Evaluation of localization uncertainty of fiducial markers due to length and position variations induced by motion in CT imaging by measurement and modeling.

PURPOSE: To quantify the variations in the length and position of fiducial markers induced by motion in axial (ACT), helical (HCT) and cone-beam CT (CBCT) imaging and associated uncertainty in image-guided radiotherapy (IGRT) by measurement and modeling. METHODS: A mobile thorax phantom containing markers of various lengths was imaged using ACT, HCT and CBCT imaging. The phantom was imaged while stationary and moving where it was moved sinusoidally with different motion amplitudes and frequency. An analytical motion model was developed that predicts the localization accuracy of IGRT based on fiducial markers in mobile phantom with ACT, HCT and CBCT. RESULTS: The apparent lengths of the markers varied with the different motion patterns and CT imaging modalities. In CBCT, the apparent length of the markers increased linearly with the motion amplitude for both half-fan and full-fan modes. In HCT and ACT, the apparent length of the markers increased or decreased non-linearly with motion parameters and speed of the imaging couch. When the marker moved opposed to couch motion the apparent lengths decreased, while they increased when the phantom moved along the direction of the imaging couch as predicted by the motion model. The position of marker centers did not shift and distance between makers did not change in CBCT images. However, in HCT and ACT, the position of marker center and distance between markers varied depending on motion parameters during imaging. The marker center could move superiorly or inferiorly and the distance between markers could increase or decrease depending on the phase of motion as predicted by the motion model. CONCLUSIONS: The variations of marker length and position due to phantom motion were quantified by measurement and modeling. These variations may lead to large positioning uncertainties in patient setup and tumor localization based on IGRT with fiducial marker registration.

Quantitative evaluation of the dosimetric effects of balloon deformation and source position in high-dose rate mammosite breast brachytherapy.

PURPOSE: To investigate quantitatively the deformation of the mammosite balloon, eccentricity of the source position and their effects on the dose delivered to the tumor lumpectomy site and critical structures. MATERIALS AND METHODS: The distances of the brachytherapy source to the surface of the mammosite balloon were measured in using radiographic images for fractions 1 to 10 for twelve patients. The dose at the balloon surface (nearly 680cGy) and prescription dose of 340cGy at 1cm from the balloon surface were calculated for the different fractions and their dependence on the balloon volume and source position were investigated. RESULTS: The position of the source can be offset from the center of the mammosite balloon by up to 6mm. Deformation of the balloon led to variations in its dimensions by up to 8mm. The dose at 1cm from the balloon surface that covers the lumpectomy site varied by up to 19% from 340cGy along the elongated diameter of the balloon and by up to 40% along the short diameter. Maximal doses to the skin, ribs and lung were 420cGy, 630cGy and 500cGy per fraction, respectively, which depended mostly on their distance from the balloon surface. CONCLUSION: The geometric variations in the shape of the balloon and position of the source can cause lack of dose coverage to the lumpectomy site or create hot dose spots in the surrounding normal tissue that might compromise intended clinical goals. Users as well as vendors should consider correction measures for the deformation of the balloons and the eccentricity of the position of the high dose source.

Quantitative evaluation of correlation of dose and FDG-PET uptake value with clinical chest wall complications in patients with lung cancer treated with stereotactic body radiation therapy.

The aim of this study was to investigate quantitatively the dosimetric factors that increase the risk of clinical complications of rib fractures or chest wall pain after stereotactic body radiation therapy (SBRT) to the lung. The correlations of clinical complications with standard-uptake values (SUV) and FDG-PET activity distributions from post-treatment PET-imaging were studied. Mean and maximum doses from treatment plans, FDG-PET activity values on post-SBRT PET scans and the presence of clinical complications were determined in fifteen patients undergoing 16 SBRT treatments for lung cancer. SBRT treatments were delivered in 3 to 5 fractions using 5 to 7 fields to prescription doses in the range from 39.0 to 60.0 Gy. The dose and FDG-PET activity values were extracted from regions of interest in the chest wall that matched anatomically. Quantitative evaluation of the correlation between dose deposition and FDG-PET activity was performed by calculating the Pearson correlation coefficient using pixel-by-pixel analysis of dose and FDG-PET activity maps in selected regions of interest associated with clinical complications. Overall, three of fifteen patients developed rib fractures with chest wall pain, and two patients developed pain symptoms without fracture. The mean dose to the rib cage in patients with fractures was 37.53 Gy compared to 33.35 Gy in patients without fractures. Increased chest wall activity as determined by FDG-uptake was noted in patients who developed rib fractures. Enhanced activity from PET-images correlated strongly with high doses deposited to the chest wall which could be predicted by a linear relationship. The local enhanced activity was associated with the development of clinical complications such as chest wall inflammation and rib fracture. This study demonstrates that rib fractures and chest wall pain can occur after SBRT treatments to the lung and is associated with increased activity on subsequent PET scans. The FDG-PET activity provides a useful parameter that can be used clinically to predict chest wall complication in lung patients.

Gross tumour volume variations in primary non-small-cell lung cancer during the course of treatment with stereotactic body radiation therapy.

INTRODUCTION: We aim to quantify the variations in the gross tumour volume (GTV) during a course of stereotactic body radiotherapy (SBRT) and determine its impact on dosimetric coverage of the GTV. METHODS: The GTVs and dose coverage for 14 patients with 16 primary non-small-cell lung tumours treated with SBRT were investigated. Initial GTVs were calculated from treatment planning CT scans. The prescribed doses ranged from 48 to 60 Gy in three to five fractions. Before each treatment, patients underwent a CBCT scan. For each CBCT scan, the GTV and the dose received by the GTV were determined and followed during the course of therapy. RESULTS: There was considerable variation in the measured GTVs during the course of therapy. Increases of up to 63.3% of volume measured by initial CBCT were detected during the first few fractions, after which GTV tended to decrease. Dose coverage (V95) for any given fraction deviated no more than 5% from optimised coverage obtained in the initial treatment plan. In the long term, all patients with follow-up scans demonstrated tumour shrinkage with no radiographic evidence of tumour recurrence. CONCLUSION: GTV, as evaluated in this study, demonstrates an initial increase in volume followed by a subsequent decrease. This volume change needs to be considered in the design of treatment plans and assignment of treatment margins.

Dosimetric consideration of transient volume enlargement induced by edema in prostate brachytherapy seed implants.

PURPOSE: To investigate enlargement of prostate volume by edema during brachytherapy seed implantation and develop a nomogram model to calculate air-kerma strength (AKS) required for implantation of the enlarged transient prostatic volume. MATERIALS AND METHODS: The prostate volume was measured prior and after seed implantation using trans-rectal ultrasound imaging in the operating room to obtain volume enlargement. A nomogram model was developed that calculates AKS required for implantation of the enlarged transient prostate volume with optimal dose coverage. RESULTS: The measured prostate enlargement in this study was up to 60% of the initial volume. The effective prostatic volume enlargement was calculated for three isotopes: 125I, 103Pd and 131Cs. The effective volume enlargement for 125I implants was relatively small (< 10%) because of its long half-life. For 103Pd and 131Cs with short half-lives, additional AKS up to 20% and 30%, respectively, might be required to provide appropriate dose coverage of possible enlarged prostatic volumes. CONCLUSIONS: Prostate volume enlargement should be considered to obtain optimal dose coverage particularly for short half-life isotopes such as 131Cs and 103Pd. The nomogram model developed in this work provides the AKS required for implants with a wide range of prostatic volume enlargements (5-100%) for three isotopes. KEYWORDS: prostate brachytherapy; nomogram; air-kerma strength; edema; volume enlargement.

SU-E-J-204: The Dosimetric Impact of Daily Setup Error and Inter-Fraction Prostate Motion on the Calculated Treatment Plan for Patients Receiving IMRT Based Radiation Therapy.

PURPOSE: Evaluate the dosimetric impact of daily setup error and inter-fraction organ motion on the radiation treatment plan. METHODS: Twelve patients undergoing definitive IMRT treatments for prostate cancer were evaluated. All patients underwent fiducial marker placement prior to treatment planning CT scan, and were treated to a dose of 8100cGy given in 45 fractions. We retrospectively created a plan for each treatment day that had a shift available. To calculate the dose the patient would have received with no setup correction, we mathematically 'negated' the shift by moving the isocenter in the opposite direction of the shift. The individualized daily plans were combined to generate an overall plan sum. The dose distribution from these uncorrected plans was compared to the actual treatment plans. RESULTS: A total of 390 shifts were negated and their corresponding plans evaluated. The mean isocenter shift based on the location of the fiducial markers was 3.3±6.5mm to the right, 1.6±5.1mm posteriorly, and 1.0±5.0mm along the caudal direction. The mean D95 dose when setup error was corrected and uncorrected for the PTV8100 volume was 8089cGy and 7303cGy (p < 0.001) and for prostate volume was 8228cGy and 7844cGy (p < 0.002). The mean V95 values when setup error was corrected and uncorrected for the PTV8100 volume was 99.9% vs. 87.3% (p < 0.0001). At an individual level, the difference in D95 value approached 1200cGy for the prostate volume and 2000cGy for the PTV8100 volume. There was no statistically significant difference in the D35 parameter for the surrounding normal tissue except for the dose received by the right hip and the penile bulb. CONCLUSION: This work indicates that significant underdosing, approaching 2000cGy for the PTV8100 volume, can occur as a Result of inaccurate patient setup, and emphasizes the importance of accurate patient setup and target localization.

SU-E-T-577: Dosimetric Comparison of Volumetric Modulated Arc Therapy (VMAT), Step and Shoot and Sliding Window IMRT for Prostate Cancer.

PURPOSE: This study aims to evaluate treatment plans generated by Step- and-Shoot (SS), Sliding Window (SW) and Volumetric Modulated Arc Therapy (VMAT) in order to assess the differences in dose volume histograms of planning target volume (PTV) and organs at risk (OAR), conformity indices, radiobiological evaluations, and plan quality for prostate cancer cases. METHODS: Six prostate cancer patients treated in our center were selected for this retrospective study. Treatment plans were generated with Eclipse version 8.9 using 10 MV photon beams. For VMAT, Varian Rapid Arc with 1 or 2 arcs, and for SS and SW IMRT, 7-9 fields were used. Each plan had three PTVs with prescription doses of 81, 59.4, and 45 Gy to prostate, to prostate and lymph nodes, and to pelvis, respectively. Doses to PTV and OAR and the conformal indices (COIN) were compared among three techniques. The equivalent uniform dose (EUD), tumor control probability (TCP) and normal tissue complication probability (NTCP) was also calculated and compared. RESULTS: The mean doses to the PTV prostate on average were 83 Gy and the percent differences of mean dose among all techniques were below 0.28. For bladder and rectum, the percent differences of mean dose among all techniques were below 2.2. The COIN did not favour any particular delivery method over the other. The TCP was higher with SS and SW for four patients and higher with VMAT for two patients. The NTCP for the rectum was the lowest with VMAT in all patients except one. CONCLUSIONS: Preliminary data shows similar target coverage in general. We will extend our study to include 15 patients to compare different approaches with statistics. We will attempt to define characteristics predictive of the superior delivery technique.

SU-E-J-02: Accuracy of Fiducial Marker Localization Using Axial and Helical CT, Cone-Beam CT and KV Imaging.

PURPOSE: To determine localization errors of fiducial markers using axial (ACT) and helical CT (HCT), cone beam CT (CBCT) and kV imaging. METHODS AND MATERIALS: A thorax phantom containing markers of various sizes (2.5, 5, 10, 20mm) was imaged using ACT, HCT, CBCT and kV imaging. The phantom was imaged with and without motion (15mm amplitude, 15 cycles/min). CT images were reconstructed at 0.625, 1.25, 2.5 and 5mm thickness. Marker location and length were measured using axial and coronal imaging. RESULTS: The measured marker size increased almost linearly with increased slice thickness used in CT reconstruction with ACT for the stationary phantom. In HCT, the marker size varied non-linearly with increase in slice thickness. Motion of the phantom induced further blurring and shifts of the center of the marker with different sizes. The 10 mm marker was elongated up to 13.5 mm and 16.2 mm in the ACT and HCT, respectively. The markers were elongated up to nearly 26 mm using axial and helical scanning modes by phantom motion. The displacement of maker center was more prominent in the HCT with a shift up to 2 mm due to slice thickness for stationary phantom. The marker center was displaced by up to 18 and 22 mm using ACT and HCT, respectively, which was even higher than 15 mm motion amplitude. KV imaging produced the sharpest marker image with the least difference between actual and measured marker sizes. CONCLUSION: Increase in slice thickness enlarged the apparent marker size and displaced the maker center in ACT and HCT. Motion led to further enlargement in the maker size and displacement of maker center that depended on the motion amplitude. These effects should be considered in CT-based image-guided radiation therapy to ensure accurate tumor localization and patient positioning with implanted markers.

External beam radiotherapy and hyperthermia in the treatment of patients with locally advanced prostate carcinoma.

BACKGROUND: The current study was conducted to evaluate the combination of external beam radiation therapy and hyperthermia in the treatment of patients with locally advanced prostate carcinoma. METHODS: Twenty-six patients were treated on a Phase I/II protocol between June 1990 and April 1993. The median age of the patients was 69 years. Nine patients had well differentiated adenocarcinoma, ten patients had moderately differentiated adenocarcinoma, and six patients had poorly differentiated adenocarcinoma. All patients had American Urologic Society Stage C2-D1 adenocarcinoma. The median pretreatment prostate specific antigen (PSA) level was 29 ng/mL (range, 6-104 ng/mL). All patients received external beam radiation therapy using a four-field technique. The median radiation dose was 6,800 centigrays (cGy) given in 200-cGy fractions. Hyperthermia was administered concurrently with radiation therapy to temperatures of 42.5 degrees C for 30 minutes using a transrectal ultrasound applicator with 3 thermometry probes, given as either a single treatment (9 patients) or as two treatments (17 patients). Overall survival (OS) and biochemical no evidence of disease (bNED) status were calculated using Kaplan-Meier analysis. A consensus conference definition of PSA failure was used. The Cox proportional hazards model was used for multivariate analysis. The median follow-up for all patients was 71 months. RESULTS: The median time to PSA nadir was 15 months with a median PSA nadir value of 1.0 ng/mL. The median and 5-year OS was 88 months and 73%, respectively, and the median and 5-year bNED survival was 36 months and 35%, respectively. Multivariate analysis revealed only the pretreatment PSA level (P = 0.03) and the PSA nadir reached (P < 0.01) to be significant predictors of bNED survival. The duration of hyperthermia therapy showed a trend toward significance for OS (P = 0.06). CONCLUSIONS: The current Phase I/II protocol evaluating the combination of prostate hyperthermia and external beam radiation therapy for the treatment of patients with locally advanced prostate carcinoma suggests prostate hyperthermia to be feasible with no apparent significant increased toxicity, although there was no significant improvement in treatment outcome when compared with other studies reported in the literature evaluating external beam radiation therapy with or without androgen suppression. However, further investigation into the duration as well as the temperature of the hyperthermia with a greater number of patients is warranted.

Stereotactic radiation in primary brain tumors in children and adolescents.

To evaluate treatment outcome and morbidity of stereotactic external-beam irradiation (SEBI) in pediatric patients, we reviewed 14 children treated with SEBI, using a 10-MV isocentric linear accelerator at McGill University between 1988 and 1994. The median follow-up was 46 months (range 6-82 months). The median age was 14 years. There were 8 low-grade astrocytomas, 3 neuromas and 4 other histologies. Twelve patients received fractionated treatments. The median collimator diameter was 2.5 cm (range 1-5 cm). The median biological effective dose delivered to the entire tumor volume was 57 Gy for astrocytomas and 43 Gy for the other histologies. The overall actuarial survival rate and disease-free survival rate at 5 years were 83 and 62%, respectively. For the patients with low-grade astrocytomas, the 5-year survival and disease-free survival rates were 100 and 60%, respectively. Four children had recurrence at a median of 37 months. Four patients developed treatment-related complications: 1 had edema alone, 2 had necrosis and 1 had edema associated with necrosis. Neither the physical nor radiobiological parameters were predictive of the treatment outcome or the treatment complications. Stereotactic irradiation is a valid option for progressive nonresectable tumors in children.

Is there a subset of patients with PSA > or = 20 ng/ml who do well after conformal beam radiotherapy?

To determine if there is a subgroup of patients with pretreatment PSA > or = 20 ng/ml with a favorable outcome after external beam radiation therapy. We analyzed retrospectively treatment outcomes of 129 patients with pretreatment PSA > or = 20 ng/ml treated in our department from 2/88-8/94. Median patient age was 70 years (range 51-89 years). Tumor stage was T1/T2ab in 68, T2c/T3 in 61 patients. Initial Gleason grade was < 7 in 82 and > or = 7 in 47 patients. Median PSA was 35 ng/ml (mean 45 ng/ml, range 20-191 ng/ml). Ninety-seven patients received four-field conformal external beam radiation therapy. No patient received surgery or hormonal therapy prior to treatment. Median central axis dose was 73 Gy (range 68-79 Gy). Covariates considered in univariate and multivariate analyses included central axis dose, pretreatment PSA, presence of perineural invasion, Gleason score, palpable tumor stage and patient age. bNED failure was defined as a PSA > or = 1.5 and rising on two consecutive determinations. Median follow up was 50 months (range 3-100 months). Overall bNED control for the entire patient population was 22% at five years. Of the covariates analyzed, dose (P < 0.01), stage (P < 0.01), Gleason Score (P < 0.01), and the presence of PNI (P = 0.01) were significant on multivariate analysis. Based on these results, patients could be stratified into two distinct groups. Group I consisted of 19 patients with favorable features including T1/T2ab disease, Gleason Score 2-6, no perineural invasion treated to a dose > 73 Gy to the central axis. Patients in Group II had at least one of the above poor prognostic features or were treated to central axis doses < 73 Gy. The bNED control was significantly higher for patients in Group I than those in Group II (58% vs. 23%, P = 0.0027). There appears to be a favorable subgroup of patients with PSA > or = 20 ng/ml where treating to doses over 73 Gy to the central axis is warranted (four-year bNED rate of 58%). However, because of the small patient numbers, these results will need to be validated with longer follow up.

Sexually dimorphic effect of an acute smoking manipulation on skin resistance but not on heart-rate during a cognitive verbal task.

In a two-day, two-session experiment where smokers male and female college-student subjects worked on a cognitive verbal task during either the first or second day, and on a cognitive spatial task on the second or first day, smoking was manipulated as an acute independent variable by requiring 10+ hours of pre-experimental abstention, and providing a cigarette during the 15-minute rest period between the two sessions. Non-smoker female and male subjects underwent the same experiment, and hence served as controls for the effects of this acute-smoking manipulation. Overall adaptation (decreased arousal) to the experiment was manifested in a significant increase in skin resistance level (SRL) in all subjects, but when this adaptation effect was statistically controlled, there was a significant smokers by sex interaction during the verbal task only, such that SRL was increased by the cigarette in males, but decreased in females. In contrast, the same analysis indicated only a marked increase in heart-rate (HR) due to smoking, which was unaffected either by sex or by whether the task was the verbal or the (easier) spatial one. We interpret the SRL results as reflecting a sex difference in the direction of transient psychological arousal, and discuss it in relation to evidence in the literature based on self reports, and to evidence (based on HR in this study and on blood pressure in other studies) on physiological (cardiovascular) arousal. Key Words: Electrodermal activity, heart-rate, psychological vs. physiological, verbal and spatial cognitive tasks.

Use of the prone position in radiation treatment for women with early stage breast cancer.

PURPOSE: The prone position has been advocated for women with large pendulous breasts undergoing breast-conserving treatment with radiation therapy. However, there is no information in the literature regarding the coverage of the target volume with this technique. The purpose of this study was to evaluate the effectiveness of the prone treatment position in including at least the biopsy cavity with a 2-cm margin. METHODS AND MATERIALS: Eleven consecutive patients who underwent CT simulation in the prone position were included in this study. Patients underwent CT simulation in the prone position using a flat platform containing an aperture for the breast to hang through in a dependent fashion. CT slices were 5-mm thick taken at 3-mm intervals. The biopsy cavity was localized and outlined on sequential CT images using the surgical clips (when present) as well as the residual seroma. A 2-cm margin was included around the biopsy cavity to define the minimal target volume (mTV). Lateral fields were used for treatment planning. The beam arrangements were considered adequate if the mTV was totally included in the lateral fields. RESULTS: Median age of the patient population was 55 years. Bra sizes ranged from 36A-44DD. The majority of patients had mammographically detected T1 lesions. Median volume of the biopsy cavity was 48 cm3. Five of 11 (45%) patients underwent reexcision of the biopsy cavity, and 6 of 11 (55%) had surgical clips placed in the biopsy cavity. Overall, 8 of 11 (73%) patients did not have the entire mTV included in the lateral opposed tangential fields in the prone position. This was especially true in patients whose biopsy cavity extended down to the chest wall. There were no other clinical factors that could predict for the adequacy of coverage in the prone position. CONCLUSION: Special attention must be paid to the location of the surgical clips to determine the proximity of the biopsy cavity to the chest wall, or CT simulation should be performed to determine the exact location of the biopsy cavity prior to selecting patients with large pendulous breasts for treatment in the prone position.

Radiation-induced, lamina-specific deletion of neurons in the primate visual cortex.

To examine the early determinants of cortical cytoarchitecture, we deleted specific neuronal classes in the primate visual cortex by ionizing irradiation at selected prenatal stages. Multiple doses of X-rays were delivered to the macaque monkey brain between embryonic day (E) 80 and E90 to block the division of cells destined to populate the superficial cortical layers, between E70 and E79 to eliminate neurons destined for the middle layers; and between E33 and E40 to delete neurons destined for the lateral geniculate nucleus (LGN) that project to the cortex. All animals were killed after birth, and their brains were processed for histological and electron microscopic analyses. Cell density and number in the LGN and visual cortex were determined by using three-dimensional, computer-aided morphometry. In animals irradiated with low doses (total of approximately 200 cGy) during the genesis of the LGN but before the onset of corticogenesis (E33-40), the LGN was reduced in both volume and number of neurons. Area 17 in these animals displayed only slight changes in cortical thickness, cell density, and area-specific cytoarchitectonic features, whereas the total surface devoted to area 17 was significantly diminished. In contrast, animals irradiated with low doses during the period of corticogenesis, after the completion of the LGN genesis, showed no significant change in the volume of the LGN or in the number of its cells. Moreover, in these animals, the surface of area 17 was not significantly altered, although the cortical layers generated at the time of irradiation had a significantly lower density and total number of cells, whereas the layers generated before and after the period of irradiation were spared. In contrast, cases exposed to high doses of X-ray (total > 300 cGy) showed more severe effects, including all layers. However, layers normally generated during irradiation were depleted and consisted of cell-sparse strata populated by densely packed neuropil (axons, small dendrites, dendritic spines, and synaptic boutons). These cell-sparse strata were situated deeper in the early irradiated animals than in the later irradiated animals, and their laminar position changed abruptly at the area 17/18 border. These results show that low doses of irradiation in a slowly developing primate brain can be used effectively to eliminate targeted classes of neurons before they reach their final position, providing an opportunity to examine the role of cell-cell interactions in the formation of circuitry and the role of specific cell classes in cortical development.

Effects of tobacco smoking and gender on interhemispheric cognitive function: performance and confidence measures.

Cognitive function in tasks involving interhemispheric processing of verbal and spatial information was studied in 31 college students in a 2 x 2 factorial design with chronic smoking status [smoker (10+ cigarettes per day) versus non-smoker (no history of smoking)] and gender as the main between-subject factors. The subjects participated in two sessions on two consecutive days. The same task was repeated within the same session with a 15 min interval: smokers were tested before and after smoking whereas non-smokers rested during the interval. Dependent behavioral variables included those of performance (speed and accuracy) and confidence (low rate of non-responding). The verbal task yielded an expected female advantage, and smoking had the gender-specific effect of increasing both speed and accuracy more clearly in males. In addition, smoking decreased the rate of non-responding (increase confidence) in women, thereby affecting preferred strategies for problem solving by shifting the female pattern towards the male pattern. The spatial task, which probably involved a more perceptual, rather than cognitive, level of functioning, produced no clear effects of smoking and gender, and yielded some laterality effects. The acute within-subject smoking manipulation wherein, among smokers, the first test was preceded by 10+ h of deprivation, whereas the second repeated task was preceded by the smoking of a cigarette (i.e. deprivation followed by partial release) did not affect the behavioral measures. In conclusion, smoking had a gender-specific effect on cognitive function: it improved the performance of males in a verbal task and increased the subjective confidence of females thereby affecting the preferred cognitive strategies for problem solving.

Radiation inactivation of human prostate cancer cells: the role of apoptosis.

Radiation-induced apoptosis detected by gel electrophoresis was measured in cells of three human prostate carcinoma cell lines (TSU, PC-3 and DU-145) and compared to their intrinsic radiosensitivities as measured by clonogenic assays. The intrinsic radiosensitivities of each cell line were defined by their alpha and beta coefficients and their surviving fraction at 2 Gy, derived from complete survival curves. The temporal expression and kinetics of radiation-induced apoptosis for DU-145 cells, the human prostate carcinoma cell line which expressed the highest rate of radiation-induced apoptosis, was characterized further by differential sedimentation and the immunofluorescence assay (Apoptag) which was specific for 3'-OH ends in cellular DNA. Cell viability was measured microscopically with trypan blue staining. Cell survival after various doses was computer-fitted to either a simple linear or a linear-quadratic equation. Twenty-four hours after a 10-Gy dose of 137Cs gamma rays, DNA fragmentation to nucleosome multimers was strongly expressed in only DU-145 cells. In this cell line, when centrifugation at 12,000g for 10 min was used to separate fragmented from large molecular weight DNA, the proportion of DNA in the supernatant increased to a maximum of approximately 17% of the total by 10-12 h after radiation treatment. Cell death 24 h after irradiation measured by trypan blue exclusion assays followed single-hit kinetics up to 80 Gy. The proportion of cells which were labeled with Apoptag displayed single-hit kinetics and yielded the same inactivation coefficient as measured by trypan blue. Together, these data indicate that the rapid (24 h) inactivation of irradiated DU-145 cells results from apoptosis and accounts for about 5% of the single-hit killing measured by clonogenic assay. Temporal studies of radiation-induced killing of DU-145 cells distinguished this rapid mechanism of cell death from the major mechanism (72-144 h). These may correlate with apoptosis and proliferative cell death, respectively. Of the three prostate cancer cell lines investigated, only DU-145 cells displayed significant levels of radiation-induced DNA fragmentation and rapid cell death, with characteristics of apoptosis. This mechanism of cell death was complete by 24 h after irradiation and was well separated in time from the death of cells by the major mechanisms which occurred after 72 h, and accounted for about 5% of cell inactivation by a single-hit mechanism.

Improved outcome in patients treated with postoperative radiation therapy for pathologic stage I/II endometrial cancer.

PURPOSE: To evaluate prognostic factors and treatment outcome for high risk pathological Stage I and II endometrial cancer patients treated with consistent postoperative radiation therapy (RT) in a single institution and to compare these results to series where RT was variably applied. METHODS AND MATERIAL: Between 1986 and 1993, 98 pathologic Stage I and II endometrial cancer patients received postoperative RT at the Fox Chase Cancer Center. Papillary serous and clear cell histologies were excluded. Fifty-five patients underwent lymph node evaluation. In 17 patients, RT consisted of intracavitary brachytherapy alone to a median dose of 21 Gy, and in 81 patients, RT consisted of external beam RT to a median dose of 45 Gy followed by intracavitary brachytherapy to a median dose of 12 Gy. Intracavitary brachytherapy generally consisted of three high dose rate implants with the dose prescribed to a depth of 0.5 cm. Median follow up was 47 months. RESULTS: The 5-year overall survival (OS), disease free survival (DFS), and freedom from pelvic recurrence (FPR) rates were 83, 85, and 89%, respectively. Pelvic recurrence either as the sole pattern of failure or combined with distant metastases was seen in 2 and 7% of patients, respectively. Distant metastases alone occurred in 4% of the patients. Univariate analysis of prognostic factors including age, grade, capillary lymphatic space invasion, depth of myometrial invasion, type of lymph node evaluation, pathologic stage, the use of brachytherapy and the number of risk factors was performed for OS, DFS, FPR, and FDM. Capillary lymphatic space invasion was the only statistically significant predictor for reduced DFS. Absence of lymph node dissection as well as a higher number of risk factors showed a trend toward poorer DFS (p = 0.06 for both). Multivariate analysis revealed older age to be the only factor significant for reduced DFS, with the presence of capillary lymphatic space invasion and the absence of a lymph node dissection showing a trend toward poorer outcome (p = 0.07). CONCLUSIONS: The results of this study suggest a continued role for the use of postoperative RT in the treatment of patients with high risk endometrial cancer and will be compared to other series with similar high-risk factors.

Application of multivariate linear discriminant analysis to lung sounds in some pulmonary diseases.

In the past 15 yrs, a number of investigators have applied spectral analysis to respiratory sounds recorded from the chest wall or the trachea in order to objectively characterize them and to relate them with different pulmonary diseases. In the present study, we have applied multivariate linear discriminant analysis to the spectral features of respiratory sounds. Lung sounds and the airflow velocity were recorded from 15 normal adults and 37 patients falling into three different disease categories: chronic obstructive lung disease, bronchial asthma and bronchiectasis. All patients had prominent adventitious lung sounds (i.e. either wheezes or crackles). Amplitude spectra of five selected inspiratory and expiratory sound segments of each subject were calculated using the Fast Fourier Transform algorithm. Multi-variate linear discriminant analysis was then applied to the normalized and averaged spectral area values calculated for 10 unequal and arbitrarily selected frequency bands for each patient in the frequency range between 80 Hz and 1 kHz. Inspiratory and expiratory sounds were treated separately. Discriminant functions were computed from the spectral area values and plotted on graphs to classify the subjects into one of the disease categories or as normal (training set). While some separation was achieved among the different disease groups, a clearer separation was evident between normals and patients as a whole on the basis both of inspiratory and expiratory sounds. Inspiratory and expiratory sound frequency bands having the largest weights in classification were determined. Admittedly, the specific results of this study are preliminary or even tentative in view of the inadequacies of sound recording and signal conditioning techniques that were available to us at the time of recording. However, we believe that the investigation serves to illustrate the potential of multivariate discriminant analysis in the diagnostic classification of patients on the basis of their lung sound patterns. We suggest that this technique be considered by investigators involved in lung sound research, because it also allows other patient variables to be combined with the selected parameters of lung sounds.

Localization of the prostatic apex for radiation treatment planning.

PURPOSE: To determine whether retrograde urethrogram, or the combination of computed tomography (CT) scan/retrograde urethrogram is more accurate for locating the magnetic resonance imaging (MRI) designated prostatic apex, and to determine whether patients treated in our department with CT/urethrogram are receiving the prescribed minimal dose to the MRI identified prostatic apex. METHODS AND MATERIALS: Seventeen patients with early stage prostate cancer were enrolled in a prospective study to determine the location of the prostatic apex. All of the patients agreed to undergo MRI in addition to retrograde urethrogram, and CT of the pelvis for three dimensional (3D) treatment planning. The prostatic apex was identified on each of the studies and measured from a reference point (the most superior portion of the pubic symphysis). The location of the prostatic apex as measured by retrograde urethrogram alone and by CT/urethrogram was compared to the location of the prostatic apex as measured by MRI. Because of MRI's ability for multiplanar capabilities, and high soft tissue contrast in the region of the prostate, it was assumed to be more accurate for identifying the location of the prostatic apex, and was used as the gold standard. RESULTS: The location of the prostatic apex as determined by the urethrogram alone was on average 5.8 mm caudad to the location on MRI (p = 0.012), while the location of the prostatic apex as determined by CT/urethrogram was 3.1 mm caudad to the location on MRI (p = 0.150). If the prostatic apex is defined at 12 mm instead of 10 mm above the urethrogram tip, the statistically significant difference between the urethrogram and the MRI is no longer present. Based on these results, all 17 patients received the minimum prescribed dose to the prostatic apex. CONCLUSION: CT/urethrogram correlates better with the location of the MRI determined prostatic apex, than does the urethrogram alone. Locating the prostatic apex 12 mm above the urethrogram tip better localizes the prostatic apex, while also avoiding the error that can potentially lead to a geographic miss. This in fact assures that all of our patients receive the minimum prescribed dose to this critical site of extraprostatic extension, while also decreasing the amount of normal tissue that is included in the treatment volume.

Management of adenocarcinoma of the esophagus with chemoradiation alone or chemoradiation followed by esophagectomy: results of sequential nonrandomized phase II studies.

PURPOSE: The incidence of adenocarcinoma of the esophagus is increasing, but the optimal treatment for this disease is unknown. We evaluated the efficacy of chemoradiation and chemoradiation followed by esophagectomy as treatment for adenocarcinoma of the esophagus in sequential prospective nonrandomized phase II studies. METHODS AND MATERIALS: Between May 1981 and June 1992, all previously untreated patients (N = 35) with potentially resectable adenocarcinoma of the esophagus (clinical Stage I or II) were treated with curative intent in sequential prospective Phase II studies. From May 1981 to August 1987, 11 patients (median age 66) were treated with concurrent chemotherapy [mitomycin C, and 5-fluorouracil (5-FU)] and radiotherapy to a median dose of 60 Gy (CRT group). From September 1987 to June 1992, 24 patients (median age 65) were treated with the same regimen of chemoradiation followed by planned esophagectomy (CRT+PE group). Of these, 12 patients (median age 62) actually underwent esophagectomy (CRT+E subgroup). RESULTS: The median overall survival was 19 months for the CRT group and 15 months for the CRT+PE group. For the CRT+E subgroup, the median overall survival was 33 months. The 3-year actuarial overall survival for the CRT and the CRT+PE groups were 36 and 28% (p = 0.949). The subset of patients treated with chemoradiation followed by esophagectomy had a 3-year actuarial overall survival of 33% (p = 0.274). The 3-year actuarial freedom from local failure rates were similar: 62% in the CRT group vs. 58% in the CRT+PE group. Of the 12 patients who underwent esophagectomy (CRT+E group), 9 (75%) were free of local failure. Four of 12 (33%) patients had no pathologic evidence of malignancy in their surgical specimen. Six of 11 patients (55%) in the CRT group were free of local failure at the time of analysis. Two of five patients in this group who had local recurrence at 2 and 10 months underwent surgical salvage with subsequent survivals of 20 and 100 months, respectively. Treatment-related mortality was 0 out of 11 in the CRT group and 2 out of 24 in the CRT+PE group. Dysphagia relief was similar in the CRT group vs. the CRT+E subgroup; however, a greater percentage of patients treated with chemoradiation alone had normal long-term swallowing function when compared to those patients also undergoing esophagectomy (100% vs. 73%). CONCLUSION: High-dose chemoradiation alone appears to provide similar survival and relief of dysphagia compared with high-dose chemoradiation followed by esophagectomy for patients with potentially resectable esophageal adenocarcinoma. Local failure may be higher in patients undergoing chemoradiation compared to chemoradiation followed by esophagectomy, but surgical salvage is possible, thus providing similar overall local control. However, because of the small number of patients in each group, these treatment modalities need to be further evaluated in a prospective randomized Phase III study.