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Arnulf Mayer

Publications and source records attributed to Arnulf Mayer.

12 recordsLinked to original sources
PubMed2006

Endogenous hypoxia markers in locally advanced cancers of the uterine cervix: reality or wishful thinking?

BACKGROUND: Tumor hypoxia is considered to be relevant for several aspects of tumor pathophysiology, for acquired treatment resistance, and tumor progression (e. g., in cancers of the uterine cervix). Therefore, there is a demand for simple and universally applicable methods allowing the estimation of oxygenation status in patient material obtained during pretherapeutic diagnostic procedures (biopsies) or surgical treatment. Protein members of the transcriptional response to hypoxia expressed in tumor tissue, e. g., hypoxia-inducible factor-1alpha (HIF-1alpha), glucose transporter-1 (GLUT-1) and carbonic anhydrase IX (CA IX) are currently being discussed as "endogenous hypoxia markers". MATERIAL AND METHODS: The (hypothetic) suitability of different markers for the assessment of the oxygenation status is reviewed on the basis of current knowledge. RESULTS: Data from studies investigating the suitability of different markers are conflicting. Although a robust induction of HIF-1alpha, GLUT-1 and CA IX by hypoxia has been demonstrated in vitro, this reaction is modulated both by confounding factors of the tumor microenvironment and intrinsic traits of malignant cells in vivo. CONCLUSION: On the basis of the available data, the suitability of "endogenous hypoxia markers" for the estimation of the oxygenation status of advanced cervix cancers seems questionable.

Biomarkers↗
PubMed2006

Impact of hemoglobin levels on tumor oxygenation: the higher, the better?

BACKGROUND AND PURPOSE: Tumor hypoxia has been linked to tumor progression, the development of treatment resistance, and thus poor prognosis. Since anemia is a major factor causing tumor hypoxia, the association between blood hemoglobin concentration (cHb) and tumor oxygenation status has been examined. PATIENTS AND METHODS: Published data on the relationship between pretreatment cHb values and tumor oxygenation (in terms of median pO(2) values, hypoxic fractions) have been summarized. Pretreatment O(2) tension measurements were performed in histologically proven experimental tumors, human breast cancers, squamous cell carcinomas of the head and neck, and cancers of the uterine cervix and of the vulva. In order to allow for a comparison between solid tumors and normal tissues, pO(2) measurements were also performed in healthy tissue in anemic and nonanemic patients. cHb was determined at the time of the pO(2) measurements. RESULTS: Based on current information from experimental and clinical studies there is increasing evidence that anemia is associated with a detrimental tumor oxygenation status. Increasing cHb values are correlated with significantly higher pO(2) values and lower hypoxic fractions. Maximum tumor oxygenation in squamous cell carcinomas is observed at normal (gender-specific) cHb values (approximately 14 g/dl in women and approximately 15 g/dl in men). Above this "optimal" Hb range, the oxygenation status tends to worsen again. In anemic patients, tumor oxygenation is compromised due to a decreased O(2) transport capacity of the blood. At the upper edge of the Hb scale, a substantial increase in the blood's viscous resistance to flow in "chaotic" tumor microvessels is thought to be mainly responsible for the observed restriction of O(2) supply. CONCLUSION: Review of relevant clinical data suggests that a maximum oxygenation status in solid tumors is to be expected in the range 12 g/dl < cHb < 14 g/dl for women and 13 g/dl < cHb < 15 g/dl for men. Considering the "optimal" cHb range with regard to tumor oxygenation, the concept of "the higher, the better" is therefore no longer valid. This finding has potentially far-reaching implications in the clinical setting (e. g., inappropriate erythropoietin treatment of nonanemic tumor patients).

Adult↗
PubMed2005

Carbonic anhydrase IX expression and tumor oxygenation status do not correlate at the microregional level in locally advanced cancers of the uterine cervix.

PURPOSE: Carbonic anhydrase IX (CA IX) can be induced by hypoxia in vitro and shows an immunohistochemical expression pattern that is predominantly found in perinecrotic tumor areas and correlates with exogenous markers of hypoxia, such as pimonidazole. CA IX might therefore serve as an endogenous marker of tumor hypoxia, although comparisons of CA IX immunostaining with direct oxygenation measurements using pO2 microsensors have thus far yielded contradictory results. EXPERIMENTAL DESIGN: Because tumor heterogeneity may be among the factors responsible for the discrepancy between the two methods, CA IX expression in tissue samples originating from oxygen microelectrode tracks of locally advanced cervical cancers was assessed in this study. Seventy-seven biopsy specimens were analyzed immunohistochemically using an anti-CA IX rabbit polyclonal antibody and semiquantitative scoring. RESULTS: CA IX expression showed no correlation with the oxygenation variables median pO2 and hypoxic fraction 2.5, 5, or 10. Cases with higher International Federation of Gynecology and Obstetrics stages (IIb-IVa) exhibited stronger expression of CA IX (P = 0.035) and CA IX expression tended to be more prevalent in node-positive patients (P = 0.051). CONCLUSIONS: These data indicate that CA IX cannot be recommended as a substitute for oxygen microelectrode measurements. That the expression of CA IX does not correlate with the oxygenation status may be due to the degree to which other factors, such as nutrient (e.g., glucose) deficiency or the action of oncogenic mutations, can modulate the in vivo expression of this protein, rendering a strict association with tumor hypoxia too unreliable for clinical use.

Antigens, Neoplasm↗
PubMed2005

Microregional expression of glucose transporter-1 and oxygenation status: lack of correlation in locally advanced cervical cancers.

PURPOSE: Glucose transporter-1 (GLUT-1), a target gene of hypoxia-inducible factor-1, has been considered a candidate endogenous marker of tumor hypoxia. Expression of GLUT-1 may also serve as an indicator for the induction of the transcriptional response to hypoxia, which has been linked to enhanced proliferation, resistance to therapy, and metastatic propagation of cancer cells. Overexpression of GLUT-1 has been shown to correlate with poor prognosis in several tumor entities, among them cancers of the uterine cervix. The validity of these hypotheses is investigated. EXPERIMENTAL DESIGN: The expression of GLUT-1 was assessed in 80 biopsies of Eppendorf oxygenation measurement tracks from locally advanced cervical cancers in 47 patients using immunohistochemistry. RESULTS: No correlation was found between the expression of GLUT-1 and oxygenation variables (median pO2, HF 2.5 and HF 5). Expression of GLUT-1 was found greater in larger tumors (P = 0.0001) and to exhibit a linear increase with Federation Internationale de Gynecologie et d' Obstetrique stage (P = 0.002). Overall survival (P = 0.004) and recurrence-free survival (P = 0.007) were significantly shorter for patients with expression of GLUT-1. In the subgroup of patients treated with surgery, this effect on prognosis was not independent when pT stage or pN stage were included in a multivariate Cox proportional hazards model. CONCLUSIONS: The suitability of GLUT-1 as an endogenous marker of tumor hypoxia seems questionable. The association with prognosis may partially depend on confounding factors.

Female↗
PubMed2005

Hypoxia in breast cancer: role of blood flow, oxygen diffusion distances, and anemia in the development of oxygen depletion.

Heterogeneously distributed hypoxic areas are a characteristic property of locally advanced breast cancers. Hypoxia results from an imbalance between the supply and consumption of oxygen (O2). Major pathogenetic mechanisms for the emergence of hypoxia are (i) structural and functional abnormalities in the tumor microvasculature, (ii) an adverse diffusion geometry, and (iii) tumor-related and therapy-induced anemia leading to a reduced O2 transport capacity of the blood. There is pronounced intertumor variability in the extent of hypoxia, which is independent of clinical size, stage, histology and grade. Hypoxia is intensified in anemic patients, especially in tumor (areas) with low perfusion rates. Tumor hypoxia is a therapeutic problem since it makes solid tumors resistant to sparsely ionizing radiation, some forms of chemotherapy, and photodynamic therapy. However, besides more direct mechanisms involved in the development of therapeutic resistance, there are, in addition, indirect machineries that can cause barriers to therapies. These include hypoxia-mediated alterations in gene expression, proteomic and genomic changes, and clonal selection. These in turn can drive subsequent events that are known to further increase resistance to therapy in addition to critically affecting long-term prognosis.

Anemia↗
PubMed2005

Hypoxia and anemia: effects on tumor biology and treatment resistance.

In locally advanced solid tumors, oxygen (O2) 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 O2 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 O2 deficiency status by a rise in blood flow rate, locally advanced tumors (or at least larger tumor areas) cannot adequately counteract the restriction in O2 supply and thus the development of hypoxia. Hypoxia-induced alteration in gene expression and thus in the proteome (< 1% O2, or < 7 mmHg), and/or genome changes (< 0.1% O2, 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 gamma-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.

Anemia↗
PubMed2004

Lack of correlation between expression of HIF-1alpha protein and oxygenation status in identical tissue areas of squamous cell carcinomas of the uterine cervix.

Hypoxia inducible factor-1alpha (HIF-1alpha) has been proposed as a candidate endogenous marker of tumor hypoxia and as a molecular mediator of hypoxia-driven malignant progression and acquired treatment resistance. In this study, HIF-1alpha expression in 68 biopsies of oxygenation measurement tracks from squamous cell carcinomas of the uterine cervix of 38 patients was assessed. Expression of HIF-1alpha was commonly found to increase as a function of distance from microvessels, at the center of tumor cell aggregations, and in the vicinity of necrotic areas. However, there was no correlation of HIF-1alpha expression with median oxygen tension (oxygen partial pressure; pO2) and hypoxic fractions (hypoxic fraction < 2.5 mm Hg, hypoxic fraction < 5 mm Hg). The results indicate that HIF-1alpha should not be used as an endogenous marker of tumor hypoxia in locally advanced squamous cell carcinomas of the uterine cervix. Additionally, no significant prognostic impact of HIF-1alpha expression was found in this group of patients.

Adult↗
PubMed2003

Oxygenation gain factor: a novel parameter characterizing the association between hemoglobin level and the oxygenation status of breast cancers.

Tumor hypoxia has been linked to acquired treatment resistance, tumor progression, and poor prognosis. Because anemia is a major causative factor for the development of hypoxia, the association between blood hemoglobin concentration (cHb) and breast cancer oxygenation was examined in this study. In addition, a novel parameter characterizing the relationship between oxygenation status and rising cHb is introduced: the oxygenation gain factor (OGF). In breast cancer patients, median cHb over the range 8.5-14.7 g/dl correlated positively with the median pO(2) (3-15 mm Hg), yielding an average OGF of 2 mm Hg.dl/g. In contrast, in normal tissues (normal breast, subcutis, and skeletal muscle) the median pO(2) values were substantially higher (52 mm Hg, 51 mm Hg, and 37 mm Hg, respectively) and remained constant irrespective of the hemoglobin level over the range from 10 to 16 g/dl (OGF = 0 in grade I anemia and nonanemic patients). Moderately lower median pO(2) values in subcutis and skeletal muscle were only observed in grade II anemia (8 g/dl < cHb < or =10 g/dl), although this would appear to be of no biological relevance. Conversely, in breast cancers, even mild anemia (grade I anemia) is a major causative factor for the development of hypoxia or anoxia.

Adult↗
PubMed2003

Impact of oxygenation status and patient age on DNA content in cancers of the uterine cervix.

PURPOSE: In carcinomas of the uterine cervix, the tumor oxygenation status has been shown to be a prognostic indicator that is independent of treatment modality. In vitro studies suggest gene amplification and polyploidization to be among the major consequences of hypoxia (with or without consecutive reoxygenation) and to be associated with treatment resistance and tumor progression. This study analyzed whether hypoxia alters net DNA content in uterine cervix cancer cells to the extent that it is identifiable by DNA image cytometry. MATERIALS AND METHODS: In 64 patients with primary cervical cancer, tumor oxygenation was assessed polarographically and correlated with cell DNA content (DNA image cytometry) in areas adjacent to the oxygen microsensor tracks in which oxygenation measurements were made. RESULTS: No correlation between DNA content (stemline position, Auer classification, and 2c deviation index) and oxygenation status was observed. However, an association between DNA content and patient age and menopausal status was found. CONCLUSION: Using DNA cytometry, hypoxia-associated genomic changes in uterine cervix cancer cells could not be detected. The impact of tumor hypoxia on the genome may be masked by the effects of alternative mechanisms of genomic instability that can also influence DNA content.

Adult↗
PubMed2002

Oxygenation status of gynecologic tumors: what is the optimal hemoglobin level?

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 (7.45-8.60 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.

Adult↗