Barry S. Rosenstein, Ph.D.

Introduction to radiation safety and monitoring
Cuaron, John J; Hirsch, Ariel E; Medich, David C; Hirsch, Joshua A; Rosenstein, Barry S
2011 Apr;8(4):259-264, Journal of the American College of Radiology : JACR
Ionizing radiation is used in diagnostic imaging, external-beam radiation therapy, brachytherapy, and nuclear medicine to diagnose and treat a number of common conditions. To ensure the safety of patients, providers, and surrounding staff members, it is important that the health care community become familiar with the terminology, common equipment, and standard practices used in radiation safety and monitoring. The authors aim to provide an introduction to radiation safety and monitoring so that health care providers and support personnel who may have contact with patients, equipment, and facilities that use radioactive material may be more aware of the policies and precautions that are in place to ensure their safety
— id: 143376, year: 2011, vol: 8, page: 259, stat: Journal Article,

Identification of SNPs associated with susceptibility for development of adverse reactions to radiotherapy
Rosenstein, Barry S
2011 Feb;12(2):267-275, Pharmacogenomics
Although cancer treatment with radiation can produce high cure rates, adverse effects often result from radiotherapy. These toxicities are manifested as damage to normal tissues and organs in the radiation field. In recognition of the substantial variation in the intrinsic response of individuals to radiation, an effort began approximately 10 years ago to discover the genetic markers, primarily SNPs, which are associated with susceptibility for the development of these adverse responses to radiation therapy. The goal of this research is to identify the SNPs that could serve as the basis of an assay to predict which cancer patients are most likely to develop complications resulting from radiotherapy. This would permit personalization and optimization of the treatment plan for each cancer patient
— id: 143378, year: 2011, vol: 12, page: 267, stat: Journal Article,

Influence of pretreatment and treatment factors on intermediate to long-term outcome after prostate brachytherapy
Stone, Nelson N; Stone, Mariana M; Rosenstein, Barry S; Unger, Pam; Stock, Richard G
2011 Feb;185(2):495-500, Journal of urology
PURPOSE: We describe how treatment factors influence biochemical freedom from failure, local control, freedom from metastasis and cause specific survival in patients treated with prostate brachytherapy. MATERIALS AND METHODS: We followed 2,111 men who underwent brachytherapy a median of 6 years (range 2 to 17). Median prostate specific antigen was 7 ng/ml. Of the men 1,455 (68.9%) had clinical stage T2a or less and 1,428 (67.6%) had Gleason score less than 7. A total of 1,171 patients (55.5%) received (125)I, 221 (10.4%) received (103)Pd and 719 (34.1%) received supplemental external beam irradiation combined with (103)Pd. Post-implant dosimetry was done 30 days after implantation with doses converted to the biologically effective dose. Prostate biopsy was done 2 years after permanent prostate brachytherapy in 586 men (27.8%). Survival functions were determined by the Kaplan-Meier method and Cox regression with proportions tested by the log rank test. RESULTS: The 12-year biochemical freedom from failure rate was 78.6%, and stage, Gleason score, prostate specific antigen and biologically effective dose were significant predictors (p = 0.007, <0.001, 0.005 and <0.001, respectively). In 964 patients at low risk the biochemical freedom from failure rate was 88.1% and significant predictors were hormonal therapy (p = 0.030), prostate specific antigen (p = 0.026) and biologically effective dose (p = 0.003). In 499 patients at intermediate risk the biochemical freedom from failure rate was 79.2% with biologically effective dose a significant predictor (p <0.001). In 648 men at high risk the biochemical freedom from failure rate was 67% and significant predictors were hormonal therapy, Gleason score and biologically effective dose (p = 0.036, <0.001 and 0.012, respectively). The local failure rate was 7.3% with biologically effective dose a significant predictor (p <0.001). Prostate biopsy was positive in 21 of 121 cases (21.5%) for a biologically effective dose of 150 Gy2 or less, in 14 of 248 (5.6%) for greater than 150 to 200 Gy2 and in 3 of 193 (1.6%) for greater than 200 Gy2 (p <0.001). The 12-year freedom from metastasis rate was 95.2% with Gleason score a significant predictor (p <0.001). Cause specific survival at 12 years was 94.5% with Gleason score and biologically effective dose significant predictors (p <0.001 and 0.027, respectively). CONCLUSIONS: Permanent prostate brachytherapy yields excellent long-term oncologic outcomes. High biologically effective dose may need to be delivered to achieve successful biochemical freedom from failure, local control and cause specific survival
— id: 143377, year: 2011, vol: 185, page: 495, stat: Journal Article,

Biomarkers and surrogate endpoints for normal-tissue effects of radiation therapy: the importance of dose-volume effects
Bentzen, Soren M; Parliament, Matthew; Deasy, Joseph O; Dicker, Adam; Curran, Walter J; Williams, Jacqueline P; Rosenstein, Barry S
2010 Mar 1;76(3 Suppl):S145-S150, International journal of radiation oncology biology physics
Biomarkers are of interest for predicting or monitoring normal tissue toxicity of radiation therapy. Advances in molecular radiobiology provide novel leads in the search for normal tissue biomarkers with sufficient sensitivity and specificity to become clinically useful. This article reviews examples of studies of biomarkers as predictive markers, as response markers, or as surrogate endpoints for radiation side effects. Single nucleotide polymorphisms are briefly discussed in the context of candidate gene and genomewide association studies. The importance of adjusting for radiation dose distribution in normal tissue biomarker studies is underlined. Finally, research priorities in this field are identified and discussed
— id: 143380, year: 2010, vol: 76, page: S145, stat: Journal Article,

Radiation exposure, the ATM Gene, and contralateral breast cancer in the women's environmental cancer and radiation epidemiology study
Bernstein, Jonine L; Haile, Robert W; Stovall, Marilyn; Boice, John D Jr; Shore, Roy E; Langholz, Bryan; Thomas, Duncan C; Bernstein, Leslie; Lynch, Charles F; Olsen, Jorgen H; Malone, Kathleen E; Mellemkjaer, Lene; Borresen-Dale, Anne-Lise; Rosenstein, Barry S; Teraoka, Sharon N; Diep, Anh T; Smith, Susan A; Capanu, Marinela; Reiner, Anne S; Liang, Xiaolin; Gatti, Richard A; Concannon, Patrick
2010 Apr 7;102(7):475-483, Journal of the National Cancer Institute
BACKGROUND: Ionizing radiation is a known mutagen and an established breast carcinogen. The ATM gene is a key regulator of cellular responses to the DNA damage induced by ionizing radiation. We investigated whether genetic variants in ATM play a clinically significant role in radiation-induced contralateral breast cancer in women. METHODS: The Women's Environmental, Cancer, and Radiation Epidemiology Study is an international population-based case-control study nested within a cohort of 52,536 survivors of unilateral breast cancer diagnosed between 1985 and 2000. The 708 case subjects were women with contralateral breast cancer, and the 1397 control subjects were women with unilateral breast cancer matched to the case subjects on age, follow-up time, registry reporting region, and race and/or ethnicity. All women were interviewed and underwent full mutation screening of the entire ATM gene. Complete medical treatment history information was collected, and for all women who received radiotherapy, the radiation dose to the contralateral breast was reconstructed using radiotherapy records and radiation measurements. Rate ratios (RRs) and corresponding 95% confidence intervals (CIs) were estimated by using multivariable conditional logistic regression. All P values are two-sided. RESULTS: Among women who carried a rare ATM missense variant (ie, one carried by <1% of the study participants) that was predicted to be deleterious, those who were exposed to radiation (mean radiation exposure = 1.2 Gy, SD = 0.7) had a statistically significantly higher risk of contralateral breast cancer compared with unexposed women who carried the wild-type genotype (0.01-0.99 Gy: RR = 2.8, 95% CI = 1.2 to 6.5; > or =1.0 Gy: RR = 3.3, 95% CI = 1.4 to 8.0) or compared with unexposed women who carried the same predicted deleterious missense variant (0.01-0.99 Gy: RR = 5.3, 95% CI = 1.6 to 17.3; > or =1.0 Gy: RR = 5.8, 95% CI = 1.8 to 19.0; P(trend) = .044). CONCLUSIONS: Women who carry rare deleterious ATM missense variants and who are treated with radiation may have an elevated risk of developing contralateral breast cancer. However, the rarity of these deleterious missense variants in human populations implies that ATM mutations could account for only a small portion of second primary breast cancers
— id: 133494, year: 2010, vol: 102, page: 475, stat: Journal Article,

Genome-Wide Association Study to Identify Single Nucleotide Polymorphisms (SNPs) Associated With the Development of Erectile Dysfunction in African-American Men After Radiotherapy for Prostate Cancer
Kerns, Sarah L; Ostrer, Harry; Stock, Richard; Li, William; Moore, Julian; Pearlman, Alexander; Campbell, Christopher; Shao, Yongzhao; Stone, Nelson; Kusnetz, Lynda; Rosenstein, Barry S
2010 Dec 1;78(5):1292-1300, International journal of radiation oncology biology physics
PURPOSE: To identify single nucleotide polymorphisms (SNPs) associated with erectile dysfunction (ED) among African-American prostate cancer patients treated with external beam radiation therapy. METHODS AND MATERIALS: A cohort of African-American prostate cancer patients treated with external beam radiation therapy was observed for the development of ED by use of the five-item Sexual Health Inventory for Men (SHIM) questionnaire. Final analysis included 27 cases (post-treatment SHIM score </=7) and 52 control subjects (post-treatment SHIM score >/=16). A genome-wide association study was performed using approximately 909,000 SNPs genotyped on Affymetrix 6.0 arrays (Affymetrix, Santa Clara, CA). RESULTS: We identified SNP rs2268363, located in the follicle-stimulating hormone receptor (FSHR) gene, as significantly associated with ED after correcting for multiple comparisons (unadjusted p = 5.46 x 10(-8), Bonferroni p = 0.028). We identified four additional SNPs that tended toward a significant association with an unadjusted p value < 10(-6). Inference of population substructure showed that cases had a higher proportion of African ancestry than control subjects (77% vs. 60%, p = 0.005). A multivariate logistic regression model that incorporated estimated ancestry and four of the top-ranked SNPs was a more accurate classifier of ED than a model that included only clinical variables. CONCLUSIONS: To our knowledge, this is the first genome-wide association study to identify SNPs associated with adverse effects resulting from radiotherapy. It is important to note that the SNP that proved to be significantly associated with ED is located within a gene whose encoded product plays a role in male gonad development and function. Another key finding of this project is that the four SNPs most strongly associated with ED were specific to persons of African ancestry and would therefore not have been identified had a cohort of European ancestry been screened. This study demonstrates the feasibility of a genome-wide approach to investigate genetic predisposition to radiation injury
— id: 114802, year: 2010, vol: 78, page: 1292, stat: Journal Article,

Establishment of a radiogenomics consortium
West, Catharine; Rosenstein, Barry S
2010 Jan;94(1):117-118, Radiotherapy & oncology
— id: 143381, year: 2010, vol: 94, page: 117, stat: Journal Article,

Establishment of a Radiogenomics Consortium
West, Catharine; Rosenstein, Barry S; Alsner, Jan; Azria, David; Barnett, Gillian; Begg, Adrian; Bentzen, Soren; Burnet, Neil; Chang-Claude, Jenny; Chuang, Eric; Coles, Charlotte; De Ruyck, Kim; De Ruysscher, Dirk; Dunning, Alison; Elliott, Rebecca; Fachal, Laura; Hall, Janet; Haustermans, Karin; Herskind, Carsten; Hoelscher, Tobias; Imai, Takashi; Iwakawa, Mayumi; Jones, Don; Kulich, Cecilia; Langendijk, Jan-Hans; O'Neils, Peter; Ozsahin, Mahmut; Parliament, Matthew; Polanski, Andrzej; Rosenstein, Barry; Seminara, Daniela; Symonds, Paul; Talbot, Chris; Thierens, Hubert; Vega, Ana; West, Catherine; Yarnold, John
2010 Apr;76(5):1295-1296, International journal of radiation oncology biology physics
— id: 143379, year: 2010, vol: 76, page: 1295, stat: Journal Article,

Polymethylmethacrylate and radioisotopes in vertebral augmentation: an explanation of underlying principles
Hirsch, Ariel E; Rosenstein, Barry S; Medich, David C; Martel, Christopher B; Hirsch, Joshua A
2009 Sep-Oct;12(5):887-891, Pain Physician
We recently reported a novel concept for combining radioactive isotope technology with polymethylmethacrylate (PMMA) cement used for vertebral augmentation and have advocated that pain physicians become aware of this new concept when treating malignant compression fractures. The use of vertebral augmentation for malignant compression fractures is steadily increasing, and the goal of this novel approach would be to stabilize the fractured vertebral body while also controlling proliferation of the tumor cells in the vertebral body that caused the vertebral fracture. This approach would therefore provide mechanical stabilization of the fractured vertebral body at the same time as direct targeting of the cancer cells causing the fracture. For our analysis, we investigated six specific radioisotopes with regard to physical and biologic properties as they would interact with PMMA and local bone metastatic disease, taking into consideration anatomical, biological and physical characteristics. The radioisotopes investigated include beta emitting (plus and minus) sources, as well as low energy and mid-energy photon sources and are: P-32, Ho-166, Y-90, I-125, F-18, and Tc-99m. We review the advantages and disadvantages of each radioisotope. In addition, this paper serves to provide pain physicians with a basic background of the biologic principles (Biologically Effective Dose) and statistical modeling (Monte Carlo method) used in that analysis. We also review the potential complications when using radioactive sources in a clinical setting. Understanding the methodologies employed in determining isotope selection empowers the practitioner by fostering understanding of this presently theoretical treatment option. We believe that embedding radioisotopes in PMMA is merely a first step in the road of local treatment for symptomatic local lesions in the setting of systemic disease
— id: 143383, year: 2009, vol: 12, page: 887, stat: Journal Article,

Development of an automated gamma-H2AX immunocytochemistry assay
Hou, Yen-Nien; Lavaf, Amir; Huang, Delphine; Peters, Sheila; Huq, Rumana; Friedrich, Victor; Rosenstein, Barry S; Kao, Johnny
2009 Mar;171(3):360-367, Radiation research
gamma-H2AX is emerging as an important marker of ionizing radiation-induced double-strand breaks. Development of a significantly automated method to quantify gamma-H2AX would have broad application in assessing physiological responses to radiation exposure. PC-3 and DU145 prostate cancer cells grown on glass cover slips and 96-well plates were irradiated and assessed for gamma-H2AX focus formation by immunofluorescence analysis. The gamma-H2AX immunofluorescence staining was performed either manually or by using a preprogrammed automated robotic liquid handling system. A computer-controlled charge-coupled device camera acquired images serially throughout the thickness of each cell. Image analysis was performed manually and/or with automated image segmentation software. A robust relationship between radiation dose and gamma-H2AX focus numbers was demonstrated with both manual and automated image analysis methods, with excellent agreement observed between the two techniques. The r(2) correlation coefficients and Z factors exceeded 0.9 and 0.5, respectively, when gamma-H2AX focus formation was correlated with radiation dose using the automated technique. Inhibition of gamma-H2AX foci by drugs readily detected with this assay. Robotic specimen preparation with automated image acquisition and analysis can be used to quantify gamma-H2AX foci in irradiated cells, and the results agree well those obtained by manual counts. These data suggest that this assay has an excellent signal-to-noise ratio and is suitable for high-throughput applications
— id: 143384, year: 2009, vol: 171, page: 360, stat: Journal Article,

American Society for Radiation Oncology (ASTRO) survey of radiation biology educators in U.S. and Canadian radiation oncology residency programs
Rosenstein, Barry S; Held, Kathryn D; Rockwell, Sara; Williams, Jacqueline P; Zeman, Elaine M
2009 Nov 1;75(3):896-905, International journal of radiation oncology biology physics
PURPOSE: To obtain, in a survey-based study, detailed information on the faculty currently responsible for teaching radiation biology courses to radiation oncology residents in the United States and Canada. METHODS AND MATERIALS: In March-December 2007 a survey questionnaire was sent to faculty having primary responsibility for teaching radiation biology to residents in 93 radiation oncology residency programs in the United States and Canada. RESULTS: The responses to this survey document the aging of the faculty who have primary responsibility for teaching radiation biology to radiation oncology residents. The survey found a dramatic decline with time in the percentage of educators whose graduate training was in radiation biology. A significant number of the educators responsible for teaching radiation biology were not fully acquainted with the radiation sciences, either through training or practical application. In addition, many were unfamiliar with some of the organizations setting policies and requirements for resident education. Freely available tools, such as the American Society for Radiation Oncology (ASTRO) Radiation and Cancer Biology Practice Examination and Study Guides, were widely used by residents and educators. Consolidation of resident courses or use of a national radiation biology review course was viewed as unlikely by most programs. CONCLUSIONS: A high priority should be given to the development of comprehensive teaching tools to assist those individuals who have responsibility for teaching radiation biology courses but who do not have an extensive background in critical areas of radiobiology related to radiation oncology. These findings also suggest a need for new graduate programs in radiobiology
— id: 143382, year: 2009, vol: 75, page: 896, stat: Journal Article,

Single nucleotide polymorphisms, apoptosis, and the development of severe late adverse effects after radiotherapy
Azria, David; Ozsahin, Mahmut; Kramar, Andrew; Peters, Sheila; Atencio, David P; Crompton, Nigel E A; Mornex, Francoise; Pelegrin, Andre; Dubois, Jean-Bernard; Mirimanoff, Rene-Olivier; Rosenstein, Barry S
2008 Oct 1;14(19):6284-6288, Clinical cancer research
PURPOSE: Evidence has accumulated in recent years suggestive of a genetic basis for a susceptibility to the development of radiation injury after cancer radiotherapy. The purpose of this study was to assess whether patients with severe radiation-induced sequelae (RIS; i.e., National Cancer Institute/CTCv3.0 grade, > or =3) display both a low capacity of radiation-induced CD8 lymphocyte apoptosis (RILA) in vitro and possess certain single nucleotide polymorphisms (SNP) located in candidate genes associated with the response of cells to radiation. EXPERIMENTAL DESIGN: DNA was isolated from blood samples obtained from patients (n = 399) included in the Swiss prospective study evaluating the predictive effect of in vitro RILA and RIS. SNPs in the ATM, SOD2, XRCC1, XRCC3, TGFB1, and RAD21 genes were screened in patients who experienced severe RIS (group A, n = 16) and control subjects who did not manifest any evidence of RIS (group B, n = 18). RESULTS: Overall, 13 and 21 patients were found to possess a total of <4 and > or =4 SNPs in the candidate genes. The median (range) RILA in group A was 9.4% (5.3-16.5) and 94% (95% confidence interval, 70-100) of the patients (15 of 16) had > or =4 SNPs. In group B, median (range) RILA was 25.7% (20.2-43.2) and 33% (95% confidence interval, 13-59) of patients (6 of 18) had > or =4 SNPs (P < 0.001). CONCLUSIONS: The results of this study suggest that patients with severe RIS possess 4 or more SNPs in candidate genes and low radiation-induced CD8 lymphocyte apoptosis in vitro
— id: 143386, year: 2008, vol: 14, page: 6284, stat: Journal Article,

Radiation-induced side effects with or without systemic therapies: prime time for prediction of individual radiosensitivity
Azria, David; Rosenstein, Barry S; Ozsahin, Mahmut
2008 Aug 1;71(5):1293-1294, International journal of radiation oncology biology physics
— id: 143388, year: 2008, vol: 71, page: 1293, stat: Journal Article,

Association of single nucleotide polymorphisms in SOD2, XRCC1 and XRCC3 with susceptibility for the development of adverse effects resulting from radiotherapy for prostate cancer
Burri, Ryan J; Stock, Richard G; Cesaretti, Jamie A; Atencio, David P; Peters, Sheila; Peters, Christopher A; Fan, Grace; Stone, Nelson N; Ostrer, Harry; Rosenstein, Barry S
2008 Jul;170(1):49-59, Radiation research
The objective of this study was to determine whether an association exists between certain single nucleotide polymorphisms (SNPs), which have previously been linked with adverse normal tissue effects resulting from radiotherapy, and the development of radiation injury resulting from radiotherapy for prostate cancer. A total of 135 consecutive patients with clinically localized prostate cancer and a minimum of 1 year of follow-up who had been treated with radiation therapy, either brachytherapy alone or in combination with external-beam radiotherapy, with or without hormone therapy, were genotyped for SNPs in SOD2, XRCC1 and XRCC3. Three common late tissue toxicities were investigated: late rectal bleeding, urinary morbidity, and erectile dysfunction. Patients with the XRCC1 rs25489 G/A (Arg280His) genotype were more likely to develop erectile dysfunction after irradiation than patients who had the G/G genotype (67% compared to 24%; P=0.048). In addition, patients who had the SOD2 rs4880 T/C (Val16Ala) genotype exhibited a significant increase in grade 2 late rectal bleeding compared to patients who had either the C/C or T/T genotype for this SNP (8% compared to 0%; P=0.02). Finally, patients with the combination of the SOD2 rs4880 C/T genotype and XRCC3 rs861539 T/C (Thr241Met) genotype experienced a significant increase in grade 2 late rectal bleeding compared to patients without this particular genotypic arrangement (14% compared to 1%; P=0.002). These results suggest that SNPs in the SOD2, XRCC1 and XRCC3 genes are associated with the development of late radiation injury in patients treated with radiation therapy for prostate adenocarcinoma
— id: 96944, year: 2008, vol: 170, page: 49, stat: Journal Article,

Stereotactic radiosurgery for thoracic malignancies
Cesaretti, Jamie A; Pennathur, Arjun; Rosenstein, Barry S; Swanson, Scott J; Fernando, Hiran C
2008 Feb;85(2):S785-S791, Annals of thoracic surgery
Radiosurgery for lung cancer is a novel and promising concept that warrants thorough review. Stereotactic body radiotherapy enables the selective delivery of an intense dose of high-energy radiation to destroy a tumor with precise targeting. The radiobiology and physics behind the use of radiosurgery are presented, followed by a discussion of promising retrospective and prospective clinical data that has been reported from Japan, Europe, and the United States. The article closes with a discussion of multidisciplinary approaches that include radiosurgery which are on the therapeutic horizon
— id: 143391, year: 2008, vol: 85, page: S785, stat: Journal Article,

Variants in the ATM gene associated with a reduced risk of contralateral breast cancer
Concannon, Patrick; Haile, Robert W; Borresen-Dale, Anne-Lise; Rosenstein, Barry S; Gatti, Richard A; Teraoka, Sharon N; Diep, T Anh; Jansen, Laila; Atencio, David P; Langholz, Bryan; Capanu, Marinela; Liang, Xiaolin; Begg, Colin B; Thomas, Duncan C; Bernstein, Leslie; Olsen, Jorgen H; Malone, Kathleen E; Lynch, Charles F; Anton-Culver, Hoda; Bernstein, Jonine L
2008 Aug 15;68(16):6486-6491, Cancer research
Between 5% and 10% of women who survive a first primary breast cancer will subsequently develop a second primary cancer in the contralateral breast. The Women's Environment, Cancer, and Radiation Epidemiology Study was designed to identify genetic and environmental determinants of contralateral breast cancer (CBC). In this study, 708 women with asynchronous CBC served as cases and 1,397 women with unilateral breast cancer served as controls. ATM, a serine-threonine kinase, controls the cellular response to DNA double-strand breaks, and has been implicated in breast cancer risk. Complete mutation screening of the ATM gene in all 2,105 study participants identified 240 distinct sequence variants; only 15 were observed in >1% of subjects. Among the rare variants, deleterious alleles resulting in loss of ATM function were associated with a nonsignificant increase in risk of CBC. In contrast, carriers of common variants had a statistically significant reduction in risk of CBC. Four of these 15 variants were individually associated with a significantly decreased risk of second primary breast cancer [c.1899-55T>G, rate ratio (RR), 0.5; 95% confidence interval (CI), 0.3-0.8; c.3161C>G, RR, 0.5; 95% CI, 0.3-0.9; c.5558A>T, RR, 0.2; 95% CI, 0.1-0.6; c.6348-54T>C RR, 0.2; 95% CI, 0.1-0.8]. These data suggest that some alleles of ATM may exert an antineoplastic effect, perhaps by altering the activity of ATM as an initiator of DNA damage responses or a regulator of p53
— id: 143387, year: 2008, vol: 68, page: 6486, stat: Journal Article,

Feasibility of accelerated whole-breast radiation in the treatment of patients with ductal carcinoma in situ of the breast
Constantine, Claire; Parhar, Preeti; Lymberis, Stella; Fenton-Kerimian, Maria; Han, Stephanie C; Rosenstein, Barry S; Formenti, Silvia C
2008 Jun;8(3):269-274, Clinical breast cancer
BACKGROUND: We report the results of a prospective trial investigating the use of accelerated, hypofractionated whole-breast radiation therapy after breast-conservation surgery for ductal carcinoma in situ (DCIS). PATIENTS AND METHODS: A total of 59 patients with a median age of 54 years (range, 36-78 years) completed a phase I/II study of hypofractionated radiation therapy for treatment of DCIS. Eligibility criteria included patients with mammographically detected DCIS, status after segmental mastectomy with negative margins, and no residual calcifications. All patients were treated with external-beam radiation therapy without a boost, over 3 weeks, to a total dose of 42 Gy to the entire breast (2.8 Gy per fraction in 15 fractions). To optimally spare heart and lung, 34 of the 59 patients (57%) were treated in the prone position. Twenty-nine of 59 patients (49%) received adjuvant hormonal therapy. RESULTS: Overall, radiation therapy was well tolerated, with modest acute toxicity limited to grade 1 radiation dermatitis (76%), breast edema (17%), and fatigue (12%). With a median follow-up of 36 months, late toxicities included grade 1 hyperpigmentation changes (85%), induration (66%), asymmetry (64%), and breast fibrosis (17%), with 3 cases of grade 2 fibrosis and 1 case of grade 2 hyperpigmentation. Among the patients with >or= 3 years of follow-up, cosmesis was scored as good to excellent in 21 patients (91%) and fair in 2 patients (9%). At the time of this report, no ipsilateral or contralateral breast recurrences have occurred. CONCLUSION: These data demonstrate the feasibility of treating the whole breast for DCIS with a hypofractionated regimen, with modest acute and late toxicity
— id: 80619, year: 2008, vol: 8, page: 269, stat: Journal Article,

Screening for ATM sequence alterations in African-American women diagnosed with breast cancer
Hirsch, Ariel E; Atencio, David P; Rosenstein, Barry S
2008 Jan;107(1):139-144, Breast cancer research & treatment
BACKGROUND: Women who are heterozygous for variants in the ataxia telangiectasia mutated (ATM) gene, ATM carriers, have been reported to be at increased risk for breast cancer compared with women who do not posses an alteration in this gene. Aside from BRCA1 and BRCA2, there are few data on breast cancer susceptibility genes in African-American women. The goal of this study was to determine whether there is evidence that ATM is a breast cancer susceptibility gene in African-American women. METHODS: One hundred thirty two African-American women were screened for ATM sequence alterations. Thirty-seven (28%) were women with a histological diagnosis of breast cancer (cases). These women were not selected on the basis of a breast cancer family history. Ninety-five (72%) were age-matched women who had not been diagnosed with breast cancer (controls). Genetic variants were identified using denaturing high performance liquid chromatography (DHPLC). RESULTS: Twenty-three of the 37 (62%) cases possessed at least one ATM variant. Fifty-eight of the 95 (61%) (P = 0.54) age-matched controls harbored at least one ATM variant. For subjects specifically possessing missense variants, 46% of cases and 48% of controls had these types of sequence variants. In addition, 19% of cases and 34% of controls possessed multiple ATM sequence variants (P = 0.07). The most common polymorphisms were the 378 T --> A which was seen in 19% of cases and 27% of controls (P = 0.22), 5557 G --> A identified in 22% of cases and 18% of controls (p = 0.40), 2685 A --> G which was detected in 11% of cases and 6% of controls (P = 0.22), and 1254 A --> G which was found in 3% of cases and 9% of controls (P = 0.36). Hence, there were no significant differences in any of the genetic variants detected between the case and control subjects. CONCLUSION: We found no statistically significant differences in the overall frequency of ATM variants, nor any specific variant type or group, between African-American women who had been diagnosed with breast cancer compared with an age-matched cohort of African-American women who did not have breast cancer. ATM, therefore, does not appear to represent a breast cancer susceptibility gene in the general African-American population
— id: 143392, year: 2008, vol: 107, page: 139, stat: Journal Article,

Radioisotopes and vertebral augmentation: dosimetric analysis of a novel approach for the treatment of malignant compression fractures
Hirsch, Ariel E; Medich, David C; Rosenstein, Barry S; Martel, Christopher B; Hirsch, Joshua A
2008 Apr;87(1):119-126, Radiotherapy & oncology
PURPOSE: Vertebral compression fractures (VCFs), a major cause of morbidity and debilitating pain, often results from secondary tumor metastases to the skeleton. Vertebral augmentation is a palliative technique developed to treat VCFs and involves the injection of polymethyl methacrylate (PMMA) to augment the fractured vertebral body. The authors investigate the feasibility of radionuclide therapy coupled with vertebral augmentation to treat both the tumor metastases and VCFs. Six therapeutic radioisotopes, uniformly mixed in a PMMA bolus, were investigated for their dosimetric properties. METHODS AND MATERIALS: The MCNP5 Monte Carlo computer code was used to characterize the therapeutic dosimetric distribution within a cortical bone phantom for a 1 mm radial bolus of isotope-infused PMMA. Based on these data, the minimum activity required for a therapeutic treatment was calculated. RESULTS: The dosimetry from beta emitting Y-90, P-32, and Ho-166 decreased to 10% of its maximum therapeutic dose (R10%) after traveling 1.20 mm, 1.03 mm, and 0.97 mm, respectively, through cortical bone. Low photon energy I-125 had a slightly larger calculated R10% of 1.32 mm. Although F-18 and Tc-99m exhibited a more uniform distribution (R10%=1.72 mm and 1.94 mm, respectively), the lower dosimetric gradients resulted in significantly greater therapeutic implant activities relative to the other isotopes studied in this report. CONCLUSIONS: Radionuclide therapy coupled with vertebral augmentation is shown to be a feasible technique for the treatment of secondary skeletal metastases and its resulting side effects. Future studies will include a full clinical investigation to determine optimal treatment isotope(s)
— id: 143389, year: 2008, vol: 87, page: 119, stat: Journal Article,

TGFB1 single nucleotide polymorphisms are associated with adverse quality of life in prostate cancer patients treated with radiotherapy
Peters, Christopher A; Stock, Richard G; Cesaretti, Jamie A; Atencio, David P; Peters, Sheila; Burri, Ryan J; Stone, Nelson N; Ostrer, Harry; Rosenstein, Barry S
2008 Mar 1;70(3):752-759, International journal of radiation oncology biology physics
PURPOSE: To investigate whether the presence of single nucleotide polymorphisms (SNPs) located within TGFB1 might be predictive for the development of adverse quality-of-life outcomes in prostate cancer patients treated with radiotherapy. METHODS AND MATERIALS: A total of 141 prostate cancer patients treated with radiotherapy were screened for SNPs in TGFB1 using DNA sequencing. Three quality-of-life outcomes were investigated: (1) prospective decline in erectile function, (2) urinary quality of life, and (3) rectal bleeding. Median follow-up was 51.3 months (range, 12-138 months; SD, 24.4 months). RESULTS: Those patients who possessed either the T/T genotype at position -509, the C/C genotype at position 869 (pro/pro, codon 10) or the G/C genotype at position 915 (arg/pro, codon 25) were significantly associated with the development of a decline in erectile function compared with those who did not have these genotypes: 56% (9 of 16) vs. 24% (11 of 45) (p = 0.02). In addition, patients with the -509 T/T genotype had a significantly increased risk of developing late rectal bleeding compared with those who had either the C/T or C/C genotype at this position: 55% (6 of 11) vs. 26% (34 of 130) (p = 0.05). CONCLUSIONS: Possession of certain TGFB1 genotypes is associated with the development of both erectile dysfunction and late rectal bleeding in patients treated with radiotherapy for prostate cancer. Therefore, identification of patients harboring these genotypes may represent a means to predict which men are most likely to suffer from poor quality-of-life outcomes after radiotherapy for prostate cancer
— id: 96946, year: 2008, vol: 70, page: 752, stat: Journal Article,

Dose to the contralateral breast from radiotherapy and risk of second primary breast cancer in the WECARE study
Stovall, Marilyn; Smith, Susan A; Langholz, Bryan M; Boice, John D Jr; Shore, Roy E; Andersson, Michael; Buchholz, Thomas A; Capanu, Marinela; Bernstein, Leslie; Lynch, Charles F; Malone, Kathleen E; Anton-Culver, Hoda; Haile, Robert W; Rosenstein, Barry S; Reiner, Anne S; Thomas, Duncan C; Bernstein, Jonine L
2008 Nov 15;72(4):1021-1030, International journal of radiation oncology biology physics
PURPOSE: To quantify the risk of second primary breast cancer in the contralateral breast (CB) after radiotherapy (RT) for first breast cancer. METHODS AND MATERIALS: The study population included participants in the Women's Environmental, Cancer, and Radiation Epidemiology study: 708 cases (women with asynchronous bilateral breast cancer) and 1399 controls (women with unilateral breast cancer) counter-matched on radiation treatment. Participants were <55 years of age at first breast cancer. Absorbed doses to quadrants of the CB were estimated. Rate ratios (RR) and 95% confidence intervals (CI) were calculated using multivariable-adjusted conditional logistic regression models. RESULTS: Across all patients, the mean radiation dose to the specific quadrant of the CB tumor was 1.1 Gy. Women <40 years of age who received >1.0 Gy of absorbed dose to the specific quadrant of the CB had a 2.5-fold greater risk for CB cancer than unexposed women (RR = 2.5, 95% CI 1.4-4.5). No excess risk was observed in women >40 years of age. Women <40 years of age with follow-up periods >5 years had a RR of 3.0 (95% CI 1.1-8.1), and the dose response was significant (excess RR per Gy of 1.0, 95% CI 0.1-3.0). CONCLUSIONS: Women <40 years of age who received a radiation dose >1.0 Gy to the CB had an elevated, long-term risk of developing a second primary CB cancer. The risk is inversely related to age at exposure and is dose dependent
— id: 143385, year: 2008, vol: 72, page: 1021, stat: Journal Article,

p53 gene mutations in SKH-1 mouse tumors differentially induced by UVB and combined subcarcinogenic benzo[a]pyrene and UVA
Wang, Yongyin; Zhou, Xueyan; Weinstein, Elhav; Maryles, Billie; Zhang, Yanzhen; Moore, Julian; Gao, Dayuan; Atencio, David P; Rosenstein, Barry S; Lebwohl, Mark; Chen, Hong-Duo; Xiao, Ting; Wei, Huachen
2008 Mar-Apr;84(2):444-449, Photochemistry & photobiology
We compared the frequency and spectra of p53 mutations in skin tumors from UVB-irradiated and benzo(a)pyrene-UVA-treated SKH-1 mice. Analysis of p53 mutations using a combination of polymerase chain reaction, denaturing high-performance liquid chromatography, and sequencing shows that the frequency and spectrum of p53 mutations in BaP-UVA-induced tumors are quite different from those in UVB-induced tumors. SKH-1 mice were treated with BaP-UVA or UVB for 30 weeks after which skin tumors were collected for analysis of p53 mutations. Among the 11 BaP-UVA-induced tumors with diameters of 5-10 mm, two displayed mutations in exon 8 yielding a mutation frequency of 18.2%. In contrast, the mutation frequency among BaP-UVA-induced tumors was 10.5%. In UVB-induced tumors, the mutation frequency in exon 8 was highly correlated with tumor size. A total of 77.8% of tumors with diameters larger than 10 mm contained p53 mutations. The overall mutation frequency among UVB-induced tumors was 17.9% in exon 8 and only 3.8% in exon 5. Hotspots for p53 mutation in UVB-induced tumors were found at codons 128 and 149 (exon 5), and at codons 268, 270, 271 and 273-276 (exon 8). In addition to widely recognized C-->T missense mutations, there were also tandem CC-->AG changes coupled with either an insertion of T, a C-->G substitution or G-->C/T mutations. All of the mutations were found at tri- or tetra-pyrimidine sites. Thirty-nine per cent of all p53 mutations occurred at codons 274 and 275; 53% occurred at codons 268-271. Two multiple mutation clusters were located at codons 268-271 and 274-276. Both BaP-UVA and UVB caused C-->T transitions at codon 275 in exon 8. A C-->T mutation at codon 294 was induced only by BaP-UVA treatment. In contrast to UVB treatment, BaP-UVA treatment did not induce any mutations in exon 5. We show that individually subcarcinogenic levels of BaP and UVA synergistically induce a novel p53-mutation fingerprint. This fingerprint could serve as a prognostic indicator for the development of BaP-UVA-induced skin tumors
— id: 143390, year: 2008, vol: 84, page: 444, stat: Journal Article,

A genetically determined dose-volume histogram predicts for rectal bleeding among patients treated with prostate brachytherapy
Cesaretti, Jamie A; Stock, Richard G; Atencio, David P; Peters, Sheila A; Peters, Christopher A; Burri, Ryan J; Stone, Nelson N; Rosenstein, Barry S
2007 Aug 1;68(5):1410-1416, International journal of radiation oncology biology physics
PURPOSE: To examine whether possession of genetic alterations in the ATM (ataxia telangiectasia) gene is associated with rectal bleeding in a dose-dependent and volume-dependent manner. METHODS AND MATERIALS: One hundred eight prostate cancer patients who underwent brachytherapy using either an (125)I implant, a (103)Pd implant, or the combination of external beam radiotherapy with a (103)Pd implant and had a minimum of 1 year follow-up were screened for DNA sequence variations in the 62 coding exons of the ATM gene using denaturing high-performance liquid chromatography. Rectal dose was reported as the volume (in cubic centimeters) of rectum receiving the brachytherapy prescription dose. The two-sided Fisher exact test was used to compare differences in proportions. RESULTS: A significant correlation between the presence of any ATM sequence alteration and Grade 1 to 2 proctitis was obtained when the radiation dose to rectal tissue was quantified. Rectal bleeding occurred in 4 of 13 patients (31%) with a variant versus 1 of 23 (4%) without a genetic alteration for patients who had <0.7 cm(3) of rectal tissue receiving the implant prescription dose (p = 0.05). Of patients in whom 0.7-1.4 cm(3) of the rectum received the implant prescription, 4 of 11 (36%) with an ATM alteration exhibited Grade 1 to 2 proctitis, whereas 1 of 21 (5%) without a variant (p = 0.04) developed this radiation-induced late effect. CONCLUSIONS: The possession of genetic variants in the ATM gene is associated with the development of radiation-induced proctitis after prostate cancer radiotherapy for patients who receive the full prescription dose to either a low or a moderate volume of rectal tissue
— id: 143393, year: 2007, vol: 68, page: 1410, stat: Journal Article,

Accelerated intensity-modulated radiotherapy to breast in prone position: dosimetric results
DeWyngaert, J Keith; Jozsef, Gabor; Mitchell, James; Rosenstein, Barry; Formenti, Silvia C
2007 Jul 15;68(4):1251-1259, International journal of radiation oncology biology physics
PURPOSE: To report the physics and dosimetry results of a trial of accelerated intensity-modulated radiotherapy to the whole breast with a concomitant boost to the tumor bed in patients treated in the prone position. METHODS AND MATERIALS: Patients underwent computed tomography planning and treatment in the prone position on a dedicated treatment platform. The platform has an open aperture on the side to allow for the index breast to fall away from the chest wall. Noncontrast computed tomography images were acquired at 2.5- or 3.75-mm-thick intervals, from the level of the mandible to below the diaphragm. A dose of 40.5 Gy was delivered to the entire breast at 2.7-Gy fractions in 15 fractions. An additional dose of 0.5 Gy was delivered as a concomitant boost to the lumpectomy site, with a 1-cm margin, using inverse planning, for a total dose of 48 Gy in 15 fractions. No more than 10% of the heart and lung volume was allowed to receive >18 and >20 Gy, respectively. RESULTS: Between September 2003 and August 2005, 91 patients were enrolled in the study. The median volume of heart that received > or =18 Gy was 0.5%, with a maximal value of 4.7%. The median volume of ipsilateral lung that received > or =20 Gy was 0.8%, with a maximum of 7.2%. CONCLUSION: This technique for whole breast radiotherapy is feasible and enables an accelerated regimen in the prone position while sparing the lung and heart
— id: 73387, year: 2007, vol: 68, page: 1251, stat: Journal Article,

Phase I-II trial of prone accelerated intensity modulated radiation therapy to the breast to optimally spare normal tissue
Formenti, Silvia C; Gidea-Addeo, Daniela; Goldberg, Judith D; Roses, Daniel F; Guth, Amber; Rosenstein, Barry S; DeWyngaert, Keith J
2007 Jun 1;25(16):2236-2242, Journal of clinical oncology
PURPOSE: To report the clinical feasibility of a trial of accelerated whole-breast intensity modulated radiotherapy, with the patient in prone position, optimally to spare the heart and lung. PATIENTS AND METHODS: Patients with stages I or II breast cancer, excised by breast conserving surgery with negative margins, were eligible for this institutional review board-approved prospective trial. Computed tomography simulation was performed with the patient prone on a dedicated breast board, in the exact position used for treatment. A dose of 40.5 Gy, delivered at 2.7 Gy in 15 fractions, was prescribed to the index breast with an additional concomitant boost of 0.5 Gy delivered to the tumor bed, for a total dose of 48 Gy to the lumpectomy site. Physics constraints consisted of limiting 5% of the heart volume to receive > or = 18 Gy and < or = 10% of the ipsilateral lung volume to receive > or = 20 Gy. RESULTS: Between September 2003 and August 2005, 91 patients were enrolled on the study. Median length of follow-up was 12 months (range, 1 to 28 months). In all patients the technique was feasible and heart and lung sparing was achieved as prescribed by the protocol. Acute toxicities consisting mostly of reversible grades 1-2 skin dermatitis (67%) and fatigue (18%) occurred in 75 patients. One patient sustained a regional recurrence rapidly followed by distant metastases. CONCLUSION: Accelerated whole breast intensity modulated radiotherapy in the prone position is feasible and it permits a drastic reduction in the volume of lung and heart tissue exposed to significant radiation.
— id: 72870, year: 2007, vol: 25, page: 2236, stat: Journal Article,

Possession of ATM sequence variants as predictor for late normal tissue responses in breast cancer patients treated with radiotherapy
Ho, Alice Y; Fan, Grace; Atencio, David P; Green, Sheryl; Formenti, Silvia C; Haffty, Bruce G; Iyengar, Preetha; Bernstein, Jonine L; Stock, Richard G; Cesaretti, Jamie A; Rosenstein, Barry S
2007 Nov 1;69(3):677-684, International journal of radiation oncology biology physics
PURPOSE: The ATM gene product is a central component of cell cycle regulation and genomic surveillance. We hypothesized that DNA sequence alterations in ATM predict for adverse effects after external beam radiotherapy for early breast cancer. METHODS AND MATERIALS: A total of 131 patients with a minimum of 2 years follow-up who had undergone breast-conserving surgery and adjuvant radiotherapy were screened for sequence alterations in ATM using DNA from blood lymphocytes. Genetic variants were identified using denaturing high performance liquid chromatography. The Radiation Therapy Oncology Group late morbidity scoring schemes for skin and subcutaneous tissues were applied to quantify the radiation-induced effects. RESULTS: Of the 131 patients, 51 possessed ATM sequence alterations located within exons or in short intron regions flanking each exon that encompass putative splice site regions. Of these 51 patients, 21 (41%) exhibited a minimum of a Grade 2 late radiation response. In contrast, of the 80 patients without an ATM sequence variation, only 18 (23%) had radiation-induced adverse responses, for an odds ratio of 2.4 (95% confidence interval, 1.1-5.2). Fifteen patients were heterozygous for the G-->A polymorphism at nucleotide 5557, which causes substitution of asparagine for aspartic acid at position 1853 of the ATM protein. Of these 15 patients, 8 (53%) exhibited a Grade 2-4 late response compared with 31 (27%) of the 116 patients without this alteration, for an odds ratio of 3.1 (95% confidence interval, 1.1-9.4). CONCLUSION: Sequence variants located in the ATM gene, in particular the 5557 G-->A polymorphism, may predict for late adverse radiation responses in breast cancer patients
— id: 93555, year: 2007, vol: 69, page: 677, stat: Journal Article,

Single nucleotide polymorphisms as predictors for development of erectile dysfunction in African-American men treated with radiotherapy for prostate cancer
Moore, J; Stock, RG; Cesaretti, JA; Stone, NN; Li, W; Peters, S; Atencio, DP; Peters, CA; Burri, R; Rosenstein, BS
2007 JAN ;69(3):S7-S7, International journal of radiation oncology biology physics
— id: 87191, year: 2007, vol: 69, page: S7, stat: Journal Article,

ATM sequence variants and risk of radiation-induced subcutaneous fibrosis after postmastectomy radiotherapy
Andreassen, Christian N; Overgaard, Jens; Alsner, Jan; Overgaard, Marie; Herskind, Carsten; Cesaretti, Jamie A; Atencio, David P; Green, Sheryl; Formenti, Silvia C; Stock, Richard G; Rosenstein, Barry S
2006 Mar 1;64(3):776-783, International journal of radiation oncology biology physics
PURPOSE: To examine the hypothesis that women who are carriers of genetic alterations in the ATM gene are more likely to develop subcutaneous fibrosis after radiotherapy for treatment of breast cancer compared with patients who do not possess DNA sequence variations in this gene. METHODS AND MATERIALS: DNA samples isolated from fibroblast cell lines established from 41 women treated with postmastectomy radiotherapy for breast cancer were screened for genetic variants in ATM using denaturing high-performance liquid chromatography (DHPLC). A minimum follow-up of 2 years enabled analysis of late effects to generate dose-response curves and to estimate the dose that resulted in a 50% incidence of Grade 3 fibrosis (ED50). RESULTS: A total of 26 genetic alterations in the expressed portions of the ATM gene, or within 10 bases of each exon in regions encompassing putative splice sites, were detected in 22 patients. The ED50 (95% confidence interval) of 60.2 (55.7-65.1) Gy calculated for patients without a sequence variation did not differ significantly from the ED50 of 58.4 (54.0-63.1) Gy for the group of patients with any ATM sequence abnormality. The ED50 of 53.7 (50.2-57.5) Gy for those patients who were either homozygous or heterozygous for the G-->A polymorphism at nucleotide 5557, which results in substitution of asparagine for aspartic acid at position 1853 of the ATM protein, was substantially lower than the ED50 of 60.8 (57.0-64.8) Gy for patients not carriers of this sequence alteration. This resulted in an enhancement ratio (ratio of the ED50 values) of 1.13 (1.05-1.22), which was significantly greater than unity. CONCLUSION: The results of this study suggest an association between the ATM codon 1853 Asn/Asp and Asn/Asn genotypes with the development of Grade 3 fibrosis in breast cancer patients treated with radiotherapy
— id: 64380, year: 2006, vol: 64, page: 776, stat: Journal Article,

Genetic variants as predictors of late adverse radiotherapy effects in breast cancer patients
Fan, G; Burri, R; Racsa, M; Green, S; Formenti, SC; Kuten, A; Ozahin, M; Haffty, BG; Stock, RG; Rosenstein, BS
2006 FEB ;66(3):S211-S211, International journal of radiation oncology biology physics
— id: 70756, year: 2006, vol: 66, page: S211, stat: Journal Article,

NYU 01-51: Phase I-II trial of hypofractionated whole breast radiation therapy for ductal carcinoma in situ (DCIS)
Formenti, SC; Wernicke, AG; Gittleman, AE; Rosenstein, BS; DeWyngaert, JK
2006 FEB ;66(3):S178-S178, International journal of radiation oncology biology physics
— id: 70755, year: 2006, vol: 66, page: S178, stat: Journal Article,

Genetic Predictors of Adverse Radiotherapy Effects: The Gene-PARE project
Ho, Alice Y; Atencio, David P; Peters, Sheila; Stock, Richard G; Formenti, Silvia C; Cesaretti, Jamie A; Green, Sheryl; Haffty, Bruce; Drumea, Karen; Leitzin, Larisa; Kuten, Abraham; Azria, David; Ozsahin, Mahmut; Overgaard, Jens; Andreassen, Christian N; Trop, Cynthia S; Park, Janelle; Rosenstein, Barry S
2006 Jul 1;65(3):646-655, International journal of radiation oncology biology physics
Purpose: The development of adverse effects resulting from the radiotherapy of cancer limits the use of this treatment modality. The validation of a test capable of predicting which patients would be most likely to develop adverse responses to radiation treatment, based on the possession of specific genetic variants, would therefore be of value. The purpose of the Genetic Predictors of Adverse Radiotherapy Effects (Gene-PARE) project is to help achieve this goal. Methods and Materials: A continuously expanding biorepository has been created consisting of frozen lymphocytes and DNA isolated from patients treated with radiotherapy. In conjunction with this biorepository, a database is maintained with detailed clinical information pertaining to diagnosis, treatment, and outcome. The DNA samples are screened using denaturing high performance liquid chromatography (DHPLC) and the Surveyor nuclease assay for variants in ATM, TGFB1, XRCC1, XRCC3, SOD2, and hHR21. It is anticipated that additional genes that control the biologic response to radiation will be screened in future work. Results: Evidence has been obtained that possession of variants in genes, the products of which play a role in radiation response, is predictive for the development of adverse effects after radiotherapy. Conclusions: It is anticipated that the Gene-PARE project will yield information that will allow radiation oncologists to use genetic data to optimize treatment on an individual basis
— id: 64378, year: 2006, vol: 65, page: 646, stat: Journal Article,

On the proposed association of the ATM variants 5557G>A and IVS38-8T>C and bilateral breast cancer
Langholz, Bryan; Bernstein, Jonine L; Bernstein, Leslie; Olsen, Jorgen H; Borresen-Dale, Anne-Lise; Rosenstein, Barry S; Gatti, Richard A; Concannon, Patrick
2006 Aug 1;119(3):724-725, International journal of cancer
— id: 143394, year: 2006, vol: 119, page: 724, stat: Journal Article,

Radiation Sensitivity of GL261 Murine Glioma Model and Enhanced Radiation Response by Flavopiridol
Newcomb, Elizabeth W; Lymberis, Stella C; Lukyanov, Yevgeniy; Shao, Yongzhao; Schnee, Tona; Devitt, Marylou; Rosenstein, Barry S; Zagzag, David; Formenti, Silvia C
2006 Jan;5(1):93-99, Cell cycle
Response of a solid tumor to radiation treatment depends, in part, on the intrinsic radiosensitivity of tumor cells, the proliferation rate of tumor cells between radiation treatments and the hypoxic state of the tumor cells. A successful radiosensitizing agent would target S-phase cells and hypoxia. Recently, we demonstrated the anti-tumor effects of flavopiridol in the GL261 murine glioma model might involve 1) recruitment of tumor cells to S-phase (Newcomb et al Cell Cycle 2004; 3:230-234) and 2) an anti-angiogenic effect on the tumor vasculature by downregulation of hypoxia-inducible factor -1alpha (HIF-1alpha) (Newcomb et al Neuro-Oncology 2005; 7:225-235). Given that flavopiridol has demonstrated radiosensitizing activity in several murine tumor models, we tested whether it would enhance the response of GL261 tumors to radiation. In the present study, we evaluated the intrinsic radiation sensitivity of the GL261 glioma model using the tumor control/cure dose of radiation assay (TCD(50)). We found that a single dose of 65 Gy (CI 57.1-73.1) was required to cure 50% of the tumors locally. Using the tumor growth delay assay, fractionated radiation (5 fractions of 5 Gy over 10 days) combined with flavopiridol (5 mg/kg) given three times weekly for 3 cycles produced a significant growth delay. Our results indicate that the GL261 murine glioma model mimics the radioresistance encountered in human gliomas, and thus should prove useful in identifying promising new investigational radiosensitizers for use in the treatment of glioma patients
— id: 62423, year: 2006, vol: 5, page: 93, stat: Journal Article,

Biologically effective dose values for prostate brachytherapy: effects on PSA failure and posttreatment biopsy results
Stock, Richard G; Stone, Nelson N; Cesaretti, Jamie A; Rosenstein, Barry S
2006 Feb 1;64(2):527-533, International journal of radiation oncology biology physics
PURPOSE: To analyze the effect of biologically effective dose (BED) values on prostate-specific antigen (PSA) failure and posttreatment biopsy. METHODS AND MATERIALS: From 1990 to 2003, 1,377 patients had prostate brachytherapy alone (I-125 or Pd-103) (571), hormonal and brachytherapy (371), and trimodality therapy (hormonal, implant, and external beam) (435). Dose was defined as the D90 (dose delivered to 90% of the gland from the dose-volume histogram). RESULTS: Freedom from PSA failure (FFPF) at 10 years was 87%. The 10-year FFPF for BED<100, >100-120, >120-140, >140-160, <160-180, >180-200, and >200 were 46%, 68%, 81%, 85.5%, 90%, 90%, and 92%, respectively (p<0.0001). BED and Gleason score had the greatest effect, with p values of p<0.0001 in multivariate analysis. Posttreatment positive biopsy rate was 7% (31/446). The positive biopsy rates for BED<or=100, >100-120, >120-140, >140-160, >160-180, >180-200, and >200 were 24% (8/33), 15% (3/20), 6% (2/33), 6% (3/52), 7% (6/82), 1% (1/72), and 3% (4/131), respectively (p<0.0001). BED was the most significant predictor of biopsy outcome in multivariate analysis (p=0.006). CONCLUSIONS: Biologically effective dose equations provide a method of comparing different isotopes and combined therapies in the brachytherapy management of prostate cancer. The effects of BED on FFPF and posttreatment biopsy demonstrate a strong dose-response relationship
— id: 143395, year: 2006, vol: 64, page: 527, stat: Journal Article,

ATM sequence variants are predictive of adverse radiotherapy response among patients treated for prostate cancer
Cesaretti, Jamie A; Stock, Richard G; Lehrer, Steven; Atencio, David A; Bernstein, Jonine L; Stone, Nelson N; Wallenstein, Sylvan; Green, Sheryl; Loeb, Karen; Kollmeier, Marisa; Smith, Michael; Rosenstein, Barry S
2005 Jan 1;61(1):196-202, International journal of radiation oncology biology physics
PURPOSE: To examine whether the presence of sequence variants in the ATM (mutated in ataxia-telangiectasia) gene is predictive for the development of radiation-induced adverse responses resulting from (125)I prostate brachytherapy for early-stage prostate cancer. MATERIALS AND METHODS: Thirty-seven patients with a minimum of 1-year follow-up who underwent (125)I prostate brachytherapy of early-stage prostate cancer were screened for DNA sequence variations in all 62 coding exons of the ATM gene using denaturing high-performance liquid chromatography. The clinical course and postimplant dosimetry for each genetically characterized patient were obtained from a database of 2,020 patients implanted at Mount Sinai Hospital after 1990. RESULTS: Twenty-one ATM sequence alterations located within exons, or in short intronic regions flanking each exon, were found in 16 of the 37 patients screened. For this group, 10 of 16 (63%) exhibited at least one form of adverse response. In contrast, of the 21 patients who did not harbor an ATM sequence variation, only 3 of 21 (14%) manifested radiation-induced adverse responses (p = 0.005). Nine of the patients with sequence alterations specifically possessed missense mutations, which encode for amino acid substitutions and are therefore more likely to possess functional importance. For this group, 7 of 9 (78%) exhibited at least one form of adverse response. In contrast, of the 28 patients who did not have a missense alteration, only 6 of 28 (21%) manifested any form of adverse response to the radiotherapy (p = 0.004). Of the patients with missense variants, 5 of 9 (56%) exhibited late rectal bleeding vs. 1 of 28 (4%) without such alterations (p = 0.002). Of those patients who were at risk for developing erectile dysfunction, 5 of 8 (63%) patients with missense mutations developed prospectively evaluated erectile dysfunction as opposed to 2 of 20 (10%) without these sequence alterations (p = 0.009). CONCLUSIONS: Possession of sequence variants in the ATM gene, particularly those that encode for an amino acid substitution, is predictive for the development of adverse radiotherapy responses among patients treated with (125)I prostate brachytherapy
— id: 143398, year: 2005, vol: 61, page: 196, stat: Journal Article,

In response to Dr. Morgan
Formenti SC; Lymberis SC; Rosenstein BS
2005 Jul 1;62(3):943-944, International journal of radiation oncology biology physics
— id: 56034, year: 2005, vol: 62, page: 943, stat: Journal Article,

NYU 03-30: Accelerated IMRT with concomitant boost after breast conservation surgery. preliminary clinical results in 70 patients
Formenti, SC; Mitchell, J; Goldberg, J; Magnolfi, C; Rosenstein, B; Remon, S; DeWyngaert, K
2005 ;63(2):S181-S182, International journal of radiation oncology biology physics
— id: 109264, year: 2005, vol: 63, page: S181, stat: Journal Article,

ATM sequence variants as predictors for late normal tissue responses in breast cancer patients treated with radiotherapy
Ho, AY; Atencio, DP; Fan, G; Green, S; Formenti, SC; Haffty, BG; Bernstein, JL; Iyengar, P; Stock, RG; Cesaretti, JA; Rosenstein, BS
2005 NOV 16 ;63(2):S457-S458, International journal of radiation oncology biology physics
— id: 58995, year: 2005, vol: 63, page: S457, stat: Journal Article,

ATM sequence variants as predictors for adverse radiation responses in breast cancer patients
Ho, AY; Atencio, DP; Fan, G; Green, S; Formenti, SC; Haffty, BG; Bernstein, JL; Stock, RG; Cesaretti, JA; Rosenstein, BS
2005 ;94(2):S178-S178, Breast cancer research & treatment
— id: 109267, year: 2005, vol: 94, page: S178, stat: Journal Article,

Cellular response to DNA damage
Kao, Johnny; Rosenstein, Barry S; Peters, Sheila; Milano, Michael T; Kron, Stephen J
2005 Dec;1066:243-258, Annals of the New York Academy of Sciences
Eukaryotic cells, from yeast to man, possess evolutionarily conserved mechanisms to accurately and efficiently repair the overwhelming majority of DNA damage, thereby ensuring genomic integrity. Important repair pathways include base excision repair, nucleotide excision repair, mismatch repair, non-homologous end-joining, and homologous recombination. Defects in DNA repair processes generally result in susceptibility to cancer and, often, abnormalities in multiple organ systems. While signal transduction pathways have been intensely studied, epigenetic changes occurring in response to DNA damage are rapidly increasing in importance. Effective radiation and chemotherapy sensitization could result from selective inhibition of DNA repair in tumor cells. DNA damage repair is a dynamic field of research where the fruits of basic research often have important clinical implications
— id: 143396, year: 2005, vol: 1066, page: 243, stat: Journal Article,

Equivalent biological effective dose (BEDeq) modeling of tumor control probability in Partial Breast Irradiation
Lymberis, SC; Rosenstein, BS; Jozsef, G; Formenti, SC; DeWyngaert, J
2005 ;63(2):2037-2037, International journal of radiation oncology biology physics
— id: 109268, year: 2005, vol: 63, page: 2037, stat: Journal Article,

Combined subcarcinogenic benzo[a]pyrene and UVA synergistically caused high tumor incidence and mutations in H-ras gene, but not p53, in SKH-1 hairless mouse skin
Wang, Yongyin; Gao, Dayuan; Atencio, David P; Perez, Evangeline; Saladi, Rao; Moore, Julian; Guevara, Denise; Rosenstein, Barry S; Lebwohl, Mark; Wei, Huachen
2005 Aug 20;116(2):193-199, International journal of cancer
Combined subcarcinogenic doses of benzo[a]pyrene (BaP) and UVA induced H-ras, but not p53, gene mutations 8 weeks before tumor emergence in SKH-1 mice. Neither UVA (40 kJ/m2) nor BaP (8 nmol) induced any tumors after mice were topically treated 3 times/week for 25 weeks. However, combined BaP-UVA treatment synergistically increased tumor incidence and multiplicity. All tumors induced by BaP-UVA were malignant. The epidermis was collected from mice treated for 2, 6 and 10 weeks. DNA from UVB- (0.3 kJ/m2) or BaP-UVA-(8 nmol and 40 kJ/m2-induced tumors was isolated and screened for H-ras and p53 mutations. Four types of point mutation, GGC-->GAC, GCC, GTC and CGC, occurred in UVB-induced tumors at H-ras codon 13; and one type of point mutation, GGA-->GAA, at codon 12. Treatment with either BaP alone or BaP-UVA for 10 weeks caused GGA-->GAA mutation at codon 12 or GGC-->GAC mutation at codon 13 in nontumor skin, respectively, as well as in tumors induced by BaP-UVA. All of the 10-week samples treated with either BaP or BaP-UVA showed detectable mutations at codons 12 and 13, but the genetic load was significantly higher in BaP-UVA-treated mice than in those exposed only to BaP. UVA alone induced mutations at codon 12 in only one-third of samples. G-->A mutations induced by BaP or BaP-UVA at position 38 of codon 13 have not been reported previously. C-->T transitions were detected in p53 hot spots of exon 8 in 2 of 19 BaP-UVA-induced tumors but were not found in nontumor skin
— id: 143397, year: 2005, vol: 116, page: 193, stat: Journal Article,

Study design: evaluating gene-environment interactions in the etiology of breast cancer - the WECARE study
Bernstein, Jonine L; Langholz, Bryan; Haile, Robert W; Bernstein, Leslie; Thomas, Duncan C; Stovall, Marilyn; Malone, Kathleen E; Lynch, Charles F; Olsen, Jorgen H; Anton-Culver, Hoda; Shore, Roy E; Boice, John D Jr; Berkowitz, Gertrud S; Gatti, Richard A; Teitelbaum, Susan L; Smith, Susan A; Rosenstein, Barry S; Borresen-Dale, Anne-Lise; Concannon, Patrick; Thompson, W Douglas
2004 ;6(3):R199-R214, Breast cancer research
INTRODUCTION: Deficiencies in cellular responses to DNA damage can predispose to cancer. Ionizing radiation can cause cluster damage and double-strand breaks (DSBs) that pose problems for cellular repair processes. Three genes (ATM, BRCA1, and BRCA2) encode products that are essential for the normal cellular response to DSBs, but predispose to breast cancer when mutated. DESIGN: To examine the joint roles of radiation exposure and genetic susceptibility in the etiology of breast cancer, we designed a case-control study nested within five population-based cancer registries. We hypothesized that a woman carrying a mutant allele in one of these genes is more susceptible to radiation-induced breast cancer than is a non-carrier. In our study, 700 women with asynchronous bilateral breast cancer were individually matched to 1400 controls with unilateral breast cancer on date and age at diagnosis of the first breast cancer, race, and registry region, and counter-matched on radiation therapy. Each triplet comprised two women who received radiation therapy and one woman who did not. Radiation absorbed dose to the contralateral breast after initial treatment was estimated with a comprehensive dose reconstruction approach that included experimental measurements in anthropomorphic and water phantoms applying patient treatment parameters. Blood samples were collected from all participants for genetic analyses. CONCLUSIONS: Our study design improves the potential for detecting gene-environment interactions for diseases when both gene mutations and the environmental exposures of interest are rare in the general population. This is particularly applicable to the study of bilateral breast cancer because both radiation dose and genetic susceptibility have important etiologic roles, possibly by interactive mechanisms. By using counter-matching, we optimized the informativeness of the collected dosimetry data by increasing the variability of radiation dose within the case-control sets and enhanced our ability to detect radiation-genotype interactions
— id: 72195, year: 2004, vol: 6, page: R199, stat: Journal Article,

Accelerated IMRT with concomitant boost after breast-conserving therapy (BCT): Preliminary clinical results and dose volume histogram (DVH) analysis
DeWyngaert, J; Lymberis, SC; MacDonald, S; Rosenstein, B; Lief, EP; Formenti, SC
2004 APR ;60(1):S386-S387, International journal of radiation oncology biology physics
— id: 48945, year: 2004, vol: 60, page: S386, stat: Journal Article,

Prone accelerated partial breast irradiation (five fractions) after breast conservation therapy with heart and lung sparing
Formenti, SC; Goldberg, J; Rosenstein, B; Dewyngaert, K
2004 ;22(14):93S-93S #870, Journal of clinical oncology
— id: 109269, year: 2004, vol: 22, page: 93S, stat: Journal Article,

Prone accelerated partial breast irradiation after breast-conserving surgery: Preliminary clinical results and dose-volume histogram analysis
Formenti, Silvia C; Truong, Minh Tam; Goldberg, Judith D; Mukhi, Vandana; Rosenstein, Barry; Roses, Daniel; Shapiro, Richard; Guth, Amber; Dewyngaert, J Keith
2004 Oct 1;60(2):493-504, International journal of radiation oncology biology physics
PURPOSE: To report the clinical and dose-volume histogram results of the first 47 patients accrued to a protocol of accelerated partial breast irradiation. Patients were treated in the prone position with three-dimensional conformal radiotherapy after breast-conserving surgery. METHODS AND MATERIALS: Postmenopausal women with Stage T1N0 breast cancer were eligible only after they had first refused to undergo 6 weeks of standard radiotherapy. Planning CT in the prone position was performed on a dedicated table. The postoperative cavity was defined as the clinical target volume, with a 1.5-cm margin added to determine the planning target volume. A total dose of 30 Gy at 6 Gy/fraction was delivered in five fractions within 10 days. RESULTS: The median age of the patients was 67.5 years (range, 51-88 years). The median tumor diameter was 9 mm (range, 1.3-19 mm). In all patients, the prescribed dose encompassed the planning target volume. The mean volume of the ipsilateral breast receiving 100% of the prescription dose was 26% (range, 10-45%), and the mean volume contained within the 50% isodose surface was 47% (range, 23-75%). The lung and heart were spared by treating in the prone position. Acute toxicity was modest, limited mainly to Grade 1-2 erythema. With a median follow-up of 18 months, only Grade 1 late toxicity occurred, and no patient developed local recurrence. CONCLUSION: These data suggest that this approach is well tolerated, with only mild acute side effects and sparing of the heart and lung
— id: 45301, year: 2004, vol: 60, page: 493, stat: Journal Article,

Phase I-II trial of hypofractionated whole breast radiation therapy for ductal carcinoma in situ (DCIS)
Gittleman, AE; Lymberis, SC; MacDonald, S; Rosenstein, BS; DeWyngaert, J; Formenti, SC
2004 APR ;60(1):S382-S382, International journal of radiation oncology biology physics
— id: 48944, year: 2004, vol: 60, page: S382, stat: Journal Article,

Preliminary clinical results of accelerated IMIRT with concomitant boost after breast conserving therapy (BCT)
Lymberis, SC; MacDonald, SM; Rosenstein, B; Liet, EP; Dewyngaert, JK; Formenti, SC
2004 JUL 15 ;22(14):91S-91S, Journal of clinical oncology
— id: 48675, year: 2004, vol: 22, page: 91S, stat: Journal Article,

Biological comparison of partial breast irradiation protocols versus standard whole breast irradiation: Implications for tumor control and normal tissue tolerance
Lymberis, SC; Rosenstein, BS; Formenti, SC
2004 APR ;60(1):S399-S400, International journal of radiation oncology biology physics
— id: 48946, year: 2004, vol: 60, page: S399, stat: Journal Article,

Biologic comparison of partial breast irradiation protocols
Rosenstein, Barry S; Lymberis, Stella C; Formenti, Silvia C
2004 Dec 1;60(5):1393-1404, International journal of radiation oncology biology physics
PURPOSE: To analyze the dose/fractionation schedules currently used in ongoing clinical trials of partial breast irradiation (PBI) by comparing their biologically effective dose (BED) values to those of three standard whole breast protocols commonly used after segmental mastectomy in the treatment of breast cancer. METHODS AND MATERIALS: The BED equation derived from the linear-quadratic model for radiation-induced cell killing was used to calculate the BEDs for three commonly used whole breast radiotherapy regimens, in addition to a variety of external beam radiotherapy, as well as high-dose-rate and low-dose-rate brachytherapy, PBI protocols. RESULTS: The BED values of most PBI protocols resulted in tumor control BEDs roughly equivalent to a 50-Gy standard treatment, but consistently lower than the BEDs for regimens in which the tumor bed receives a total dose of either 60 Gy or 66 Gy. The BED values calculated for the acute radiation responses of erythema and desquamation were nearly all lower for the PBI schedules, and the late-response BEDs for most PBI regimens were in a similar range to the BEDs for the standard treatments. CONCLUSION: Biologically effective dose modeling raises the concern that inadequate doses might be delivered by PBI to ensure optimal in-field tumor control
— id: 64382, year: 2004, vol: 60, page: 1393, stat: Journal Article,

ATM sequence variants and adverse radiotherapy response in breast cancer patients
Rosenstein, BS; Andreassen, CN; Alsner, J; Overgaard, M; Cesaretti, JA; Atencio, DA; Green, S; Formenti, SC; Stock, RG; Overgaard, J
2004 APR ;60(1):S207-S208, International journal of radiation oncology biology physics
— id: 48940, year: 2004, vol: 60, page: S207, stat: Journal Article,

Para-Amino Benzoic Acid (PABA) modulates expression and stability of CDC25A in tumor cells and enhances radiosensitivity in vitro and in vivo
Xavier, S; Roth, J; Caunt, M; Akalu, A; Rodriguez, D; MacDonald, S; Devitt, M; Rosenstein, B; Formenti, SC; Brooks, PC
2004 ;60(1):S360-S361 #2038, International journal of radiation oncology biology physics
— id: 109272, year: 2004, vol: 60, page: S360, stat: Journal Article,

Designing and implementing quality control for multi-center screening of mutations in the ATM gene among women with breast cancer
Bernstein, Jonine L; Teraoka, Sharon; Haile, Robert W; Borresen-Dale, Anne-Lise; Rosenstein, Barry S; Gatti, Richard A; Diep, Anh T; Jansen, Laila; Atencio, David P; Olsen, Jorgen H; Bernstein, Leslie; Teitelbaum, Susan L; Thompson, W Douglas; Concannon, Patrick
2003 May;21(5):542-550, Human mutation
Epidemiologic studies of breast and other cancers are increasingly turning toward large, multi-center designs in order to obtain adequate power to detect low-penetrance susceptibility alleles. The size of such studies often makes it necessary to distribute the genetic screening efforts to multiple sites. Careful standardization of screening methodology and quality control across sites is required for such multi-center screening designs to be efficient. In this report, we illustrate our approach to these challenges in the context of the WECARE (Women's Environment, Cancer and Radiation Epidemiology) Study, a multi-center population-based genetic epidemiologic study of women with unilateral and bilateral breast cancer. We provide optimized conditions for screening the ataxia-telangiectasia gene (ATM) for variation by denaturing high-performance liquid chromatography (DHPLC) and describe the results of two independent quality control studies at four international centers employing these conditions. Finally, we report novel mutations in the ATM gene identified both in patients with ataxia-telangiectasia and in patients with unilateral or bilateral breast cancer
— id: 143399, year: 2003, vol: 21, page: 542, stat: Journal Article,

Hypo-fractionated partial breast radiation after breast-conserving surgery: preliminary clinical results and dose volume histogram (DVH) analysis
Truong M; Rosenstein B; Goldberg J; Cho C; DeWyngaert KJ; Formenti SC
2003 Oct 1;57(2 Suppl):S367-S368, International journal of radiation oncology biology physics
— id: 39081, year: 2003, vol: 57, page: S367, stat: Journal Article,

Toward a consensus on radiobiology teaching to radiation oncology residents
Dynlacht, Joseph R; Dewhirst, Mark W; Hall, Eric J; Rosenstein, Barry S; Zeman, Elaine M
2002 May;157(5):599-606, Radiation research
There are approximately 82 radiation oncology residency programs in the United States, which provide training opportunities for about 400 residents. All accredited radiation oncology residency programs must have at least one basic scientist on the faculty, and it is these individuals who often assume, wholly or in part, the responsibility of teaching radiation and cancer biology to radiation oncology residents in preparation for the American College of Radiology (ACR) In-Training Examination in Radiation Oncology and the American Board of Radiology (ABR) written examinations. In response to a perceived lack of uniformity in radiation and cancer biology curricula currently being taught to residents and a perceived lack of guidance for instructors in formulating course content for this population, a special session was presented at the Forty-eighth Annual Radiation Research Society meeting on April 23, 2001. The session, entitled 'Toward a Consensus on Radiobiology Teaching to Radiation Oncology Residents', was focused on issues related to teaching radiobiology to radiation oncology residents and targeted for individuals who actively teach radiation and cancer biology as well as coordinators of residency training programs. The speakers addressed current challenges and future problems facing instructors and programs. Among these were lack of feedback on resident performance on ABR and ACR written examinations and on course content, uncertainty about what topics residents must know to pass the ABR examination, and, in the near future, a reduction (due to retirement) of instructors qualified to teach radiobiology. This article provides a synopsis of the information that was presented during that session, offers a glimpse into how the ABR and ACR examinations are prepared and details of the content of past and future examinations, and summarizes the activities of the Joint Working Group on Radiobiology Teaching which was formed to educate instructors, to establish a consensus for course curricula, and to improve the overall quality of resident teaching
— id: 143401, year: 2002, vol: 157, page: 599, stat: Journal Article,

T1 stage breast cancer: adjuvant hypofractionated conformal radiation therapy to tumor bed in selected postmenopausal breast cancer patients--pilot feasibility study
Formenti, Silvia C; Rosenstein, Barry; Skinner, Kristin A; Jozsef, Gabor
2002 Jan;222(1):171-178, Radiology
PURPOSE: To explore the feasibility of a short course of hypofractionated conformal radiation therapy to the tumor bed as part of a breast preservation protocol in postmenopausal patients with nonpalpable pT1N0 stage breast cancer. MATERIALS AND METHODS: The tumor bed was imaged at computed tomography (CT) in the prone position on a dedicated table. The same table and position were used for treatment with a 4-MV linear accelerator. The planning target volume was the tumor bed plus a 1-2-cm margin defined at postmastectomy CT. A regimen of five fractions was tested in this pilot dose study. Cosmesis was assessed by patients and physicians before treatment and 36 months after treatment. RESULTS: Ten consecutive patients who were eligible for the study were assigned to one of three dose-per-fraction regimens; nine were treatable with the proposed technique on the basis of CT findings. Patients received five fractions over 10 days (total dose range, 25-30 Gy): Three received 5.0 Gy per fraction; four, 5.5 Gy; and two, 6.0 Gy. At minimum follow-up of 36 months (range, 36-53 months), all patients were alive and disease free with good to excellent cosmesis. CONCLUSION: Hypofractionated conformal breast radiation therapy is feasible. Further studies are warranted
— id: 34946, year: 2002, vol: 222, page: 171, stat: Journal Article,

ATM mutations in female breast cancer patients predict for an increase in radiation-induced late effects
Iannuzzi, Christopher M; Atencio, David P; Green, Sheryl; Stock, Richard G; Rosenstein, Barry S
2002 Mar 1;52(3):606-613, International journal of radiation oncology biology physics
PURPOSE: Mutation of the ATM gene may be associated with enhanced radiosensitivity and increased radiation-induced morbidity. Denaturing high performance liquid chromatography (DHPLC) is a powerful new technique proven to be sensitive and accurate in the detection of missense mutations, as well as small deletions and insertions. We screened female breast cancer patients for evidence of ATM gene alterations using DHPLC. This study attempted to determine whether breast cancer patients who develop severe radiotherapy (RT)-induced effects are more likely to possess ATM mutations than patients who display normal radiation responses. METHODS AND MATERIALS: Forty-six patients with early-stage breast carcinoma underwent limited surgery and adjuvant RT. DNA was isolated from blood lymphocytes, and each coding exon of the ATM gene was amplified using polymerase chain reaction. Genetic variants were identified using DHPLC by comparing test patterns with a known wild-type pattern. All variants were subjected to DNA sequencing and compared with wild-type sequences for evidence of a mutation. A retrospective review was performed, and the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer acute and late morbidity scoring schemes for skin and subcutaneous normal tissues were applied to quantify the radiation-induced effects. RESULTS: Nine ATM mutations were identified in 6 patients (8 novel and 1 rare). The median follow-up was 3.2 years (range 1.3-10.3). A significant correlation between ATM mutation status and the development of Grade 3-4 subcutaneous late effects was found. All 3 of the patients (100%) who manifested Grade 3-4 subcutaneous late sequelae possessed ATM mutations, whereas only 3 (7%) of the 43 patients who did not develop this form of severe toxicity harbored an ATM mutation (p = 0.001). One ATM mutation carrier developed Grade 4 soft tissue necrosis after RT and required hyperbaric oxygen. All 3 patients manifesting Grade 3-4 late subcutaneous responses in fact harbored 2 ATM mutations. In contrast, none of the 3 ATM carriers who had a single mutation developed a severe subcutaneous reaction. ATM mutation status did not predict for a significant increase in early effects. Of the 23 patients with Grade 2-3 moist desquamation, 4 (17%) had an ATM mutation compared with 2 (9%) of 23 patients without desquamation (p = 0.7). CONCLUSION: Possession of an ATM mutation, particularly when 2 are present, may be predictive of an increase in subcutaneous late tissue effects after RT for breast cancer and may subsequently prove to be a relative contraindication to standard management. These patients may be better served with reduced doses of radiation. Equivalent local control remains to be tested, but this germline alteration may radiosensitize normal tissues, as well as the tumor itself. DHPLC is effective in the identification of these patients. A larger study is required to confirm these findings
— id: 143402, year: 2002, vol: 52, page: 606, stat: Journal Article,

Toward a national consensus: teaching radiobiology to radiation oncology residents
Zeman, Elaine M; Dynlacht, Joseph R; Rosenstein, Barry S; Dewhirst, Mark W
2002 Nov 1;54(3):861-872, International journal of radiation oncology biology physics
PURPOSE: The ASTRO Joint Working Group on Radiobiology Teaching, a committee composed of members having affiliations with several national radiation oncology and biology-related societies and organizations, commissioned a survey designed to address issues of manpower, curriculum standardization, and instructor feedback as they relate to resident training in radiation biology. METHODS AND MATERIALS: Radiation biology instructors at U.S. radiation oncology training programs were identified and asked to respond to a comprehensive electronic questionnaire dealing with instructor educational background, radiation biology course content, and sources of feedback with respect to curriculum planning and resident performance on standardized radiation biology examinations. RESULTS: Eighty-five radiation biology instructors were identified, representing 73 radiation oncology residency training programs. A total of 52 analyzable responses to the questionnaire were received, corresponding to a response rate of 61.2%. CONCLUSION: There is a decreasing supply of instructors qualified to teach classic, and to some extent, clinical, radiobiology to radiation oncology residents. Additionally, those instructors with classic training in radiobiology are less likely to be comfortable teaching cancer molecular biology or other topics in cancer biology. Thus, a gap exists in teaching the whole complement of cancer and radiobiology curricula, particularly in those programs in which the sole responsibility for teaching falls to one faculty member (50% of training programs are in this category). On average, the percentage of total teaching time devoted to classic radiobiology (50%), clinical radiobiology (30%), and molecular and cancer biology (20%) is appropriate, relative to the current makeup of the board examination. Nevertheless large variability exists between training programs with respect to the total number of contact hours per complete radiobiology course (ranging from approximately 10 to >50 h). A number of lecture topics, particularly in clinical radiobiology, are covered by fewer than 60% of training programs. A sizeable minority of radiation biology instructors are dissatisfied with the feedback they receive with respect to both course content and the performance of their residents on standardized radiobiology examinations administered by the American College of Radiology and/or the American Board of Radiology
— id: 143400, year: 2002, vol: 54, page: 861, stat: Journal Article,

Screening breast cancer patients for ATM mutations and polymorphisms by using denaturing high-performance liquid chromatography
Atencio, DP; Iannuzzi, CM; Green, S; Stock, RG; Bernstein, JL; Rosenstein, BS
2001 NOV ;38(2-3):200-208, Environmental & molecular mutagenesis
All 62 coding exons of the ATM gene, along with 10-20 bases of the intronic region flanking each exon, were screened for DNA base sequence alterations by using denaturing high-performance liquid chromatography (DHPLC) in a series of 52 breast cancer patients. Six (12%) of these patients exhibited a total of eight different novel germ-line mutations that do not represent common polymorphisms. Of these, three patients possessed four nonconservative missense mutations while two conservative missense and two synonymous mutations were detected in the other three patients. In addition, 43 patients were found to have a total of 141 DNA sequence variations representing 21 different common polymorphisms and rare variants. An analysis of the relationship between the presence of a novel ATM mutation and either patient demographics or tumor properties demonstrated a significant difference between African Americans (3/ 7 = 43%) and other ethnic groups (3/45 = 7%, P = 0.026). None of the other characteristics examined was found to be related to mutation status. (C) 2001 Wiley-Liss, Inc
— id: 54814, year: 2001, vol: 38, page: 200, stat: Journal Article,

Adjuvant hypofractionated conformal radiation to the tumor bed in selected post-menopausal women with T1 breast cancers: A pilot-feasibility study
Formenti, SC; Rosenstein, BS; Jozsef, G
2001 ;7(6):548-548 #P34, Cancer journal
— id: 109273, year: 2001, vol: 7, page: 548, stat: Journal Article,

ATM heterozygosity and breast cancer: screening of 37 breast cancer patients for ATM mutations using a non-isotopic RNase cleavage-based assay
Drumea KC; Levine E; Bernstein J; Shank B; Green S; Kaplan E; Mandell L; Cropley J; Obropta J; Braccia I; Krupnik A; Rosenstein BS
2000 May;61(1):79-85, Breast cancer research & treatment
Based upon the results of several epidemiologic studies, it has been suggested that women who are carriers for a mutation in the ataxia telangiectasia-mutated (ATM) gene are susceptible for the development of breast cancer. Therefore, 37 consecutive breast cancer patients were screened for the presence of a germline ATM mutation using a non-isotopic RNase cleavage-based assay (NIRCA). This paper reports the first use of NIRCA for detection of ATM mutations in breast cancer patients. Using this assay, no ATM mutations were found in our patient population. This result is similar to the findings of other studies that have employed approaches complementary to NIRCA
— id: 39548, year: 2000, vol: 61, page: 79, stat: Journal Article,

p53 mutations in basal cell carcinomas arising in routine users of sunscreens
Rosenstein, B S; Phelps, R G; Weinstock, M A; Bernstein, J L; Gordon, M L; Rudikoff, D; Kantor, I; Shelton, R; Lebwohl, M G
1999 Nov;70(5):798-806, Photochemistry & photobiology
Sun exposure histories were obtained from a series of patients age 35 or younger following diagnosis and removal of a basal cell carcinoma (BCC). The DNA was extracted from tumor biopsy samples derived from BCC of 10 patients who reported that they did not use sunscreens during youth (age 18 or younger) and 10 patients who routinely employed sunscreens during this age period. Exons 5-9 of the p53 gene were then amplified in three fragments from these samples using a nested polymerase chain reaction (PCR) approach and screened for mutations using an RNA heteroduplex assay. All PCR products displaying evidence of a mutation were sequenced. It was found that 6 of the 10 patients who were not routine sunscreen users displayed mutations in these p53 exons. All of the mutations were located at dipyrimidine sites, five of the six were C-->T transitions and one mutation was a tandem double mutation, consistent with a role for solar UVB in BCC formation. In contrast, only one p53 mutation was detected in the group of 10 patients who routinely employed sunscreens during childhood and adolescence. Hence, a significantly (P = 0.029) lower level of p53 mutations was detected in the BCC obtained from sunscreen users compared with tumors derived from nonusers. These findings suggest that the mechanisms involved in the etiology of skin carcinogenesis differ in sunscreen users compared with people who did not routinely employ sunscreens. These data are also indicative of a protective effect associated with sunscreen use against the formation of p53 mutations. It is possible that the patients who were diagnosed with BCC despite their use of sunscreens possessed a genetic susceptibility for skin cancer formation and developed BCC through a p53-independent pathway. Alternatively, solar UVA wavelengths, that were generally not blocked by the suncare products employed by the sunscreen users, may have played a significant role in BCC development through induction of a mutation(s) in an oncogene and/or a tumor suppressor gene, other than p53, for these patients
— id: 111791, year: 1999, vol: 70, page: 798, stat: Journal Article,

p53 mutations in basal cell carcinomas arising in routine sunscreen users
Rosenstein, B; Phelps, R; Weinstock, M; Bernstein, J; Gordon, M; Rudikoff, D; Kantor, I; Shelton, R; Lebwohl, M
1999 JUN ;69(2):33S-33S, Photochemistry & photobiology
— id: 53988, year: 1999, vol: 69, page: 33S, stat: Journal Article,