Experimental perfusion of various organs has primarily been used in transplantation medicine to study the physiology, pathophysiology and metabolism of tissues and cells. The purpose of this study was to establish an experimental model for the extracorporeal perfusion of the human uterus with recirculation of a modified, oxygenated Krebs-Henselait solution, in comparison with a non-recirculating perfusion system. With consent of the patients we obtained 25 uteri after standard hysterectomy. We performed an isovolumetric exchange of the perfusion medium at different intervals from 1 to 6 h and examined pH, pO(2), pCO(2), lactate, lactate dehydrogenase and creatine kinase by taking arterial and venous samples every hour for 24 h. We found the perfusions to be adequate when maintaining flow rates at 15-35 ml/min and at pressures ranging from 70 to 130 mmHg. Isovolumetric exchange of the perfusate every 3-4 h was the maximum interval to keep pH, the arterio-venous gradients of pO(2) and pCO(2), and the other biochemical parameters in physiological ranges. Examination by light and electron microscopy showed well-preserved features of myometrial and endometrial tissue. However, a 6 h exchanging interval led to increasing hypoxic and cytolytic parameters during the whole perfusion period. X-ray studies using digital subtraction angiography and perfusion studies with methylene blue demonstrated the homogeneous distribution of the perfusion fluid throughout the entire organ.
Oxytocin (OT) and the oxytocin receptor (OTR) seem to be less important for uterine contractility-associated disorders of the non-pregnant uterus compared to the pregnant uterus. In the present study, we investigated the mutual dependence of OTR, OT and 17beta-estradiol (E(2)) with regard to the localization of OTR in the non-pregnant uterus. Utilizing our established model for extracorporeal perfusion of the human uterus, we perfused 15 human uteri for 27 h under physiological conditions without oestradiol (group A, n = 5) or with high E(2) stimulation (group B, n = 5) followed by OT stimulation for both groups during the last 3 h of the experiment. Negative controls (n = 5) remained in perfusions for 27 h without any further hormone treatment. Gene expression of the myometrial OTR in both groups was compared using reverse transcriptase triple primer PCR. Stimulation with E(2) and OT led to significantly higher OTR gene expression than stimulation with OT alone. We also showed that concentrations of OTR transcripts increase from the lower uterine segment to the uterine fundus. However, maximum OTR levels of the uterine fundus in group B did not reach concentrations of specimens of third trimester of pregnancy which were used as positive controls. We conclude that our experimental model simulates a situation similiarly to the stimulated non-pregnant uterus in the therapeutic concepts of assisted reproduction. The data presented demonstrate that the dynamics of OTR expression can be modulated by stimulation with E(2) and OT, not only in the pregnant but also in the non-pregnant uterus.
We have generated an immunoglobulin G1 (IgG1) murine monoclonal anti-idiotype antibody (Ab2) designated ACA125, which mimics a specific epitope on the tumor-associated antigen CA125. This antigen is expressed by most of malignant ovarian tumors. Patients with CA125-positive tumors are immunologically tolerant to CA125. We used ACA125 as a surrogate for the tumor-associated antigen CA125 for vaccine therapy of 16 patients with advanced epithelial ovarian cancer or recurrences. Each of the patients received a minimum of 3 injections up to 19 injections of the complete anti-idiotype MAb ACA125 at a dosage of 2 mg per injection. Nine of 16 patients developed anti-anti-idiotypic (Ab3) responses to the ACA125. All 9 patients generated specific anti-CA125 antibody demonstrated by reactivity with purified CA125. Nine of 16 patients developed a CA125-specific cellular immune response by their peripheral blood lymphocytes (PBL) and 3 of 16 showed an increase in gamma-interferon concentrations accompanied by Ab3 responses. Toxicity was limited to abdominal pain in one case, which led to the withdrawal of further immunizations. The median progression free survival in those patients, who showed a specific immune response to the tumor-associated antigen CA125, was 11.0 +/- 5.6 months without any other therapy, in contrast to 8.0 +/- 4.2 months in the anti-anti-idiotype negative group. This is the first report of the induction of a specific active immunity to the tumor-associated antigen CA125 in patients with advanced ovarian cancer treated with an anti-idiotype antibody that "mimics" CA125. Patients showed the development of a specific humoral and cellular immune response to an otherwise nonimmunogenic tumor antigen. The immune responses in patients treated with this anti-idiotype vaccine, the low rate of side effects, and the improved time to progression after the induction of a specific immune response against the tumor-associated antigen CA125 justify follow-up clinical trials in advanced ovarian cancer patients with minimal residual disease in an adjuvant approach.
This study documents values of biochemical markers of bone remodeling in 106 patients with breast cancer. Based on scintigraphic and radiological findings, patients were divided into 3 groups: 19 patients with bone metastases, 65 patients without bone metastases and normal bone scintigrams, and 22 patients with pathological, non-malignant findings on scintigraphy without proof of bone metastases. Urinary cross-linked type I collagen N-telopeptides (NTx) and serum cross-linked type I collagen C-telopeptides (ICTP) were assessed as markers of bone resorption. Bone alkaline phosphatase (BAP) was assessed as a marker of bone formation. All three markers were significantly higher in patients with bone metastases compared to both patients without skeletal recurrence and those with pathological, non-malignant scintigraphic findings (p < 0.01). There were no statistically significant differences between the latter two groups. The clinical sensitivity for diagnosing bone metastases was 44% for NTx, 65% for ICTP, and 26% for BAP, respectively. The clinical specificitiy for discriminating patients with bone disease from those without were 79%, 91%, and 92% for NTx, ICTP, and BAP, respectively. In conclusion, markers of bone remodeling are increased in patients with breast cancer metastatic to the skeleton. The sensitivity of the markers presented in this paper did not seem to be sufficient enough for early identification of patients with subclinical bone recurrence in a clinical practice setting.
Taken together, our data demonstrate that the dynamics of oxytocin receptor expression can be affected by stimulation with 17-beta-estradiol and oxytocin not only in the pregnant uterus, but also in the nonpregnant uterus. Therefore, dyscontractile phenomena of the nonpregnant myometrium also may be mediated via 17-beta-estradiol, oxytocin and the oxytocin receptor.
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