Gestational trophoblastic tumors in Norway, 1968-1997: patient characteristics, treatment, and prognosis.

OBJECTIVES: The aim of this study was to give an overview of the Norwegian population of gestational trophoblastic tumors (GTT), diagnosed during 1968-1997 and treated with chemotherapy at the Norwegian Radium Hospital (NRH), with regard to patient characteristics, treatment, and prognosis. METHODS: The cases were grouped according to a modified version of the WHO scoring system. Staging was performed retrospectively according to the systems adopted by FIGO. Survival estimates were calculated by the method described by Kaplan and Meier. Cox regression models were used to find the best classification system with regard to prognosis (disease-free survival). RESULTS: A total of 141 cases, 106 invasive moles (IM) and 35 choriocarcinomas (CC), were diagnosed in Norway and treated with chemotherapy at the NRH in the period 1968-1997. Altogether, 56% of the patients were assigned to the low-risk category, 20% to the medium-risk category, and 15% to the high-risk category. Most cases were classified into the clinical stages I (69%) and III (23%). The overall 5-year survival rate was 96%. A more favorable prognosis was seen in patients diagnosed in the 1980s and 1990s compared with those diagnosed in the 1970s (P = 0.04). Five patients had progressive disease and died from the disease. Nine patients relapsed. The prognosis (disease-free survival) was more favorable for IM compared with CC (P < 0.01). The FIGO classification system seemed to be a better predictor of disease-free survival than the WHO scoring system. CONCLUSIONS: This study showed that the prognosis of patients with GTT improved in the 1980s and 1990s in Norway, and that the FIGO system might be the best predictor of disease-free survival.

Assessment of tumor oxygenation in human cervical carcinoma by use of dynamic Gd-DTPA-enhanced MR imaging.

Increased knowledge of the physiological basis behind the signal enhancement in tumors during dynamic contrast-enhanced magnetic resonance (MR) imaging may be useful in development of predictive assays based on this technique. In the present work, the relative signal intensity (RSI) increase in gadopentetate dimeglumine (Gd-DTPA)-enhanced MR images of patients with cervical carcinoma was related to tumor perfusion, vascular density, cell density, and oxygen tension (pO(2)). The patients were subjected to MR imaging before the start of treatment (N = 12) and after two weeks of radiotherapy (N = 8). Perfusion was determined from the kinetics of contrast agent in tumors and arteries, vascular density and cell density were determined from tumor biopsies, and pO(2) was determined by polarographic needle electrodes. The maximal RSI was correlated to perfusion (P = 0.002) and cell density (P = 0.004), but was not related to vascular density. There was also a correlation between pO(2) and perfusion (P < 0.001). Moreover, pO(2) tended to be correlated to cell density (P = 0.1), but was not related to vascular density. There was a significant correlation between RSI and pO(2), regardless of whether the median pO(2) (P < 0.001) or the fraction of pO(2) readings below 2.5 mmHg (P < 0.001), 5 mmHg (P < 0.0001), or 10 mmHg (P < 0.001) was considered. Our results suggest that the Gd-DTPA-induced signal enhancement in MR images of cervical tumors is influenced by both perfusion and cell density. These parameters are also of major importance for tumor oxygenation, leading to a correlation between signal enhancement and oxygenation. Dynamic contrast-enhanced MR imaging may therefore possibly be useful in prediction of treatment outcome.

Intra- and intertumor heterogeneity in blood perfusion of human cervical cancer before treatment and after radiotherapy.

Knowledge of the intratumor heterogeneity in blood perfusion may lead to increased understanding of tumor response to treatment. In the present work, absolute perfusion values, in units of ml/g.min, were determined in 20 tumor subregions of patients with cervical cancer before treatment (n = 12) and after 2 weeks of radiotherapy (n = 8), by using a method based on contrast-enhanced magnetic resonance imaging. The aims were to evaluate the intratumor heterogeneity in perfusion in relation to the intertumor heterogeneity and to search for changes in the heterogeneities during the early phase of therapy. The intra- and intertumor heterogeneity in perfusion were estimated from components of one-way analyses of variance. The mean perfusion differed significantly among the patients before treatment, ranging from 0.044 to 0.12 ml/g x min. Large differences in perfusion were also observed within individual tumors. The heterogeneity was largest in the best perfused tumors, perfusion values ranging, e.g., from 0.055 to 0.29 ml/g x min were observed. The intratumor heterogeneity was similar to the intertumor heterogeneity. The mean perfusion generally increased or tended to increase during radiotherapy, ranging from 0.064 ml/g x min to 0.13 ml/g x min after 2 weeks of treatment. There was a tendency of increased intratumor heterogeneity in perfusion after therapy, consistent with the higher mean value; a difference in perfusion of more than a factor of 10 was seen within some tumors. These results suggest that cervix tumors contain a significant amount of poorly perfused subregions with high treatment resistance. Moreover, the perfusion and perfusion heterogeneity may increase during the early phase of radiotherapy and influence tumor response.

Hypoxia-induced treatment failure in advanced squamous cell carcinoma of the uterine cervix is primarily due to hypoxia-induced radiation resistance rather than hypoxia-induced metastasis.

Poor outcome of treatment in advanced cervix carcinoma has been shown to be associated with poor oxygenation of the primary tumour. Hypoxia may cause radiation resistance and promote lymph-node metastasis. The purpose of the study reported here was to investigate whether hypoxia-induced treatment failure in advanced cervix carcinoma is primarily a result of hypoxia-induced radiation resistance or the presence of hypoxia-induced lymph-node metastases at the start of treatment. Thirty-two patients with squamous cell carcinoma of the uterine cervix were included in the study. Radiation therapy was given with curative intent as combined external irradiation and endocavitary brachytherapy. The oxygenation status of the primary tumour was measured prior to treatment using the Eppendorf PO2 Histograph. Pelvic and para-aortal lymph-node metastases were detected by magnetic resonance imaging at the time of initial diagnosis. The primary tumours of the patients with metastases (n = 18) were significantly more poorly oxygenated than those of the patients without metastases (n = 14). Multivariate Cox regression analyses involving biological and clinical parameters identified the tumour subvolume having PO2 values below 5 mmHg (HSV (pO2 < 5 mmHg) as the only significant, independent prognostic factor for locoregional control, disease-free survival and overall survival. The probabilities of locoregional control, disease-free survival and overall survival were significantly lower for the patients with HSV (PO2 < 5 mmHg) above the median value than for those with HSV (PO2 < 5 mmHg) below the median value. On the other hand, the outcome of treatment was not significantly different for the patients with metastases and the patients without metastases at the start of treatment, irrespective of clinical end-point. Consequently, treatment failure was primarily a result of hypoxia-induced radiation resistance rather than hypoxia-induced lymph-node metastasis, suggesting that novel treatment strategies aiming at improving tumour oxygenation or enhancing the radiation sensitivity of hypoxic tumour cells may prove beneficial in attempts to improve the radiation therapy of advanced cervix carcinoma.

Randomized study on adjuvant chemotherapy in stage I high-risk ovarian cancer with evaluation of DNA-ploidy as prognostic instrument.

PURPOSE: Adjuvant chemotherapy versus observation and chemotherapy at progression was evaluated in 162 patients in a prospective randomized multicenter study. We also evaluated DNA-measurements as an additional prognostic factor. PATIENTS AND METHODS: Patients received adjuvant carboplatin AUC 7 every 28 days for six courses (n = 81) or no adjuvant treatment (n = 81). Eligibility included surgically staged and treated patients with FIGO stage I disease, grade 1 aneuploid or grade 2 or 3 non-clear cell carcinomas or clear cell carcinomas. Disease-free (DFS) and disease-specific (DSS) survival were end-points. RESULTS: Median follow-up time was 46 months and progression was observed in 20 patients in the treatment group and 19 in the control group. Estimated five-year DFS and DSS were 70% and 86% in the treatment group and 71% and 85% in the control group. The hazard ratio was 0.98 (95% confidence interval (95% CI): 0.52-1.83) regarding DFS and 0.94 (95% CI: 0.37-2.36) regarding DSS. No significant differences in DFS or DSS could be seen when the log-rank test was stratified for prognostic variables. Therefore, data from both groups were pooled for the analysis of prognostic factors. DNA-ploidy (P = 0.003), extracapsular growth (P = 0.005), tumor rupture (P = 0.04), and WHO histologic grade (P = 0.04) were significant independent prognostic factors for DFS with P < 0.0001 for the model in the multivariate Cox analysis. FIGO substage (P = 0.01), DNA ploidy (P < 0.05), and histologic grade (P = 0.05) were prognostic for DSS with a P-value for the model < 0.0001. CONCLUSIONS: Due to the small number of patients the study was inconclusive as regards the question of adjuvant chemotherapy. The survival curves were superimposable, but with wide confidence intervals. DNA-ploidy adds objective independent prognostic information regarding both DFS and DSS in early ovarian cancer.

Changes in tumor oxygen tension during radiotherapy of uterine cervical cancer: relationships to changes in vascular density, cell density, and frequency of mitosis and apoptosis.

PURPOSE: Changes in oxygen tension (pO(2)) during the early phase of fractionated radiotherapy were studied in 22 patients with uterine cervical cancer. The aims were to investigate (a) whether possible changes in pO(2) differed among and within tumors and (b) whether the changes could be attributed to changes in vascular density, cell density, and frequency of mitosis and apoptosis. METHODS AND MATERIALS: The pO(2) was measured polarographically in four regions of the tumors before treatment and after 2 weeks of radiotherapy. The vascular density, cell density, and frequency of mitosis and apoptosis were determined from biopsies taken from the tumor regions after each pO(2) measurement. RESULTS: The changes in pO(2) during therapy differed among the tumors and were correlated to pO(2) before treatment (p < 0.001). The direction of the changes was consistent throughout the tumors; all regions in tumors with increased oxygenation had increased or no change in pO(2) and vice versa. The tumors with increased pO(2) (n = 10) had a large decrease in cell density and a significant increase in apoptotic frequency. In contrast, the tumors with decreased pO(2) (n = 10) had a smaller decrease in cell density (p = 0.014) and no significant increase in apoptotic frequency. Vascular density and mitotic frequency showed no change during therapy; however, vascular damage other than decreased vascular density was observed. CONCLUSION: These results indicate that the oxygenation of cervix tumors generally changes during the early phase of radiotherapy. The change depends on the balance between the factor leading to an increase and that leading to a decrease in oxygenation; i.e., decreased cell density and vascular damage, respectively. Increased apoptotic frequency may contribute to a large decrease in cell density and hence increased oxygenation during therapy.

Treatment outcome in advanced squamous cell carcinoma of the uterine cervix: relationships to pretreatment tumor oxygenation and vascularization.

Poor outcome of treatment was found to be associated with low oxygen tension in the primary tumor and not with high intratumor microvessel density in 40 patients with advanced squamous cell carcinoma of the uterine cervix. Multivariate Cox regression analysis identified the total volume of the hypoxic tumor regions, i. e. the tumor subvolume having pO(2) values below 5 mmHg, as a significant prognostic factor for locoregional control, disease-free survival, and overall survival. Other important prognostic factors, identified by univariate Cox regression analysis, were tumor volume, the fraction of pO(2) readings giving pO(2) values below 5 mmHg, and tumor stage.

High lactate levels predict likelihood of metastases, tumor recurrence, and restricted patient survival in human cervical cancers.

Pathophysiological parameters such as vascular density and tissue oxygen pressure can influence tumor malignancy and patient survival. Observations from our group showed that metastatic spread of carcinomas of the uterine cervix and of head and neck cancers was closely correlated with the lactate concentration in the primary lesion. Because these results were obtained in a low number of patients, the present investigation was performed to verify such a correlation in a larger population. Cryobiopsies were taken at first diagnosis of cervical cancer from 34 patients. Tissue concentrations of ATP, glucose, and lactate in viable tumor regions of these biopsies were measured microscopically using the technique of imaging bioluminescence. There was no correlation between stage or grade and any of the metabolic parameters measured. ATP and glucose concentrations were not significantly different in metastatic and nonmetastatic primary tumors (P>0.05). However, lactate concentrations were significantly higher (P = 0.001) in tumors with metastatic spread (mean +/- SD, 10.0+/-2.9 micromol/g; n = 20) compared with malignancies in patients without metastases (6.3+/-2.8 micromol/g; n = 14). The majority of patients who suffered a recurrence of the disease (17 of a total of 22 patients) or died (15 of 20) within the observation period of up to 8 years belonged to the metastatic, i.e., high lactate group. A Kaplan-Meier analysis of the data showed that the overall and disease-free survival probabilities of patients having low tumor lactate values were significantly higher compared with patients with high tumor lactate concentrations (P = 0.015 and 0.014, respectively). We conclude that tumor lactate content may be used as a prognostic parameter in the clinic. Furthermore, these findings are in accordance with data from the literature showing that the presence of hypoxia in cervical tumors is associated with a poorer patient survival.

Disease control of uterine cervical cancer: relationships to tumor oxygen tension, vascular density, cell density, and frequency of mitosis and apoptosis measured before treatment and during radiotherapy.

Identification of biological parameters of major importance for the control of malignant diseases can be useful for the design of optimal treatment regimes for individual patients. Tumor oxygen tension (pO2), vascular density, cell density, and frequency of mitosis and apoptosis were measured before treatment (40 patients) and after 2 weeks of radiotherapy (22 patients) in patients with uterine cervical cancer. The aim was to investigate whether one of the parameters was more important for disease control than the others. Three sets of data were considered; the pretreatment parameters, the parameters measured after 2 weeks of radiation, and the changes in the parameters during this time. The pO2 was measured polarographically; the other parameters were determined by histological analyses of tumor biopsies. Hypoxic subvolume (HSV5), ie., the fraction of pO2 readings <5 mm Hg multiplied with tumor volume, showed the strongest correlation to control. Patients with a small HSVs before treatment had a higher control probability after a median follow-up time of 50 months than patients with a large HSV5 (P < 0.001). All other parameters or changes in parameters showed impaired correlation to control compared with pretreatment HSV5. The present results suggest that pretreatment oxygenation is more important for disease control of cervical cancer than the oxygenation after 2 weeks of radiotherapy or the changes in oxygenation during this time. Moreover, vascular density, cell density, and frequency of mitosis and apoptosis before treatment or after 2 weeks of therapy are probably not as important as pretreatment oxygenation as well. Although significant correlations between disease control and some of the parameters other than pretreatment oxygenation can occur in studies based on a large number of patients, the specificity of these parameters in the prediction of control is probably not as high as for oxygenation.

Long-term follow-up of neoadjuvant cisplatin and 5-fluorouracil chemotherapy in bulky squamous cell carcinoma of the cervix.

Fifteen patients with bulky (designated as > 3 cm largest diameter) FIGO stage Ib or IIa squamous cervical cancer were treated with cisplatin (100 mg/m2 on day 1) and 5-fluorouracil (1000 mg/m2 continuously on days 1-5) administered intravenously at 21-day intervals for a total of two or three courses before planned radical hysterectomy. A complete clinical response was noted in four patients and a partial response in ten patients, which represents a 93% overall response rate. One patient had stable disease (two courses of chemotherapy), and none had progressive disease. Median tumor volume was 78.5 cm3 and 2.5 cm3 at diagnosis and after neoadjuvant chemotherapy, respectively (p < 0.001). This indicates that chemotherapy resulted in a 97% median reduction of tumor volume. Median overall and disease-free survival was not reached, and the actuarial five-year survival rate was 73% and 67%, respectively. There was no grade 4 toxicity. Myelosuppression was acceptable; however, two patients experienced significant ototoxicity, and in two patients serum creatinine increased. All patients with major toxicity received two cycles of chemotherapy only. The improved local control and survival in our series are in accordance with other results reported, but need to be confirmed in a randomized prospective trial.

Normobaric oxygen treatment during radiotherapy for carcinoma of the uterine cervix. Results from a prospective controlled randomized trial.

BACKGROUND AND PURPOSE: Hypoxia, a frequent characteristic of cervical cancer, is associated with reduced sensitivity to irradiation and thus may be a source of radiotherapy failure. This study was planned to test the hypothesis, that inhalation of oxygen during radiotherapy may increase the radiation effect on the tumor and improve loco-regional control and overall survival. MATERIAL AND METHODS: From 1963 to 1965, a consecutive series of 208 patients with cervical cancer stage II/III who were to be treated by external irradiation plus radium inserts, were included in this study. They were randomly assigned to either receive oxygen inhalations during the radiotherapy sessions or just breathing air. Due to technical reasons the oxygen group was divided. For the first 10 months, they did receive oxygen during the radium inserts only, the last 13 months during all radiotherapy sessions. RESULTS: After median 33 years follow-up, there are no differences in overall survival, cancer-specific survival or loco-regional control. Subgroup analysis shows significantly improved loco-regional control in the stage IIB patients, with squamous cell carcinoma who received oxygen during all radiotherapy sessions. This improvement was especially pronounced among the patients who also received blood transfusions. CONCLUSIONS: There was no influence of normobaric oxygen treatment on the overall outcome to radiotherapy in patients with stage II cervical cancer, but subgroup analyses support the hypothesis that there is tumor areas of hypoxia-based radioresistance that may be counteracted by oxygen administration.

Tumour hypoxia and vascular density as predictors of metastasis in squamous cell carcinoma of the uterine cervix.

Some clinical studies involving several histological types of cancer have suggested that high vascular density in the primary tumour promotes metastasis. Other studies have suggested that a high incidence of metastases is associated with low oxygen tension in the primary tumour. The purpose of the study reported here was to search for correlations between incidence of metastases and oxygen tension or vascular density in the same population of patients. Thirty-eight consecutive patients with squamous cell carcinoma of the uterine cervix were included in a prospective study. Pelvic, iliac and retroperitoneal lymph node metastases were detected by magnetic resonance imaging at the time of initial diagnosis. Oxygen tension was measured polarographically using the Eppendorf pO2 Histograph 6650. Vascular density was determined by histological examination of tumour biopsies. The primary tumours of the patients with metastases (n = 19) were more poorly oxygenated than those of the patients without metastases (n = 19). Thus, the fractions of the pO2 readings resulting in values below 5 mmHg and 10 mmHg were significantly higher for the former group of patients than for the latter (P = 0.03 and 0.02 respectively). In contrast, the vascular density of the primary tumour was not significantly different for the two groups of patients. The present study suggests that a high incidence of metastases in squamous cell carcinoma of the uterine cervix is associated with poor oxygenation of the primary tumour and not with a high vascular density.

Prognosis of 2,800 patients with epithelial ovarian cancer diagnosed during 1975-94 and treated at the Norwegian Radium Hospital.

BACKGROUND: Ovarian cancer patients have a poor prognosis. In Norway, however, the prognosis has improved steadily since the 1950s, the age-adjusted 5-year relative survival reaching 37% in 1989 93. The aim of the present study was to explore the prognosis of patients with epithelial ovarian cancer diagnosed during 1975-94 (the prepaclitaxel period) and treated at The Norwegian Radium Hospital. METHOD: Relative risks (RR) of dying and 95% confidence intervals (95% CI) were derived from multivariate Cox proportional hazards regression models. RESULTS: A total of 2,769 patients with epithelial ovarian cancer were included in the present study. Altogether 54% of the patients were diagnosed with advanced stage disease (stages III and IV), whereas 32% were diagnosed with stage I disease. The prognosis of the patients improved from the 1970s to the 1990s, mainly due to increased short-term survival. In multivariate survival analysis, the RR of dying decreased with period of diagnosis. An RR of 0.77 (95% CI=0.66-0.89) was seen in 1990-94 compared with 1975-79. CONCLUSION: The short-term survival of patients with epithelial ovarian cancer improved from the late 1970s to the early 1990s. However, no major improvement in the long-term survival was seen.

Oxygen tension and vascular density in adenocarcinoma and squamous cell carcinoma of the uterine cervix.

The prognosis of patients with carcinoma of the uterine cervix has been shown to depend on the oxygenation and vascularization status of the tumors. The purpose of the study reported here was to search for possible differences in oxygen tension and vascular density between adenocarcinomas and squamous cell carcinomas. Ten patients with adenocarcinoma and forty patients with squamous cell carcinoma were included in the study. Oxygen tension was measured polarographically using the Eppendorf pO2 Histograph 6650. Vascular density was determined by histological examination of tumor biopsies. The adenocarcinomas were significantly better oxygenated than the squamous cell carcinomas. The squamous cell carcinomas and the adenocarcinomas did not differ significantly in vascular density. The difference in prognosis between patients with adenocarcinoma and patients with squamous cell carcinoma is probably not attributable to differences in tumor oxygenation or vascularization.

Oxygen tension in human tumours measured with polarographic needle electrodes and its relationship to vascular density, necrosis and hypoxia.

BACKGROUND AND PURPOSE: The use of polarographic needle electrodes for measurement of oxygen tension (pO2) in tumours requires documentation of the validity of the method. In the present work the pO2 values measured polarographically with the Eppendorf pO2 histograph in human tumours were compared with the histological appearance of the tumour tissue, i.e. vascular density, fraction of necrosis and fraction of hypoxic tissue, to investigate whether the measurements reflected the expected pO2. MATERIALS AND METHODS: The pO2 was measured in cervix tumours in patients and in human melanoma xenografted tumours in athymic mice. Vascular density was determined in the cervix tumours by histological analysis of biopsies from the pO2 measurement tracks. Fraction of necrosis and fraction of hypoxic tissue, i.e. tissue binding the hypoxia marker pimonidazole, were determined in the melanomas by analysis of histological sections from the tumour planes in which the pO2 measurements were performed. RESULTS: The pO2 distributions showed large intratumour heterogeneity. In cervix tumours, tumour regions with vascular density (vascular length per unit tissue volume) in the range of 47-77 mm/mm3 showed higher pO2 than tumour regions with vascular density in the range of 20-47 mm/mm3, which in turn showed higher pO2 than tumour regions with vascular density in the range of 0-20 mm/mm3. In melanomas, tumour regions in which necrosis and hypoxia constituted more than 50% of the tissue showed lower pO2 than other tumour regions. CONCLUSIONS: The pO2 measured in the tumours was consistent with the histological appearance of the tissue in which the measurements were performed, suggesting that reliable pO2 distributions of tumours can be obtained with polarographic needle electrodes.

Polarographic measurement of pO2 in cervix carcinoma.

The outcome of radiation therapy of cervix carcinoma might depend on the oxygenation of the tumor tissue. An adequate method for measurement of tumor oxygen tension (pO2) is therefore needed. The purpose of the work reported here was dual: (1) to investigate whether polarographic pO2 measurements with the Eppendorf pO2 Histograph 6650 are sufficiently sensitive to detect differences in tumor pO2 before and after blood transfusion of anemic patients and between poorly and well-vascularized tumor tissue, and (b) to investigate whether accurate tumor, pO2 measurements require extensive mapping of tumor temperature and the avoidance of anesthesia. Nineteen patients with squamous cell carcinoma of the uterine cervix FIGO stages Ib to IVb were included in the study. Vascular density was determined by histological examination of tumor biopsies. Propofol was used as a single anesthetic agent. Tumor pO2 distributions recorded before and after the administration of propofol were not different (P > 0.05). The temperatures measured in the tumor periphery and center did not differ from the rectal temperature (P > 0.05), suggesting that tumor pO2 measurements can be based on the rectal temperature. Increased hemoglobin concentrations after blood transfusion resulted in increased tumor oxygenation in 50% of the patients (P < 0.001). The pO2 frequency distributions of the susceptible tumors showed increased 50th percentiles but unchanged 10th percentiles, suggesting that transfusion cannot reduce the fraction of radiation-resistant hypoxic tumor cells extensively. Tumor tissue with high vascular density showed higher pO2 values than tumor tissue with low vascular density (P < 0.001). In conclusion, polarographic measurement of tumor pO2 with the Eppendorf pO2 Histograph 6650 is a sensitive method for assessment of the oxygenation of cervix carcinoma. Reliable tumor pO2 measurements can be performed in patients given propofol anaesthesia and without extensive mapping of tumor temperature.

Incidence of radiation-induced insufficiency fractures of the female pelvis: evaluation with MR imaging.

OBJECTIVE: The purpose of this study was to assess the incidence, time of appearance, and evolution of radiation-induced insufficiency fractures of the female pelvis with MR imaging. SUBJECTS AND METHODS: Eighteen women (nine premenopausal and nine postmenopausal) with advanced cervical carcinoma were studied prospectively with MR imaging. The examinations totaled 216 and were scheduled before radiation therapy, three times during radiation therapy, and eight times after radiation therapy. T1-weighted and short inversion time inversion recovery images were obtained. The images were evaluated by two radiologists in consensus. The criterion for fracture was edema, indicated by an area of high signal intensity on short inversion time inversion recovery images and corresponding low signal intensity on T1-weighted images. CT scans (n = 61) and bone scans (n = 58) were used to confirm each diagnosis of fracture. RESULTS: Sixteen (89%) of 18 patients (seven premenopausal and nine postmenopausal) showed findings compatible with insufficiency fractures. Thirteen patients had more than one lesion. The first fracture was detected between 3 and 12 months after the end of radiation therapy. During the study, the fractures associated with edema subsided without treatment in 41 (79%) of 52 lesions in 15 (94%) of 16 patients. Fractures were confirmed with additional imaging in all 16 patients (CT in 14 patients and bone scanning in nine patients). CONCLUSION: Radiation-induced insufficiency fractures were frequently seen in premenopausal and postmenopausal women within 12 months after radiation therapy. Multiple fractures developed within 24 months. Twenty-one percent of the lesions healed during the observation period of 30 months.

Oxygen tension and vascular density in human cervix carcinoma.

Hypoxia-induced radiation resistance has been proposed to be a consequence of low vascular density in tumours. The purpose of the study reported here was to investigate possible relationships between pretreatment oxygen tension (pO2) and vascular density in patients with cervix carcinoma. Tumour pO2 was measured by the use of polarographic needle electrodes. Biopsies were taken from the electrode tracks and vascular density and tissue composition, i.e. volume fraction of carcinoma tissue, stroma and necrosis, were determined by stereological analysis. The vascular density of individual biopsies was related to the median pO2 of the corresponding electrode track. Tumour regions with vascular density below 24 mm mm(-3) always showed low pO2, whereas tumour areas with vascular density above 24 mm mm(-3) could show a high or a low pO2. This indicates the existence of a threshold value of about 24 mm mm(-3) for vascular density in cervix carcinoma; a vascular density above this value is probably needed before high pO2 can occur. Low vascular density might, therefore, be a useful predictor of hypoxia-induced radiation resistance in cervix carcinoma. High vascular density, on the other hand, can probably not be used to exclude radiation resistance. The differences in pO2 among tumour regions with high vascular density were not a consequence of differences in the amount of necrosis or stroma or in the haemoglobin concentration in peripheral blood of the patients. Model calculations indicated that these differences in pO2 could be explained by differences in the oxygen delivery alone and by differences in the oxygen consumption rate alone.