S.M. Hahn

OBJECTIVE: To provide health-care providers, patients, and the general public with a responsible assessment of currently available data on the diagnosis and management of ductal carcinoma in situ (DCIS). PARTICIPANTS: A non-Department of Health and Human Services, nonadvocate, 14-member panel representing the fields of oncology, radiology, surgery (general and reconstructive), pathology, radiation oncology, internal medicine, epidemiology, biostatistics, nursing, obstetrics and gynecology, preventative medicine and population health, and social work. In addition, 22 experts from pertinent fields presented data to the panel and conference audience. EVIDENCE: Presentations by experts and a systematic review of the literature prepared by the Minnesota Evidence-based Practice Center, through the Agency for Healthcare Research and Quality. Scientific evidence was given precedence over anecdotal experience. CONFERENCE PROCESS: The panel drafted its statement based on scientific evidence presented in open forum and on published scientific literature. The draft statement was presented on the final day of the conference and circulated to the audience for comment. The panel released a revised statement later that day at http://consensus.nih.gov. This statement is an independent report of the panel and is not a policy statement of the National Institutes of Health or the Federal Government. CONCLUSIONS: Clearly, the diagnosis and management of DCIS is highly complex with many unanswered questions, including the fundamental natural history of untreated disease. Because of the noninvasive nature of DCIS, coupled with its favorable prognosis, strong consideration should be given to elimination of the use of the anxiety-producing term "carcinoma" from the description of DCIS. The outcomes in women treated with available therapies are excellent. Thus, the primary question for future research must focus on the accurate identification of patient subsets diagnosed with DCIS, including those persons who may be managed with less therapeutic intervention without sacrificing the excellent outcomes presently achieved. Essential in this quest will be the development and validation of accurate risk stratification methods based on a comprehensive understanding of the clinical, pathological, and biological factors associated with DCIS.

Nitroxide compounds are stable free radicals which were previously investigated as hypoxic cell radiosensitizers. The stable nitroxide 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (Tempol) has recently been shown to protect aerated cells in culture against superoxide generated from hypoxanthine/xanthine oxidase, hydrogen peroxide, and radiation-induced cytotoxicity and to modestly sensitive hypoxic cultured cells. To extend these observations from the cellular level to the whole animal, the toxicity, pharmacology, and in vivo radioprotective effects of Tempol were studied in C3H mice. The maximum tolerated dose of Tempol administered i.p. was found to be 275 mg/kg, which resulted in maximal Tempol levels in whole blood 5-10 min after injection. Mice were exposed to whole-body radiation in the absence or presence of injected Tempol (275 mg/kg) 5-10 min after administration. Tempol treatment provided significant radioprotection (P less than 0.0001); the dose of radiation at which 50% of Tempol-treated mice die at 30 days was 9.97 Gy, versus 7.84 Gy for control mice. Tempol represents a new class of in vivo, non-sulfur-containing radiation protectors. Given the potential for hypoxic radiosensitization and aerobic cell radioprotection, Temporal or other analogues may have potential therapeutic application.

Nitroxides are redox-sensitive probes, which are useful in noninvasively delineating tissue heterogeneity especially with respect to metabolic activity and tissue oxygenation. Recent studies have shown that nitroxides are in vitro and in vivo radioprotectors and selectively protect normal tissue compared to tumor tissue. It has been postulated that the basis for selective radioprotection of normal tissues is greater bioreduction of nitroxides in tumor tissue compared to normal tissue. The aim of the present study was to investigate the distribution and lifetime of nitroxides in tumor and normal tissues. Mice were implanted with tumor cells (RIF-1) in the thigh, and the tumor was allowed to grow to about 10-15 mm in diameter. After i.v. infusion of nitroxides, in vivo electron paramagnetic resonance spectroscopy and imaging of the tumor were performed using a specially built bridged-loop surface resonator. The pharmacokinetic and spatial distribution of the nitroxides in tumor tissue were followed and compared with those in normal tissue. Three-dimensional spatial images showed significant heterogeneity in the nitroxide distribution as well as reduction rates. The nitroxide reduction rates were significantly higher in tumors than in the normal tissue. Measurements using spin label oximetry showed a substantial difference in the level of oxygenation between normal tissue (muscle) and tumor tissue. Average pO2 levels in tumor tissue were found to be 3-fold lower than in a corresponding volume of normal tissue. The lower pO2 levels in tumor compared to normal tissue may explain the more rapid reduction of nitroxides in these tissues. This study demonstrates that electron paramagnetic resonance imaging can perform noninvasive anatomical as well as functional imaging and provide in vivo physiological information regarding cellular metabolism in tumor and normal tissues.

The protective effect of stable nitroxide radicals against oxidative damage was studied using cardiomyocyte cultures obtained from newborn rats. Monolayered cardiomyocytes were exposed to H2O2 and the effect on spontaneous beating and leakage of LDH was determined. Hydrogen peroxide irreversibly blocked rhythmic beating and resulted in a significant membrane injury as shown by release of LDH. The injury was prevented by catalase which removes H2O2 and by cell-permeable, metal-chelating agents such as desferrioxamine or bipyridine. In contrast, reagents which are excluded from the cell such as superoxide dismutase or DTPA did not protect the cells against H2O2. Five- and six-membered ring, stable nitroxide radicals which have previously been shown to chemically act as low-molecular weight, membrane-permeable, SOD-mimetic compounds provided full protection. The nitroxides prevented leakage of LDH and preserved normal cardiomyocyte contractility, presumably by intercepting intracellular O2-radicals. Alternatively, protection may result through nitroxides reacting with reduced transition metal ions or by detoxifying secondary organic radicals.

BACKGROUND AND OBJECTIVES: Interstitial photodynamic therapy (PDT) is an emerging modality for the treatment of solid organ disease. Our group at the University of Pennsylvania has performed extensive studies that demonstrate the feasibility of interstitial PDT for prostate cancer. Our preclinical and clinical experience is herein detailed. STUDY DESIGN/MATERIALS AND METHODS: We have treated 16 canines in preclinical studies, and 16 human subjects in a Phase I study, using motexafin lutetium-mediated PDT for recurrent prostate adenocarcinoma. Dosimetry of light fluence, drug level and oxygen distribution for these patients were performed. RESULTS: We demonstrate the safe and comprehensive treatment of the prostate using PDT. However, there is significant variability in the dose distribution and the subsequent tissue necrosis throughout the prostate. CONCLUSIONS: PDT is an attractive option for the treatment of prostate adenocarcinoma. However, the observed variation in PDT dose distribution translates into uncertain therapeutic reproducibility. Our future focus will be on the development of an integrated system that is able to both detect and compensate for dose variations in real-time, in order to deliver a consistent overall PDT dose distribution.