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population is low. However, loss of PG function of about 5%/ 1 Gy of mean dose has been reported, suggesting that mean doses encountered in this study are significant with potential to impact salivary function and thereby affect QOL in these patients. Modifying treatment fields to block portions of bilateral PGs can substantially reduce mean parotid dose without compromising target volume coverage. Further study is required to determine the clinical and QOL impact of these changes. Author Disclosure: M.M. Shah: A. Employee; Henry Ford Hospital. K.N. Barton: A. Employee; Henry Ford Hospital. R. Yechieli: A. Employee; Henry Ford Hospital. S. Leadership; Michigan State Medical Society Executive Committee. F. Siddiqui: A. Employee; Henry Ford Hospital. S. Leadership; Vice Chair Radiation Oncology. A. Gopal: A. Employee; Henry Ford Hospital.

Purpose/Objective(s): Prior studies have suggested a significant increase in cardiac toxicity following thoracic radiation therapy (RT) for lung cancer. In RTOG 0617 study evaluating the benefit of dose escalation in non-small cell lung cancer, factors predictive of less favorable OS on multivariate analysis included heart volume> 5 Gy. We wanted to evaluate the risk of cardiac cause specific (CCS) death in patients with Stage III lung cancer who received external beam radiation (XRT) in a large population-based analysis. Materials/Methods: Patients diagnosed in 1990-1997 with stage III lung cancer registered in the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program were included. CCS survival was compared between patients treated with definitive XRT, definitive surgery, and surgery combined with XRT using Kaplan Meier Analysis. Heart disease was the primary endpoint; deaths from other causes were censored, and surviving patients were censored at 10 years. Cox proportional hazard ratio was used to calculate the hazard of death from heart disease. Results: A total of 60,308 patients were analyzed. Median CCS survival was not significantly between patients who received definitive XRT compared to definitive surgery (106.00 months and 108.37 months, P Z 0.428). Compared to both definitive XRT and definitive surgery, CCS survival was improved in patients who received combined surgery and radiation (112.05 months, P < 0.001). Multivariable analysis revealed increased age (HR Z 1.06, 95% 1.05-1.06), African American race (HR Z 1.503, 95% CI Z 1.27-1.74), and male gender (HR Z 1.43, 95% CI Z 1.28-1.59) is associated with increased risk of CCS mortality. Treatment modality and site laterality were not associated with a significant increase in CCS risk. Conclusions: Risk from CCS death due to XRT was not increased compared to those that received surgery in patients with stage III lung cancer. Adjuvant XRT does not increase risk to CCS death in patients who undergo surgery for lung cancer. CCS mortality continues to decrease over time with improvements in radiation techniques. Author Disclosure: A. Pham: None. S. Arora: None. A. Wernicke: None. D. Nori: None. K. Chao: None. B. Parashar: None.

Purpose/Objective(s): The aim of this study is to build the estimator of toxicity using artificial neural network (ANN) for head and neck cancer patients Materials/Methods: An ANN can combine variables into a predictive model during training and considered all possible correlations of variables. We constructed an ANN based on the data from 73 patients with advanced H and N cancer treated with external beam radiotherapy and/or chemotherapy at our institution. For the toxicity estimator we defined input data including age, sex, site, stage, pathology, status of chemo, technique of external beam radiation therapy (EBRT), length of treatment, dose of EBRT, status of post operation, length of follow-up, the status of local recurrences and distant metastasis. These data were digitized based on the significance and fed to the ANN as input nodes. We used 20 hidden nodes (for the 13 input nodes) to take care of the correlations of input nodes. For training ANN, we divided data into three subsets such as training set, validation set and test set. Finally, we built the estimator for the toxicity from ANN output. Results: We used 13 input variables including the status of local recurrences and distant metastasis and 20 hidden nodes for correlations.more » 59 patients for training set, 7 patients for validation set and 7 patients for test set and fed the inputs to Matlab neural network fitting tool. We trained the data within 15% of errors of outcome. In the end we have the toxicity estimation with 74% of accuracy. Conclusion: We proved in principle that ANN can be a very useful tool for predicting the RT outcomes for high risk H and N patients. Currently we are improving the results using cross validation.« less

Advances in the understanding of hepatocyte engraftment and repopulation of the host liver have already led to the use of hepatocyte transplantation (HT) with some success in the treatment of inherited and acquired liver diseases. Wider application of HT is severely limited by the unavailability of large number of transplantable hepatocytes and difficulties associated with transplanting an adequate number of cells for achieving therapeutically satisfactory levels of metabolic correction. Therefore, there is a need for preparative regimens that provide a growth advantage to the transplanted (healthy) hepatocytes over the host's own (diseased) hepatocytes so that the former can repopulate the host liver. We have recently shown that when the liver of recipient rats was subjected to radiotherapy and partial hepatectomy before HT, the transplanted hepatocytes engrafted in and massively repopulated the liver, and also ameliorated the adverse clinical and histopathological changes associated with hepatic irradiation. This protocol was then used as a preparative regimen for transplanting normal hepatocytes into jaundice mutant rats (Gunn strain), which lack hepatic bilirubin-uridinediphosphoglucuronate glucuronosyltransferase and is a model of Crigler-Najjar syndrome Type I. The results showed long-term correction of the metabolic abnormality, suggesting that the transplanted hepatocytes repopulated an irradiated liver and were metabolically functional. This strategy could be useful in the treatment of various genetic, metabolic, or malignant diseases of the liver.

Although liver-directed gene therapy arrived later than gene therapy directed at bone marrow cells, intrinsic advantages of the liver as a target organ make it likely that gene therapy for liver diseases will be among the first therapeutically relevant applications of this treatment modality at the onset of the 21st century. Vectorology for gene transfer to the liver is advancing rapidly, and it is safe to predict that gene therapy vehicles that will be in clinical use a decade from now, have not yet been developed. None of the currently available modes of gene transfer to the liver is optimal for all types of applications. Nonetheless, the concerted effort of many investigators has provided a wide choice of non-viral and viral vectors for gene transfer to the liver for use in specific situations. Original strategies for liver-directed gene therapy included substitution of missing gene products, overexpression of intrinsic or extrinsic genes and inhibition of expression of specific genes. To the list is now added the possibility of site-specific correction or generation of mutations within specific genes in somatic cells of living adult animals. Thus, despite some initial faux pas, liver-directed gene therapy is poised to make an important impact on health care in the year 2000 and beyond.

Development of new therapies for human hepatitis B virus infection (HBV) would be greatly facilitated by the availability of a suitable small-animal model for HBV virus production in vivo. To develop a murine model for HBV production, we established an immortalized, cloned liver cell line by transferring the Simian Virus 40 Large T-Antigen into primary human hepatocytes. These cells were stably transfected with a full-length HBV genome to generate a clone that expresses HBV genes and replicates HBV. The HBV-producing cells were transplanted into the livers of mice with combined immunodeficiency (Rag-2 deficient) by intrasplenic injection. Survival of the engrafted human hepatocytes was shown in several ways: fluorescent in situ hybridization (FISH) with a human-chromosome-specific DNA probe (human alpha satellite), dot-blot hybridization of the genomic DNA extracted from liver biopsy specimens with a human-specific Alu repetitive DNA probe, Blur-8, as well as with an HBV DNA probe, and secretion of human proteins into plasma. Histological examination of mouse liver up to 8 months following human cell transplant shows completely normal architecture. Determination of plasma HBV DNA levels indicated that engrafted cells secreted 3x10(7) to 3x10(8) virions per mL into the blood, and HBsAg was detected in plasma. This new murine model of HBV viremia should be useful for in vivo HBV studies.

Crigler–Najjar syndrome type I is characterized by unconjugated hyperbilirubinemia resulting from an autosomal recessive inherited deficiency of hepatic UDP-glucuronosyltransferase (UGT) 1A1 activity. The enzyme is essential for glucuronidation and biliary excretion of bilirubin, and its absence can be fatal. The Gunn rat is an excellent animal model of this disease, exhibiting a single guanosine (G) base deletion within the UGT1A1 gene. The defect results in a frameshift and a premature stop codon, absence of enzyme activity, and hyperbilirubinemia. Here, we show permanent correction of the UGT1A1 genetic defect in Gunn rat liver with site-specific replacement of the absent G residue at nucleotide 1206 by using an RNA/DNA oligonucleotide designed to promote endogenous repair of genomic DNA. The chimeric oligonucleotide was either complexed with polyethylenimine or encapsulated in anionic liposomes, administered i.v., and targeted to the hepatocyte via the asialoglycoprotein receptor. G insertion was determined by PCR amplification, colony lift hybridizations, restriction endonuclease digestion, and DNA sequencing, and confirmed by genomic Southern blot analysis. DNA repair was specific, efficient, stable throughout the 6-month observation period, and associated with reduction of serum bilirubin levels. Our results indicate that correction of the UGT1A1 genetic lesion in the Gunn rat restores enzyme expression and bilirubin conjugating activity, with consequent improvement in the metabolic abnormality.

Purpose/Objective(s): Cranial irradiation is an effective treatment modality for both primary and metastatic brain tumors, yet it induces cognitive decline in a substantial number of patients. Recent investigations have revealed a link between radiation-induced cognitive dysfunction and the loss of neural stem cells (NSCs) in the hippocampus. Previously, we showed that FTY720, an agent recently approved by the FDA for treatment of multiple sclerosis, provided radioprotection for NSCs but not tumor cells in vitro. We now examined the ability of fingolimod to mitigate neurocognitive deficits, induced by whole brain irradiation (WBI), in a mouse model. Materials/Methods: Six-week-old C57/Bl/6J mice were randomized to four experimental groups: (1) WBI + FTY720, (2) WBI + drug vehicle control, (3) sham irradiation + FTY720, and (4) sham irradiation + vehicle. There were 12 mice in each group. Following a single dose of radiation, 7 Gy or 0 Gy (sham), FTY720 or vehicle was given to mice via i.p. injections three times a week for six weeks. Spatial memory was tested using Morris water maze studies. The mice were trained to locate a submerged hidden platform in daily sessions for five days; this was followed by a single probe trial with no platform. The average latency time (length of time to find the platform in water) was calculated for each animal in each trial. Additional behavioral studies included open field, elevated plus maze, and cued fear conditioning studies, testing locomotor activity, anxiety, and amygdaladriven cued response respectively. All data were analyzed using STATA statistical software. Results: In irradiated mice (WBI + vehicle), spatial memory deficits were manifested by significantly longer latency times compared to the nonirradiated controls (sham + vehicle), p < 0.05. Administration of FTY720 fully attenuated radiation-induced memory dysfunction: latency times of irradiated mice treated with FTY720 (WBI + FTY720) were not significantly different from those of non-irradiated controls (sham + vehicle). The latency times of non-irradiated mice treated with FTY720 (sham + FTY720) were equal to those of the non-irradiated vehicle controls (sham + vehicle) as well as of the irradiated FTY720-treated group (WBI + FTY720). There were no statistically significant differences between any of the groups in the open field, elevated plus maze, or fear conditioning studies. Conclusions: We found FTY720 to attenuate radiation-induced spatial memory dysfunction in vivo. Combined with our previous data demonstrating the radioprotective effects of FTY720 on hippocampal neural precursor cells but not tumor cells in vitro, these results provide a strong rationale for testing the efficacy of this FDA-approved agent as a neuroprotector in patients undergoing whole brain radiation therapy. Author Disclosure: A. Stessin: None. M. Banu: None. J. Boockvar: None. B. Parashar: None. D. Nori: None. C. Chao: None. A. Wernicke: None.

Purpose: Cs‐131, I‐125 and Pd‐103, have been used for permanent implant brachytherapy. Cs‐131 has shorter half‐life — 9.7 days as compared to I‐125 and Pd‐103 — 59.4 and 17.0 days, respectively. It is likely more biologically efficient for tumor cell kill as the initial dose rate from Cs‐131(23.9 cGy/h) is 4 times higher than that of I‐125(5.8 cGy/h) and twice of Pd‐103(13.62 cGy/h). These isotopes differ in their average gamma‐ray energies (30.4keV, 28.5keV and 20.8keV, respectively). This study examines the dosimetric differences amongst these isotopes when used as a permanent implant for patients with resected brain metastasis with regard to exposure of normal brain tissue and the potential for developing radiation necrosis (RN). Methods: 24 patients with a single newly diagnosed and resected brain metastasis were implanted with Cs‐131. Post‐op dosimetry plans were generated for Cs‐131, I‐125 model #6711 and Pd‐103 model #200. The prescription dose was 80 Gy to 5mm depth from the surface cavity. The mean air kerma strength for the Cs‐131, I‐125 and Pd‐103 seeds were 2.4U, 0.6985U and 2.11U respectively. The volume of brain tissue exposed to radiation at 100%, 80% and 50% isodose lines were compared for each isotope. Results: Significantly larger volume of brain tissue exposed to radiation, with the use of I‐125 when compared to both Cs‐131 (p less than 0.00005) and Pd‐103 (p less than 0.00004). There is no significant difference when comparing Cs‐131 to Pd‐103 (p=0.26605). Conclusion: In this analysis, we report that Cs‐131 and Pd‐103 expose less normal brain tissue to radiation when compared to I‐125, thus providing a dosimetric superiority and subjecting less tissue to RN. In addition, Cs‐131 has the shortest T1/2 and in our trial with a median follow up of 10 months, all 24 patients have 100% local control while experiencing 0% incidence of RN.

Purpose: Presently, various forms of quality indices (QI) are used to compare and evaluate stereotactic treatment plans with no single QI accepted as universal. In this work we evaluate and compare the performance of 11 previously reported QI: 5 conformity (CI), 5 homogeneity (HI), and 1 dose gradient (DGI) indices as a function of target size, site, and mode of treatment. A novel unified quality function (UQF) which combines conformity, homogeneity and dose gradient is presented and investigated. Methods: 27 spine SRS, 8 pelvic SBRT and 34 lung SBRT cases were analyzed using an in‐house wxPython program which imports treatment plan data and calculates various quality indices, dose volume tables, displays 3D dose/CT images, cumulative and differential DVHs. Results: Mean spine, pelvis and lung coverages were 0.91, 0.93, 0.85 respectively. Mean maximum target dose was best for pelvis (108%), followed by the lung (115%) and the spine (118%). Mean minimum target dose was best for the lung (95%), followed by pelvis (94%) and spine (88%). Mean DGI were 4.6, 5.2 and 7.54 for the pelvis, spine and lung. UQF scores the best for pelvis (0.2), followed by spine (0.28) and the lung (0.42). IMRT spine plans had better mean coverages (0.94), and lower maximum target dose (114%), while VMAT plans had better minimum target dose (89%). Conclusion: Mean CI, HI and DGI show various sensitivities to the treatment site, size and the delivery type (VMAT or IMRT). All CI except coverage show large variations with volume < 130 cc while all 5 HI show little dependence on the PTV volume. DGI values fall sharply for the lung (from 15 to 6) and spine (from 10 to 5) as the PTV increases to about 100 cc, while pelvic DGI stays about 5 for all PTV sizes.

Purpose: We examined the effects of large breast separation (BS) on dosimetric and positional differences of radiation treatment plans of locally advanced breast cancers during a free-breathing respiratory cycle. Materials and Methods: Computed tomography (CT) datasets of 18 patients were acquired using 3D, 4D-0% (end-inspiration), and 4D-50% (end-exhalation). BS was examined in relation to the positional and dosimetric changes to organs-at-risk (OAR). Based on dosimetric analysis of all three plans, we compared 4D-0% and 4D-50% for V 5 , V 10 , and V 20 to 3D for heart and ipsilateral lung. Using 4D-0% and 4D-50% CTs, we recorded positional variations of the organs′ centroid (centers of mass) and their effects on dosimetry. Results: Median BS was 23.95 cm (range: 16.86-29.48 cm). There was a strong positive correlation between BS and dose to the ipsilateral lung for V 5 , V 10 , and V 20 , with the greatest linearity observed at V 20 (R 2 = 0.23). At BS ≥27 cm, the dose increased during inspiration at V 5 , V 10 , and V 20 (P < 0.05). When comparing 4D and 3D for the heart, V 5 and V 10, decreased by average of 0.94% and 0.96% (P < 0.008), respectively. Conclusions: This study offers the first evidence of the impact of a large BS on radiation dose to the ipsilateral lung.

Objective To describe the complications and adverse effects of postoperative radiotherapy in patients with Fanconi anemia (FA). Design Cohort study. Setting Patients with FA treated at community and tertiary care hospitals throughout the United States. Patients The study included patients with FA who were enrolled in the International FA Registry (IFAR) and who developed head and neck squamous cell carcinoma and received postoperative radiotherapy. Main Outcome Measures Demographics of patients with FA and adverse effects and dosages of radiotherapy. Results Twelve patients with FA (7 men and 5 women) were identified. They developed cancers at a mean age of 35.5 years (age range, 20-48 years). The sites of primary cancer were the oral cavity (n = 8), larynx (n = 2), pharynx (n = 1), and unknown (n = 1). The median radiation dose was 5590 cGy (range, 2500-7020 cGy). The most common adverse effects were mucositis (n = 9), dysphagia (n = 8), and pancytopenia (n = 6). Other complications included esophageal stenosis, laryngeal edema, and wound breakdown. Radiotherapy could not be completed in 5 cases. Overall, 8 patients died, 4 during the course of radiotherapy. The postoperative disease-free survival time ranged from 0 to 55 months. Conclusions Patients with FA have a high rate of complications from radiotherapy. Common adverse effects, particularly mucositis, are especially prevalent and difficult to manage in this population. Pancytopenia is common and may lead to further complications, particularly bleeding and infection. Overall survival is poor. Further study of the response to radiotherapy in patients with FA should be attempted to establish appropriate dosages to balance treating disease while limiting adverse effects.

Purpose: To assess target movement for SBRT patients receiving hypo‐ fractionated radiation for lung. Knowledge of the magnitude of these movements can determine optimal margins around the GTV. Methods: We use the Elekta stereotactic body frame (SBF) to deliver an average of four fractions to lesions of diameter less than 4 cm. The SBF is an effective immobilizer utilizing a vacuum bag that conforms to the body. A patient is set up reproducibly in the SBF using its laser pointers. Its fiducial marks are used to stereotactically localize the target. The SBF's stereotactic coordinates are then used to set up the target to isocenter. We obtain a verification CT prior to each fraction for localization of the target. To quantify target movement, we have recorded its deviation from its initial position based on the treatment planning CT. We have then averaged these deviations over the number of fractions to obtain a mean deviation and its standard deviation per patient for each of the three directions. Results: For 35 patients that have received SBRT for lung lesions, we have calculated the weighted mean, the error of the mean and the sample standard deviation for the three stereotactic coordinates, Lateral, AP and Longitudinal of the centroid of the GTV that was outlined by the same physician on each of the verification CT's. The means are: ×3.16 +/− 0.1, 1.27 +/− 0.09 and 0.66 +/− 0.31 mm. The sample standard deviations are: 4.33, 4.35 and 4.24 mm. Conclusions: Internal target motion is the main contributor to its positional uncertainty for our SBRT setup. Assuming a normal parent distribution of the deviations, a uniform margin of 1 cm will provide sufficient coverage of the target for 98% of the times. This is confirmed by the actual distribution of our sample.

Purpose: In lungSBRT seeds left from a prior intraoperative brachytherapy may perturb the dose distribution near the target. We investigate the dosimetric effects of seeds present in the beam paths. Methods: BEAMnrc dosxyznrc code was used to generate 3D dose distributions for different seed arrangements using five 6 MV SBRT fields. A custom C++/Python code was developed to assign seeds of variable quantity and configuration to selected voxels with the Cs‐131 seed density. Two configurations of seed placement were considered: 1) an “odd” number of seeds per row, with the central column shadowing the isocenter, and 2) an “even” number of seeds per row without the isocenter shadowing. Results: For the “odd” configuration the isocenter dose decreased sharply with the number of seeds shadowing the isocenter (from 1.8% for 1 seed to 13.1% for 11 seeds). Adding more seeds in each row lowered the dose by additional 2.4% and this decrease was almost independent of the number of added seeds. A much smaller dose reduction (

Complete androgen insensitivity is a rare X-linked disorder characterized by a female phenotype in a chromosomally male individual. Malignant transformation of the un-descended testis is a rare phenomena compared to other inter-sex syndromes. This is a case of a 32-year-old female who was diagnosed with androgen insensitivity and presented to the emergency room with pelvic pain. Later the pelvic pain was found to be due to testicular masses, one of which was pure seminoma. We reviewed the literature emphasizing the biochemical and endocrinologic abnormalities leading to the syndrome, as well as the potential for malignant changes of the un-descended testes, diagnosis, and therapeutic management. We discuss the importance of early diagnosis and the consequence associated with misdiagnosis.

Purpose: To investigate feasibility and safety of GliaSite brachytherapy for treatment of central nervous system (CNS) tumors following neurosurgical resection. We report mature results of long-term follow-up, outcomes and toxicity. Materials and Methods: In the period from 2004 to 2007, 10 consecutive adult patients with recurrent, newly diagnosed, and metastatic brain malignancies underwent GliaSite brachytherapy following maximally safe neurosurgical resection. While 6/10 (60%) patients were treated for recurrence, having previously been treated with external beam radiotherapy (EBRT), 4/10 (40%) received radiotherapy (RT) for the first time. A median dose of 52.0 Gy (range, 45.0 - 60.0 Gy) was prescribed to 0.5 cm - 1.0 cm from the balloon surface. Radiation Therapy Oncology Group (RTOG) criteria were used to assess toxicities associated with this technique. Follow-up was assessed with MRI scans and was available on all enrolled patients. Results: Median follow-up was 38 months (range, 18 - 57 months). Mean size of GliaSite balloon was 3.4 cm (range, 2.0 - 4.0 cm). Median survival was 14.0 months for the entire cohort after the treatment. The 17.6 and 16.0 months average survival for newly diagnosed and recurrent high grade gliomas (HGG), respectively, translated into a three-month improvement in survival in patients with newly diagnosed HGG compared to historical controls (P = 0.033). There were no RTOG grades 3 or 4 acute or late toxicities. Follow-up magnetic resonance imaging (MRI) imaging did not identify radiation necrosis. Conclusions: Our data indicate that treatment with GliaSite brachytherapy is feasible, safe and renders acceptable local control, acute and long-term toxicities. We are embarking on testing larger numbers of patients with this treatment modality.

Purpose: To measure the output of IORT applicators used with the miniaturized 50 kVp X‐Ray source of the Axxent electronic brachytherapy system. Method and Materials:Brachytherapydose calculations are based on a set of measured or calculated dosimetry parameters for the Axxent X‐Ray source. They are used to calculate dose when the X‐Ray source is surrounded by soft tissue. Clinical examples are partial breast irradiation or intracavitary vaginal applications. In situations though, where the X‐Ray source is within an applicator external to the tissue, direct output measurements for the specific treatment geometry are needed. The Axxent shielded test fixture was first used to obtain a calibration factor for a pinpoint chamber. The fixture allows for both the chamber and the source to be inserted in separate channels within a phantom. The source dwell position is set directly opposite to the chamber and at a set distance. The TG43 parameters and the dwell time are used to calculate the dose at the chamber's location. The calibration factor is obtained from the chamber's reading. The applicator with the radiation source inside is then made to touch the phantom. The chamber is positioned within the phantom at the appropriate depth. The output calculation is based on the chamber's reading and the source's dwell time and is referenced to a nominal Air Kerma Strength. We have supplemented our chamber measurements with relative GAFCHROMIC film dosimetry at various depths in a Solid Water phantom. Results: We have used the Axxent radiation source to deliver a single doseradiation treatment intra‐operatively. A table of dwell times vs. dose for various applicators is prepared for use in the O.R. Conclusion: We have found the use of a list of dwell times versus prescription dose and applicator type easy and convenient to implement during IORT cases.

Aim: To evaluate the maximum differential cervical spinal (C-spine) cord dose in intensity-modulated radiation therapy (IMRT) plans of patients undergoing radiotherapy for treatment of head and neck cancer. Materials and Methods: The C-spine of ten head and neck cancer patients that were planned using IMRT and each cervical vertebral body and the right and left sides was contoured by splitting the cord in the center. Dose-volume histograms (DVH) and maximum point doses were obtained for each contour and compared. Results: The dose to the cord varied with the location of the primary tumor but such variation was not consistently seen. This report provides information that is critical for planning reirradiation treatments. We recommend that contouring of the C-spine cord with IMRT should include outlining of each cervical cord level and identification of the right and the left sides of the cord on each plan.