Biomedical subjects
Publications and source records attributed to M Höckel.
The transversus and rectus abdominis musculoperitoneal (TRAMP) flap, a novel composite flap supplied by the deep inferior epigastric vessels, was used successfully for partial vulvovaginal reconstruction following anterior and posterior exenteration. The full potential of the TRAMP flap in vulvovaginal reconstruction is being investigated further.
The oxygen tension of human tumours has often been thought to alter tumour response to radiation therapy. The purpose of this analysis is to determine to what extent the observed results of radiotherapy fit predictions based on in situ human tumour pO2 distributions. The radiation dose-response curve for patients treated with radiation alone for squamous cell cancers of the cervix and oropharynx were calculated based on published data. pO2 histograms were obtained from 30 women with cervical cancer and 11 patients with neck nodes from head and neck cancers. An average of 76 +/- 35 (range 28-174) measurements were made from each patient. Hypoxia was assumed to be a purely dose-modifying factor with a maximum OER of 2.5. Assuming patients are treated with daily radiation doses of 2 Gy, the squamous cell carcinoma alpha/beta ratio is 10 Gy, and that tumours have a mean of 10(8) clonogens, it was possible to estimate tumour control probability. Tumour oxygenation was an extremely important modifier of the slope of the dose-response curve and alone was sufficient to account for the slope of the clinically observed dose-response curve for neck nodes. The response curve for uterine cervical cancers is very shallow, and the oxygen distribution did not completely account for heterogeneity of response of these tumours. The results support the conclusion that oxygen tension distribution is an important modifier of human radiation treatment response.
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.
In spite of the development of various techniques for the formation of a neovagina, the longterm results are often disappointing, especially if the simpler methods (dilation, ectopic pouch formation, epithelium transfer) have been applied. The more complex surgical techniques such as musculo/fasciocutaneous and colon flaps are associated with a significant risk of severe complications. For certain operative situations necessitating vaginal reconstruction, adequate procedures are still missing. Based on surgico-anatomic investigation of the vascular territories of the myoperitoneal anterior abdominal wall, we introduce the use of myoperitoneal composite flaps from the deep inferior epigastric artery angiosome as a novel surgical principle for vaginal reconstruction and report on the experience with the first two patients.
Both the gain of new tumor biological insights, particularly the relevance of tumor oxygenation and vascularity in addition to tumor volume for disease progression and resistance towards therapy, and the development of novel ablative and reconstructive pelvic surgical techniques may lead to a paradigm shift in the treatment of cancer of the uterine cervix. With respect to stage, size, and predicted tumor biological features, either less radical or extended radical surgical treatment should be investigated in clinical trials with standard therapy (abdominal radical hysterectomy and pelvic/periaortic lymph node dissection for early-stage disease and percutaneous/intracavitary radiation for locally advanced disease) as control. Improving the therapeutic index and increasing the therapeutic window in cervical cancer appear to be an exciting challenge for surgical gynecology in the future.
BACKGROUND: By using the Combined Operative and Radiotherapeutic Treatment (CORT) procedure, pelvic side-wall recurrences of gynecologic malignancies arising in a previously irradiated pelvis may be locally controlled. Local control of central relapses may be achieved by exenteration alone. If, in cervical cancer, both relapse patterns are biologically different (as hypothesized by some investigators), distinct disease courses after local treatment may be expected. METHODS: Since June, 1989, 32 pelvic recurrences of cervical cancer were treated for local control in this institution. The median size of the recurrent tumors was 5 cm (range, 2-9 cm); 84% of the patients had been extensively irradiated in the pelvis. Therapy of 14 centrally located recurrences was exenteration alone. In 18 patients with relapses fixed to the pelvic wall and histologically confirmed intralesional resection planes, the CORT procedure was applied. RESULTS: After a median observation of 24 months (range, 5-48 months) 7 patients with central recurrences and 11 patients with pelvic wall recurrences had progressive disease in the pelvis and/or distantly. The site of recurrent tumor progression was similar in both groups. Stratified Kaplan-Meier and univariate Cox regression analysis identified recurrent tumor size, age, and recurrence-free intervals, but not relapse location as prognostic factors. Only size of the recurrent tumor significantly influenced survival in the multivariate Cox analysis. CONCLUSIONS: These results suggest that central and pelvic wall recurrences of cervical cancer do not exhibit pronounced biologic differences. Patients with large (> or = 5 cm) recurrences have a poor prognosis in spite of extended radical treatment irrespective of tumor location. Efforts should be made to detect isolated pelvic relapses at a smaller tumor size to enhance the chance for long term survival after local control by exenteration and CORT.
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)
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This technical note introduces a modified Syed-Neblett type perineal template for high-dose-rate interstitial brachytherapy of gynecologic malignancies. The template can easily be disassembled after the insertion of the central needles into the pelvis allowing the cystoscopic and rectoscopic control of the needle positions. Thus needles penetrating the bladder or the rectum are recognized and can be repositioned before reassembling the template. Elimination of hot irradiation zones in tumor-free bladder and rectum walls might lead to reduction of severe late complications without compromising the therapeutic efficacy.
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.
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.
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.
CORT has been developed to treat recurrent gynaecological malignancies infiltrating the pelvic wall unilaterally. The surgical part consists of: (i) staging laparotomy/lymphadenectomy, (ii) maximum tumour resection at the pelvic wall and exenteration of infiltrated central pelvic organs, (iii) implantation of guiding tubes on the residual tumour/tumour bed on the pelvic wall, (iv) pelvic wall plasty with muscle, musculocutaneous and omentum flaps, (v) operative reconstruction of bowel, bladder and perineo-vulvo-vaginal functions. Radiation is performed as interstitial high dose rate brachytherapy through the implanted tubes. Patients without prior pelvic irradiation receive in addition, whole pelvis teletherapy. CORT has been evaluated in a prospective phase I and II trial at the University of Mainz. Within a 3-year period, 21 patients with pelvic wall recurrences from various gynaecological primary tumours were treated. Seventeen patients had been irradiated as (part of) the previous therapy with a median total mid-pelvic dose of 65 Gy (range 40-100 Gy). There was no operative mortality. Five patients developed complications necessitating surgical intervention. One patient died from fatal thromboembolism 6 months after CORT without evidence of tumour progression. In 14 patients, local tumour control has been achieved. After a median follow-up period of 27 months (range 6-38 months) Kaplan-Meier life table analysis revealed an actuarial survival probability of 55% (recurrence-free 49%). We conclude from these preliminary results, that the CORT procedure for the treatment of pelvic wall recurrences is feasible and may lead to encouraging therapeutic success in selected patients, whose situation had been hopeless so far.
CORT is a new radiosurgical treatment concept for patients with recurrent gynecologic malignancies infiltrating the pelvic wall. The operative part consists of (i) staging laparotomy; (ii) maximum debulking of the tumor from the pelvic wall and exenteration of infiltrated central pelvic organs; (iii) implantation of brachytherapy guiding tubes on the residual tumor/tumor bed at the pelvic wall; (iv) pelvic wall plasty with muscle and omentum flaps to create a protective distance between the tubes and the pelvic hollow organs and to induce therapeutic angiogenesis; and (v) surgical reconstruction of bowel, bladder, and vulvoperineovaginal functions. Radiation is given postoperatively as fractionated HDR brachytherapy via the implanted tubes. Patients without prior pelvic radiation also receive preoperative whole pelvis teletherapy. Eighteen patients with recurrent malignancies infiltrating one pelvic wall have been treated with CORT in a prospective phase I/II trial at the University of Mainz. Fourteen patients had a history of radiation therapy with midpelvic doses of 40-100 Gy (median, 65 Gy) as primary treatment. Eleven patients (61%) are without evidence of disease at 6-32 months (median, 15 months) follow-up. Four patients have died from pelvic progression and distant metastases, and two patients are alive with disease after 12 months. There was no operative mortality; however, one patient succumbed from fatal thromboembolism 6 months after therapy. Three patients with prior radiation of greater than 75 Gy had to be treated for intestinal fistulas. We conclude that CORT is feasible with encouraging preliminary results.
Ascending infection is a serious threat in pregnancies complicated by preterm premature rupture of the membranes (PROM). In a controlled randomized prospective pilot study (n = 18) we have evaluated the effect of intravenous IgM enriched immunoglobulin given to the mothers 24-48 hours after preterm PROM in reducing ascending infection. Using a validated infection score from laboratory and clinical data at birth, we found a significant reduction of probable infection in the neonates of the treatment group compared to the control group (p = 0.0022). Histopathological investigation of the placentas, membranes and umbilical cords revealed significantly lower stages and grades of chorioamnionitis in the treatment group (p = 0.036). From these preliminary results we conclude, that intravenous broad spectrum immunoglobulin given antenatally to patients with preterm PROM may reduce ascending infection. However, studies with a much larger cohort of patients are necessary to confirm these preliminary results and to detect potential clinical benefits from this treatment mode.
The pelvic exenteration procedure must be considered a multimodal therapeutic concept from a humanistic-medical point of view. Careful patient selection, radical resection of all tumor-infiltrated organs, complete interdisciplinary organ reconstruction, and optimal perioperative management including full psychosomatic rehabilitation are mandatory. This concept should only be realized in medical centers with highly sophisticated infrastructures.
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.
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).