Radiation oncology investigations最新文献

RSR13, 2[4-[[(3,5dimethylanilino)carbonyl]methyl]phenoxy]-2-methylpropion ic acid, a synthetic allosteric modifier of hemoglobin, reduces the affinity of hemoglobin for oxygen. The experiments reported here examined the effect of treatment with RSR13, combined with oxygen breathing, on the radiation response of EMT6 mammary tumors in BALB/c mice and of two normal tissues. RSR13 plus oxygen breathing increased the response of EMT6 tumors to irradiation. RSR13 had no discernible effects on tumors rendered maximally hypoxic by nitrogen asphyxiation, no discernible cytotoxic effects in EMT6 tumors, and no effect on the viability or radiation response of EMT6 cells in vitro under either aerobic or hypoxic conditions. The effects of RSR13 therefore reflect changes in tumor oxygenation, rather than a direct cytotoxic or radiosensitizing effect of the drug. RSR13 plus oxygen reduced the hypoxic fraction to 9% from the value of 24% found in both air-breathing and oxygen-breathing mice. Treatment with RSR13 plus oxygen did not alter the radiation response of the bone marrow progenitor cells (CFU-S) or acute radiation reactions in the skin. The improvement in tumor radiation response produced by treatment with RSR13 plus oxygen, combined with the absence of enhanced radiation reactions in the normal tissues, support further testing of RSR13 as an adjunct to radiotherapy.

Gene therapy is an evolving discipline which today relies primarily on viral systems for gene transfer. The primary reason that plasmid vectors have not been widely used for gene therapy trials is their relatively low rate of stable gene transfer. We show here that both ionizing irradiation and hydrogen peroxide can each increase the gene transfer efficiency of plasmids. Hydrogen peroxide improves gene transfer in a linear dose-dependent manner. At equitoxic doses, hydrogen peroxide improves gene transfer by 20-fold over untreated cells and approximately 5 times above that seen for radiation, and this improvement correlates with both the total amount of DNA damage induced and the amount of residual damage after 4 hr of repair. These data suggest that DNA damaging agents may be useful to improve human gene therapy.

Radiation dose prescription, interpretation, and planning can be problematic for brachytherapy due to high spatial heterogeneity, varying and various dose rates, absence of superimposed calculated isodose distributions onto affected tissues, and lack of dose volume histograms. A new treatment planner has been developed to reduce these limitations in brachytherapy planning. The PC-based planning system uses a CT-simulator to sequentially scan the patient to generate orthogonal images (to localize seed positions) and subsequently axially scan the patient. This sequential scanning procedure avoids using multiple independent patient scans, templates, external frames, or fiducial markers to register the reconstructed seed positions with patient contours. Dose is computed after assigning activity to (low dose rate) Ir192, linear Cs137, or I125 seeds or dwell times (high dose rate) to the Ir192 source. The planar isodose distribution is superimposed onto axial, coronal, or sagittal views of the tissues following image reconstruction. The treatment plan computes (1) direct and cumulative volume dose histograms for individual tissues, (2) the average, standard deviation, and coefficient of skewness of the dose distribution within individual tissues, (3) an average (over all tissue pixels) survival probability (S) and average survival dose DASD for a given radiation treatment, (4) normal tissue complication probability (NTCP) delivered to a given tissue. All four computed quantities account for dose heterogeneity. These estimates of the biological response to radiation from laboratory-based studies may help guide the evaluation of the prescribed low- or high-dose rate therapy in retrospective and prospective clinical studies at a number of treatment sites.

To evaluate the role of detailed pathologic features in predicting outcome for early-stage prostate cancer treated with I-125 brachytherapy. The pretreatment biopsy slides of 103 patients with T1/T2 and Gleason scores of 4-7 prostatic carcinoma, which was treated by transperineal I-125 implantation, were reviewed retrospectively by a single pathologist (P.B.G.). Biochemical tumor control rates [prostate-specific antigen (PSA) below 1.0] were correlated with pretreatment PSA, Gleason score, the amount of tumor in the biopsy samples, and the presence of perineural invasion. In Cox proportional-hazard, multivariate analysis, the strongest predictors of failure were pretreatment PSA above 10 ng/ml (P = 0.013) and the length of the biopsy specimen replaced by tumor (P = 0.15). The percent of biopsy tissue replaced by tumor (P = 0. 74), perineural invasion (P = 0.78), and Gleason score (P = 0.66) were less predictive of prognosis. It was concluded that pretreatment PSA is the strongest predictor of biochemical failure. Detailed assessment of pathological features on needle biopsy added little prognostic information beyond that of pretreatment PSA alone. Like all other prognostic parameters for prostate cancer, there is considerable overlap in pathologic features between those patients who will or will not be controlled biochemically.

The purpose of this paper is to determine whether using off-axis isoseparation curves to optimize the collimator rotation angle improves dose homogeneity. Eleven intact breast irradiation patients underwent computerized tomography (CT) treatment planning with 1 cm abutting slices. Central plane treatment planning, using 6 MV photons, tissue inhomogeneity corrections, and isocentric opposed tangent treatment fields, was performed. Collimators were rotated to match chest wall slope through the use of a beam's-eye-view setting. Patient separations were measured from the apex of the breast to the posterior field border on each axial CT slice. Sagittal-plane isoseparation curves were constructed from these measurements. Using these curves, the collimator rotation that minimized off-axis separation differences was determined. A comparison of off-axis dose inhomogeneity was performed for patients with a > or =10 degrees difference between this optimized collimator angle and the angle determined by chest wall slope. These comparative treatment plans differed only with respect to collimator angle rotation. The mean optimal collimator rotation angle differed significantly from the mean rotation angle which matched the chest wall slope (5.4 degrees vs. 11 degrees, respectively, P < 0.001). Four of the 11 patients had rotation angle differences of 10 degrees. In these patients, the optimization of collimator angle reduced the percentage of breast volume to "that" received > or =110% of the prescribed dose. For the patient with the largest breast size to the patient with the smallest breast size the decreases were, respectively, 5% (15% to 10%), 3% (24% to 21%), 1% (4% to 3%), and 1% (0.9% to 0%). The mean reduction in dose inhomogeneity was greatest in the inferior breast quadrants. At 6 cm and 4 cm off axis, the mean reductions in the percentages of the breast tissue to "that" received 110% of the prescribed dose were respectively 15.1% and 5.3 %. Optimizing the collimator angle through the use of isoseparation curves decreases dose inhomogeneity. The greatest improvements are in the inferior quadrants of the intact breast. The improved dose homogeneity may have clinical relevance in the treatment of patients with large breast sizes.

Two normal, two tumour, one transformed fibroblast cell line established from Ataxia telangiectasia (AT) patients and one corrected AT hybrid were characterised with regard to alpha, beta, SF2, and D values. Survival of 60Co gamma-irradiated tumour and transformed cells was markedly reduced when the Na+, K+-ATPase inhibitor ouabain was present 1 hr before and 3 hr post irradiation. Under these conditions, the radiosensitivity in normal cells remained virtually unchanged. Suppression of repair was found to play a role in the ouabain-induced inhibition of the cell survival. In A549 lung carcinoma cells, addition of 10(-8) M ouabain decreases the sublethal damage recovery ratio from 56.5 to 13.3. The same drug concentration decreases the recovery ratio in L132 epithelial cells only from 5.1 to 4.9. The fast repair component, as measured over the first 1.5 hr after irradiation, decreases from 1.83 to 0.36 hr(-1) in A549 cells and from 0.35 to 0.16 hr(-1) in HeLa cells. For 2 Gy fractions, the presence of 10(-8) M ouabain 1 hr before irradiation and 3 hr after irradiation induces dose enhancement ratios of 1.15-1.5. A more pronounced effect on cell inactivation may be expected from multiple fractions. The concentrations required to downregulate sublethal damage repair fall within the range where cardiac glycosides are used clinically. Application of these drugs in radiotherapy thus seems feasible.

Thirty-seven of 317 patients with pituitary adenoma who underwent transsphenoidal operation from 1989 to 1996 received adjuvant gamma knife radiosurgery. Gamma knife surgery was performed mainly in patients with endocrinologically inactive tumor for tumor regrowth invading the cavernous sinus, and in patients with endocrinologically active tumor for incomplete removal invading the cavernous sinus. The maximum radiation dose was 25-60 Gy. The periphery of the tumor usually received 50% of the maximum dose. Thirteen patients were followed up for longer than 2 years (mean 45 months) after combined therapy. Magnetic resonance imaging (MRI) showed changes in signal intensity on both T1- and T2-weighted images as early as 3 months after radiotherapy. Serial MRI showed all 13 patients had achieved excellent response. Patients with endocrinologically active tumors showed normalized hormone levels 24 months after gamma knife surgery except for one patient with acromegaly. The basal value of pituitary hormones remained normal during the follow-up period, and four female patients became pregnant without hormonal therapy. Combined transsphenoidal surgery and gamma knife radiosurgery can preserve normal pituitary function and eradicate adenoma invading the cavernous sinus.

The objective of this paper was to evaluate the acute urinary morbidity associated with I-125 interstitial implantation of the prostate gland. From 1991-1995, 117 patients underwent ultrasound (U/S)-guided implantation of the prostate gland. Median dose to 90% of the gland (d90) was 14.68 Gy (range = 1.65-21.75 Gy). The patients' urinary symptoms were recorded pre-implantation and at regular intervals after implantation using the International Prostate Symptom Score (IPSS), a self-assessment questionnaire in which patients scored 7 symptoms: incomplete emptying, frequency, intermittency, urgency, weak stream, straining, and nocturia. Median follow-up was 12 months. The natural history of implant-related urinary symptoms was assessed in this manner. In addition, dosimetric factors including U/S prostate volume, total activity, activity per seed, dose volume histogram (DVH) values for dose to gland, and dose area histogram (DAH) values for dose to urethra and bladder were examined for correlation to the severity of each symptom as well as to total IPSS (sum of the individual symptom scores). Total IPSS peaked at 1 month post-implant and gradually returned to approximately baseline at 24 months. Total IPSS directly correlated with total activity and DVH for the prostate. Total IPSS, however, did not correlate with bladder or urethral DAH. With the exception of frequency, individual symptoms did not correlate with dose to gland, bladder, or urethra. Frequency scores did, however, correlate not only with dose to prostate gland but also dose to urethra. The acute urinary side effects of I-125 prostate implantation are transient and peak at 1 month post-implant. The severity of the urinary irritative symptoms developed are closely related to total dose to the gland. Urethral dose appears to affect frequency most significantly. Urinary symptoms, therefore, may be a limiting factor when considering dose escalation with I-125.

Postoperative computed tomography (CT)-based dosimetric analysis of transperineal ultrasound-guided conformal prostate brachytherapy provides detailed information regarding the coverage and uniformity of the implant. However, there is no generally accepted standard for the optimal timing of the postoperative dosimetry. This report details dosimetric analysis and the effect of timing based upon CT and orthogonal film evaluation for ten unselected patients implanted with either iodine-125 (125I) or palladium-103 (103Pd). Within 2 hours after implantation, patients underwent a CT scan and the first of four sequential sets of orthogonal films. Subsequent orthogonal films were obtained on days 3, 14, and 28 postimplant. CT-based dosimetry revealed coverage of the prostate to the prescribed minimal peripheral dose (mPD) at 93.1 +/- 3.6% of the volume, the prostate volume receiving 150% of mPD was 38.2 +/- 8.7%, and the urethral and rectal doses were 114 +/- 12% and 78 +/- 19% of mPD, respectively. The implanted seeds seen on orthogonal films acted as markers for temporal changes in prostate dimensions, and the standard deviation of each dimension was used as input in an ellipsoidal volume calculation. Seed coordinates were self normalized to the center of gravity of each two-dimensional view and were measured relative to the linear regression line in the superior-inferior direction. The reproducibility of the anteroposterior (AP) film setup in terms of temporal variation in the angle of the regression line was markedly better than that of the lateral films, 1.8 degrees +/- 1.2 degrees vs. 4.3 degrees +/- 2.6 degrees, respectively. Dimensional contraction from day 0 to day 28 averaged 11.3% in the superior-inferior direction, 8.5% in the AP/PA (posteroanterior) direction, and 2.5% in the right-left lateral direction. This translated into a volume change of 20.9% (ranged 11.6-31.6%), which was determined by using the ellipsoid method. The half-life for edema resolution was 10.6 +/- 1.8 days (range 8.6-14.3 days). However, because of variability in the degree and extent of edema and its rate of resolution, we believe that it may be futile to define a single point in time as the most accurate indicator of the postoperative dose distribution. Rather, it may be preferable to accept universal standardization of timing and methodology for CT-based postoperative dosimetry, which would facilitate comparison of results between centers and maximize the information content of that single measurement. We conclude that day 0 represents the optimal time, because dosimetric evaluation at that time minimizes patient discomfort and inconvenience (a catheter is already in place), provides information about edema when it is near its maximum extent, and provides prompt closure of the learning loop and, as such, hopefully will result in improved implantation techniques and results.

Interleukin-12 (IL-12), a naturally occurring cytokine, has demonstrated antitumor activity in several murine solid tumors. The Lewis lung carcinoma was used to study the most effective scheduling of recombinant murine interleukin-12 (rmIL-12) administration with fractionated radiation therapy. The effect of the schedule of rmIL-12 administration alone or along with a 1- or 2-week fractionated radiation therapy regimen was examined. Beginning rmIL-12 prior to or at the same time as radiation therapy and extending rmIL-12 through the radiation regimen and beyond produced the longest tumor growth delays. Those treatment regimens which were most effective against the primary tumor were also most effective in decreasing the number of lung metastases on day 20. To further assess the immunotherapeutic effects from rmIL-12 administration, the efficacy of rmIL-12 with fractionated radiation therapy delivered to a right hind-limb tumor was measured as tumor growth delay in an unirradiated left hind-limb tumor. There was some difference in the tumor growth delay between the unirradiated tumor in the animals bearing an irradiated tumor in the contralateral leg, and the tumors in animals receiving rmIL-12 only. Recombinant murine granulocyte-macrophage-colony stimulating factor (rmGM-CSF) was also an antitumor agent active against the Lewis lung carcinoma and produced an additive effect in combination with fractionated radiation therapy in this tumor. rmIL-12 was a radiation sensitizer in the Lewis lung carcinoma. When rmIL-12 (45-microg/kg) and rmGM-CSF (45 microg/kg) were administered together with fractionated radiation therapy, a marked increase in tumor growth delay resulted. This treatment combination also nearly ablated lung metastases on day 20 in these animals. These results may serve as a useful guide in developing clinical protocols, including rmIL-12 and fractionated radiation therapy.