Nazi, collaborator or opponent? The role of the pathologist Robert Rössle in the Third Reich.

For many, Robert Rössle is one of the most important pathologists of the first half of the 20th century. His research in the fields of inflammation, constitution, growth and age, and immunity gave him the status of a pioneer. Because he was not a nominal member of the Nazi Party (NSDAP), Rössle did not have to undergo denazification proceedings and was able to continue his academic career seamlessly after 1945. Only recently, the question of Rössle's actual role in the Third Reich has been raised - in connection with a possible renaming of the Robert-Rössle-Straße in Berlin. Our paper takes this issue as an opportunity to critically examine Rössle's involvement in National Socialism. For this study, all available literature and extensive primary material on Rössle from various archives was reviewed and evaluated with regard to the question posed. The investigations show that Rössle held a number of offices in the administrative apparatus of the Nazi state even though not being a party member. They gave him access to high-ranking representatives and most likely also knowledge about medical crimes. Rössle researched and published on hereditary biology and racial hygiene issues, thus supporting the ideology of the Nazi State. Robert Rössle must be regarded as an early proponent of racial hygiene, political collaborator and profiteer of the Third Reich. However, it remains unclear whether he was directly involved in human experiments. There is no evidence that he critically distanced himself from his role in the Third Reich after 1945.

Transport of treosulfan and temozolomide across an in-vitro blood-brain barrier model.

In vitro, treosulfan (TREO) has shown high effectiveness against malignant gliomas. However, a first clinical trial for newly diagnosed glioblastoma did not show any positive effect. Even though dosing and timing might have been the reasons for this failure, it might also be that TREO does not reach the brain in sufficient amount. Surprisingly, there are no published data on TREO uptake into the brain of patients, despite extensive research on this compound. An in-vitro blood-brain barrier (BBB) model consisting of primary porcine brain capillary endothelial cells was used to determine the transport of TREO across the cell monolayer. Temozolomide (TMZ), the most widely used cytotoxic drug for malignant gliomas, served as a reference. An HPLC-ESI-MS/MS procedure was developed to detect TREO and TMZ in cell culture medium. Parallel to the experimental approach, the permeability of TREO and the reference substance across the in-vitro BBB was estimated on the basis of their physicochemical properties. The detection limit was 30 nmol/l for TREO and 10 nmol/l for TMZ. Drug transport was measured in two directions: influx, apical-to-basolateral (A-to-B), and efflux, basolateral-to-apical (B-to-A). For TREO, the A-to-B permeability was lower (1.6%) than the B-to-A permeability (3.0%). This was in contrast to TMZ, which had higher A-to-B (13.1%) than B-to-A (7.2%) permeability values. The in-vitro BBB model applied simulated the human BBB properly for TMZ. It is, therefore, reasonable to assume that the values for TREO are also meaningful. Considering the lack of noninvasive, significant alternative methods to study transport across the BBB, the porcine brain capillary endothelial cell model was efficient to collect first data for TREO that explain the disappointing clinical results for this drug against cerebral tumors.

Can in-vitro chemoresponse assays help find new treatment regimens for malignant gliomas?

Various in-vitro chemosensitivity and resistance assays (CSRAs) have been demonstrated to be helpful decision aids for non-neurological tumors. Here, we evaluated the performance characteristics of two CSRAs for glioblastoma (GB) cells. The chemoresponse of fresh GB cells from 30 patients was studied in vitro using the ATP tumor chemoresponse assay and the chemotherapy resistance assay (CTR-Test). Both assay platforms provided comparable results. Of seven different chemotherapeutic drugs and drug combinations tested in vitro, treosulfan plus cytarabine (TARA) was the most effective, followed by nimustine (ACNU) plus teniposide (VM26) and temozolomide (TMZ). Whereas ACNU/VM26 and TMZ have proven their clinical value for malignant gliomas in large randomized studies, TARA has not been successful in newly diagnosed gliomas. This seeming discrepancy between in vitro and clinical result might be explained by the pharmacological behavior of treosulfan. Our results show reasonable agreement between two cell-based CSRAs. They appear to confirm the clinical effectiveness of drugs used in GB treatment as long as pharmacological preconditions such as overcoming the blood-brain barrier are properly considered.

Commentary on Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial (Lancet Oncol. 2009;10:459-466).

Recently, un update of the important European Organization for Research and Treatment of Cancer study 26981 was published without correcting deficiencies that already were known and publicized in 2008. In the current commentary, the author specifies those issues to help prevent incorrect conclusions and discusses reasons why the journal that published the update dismissed a letter clarifying those shortcomings.

Boron neutron capture therapy for glioblastoma: is it worth pursuing?

Presently glioblastomas are incurable brain tumors. The prospect of treating this deadly disease has been the major justification for the current programs of boron neutron capture therapy (BNCT) throughout the world. However, based on pharmacological and cell biological considerations, it is improbable that BNCT will ever be an effective therapy for this tumor. Indeed, a review of the published literature over the last 50 years fails to provide justification for developing BNCT past its present experimental stage.