Peter Hau | University of Regensburg (original) (raw)

Papers by Peter Hau

Journal of cancer research and clinical oncology, 2018

We evaluated patterns of tumor growth in patients with newly diagnosed MGMT-non-methylated gliobl... more We evaluated patterns of tumor growth in patients with newly diagnosed MGMT-non-methylated glioblastoma who were assigned to undergo radiotherapy in conjunction with bevacizumab/irinotecan (BEV/IRI) or standard temozolomide (TMZ) within the randomized phase II GLARIUS trial. In 142 patients (94 BEV/IRI, 48 TMZ), we reviewed magnetic resonance imaging scans at baseline and first tumor recurrence. Based on contrast-enhanced T1-weighted and fluid-attenuated inversion recovery images, we assessed tumor growth patterns and tumor invasiveness. Tumor growth patterns were classified as either multifocal or local at baseline and recurrence; at first recurrence, we additionally assessed whether distant lesions appeared. Invasiveness was determined as either diffuse or non-diffuse. Associations with treatment arms were calculated using Fisher's exact test. At baseline, 115 of 142 evaluable patients (81%) had a locally confined tumor. Between treatment arms, there was no significant differe...

Neuro-oncology, Nov 1, 2016

BACKGROUND: The phase II GLARIUS trial assigned patients with newly diagnosed, O-6-methylguanine-... more BACKGROUND: The phase II GLARIUS trial assigned patients with newly diagnosed, O-6-methylguanine-DNA methyltransferase (MGMT) non-methylated glioblastoma in a 2:1 ratio to experimental bevacizumab/ irinotecan (BEV/IRI) or standard temozolomide (TMZ). BEV/IRI prolonged progression-free survival but overall survival (OS) was similar in both treatment arms. Whether elderly patients derive benefit from BEV/ IRI treatment is a controversial issue. To address this, the association of age and BEV/IRI treatment was assessed in a subgroup analysis. METHODS: Patients included in the modified ITT population were grouped according to their age at tumor diagnosis into a <65 years or ≥65 years group. Characteristics (sex, Karnofsky Performance Score (KPS), extent of resection, and mini-mental status examination (MMSE) score) were then evaluated between groups. In a Kaplan-Meier analysis, we compared overall survival (OS) between age groups in each treatment arm. A Cox regression analysis served to detect whether age was an independent prognostic factor. RESULTS: In the BEV/IRI arm, 95 patients were younger than 65 and 21 were at least 65 years old. In the TMZ arm, 41 patients were <65 and 13 ≥65 years old. In each treatment arm, canonical prognostic factors (KPS, extent of resection) were balanced between age groups. Among patients treated with BEV/IRI, those <65 years survived significantly longer than those ≥65 (median OS, 17.5 vs. 13.4 months, p<0.001). Among TMZ treated patients, no significant difference was found between age groups (median OS, 20.0 vs. 17.3 months, p=0.567). In the Cox model, age emerged as an independent prognostic factor in BEV/IRI treated patients only (Hazard Ratio, 2.72, p<0.001). CONCLUSIONS: In the GLARIUS trial, patients <65 years derived significantly more benefit from BEV/IRI treatment as compared with elderly patients ≥65. However, the small sample size limits our analysis.

The Lancet, 2019

BACKGROUND There is an urgent need for more effective therapies for glioblastoma. Data from a pre... more BACKGROUND There is an urgent need for more effective therapies for glioblastoma. Data from a previous unrandomised phase 2 trial suggested that lomustine-temozolomide plus radiotherapy might be superior to temozolomide chemoradiotherapy in newly diagnosed glioblastoma with methylation of the MGMT promoter. In the CeTeG/NOA-09 trial, we aimed to further investigate the effect of lomustine-temozolomide therapy in the setting of a randomised phase 3 trial. METHODS In this open-label, randomised, phase 3 trial, we enrolled patients from 17 German university hospitals who were aged 18-70 years, with newly diagnosed glioblastoma with methylated MGMT promoter, and a Karnofsky Performance Score of 70% and higher. Patients were randomly assigned (1:1) with a predefined SAS-generated randomisation list to standard temozolomide chemoradiotherapy (75 mg/m per day concomitant to radiotherapy [59-60 Gy] followed by six courses of temozolomide 150-200 mg/m per day on the first 5 days of the 4-week course) or to up to six courses of lomustine (100 mg/m on day 1) plus temozolomide (100-200 mg/m per day on days 2-6 of the 6-week course) in addition to radiotherapy (59-60 Gy). Because of the different schedules, patients and physicians were not masked to treatment groups. The primary endpoint was overall survival in the modified intention-to-treat population, comprising all randomly assigned patients who started their allocated chemotherapy. The prespecified test for overall survival differences was a log-rank test stratified for centre and recursive partitioning analysis class. The trial is registered with ClinicalTrials.gov, number NCT01149109. FINDINGS Between June 17, 2011, and April 8, 2014, 141 patients were randomly assigned to the treatment groups; 129 patients (63 in the temozolomide and 66 in the lomustine-temozolomide group) constituted the modified intention-to-treat population. Median overall survival was improved from 31•4 months (95% CI 27•7-47•1) with temozolomide to 48•1 months (32•6 months-not assessable) with lomustine-temozolomide (hazard ratio [HR] 0•60, 95% CI 0•35-1•03; p=0•0492 for log-rank analysis). A significant overall survival difference between groups was also found in a secondary analysis of the intention-to-treat population (n=141, HR 0•60, 95% CI 0•35-1•03; p=0•0432 for log-rank analysis). Adverse events of grade 3 or higher were observed in 32 (51%) of 63 patients in the temozolomide group and 39 (59%) of 66 patients in the lomustine-temozolomide group. There were no treatment-related deaths. INTERPRETATION Our results suggest that lomustine-temozolomide chemotherapy might improve survival compared with temozolomide standard therapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter. The findings should be interpreted with caution, owing to the small size of the trial. FUNDING German Federal Ministry of Education and Research.

Neuro-oncology, Nov 1, 2015

International Journal of Molecular Sciences, 2018

Glioblastoma remains a fatal diagnosis. Previous research has shown that metformin, which is an i... more Glioblastoma remains a fatal diagnosis. Previous research has shown that metformin, which is an inhibitor of complex I of the respiratory chain, may inhibit some brain tumor initiating cells (BTICs), albeit at dosages that are too high for clinical use. Here, we explored whether a combined treatment of metformin and diclofenac, which is a non-steroidal anti-inflammatory drug (NSAID) shown to inhibit glycolysis by interfering with lactate efflux, may lead to additive or even synergistic effects on BTICs (BTIC-8, -11, -13 and -18) and tumor cell lines (TCs, U87, and HTZ349). Therefore, we investigated the functional effects, including proliferation and migration, metabolic effects including oxygen consumption and extracellular lactate levels, and effects on the protein level, including signaling pathways. Functional investigation revealed synergistic anti-migratory and anti-proliferative effects of the combined treatment with metformin and diclofenac on BTICs and TCs. Signaling pathwa...

Current Pharmaceutical Biotechnology, 2011

ABSTRACT High-grade gliomas are the most common primary tumors in the central nervous system (CNS... more ABSTRACT High-grade gliomas are the most common primary tumors in the central nervous system (CNS) in adults. Despite efforts to improve treatment by combination therapies (neurosurgery, radio- and chemotherapy), high-grade glioma patients still have a grim prognosis, indicating an urgent need for new therapeutic approaches. The molecular processes of gliomagenesis are being unraveled, and novel targeted therapeutic strategies to defy high-grade gliomas are emerging. Transforming growth factor-beta (TGF-β), in particular the TGF-β2 isoform, has been identified as a key factor in the progression of malignant gliomas. TGF-β2, originally described as "glioblastoma-derived T-cell suppressor factor", is associated with the immuno-suppressed status of patients with glioblastoma, and is therefore responsible for loss of tumor immune surveillance. Elevated TGF-β2 levels in tumors and in the plasma of patients have been associated with advanced disease stage and poor prognosis. Consequently, a targeted strategy to modulate TGF-β2 signaling is highly promising. The antisense oligonucleotide trabedersen (AP 12009) that specifically blocks TGF-β2 mRNA will be the main focus of this review. In three phase I/II studies and a randomized, active-controlled dose-finding phase IIb study, trabedersen treatment of high-grade glioma patients with recurrent or refractory tumor disease led to long-lasting tumor responses and so far promising survival data. On the basis of these data the currently ongoing phase III study SAPHIRRE was initiated.

Current Medicinal Chemistry, 2008

Clinical Neuropathology, 2014

Polyarteritis nodosa (PAN) is a necrotizing vasculitis of small to-medium-sized vessels, rarely a... more Polyarteritis nodosa (PAN) is a necrotizing vasculitis of small to-medium-sized vessels, rarely associated with hematologic neoplasms. We report a 44-year-old man with a history of monoclonal gammopathy of undetermined significance (MGUS) who presented with rapidly progressing sensorimotor peripheral neuropathy. Two weeks after onset the patient developed severe acute acral and retinal ischemia. MR-angiography and nerve biopsy revealed a systemic necrotizing vasculitis (PAN type). At this time, bone marrow biopsy identified a smoldering multiple myeloma. Immediate immunosuppressive and anti-neoplastic treatment (steroids, immunoglobulins, bortezomib combined with cyclophosphamide followed by lenalidomide maintenance) resulted in a favorable clinical outcome. After 4 years, the patient is in good clinical condition with sustained partial remission from myeloma and without evidence of relapse of PAN. This is a remarkable case of a histologically confirmed peripheral neuropathy due to polyarteritis nodosa associated with progression of MGUS to multiple myeloma. Immediate diagnosis and combined immunosuppressive and anti-neoplastic treatment may improve the outcome of this potentially life-threatening clinical condition.

Clinical Chemistry, 2004

Background: Eph receptors and their ligands, the ephrins, represent a large class of cell-cell co... more Background: Eph receptors and their ligands, the ephrins, represent a large class of cell-cell communication molecules with well-defined developmental functions. Their role in healthy adult tissues and in human disease is still largely unknown, although diverse roles in carcinogenesis have been postulated. Methods: We established a set of fluorescent PCR probes and primers for the definition of individual gene expression profiles of 12 different Eph receptors and 8 ephrins in 13 different healthy tissues. The mRNA expression profiles were studied in human lung, colorectal, kidney, liver, and brain cancers. Results: The family of Eph receptors/ephrins was widely expressed in adult tissues with organ-site-specific patterns: EphB6 was highest in the thymus, compatible with an involvement in T-cell maturation. Brain and testis shared a unique pattern with EphA6, EphA8, and EphB1 being the most prominent. EphA7 had a high abundance in the kidney vasculature. Ephrin-A3 was up-regulated 26-fold in lung cancer, and EphB2 was up-regulated 9-fold in hepatocellular carcinoma. EphA8 was down-regulated in colon cancer, and EphA1/EphA8 was down-regulated in glioblastomas. Conclusion: Eph/Ephrin genes are widely expressed in all adult organs with certain organ-site-specific patterns. Because their function in adult tissues remains unknown, further analysis of their role in disease may disclose new insights beyond their well-defined meaning in development.

Chronobiology International, 2006

Seasonal distribution of birth rates was only recently described in patients with high-grade glio... more Seasonal distribution of birth rates was only recently described in patients with high-grade gliomas. We analyzed 501 cases from the database of a Regional Cancer Center in Bavaria to assess annual periodicity in the birth dates of glioma patients. Prior to analysis, the number of births per month was normalized [number of births x 100,000/total number of births in Germany] to obtain birth rates per month. The approximation of the time series data by a one-year cosine model found that the glioblastoma birth rate exhibits a statistically significant annual variation, with the peak rate in January. Vitamin intake, infections, and other as-yet-unknown factors and exposures during pre- and perinatal early life may contribute to the seasonality of birth rate in patients with brain tumors.

Cancer Research, 2008

The prognosis of patients suffering from glioblastoma (GBM) is dismal despite multimodal therapy.... more The prognosis of patients suffering from glioblastoma (GBM) is dismal despite multimodal therapy. Although chemotherapy with temozolomide may contain tumor growth for some months, invariable tumor recurrence suggests that cancer stem cells (CSC) maintaining these tumors persist. We have therefore investigated the effect of temozolomide on CD133 + and CD133 À GBM CSC lines. Although differentiated tumor cells constituting the bulk of all tumor cells were resistant to the cytotoxic effects of the substance, temozolomide induced a dose-and time-dependent decline of the stem cell subpopulation. Incubation with sublethal concentrations of temozolomide for 2 days completely depleted clonogenic tumor cells in vitro and substantially reduced tumorigenicity in vivo. In O 6 -methylguanine-DNA-methyltransferase (MGMT)-expressing CSC lines, this effect occurred at 10-fold higher doses compared with MGMT-negative CSC lines. Thus, temozolomide concentrations that are reached in patients were only sufficient to completely eliminate CSC in vitro from MGMTnegative but not from MGMT-positive tumors. Accordingly, our data strongly suggest that optimized temozolomide-based chemotherapeutic protocols might substantially improve the elimination of GBM stem cells and consequently prolong the survival of patients. [Cancer Res 2008;68(14):

Cancer Research, 2007

Although glioblastomas show the same histologic phenotype, biological hallmarks such as growth an... more Although glioblastomas show the same histologic phenotype, biological hallmarks such as growth and differentiation properties vary considerably between individual cases. To investigate whether different subtypes of glioblastomas might originate from different cells of origin, we cultured tumor cells from 22 glioblastomas under medium conditions favoring the growth of neural and cancer stem cells (CSC). Secondary glioblastoma (n = 7)-derived cells did not show any growth in the medium used, suggesting the absence of neural stem cell-like tumor cells. In contrast, 11/15 primary glioblastomas contained a significant CD133 + subpopulation that displayed neurosphere-like, nonadherent growth and asymmetrical cell divisions yielding cells expressing markers characteristic for all three neural lineages. Four of 15 cell lines derived from primary glioblastomas grew adherently in vitro and were driven by CD133 À tumor cells that fulfilled stem cell criteria. Both subtypes were similarly tumorigenic in nude mice in vivo. Clinically, CD133 À glioblastomas were characterized by a lower proliferation index, whereas glial fibrillary acidic protein staining was similar. GeneArray analysis revealed 117 genes to be differentially expressed by these two subtypes. Together, our data provide first evidence that CD133 + CSC maintain only a subset of primary glioblastomas. The remainder stems from previously unknown CD133 À tumor cells with apparent stem cell-like properties but distinct molecular profiles and growth characteristics in vitro and in vivo.

Cancer, 2003

BACKGROUND. Survival after first-line therapy is poor for patients with glioblastoma. The role of... more BACKGROUND. Survival after first-line therapy is poor for patients with glioblastoma. The role of second-line treatment for recurrent disease is controversial. The authors studied the outcome in a subset of patients with glioblastoma who were selected for an aggressive reintervention strategy at the time of progression. Their objectives were to improve patients' overall survival with sustained quality of life and to make comparisons with overall survival in unselected patients.

Cancer, 2004

BACKGROUND. Doxorubicin exhibits high efficacy in malignant glioma cell cultures.

Cancer, 2001

BACKGROUND. Resistance to chemotherapeutic agents and poor blood-brain barrier penetration are ma... more BACKGROUND. Resistance to chemotherapeutic agents and poor blood-brain barrier penetration are major limitations in the treatment of malignant glioma. To improve drug delivery across the blood-brain barrier, the authors used doxorubicin as liposomal encapsulated formulation (Caelyx, Scheringh-Plough, Munich, Germany) in therapy of recurrent malignant glioma.

Brain Pathology, 2008

High-grade oligodendroglial tumors, that is, anaplastic oligodendroglial tumors and glioblastomas... more High-grade oligodendroglial tumors, that is, anaplastic oligodendroglial tumors and glioblastomas with oligodendroglial component, differ significantly in terms of prognosis and response to chemotherapy. Differentiation might be difficult because the histological differences are vague and reliable markers are not established. We correlated the presence of putative cancer stem cells (CSC) in high-grade oligodendroglial tumors (WHO grades III and IV) with clinical outcome. Tumors with favorable prognosis neither contained CSC nor did they show CD133 expression. Tumor cells resembled lineage-restricted progenitor cells with limited proliferative capacity and differentiation profile. In contrast, CD133 expression and stem cell-like tumor cells characterized tumors with poor prognosis. They showed neurosphere-like growth, differentiated into cells of all neural lineages, and were tumorigenic in nude mice. In our series, CSC and expression of CD133 predicted the clinical course of disease better than the histological grading. To confirm these results, we retrospectively analyzed 36 high-grade oligodendroglial tumors. Again, CD133 expression indicated shorter survival and predicted clinical outcome more reliable than the histological assessment.

BMC Cancer, 2009

Background: Although Temozolomide is effective against glioblastoma, the prognosis remains dismal... more Background: Although Temozolomide is effective against glioblastoma, the prognosis remains dismal and new regimens with synergistic activity are sought for.

Biological Rhythm Research, 2005

ABSTRACT

Annals of Oncology, 2011

Background: Sagopilone (ZK 219477), a lipophylic and synthetic analog of epothilone B, that cross... more Background: Sagopilone (ZK 219477), a lipophylic and synthetic analog of epothilone B, that crosses the blood-brain barrier has demonstrated preclinical activity in glioma models.

Aktuelle Neurologie, 2008