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.

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.

Regional distribution of high-affinity L-tryptophan uptake in rat brain.

L-tryptophan is accumulated by slices of seven regions of the rat brain in a saturable, energy-depending fashion, with K(m)-values ranging from 53 to 142 muM. The maximal number of L-tryptophan accumulating sites differs only by about two-fold for the brain regions investigated. The regional distribution of the high-affinity L-tryptophan uptake does not correlate with the amount of serotonin synaptosomal uptake and apparent receptor binding. It is assumed that a specific role of the L-tryptophan uptake system within the serotoninergic system in the brain is questionable.

[Piroxicam gel versus diclofenac gel in active gonarthroses]. / Piroxicam-Gel versus Diclofenac-Gel bei aktivierten Gonarthrosen.

In this single-blind comparative study 97 patients suffering from activated gonarthrosis were treated with either 4 x 40 mg of diclofenac gel or 4 x 5 mg piroxicam gel. Owing to protocol violations, 28 patients were not included in the statistical evaluation. During the course of the treatment, a marked decrease in signs and symptoms was observed in the 69 patients included in the evaluation. In 80% of the patients, the treating physician assessed the efficacy of piroxicam gel as "good" or "excellent", in only 20% it was assessed as "moderate". In the diclofenac group, assessment of the results was positive in 74% of the patients. In 24% of the patients of this group, the physician's assessment of the success of the treatment was "not satisfactory". The majority of physicians and patients were satisfied with the toleration of the drugs used in this study. Only 2 patients (5.6%) of the piroxicam group and 4 patients (12.2%) of the diclofenac group were critical of local toleration. The results of this clinical trial show that the preparations used here are appropriate for local therapy of distortions of the ankle joint.

Total mesometrial resection: high resolution nerve-sparing radical hysterectomy based on developmentally defined surgical anatomy.

Total mesometrial resection (TMMR) is characterized by: i). the en bloc resection of the uterus, proximal vagina, and mesometrium as a developmentally defined entity; ii). transection of the rectouterine dense subperitoneal connective tissue above the level of the exposed inferior hypogastric plexus; and iii). extended pelvic/periaortic lymph node dissection preserving the superior hypogastric plexus. Since July 1998 we have studied prospectively the outcome in patients treated with TMMR for cervical carcinoma FIGO stages IB, IIA, and selected IIB. By July 2002, 71 patients with cervical cancer stages pT1b1 (n = 48), pT1b2 (n = 8), pT2a (n = 3), pT2b (n = 12) had undergone TMMR without adjuvant radiation. Fifty-four percent of the patients exhibited histopathologic high risk factors. At a median observation period of 30 months (9-57 months) two patients relapsed locally, two patients developed pelvic and distant recurrences and two patients only distant recurrences. Three patients died from their disease. Grade 1 and 2 complications occurred in 20 patients, no patient had grade 3 or 4 complications. No severe long-term impairment of pelvic visceral functions related to autonomic nerve damage was detected. Based on these preliminary results, we believe TMMR achieves a promising therapeutic index by providing a high probability of locoregional control at minimal short and long-term morbidity.

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.