Arnulf Mayer - Academia.edu (original) (raw)

Papers by Arnulf Mayer

Cancers, 2020

Following the introduction of immune checkpoint inhibitors, a substantial prolongation of the ove... more Following the introduction of immune checkpoint inhibitors, a substantial prolongation of the overall survival has been achieved for many patients with multiple brain metastases from melanoma. However, heterogeneity between individual tumor responses is incompletely understood. In order to determine the impact of the individual tumor phenotype on the prognosis of melanoma patients, we examined surgical sections from 33 patients who were treated with radiotherapy (whole-brain radiotherapy, WBRT, stereotactic radiotherapy, STX, or both) and Ipilimumab. We analyzed multiplex staining of the hypoxia marker GLUT-1, the adenosine (ADO)-associated enzymes CD73 and CD39, and CD8, a marker of cytotoxic T lymphocytes (CTL) on a single-cell basis using QuPath. Additionally, the MOSAIC interaction analysis algorithm was used to explore the hypothesis that CTL systematically avoid GLUT-1high tumor areas. Our results revealed, that a strong GLUT-1 expression, low numbers of CTL, or exclusion of C...

Advances in experimental medicine and biology

Tumor hypoxia is a hallmark of solid malignant tumor growth, profoundly influences malignant prog... more Tumor hypoxia is a hallmark of solid malignant tumor growth, profoundly influences malignant progression and contributes to the development of therapeutic resistance. Pathogenesis of tumor hypoxia is multifactorial, with contributions from both acute and chronic factors. Spatial distribution of hypoxia within tumors is markedly heterogeneous and often changes over time, e.g., during a course of radiotherapy. Substantial changes in the oxygenation status can occur within the distance of a few cell layers, explaining the inability of currently used molecular imaging techniques to adequately assess this crucial trait. Due to the possible importance of tumor hypoxia for clinical decision-making, there is a great demand for molecular tools which may provide the necessary resolution down to the single cell level. Exogenous and endogenous markers of tumor hypoxia have been investigated for this purpose. Their potential use may be greatly enhanced by multiparametric in situ methods in exper...

Oncotarget, Jan 26, 2017

High-grade neuroepithelial tumor of the central nervous system with BCOR alteration (HGNET-BCOR) ... more High-grade neuroepithelial tumor of the central nervous system with BCOR alteration (HGNET-BCOR) is a rare, highly malignant tumor. At the time of this publication, no standard protocol exists to treat this tumor entity. In this work, we tested the responsiveness of the primary culture PhKh1 derived from tumor tissue from a pediatric HGNET-BCOR patient (P1) to inhibitors of the Sonic hedgehog pathway combined with radiation. The SMO inhibitors vismodegib and itraconazole had low effect on the proliferation of the PhKh1 cells. However, the GLI inhibitor arsenic trioxide reduced the expression of GLI target genes in the PhKh1 cells and in combination with radiotherapy significantly decreased their clonogenic potential. PhKh1 cells resistant to arsenic trioxide were characterized by the overexpression of molecular chaperones. We combined arsenic trioxide and radiation in the relapse therapy protocol of P1, achieving complete remission after seven weeks. Clinical remission lasted for si...

International Journal of Oncology, 2010

Perturbation of the normal tissue architecture in solid malignant tumors is perceived to be the c... more Perturbation of the normal tissue architecture in solid malignant tumors is perceived to be the consequence of actively migrating cancer cells which invade the adjacent normal host tissue. The opposite, invasion of cancer cell clusters by a vascularized stroma, has not been considered. The latter process should, however, be expected to occur since the hypoxic cores of tumor cell aggregates, under the control of HIF-1, are known to secrete cytokines (e.g., bFGF, VEGF) which attract fibroblasts and induce blood vessel formation. In this study, the expression of glucose transporter (GLUT)-1, a major HIF-1 target gene, was examined in 51 squamous cell carcinomas of the uterine cervix by immunohistochemistry to identify the localization of hypoxic tumor cell areas. The relationship of the expression pattern of GLUT-1 with the localization and morphology of the tumor stroma was analyzed. We identified three recurrent histological signs which represent strong evidence in favor of an invasion of solid tumor masses by actively migrating stromal cells. According to our findings, the histological structure of squamous cell carcinomas of the uterine cervix may in part result from the interplay between the inherent tendency of neoplastic epithelial cells to expand in the form of coherent aggregates and the fragmentation of these aggregates by invading, finger-or wedge-like stromal protrusions which carry new blood vessels, driven by gradients of hypoxia-induced pro-angiogenic, pro-migratory and growth-promoting molecules emanating from the hypoxic core.

Annals of translational medicine, 2015

Advances in experimental medicine and biology, 2016

Systematic studies on the oxygenation status of solid tumors have shown that the development of h... more Systematic studies on the oxygenation status of solid tumors have shown that the development of hypoxic/anoxic tissue subvolumes is a pathophysiological trait in a wide range of human malignancies. As a result of this characteristic property, adenosine (ADO) accumulation (range: 50-100 μM) occurs caused by intra- and extracellular generation of ADO. Extracellular nucleotide catabolism by hypoxia-/HIF-1α-sensitive, membrane-associated ecto- 5'- nucleotidases most probably is the major source of ADO in the halo of cancer cells upon specific genetic alterations taking place during tumor growth. Extracellular ADO can act through autocrine and paracrine pathways following receptor-binding and involving different intracellular signalling cascades. Hypoxia-driven receptor activation can lead to a broad spectrum of strong immune-suppressive properties facilitating tumor escape from immune control (e.g., inhibition of CD4(+), CD8(+), NK and dendritic cells, stimulation of Treg cells). In...

Future oncology (London, England), Jan 30, 2015

The introduction of small molecule BRAF(V600) kinase inhibitors represents a milestone in the tar... more The introduction of small molecule BRAF(V600) kinase inhibitors represents a milestone in the targeted therapy of patients with metastatic melanoma by a significant increase in therapeutic efficacy in terms of overall and progression-free survival compared with conventional chemotherapy. Beside BRAF(V600) inhibitor treatment, radiotherapy is a further mainstay for the therapy of metastatic melanoma and thus a concomitant or sequential application of BRAF(V600) inhibitors and radiotherapy is inevitable. Recent reports show a significant radiosensitization of the irradiated healthy tissue in patients with melanoma after the combination of radiotherapy and BRAF(V600) inhibitors, evoking concern in clinical practice. We review interactions of BRAF(V600) inhibitors and radiation with regard to antitumor effects and an increased radiotoxicity in the healthy tissue.

Strahlentherapie und Onkologie

Strahlentherapie und Onkologie, 2015

It is currently unclear whether adjuvant therapy for WHO grade III anaplastic astrocytomas (AA) s... more It is currently unclear whether adjuvant therapy for WHO grade III anaplastic astrocytomas (AA) should be carried out as combined chemoradiotherapy with temozolomide (TMZ)--analogous to the approach for glioblastoma multiforme--or as radiotherapy (RT) alone. A retrospective analysis of data from 90 patients with AA, who were treated between November 1997 and February 2014. Assessment of overall (OS) and progression-free survival (PFS) was performed according to treatment categories: (1) 50%, RT + TMZ according to protocol, (2) 11%, RT + TMZ with dose reduction, (3) 26%, RT alone, and (4) 13%, individualized, primarily palliative therapy. No dose reduction was necessary in the RT alone group. Median OS was 85, 69, and 43 months for treatment categories 1/2, 3, and 4, respectively. These differences were not statistically significant. PFS was 35, 29, 48, and 33 months for categories 1, 2, 3, and 4, respectively; again without significant differences between categories. In a subgroup of 39 patients with known IDH1 R132H status, the presence of this mutation correlated with significantly longer OS (p = 0.01) and PFS (p = 0.002). Complete or partial tumor resection and younger age also correlated with a significantly better prognosis, and this influence persisted in multivariate analysis. In the IDH1 R132H subgroup analysis, only this marker retained an independent prognostic value. A general superiority of combined chemoradiotherapy compared to RT alone could not be demonstrated. Biomarkers for predicting the benefits of combination therapy using RT and TMZ are needed for patients with AA.

Tumori, Jan 8, 2015

This retrospective analysis aimed to evaluate the stability of spinal metastases in malignant mel... more This retrospective analysis aimed to evaluate the stability of spinal metastases in malignant melanoma patients following radiotherapy (RT), and to assess prognostic factors for survival. Forty-one patients with malignant melanoma and osteolytic spinal bone metastases were irradiated at the university clinics of Heidelberg and Mainz between July 2003 and October 2013. Three and six months after palliative RT, only 20 and 15 patients, respectively, were still alive and were therefore assessed for spinal stability using the Taneichi score based on CT imaging. Additionally, overall survival (OS) and bone survival (BS) rates as well as prognostic factors for BS were evaluated for all study patients. Before RT, 19 patients (46.3%) were rated unstable. In the surviving patients, none of the unstable metastases were classified as stable 6 months after RT. Five-year OS was 23.3% and median BS was 4 months (range 0.5-29.8). Accordingly, only 36.6% of the patients were still alive 6 months af...

BMC cancer, Jan 12, 2014

Strongly increased uptake of glucose is a hallmark of solid malignant tumors. This phenotype can ... more Strongly increased uptake of glucose is a hallmark of solid malignant tumors. This phenotype can be triggered by hypoxia-induced gene expression changes or can occur independently of hypoxia as a consequence of malignant transformation itself, and is often referred to as the Warburg effect. The glycolytic phenotype has been associated with malignant progression and resistance to radio- and chemotherapy. We have chosen squamous cell carcinomas of the vulva (SCC-V) as a representative solid tumor entity to study the central players of this pathway, namely glucose transporter (GLUT)-1, carbonic anhydrase (CA) IX, hexokinase (HK)-2 and pyruvate kinase (PK)-M2, and have investigated their relationships to tumor microvessels (CD34, αSMA) and proliferation (Ki67). Expression of these proteins was analyzed in 38 SCC-Vs, 5 vulvar dysplasias and 10 non-neoplastic squamous epithelia of the vulva using multiparametric immunohistochemistry in registered serial sections (MIRSS). Expression of GLU...

Advances in experimental medicine and biology, 2011

Based on studies performed with a selected mouse monoclonal anti-transketolase- like (TKTL)-1 ant... more Based on studies performed with a selected mouse monoclonal anti-transketolase- like (TKTL)-1 antibody (clone JFC12T10), overexpression of TKTL-1 has been shown to be correlated with poor survival and increased metastatic spread in several human tumor entities. Since the clinical aggressiveness mediated by TKTL-1 has been partially related to resistance to hypoxia,we originally aimed to explore the influence of hypoxia on the expression of TKTL-1. Unexpectedly, results of our experiments indicated that the antibody clone JFC12T10 lacks target specificity. Since the majority of data on the role of TKTL-1 in human cancer is based upon studies performed with this antibody clone, we subsequently re-evaluated the expression of TKTL-1 in six different cancer cell lines (HeLa, MCF-7, A549, HT-1080, M21 and TF-1). Using RT-PCR and consecutive sequence analysis, we show that transketolase (TKT), not TKTL-1, is the dominant isoform of transketolases in the cell lines analyzed. Our data argue ...

Advances in experimental medicine and biology, 2011

In malignant urogenital tumors, tissue oxygenation is compromised and very heterogeneous,with ste... more In malignant urogenital tumors, tissue oxygenation is compromised and very heterogeneous,with steep and fluctuating spatio-temporal oxygen gradients signaling a complex instability in tumor oxygenation (complex "4D-heterogeneity"). Tumor hypoxia is highly dynamic, and rapidly changing pO(2) gradients may be key factors driving hypoxia-dependent adaptive processes leading to malignant progression. The grand median oxygen tension in malignant urogenital tumors is 7-11 mmHg. In contrast, benign leiomyomas of the uterus are severely, but uniformly, hypoxic with only shallow oxygen gradients ("static hypoxia"). In these benign tumors, the median pO(2) is 1 mmHg and signs of hypoxia-driven processes are missing.

Advances in experimental medicine and biology, 2010

Results from our laboratory have put a question mark on the existence of a direct quantitative re... more Results from our laboratory have put a question mark on the existence of a direct quantitative relationship between tumor hypoxia and HIF-mediated protein expression in cancers of the uterine cervix. In the present study, this subject has been further explored by the analysis of HIF-related marker expression in a benign tumor entity - uterine leiomyomas - using immunohistochemistry, western blotting and RT-PCR. The oxygenation status of 17 leiomyomas was assessed by means of intraoperative polarographic needle electrode measurements. Results show that these tumors are severely and uniformly hypoxic, but do not induce HIF-1alpha, HIF-2alpha, glucose transporter (GLUT)-1 or carbonic anhydrase (CA) IX. Furthermore, this downregulation of the HIF-system was not caused by an overexpression of the hypoxia-inducible prolyl hydroxylase domain proteins (PHDs) 2 and 3. Compared with normal myometrium, leiomyomas also show a poorer vascularization. Conversely, leiomyosarcomas show abundant exp...

ABSTRACT Adipose tissue has emerged as an important endocrine regulator by secreting hormones ref... more ABSTRACT Adipose tissue has emerged as an important endocrine regulator by secreting hormones referred to as adipokines. Recent studies showed that adipose tissue considerably responds to hypoxia. Although the impact of white adipose tissue on regulative processes is established, the importance of brown adipose tissue in adults has emerged just recently. Brown (BA) and white adipocytes (WA) were cultured either in the presence of chemical hypoxia-mimetics or under hypoxic atmosphere of 1% oxygen. Expression of hypoxia-inducible factor 1α (HIF- 1α) was assessed by western blot. The expression levels of several known HIF-1α-regulated proteins [vascular endothelial growth factor (VEGF), leptin, adiponectin, and angiotensinogen (AGT)] were quantified. Both chemical hypoxia-mimetics and physical hypoxia led to increased nuclear HIF-1α expression and to decreased cytoplasmatic adiponectin in both cell types. In contrast, VEGF and AGT expression did not change upon hypoxic stimulation. Leptin was exclusively detectable in WA, while uncoupling-protein 1 (UCP-1) was expressed in BA only. WA and BA are sensitive to hypoxia, in which HIF-1α expression is induced. Protein expression of adiponectin is hypoxia-dependent, whereas AGT, VEGF, leptin, and UCP-1 expression do not change secondary to hypoxia.

Strahlentherapie und Onkologie, 2014

Zeitschrift für Gastroenterologie, 2010

Transfusion Clinique et Biologique, 2005

In locally advanced solid tumors, oxygen (O 2) delivery is frequently reduced or even abolished. ... more In locally advanced solid tumors, oxygen (O 2) delivery is frequently reduced or even abolished. This is due to abnormalities of the tumor microvasculature, adverse diffusion geometries, and tumor-associated and/or therapy-induced anemia. Up to 50-60% of locally advanced solid tumors may exhibit hypoxic and/or anoxic tissue areas that are heterogeneously distributed within the tumor mass. In approximately 30% of pretreatment patients, a decreased O 2 transport capacity of the blood as a result of tumor-associated anemia can greatly contribute to the development of tumor hypoxia. While normal tissues can compensate for this O 2 deficiency status by a rise in blood flow rate, locally advanced tumors (or at least larger tumor areas) cannot adequately counteract the restriction in O 2 supply and thus the development of hypoxia. Hypoxia-induced alteration in gene expression and thus in the proteome (<1% O 2 , or <7 mmHg), and/or genome changes (<0.1% O 2 , or <0.7 mmHg) may promote tumor progression via mechanisms enabling cells to overcome nutritive deprivation, to escape from the hostile metabolic microenvironment and to favor unrestricted growth. Sustained hypoxia may thus lead to cellular changes resulting in a more clinically aggressive phenotype. In addition, hypoxia is known to directly or indirectly confer resistance to X-and c-radiation, and some chemotherapies leading to treatment failures. Whereas strong evidence has accumulated that hypoxia plays a pivotal role in tumor progression and acquired treatment resistance, the mechanism(s) by which treatment efficacy and survival may be compromised by anemia (independent of hypoxia) are not fully understood.

The International Journal of Biochemistry & Cell Biology, 2012

Contrary to conventional belief, the mitochondria of most cancer cells usually function normally,... more Contrary to conventional belief, the mitochondria of most cancer cells usually function normally, i.e., their respiratory capacity is not fundamentally impaired as compared to normal cells. Strong evidence against the misconception of mitochondrial dysfunction is provided by in vivo data clearly showing that O 2 availability is the major determinant of the O 2 consumption rate of cancer cells, independent of the means for increasing availability (e.g., by increasing blood flow or by elevating arterial O 2 content, the latter being accomplished either by an increase in the hemoglobin level and/or arterial hyperoxia). Additional support against the Warburg effect in its original concept comes from normal temperature coefficients (Q 10) for O 2 consumption rates of malignant cells. Thus, the Warburg hypothesis postulating that mitochondrial dysfunction in cancer cells forces them to generate energy with a poor ATP yield through glycolysis appears to be elusive. Instead, due to a "reprogrammed" cancer cell metabolism, glycolysis is used to produce intermediates as building blocks for various biosynthetic pathways of cancer cells.

Strahlentherapie und Onkologie, 2002

Background: Tumor hypoxia has been linked to the development of treatment resistance, tumor progr... more Background: Tumor hypoxia has been linked to the development of treatment resistance, tumor progression, and poor prognosis. Since anemia is a major causative factor for the development of hypoxia, the association between blood hemoglobin concentration (cHb) and tumor oxygenation was examined in this study. Patients and Methods: Pretreatment O 2 tension (pO 2) measurements were performed in 59 primary carcinomas of the uterine cervix in which a stringent histopathologic examination of the electrode tracks was mandatory in order to exclude measurements in necrotic, stromal or normal cervical tissue. In addition, pO 2 readings in twelve primary cancers and 17 local recurrences of vulvar cancers were included in this study. cHb was determined at the time of pO 2 measurements. Results: Data presented clearly show that an optimal Hb level with regard to the median pO 2 values of cervical and vulvar cancers should prevail at cHb values of between 12 and 14 g/dl (7.45-8.69 mmol/l). In anemic patients (cHb < 12 g/dl), the deterioration of the tumor oxygenation status can be explained by a reduced O 2 transport capacity. At cHb values > 14 g/dl, a worsening of the tumor oxygenation is apparent, most probably due to a drop in perfusion following a drastic increase in viscous resistance to flow. This pathogenetic mechanism is thought to counteract and finally to abrogate the high O 2 transport capacity in this cHb range. Conclusions: This study suggests that cHb values of between 12 and 14 g/dl are optimal with regard to the oxygenation status in the tumor entities investigated, a finding which may have far-reaching implications in the clinical setting.

Cancers, 2020

Following the introduction of immune checkpoint inhibitors, a substantial prolongation of the ove... more Following the introduction of immune checkpoint inhibitors, a substantial prolongation of the overall survival has been achieved for many patients with multiple brain metastases from melanoma. However, heterogeneity between individual tumor responses is incompletely understood. In order to determine the impact of the individual tumor phenotype on the prognosis of melanoma patients, we examined surgical sections from 33 patients who were treated with radiotherapy (whole-brain radiotherapy, WBRT, stereotactic radiotherapy, STX, or both) and Ipilimumab. We analyzed multiplex staining of the hypoxia marker GLUT-1, the adenosine (ADO)-associated enzymes CD73 and CD39, and CD8, a marker of cytotoxic T lymphocytes (CTL) on a single-cell basis using QuPath. Additionally, the MOSAIC interaction analysis algorithm was used to explore the hypothesis that CTL systematically avoid GLUT-1high tumor areas. Our results revealed, that a strong GLUT-1 expression, low numbers of CTL, or exclusion of C...

Advances in experimental medicine and biology

Tumor hypoxia is a hallmark of solid malignant tumor growth, profoundly influences malignant prog... more Tumor hypoxia is a hallmark of solid malignant tumor growth, profoundly influences malignant progression and contributes to the development of therapeutic resistance. Pathogenesis of tumor hypoxia is multifactorial, with contributions from both acute and chronic factors. Spatial distribution of hypoxia within tumors is markedly heterogeneous and often changes over time, e.g., during a course of radiotherapy. Substantial changes in the oxygenation status can occur within the distance of a few cell layers, explaining the inability of currently used molecular imaging techniques to adequately assess this crucial trait. Due to the possible importance of tumor hypoxia for clinical decision-making, there is a great demand for molecular tools which may provide the necessary resolution down to the single cell level. Exogenous and endogenous markers of tumor hypoxia have been investigated for this purpose. Their potential use may be greatly enhanced by multiparametric in situ methods in exper...

Oncotarget, Jan 26, 2017

High-grade neuroepithelial tumor of the central nervous system with BCOR alteration (HGNET-BCOR) ... more High-grade neuroepithelial tumor of the central nervous system with BCOR alteration (HGNET-BCOR) is a rare, highly malignant tumor. At the time of this publication, no standard protocol exists to treat this tumor entity. In this work, we tested the responsiveness of the primary culture PhKh1 derived from tumor tissue from a pediatric HGNET-BCOR patient (P1) to inhibitors of the Sonic hedgehog pathway combined with radiation. The SMO inhibitors vismodegib and itraconazole had low effect on the proliferation of the PhKh1 cells. However, the GLI inhibitor arsenic trioxide reduced the expression of GLI target genes in the PhKh1 cells and in combination with radiotherapy significantly decreased their clonogenic potential. PhKh1 cells resistant to arsenic trioxide were characterized by the overexpression of molecular chaperones. We combined arsenic trioxide and radiation in the relapse therapy protocol of P1, achieving complete remission after seven weeks. Clinical remission lasted for si...

International Journal of Oncology, 2010

Perturbation of the normal tissue architecture in solid malignant tumors is perceived to be the c... more Perturbation of the normal tissue architecture in solid malignant tumors is perceived to be the consequence of actively migrating cancer cells which invade the adjacent normal host tissue. The opposite, invasion of cancer cell clusters by a vascularized stroma, has not been considered. The latter process should, however, be expected to occur since the hypoxic cores of tumor cell aggregates, under the control of HIF-1, are known to secrete cytokines (e.g., bFGF, VEGF) which attract fibroblasts and induce blood vessel formation. In this study, the expression of glucose transporter (GLUT)-1, a major HIF-1 target gene, was examined in 51 squamous cell carcinomas of the uterine cervix by immunohistochemistry to identify the localization of hypoxic tumor cell areas. The relationship of the expression pattern of GLUT-1 with the localization and morphology of the tumor stroma was analyzed. We identified three recurrent histological signs which represent strong evidence in favor of an invasion of solid tumor masses by actively migrating stromal cells. According to our findings, the histological structure of squamous cell carcinomas of the uterine cervix may in part result from the interplay between the inherent tendency of neoplastic epithelial cells to expand in the form of coherent aggregates and the fragmentation of these aggregates by invading, finger-or wedge-like stromal protrusions which carry new blood vessels, driven by gradients of hypoxia-induced pro-angiogenic, pro-migratory and growth-promoting molecules emanating from the hypoxic core.

Annals of translational medicine, 2015

Advances in experimental medicine and biology, 2016

Systematic studies on the oxygenation status of solid tumors have shown that the development of h... more Systematic studies on the oxygenation status of solid tumors have shown that the development of hypoxic/anoxic tissue subvolumes is a pathophysiological trait in a wide range of human malignancies. As a result of this characteristic property, adenosine (ADO) accumulation (range: 50-100 μM) occurs caused by intra- and extracellular generation of ADO. Extracellular nucleotide catabolism by hypoxia-/HIF-1α-sensitive, membrane-associated ecto- 5'- nucleotidases most probably is the major source of ADO in the halo of cancer cells upon specific genetic alterations taking place during tumor growth. Extracellular ADO can act through autocrine and paracrine pathways following receptor-binding and involving different intracellular signalling cascades. Hypoxia-driven receptor activation can lead to a broad spectrum of strong immune-suppressive properties facilitating tumor escape from immune control (e.g., inhibition of CD4(+), CD8(+), NK and dendritic cells, stimulation of Treg cells). In...

Future oncology (London, England), Jan 30, 2015

The introduction of small molecule BRAF(V600) kinase inhibitors represents a milestone in the tar... more The introduction of small molecule BRAF(V600) kinase inhibitors represents a milestone in the targeted therapy of patients with metastatic melanoma by a significant increase in therapeutic efficacy in terms of overall and progression-free survival compared with conventional chemotherapy. Beside BRAF(V600) inhibitor treatment, radiotherapy is a further mainstay for the therapy of metastatic melanoma and thus a concomitant or sequential application of BRAF(V600) inhibitors and radiotherapy is inevitable. Recent reports show a significant radiosensitization of the irradiated healthy tissue in patients with melanoma after the combination of radiotherapy and BRAF(V600) inhibitors, evoking concern in clinical practice. We review interactions of BRAF(V600) inhibitors and radiation with regard to antitumor effects and an increased radiotoxicity in the healthy tissue.

Strahlentherapie und Onkologie

Strahlentherapie und Onkologie, 2015

It is currently unclear whether adjuvant therapy for WHO grade III anaplastic astrocytomas (AA) s... more It is currently unclear whether adjuvant therapy for WHO grade III anaplastic astrocytomas (AA) should be carried out as combined chemoradiotherapy with temozolomide (TMZ)--analogous to the approach for glioblastoma multiforme--or as radiotherapy (RT) alone. A retrospective analysis of data from 90 patients with AA, who were treated between November 1997 and February 2014. Assessment of overall (OS) and progression-free survival (PFS) was performed according to treatment categories: (1) 50%, RT + TMZ according to protocol, (2) 11%, RT + TMZ with dose reduction, (3) 26%, RT alone, and (4) 13%, individualized, primarily palliative therapy. No dose reduction was necessary in the RT alone group. Median OS was 85, 69, and 43 months for treatment categories 1/2, 3, and 4, respectively. These differences were not statistically significant. PFS was 35, 29, 48, and 33 months for categories 1, 2, 3, and 4, respectively; again without significant differences between categories. In a subgroup of 39 patients with known IDH1 R132H status, the presence of this mutation correlated with significantly longer OS (p = 0.01) and PFS (p = 0.002). Complete or partial tumor resection and younger age also correlated with a significantly better prognosis, and this influence persisted in multivariate analysis. In the IDH1 R132H subgroup analysis, only this marker retained an independent prognostic value. A general superiority of combined chemoradiotherapy compared to RT alone could not be demonstrated. Biomarkers for predicting the benefits of combination therapy using RT and TMZ are needed for patients with AA.

Tumori, Jan 8, 2015

This retrospective analysis aimed to evaluate the stability of spinal metastases in malignant mel... more This retrospective analysis aimed to evaluate the stability of spinal metastases in malignant melanoma patients following radiotherapy (RT), and to assess prognostic factors for survival. Forty-one patients with malignant melanoma and osteolytic spinal bone metastases were irradiated at the university clinics of Heidelberg and Mainz between July 2003 and October 2013. Three and six months after palliative RT, only 20 and 15 patients, respectively, were still alive and were therefore assessed for spinal stability using the Taneichi score based on CT imaging. Additionally, overall survival (OS) and bone survival (BS) rates as well as prognostic factors for BS were evaluated for all study patients. Before RT, 19 patients (46.3%) were rated unstable. In the surviving patients, none of the unstable metastases were classified as stable 6 months after RT. Five-year OS was 23.3% and median BS was 4 months (range 0.5-29.8). Accordingly, only 36.6% of the patients were still alive 6 months af...

BMC cancer, Jan 12, 2014

Strongly increased uptake of glucose is a hallmark of solid malignant tumors. This phenotype can ... more Strongly increased uptake of glucose is a hallmark of solid malignant tumors. This phenotype can be triggered by hypoxia-induced gene expression changes or can occur independently of hypoxia as a consequence of malignant transformation itself, and is often referred to as the Warburg effect. The glycolytic phenotype has been associated with malignant progression and resistance to radio- and chemotherapy. We have chosen squamous cell carcinomas of the vulva (SCC-V) as a representative solid tumor entity to study the central players of this pathway, namely glucose transporter (GLUT)-1, carbonic anhydrase (CA) IX, hexokinase (HK)-2 and pyruvate kinase (PK)-M2, and have investigated their relationships to tumor microvessels (CD34, αSMA) and proliferation (Ki67). Expression of these proteins was analyzed in 38 SCC-Vs, 5 vulvar dysplasias and 10 non-neoplastic squamous epithelia of the vulva using multiparametric immunohistochemistry in registered serial sections (MIRSS). Expression of GLU...

Advances in experimental medicine and biology, 2011

Based on studies performed with a selected mouse monoclonal anti-transketolase- like (TKTL)-1 ant... more Based on studies performed with a selected mouse monoclonal anti-transketolase- like (TKTL)-1 antibody (clone JFC12T10), overexpression of TKTL-1 has been shown to be correlated with poor survival and increased metastatic spread in several human tumor entities. Since the clinical aggressiveness mediated by TKTL-1 has been partially related to resistance to hypoxia,we originally aimed to explore the influence of hypoxia on the expression of TKTL-1. Unexpectedly, results of our experiments indicated that the antibody clone JFC12T10 lacks target specificity. Since the majority of data on the role of TKTL-1 in human cancer is based upon studies performed with this antibody clone, we subsequently re-evaluated the expression of TKTL-1 in six different cancer cell lines (HeLa, MCF-7, A549, HT-1080, M21 and TF-1). Using RT-PCR and consecutive sequence analysis, we show that transketolase (TKT), not TKTL-1, is the dominant isoform of transketolases in the cell lines analyzed. Our data argue ...

Advances in experimental medicine and biology, 2011

In malignant urogenital tumors, tissue oxygenation is compromised and very heterogeneous,with ste... more In malignant urogenital tumors, tissue oxygenation is compromised and very heterogeneous,with steep and fluctuating spatio-temporal oxygen gradients signaling a complex instability in tumor oxygenation (complex "4D-heterogeneity"). Tumor hypoxia is highly dynamic, and rapidly changing pO(2) gradients may be key factors driving hypoxia-dependent adaptive processes leading to malignant progression. The grand median oxygen tension in malignant urogenital tumors is 7-11 mmHg. In contrast, benign leiomyomas of the uterus are severely, but uniformly, hypoxic with only shallow oxygen gradients ("static hypoxia"). In these benign tumors, the median pO(2) is 1 mmHg and signs of hypoxia-driven processes are missing.

Advances in experimental medicine and biology, 2010

Results from our laboratory have put a question mark on the existence of a direct quantitative re... more Results from our laboratory have put a question mark on the existence of a direct quantitative relationship between tumor hypoxia and HIF-mediated protein expression in cancers of the uterine cervix. In the present study, this subject has been further explored by the analysis of HIF-related marker expression in a benign tumor entity - uterine leiomyomas - using immunohistochemistry, western blotting and RT-PCR. The oxygenation status of 17 leiomyomas was assessed by means of intraoperative polarographic needle electrode measurements. Results show that these tumors are severely and uniformly hypoxic, but do not induce HIF-1alpha, HIF-2alpha, glucose transporter (GLUT)-1 or carbonic anhydrase (CA) IX. Furthermore, this downregulation of the HIF-system was not caused by an overexpression of the hypoxia-inducible prolyl hydroxylase domain proteins (PHDs) 2 and 3. Compared with normal myometrium, leiomyomas also show a poorer vascularization. Conversely, leiomyosarcomas show abundant exp...

ABSTRACT Adipose tissue has emerged as an important endocrine regulator by secreting hormones ref... more ABSTRACT Adipose tissue has emerged as an important endocrine regulator by secreting hormones referred to as adipokines. Recent studies showed that adipose tissue considerably responds to hypoxia. Although the impact of white adipose tissue on regulative processes is established, the importance of brown adipose tissue in adults has emerged just recently. Brown (BA) and white adipocytes (WA) were cultured either in the presence of chemical hypoxia-mimetics or under hypoxic atmosphere of 1% oxygen. Expression of hypoxia-inducible factor 1α (HIF- 1α) was assessed by western blot. The expression levels of several known HIF-1α-regulated proteins [vascular endothelial growth factor (VEGF), leptin, adiponectin, and angiotensinogen (AGT)] were quantified. Both chemical hypoxia-mimetics and physical hypoxia led to increased nuclear HIF-1α expression and to decreased cytoplasmatic adiponectin in both cell types. In contrast, VEGF and AGT expression did not change upon hypoxic stimulation. Leptin was exclusively detectable in WA, while uncoupling-protein 1 (UCP-1) was expressed in BA only. WA and BA are sensitive to hypoxia, in which HIF-1α expression is induced. Protein expression of adiponectin is hypoxia-dependent, whereas AGT, VEGF, leptin, and UCP-1 expression do not change secondary to hypoxia.

Strahlentherapie und Onkologie, 2014

Zeitschrift für Gastroenterologie, 2010

Transfusion Clinique et Biologique, 2005

In locally advanced solid tumors, oxygen (O 2) delivery is frequently reduced or even abolished. ... more In locally advanced solid tumors, oxygen (O 2) delivery is frequently reduced or even abolished. This is due to abnormalities of the tumor microvasculature, adverse diffusion geometries, and tumor-associated and/or therapy-induced anemia. Up to 50-60% of locally advanced solid tumors may exhibit hypoxic and/or anoxic tissue areas that are heterogeneously distributed within the tumor mass. In approximately 30% of pretreatment patients, a decreased O 2 transport capacity of the blood as a result of tumor-associated anemia can greatly contribute to the development of tumor hypoxia. While normal tissues can compensate for this O 2 deficiency status by a rise in blood flow rate, locally advanced tumors (or at least larger tumor areas) cannot adequately counteract the restriction in O 2 supply and thus the development of hypoxia. Hypoxia-induced alteration in gene expression and thus in the proteome (<1% O 2 , or <7 mmHg), and/or genome changes (<0.1% O 2 , or <0.7 mmHg) may promote tumor progression via mechanisms enabling cells to overcome nutritive deprivation, to escape from the hostile metabolic microenvironment and to favor unrestricted growth. Sustained hypoxia may thus lead to cellular changes resulting in a more clinically aggressive phenotype. In addition, hypoxia is known to directly or indirectly confer resistance to X-and c-radiation, and some chemotherapies leading to treatment failures. Whereas strong evidence has accumulated that hypoxia plays a pivotal role in tumor progression and acquired treatment resistance, the mechanism(s) by which treatment efficacy and survival may be compromised by anemia (independent of hypoxia) are not fully understood.

The International Journal of Biochemistry & Cell Biology, 2012

Contrary to conventional belief, the mitochondria of most cancer cells usually function normally,... more Contrary to conventional belief, the mitochondria of most cancer cells usually function normally, i.e., their respiratory capacity is not fundamentally impaired as compared to normal cells. Strong evidence against the misconception of mitochondrial dysfunction is provided by in vivo data clearly showing that O 2 availability is the major determinant of the O 2 consumption rate of cancer cells, independent of the means for increasing availability (e.g., by increasing blood flow or by elevating arterial O 2 content, the latter being accomplished either by an increase in the hemoglobin level and/or arterial hyperoxia). Additional support against the Warburg effect in its original concept comes from normal temperature coefficients (Q 10) for O 2 consumption rates of malignant cells. Thus, the Warburg hypothesis postulating that mitochondrial dysfunction in cancer cells forces them to generate energy with a poor ATP yield through glycolysis appears to be elusive. Instead, due to a "reprogrammed" cancer cell metabolism, glycolysis is used to produce intermediates as building blocks for various biosynthetic pathways of cancer cells.

Strahlentherapie und Onkologie, 2002

Background: Tumor hypoxia has been linked to the development of treatment resistance, tumor progr... more Background: Tumor hypoxia has been linked to the development of treatment resistance, tumor progression, and poor prognosis. Since anemia is a major causative factor for the development of hypoxia, the association between blood hemoglobin concentration (cHb) and tumor oxygenation was examined in this study. Patients and Methods: Pretreatment O 2 tension (pO 2) measurements were performed in 59 primary carcinomas of the uterine cervix in which a stringent histopathologic examination of the electrode tracks was mandatory in order to exclude measurements in necrotic, stromal or normal cervical tissue. In addition, pO 2 readings in twelve primary cancers and 17 local recurrences of vulvar cancers were included in this study. cHb was determined at the time of pO 2 measurements. Results: Data presented clearly show that an optimal Hb level with regard to the median pO 2 values of cervical and vulvar cancers should prevail at cHb values of between 12 and 14 g/dl (7.45-8.69 mmol/l). In anemic patients (cHb < 12 g/dl), the deterioration of the tumor oxygenation status can be explained by a reduced O 2 transport capacity. At cHb values > 14 g/dl, a worsening of the tumor oxygenation is apparent, most probably due to a drop in perfusion following a drastic increase in viscous resistance to flow. This pathogenetic mechanism is thought to counteract and finally to abrogate the high O 2 transport capacity in this cHb range. Conclusions: This study suggests that cHb values of between 12 and 14 g/dl are optimal with regard to the oxygenation status in the tumor entities investigated, a finding which may have far-reaching implications in the clinical setting.