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- Reipert, B M, et al.
(author)
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The prospective Hemophilia Inhibitor PUP Study reveals distinct antibody signatures prior to FVIII inhibitor development
- 2020
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In: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 4:22, s. 5785-5796
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Journal article (peer-reviewed)abstract
- Preventing factor VIII (FVIII) inhibitors following replacement therapies with FVIII products in patients with hemophilia A remains an unmet medical need. Better understanding of the early events of evolving FVIII inhibitors is essential for risk identification and the design of novel strategies to prevent inhibitor development. The Hemophilia Inhibitor Previously Untreated Patients (PUPs) Study (HIPS; www.clinicaltrials.gov #NCT01652027) is the first prospective cohort study to evaluate comprehensive changes in the immune system during the first 50 exposure days (EDs) to FVIII in patients with severe hemophilia A. HIPS participants were enrolled prior to their first exposure to FVIII or blood products ("true PUPs") and were evaluated for different immunological and clinical parameters at specified time points during their first 50 EDs to a single source of recombinant FVIII. Longitudinal antibody data resulting from this study indicate that there are 4 subgroups of patients expressing distinct signatures of FVIII-binding antibodies. Subgroup 1 did not develop any detectable FVIII-binding immunoglobulin G (IgG) antibodies. Subgroup 2 developed nonneutralizing, FVIII-binding IgG1 antibodies, but other FVIII-binding IgG subclasses were not observed. Subgroup 3 developed transient FVIII inhibitors associated with FVIII-binding IgG1 antibodies, similar to subgroup 2. Subgroup 4 developed persistent FVIII inhibitors associated with an initial development of high-affinity, FVIII-binding IgG1 antibodies, followed by IgG3 and IgG4 antibodies. Appearance of FVIII-binding IgG3 was always associated with persistent FVIII inhibitors and the subsequent development of FVIII-binding IgG4. Some of the antibody signatures identified in HIPS could serve as candidates for early biomarkers of FVIII inhibitor development.
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- Jaraj, D., et al.
(author)
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Long-Term Prognostication for 20 114 Women With Small and Node-Negative Breast Cancer (T1abN0)
- 2021
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In: Jnci Cancer Spectrum. - : Oxford University Press (OUP). - 2515-5091. ; 5:1
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Journal article (peer-reviewed)abstract
- Background: Although small, node-negative breast cancer (ie, T1abN0) constitutes 20% of all newly diagnosed breast cancers, data on prognosis and prognostic factors are limited. Methods: We conducted a population-based cohort study including 20 114 Swedish women treated for T1abN0 breast cancer from 1977 onward. Patient and tumor data were collected from Swedish breast cancer registries. Cohort subjects were followed through linkage to the Cause of Death Register. We calculated the cumulative incidence of breast cancer-specific and overall death and used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: During a median follow-up of 9.1 years (range = 0-38), 915 women died of breast cancer and 5416 of any cause. The 10-, 20-, and 30-year cumulative incidences of breast cancer death were 3.4% (95% CI = 3.1% to 3.7%), 7.6% (95% CI = 7.1% to 8.2%), and 10.5% (95% CI = 9.6% to 11.4%), respectively. The multivariable hazard ratios and 95% confidence intervals of breast cancer death were 0.92 (95% CI = 0.88 to 0.97) for each additional calendar year of diagnosis, 4.38 (95% CI = 2.79 to 6.87) for grade 3 vs grade 1 tumors, 0.43 (95% CI = 0.31 to 0.62) for progesterone receptor-positive vs progesterone receptor-negative disease, and 2.01 (95% CI = 0.99 to 4.07) for HER2-positive vs HER2-negative disease. Women with grade 3 vs grade 1 tumors had a 56% increased risk of death from any cause (HR = 1.56, 95% CI = 1.30 to 1.88). Conclusions: The risk of breast cancer death in T1abN0 disease continues to increase steadily beyond 10 years after diagnosis, has improved over time, and varies substantially by tumor characteristics.
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- Efe, C., et al.
(author)
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Efficacy and Safety of Mycophenolate Mofetil and Tacrolimus as Second-line Therapy for Patients With Autoimmune Hepatitis
- 2017
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In: Clinical Gastroenterology and Hepatology. - : Elsevier BV. - 1542-3565 .- 1542-7714. ; 15:12
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Journal article (peer-reviewed)abstract
- BACKGROUND & AIMS: Predniso(lo) ne, alone or in combination with azathioprine, is the standard-of-care (SOC) therapy for autoimmune hepatitis (AIH). However, the SOC therapy is poorly tolerated or does not control disease activity in up to 20% of patients. We assessed the efficacy of mycophenolate mofetil (MMF) and tacrolimus as second-line therapy for patients with AIH. METHODS: We performed a retrospective study of data (from 19 centers in Europe, the United States, Canada, and China) from 201 patients with AIH who received second-line therapy (121 received MMF and 80 received tacrolimus), for a median of 62 months (range, 6-190 mo). Patients were categorized according to their response to SOC. Patients in group 1 (n = 108) had a complete response to the SOC, but were switched to second-line therapy as a result of side effects of predniso(lo) ne or azathioprine, whereas patients in group 2 (n = 93) had not responded to SOC. RESULTS: There was no significant difference in the proportion of patients with a complete response to MMF (69.4%) vs tacrolimus (72.5%) (P = .639). In group 1, MMF and tacrolimus maintained a biochemical remission in 91.9% and 94.1% of patients, respectively (P = .682). Significantly more group 2 patients given tacrolimus compared with MMF had a complete response (56.5% vs 34%, respectively; P = .029) There were similar proportions of liver-related deaths or liver transplantation among patients given MMF (13.2%) vs tacrolimus (10.3%) (log-rank, P = .472). Ten patients receiving MMF (8.3%) and 10 patients receiving tacrolimus (12.5%) developed side effects that required therapy withdrawal. CONCLUSIONS: Long-term therapy with MMF or tacrolimus generally was well tolerated by patients with AIH. The agents were equally effective in previous complete responders who did not tolerate SOC therapy. Tacrolimus led to a complete response in a greater proportion of previous nonresponder patients compared with MMF.
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- Efe, Cumali, et al.
(author)
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Tacrolimus and Mycophenolate Mofetil as Second-Line Therapies for Pediatric Patients with Autoimmune Hepatitis
- 2018
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In: Digestive Diseases and Sciences. - : SPRINGER. - 0163-2116 .- 1573-2568. ; 63:5, s. 1348-1354
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Journal article (peer-reviewed)abstract
- We studied the efficacy and safety of mycophenolate mofetil (MMF) and tacrolimus as second-line therapy in pediatric patients with autoimmune hepatitis (AIH) who were intolerant or non-responders to standard therapy (corticosteroid and azathioprine). We performed a retrospective study of data from 13 centers in Europe, USA, and Canada. Thirty-eight patients (< 18 years old) who received second-line therapy (18 MMF and 20 tacrolimus), for a median of 72 months (range 8-182) were evaluated. Patients were categorized into two groups: Group 1 (n = 17) were intolerant to corticosteroid or azathioprine, and group 2 (n = 21) were non-responders to standard therapy. Overall complete response rates were similar in patients treated with MMF and tacrolimus (55.6 vs. 65%, p = 0.552). In group 1, MMF and tacrolimus maintained a biochemical remission in 88.9 and 87.5% of patients, respectively (p = 0.929). More patients in group 2 given tacrolimus compared to MMF had a complete response, but the difference was not statistically significant (50.0 vs. 22.2%, p = 0.195). Biochemical remission was achieved in 71.1% (27/38) of patients by tacrolimus and/or MMF. Decompensated cirrhosis was more commonly seen in MMF and/or tacrolimus non-responders than in responders (45.5 vs. 7.4%, p = 0.006). Five patients who received second-line therapy (2 MMF and 3 tacrolimus) developed side effects that led to therapy withdrawal. Long-term therapy with MMF or tacrolimus was generally well tolerated by pediatric patients with AIH. Both MMF and tacrolimus had excellent efficacy in patients intolerant to corticosteroid or azathioprine. Tacrolimus might be more effective than MMF in patients failing previous therapy.
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- Hagstrom, H., et al.
(author)
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Morbidity, risk of cancer and mortality in 3645 HFE mutations carriers
- 2021
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In: Liver International. - : Wiley. - 1478-3223 .- 1478-3231. ; 41:3, s. 545-553
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Journal article (peer-reviewed)abstract
- Background & Aims Mutations in the HFE gene can lead to hereditary haemochromatosis (HH) and have been suggested to increase the risk of extra-hepatic diseases, especially breast and colorectal cancer. Here we investigated long-term outcomes of Swedish patients with HFE mutations. Methods We identified 3645 patients with a homozygous p.C282Y (62%) or a compound heterozygous p.C282Y/p.H63D (38%) mutation from eight centres in Sweden between 1997 and 2017. These were matched 1:10 by age, sex and county of residence to reference individuals from the general population. We ascertained incident outcomes until the end of 2017 by linkage to national registers. Studied outcomes were HH, cirrhosis, hepatocellular carcinoma (HCC), breast cancer (in women), colorectal cancer, type 1 and 2 diabetes, hypothyroidism, Parkinson's disease and mortality. Cox proportional hazards regression was used to estimate hazard ratios for these outcomes. Results Median age at diagnosis was 52 years, 44% were females. During a mean follow-up of 7.9 years, we found an increased risk for HCC, HH, cirrhosis, type 2 diabetes, osteoarthritis and death. Excess mortality was only seen in men. No increased risk was seen for colorectal or breast cancer. Liver-related outcomes were rare, with a cumulative incidence of HFE mutation carriers in a university hospital setting had an increased risk for mortality in men, along with increased risks of cirrhosis, HCC, diabetes type 2, and osteoarthritis. In general, the absolute risk for adverse outcomes was low and no increased risk for colon or breast cancer was observed.
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