Ablation of Fbxw7 Eliminates Leukemia-Initiating Cells by Preventing Quiescence

SummaryImatinib eradicates dividing progenitor cells of chronic myeloid leukemia (CML) but does not effectively target nondividing leukemia-initiating cells (LICs); thus, the disease often relapse after its discontinuation. We now show that Fbxw7 plays a pivotal role in maintenance of quiescence in LICs of CML by reducing the level of c-Myc. Abrogation of quiescence in LICs by Fbxw7 ablation increased their sensitivity to imatinib, and the combination of Fbxw7 ablation with imatinib treatment resulted in a greater depletion of LICs than of normal hematopoietic stem cells in mice. Purging of LICs by targeting Fbxw7 to interrupt their quiescence and subsequent treatment with imatinib may thus provide the basis for a promising therapeutic approach to CML

Drug retention of 7 biologics and tofacitinib in biologics-naïve and biologics-switched patients with rheumatoid arthritis: The ANSWER cohort study

Background: This multi-center, retrospective study aimed to clarify retention rates and reasons for discontinuation of 7 biological disease-modifying antirheumatic drugs (bDMARDs) and tofacitinib (TOF), one of the janus kinase inhibitors, in bDMARDs-naïve and bDMARDs-switched patients with rheumatoid arthritis (RA). Methods: This study assessed 3897 patients and 4415 treatment courses with bDMARDs and TOF from 2001 to 2019 (2737 bDMARDs-naïve courses and 1678 bDMARDs-switched courses [59.5% of switched courses were their second agent], female 82.3%, baseline age 57.4 years, disease duration 8.5 years; rheumatoid factor positivity 78.4%; Disease Activity Score in 28 joints using erythrocyte sedimentation rate 4.3; concomitant prednisolone [PSL] dose 6.1 mg/day [usage 42.4%], and methotrexate [MTX] dose 8.5 mg/week [usage 60.9%]). Treatment courses included abatacept (ABT; n = 663), adalimumab (ADA; n = 536), certolizumab pegol (CZP; n = 226), etanercept (ETN; n = 856), golimumab (GLM; n = 458), infliximab (IFX; n = 724), tocilizumab (TCZ; n = 851), and TOF (n = 101/only bDMARDs-switched cases). Drug discontinuation reasons (categorized into lack of effectiveness, toxic adverse events, non-toxic reasons, or remission) and rates were estimated at 36 months using Gray's test and statistically evaluated after adjusted by potential clinical confounders (age, sex, disease duration, concomitant PSL and MTX usage, starting date, and number of switched bDMARDs) using the Fine-Gray model. Results: Cumulative incidence of drug discontinuation for each reason was as follows: lack of effectiveness in the bDMARDs-naïve group (from 13.7% [ABT] to 26.9% [CZP]; P < 0.001 between agents) and the bDMARDs-switched group (from 18.9% [TCZ] to 46.1% [CZP]; P < 0.001 between agents); toxic adverse events in the bDMARDs-naïve group (from 4.6% [ABT] to 11.2% [ETN]; P < 0.001 between agents) and the bDMARDs-switched group (from 5.0% [ETN] to 15.7% [TOF]; P = 0.004 between agents); and remission in the bDMARDs-naïve group (from 2.9% [ETN] to 10.0% [IFX]; P < 0.001 between agents) and the bDMARDs-switched group (from 1.1% [CZP] to 3.3% [GLM]; P = 0.9 between agents). Conclusions: Remarkable differences were observed in drug retention of 7 bDMARDs and TOF between bDMARDs-naïve and bDMARDs-switched cases.Ebina K., Hirano T., Maeda Y., et al. Drug retention of 7 biologics and tofacitinib in biologics-naïve and biologics-switched patients with rheumatoid arthritis: The ANSWER cohort study. Arthritis Research and Therapy 22, 142 (2020); https://doi.org/10.1186/s13075-020-02232-w

Drug retention of secondary biologics or JAK inhibitors after tocilizumab or abatacept failure as first biologics in patients with rheumatoid arthritis -the ANSWER cohort study-

Objectives: The aim of this multicenter, retrospective study was to clarify the retention of secondary biological disease-modifying antirheumatic drugs (bDMARDs) or Janus kinase inhibitors (JAKi) in patients with rheumatoid arthritis (RA) who were primarily treated by tocilizumab (TCZ) or abatacept (ABT) as first bDMARDs. Method: Patients who were treated by either TCZ (n = 145) or ABT (n = 76) and then switched to either tumor necrosis factor inhibitors (TNFi), TCZ, ABT, or JAKi (including only cases switched from TCZ) from 2001 to 2019 (female 81.0%, age 59.5 years, disease duration 8.8 years; rheumatoid factor positivity 75.4%; Disease Activity Score in 28 joints using C-reactive protein 3.7; concomitant prednisolone (PSL) dose 6.0 mg/day (51.8%) and methotrexate (MTX) dose 8.0 mg/week (56.1%); 81.9% discontinued first bDMARDs due to lack of effectiveness) were included. Drug retention and discontinuation reasons were estimated at 24 months using the Kaplan-Meier method and adjusted for potential confounders by Cox proportional hazards modeling. Results: Drug retentions for each of the reasons for discontinuation were as follows: lack of effectiveness in TCZ-switched group (TNFi (59.5%), ABT (82.2%), and JAKi (84.3%); TNFi vs. ABT; P = 0.009) and ABT-switched group (TNFi (79.6%) and TCZ (92.6%); P = 0.053). Overall retention excluding non-toxic reasons and remission for discontinuation were TNFi (49.9%), ABT (72.7%), and JAKi (72.6%) (TNFi vs. ABT; P = 0.017) in the TCZ-switched group and TNFi (69.6%) and TCZ (72.4%) (P = 0.44) in the ABT-switched group. Conclusions: Switching to ABT in TCZ-treated patients led to higher retention as compared with TNFi. Switching to TCZ in ABT-treated patients tended to lead to higher retention due to effectiveness, although total retention was similar as compared with TNFi.Key Point• This is the first retrospective, multi-center study aimed to clarify the retention rates of secondary bDMARDs or JAKi in patients with RA who were primarily being treated by TCZ or ABT as the first bDMARDs.This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: https://doi.org/10.1007/s10067-020-05015-5Ebina K., Hirano T., Maeda Y., et al. Drug retention of secondary biologics or JAK inhibitors after tocilizumab or abatacept failure as first biologics in patients with rheumatoid arthritis -the ANSWER cohort study-. Clinical Rheumatology 39, 2563 (2020

Drug tolerability and reasons for discontinuation of seven biologics in elderly patients with rheumatoid arthritis -The ANSWER cohort study-

Background The aim of this study is to evaluate the retention rates and reasons for discontinuation for seven biological disease-modifying antirheumatic drugs (bDMARDs) in a real-world setting of elderly patients (65 years of age or older) with rheumatoid arthritis (RA). Methods This multi-center, retrospective study assessed 1,098 treatment courses of 661 patients with bDMARDs from 2009 to 2018 (females, 80.7%; baseline age, 71.7 years; disease duration 10.5 years; rheumatoid factor positivity 81.3%; Disease Activity Score in 28 joints using erythrocyte sedimentation rate, 4.6; concomitant prednisolone dose 2.8 mg/day (45.6%) and methotrexate dose 4.4 mg/week (56.4%); and 60.2% patients were bio-naïve). Treatment courses included abatacept (ABT; n = 272), tocilizumab (TCZ; n = 234), etanercept (ETN; n = 184), golimumab (GLM; n = 159), infliximab (IFX; n = 101), adalimumab (ADA; n = 97), and certolizumab pegol (CZP; n = 51). Drug retention rates and discontinuation reasons were estimated at 36 months using the Kaplan-Meier method and adjusted for potential clinical confounders (age, sex, disease duration, concomitant PSL and MTX, starting date and switched number of bDMARDs) by Cox proportional hazards modeling. Results A total of 51.2% of treatment courses were stopped, with 25.1% stopping due to lack of effectiveness, 11.8% due to toxic adverse events, 9.7% due to non-toxic reasons, and 4.6% due to remission. Drug retention rates for each discontinuation reason were as follows; lack of effectiveness [from 55.4% (ETN) to 81.6% (ABT); with significant differences between groups (Cox P<0.001)], toxic adverse events [from 79.3% (IFX) to 95.4% (ABT), Cox P = 0.043], and remission [from 94.2% (TCZ) to 100.0% (CZP), Cox P = 0.58]. Finally, overall retention rates excluding non-toxic reasons and remission for discontinuation ranged from 50.0% (ETN) to 78.1% (ABT) (Cox P<0.001).Ebina K., Hashimoto M., Yamamoto W., et al. (2019) Drug tolerability and reasons for discontinuation of seven biologics in elderly patients with rheumatoid arthritis -The ANSWER cohort study-. PLoS ONE 14, e0216624. doi: https://doi.org/10.1371/journal.pone.0216624

Drug tolerability and reasons for discontinuation of seven biologics in 4466 treatment courses of rheumatoid arthritis - The ANSWER cohort study

Background: The aim of this study is to evaluate the retention rates and reasons for discontinuation for seven biological disease-modifying antirheumatic drugs (bDMARDs) in a real-world setting of patients with rheumatoid arthritis (RA). Methods: This multi-center, retrospective study assessed 4466 treatment courses of 2494 patients with bDMARDs from 2009 to 2017 (females, 82.4%; baseline age, 57.4 years; disease duration 8.5 years; rheumatoid factor positivity 78.6%; Disease Activity Score in 28 joints using erythrocyte sedimentation rate, 4.3; concomitant prednisolone (PSL) 2.7 mg/day (43.1%) and methotrexate (MTX) 5.0 mg/week (61.8%); and 63.6% patients were bio-naïve). Treatment courses included tocilizumab (TCZ; n = 895), etanercept (ETN; n = 891), infliximab (IFX; n = 748), abatacept (ABT; n = 681), adalimumab (ADA; n = 558), golimumab (GLM; n = 464), and certolizumab pegol (CZP; n = 229). Drug retention rates and discontinuation reasons were estimated at 36 months using the Kaplan-Meier method and adjusted for potential confounders (age, sex, disease duration, concomitant PSL and MTX, and switched number of bDMARDs) using Cox proportional hazards modeling. Results: A total of 56.9% of treatment courses were stopped, with 25.8% stopping due to lack of effectiveness, 12.7% due to non-toxic reasons, 11.9% due to toxic adverse events, and 6.4% due to disease remission. Drug retention rates for each discontinuation reason were as follows: lack of effectiveness [from 65.5% (IFX) to 81.7% (TCZ); with significant differences between groups (Cox P < 0.001)], toxic adverse events [from 81.8% (IFX) to 94.0% (ABT), Cox P < 0.001], and remission [from 92.4% (ADA and IFX) to 97.7% (ETN), Cox P < 0.001]. Finally, overall retention rates excluding non-toxic reasons and remission for discontinuation ranged from 53.4% (IFX) to 75.5% (ABT) (Cox P < 0.001). Conclusions: TCZ showed the lowest discontinuation rate by lack of effectiveness, ABT showed the lowest discontinuation rate by toxic adverse events, ADA and IFX showed the highest discontinuation rate by remission, and ABT showed the highest overall retention rates (excluding non-toxic reasons and remission) among seven bDMARDs in the adjusted model.Ebina K., Hashimoto M., Yamamoto W., et al. Drug tolerability and reasons for discontinuation of seven biologics in 4466 treatment courses of rheumatoid arthritis - The ANSWER cohort study. Arthritis Research and Therapy 21, 91 (2019); https://doi.org/10.1186/s13075-019-1880-4

Drug retention and discontinuation reasons between seven biologics in patients with rheumatoid arthritis -The ANSWER cohort study-

The purpose of this study was to evaluate the retention and discontinuation reasons of seven biological disease-modifying antirheumatic drugs (bDMARDs) in a real-world setting of patients with rheumatoid arthritis (RA). 1,037 treatment courses with bDMARDs from 2009 to 2016 [female, 81.8%; baseline age, 59.6 y; disease duration 7.8 y; rheumatoid factor positivity 81.5%; Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28-ESR), 4.4; concomitant prednisolone 43.5% and methotrexate 68.6%; Bio-naïve, 57.1%; abatacept (ABT), 21.3%; tocilizumab (TCZ), 20.7%; golimumab (GLM), 16.9%; etanercept (ETN), 13.6%; adalimumab (ADA), 11.1%; infliximab (IFX), 8.5%; certolizumab pegol (CZP), 7.9%] were included in this multi-center, retrospective study. Drug retention and discontinuation reasons at 36 months were estimated using the Kaplan-Meier method and adjusted by potent confounders using Cox proportional hazards modeling. As a result, 455 treatment courses (43.9%) were stopped, with 217 (20.9%) stopping due to inefficacy, 113 (10.9%) due to non-toxic reasons, 86 (8.3%) due to toxic adverse events, and 39 (3.8%) due to remission. Drug retention rates in the adjusted model were as follows: total retention (ABT, 60.7%; ADA, 32.7%; CZP, 43.3%; ETN, 51.9%; GLM, 45.4%; IFX, 31.1%; and TCZ, 59.2%; P < 0.001); inefficacy (ABT, 81.4%; ADA, 65.7%; CZP, 60.7%; ETN, 71.3%; GLM, 68.5%; IFX, 65.0%; and TCZ, 81.4%; P = 0.015), toxic adverse events (ABT, 89.8%; ADA, 80.5%; CZP, 83.9%; ETN, 89.2%; GLM, 85.5%; IFX, 75.6%; and TCZ, 77.2%; P = 0.50), and remission (ABT, 95.5%; ADA, 88.1%; CZP, 91.1%; ETN, 97.5%; GLM, 94.7%; IFX, 86.4%; and TCZ, 98.4%; P < 0.001). In the treatment of RA, ABT and TCZ showed higher overall retention, and TCZ showed lower inefficacy compared to IFX, while IFX showed higher discontinuation due to remission compared to ABT, ETN, GLM, and TCZ in adjusted modeling.Ebina K., Hashimoto M., Yamamoto W., et al. (2018) Drug retention and discontinuation reasons between seven biologics in patients with rheumatoid arthritis -The ANSWER cohort study-. PLoS ONE 13(3): e0194130. doi: 10.1371/journal.pone.0194130

Drug retention of sarilumab, baricitinib, and tofacitinib in patients with rheumatoid arthritis: the ANSWER cohort study

Objectives: The aim of this multicenter, retrospective study was to clarify the retention rates of sarilumab (SAR), baricitinib (BAR), and tofacitinib (TOF) in patients with rheumatoid arthritis (RA). Methods: Patients treated with either SAR (n = 62), BAR (n = 166), or TOF (n = 185) (females, 80.9%; age, 61.0 years; disease duration, 11.1 years; rheumatoid factor positivity, 84.4%; Disease Activity Score in 28 joints using erythrocyte sedimentation rate, 4.3; concomitant prednisolone dose, 5.3 mg/day [47.0%] and methotrexate dose, 8.8 mg/week [58.4%]; biologics- or Janus kinase inhibitors-switched cases 78.4%) were included. The reasons for drug discontinuation were classified into 4 major categories (lack of effectiveness, toxic adverse events, non-toxic reasons, and remission) by each attending physician. The drug retention rate was estimated at 18 months using the Kaplan–Meier method and adjusted for potential confounders by Cox proportional hazards modeling. Results: The discontinuation rates of SAR, BAR, and TOF for the corresponding reasons were as follows, respectively: lack of effectiveness (15.7%, 15.6%, and 21.5%; P = 0.84), toxic adverse events (15.8%, 12.1%, and 12.3%; P = 0.35), non-toxic reasons (10.9%, 7.7%, and 6.8%; P = 0.35), and remission (0.0%, 2.8%, and 0.0%; P = 1.0). The overall retention rates excluding non-toxic reasons and remission were as follows: 68.8% for SAR, 72.5% for BAR, and 66.7% for TOF (P = 0.54). Conclusions: After adjustment by potent confounders, SAR, BAR, and TOF showed similar discontinuation rates due to lack of effectiveness and toxic adverse events.Key Points• This is the first retrospective multicenter study that aimed to clarify the retention rates and reasons for discontinuation of SAR, BAR, and TOF in patients with RA.This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: https://doi.org/10.1007/s10067-021-05609-7Ebina K., Hirano T., Maeda Y., et al. Drug retention of sarilumab, baricitinib, and tofacitinib in patients with rheumatoid arthritis: the ANSWER cohort study. Clinical Rheumatology 40, 2673 (2021

Factors affecting drug retention of Janus kinase inhibitors in patients with rheumatoid arthritis: the ANSWER cohort study

This multi-center, retrospective study aimed to clarify the factors affecting drug retention of the Janus kinase inhibitors (JAKi) including baricitinib (BAR) and tofacitinib (TOF) in patients with RA. Patients were as follows; females, 80.6%; age, 60.5 years; DAS28-ESR, 4.3; treated with either BAR (n = 166) or TOF (n = 185); bDMARDs- or JAKi-switched cases (76.6%). The reasons for drug discontinuation were classified into four major categories. The drug retention was evaluated at 24 months using the Kaplan–Meier method and multivariate Cox proportional hazards modelling adjusted by confounders. Discontinuation rates for the corresponding reasons were as follows; ineffectiveness (22.3%), toxic adverse events (13.3%), non-toxic reasons (7.2%) and remission (0.0%). Prior history of anti-interleukin-6 receptor antibody (aIL-6R) ineffectiveness significantly increased the risk of treatment discontinuation due to ineffectiveness (p = 0.020). Aging (≥ 75 years) (p = 0.028), usage of PSL ≥ 5 mg/day (p = 0.017) and female sex (p = 0.041) significantly increased the risk of treatment discontinuation due to toxic adverse events. Factors not associated with treatment discontinuation were: number of prior bDMARDs or JAKi, concomitant MTX usage, difference of JAKi, and prior use of TNF inhibitor, CTLA4-Ig or other JAKi.Ebina K., Hirano T., Maeda Y., et al. Factors affecting drug retention of Janus kinase inhibitors in patients with rheumatoid arthritis: the ANSWER cohort study. Scientific Reports 12, 134 (2022); https://doi.org/10.1038/s41598-021-04075-0

Carbon ion radiotherapy for basal cell adenocarcinoma of the head and neck: preliminary report of six cases and review of the literature

<p>Abstract</p> <p>Background</p> <p>Basal cell adenocarcinoma accounts for approximately 1.6% of all salivary gland neoplasms. In this report, we describe our experiences of treatment for BCAC with carbon ion radiotherapy in our institution.</p> <p>Methods</p> <p>Case records of 6 patients with diagnosis of basal cell adenocarcinoma of the head and neck, who were treated by carbon ion radiotherapy with 64.0 GyE/16 fractions in our institution, were retrospectively reviewed.</p> <p>Results</p> <p>In a mean follow-up period of 32.1 months (14.0-51.3 months), overall survival and local control rates of 100% were achieved. Only one grade 4 (CTCAE v3.0) late complication occurred. There was no other grade 3 or higher toxicity.</p> <p>Conclusions</p> <p>Carbon ion radiotherapy should be considered as an appropriate curative approach for treatment of basal cell adenocarcinoma in certain cases, particularly in cases of unresectable disease and postoperative gross residual or recurrent disease.</p