up to her death of tumour 17 months later. Table 1 Characteristics of patients Patient Age/sex at diagnosis HCV GT Antiviral therapy Vasculitis at diagnosis Cryocrit at diagnosis (%) Year of relapse (after SVR) Vasculitis at relapse Cryocrit at relapse (%) Disease concomitant to relapse 1 69/F 1b SOF/LED Kidney disease, skin ulcers, neuropathy 3 1.5 Kidney disease, skin ulcers 10 Upper respiratory tract infection 2 52/M 1b SOF/SIM Neuropathy, purpura, arthralgia 4 1.8 Neuropathy, purpura, kidney disease 1 Flu-like syndrome 3 82/F 1b SOF/SIM Neuropathy, purpura, skin ulcers, kidney disease 7 2.5 Purpura 2 Respiratory infection of unknown aetiology 4 38/F 1b PEG-IFN/ RIBA Neuropathy, purpura 3 13 Purpura 2 Unresectable lung adenocarcinoma Patient Age/sex at diagnosis HCV GT Antiviral therapy Vasculitis at diagnosis Cryocrit at diagnosis (%) Year of relapse (after SVR) Vasculitis at relapse Cryocrit at relapse (%) Disease concomitant to relapse 1 69/F 1b SOF/LED Kidney disease, skin ulcers, neuropathy 3 1.5 Kidney disease, skin ulcers 10 Upper respiratory tract infection 2 52/M 1b SOF/SIM Neuropathy, purpura, arthralgia 4 1.8 Neuropathy, purpura, kidney disease 1 Flu-like syndrome 3 82/F 1b SOF/SIM Neuropathy, purpura, skin ulcers, kidney disease 7 2.5 Purpura 2 Respiratory infection of unknown aetiology 4 38/F 1b PEG-IFN/ RIBA Neuropathy, purpura 3 13 Purpura 2 Unresectable lung adenocarcinoma F: female; M: male; GT: genotype; PEG-IFN/RIBA: pegylated interferon + ribavirin; SOF/LED: sofosbuvir + ledipasvir; SOF/SIM: sofosvubir + simeprevir; SVR: sustained virologic response. Table 1 Characteristics of patients Patient Age/sex at diagnosis HCV GT Antiviral therapy Vasculitis at diagnosis Cryocrit at diagnosis (%) Year of relapse (after SVR) Vasculitis at relapse Cryocrit at relapse (%) Disease concomitant to relapse 1 69/F 1b SOF/LED Kidney disease, skin ulcers, neuropathy 3 1.5 Kidney disease, skin ulcers 10 Upper respiratory tract infection 2 52/M 1b SOF/SIM Neuropathy, purpura, arthralgia 4 1.8 Neuropathy, purpura, kidney disease 1 Flu-like syndrome 3 82/F 1b SOF/SIM Neuropathy, purpura, skin ulcers, kidney disease 7 2.5 Purpura 2 Respiratory infection of unknown aetiology 4 38/F 1b PEG-IFN/ RIBA Neuropathy, purpura 3 13 Purpura 2 Unresectable lung adenocarcinoma Patient Age/sex at diagnosis HCV GT Antiviral therapy Vasculitis at diagnosis Cryocrit at diagnosis (%) Year of relapse (after SVR) Vasculitis at relapse Cryocrit at relapse (%) Disease concomitant to relapse 1 69/F 1b SOF/LED Kidney disease, skin ulcers, neuropathy 3 1.5 Kidney disease, skin ulcers 10 Upper respiratory tract infection 2 52/M 1b SOF/SIM Neuropathy, purpura, arthralgia 4 1.8 Neuropathy, purpura, kidney disease 1 Flu-like syndrome 3 82/F 1b SOF/SIM Neuropathy, purpura, skin ulcers, kidney disease 7 2.5 Purpura 2 Respiratory infection of unknown aetiology 4 38/F 1b PEG-IFN/ RIBA Neuropathy, purpura 3 13 Purpura 2 Unresectable lung adenocarcinoma F: female; M: male; GT: genotype; PEG-IFN/RIBA: pegylated interferon + ribavirin; SOF/LED: sofosbuvir + ledipasvir; SOF/SIM: sofosvubir + simeprevir; SVR: sustained virologic response. In all of our patients, a remarkably late (1.5–13 years after antiviral therapy) relapse of HCV-cured cryogloblulinaemic vasculitis occurred in coincidence with infections or with the diagnosis of lung adenocarcinoma, that was in both cases non-mucinous and positive for pneumocyte marker expression (thyroid transcription factor (TTF)-1 and Napsin A). These conditions share an increased production of immune complexes [6], suggesting their role in reactivating MC vasculitis after HCV clearance. B cell clones expressing a B cell receptor (BCR) with both anti-HCV and RF activity are typically found in MC and persist in the peripheral blood of some patients after clearance of virus [3]. Persistence of B cell clones beyond HCV might relay on their RF activity prompting susceptibility to stimulation by immune complexes [7], which may lead, under conditions of abundant production, to their activation and expansion and to disease relapse. We assessed BCR clonality in two patients. In one case we found persistence of a large B cell clone together with MC vasculitis. In another case (number 3) no circulating B cell clones were detected either before antiviral therapy or at relapse, possibly because of exclusive homing to lymphoid tissue, bone marrow or liver [8]. On a practical ground, B cell depletion with rituximab might be effective for preventing or treating relapses in HCV-cured MC patients. Funding: This work was supported in part by the Intramural Research Program of Sapienza University of Rome (C26A15AKF7) and by the Istituto Pasteur Italia- Fondazione Cenci Bolognetti (Prot.76). Disclosure statement: The authors have declared no conflicts of interest. References 1 Gragnani L , Visentini M , Fognani E et al. Prospective study of guideline-tailored therapy with direct-acting antivirals for hepatitis C virus-associated mixed cryoglobulinemia . Hepatology 2016 ; 64 : 1473 – 82 . Google Scholar Crossref Search ADS PubMed 2 Saadoun D , Pol S , Ferfar Y et al. Efficacy and safety of sofosbuvir plus daclatasvir for treatment of HCV-associated cryoglobulinemia vasculitis . Gastroenterology 2017 ; 153 : 49 – 52 . Google Scholar Crossref Search ADS PubMed 3 Del Padre M , Todi L , Mitrevski M et al. Reversion of anergy signatures in clonal CD21low B cells of mixed cryoglobulinemia after clearance of HCV viremia . Blood 2017 ; 130 : 35 – 8 . Google Scholar Crossref Search ADS PubMed 4 Solllma S , Milazzo L , Peri AM et al. Persistent mixed cryoglobulinaemia vasculitis despite hepatitis C virus eradication after interferon-free antiviral therapy . Rheumatology 2016 ; 55 : 2084 – 5 . Google Scholar Crossref Search ADS PubMed 5 Landau DA , Saadoun D , Halfon P et al. Relapse of hepatitis C virus-associated mixed cryoglobulinemia vasculitis in patients with sustained viral response . Arthritis Rheum 2008 ; 58 : 604 – 11 . Google Scholar Crossref Search ADS PubMed 6 Ohyama K , Yoshimi H , Aibara N et al. Immune complexome analysis reveals the specific and frequent presence of immune complex antigens in lung cancer patients: a pilot study . Int J Cancer 2017 ; 140 : 370 – 80 . Google Scholar Crossref Search ADS PubMed 7 Sang A , Niu H , Cullen J et al. Activation of rheumatoid factor-specific B cells is antigen dependent and occurs preferentially outside of germinal centers in the lupus-prone NZM2410 mouse model . J Immunol 2014 ; 193 : 1609 – 21 . Google Scholar Crossref Search ADS PubMed 8 Vallat L , Benhamou Y , Gutierrez M et al. Clonal B cell populations in the blood and liver of patients with chronic hepatitis C virus infection . Arthritis Rheum 2004 ; 50 : 3668 – 78 . Google Scholar Crossref Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Journal

RheumatologyOxford University Press

Published: Oct 1, 2018

References

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