Milling as a route to porous graphitic carbons from biomass.

This paper reports a simple way to produce porous graphitic carbons from a wide range of lignocellulosic biomass sources, including nut shells, softwood sawdust, seed husks and bamboo. Biomass precursors are milled and sieved to produce fine powders and are then converted to porous graphitic carbons by iron-catalysed graphitization. Graphitizing the raw (unmilled) biomass creates carbons that are diverse in their porosity and adsorption properties. This is due to the inability of the iron catalyst precursor to penetrate the structure of dense biomass material. Milling enables much more efficient impregnation of the biomass and produces carbons with homogeneous properties. Lignocellulosic biomass (particularly waste biomass) is an attractive precursor to technologically important porous graphitic carbons as it is abundant and renewable. This simple method for preparing the biomass enables a wide range of biomass sources to be used to produce carbons with homogeneous properties. This article is part of the theme issue 'Bio-derived and bioinspired sustainable advanced materials for emerging technologies (part 2)'.

Clinical outcome for chemoradiotherapy in carcinoma of the cervix.

AIMS: Two recent meta-analyses have shown a survival advantage for the addition of concurrent chemotherapy to radiotherapy in the treatment of cervical cancer. However, there is insufficient information available on late toxicity and few data from UK practice. The aims of this study were to examine treatment outcomes (survival and toxicity) in patients with cervical cancer treated with chemoradiation and to compare these with outcomes in patients treated with radiation alone. MATERIALS AND METHODS: Between July 2000 and December 2003, 75 patients with cervical cancer were treated with chemoradiation. Case notes were reviewed retrospectively. Acute and late toxicity were recorded, with late toxicity graded using the Franco-Italian glossary. The median age was 47 years. All patients were staged with examination under anaesthesia and magnetic resonance imaging scans. Forty-two patients were treated with concurrent chemoradiation alone and 33 patients were treated with a combination of neoadjuvant and concurrent chemoradiation. This was due to waiting list problems. The chemotherapy used was cisplatin 40 mg/m(2) weekly with radiotherapy, (the neoadjuvant dose was 60 mg/m(2) 3 weekly). External beam radiotherapy was given to the pelvis (40-45 Gy/20 fractions/4 weeks) followed by low dose rate brachytherapy (22.5-32.5 Gy to point A). Patients who were unable to have brachytherapy were given an external beam boost (15-20 Gy/8-10 fractions). RESULTS: The 3-year overall survival rate was 70%, with an estimated 5-year overall survival rate of 60%. The 3-year disease-free survival was 63.6%, with an estimated 5-year disease-free survival rate of 55%. Compared with the cohort of 183 patients from the Christie Hospital in a 1993 audit, there was a trend towards improved overall survival from 49 to 60% (P=0.06), which may become significant with longer follow-up. There were seven patients (9.3%) with grade 3 toxicity and no cases of grade 4 toxicity. In comparison with patients treated in the 1993 audit, the late toxicity rate has increased from 3.4 to 9.3%, but this was not statistically significant (P=0.14). CONCLUSION: There was a trend towards improved survival with concurrent chemoradiation in this cohort of patients that may become significant with longer follow-up.

Salvaging locoregional recurrence with radiotherapy after surgery in early cervical cancer.

AIMS: To determine the outcome and morbidity after radiotherapy for locally recurrent cervical cancer. MATERIALS AND METHODS: Women who presented with locally recurrent cervical cancer after surgery alone during 1985 and 1997 were identified from the hospital database. Data were collected and analysed to include the stage at first diagnosis, staging investigations before surgery, the surgical procedure, the indication for radiotherapy, the type of radiotherapy, morbidity and survival. RESULTS: In total, 130 women had radical external beam radiotherapy and/or intracavitary brachytherapy for locoregional recurrence during the defined study period. The 5-year disease-specific survival for the study population was 40.2%. Women who were treated for vault recurrence had a significantly better 5-year disease-free survival compared with women who developed nodal recurrence alone (55.4% vs 12.5%). This group of women also had a significantly slower rate of disease progression after radiotherapy than women with nodal recurrence (48.7% vs 87.5%, P=0.0001). CONCLUSION: Radical radiotherapy alone is able to salvage 55% of vaginal vault recurrences after surgery for cervical cancer with minimal late toxicity. Salvage rates in women with pelvic nodal recurrences are considerably lower. Chemoradiotherapy using intensity-modulated radiotherapy to deliver an escalated radiotherapy dose needs to be pursued to improve locoregional control.

Carbonic anhydrase (CA IX) expression, a potential new intrinsic marker of hypoxia: correlations with tumor oxygen measurements and prognosis in locally advanced carcinoma of the cervix.

There is increasing evidence that hypoxia-regulated gene expression influences tumor aggressiveness, contributing to the poorer outcome of patients with hypoxic tumors. The role of the transcriptional complex hypoxia-inducible factor-1 as an important mediator of hypoxia-regulated gene expression is one of the best documented pathways. Recently, it has emerged that certain tumor-associated carbonic anhydrases (CAs) can be added to the list of known hypoxia-inducible factor-responsive genes. Here we show that the immunohistochemical expression of the tumor-associated CA IX is correlated with the level of hypoxia in human cervical tumors. We performed a prospective study in 68 patients where needle electrodes were used to make direct measurements of tumor oxygenation levels. CA IX expression was evaluated immunohistochemically in pretreatment tumor biopsies. There was a significant positive correlation between the level of tumor hypoxia (HP5) and the extent of CA IX expression. A retrospective study of 130 squamous cell cervical carcinomas demonstrated that a semiquantitative immunohistochemical analysis of CA IX expression in tumor biopsies is a significant and independent prognostic indicator of overall survival and metastasis-free survival after radiation therapy. These studies provide clinical evidence that CA IX expression is up-regulated in hypoxic human cervical tumors and is associated with a poor prognosis. CA IX may act as an intrinsic marker of tumor hypoxia and poor outcome after radiation therapy. The level of CA IX expression may be used to aid in the selection of patients who would benefit most from hypoxia-modification therapies or bio-reductive drugs.

Irradiation of bovine aortic endothelial cells enhances the synthesis and secretion of sulphated glycosaminoglycans.

The effect of X-irradiation on the synthesis of heparan sulphate (HS) and chondroitin/dermatan sulphate (CS/DS) by bovine aortic endothelial cells (BAEC), was studied by measuring the incorporation of [35S]sulphate and [3H]glucosamine into newly synthesized glycosaminoglycan (GAG) chains. Medium extracts from irradiated cultures (5Gy) were found to contain approx. 130% more HS and 200% more CS/DS than unirradiated controls. Smaller increases were observed in cellular extracts, irradiated cultures (5Gy) containing approx. 60% more HS and 100% more CS/DS than unirradiated controls. Structural studies showed no significant changes occurred upon irradiation in either the amounts or distribution of N- and O-sulphate groups in the HS molecule. Values for N-sulphation of 41.1% control and 41.5% irradiated (5Gy) were obtained, the corresponding values for O-sulphation being 19.9% control and 20.2% irradiated. Isotope incorporation data indicated that sulphation of CS/DS may decrease after irradiation, however, analysis of chondroitin ABC lyase derived disaccharides showed no changes in the proportion of non-sulphated and O-sulphated disaccharides. The present study indicates that X-irradiation stimulates the synthesis and secretion of HS and CS/DS proteoglycans (PGs) by BAEC. This could be relevant to many features which are found to be indicative of radiation-induced damage.

High tumor angiogenesis is associated with poorer survival in carcinoma of the cervix treated with radiotherapy.

The purpose of this study was to examine the relationship between tumor angiogenesis and prognosis in carcinoma of the cervix treated with radiotherapy with a median follow-up time of 55 months. A retrospective study was carried out on 111 patients. Formalin-fixed, paraffin-embedded tumor biopsies were stained with anti-factor VIII using immunohistochemistry. Tumor angiogenesis was assessed by scoring the distance to the closest microvessel from random points within the tumor and the intratumor microvessel density (IMD) in the areas of highest neovascularization. High vascularity, as measured by both methods, was associated with a poor prognosis but was only significant for IMD. The 5-year survival rates for tumors with high versus low values were 50 and 65%, respectively. IMD was a significant prognostic factor within a Cox multivariate analysis. Higher tumor vascularity was associated with lower overall survival and locoregional control, but this association was not significant in the case of metastasis-free survival. The method used to assess tumor vascularity is important. The level of angiogenesis in carcinoma of the cervix is an independent prognostic parameter.

Quantitation of endothelial cell specific protein E-9 employing a single monoclonal antibody in an indirect sandwich ELISA.

An indirect enzyme-linked immunosorbent assay is described for the quantitation of protein E-9 which is specifically expressed on human vascular endothelial cells. The assay capitalizes on the dimeric structure of the E-9 protein by utilizing a single monoclonal antibody as both the capture and detection reagent. Detection is achieved by conjugating the Mab with biotin and is followed by the addition of streptavidin peroxidase to provide high sensitivity. Bound activity is measured by enhanced chemiluminescence utilizing standard Amerlite chemistry. The optimised assay is reproducible and is highly sensitive. Using this assay it was possible to detect the presence of E-9 protein in tissue culture media of endothelial cells and in serum samples--in one case even at 1/100 dilution. In vitro, X irradiation resulted in a greater than two-fold increase (P < or = 0.005) in the level of E-9 protein in culture supernatants of human umbilical vein endothelial cells (HUVEC). There are potential applications for measurements of E-9 protein in body fluids and tissue extracts from patients with a vast variety of diseases characterised by vascular endothelial damage and/or activation.

Pretreatment plasma TGF beta 1 levels are prognostic for survival but not morbidity following radiation therapy of carcinoma of the cervix.

PURPOSE: To determine whether pretreatment plasma-transforming growth factor beta 1 (TGF beta 1) levels are prognostic for tumor control and late morbidity following radiation therapy in carcinoma of the cervix. METHODS AND MATERIALS: The study was comprised of 79 patients undergoing radiotherapy with curative intent for Stage I-III carcinoma of the cervix. TGF beta 1 levels were analyzed using ELISA. Late morbidity was measured using the Franco-Italian glossary. Data were available for the pretreatment levels of circulating tumor markers that represent disease burden, and for peripheral blood lymphocyte radiosensitivity measured as SF2. RESULTS: Pretreatment TGF beta 1 levels were a significant prognostic factor for survival and local control. There were weak significant correlations of TGF beta 1 levels with disease stage and the levels of circulating tumor markers (CA125, TPA). There was a weak significant correlation between TGF beta 1 levels and normal cell radiosensitivity (lymphocyte SF2). There was no relationship between TGF beta 1 levels and grade of morbidity and pretreatment TGF beta 1 levels were not a significant prognostic factor for the probability of developing late morbidity. CONCLUSION: In carcinoma of the cervix, pretreatment TGF beta 1 levels reflect tumor burden and are a significant prognostic factor for survival. Despite an underlying weak relationship of TGF beta 1 levels with intrinsic normal cell radiosensitivity, pretreatment levels are not prognostic for the probability of developing late complications. This finding does not rule out the possible usefulness of measurements toward the end of treatment once tumor burden has been reduced.

The intrinsic radiosensitivity of cervical carcinoma: correlations with clinical data.

PURPOSE: The aims of the work were to study the intrinsic radiosensitivity of tumor biopsies from patients with cervical carcinoma and to correlate the data with information on patient age, disease stage, differentiation status, tumor volume, and tumor ploidy. METHODS AND MATERIALS: Radiosensitivity was assessed for 145 tumors in vitro as surviving fraction at 2 Gy (SF2) using a clonogenic assay. RESULTS: Although the clonogens in tumors classified as Stage I or II tended to be more radiosensitive than in Stage III or IV disease, the difference was not statistically significant (p > 0.15). There was also no significant difference in the intrinsic radiosensitivity of well, moderately, or poorly differentiated tumors or between squamous cell carcinoma and adenocarcinoma (p > 0.53). There was no correlation between patient age and tumor radiosensitivity (p = 0.49). Large volume (> or = 4 cm) disease was more radioresistant than small volume (< 4 cm) disease, but the difference was not significant (p = 0.08). Finally, diploid tumors tended to be more radioresistant than aneuploid tumors (p = 0.07). CONCLUSION: The intrinsic radiosensitivity of cervix tumors is independent of disease stage, tumor grade, and patient age. Weak trends, however, were observed of increased tumor radioresistance for large volume disease and diploid tumors, suggesting that tumor SF2 may not be a completely independent parameter.

Incorporating biologic measurements (SF(2), CFE) into a tumor control probability model increases their prognostic significance: a study in cervical carcinoma treated with radiation therapy.

PURPOSE: To assess whether incorporation of measurements of surviving fraction at 2 Gy (SF(2)) and colony-forming efficiency (CFE) into a tumor control probability (tcp) model increases their prognostic significance. METHODS AND MATERIALS: Measurements of SF(2) and CFE were available from a study on carcinoma of the cervix treated with radiation alone. These measurements, as well as tumor volume, dose, and treatment time, were incorporated into a Poisson tcp model (tcp(alpha,rho)). Regression analysis was performed to assess the prognostic power of tcp(alpha,rho) vs. the use of either tcp models with biologic parameters fixed to best-fit estimates (but incorporating individual dose, volume, and treatment time) or the use of SF(2) and CFE measurements alone. RESULTS: In a univariate regression analysis of 44 patients, tcp(alpha,rho) was a better prognostic factor for both local control and survival (p < 0.001 and p = 0.049, respectively) than SF(2) alone (p = 0.009 for local control, p = 0.29 for survival) or CFE alone (p = 0.015 for local control, p = 0.38 for survival). In multivariate analysis, tcp(alpha,rho) emerged as the most important prognostic factor for local control (p < 0.001, relative risk of 2.81). After allowing for tcp(alpha,rho), CFE was still a significant independent prognostic factor for local control, whereas SF(2) was not. The sensitivities of tcp(alpha,rho) and SF(2) as predictive tests for local control were 87% and 65%, respectively. Specificities were 70% and 77%, respectively. CONCLUSIONS: A Poisson tcp model incorporating individual SF(2), CFE, dose, tumor volume, and treatment time was found to be the best independent prognostic factor for local control and survival in cervical carcinoma patients.

Lymphocyte radiosensitivity is a significant prognostic factor for morbidity in carcinoma of the cervix.

PURPOSE: To study the relationship between pretreatment peripheral blood lymphocyte radiosensitivity and morbidity following radiation therapy. METHODS AND MATERIALS: A prospective study was carried out in which patients with carcinoma of the cervix underwent radiation therapy. Intrinsic radiosensitivity was measured on pretreatment peripheral blood lymphocytes, using a limiting dilution clonogenic assay. Late morbidity was assessed using the Franco-Italian glossary. Results were correlated in an actuarial analysis. RESULTS: There were no correlations between the measured lymphocyte radiosensitivity (SF2) and colony-forming efficiency, patient age, tumor grade, or disease stage. For 83 patients, lymphocyte SF2 was a significant prognostic factor for the probability of developing both any (p = 0.002) and Grade 3 (p = 0.026) morbidity. In 174 patients, stage showed borderline significance as a prognostic factor for morbidity (p = 0.056). However, the type of treatment (intracavitary alone, intracavitary plus parametrial irradiation, single insertion plus whole-pelvis irradiation) was significantly associated with the probability of developing late complications (p = 0.013). There was a weak significant inverse correlation between lymphocyte SF2 and grade of morbidity (r = -0.34, p = 0.002). CONCLUSION: These data highlight the importance of normal cell radiosensitivity as a factor determining radiation therapy response. They also show that peripheral blood lymphocyte SF2 is a highly significant prognostic factor for the probability of developing late radiation morbidity, and that carcinoma of the cervix is a good model for testing radiobiologic principles in the clinic.

Changes in oxygenation during radiotherapy in carcinoma of the cervix.

PURPOSE: The aim of this study was to investigate changes in tumor oxygenation, assessed by polarographic needle electrode measurements, following fractionated external beam radiotherapy in carcinoma of the cervix. METHODS AND MATERIALS: Normal and tumor tissue oxygenation was measured in 19 patients prior to radiotherapy and after 40-45 Gy of external beam radiotherapy delivered in 20 fractions over 4 weeks. All measurements were performed during anesthesia. RESULTS: There was no significant difference in the level of normal tissue oxygenation pre- and post radiotherapy. The individual patient median tumor pO2 values ranged from 0 to 31 mmHg pre-radiotherapy and 1 to 61 mmHg post-radiotherapy. The mean of the 19 median pO2 values increased from 8 (SD +/- 10) mmHg to 20 (+/- 20) mmHg following external beam radiotherapy. The increase was significant by paired Wilcoxon test (p = 0.011). There was also a significant fall in the proportion of values < 5 mmHg (p = 0.040). Although this value remained constant, or fell, in the majority of patients (15/19), it increased in 4 tumors. Tumor size pre- and postradiotherapy did not correlate with the level of pretreatment oxygenation; neither did the change in tumor size and change in level of oxygenation. CONCLUSION: The level of tumor oxygenation increased in the majority of patients (15/19) following 40-45 Gy of radiotherapy in carcinoma of the cervix.

A correlation between residual DNA double-strand breaks and clonogenic measurements of radiosensitivity in fibroblasts from preradiotherapy cervix cancer patients.

PURPOSE: To study the relationship between residual DNA damage and clonogenic measurements of radiosensitivity in fibroblasts from pretreatment cervix cancer patients. METHODS AND MATERIALS: Early passage vaginal fibroblasts from nine preradiotherapy cervix cancer patients and two radiosensitive skin fibroblast cell strains were studied. Cell survival was measured by clonogenic assay following both high and low dose rate irradiation. Residual DNA damage was measured using pulsed-field gel electrophoresis (PFGE) after irradiating radiolabeled, plateau-phase cells at 37 degrees C and allowing 24 h for repair. DNA damage was expressed both in terms of the residual damage slope (fitted to data from 60 to 150 Gy) and the fraction of activity released (FAR) following 150 Gy. RESULTS: The surviving fraction at 2 Gy (SF2) values after high dose rate irradiation for the vaginal fibroblasts ranged from 0.15 to 0.32 (a 2.2-fold difference). When the two radiosensitive cell strains were included, residual damage, expressed as the residual damage slope, correlated with alpha (r = 0.82, p = 0.002), D bar (r = -0.91, p < 0.001) and SF2 (p = -0.79, p = 0.004), and when the vaginal fibroblasts alone were studied, the residual damage slope again correlated with clonogenic survival, although less strongly [alpha (r = 0.66, p = 0.053), D bar (r = -0.83, p = 0.006), and SF2 (r = -0.63, p = 0.07)]. Within the group of vaginal fibroblasts there was a 4.0-fold difference in residual DNA damage slope. When residual damage was expressed as FAR at 150 Gy, then for all cell strains the correlations were alpha: r = 0.78, p = 0.004, D bar: r = -0.86, p = 0.001, and SF2: r = -0.78, p = 0.004, and for the vaginal fibroblast strains alone the correlations were alpha: r = 0.60, p = 0.088, D bar: r = -0.75, p = 0.02, and SF2: r = 0.62, p = 0.077. CONCLUSION: This study confirms previous findings that residual DNA damage correlates with clonogenic survival in fibroblasts. In addition, it demonstrates a correlation for fibroblasts from pretreatment cervix cancer patients demonstrating a relatively small range of SF2 values.

CT scanning in intracavitary therapy: unexpected findings in "straightforward" insertions.

Since 1980, pelvic CT scanning has been performed in 40% of patients who underwent afterloading intracavitary treatment for carcinoma of the cervix. The unexpected findings of uterine perforation are reported in 3% of these patients and the consequences are discussed.

Dose-incidence curves for tumour control and normal tissue injury, in relation to the response of clonogenic cells.

A probit analysis has been made of data from the literature on local control of tumours and injury to normal tissue as a function of dose of radiation. Fifteen series were analysed for local tumour control in man and ten series for complications. The analysis yielded values for the D50 dose (50% incidence of effect) and the probit width (K), a measure of the steepness of the dose-incidence curve. The same analyses were made of data for rodents. Broadly, K was proportional to D50 in the ratio 1:7, with no major differences between tumours and reported complications. D50 was plotted as a function of dose per fraction for four normal tissues and two tumours in rodents. D50 decreased more rapidly with increasing dose per fraction for the normal tissues than for tumours. The probit width, K, varied inversely with increasing dose per fraction for normal tissues and this contrasted with the tumour response. Thus with increasing dose per fraction, the threshold for effect decreased and the steepness of the ensuing dose-incidence curve increased, relatively more rapidly for normal tissue than for tumour. These curves of gross response have been analysed also by the double negative log method of Gilbert [23], in an attempt to estimate the number and survival characteristics of "tissue-rescuing cells". These were calculated to be less than 1 in 10(4) of the numbers of clonogenic cells measured by excision assays. The D0 values of the derived survival curves for these tissue-rescuing cells were higher than those measured by excision assays.

Stage III carcinoma of cervix. The importance of increasing age and extent of parametrial infiltration.

The relative importance of a number of potential prognostic factors was analysed for a sequential group of 296 patients with stage III carcinoma of the cervix who had been treated in a mature prospective clinical trial. Using a log-rank analysis of survival curves generated by the life-table method increasing age (p = 0.05) and extent of parametrial infiltration (p = 0.001) were found to be significantly related to prognosis. These two factors were further demonstrated to be independent variables and, of the two, parametrial extension (p = 0.002) was more significant than increased age (p = 0.035). Involvement of the lower third of the vagina, the presence of bullous oedema and the histological differentiation of the disease were not prognostically significant in this study. It is suggested that tumour volume as defined by extent of parametrial infiltration is a sufficiently good prognostic factor to be incorporated into a revised staging system.

Radiosensitivity testing of primary cervical carcinoma: evaluation of intra- and inter-tumour heterogeneity.

Biopsies from 89 patients with cervical carcinoma were studied using a clonogenic assay to obtain values for the surviving fraction at 2 Gy (SF2). Heterogeneity in intrinsic radiosensitivity was investigated by independently processing multiple biopsies from 18 tumors. No significant differences between intra-tumour SF2 values were demonstrated (p = 0.30). The results have shown that intra-tumour heterogeneity is not a limitation to radiosensitivity testing using the Courtenay-Mills assay. A wide range of values (0.13-0.97) for SF2 was obtained with a mean value of 0.47 +/- 0.18 (+/- 1 S.D., CV = 38%) for 52 squamous cell carcinomas and 0.59 +/- 0.27 for four adenocarcinomas. There were statistically significant differences between the individual tumours (p less than 0.001). From the analysis-of-variance of all the SF2 results it appears to be the surviving fractions below about 0.40 and those above about 0.7 which show significant differences in radiosensitivity between pairs of tumours (p = 0.05). Also 36% of the values of SF2 show significant differences from the mean SF2 of all tumours. The storage of tumour cell suspensions in liquid nitrogen improved the colony-forming efficiency (CFE) but it did not alter the radiosensitivity.

Bladder base dosage in patients undergoing intracavitary therapy.

The maximum dose rate being delivered to the base of the bladder during intracavitary therapy was assessed in 20 patients by CAT scanning during treatment. This value was compared with the I.C.R.U. bladder reference point dose rate calculated from lateral radiographs taken after insertion. The ratio of the maximum bladder base dose rate to the I.C.R.U. reference dose rate varied from 1.01 to 3.59. In ten patients the maximum bladder dose rate was not in the midline. Re-examination of five patients revealed significant changes in bladder base dose rate in two due to changes in applicator positioning and packing. The bladder base dose rate on the vertical plane through the middle of the vaginal ovoids was within +/- 25% of the maximum bladder base dose rate in 22/25 examinations.

Tumour oxygenation levels correlate with dynamic contrast-enhanced magnetic resonance imaging parameters in carcinoma of the cervix.

BACKGROUND AND PURPOSE: The Eppendorf pO(2) histograph is the 'gold standard' method for measuring tumour oxygenation. The method is not suitable for widespread application because its use is limited to accessible tumours. A non-invasive imaging technique would be an attractive alternative. Therefore, the relationships between tumour oxygenation and dynamic contrast-enhanced magnetic resonance imaging (MRI) parameters were investigated. MATERIALS AND METHODS: The study comprised 30 patients with carcinoma of the cervix. Tumour oxygenation was measured pre-treatment as median pO(2) and the proportion of values less than 5 mmHg (HP5) using a pO(2) histograph. Repeat measurements were obtained for nine patients following 40-45 Gy external beam radiotherapy giving a total of 39 measurements. Dynamic contrast-enhanced MRI using gadolinium was performed prior to obtaining the oxygenation data. Time/signal intensity curves were generated to obtain two standard parameters: maximum enhancement over baseline (SI-I) and the rate of enhancement (SI-I/s). RESULTS: Using the 39 measurements, there was a significant correlation between SI-I and both median pO(2) (r=0.59; P<0.001) and HP5 (r=-0. 49; P=0.002). There was a weak, borderline significant correlation between SI-I/s and both median pO(2) (r=0.29; P=0.071) and HP5 (r=-0. 34; P=0.037). There was a significant relationship between tumour size and SI-I (r=0.54; P<0.001), but not SI-I/s. In 29 tumours, where data were available, there was no relationship between histological assessment of tumour angiogenesis (intra-tumour microvessel density; IMD) and either MRI parameter. CONCLUSIONS: Tumour oxygenation levels measured using a pO(2) histograph correlate with dynamic contrast-enhanced MRI parameters. Therefore, non-invasive dynamic MRI may be a method for measuring hypoxia in human tumours.

Apoptosis, intrinsic radiosensitivity and prediction of radiotherapy response in cervical carcinoma.

Apoptosis is an important mechanism of cell death in tumours and it is seen both prior to and following radiotherapy. In this study patients with proven carcinoma of the cervix had measurement made of the percentage of apoptotic cells (apoptotic index or AI) in pre-therapy biopsies. Measurements of intrinsic radiosensitivity (SF2), already shown to be a predictor of outcome, had previously been made on the same pre-therapy biopsies. Mitotic index (MI) and Ki-67 antigen staining were also recorded as markers for proliferation. Patients were divided into those with an AI above or below the median and in general increasing apoptosis was associated with poor prognosis. The 5-year survival rate for tumours with an AI below the median was 79% and was significantly greater than the rate of 47% for those with an AI above the median (p = 0.003). There was also a significantly increased 5-year local recurrence-free rate for patients with an AI below the median compared with those with an AI above the median (79 versus 61%, p = 0.012). In addition, AI and SF2 acted as independent prognostic indicators. Patients with both an SF2 and AI value above the median did badly (25% 5-year survival, 46% local control) compared with those with an SF2 and AI below the median (80% 5-year survival, 100% local control). Apoptosis showed correlation with MI (n = 66, r = 0.34, p = 0.002) and cell staining for the Ki-67 antigen (n = 57, r = 0.25, p = 0.03), but neither MI nor Ki-67 were related to patient outcome. This suggests that while apoptosis may be a reflection of tumour proliferation this cannot in itself explain the ability of apoptosis to predict clinical outcome for this series of patients. The study raises the possibility of AI and SF2 being used together as predictors of tumour response to radiotherapy.