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Savak Teymoorian,1 E Randy Craven,2 Lannhi Nguyen,1 Erica Werts2 1Harvard Eye Associates, Laguna Hills, CA, USA; 2Allergan, an AbbVie company, Irvine, CA, USACorrespondence: Savak Teymoorian, Harvard Eye Associates, 23961 Calle de la Magdalena, Suite 300, Laguna Hills, CA, 92653, USA, Tel +1 (949) 951-2020, Email sev@powerupdoc.comPurpose: A sustained-release, biodegradable, intracameral 10-μg bimatoprost implant (Durysta) is approved for single administration per eye to lower intraocular pressure (IOP) in open-angle glaucoma (OAG) and ocular hypertension (OHT). The purpose of this study was to evaluate the IOP-lowering effectiveness and safety of a single implant administration per eye in patients with OAG or OHT in a real-world clinical setting.Methods: This was a retrospective, single-site study involving 105 consecutive adult patients with OAG or OHT treated with the bimatoprost implant in 1 or both eyes in routine clinical practice. Available medical records of the patients for 12 months or longer after the initial implant administration were reviewed, and data including IOP, IOP-lowering medication and procedure use, and safety outcomes were collected and analyzed. The analysis used ranges of follow-up because of the real-world setting.Results: The study included 197 eyes (85.3% diagnosed with OAG, 94.9% pseudophakic, and 83.8% with angle grade 4). IOP reduction was observed through 1 year after the bimatoprost implant administration. Mean IOP was 16.6 mmHg at baseline and 13.3 mmHg at 11– 13 months, with the mean number of topical IOP-lowering medications used reduced from 1.4 at baseline to 0.2 at 11– 13 months. IOP and IOP-lowering medication use were similarly reduced in eyes treated with both selective laser trabeculoplasty (SLT) and bimatoprost implant (including 66 eyes with their last SLT before implant administration and 28 eyes with their last SLT after implant administration). There were no cases of treatment-emergent corneal edema after bimatoprost implant administration, and no eye required implant removal.Conclusion: A single bimatoprost implant administration safely and effectively reduced IOP for up to 1 year and decreased the need for topical IOP-lowering medications in eyes with OAG or OHT with or without previous or subsequent SLT.Keywords: biodegradable implant, drug delivery system, intraocular injection, prostaglandin analog

Purpose: Intraoperative planning with transrectal ultrasound (US) is used for accurate seed placement and optimal dosimetry in prostate brachytherapy. However, prostate magnetic resonance imaging (MRI) has shown superiority in delineation of prostate anatomy. Accordingly, MRI/US fusion may be useful for accurate intraoperative planning. We analyzed planning with MRI/US fusion to compare differences in dosimetry and volume to that derived from the postoperative computed tomography (CT). Material and methods: Twenty patients underwent preoperative prostate MRI, which was fused intraoperatively with US during prostate brachytherapy. Intraoperative 125I or 103Pd seed placement was modified by the use of MRI fusion when indicated. Following implantation, dose comparisons were made between data derived from MRI/US and that from post-operative CT scans. Plan parameters analyzed included the D90 (dose to 90% of the prostate), rectal D30, V30 (volume of the rectum receiving 30 percent of dose), and prostate V100. Results: The median number of seeds implanted per patient was seventy-six. The MRI measured prostate volume, which was on average 4.47 cc larger than the CT measured prostate volume. In 9 patients, the apex of the prostate was better identified under MRI with the fusion protocol, and an average of 4 fewer seeds were required to be placed in the apex/urinary sphincter region. Both MRI and US individually showed a reduced intraoperative prostate D90 in comparison to the postoperative CT, with a larger mean difference for MRI in comparison with US (9.71 vs. 4.31 Gy, p = 0.007). This was also true for the prostate V100 (5.18 vs. 2.73 cc, p = 0.009). Post-operative CT underestimated rectal D30 and V30 in comparison to both MRI and US with MRI showing a larger mean difference than US for D30 (40.64 vs. 35.92 Gy, p = 0.04) and V30 (50.20 vs. 44.38 cc, p = 0.009). Conclusions: The MRI/US fusion demonstrated greater prostate volume compared to standard CT/US based planning likely due to the better resolution of the prostate apex. Furthermore, rectal dose was underestimated with CT vs. MRI based planning. Additional study is required to assess long-term clinical implications of disease control and effects on long-term toxicity, especially as related to the rectum and urinary sphincter. MRI/US intraoperative fusion may improve prostate dosimetry while sparing the rectum and urethra, potentially impacting disease control and late toxicity. [ABSTRACT FROM AUTHOR]

This patient case-study represents the introduction of radiotherapy in the management of extra-cranial vascular malformations, a topic with virtually no supported literature before our case study. In those patients refractory to established therapies and facing the inevitability of mutilating amputation, radiotherapy may be a viable option to preserve the limb. [ABSTRACT FROM PUBLISHER]

A dosimetric comparison was performed on external-beam three-dimensional conformal partial breast irradiation (PBI) and whole breast irradiation (WBI) plans for patients enrolled in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-39/Radiation Therapy Oncology Group (RTOG) 0413 protocol at our institution. Twenty-four consecutive patients were treated with either PBI (12 patients) or WBI (12 patients). In the PBI arm, the lumpectomy cavity was treated to a total dose of 38.5 Gy at 3.85 Gy per fraction twice daily using a four-field noncoplanar beam setup. A minimum 6 h interval was required between fractions. In the WBI arm, the whole breast including the entirety of the lumpectomy cavity was treated to a total dose of 50.4 Gy at 1.8 Gy per fraction daily using opposed tangential beams. The lumpectomy cavity volume, planning target volume for evaluation (PTV_EVAL), and critical structure volumes were contoured for both the PBI and WBI patients. Dosimetric parameters, dose volume histograms (DVHs), and generalized equivalent uniform dose (gEUD) for target and critical structures were compared. Dosimetric results show the PBI plans, compared to the WBI plans, have smaller hot spots in the PTV_EVAL (maximum dose: 104.2% versus 110.9%) and reduced dose to the ipsilateral breast (V50: 48.6% versus 92.1% and V100: 10.2% versus 50.5%), contralateral breast (V3: 0.16% versus 2.04%), ipsilateral lung (V30: 5.8% versus 12.7%), and thyroid (maximum dose: 0.5% versus 2.0%) with p values ≤0.01. However, similar dose coverage of the PTV_EVAL (98% for PBI and 99% for WBI, on average) was observed and the dose difference for other critical structures was clinically insignificant in both arms. The gEUD data analysis showed the reduction of dose to the ipsilateral breast and lung, contralateral breast and thyroid. In addition, preliminary dermatologic adverse event assessment data suggested reduced skin toxicity for patients treated with the PBI technique. [ABSTRACT FROM AUTHOR]

The article examines the efficiency of the Allegheny General Modification of the Harvard/NSABP/RTOG scoring scale in analyzing the outcome of the breast cancer treatment. It states that the modified scoring scale aims to reestablish a baseline in the previously treated breast and allow a meaningful and equivalent assessment of potential therapeutic change following retreatment.

Follicular cysitis is a proliferative benign lesion which can act locally malignant. Conservative management is best; however, when this fails, surgical resection is necessary up to and including cystectomy in extreme refractory cases. We present a clinical review and our results using radiation in this disease in a woman facing cystectomy. [ABSTRACT FROM AUTHOR]

Purpose: To investigate radiation dose to the heart in 60 patients with left-sided breast cancer who were treated with balloon-based high-dose-rate brachytherapy using MammoSite or Contura applicators. Methods and Materials: We studied 60 consecutive women with breast cancer who were treated with 34 Gy in 10 twice-daily fractions using MammoSite (n = 37) or Contura (n = 23) applicators. The whole heart and the left and right ventricles were retrospectively delineated, and dose–volume histograms were analyzed. Multiple dosimetrics were reported, such as mean dose (Dmean); relative volume receiving 1.7, 5, 10, and 20 Gy (V1.7, V5, V10, and V20, respectively); dose to 1 cc (D1cc); and maximum point dose (Dmax). Biologic metrics, biologically effective dose and generalized equivalent uniform dose were computed. The impact of lumpectomy cavity location on cardiac dose was investigated. Results: The average ± standard deviation of Dmean was 2.45 ± 0.94 Gy (range, 0.56–4.68) and 3.29 ± 1.28 Gy (range, 0.77–6.35) for the heart and the ventricles, respectively. The average whole heart V5 and V10 values were 10.2% and 1.3%, respectively, and the heart Dmax was >20 Gy in 7 of 60 (11.7%) patients and >25 Gy in 3 of 60 (5%) patients. No cardiac tissue received ≥30 Gy. The V1.7, V5, V10, V20, and Dmean values were all higher for the ventricles than for the whole heart. For balloons located in the upper inner quadrant of the breast, the average whole heart Dmean was highest. The Dmean, biologically effective dose, and generalized equivalent uniform dose values for heart and ventricles decreased with increasing minimal distance from the surface of the balloon. Conclusions: On the basis of these comprehensive cardiac dosimetric data, we recommend that cardiac dose be routinely reported and kept as low as possible in balloon-based high-dose-rate brachytherapy treatment planning for patients with left-sided breast cancer so the correlation with future cardiac toxicity data can be investigated. [ABSTRACT FROM AUTHOR]

Purpose: To update the Allegheny General Hospital experience of high-risk Stage I non–small-cell lung cancer patients treated with sublobar resection and intraoperative 125I Vicryl mesh brachytherapy. Methods and Materials: Between January 5, 1996 and February 19, 2008, 145 patients with Stage I non–small-cell lung cancer who were not lobectomy candidates because of cardiopulmonary compromise underwent sublobar resection and placement of 125I seeds along the resection line. The 125I seeds embedded in Vicryl suture were attached with surgical clips to a sheet of Vicryl mesh, inserted over the target area, and prescribed to a 0.5-cm planar margin. Results: The mean target area, total activity, number of seeds implanted, and prescribed total dose was 33.3 cm2 (range, 18.0–100.8), 20.2 mCi (range, 11.1–29.7), 46 (range, 30–100), and 117 Gy (range, 80–180), respectively. The median length of the surgical stay was 6 days (range, 1–111), with a perioperative mortality rate of 3.4%. At a median follow-up of 38.3 months (range, 1–133), 6 patients had developed local recurrence (4.1%), 9 had developed regional failure (6.2%), and 25 had distant failure (17.2%). On multivariate analysis, no patient- or tumor-specific factors or surgical or dosimetric factors were predictive of local recurrence. The overall median survival was 30.5 months with a 3- and 5-year overall survival rate of 65% and 35%, respectively. Conclusion: 125I brachytherapy for high-risk, Stage I non–small-cell lung cancer after sublobar resection is well tolerated and associated with a low local failure rate. [ABSTRACT FROM AUTHOR]

Purpose: Electron or photon boost immediately following whole-breast irradiation performed after conservation surgery for early-stage breast cancer is the accepted standard of care. This regimen frequently results in Grade III dermatitis, causing discomfort or treatment interruption. Herein, we compare patients treated with whole-breast irradiation followed by boost compared with a cohort with a planned intercurrent radiation boost. Methods and Materials: The records of 650 consecutive breast cancer patients treated at Allegheny General Hospital (AGH) between 2000 and 2008 were reviewed. Selected for this study were 327 patients with T1 or T2 tumors treated with external beam radiotherapy postlumpectomy. One hundred and sixty-nine patients were treated by whole-breast radiotherapy (WBRT) followed by boost at completion. One hundred fifty-eight were treated with a planned intercurrent boost (delivered following 3,600 cGy WBRT). The mean whole breast radiation dose in the conventionally treated group was 5,032 cGy (range, 4500–5400 cGy), and the mean whole breast dose was 5,097 cGy (range, 4860–5040 cGy) in the group treated with a planned intercurrent boost. Results: The occurrence of Grade III dermatitis was significantly reduced in the WBRT/intercurrent boost group compared with the WBRT/boost group (0.6% vs. 8.9%), as was the incidence of treatment interruption (1.9% vs. 14.2%). With a median follow-up of 32 months and 27 months, respectively, no significant difference in local control was identified. Conclusions: Patients treated with intercurrent boost developed less Grade III dermatitis and unplanned treatment interruptions with similar local control. [Copyright &y& Elsevier]

Introduction: This study evaluated the intraocular pressure (IOP)-lowering efficacy and safety of a single intracameral administration of bimatoprost implant 10 µg in adults with open-angle glaucoma or ocular hypertension., Methods: Two identically designed, randomized, 20-month, parallel-group, phase 3 clinical trials (one study eye/patient) compared three administrations of 10- or 15-µg bimatoprost implant (day 1, weeks 16 and 32) with twice-daily topical timolol maleate 0.5%. An open-label, 24-month, phase 1/2 clinical trial compared one or two implants administered in the study eye with once-daily topical bimatoprost 0.03% in the fellow eye. Separate analyses of the pooled phase 3 and phase 1/2 study datasets evaluated outcomes in the 10-µg bimatoprost implant and comparator treatment arms after a single implant administration, up to the time of implant re-administration or rescue with IOP-lowering medication., Results: In the phase 3 studies, 10-µg bimatoprost implant single administration demonstrated IOP reductions (hour 0) of 4.9-7.0 mmHg through week 15 from a mean (standard deviation, SD) baseline IOP of 24.5 (2.6) mmHg (n = 374); IOP in the topical timolol BID group was reduced by 6.0-6.3 mmHg from a mean (SD) baseline IOP of 24.5 (2.6) mmHg (n = 373). In the phase 1/2 study (n = 21), median time to use of additional IOP-lowering treatment (Kaplan-Meier analysis) was 273 days (approximately 9 months), and 5 of 21 enrolled patients (23.8%) required no additional IOP-lowering treatment up to 24 months after single administration. In each study, after a single implant administration there were no reports of corneal edema, corneal endothelial cell loss, or corneal touch, and no patients had 20% or greater loss in corneal endothelial cell density., Conclusions: Bimatoprost implant single administration lowers IOP and has a favorable safety profile. Additional studies are needed to further evaluate the duration of effect and factors predicting long-term IOP lowering after a single implant administration., Trial Registration Numbers: ClinicalTrials.gov NCT02247804, NCT02250651, and NCT01157364., (© 2022. The Author(s).)

Background: The 0.2 µg/day fluocinolone acetonide (FAc) implant delivers continuous, low-dose, intravitreal corticosteroid for the treatment of diabetic macular oedema (DMO). This ongoing, 3-year, observational clinical trial provides long-term, 'real-world' safety results for the FAc implant in DMO., Methods: This 24-month interim analysis of a prospective, observational study investigated patients with DMO receiving the commercially available intravitreal 0.2 µg/day FAc implant. The primary outcome was incidence of intraocular pressure (IOP)-lowering procedures. Other IOP-related signals and their relationship to previous corticosteroid exposure, best-corrected visual acuity, central subfield thickness (CST), ocular adverse events and frequency of other treatments were also measured., Results: Data were collected from 95 previously steroid-challenged patients (115 study eyes) for up to 36 months pre-FAc and 24 months post-FAc implant. Mean IOP for the overall population remained stable post-FAc compared with pre-FAc implant. IOP-related procedures remained infrequent (two IOP-lowering surgeries pre-FAc; two trabeculoplasties and four IOP-lowering surgeries post-FAc). Mean visual acuity was stable post-FAc (mean improvement of 1-3 letters) and fewer DMO treatments were required per year following FAc implant. Mean CST was significantly reduced at 24 months post-FAc implant (p<0.001) and the percentage of patients with CST ≤300 µm was significantly increased (p=0.041)., Conclusion: Few IOP-related procedures were reported during the 24 months post-FAc implant. Positive efficacy outcomes were noted after treatment, with stabilisation of vision and reduction in inflammation, demonstrated by CST. The FAc implant has a favourable benefit-risk profile in the management of DMO, especially when administered after a prior steroid challenge., Trial Registration Number: NCT02424019., Competing Interests: Competing interests: SEM has received clinical trial research funds from Alimera Sciences, Chengdu Kanghong Biotechnology, Clearside Biomedical and Genentech. DFK has received research support from Adverum, Alimera Sciences, Allergan, EyePoint and Graybug Pharmaceuticals, received consultant fees from Adverum, Alimera Sciences, Allergan, BVI, EyePoint, Genentech, Mallinckrodt, Notal Vision, Novartis, Physician Recommended Neutriceuticals and Regeneron, and participated in speakers bureau for Alimera Sciences, Allergan, EyePoint, Genentech, Mallinckrodt, Notal Vision, Physician Recommended Neutriceuticals, Regeneron and Spark Therapeutics. DBR has received personal fees from Alimera Sciences, Allergan and Genentech. DE has received personal fees from Alimera Sciences, Allergan, Clearside, EyePoint, Genentech, Gyroscope, Kodiak, Network Eye, Notal Vision, Novartis and Regeneron, received research support from Alimera Sciences, Allergan, Chengdu, Clearside, DORC, Genentech, Gyroscope, Kodiak NGM, Mylan, Network Eye, Novartis, Ophthotech, Ophthea and Recens Medical and received equity from Boston Image Reading Center, Hemera Biopharmaceuticals and US Retina. NMH has received research support from Gemini, Gyroscope, Roche and Genentech, received consultant fees from Acucela, Alimera Sciences, Allegro, Allergan, Clearside, Genentech, Katalyst, Lineage Cell Therapeutics, Notal Vision, Novartis, Regeneron, and Spark, and has patents and stock ownership with Katalyst. SK and EW are employees of Alimera Sciences., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To retrospectively compare radiation toxicity in patients treated with concurrent anastrozole and whole breast irradiation versus women treated sequentially with whole breast irradiation followed by hormonal suppression., Methods: The records of 249 consecutive estrogen or progesterone receptor positive breast cancer patients treated with breast-conserving surgery and postoperative whole breast irradiation were reviewed. Of total, 57 patients (the concurrent anastrozole group) received concurrent anastrozole prior to and during radiotherapy. In 126 patients (the sequential group), adjuvant hormone suppression therapy (anastrozole, other aromatase inhibitors, or tamoxifen) was administered after the completion of breast irradiation. In 66, women either concurrent tamoxifen was given with radiation or the sequence of hormonal therapy was not known. These women were excluded from the analysis., Results: The frequency of acute grade 2 radiation dermatitis (24.6% in the concurrent anastrozole group vs. 20.6% in the sequential group; P = 0.55), grade 3 radiation dermatitis (8.8% vs. 7.1%; P = 0.77) and treatment interruptions due to skin reactions (14.0% vs. 11.2%; P = 0.69) did not differ between groups. The rates of clinically detectable breast fibrosis were not different (24.2% vs. 24.7%; P = 0.97). With a median follow-up of 28 months and 30.8 months, respectively, 1 local failure occurred in the concurrent anastrozole group and 5 in the sequential group., Conclusions: Anastrozole, administered concurrently with whole breast irradiation, did not increase acute or late morbidity when compared with sequential administration of radiation and hormonal suppression therapy.

Objective: To compare tumor control and changes in audiometric parameters of acoustic neuroma patients treated with either linac-based stereotactic radiosurgery (SRS) or stereotactic radiotherapy (SRT) at Allegheny General Hospital., Study Design: Twenty-three patients with acoustic neuroma were treated between February 2003 and April 2009 with either SRS (n = 13) or SRT (n = 10). The median age for all patients was 69 years and the median size of lesions was 1.2 cm (range 0.5-2.2 cm). The prescribed dose was a single dose of 1250 cGy for all SRS patients compared to 2500 cGy in 5 daily fractions for SRT patients. All patients had pre- and post-procedure audiometry including hearing acuity assessed using pure tone average (PTA), speech discrimination score (SDS), and speech reception threshold (SR). The results of treatment type and tumor variables resulting in hearing degradation were evaluated and compared., Results: At a median follow-up of 13 months (range 3-36 months), only 1 of 13 patients treated with SRS and 2 of 10 patients treated with SRT develped progression of disease. However; all patients developed deterioration in PTA, SDS, or SR on the treated side. There were no statistically significant audiometric differences between patients treated with SRT or SRS and tumor response was similar regardless of irradiation technique., Conclusion: Both SRS and SRT provide excellent local control rates for the treatment of acoustic neuroma. While SRS demonstrated a trend toward worsening of SDS and the treatment of lesions >1.2 cm demonstrated a trend toward worsening of PTA, neither reached statistical significance. Our data suggest that single dose irradiation using the SRS technique should be considered primarily for patient convenience. All patients treated with radiotherapy for acoustic neuromas should undergo formal hearing testing before and after treatment.

The objective of this work is to evaluate the interfractional biological effective dose (BED) variation in MammoSite high dose rate (HDR) brachytherapy. Dose distributions of 19 patients who received 34 Gy in 10 fractions were evaluated. A method was employed to account for nonuniform dose distribution in the BED calculation. Furthermore, a range of alpha/beta values was utilized for specific clinical end points: fibrosis, telangiectasia, erythema, desquamation and breast carcinoma. Two scenarios were simulated to calculate the BED value using: i) the same dose distribution of fraction 1 over fractions 2-10 (constant case, CC), and ii) the actual delivered dose distribution for each fraction 1-10 (interfractiondose variation case, IVC). Although the average BED difference (IVC - CC) was < 0.7 Gy for all clinical endpoints, the range of difference for fibrosis and telangiectasia reached -11% to +3% and -9% to +9% for one of the patients, respectively. By disregarding high inhomogeneity in HDR brachytherapy, the conventional BED calculation tends to overestimate the BED for fibrosis by 16% on average, while it underestimates the BED for erythema (7.6%) and desquamation (10.2%). In conclusion, the BED calculation accounting for the nonuniform dose distribution provides a more clinically relevant description of the clinical delivered dose. Though the average BED difference was clinically insignificant, the maximum difference of BED for late effects can differ by a single fractional dose (10%) for a specific patient due to the interfraction dose variation in MammoSite treatment.

Ablation of neoplastic disease by freezing has found increasing utility as a potential therapeutic modality. To assess the effect of cooling temperatures on cellular radiation response, an established human cervical carcinoma cell line (HTB35) was subjected to holding temperatures of 0, 5, or 15 degrees C for up to 24 h before irradiation. Survival was measured by in vitro clonogenic assay of colonies containing at least 50 cells. Cooling for up to 12 h did not significantly decrease survival, but after 24 h survival fell to 75% of control cultures grown at 37 degrees C. X-irradiation immediately after cooling for 24 h resulted in 1.6-fold enhanced radiosensitivity. However, the radiosensitizing effect decayed rapidly if the cooled cells were returned to normal growth temperature for 6 h or longer before irradiation and subculture. Both temperature and cooling duration influenced the radiation response. With 0, 5, or 15 degrees C, radiosensitivity increased after 3, 6, or 12 h, respectively, and progressively rose with up to 24 h of cooling. By flow cytometric analysis, no statistically significant difference was observed in the S-phase fraction between control cells and those cooled to 0 degree C for 24 h. These data demonstrate cooling-enhanced in vitro radiation sensitivity which is dependent upon cooling temperature, duration, and rewarming interval before irradiation. While cell cycle redistribution does not appear to be a factor in the increased radiosensitivity, differences in the radiation survival curves between cooled versus normothermic cells suggest that diminished capacity for sublethal damage repair may be a significant influence on the changes which were observed.

Purpose: Multifraction irradiation may contribute to radiation therapy treatment failure if selection of radiation resistant subpopulations occurs. We sought to determine whether surviving cells following daily fraction irradiation of two human cervical squamous cell carcinoma lines would express different radiation survival characteristics compared to the unirradiated parent., Methods and Materials: A late-passage line (HTB35) and an early-passage line (RECA) received daily 2 Gy x-irradiation. Two new stable HTB35 cell lines were established after 40 and 60 Gy (HTB35-40 and HTB35-60). A single line was established from RECA after 30 Gy (RECA-30). High dose rate (74 cGy/min) acute radiation survival curves were prepared from the three new lines and the unirradiated parents. Potentially lethal damage repair (PLDR) and sublethal damage repair (SLDR) responses were detailed for HTB35, HTB35-40 and HTB35-60. Low dose rate (1.27 cGy/min) survival was measured for HTB35 and HTB35-60. Clones were derived from HTB35 and from HTB35-60 and the surviving fraction at 2 Gy (SF2) values were determined., Results: The two parent lines (HTB35 and RECA) differed in acute radiation survival. The surviving lines following multifraction irradiation (HTB35-40, HTB35-60, and RECA-30) showed no change in acute radiation response compared to the appropriate parent. HTB35-40 and HTB35-60 were repair proficient, demonstrating similar PLDR and SLDR recovery ratios as the parent. Likewise, acute, low dose rate survival of HTB35 and HTB35-60 was similar. Nine clones derived from HTB35 lacked a consistent difference in SF2 compared to the original culture. A single clone of seven derived from HTB35-60 was consistently radiation resistant (SF2 = 0.81 +/- 0.06) compared to the original culture (SF2 = 0.50 +/- 0.09)., Conclusion: No evidence was obtained that cell lines generated following multiple daily fractions of x-irradiation in vitro possessed acute radiation survival or repair characteristics that were different from the unirradiated parent.

Our previous studies suggested that a defect in the hemopoietic microenvironment of bone marrow occurred in the anemia of chronic inflammatory disease. We examined the in vivo hemopoietic and marrow stromal cell (MSC) response of shielded marrow to 5000 rad leg-irradiation (5000 rad LI), the in vitro growth of BFUE, CFUE, and CFUC in co-culture with MSC, and the in vitro characteristics of MSC. One month after 5000 rad LI, erythroblasts and MSC fell to 18% and 26% respectively. BFUE and CFUE in shielded marrow increased 1.5 to 2 times. Total CFUS and CFUC were normal. In co-culture, small numbers of MSC enhanced BFUE and CFUE, but suppressed CFUC. MSC in colonies were polygonal cells with a plating efficiency of 10 per 10(6) nucleated marrow cells and 1 per 10(6) spleen or nucleated blood cells. MSC were not phagocytic and did not stain with nonspecific esterase. We conclude that in mice with an inflammatory response to 5000 rad LI: 1) Erythroblasts and MSC decreased while erythroid progenitors (BFUE and CFUE) increased in the shielded marrow, 2) MSC stimulated BFUE and CFUE in co-culture, 3) MSC in colonies were adherent, large polygonal cells that may enhance erythroid maturation in the bone marrow.

Hemopoietic insufficiency resulting from single or multiple agents used in cancer therapy often becomes a dose limiting toxicity. Since hyperthermia is finding increased clinical application with whole body or extended field treatments for a variety of neoplastic diseases, we wished to examine its potential effects on normal bone marrow. One hind leg of anesthetized mice received up to one hour water bath heating to 41-44 degrees C. With temperatures of 42 degrees C or greater, there was a dose and heating time dependent initial depletion of both CFU-S and CFU-GM that was not appreciably affected by migration of stem cells to or from the heated field. CFU-S and CFU-GM returned to normal values by 2 to 3 weeks after 1 hour heating to 42 degrees C. However, at 43 degrees or 44 degrees C for 1 hour, CFU-GM only transiently returned to normal, falling to 55% and 33% of control respectively by 3 months. Total nucleated cell counts reflected a similar dose and time dependent depletion and repopulation. Finally, bone marrow differential counts from heated marrow suggested that equivalent repopulation along each differentiation pathway occurred during recovery after thermal injury. These data indicate that temperatures greater than 42 degrees C for one hour caused a long term delay in hemopoietic repopulation, which may contribute to a significant toxicity when hyperthermia is used in combination with chemotherapeutic drugs or local irradiation incorporating the same treatment field.

Increasing evidence suggests a role for reactive free radical oxygen species in the multi-stage events of chemical carcinogenesis. We hypothesized that variations in the level of superoxide dismutase (SOD), a major endogenous antioxidant enzyme, may account in part for variations in susceptibility to cancer induced by polycyclic aromatic hydrocarbons (PAH). The SOD activity of mammary epithelial cells from rats with varying susceptibility to dimethylbenz[a]anthracene (DMBA)-induced breast cancer was assayed. Ageing, pregnancy and previous multiple pregnancies reduce susceptibility of Sprague--Dawley female rats to DMBA. These decreases in susceptibility were correlated with increased levels of SOD activity. Only minor differences in SOD activity was observed in mammary epithelium of genetic strains of rats with differences in susceptibility to DMBA. These data suggest that, in models where physiological differences may account for variations in effectiveness of PAH to induce mammary cancer, SOD activity is inversely correlated with breast cancer susceptibility and support the hypothesis that cancer susceptibility may be partially mediated through reactive free radical oxygen intermediates.