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Active breathing coordinator (ABC)-assisted deep inspiration breath hold (DIBH) is an important organ sparing radiation therapy (RT) technique for left-sided breast cancer patients. Patients with advanced breast cancer undergoing chest wall and regional nodal irradiation often require a field matching technique. While field matching has been demonstrated to be safe and effective in free breathing patients, its safety and accuracy in DIBH/ABC use has not been previously reported.To report the accuracy, feasibility, and safety of field matching with ABC/DIBH for patients receiving breast/chest wall irradiation with nodal irradiation using a three-field technique.From December 2012 to May 2018, breast cancer patients undergoing ABC/DIBH-based RT at a single institution were reviewed. For each fraction, the amount of overlap/gap between the supraclavicular and the tangential field were measured and recorded. Patient characteristics, including acute and delayed skin toxicities, were analyzed.A total of 202 patients utilized ABC/DIBH and 4973 fractions had gap/overlap measurements available for analysis. The average gap/overlap measured at junction was 0.28 mm ± 0.99 mm. A total of 72% of fractions had no measurable gap/overlap (0 mm), while 5.6% had an overlap and 22.7% a gap. There was no significant trend for worsening or improvement of gap/overlap measurements with increasing fraction number per patient. OSLD measurements were compared to the planned dose. The median dose 1 cm above the junction was 106% ± 7% of planned dose (range 94%-116%). One centimeter below the junction, the median dose was 114% ± 11% of planned dose (range 95%-131%). At the junction, the median dose was 106% ± 16.3% of planned dose (range 86%-131%). Acute skin toxicity was similar to historically reported values (grade 3, 5.4%, grade 4, 0%).ABC-assisted DIBH is a safe and technically feasible method of delivering RT in the setting of complex matching field technique for breast and regional nodal treatments.

Breast irradiation has evolved significantly over the last several decades. Accelerated partial breast and stereotactic breast irradiation have evolved as strategies to reduce irradiated volumes, preserve appropriate oncologic control, and improve cosmetic outcome. The sequencing and/or combination of stereotactic partial breast irradiation with novel systemic agents is of great interest to the oncologic community. Here we explore the landscape of modern trials and opine on the future of partial breast irradiation.

Describe an early-adopting institution's experience with online adaptive radiation for stereotactic partial breast irradiation.Retrospective review of 22 women treated between May 2021 and March 2022 with adaptive stereotactic partial breast irradiation. A total of 106 of 110 fractions were evaluated for dosimetric changes in target coverage and organ-at-risk (OAR) dose. Patient set up with stereotactic wooden frame and adapted per fraction. Treatment and planning times were collected prospectively by radiation therapists.Scheduled PTVAdaptive stereotactic breast irradiation resulted in improved target coverage with equivalent dosing to OARs in an efficient and tolerated treatment time. Improved target coverage allowed for decreased PTV margins compared to prior trial protocols that may improve acute and late toxicities.

PURPOSE: Many women diagnosed with breast cancer have survived previous cancer yet little is known about the impact of previous cancer on overall and cancer-specific survival. METHODS: This population-based cohort study using SEER-Medicare data included women (age ≥66 years) diagnosed with breast cancer between 2005–2015. Separately by breast cancer stage, we estimated effect of previous cancer on overall survival using Cox regression and on cause-specific survival using competing risk regression; all survival analyses adjusted for covariates. RESULTS: Of 138,576 women diagnosed with breast cancer, 8% had a previous cancer of another organ site, most commonly colorectal or uterine cancer or melanoma. Many of these women (46.3%) were diagnosed within 5 years of breast cancer. For all breast cancer stages except IV wherein there was no difference, women with vs. without previous cancer had worse overall survival. This survival disadvantage was driven by deaths due to the previous cancer and other causes. In contrast, women with previous cancer generally had favorable breast-cancer specific survival, although this varied by stage. Overall survival varied by previous cancer type, timing, and stage; previous lung cancer, cancer diagnosed within 1 year of incident breast cancer, and previous cancer at a distant stage were associated with the worst survival. In contrast, women with a previous melanoma had equivalent overall survival to women without previous cancer. CONCLUSION: We observed variable impact of previous cancer on overall and breast-cancer specific survival depending on breast cancer stage at diagnosis and the type, timing, and stage of previous cancer.

Background Advanced radiotherapeutic treatment techniques limit the cognitive morbidity associated with whole-brain radiotherapy (WBRT) for brain metastasis through avoidance of hippocampal structures. However, achieving durable intracranial control remains challenging. Methods We conducted a single-institution single-arm phase II trial of hippocampal-sparing whole brain irradiation with simultaneous integrated boost (HSIB-WBRT) to metastatic deposits in adult patients with brain metastasis. Radiation therapy consisted of intensity-modulated radiation therapy delivering 20 Gy in 10 fractions over 2–2.5 weeks to the whole brain with a simultaneous integrated boost of 40 Gy in 10 fractions to metastatic lesions. Hippocampal regions were limited to 16 Gy. Cognitive performance and cancer outcomes were evaluated. Results A total of 50 patients, median age 60 years (interquartile range, 54–65), were enrolled. Median progression-free survival was 2.9 months (95% CI: 1.5–4.0) and overall survival was 9 months. As expected, poor survival and end-of-life considerations resulted in a high exclusion rate from cognitive testing. Nevertheless, mean decline in Hopkins Verbal Learning Test–Revised delayed recall (HVLT-R DR) at 3 months after HSIB-WBRT was only 10.6% (95% CI: −36.5‒15.3%). Cumulative incidence of local and intracranial failure with death as a competing risk was 8.8% (95% CI: 2.7‒19.6%) and 21.3% (95% CI: 10.7‒34.2%) at 1 year, respectively. Three grade 3 toxicities consisting of nausea, vomiting, and necrosis or headache were observed in 3 patients. Scores on the Multidimensional Fatigue Inventory 20 remained stable for evaluable patients at 3 months. Conclusions HVLT-R DR after HSIB-WBRT was significantly improved compared with historical outcomes in patients treated with traditional WBRT, while achieving intracranial control similar to patients treated with WBRT plus stereotactic radiosurgery (SRS). This technique can be considered in select patients with multiple brain metastases who cannot otherwise receive SRS.

PURPOSE: The time it takes a performing site to activate a clinical trial can directly affect the ability to provide innovative and state-of-the-art care to patients. We sought to understand the process of activating an oncology clinical trial at a matrix National Cancer Institute–designated comprehensive cancer center. METHODS: A multidisciplinary team of stakeholders within the cancer center, university, and affiliate hospitals held a retreat to map out the process of activating a clinical trial. We applied classical quality improvement and Six Sigma methodology to determine bottlenecks and non–value-added time in activating a clinical trial. During this process, attention was paid to time to pass through each step, and perceived barriers and bottlenecks were identified through group discussions. RESULTS: The process map identified 66 steps with 12 decision points to activate a new clinical trial. The following two steps were instituted first: allow parallel scientific committee and institutional review board (IRB) review and allow the clinical research coordination committee, a group that determines university interest and feasibility, to review protocols independent of the IRB and scientific committee approval. The clinical research coordination committee continues to track the activation time, and this framework is used to identify additional improvement steps. CONCLUSION: By applying quality improvement methodologies and Six Sigma principles, we were able to identify redundancies in the process to activate a clinical trial. This allowed us to redesign the process of activating a clinical trial at a matrix comprehensive cancer center. More importantly, the process map provides a framework to maintain these gains and implement additional changes and serves as an example to deploy across the campus and at other similar institutions.

Accurate and efficient delineation of the clinical target volume (CTV) is of utmost significance in post-operative breast cancer radiotherapy. However, CTV delineation is challenging as the exact extent of microscopic disease encompassed by CTV is not visualizable in radiological images and remains uncertain. We proposed to mimic physicians’ contouring practice for CTV segmentation in stereotactic partial breast irradiation (S-PBI) where CTV is derived from tumor bed volume (TBV) via a margin expansion followed by correcting the extensions for anatomical barriers of tumor invasion (e.g. skin, chest wall). We proposed a deep-learning model, where CT images and the corresponding TBV masks formed a multi-channel input for a 3D U-Net based architecture. The design guided the model to encode the location-related image features and directed the network to focus on TBV to initiate CTV segmentation. Gradient weighted class activation map (Grad-CAM) visualizations of the model predictions revealed that the extension rules and geometric/anatomical boundaries were learnt during model training to assist the network to limit the expansion to a certain distance from the chest wall and the skin. We retrospectively collected 175 prone CT images from 35 post-operative breast cancer patients who received 5-fraction partial breast irradiation regimen on GammaPod. The 35 patients were randomly split into training (25), validation (5) and test (5) sets. Our model achieved mean (standard deviation) of 0.94 (±0.02), 2.46 (±0.5) mm, and 0.53 (±0.14) mm for Dice similarity coefficient, 95th percentile Hausdorff distance, and average symmetric surface distance respectively on the test set. The results are promising for improving the efficiency and accuracy of CTV delineation during on-line treatment planning procedure.

Pre-operative endocrine therapy use in post-menopausal women with localized, ER-positive breast cancer affords comparable rates of response and breast preservation, but lower toxicity relative to chemotherapy. Pre-operative endocrine therapy exerts selective pressure on cancer cells and promote evolution and/or enrichment of pathogenic alternations such as ESR1 mutations and other cellular adaptations. How such endocrine therapy-induced adaptations alter response to radiation therapy remains poorly defined. In this study, we show that diverse mechanisms that confer endocrine therapy resistance also drive radiation resistance by reprogramming of DNA repair pathways. We also show that BRD4, a member of bromodomain and extraterminal domain (BET) family of proteins, mediates such DNA repair reprogramming. BRD4 also plays a key role in trascriptional reprogramming in ER-positive breast cancer cells that confers endocrine therapy resistance. Thus, OTX015, a BET inhibitor with a favorable safety profile in early stage clinical trials, reverses both endocrine therapy resistance and radiation resistance in ER-positive breast cancer cells and tumors. Our findings are also consistent with reports that tamoxifen-resistant breast cancer cells are resistant to DNA damaging chemotherapeutic agents such as adriamycin and cisplatin. Overall, our findings suggest that endocrine therapy resistance in the pre-operative setting serves as a biomarker for reduced response to adjuvant radiation therapy, and that pharmacological BET inhibition reverses radiation resistance in such patients. The increasing use of “window of opportunity” studies to assess response to endocrine therapy in the pre-operative setting will further facilitate personalization of radiation treatments in these patients based on their response to endocrine therapy. Thus, we provides a therapeutic rationale for personalization of radiation treatments in breast cancer patients based on their response to endocrine therapy. We also provide a molecularly targeted approach for reversing radiation resistance in such patients. Thus, our study provides a framework for advancing Precision Radiation Oncology in breast cancer patients. Citation Format: SM Nashir Udden, Asal Rahimi, Dong W. Nathan Kim, Prasanna Alluri. Towards Precision Radiation Oncology: Endocrine Therapy Resistance as a Biomarker for Radiation Resistance in ER-Positive Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-02-08.

In 2019, our institution became the second in the world to go live with GammaPod (Xcision Medical Systems, LLC, Columbia, MD), a device dedicated for stereotactic radiation therapy of breast cancer, with breast immobilization, real-time imaging, and highly-conformal dosimetry. At our institution, GammaPod is used for 5-fraction adjuvant partial breast irradiation, single-fraction tumor cavity boost before whole-breast irradiation, single-fraction preoperative radiation, and (in poor surgical candidates), single-fraction definitive radiation. Here, we describe our workflow, observed procedure step times, and homegrown techniques for improved efficiency in our institutional experience of 93 patients treated between 2019 and 2021.

PURPOSE We report on our early experience of our prospective multicenter phase 1 dose- escalation study of single-fraction stereotactic partial breast irradiation (S-PBI) for early stage breast cancer after partial mastectomy using a robotic stereotactic radiation system. METHODS AND MATERIALS Thirty women with in situ or invasive breast cancer stage 0, I, or II with tumor size

The role of local therapy as a sole therapy or part of a combined approach in treating metastatic cancer continues to evolve. The most obvious requirements for prudent implementation of local therapies like stereotactic ablative radiotherapy (SAbR) to become mainstream in treating oligometastases are (1) Clear guidance as to what particular patients might benefit, and (2) Confirmation of improvements in outcome after such treatments via clinical trials. These future directional requirements are non-negotiable. However, innovation and research offer many more opportunities to understand and improve therapy. Identifying candidates and personalizing their therapy can be afforded via proteomic, genomic and epigenomic characterization techniques. Such molecular profiling along with liquid biopsy opportunities will both help select best therapies and facilitate ongoing monitoring of response. Technologies both to find targets and help deliver less-toxic therapy continue to improve and will be available in the marketplace. These technologies include molecular-based imaging (eg, PET-PSMA), FLASH ultra-high dose rate platforms, Grid therapy, PULSAR adaptive dosing, and MRI/PET guided linear accelerators. Importantly, a treatment approach beyond oligometastastic could evolve including a rationale for using SAbR in the oligoprogressive, oligononresponsive, oligobulky and oligolethal settings as well as expansion beyond oligo- toward even plurimetastastic disease. In any case, lessons learned and experiences required by the implementation of using SAbR in oligometastatic cancer will be revisited.

Efficient, reliable and reproducible target volume delineation is a key step in the effective planning of breast radiotherapy. However, post-operative breast target delineation is challenging as the contrast between the tumor bed volume (TBV) and normal breast tissue is relatively low in CT images. In this study, we propose to mimic the marker-guidance procedure in manual target delineation. We developed a saliency-based deep learning segmentation (SDL-Seg) algorithm for accurate TBV segmentation in post-operative breast irradiation. The SDL-Seg algorithm incorporates saliency information in the form of markers' location cues into a U-Net model. The design forces the model to encode the location-related features, which underscores regions with high saliency levels and suppresses low saliency regions. The saliency maps were generated by identifying markers on CT images. Markers' locations were then converted to probability maps using a distance-transformation coupled with a Gaussian filter. Subsequently, the CT images and the corresponding saliency maps formed a multi-channel input for the SDL-Seg network. Our in-house dataset was comprised of 145 prone CT images from 29 post-operative breast cancer patients, who received 5-fraction partial breast irradiation (PBI) regimen on GammaPod. The performance of the proposed method was compared against basic U-Net. Our model achieved mean (standard deviation) of 76.4 %, 6.76 mm, and 1.9 mm for DSC, HD95, and ASD respectively on the test set with computation time of below 11 seconds per one CT volume. SDL-Seg showed superior performance relative to basic U-Net for all the evaluation metrics while preserving low computation cost. The findings demonstrate that SDL-Seg is a promising approach for improving the efficiency and accuracy of the on-line treatment planning procedure of PBI, such as GammaPod based PBI., Comment: https://iopscience.iop.org/article/10.1088/1361-6560/ac176d

Our purpose was to evaluate cosmetic changes after 5-fraction adjuvant stereotactic partial breast irradiation (S-PBI).Seventy-five women with in situ or invasive breast cancer stage 0, I, or II, with tumor size ≤3 cm, were enrolled after lumpectomy in a phase 1 dose escalation trial of S-PBI into cohorts receiving 30, 32.5, 35, 37.5, or 40 Gy in 5 fractions. Before S-PBI, 3 to 4 gold fiducial markers were placed in the lumpectomy cavity for tracking with the Synchrony respiratory tracking system. S-PBI was delivered with a CyberKnife robotic radiosurgery system. Patients and physicians evaluated global cosmesis using the Harvard Breast Cosmesis Scale. Eight independent panelists evaluated digital photography for global cosmesis and 10 subdomains at baseline and follow-up. McNemar tests were used to evaluate change in cosmesis, graded as excellent/good or fair/poor, from baseline to year 3. Wilcoxon signed rank tests were used to evaluate change in subdomains. Cohen's kappa (κ) statistic was used to estimate interobserver agreement (IOA) between raters, and Fleiss' κ was used to estimate IOA between panelists.Median cosmetic follow-up was 5, 5, 5, 4, and 3 years for the 30, 32.5, 35, 37.5, and 40 Gy cohorts. Most patients reported excellent/good cosmesis at both baseline (86.3%) and year 3 (89.8%). No dose cohort had significantly worsened cosmesis by year 3 on McNemar analysis. No cosmetic subdomain had significant worsening by year 3. IOA was fair for patient-physician (κ = 0.300, P.001), patient-panel (κ = 0.295, P.001), physician-panel (κ = 0.256, P.001), and individual panelists (Fleiss κ = 0.327, P.001).Dose escalation of S-PBI from 30 to 40 Gy in 5 fractions for early stage breast cancer was not associated with a detectable change in cosmesis by year 3. S-PBI is a promising modality for treatment of early stage breast cancer.

This study reports predictive dosimetric and physiologic factors for fat necrosis after stereotactic-partial breast irradiation (S-PBI).Seventy-five patients with ductal carcinoma-in situ or invasive nonlobular epithelial histologies stage 0, I, or II, with tumor size3 cm were enrolled in a dose-escalation, phase I S-PBI trial between January 2011 and July 2015. Fat necrosis was evaluated clinically at each follow-up. Treatment data were extracted from the Multiplan Treatment Planning System (Cyberknife, Accuray). Univariate and stepwise logistic regression analyses were conducted to identify factors associated with palpable fat necrosis.With a median follow-up of 61 months (range: 4.3-99.5 months), 11 patients experienced palpable fat necrosis, 5 cases of which were painful. The median time to development of fat necrosis was 12.7 months (range, 3-42 months). On univariate analyses, higher V32.5-47.5 Gy (P.05) and larger breast volume (P.01) were predictive of any fat necrosis; higher V35-50 Gy (P.05), receiving 2 treatments on consecutive days (P = .02), and higher Dmax (P = .01) were predictive of painful fat necrosis. On multivariate analyses, breast volume larger than 1063 cmEarly-stage breast cancer patients treated with breast conserving surgery and S-PBI in our study had a fat necrosis rate comparable to other accelerated partial breast irradiation modalities, but S-PBI is less invasive. To reduce risk of painful fat necrosis, we recommend not delivering fractions on consecutive days; limiting V42.550 cm

The purpose of this study was to evaluate the utility of moderate deep inspiration breathhold (mDIBH) in reducing heart exposure in left breast cancer patients who have unfavorable cardiac anatomy and need internal mammary lymph node (IMLN) radiation therapy (RT).We used maximum heart distance (MHD), defined as the maximum distance of the heart within the treatment field,1 cm as a surrogate for unfavorable cardiac anatomy. Twenty-two left breast cancer patients with unfavorable cardiac anatomy requiring IMLN-RT underwent free-breathing (FB) and mDIBH computed tomography simulation and planning. Three-dimensional partially wide tangents (3D-PWTs) and intensity modulated RT plans were generated. Dose-volume histograms were used to compare heart and lung dosimetric parameters. Duration of treatment delivery was recorded for all fractions.MHD decreased significantly in mDIBH scans. mDIBH significantly reduced mean heart dose (222.7 vs 578.4 cGy; P.0001) and percentage of left lung receiving doses ≥20 Gy (V20; 31.93 vs 38.41%; P = .0006) in both 3D-PWT and intensity modulated RT plans. The change in MHD after breathhold reliably predicted mean heart dose reduction after mDIBH. Radiation was effectively delivered in 11.31 ± 3.40 minutes with an average of 10.06 ± 2.74 breathholds per fraction.mDIBH is efficient and can effectively decrease mean heart dose in patients with unfavorable cardiac anatomy who need IMLN-RT, thus simplifying planning and delivery for them. The reduction in mean heart dose is proportional to the reduction in maximum heart distance.

Microwave imaging (MI) technology has come a long way to introduce a noninvasive, inexpensive, fast, convenient, and safe screening tool for clinical breast monitoring. However, there is a niche between the existing understanding of MI by engineers versus clinicians. Our manuscript targets that niche and highlights the state of the art in MI technology compared to the existing breast cancer detection modalities (mammography, ultrasound, molecular imaging, and magnetic resonance). The significance of our review article is in consolidation of up-to-date breast clinician views with the practical needs and engineering challenges of a novel breast screening modality. We summarize breast tissue abnormalities and highlight the benefits as well as potential drawbacks of the MI as a cancer detection methodology. Our goal is to present an article that MI researchers as well as practitioners in the field can use to assess the viability of the MI technology as a competing or complementary modality to the existing means of breast cancer screening.

Primary synovial chondromatosis is a rare benign condition of uncertain etiology manifested by synovial proliferation. In the radiology literature, there is only 1 prior case report of primary synovial chondromatosis involving the subtalar joint with only partial description of the imaging appearance. We present a 28-year-old female with primary synovial chondromatosis of the subtalar joint and conduct a literature review of the imaging features of primary synovial chondromatosis presenting in the feet.

Recurrence is a significant prognostic factor in patients with triple negative breast cancer, and the ability to accurately predict it is essential for treatment optimization. Machine learning is a preferred strategy for recurrence prediction. Most current predictive models are built based on single classifier and trained through a single objective. However, since many classifiers are available, selecting an optimal model is challenging. On the other hand, a single objective may not be a good measure to guide model training. We proposed a new multi-classifier multi-objective (MCMO) recurrence predictive model. Specifically, new similarity-based sensitivity and specificity were defined and considered as the two objective functions simultaneously during training. Also the evidential reasoning (ER) approach was used for fusing the output of each classifier to obtain more reliable outcome. Using the proposed MCMO model, we achieved a predictive area under the receiver operating characteristic curve (AUC) of 0.9 with balanced sensitivity and specificity. Furthermore, MCMO outperformed all the individual classifiers, and yielded more reliable results than other commonly used optimization and fusion methods.

BACKGROUND Triple-negative breast cancer (TNBC) lacks estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2)/neu receptors, and is aggressive and therapeutically challenging. Genetic ancestry testing is an emerging medical field. Mitochondrial DNA (mtDNA), which is distinct from nuclear DNA, is maternally inherited and allows for origin determination. Patients with TNBC tend to be younger and are more likely to be African American, making this an ideal disease for mtDNA exploration. To the authors' knowledge, the current study is the first to perform mtDNA for self-described African American, White, and Hispanic patients with TNBC to identify mtDNA patterns. METHODS Patients with TNBC who were at any stage of therapy/survivorship were included. Self-reported ethnicity was confirmed at the time of the prospective buccal swab. Haplogroup prediction was performed on sequencing of hypervariable region 1. Using sequence similarity scores and lineage databases, sequence patterns were determined. Data regarding presentation and treatment, tumor features, and outcomes was collected. RESULTS A total of 92 patients were included: 31 self-described African American, 31 White, and 30 Hispanic individuals. Hispanic patients were found to have the largest tumor size (4.5 cm; P = .01) and youngest age (41 years; P

We conducted a randomized, double-blind, vehicle-controlled clinical trial to investigate the use of a new proprietary hyaluronan (HA) formulation for the prevention of acute skin toxicity in breast cancer patients undergoing radiotherapy (RT). Thirty women with breast cancer undergoing whole breast RT were enrolled. Each patient was randomly assigned to HA formulation (study cream, S) on the medial or lateral half of the irradiated breast and the control cream (placebo, P) on the other half. The primary endpoint was physician’s evaluation of skin symptoms at week 5 during RT and week 2 post-RT. We also collected patients’ independent assessment of skin after RT, patient’s product preference, and an independent physician panel assessment of skin reactions based on photographs. Twenty-eight patients were evaluable. On physician’s evaluation, there was no significant difference in radiation dermatitis between S and P and no overall preference to either cream at week 5 during or week 2 post-RT. More patients preferred S in evaluating skin appearance and skin reactions, but this did not reach statistical significance. Univariate analysis showed that physicians had an overall preference to the S cream at week 2 post-RT in patients with larger breasts. On the independent panel assessment, 3 reviewers saw no significant difference in radiation toxicity, whereas one reviewer reported better skin outcome with S cream at week 5. We found a nonstatistically significant patient preference but overall no significant radioprotective effects for this HA formulation compared with placebo except in patients with larger breasts. The study was registered at www.clinicaltrials.gov (NCT02165605).

Several improvements in breast cancer radiation delivery have been realized using new techniques over the past several decades. As an example, for early stage disease, there has been active investigation of partial breast irradiation (PBI) vs whole breast irradiation. Although still investigational, PBI reduces the treatment volumes, doses to organs at risk, and may improve cosmesis. Over the past 2 decades PBI has been delivered via interstitial brachytherapy, intracavitary brachytherapy, intraoperative radiation therapy, or 3-dimensional external beam radiation therapy. More recently, there has been growing evidence that supports stereotactic body radiation therapy as a safe and effective new treatment for early stage breast cancer. This article describes this new treatment opportunity and reviews the emerging data of stereotactic partial breast irradiation.

Compared to conventional photon-based external beam radiation (PhXRT), carbon ion radiotherapy (CIRT) has superior dose distribution, higher linear energy transfer (LET), and a higher relative biological effectiveness (RBE). This enhanced RBE is driven by a unique DNA damage signature characterized by clustered lesions that overwhelm the DNA repair capacity of malignant cells. These physical and radiobiological characteristics imbue heavy ions with potent tumoricidal capacity, while having the potential for simultaneously maximally sparing normal tissues. Thus, CIRT could potentially be used to treat some of the most difficult to treat tumors, including those that are hypoxic, radio-resistant, or deep-seated. Clinical data, mostly from Japan and Germany, are promising, with favorable oncologic outcomes and acceptable toxicity. In this manuscript, we review the physical and biological rationales for CIRT, with an emphasis on DNA damage and repair, as well as providing a comprehensive overview of the translational and clinical data using CIRT.

296 Background: Initiating a new clinical trial is burdensome and complex. The time to activate a clinical trial can directly affect the ability to provide innovative, state-of-the-art care to patients. We sought to understand the process of activating an oncology clinical trial at a matrix National Cancer Institute-designated, comprehensive cancer center. Methods: A multidisciplinary team of stakeholders within the cancer center, university, and affiliate hospitals held a retreat to map out the process of activating a clinical trial from packet receipt to enrollment of the first patient. We applied classical QI and Six Sigma methodology to determine bottlenecks and redundancies in activating a clinical trial. During this process, particular attention was paid to time to pass through each step and perceived barriers and bottlenecks were identified through group discussions. The time to activation was measured from the day the trial packet was received until the time when the trial was open for enrollment. Results: The process map identified 66 steps with 12 decision points to activate a new clinical trial. The following two steps were instituted first: 1) allow parallel scientific committee and institutional review board (IRB) review and 2) allow the clinical research coordination committee to review protocols for feasibility and university interest separate from the IRB approval process. These changes resulted in a mean time-to-activation change from 194 days at baseline to 135 days after these changes were implemented. The committee continues to track the activation time and this frame work is used to identify additional improvement steps. Conclusions: By applying quality improvement methodologies and Six Sigma principles, we were able to redesign redundant aspects of the process of activating a clinical trial at a matrix comprehensive cancer center. This was associated with a reduction of time to activation of trials. More importantly, the process map provides a framework to maintain these gains and implement further changes.

OBJECTIVE. A novel technique of placing gold fiducial markers in the breast using ultrasound guidance was developed and performed in 51 of 55 consecutive postlumpectomy patients enrolled in a phase I dose escalation trial of accelerated partial-breast irradiation (APBI) using robotic-based stereotactic body radiation therapy (SBRT). CONCLUSION. All 51 postoperative patients underwent successful fiducial placement without complications. Our technique of placing gold fiducial markers in proximity to the seroma cavity is considered safe and effective for breast cancer patients being treated with APBI using robotic-based SBRT.

Triple-negative breast cancer (TNBC) lacks estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2)/neu receptors, and is aggressive and therapeutically challenging. Genetic ancestry testing is an emerging medical field. Mitochondrial DNA (mtDNA), which is distinct from nuclear DNA, is maternally inherited and allows for origin determination. Patients with TNBC tend to be younger and are more likely to be African American, making this an ideal disease for mtDNA exploration. To the authors' knowledge, the current study is the first to perform mtDNA for self-described African American, White, and Hispanic patients with TNBC to identify mtDNA patterns.Patients with TNBC who were at any stage of therapy/survivorship were included. Self-reported ethnicity was confirmed at the time of the prospective buccal swab. Haplogroup prediction was performed on sequencing of hypervariable region 1. Using sequence similarity scores and lineage databases, sequence patterns were determined. Data regarding presentation and treatment, tumor features, and outcomes was collected.A total of 92 patients were included: 31 self-described African American, 31 White, and 30 Hispanic individuals. Hispanic patients were found to have the largest tumor size (4.5 cm; P = .01) and youngest age (41 years; P.0001). Eight patients were BRCA1/2 mutation carriers. There were no differences noted among groups with regard to surgery, lymph node metastases, or survival. Analysis revealed Nigerian, Cameroon, or Sierra Leone ancestry and haplogroups A, U, H, or B to be the most common mtDNA patterns. Twelve discordances (13%) between mtDNA analysis and self-described ethnicity were identified among the 92 patients. The highest discordance (26%; 8 patients) was noted in self-described Hispanic patients: 3 had Nigerian ancestry, and 1 individual demonstrated haplogroup K mtDNA (Ashkenazi Jewish ancestry).Discordance between self-reported ethnicity and mtDNA analysis was identified in 13% of patients with TNBC. The identification of mtDNA patterns with a predisposition toward TNBC may allow for risk stratification. Cancer 2017;107-113. © 2016 American Cancer Society.

Purpose To evaluate the tolerability of a dose-escalated 5-fraction stereotactic body radiation therapy for partial-breast irradiation (S-PBI) in treating early-stage breast cancer after partial mastectomy; the primary objective was to escalate dose utilizing a robotic stereotactic radiation system treating the lumpectomy cavity without exceeding the maximum tolerated dose. Methods and Materials Eligible patients included those with ductal carcinoma in situ or invasive nonlobular epithelial histologies and stage 0, I, or II, with tumor size Results In all, 75 patients were enrolled, with a median age of 62 years. Median follow-up for 5 cohorts was 49.9, 42.5, 25.7, 20.3, and 13.5 months, respectively. Only 3 grade 3 toxicities were experienced. There was 1 dose-limiting toxicity in the overall cohort. Ten patients experienced palpable fat necrosis (4 of which were symptomatic). Physicians scored cosmesis as excellent or good in 95.9%, 100%, 96.7%, and 100% at baseline and 6, 12, and 24 months after S-PBI, whereas patients scored the same periods as 86.5%, 97.1%, 95.1%, and 95.3%, respectively. The disagreement rates between MDs and patients during those periods were 9.4%, 2.9%, 1.6%, and 4.7%, respectively. There have been no recurrences or distant metastases. Conclusion Dose was escalated to the target dose of 40 Gy in 5 fractions, with the occurrence of only 1 dose-limiting toxicity. Patients felt cosmetic results improved within the first year after surgery and stereotactic body radiation therapy. Our results show minimal toxicity with excellent cosmesis; however, further follow-up is warranted in future studies. This study is the first to show the safety, tolerability, feasibility, and cosmesis results of a 5-fraction dose-escalated S-PBI treatment for early-stage breast cancer in the adjuvant setting.

Production from two multilateral pads in the Horn River Basin is compared to microseismic-derived parameters. Microseismic was recorded on a near-surface array in both cases. The number of events recorded on each well tends to have a positive correlation to that well's initial production, while the magnitude of those events does not tend to be a good indicator of production in all zones. Fracture models created from located microseismic events also tend to correlate well to production: modeled fracture area, fracture volume and stimulated reservoir volume all show positive correlations. The method in which the rock fractures can also be an indicator of initial production. Wells with higher percentages of dip-slip type rock failures, which can be associated with hydraulic fractures, tend to have higher initial production. In contrast, wells with a larger proportion of strike-slip events, which are typical of fault reactivations in this zone, tend to have diminished production compared to neighboring wells with fewer reactivation events. By understanding what microseismic parameters positively and negatively impact initial production, operators can optimize well production. This can be done in real-time or in installments during lengthy completions programs through the identification of failure type, fracture geometry, and the relative number of events being recorded.

Evaluating hydraulic fracturing treatments by employing passive seismic monitoring technology has become an accepted industry practice and standard in the last decade foremost for unconventional resources. Due to microseismic monitoring it is now understood that the fracture created during hydraulic stimulation greatly deviates from the planar bi-wing textbook example that has been an accepted image in the industry for a long time. In heavily fractured ultra-low permeability shales, the fracture network is highly complex; it is therefore imperative to accurately image this network in order to understand the response of the formation to the treatment as well as the effect of the treatment on production in order to optimize the wellbore completion and the stimulation treatment (Neuhaus et al., 2012). Neuhaus et al. (2012) showcased a multidisciplinary approach to microseismic monitoring by performing an integrated analysis of data acquired during the stimulation of five wellpads completed in the Marcellus Shale. The case study provided a detailed investigation of the microseismic data in conjunction with other data, such as well logs and cores, reservoir properties, and information on regional and local geology. It determined how factors related to the geology of the reservoir and to the stimulation approach impacted the microseismic results. These observations were then used to relate changes in the microseismicity, changes in the geology, and changes in the stimulation method to changes in production in order to optimize field development and the completion design of the wellbores. Recommendations regarding the wellbore azimuth and completion strategy were obtained from the integrated analysis as well as an optimum wellbore spacing. Distinguishing between the total stimulated rock volume (SRV) where microseismic activity was observed and the part of the SRV that contains proppant filled fractures and will therefore be productive in the long term allowed for sophisticated wellbore spacing determination which was performed for one of the pads in the study area. The distribution of proppant filled fractures can also be used to illustrate the containment of proppant within the DFN to evaluate the optimal wellbore spacing, stage length and spacing, as well as landing depth of the wellbore. The microseismic data set used in this case study was acquired with a permanently-installed near-surface array consisting of 101 stations. The wide azimuth, large-aperture, and high fold geometry of the deployed surface array allowed for a consistent resolution under the 18 square mile footprint of the array. Furthermore, the rich sampling of the seismic wavefront provides a high-confidence estimate of event magnitude as well as the failure mechanism for every event which is the crucial input for Discrete Fracture Network (DFN) modelling from microseismic used to evaluate the distribution of proppant and quantify propped half-lengths for the individual treatments (Duncan and Williams-Stroud, 2009; Neuhaus et al., 2012; McKenna and Toohey, 2013). Analyzing the microseismic data in a spatio-temporal sense then enables the reservoir engineer to obtain a system permeability, quantifying the ability to deliver hydrocarbons into the hydraulic fracture system and through the fracture network back to the wellbore, and ultimately predicting production. Overall, the workflow outlined in this extended abstract closes the loop between microseismic data, treatment optimization, and wellbore productivity.

Purpose: To develop a clinical workflow and to commission the process of creating custom 3d printed boluses for radiation therapy. Methods: We designed a workflow to create custom boluses using a commercial 3D printer. Contours of several patients were deformably mapped to phantoms where the test bolus contours were designed. Treatment plans were created on the phantoms following our institutional planning guideline. The DICOM file of the bolus contours were then converted to stereoLithography (stl) file for the 3d printer. The boluses were printed on a commercial 3D printer using polylactic acid (PLA) material. Custom printing parameters were optimized in order to meet the requirement of bolus composition. The workflow was tested on multiple anatomical sites such as skull, nose and chest wall. The size of boluses varies from 6×9cm2 to 12×25cm2. To commission the process, basic CT and dose properties of the printing materials were measured in photon and electron beams and compared against water and soft superflab bolus. Phantoms were then scanned to confirm the placement of custom boluses. Finally dose distributions with rescanned CTs were compared with those computer-generated boluses. Results: The relative electron density(1.08±0.006) of the printed boluses resemble those of liquid tap water(1.04±0.004). The dosimetricmore » properties resemble those of liquid tap water(1.04±0.004). The dosimetric properties were measured at dmax with an ion chamber in electron and photon open beams. Compared with solid water and soft bolus, the output difference was within 1% for the 3D printer material. The printed boluses fit well to the phantom surfaces on CT scans. The dose distribution and DVH based on the printed boluses match well with those based on TPS generated boluses. Conclusion: 3d printing provides a cost effective and convenient solution for patient-specific boluses in radiation therapy.« less

Purpose: To evaluate the dosimetric impact on treatment planning for partial breast stereotactic irradiation using Cyberknife with MLC versus Iris Cone. Methods: Ten patients whom underwent lumpectomy for DCIS or stage I invasive non-lobular epithelial breast cancer were included in this study. All patients were previously treated on the Cyberknife using Iris cone with the prescription dose of 37.5Gy in 5 fractions covering at least 95% of PTV on our phase I SBRT 5 fraction partial breast irradiation trial. Retrospectively, treatment planning was performed and compared using the new Cyberknife M6 MLC system for each patient. Using the same contours and critical organ constraints for both MLC and Iris cone plans, the dose on target and critical organs were analyzed accordingly. Results: Dose to critical organs such as ipsilateral lung, contralateral lung, heart, skin, ipsilateral breast, and rib were analyzed, as well as conformity index and high dose spillage of the target area. In 9 of 10 patients, the MLC plans had less total ipsilateral breast volume encompassing the 50% prescription isodose (mean:22.3±8.2% MLC vs. 31.6±8.0 Iris, p=0.00014) .The MLC plans mean estimated treatment delivery time was significantly less than the Iris plans (51±3.9min vs. 56.2±9min, p=0.03) Both MLC and Iris cone plans were able to meet all dose constraints and there was no statistical difference between those dose constraints. Conclusion: Both MLC and Iris Cone can deliver conformal dose to a partial breast target and satisfy the dose constraints of critical organs. The new Cyberknife with MLC can deliver a more conformal dose in the lower dose region and spare more ipsilateral breast tissue to the 50% prescription isodose. The treatment time for partial breast SBRT plans was also reduced using MLC. Project receives research support from Accuray Inc.

Objective To investigate the prognostic significance of p16 in patients with hypopharyngeal squamous cell carcinoma (HPSCC) and to evaluate the relationship between p16 and human papillomavirus (HPV). Unlike in oropharyngeal SCC (OPSCC), the prognostic significance of p16 in HPSCC and its association with HPV is unclear. Design Retrospective medical chart review. Setting University tertiary referral center. Patients A total of 27 patients with HPSCC treated with definitive radiation therapy between 2002 and 2011 whose tissue was available for immunohistochemical analysis. Interventions Twenty-two patients were treated with chemoradiation, and 5 with radiation alone. All tumor biopsy specimens were analyzed for p16 and, when sufficient tissue was available, for HPV DNA. Main Outcome Measures Overall survival (OS), locoregional control (LRC), disease-free survival (DFS), and laryngoesophageal dysfunction–free survival (LEDFS) were analyzed according to p16 status. Results Findings for p16 were positive in 9 tumors and negative in 18 tumors. Median follow-up was 29.3 months. There was no significant difference in OS, LRC, DFS, or LEDFS for patients with p16-positive vs p16-negative tumors. Only 1 of the 19 tumors tested for HPV was found to be HPV positive. When used as a test for HPV, p16 had a positive predictive value of 17%. Conclusions In contrast to OPSCC, p16 expression in patients with HPSCC had a low positive predictive value for HPV and did not predict improved OS, LRC, DFS, or LEDFS. Thus, for HPSCC, p16 is not a prognostic biomarker. Caution must be taken when extrapolating the prognostic significance of p16 in patients with OPSCC to patients with head and neck SCC of other subsites.

A seismic attribute is a transformation of the original seismic data that can help determine the rock type and fluid characters. AVO attribute analysis is a proven method for confirming seismic amplitude anomalies associated with gas anomalies. AVO analysis examines the intensity of seismic reflections at varying source-receiver distances (offset). The major risk with AVO analysis is whether seismic amplitude anomalies represent commercial or non-commercial gas accumulations. Combining AVO and absorption attributes using ANN reduces this risk. Further risk reduction is accomplished thorough investigation of the different types of absorption attributes and enhancing the ANN training with petrophysical information derived from well logs. We demonstrate that the high frequency content of the seismic response attenuates more as it propagates through gas-bearing reservoirs and, unlike AVO, the absorption attribute is impacted by the amount of gas saturation. Furthermore, we demonstrate how the correlation between shallow gas and shallow seismic amplitudes improves as we include different types of well logs with proper calibration. The ANN, trained by the suite of logs and different frequency-related attributes, enhances the ability to detect undeveloped pockets of shallow gas. Gas has a very marked effect on both density and neutron logs, resulting in lower bulk density and lower apparent neutron porosity. Therefore, combining neutron and density logs and training neural networks based on the well logs with AVO and AQF attributes, instead of just training based on attributes alone, increases the certainty of suspected gas pockets. The real power comes from being able to tie absorption and AVO anomalies with other frequency attributes.

Purpose: Active breathing control (ABC) has been used to reduce treatment margin due to respiratory organ motion by enforcing temporary breath-holds. However, in practice, even if the ABC device indicates constant lung volume during breath-hold, the patient may still exhibit minor chest motion. Consequently, therapists are given a false sense of security that the patient is immobilized. This study aims at quantifying such motion during ABC breath-holds by monitoring the patient chest motion using a surface photogrammetry system, VisionRT. Methods: A female patient with breast cancer was selected to evaluate chest motion during ABC breath-holds. During the entire course of treatment, the patient’s chest surface was monitored by a surface photogrammetry system, VisionRT. Specifically, a user-defined region-of-interest (ROI) on the chest surface was selected for the system to track at a rate of ∼3Hz. The surface motion was estimated by rigid image registration between the current ROI image captured and a reference image. The translational and rotational displacements computed were saved in a log file. Results: A total of 20 fractions of radiation treatment were monitored by VisionRT. After removing noisy data, we obtained chest motion of 79 breath-hold sessions. Mean chest motion in AP direction during breath-holds is 1.31mm with 0.62mm standard deviation. Of the 79 sessions, the patient exhibited motion ranging from 0–1 mm (30 sessions), 1–2 mm (37 sessions), 2–3 mm (11 sessions) and >3 mm (1 session). Conclusion: Contrary to popular assumptions, the patient is not completely still during ABC breath-hold sessions. In this particular case studied, the patient exhibited chest motion over 2mm in 14 out of 79 breath-holds. Underestimating treatment margin for radiation therapy with ABC could reduce treatment effectiveness due to geometric miss or overdose of critical organs. The senior author receives research funding from NIH, VisionRT, Varian Medical Systems and Elekta

1057 Background: To evaluate tolerability of escalating doses of 5 fraction SBRT PBI in treating early stage breast cancer after partial mastectomy on a phase I dose escalation trial. The primary o...