SU-E-T-400: SBRT Dose Verification Using Monte Carlo Simulation.

PURPOSE: To verify the SBRT plans on CMS Xio treatment planning system using the Monte Carlo simulation and investigate the related issues. METHODS: The SBRT plans with 6 MV were created on CMS Xio treatment planning system with superposition algorithm. The same patient's CT, beam geometry and MUs were used in the Monte Carlo simulation (MC) on MCSIM. MCSIM is an EGS4-based MC dose calculation system for photon and electron beams. The Monte Carlo plans were compared with the Xio plans to verify Xio superposition algorithm for SBRT. The electron disequilibrium was particularly investigated by comparing the DVHs for a 2-mm thick peel of the GTV. The beam energy was changed from 6 MV to 10 MV for MC to test energy effect on SBRT dosimetry. RESULTS: Six SBRT lung plans created on Xio and delivered on Varian 21 EX linac were included in this study. The tumor GTV ranged from 1.4 cc to 11 cc and the dose ranged from 1950 cGy to 5400 cGy. The comparisons were made in terms of DVHs, mean doses, minimal doses, and maximal doses for GTV. The results showed all the dose values of Xio plans agreed with MC to within 2% with only two exceptions of 3% and 5%. The dose distribution in the peel of GTV followed the same pattern as the whole GTV. This indicated the Xio superposition algorithm has well accounted for electron disequilibrium. The 10-MV beams had both hot and cold spots from DVH comparison. This may be due to the large build-up region for high energy beams. CONCLUSIONS: The Xio superposition algorithm has adequately accounted for electron disequilibrium and can perform accurate dose calculation for SBRT. Compared to high energy beams, 6 MV is preferable in terms of the GTV coverage and dose homogeneity.

Pulmonary hilar stereotactic body radiation therapy in the rat.

Stereotactic Body Radiation therapy (SBRT) is an emerging modality of treatment for early stage non-small cell lung carcinoma. Concerns have arisen related to increased toxicities for medial tumors. We have developed a model of high dose, hypofractionated radiotherapy to the pulmonary hilum using the Leksell Gamma-Knife. Sprague-Dawley rats received hypofractionated SBRT to the unilateral lung hilum using a custom immobilization device on the Gamma Knife. Each animal was individually scanned, treatment planned, and treated with either two 4 mm or one 8 mm collimated shots at escalating doses of 20, 40, and 80 Gy to the 50% isodose volume, encompassing the right mainstem bronchus. All animals were carefully followed post-treatment and imaged by plain film and CT. In addition, histopathological analysis of all rats was performed at selected time points. Animals treated with 4 mm collimated shots demonstrated no appreciable changes on plain films or sequential, follow-up CT scans, or histopathologically. Animals irradiated with the 8 mm collimator were less active, gained weight at a reduced rate, and demonstrated histopathological changes in 7/34 animals six months post-irradiation. Cellular atypia and interstitial pneumonitis were found, three of the seven of the animals showed clear bronchial damage and two showed vascular damage. Significant volume and time effects were found. Utilizing a novel Gamma Knife based animal model to study SBRT toxicity, it was found that the bronchus will tolerate small volumes of very high dose radiotherapy. It was postulated that radiation of the surrounding support stroma and normal tissue are important in the etiology of bronchial or hilar damage.

Impact of intravesical chemotherapy on recurrence rate of recurrent superficial transitional cell carcinoma of the bladder: results of a meta-analysis.

BACKGROUND: The impact of in tranvesical chemotherapy on preventing recurrence of superficial transitional cell carcinoma of the bladder is controversial. The objective of this report is to present a meta-analysis of the available clinical trial data to quantify the effect of intravesical chemotherapy on tumor recurrence following trans-urethral resection (TURB) in patients with recurrent superficial bladder cancer. METHODS: A prospective study protocol outlining a meta-analysis was developed followed by a thorough search of the existing published literature using strict eligibility criteria. Eight randomized trials were found which met protocol specifications. These studies contained data on 1,609 patients which were statistically combined using a fixed effects model (Peto). The outcome of interest was the proportion of patients with tumor recurrence at one, two and three years post-TURB. RESULTS: Combining all 8 studies using 1 year recurrence as the outcome measure yielded a Peto odds ratio (ORp) of 0.62, demonstrating a 38% reduction in one year recurrence among patients treated with intravesical chemotherapy versus TURB alone. Using 2 and 3 year recurrence as the outcome measure yielded ORp's of 0.46 and 0.35 respectively, favoring TURB + intravesical chemotherapy versus TURB alone. A statistical test for heterogeneity (Q) showed the 2 and 3 year outcome data to be heterogeneous (i.e. the studies are not measuring an effect of the same magnitude). Sensitivity analyses showed that drug type appeared to account for the observed heterogeneity with a stratified analysis demonstrating that adriamycin is less effective in reducing subsequent tumor recurrences than all other drugs studied. CONCLUSION: Intravesical chemotherapy appears to have a major impact on decreasing the chance of recurrence of recurrent superficial bladder cancer. Three year recurrence is decreased by as much as 70% when compared with TURB alone. These data are in contrast to prior analyses suggesting only modest efficacy of such treatment in this clinical setting.

Single-agent DTIC versus combination chemotherapy with or without immunotherapy in metastatic melanoma: a meta-analysis of 3273 patients from 20 randomized trials.

It is currently unclear whether any combination therapy for the treatment of metastatic melanoma is superior to standard single-agent dacarbazine (DTIC) in terms of tumour response and overall survival. The available randomized clinical trial data were combined in a meta-analysis to address this question. Initially a thorough MEDLARS search was conducted covering the time period from January 1970 to January 1999. This literature search was supplemented by manual searches of study bibliographies (including review articles) and review of relevant textbooks. The meta-analysis was performed according to a prospective protocol using strict study eligibility criteria. Data derived from randomized controlled trials comparing single-agent DTIC with combination chemo/immunotherapy were combined using a fixed effects model. Data were stratified into three combination therapy groups: DTIC-containing regimens, non-DTIC-containing therapy, and chemotherapy plus immunotherapy. The primary outcome of interest was the proportion of patients demonstrating a complete or partial response to treatment. A total of 20 randomized trials comprising 3273 patients were initially combined in a meta-analysis. This yielded an odds ratio (OR) of 1.23 (95% confidence interval [CI] 1.02-1.48), demonstrating that combination drug therapies are associated with a 23% increase in response rate compared with single-agent DTIC. The combination of DTIC plus interferon-alpha produced a tumour response rate 53% greater (95% CI 1.10-2.13) than that seen with DTIC alone. This increase was greater than that seen with DTIC-containing multi-drug regimens, which had an OR of 1.33 (95% CI 0.99-1.78). No difference in overall survival was demonstrated. Non-DTIC-containing treatment programmes showed no advantage over DTIC in terms of tumour response rate (OR = 0.77, 95% CI 0.45-1.32). The combination of DTIC and interferon-alpha appears more active than standard single-agent DTIC in metastatic melanoma. Further randomized clinical trials employing a DTIC plus interferon arm are necessary to confirm these results.

Intravesical chemotherapy prophylaxis in primary superficial bladder cancer: a meta-analysis of 3703 patients from 11 randomized trials.

The impact of intravesical chemotherapy prophylaxis on recurrence of superficial transitional cell carcinoma of the bladder is poorly defined. The objective of this report is to present a meta-analysis of the available clinical trial data to quantify the effect of intravesical chemotherapy on tumor recurrence following complete transurethral resection (TURB) in patients with newly diagnosed superficial bladder cancer. A prospective protocol outlining the above meta-analysis was initially developed followed by a thorough search of the existing published literature using strict eligibility criteria. Eleven randomized trials were found that met protocol specifications. These studies contained data on 3703 patients that were statistically combined using a fixed effects model (Peto). The outcome of interest was the proportion of patients recurring at 1, 2, and 3 years post-TURB. Combining all 11 studies using 1-year recurrence as the outcome measure yielded a Peto odds ratio (ORp) of 0.56, demonstrating a 44% reduction in 1-year recurrence among patients treated with intravesical chemotherapy versus those treated with TURB alone. A statistical test for heterogeneity (Q) showed these data to be heterogenous (the studies are not measuring an effect of the same size). Sensitivity analyses were performed to determine sources of heterogeneity. These tests suggest that chemotherapy treatment schedule may account for the wide variation in tumor recurrence rates across studies. When the available clinical trial data were stratified by duration of treatment, the meta-analysis showed that intravesical chemotherapy decreased tumor recurrence from 30% to 80% depending on the outcome of interest (i.e., recurrence at 1, 2, or 3 years post-TURB). Intravesical chemotherapy appears to have a major impact on decreasing the chance of recurrence of superficial transitional cell carcinoma of the bladder. This is in contrast to prior analyses suggesting only modest efficacy in this clinical setting (i.e., on the order of a 14% reduction in recurrence).

Superior vena cava obstruction due to prostate carcinoma.

Superior vena cava obstruction (SVCO) is considered an oncologic emergency commonly associated with lung carcinoma. The case presented here is that of a 48-year-old man presenting with SVCO, which was diagnosed as metastatic prostate carcinoma localized to the chest. He was treated with goserelin and aggressive radiotherapy with a drop in his prostate-specific antigen levels and symptomatic relief that lasted approximately 12 months. SVCO recurred locally in the chest and the patient died 24 months after diagnosis. This represents a rare presentation of prostate carcinoma and underlines the necessity for tissue diagnosis before local radiotherapy.

Treatment resistant small cell carcinoma of the cervix.

BACKGROUND: Small cell undifferentiated carcinoma of the cervix is an uncommon malignancy with a poor prognosis. Treatment of localized disease has an approximate 40% 5-year survival with multimodality therapies. CASE REPORT: We describe the case of a 24-year-old woman with small cell carcinoma of the cervix that recurred locally despite intensive chemotherapy and radiotherapy. Hysterectomy was performed and the patient is now 18 months disease free. Following treatment, the pathological appearance of the tumor had changed from a typical small cell neuroendocrine malignancy to a more intermediate neuroendocrine cell type. CONCLUSION: Small cell carcinoma of the cervix is a rare aggressive malignancy that may require cytostatic multimodality therapy including chemotherapy, radiotherapy and surgery, even in early stage disease.

Optimal photon energies for IUdR K-edge radiosensitization with filtered x-ray and radioisotope sources.

The purpose of this work is to determine the most physically effective radiation energy for K-edge absorption of x- or gamma-rays by iododeoxyuridine (IUdR) on Chinese hamster ovary (CHO) cells. Brachytherapy sources (Sm-145, I-125, Yb-169 and Am-241) and x-ray beams (30 kVp, 100 kVp and 100 kVp with gold, gadolinium, lead or tungsten filtration) were investigated for their preferential absorption qualities by IUdR sensitized DNA. The 30 kVp, 100 kVp and 100 kVp with tungsten filtration were then used to irradiate CHO cells, with or without IUdR incorporation (i.e. 10(-5) M of IUdR for 3 days). Radiation absorption calculations were performed to determine the increase in energy absorption in DNA with and without IUdR incorporated. In order to measure the in vitro biological effects of K-edge absorption, cell survival experiments were performed. The radiation physics calculations yielded an iodine dose enhancement ratio (DER) of 1.4+/-0.15. 1.8+/-0.15 and 2.7+/-0.15 for the 30 kVp, 100 kVp and tungsten filtered 100 kVp respectively, for 18% IUdR replacement of thymidine in DNA. The corresponding cell sensitization enhancement ratios (SER), determined from the cell survival assay, were determined to be 1.24+/-0.2, 1.8+/-0.2 and 2.3+/-0.3 for the 30 kVp, 100 kVp and tungsten filtered 100 kVp respectively, for cells with 18+/-2% IUdR incorporation. These SER values are in reasonable agreement with the DER values of 1.4, 1.8 and 2.7. From these radiation calculations and radiobiology experiments we confirm that using x-radiation energies above the K-edge of iodine (33.2 keV) can have a significant effect on cell survival. This effect is due mainly to the increase in the local dose to the DNA for IUdR-sensitized cells compared with the normal DNA which lacks the iodine contrast agent. Our results support the clinical application of IUdR and low-energy brachytherapy, perhaps using new technologies such as the x-ray needle or new isotopes such as Yb-169.

Chemotherapy response rates in recurrent/progressive pediatric glioma; results of a systematic review.

The optimum treatment strategy for recurrent childhood glioma is unknown. This report presents a systematic analysis of the currently available clinical data on chemotherapeutic management of this disease. A study protocol was prospectively developed outlining the objectives and methods of analysis including literature search strategy, eligibility criteria for published trials to be included, key data elements to be extracted and a plan for statistical analysis. Summary statistics were analyzed for the primary outcome variables. Data on recognized prognostic factors were recorded in order to adjust the outcome measures for these factors. A total of 27 non-randomized clinical trails were included in the analysis. Studies were stratified into 6 chemotherapy classes based on the frequency of drug used across studies. Average median response (complete + partial) across all drug categories was approximately 14% (range 10.4-23.5%). Adding patients with stable disease to complete and partial responders at least doubled average median response rates. Time to tumor progression ranged from 29.4 weeks to 49.7 weeks. The most frequently used drugs were the platinum analogs which demonstrated a mean TTP of 42.0 = /-23.4 weeks. Small sample sizes and the overall poor quality of the available data precluded definitive conclusions regarding the clinical impact of the various drug classes on the natural history of this disease.

DRINK: a biogeochemical source term model for low level radioactive waste disposal sites.

Interactions between element chemistry and the ambient geochemistry play a significant role in the control of radionuclide migration in the geosphere. These same interactions influence radionuclide release from near surface, low level radioactive waste, disposal sites once physical containment has degraded. In situations where LLW contains significant amounts of metal and organic materials such as cellulose, microbial degradation in conjunction with corrosion can significantly perturb the ambient geochemistry. These processes typically produce a transition from oxidising to reducing conditions and can influence radionuclide migration through changes in both the dominant radionuclide species and mineral phases. The DRINK (DRIgg Near field Kinetic) code is a biogeochemical transport code designed to simulate the long term evolution of the UK low level radioactive waste disposal site at Drigg. Drigg is the UK's principal solid low level radioactive waste disposal site and has been receiving waste since 1959. The interaction between microbial activity, the ambient geochemistry and radionuclide chemistry is central to the DRINK approach with the development of the ambient pH, redox potential and bulk geochemistry being directly influenced by microbial activity. This paper describes the microbial aspects of the code, site data underpinning the microbial model, the microbiology/chemistry interface and provides an example of the code in action.

Non-steroidal glucocorticoid-like substances: receptor binding and in vivo activity.

Compounds of general structure I, prepared by a Diels-Alder reaction with diene 3, are relatives of the known potent glucocorticoid II but possess a markedly modified C- and D-ring environment. Despite these structural changes, 4, 5, 9, 10, 12a, 13, and 14 bound to the glucocorticoid receptor with an affinity which approximated that of the reference standard, 6-alpha-methylprednisolone. Four of these compounds not only exhibited antiinflammatory activity in the alpha-tocopherol pouch test but also exhibited marked adrenal suppression and other typical glucocorticoid properties at doses in the same range as the effective antiinflammatory doses.

Molecular evidence for the expression of Schwann cell markers in human neuroblastoma.

Human neuroblastoma (NB) cell lines have been suggested to represent a model of neural crest differentiation. The expression of several Schwann-cell-associated antigens was examined by flow cytometry and Northern blot analysis. Variable reactivity of the human NB cell lines was found in both the level and pattern of reactivity. Retinoic acid treatment of cell line SMS-KAN resulted in a neuron-like morphological differentiation and a decrease in several of the glial markers under study. Similarly, Northern blot analysis illustrated myelin-associated glycoprotein expression, and decreased expression of this message with retinoic acid treatment was consistent with the neuron-like morphological changes. Overall, human NB in vitro was found to be multipotential, but we have shown that it is capable of expressing several Schwann cell markers which are modulated during induced differentiation.

Induced morphological changes in human small cell lung carcinoma cells.

Several theories suggest that lung carcinomas are not totally separate entities, but are derived from a common precursor, probably of endodermal origin. The histological classification of lung cancers is complex, with much overlap between groups broadly designated as small cell (SCLC), squamous cell, adenocarcinoma and all others simply termed non-small cell. It is shown here that in vitro exposure of classic, non-adherent SCLC lines to 10 microM 5' bromodeoxyuridine (BrdU) results in a rapid cell-line dependent change to a morphology consistent with an adherent, non-small cell phenotype. Accompanying this morphological shift is a decreased expression of the amplified N-myc protooncogene. These induced changes underline the morphological relatedness of lung carcinoma cell lines.

Human melanoma-associated antigen expression on human neuroblastoma cells: effects of differentiation inducers.

We have described two human melanoma-associated antigens (HMAA), recognized by the murine monoclonal antibodies LS62 and LS109. LS62 recognizes the neuroglandular antigen (NGA), which is overexpressed in neoplastic melanocytes as well as in several tissues of neuroectodermal origin. These antibodies were used to screen six neuroblastoma cell lines and one neuroepithelioma cell line. A melanoma cell line, G361, known to express the two antigens, was used as the positive control. Variable expression of the two antigens was detected in neuroblastoma cells. The surface expression of NGA and of the LS109 antigen was modulated in parallel with the morphological differentiation induced by retinoic acid, 5-bromodeoxyuridine, or cyclic AMP analog/activators. The modulation of the expression of the two HMAA was detected in G361 melanoma cells and in one of the neuroblastoma cell lines, SK-N-SH. These results suggest altered expression of both antigens during melanoma and neuroblastoma cell differentiation in culture.

Effects of retinoic acid and bromodeoxyuridine on human melanoma-associated antigen expression in small cell lung carcinoma cells.

The dispersed neuroendocrine system includes cells with different embryological derivations, sharing a common neuroendocrine (NE) program, as indicated by the expression of NE markers, some of which are shared antigenic determinants. We report here that the small cell lung carcinoma cells NCI-H69 express the two human melanoma-associated antigens (HMAA) NGA/LS62 an LS109. Incubation of NCI-H69 cells with maturational inducers, such as retinoic acid and bromodeoxyuridine (BrdU), upregulated the expression of both HMAA. Exposure to BrdU for 4 weeks induced the appearance of a different phenotype in subpopulations of NCI-H69 cells, which became epithelioid, substrate-adherent, grew in monolayer and continued to express NE-associated antigens in variable amount. The shift in phenotype was not reversible after BrdU withdrawal and was maintained for at least 6 months in continuous culture. The substrate adhesion of NCI-H69 cells was paralleled by a change in NGA glycosylation pattern, thus suggesting a possible functional role for NGA in cell substrate adhesion/recognition.

Melanocytic differentiation of human neuroblastoma: expression of a human melanosome-associated antigen.

Five human neuroblastoma cell lines were examined for expression of a human melanosome-associated antigen (HMSA). Only cell line SK-N-SH reacted with a monoclonal antibody, HMSA-2, shown to recognize melanosomal glycoproteins. To further characterize the melanocytic lineages of SK-N-SH, three morphologically distinct clones designated SK-N-SH-N (neuroblast type), SK-N-SH-F (fibroblast type), and SK-N-SH-EP (epithelial type) were established by colony formation cloning. By fluorescence-activated cell sorter analysis and tyrosinase assay, we found that only SK-N-SH-EP and SK-N-SH-F reacted with HMSA-2 and had tyrosinase activity. These results suggest that epithelial-type and fibroblast-type cells appear to possess the melanocytic potential, but not neuroblast-type cells. Furthermore, SK-N-SH-EP was found to spontaneously convert to neuroblast-type or fibroblast-type cells, whereas SK-N-SH-N and SK-N-SH-F clones have remained morphologically stable. Our results suggest that at least one neuroblastoma cell line, SK-N-SH, may be an excellent model for investigating clonal maturation and the melanocytic differentiation of neuroblastoma.

Alterations in plasminogen activator and inhibitor activity during the differentiation of a human neuroblastoma cell line, SMS-KAN.

The fibrinolytic enzyme profile of SMS-KAN human neuroblastoma cells was found to vary dramatically during the differentiation process. Five maturational agents--retinoic acid, dibutyryl cAMP, 5-bromodeoxyuridine, sodium butyrate and phorbol myristate acetate were tested for their effects on cellular morphology, DNA synthesis, plasminogen activator (PA) and PA inhibitor (PAI) activity. SMS-KAN cells secrete urokinase (UK) and tissue PA (tPA) as well as a possibly unique PAI. Treatment of cells with 1 microM RA resulted in an inhibition of proliferation, extension of neurite-like processes indicative of differentiation, as well as a switch from secretion of UK to tPA and a reduction in PAI secretion. Other agents which caused neural process formation and decreased cell proliferation also induced alterations in PA/PAI while agents which had no detectable effect on cell growth induced little change in the fibrinolytic enzyme profile.