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Background: Acquired hemophilia A (AHA) is an autoimmune bleeding disorder caused by neutralizing antibodies against coagulation factor VIII. Immunosuppressive therapy (IST) is standard of care to eradicate autoantibody production and protect from further bleeding but carries a risk of severe infection and mortality in frail patients with AHA. Recently, emicizumab has been studied for its potential to reduce the need for early and aggressive IST., Objectives: To compare outcomes of 2 studies that used either IST (GTH-AH 01/2010; N = 101) or prophylaxis with emicizumab (GTH-AHA-EMI; N = 47) early after diagnosis of AHA., Methods: Baseline characteristics were balanced by propensity score matching. Primary endpoint was the rate of clinically relevant new bleeds during the first 12 weeks; secondary endpoints were adverse events and overall survival., Results: The negative binominal model-based bleeding rate was 68% lower with emicizumab as compared with IST (incident rate ratio, 0.325; 95% CI, 0.182-0.581). No difference was apparent in the overall frequency of infections (emicizumab 21%, IST 29%) during the first 12 weeks, but infections were less often fatal in emicizumab-treated patients (0%) compared with IST-treated patients (11%). Thromboembolic events occurred less often with emicizumab (2%) than with IST (7%). Overall survival after 24 weeks was better with emicizumab (90% vs 76%; hazard ratio, 0.44; 95%, CI, 0.24-0.81)., Conclusion: Using emicizumab instead of IST in the early phase after initial diagnosis of AHA reduced bleeding and fatal infections and improved overall survival., Competing Interests: Declaration of competing interests C.H. reports honoraria for lectures or consultancy from Bayer, BMS, SOBI, Daiichi Sankyo, Roche/Chugai, Pfizer, Sanofi, and Takeda. R.K. reports institutional grants for research and studies from Bayer, CSL Behring, Novo Nordisk, Octapharma, and SOBI, and honoraria for lectures or consultancy from Bayer, Biotest, BioMarin, CSL Behring, Grifols, LFB, Novo Nordisk, Octapharma, Pfizer, Roche/Chugai, Sanofi, SOBI, and Takeda. U.J.S. reports institutional grants for research and studies from Octapharma and honoraria for lectures or consultancy from Bayer, SOBI, CSL Behring, and Pfizer. R.G. reports institutional grants for research and studies from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, Abbvie, Gilead, and Daiichi Sankyo, and honoraria for lectures or consultancy from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, Abbvie, Gilead, Daiichi Sankyo, and Sanofi. P.K. reports institutional grants for research and studies from Ablynx/Sanofi, Novo Nordisk, Roche, and Takeda, and honoraria for lectures or consultancy from Ablynx/Sanofi, Alexion, Biotest, CSL Behring, Novo Nordisk, Roche, Takeda, and Technoclone. J.O. reports institutional grants for research and studies from Bayer, Biotest, CSL Behring, Octapharma, Pfizer, SOBI, and Takeda, and honoraria for lectures or consultancy from Bayer, Biogen Idec, BioMarin, Biotest, CSL Behring, Chugai, Freeline, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Sparks, SOBI, and Takeda. W.M. reports institutional grants for research and studies from Bayer, Biotest, CSL Behring, LFB, Novo Nordisk, Octapharma, Pfizer, and Takeda/Shire, and honoraria for lectures or consultancy from Bayer, BioMarin, Biotest, CSL Behring, Chugai, Freeline, LFB, Novo Nordisk, Octapharma, Pfizer, Regeneron, Roche, Sanofi, Takeda/Shire, and uniQure. C.P. reports institutional grants for research and studies from Chugai/Roche, Takeda, Zacros, and LeoPharma, and honoraria for lectures or consultancy from Bayer, BioMarin, Chugai/Roche, CSL Behring, Novo Nordisk, Pfizer, BMS, SOBI, and Takeda. K.T.G. reports honoraria for lectures or consultancy from Takeda, Roche, Grifols, and SOBI. I.P. reports institutional grants for research and studies from Takeda and honoraria for lectures or consultancy from BMS and Novo Nordisk. K.H. reports institutional grants for research and studies from Bayer, CSL Behring, Novo Nordisk, Pfizer, and SOBI, and honoraria for lectures or consultancy from Bayer, Biotest, Chugai, CSL Behring, LFB, Novo Nordisk, Pfizer, Roche, SOBI, and Takeda. H.E. reports institutional grants for research and studies from Bayer Vital and CSL Behring and honoraria for lectures or consultancy from Bayer Vital, BioMarin, CSL Behring, Novo Nordisk, Pfizer, Roche, and SOBI. C.W. has nothing to disclose. D.S. has nothing to disclose. S.W. reports institutional grants for research and studies from Biotest and Octapharma, and honoraria for lectures or consultancy from Biotest and Stago. A.T. reports institutional grants for research and studies from Bayer, Biotest, Chugai, Novo Nordisk, Octapharma, Pfizer, Roche, SOBI, and Takeda, and honoraria for lectures or consultancy from Bayer, BioMarin, Biotest, Chugai, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, SOBI, and Takeda., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Acquired haemophilia A is caused by neutralising autoantibodies against coagulation factor VIII, leading to severe bleeding. Standard treatment involves immunosuppressive therapy, which is associated with adverse events and mortality in the frail population of patients with acquired haemophilia A. This study investigated whether emicizumab, a factor VIIIa mimetic antibody, protects patients with acquired haemophilia A from bleeding and allows deferral of immunosuppression during the first 12 weeks after diagnosis., Methods: We report final results of an open-label, single-arm, phase 2 clinical trial. Adult patients with acquired haemophilia A from 16 haemophilia treatment centres in Germany and Austria were eligible if they had not previously received immunosuppression. Patients received emicizumab subcutaneously (6 and 3 mg/kg on days 1 and 2, 1·5 mg/kg weekly until week 12), but no immunosuppression. Follow-up was until week 24. The primary endpoint was the number of clinically relevant bleeds per patient-week until week 12. Emicizumab was considered effective if the mean bleeding rate was significantly below 0·15 bleeds per patient-week, the rate observed in a previous study of patients with acquired haemophilia A treated with bypassing agents and immunosuppression but no emicizumab. The study is registered with clinicaltrials.gov, NCT04188639 and is complete., Findings: Of 49 patients screened from March 25, 2021, to June 10, 2022, 47 were enrolled (23 women, 24 men). Median age was 76 years (IQR 66-80), 46 (98%) of 47 patients were White, median factor VIII activity was 1·4 IU/dL (0·3-5·6), and median inhibitor concentration was 11·4 Bethesda units per mL (3·9-42·7). Mean breakthrough bleeding rate was 0·04 bleeds per patient-week (upper 97·5% CI 0·06). 33 (70%) of 47 patients had no bleeding events, seven patients (15%) had one bleed, six patients (13%) had two bleeds, and one patient (2%) had three bleeds. Adverse events of grade 3 or worse included COVID-19 (n=2), acute kidney injury (n=2), and stroke (n=1). Four of 47 patients died, including two deaths related to bleeding, one from COVID-19, and one from cardiac arrest (none were judged as related to emicizumab)., Interpretation: This study suggests that emicizumab prophylaxis prevents bleeding in patients with acquired haemophilia A and that immunosuppressive therapy can be deferred while patients are receiving this treatment. The low number of thromboembolic events, severe infections, and fatalities observed in this study are promising., Funding: This study was supported by funding from Hoffman-La Roche., Competing Interests: Declaration of interests AT reports institutional grants for research and studies from Bayer, Biotest, Chugai, Novo Nordisk, Octapharma, Pfizer, Roche, SOBI, and Takeda, and honoraria for lectures or consultancy from Bayer, Biomarin, Biotest, Chugai, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Roche, SOBI, and Takeda. CH reports honoraria for lectures or consultancy from Bayer, SOBI, Roche, Pfizer, and Takeda. PK reports institutional grants for research and studies from Ablynx–Sanofi, Novo Nordisk, Roche, and Takeda, and honoraria for lectures or consultancy from Ablynx–Sanofi, Alexion, Biotest, CSL Behring, Novo Nordisk, Roche, Takeda, and Technoclone. RG reports institutional grants for research and studies from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, Abbvie, Gilead, and Daiichi Sankyo, and honoraria for lectures or consultancy from Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, BMS, MSD, Sandoz, Abbvie, Gilead, Daiichi Sankyo, and Sanofi. JO reports institutional grants for research and studies from Bayer, Biotest, CSL Behring, Octapharma, Pfizer, SOBI, and Takeda, and honoraria for lectures or consultancy from Bayer, Biogen Idec, Biomarin, Biotest, CSL Behring, Chugai, Freeline, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Sparks, SOBI, and Takeda. UJS reports institutional grants for research and studies from Octapharma, and honoraria for lectures or consultancy from Bayer, SOBI, CSL Behring, and Pfizer. WM reports institutional grants for research and studies from Bayer, Biotest, CSL Behring, LFB, Novo Nordisk, Octapharma, Pfizer, and Takeda–Shire, and honoraria for lectures or consultancy from Bayer, Biomarin, Biotest, CSL Behring, Chugai, Freeline, LFB, Novo Nordisk, Octapharma, Pfizer, Regeneron, Roche, Sanofi, Takeda–Shire, and uniQure. CP reports institutional grants for research and studies from Chugai–Roche, Takeda, Zacros, and LeoPharma, and honoraria for lectures or consultancy from Bayer, Biomarin, Chugai–Roche, CSL Behring, Novo Nordisk, Pfizer, BMS, SOBI, and Takeda. KT-G reports honoraria for lectures or consultancy from Grifols, SOBI, Takeda, and Roche. KH reports institutional grants for research and studies from Bayer, CSL Behring, Novo Nordisk, Pfizer, and SOBI, and honoraria for lectures or consultancy from Bayer, Biotest, Chugai, CSL Behring, LFB, Novo Nordisk, Pfizer, Roche, SOBI, and Takeda. JP reports institutional grants for research and studies from Bayer, CSL Behring, and Pfizer, and honoraria for lectures or consultancy from Takeda, Bayer, and CSL Behring. PM reports institutional grants for research and studies from Baxter Innovations, Bayer, LFB, SOBI, Octapharma, Pfizer, and Roche, and honoraria for lectures or consultancy from Alexion, AstraZeneca, Biotest, CSL Behring, Shire, Octapharma, Pfizer, Roche, and Takeda. CD reports honoraria for lectures or consultancy from Novo Nordisk, Roche, and Takeda. SW reports institutional grants for research and studies from Biotest and Octapharma, and honoraria for lectures or consultancy from Biotest and Stago. RK reports institutional grants for research and studies from Bayer, CSL Behring, Novo Nordisk, Octapharma, and SOBI, and honoraria for lectures or consultancy from Bayer, Biotest, Biomarin, CSL Behring, Grifols, LFB, Novo Nordisk, Octapharma, Pfizer, Roche–Chugai, Sanofi, SOBI, and Takeda. CS, CW, DS, MM, and FJP have nothing to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

In order to characterise soft tissue tumours, pathologists often utilise specialised additional tests, or may seek opinions from subspecialist pathologists due to rarity or complex morphology. Additionally, further review may be sought by subspecialist sarcoma pathologists, such as those at our tertiary referral centre in Sydney, Australia. The aim of this study was to examine the impact on diagnosis and management of this external review, following diagnosis at a specialised sarcoma unit. We collated the results of all additional external ancillary tests and specialist reviews over a 10-year period and characterised the impact on the preliminary diagnosis as 'confirmed', 'new' or 'no clear diagnosis'. We subsequently noted whether the additional findings resulted in a clinically significant change in management. Of the 136 cases sent away, 103 patients had their initial diagnosis confirmed, 29 patients received a new diagnosis and, for four patients, the diagnosis remained uncertain. Nine of the 29 patients receiving a new diagnosis had their management altered. This study demonstrated that within our specialised sarcoma unit, the majority of diagnoses provided by our specialist pathologists are confirmed on additional external testing and review, but external review does provide additional assurance and benefit to the patient., (Copyright © 2023 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

The EUROPE phase 2 trial investigated the predictive value of biomarkers on the clinical efficacy of single agent romiplostim (ROM) treatment in patients with lower-risk myelodysplastic neoplasms (LR-MDS) and thrombocytopenia within the 'European Myelodysplastic Neoplasms Cooperative Group' (EMSCO) network. A total of 77 patients with LR-MDS and a median platelet count of 25/nl were included, all patients received ROM at a starting dose of 750 μg by SC injection weekly. Thirty-two patients (42%) achieved a hematologic improvement of platelets (HI-P) with a median duration of 340 days. Neutrophil (HI-N) and erythroid (HI-E) responses were observed in three (4%) and seven (9%) patients, respectively. We could not confirm previous reports that HI-P correlated with baseline endogenous thrombopoietin levels and platelet transfusion history, but SRSF2 mutation status and hemoglobin levels at baseline were significantly linked to HI-P. Sequential analysis of variant allelic frequency of mutations like SRSF2 did not reveal an impact of ROM on clonal evolution in both responders and non-responders. In summary, our study confirms the safety and efficacy of ROM in LR-MDS patients and may allow to better define subgroups of patients with a high likelihood of response., (© 2022. The Author(s).)

Aims/hypothesis: Individuals with type 2 diabetes mellitus and subclinical inflammation have stimulated coagulation, activated platelets and endothelial dysfunction. Recent studies with the direct factor Xa inhibitor rivaroxaban in combination with low-dose aspirin demonstrated a significant reduction of major cardiovascular events, especially in individuals with type 2 diabetes and proven cardiovascular disease. Therefore, we asked the question of whether treatment with rivaroxaban could influence endothelial function, arterial stiffness and platelet activation., Methods: We conducted a multi-centre, prospective, randomised, open-label trial in 179 participants with type 2 diabetes (duration 2-20 years), subclinical inflammation (high-sensitivity C-reactive protein 2-10 mg/l) and at least two traits of the metabolic syndrome to compare the effects of the direct factor Xa inhibitor rivaroxaban (5 mg twice daily) vs aspirin (100 mg every day) on endothelial function (assessed by forearm occlusion plethysmography), skin blood flow (assessed by laser-Doppler fluxmetry), arterial stiffness (assessed by pulse wave velocity) and serum biomarkers of endothelial function and inflammation. Furthermore, we investigated phosphorylation of vasodilator-stimulated phosphoprotein (VASP) in platelets, the concentration of platelet-derived microparticles (PMPs) and the effects of isolated PMPs on HUVEC proliferation in vitro., Results: Rivaroxaban treatment for 20 weeks (n = 89) resulted in a significant improvement of post-ischaemic forearm blood flow (3.6 ± 4.7 vs 1.0 ± 5.2 ml/100 ml, p = 0.004), a numerically increased skin blood flow and reduced soluble P-Selectin plasma level vs aspirin. We did not find significant differences of arterial stiffness or further biomarkers. Neither rivaroxaban nor aspirin influenced VASP phosphorylation of platelets. The number of PMPs increased significantly with both rivaroxaban (365.2 ± 372.1 vs 237.4 ± 157.1 μl -1 , p = 0.005) and aspirin (266.0 ± 212.7 vs 201.7 ± 162.7 μl -1 , p = 0.021). PMPs of rivaroxaban-treated participants stimulated HUVEC proliferation in vitro compared with aspirin. Rivaroxaban was associated with a higher number of bleeding events., Conclusions/interpretation: Our findings indicate that the direct factor Xa inhibitor rivaroxaban improved endothelial function in participants with type 2 diabetes and subclinical inflammation but also increased the risk of bleeding., Trial Registration: ClinicalTrials.gov NCT02164578., Funding: The study was supported by a research grant from Bayer Vital AG, Germany., (© 2021. The Author(s).)

Purpose: To determine the DNA protective effects of a standard coffee beverage in comparison to water consumption., Methods: The single-blind, randomised controlled study with parallel design included healthy women (n = 50) and men (n = 50) recruited from the general Central European population. The subjects were randomised in a coffee and a control group, with stratification for sex and body mass index. The study comprised two periods of 4 weeks: a preconditioning period, with daily consumption of at least 500 ml water but no coffee, nor tea, nor any other caffeine-containing product. During the subsequent intervention period the coffee group consumed 500 ml of freshly brewed dark roast coffee blend per day, the control group consumed water instead. On the last day of each period, blood was drawn and analysed by comet assay (single-cell gel electrophoresis) to assess the level of DNA damage (strand breakage)., Results: At the end of the intervention period the mean level of DNA strand breaks in the coffee group has decreased in comparison to the control group [difference in means 0.23% TI (tail intensity), p = 0.028]. The mean change from baseline (delta value) was - 23% in the coffee group (p = 0.0012). Effects of coffee intake were similar for men and women. During intervention, neither group showed any significant change in body weight or calorie intake., Conclusions: Our results indicate that regular consumption of a dark roast coffee blend has a beneficial protective effect on human DNA integrity in both, men and women.

The dominant anthocyanins in blackcurrant are delphinidin-3-O-rutinoside and cyanidin-3-O-rutinoside. Data on their absorption and distribution in the human body are limited. Therefore, we performed a human pilot study on five healthy male volunteers consuming a blackcurrant ( Ribes nigrum L.) extract. The rutinosides and their degradation products gallic acid and protocatechuic acid were determined in plasma and urine. The rutinosides' concentrations peaked in both plasma and urine samples within 2 h of extract ingestion. The recoveries of delphinidin-3-O-rutinoside and cyanidin-3-O-rutinoside from urine samples were 0.040 ± 0.011% and 0.048 ± 0.016%, respectively, over a 48 h period. Protocatechuic acid concentration increased significantly after ingestion of the blackcurrant extract. Our results show that after ingestion of a blackcurrant extract containing delphinidin-3-O-rutinoside and cyanidin-3-O-rutinoside, significant quantities of biologically active compounds circulated in the plasma and were excreted via urine. Furthermore, these results contribute to the understanding of anthocyanin metabolism in humans.

Aim: Superficial soft tissue sarcomas (S-STS) are generally considered low-risk tumors and have an excellent prognosis when treated with appropriate surgery and adjuvant therapy. However, they are often misdiagnosed then mistreated, leading to significant morbidity. This study aims to examine the patterns of care and outcomes of patients with S-STS, comparing those initially managed through sarcoma units versus elsewhere., Methods: Patients with S-STS from Prince of Wales Hospital in NSW (1995-2013) and Peter MacCallum Cancer Centre in Victoria (2009-2013) were identified from a national sarcoma database. Baseline variables, treatment and disease outcomes were recorded. Statistical tests performed included univariate and multivariate analyses, chi-square tests, as well as the Kaplan-Meier method for 5-year local recurrence and survival rates., Results: Eighty-nine patients were identified, with 35% initially managed at a sarcoma unit and 65% elsewhere. Patients initially managed at sarcoma units had larger tumors (>5 cm 39% vs 17%; P  =  0.036) with a trend to higher grade (61% vs 48%; P = 0.39). Patients that were initially managed outside a sarcoma unit more often underwent open surgical biopsies (P < 0.0005), had multiple operations (P < 0.0005) and had higher rates of local recurrences (24% vs 6.5%, P  =  0.038). They also had lower 5-year local recurrence-free survival rates (P = 0.022), but had higher metastasis-free survival (P = 0.014). On multivariate analysis, only larger STS size and male gender predicted for poorer metastasis-free survival (P = 0.042 and 0.018, respectively)., Conclusion: Patients with S-STS initially managed outside specialized sarcoma units undergo more operations, with risk of greater morbidity, and have greater risk of local recurrence., (© 2018 John Wiley & Sons Australia, Ltd.)

The aim of the present study was to explore the relation of controlled dietary acrylamide (AA) intake with the excretion of AA-related urinary mercapturic acids (MA), N-acetyl-S-(carbamoylethyl)-L-cysteine (AAMA) and N-acetyl-S-(1-carbamoyl-2-hydroxyethyl)-L-cysteine (GAMA). Excretion kinetics of these short-term exposure biomarkers were monitored under strictly controlled conditions within a duplicate diet human intervention study. One study arm (group A, n = 6) ingested AA via coffee (0.15-0.17 µg/kg bw) on day 6 and in a meal containing an upper exposure level of AA (14.1-15.9 μg/kg bw) on day 10. The other arm (group B) was on AA minimized diet (washout, 0.05-0.06 µg/kg bw) throughout the whole 13-day study period. On day 6, these volunteers ingested 13 C 3 D 3 -AA (1 μg/kg bw). In both arms, urinary MA excretion was continuously monitored and blood samples were taken to determine hemoglobin adducts. Ingestion of four cups of coffee resulted in a slightly enhanced short-term biomarker response within the background range of group B. At the end of the 13-day washout period, group B excreted an AAMA baseline level of 0.14 ± 0.10 µmol/d although AA intake was only about 0.06 µmol/d. This sustained over-proportional AAMA background suggested an endogenous AA baseline exposure level of 0.3-0.4 µg/kg bw/d. The excretion of 13 C 3 D 3 -AA was practically complete within 72-96 h which rules out delayed release of AA (or any other MA precursor) from deep body compartments. The results provide compelling support for the hypothesis of a sustained endogenous AA formation in the human body.

Scope: Intervention studies provide evidence that long-term coffee consumption correlates with reduced DNA background damage in healthy volunteers. Here, we report on short-term kinetics of this effect, showing a rapid onset after normal coffee intake., Methods and Results: In a short-term human intervention study, we determined the effects of coffee intake on DNA integrity during 8 h. Healthy male subjects ingested coffee in 200 mL aliquots every second hour up to a total volume of 800 mL. Blood samples were taken at baseline, immediately before the first coffee intake and subsequently every 2 h, prior to the respective coffee intake. DNA integrity was assayed by the comet assay. The results show a significant (p < 0.05) reduction of background DNA strand breaks already 2 h after the first coffee intake. Continued coffee intake was associated with further decrements in background DNA damage within the 8 h intervention (p < 0.01 and p < 0.001, respectively). Mean tail intensities (TIs%) decreased from 0.33 TI% (baseline, 0 h) to 0.22 TI% (within 8 h coffee consumption)., Conclusion: Repeated coffee consumption was associated with reduced background DNA strand breakage, clearly measurable as early as 2 h after first intake resulting in a cumulative overall reduction by about one-third of the baseline value., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Transtympanic electrical stimulation, either in the form of round window or promontory placement of electrode prior to cochlear implantation is an accepted and commonly used psychophysical tool. Certain response parameters have been identified as predictors of outcome. This study compared the subjective auditory responses generated by promontory electrical stimulation (PES) with those from two noninvasive modalities, namely peritympanic electrical stimulation (PTES) and transcranial magnetic stimulation (TMS). Ten postlingually deafened adult cochlear implant candidates were studied. Standard psychophysical parameters were obtained from patients undergoing PES and PTES. A more subjective form of evaluation was conducted for TMS. Subsequently, nine patients received the multichannel Nucleus (Cochlear Corp., Denver, CO, U.S.A.) implant and one patient a Clarion (Advanced Bionics, Sylmar, CA, U.S.A.) implant. Compared with PES. PTES elicited increased threshold responses with similar dynamic ranges between 50 and 400 Hz of stimulation. The differences were, by and large, insignificant. PTES appeared to be a useful alternative in selected individuals owing to its noninvasiveness. TMS, on the other hand, was incapable of clearly inducing auditory percepts. It also produced concomitant facial and trigeminal stimulation, limiting its potential use as a prognostic tool.