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Purpose: To highlight the current evidence and the limitations in data to support a personalized approach in breast oncology radiation therapy management and define steps needed for clinical implementation. Methods and Materials: A critical review of the current literature on the use of genomics in breast radiation therapy was undertaken by a group of breast radiation oncologists to discuss current data, future directions, and challenges. Results: A summary of the existing data, ongoing clinical trials, and future directions is provided. The authors note many groups have developed radiation-specific genomic assays, which demonstrate promise in prediction of local control and benefit from radiation therapy; however, prospective validation of their utility is needed. Limitations continue to exist in our understanding of tumor biology and how it can be integrated into clinical practice. Conclusions: Given the relative ubiquity of breast radiation therapy, the variety of dose and fractionation approaches, and the current data to support a personalized approach, it is our belief that the delivery of breast radiation therapy is uniquely poised for a genomically personalized radiation therapy approach. Prospective clinical trials implementing genomic signatures are needed at this time to advance the field.

Background: Utilizing the linear quadratic model and the radiosensitivity index (RSI), we have derived an expression for the genomically adjusted radiation dose (GARD) to model radiation dose effect. We hypothesize GARD is associated with local recurrence and can be used to optimize individual triple negative breast cancer (TNBC) radiation dose. Methods: TN patients from two independent datasets were assessed. The first cohort consisted of 58 patients treated at 5 European centers with breast conservation surgery followed by adjuvant radiotherapy (RT). The second dataset consisted of 55 patients treated with adjuvant radiation therapy. Findings: In cohort 1, multivariable analysis revealed that as a dichotomous variable (HR: 2.5 95% CI 1–7.1; p = .05), GARD was associated with local control. This was confirmed in the second independent dataset where GARD was the only significant factor associated with local control (HR: 4.4 95% CI 1.1–29.5; p = .04). We utilized GARD to calculate an individualized radiation dose for each TN patient in cohort 2 by determining the physical dose required to achieve the GARD target value (GARD ≥ 21). While 7% of patients were optimized with a dose of 30 Gy, 91% of patients would be optimized with 70 Gy. Interpretation: GARD is associated with local control following whole breast or post-mastectomy radiotherapy (RT) in TN patients. By modeling RT dose effect with GARD, we demonstrate that no single dose is optimal for all patients and propose the first dose range to optimize RT at an individual patient level in TNBC. Keywords: Genomically adjusted radiation dose, Personalized radiotherapy, Radiotherapy, Breast cancer

Adjuvant breast radiation therapy after breast conservation surgery is recommended as it yields significant reduction in the risk of local recurrence, and confers a potential overall survival benefit. Although the standard breast radiation regimen has historically been delivered over 5–7 weeks; more novel, shorter courses of breast radiation are currently being employed, offering the advantage of more convenience and less time-commitment. Herein, we review the recent literature substantiating these abbreviated radiation treatment approaches and the methods of delivery thereof. In addition, we discuss imaged guided techniques currently being utilized to further refine the delivery of adjuvant breast radiation therapy.

Background: This practice parameter was revised collaboratively by the American College of Radiology (ACR), and the American Radium Society. This practice parameter provides updated reference literature regarding radiation oncology practice and its key personnel., Methods: This practice parameter was developed according to the process described under the heading The Process for Developing ACR Practice Parameters and Technical Standards on the ACR website ( https://www.acr.org/Clinical-Resources/Practice-Parameters-and-Technical-Standards ) by the Committee on Practice Parameters-Radiation Oncology of the ACR Commission on Radiation Oncology in collaboration with the American Radium Society., Results: This practice parameter provides a comprehensive update to the reference literature regarding radiation oncology practice in general. The overall roles of the radiation oncologist, the Qualified Medical Physicist, and other specialized personnel involved in the delivery of external-beam radiation therapy are discussed. The use of radiation therapy requires detailed attention to equipment, patient and personnel safety, equipment maintenance and quality assurance, and continuing staff education. Because the practice of radiation oncology occurs in a variety of clinical environments, the judgment of a qualified radiation oncologist should be used to apply these practice parameters to individual practices. Radiation oncologists should follow the guiding principle of limiting radiation exposure to patients and personnel while accomplishing therapeutic goals., Conclusion: This practice parameter can be used as an effective tool to guide radiation oncology practice by successfully incorporating the close interaction and coordination among radiation oncologists, medical physicists, dosimetrists, nurses, and radiation therapists., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Clozapine is the most effective medication for treatment-resistant psychosis, but evidence points to substantial underuse, especially within early intervention psychosis (EIP) services. We explored clinicians' views on perceived barriers and facilitators to offering patients clozapine within EIP services. A cross-sectional survey was distributed electronically to clinicians practising in EIP services across England. A mixed methods approach was used to assess barriers to clozapine, and attitudes and opinions concerning clozapine underutilisation. Based on the barriers identified in the literature, clinicians were asked to rate each one (scale:1-7) based on importance, with a higher score indicating higher importance. Clinicians were also asked open-ended questions on barriers to clozapine and how access can be improved in EIP services. Quantitative data were analysed using descriptive and inferential statistics, and qualitative responses were analysed thematically. One hundred and nineteen EIP clinicians from 35 services in England completed the survey. In total, 37% (n = 45) of clinicians perceived that clozapine was under-prescribed in their EIP service. The most important barrier to utilising clozapine were patient concerns with side effects, followed by monitoring requirements and clinician concerns with side effects. Thematic analysis identified 17 perceived barriers, which were grouped into three major themes: administrative (5 subthemes), clinician-related (6 subthemes), and patient-related (6 subthemes). Perceived facilitators to improving clozapine use were greater training, improved resources, and optimised monitoring. The main barriers to clozapine in EIP services, as identified by clinicians, are patient concerns regarding side effects and monitoring requirements. Identified facilitators for improved clozapine use include clinician training, improved resources, guidelines, and point-of-care testing., (© 2023. The Author(s).)

Accurate coregistration of computed tomography (CT) and magnetic resonance (MR) imaging can provide clinically relevant and complementary information and can serve to facilitate multiple clinical tasks including surgical and radiation treatment planning, and generating a virtual Positron Emission Tomography (PET)/MR for the sites that do not have a PET/MR system available. Despite the long-standing interest in multimodality co-registration, a robust, routine clinical solution remains an unmet need. Part of the challenge may be the use of mutual information (MI) maximization and local phase difference (LPD) as similarity metrics, which have limited robustness, efficiency, and are difficult to optimize. Accordingly, we propose registering MR to CT by mapping the MR to a synthetic CT intermediate (sCT) and further using it in a sCT-CT deformable image registration (DIR) that minimizes the sum of squared differences. The resultant deformation field of a sCT-CT DIR is applied to the MRI to register it with the CT. Twenty-five sets of abdominopelvic imaging data are used for evaluation. The proposed method is compared to standard MI- and LPD-based methods, and the multimodality DIR provided by a state of the art, commercially available FDA-cleared clinical software package. The results are compared using global similarity metrics, Modified Hausdorff Distance, and Dice Similarity Index on six structures. Further, four physicians visually assessed and scored registered images for their registration accuracy. As evident from both quantitative and qualitative evaluation, the proposed method achieved registration accuracy superior to LPD- and MI-based methods and can refine the results of the commercial package DIR when using its results as a starting point. Supported by these, this manuscript concludes the proposed registration method is more robust, accurate, and efficient than the MI- and LPD-based methods., (© 2022 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Purpose: The volume of Venezia applicator with vaginal caps can be relatively large compared to target volumes. This study investigated the dosimetric and radiobiological effects of applicator volume removal for cervical cancer patients treated with Venezia (VZ) and tandem and split-ring (TSR) applicators used in the clinic., Material and Methods: A total of 40 patients (101 plans) with stage IIA-IIIC cervical cancer were retrospectively reviewed. Thirty patients were treated with VZ and ten patients were treated with TSR. Applicators were contoured on planning CTs where target contours were involved. Applicator contours were subtracted from the target contours. External beam radiation therapy (EBRT) and brachytherapy doses were calculated in biologically equivalent doses in 2 Gy fractions (EQD 2 ) and combined using full parameter addition for dose-volume histogram (DVH) parameters of composited dose. D 90% , D 50% , V 100% , V 150% , V 200% , and tumor control probability (TCP) were evaluated and compared for targets after applicator exclusion., Results: The average volume changes in gross tumor volume (GTV), high-risk clinical target volume (HR-CTV), and intermediate-risk clinical target volume (IR-CTV) after VZ applicator exclusion were 1.4 ±1.5 cm 3 , 15.7 ±6.6 cm 3 , and 33.8 ±15.1 cm 3 , respectively. VZ exclusion resulted in significant changes ( p < 0.05) in small volume parameters (D 50% ) and high-dose parameters (V 150% and V 200% ) for HR-CTV and IR-CTV. Dosimetric impact of TSR exclusion on targets was not significant. There was no significant change in TCP after applicator exclusion., Conclusions: Venezia applicator with vaginal caps has significant impact on small volume and high-dose DVH parameters of the target. Applicator contour exclusion is recommended for dosimetric evaluation when Venezia applicator is used., Competing Interests: The authors report no conflict of interest., (Copyright © 2022 Termedia.)

Purpose: The in vivo dosimetric monitoring in HDR brachytherapy is important for improving patient safety. However, there are very limited options available for clinical application. In this study, we present a new in vivo dose measurement system with a plastic scintillating detector (PSD) for GYN HDR brachytherapy., Methods: An FDA approved PSD system, called OARtrac (AngioDynamics, Latham, NY), was used with various applicators for in vivo dose measurements for GYN patients. An institutional workflow was established for the clinical implementation of the dosimetric system. Action levels were proposed based on the measurement and system uncertainty for measurement deviations. From October 2018 to September 2019, a total of 75 measurements (48 fractions) were acquired from 14 patients who underwent HDR brachytherapy using either a multichannel cylinder, Venezia applicator, or Syed-Neblett template. The PSDs were placed in predetermined catheters/channels. A planning CT was acquired for treatment planning in Oncentra (Elekta, Version-4.5.2) TPS. The PSDs were contoured on the CT images, and the PSD D 90% values were used as the expected doses for comparison with the measured doses., Results: The mean difference from patient measurements was -0.22% ± 5.98%, with 26% being the largest deviation from the expected value (Syed case). Large deviations were observed when detectors were placed in the area where dose rates were less than 1 cGy/s., Conclusions: The establishment of clinical workflow for the in vivo dosimetry for both the intracavitary and interstitial GYN HDR brachytherapy will potentially improve the safety of the patient treatment., (Copyright © 2020 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Routine treatment of clinically uninvolved internal mammary nodes in breast cancer patients requiring post-mastectomy radiation therapy is controversial. The purpose of this study was to measure the incidental radiation dose to the internal mammary lymph nodes not included in the planning target volume (PTV) in women with breast cancer receiving post-mastectomy radiation therapy. This retrospective protocol utilized CT-based 3D conformal treatment plans. Fifty consecutive patients were included in the analysis: 25 left breast and 25 right breast patients. 3D conformal treatment plans chest wall tangent fields and matched supraclavicular were used. All plans were prescribed to a total dose of 50 Gy in 25 fractions to the chest wall and 46 Gy in 23 fractions to the supraclavicular field. The internal mammary node chain was intentionally not included in the target volume. For purposes of this study, internal mammary vessels were contoured following the Radiation Therapy Oncologist Group atlas with a 7-mm PTV expansion, utilizing original CT simulation images. The internal mammary nodes were contoured in between the first 3 and first 5 intercostal spaces for comparison. Percent volume of internal mammary node PTV receiving 95 % of the prescribed dose (47.5 Gy) with 7-mm expansion and first 5 intercostal spaces for all patients was 25.2 % (range 0.04-97.6 %, standard deviation (SD) 23.5). The mean internal mammary node dose for all patients was 24.98 Gy (range 3.54-55.93 Gy, SD 16). Results of this study suggest the incidental dose to the internal mammary nodes does not achieve clinically significant therapeutic levels in post-mastectomy breast cancer patients treated with standard 3D conformal radiation therapy chest wall irradiation. If risk factors for microscopic involvement are present, internal mammary nodes must be specifically included in target volumes in order to be adequately treated.

Purpose: To develop a tri-modality image fusion method for better target delineation in image-guided radiotherapy for patients with brain tumors., Methods: A new method of tri-modality image fusion was developed, which can fuse and display all image sets in one panel and one operation. And a feasibility study in gross tumor volume (GTV) delineation using data from three patients with brain tumors was conducted, which included images of simulation CT, MRI, and 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) examinations before radiotherapy. Tri-modality image fusion was implemented after image registrations of CT+PET and CT+MRI, and the transparency weight of each modality could be adjusted and set by users. Three radiation oncologists delineated GTVs for all patients using dual-modality (MRI/CT) and tri-modality (MRI/CT/PET) image fusion respectively. Inter-observer variation was assessed by the coefficient of variation (COV), the average distance between surface and centroid (ADSC), and the local standard deviation (SDlocal). Analysis of COV was also performed to evaluate intra-observer volume variation., Results: The inter-observer variation analysis showed that, the mean COV was 0.14(± 0.09) and 0.07(± 0.01) for dual-modality and tri-modality respectively; the standard deviation of ADSC was significantly reduced (p<0.05) with tri-modality; SDlocal averaged over median GTV surface was reduced in patient 2 (from 0.57 cm to 0.39 cm) and patient 3 (from 0.42 cm to 0.36 cm) with the new method. The intra-observer volume variation was also significantly reduced (p = 0.00) with the tri-modality method as compared with using the dual-modality method., Conclusion: With the new tri-modality image fusion method smaller inter- and intra-observer variation in GTV definition for the brain tumors can be achieved, which improves the consistency and accuracy for target delineation in individualized radiotherapy.

Background: The TARGIT-A trial compared risk-adapted radiotherapy using single-dose targeted intraoperative radiotherapy (TARGIT) versus fractionated external beam radiotherapy (EBRT) for breast cancer. We report 5-year results for local recurrence and the first analysis of overall survival., Methods: TARGIT-A was a randomised, non-inferiority trial. Women aged 45 years and older with invasive ductal carcinoma were enrolled and randomly assigned in a 1:1 ratio to receive TARGIT or whole-breast EBRT, with blocks stratified by centre and by timing of delivery of targeted intraoperative radiotherapy: randomisation occurred either before lumpectomy (prepathology stratum, TARGIT concurrent with lumpectomy) or after lumpectomy (postpathology stratum, TARGIT given subsequently by reopening the wound). Patients in the TARGIT group received supplemental EBRT (excluding a boost) if unforeseen adverse features were detected on final pathology, thus radiotherapy was risk-adapted. The primary outcome was absolute difference in local recurrence in the conserved breast, with a prespecified non-inferiority margin of 2·5% at 5 years; prespecified analyses included outcomes as per timing of randomisation in relation to lumpectomy. Secondary outcomes included complications and mortality. This study is registered with ClinicalTrials.gov, number NCT00983684., Findings: Patients were enrolled at 33 centres in 11 countries, between March 24, 2000, and June 25, 2012. 1721 patients were randomised to TARGIT and 1730 to EBRT. Supplemental EBRT after TARGIT was necessary in 15·2% [239 of 1571] of patients who received TARGIT (21·6% prepathology, 3·6% postpathology). 3451 patients had a median follow-up of 2 years and 5 months (IQR 12-52 months), 2020 of 4 years, and 1222 of 5 years. The 5-year risk for local recurrence in the conserved breast was 3·3% (95% CI 2·1-5·1) for TARGIT versus 1·3% (0·7-2·5) for EBRT (p=0·042). TARGIT concurrently with lumpectomy (prepathology, n=2298) had much the same results as EBRT: 2·1% (1·1-4·2) versus 1·1% (0·5-2·5; p=0·31). With delayed TARGIT (postpathology, n=1153) the between-group difference was larger than 2·5% (TARGIT 5·4% [3·0-9·7] vs EBRT 1·7% [0·6-4·9]; p=0·069). Overall, breast cancer mortality was much the same between groups (2·6% [1·5-4·3] for TARGIT vs 1·9% [1·1-3·2] for EBRT; p=0·56) but there were significantly fewer non-breast-cancer deaths with TARGIT (1·4% [0·8-2·5] vs 3·5% [2·3-5·2]; p=0·0086), attributable to fewer deaths from cardiovascular causes and other cancers. Overall mortality was 3·9% (2·7-5·8) for TARGIT versus 5·3% (3·9-7·3) for EBRT (p=0·099). Wound-related complications were much the same between groups but grade 3 or 4 skin complications were significantly reduced with TARGIT (four of 1720 vs 13 of 1731, p=0·029)., Interpretation: TARGIT concurrent with lumpectomy within a risk-adapted approach should be considered as an option for eligible patients with breast cancer carefully selected as per the TARGIT-A trial protocol, as an alternative to postoperative EBRT., Funding: University College London Hospitals (UCLH)/UCL Comprehensive Biomedical Research Centre, UCLH Charities, National Institute for Health Research Health Technology Assessment programme, Ninewells Cancer Campaign, National Health and Medical Research Council, and German Federal Ministry of Education and Research., (Copyright © 2014 Vaidya et al. Open Access article distributed under the terms of CC BY-NC-ND. Published by Elsevier Ltd. All rights reserved.)

Pharmaceuticals have been detected in the soil environment where there is the potential for uptake into crops. This study explored the fate and uptake of pharmaceuticals (carbamazepine, diclofenac, fluoxetine, propranolol, sulfamethazine) and a personal care product (triclosan) in soil-plant systems using radish (Raphanus sativus) and ryegrass (Lolium perenne). Five of the six chemicals were detected in plant tissue. Carbamazepine was taken up to the greatest extent in both the radish (52 μg/g) and ryegrass (33 μg/g), whereas sulfamethazine uptake was below the limit of quantitation (LOQ) (<0.01 μg/g). In the soil, concentrations of diclofenac and sulfamethazine dropped below the LOQ after 7 days. However, all pharmaceuticals were still detectable in the pore water at the end of the experiment. The results demonstrate the ability of plant species to accumulate pharmaceuticals from soils with uptake apparently specific to both plant species and chemical. Results can be partly explained by the hydrophobicity and extent of ionization of each chemical in the soil.

Methylation of arsenic in soil influences its environmental behavior and accumulation by plants, but little is known about the factors affecting As methylation. As speciation was determined in the pore waters of six soils from diverse geographical locations over 54 days of incubation under flooded conditions. The concentration of methylated As (monomethylarsonic acid, MMA, and dimethylarsinic acid, DMA) varied from 0 to 85 μg L(-1) (0 - 69% of the total As in pore water). Two Bangladeshi paddy soils contaminated by irrigation of As-laden groundwater produced large concentrations of inorganic As but relatively little methylated As. Two contaminated paddy soils from China produced a transient peak of DMA during the early phase of incubation. Methylated As represented considerable proportions of the total soluble As in the two uncontaminated soils from the UK and U.S. The copy number of the microbial arsenite methyltransferase gene (arsM) correlated positively with soil pH. However, pore-water methylated As correlated negatively with pH or arsM copy number, and positively with dissolved organic C. GeoChip assay revealed considerable arsM diversity among the six soils, with 27-35 out of 66 sequences in the microarray being detected. As speciation in rice plants grown in the soils generally mirrored that in the pore water. The results suggest that methylated As species in plants originated from the soil and As methylation in soil was influenced strongly by the soil conditions.

Objectives: This randomized controlled trial was conducted to examine immune recovery following breast cancer (BC) therapy and evaluate the effect of mindfulness-based stress reduction therapy (MBSR) on immune recovery with emphasis on lymphocyte subsets, T cell activation, and production of T-helper 1 (Th1; interferon [IFN]-γ) and T-helper 2 (Th2; interleukin-4 [IL-4]) cytokines., Method: Participants who completed the study consisted of 82 patients diagnosed with Stage 0-III BC, who received lumpectomy and adjuvant radiation ± chemotherapy. Patients were randomized into an MBSR(BC) intervention program or a control (usual care) group. Immune cell measures were assessed at baseline and within 2 weeks after the 6-week intervention. The numbers and percentages of lymphocyte subsets, activated T cells, and Th1 and Th2 cells in peripheral blood samples were determined by immunostaining and flow cytometry., Results: Immune subset recovery after cancer treatment showed positive associations with time since treatment completion. The B and natural killer (NK) cells were more susceptible than T cells in being suppressed by cancer treatment. Women who received MBSR(BC) had T cells more readily activated by the mitogen phytohemagglutinin (PHA) and an increase in the Th1/Th2 ratio. Activation was also higher for the MBSR(BC) group if <12 weeks from the end of treatment and women in MBSR(BC) <12 weeks had higher T cell count for CD4(+)., Conclusion: MBSR(BC) promotes a more rapid recovery of functional T cells capable of being activated by a mitogen with the Th1 phenotype, whereas substantial recovery of B and NK cells after completion of cancer treatment appears to occur independent of stress-reducing interventions.

National Comprehensive Cancer Network (NCCN) guidelines for female breast cancer treatment and surveillance are well established, but similar guidelines on male breast cancers are less recognized. As an NCCN institution, our objective was to examine practice patterns and follow-up for male breast cancer compared to established guidelines for female patients. After Institutional Review Board approval, a prospective breast database from 1990 to 2009 was queried for male patients. Medical records were examined for clinico-pathological factors and follow-up. The 5-year survival rates with 95% confidence intervals were estimated using Kaplan-Meier method and Greenwood formula. Of the 19,084 patients in the database, 73 (0.4%) were male patients; 62 had complete data. One patient had bilateral synchronous breast cancer. The median age was 68.8 years (range 29-85 years). The mean/median invasive tumor size was 2.2/1.6 cm (range 0.0-10.0 cm). All cases had mastectomy (29 with axillary node dissection, 23 with sentinel lymph node biopsy only, 11 with sentinel node biopsy followed by completion axillary dissection). Lymph node involvement occurred in 25/63 (39.7%). Based on NCCN guidelines, chemotherapy, hormonal therapy, and radiation are indicated in 34 cases, 62 cases, and 14 cases, respectively. Only 20/34 (59%) received chemotherapy, 51/62 (82%) received hormonal therapy, and 10/14 (71%) received post-mastectomy radiation. Median follow-up was 26.2 months (range: 1.6-230.9 months). The 5-year survival estimates for node positive and negative diseases were 68.5% and 87.5%, respectively (p = 0.3). Despite the rarity of male breast cancer, treatment options based on current female breast tumors produce comparable results to female breast cancer. Increased awareness and a national registry for patients could help improve outcomes and tailor treatment recommendations to the male variant., (© 2011 Wiley Periodicals, Inc.)

To detect the molecular changes of malignancy in histologically normal breast (HNB) tissues, we recently developed a novel 117-gene-malignancy-signature. Here we report validation of our leading malignancy-risk-genes, topoisomerase-2-alpha (TOP2A), minichromosome-maintenance-protein-2 (MCM2) and "budding-uninhibited-by-benzimidazoles-1-homolog-beta" (BUB1B) at the protein level. Using our 117-gene malignancy-signature, we classified 18 fresh-frozen HNB tissues from 18 adult female breast cancer patients into HNB-tissues with low-grade (HNB-LGMA; N = 9) and high-grade molecular abnormality (HNB-HGMA; N = 9). Archival sections of additional HNB tissues from these patients, and invasive ductal carcinoma (IDC) tissues from six other patients were immunostained for these biomarkers. TOP2A/MCM2 expression was assessed as staining index (%) and BUB1B expression as H-scores (0-300). Increasing TOP2A, MCM2, and BUB1B protein expression from HNB-LGMA to HNB-HGMA tissues to IDCs validated our microarray-based molecular classification of HNB tissues by immunohistochemistry. We also demonstrated an increasing expression of TOP2A protein on an independent test set of HNB/benign/reductionmammoplasties, atypical-ductal-hyperplasia with and without synchronous breast cancer, DCIS and IDC tissues using a custom tissue microarray (TMA). In conclusion, TOP2A, MCM2, and BUB1B proteins are potential molecular biomarkers of malignancy in histologically normal and benign breast tissues. Larger-scale clinical validation studies are needed to further evaluate the clinical utility of these molecular biomarkers.

The development of novel technologies for the safe and effective delivery of radiation is critical to advancing the field of radiation oncology. The Emerging Technology Committee of the American Society for Therapeutic Radiology and Oncology appointed a Task Group within its Evaluation Subcommittee to evaluate new electronic brachytherapy methods that are being developed for, or are already in, clinical use. The Task Group evaluated two devices, the Axxent Electronic Brachytherapy System by Xoft, Inc. (Fremont, CA), and the Intrabeam Photon Radiosurgery Device by Carl Zeiss Surgical (Oberkochen, Germany). These devices are designed to deliver electronically generated radiation, and because of their relatively low energy output, they do not fall under existing regulatory scrutiny of radioactive sources that are used for conventional radioisotope brachytherapy. This report provides a descriptive overview of the technologies, current and future projected applications, comparison of competing technologies, potential impact, and potential safety issues. The full Emerging Technology Committee report is available on the American Society for Therapeutic Radiology and Oncology Web site., (Copyright 2010. Published by Elsevier Inc.)

Purpose: The tangential-beam technique frequently presents challenges in homogeneity of radiation dose to the target. To ensure an adequate dose to the skin, a bolus is often used. Tomotherapy has already been shown to improve target conformity and homogeneity in other disease sites. Because of the tangential delivery technique and lack of flattening filter in TomoTherapy accelerators, we hypothesize that during chest wall irradiation using tomotherapy, the skin dose will be adequate without bolus., Materials and Methods: This study compares the dosimetric differences between tomotherapy chest wall irradiation and traditional linear accelerator-based tangential-beam technique. Tomotherapy treatment plans with and without bolus were compared with tangentialbeam plans. Plans were also generated for phantom studies, and point doses were measured using MOSFET dosimetry to verify the adequate skin dose. Monte Carlo simulations of static beams of both techniques were performed, and dosimetry was compared., Results: Monte Carlo simulations and measurements confirmed that beams from tomotherapy deliver a higher skin dose than a standard linear accelerator. Skin dose also increases with the incident angle of the beams., Conclusion: Because of the characteristics of the tomotherapy beam and delivery technique, chest wall treatment plans from tomotherapy showed adequate skin dose [more than 75% of prescribed planning target volume (PTV) dose] even without bolus.

The purpose of this paper is to validate a dose mapping program using optical flow method (OFM), and to demonstrate application of the program in radiotherapy follow-up evaluation. For the purpose of validation, the deformation matrices between four-dimensional (4D) CT data of different simulated respiration phases of a phantom were calculated using OFM. The matrices were then used to map doses of all phases to a single-phase image, and summed in equal time weighting. The calculated dose should closely represent the dose delivered to the moving phantom if the deformation matrices are accurately calculated. The measured point doses agreed with the OFM calculations better than 2% at isocenters, and dose distributions better than 1mm for the 50% isodose line. To demonstrate proof-of-concept for the use of deformable image registration in dose mapping for treatment evaluation, the treatment-planning CT was registered with the post-treatment CT image from the positron emission tomography (PET)/CT resulting in a deformation matrix. The dose distribution from the treatment plan was then mapped onto the restaging PET/CT using the deformation matrix. Two cases in which patients had thoracic malignancies are presented. Each patient had CT-based treatment planning for radiotherapy and restaging fluorodeoxy glucose (FDG)-PET/CT imaging 4-6 weeks after completion of treatments. Areas of pneumonitis and recurrence were identified radiographically on both PET and CT restaging images. Local dose and standard uptake values for pneumonitis and recurrence were studied as a demonstration of this method. By comparing the deformable mapped dose to measurement, the treatment evaluation method which is introduced in this manuscript proved to be accurate. It thus provides a more accurate analysis than other rigid or linear dose-image registration when used in studying treatment outcome versus dose.

Background: The importance of negative final resection margins for optimal local control has been established for women with ductal carcinoma in situ (intraductal carcinoma) undergoing breast conservation treatment. This study evaluated long-term outcome after breast conservation treatment and whether reexcision or the presence of residual tumor in the reexcision specimen predicted for local recurrence in patients with ductal carcinoma in situ with negative margins., Methods: The study cohort consisted of 192 women with ductal carcinoma in situ treated with breast conservation treatment at the University of Pennsylvania from 1978 to 2000. Analysis was performed for unilateral, mammographically detected, intraductal breast carcinomas. Study endpoints of interest included rates of local recurrence, overall survival, and cause-specific survival. The median follow-up was 6.2 years (mean, 7 years; range, 0.1-21.4 years)., Results: The 10-year overall survival and 10-year cause-specific survival rates were 87% and 99%, respectively. There were 11 local failures (6%) in the treated breast, with a 10-year actuarial local failure rate of 10% and a median time to local failure of 7.4 years (mean, 6.6 years; range, 1.6-10.2 years). Among the subset of 124 patients with negative final resection margins, there was no statistically significant difference in the 8-year actuarial local recurrence rates among patients who underwent single excision (7%), reexcision with residual tumor (8%), or reexcision with no residual tumor (0%)., Discussion: The use of breast conservation treatment in patients with ductal carcinoma in situ remains an effective and durable treatment approach. The need for reexcision to achieve negative margins and the presence of residual ductal carcinoma in situ in the reexcision specimen do not negatively impact local recurrence rates in the current study. These findings suggest that requiring more than one surgery to obtain clear resection margins is not an adverse prognostic factor for local failure.

Microtubule-disrupting agents such as the taxanes comprise some of the most clinically useful chemotherapeutic agents and invoke the spindle checkpoint in proliferating cells. A robust spindle checkpoint in turn may forestall mitotic catastrophe, potentially providing a mechanism that permits cancer cells to survive transient exposure to these drugs. Previous reports on G2-M cell cycle progression by histone deacetylase inhibitors suggested a potential role in modulating the therapeutic efficacy of microtubule-disrupting agents. As both classes of agents are generally administered in clinical trials as pulse treatments, we investigated in human cancer cells the effects of brief treatments with the histone deacetylase inhibitor trichostatin A (TSA) alone or with nocodazole or paclitaxel (Taxol) on cell cycle progression and the spindle checkpoint. Treatment of synchronized cells with 200 ng/ml of TSA alone for eight hours to completely block class I and II HDACs did not interfere with progression into mitosis with chromosomal condensation as confirmed by MPM-2 expression. TSA treatment at this concentration surprisingly did not interfere with formation of the mitotic spindle or centrosomal separation, but instead led to missegregation of chromosomes, suggesting effects on the spindle checkpoint. Consistent with this hypothesis, TSA abrogated the phosphorylation and kinetochore localization of the mitotic checkpoint protein BubR1 and the phosphorylation of histone H3 after paclitaxel and nocodazole treatment. These effects in turn led to rapid cell death and considerably reduced clonogenic survival. These results together suggest that by inactivating the spindle checkpoint, TSA can potentiate the lethal effects of microtubule-disrupting drugs, a strategy that might be usefully exploited for optimizing anticancer therapy.

Drugs that disrupt microtubule dynamics include some of the most important of cancer chemotherapies. While these drugs, which include paclitaxel (Taxol), are known to invoke the mitotic checkpoint, the factors that determine cancer cell killing remain incompletely characterized. Cells that are relatively resistant to killing by these drugs block robustly in mitosis, whereas cells sensitive to killing block only transiently in mitosis before undergoing nuclear fragmentation and death. Passage through mitosis was an absolute requirement of drug-induced death, because death was markedly reduced in cells blocked at both G(1)-S and G(2). Cell killing was at least in part linked to the absence or inactivation of BubR1, a kinetochore-associated phosphoprotein that mediates the mitotic checkpoint. Sensitivity to paclitaxel correlated with decreased BubR1 protein expression in human cancer cell lines, including those derived from breast and ovarian cancers. Silencing of BubR1 via RNA interference inactivated the mitotic checkpoint in drug-resistant cells, and reversed resistance to paclitaxel and nocodazole. Together, these results suggest that the mitotic checkpoint is an important determinant of the efficacy of microtubule-targeting drugs in killing cancer cells, potentially providing novel targets for increasing treatment efficacy.

Although magnetic resonance imaging (MRI) for patients with mammographically occult breast cancer with axillary lymphadenopathy has been accepted for staging, treatment outcome data in this patient group is lacking. In this study, 16 patients, median age of 45 years (range, 27-66 years), presented with malignant axillary lymphadenopathy, negative mammograms, negative breast physical examination, and abnormal breast MRI. All 16 patients were found to have >/= 1 suspicious lesions on breast MRI. Ten patients had a solitary enhancing lesion; 1 patient had 2 enhancing lesions; 3 patients had 3 enhancing lesions; 1 patient had a mass lesion and diffuse patchy enhancement in the breast; and 1 patient had regional enhancement but no discrete lesion on MRI. Six patients underwent breast-conservation surgery using MRI-guided wire localization and 10 patients had modified radical mastectomy. Fourteen patients received adjuvant chemotherapy and the remaining 2 patients received neoadjuvant chemotherapy. With a median follow-up of 5 years (range, 1.2-7.6 years), the 5-year actuarial local control was 100%, relapse-free survival was 74%, and overall survival was 87%. Three patients developed distant metastases. Two patients died from distant metastases, and 1 patient is alive with metastatic disease. One patient had a relapse in the contralateral axilla and was treated with paclitaxel and is disease free. Although the patient population is small, the outcome after treatment for this group of patients with a mammographically occult, MRI-detected breast cancer presenting with axillary adenopathy is similar to the expected outcome for patients with breast cancer with positive axillary lymph nodes.

Purpose: To determine the 15-year outcomes for women with early stage breast cancer after breast conservation therapy., Methods and Materials: Between 1977 and 1990, 937 women with Stage I and II breast carcinoma (55% T1N0, 16% T2N0, 18% T1N1, and 11% T2N1) underwent lumpectomy, axillary lymphadenectomy, and definitive irradiation. The median patient age was 52 years. Of the 937 patients, 375 (40%) received adjuvant chemotherapy and/or hormonal therapy, including 249 (92%) of the 270 women with pathologically positive nodes. The median follow-up was 10.1 years., Results: For the overall group, the 15-year overall survival rate was 71%, and the rate of freedom from distant metastases was 76%. The 15-year local failure rate was 19%. The 15-year contralateral breast cancer rate was 12%. The most common first events were distant failure (13%), local failure (10%), contralateral breast cancer (7%), and second malignant neoplasms (6%). The local failure rate at 10 years for favorable subsets of tumors characterized by mammographic detection, resection with negative margins, treatment with chemotherapy, and treatment with hormones was 8%, 10%, 10%, and 7%, respectively. Local failures were most commonly observed within (true recurrence), or just outside (marginal miss), the primary tumor bed (66%, 85 of 128). The rate of true recurrence or marginal miss at 5, 10, and 15 years was 5%, 10%, and 12%, respectively., Conclusion: These high rates of survival and local control confirm that breast conservation therapy yields favorable results in women with early breast cancer into the second decade after treatment.

Three female patients presented with malignant axillary lymphadenopathy presumed to be from primary breast cancer. No evidence of primary cancer was found in the breast on either mammography or breast magnetic resonance imaging (MRI). All 3 patients underwent axillary lymph node dissection and systemic chemotherapy followed by radiation therapy to the breast and regional lymph nodes. Two patients remain relapse free with a follow-up of 3.7 years each. The third patient achieved locoregional control in the ipsilateral breast and regional lymph nodes but relapsed in the contralateral axilla. These 3 cases illustrate the potential for breast conservation treatment for patients presenting with axillary adenopathy from a presumed primary breast cancer but without either mammographic or breast MRI findings.