Approaches to the treatment of hypereosinophilic syndromes: a workshop summary report

Hypereosinophilic syndromes are a heterogeneous group of uncommon disorders characterized by the presence of marked peripheral blood eosinophilia, tissue eosinophilia, or both, resulting in a wide variety of clinical manifestations. Although corticosteroids are the first-line therapy for many of these disorders, approaches to the treatment of patients who do not tolerate or are unresponsive to corticosteroids are poorly standardized. A multidisciplinary group of 37 clinicians and scientists participated in a workshop held in May 2005 in Bern, Switzerland to discuss current and future approaches to therapy for 3 eosinophil-mediated disorders: hypereosinophilic syndrome, Churg-Strauss syndrome, and eosinophil-associated gastrointestinal disease. The goal of the workshop was to summarize available data regarding treatment of these disorders to identify the most promising therapies and approaches for further study. There was consensus among all of the participants that the identification of markers of disease progression to assess treatment responses is a research priority for all 3 disorders. Furthermore, the need for newer therapeutic strategies and novel drugs, as well as multicenter trials to assess all treatment modalities, was emphasized.

Treatment of patients with the hypereosinophilic syndrome with mepolizumab

BACKGROUND: The hypereosinophilic syndrome is a group of diseases characterized by persistent blood eosinophilia, defined as more than 1500 cells per microliter with end-organ involvement and no recognized secondary cause. Although most patients have a response to corticosteroids, side effects are common and can lead to considerable morbidity. METHODS: We conducted an international, randomized, double-blind, placebo-controlled trial evaluating the safety and efficacy of an anti-interleukin-5 monoclonal antibody, mepolizumab, in patients with the hypereosinophilic syndrome. Patients were negative for the FIP1L1-PDGFRA fusion gene and required prednisone monotherapy, 20 to 60 mg per day, to maintain a stable clinical status and a blood eosinophil count of less than 1000 per microliter. Patients received either intravenous mepolizumab or placebo while the prednisone dose was tapered. The primary end point was the reduction of the prednisone dose to 10 mg or less per day for 8 or more consecutive weeks. RESULTS: The primary end point was reached in 84% of patients in the mepolizumab group, as compared with 43% of patients in the placebo group (hazard ratio, 2.90; 95% confidence interval [CI], 1.59 to 5.26; P<0.001) with no increase in clinical activity of the hypereosinophilic syndrome. A blood eosinophil count of less than 600 per microliter for 8 or more consecutive weeks was achieved in 95% of patients receiving mepolizumab, as compared with 45% of patients receiving placebo (hazard ratio, 3.53; 95% CI, 1.94 to 6.45; P<0.001). Serious adverse events occurred in seven patients receiving mepolizumab (14 events, including one death; mean [+/-SD] duration of exposure, 6.7+/-1.9 months) and in five patients receiving placebo (7 events; mean duration of exposure, 4.3+/-2.6 months). CONCLUSIONS: Our study shows that treatment with mepolizumab, an agent designed to target eosinophils, can result in corticosteroid-sparing for patients negative for FIP1L1-PDGFRA who have the hypereosinophilic syndrome. (ClinicalTrials.gov number, NCT00086658 [ClinicalTrials.gov].).

Hypereosinophilic syndrome: a multicenter, retrospective analysis of clinical characteristics and response to therapy

BACKGROUND: Hypereosinophilic syndrome (HES) is a heterogeneous group of rare disorders defined by persistent blood eosinophilia > or =1.5 x 10(9)/L, absence of a secondary cause, and evidence of eosinophil-associated pathology. With the exception of a recent multicenter trial of mepolizumab (anti-IL-5 mAb), published therapeutic experience has been restricted to case reports and small case series. OBJECTIVE: The purpose of the study was to collect and summarize baseline demographic, clinical, and laboratory characteristics in a large, diverse cohort of patients with HES and to review responses to treatment with conventional and novel therapies. METHODS: Clinical and laboratory data from 188 patients with HES, seen between January 2001 and December 2006 at 11 institutions in the United States and Europe, were collected retrospectively by chart review. RESULTS: Eighteen of 161 patients (11%) tested were Fip1-like 1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRA) mutation-positive, and 29 of 168 patients tested (17%) had a demonstrable aberrant or clonal T-cell population. Corticosteroid monotherapy induced complete or partial responses at 1 month in 85% (120/141) of patients with most remaining on maintenance doses (median, 10 mg prednisone equivalent daily for 2 months to 20 years). Hydroxyurea and IFN-alpha (used in 64 and 46 patients, respectively) were also effective, but their use was limited by toxicity. Imatinib (used in 68 patients) was more effective in patients with the FIP1L1-PDGFRA mutation (88%) than in those without (23%; P < .001). CONCLUSION: This study, the largest clinical analysis of patients with HES to date, not only provides useful information for clinicians but also should stimulate prospective trials to optimize treatment of HES.

Alternde Gesellschaft. Soziale Herausforderungen des längeren Lebens

Das gesellschaftliche Bild des Alters und seine Realität haben sich stark verändert - Menschen können im Durchschnitt bis in das achtzigste Lebensjahr ein aktives Leben führen. Hegemoniale Altersbilder von den fitten und jungen Alten nehmen diese Situation auf. Aber es gibt auch Ambivalenzen: Angesichts wachsender sozialer Ungleichheit kommen längst nicht alle Älteren in den Genuss eines guten Alters. Der Band diskutiert die Situation der "Neuen Alten" aus sozialwissenschaftlichen, ökonomischen, religionswissenschaftlichen und theologischen Perspektiven.

Soziales Europa?

Nach innen heterogen, konfrontiert mit den Folgen einer massiven Finanz- und Schuldenkrise und gekennzeichnet von zunehmender sozialer Ungleichheit, nach außen hart gegen Flüchtlinge und Migranten und auf den Schutz der eigenen ökonomischen Interessen bedacht, scheint die Europäische Union von der Idee eines 'sozialen Europa' weit entfernt. Gleichwohl ist das Projekt einer europäischen Einigung fest mit der Vorstellung eines 'europäischen Sozialmodells' verbunden, in dem die verlässliche soziale Absicherung der Menschen in Europa hohe Priorität geniesst, auch wenn über die Form der Umsetzung intensiv gestritten wird. Im europäischen sozialen Protestantismus, der die wohlfahrtsstaatlichen Kulturen Europas in vielfältiger Weise geprägt hat, wird die Frage nach Möglichkeit und Gestalt einer möglichst effektiven, effizienten und gerechten sozialen Absicherung im europäischen Kontext in unterschiedlicher Weise diskutiert. Der Band informiert über institutionell-politische Strukturen, soziale Problemkonstellationen, ökonomische und politische Optionen und sozialethische Grundprinzipien für die Gestaltung eines 'sozialen Europa' und bietet Diskussionsstände aus vielfältigen Perspektiven des europäischen Protestantismus.

Soziales Europa?

Das weitverbreitete Konzept eines 'europäischen Sozialmodells' wird dargestellt und anhand eines konkreten Problems - der auch als 'Prekarisierung der Arbeit' bekannten Zunahme mangelhaft gesicherter und insofern problematischer Arbeitsverhältnisse im zeitgenössischen Europa - einem ethischen Realitätstest unterzogen. In einem Ausblick werden Schlussfolgerungen für die Weiterentwicklung dieses Modells gezogen.

Cilengitide treatment of newly diagnosed glioblastoma patients does not alter patterns of progression

The integrin antagonist cilengitide has been explored as an adjunct with anti-angiogenic properties to standard of care temozolomide chemoradiotherapy (TMZ/RT → TMZ) in newly diagnosed glioblastoma. Preclinical data as well as anecdotal clinical observations indicate that anti-angiogenic treatment may result in altered patterns of tumor progression. Using a standardized approach, we analyzed patterns of progression on MRI in 21 patients enrolled onto a phase 2 trial of cilengitide added to TMZ/RT → TMZ in newly diagnosed glioblastoma. Thirty patients from the experimental treatment arm of the EORTC/NCIC pivotal TMZ trial served as a reference. MRIcro software was used to map location and extent of initial preoperative and recurrent tumors on MRI of both groups into the same stereotaxic space which were then analyzed using an automated tool of image analysis. Clinical and outcome data of the cilengitide-treated patients were similar to those of the EORTC/NCIC trial except for a higher proportion of patients with a methylated O(6)-methylguanyl-DNA-methyltransferase gene promoter. Analysis of recurrence pattern revealed neither a difference in the size of the recurrent tumor nor in the distance of the recurrences from the preoperative tumor location between groups. Overall frequencies of distant recurrences were 20 % in the reference group and 19 % (4/21 patients) in the cilengitide group. Compared with TMZ/RT → TMZ alone, the addition of cilengitide does not alter patterns of progression. This analysis does not support concerns that integrin antagonism by cilengitide may induce a more aggressive phenotype at progression, but also provides no evidence for an anti-invasive activity of cilengitide in patients with newly diagnosed glioblastoma.

Emerging Areas in Atmospheric Photochemistry

Sunlight is a major driving force of atmospheric processes. A detailed knowledge of atmospheric photochemistry is therefore required in order to understand atmospheric chemistry and climate. Considerable progress has been made in this field in recent decades. This contribution will highlight a set of new and emerging ideas (and will therefore not provide a complete review of the field) mainly dealing with long wavelength photochemistry both in the gas phase and on a wide range of environmental surfaces. Besides this, some interesting bulk photochemistry processes are discussed. Altogether these processes have the potential to introduce new chemical pathways into tropospheric chemistry and may impact atmospheric radical formation.