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K Schlenger

Publications and source records attributed to K Schlenger.

At least 19 recordsLinked to original sources
PubMed2001

Association between host tissue vascularity and the prognostically relevant tumor vascularity in human cervical cancer.

For many human solid tumors including carcinoma of the uterine cervix it has been shown that vascularity is linked to the malignant potential of the neoplasm. However, tumor microvessel density might not just represent the angiogenic potential of the neoplastic cells but could also be influenced by the primary vascularization of the host tissue. Vascular densities were assessed by systematic random sampling of normal cervical stroma and of cervical cancer tissue in surgical specimens of 52 consecutive patients. Spatially defined tumor vascular densities were related to the vascular density of the normal cervix, tumor size and survival probability. Median vascular densities of the normal cervix, tumor periphery and tumor core were 53 (range 16-105), 66 (range 24-181) and 31 (range 3-117) microvessels per mm2, respectively. Vascular densities of the tumor periphery were related to the vascular densities of the normal cervical stroma and did not depend on tumor size, whereas the vascular densities of the tumor core were independent of the vascular densities of the normal cervical stroma and decreased with increasing tumor size. Microvascular 'hot spots' were detected in the tumor periphery in 67% and in the tumor core regions in 33% of the cases. 'Hot spot' vascular densities were independent of tumor size but significantly (p=0.001) correlated with the vascular densities of the normal cervical stroma. Patients with high tumor 'hot spot' vascular densities (> or =40 vessels/counting field) had significantly (p=0.01) poorer survival probability than patients with low tumor 'hot spot' vascular densities (<40 vessels/counting field). Growth of cervical cancer is accompanied by hypervascularity at the periphery and hypovascularity within the tumor core upon comparison with the vascular density of the normal cervical stroma remote from the invasion front. Our study confirms the prognostic relevance of 'hot spot' vascular density in cancer of the uterine cervix. The association between normal cervix microvascular density remote from the tumor and the 'hot spot' vascular density of the tumor suggests an influence of the local host tissue vascularity on the tumor's aggressiveness.

Adenocarcinoma↗
PubMed2000

[Angiogenesis in cervical cancer].

Angiogenesis is a factor of spread and metastatization. This fact has been established for many malignancies, but the data concerning cervical cancer are rather conflicting. In a study including 42 patients affected by cervical cancer stages IB to IVA, the authors assess the mean capillary density and the correlations between this parameter and the other anatomoclinical parameters: the VEGF expression, tumoral oxygenation and the data obtained from dynamic MRI. The histologic assessment of the capillary density and the data obtained by dynamic MRI enable us at the same time to quantify the tumoral angiogenesis and establish the prognosis. The two methods could be used routinely as markers of prognosis. VGEF surely plays a role in angiogenesis linked with cervical cancer growth, but its regulation is not definitively clear at the moment. The impact of tumoral oxygenation (whose place as a prognostic marker is clearly established) on tumoral angiogenesis and vessels' permeability as well as its control is currently not clearly established. Further studies on larger populations are necessary.

Adult↗
PubMed1999

Hypoxic cervical cancers with low apoptotic index are highly aggressive.

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.

Apoptosis↗
PubMed1999

Expression of tenascin in human cervical cancer--association of tenascin expression with clinicopathological parameters.

OBJECTIVE: 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. METHOD: 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. RESULTS: In normal cervical tissue (n = 5) and in cervical carcinoma in situ (n = 10) only vessel walls showed a weak tenascin cross-reactivity, whereas tenascin was not expressed in the epithelial layer or the underlying connective tissue. In invasive cervical carcinoma (n = 89) tenascin expression was markedly increased. In 84% (n = 75) of the cases examined a strong tenascin immunoreactivity was noted around and within the tumor cell nests. Sixteen percent (n = 14) of infiltrating cervical carcinomas showed no tenascin immunoreactivity. A definite correlation was found between weak or no tenascin expression and slight desmoplastic mesenchymal reactivity (n = 42/91%, P < 0.001), lymphatic space invasion (n = 54/81%, P < 0.001), and lymph node metastases (n = 30/77%, P < 0.05). Tenascin-positive patients had a significantly better prognosis than tenascin-negative patients (mean survival time of 56.5 +/- 4.1 months versus 31.9 +/- 5.6 months, P < 0.05). CONCLUSION: Based on these findings we discuss that the appearance of tenascin is an indicator of an adequate biological defense in cervical cancer patients. The tenascin staining may therefore be useful for detecting a subgroup of invasive cancer patients missing tenascin reactivity with alterations of stromal defense and a poorer prognosis.

Carcinoma in Situ↗
PubMed1998

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 the patients' 5-year survival probabilities. In the cohort of patients with pelvic relapses, median tumor pO2 < 4 mmHg indicated a significantly shorter median survival time as compared to median tumor pO2 > or = 4 mmHg. Our results further support our thesis that in cervical cancer, tumor hypoxia and clinical aggressiveness in terms of resistance to therapy and tumor dissemination, are interrelated.

Adenocarcinoma↗
PubMed1997

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 inferior epigastric artery. "Choke" arteries to the superior epigastric artery and also to the intercostal arteries (X, XI, and XII) have been shown to be common features. From the anatomic point of view, these observations offer the possibility of mobilizing large parts of the transversus abdominis muscle together with the rectus abdominis muscle for reconstructive surgery.

Abdominal Muscles↗
PubMed1996

Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix.

Experimental tumors contain a significant fraction of microregions that are chronically or transiently hypoxic. Experimental evidence showing that hypoxia (and subsequent reoxygenation) 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 pO2 readings <10 mm Hg, referred to as 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-pO2 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 regression 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.

Cell Hypoxia↗
PubMed1996

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 hypoxia on survival is related to radiobiological mechanisms caused by hypoxia per se, which may include (1) the reduced oxygen enhancement effect, (2) increased radioresistance due to expression of genes for cell cycle delay and stress proteins, and/or (3) accelerated tumor progression to more radioresistant and metastatic variants by increased genetic heterogeneity.

Journal Article↗
PubMed1995

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 paraffin sections of two cylindrical 2 x 20-mm core biopsies obtained transvaginally from the 12 and 6 o'clock positions of each tumor and then immunohistochemically stained for Factor VIII-related antigen. The oncologic relevance of tumor vascularity is studied in an open prospective trial. RESULTS: Tumor vascularity was quantified in 42 patients with cervical cancers > 3 cm in largest diameter, FIGO stages Ib-IVa. This new parameter representing pathophysiological tumor-host interactions was independent of various other patient and tumor characteristics, including age, FIGO stage, tumor size, differentiation, lymph node metastases and lymphatic space involvement. Thirty-nine patients were treated with curative intent either by primary surgery (n = 22) or radiation (n = 17). After a median observation time of 18 months (range 4-41 months), the patients with higher tumor vascularity (mean DTCMV < 83 microns) had significantly shorter disease-free (P = 0.025) and overall (P = 0.032) survival probabilities than patients with lower tumor vascularity (mean DTCMV > or = 83 microns). Cox regression analysis identified tumor vascularity as the strongest independent prognostic factor in this group of patients. CONCLUSIONS: The assessment of tumor microvascularity by computerized image analysis of defined tumor biopsies could become a novel means of predicting tumor aggressiveness in non-early cervical cancer.

Adenocarcinoma↗
PubMed1994

How to improve the uterotomy healing. I. Effects of fibrin and tumor necrosis factor-alpha in the rat uterotomy model.

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 presence of fibrin alone or with fibrin containing tumor necrosis factor-alpha (TNF-alpha-fibrin) compared to controls. The fibrin matrix incorporated into rat uterotomies reduced wound hemorrhage and led to a 45% increase of early (Day 3) bursting pressure (not significant). With 20 micrograms TNF-alpha in the fibrin matrix, Day 3 bursting pressure was elevated by more than 100% (P < 0.05). Histologically, inflammation and granulation tissue formation was markedly enhanced. Two micrograms of TNF-alpha/wound did not show any effect and 200 micrograms TNF-alpha even led to a decrease in early bursting strength. After 1 week, no differences in bursting pressure or wound histology could be detected between uterotomies treated with fibrin or TNF-alpha-fibrin compared to controls. The rat uterotomy model appears to be suitable for investigating new biological means to improve uterine wound healing.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Oxygen tension distributions are sufficient to explain the local response of human breast tumors treated with radiation alone.

PURPOSE: Several factors are known to influence the probability of tumor control after radiation. These include tumor oxygen tension distribution, glutathione content, intrinsic radiation sensitivity, rate of repopulation, tumor size, physician skill, etc. The relative impact of oxygen on human tumor response is unknown. The purpose of this analysis is to determine to what extent the observed shape of the radiation response curve for human tumors can be predicted by the tumor oxygenation status. METHODS AND MATERIALS: The radiation dose response curve for patients treated with radiation alone for breast cancer was calculated based on pooled data. Tumor control rates as a function of radiation dose were fitted to a probit curve. Twenty-two women with breast cancer in Mainz (Germany) and at Stanford University had pO2 measurements made of their tumors. An average of 87 +/- 58 (range 21 to 300) measurements were made from each patient. Hypoxia was assumed to be a purely dose modifying factor with a maximum oxygen enhancement ratio of 2.5. Assuming patients are treated with daily radiation doses of 2 Gy, the breast cancer alpha/beta ratio is 10 Gy, tumors have a mean of 10(8) stem cells, and using the linear quadratic formula for modelling surviving fraction, it was possible to estimate tumor control probability. RESULTS: Tumor oxygenation was an extremely important modifier of the shape of the dose response curve and alone was sufficient to account for the slope of the observed dose response curve for human breast carcinoma. Tumor size distribution had a smaller effect on the shape and the slope of the dose response curve. Two models of radiation induced reoxygenation were tested, one that allowed full reoxygenation to the baseline state between the daily radiation fractions and another with no reoxygenation between fractions. The clinical data fell between these two models in accordance with the expected incomplete reoxygenation between treatments. CONCLUSION: The results support the conclusion that in human breast carcinoma, oxygen tension distribution is a critical modifier of radiation treatment response.

Breast Neoplasms↗
PubMed1993

Therapeutic angiogenesis.

We have proposed the term "therapeutic angiogenesis" to describe the induction or stimulation of neovascularization for the treatment or prevention of pathological clinical situations characterized by local hypovascularity. Evidence also shows that "clinically normal" healing and tissue regeneration can be improved or accelerated by therapeutic angiogenesis. Traditionally, therapeutic angiogenesis has been achieved by surgical methods, ie, the transposition of autologous tissues with uncompromised vasculature and high angiogenic potential such as omentum majus flaps and muscle flaps. Recent advances in the understanding of the biological process of neovascularization as well as the discovery and cloning of angiogenic cytokines may add a new clinical tool: therapeutic angiogenesis by pharmaceutical methods. Based on the results of animal studies and preliminary clinical trials, this review is aimed to give a state-of-the-art compilation of (1) those angiogenesis factors that appear promising in clinical application for therapeutic angiogenesis and (2) the surgical indication fields with near-term potential for therapeutic angiogenesis by use of angiogenic cytokines.

Angiogenesis Inducing Agents↗
PubMed1993

Tumor oxygenation: a new predictive parameter in locally advanced cancer of the uterine cervix.

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 pO2 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 cervical cancers entered the study. Tumor oxygenation measured in these 50 patients was independent from various patient and tumor characteristics, including hemoglobin concentration, FIGO stage, and tumor size. Thirty-three patients receiving standard radiotherapy with or without chemotherapy (RT +/- CT) were analyzed for treatment outcome. Intratumoral pO2 histography revealed median pO2 < or = 10 mm Hg (low pO2 tumors) in 15 of the 33 patients; in 19 tumors pO2 fractions < or = 5 mm Hg (low pO2 fractions) were found. After a median follow-up of 24 months (range 6 to 40 months) Kaplan-Meier life table analysis showed significantly shorter survival and recurrence-free survival for patients with low pO2 tumors treated with RT +/- CT. According to the Cox proportional hazards model the low pO2 fraction was the most powerful single predictor of survival and recurrence-free survival. The results of this study are consistent with the view that radiobiologically hypoxic tumors are less radiocurable but mechanisms of treatment failure other than the effect of hypoxia on the radiation response cannot be excluded. Intratumoral pO2 histography in advanced cervical cancers enables pretherapeutic selection of low pO2 tumors as candidates for modified treatment approaches.

Adult↗
PubMed1993

Intratumoral pO2 predicts survival 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 non-surgical treatment modalities (e.g. standard irradiation, certain anticancer agents). 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. A clinically applicable standardized procedure has been established which enables the determination of intratumoral oxygen tensions in advanced cervical cancers by use of a computerized polarographic needle electrode histography system. Tumor oxygenation as measured by this method represents a novel tumor feature which can be individually determined for each tumor and which is independent from other known oncological parameters. The results of an interim analysis of an open prospective clinical trial to evaluate the prognostic significance of tumor oxygenation based on the survival data of the first 31 patients are presented. Fifteen patients have been treated by primary radiation, 11 patients received multimodality therapy including irradiation. After a median follow-up of 19 months (range 5-31 months), Kaplan-Meier-life table analysis showed significantly lower survival and recurrence-free survival for patients with a median pO2 of < or = 10 mmHg compared to those with better oxygenated tumors (median pO2 > 10 mmHg). The Cox proportional hazards model revealed that the median pO2 and the clinical stage according to the FIGO are independent, highly significant predictors of survival and recurrence-free survival. We conclude from these preliminary results 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.

Adult↗
PubMed1991

Oxygenation of carcinomas of the uterine cervix: evaluation by computerized O2 tension measurements.

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.

Adenocarcinoma↗