Biomedical subjects

Mitchell S Anscher

Publications and source records attributed to Mitchell S Anscher.

11 recordsLinked to original sources

PubMed2003

Soluble TGFbeta type II receptor gene therapy ameliorates acute radiation-induced pulmonary injury in rats.

PURPOSE: To assess whether administration of recombinant human adenoviral vector, which carries soluble TGFbeta1 Type II receptor (TbetaRII) gene, might reduce the availability of active TGFbeta1 and thereby protect the lung from radiation-induced injury. METHODS AND MATERIALS: Female Fisher 344 rats were given a single 30 Gy dose of right hemithoracic irradiation 24 h after the injections of control (AdGFP) or treatment (AdexTbetaRII-Fc) vectors. Different end points were assessed to look for lung tissue damage. RESULTS: There was a significant increase in the plasma level of soluble TbetaRII 24 h and 48 h after injection of treatment vector. In the radiation (RT) + AdexTbetaRII-Fc group, there was a significant reduction in respiratory rate at 4 weeks after treatment as compared to the RT-alone group. Histologic results revealed a significant reduction in lung damage and decrease in the number and activity of macrophages in the RT + AdexTbetaRII-Fc group as compared to the RT-alone group. The tissue level of active TGFbeta1 was significantly reduced in rats receiving RT + AdexTbetaRII-Fc treatment. There was also an upregulation of transmembrane TbetaRII in lung tissue in the RT-alone group as compared to the RT + gene therapy rats. CONCLUSIONS: This study shows the ability of AdexTbetaRII-Fc gene therapy to induce an increase in circulating levels of soluble receptors, to reduce the tissue level of active TGFbeta1, and consequently to ameliorate acute radiation-induced lung injury.

Adenoviridae↗

PubMed2003

Risk of long-term complications after TFG-beta1-guided very-high-dose thoracic radiotherapy.

PURPOSE: To report the incidence of late complications in long-term survivors of very-high-dose thoracic radiotherapy (RT) treated on a prospective clinical trial. METHODS AND MATERIALS: Patients with locally advanced or medically inoperable non-small-cell lung cancer received three-dimensional conformal RT to the primary tumor and radiographically involved lymph nodes to a dose of 73.6 Gy at 1.6 Gy twice daily. If the plasma transforming growth factor-beta1 (TGF-beta1) level was normal after 73.6 Gy, additional twice-daily RT was delivered to successively higher total doses until the maximal tolerated dose was reached. Patients within a given dose level were followed for 6 months before escalation to the next dose level was permitted. Late complications were defined according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria. RESULTS: Thirty-eight patients were enrolled between 1996 and 1999. Twenty-four patients were not eligible for radiation dose escalation beyond 73.6 Gy because of persistently abnormal TGF-beta1 levels. Fourteen patients received dose escalation (80 Gy in 8; 86.4 Gy in 6). Grade 3 or greater late complications occurred in 4 of 24, 1 of 8, and 2 of 6 patients treated to 73.6, 80, and 86.4 Gy, respectively. The corresponding patient numbers with late Grade 4-5 toxicity were 3 of 24, 0 of 6, and 0 of 8. Overall, 7 (18%) of the 38 patients developed Grade 3-5 late toxicity. Nonpulmonary complications predominated (4 of 7). Five (71%) of seven serious complications developed within 11 months after RT; however, the remaining two complications (29%) occurred very late (at 43 and 62 months). The 5-year actuarial risk of late Grade 3-5 complications was 33%. CONCLUSION: Long-term survivors of very-high-dose RT for non-small-cell lung cancer have a significant risk of severe treatment-related complications. At these high dose levels, the predominant toxicity may no longer be pulmonary. All Grade 4-5 complications occurred in patients whose dose was limited to 73.6 Gy because of a persistently elevated TGF-beta1. Thus, persistently elevated plasma TGF-beta1 levels toward the end of RT may identify patients at greatest risk of severe complications.

Adult↗

PubMed2003

M6P/IGF2R loss of heterozygosity in head and neck cancer associated with poor patient prognosis.

BACKGROUND: The mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R) encodes for a multifunctional receptor involved in lysosomal enzyme trafficking, fetal organogenesis, cytotoxic T cell-induced apoptosis and tumor suppression. The purpose of this investigation was to determine if the M6P/IGF2R tumor suppressor gene is mutated in human head and neck cancer, and if allelic loss is associated with poor patient prognosis. METHODS: M6P/IGF2R loss of heterozygosity in locally advanced squamous cell carcinoma of the head and neck was assessed with six different gene-specific nucleotide polymorphisms. The patients studied were enrolled in a phase 3 trial of twice daily radiotherapy with or without concurrent chemotherapy; median follow-up for surviving patients is 76 months. RESULTS: M6P/IGF2R was polymorphic in 64% (56/87) of patients, and 54% (30/56) of the tumors in these informative patients had loss of heterozygosity. M6P/IGF2R loss of heterozygosity was associated with a significantly reduced 5 year relapse-free survival (23% vs. 69%, p = 0.02), locoregional control (34% vs. 75%, p = 0.03) and cause specific survival (29% vs. 75%, p = 0.02) in the patients treated with radiotherapy alone. Concomitant chemotherapy resulted in a better outcome when compared to radiotherapy alone only in those patients whose tumors had M6P/IGF2R loss of heterozygosity. CONCLUSIONS: This study provides the first evidence that M6P/IGF2R loss of heterozygosity predicts for poor therapeutic outcome in patients treated with radiotherapy alone. Our findings also indicate that head and neck cancer patients with M6P/IGF2R allelic loss benefit most from concurrent chemotherapy.

Adult↗

PubMed2003

Radiation-induced lung injury.

Radiation therapy (RT) for thoracic-region tumors often causes lung injury. The incidence of lung toxicity depends on the method of assessment (eg, radiographs, patient's symptoms, or functional endpoints such as pulmonary function tests). Three-dimensional (3D) treatment planning tools provide dosimetric predictors for the risk of symptomatic RT-induced lung injury and allow for beams to be selected to minimize these risks. A variety of cytokines have been implicated as indicators/mediators of lung injury. Recent work suggests that injury-associated tissue hypoxia perpetuates further injury. Sophisticated planning/delivery methods, such as intensity modulation, plus radioprotectors such as amifostine, hold promise to reduce the incidence of RT-induced lung injury.

Animals↗

PubMed2003

Normal tissue effects: reporting and analysis.

Any effective cancer therapy developed to date is associated with a spectrum of normal tissue effects of varying incidence and severity. With an increasing number of novel therapeutic approaches undergoing clinical testing and an increased effort to optimize the established treatment modalities, methods for reliable quantification of normal tissue effects have become a key element in advancing cancer care. Here, we present a review of many of the issues involved in reporting and analyzing clinical normal tissue effect data. A distinction is introduced between explorative (science-driven) and pragmatic (patient-centered) studies. The desirable properties of criteria for reporting and grading toxicity are discussed from a biological and clinical perspective. Validation of toxicity criteria and the statistical issues involved in analyzing this type of data are presented with special emphasis on descriptors of the time evolution of toxicity. Finally, we discuss surrogate markers for late effects, mechanistic studies, and the design of clinical studies with normal tissue endpoints as a primary outcome. It is concluded that a consensus is required on guidelines for the reporting of normal tissue effects to improve the comparability of published reports on treatment outcome.

Antineoplastic Agents↗

PubMed2003

Effects of radiation on normal tissue: consequences and mechanisms.

The use of radiation therapy to treat cancer inevitably involves exposure of normal tissues. As a result, patients may experience symptoms associated with damage to normal tissue during the course of therapy for a few weeks after therapy or months or years later. Symptoms may be due to cell death or wound healing initiated within irradiated tissue, and may be precipitated by exposure to further injury or trauma. Many factors contribute to risk and severity of normal tissue reactions; these factors are site specific and vary with time after treatment. Treatments that reduce the risk or severity of damage to normal tissue or that facilitate the healing of radiation injury are being developed. These could greatly improve the quality of life of patients treated for cancer.

Animals↗

PubMed2002

A small molecular weight catalytic metalloporphyrin antioxidant with superoxide dismutase (SOD) mimetic properties protects lungs from radiation-induced injury.

Radiation therapy (RT) is an important therapeutic modality in the treatment of thoracic tumors. The maximum doses to these tumors are often limited by the radiation tolerance of lung tissues. Lung injury from ionizing radiation is believed to be a consequence of oxidative stress and a cascade of cytokine activity. Superoxide dismutase (SOD) is a key enzyme in cellular defenses against oxidative damage. The objective of this study was to determine whether the SOD mimetic AEOL 10113 [manganese (III) mesotetrakis (N-ethylpyridinium-2-yl) porphyrin (MnTE-2-PyP(5+))] increases the tolerance of lung to ionizing radiation. AEOL 10113 was able to significantly reduce the severity of RT-induced lung injury. This was strongly supported with histopathology results and measurements of collagen deposition (hydroxyproline content). There was a significant reduction in the plasma level of the profibrogenic cytokine transforming growth factor-beta (TGF-beta) in the group of rats receiving RT + AEOL 10113. In conclusion, the novel SOD mimetic, AEOL 10113, demonstrates a significant protective effect from radiation-induced lung injury.

Animals↗

PubMed2002

Gastrointestinal toxicity of transperineal interstitial prostate brachytherapy.

PURPOSE: To characterize the severity and time course of rectal toxicity following transperineal prostate brachytherapy using prospectively recorded data, and to determine factors associated with toxicity. METHODS AND MATERIALS: One hundred thirty-four patients with prostate cancer treated with transperineal brachytherapy from 1997 to 1999 had rectal toxicity data available for analysis. Patients with Gleason score (GS) > 6, prostate-specific antigen (PSA) > 6, or stage > T2a were treated initially with external beam radiation therapy followed by brachytherapy boost; patients with none of these features were treated with brachytherapy alone. Both iodine-125 and palladium-103 sources were used, and loaded according to a modified Quimby distribution. At each follow-up, toxicity was recorded according to a modified RTOG gastrointestinal scale. RESULTS: Thirty-nine percent of patients experienced gastrointestinal toxicity, mostly Grade 1. Median duration of symptoms was 6 months. Two patients experienced Grade 3 toxicity, both of whom had minimal symptoms until their 12-month follow-up. There was no Grade 4 or 5 toxicity. The addition of external beam radiation therapy (p = 0.003), higher clinical stage (p = 0.006), and Caucasian race (p = 0.01) were associated with increased incidence of toxicity. CONCLUSION: Most patients with rectal toxicity have very mild symptoms. There is a small risk of severe late toxicity. External beam radiation, higher stage, and race are associated with toxicity.

Adult↗

PubMed2002

The time course of radiation therapy-induced reductions in regional perfusion: a prospective study with >5 years of follow-up.

PURPOSE: To assess the time-dependence of radiation therapy (RT)-induced reductions in regional lung perfusion, as measured by single photon emission computed tomography (SPECT) lung perfusion scans. METHODS AND MATERIALS: Between 1991 and 1999, 79 patients had SPECT lung perfusion scans before and serially after RT. Changes in regional perfusion were correlated with regional dose using 3D planning tools and image fusion (PLUNC-Plan UNC). Multiple post-RT follow-up scans were evaluated to determine the temporal nature of RT-induced regional perfusion changes. To facilitate the comparison of dose-response curves (DRCs) at different post-RT intervals, each DRC was fit to a linear model and thus described by its slope. RESULTS: There was a dose-dependent reduction in regional perfusion at nearly all time points post-RT (p = 0.0001). The slope of the DRCs for RT-induced reductions in regional perfusion became steeper at essentially each successive follow-up interval (p = 0.0001). However, the increases in slope became progressively smaller at later follow-up intervals. Overall, about 80% of the long-term RT-induced regional perfusion injury was manifest within 12 months post-RT. CONCLUSION: There is a progression of RT-induced reductions in regional perfusion, with most of this injury manifest within 12 months post-RT. Additional regional injury appears to evolve for years.

Adult↗

PubMed2002

Radioprotection of lungs by amifostine is associated with reduction in profibrogenic cytokine activity.

Radiation-induced pulmonary toxicity causes significant morbidity and mortality in patients irradiated for lung cancer, breast cancer, lymphoma or thymoma. Amifostine is an important drug in the emerging field of cytoprotection. Recent advances in our understanding of the mechanism of radiation-induced injury at the molecular and cellular levels have stimulated interest in the development of effective radioprotective strategies. Accumulation of macrophages with associated production of reactive oxygen species (ROS) and production and activation of cytokines is a key process involved in the pathophysiology of radiation injury in the lung. The purpose of this study was to determine whether the mechanism of radioprotection by amifostine includes reduction in both macrophage activity and the expression and activation of profibrogenic cytokines. Our results demonstrated a reduction in both functional and histological radiation-induced lung injury by amifostine. In addition, this study is the first to demonstrate that amifostine given prior to irradiation reduced both the accumulation of macrophages and the expression/activation of lung tissue Tgfb1 which was followed by the reduction of plasma Tgfb1 levels during the development of radiation-induced lung injury. Future studies are needed to determine whether administration of amifostine both during and after radiotherapy may further increase its radioprotective effect.

Amifostine↗

PubMedDate not supplied

Assessment of the protective effect of amifostine on radiation-induced pulmonary toxicity.

The objective of this study was to assess the radioprotective effects of amifostine in the rat model of radiation-induced lung injury using fractionated doses of radiation, to determine whether amifostine given before irradiation protects tumor from radiation cytotoxicity, and to determine whether changes in plasma levels of transforming growth factor (TGF)-beta correlate with radioprotective effect of amifostine. R3230 AC mammary adenocarcinoma was transplanted on the right posterior chest wall of female Fisher-344 rats. Both tumor-bearing and non-tumor-bearing animals were irradiated to the tumor or right lung using 4 MV photons and fractionated dose of 35 Gy/5 fractions/5 days. Animals with tumors and those without were randomized into 4 groups, respectively (8 to 10 rats per group), to receive (1) radiation alone; (2) radiation + amifostine; (3) amifostine alone; (4) sham radiation. Amifostine (150 mg/kg) was given intraperitoneally 30 minutes before each fraction of irradiation. The tumor size was measured twice a week. Breathing rate was assessed every 2 weeks. TGF-beta levels in plasma were assessed monthly after treatment. Six months after irradiation, animals were euthanized and lung tissue was processed for hydroxyproline content analysis. A significant increase in breathing frequency started 9 weeks after irradiation in animals that received radiation only. In the radiation + amifostine group, there was both a delay and a significantly lower peak in breathing frequency (P < .001). Hydroxyproline content was higher in the radiation-alone group than in rats given amifostine prior to radiation (P < .05). The TGF-beta levels in plasma showed an increase from 1 to 3 months after radiation, peaking at 2 months in the rats with (2.80 +/- 0.23) or without (5.32 +/- 1.21) amifostine compared to sham irradiation. TGF-beta levels were significantly lower at 1 to 3 months in rats receiving amifostine plus radiation versus those receiving radiation alone. Tumor growth delay and regrowth rate after radiation were not different between radiation-alone and radiation + amifostine groups. This study confirms the protective effect of amifostine in reducing radiation-induced pulmonary toxicity. No tumor protection was demonstrated after fractionated radiotherapy. The reduction in pulmonary injury with amifostine in paralleling lower plasma levels of TGF-beta, suggesting that monitoring plasma levels of this cytokine may reflect the efficacy of an intervention aimed at preventing radiation-induced lung injury.

Adenocarcinoma↗