EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurrent Attacks

BACKGROUND AND AIMS: Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. APPROACH AND RESULTS: EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months before the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a health care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic δ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ-aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased health care utilization. CONCLUSIONS: Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as well as chronic symptoms that adversely influenced day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies. (Hepatology 2020;71:1546-1558)

EXPLORE: A prospective, multinational natural history study of patients with acute hepatic porphyria with recurrent attacks

BACKGROUND AND AIMS: Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. APPROACH AND RESULTS: EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months before the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a health care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic δ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ-aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased health care utilization. CONCLUSIONS: Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as well as chronic symptoms that adversely influenced day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies. (Hepatology 2020;71:1546-1558)

Characteristics and outcome of patients with low-/intermediate-risk acute promyelocytic leukemia treated with arsenic trioxide - an international collaborative study

The aim of this study was to characterize a large series of 154 patients with acute promyelocytic leukemia (APL; median age, 53 years; range, 18-90 years) and evaluate real-life outcome after up-front treatment with arsenic trioxide (ATO) and alltrans retinoic acid (ATRA). All patients were included in the prospective NAPOLEON registry (NCT02192619) between 2013 and 2019. APL was de novo in 91% (n=140) and therapy-related in 9% (n=14); 13% (n=20) were older than 70 years. At diagnosis bleeding/hemorrhage was present in 38% and thrombosis in 3%. Complete remission was achieved in 152 patients (99%), whereas two patients (1%) experienced induction death within 18 days after start of therapy. With a median follow-up of 1.99 years (95%-CI, 1.61-2.30 years) 1-year and 2-years overall survival (OS) rates were 97% (95%-CI, 94-100%) and 95% (95%-CI, 91-99%), respectively. Age above 70 years was associated with a significantly shorter OS (P<0.001) as compared to younger patients. So far no relapses were observed. Six patients (4%) died in CR after in median 0.95 years after diagnosis (range, 0.18-2.38 years). Our data confirm the efficiency and durability of ATO/ATRA in the primary management of adult low-/ intermediate-risk APL patients in the real life setting, irrespective of age

EXPLORE: A Prospective, Multinational, Natural History Study of Patients with Acute Hepatic Porphyria with Recurren

Background and Aims: Acute hepatic porphyria comprises a group of rare genetic diseases caused by mutations in genes involved in heme biosynthesis. Patients can experience acute neurovisceral attacks, debilitating chronic symptoms, and long-term complications. There is a lack of multinational, prospective data characterizing the disease and current treatment practices in severely affected patients. Approach and Results: EXPLORE is a prospective, multinational, natural history study characterizing disease activity and clinical management in patients with acute hepatic porphyria who experience recurrent attacks. Eligible patients had a confirmed acute hepatic porphyria diagnosis and had experienced ≥3 attacks in the prior 12 months or were receiving prophylactic treatment. A total of 112 patients were enrolled and followed for at least 6 months. In the 12 months before the study, patients reported a median (range) of 6 (0-52) acute attacks, with 52 (46%) patients receiving hemin prophylaxis. Chronic symptoms were reported by 73 (65%) patients, with 52 (46%) patients experiencing these daily. During the study, 98 (88%) patients experienced a total of 483 attacks, 77% of which required treatment at a health care facility and/or hemin administration (median [range] annualized attack rate 2.0 [0.0-37.0]). Elevated levels of hepatic δ-aminolevulinic acid synthase 1 messenger ribonucleic acid levels, δ-aminolevulinic acid, and porphobilinogen compared with the upper limit of normal in healthy individuals were observed at baseline and increased further during attacks. Patients had impaired quality of life and increased health care utilization. Conclusions: Patients experienced attacks often requiring treatment in a health care facility and/or with hemin, as well as chronic symptoms that adversely influenced day-to-day functioning. In this patient group, the high disease burden and diminished quality of life highlight the need for novel therapies

Die digitale Diaphanoskopie der Nasennebenhöhlen

Einleitung: In dieser klinischen Studie wurden diaphanoskopische Untersuchungen sowohl an Patienten, die an einer Rhinosinusitis erkrankt sind, als auch an gesunden Probanden durchgeführt. Die Lichtbildaufnahmen wurden mit verschiedenen Methoden der Bildbearbeitung ausgewertet und mit den CT-Bildern der untersuchten Probanden verglichen. Ziel war es festzustellen, ob die Unterscheidung von gesunden und an Rhinosinusitis erkrankten Personen mit Hilfe der Diaphanoskopie untersucherunabhängig möglich ist. Methodik: Die Probanden (n=30) führten einen Applikator in den Mund ein, aus dessen Enden Weißlicht ausgestrahlt wurde. Das Licht strahlte durch den Gaumen und die Nasennebenhöhlen und ergab dann unterhalb der Augen ein von außen sichtbares Streuchlichtmuster. Anschließend wurde eine Lichtbildaufnahme des Gesichtsbereichs unterhalb der Augen der Probanden angefertigt, die mit Hilfe von Bildauswertungsalgorithmen auf Form, Intensität und andere Merkmale, der nun durch die Ausleuchtung enstandenen charakteristischen Lichtsicheln unter den Augen, analysiert und mit dem Goldstandard Computertomografie verglichen wurde.Ergebnisse: Eine Beurteilung der Nasennebenhöhlen ist mittels der digitalen Diaphanoskopie mit hoher Sensitivität und Spezifität möglich. Bei allen Probanden zeigte sich eine hohe Korrelation der digital bestimmten Bildlichtsegmente mit der CT, die statistisch belegbar war.Schlussfolgerung: Die digitale Diaphanoskopie hat in der täglichen Praxis zur Beurteilung der Nasennebenhöhlen neben der Computertomografie seine Berechtigung.Der Erstautor gibt keinen Interessenkonflikt an

Einsatz von demineralisierter humaner Knochenmatrix (DBM) als Trägermaterial im Tissue Engineering von humanen Knorpelgeweben

Demineralisierte Knochenmatrix (DBM) bovinen Ursprungs zeigte in früheren Studien in vitro als auch in vivo viel versprechende Ergebnisse. Seit dem Auftreten der Kreutzfeld-Jakob-Krankheit ist die Anwendung von DBM bovinen Ursprungs kritisch zu sehen. In jüngster Zeit wurde DBM humanen Ursprungs als geeignetes Biomaterial bei der Differenzierung von mesenchymalen Stammzellen in Chondrozyten wiederentdeckt. In dieser Studie sollte DBM als Trägermaterial von Chondrozytenkulturen in vitro getestet werden. Dazu besiedelten wir demineralisierte Spongiosa, welche zur Sterilisation u.a. mit Peressigsäure behandelt wurde, mit humanen Chondrozyten des Nasenseptums in unterschiedlichen Zellkonzentrationen. Es konnten sich allerdings nach Kultivierung keine vitalen Zellen darstellen lassen. In weitergehenden auf Toxizität prüfenden Untersuchungen zeigte sich, dass das Vorhandensein von DBM zum fehlenden Nachweis von vitalen Zellen führte und Zellkulturmedium, welches mit DBM kultiviert wurde in einem anderen Ansatz das Zellwachstum der Chondrozyten hemmte. Eine Freisetzung von H+ -Ionen als Zeichen eines toxischen Effektes von DBM auf die Zellen konnte mittels pH- Metrie ebenso wenig wie ein möglicher Austritt von Peressigsäure aus DBM beobachtet werden. In der Immunhistochemie und im Western Blot wurden die Ansätze auf Kollagen Typ I, II und Kaspase untersucht. Mit den Zytotoxizitäts- und Proliferationsuntersuchungen mittels ELISA testeten wir die Wirkung von DBM auf Chondrozyten in Abhängigkeit von der Konzentration des DBM und der Dauer der Einwirkung von DBM auf die Zellen. Als nächster Schritt ist die Gaschromatografie zur Überprüfung einer eventuellen Freisetzung von Peressigsäure und Chloroform aus dem DBM geplant