bluuebunny/crossref_metadata_2025 huggingface dataset:
Neutron therapy program at the national accelerator centre, South Africa: Preliminary results
Authors: Stannard Clare , Vernimmen Frederik , Jones Dan , Wilson Jennifer , van Wijk Leon , Brennan Sean , Schreuder Nick , Symons Julyan , Levin Victor , Mills Elwin , Alberts Albert , Werner Dudley , Smit Ben , Schmitt Gerd
Published: February 2007

Neutron therapy with a p(66)/Be isocentric beam started at the National Accelerator Centre (NAC) in September 1988 and proton therapy with a 200 MeV horizontal beam started in September 1993. A total of 608 patients have been treated in the neutron therapy program and the preliminary results show: 1) no statistical differences in survival and disease‐free probability between 60Co, neutron therapy, and accelerated neutron therapy for head and neck cance; 2) 1‐ and 2‐year complete response rates of 63% and 51% and survival probabilities of 90% and 73%, respectively, for advanced salivary gland tumours; 3) complete response rates of 67% for macroscopic residual soft tissue sarcomas, 60% for irresectable tumours of less than 10 cm in diameter, and 0% for tumours of more than 10 cm in diamete; 4) local control rates of 64% and 76% for advanced breast carcinomas treated with 17 and 19 Gy, respectively; 5) complete response rate of 50% for macroscopic residual uterine sarcomas; and 6) complete response rates of 45% for advanced maxillary antral carcinomas, 33% for irresectable osteosarcomas, and 38% for chondrosarcomas. With the constant patient accrual and reliable operation of the therapy facilities the NAC could play a major role in defining the future of high‐energy neutrons in radiation treatment. © 1995 Wiley‐Liss, Inc.
Modification of ataxia telangiectasia cellular radiation sensitivity and resistant dna synthesis by transformation with episomally maintained vectors
Authors: Jung Mira Oh , Zhang Yin , Salehi Zahra , Kern Francis , Dritschilo Anatoly
Published: February 2007

Ataxia telangiectasia (AT) is a complex, multisystemic human genetic disease characterized by its extreme cellular radiation sensitivity and resistant DNA synthesis. Using vector mediated gene transfer with a cDNA library from radiation resistant human tumor cells, we have isolated a clone of transformed AT cells in which both resistant DNA synthesis and radiation sensitivity have been corrected to normal human fibroblast levels. Plasmid rescue and polymerase chain reaction amplifications permitted the identification of seven candidate cDNAs present in these transformed cells. The results of these experiments provide a strategy for investigating the molecular factors that affect radiation resistance and those AT cellular defects which may be responsible for the acute radiation sensitivity of AT. © 1995 Wiley‐Liss, Inc.
Nitric oxide modulation enhances the in vivo protection from lethal irradiation by stem cell factor
Authors: Liebmann James , Deluca Anne Marie , Coffin Deborah , Venzon David J. , Wink David A. , Mitchell James B.
Published: February 2007

Stem cell factor (SCF; c‐kit ligand) and nitric oxide are whole body radiation protectors that presumably act by different mechanisms. The purpose of the present study was to determine if nitric oxide, delivered to mice by the nitric oxide releasing agent DEA/NO, combined with SCF would provide enhanced radiation protection in C3H mice compared with the protection afforded by either agent alone. Mice were exposed to whole body irradiation and assessed for survival at 30 days after irradiation. The radiation LD50/30 for control mice was 789 cGy. Treatment of mice preirradiation with SCF (100 μg/kg at ‐20 and ‐4 hr) or DEA/NO (70 mg/kg at ‐10 min) increased the radiation LD50/30 to 983 and 1,100 cGy, respectively (P < 0.00001 for either SCF or DEA/NO vs. control mice). The combination of SCF and DEA/NO increased the LD50/30 to 1,246 cGy (dose modifying factor of 1.58 compared to control mice; P < 0.00001 for the combination vs. either agent alone). These data confirm that SCF and nitric oxide are in vivo radiation protectors and that their radioprotective effects are at least additive when these agents are given together. © 1995 Wiley‐Liss, Inc

This article is a US Government work and, as such, is in the public domain in the United States of America.

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Antiangiogenic agents can increase tumor oxygenation and response to radiation therapy
Authors: Teicher Beverly A. , Dupuis Norman , Kusomoto Tetsuya , Robinson Michael F. , Liu Fang , Menon Krishna , Coleman C. Norman
Published: February 2007

The Lewis lung carcinoma growing subcutaneously in the hind leg of male C57BL mice is very hypoxic, having 92% of the pO2 measurements ≤ 5 mmHg as determined with a polarographic oxygen electrode. Administration of a perflubron emulsion (8 ml/kg) along with carbogen breathing increased the tumor oxygen level so that 82% of the pO2 readings were ≤ 5 mmHg. Treating tumor‐bearing animals with TNP‐470 (30 mg/kg, s.c.) on alternate days and minocycline (10 mg/kg, i.p.) daily beginning on day 4 after tumor cell implantation resulted in decreased hypoxia in the tumors on day 9 when pO2 measurements were made. The percent of pO2 readings ≤ 5 mmHg in the tumors of the TNP‐470/ minocycline‐treated animals was 75%, which upon administration of the perflubron emulsion along with carbogen breathing was reduced to 45%. Therapeutically daily fractionated radiation (2, 3, or 4 Gy ≤ 5) was used as an oxygen‐dependent cytotoxic modality. The radiation response of the rumors in TNP‐470/minocycline‐treated animals was greater than that in the untreated tumors. The addition of carbogen breathing for 1 hr prior to and during radiation delivery further increased the radiation response so that overall there was a 2.2‐fold increase in the tumor growth delay produced by the fractionated radiation in the animals treated with TNP‐470/minocycline compared with untreated animals. Administration of the perflubron emulsion along with carbogen breathing prior to and during radiation delivery resulted in a 3.4‐fold increase in tumor growth delay by the fractionated radiation regimens in the TNP‐470/minocycline‐treated animals compared with the tumor growth delay obtained with radiation alone. There was a linear relationship between decrease in the percent of pO2 readings ≤ 5 mmHg and tumor growth delay at each radiation dose indicating that the diminution in tumor hypoxia produced by these treatments may be directly responsible for the increase in the effectiveness of the radiation therapy. © 1995 Wiley‐Liss, Inc.
Topical administration of antimicrobial agents to prevent irradiation mucositis of the oral cavity and oropharynx: A pilot study
Authors: Kaanders Johannes H. A. M. , Pop Lucas A. M. , Muytjens Harry L. , Bruaset Ingolv , van Daal Willem A. J.
Published: February 2007

The value of topical administration of antimicrobial agents to prevent irradiation mucositis of the oral cavity and oropharynx was investigated in this pilot study. Thirty‐six patients receiving radiotherapy for head and neck cancer were included. Lozenges containing polymyxin E, tobramycin, and amphotericin B (PTA‐lozenges) were administered during and after the course of irradiation to eradicate gram‐negative bacilli and yeasts. Mucosal reactions and dysphagia were assessed and oropharyngeal cultures were obtained. Thirty‐six patients treated in a previous period served as controls. Sixteen of the 36 patients in each group received irradiation predominantly to the oral mucosa. Confluent mucositis was observed in only 1 of 16 patients receiving PTA‐lozenges but in 10 of the 16 patients of the control group (P = 0.001). Average duration of mucositis was also less with PTA‐lozenges as well as dysphagia. Mucosal reactions and dysphagia in the patients who had mainly oropharyngeal mucosa in the treatment volume were not reduced. Persistent colonization by gram‐negative bacilli occurred in only three patients. It is concluded that topical administration of polymyxin E, tobramycin, and amphotericin B may reduce irradiation mucositis of the oral cavity. The underlying mechanism must be further elucidated. © 1995 Wiley‐Liss, Inc.
Magnetic resonance imaging following interstitial implantation of pelvic malignancies
Authors: Erickson Beth A. , Erickson Scott J. , Prost Robert W. , Albano Katherine , Gillin Michael T. , Foley W. Dennis
Published: February 2007

The purpose of this study was to develop a magnetic resonance imaging (MRI) technique that will permit artifact‐free visualization of implanted needles in relation to tumor volume and normal internal anatomy for treatment planning after interstitial implantation of pelvic malignancies. Development of an MRI‐compatible template and needle system is described in two patients. The system consists of a modified plastic Syed‐Neblett template and vaginal obturator with sleeve accommodating plastic flexiguides loaded with titanium obturators. Visualization of the flexiguides loaded with titanium obturators and their relationship to normal structures and tumor volume were assessed following MRI scanning. The images obtained reveal no scatter artifact from the flexiguides. It was possible to distinguish the flexiguides from the soft tissues and evaluate their relationship to tumor and normal internal anatomy. In conclusion, MRI following trans‐perineal interstitial implantation of pelvic malignancies is possible and may ultimately be superior to computed tomography (CT) in defining the relationship of the needles to tumor volume as well as the normal internal structures. Further work will determine the optimum techniques for MRI‐based dosimetric analysis of transperineal interstitial implantation of pelvic malignancies. © 1995 Wiley‐Liss, Inc.
Overexpression of the gamma‐glutamyltranspeptidase transgene does not alter the gamma irradiation sensitivity of the IB3–1 normal bronchoepithelial or A549 human lung carcinoma cell line
Authors: Roscnstein Maury , Epperly Michael , Hughey Rebecca P. , Prezioso Joseph , Greenberger Joel S.
Published: February 2007

We investigated the effect of overexpression of the gene for gamma‐glutamyltranspeptidase (GGTP) on the gamma irradiation sensitivity of human bronchoepithelial cell line IB3–1 or A549 lung carcinoma cells. The enzyme has been considered a putative radioprotector because it is the only enzyme capable of degrading extracellular glutathione to ultimately provide cysteine for resynthesis of intracellular glutathione. Clonal sublines of each cell line were isolated after transfection with a plasmid containing both the rat GGTP cDNA and neor gene, and selected in G418. Each transfected clone demonstrated a different degree of GGTP enzymatic expression by biochemical analysis. The D0 of parent IB3–1 cells was 1.434 ± 0.138 Gy, n 2.331 ± 0.685, and was unchanged by GGTP overexpression, D0 1.932 ± 0.690 Gy (P = 0.133), n 2.916 ± 2.7 (P = 0.628). In contrast, overexpression of the MnSOD transgene in IB3–1 cells increase the shoulder on the irradiation survival curve for IB3–1 cells, showing significant increase in the shoulder, D0 1.239 ± 0.1 Gy (P = 0.079), n 7.276 ± 0.1 (P < 0.001). Lung cancer cell line A549 was subcloned after expression of the GGTP transgene, and clonal subline 22 demonstrated stably increased GGTP activity and protein production by Western analysis. The parental A549 line was also redoned by limiting dilution. A series of clonal sublines of clonal line 22 expressed up to a 97‐fold increase in GGTP expression compared to control clones. In clonogenic cell survival assays in the presence or absence of added glutathione, no difference in irradiation sensitivity was detected between parent or GGTP transfected and overexpressing subclones despite an increase in GGTP activity. The D0 of the subclone 10 of parent A549 cells was 1.6 ± 0.40 Gy and n was 4.8 ± 3.0, α 0.13 ± 0.10, β 0.052 ± 0.02; while the D0 for GGTP overexpressing clone 17, a subclone of line 22, was 1.3 ± 0.05 Gy, n 2.6 ± 0.18, a 0.279 ± 0.01, p 0.059 ± 0.01. The cell lines were not significantly different with respect to D0 (P = 0.55), indicating no significant effect of GGTP overexpression on radiosensitivity. Thus, GGTP overexpression in either normal lung bronchoalveolar cell line IB3–1 or lung cancer cell line A549 does not induce radioresistance in vitro. © 1995 Wiley‐Liss, Inc.
Effect of intratumoral injections of a perfluorochemical emulsion on tumor radiosensitivity
Authors: Rockwell Sara
Published: February 2007

Past studies in several laboratories have shown that intravenous administration of perfluorochemical emulsions (PFC‐E) combined with the breathing of oxygen, carbogen, or hyperbaric oxygen improves the oxygenation of solid tumors and increases the response of these malignancies to radiation and cytotoxic drugs. It has been suggested that direct intratumoral (IT) injection of PFC‐E would also be effective in improving the response of tumors to radiation. The experiments reported here test this hypothesis, using a high quality PFC‐E (Oxygent™, Alliance Pharmaceutical Corp., San Diego, CA) and a well‐defined mouse tumor model system, EMT6 mouse mammary tumors implanted into syngeneic BALB/c Rw mice. Tumor response was assayed using both a clonogenic assay and a tumor growth assay. The IT injections tested did not improve the response of tumors to radiation in either air breathing or carbogen breathing hosts. In contrast, intravenous injections of Oxygent™, combined with carbogen breathing, were effective in increasing the response of tumors to irradiation. These studies provide additional evidence that intravenous administration of PFC‐E may be valuable as an adjunct to radiotherapy, but provide no evidence that the direct IT administration of these agents would be of value. © 1995 Wiley‐Liss, Inc.
Protein kinase C inhibitor as a potent inhibitor of accelerated repopulation during radiotherapy: I. growth inhibitory, cytotoxic, and indirect radiosensitizing effects of a staurosporine derivative (UCN‐01) in vitro
Authors: Urano Muneyasu , Reynolds Regina , Begley James
Published: February 2007

Recently, various chemicals that attack the regulatory system for cell growth have been developed as potential antitumor agents. We have tested the effect of an inhibitor of protein kinase C (PKC) on cell proliferation and cytotoxicity together with the interaction with radiations. A staurosporine derivative, UCN‐01 (7‐hydroxy staurosporine), was selected because of its relative specificity to PKC. Mouse FSa‐II fibrosarcoma cells were cultured in McCoy's 5a medium in 60 mm Petri dishes. To investigate cell proliferation, the number of cells was counted after trypsinization. Cell survival following drug treatment with or without irradiation was obtained by the in vitro colony formation assay; namely, single cells were plated and treatment was initiated ∼20 hr later. After drug treatment, cells were washed and incubated with fresh medium at 37°C for 7–9 days for colony formation. Survival was determined by normalizing with plating efficiency and cell multiplicity. The growth of FSa‐II cells was inhibited with 100–500 nM UCN‐01 during a 3 day treatment period, whereas no significant growth inhibition was observed following a treatment with 50 nM. In one of these experiments, cells treated with UCN‐01 for 3 days were replated in drug‐free medium. Cells pretreated with 100 nM quickly resumed their proliferation, but cells pretreated with 250 or 500 nM showed a substantial delay of repopulation. Cell survival studies showed the cytotoxic effect of UCN‐01 on FSa‐II cells. Survival curves were best‐fitted by the linear‐quadratic equation. To study whether the growth inhibition is due to the cytotoxic effect or this agent inhibiting cell proliferation, the effect of UCN‐01 on repopulation during fractionated irradiation was investigated. This result confirmed that this agent has a growth inhibitory effect on tumor cells together with a cytotoxic effect, although its synergism with radiation is weak. This result suggests that it can inhibit the cell repopulation during fractionated doses; thus, it could reduce the tumor control dose if used during the course of fractionated radiotherapy. © 1995 Wiley‐Liss, Inc.
Prostate irradiation as an alternative to the conventional management of benign prostatic hypertrophy
Authors: Costleigh Brian , Keit Joan , Miyamoto Curtis , Mieszkalski Glenn , Brady Luther W. , Micaily Bizhan
Published: February 2007

To help determine the efficacy of radiation therapy (RT) as an alternative to conventional treatment of benign prostatic hypertrophy (BPH), seven patients were treated at Hahnemann University Hospital (Philadelphia, PA), between November 1981 and May 1988, with megavoltage RT for BPH. Indications for treatment included severely symptomatic disease while having medical contraindications to, or refusal of conventional treatments. Doses ranged from 2,000 to 2,400 cGy, using 300–400 cGy fractions twice per week for 2.5–3 weeks. Radiation was delivered using 6 MV photons. All patients experienced good relief of both irritative and obstructive symptoms. Six of seven patients remained free of recurrent symptoms. There were no short‐ or long‐term complications. These preliminary data suggest that there may be a future role for RT in the treatment of BPH in the medically inoperable patient. However, further study is needed before this can be seriously considered a standard treatment alternative. © 1995 Wiley‐Liss, Inc.
Accelerated radiation therapy of 2 Gy b.i.d. to 70 Gy in 3.5 weeks in glioblastoma multiforme
Authors: Vikram Bhadrasain , Maker Howard , Pisch Julianna , Chadha Manject , Mishra Shanti , Bcrgland Richard
Published: February 2007

Review of the literature suggests that repopulation during radiation therapy (RT) might be an important cause of failure in glioblastoma multiforme (GBM) and that shortening the overall treatment time might be beneficial. We undertook this study in order to evaluate the safety and effectiveness of accelerated RT (ART) in GBM. We treated 48 patients with histologically proven GBM by ART (patients with anaplastic astrocytoma were excluded). Median age was 60 years (range 31–74 years). Karnofsky performance status (KPS) prior to ART ranged from 40 to 90 (median 55). ART started 7–22 days (median 14 days) after resection/biopsy. Whole brain ART 40 Gy in 2 weeks was followed by cone‐down ART to 30 Gy in 1.5 weeks. The interfraction interval was 4–6 hr. No chemotherapy was given. The treatment was well tolerated and the acute toxicity was quite unremarkable. The observed survival rate at 12, 18, and 24 months was 30%, 11%, and 5%, respectively. The median survival time was 44 weeks. The overwhelming cause of death was persistent/recurrent cancer at the original tumor site. Serial computed tomographic (CT) scans typically revealed reduction in the size of the tumor over 2–3 months initially, followed by a period of stability and then rapid recurrence and death. Late toxicity was obvious only in one patient who developed bilateral blindness 1 year after treatment, having received a dose of 55 Gy in 3.5 weeks to the optic chiasm. In conclusion, 70 Gy in 3.5 weeks could be delivered to patients with GBM without excessive acute or late toxicity. The short treatment time is an advantage for these patients with a limited life expectancy. The survival rates are comparable to, but not notably better than, several contemporary series with conventional RT plus chemotherapy and/or halogenated pyrimidine radiosensitizers. While alternative dose/fractionation regimes might be more successful, the results of this study failed to support our hypothesis that repopulation during RT is an important reason for the failure of treatment in GBM. © 1995 Wiley‐Liss, Inc.
Intraoperative radiotherapy for the treatment of soft tissue sarcomas of central anatomical sites
Authors: Calvo Felipe A. , Azinovic Ignacio , Martinez Rafael , Aristu Javier , Abuchaibe Oscar , Pardo Fernando , Alvarez‐Cienfuegos Javier , Berian Jose M. , Cañadelly Jose
Published: February 2007

The results of intense therapy for soft tissue sarcomas located in central anatomic sites using an intraoperative electron boost (10–20 Gy) during surgery, integrated in a multimodal approach including external beam irradiation with or without chemotherapy, are analyzed. The relevant clinical data include a total of 30 patients treated, 13 recurrent tumors, 11 primary locally advanced stages, 15 high grade lesions, common location in the trunk (10 cases) and retroperitoneum (8 cases), and macroscopic residual disease after surgery in 9 cases. The median follow‐up time for the entire series is 25 months (range 4–98+ months).

Severe toxicity related to the combined therapy includes peripheral neuropathy in 3 patients, 1 myelopathy, 1 chronic enteritis, 1 rectovaginal fistula, and 1 lethal sepsis. Overall local control rate is 53% (65% in cases with microscopic residual disease and 35% in confirmed macrotumor residue). Subgroup analysis of local control shows a value of 72% (13/18) in patients with lesions of <10 cm in maximum dimension and 28% with tumors >10 cm (4/12). Actuarial survival rates are 36% for the entire series and 53% and 20% for patients with primary and recurrent disease, respectively. It is concluded that intraoperative radiotherapy (IORT) is feasible to be integrated in multidisciplinary programs as a local intensification treatment technique. Peripheral nerves are dose‐limiting structures for IORT trials. Local tumor control rates in central sarcomas appear to be related to the status of postsurgical margins and tumor size. Long‐term survivors are followed with no evidence of disease both in primary (81+ months) and recurrent disease (98+ months) patients. © 1995 Wiley‐Liss, Inc.
Management of locally advanced/unresectable rectal cancer
Authors: Minsky Bruce D.
Published: February 2007

The standard treatment for locally advanced/unresectable rectal cancer is preoperative radiation therapy followed by surgery. The primary goals of the preoperative treatment are to convert the cancer to a resectable status and to decrease the incidence of local failure. Phase I/II non‐randomized data suggest that the most effective treatment is preoperative combined modality therapy followed by maximal surgical resection and intraoperative radiation therapy. In patients who cannot receive preoperative therapy, the use of maximal surgical resection plus intraoperative radiation therapy may be of benefit, however, it remains investigational. © 1995 Wiley‐Liss, Inc.
Toxicity associated with boronophenylalanine and cranial neutron irradiation
Authors: Cano William G. , Solares Guido R. , Dipetrillo Thomas A. , Meylaerts Sven A. G. , Lin Shan C. , Zamenhof Robert G. , Saris Stephen C. , Duker Jay S. , Goad Elizabeth , Madoc‐Jones Hywel , Wazer David E.
Published: February 2007

Boron neutron capture therapy (BNCT) involves administration of a tumor selective boron compound followed by neutron irradiation directed at the target organ. Several studies have shown antitumor activity in animal models with BNCT using the amino acid analog boronophenylalanine (BPA). This study investigates the pharmacological toxicity of BPA in rabbits and the acute (14 days) and subacute (100 days) radiotoxicity of cranial BNCT with BPA in normal mice. To assess the toxicity of BPA alone the drug was administered orally in either a single dose of 5,000 mg/kg or 5 divided doses of 1,000 mg/kg/day to rabbits which were subsequently sacrificed at 2.5 or 4.5 weeks. To study the radiotoxic effects of BNCT mice were given BPA orally followed by cranial irradiation with a thermal neutron beam 3 hr later, with resulting brain doses ranging from 1,100 to 2,750 cGy‐Eq [compound‐relative biological effectiveness (C‐RBE) of 1.3 for 10B, 3.2 for neutrons, and 1.0 for gammas]. Mice were sacrificed 14 or 100 days after irradiation to study acute and subacute radiation toxicity, respectively. BPA alone demonstrated no discernible toxicity at the doses and schedules administered. BNCT resulted in a dose‐independent acute dilatation of the cerebral ventricles and mild cerebral atrophy. No neurologic deterioration could be detected in animals exposed to 2,200 cGy‐Eq or lower but acute clinical morbidity was evident at 2,750 cGy‐Eq, possibly related to non‐neural toxicity. Mice exposed to a dose of 2,750 cGy‐Eq to the brain also presented with moderately severe gastrointestinal toxicity consisting of epithelial hyperplasia or atrophy and necrosis. Animals exposed to lower doses showed no significant gastrointestinal radiotoxicity. All animals sacrificed at 100 days that received 2,200 cGy‐Eq developed bilateral posterior subcapsular cataracts. Lower doses had a minimal ocular toxic effect. It is concluded that there was no discernible toxicity from BPA administration at daily doses 10 times higher than those required for proposed therapeutic applications. Single‐fraction BNCT irradiations to the head showed significant ocular toxicity with a threshold between 1,650 and 2,200 cGy‐Eq; gastrointestinal toxicity with a threshold between 2,200 and 2,750 cGy‐Eq; and neural toxicity with a threshold ≦l,100 cGy‐Eq for histopathologic lesions. © 1995 Wiley‐Liss, Inc.
Utilization of 125I monoclonal antibody in the management of primary glioblastoma multiforme
Authors: Miyamoto Curtis , Brady Luther W. , Rackover Michael , Emrich Jacqueline , Class Reiner , Bender Hans , Dadparvar Simin , Woo David , Young Timothy , Eshleman Jeffrey , Dilling Thomas , Micaily Bizhan , Steplewski Zenon , Koprowski Hilary , Black Perry , Nair Somnath , McCormack Thomas
Published: February 2007

The objective of this study was to assess the toxicity and potential efficacy of the adjuvant administration of an iodine 125 (125I)‐labeled monoclonal antibody 425 for primary glioblastoma multiforme. From January 29, 1987, to October 1, 1993, 60 patients with a diagnosis of glioblastoma multiforme received an average of three intravenous or intraarterial injections of 125I‐labeled antiepidermal growth factor receptor monoclonal antibody (1251425). All patients had biopsy or resection followed by postoperative radiation therapy. Patients were included who had either stereotactic irradiation or brachytherapy (5 patients), or who were not candidates for these treatments. Stratification was made by Karnofsky performance status (KPS) and age. Treatments were administered on an outpatient basis. The mean KPS was 78, and the total cumulative dose of 125I 425 was approximately 150 mCi. Among this entire group were 6 patients who received 10–80 mg of unlabeled “blocking” 425 to block binding sites on non‐tumor cells prior to the second intravenous infusion of 125I 425. No patients were excluded from the statistical analysis. The median actuarial survival for all patients treated adjuvantly for glioblastoma multiforme was 13 months. Both age and KPS correlated positively with survival, as would be expected. The toxicity from the administration of repeated doses of 125I 425 was low. No patient had chronic toxicity attributed to the monoclonal antibody therapy. Acute toxicity was observed in 1 patient who received a single dose >60 mCi. We conclude that the repeated administration of 1251425 is safe and may have some benefit in the management of primary glioblastoma multiforme. This may be especially true for patients who do not qualify for other forms of more aggressive management. A prospective randomized trial should be performed. © 1995 Wiley‐Liss, Inc.
Response predictors for high‐grade gliomas given definitive irradiation
Authors: Shaeffer James , Zhu An , Leslie Susan , Kolm Paul , El‐Mahdi Anas M.
Published: February 2007

The prognostic significance of the following 9 variables was assessed using archival specimens from a series of patients with high‐grade astrocytic gliomas treated definitively with irradiation: histologic grade, patient age, tumor nuclear roundness factor (TNRF), tumor nuclear area (TNA), mitotic index, cell density, necrosis, giant cells, and pseudopalisading cells (PPC). Using univariate analysis, 7 of the 9 variables were significantly related to overall survival: patient age (P < 0.0001), mitotic index (P < 0.0001), cell density (P = 0.0004), histologic grade (P = 0.0005), necrosis (P =0.0042), PPC (P = 0.0016), and TNRF (P = 0.0232). When adjusted for age, 4 variables were significantly related to overall survival: histologic grade, mitotic index, cell density, and TNRF. When adjusted for both age and grade, 3 previously significant variables (mitotic index, cell density, and TNRF) were no longer significant, indicating possible redundancy with grade. When each variable was adjusted for every other variable, only age remained independently and significantly (P = 0.0022) predictive for overall survival. None of the 9 variables was significantly related to disease‐free survival. © 1995 Wiley‐Liss, Inc.
Three‐dimensional external‐beam radiation treatment planning and real‐time dose verification of pituitary adenoma: Clinical and physical considerations
Authors: Ahmad M. , Fontenla D. P. , Lai P. P. , Del Rowe J. , Yaparpalvi R. , Deore S. M. , Curran J. , Wojcicka J. , Vikram B.
Published: February 2007

The purpose of this study is to establish protocols for simulation and external‐beam radiotherapy of pituitary tumors and to examine the performance of a new 3‐dimensional treatment planning system (3‐D RTP). The asymmetric collimation feature of a dual‐energy photon beam linear accelerator allows the user to set up half‐beam treatment fields posterior to the orbits with no divergence to anterior structures.

Treatment planning was performed with a relatively new Food and Drug Adminisration (FDA)‐approved 3‐D RTP system. Computerized tomographic (CT) scans used by this system to generate isodose distributions and dose‐volume histograms were obtained directly from the scanner which is connected via ethernet cabling to the 3D treatment planning system. These were used for evaluating the dose distribution to the treatment volume, clinical target volume, gross tumor volume, and certain critical organs. Using 6 and 18 MV photon beams, different configurations of standard treatment techniques for pituitary tumors, i.e., a 190° flying wedge arc, 3‐fields (an anterior plus a lateral wedged pair), and a pair of lateral fields, were studied and the resulting dose distributions were analyzed. Real‐time dose measurements on patients using diode dosimetry were made and compared with computed dose values.

With regard to minimizing radiation dose to surrounding structures, (i.e., lens, temporal lobes, spinal cord, etc.) the 190° flying wedge arc technique gave the best isodose distributions, followed by 3 fields (an anterior plus a lateral wedged pair). The opposing lateral fields gave the highest integral dose to the temporal lobes. The dose measured on the patient during the treatment agrees to within ±2% with the computed dose.

The protocols presented in this work for simulation, immobilization, and treatment planning of patients with pituitary tumors provide the optimum dose distributions in the target volume with reduced irradiation of surrounding non‐target tissues, and can be easily implemented in a radiation oncology department. The presence of a real‐time dose‐measuring system plays an important role in verifying the actual delivery of radiation dose. © 1995 Wiley‐Liss, Inc.
Localized subclinical radiation enteropathy prolongs intestinal transit time: An experimental study in a rat model
Authors: Hauer‐Jensen Martin , Theus John W. , Bradley Jeffrey D. , Baker Max L. , Langberg C. W.
Published: February 2007

Intestinal dysmotility is a prominent feature of chronic radiation enteropathy. This study addressed the question whether localized radiation enteropathy without anatomical obstruction influences stomach to cecum transit time. Male rats were orchiectomized and a loop of ileum was sutured to the inside of the scrotum. After 3 weeks postoperative recovery, the “scrotal hernia” containing the transposed intestine was irradiated with 18 twice‐daily fractions of 2.8 Gy, or 9 daily fractions of 5.6 Gy orthovoltage X‐rays. Control animals were operated and sham‐irradiated. Stomach to cecum transit time was assessed 26 weeks after irradiation. A 1‐ml bolus of barium suspension was administered by gavage and diagnostic X‐ray films were obtained at 0,1, 2,2.5, 3, 3.5, and 4 hr. Transit time was defined as the time to the first X‐ray that showed unequivocal contrast filling of the cecum. Normal range and day‐to‐day variability were assessed in normal, unoperated control rats. After completion of transit studies, the rats were euthanized, samples from shielded and irradiated intestine were procured, and radiation injury was assessed with a histopathological scoring system. Median stomach to cecum transit time in unoperated controls was 2.25 hr. The surgical procedure and aging did not significantly affect transit time. Transit time was significantly prolonged both in the 2.8 Gy × 18 group (P = 0.02) and in the 5.6 Gy × 9 group (P = 0.0001). The association between histopathologic radiation injury and transit time did not reach statistical significance. We conclude that non‐obstructing radiation injury in the distal ileum significantly prolongs intestinal transit time and that small bowel follow‐through with barium contrast may be used to assess radiation enteropathy in this animal model. © 1995 Wiley‐Liss, Inc.
Treatment decisions in elderly breast cancer patients
Authors: Konski Andre , Marsa Gerald , Mueller William , Cobau Charles , Horvath William , Zeidner Steven , Schaefer Paul , Shaikh Bahu , Mali John , Smith Mary , Eggleston William
Published: February 2007

The purpose of this study was to investigate the patterns of care in women over the age of 65 years presenting with breast cancer. Tumor registry data from three different sized and geographically located hospitals in northwest Ohio were reviewed and analyzed. Three hundred forty‐five patients were eligible for analysis. An age difference was noted between those patients receiving lumpectomy only compared to those patients receiving mastectomy or lumpectomy and radiation. The majority of patients with regional disease received hormonal therapy. Only two of six patients with positive lumpectomy margins experienced a local recurrence. The tumor volume was statistically significantly higher in patients who experienced a local recurrence. In conclusion, treatment for elderly patients with breast cancer should be based on physiologic not chronologic age. © 1995 Wiley‐Liss, Inc.
Prostate brachytherapy: Improvements in prostate volume measurements and dose distribution using interactive ultrasound guided implantation and three‐dimensional dosimetry
Authors: Stone Nelson N. , Stock Richard G. , Keith DeWyngaert J. , Tabert Andrea
Published: February 2007

Improvements in prostate volume measurements and in dose distribution have led to an increase in the use of brachytherapy for prostate cancer. The addition of interactive ultrasound and three‐dimensional dosimetry has also enhanced the treatment plan. We investigated the effect of these changes on implant outcome in patients with localized carcinoma of the prostate who were treated with these new techniques. Two hundred twenty‐one men with an elevated prostate specific antigen (PSA) or abnormal digital rectal examination (DRE) had transrectal ultrasound evaluation and needle biopsy of the prostate. Prostate volume was determined by ellipsoid and planimetry techniques. Differences of at least 5%, 10%, 15%, 25%, and 50% between the two techniques were found in 170 (77%), 130 (59%), 102 (46%), 53 (24%), and 11 (5%), respectively. In addition, the ellipsoid measurements, which approximate the caliper measurements of the open retropubic implants, were found to underestimate gland volume by 10% in 47 patients (21%), 15% in 39 (18%), 25% in 28 (13%), and 50% in 8 (4%). In 75 patients who had 125I implant the dose to 90% (D90) of the gland increased from 7,619 to 15,806 cGy (P < 0.02) by distributing the majority (70%) of the activity in the periphery and by increasing the total implanted activity by 35%. Despite this peripheral dose placement and increased activity, there was no increase in dose to the anterior rectal wall. We conclude that accurate prostate gland determinations (by planimetry), a peripheral activity distribution, and a 35% increase in implanted activity are necessary in order to ensure adequate dose coverage to the prostate gland when implanting 125I. These changes also may be accomplished without an increase in rectal dose and subsequent radiation proctitis. © 1995 Wiley‐Liss, Inc.
Standardized treatment planning for high dose rate vaginal cuff brachytherapy
Authors: Petereit Daniel G. , Edwards Scott A. , Thomadsen Bruce R. , Fowler Jack F. , Buchler Dolores A. , Kinsella Timothy J.
Published: February 2007

The purpose of this study was to establish the efficacy of standardized treatment planning for high dose rate (HDR) vaginal cuff brachytherapy in order to simplify and shorten the brachytherapy procedure. Two separate but related studies are presented. The first examined the reproducibility of treatment planning by assessing interoperator variability. This provided a baseline assessment of variability to evaluate standardized treatment planning in the second study. The second study examined interpatient variability in which the treatment plans of 20 patients were investigated by two different treatment methods. The first method used the dosimetry of the first insertion for the next insertion, while the other method utilized a standardized plan for all insertions dependent upon ovoid size. The dose was prescribed to the vaginal surface using either applicator points or dose points. Based on multiple calculations, a graph of distance vs. dose was generated to determine the dose to the bladder and rectum for a given implant. In the first study, interoperator variability was acceptable with a standard deviation of 0.4% of the prescribed dose using dose points for the worst case. Applicator points were less reproducible with a worst‐case standard deviation of 2.1% of the prescribed dose. In the second study, implementing initial dosimetric plans for the second implant for an individual patient yielded a worst‐case standard deviation of 2.4% of the prescribed dose. The use of standardized treatment plans for all implants was also efficacious with a worst‐case standard deviation of 1.7% of the prescribed dose. Treatment plans were always more reproducible when calculated to dose points rather than applicator points. Analysis of maximum bladder and rectal doses provided acceptable late tissue doses as predicted by the linear quadratic model. In conclusion, standardized dosimetry plans for vaginal cuff insertion are feasible and reliable in producing precise delivery of vaginal surface doses. The use of dose vs. distance curves facilitates rapid planning by providing a close approximation of the maximum bladder and rectal doses. © 1995 Wiley‐Liss, Inc.
Tumor size does not limit radiation‐inducible gene therapy in a human xenograft model
Authors: Mauceri Helena J. , Hallahan Dennis E. , Lee Henry , Beckett Michael A. , Sukhatme Vikas , Weichselbaum Ralph R.
Published: February 2007

Tumor size has been reported to be a limiting factor in both radiotherapy (RT) and gene therapy. Therefore, we assessed the effects of tumor necrosis factor‐alpha (TNF‐α) gene therapy and radiation in relatively large tumors in a human xenograft system. We linked DNA sequences from the promoter region of the radiation‐inducible gene Egr‐1 to the cDNA sequence that encodes human TNF‐α, a radiosensitizing cytokine. The Egr‐TNF construct was transfected into the human hematopoietic cell line HL525. Stable transfectants, exhibiting radiation inducibility of TNF‐α in vitro (clone 2 cells), were directly injected into xenografts of a radioresistant human squamous cell carcinoma cell line, SQ‐20B. In a previous study, 100 mm3 tumors treated with radiation and clone 2 cells demonstrated significant tumor control (P < 0.0001) when compared with tumors treated with clone 2 alone or radiation alone. In the present study, 450 mm3 xenografts treated with clone 2 cells and radiation were significantly smaller (P < 0.01) at the nadir of regression than tumors treated with radiation alone. Because the radiation dose was held constant (40 Gy) in both 100 and 450 mm3 xenografts, only one cure was noted in the larger tumors. These data support an interactive anti‐tumor effect in vivo between radiation and TNF‐α gene therapy which is equal in both small and large human tumor xenograft models. © 1995 Wiley‐Liss, Inc.
Mini review: Multistep process of ultraviolet‐induced nonmelanoma skin carcinogenesis
Authors: Bleuel Kerstin , Figueroa Reynel , Härle Cosima , Popp Susanne , Vormwald‐Dogan Vera , Boukamp Petra
Published: February 2007

Ultraviolet (UV)‐induced nonmelanoma skin cancer requires a number of genetic changes before tumors can develop. To determine the sequence of these changes; we performed a series of functional studies by investigating the spontaneously immortalized human skin keratinocyte HaCaT cell line. We established a multistep in vitro carcinogenesis model that allowed us to place known (mutational inactivation of the tumor suppressor gene p53, ras oncogene activation) and novel (loss of chromosome 3p as carrier of “senescence” gene(s) and chromosome 15 as carrier of a tumor suppressor gene as well as telomerase up‐regulation) genetic alterations involved in the process of skin carcinogenesis in chronological order. © 1995 Wiley‐Liss, Inc.
Use of amphotropic retroviruses expressing human papillomavirus 16 E6 and E7 to determine the consequences of acute expression of the viral oncogenes and to establish immortalized human cell lines
Authors: Galloway D. A. , Halbert C. L. , Demers G. W. , Foster S. A. , Blanton R. A. , Merrick D. , Klingelhutz A. , McDougall J. K.
Published: February 2007

We developed a series of amphotropic retroviruses expressing the E6 and E7 oncogenes from human papillomavirus (HPV) 16 and HPV 6. LXSN16E6E7 efficiently immortalized a wide variety of primary cell types, including epithelia from foreskin, cervix, breast, oral cavity, urogenital region, kidney, prostate, ovary, etc., as well as smooth muscle cells, endothelial cells, fibroblasts, hepatocytes, melanocytes, and others. Rare clones of keratinocytes were established by expression of E7 alone, and breast cells that had bypassed M0 were immortalized by E6 alone. However, in general, efficient immortalization required both E6 and E7 of HPV 16. The immortalized cell lines were nontumorigenic in nude mice and retained many of the differentiated characteristics of the primary cells; however, they invariably had chromosomal abnormalities.

Acute expression of E6 or E7 did not alter the doubling time of cells in culture; however, E7 disrupted normal suprabasal quiescence. No increase in aneuploidy or alteration in the rate of telomere shortening was observed before crisis, and cells continued to express markers of epithelial differentiation in organotypic culture. The ability of cells to bypass growth arrest signals was altered by the HPV oncogenes. © 1995 Wiley‐Liss, Inc.
Extended abstract: Abrogation of cell cycle checkpoint control in preneoplastic cells
Authors: Tlsty Thea D.
Published: February 2007

Genomic integrity is maintained by a network of cellular activities that assesses the status of the genome at a given point in time and that provides signals to proceed with or to halt cell cycle progression. Recent studies have identified cellular proteins that are the targets for the viral oncoproteins involved in these processes. We demonstrate that the expression of human papilloma virus type 16 E6 and E7 oncoproteins in normal mortal cells disrupts the integration of the network of signals that maintain genomic integrity. © 1995 Wiley‐Liss, Inc.
In vitro multistep human prostate epithelial cell models for studying prostate carcinogenesis
Authors: Rhim J. S. , Peehl D. M. , Webber M. M. , Jay G. , Dritschilo A.
Published: February 2007

We have recently developed in vitro multistep human prostate epithelial (HPE) cell models that are suitable for studying prostate carcinogenesis. We have shown the stepwise immortalization and transformation of adult HPE cells grown in serum‐free medium by a combination of human papilloma virus (HPV)‐18 and v‐Ki‐ras. These observations are consistent with molecular studies on human prostate adenocarcinomas that suggest that both the activated ras gene and HPVs play a role in prostate carcinogenesis. We also established adult HPE cells grown in serum‐free medium and immortalized by Polybrene‐induced DNA transfection with a plasmid containing an origin‐defective SV40 genome. The subsequent addition of v‐Ki‐ras gene to these cells induced morphological alteration and tumors when they were transplanted into nude mice. In addition, we have achieved the neoplastic conversion of a nontumorigenic SV40‐immortalized fetal HPE line by v‐Ki‐ras gene. These cell lines should be useful in defining the multistep mechanisms of carcinogenesis of the prostate. © 1995 Wiley‐Liss, Inc.
Signal‐transduction pathways in androgen‐dependent and androgen‐independent prostate tumor cells
Authors: Ramsamooj Priya , Jung Mira
Published: February 2007

We have investigated the differential responses of androgen‐dependent prostate tumor cell line LNCaP and androgen‐independent prostate tumor cell line PC‐3 to various effectors at the level of mitogen‐activated protein kinase (MAPK) signal‐transduction intermediates. We have examined the change in protein levels of ras, raf, mek1,2, and erk1,2 in LNCaP and PC‐3 cells following treatment with dihydrotestosterone (DHT), estradiol (E2), ionizing radiation, tumor necrosis factor alpha (TNFα), ZnSO4, and CdSO4, DHT treatment of androgen‐dependent LNCaP cells resulted in an increase in cellular ras protein levels by 1 hour after treatment, whereas ras levels decreased 0.5 hours after DHT treatment of androgen‐independent PC‐3 cells. These data indicate that, in fact, DHT does invoke a differential response in androgen‐dependent compared to androgenindependent prostate tumor cells. E2 treatment resulted in a change in ras levels for LNCaP cells, but not for PC‐3 cells, which is further evidence of a differential response in these prostate tumor cells. Ionizing radiation, TNFα, and CdSO4 treatment showed no effect on signal‐transduction intermediates; however, ZnSO4 treatment of LNCaP cells resulted in an increase in ras protein levels and a decrease in raf‐1 protein levels. No change in ras levels was observed in PC‐3 cells upon ZnSO4 treatment. Our data show few differences in the signal‐transduction intermediates of the MAPK pathway in LNCaP and PC‐3 prostate tumor cells in response to tested stimuli. These results and the observation that cellular mek1,2 and erk1,2 protein levels were constituitively elevated support the hypothesis that MAPK‐independent signal transduction may be occurring in these prostate cells. © 1995 Wiley‐Liss, Inc.