Author
Karlheinz Schlenger
Bio: Karlheinz Schlenger is an academic researcher from University of Mainz. The author has contributed to research in topics: Tumor hypoxia & Tumor Oxygenation. The author has an hindex of 20, co-authored 26 publications receiving 5725 citations.
Papers
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TL;DR: Tumor oxygenation as measured with a standardized polarographic method proved to be a powerful new pretherapeutic prognostic parameter providing important information on malignant progression in terms of extracervical tumor spread and radioresistance in advanced cervical cancers.
Abstract: Experimental tumors contain a significant fraction of microregions that are chronically or transiently hypoxic. Experimental evidence showing that hypoxia (and subsequent reoxyenation) may have a profound impact on malignant progression and on responsiveness to therapy is growing. The clinical relevance of tumor oxygenation in human solid malignancies is under investigation. We have developed and validated a clinically applicable method for measurement of tumor oxygenation in locally advanced cancer of the uterine cervix using a computerized polarographic electrode system. Applying this procedure in patients with cervical cancers ≥3 cm in diameter, who gave informed consent, we have been studying the clinical relevance of tumor oxygenation prospectively since 1989. As of June 1995, 103 patients with advanced cancers of the uterine cervix [Federation Internationale des Gynaecologistes et Obstetristes (FIGO) stages Ib, bulky ( n = 13), IIa and IIb ( n = 51), IIIa and IIIb ( n = 34), and IVa and IVb ( n = 5)] had entered the study. Fifty % of the patients had carcinomas with median pO 2 readings hypoxic tumors. Tumor oxygenation was found to be independent of various patient demographics and also of pretreatment tumor characteristics, such as clinical tumor stage and size, histological type, and differentiation. However, histopathological examination of the surgical specimens following radical tumor resection in 47 patients showed that low-pO 2 tumors exhibited larger tumor extensions and more frequent (occult) parametrial spread, as well as lymph-vascular space involvement, compared to well-oxygenated tumors of similar clinical stage and size. Forty-two patients completing primary radiation therapy and 47 patients who underwent radical surgery were analyzed for treatment outcome after a median observation period of 28 months (range, 3–76 months). Patients with hypoxic tumors had significantly worse disease-free and overall survival probabilities compared to patients with nonhypoxic tumors. Cox regession analysis identified tumor oxygenation and FIGO stage as the most important independent prognostic factors. The poorer outcome of the patients with hypoxic tumors was mainly due to locoregional failures with and without distant metastases, irrespective of whether surgery or radiation was applied as primary treatment. Tumor oxygenation as measured with a standardized polarographic method proved to be a powerful new pretherapeutic prognostic parameter providing important information on malignant progression in terms of extracervical tumor spread and radioresistance in advanced cervical cancers.
1,766 citations
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TL;DR: The oxygenation pattern in breast cancers and the occurrence of hypoxia and/or anoxia did not correlate with either the pathological stages and histological grades or with a series of clinically relevant parameters.
Abstract: Direct oxygen partial pressure (pO2) readings in breast cancers, in fibrocystic disease, and in the normal breast have been obtained using a novel technique which allows for the systematic evaluation of the oxygenation status as a function of pathological staging and histological grading. Measurements were performed in awake pre- and postmenopausal patients with well-defined arterial blood gas status. The measuring procedure encompasses a computerized electrode movement in the tissue which avoids significant compression artifacts and allows routine measurement in human tumors before, during, and after treatment. Using this reliable technique, pO2 measurements in the normal breast and in fibrocystic disease resulted in oxygenation patterns which were characteristic for normal, adequately supplied tissues. The median pO2 values were 65 and 67 mm Hg, respectively, with no pO2 readings below 12.5 mm Hg in the normal breast, and less than or equal to 5 mm Hg in fibrocystic disease, respectively. In contrast, in breast cancers the median pO2 value was 30 mm Hg (pooled data for pathological stages T1-T4). To date, 6 of 15 breast cancers exhibited pO2 values between zero and 2.5 mm Hg, i.e., tissue areas with less than half-maximum radiosensitivity. The oxygenation pattern in breast cancers and the occurrence of hypoxia and/or anoxia did not correlate with either the pathological stages and histological grades or with a series of clinically relevant parameters. No significant differences were found between pre- and postmenopausal tumors and between lobular and ductal carcinomas. Tumor-to-tumor variability in the oxygenation pattern was more pronounced than intra-tumor heterogeneity. pO2 variations within a tumor cannot be predicted, e.g., as a function of the measuring site (tumor center versus periphery).
976 citations
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TL;DR: Preliminary results suggest that tumor oxygenation as determined with this standardized procedure appears to be a new independent prognostic factor influencing survival in advanced cancer of the uterine cervix.
783 citations
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TL;DR: The clinical results presented strongly support the hypothesis derived from experimental studies that the selection of apoptosis-insensitive neoplastic cell phenotypes in a hypoxic microenvironment is an important mechanism for malignant progression in solid tumors.
Abstract: There is evidence from experimental work that hypoxia induces apoptosis in apoptosis-sensitive neoplastic cells and that this apoptotic sensitivity is lost during malignant progression. Oxygenation profiles and apoptotic indices in human squamous cell cancer of the uterine cervix have been determined, and a subgroup of tumors has been identified with low apoptotic index despite pronounced hypoxia representing carcinomas that consist of neoplastic cells with diminished apoptotic potential. These hypoxic low-apoptotic tumors show a high probability for lymphatic spread and for recurrence despite adjuvant treatment with radiation or chemotherapy in addition to radical surgery. The clinical results presented strongly support the hypothesis derived from experimental studies that the selection of apoptosis-insensitive neoplastic cell phenotypes in a hypoxic microenvironment is an important mechanism for malignant progression in solid tumors.
352 citations
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TL;DR: From these studies there is clear indication that the oxygenation status of individual tumors cannot be predicted on the basis of staging and/or grading, predominantly because of the pronounced tumor-to-tumor variabilities.
Abstract: Direct oxygen partial pressure (pO2) readings in cancers of the cervix and in the normal cervix of nulliparous or parous women were obtained using a computerized pO2 histography system. The oxygenation status of the tumors was evaluated as a function of clinical staging and histological grading. pO2 measurements were performed with a customized electrode system in conscious pre- and postmenopausal, untreated patients with well-defined arterial blood gas status. With this technique, pO2 measurements in the normal cervix of nulliparous women resulted in oxygenation patterns which were characteristic for normal, adequately supplied tissues (median pO2, 48 mm Hg) with approximately 1% of the pO2 values grouped between zero and 2.5 mm Hg, i.e., in a range with less than half-maximum radiosensitivity. As a rule, the mean (and median) pO2 values were distinctly lower in the normal cervix of parous women (most probably due to scar formation following vaginal delivery) and in malignancies. In the normal cervix of parous women the median pO2 value was 13 mm Hg (with approximately 14% of the pO2 readings in the lowest class), 14 mm Hg in International Federation of Gynecologists and Obstetricians I/II tumors (2% of the readings in the lowest pO2 class), and 11 mm Hg in International Federation of Gynecologists and Obstetricians III/IV cancers (1% of the pO2 data in the lowest class). To date, 5 of 18 cervical cancers exhibited pO2 values between zero and 2.5 mm Hg. The oxygenation pattern in cervical cancers and the occurrence of hypoxia and/or anoxia did not correlate with either the clinical stages and histological grades or with a series of clinically relevant parameters (e.g., tumor size). No significant differences were found between pre- and postmenopausal tumors, between squamous cell carcinomas and adenocarcinomas, and between endophytic or exophytic tumors. From these studies there is clear indication that the oxygenation status of individual tumors cannot be predicted on the basis of staging and/or grading, predominantly because of the pronounced tumor-to-tumor variabilities. Evaluation of the tissue oxygenation of individual tumors is thus mandatory to prove that tumor oxygenation can predict the overall prognosis and/or treatment outcome.
329 citations
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TL;DR: Cells undergo a variety of biological responses when placed in hypoxic conditions, including activation of signalling pathways that regulate proliferation, angiogenesis and death, and many elements of the hypoxia-response pathway are good candidates for therapeutic targeting.
Abstract: Cells undergo a variety of biological responses when placed in hypoxic conditions, including activation of signalling pathways that regulate proliferation, angiogenesis and death. Cancer cells have adapted these pathways, allowing tumours to survive and even grow under hypoxic conditions, and tumour hypoxia is associated with poor prognosis and resistance to radiation therapy. Many elements of the hypoxia-response pathway are therefore good candidates for therapeutic targeting.
4,847 citations
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TL;DR: Observations to date suggest that oxidative stress, chronic inflammation, and cancer are closely linked.
3,922 citations
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TL;DR: Current knowledge of blood flow and perfusion-related parameters, which usually go hand in hand and in turn define the cellular metabolic microenvironment of human malignancies, are summarized for predicting the acute and/or long-term response of tumors to therapy.
Abstract: The objective of this review article is to summarize current knowledge of blood flow and perfusion-related parameters, which usually go hand in hand and in turn define the cellular metabolic microenvironment of human malignancies. A compilation of available data from the literature on blood flow, oxygen and nutrient supply, and tissue oxygen and pH distribution in human tumors is presented. Whenever possible, data obtained for human tumors are compared with the respective parameters in normal tissues, isotransplanted or spontaneous rodent tumors, and xenografted human tumors. Although data on human tumors in situ are scarce and there may be significant errors associated with the techniques used for measurements, experimental evidence is provided for the existence of a compromised and anisotropic blood supply to many tumors. As a result, O2-depleted areas develop in human malignancies which coincide with nutrient and energy deprivation and with a hostile metabolic microenvironment (e.g., existence of severe tissue acidosis). Significant variations in these relevant parameters must be expected between different locations within the same tumor, at the same location at different times, and between individual tumors of the same grading and staging. Furthermore, this synopsis will attempt to identify relevant pathophysiological parameters and other related areas future research of which might be most beneficial for designing individually tailored treatment protocols with the goal of predicting the acute and/or long-term response of tumors to therapy.
3,379 citations
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TL;DR: Because malignant tumors no longer execute functions necessary for homeostasis (such as the production of adequate amounts of adenosine triphosphate), the physiology-based definitions of the term "hypoxia" are not necessarily valid for malignant tumor patients.
Abstract: Tissue hypoxia results from an inadequate supply of oxygen (O(2)) that compromises biologic functions. Evidence from experimental and clinical studies increasingly points to a fundamental role for hypoxia in solid tumors. Hypoxia in tumors is primarily a pathophysiologic consequence of structurally and functionally disturbed microcirculation and the deterioration of diffusion conditions. Tumor hypoxia appears to be strongly associated with tumor propagation, malignant progression, and resistance to therapy, and it has thus become a central issue in tumor physiology and cancer treatment. Biochemists and clinicians (as well as physiologists) define hypoxia differently; biochemists define it as O(2)-limited electron transport, and physiologists and clinicians define it as a state of reduced O(2) availability or decreased O(2) partial pressure that restricts or even abolishes functions of organs, tissues, or cells. Because malignant tumors no longer execute functions necessary for homeostasis (such as the production of adequate amounts of adenosine triphosphate), the physiology-based definitions of the term "hypoxia" are not necessarily valid for malignant tumors. Instead, alternative definitions based on clinical, biologic, and molecular effects that are observed at O(2) partial pressures below a critical level have to be applied.
2,539 citations
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TL;DR: Solid tumours contain regions at very low oxygen concentrations (hypoxia), often surrounding areas of necrosis, which provides an opportunity for tumour-selective therapy, including prodrugs activated by Hypoxia, hypoxia-specific gene therapy, targeting the hypoxIA-inducible factor 1 transcription factor, and recombinant anaerobic bacteria.
Abstract: Solid tumours contain regions at very low oxygen concentrations (hypoxia), often surrounding areas of necrosis. The cells in these hypoxic regions are resistant to both radiotherapy and chemotherapy. However, the existence of hypoxia and necrosis also provides an opportunity for tumour-selective therapy, including prodrugs activated by hypoxia, hypoxia-specific gene therapy, targeting the hypoxia-inducible factor 1 transcription factor, and recombinant anaerobic bacteria. These strategies could turn what is now an impediment into a significant advantage for cancer therapy.
2,428 citations