Variation of vascular density within and between tumors of the uterine cervix and its predictive value for radiotherapy.

Vascular density in different regions of a number of uterine cervix carcinomas was determined by morphometric analysis of stained histologic sections. Variance analysis indicated a larger inter- than intra-tumoral inhomogeneity of the vasculature, suggesting a certain individual vascularization pattern in these tumors. As indicated by a retrospective study of archival biopsies, this pattern has a predictive value in regard to the efficacy of radiotherapy.

Flow cytometric analysis of primary cervical and vulvar carcinomas and their metastases.

In a series of 25 patients with cervical carcinoma and 35 patients with vulvar carcinoma, clinically classified (FIGO) as Stage I and Ib, respectively, DNA ploidy and S-phase cell fraction were estimated in paraffin-embedded samples of the primary tumors and their metastases by means of flow cytometry (FCM). The two groups of patients were selected cases in whom lymph nodes removed at radical operation were histopathologically verified as metastatic ones. Prevailing part of primary tumors of both anatomic sites had diploid DNA content and low S-phase fraction. Irrespective of the DNA content and low proliferative activity the early stage carcinomas behaved aggressively as indicated by the presence of metastases, the DNA content of which corresponded in most of the cases with that of primary tumor. It appears that prediction of the tumor growth based only on cytogenetic and cytokinetic parameters may be connected with difficulties.

Vascular density in carcinoma of the uterine cervix and its predictive value for radiotherapy.

The vascular density (VD) in stage-III tumors of the uterine cervix was determined by morphometric analysis of histologic, Masson-trichrome stained sections prepared from biopsies. In a retrospective study, VD was found to be related to results of radiotherapy, larger VD being associated with prolonged survival, in agreement with similar observations made earlier with stage-IB and -IIA tumors of the cervix. In a complementary study the variation of VD within tumors was investigated in relation to the variation between tumors using surgically removed cervical carcinomas in stage IB. Statistically significant F-ratios were calculated, suggesting a more or less individual pattern of vascularization of the tumors despite a considerable intra-tumoral heterogeneity of the vasculature. It is concluded that VD may reflect oxygenation of neoplastic tissue, and may have a predictive value in regard to the response of tumors to irradiation.

Prognostic significance of vascular density and a malignancy grading in radiation treated uterine cervix carcinoma.

In a retrospective study of 95 patients with squamous cell carcinoma of the uterine cervix (Stage IB, IIA, III) treated by radiation only, pretreatment biopsy material was used for assessment of the prognostic value of histopathological multifactorial malignancy grading and a morphometric estimation of vascular density in stroma. By comparison of the two systems, vascular density has been proved superior to malignancy grading with respect to prognostic value.

[Tumor vascularity: its possible prognostic and therapeutic value]. / Gefässdichte in Tumoren: ihr möglicher prognostischer und therapeutischer Wert.

Three studies have been conducted in order to find out a correlation between the degree of tumor vascularization and local recurrences or the survival of patients after radiotherapy. The results have been reviewed. They show a better effect of radiotherapy in tumors with dense capillary vascularization than in tumors with poor vascularization. The prognostic value of tumor vascularization is discussed with regard to the individualization of radiotherapy, considering especially the clinical application of sensitizing substances for hypoxic cells. The conclusion is drawn that, in order to obtain another valuable diagnostic parameter, an index of vascularization should be routinely defined when establishing the histopathologic features.

Tumor vascularization, hypoxia, staging of tumors and radiocurability.

Retrospective, morphometric analysis of histological preparations from cervical cancers indicate that the stromal component of the neoplastic tissue is richer in vascular elements in the cases in which the patients have a prolonged survival after radiotherapy. The finding supports earlier observations which indicate a relationship between intercapillary distance and radiocurability of cervical cancers. The routine determination of a vascularity index V, denoting the grade of vascular density in the neoplastic tissue, is suggested as a complementary parameter for the classification of tumours. Access to such an index could promote a more individualized tumor therapy, especially in regard to the control of radioresistant, hypoxic cells.

A morphometric study of vascularization in uterine cervix cancers.

The stromal, parenchymal, and vascular cellular constituents were identified and their relative proportion determined in biopsy specimens derived from untreated uterine cervix carcinomas. In the stroma of the tumors that eventually responded well to radiation treatment resulting in a prolonged survival of the patients, the proportion of vascular cells was increased in comparison to the cases that were associated with a poor patient survival. The observations were interpreted in terms of the radiobiological oxygen effect reflecting the radiosensitivity variation of cells in tumor areas vascularized to varying extent. It was concluded that the determination of a tumor vascularity index as a routine parameter would be of a great prognostic value and would contribute to the characterization of individual tumors, leading to improved therapeutic efficiency.

Irradiation scheme using three daily fractions in the radiation therapy of pharyngeal and oral carcinomas.

A group of 34 patients were treated by irradiation using 3 daily fractions of 1 Gy each at 4 h intervals. The overall TD in all of the patients was 60 Gy administered within 26 days. The irradiation was carried out by telecurietherapy utilizing 60Co. Twenty-eight patients had the tumor in the oropharynx, 1 in the hypopharynx, 1 in the oro- and hypopharynx and 4 in the oral cavity. There was a prevalence of advanced clinical stages. At present 25 of the patients are living, 21 of them without clinical symptoms of the disease. The skin reacted to irradiation only with a slight erythema and hyperpigmentation. Irradiation reactions in the oropharyngeal and oral mucosa were grave and were accompanied by significant subjective complaints. No post-irradiation complications were observed.

Prognostic significance of lymphocytic infiltration in radiation-treated uterine cervix carcinoma.

In a retrospective series of 45 patients with uterine cervix carcinoma Stage Ib and IIa who had been treated by radiation, biopsy material obtained prior to treatment was reevaluated for the presence of lymphocytic infiltration. The analysis based on 5 degrees of the intensity of stromal reaction has shown that the presence of lymphocytic infiltration, the intensity of which was significantly related to the proportion of blood vessels in stroma, was connected with a favorable outcome of treatment. The results suggest that vascular density being the determinant factor in oxygenation of the cancer tissue and its radiotherapeutic control may also play an important role in the immunological reaction against the tumor.

Dynamic dose-fractionation combined with oxygen breathing at ambient pressure and high-dose metronidazole in head and neck, and uterine cervix cancer.

The paper summarizes the results of dynamic dose-fractionation combined with oxygen breathing at ambient pressure and metronidazole in head and neck, and uterine cervix cancer. The patients were given high oral doses of metronidazole (5-6 g/m2) three hours before dose fractions (4.5 Gy for two days) initiating the radiation treatment series. After successive daily irradiation with 2 X 1 Gy in 8 hours interval (without metronidazole) to the tumor dose 29 Gy, 5-day radiation free interval was inserted and then the identical treatment series was repeated to the total dose 60 Gy. Nausea and vomiting were the principal toxic symptoms which were rather severe in gynecological patients. The benefit of metronidazole combination was studied in comparison with a group of patients given dynamic dose-fractionation with breathing of oxygen only. Preliminary analysis of the data suggests that the combination with radiosensitizer has not produced an increase in the curability of cancer in these particular sites.

Oxygen tension and prediction of the radiation response. Polarographic study in human breast cancer.

Serial polarographic measurement of the tissue oxygen tension (pO2) was made in the course of fractionated irradiation (preoperative or sole treatment) of advanced breast cancer in 24 patients. In responsive tumors increase in pO2 appeared sooner before expressive tumor size reduction became noticeable. Repeated recording of unchanged pO2 values has proved to be a good prognostic indicator of local failure. The study made on this tumor model has shown that serial polarographic pO2 determinations with suitable electrodes causing minimal trauma and providing consistent and reproductive data about changes in tumor microcirculation and oxygenation, may enlarge the scale of indicators of the radiation response.

Vascularization and radiocurability in cancer of the uterine cervix. A retrospective study.

The proportion of vascular elements in relation to the parenchymal and stromal components was determined by morphometric analysis of the histologic preparations from biopsies of uterine cervix cancers. In all cases, the material was obtained from tumors in Stages Ib and IIa before any therapy was initiated. In the 23 cases in which radiation treatment of the lesions resulted in a survival longer than 5 years, the proportion of blood vessels in the neoplastic tissue was found to be larger, and especially the stromal components were richer in vascular elements than in the 22 cases in which survival was shorter than 5 years. It was concluded that vascular density at least in cervical cancers of the stages studied can be a diagnostic parameter of a prognostic value as well as of a therapeutic usefulness.

Radiation-induced changes in cell proliferation kinetics in uterine cervix cancer.

In vitro double labeling autoradiography for measuring the labeling index, duration of S phase and potential doubling time has been used to assess the effect of a single and fractionated test dose of irradiation in uterine cervix cancer applied in 21 patients. Tumor-labeling index fell significantly in those tumors which had a high labeling index before irradiation, and these cases were found later to exhibit a good radiation response. Duration of S phase which ranged between 9 and 27 hours prior to irradiation was increased. Differences between the potential doubling time and the actual doubling time suggest a massive cell loss in tumors which were, for the most part, of exophytic type. Fractionated irradiation provides more reliable informations than a single dose and is useful for investigation of dynamic changes in the kinetics of an asynchronous cell population.

Changes in blood flow of growing experimental tumor determined by the clearance of 133Xe.

133Xe clearance method has been employed for measurement of the blood flow in 6C3HED lymphosarcoma implanted in flank of C3H mice. In small tumors (9-day old) the mean rate of blood flow was 9.4 +/- 5.0 ml/100g/min. but with progressing growth of tumors the rate of blood flow significantly decreased. In large tumors (14-day old) the mean rate of the blood flow was only 5.4 +/- 2.8. Our results demonstrate that this type of tumor, similarly as most of transplanted tumors are not well perfused and, that there is an inverse relationhip between the blood flow and the tumor size.

Cytokinetic analysis at various ages of an ascites tumor after radiation.

A cytokinetic analysis has been made of 5-day and of 10-day old murine 6C3HED ascites lymphosarcoma (Gardner) by using a growth curve, percentage of labeled mitoses curves, and continuous labeling curves. The doubling time increased from 36 h in the proliferative phase of growth to 252h in the stationary phase. The slowing down of the growth rate was due to prolongation of the cell cycle time, with greatest extension in G1 and increased cell loss. The measurement of the kinetic parameters made immediately after irradiation with a whole-body single dose of 3 Gy (300 rad) showed an increase in duration of the cell cycle in the 5-day-old tumor, while in the 10-day-old tumor the cell cycle time was decreased due to reduce length in the G1 phase.