Patterns, predictors and prognostic relevance of high-grade hematotoxicity after temozolomide or temozolomide-lomustine in the CeTeG/NOA-09 trial.

PURPOSE: In the randomized phase III trial CeTeG/NOA-09, temozolomide (TMZ)/lomustine (CCNU) combination therapy was superior to TMZ in newly diagnosed MGMT methylated glioblastoma, albeit reporting more frequent hematotoxicity. Here, we analyze high grade hematotoxicity and its prognostic relevance in the trial population. METHODS: Descriptive and comparative analysis of hematotoxicity adverse events ≥ grade 3 (HAE) according to the Common Terminology of Clinical Adverse Events, version 4.0 was performed. The association of HAE with survival was assessed in a landmark analysis. Logistic regression analysis was performed to predict HAE during the concomitant phase of chemotherapy. RESULTS: HAE occurred in 36.4% and 28.6% of patients under CCNU/TMZ and TMZ treatment, respectively. The median onset of the first HAE was during concomitant chemotherapy (i.e. first CCNU/TMZ course or daily TMZ therapy), and 42.9% of patients with HAE receiving further courses experienced repeat HAE. Median HAE duration was similar between treatment arms (CCNU/TMZ 11.5; TMZ 13 days). Chemotherapy was more often discontinued due to HAE in CCNU/TMZ than in TMZ (19.7 vs. 6.3%, p = 0.036). The occurrence of HAE was not associated with survival differences (p = 0.76). Regression analysis confirmed older age (OR 1.08) and female sex (OR 2.47), but not treatment arm, as predictors of HAE. CONCLUSION: Older age and female sex are associated with higher incidence of HAE. Although occurrence of HAE was not associated with shorter survival, reliable prediction of patients at risk might be beneficial to allow optimal management of therapy and allocation of supportive measures. TRIAL REGISTRATION: NCT01149109.

Re-irradiation for recurrent glioblastoma multiforme: a critical comparison of different concepts.

PURPOSE: Purpose of this study was to investigate outcome and toxicity of re-irradiation for recurrent primary glioblastoma (rGBM). We evaluated a group of patients with rGBM and identical primary treatment comprising adjuvant radiotherapy (30â€¯× 2 Gy) with concurrent temozolomide (TMZ). METHODS: In this retrospective study of 46 patients, all received adjuvant or definitive normofractionated radiotherapy to a pretreated area, some with concurrent chemotherapy. Impact of different clinical, histological, or epidemiological factors on survival and radiation toxicity was reviewed. RESULTS: Of 46 patients, 40 completed the intended therapy. Overall survival (OS) was 20 months (range 6-72 months). Overall survival and progression-free survival after re-irradiation (OS2 and PFS2) were 9.5 and 3.4 months (range 2-40 and 0.7-44 months). Simultaneous systemic therapy improved PFS2 and OS2 (4.3 vs. 2.0, p < 0.001 and 12 vs. 4 months, p = 0.13, respectively). Therapy with TMZ or bevacizumab improved PFS2 vs. nitrosureas (6.6 vs. 2.9, p = 0.03 and 5.1 vs. 2.9 months, p = 0.035, respectively). TMZ also improved PFS2 and OS2 vs. all other systemic therapies (6.6 vs. 4, p < 0.001 and 17 vs. 10 months, p = 0.1). In a subgroup analysis for patients with methylation of the MGMT promoter, doses of >36 Gy as well as TMZ vs. no systemic therapy improved PFS2 (p = 0.045 and p = 0.03, respectively). 27.5% of all patients had no acute toxicity. Three patients with acute and four patients with late grade 3 toxicities were reported. CONCLUSION: Normofractionated radiotherapy is a feasible option for rGBM with a good toxicity profile. Simultaneously applied systemic therapy was associated with improved outcome. For MGMT promoter-methylated histology, higher radiation doses improved survival.

Fatigue in multiple sclerosis: a comparison of different rating scales and correlation to clinical parameters.

OBJECTIVES: Fatigue is one of the most common, yet poorly defined, disabling symptoms in patients with multiple sclerosis (MS). To delineate more clearly the frequency and type of fatigue, we first compared four widely used fatigue scales in consecutive MS patients. Secondly, to further clarify the nature of fatigue, we investigated its relation to physical disability, course of the disease, immunotherapy, and depression. PATIENTS AND METHODS: Between February and September 2000, 151 consecutive MS patients entering our outpatient clinic (94 relapsing-remitting, 50 secondary progressive, and 7 primary progressive patients; mean age 29.0 +/- 7.3 years, mean disease duration 9.9 +/- 6.7 years, median EDSS 3.5) filled in a standardized questionnaire induding four fatigue scales--Fatigue Severity Scale (FSS), MS-specific FSS (MFSS), Modified Fatigue Impact Scale (MFIS), and Visual Analogue Scale (VAS). Patients were included in the 'MS-related fatigue group' (MS-F) when they stated in the questionnaire that fatigue: 1) is one of their three most disabling symptoms; 2) occurs daily or on most of the days; and 3) limits their activities at home or at work Patients fulfilling none of these criteria were classified as 'MS-related nonfatigue group' (MS-NF). Depression was measured by Beck's Depression Inventory (BDI). RESULTS: Although all scales showed significant differences between MS-F and MS-NF, correlation between these scales was, at best moderate (correlation coeffcients ranging from 0.06 to 0.56). The most discriminative scales were FSS and MFIS, showing no overlap of the 10th and 90th percentiles for the MS-F and MS-NF groups, with cut-off values of 4.6 and 38, respectively. Depression (BDI > or = 18) was present in 24 of 148 patients who filled in the BDI (16%). FSS was significantly correlated with physical disability (r=0.33, p<0.0001) and BDI (r=0.41, p<0.0001), but not with age, disease duration, clinical activity, and treatment with interferon-beta. In multivariate analysis, however, only BDI independently predicted fatigue. CONCLUSIONS: The association of fatigue and depression suggests that there might be either common underlying mechanisms or interdependence by a cause-and-effect relationship that requires further investigation. The weak correlation within various fatigue scales is best explained by the fact that fatigue is a multidimensional symptom and, therefore, the available tests measure and weight different aspects of fatigue. Our findings underline the necessity for a more exact definition of fatigue and the development of more valid tools if these are to be used to evaluate treatments.

Microglial phagocytosis of apoptotic inflammatory T cells leads to down-regulation of microglial immune activation.

Apoptotic cell death is an established mechanism to terminate an inflammatory response in rodent or human brains. Microglia, as the resident phagocyte, is a strong candidate for the clearance of apoptotic lymphocytes. Apoptosis was induced in cultured autologous thymocytes and in myelin basic protein (MBP)-specific, encephalitogenic T cells from Lewis rats by the addition of 0.1 microg/ml methylprednisolone. The amount of phagocytosis of apoptotic cells was assessed using an in vitro phagocytosis assay. Supernatants were collected to measure microglial cytokine secretion. The state of immune activation in microglia was investigated by a T cell proliferation assay and by flow cytometric analysis of microglial surface expression of immune molecules. Microglia ingested specifically apoptotic cells (apoptotic thymocytes as well as MBP-specific T cells) in contrast to nonapoptotic control cells (p < 0.0001). Subsequent secretion of the proinflammatory cytokines TNF-alpha and IL-12 was significantly decreased, while the secretion of IL-10 and TGF-beta was not affected. Furthermore, ingestion of apoptotic cells led to increased microglial MHC class II expression without concomitant increase in MHC class I, costimulatory molecules, and ICAM expression. The Ag-specific activation of MBP-specific T cells in cocultures with microglia that had ingested apoptotic cells was significantly less than that of identical T cells that interacted with nonphagocytosing microglia. Together with negative results obtained in a trans-well system, this is in support of a cell contact-mediated effect. Microglia might play an important role in the clearance of apoptotic cells. The uptake of apoptotic cells by microglia is tolerogenic and results in a reduced proinflammatory cytokine production and a reduced activation of encephalitogenic T cells. This might help to restrict an autoimmune inflammation and minimize damage in the inflamed brain.

[Glucocorticosteroid therapy in optic neuritis and multiple sclerosis. Evidence from clinical studies and practical recommendations]. / Glukokortikosteroid-Therapie bei Optikusneuritis und Multipler Sklerose. Evidenz aus klinischen Studien und praktische Empfehlungen.

High-dose intravenous glucocorticosteroids (GS) are the treatment of choice for acute relapses in patients with multiple sclerosis. We review the evidence from published trials on GS treatment in MS. Several controlled clinical trials have proven the efficacy of high-dose GS in accelerating the recovery from acute attacks. With serial MRI recordings, a reduction in the number of enhancing lesions has been observed after high-dose GS treatment. Definitive long-term effects of GS on disease evolution could not been demonstrated. There is now evidence that ultra-high doses of GS might be superior in comparison to standard pulse treatment regarding relapse rate and disease progression. In experimental autoimmune encephalomyelitis (EAE), an animal model for some features of MS, doses of up to 50 mg/kg methylprednisolone markedly augmented T cell apoptosis in situ, leading to a faster clearance of inflammatory infiltrates. Apoptosis in peripheral blood leukocytes could also be detected after i.v. GS treatment in MS patients. In a recent MRI study, ultra-high doses of GS were significantly more effective in reducing contrast-enhancing lesions and in maintaining blood-brain barrier integrity after a clinical relapse. Further clinical trials are necessary to study the long-term effects of ultra-high doses of GS on disease progression and disability.

Antigen processing in populations of mature murine dendritic cells is caused by subsets of incompletely matured cells.

Immature dendritic cells (DC), such as freshly isolated Langerhans cells (LC), are excellent at processing native protein Ag. During short term culture they shut off MHC class II synthesis and down-regulate their processing capacity. They retain, however, the MHC/peptide complexes, up-regulate adhesion and costimulatory molecules, and acquire the ability to sensitize T cells. Two reports describing substantial processing activity in populations of mature DC prompted us to undertake an extensive comparative study of the Ag-processing capacities of immature vs mature DC. We used a panel of 17 peptide-specific T cell hybridomas restricted by six different MHC class II molecules: I-Ab, I-A(d), I-E(d), hybrid I-A beta dE alpha, I-Ak, and I-Ek. Side by side comparisons revealed in all cases that freshly isolated LC were superior to cultured mature LC in their ability to process native proteins. With some hybridomas, however, we found a considerable degree of processing by populations of cultured LC at high doses of Ag or Ag-presenting cells. This activity, however, did not correlate with the MHC haplotype. Direct comparison over wide ranges of DC doses or Ag doses showed that it was always less than that of corresponding fresh immature LC. Immunoperoxidase staining of cytospins and flow cytometry with mAb In1 disclosed a small (20% maximum) subset of cultured LC expressing the MHC class II-associated invariant chain, indicating ongoing biosynthesis of this molecule and, thus, incomplete maturation of these LC. Therefore, the residual processing activity observed in populations of mature DC may be explained by small subpopulations of incompletely matured DC.