Computational modeling of nanoscale and microscale particle deposition, retention and dosimetry in the mouse respiratory tract.

Comparing effects of inhaled particles across rodent test systems and between rodent test systems and humans is a key obstacle to the interpretation of common toxicological test systems for human risk assessment. These comparisons, correlation with effects and prediction of effects, are best conducted using measures of tissue dose in the respiratory tract. Differences in lung geometry, physiology and the characteristics of ventilation can give rise to differences in the regional deposition of particles in the lung in these species. Differences in regional lung tissue doses cannot currently be measured experimentally. Regional lung tissue dosimetry can however be predicted using models developed for rats, monkeys, and humans. A computational model of particle respiratory tract deposition and clearance was developed for BALB/c and B6C3F1 mice, creating a cross-species suite of available models for particle dosimetry in the lung. Airflow and particle transport equations were solved throughout the respiratory tract of these mice strains to obtain temporal and spatial concentration of inhaled particles from which deposition fractions were determined. Particle inhalability (Inhalable fraction, IF) and upper respiratory tract (URT) deposition were directly related to particle diffusive and inertial properties. Measurements of the retained mass at several post-exposure times following exposure to iron oxide nanoparticles, micro- and nanoscale C60 fullerene, and nanoscale silver particles were used to calibrate and verify model predictions of total lung dose. Interstrain (mice) and interspecies (mouse, rat and human) differences in particle inhalability, fractional deposition and tissue dosimetry are described for ultrafine, fine and coarse particles.

Outcome for surgically staged localized prostate cancer treated with external beam radiation therapy.

PURPOSE: A retrospective analysis was performed on patients with surgically staged localized prostate cancer treated with external beam radiation therapy for 10-year overall, cause specific and disease-free survivals based on lack of clinical recurrence and 2 separate prostate specific antigen criteria for cure. MATERIALS AND METHODS: We analyzed 145 patients who received external beam radiation therapy after a negative staging pelvic lymphadenectomy for prostate cancer. Followup data were available for 129 patients (90%). Disease was stage A in 29 patients (22.5%), stage B in 64 (49.6%), stage B2/C in 2 (17%) and stage C in 14 (10.9%). Average potential followup from date of diagnosis was 11.5 years (minimum 7.2). Of the patients 87 potentially can be followed for longer than 10 years. Disease-free survival was based on a normal digital rectal examination, lack of symptoms suspicious for metastasis and application of 2 separate prostate specific antigen criteria of 4 ng./ml. or less (group 1), or 1.5 ng./ml. or less (group 2). Survival was analyzed with the Kaplan-Meier actuarial method. RESULTS: Actuarial overall survival at 10 and 15 years was 63.7 and 49.6, respectively, and cause specific survival was 84.2 and 80%, respectively. Disease-free survival was 54.5 and 32.4%, respectively, for group 1, and 42.3 and 9.6%, respectively, for group 2. CONCLUSIONS: The improved patient selection inherent in surgical staging before definitive external beam radiation therapy provides for improved overall and cause specific survival over that of patients without surgical staging. Biochemical disease-free survival also appears to be improved.

T1 breast carcinoma in women 70 years of age and older may not require axillary lymph node dissection.

BACKGROUND: The current trend in breast cancer treatment is toward breast conservation and selective use of axillary lymph node dissection. Patient eligibility criteria for treatment without axillary dissection are evolving. METHODS: We retrospectively reviewed the tumor registry over a 10-year period at Naval Medical Center San Diego and included all women aged 70 and older with T1 breast carcinoma (n = 78). Data included tumor size, surgical therapy, post-operative therapy, recurrence, and survival. The women were divided into groups by the approach taken toward the axilla. RESULTS: No patient was given adjuvant chemotherapy. There were no axillary cancer recurrences in our patients. No statistically significant difference existed, regardless of the approach to the axilla, in recurrence or survival between groups. CONCLUSION: Axillary dissection in this population did not influence postoperative treatment, decrease recurrence, or improve survival. Our study suggests breast cancer treatment in this population should not include axillary dissection.

Grading inaccuracies in diagnostic biopsies revealing prostatic adenocarcinoma: implications for definitive radiation therapy.

PURPOSE: A critical determinant of prognosis in prostate cancer is grade of disease. Historically, this has been determined by biopsy of the prostate using transperineal, transrectal, or transurethral approaches. Several reports in the literature reveal that these biopsies often underestimate the histologic grade of the tumor when compared with subsequent radical prostatectomy specimens. METHODS AND MATERIALS: Data from the literature were analyzed to assess the magnitude of this bias towards undergrading. Grade of biopsy specimens (well-differentiated = Gleason score 2-4; moderately differentiated = Gleason 5-7; poorly differentiated = Gleason 8-10) were correlated with the ultimate prostatectomy grade. Analysis was made of tendency to undergrade specimens using strict criteria of data inclusion for needle biopsies, and more relaxed criteria for all types of prostate biopsies. RESULTS: Grading accuracy from needle biopsies was 71%, with 23% undergraded and 6% overgraded. A chi-square test on equal chance of under- vs. overgrading yielded p = 0.022. Grading accuracy from needle, open perineal, and transurethral biopsies was 65%, with 23% undergraded and 12% overgraded. A similar chi-square test yielded p = 0.007. In both cases, there appears to exist a significant bias towards undergrading. CONCLUSIONS: In addition to other well-documented factors that confound comparisons between radiation therapy and surgical series in carcinoma of the prostate, grade migration exists as well. The equivalence of radiation therapy and surgery with respect to overall survival in this disease is accomplished despite these biases.

Enhancement of heme oxygenase-1 synthesis by glutathione depletion in Chinese hamster ovary cells.

Chinese hamster ovary cells cultured in vitro were used to assess the role of glutathione metabolism in the induction of the 32-kDa stress protein. Enhanced synthesis of the 32-kDa protein was observed after cells were incubated with CdCl2 or diethylmaleate and protein was subjected to SDS-PAGE followed by fluorography. Concomitantly, in both cell preparations an increase in heme oxygenase activity was observed. Proteins from CdCl2- and diethylmaleate-treated cells were subjected to Western blotting and protein crossreacting with either rabbit antibody to rat liver heme oxygenase-1 (32,000 Mr) or rat testis heme oxygenase-2 (36,000 Mr) quantitated. The analysis indicated that the CdCl2 treatment increased the intensity of the HO-1 band 5.5-fold while the diethylmaleate treatment increased it three-fold relative to control. Neither treatment affected the intensity of HO-2 antibody binding. Incubation of cells with buthionine sulfoximine, under conditions which resulted in greater than or equal to 90% of the intracellular glutathione being depleted, enhanced synthesis of a 32-kDa protein when assayed by SDS-PAGE. This protein exhibited a Mr similar to the 32-kDa protein induced by either CdCl2 or diethylmaleate treatment. Proteins from buthionine sulfoximine and diethylmaleate-treated cells were mixed together and subjected to 2D PAGE. The resulting fluorograph demonstrated that both treatments produced identical patterns. In contrast, incubation of cells in diamide, a thiol oxidizing compound, resulted in enhanced synthesis of the 110-, 90-, and 73-kDa heat shock proteins but not the 32-kDa protein. The data presented have shown that depletion of glutathione by two independent methods, conjugation and inhibition of synthesis, enhances the synthesis of a 32-kDa protein identified as heme oxygenase-1; oxidation of glutathione, on the other hand did not. We interpret this to indicate that glutathione depletion rather than conjugation or oxidation represents one pathway for induction of heme oxygenase-1.

Depletion of glutathione after gamma irradiation modifies survival.

The relationship between the intracellular glutathione (GSH) concentration and the aerobic radiation response was studied in Chinese hamster ovary cells. Various degrees of GSH depletion were produced by exposure to buthionine sulfoximine (BSO) and/or diethyl maleate (DEM). Diethyl maleate did not act as a classical radiosensitizer under the experimental conditions employed, nor did exposure to DEM/BSO nonspecifically affect protein thiols as measured by thiol blotting. Dose-response curves were obtained using cells irradiated in the absence or presence of DEM/BSO, which decreased GSH levels by 90-95%. Exposure to DEM/BSO did not affect the formation of DNA single-strand breaks or DNA-protein crosslinks measured immediately after irradiation performed at ice temperatures. Analysis of survival curves indicated that the Dq was decreased by 18% when GSH depletion occurred prior to, during, and after irradiation. The DEM/BSO exposure did not affect D0. To study postirradiation conditions, cells were exposed to 10 microM DEM prior to and during irradiation, which was performed at ice temperatures. Levels of GSH were depleted by 75% by this protocol. Immediately after irradiation, the cells were rapidly warmed by the addition of 37 degrees C growth medium containing either 10 or 90 microM DEM. Addition of 10 microM DEM after irradiation did not affect the degree of depletion, which remained constant at 75%. In contrast, GSH depletion was increased to 90% 10 min after addition of the 90 microM DEM. Addition of 90 microM DEM after irradiation produced a statistically significant difference in survival compared to addition of 10 microM DEM. In a second depletion protocol, cells were exposed to 100 microM DEM at room temperature for 5 min, irradiated, incubated at 37 degrees C for 1 h, washed, and then incubated in 50 microM BSO for 24 h. This depletion protocol reduced survival by a factor of 2.6 compared to cells not exposed to the combination of DEM/BSO. Survival was not affected if the cells were exposed to the DEM or BSO alone. This was interpreted to indicate that survival was not affected by GSH depletion occurring after irradiation unless depletion was rapid and sustained. The rate of repair of sublethal and potentially lethal damage was measured and found to be independent of the DEM/BSO exposure. These experimental results in addition to previous ones (Freeman and Meredith, Int. J. Radiat. Oncol. Biol. Phys. 13, 1371-1375, 1987) were interpreted to indicate that under aerobic conditions GSH depletion may alter the expression of radiation damage by affecting metabolic fixation.