Final results from the prospective phase III WSG-ARA trial: impact of adjuvant darbepoetin alfa on event-free survival in early breast cancer.

BACKGROUND: WSG-ARA plus trial evaluated the effect of adjuvant darbepoetin alfa (DA) on outcome in node positive primary breast cancer (BC). PATIENTS AND METHODS: One thousand two hundred thirty-four patients were randomized to chemotherapy either with DA (DA+; n = 615) or without DA (DA-; n = 619). DA (500 µg q3w) was started at hemoglobin (Hb) levels <13.0 g/dl (<12 g/dl after DA label amendment) and stopped at Hb levels ≥14.0 g/dl (12 g/dl after label amendment). Primary efficacy end point was event-free survival (EFS); secondary end points were toxicity, quality of life (QoL) and overall survival (OS). RESULTS: Venous thrombosis (DA+: 3.0%, DA-: 1.0%; P = 0.013) was significantly higher for DA+, but not pulmonary embolism (0.3% in both arms). Median Hb levels were stable in DA+ (12.6 g/dl) and decreased in DA- (11.7 g/dl). Hb levels >15 g/dl were reported in 0.8% of cycles. QoL parameters did not significantly differ between arms. At 39 months, DA had no significant impact on EFS (DA+: 89.3%, DA-: 87.5%; Plog-rank = 0.55) or OS (DA+: 95.5%, DA-: 95.4%; Plog-rank = 0.77). CONCLUSIONS: DA treatment did not impact EFS or OS in routine adjuvant BC treatment.

Randomized phase 2 trial on refinement of early-stage NSCLC adjuvant chemotherapy with cisplatin and pemetrexed versus cisplatin and vinorelbine: the TREAT study.

BACKGROUND: Adjuvant chemotherapy is beneficial in non-small-cell lung cancer (NSCLC). However, balancing toxicity and efficacy mandates improvement. PATIENTS AND METHODS: Patients with completely resected stages IB-pT3N1 NSCLC were randomly assigned to either four cycles cisplatin (C: 50 mg/m(2) day (d)1 + 8) and vinorelbine (V: 25 mg/m(2) d1, 8, 15, 22) q4 weeks or four cycles cisplatin (75 mg/m(2) d1) and pemetrexed (Px: 500 mg/m(2) d1) q3 weeks. Primary objective was the clinical feasibility rate (no grade (G)4 neutropenia/thrombocytopenia or thrombocytopenia with bleeding, no G3/4 febrile neutropenia or non-hematological toxicity; no premature withdrawal/death). Secondary objectives were drug delivery and efficacy. RESULTS: One hundred and thirty two patients were randomized (stages: 38% IB, 10% IIA, 47% IIB, 5% pT3pN1; histology: 43% squamous, 57% non-squamous). The feasibility rates were 95.5% (cisplatin and pemetrexed, CPx) and 75.4% (cisplatin and vinorelbine, CVb) (P = 0.001); hematological G3/4 toxic effects were 10% (CPx) and 74% (CVb) (P < 0.001), non-hematological toxic effects were comparable (33% and 31%, P = 0.798). Delivery of total mean doses was 90% of planned with CPx, but 66% (cisplatin) and 64% (vinorelbine) with CVb (P < 0.0001). The median number of cycles [treatment time (weeks)] was 4 for CPx (11.2) and 3 for CVb (9.9). Time to withdrawal from therapy differed significantly between arms favoring CPx (P < 0.001). CONCLUSION: Adjuvant chemotherapy with CPx is safe and feasible with less toxicity and superior dose delivery compared with CVb.

Alterations of intratumoral pharmacokinetics of 5-fluorouracil in head and neck carcinoma during simultaneous radiochemotherapy.

The kinetics of local drug uptake and metabolism of the anticancer drug 5-fluorouracil (5-FU) has been monitored by means of 19F nuclear magnetic resonance spectroscopy in 17 patients with neck tumors during concurrent radiochemotherapy. All of the patients underwent an accelerated hyperfractionated, concomitant-boost radiochemotherapy with 5-FU [600 or 1000 mg/m2 of body surface (b.s.)] and carboplatin (70 mg/m2 of b.s.). Serial 19F nuclear magnetic resonance spectra were obtained during and after the administration of 5-FU in a 15-T scanner with the use of a 5-cm diameter surface coil positioned on a cervical lymph node metastasis. Examinations were performed at day 1 of therapy and, in 13 patients, also after 43.5 Gy of irradiation at day 1 of the second chemotherapy cycle. Resonances of 5-FU and the catabolites 5,6-dihydro-5-fluorouracil (DHFU) and alpha-fluoro-beta-alanine (FBAL) were resolved in the tumor spectra. The median of the 5-FU and FBAL levels was significantly higher (more than 2-fold) at the second compared with the first examination, whereas the level of DHFU did not change. This effect could indicate an increased delivery of 5-FU into the interstitial space of the tumor in the course of the combined treatment, which would result in an enhanced exposure of the tumor cells to the drug. A potential mechanism for synergy between radio- and chemotherapy is discussed, but alternative mechanisms are also being considered. The findings indicate that a method is available to rationally address the design of dosing schedules in concurrent therapy regimens.

Uterine cervical carcinoma: comparison of standard and pharmacokinetic analysis of time-intensity curves for assessment of tumor angiogenesis and patient survival.

Dynamic studies of Gd-based contrast agents in magnetic resonance imaging (MRI) are increasingly being used for tumor characterization as well as for therapy response monitoring. Because detailed knowledge regarding the pathophysiological properties, which in turn are responsible for differences in contrast enhancement, remains fairly undetermined, it was the aim of this study to: (a) examine the association of standard and pharmacokinetic analysis of time-intensity curves in dynamic MRI with histomorphological markers of tumor angiogenesis [microvessel density (MVD) and vascular endothelial growth factor (VEGF)]; and (b) determine the ultimate value of a histomorphological and a dynamic MRI approach by the correlation of those data with disease outcome in patients with primary cancer of the uterine cervix. Pharmacokinetic parameters (amplitude, A; exchange rate constant, k21) and standard parameters [the maximum signal intensity increase over baseline (SI-I) and the steepest signal intensity-upslope per second (SI-U/s)] were calculated from a contrast-enhanced dynamic MRI series in 37 patients with biopsy-proven primary cervical cancer. On the surgical whole mount specimens, histomorphological markers of tumor angiogenesis (MVD and VEGF) were compared to MRI-derived parameters. For MRI and histomorphological data, Kaplan-Meier survival curves were calculated and compared using log-rank statistics. A significant association was found between MVD and A (P < 0.01) and SI-I (P < 0.05). No significant relationships were observed between VEGF expression and all dynamic MRI parameters. Kaplan-Meier curves based on k21 and SI-U/s showed that tumors with high k21 and SI-U/s values had a significantly (P < 0.05 and 0.001, respectively) worse disease outcome than did tumors with low k21 and SI-U/s values. None of the histomorphological gold standard markers for assessing tumor angiogenesis (MVD and VEGF) had any significant power to predict patient survival. It is concluded that in patients with uterine cervical cancer: (a) the pathophysiological basis for differences in dynamic MRI is MVD but not VEGF expression; (b) a functional, dynamic MRI approach (both standard and pharmacokinetic analysis) may be better suited to assess angiogenic activity in terms of patient survival than are the current histomorphological-based markers of tumor angiogenesis; and (c) compared with standard analysis, a simple pharmacokinetic analysis of time-intensity curves is not superior to assess MVD or patient survival.

Angiogenesis of uterine cervical carcinoma: characterization by pharmacokinetic magnetic resonance parameters and histological microvessel density with correlation to lymphatic involvement.

Dynamic studies of Gd-based contrast agents in magnetic resonance imaging (MRI) are increasingly being used for tumor characterization as well as therapy response monitoring. Because detailed knowledge regarding the pathophysiological properties, which in turn are responsible for differences in contrast enhancement, remains fairly undetermined, it was the aim of this project to: (a) examine the relationship between contrast-enhanced dynamic MRI-derived characteristics and histological microvessel density counts, a recognized surrogate of tumor angiogenesis, from primary or recurrent cancers of the uterine cervix; and (b) correlate these parameters with lymphatic involvement to characterize tumor aggressiveness in terms of lymphatic spread. Pharmacokinetic parameters (amplitude, A; exchange rate constant, k21) were calculated from a contrast-enhanced dynamic MRI series in 55 patients (ages 25-72 years; mean, 50 years) with biopsy-proven primary (n = 42) or recurrent (n = 13) uterine cervical cancer. Both pharmacokinetic parameters were correlated to histologically determined microvessel density counts (factor VIII-related antigen) and other pathological tumor characteristics obtained from the operative specimens after radical surgery. In addition, the magnetic resonance and histological data were correlated to the presence or absence of lymphatic system involvement. Pharmacokinetic MRI-derived parameters (A and k21) increased with increasing histological microvessel density counts with r = 0.41 and 0.50, respectively. Lymphatic involvement was more comprehensibly assessed by the pharmacokinetic parameter k21 compared with histological microvessel density, resulting in a higher sensitivity, overall accuracy, and comparable specificity. Contrast-enhanced MRI parameters might prove to be applicable for estimation of tumor angiogenesis in uterine cervical cancer; thus, MRI may become an additional tool to characterize malignant progression in terms of lymphatic involvement in uterine cervical cancer.

High efficacy of fractionated stereotactic radiotherapy of large base-of-skull meningiomas: long-term results.

PURPOSE: Large skull-base meningiomas are difficult to treat due to their proximity or adherence to critical structures. We analyzed the long-term results of patients with skull-base meningiomas treated by a new approach with high-precision fractionated stereotactic radiotherapy. PATIENTS AND METHODS: One hundred eighty-nine patients with benign meningiomas were treated with conformal fractionated stereotactic radiotherapy between 1985 and 1998. Patients were undergoing a course of radiotherapy either as primary treatment, following subtotal resection, or for recurrent disease. The median target volume was 52.5 mL (range, 5.2 to 370 mL). The mean radiation dose was 56.8 Gy (+/- 4.4 Gy). Follow-up examinations, including magnetic resonance imaging, were performed at 6-month intervals thereafter. RESULTS: The median follow-up period was 35 months (range, 3 months to 12 years). Overall actuarial survival for patients with World Health Organization (WHO) grade I meningiomas was 97% after 5 years and 96% after 10 years. Local tumor failure was observed in three of 180 patients with WHO grade I tumors and was significantly higher in two of nine patients with WHO grade II tumors. A volume reduction of more than 50% was observed in 26 patients (14%). Preexisting cranial nerve symptoms resolved completely in 28% of the patients. Clinically significant treatment-induced toxicity was seen in 1.6% of the patients. No treatment-related deaths occurred. CONCLUSION: The results of this study demonstrate that fractionated stereotactic radiotherapy is safe and effective in the therapy of subtotally resected or unresectable meningiomas. The overall morbidity and incidence subacute and late side effects of this conformal radiotherapy approach were low.

Angiogenic activity of cervical carcinoma: assessment by functional magnetic resonance imaging-based parameters and a histomorphological approach in correlation with disease outcome.

Angiogenesis plays a fundamental role in tumor growth and metastasis. What is needed is a quantitative, noninvasive, and repeatable assay to estimate functional angiogenic activity of the entire tumor. The aims of the present study were to: (a) examine the relationship between functional magnetic resonance imaging (MRI)-based parameters with established histomorphological markers of tumor angiogenesis [histological microvessel density (HMVD) and vascular endothelial growth factor expression (VEGF)]; and (b) determine the ultimate value of both approaches to assess functional angiogenic active hotspots as markers of disease outcome in patients with cancer of the uterine cervix. Pharmacokinetic parameters (amplitude A, tissue exchange rate constant k21) were calculated from contrast-enhanced dynamic MRI series in 57 patients (mean age, 49 +/- 14 years) with biopsy proven uterine cervical cancer. Both pharmacokinetic parameters were correlated to histomorphologically determined areas of high HMVD and VEGF expression obtained from the operative specimens after radical surgery. In addition, the functional MRI and histomorphological data were used to assess disease outcome. A significant association was found between HMVD and the amplitude A (P < 0.001) and a less pronounced association with k21, (P < 0.05), respectively. No significant associations were found between the pharmacokinetic parameters (A, k21) and VEGF expression. When stratified into high and low median k21 groups, median k21 values >5.4 min(-1) were the only significant (P < 0.05) factors in predicting poor patient survival. None of the histomorphological markers of angiogenesis (HMVD or VEGF expression) showed any predictive power. We have found that: (a) focal hotspots of HMVD are the pathophysiological basis for differences in functional MRI; (b) areas of high microvessel density and microvessel permeability do not necessarily coincide, as demonstrated by the histomorphological and functional MRI findings; (c) the functional angiogenic activity of a tumor may not be sufficiently characterized by a histomorphological approach but rather by a functional MRI-based approach; and (d) functional MRI-based analysis may assess tumor angiogenic activity in terms of disease outcome more comprehensively than the histomorphological approach.

The exercise renogram and its interpretation.

UNLABELLED: The exercise renogram is a rarely used diagnostic procedure, but it may visualize an exercise-induced change in renal function related to the pathophysiology of essential hypertension, which could greatly increase interest in this examination. The aim of this study was to demonstrate the interpretative approach and the terminology which is used to describe results of exercise renography, using a population of hypertensives with renovascular disease. METHODS: We reviewed the examinations of 70 hypertensives who had supine renography as well as exercise renography with a 60-80 W work load. Forty-eight patients were examined with 99mTc-MAG3 and 22 with 131I hippurate. The renographic and angiography results were recorded as well as the antihypertensive drugs used and the site of vascular lesions. RESULTS: Thirty-three hypertensives developed a bilateral-abnormal exercise renogram, which appears to be associated with primary hypertension. Eight individuals responded to exercise with a unilateral-abnormal exercise renogram, in a kidney behind a stenosis. Only 19 patients had a normal exercise renogram, and 10 had only one functioning kidney. Pathology recognized but unrelated to the intervention included nonfunctioning and small kidneys and pelvic retention. CONCLUSION: Exercise renography's only indication is for recognition of pathology unique to hypertension, since other function disturbances were recognized in resting renograms.

Usual interstitial pneumonia. Quantitative assessment of high-resolution computed tomography findings by computer-assisted texture-based image analysis.

RATIONALE AND OBJECTIVES: The authors developed a texture-based pattern recognition and segmentation tool for the quantitation of high-resolution computed tomography (HRCT) findings in usual interstitial pneumonia (UIP). METHODS: In HRCT images of five patients with UIP and five patients without UIP, 1022 regions of interest (ROIs) of 5 x 5 pixels were classified by the examiner to be normal, emphysematous, ground-glass lesion, intralobular fibrosis, vessel, or bronchus section. The classes and the texture parameters calculated in the ROIs were the basis for the decision rule, using a multivariate discrimination analysis. The classification was compared with the examiner's diagnosis in 1889 new randomly selected ROIs. RESULTS: Depending on the structure, the sensitivity (the probability that a structure would be recognized correctly) was 68.7% to 80.7%. If the system classified a structure as normal, ground glass or fibrotic region, this was correct in 77.3% to 88.1%. However, the system's diagnosis of a bronchus section was correct in only 16.2%. The overall accuracy was 70.7%. CONCLUSIONS: Texture-based segmentation may be a valuable tool to aid the quantitative assessment of parenchymal disease in HRCT images.

Usability of semiautomatic segmentation algorithms for tumor volume determination.

RATIONALE AND OBJECTIVES: Tumor volume is an important parameter for clinical decision making. At present, semiautomatic image segmentation is not a standard for tumor volumetry. The aim of this work was to investigate the usability of semiautomatic algorithms for tumor volume determination. METHODS: Semiautomatic region- and volume-growing, isocontour, snakes, hierarchical, and histogram-based segmentation algorithms were tested for accuracy, contour variability, and time performance. The test were performed on a newly developed organic phantom for the simulation of a human liver and liver metastases. The real tumor volumes were measured by water displacement. These measured volumes were used as the gold standard for determining the accuracy of the algorithms. RESULTS: Variability of the segmented volumes ranging from 3.9 +/- 3.2% (isocontour algorithm) to 11.5 +/- 13.9% (hierarchical segmentation) was observed. The segmentation time per slice varied between 32 (volume-growing) and 72 seconds (snakes) on an IBM/RS6000 workstation. CONCLUSIONS: Only the region-growing and isocontour algorithms have the potential to be used for tumor volumetry. However, further improvements of these algorithms are necessary before they can be placed into clinical use.

Improved therapeutic response by distinct timing of multiple heat treatments during interstitial radiation in the Dunning R3327 prostate tumor model.

PURPOSE: As a continuation of a previous study showing the efficacy of a single local tumor heat treatment (LTH) in combination with interstitial radiation (IR) in the Dunning tumor system R3327 (subline AT1), we evaluated higher doses and/or lower dose rates with an extended time course of IR treatment, which allowed greater flexibility for LTH applications. METHODS: IR was carried out by the insertion of one removable 192Ir seed into the center of a R3327-AT1 tumor, transplanted s.c. into the distal thigh of Copenhagen rats. LTH (43.5 degrees C, for 35 min) varied from one treatment just before IR to multiple applications beginning at 0 h and repeated every 48 h or 72 h. RESULTS: The Dunning subline R3327-AT1 is a very thermoresistant tumor, which did not reveal any thermal response when heated up to 44.5 degrees C for 35 min. IR alone produced a delay in tumor growth, related to dose and dose rates of 18-53 cGy/h. During longer treatment times, a single LTH just before the IR was no more effective than IR alone. Thermoradiotherapy with multiple LTH treatments given at intervals of between 48 h and 72 h resulted in a clear increase in growth delay. Radiosensitization was highest in all dose-rate groups where LTH was applied every 72 h during a complete course of IR. CONCLUSIONS: These results demonstrate the importance of administering a sequence of multiple applications of LTH during continuous low-dose-rate irradiation and they substantiate our earlier findings, with shorter exposure times, where one LTH given every 72 h appeared to be most efficient in the combined treatment of the Dunning rat prostate tumor R3327-AT1.

Afferent-efferent vessel dysfunction appears to be a specific characteristic of a large subset of patients with essential hypertension.

Exercise renography makes it possible to subdivide essential hypertensives (EHs) into two distinct populations. Fifty to 60% develop exercise-mediated renal dysfunction and a transitory, severe reduction of glomerular filtration. The other subset of EHs does not have exercise-mediated renal dysfunction. We hoped to learn whether the disturbance is also present while EHs rest. Twenty-six EHs and 21 normotensive controls were studied with a resting sequential renogram using Tc-99m-mercaptoacetyl-triglycine (MAG3), a tracer excreted primarily by proximal tubular cells. EHs also had an exercise renogram. All persons had three consecutive 10-min dual-tracer infusion clearance determinations with 111In-DTPA and 131I-hippurate, for the simultaneous determination of glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). To demonstrate the accuracy of the clearance procedure we sought to reproduce Hollenberg's results which show greater flow variability in EH than in normotension. Following this, the variability (VAR) of the GFR and ERPF as well as the variability fraction (VF), the ratio of GFR variability divided into the ERPF variability, were calculated. Hollenberg's results were reproduced. Sixteen of 26 essential hypertensives developed exercise-mediated renal dysfunction. GFR-VAR in EH differed from controls. The VF suggests that EHs with a bilateral abnormal exercise renogram have a more pronounced GFR variability than those EH with a normal exercise renogram. The results point to intraglomerular pressure fluctuations in patients with EH, and the VF suggests that this may be more pronounced in EHs with a bilateral abnormal exercise renogram than in those with a normal exercise renogram. It is hypothesized that the variable GFR provokes renin secretion in EH.

Exercise activates renal dysfunction in hypertension.

A bilateral, exercise-mediated renal functional abnormality was first described more than a decade ago. The disturbance is specific for hypertension, is seen in different forms of hypertension, and has been studied most extensively in hypertensives with renovascular disease. The bilateral-abnormal exercise renogram identifies the disturbance. Hypertensives with unilateral renovascular disease were studied in the continuing evaluation of the bilateral function disturbance. We examined 31 hypertensives with documented unilateral renovascular disease, all of whom had renography at rest and during 60 to 80 W ergometric exercise. An additional seven normotensives and 17 essential hypertensives served as controls, and had the same sequence of studies. All patients reported upon continued on to an infusion clearance with 131I-hippurate and 111In-diethylenetriamine pentaacetic acid to determine glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) at rest, and during 25 W ergometric exercise. Eighteen of 31 hypertensives with unilateral renovascular disease were found to have a bilateral-abnormal exercise renogram. Clearance examinations in these identified a prominent reduction of the GFR and a lesser decrease in the ERPF during exercise. Hypertensives with normal exercise renograms did not have the exercise mediated abnormal clearance pattern. Similar results were observed in the control population of essential hypertensives, 65% of whom developed the functional disturbance. The seven normotensives controls did not exhibit the exercise mediated function changes. We conclude that an exercise-mediated bilaterally occurring functional disturbance exists in certain hypertensives, who then have a bilateral-abnormal exercise renogram. Associated with this is a distinctly abnormal clearance during exercise which is characterized by a low filtration fraction.

Differential sensitivity of three sublines of the rat Dunning prostate tumor system R3327 to radiation and/or local tumor hyperthermia.

To better understand the relationship of the growth characteristics of tumor tissues and their response to ionizing radiation alone and in combination with local tumor hyperthermia, we compared three different tumor sublines of the Dunning rat prostate carcinoma R3327. This report includes results obtained with the anaplastic AT1 subline (volume doubling time 5.2 days), the moderately differentiated mucin-secreting HI subline (volume doubling time about 9 days) and the well-differentiated, hormone-dependent H subline (volume doubling time about 17 days). The effects of single doses of photons (10 to 40 Gy) with and without local tumor hyperthermia (35 min immersion at 43.5 degrees C) were quantified by growth delay. The time to reach five times the volume at the time of treatment after 30 Gy alone was found to be 56.0, 134.9 and 184.0 days for the R3327-AT1, HI and H tumors, respectively. The R3327-H tumor was more radiosensitive than the AT1 or HI subline. Five of nine R3327-H tumors were controlled locally with a single dose of photons (40 Gy). Local tumor hyperthermia alone induced growth delay in both differentiated tumors, while the anaplastic tumor subline did not respond. Combined treatment modalities with heat applied directly after irradiation revealed isoeffective thermal enhancement ratios for 30 Gy which decreased from 1.59 for the AT1 tumor and 1.42 for the HI tumor to 1.23 in the well-differentiated subline R3327-H.

Proton MR spectroscopic evaluation of suspicious brain lesions after stereotactic radiotherapy.

BACKGROUND AND PURPOSE: The radiologic assessment of suspicious brain lesions after stereotactic radiotherapy of brain tumors is difficult. The purpose of our study was to define parameters from single-voxel proton MR spectroscopy that provide a probability measure for differentiating neoplastic from radiation-induced, nonneoplastic lesions. METHODS: Seventy-two lesions in 56 patients were examined using a combined MR imaging and MR spectroscopy protocol (point-resolved spectroscopy, TE = 135 ms). Signal intensities of cholines, creatines, N-acetyl aspartate, and the presence of lactate and lipid resonances were correlated to final diagnoses established by clinical and MR imaging follow-up, positron emission tomography studies, or biopsy/surgery. Statistical analysis was performed using the t test, linear discriminant analysis, and k nearest-neighbor method. RESULTS: Significantly increased signal intensity ratios I(tCho)/I(tCr) (P <.0001) and I(tCho)/I(NAA) (P <.0001) were observed in neoplastic (n = 34) compared with nonneoplastic lesions (n = 32) and contralateral normal brain (n = 33). Analysis of I(tCho)/I(tCr) and I(tCho)/I(NAA) data yielded correct retrospective classification as neoplastic and nonneoplastic in 82% and 81% of the lesions, respectively. Neither I(NAA)/I(tCr) nor signal intensitities of lactate or lipids were useful for differential diagnosis. CONCLUSION: Metabolic information provided by proton MR spectroscopy is useful for the differentiation of neoplastic and nonneoplastic brain lesions after stereotactic radiotherapy of brain tumors.

Locally advanced breast carcinoma: evaluation of mammography in the prediction of residual disease after induction chemotherapy.

BACKGROUND: We aimed to assess the mammographic features of locally advanced breast carcinoma treated with neoadjuvant chemotherapy and to evaluate morphological criteria that determine the value of mammography in therapy monitoring. MATERIALS AND METHODS: We reviewed the pre- and post-therapeutic mammograms of 44 patients with stage III-breast carcinoma with regard to tumor characteristics and malignant calcifications and compared to histopathological results. RESULTS: Delineation of the tumor proved to be the most significant criterion. In 34 tumors more than 50% of the lesion was defined; these showed a high correlation between the mammographically determined tumor diameter and that determined on histopathological examination (r = 0.77). Less than 50% of the mass was definable in 14 tumors; here the correlation between mammographically and histopathologically determined tumor diameter was low (r = -0.19). CONCLUSIONS: The diagnostic value of mammography in the evaluation of tumor response to induction chemotherapy depends primarily on the extent to which the tumor can be delineated from the adjacent breast tissue. For tumors whose margins can be defined by more than 50% on the baseline mammogram, the diagnostic reliability of mammography is high. Ill-defined masses should preferably be assessed with other imaging procedures such as ultrasonography or magnetic resonance imaging.

Interstitial radiation and hyperthermia in the Dunning R3327 prostate tumour model: therapeutic efficacy depends on radiation dose-rate, sequence and frequency of heating.

To determine the most effective means by which to apply the combined treatments of local tumour hyperthermia (LTH) with interstitial low dose-rate irradiation (IRT) we examined the significance of such factors as dose-rate of radiation, and the sequence and frequency of hyperthermia applications in the anaplastic Dunning prostate tumour subline R3327-AT1. IRT was carried out by the insertion of a single Ir-192 seed into the center of the tumour. For LTH treatments, the tumour-bearing leg was positioned in a circulating constant temperature water bath (43.5 +/- 0.1 degrees C) for 35 min. Neither LTH treatment alone nor the insertion of a dummy seed produced any change in tumour growth compared with sham-treated controls. With regard to the sequence of heating and IRT our results showed that during a 72-h treatment time (30 Gy, 40 cGy/h) a single heat treatment given just before the start of IRT was more efficient (TER = 1.47) in terms of growth delay than LTH given in the middle or the end of radiation treatment (TER approximately 1.0). The growth delay for both the 20 and 40 cGy/h groups appear to be linear with increasing dose for the IRT as well as the IRT + LTH groups. The higher dose-rate was more effective especially with respect to long-term delay in tumour growth in some of the animals. As TER at 40 cGy/h decreased subsequently with increasing treatment time from 1.47 to 1.25 at 60 Gy, we conclude that for treatment times > 72 h, one LTH just before IRT might not be sufficient. If multiple heat treatments are applied during a comparable time course, two LTH treatments one just before the start, the other at the end yielded the greatest local tumour control. In contrast, three LTH given daily were not more effective than the one LTH given just before the start of IRT. These data indicate a clear thermal enhancement of low dose-rate irradiation, with maximal sensitization when hyperthermia was given just before IRT. For multiple heatings a better understanding of the underlying mechanisms of sequencing and timing hopefully provides guidelines how to apply optimally both modalities in the treatment of cancer.

MR tissue characterization of intracranial tumors by means of texture analysis.

Tissue characterization of the human brain has been performed by texture analysis of proton relaxation time images using a standard MR whole body imager operating at 1.5 T. A combined CP/CPMG multi-echo, multislice sequence was used to measure T1 and T2 in each pixel with an uncertainty not exceeding 10%. In a prospective clinical study, 12 patients with histologically confirmed brain tumors were investigated. For each ROI in the calculated T1 and T2 parameter images, texture parameters originating from the grey level distribution, the gradient distribution, the grey level co-occurrence matrix, and the grey level runlength histogram were used for classification and discrimination between tissues. All regions corresponding to the normal brain tissue (white matter, grey matter, cerebrospinal fluid) were successfully discriminated from each other as well as from the pathological tissue parts (edema and tumor). The classification of 10 edematous and 8 tumorous tissue regions yielded only one misclassification. Together with additional rules, these discrimination rules formed the knowledge base of an expert system for segmentation of the brain images. In cases of tumors without Gd-DTPA contrast medium uptake or in cases of Gd-DTPA contraindication, segmentated images can help solve nontrivial diagnostical problems such as delineating the target volume in radiation therapy.

MR image texture analysis--an approach to tissue characterization.

The role and value of texture analysis in the quantification of medical images is reviewed and the various methods described. The promise in magnetic resonance imaging is discussed and the coordinated research programme being carried out within the framework of the European Economic Community Concerted Action on Tissue Characterization by MRS and MRI is outlined. Tissue characterization of the human brain has been performed by texture analysis of proton relaxation time images using a standard MR whole body imager operating at 1.5 T and the results are presented.

Intracranial meningeomas: time- and dose-dependent effects of irradiation on tumor microcirculation monitored by dynamic MR imaging.

The purpose of this study was the characterization of the time- and dose-dependent effects of irradiation on tumor microcirculation by means of dynamic MR imaging and correlation of the estimated data with tumor response in patients with meningeomas. Dynamic MR imaging studies were performed in 20 patients with intracranial meningeomas prior to (n = 20) and at 6 (n = 17), 18 (n = 17), and 50 wk (n = 14) after the end of radiotherapy. In seven of these patients, dynamic measurements were also performed during fractionated radiotherapy after approximate 20 Gy and 54 Gy. During and after short-time infusion of gadopentetate dimeglumine, the kinetics of lesion response was resolved using a strongly T1-weighted saturation recovery TurboFLASH (SRTF) sequence. The signal-time courses of the suspected lesions were analyzed using a pharmacokinetic two-compartment model. The calculated parameters amplitude A (reflecting gadopentetate dimeglumine accumulation in the extracellular space) and exchange rate constant k21 (depending on vascular permeability and blood flow) were displayed as color-coded images and analyzed as a function of time of therapy and radiation dose. All meningeomas showed a high exchange rate constant k21 (median, 5.7 min-1; range, 1.9-23.0 min-1) and a high amplitude A (median, 1.5 arbitrary units; range, 1.1-2.7) prior to X-ray treatment. During radiotherapy we found a dose related significant (p < .01) increase of k21 accompanied by an increase of the amplitude A as compared to the pretreatment values. Analysis of tumor volume 6, 18, and 50 wk after X-ray treatment revealed two different groups. In the responder group (n = 13) the median of the tumor volume decreased from 10.0 to 7.5 cm3. For this group, we found a significant drop (p < .01) of the median of the amplitude A and a decrease of the exchange rate constant k21. In the nonresponder group (n = 4) the median of the tumor volume increased after radiation from 3.5 to 4.5 cm3. The pharmacokinetic analysis revealed a decrease of the amplitude A-and an increase of the exchange rate constant k21. The response of meningeomas to radiotherapy is influenced by the effect of X-rays on tumor microcirculation. This effect on tumor microcirculation can be derived by analysis of pharmacokinetic maps obtained from dynamic MR images. Furthermore, these pharmacokinetic maps can possibly be used to differentiate groups of patients who respond or do not respond to radiotherapy and, thus, could benefit from another treatment modality.