TY  - JOUR
A1  - Rieger, Johannes
A1  - Bähr, Oliver
A1  - Maurer, Gabriele D.
A1  - Hattingen, Elke
A1  - Franz, Kea
A1  - Brucker, Daniel
A1  - Walenta, Stefan
A1  - Kämmerer, Ulrike
A1  - Coy, Johannes F.
A1  - Weller, Michael
A1  - Steinbach, Joachim P.
T1  - ERGO: A pilot study of ketogenic diet in recurrent glioblastoma
JF  - International Journal of Oncology
N2  - Limiting dietary carbohydrates inhibits glioma growth in preclinical models. Therefore, the ERGO trial (NCT00575146) examined feasibility of a ketogenic diet in 20 patients with recurrent glioblastoma. Patients were put on a low-carbohydrate, ketogenic diet containing plant oils. Feasibility was the primary endpoint, secondary endpoints included the percentage of patients reaching urinary ketosis, progression-free survival (PFS) and overall survival. The effects of a ketogenic diet alone or in combination with bevacizumab was also explored in an orthotopic U87MG glioblastoma model in nude mice. Three patients (15%) discontinued the diet for poor tolerability. No serious adverse events attributed to the diet were observed. Urine ketosis was achieved at least once in 12 of 13 (92%) evaluable patients. One patient achieved a minor response and two patients had stable disease after 6 weeks. Median PFS of all patients was 5 (range, 3-13) weeks, median survival from enrollment was 32 weeks. The trial allowed to continue the diet beyond progression. Six of 7 (86%) patients treated with bevacizumab and diet experienced an objective response, and median PFS on bevacizumab was 20.1 (range, 12-124) weeks, for a PFS at 6 months of 43%. In the mouse glioma model, ketogenic diet alone had no effect on median survival, but increased that of bevacizumab-treated mice from 52 to 58 days (p<0.05). In conclusion, a ketogenic diet is feasible and safe but probably has no significant clinical activity when used as single agent in recurrent glioma. Further clinical trials are necessary to clarify whether calorie restriction or the combination with other therapeutic modalities, such as radiotherapy or anti-angiogenic treatments, could enhance the efficacy of the ketogenic diet.
KW  - feasibility
KW  - glucose
KW  - glioma
KW  - metabolism
KW  - ketogenic diet
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-121170
VL  - 44
IS  - 6
ER  - 
TY  - JOUR
A1  - Harter, Patrick N.
A1  - Bernatz, Simon
A1  - Scholz, Alexander
A1  - Zeiner, Pia S.
A1  - Zinke, Jenny
A1  - Kiyose, Makoto
A1  - Blasel, Stella
A1  - Beschorner, Rudi
A1  - Senft, Christian
A1  - Bender, Benjamin
A1  - Ronellenfitsch, Michael W.
A1  - Wikman, Harriet
A1  - Glatzel, Markus
A1  - Meinhardt, Matthias
A1  - Juratli, Tareq A.
A1  - Steinbach, Joachim P.
A1  - Plate, Karl H.
A1  - Wischhusen, Jörg
A1  - Weide, Benjamin
A1  - Mittelbronn, Michel
T1  - Distribution and prognostic relevance of tumor-infiltrating lymphocytes (TILs) and PD-1/PD-L1 immune checkpoints in human brain metastases
JF  - Oncotarget
N2  - The activation of immune cells by targeting checkpoint inhibitors showed promising results with increased patient survival in distinct primary cancers. Since only limited data exist for human brain metastases, we aimed at characterizing tumor infiltrating lymphocytes (TILs) and expression of immune checkpoints in the respective tumors. Two brain metastases cohorts, a mixed entity cohort (n = 252) and a breast carcinoma validation cohort (n = 96) were analyzed for CD3+, CD8+, FOXP3+, PD-1+ lymphocytes and PD-L1+ tumor cells by immunohistochemistry. Analyses for association with clinico-epidemiological and neuroradiological parameters such as patient survival or tumor size were performed. TILs infiltrated brain metastases in three different patterns (stromal, peritumoral, diffuse). While carcinomas often show a strong stromal infiltration, TILs in melanomas often diffusely infiltrate the tumors. Highest levels of CD3+ and CD8+ lymphocytes were seen in renal cell carcinomas (RCC) and strongest PD-1 levels on RCCs and melanomas. High amounts of TILs, high ratios of PD-1+/CD8+ cells and high levels of PD-L1 were negatively correlated with brain metastases size, indicating that in smaller brain metastases CD8+ immune response might get blocked. PD-L1 expression strongly correlated with TILs and FOXP3 expression. No significant association of patient survival with TILs was observed, while high levels of PD-L1 showed a strong trend towards better survival in melanoma brain metastases (Log-Rank p = 0.0537). In summary, melanomas and RCCs seem to be the most immunogenic entities. Differences in immunotherapeutic response between tumor entities regarding brain metastases might be attributable to this finding and need further investigation in larger patient cohorts.
KW  - B7-H1
KW  - PD-L1
KW  - immunoresistance
KW  - immunosurveillance
KW  - safety
KW  - survival
KW  - expression
KW  - melanoma
KW  - breast cancer
KW  - PC-1 blockade
KW  - cell lung cancer
KW  - tumor-infiltrating lymphocytes
KW  - brain metastases
KW  - PD-1
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-137107
VL  - 6
IS  - 38
SP  - 40836
EP  - 40849
ER  - 
TY  - JOUR
A1  - Zeiner, Pia S.
A1  - Preusse, Corinna
A1  - Golebiewska, Anna
A1  - Zinke, Jenny
A1  - Iriondo, Ane
A1  - Muller, Arnaud
A1  - Kaoma, Tony
A1  - Filipski, Katharina
A1  - Müller-Eschner, Monika
A1  - Bernatz, Simon
A1  - Blank, Anna-Eva
A1  - Baumgarten, Peter
A1  - Ilina, Elena
A1  - Grote, Anne
A1  - Hansmann, Martin L.
A1  - Verhoff, Marcel A.
A1  - Franz, Kea
A1  - Feuerhake, Friedrich
A1  - Steinbach, Joachim P.
A1  - Wischhusen, Jörg
A1  - Stenzel, Werner
A1  - Niclou, Simone P.
A1  - Harter, Patrick N.
A1  - Mittelbronn, Michel
T1  - Distribution and prognostic impact of microglia/macrophage subpopulations in gliomas
JF  - Brain Pathology
N2  - While the central nervous system is considered an immunoprivileged site and brain tumors display immunosuppressive features, both innate and adaptive immune responses affect glioblastoma (GBM) growth and treatment resistance. However, the impact of the major immune cell population in gliomas, represented by glioma-associated microglia/macrophages (GAMs), on patients’ clinical course is still unclear. Thus, we aimed at assessing the immunohistochemical expression of selected microglia and macrophage markers in 344 gliomas (including gliomas from WHO grade I–IV). Furthermore, we analyzed a cohort of 241 IDH1R132H-non-mutant GBM patients for association of GAM subtypes and patient overall survival. Phenotypical properties of GAMs, isolated from high-grade astrocytomas by CD11b-based magnetic cell sorting, were analyzed by immunocytochemistry, mRNA microarray, qRT-PCR and bioinformatic analyses. A higher amount of CD68-, CD163- and CD206-positive GAMs in the vital tumor core was associated with beneficial patient survival. The mRNA expression profile of GAMs displayed an upregulation of factors that are considered as pro-inflammatory M1 (eg, CCL2, CCL3L3, CCL4, PTGS2) and anti-inflammatory M2 polarization markers (eg, MRC1, LGMN, CD163, IL10, MSR1), the latter rather being associated with phagocytic functions in the GBM microenvironment. In summary, we present evidence that human GBMs contain mixed M1/M2-like polarized GAMs and that the levels of different GAM subpopulations in the tumor core are positively associated with overall survival of patients with IDH1R132H-non-mutant GBMs.
KW  - glioma
KW  - glioma-associated microglia and macrophages;
KW  - immune polarization
KW  - tumor microenvironment
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-233897
VL  - 29
ER  -