0000000000222254
AUTHOR
Karlheinz Schlenger
Therapeutic Angiogenesis in Surgery and Oncology
The aim of this presentation is to demonstrate the pathological importance of microenvironmental tissue hypoxia and to elucidate a general treatment concept for this situation which we have termed therapeutic angiogenesis 1. Hypoxia not only represents an insufficient oxygen supply for the cells of a given tissue area but is also regarded as an indicator for their metabolic deprivation and the concomitant accumulation of waste products. Therapeutic angiogenesis applied either with clinically established methods or using novel ways, which are the objectives of laboratory research and clinical trials at present, or in so far hypothetical forms, should lead to an expansion of the functional mi…
Tumor Vascularity, Hypoxia, and Malignant Progression in Solid Neoplasms
Malignant progression designates the biologic process which transforms a phenotypically normal cell fixed and cooperating within a tissue into a disseminated therapy-resistant lethal disease. In clinical terms this process consists of three major steps (Fig. 1): () the transition from regulated to deregulated cell proliferation, () the emerging ability of the neoplastic cell collectives to induce angiogenesis and to invade other tissues, () the development of metastases and of resistance towards anti-tumor therapies.
Impact of oxygenation status and patient age on DNA content in cancers of the uterine cervix.
Abstract 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. Methods and materials In 64 patients with primary cervical cancer, tumor oxygenation was assessed polarographically and correlated with cell DNA content…
The Vascular Anatomy of the Inner Anterior Abdominal Wall with Special Reference to the Transversus and Rectus Abdominis Musculoperitoneal (TRAMP) Composite Flap for Vaginal Reconstruction
This study was designed to clarify the vascularization of the inner anterior abdominal wall with respect to the novel transversus and rectus abdominis musculoperitoneal (TRAMP) flap, which was introduced recently for vaginal reconstruction. A series of human cadavers was injected with a lead oxide-gelatine mixture by means of the deep inferior epigastric artery and subsequently dissected and examined by radiography. In all cases we found that the blood supply of the entire rectus abdominis muscle from the symphysis to the costal arch and that of the medial 10 to 15 cm of the transversus abdominis muscle, as well as the underlying peritoneum, was provided by several branches of the deep infe…
Five-year experience with combined operative and radiotherapeutic treatment of recurrent gynecologic tumors infiltrating the pelvic wall
BACKGROUND. Whereas 25 to 50% of selected patients with gynecologic tumors who relapse centrally in an irradiated pelvis can be salvaged by exenteration, postirradiation recurrence infiltrating the pelvic side wall generally has been fatal. We have designed the combined operative and radiotherapeutic treatment (CORT) procedure for the treatment of postirradiation recurrence infiltrating the pelvic wall and developed several new techniques for its realization. The aim of the surgery is as follows : (1) total resection of the tumor with only a microscopic margin (R1) at the pelvic wall, preserving the bony pelvis and the neurovascular support of the leg ; (2) modulation of the therapeutic ind…
Expression of tenascin in human cervical cancer--association of tenascin expression with clinicopathological parameters.
Tenascin is an extracellular matrix glycoprotein, relevant for embryonal and fetal development, which is reexpressed in the stroma of benign and malignant tumors. Little is known about the molecular interaction of tenascin during neoplastic transformation and tumor progression in cervical cancer.We studied the expression of tenascin in normal tissue of the cervix uteri, cervical carcinoma in situ, and invasive cervical carcinoma in paraffin sections by immunohistochemistry using a monoclonal antibody. Tenascin immunoreactivity was compared with various prognostic parameters.In normal cervical tissue (n = 5) and in cervical carcinoma in situ (n = 10) only vessel walls showed a weak tenascin …
Hypoxia-stimulated expression of angiogenic growth factors in cervical cancer cells and cervical cancer-derived fibroblasts
It is generally accepted that local growth of solid tumors and their ability to establish distant metastases are dependent on the formation of new blood vessels arising from preexisting ones (angiogenesis). The angiogenic response of the host is mediated by angiogenic molecules that are released from cancer and normal stroma cells, especially fibroblasts. The goal of the present study was to quantitatively compare the expression of the two most important angiogenic growth factors (VEGF, angiogenin) of cervical cancer cells (HeLa and Me-180) with that of cervical cancer-derived fibroblasts (from one tumor/patient) under defined normoxic and hypoxic conditions in vitro. The growth kinetics of…
Tumor Vascularity—A Novel Prognostic Factor in Advanced Cervical Carcinoma
Objective: In the search for the optimal treatment of advanced cervical cancer, the identification of valid prognostic factors obtainable without histopathologic investigation of the entire tumor and the locoregional lymph nodes is of paramount interest. Tumor microvessel density has recently been demonstrated to correlate strongly with disease aggressiveness in breast cancer and other malignancies. Methods: We established a computerized image analysis system to quantify tumor microvascularity by using the closest-individual method, which determines the distribution of distances from random points within the tumor to the closest microvessel (DTCMV). Tumor microvascularity was assessed in pa…
Pathophysiological approaches to identifying tumor hypoxia in patients
The present report summarizes observations of the authors on tumor oxygenation and on techniques for characterizing tumor hypoxia in patients. Cryospectrophotometric measurements of HbO2 saturations in tumor microvessels allow for estimates of the proportion of well oxygenated tissue regions. Labeling of tissue areas at oxygen (O2) tensions (pO2) less than 10 mm Hg with misonidazole may be used for a general characterization of the oxygenation status in patient tumors rather than for the determination of the radiobiologically hypoxic cell fraction. Quantitative bioluminescence and single photon imaging make it possible to determine ATP concentrations in absolute terms with a spatial resolut…
Oxygenation of Mammary Tumors: From Isotransplanted Rodent Tumors to Primary Malignancies in Patients*
The role of oxygen in tumor cell proliferation, radiosensitivity, cytotoxicity of anticancer drugs and hyperthermia treatment has been the subject of a series of investigations (for reviews see Hall, 1988; Teicher et al., 1990, Vaupel et al., 1989a; Vaupel, 1990a,b). Despite the apparent importance of tumor oxygenation, data on pO2 values in solid tumors are mostly derived from experiments on rodents which might not necessarily reflect the variability of the clinical situation. Due to feasible techniques available now, considerable advances have been made in the past few years in the assessment of tumor hypoxia in patients (for reviews see Vaupel et al., 1989a; Vaupel, 1990a). The latter in…
Blood Flow and Tissue Oxygenation of Human Tumors: An Update
It is generally accepted that tumor microcirculation, blood flow, oxygen and nutrient supply, tissue pH distribution, and the bioenergetic status (factors which are usually closely linked and which define the so-called cellular microenvironment) can markedly influence the therapeutic response of malignant tumors. Tumor blood flow is the major determinant for intra-tumor pharmacokinetics and (through modulation of the cellular microenvironment) of pharmacody-namics. The oxygen supply greatly determines the radiosensitivity of the tumors to be treated. The oxygen enhancement ratio, i.e., the ratio of doses with and without oxygen to produce the same biological effect is 2.7 to 3.0. O2 partial…
Intratumoral PO2 Histography as Predictive Assay in Advanced Cancer of the Uterine Cervix
Experimental evidence suggests that the hypoxic fraction in a solid tumor may increase its malignant potential and reduce its sensitivity towards nonsurgical treatment modalities such as standard irradiation and certain anticancer agents1–5. However, the clinical importance of tumor hypoxia remains uncertain since valid methods for the routine measurement of intratumoral O2-tensions in patients have so far been lacking.
Tumor hypoxia in pelvic recurrences of cervical cancer.
We have previously demonstrated in primary cancer of the uterine cervix that tumor hypoxia, as determined polarographically, is strongly associated with clinical malignant progression of the disease. Having applied a similar methodological approach to investigate loco-regional relapses, we found a pronounced shift to more hypoxic oxygenation profiles in the recurrent tumors than in the primary tumors. Median pO2 values in 53 pelvic recurrences were significantly lower than the median pO2 values of 117 primary tumors of comparable sizes (7.1 +/- 1.1 mmHg vs. 12.1 +/- 1.0 mmHg, p = 0.0013). The differences in tumor oxygenation between primary and recurrent tumors mirrored the differences in t…
Hypoxia and radiation response in human tumors
This study demonstrates by an updated analysis of an ongoing prospective study that tumor oxygenation, as measured with a validated standardized polarographic needle electrode method before treatment, powerfully predicts the prognosis of patients receiving radiotherapy for intermediate and advanced stage cancer of the uterine cervix. First evidence for a host component in tumor oxygenation based on a significant correlation between median pO 2 values determined in normal subcutaneous fatty tissue and in cervical cancer is also presented. Further investigations are necessary to clarify whether tumor hypoxia is just a marker of intrinsic tumor aggressiveness or whether the negative impact of …
Tumor oxygenation: a new predictive parameter in locally advanced cancer of the uterine cervix.
Abstract Experimental evidence suggests that hypoxia may increase the malignant potential and reduce the sensitivity toward nonsurgical treatment modalities in solid rodent tumors. However, the importance of tumor hypoxia in human malignancies is still uncertain. We have developed a clinically applicable standardized procedure for the determination of intratumoral p O 2 in advanced cervical cancers by use of a computerized polarographic needle electrode histograph. To evaluate the significance of tumor oxygenation as a new oncologic parameter we initiated an open prospective clinical trial at the University of Mainz Medical Center in June 1989. Until October 1992 50 patients with advanced c…
Tumor blood flow: The principal modulator of oxidative and glycolytic metabolism, and of the metabolic micromilieu of human tumor xenograftsin vivo
We have investigated therapeutically relevant pathophysiological parameters of human breast and lung cancer xenografts in nude rats. All lung cancers and one breast cancer exhibited rapid growth and high blood flow values paralleled by high metabolic rates. The tissue of these tumors was well oxygenated up to very advanced growth stages. Xenografts from other breast cancer cell lines grew much more slowly, were poorly perfused, and exhibited low metabolic rates. Here, tumor hypoxia and tissue acidosis were evident. These results indicate that significant differences in the metabolic micromilieu can be detected in human tumors; these are due to varying perfusion rates and may be partly respo…
How to Improve the Uterotomy Healing
Abstract Suboptimal uterotomy healing following cesarean delivery or metroplastic operations may lead to considerable complications. New insights in the biology of wound healing and the availability of a variety of biologic response modifiers open the possibility to modulate the process of wound healing in order to gain clinical benefits. Can uterotomy healing be improved by local application of biosubstances? We developed an uterotomy model in the rat and measured the bursting pressure at defined times postwounding as a functional parameter of wound healing. In addition, the healing process was assessed by serial light microscopic histology. Uterotomy healing was investigated in the presen…