Metastatic Myxofibrosarcoma with Durable Response to Temozolomide Followed by Atezolizumab: A Case Report.

Myxofibrosarcoma (MFS) is a well-recognized histotype of soft tissue sarcomas that generally presents with localized disease. Herein, we describe the case of a patient with metastatic MFS who experienced durable response to sixth-line therapy with temozolomide. Upon further progression, his tumor was notable for a high tumor mutational burden, and he was subsequently treated with seventh-line immunotherapy, atezolizumab, achieving a second durable response. This case highlights the role of immunotherapy after administration of alkylating agents. Review of the literature indicates that recurrent tumors treated with alkylating agents often experience hypermutation as a means of developing resistance and that checkpoint inhibitors are subsequently effective in these tumors. KEY POINTS: To the authors' knowledge, this is the first report of a patient with myxofibrosarcoma with high tumor mutational burden after administration of temozolomide monotherapy. Hypermutation may be a resistance mechanism for patients with soft tissue sarcoma who develop resistance to alkylating agents. Checkpoint inhibition may be effective therapy in patients with soft tissue sarcoma with high tumor mutational burden as a consequence of alternate systemic therapy resistance.

Marital Status and Overall Survival in Patients with Resectable Pancreatic Cancer: Results of an Ancillary Analysis of NRG Oncology/RTOG 9704.

BACKGROUND: Several registry-based analyses suggested a survival advantage for married versus single patients with pancreatic cancer. The mechanisms underlying the association of marital status and survival are likely multiple and complex and, therefore, may be obscured in analyses generated from large population-based databases. The goal of this research was to characterize this potential association of marital status with outcomes in patients with resected pancreatic cancer who underwent combined modality adjuvant therapy on a prospective clinical trial. MATERIALS AND METHODS: This is an ancillary analysis of 367 patients with known marital status treated on NRG Oncology/RTOG 97-04. Survival analysis was performed using the Kaplan-Meier method and compared using the log-rank test. Multivariate analysis was performed using the Cox proportional hazards regression model. RESULTS: Of 367 patients, 271 (74%) were married or partnered and 96 (26%) were single. Married or partnered patients were more likely to be male. There was no association between marital status and overall survival (OS) or disease-free survival (DFS) on univariate (hazard ratio [HR], 1.09 and 1.01, respectively) or multivariate analyses (HR, 1.05 and 0.98, respectively). Married or partnered male patients did not have improved survival compared with female or single patients. CONCLUSION: Ancillary analysis of data from NRG Oncology/RTOG 97-04 demonstrated no association between marital and/or partner status and OS or DFS in patients with resected pancreatic cancer who received adjuvant postoperative chemotherapy followed by concurrent external beam radiation therapy and chemotherapy. Clinical trial identification number. NCT00003216. IMPLICATIONS FOR PRACTICE: Several population-based studies have shown an epidemiological link between marital status and survival in patients with pancreatic cancer. A better understanding of this association could offer an opportunity to improve outcomes through psychosocial interventions designed to mitigate the negative effects of not being married. Based on the results of this analysis, patients who have undergone a resection and are receiving adjuvant therapy on a clinical trial are unlikely to benefit from such interventions. Further efforts to study the association between marital status and survival should be focused on less selected subgroups of patients with pancreatic cancer.

Risk Factors Leading to Complications in Early-Stage Breast Cancer Following Breast-Conserving Surgery and Intraoperative Radiotherapy.

OBJECTIVE: The aim of this study was to evaluate outcomes after breast-conserving surgery (BCS) and intraoperative radiotherapy (IORT), and to identify risk factors associated with complications. MATERIALS/METHODS: We evaluated patients with early-stage breast cancer treated from January 1, 2011 to January 31, 2014 with BCS and IORT at a single institution. The presence of breast cancer recurrences, complications, or fat necrosis were assessed at subsequent follow-up visits using physical examination and breast imaging. RESULTS: Overall, 113 patients, of whom three were undergoing bilateral treatments, were identified. The median length of time for IORT was 29 min and 36 s (range 15:50-59:00). Fifteen patients received additional external beam radiotherapy (EBRT), and the median follow-up was 40.3 months (range 1.6-58.3) for all patients. To date, one biopsy-proven ipsilateral recurrence has been noted (0.9%), for which the patient elected to undergo a mastectomy. Nine patients were found to have wound complications (7.7%) and two had fat necrosis (1.7%) on follow-up. Of all the evaluated risk factors, only applicator size (p < 0.01) had a statistically significant association with an increase in complications. CONCLUSIONS: With a short follow-up, IORT appears to be a safe treatment modality for a select group of patients, leading to a reasonable increase in operating room time and complication rates following BCS. The utilization of larger applicators at the time of IORT was associated with an increase in wound complications and fat necrosis.

Sonication of Arthroplasty Implants Improves Accuracy of Periprosthetic Joint Infection Cultures.

BACKGROUND: There is evidence that sonication of explanted prosthetic hip and knee arthroplasty components with culture of the sonication fluid may enhance diagnostic sensitivity. Previous studies on the use of implant sonicate cultures have evaluated diagnostic thresholds but did not elaborate on the clinical importance of positive implant sonicate cultures in the setting of presumed aseptic revisions and did not utilize consensus statements on periprosthetic joint infection (PJI) diagnosis when defining their gold standard for infection. QUESTIONS/PURPOSES: (1) How do implant sonicate cultures compare with preoperative synovial fluid cultures and intraoperative tissue cultures in the diagnosis of PJI in both THA and TKA when compared against Musculoskeletal Infection Society (MSIS) criteria for PJI? (2) Utilizing implant sonicate cultures, what is the relative prevalence of bacterial species identified in PJIs? (3) What is the incidence of positive implant sonicate cultures in the setting of presumed aseptic revision hip and knee arthroplasty procedures, and what treatments did they receive? METHODS: Between 2012 and 2016 we performed implant sonicate fluid cultures on surgically removed implants from 565 revision THAs and TKAs. Exclusion criteria including insufficient data to determine Musculoskeletal Infection Society (MSIS) classification, fungal-only cultures, and absence of reported colony-forming units decreased the number of procedures to 503. Procedures represented each instance of revision surgery (sometimes multiple in the same patient). Of those, a definitive diagnosis of infection was made using the MSIS criteria in 178 of 503 (35%), whereas the others (325 of 503 [65%]) were diagnosed as without infection. A total of 53 of 325 (16%) were considered without infection based on MSIS criteria but had a positive implant sonicate culture. Twenty-five of 53 (47%) of these patients were followed for at least 2 years. The diagnosis of PJI was determined using the MSIS criteria. RESULTS: Sensitivity of implant sonicate culture was greater than synovial fluid culture and tissue culture (97% [89%-99%] versus 57% [44%-69%], p < 0.001; 97% [89%-99%] versus 70% [58%-80%], p < 0.001, respectively). The specificity of implant sonicate culture was not different from synovial fluid culture or tissue culture with the numbers available (90% [72%-97%] versus 100% [86%-100%], p = 0.833; 90% [72%-97%] versus 97% [81%-100%], p = 0.317, respectively). Coagulase-negative Staphylococcus was the most prevalent organism for both procedure types. In PJIs, the five most frequent bacteria identified by synovial fluid, tissue, and/or implant sonicate cultures were coagulase-negative Staphylococcus (26% [89 of 267]), methicillin-susceptible Staphylococcus aureus (19% [65 of 267]), methicillin-resistant S. aureus (12% [43 of 267]), α-hemolytic Streptococci (5% [19 of 267]), and Enterococcus faecalis (5% [19 of 267]). Fifty-three of 325 (16%) presumed aseptic revisions had a positive sonication culture. Thirty-four percent (18 of 53) of culture-positive aseptic revision patients received antibiotic treatment for infection and 8% (4 of 53) underwent a secondary revision. CONCLUSIONS: The routine use of implant sonicate cultures in arthroplasty revisions improves the diagnostic sensitivity for detecting the presence of bacteria in both clinical and occult infections. Future studies will need to refine colony-forming unit thresholds for determining clinical infection and indications for treatment. LEVEL OF EVIDENCE: Level III, diagnostic study.

National Evaluation of the New Commission on Cancer Quality Measure for Postmastectomy Radiation Treatment for Breast Cancer.

BACKGROUND: Current guidelines recommend postmastectomy radiotherapy (PMRT) for patients with ≥4 positive lymph nodes and suggest strong consideration of PMRT in those with 1-3 positive nodes. These recommendations were incorporated into a Commission on Cancer quality measure in 2014. However, national adherence with these recommendations is unknown. Our objectives were to describe PMRT use in the United States in patients with stage I to III invasive breast cancer and to examine possible factors associated with the omission of PMRT. METHODS: From the National Cancer Data Base, 753,536 mastectomies at 1123 hospitals were identified from 1998 to 2011. PMRT use over time was examined using random effects logistic regression analyses, adjusting for patient, tumor, and hospital characteristics. Analyses were stratified by nodal status (≥4 nodes positive, 1-3 nodes positive, node negative). RESULTS: The proportion of patients receiving PMRT increased from 1998 to 2011 (>4 positive nodes: 56.2 to 66.6 %; 1-3 positive nodes: 28.0 to 39.1 %; node-negative: 8.3 to 10.0 %, p < 0.001 for all). In adjusted analyses, patients with ≥4 positive nodes were more likely to have PMRT omitted if they had smaller tumors. Patients with 1-3 positive nodes were more likely to have PMRT omitted if they had lower grade or smaller tumors. Irrespective of patients' nodal status, PMRT utilization rates decreased as age increased. CONCLUSIONS: Though PMRT rates increased over time in patients with ≥4 and 1-3 positive nodes, PMRT in patients with ≥4 positive nodes remains underutilized. Feedback to hospitals using the new Commission on Cancer PMRT measure may help to improve adherence rates.

ACR Appropriateness Criteria® Borderline and Unresectable Pancreas Cancer.

The American College of Radiology Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. The panel reviewed the pertinent literature and voted on five variants to establish appropriate recommended treatment of borderline and unresectable pancreatic cancer. The guidelines reviewed the use of radiation, chemotherapy, and surgery. Radiation technique, dose, and targets were evaluated, as was the recommended chemotherapy, administered either alone or concurrently with radiation. This report will aid clinicians in determining guidelines for the optimal treatment of borderline and unresectable pancreatic cancer.

Assessment of multimodality therapy use for extremity sarcoma in the United States.

BACKGROUND: Extremity sarcoma national guidelines offer several stage-specific treatment options; therefore, treatment approaches are not standardized. Our objectives were to examine multimodality treatment trends, practice patterns, and factors associated with neoadjuvant or postoperative adjuvant therapy utilization. METHODS: Using the National Cancer Data Base (2000-2009), treatment of non-metastatic extremity sarcoma was examined. Regression models were developed to identify factors associated with neoadjuvant or postoperative adjuvant therapy receipt and treatment sequence. RESULTS: Twenty-two thousand fifty-one patients underwent resection (stage I: 45.2%, stage II: 27.7%, stage III: 27.1%). Over 10 years, neoadjuvant radiation (6.4-11.6%, P < 0.001) and chemotherapy utilization (1.4-1.8%, P = 0.037) increased, while postoperative radiation (34.3-29.2%, P = 0.023) and trimodality therapy decreased (10.5-9.6%, P = 0.002). After adjusting for age, comorbidities, and histology, patients with large high-grade tumors treated at high-volume academic centers were more likely to receive neoadjuvant therapy (all P < 0.001). Postoperative chemotherapy utilization was associated with younger age, synovial histology, high grade, and surgical margins (all P < 0.001). CONCLUSIONS: Utilization of neoadjuvant therapy for extremity sarcoma has increased over time. Practice patterns are not only related to tumor size, grade, histology, and margins but also hospital type. Opportunities remain to better define the most effective multimodality treatment for extremity sarcoma.

Examination of national lymph node evaluation practices for adult extremity soft tissue sarcoma.

BACKGROUND AND OBJECTIVES: Lymph node evaluation recommendations for extremity soft tissue sarcoma (ESTS) are absent from national guidelines. Our objectives were (1) to assess rates and predictors of nodal evaluation, and (2) to assess rates and predictors of nodal metastases. METHODS: ESTS patients from the National Cancer Data Base (2000-2009) were assessed, and regression models were used to identify factors associated with nodal evaluation and metastases. RESULTS: Of 27,536 ESTS patients, 1,924 (7%) underwent nodal evaluation, and of these, 290 (15%) had nodal metastases. Nodal evaluation was most frequently performed for rhabdomyosarcoma (15.6%), angiosarcoma (10.0%), clear cell sarcoma (39.3%), epithelioid sarcoma (28.1%), and synovial sarcoma (9.3%). On multivariable analysis, factors associated with nodal evaluation included histologic subtype, tumor size, and grade. Nodal metastasis rates were highest among patients with rhabdomyosarcoma (32.1%), angiosarcoma (24.1%), clear cell sarcoma (27.7%), and epithelioid sarcoma (31.8%). On multivariable analysis, factors associated with nodal metastases included histologic subtype, tumor size, and grade. CONCLUSIONS: Nodal evaluation rates are highest among certain expected subtypes but are generally low. However, nodal metastasis rates for many histologic subtypes in patients selected for lymph node evaluation may be higher than previously reported. Multi-institutional studies should address nodal evaluation for ESTS.

Immunotherapy and Radiotherapy Combinations for Sarcoma.

Sarcomas are a heterogeneous group of bone and soft tissue tumors. Survival outcomes for advanced (unresectable or metastatic) disease remain poor, so therapeutic improvements are needed. Radiotherapy plays an integral role in the neoadjuvant and adjuvant treatment of localized disease as well as in the treatment of metastatic disease. Combining radiotherapy with immunotherapy to potentiate immunotherapy has been used in a variety of cancers other than sarcoma, and there is opportunity to further investigate combining immunotherapy with radiotherapy to try to improve outcomes in sarcoma. In this review, we describe the diversity of the tumor immune microenvironments for sarcomas and describe the immunomodulatory effects of radiotherapy. We discuss studies on the timing of radiotherapy relative to immunotherapy and studies on the radiotherapy dose and fractionation regimen to be used in combination with immunotherapy. We describe the impact of radiotherapy on the tumor immune microenvironment. We review completed and ongoing clinical trials combining radiotherapy with immunotherapy for sarcoma and propose future directions for studies combining immunotherapy with radiotherapy in the treatment of sarcoma.

Characterization of brass mesh bolus for electron beam therapy.

Purpose. Bolus is often required for targets close to or on skin surface, however, standard bolus on complex surfaces can result in air gaps that compromise dosimetry. Brass mesh boluses (RPD, Inc., Albertville, MN) are designed to conform to the patient's surface and reduce air gaps. While they have been well characterized for their use with photons, minimal characterization exists in literature for their use with electrons.Methods and materials.Dosimetric characteristics of brass mesh bolus was investigated for use with 6, 9 and 12 MeV electrons using a 10 × 10 cm2applicator on standard multi-energy LINAC. Measurements for bolus equivalence and percentage depth doses (PDDs) under brass mesh, as well as surface dose measurements were performed on solid water and a 3D printed resin breast phantom (Anycubic Photon MonoX, Shenzhen, China) using Markus®parallel-plate ionization chamber (Model 34045, PTW Freiburg, Germany), thermoluminescent detectors (TLD) and EBRT film. After obtaining surface dose measurements, these were compared to dose calculated on the Pinnacle3 treatment planning system (TPS, 16.2, Koninklijke Philips N.V.).Results. Measurements of surface dose under brass mesh showed consistently higher dose than without bolus, confirming that brass mesh can increase the PDD at surface up to ∼ 94% of dose at dmax, depending on incident electron energy. This increase is equivalent to using ∼ 7.2 mm water equivalent bolus for 6 MeV, ∼ 3.6 mm for 9 MeV and ∼ 2.2 mm bolus for 12 MeV electrons. TPS results showed close agreement within-vivomeasurements, confirming the potential for brass mesh as bolus for electron irradiation, provided blousing effect is correctly modelled.Conclusions. To increase electron surface dose, a brass mesh can be used with equivalent effect of water-density bolus varying with electron energy. Proper implementation could allow for ease of treatment, as well as increase bolus conformality in electron-only plans.

Evolution of Radiation Therapy in Pancreas Cancer Management toward MRI-Guided Adaptive Radiation Therapy.

Pancreas cancer has a poor prognosis despite aggressive treatment and is the fourth leading cause of cancer death in the United States. At diagnosis, most patients have either metastatic or locally advanced disease. In this article, we review the evolution of treatments in locally advanced pancreas cancer (LAPC) and discuss the various radiation therapy fractionation schemes. Furthermore, we examine the data supporting dose escalation and the delivery of ablative biologically effective doses in the setting of LAPC. Finally, we review the role of MRI-guided radiation therapy in escalating dose while sparing organs at risk in the era of stereotactic magnetic resonance-guided adaptive radiation therapy.

Impact of breast MRI in women eligible for breast conservation surgery and intra-operative radiation therapy.

PURPOSE: The current standard of care for women diagnosed with early stage breast cancer is breast-conserving surgery (BCS) followed by external beam radiation therapy, commonly delivered over 3-6 weeks. As an alternative, select patients can undergo intra-operative radiation therapy (IORT) at the time of BCT. This technique delivers a single fraction of radiation at the time of surgery, enabling patients to undergo both surgery and radiation in a single session. Our current study analyzed the value of incorporating breast MRI into the routine work-up of patients deemed eligible for IORT, to quantify the impact on patient eligibility and requirement for additional work-up. MATERIALS AND METHODS: We retrospectively identified patients treated by a single surgeon who were eligible for IORT based on institutional eligibility criteria which included: women age ≥55, grades 1-2, size <3 cm, estrogen receptor (ER) positive, Her-2 neu non-amplified and low/intermediate Ki-67, unifocal invasive ductal/mixed histology carcinomas. All patients must have undergone a physical exam and bilateral diagnostic mammography with ultrasound. From this population, we identified all patients who had undergone bilateral breast MRI as part of pre-operative evaluation. RESULTS: A total of 215 women were identified who met all eligibility criteria. MRI detected additional abnormalities in the breast in 89 patients (41%). Sixty-eight women underwent additional biopsies, with a total of 117 separate lesions biopsied. Of these, pathology was benign in 61 (52.1%), atypical ductal hyperplasia (ADH) in 21 (18%), ductal carcinoma in-situ (DCIS) in 17 (14.5%) and invasive disease in 18 (15.4%). Six patients had MRI-detected abnormalities in the contralateral breast only, with biopsies identifying invasive disease (3), DCIS (1) and benign (2) findings. MRI showed abnormalities in both breasts in 6 patients and 18 additional lesions were biopsied which reveled invasive carcinoma (6), DCIS (7), ADH (3) and benign findings (2). Fifteen patients had either multifocal/multicentric disease or index lesion >3 cm on MRI and were deemed ineligible for IORT. Based on either MRI size or biopsy results, management was ultimately changed for 27 patients (12.5%). Extramammary findings were observed in 17 patients and 11 of these patients underwent further imaging studies all of which returned negative results. CONCLUSION: Preoperative bilateral breast MRI is a valuable tool in the proper selection of patients best suited for IORT. Even in highly selected, favorable risk patients, MRI detected additional lesions that changed surgical and radiation therapy recommendations in 12.5% of patients. However, the cost/benefit ratio needs to be taken into consideration given the high frequency of benign biopsies and additional radiological work-up.

Radiation Therapy Field Design and Lymphedema Risk After Regional Nodal Irradiation for Breast Cancer.

PURPOSE: The occurrence of upper extremity lymphedema after regional nodal irradiation (RNI) for breast cancer treatment varies significantly based on patient and treatment factors. The relationship between the radiation therapy (RT) field design and lymphedema risk is not well-characterized. The present study sought to correlate the variations in RT field design with lymphedema outcomes. METHODS AND MATERIALS: Women with stage II-IV breast cancer receiving RNI after breast surgery that included sentinel lymph node biopsy or axillary dissection were identified. Their arm circumference was measured before RT and at each follow-up visit to assess for lymphedema. Nodal RT fields were defined using a trifurcated system. Group 1 excluded the upper level I and II axilla, defined by the lateral border of the nodal field encompassing less than one-third of the humeral head. Group 2 included the upper level I and II axilla, defined by the lateral border of the nodal field encompassing more than one-third of the humoral head treated with an anterior oblique beam. Group 3 included the upper level I and II axilla the same as for group 2 but with parallel-opposed beams delivering a significant dose to the musculature posterior to the axilla. RESULTS: From 1999 to 2013, 526 women received RNI. The median post-RT follow-up was 5.5 years. For the 492 women meeting the inclusion criteria, the cumulative incidence of lymphedema was 23.5% at 2 years and 31.8% at 5 years. On univariate analysis, the patients in group 1 had a lower 5-year lymphedema rate (7.7%) than those in group 2 (37.1%) and group 3 (36.7%; P < .0001). On multivariate analysis, inclusion of the upper level I and II axilla (groups 2 and 3) remained significantly associated with increased lymphedema risk. CONCLUSIONS: Variations in the RT field design significantly affect the development of lymphedema after RNI. In particular, the upper level I and II axilla appear to be important regions for lymphedema risk after axillary dissection.

Indoleamine 2,3-dioxygenase 1 and overall survival of patients diagnosed with esophageal cancer.

BACKGROUND: Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme with immunomodulatory properties that has emerged as a potential immunotherapeutic target in human cancer. However, the role, expression pattern, and relevance of IDO1 in esophageal cancer (EC) are poorly understood. Here, we utilize gene expression analysis of the cancer genome atlas (TCGA) and immunohistochemistry (IHC) to better understand the role and prognostic significance of IDO1 in EC. RESULTS: High IDO1 mRNA levels were associated with worse overall survival (OS) in both esophageal squamous cell carcinoma (SCC) (P = 0.02) and adenocarcinoma (AC) (P = 0.036). High co-expression of IDO1 and programmed death ligand 1 (PD-L1) was associated with worse OS in SCC (P = 0.0031) and AC (P = 0.0186). IHC for IDO1 in SCC showed a significant correlation with PD-L1 (P < 0.0001) and CD3ε (P < 0.0001). CONCLUSIONS: EC with high IDO1 and PD-L1 expression is significantly correlated with decreased patient survival, and may correlate with increased T-cells. These data suggest that simultaneous inhibition of IDO1 and PD-(L)1 may overcome important barriers to T-cell mediated immune rejection of EC. MATERIALS AND METHODS: mRNA expression data from TCGA (SCC N = 87; AC N = 97). IHC in a second cohort of EC (N = 93) were stained for IDO1, PD-L1, and CD3ε, followed by light microscopic analysis.

Assessing long-term complications in patients undergoing immediate postmastectomy breast reconstruction and adjuvant radiation.

PURPOSE: The purpose of this article is to report the long-term rate and timing of complications associated with postmastectomy radiation therapy (PMRT) following immediate breast reconstruction in a large patient population. METHODS AND MATERIALS: We identified and reviewed the charts of all patients with stages I through IIIC breast cancer who underwent mastectomy with immediate reconstruction followed by subsequent radiation therapy between November 1997 and May 2010. We aimed to assess the rate of major complications, defined as events requiring a separate and distinct procedure. Statistical analysis between variables was evaluated using Fisher exact test and Pearson χ2 Elder et al. (2005) test. RESULTS: In total, 134 patients met inclusion criteria for having adequate long-term follow-up and documentation. The median follow-up for all patients was 77.4 months (range, 6-185 months). The overall major complication rate was found to be 44%. Nine patients (6.7%) experienced complications for which a secondary procedure could not be performed to retain a reconstructed breast. The average time between initiation of PMRT and the first major complication was 13.5 months, with 68.3% of first major complications occurring within 1 year of PMRT initiation and 81.7% within 2 years. The difference in incidence of major complications for patients undergoing immediate tissue expander/implant reconstruction followed by PMRT was not statistically different when compared with that for patients with immediate autologous tissue reconstruction followed by PMRT (47.3% vs 30.4%, P = .168). CONCLUSIONS: The risk of first major complications and reconstruction loss in patients undergoing PMRT on immediately reconstructed breasts is greatest within 1 year of beginning radiation therapy and decreases significantly with time. Immediate autologous tissue reconstruction followed by PMRT can be performed with reasonable complication rates.

Radiotherapy of MRI-detected involved internal mammary lymph nodes in breast cancer.

BACKGROUND: The internal mammary (IM) lymph node chain, along with the axillary nodal basin, is a first-echelon breast lymphatic draining site. A growing body of evidence supports irradiation of this region in node-positive breast cancer. This study evaluated the effectiveness of radiotherapy in treating magnetic resonance imaging (MRI)-detected abnormal IM lymph nodes in newly-diagnosed non-metastatic breast cancer. METHODS: A structured query was performed on an electronic institutional database to identify women with radiographic evidence of abnormal IM node(s) on breast MRI from 2005 to 2013. Manual review narrowed inclusion to patients with a primary diagnosis of non-metastatic breast cancer with abnormal IM node(s) based on pathologic size criteria and/or abnormal enhancement. RESULTS: Of the 7070 women who underwent pre-treatment MRI, 19 (0.3%) were identified on imaging to have a total of 25 abnormal pre-treatment IM lymph nodes, of which 96% were located in the first two intercostal spaces and 4% in the third space. A majority of the primary tumors were high-grade (94.7%) and hormone-receptor negative (73.7%), while 47.4% overexpressed HER-2/neu receptor. Axillary nodal disease was present in 89.5% of patients, while one patient had supraclavicular involvement. At a median follow-up of 38 months, 31.6% of patients had developed metastatic disease and 21.1% had died from their disease. Of the patients who received IM coverage, none had progressive disease within the IM lymph node chain. CONCLUSIONS: Radiologic evidence of pre-treatment abnormal IM chain lymph nodes was associated with advanced stage, high grade, and negative estrogen receptor status. The majority of positive lymph nodes were located within the first two intercostal spaces, while none were below the third. Radiation of the IM chain in combination with modern systemic therapy was effective in achieving locoregional control without surgical resection in this cohort of patients.

Hypofractionated Conformal Radiotherapy with Concurrent Full-Dose Gemcitabine Versus Standard Fractionation Radiotherapy with Concurrent Fluorouracil for Unresectable Pancreatic Cancer: a Multi-Institution Experience.

PURPOSE/OBJECTIVE(S): The purpose of this study was to compare oncologic outcomes and toxicity profile of hypofractionated conformal radiotherapy (RT) with concurrent full-dose gemcitabine versus standard fractionation RT with concurrent 5-fluorouracil (5-FU) in the treatment of unresectable non-metastatic pancreatic cancer. MATERIALS/METHODS: Patients with unresectable non-metastatic adenocarcinoma of the pancreas treated at three institutions were included. All patients were treated with chemoradiotherapy (CRT) consisting of either hypofractionated RT to the gross disease concurrent with a full-dose gemcitabine-based regimen versus standard fractionation RT to the tumor and elective nodes concurrent with 5-FU. End points included rates of gastrointestinal (GI) toxicities, overall survival (OS), and distant metastasis free survival (DMFS). RESULTS: From January 1999 to December 2009, 170 patients were identified (118 RT/gemcitabine, 52 RT/5-FU). There were no differences in demographic or clinical factors. Acute GI toxicities (grades <3 versus ≥3) were 82.2 and 17.8 %, respectively, for patients treated with RT/gemcitabine and 78.9 and 21.2 % for those treated with RT/5-FU (p = 0.67). Late GI toxicities (grades <3 versus ≥3) were 88.1 and 11.9 %, respectively, for RT/gemcitabine and 80.8 and 19.2 % for RT/5-FU (p = 0.23). OS for RT/gemcitabine and RT/5-FU were 52 versus 36 % at 1 year and 14 versus 6 % at 2 years favoring the RT/gemcitabine group (p = 0.02). DMFS at 1 and 2 years for RT/gemcitabine were 41 and 11 % versus 24 and 4 % for RT/5-FU (p = 0.02). CONCLUSIONS: RT/gemcitabine was equivalent in toxicity to RT/5-FU but was associated with superior OS and DMFS. When RT is used in the treatment of unresectable pancreatic cancer, hypofractionated conformal RT with concurrent full-dose gemcitabine may be the preferred approach.

Contouring Guidelines for the Axillary Lymph Nodes for the Delivery of Radiation Therapy in Breast Cancer: Evaluation of the RTOG Breast Cancer Atlas.

PURPOSE: The purpose of this study was to identify the axillary lymph nodes on pretreatment diagnostic computed tomography (CT) of the chest to determine their position relative to the anatomic axillary borders as defined by the Radiation Therapy Oncology Group (RTOG) breast cancer atlas for radiation therapy planning. METHODS AND MATERIALS: Pretreatment diagnostic CT chest scans available for 30 breast cancer patients with clinically involved lymph nodes were fused with simulation CT. Contouring of axillary levels I, II, and III according to the RTOG guidelines was performed. Measurements were made from the area of distal tumor to the anatomic borders in 6 dimensions for each level. RESULTS: Of the 30 patients, 100%, 93%, and 37% had clinical involvement of levels I, II, and III, respectively. The mean number of lymph nodes dissected was 13.6. The mean size of the largest lymph node was 2.4 cm. Extracapsular extension was seen in 23% of patients. In 97% of patients, an aspect of the involved lymph node lay outside of the anatomic border of a level. In 80% and 83% of patients, tumor extension was seen outside the cranial (1.78 ± 1.0 cm; range, 0.28-3.58 cm) and anterior (1.27 ± 0.92 cm; range, 0.24-3.58 cm) borders of level I, respectively. In 80% of patients, tumor extension was seen outside the caudal border of level II (1.36 ± 1.0 cm, range, 0.27-3.86 cm), and 0% to 33% of patients had tumor extension outside the remaining borders of all levels. CONCLUSIONS: To cover 95% of lymph nodes at the cranial and anterior borders of level I, an additional clinical target volume margin of 3.78 cm and 3.11 cm, respectively, is necessary. The RTOG guidelines may be insufficient for coverage of axillary disease in patients with clinical nodal involvement who are undergoing neoadjuvant chemotherapy, incomplete axillary dissection, or treatment with intensity modulated radiation therapy. In patients with pretreatment diagnostic CT chest scans, fusion with simulation CT should be considered for tumor delineation.

A cost-effective technique for cardiac sparing with deep inspiration-breath hold (DIBH).

Deep inspiration breath hold (DIBH) is an effective technique to reduce cardiac and pulmonary dose during breast radiotherapy (RT). However, as a result of expense and the technical challenges of program implementation, DIBH has not been widely adopted in clinical practice. This report describes a program for DIBH this is relatively inexpensive to implement and has little impact on patient throughput. Multiple redundant mechanisms are incorporated to assure accurate and safe delivery of RT during DIBH. Laser alignment verifies that chest wall excursion is reliably reproduced and maintained during treatment. Chest wall excursion is also monitored independently using an infrared camera trained on a reflective marker on the chest wall. This system automatically triggers "beam off" in the event of movement of the target beyond pre-determined thresholds. Finally, physician review of cine imaging obtained during treatment provides an off-line verification of accurate RT delivery. The approach described herein lowers the investment necessary for implementation of DIBH and may facilitate broader adoption of this valuable technique.

Discovery and Characterization of ML398, a Potent and Selective Antagonist of the D4 Receptor with in Vivo Activity.

Herein, we report the structure-activity relationship of a chiral morpholine-based scaffold, which led to the identification of a potent and selective dopamine 4 (D4) receptor antagonist. The 4-chlorobenzyl moiety was identified, and the compound was designated an MLPCN probe molecule, ML398. ML398 is potent against the D4 receptor with IC50 = 130 nM and K i = 36 nM and shows no activity against the other dopamine receptors tested (>20 µM against D1, D2S, D2L, D3, and D5). Further in vivo studies showed that ML398 reversed cocaine-induced hyperlocomotion at 10 mg/kg.