The radiopharmaceutical radium-223 has immunomodulatory effects in patients and facilitates anti-programmed death receptor-1 therapy in murine models of bone metastatic prostate cancer.

BACKGROUND & PURPOSE: Radium-223 (Ra223) improves survival in metastatic prostate cancer (mPC), but its impact on systemic immunity is unclear, and biomarkers of response are lacking. We examined markers of immunomodulatory activity during standard clinical Ra223 and studied the impact of Ra223 on response to immune checkpoint inhibition (ICI) in preclinical models. MATERIALS & METHODS: We conducted a single-arm biomarker study of Ra223 in 22 bone mPC patients. We measured circulating immune cell subsets and a panel of cytokines before and during Ra223 therapy and correlated them with overall survival (OS). Using two murine mPC models-orthotopic PtenSmad4-null and TRAMP-C1 grafts in syngeneic immunocompetent mice-we tested the efficacy of combining Ra223 with ICI. RESULTS: Above-median level of IL-6 at baseline was associated with a median OS of 358 versus 947 days for below levels; p = 0.044, from the log-rank test. Baseline PlGF and PSA inversely correlated with OS (p = 0.018 and p = 0.037, respectively, from the Cox model). Ra223 treatment was associated with a mild decrease in some peripheral immune cell populations and a shift in the proportion of MDSCs from granulocytic to myeloid. In mice, Ra223 increased the proliferation of CD8+ and CD4+ helper T cells without leading to CD8+ T cell exhaustion in the mPC lesions. In one of the models, combining Ra223 and anti-PD-1 antibody significantly prolonged survival, which correlated with increased CD8+ T cell infiltration in tumor tissue. CONCLUSION: The inflammatory cytokine IL-6 and the angiogenic biomarker PlGF at baseline were promising outcome biomarkers after standard Ra223 treatment. In mouse models, Ra223 increased intratumoral CD8+ T cell infiltration and proliferation and could improve OS when combined with anti-PD-1 ICI.

Disparities in testicular cancer incidence, mortality, and place of death trends from 1999 to 2020: A comprehensive cohort study.

BACKGROUND: Testicular cancer (TC) mortality rates have decreased over time, however it is unclear whether these improvements are consistent across all communities. AIMS: The aim of this study was to analyze trends in TC incidence, mortality, and place of death (PoD) in the United States between 1999-2020 and identify disparities across race, ethnicity, and geographic location. METHODS AND RESULTS: This cross-sectional study used CDC WONDER and NAACCR, to calculate age-adjusted rates of TC incidence and mortality, respectively. PoD data for individuals who died of TC were collected from CDC WONDER. Using Joinpoint analysis, longitudinal mortality trends were evaluated by age, race, ethnicity, US census region, and urbanization category. TC stage (localized vs metastatic) trends were also evaluated. Univariate and multivariate regression analysis identified demographic disparities for PoD. A total of 8,456 patients died of TC from 1999-2020. Average annual percent change (AAPC) of testicular cancer-specific mortality (TCSM) remained largely stable (AAPC, 0.4; 95% CI -0.2 to 0.9; p = 0.215). Men ages 25-29 experienced a significant increase in TCSM (AAPC, 1.3, p = 0.003), consistent with increased metastatic testicular cancer-specific incidence (TCSI) trend for this age group (AAPC, 1.6; p < 0.01). Mortality increased for Hispanic men (AAPC, 1.7, p < 0.001), with increased metastatic TCSI (AAPC, 2.5; p < 0.001). Finally, younger (<45), single, and Hispanic or Black men were more likely to die in medical facilities (all p < 0.001). The retrospective study design is a limitation. CONCLUSION: Significant increases in metastatic TC were found for Hispanic men and men aged 25-29 potentially driving increasing testicular cancer specific mortality in these groups. Evidence of racial and ethnic differences in place of death may also highlight treatment disparities.

US Cancer Mortality Trends Among Hispanic Populations From 1999 to 2020.

Importance: Advances in cancer research and treatment access have led to decreasing cancer mortality in the US; however, cancer remains the leading cause of death among Hispanic individuals. Objective: To evaluate longitudinal cancer mortality trends from 1999 to 2020 among Hispanic individuals by demographic characteristics and to compare age-adjusted cancer death rates between the Hispanic population and other racial and ethnic populations during 2000, 2010, and 2020. Design, Setting, and Participants: This cross-sectional study obtained age-adjusted cancer death rates among Hispanic individuals of all ages between January 1999 and December 2020, using the Centers for Disease Control and Prevention WONDER database. Cancer death rates in other racial and ethnic populations were extracted for 2000, 2010, and 2020. Data were analyzed from October 2021 to December 2022. Exposures: Age, gender, race, ethnicity, cancer type, and US census region. Main Outcomes and Measures: Trends and average annual percent changes (AAPCs) in age-adjusted cancer-specific mortality (CSM) rates among Hispanic individuals were estimated by cancer type, age, gender, and region. Results: From 1999 to 2020, 12 644 869 patients died of cancer in the US, of whom 690 677 (5.5%) were Hispanic; 58 783 (0.5%) were non-Hispanic American Indian or Alaska Native; 305 386 (2.4%), non-Hispanic Asian or Pacific Islander; 1 439 259 (11.4%), non-Hispanic Black or African American; and 10 124 361 (80.1%), non-Hispanic White. For 26 403 patients (0.2%), no ethnicity was stated. The overall CSM rate among Hispanic individuals decreased by 1.3% (95% CI, 1.2%-1.3%) annually. Overall CSM rate decreased more for Hispanic men (AAPC, -1.6%; 95% CI, -1.7% to -1.5%) compared with women (AAPC, -1.0%; 95% CI, -1.0% to -0.9%). While death rates among Hispanic individuals decreased for most cancer types, mortality rates for liver cancer (AAPC, 1.0%; 95% CI, 0.6%-1.4%) increased among Hispanic men, and rates of liver (AAPC, 1.0%; 95% CI, 0.8%-1.3%), pancreas (AAPC, 0.2%; 95% CI, 0.1%-0.4%), and uterine (AAPC, 1.6%; 95% CI, 1.0%-2.3%) cancers increased among Hispanic women. Overall CSM rates increased for Hispanic men aged 25 to 34 years (AAPC, 0.7%; 95% CI, 0.3%-1.1%). By US region, liver cancer mortality rates increased significantly in the West for both Hispanic men (AAPC, 1.6%; 95% CI, 0.9%-2.2%) and Hispanic women (AAPC, 1.5%; 95% CI, 1.1%-1.9%). There were differential findings in mortality rates when comparing Hispanic individuals with individuals belonging to other racial and ethnic populations. Conclusions and Relevance: In this cross-sectional study, despite overall CSM decreasing over 2 decades among Hispanic individuals, disaggregation of data demonstrated that rates of liver cancer deaths among Hispanic men and women and pancreas and uterine cancer deaths among Hispanic women increased from 1999 to 2020. There were also disparities in CSM rates among age groups and US regions. The findings suggest that sustainable solutions need to be implemented to reverse these trends among Hispanic populations.

Shaped-Charge Learning Architecture for the Human-Machine Teams.

In spite of great progress in recent years, deep learning (DNN) and transformers have strong limitations for supporting human-machine teams due to a lack of explainability, information on what exactly was generalized, and machinery to be integrated with various reasoning techniques, and weak defense against possible adversarial attacks of opponent team members. Due to these shortcomings, stand-alone DNNs have limited support for human-machine teams. We propose a Meta-learning/DNN → kNN architecture that overcomes these limitations by integrating deep learning with explainable nearest neighbor learning (kNN) to form the object level, having a deductive reasoning-based meta-level control learning process, and performing validation and correction of predictions in a way that is more interpretable by peer team members. We address our proposal from structural and maximum entropy production perspectives.

Using machine learning for healthcare treatment planning.

We present a methodology for using machine learning for planning treatments. As a case study, we apply the proposed methodology to Breast Cancer. Most of the application of Machine Learning to breast cancer has been on diagnosis and early detection. By contrast, our paper focuses on applying Machine Learning to suggest treatment plans for patients with different disease severity. While the need for surgery and even its type is often obvious to a patient, the need for chemotherapy and radiation therapy is not as obvious to the patient. With this in mind, the following treatment plans were considered in this study: chemotherapy, radiation, chemotherapy with radiation, and none of these options (only surgery). We use real data from more than 10,000 patients over 6 years that includes detailed cancer information, treatment plans, and survival statistics. Using this data set, we construct Machine Learning classifiers to suggest treatment plans. Our emphasis in this effort is not only on suggesting the treatment plan but on explaining and defending a particular treatment choice to the patient.

The RNA-Seq data analysis shows how the ontogenesis defines aging.

This paper presents a global statistical analysis of the RNA-Seq results of the entire Mus musculus genome. We explain aging by a gradual redistribution of limited resources between two major tasks of the organism: its self-sustenance based on the function of the housekeeping gene group (HG) and functional differentiation provided by the integrative gene group (IntG). All known disorders associated with aging are the result of a deficiency in the repair processes provided by the cellular infrastructure. Understanding exactly how this deficiency arises is our primary goal. Analysis of RNA production data of 35,630 genes, from which 5,101 were identified as HG genes, showed that RNA production levels in the HG and IntG genes had statistically significant differences (p-value <0.0001) throughout the entire observation period. In the reproductive period of life, which has the lowest actual mortality risk for Mus musculus, changes in the age dynamics of RNA production occur. The statistically significant dynamics of the decrease of RNA production in the HG group in contrast to the IntG group was determined (p-value = 0.0045). The trend toward significant shift in the HG/IntG ratio occurs after the end of the reproductive period, coinciding with the beginning of the mortality rate increase in Mus musculus indirectly supports our hypothesis. The results demonstrate a different orientation of the impact of ontogenesis regulatory mechanisms on the groups of genes representing cell infrastructures and their organismal functions, making the chosen direction promising for further research and understanding the mechanisms of aging.

Longitudinal Analysis of Bladder Cancer-Specific Mortality Trends in the United States.

BACKGROUND: Bladder cancer is the tenth leading cause of cancer death in the United States (US). Advances in diagnosis, imaging, and treatments have led to improvements in bladder cancer management. OBJECTIVE: To evaluate longitudinal bladder cancer mortality trends from 1999-2020 in the US by gender, race, ethnicity, age, geographic region, and urbanization category. METHODS: Age-adjusted bladder cancer death and incidence rates of individuals in the US of all ages between 1999-2020 were obtained using the CDC WONDER and NAACCR databases. Trends and average annual percent changes (AAPC) in age-adjusted Bladder Cancer-Specific Mortality (BCSM) and incidence rates were estimated. Data were analyzed from May 2023 to October 2023. RESULTS: From 1999-2020, overall BCSM decreased by 0.4% annually, with a dramatic decrease in deaths between 2015-2020 (AAPC: -2.0% [95% CI: -2.6,-1.3]). However, BCSM rates and metastatic malignant bladder cancer incidence rates from 1999-2020 increased for individuals≥85 years old (AAPC for BCSM: 0.8% [95% CI:0.5,1.1]; AAPC for metastatic malignant incidence: 2.5% [95% CI: 2.0,2.9]). Increases in BCSM were found for certain years in the South, in rural areas, and for Non-Hispanic White and Asian or Pacific Islander individuals. CONCLUSIONS: Overall mortality from bladder cancer has been decreasing in the US over two decades. Upon disaggregation, increasing trends were found for BCSM and for metastatic malignant bladder cancer incidence for individuals≥85 years old from 1999-2020. Further evaluation of these trends is essential to understand how to target specific populations to improve patient outcomes.

Definitive high-dose, proton-based radiation for unresected mobile spine and sacral chordomas.

BACKGROUND/PURPOSE: Treatment of spine and sacral chordoma generally involves surgical resection, usually in conjunction with radiation therapy.In certain locations, resection may result in significant neurological dysfunction, so definitive radiation has been used as an alternative to surgery. The purpose of this study is to report the results of high-dose, proton-based definitive radiotherapy for unresected spinal and sacral chordomas. MATERIALS/METHODS: Retrospective review of 67 patients with newly diagnosed, unresected spinal chordomas treated with high-dose definitive, proton-based radiotherapy at our center from 1975 to 2019. RESULTS: Reasons for radiotherapy alone included medical inoperability and/or concern for neurological dysfunction based on spine level or patient choice. Tumor locations included cervical (n = 10), thoracic (n = 1), lumbar (n = 4) spine, and sacrum (n = 52). Median maximal tumor diameter was 7.4 cm (range 1.8-25 cm). Median total dose was 77.4 Gy (RBE) (range 73.8-85.9 Gy RBE). Analysis with median follow-up of 56.2 months (range, 4-171.7 months) showed overall survival of 83.5 % (95%CI: 69.4-91.5%) and 65.9% (95%CI: 47.3-79.3%), disease-free survival of 64% (95%CI: 49.3-75.4) and 44.1% (95%CI: 27.8-59.2%), local control of 81.8% (95%CI: 67.6-90.2%) and 63.6% (95%CI: 44.7-77.5%), and distant control of 77.4% (95%CI: 63.6-86.5%) and 72.5% (95%CI: 55.7-83.8%) at 5 and 8 years respectively. The most common late side effect was insufficiency fracture. CONCLUSION: These results continue to support the use of high-dose definitive radiotherapy for patients with medically inoperable or otherwise unresected mobile spine or sacrococcygeal chordomas. There is a trend towards better disease-free survival with doses > 78 Gy (RBE).

Risk of Developing Breast Reconstruction Complications: A Machine-Learning Nomogram for Individualized Risk Estimation with and without Postmastectomy Radiation Therapy.

BACKGROUND: The purpose of this study was to create a nomogram using machine learning models predicting risk of breast reconstruction complications with or without postmastectomy radiation therapy. METHODS: Between 1997 and 2017, 1617 breast cancer patients undergoing mastectomy and breast reconstruction were analyzed. Those with autologous, tissue expander/implant, and single-stage direct-to-implant reconstruction were included. Postmastectomy radiation therapy was delivered either with three-dimensional conformal photon or proton therapy. Complication endpoints were defined based on surgical reintervention operative notes as infection/necrosis requiring débridement. For implant-based patients, complications were defined as capsular contracture requiring capsulotomy and implant failure. For each complication endpoint, least absolute shrinkage and selection operator-penalized regression was used to select the subset of predictors associated with the smallest prediction error from 10-fold cross-validation. Nomograms were built using the least absolute shrinkage and selection operator-selected predictors, and internal validation using cross-validation was performed. RESULTS: Median follow-up was 6.6 years. Among 1617 patients, 23 percent underwent autologous reconstruction, 39 percent underwent direct-to-implant reconstruction, and 37 percent underwent tissue expander/implant reconstruction. Among 759 patients who received postmastectomy radiation therapy, 8.3 percent received proton-therapy to the chest wall and nodes and 43 percent received chest wall boost. Internal validation for each model showed an area under the receiver operating characteristic curve of 73 percent for infection, 75 percent for capsular contracture, 76 percent for absolute implant failure, and 68 percent for overall implant failure. Periareolar incisions and complete implant muscle coverage were found to be important predictors for infection and capsular contracture, respectively. In a multivariable analysis, we found that protons compared to no postmastectomy radiation therapy significantly increased capsular contracture risk (OR, 15.3; p < 0.001). This was higher than the effect of photons with electron boost versus no postmastectomy radiation therapy (OR, 2.5; p = 0.01). CONCLUSION: Using machine learning, these nomograms provided prediction of postmastectomy breast reconstruction complications with and without radiation therapy. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Low-dose preoperative radiation, resection, and reduced-field postoperative radiation for soft tissue sarcomas.

BACKGROUND AND OBJECTIVES: Radiotherapy (RT) enables conservative surgery for soft tissue sarcoma (STS). RT can be delivered either pre-operatively (PreRT) or postoperatively (PORT), yet in some patients, neither approach is fully satisfactory (e.g., urgent surgery or wound healing risk prevents PreRT, yet PORT alone cannot cover the entire surgical field). We hypothesized that, in such situations, low-dose PreRT (LD-PreRT) would decrease the risk of intraoperative tumor seeding and thus permit PORT to a reduced volume (covering the high-risk tumor bed but not all surgically manipulated tissues). METHODS: We identified a single-institution retrospective cohort of 78 patients treated with LD-PreRT (10-30 Gy), resection, and PORT between 1980 and 2018. RESULTS: At a median follow-up of 8.2 years, 8-year overall survival (OS) was 65.9%, disease-free survival (DFS) 50.5%, and local control (LC) 76.7%; in 45 patients with extremity/superficial trunk (E/ST) STS, 8-year LC was 80.9%. Both before and after propensity score adjustment, there were no differences in OS, DFS, or LC between this cohort and a separate cohort of 394 STS (221 E/ST-STS) patients treated with surgery and PORT alone. CONCLUSIONS: In patients for whom neither PreRT nor PORT alone is optimal, LD-PreRT may prevent intraoperative tumor seeding and enable PORT to a reduced volume while preserving oncologic outcomes.

Brain-Specific Relative Biological Effectiveness of Protons Based on Long-term Outcome of Patients With Nasopharyngeal Carcinoma.

PURPOSE: Uncertainties in relative biological effectiveness (RBE) constitute a major pitfall of the use of protons in clinics. An RBE value of 1.1, which is based on cell culture and animal models, is currently used in clinical proton planning. The purpose of this study was to determine RBE for temporal lobe radiographic changes using long-term follow-up data from patients with nasopharyngeal carcinoma. METHODS AND MATERIALS: Five hundred sixty-six patients with newly diagnosed nasopharyngeal carcinoma received double-scattering proton therapy or intensity modulated radiation therapy at our institutions. The 2 treatment cohorts were well matched. Proton dose distributions were simulated using Monte Carlo and compared with those obtained from the proton clinical treatment planning system. Late treatment effect was defined as development of enhancement of temporal lobe on T1-weighted magnetic resonance imaging, with or without accompanying clinical symptoms. The tolerance dose was calculated with receiving operator characteristic analysis and the Youden index. Tolerance curves, expressed as a cumulative dose-volume histogram, were generated using the cutoff points. RESULTS: With a median follow-up period >5 years for both cohorts, 10% of proton patients and 4% of patients undergoing intensity modulated radiation therapy developed temporal lobe enhancement in unilateral temporal lobe. There was no significant difference in dose distributions between the Monte Carlo method and treatment planning system. The tolerance dose-volume levels were V10 (26.1%), V20 (21.9%), V30 (14.0%), V40 (7.7%), V50 (4.8%), and V60 (3.3%) for proton therapy (P < .03). Comparison of the two tolerance curves revealed that tolerance doses of proton treatments were lower than that of photon treatments at all dose levels. The dose tolerance at D1% was 58.56 Gy for protons and 69.07 Gy for photons. The RBE for temporal lobe enhancement from proton treatments were calculated to be 1.18. CONCLUSIONS: Using long-term clinical outcome of patients with nasopharyngeal carcinoma, our data suggest that the RBE for temporal lobe enhancement is 1.18 at D1%. A prospective study in a large cohort would be necessary to confirm these findings.

Physician-Machine Interaction in the Decision Making Process.

We propose an approach to decision support systems (DSS) that starts with the user first making their own unassisted decision αU and providing this decision as an input to the algorithm. Then, if the decision based of machine learning (ML) disagrees with the user's initial decision, it iteratively works with the user to converge to a common decision or at least make the user reconsider input values that are inconsistent with αU. We provide a detailed description of this approach along with examples, and then discuss potential benefits and limitations of this approach.

Long-term health-related quality of life in pediatric brain tumor survivors receiving proton radiotherapy at <4 years of age.

BACKGROUND: The purpose of this analysis is to report long-term health-related quality of life (HRQoL) among brain tumor survivors treated with proton therapy (PRT) at a very young age. METHODS: Fifty-nine children <4 years old received PRT between 2000 and 2011. Forty families participated. HRQoL was assessed by child self-report (CSR; age ≥5) and parent proxy report (PPR; age 2+) using the PedsQL Core. RESULTS: The median age was 2.5 years (range, 0.3-3.8) at PRT and 9.1 years (5.5-18) at last follow-up. The most common diagnoses were ependymoma (n = 22) and medulloblastoma (n = 7). Median follow-up is 6.7 years (3-15.4). Follow-up mean CSR and PPR scores were: total core (78.4 and 72.9), physical (82.9 and 75.2), psychosocial (76.0 and 71.6), emotional (74.4 and 70.7), social (81.2 and 75.1), and school (72.4 and 69.9). Parent-reported HRQoL fell within a previously defined range for healthy children in 37.5% of patients, and for children with severe health conditions in 45% of patients. PPR HRQoL was stable from baseline to last follow-up among all domains except for social functioning. History of gastrostomy tube was significantly associated with poorer CSR and PPR HRQoL on multivariable analysis. Ninety percent of children functioned in a regular classroom, 14 (36%) used a classroom aid, 9 (23%) used an outside tutor, and 18 (46%) had an individualized education plan. CONCLUSION: Long-term HRQoL among brain tumor survivors treated with PRT at a very young age is variable, with over a third achieving HRQoL levels commensurate with healthy children. KEY POINTS: 1. One third of survivors reported long-term HRQoL scores comparable to those of healthy children.2. Treatment for hydrocephalus or a feeding tube was associated with significantly lower HRQoL.3. Total core HRQoL scores remained stable from baseline to last follow-up.

Volumetric and actuarial analysis of brain necrosis in proton therapy using a novel mixture cure model.

BACKGROUND AND PURPOSE: High-dose fractionated radiotherapy is often necessary to achieve long-term tumor control in several types of tumors involving or within close proximity to the brain. There is limited data to guide on optimal constraints to the adjacent nontarget brain. This investigation explored the significance of the three-dimensional (3D) dose distribution of passive scattering proton therapy to the brain with other clinicopathological factors on the development of symptomatic radiation necrosis. MATERIALS AND METHODS: All patients with head and neck, skull base, or intracranial tumors who underwent proton therapy (minimum prescription dose of 59.4 Gy(RBE)) with collateral moderate to high dose radiation exposure to the nontarget brain were retrospectively reviewed. A mixture cure model with respect to necrosis-free survival was used to derive estimates for the normal tissue complication probability (NTCP) model while adjusting for potential confounding factors. RESULTS: Of 179 identified patients, 83 patients had intracranial tumors and 96 patients had primary extracranial tumors. The optimal dose measure obtained to describe the occurrence of radiation necrosis was the equivalent uniform dose (EUD) with parameter a = 9. The best-fit parameters of logistic NTCP models revealed D50 = 57.7 Gy for intracranial tumors, D50 = 39.5 Gy for extracranial tumors, and γ50 = 2.5 for both tumor locations. Multivariable analysis revealed EUD and primary tumor location to be the strongest predictors of brain radiation necrosis. CONCLUSION: In the current clinical volumetric data analyses with multivariable modelling, EUD was identified as an independent and strong predictor for brain radiation necrosis from proton therapy.

Lifestyle Counseling and Long-term Clinical Outcomes in Patients With Diabetes.

OBJECTIVE: To investigate the relationship between lifestyle counseling in primary care settings and clinical outcomes in patients with diabetes. RESEARCH DESIGN AND METHODS: We retrospectively studied hyperglycemic adults with diabetes treated at primary care practices between 2000 and 2014. We analyzed the relationship between frequency of lifestyle counseling (identified using natural language processing of electronic notes) and a composite outcome of death and cardiovascular events during subsequent follow-up. RESULTS: Among patients with monthly counseling or more, 10-year cumulative incidence of the primary outcome was 33.0% compared with 38.1% for less than monthly counseling (P = 0.0005). In multivariable analysis, higher frequency of lifestyle counseling was associated with lower incidence of the primary outcome (hazard ratio 0.88 [95% CI 0.82-0.94]; P < 0.001). CONCLUSIONS: More frequent lifestyle counseling was associated with a lower incidence of cardiovascular events and death among patients with diabetes.

Individualization of Clinical Target Volume Delineation Based on Stepwise Spread of Nasopharyngeal Carcinoma: Outcome of More Than a Decade of Clinical Experience.

PURPOSE: Radiation-related toxicity in nasopharyngeal carcinoma (NPC) is common. There are no well-established guidelines for clinical target volume (CTV) delineation with long-term follow-up. Current consensus continues to rely heavily on bony landmarks and fixed margins around the gross tumor volume (GTV), an approach used to define fields in the conventional 2- and 3-dimensional radiation therapy era. METHODS AND MATERIALS: We retrospectively evaluated patients with newly diagnosed nonmetastatic NPC treated with definitive radiation therapy using a technique of CTV delineation based on individual tumor extent and the orderly stepwise pattern of tumor spread. Dosimetric comparisons were made between national protocol HN001 and our contouring strategies on a representative early- and advanced-stage NPC. The primary endpoints were patterns of failure and local control; secondary endpoints included regional control and survival, estimated using the Kaplan-Meier method. RESULTS: Between 1999 and 2013, 73 patients (88% with stage 3-4 disease) were treated with median follow-up of 90 months for surviving patients. Median dose to GTV was 70 Gy. Four patients developed local recurrence and 1 patient developed regional recurrence. All locoregional recurrences occurred within the high-dose GTV. The 5-year local control, regional control, and overall survival was 94% (95% confidence interval [CI], 85%-98%), 99% (95% CI, 90%-100%), and 84% (95% CI, 73%-91%), respectively. Compared with HN001, our contouring strategy resulted in 62% and 36% reduction in CTV for T1 and T4 disease, respectively. In the T1 tumor, the reduction of doses to the contralateral parotid, optic nerve, and cochlea were 54%, 50%, 34% respectively. In the T4 case, there was a decrease of optic chiasm dose of 46% and contralateral optic nerve of 37%. There were 10 grade 3 toxicities. There was no grade 2 or higher xerostomia and no grade 4/5 toxicity. CONCLUSIONS: Our long-term experience with individualized CTV delineation based on stepwise patterns of spread results in excellent local control, with no recurrence outside the GTV.

Characteristics and Predictors for Secondary Leukemia and Myelodysplastic Syndrome in Ewing and Osteosarcoma Survivors.

PURPOSE: Long-term survivors of Ewing sarcoma (ES) and osteosarcoma may be at risk for therapy-related acute leukemia or myelodysplastic syndrome (t-AL/MDS). METHODS AND MATERIALS: We retrospectively reviewed the clinicopathologic characteristics of 1071 patients with osteosarcoma (n = 757) and ES (n = 314) who were treated between 1985 and 2014. Multivariable competing risk analysis was used to analyze predictors of t-AL/MDS, including a radiation dose (≥55.8 Gy vs <55.8 Gy) × disease site (pelvis/spine vs other) interaction term. A supplemental nested case-control study was conducted to assess the association between cumulative chemotherapy dose and t-AL/MDS. RESULTS: The median follow-up for surviving patients was 97 months (range, 0.03-380). Twenty patients developed t-AL/MDS, all of whom received chemotherapy and 15 of whom were treated with radiation therapy. Radiation therapy to ≥55.8 Gy was associated with development of t-AL/MDS (adjusted hazard ratio, 2.89; 95% confidence interval [CI], 1.23-6.80; P = .015), and there was a significant radiation dose × disease site interaction term (adjusted hazard ratio, 6.70; 95% CI, 2.71-16.53; Pinteraction < .001). The 5-year cumulative incidence of t-AL/MDS in patients receiving ≥55.8 Gy radiation therapy to the pelvis or spine was 5.0% (95% CI, 0.9-14.9) for osteosarcoma and 10.7% for ES (95% CI, 3.3-23.2). In our nested case-control study, cumulative doses of ifosfamide and etoposide were associated with development of t-AL/MDS. CONCLUSIONS: Patients with osteosarcoma and ES receiving ≥55.8 Gy of radiation therapy to the pelvis or spine appear to be at increased risk for t-AL/MDS. Treatment with high cumulative doses of chemotherapy may further augment this risk.

Myxoid Liposarcoma: Treatment Outcomes from Chemotherapy and Radiation Therapy.

INTRODUCTION: Myxoid liposarcoma (MLS) is a subtype of liposarcoma characterized morphologically by lipomatous differentiation with a myxoid stroma. The purpose of this study was to review clinical and pathological information for patients treated for MLS at our institution to better understand neoadjuvant and adjuvant therapy. MATERIALS AND METHODS: An institutional database of sarcomas was queried for patients who were treated for MLS at our institution between 1992 and 2013. Survival curves were constructed using Kaplan-Meier analysis, and univariate and multivariate statistics were performed using the Cox-proportional hazards model and using linear regression. RESULTS: A total of 85 patients with myxoid liposarcoma were identified. The mean and median histologic response rate to treatment for patients who received preoperative radiation therapy was 77.6%. Five-year disease-free survival, distant metastasis-free survival, local recurrence-free survival, and overall survival were 78.6% (95% CI: 67.8-86.1), 84.7% (95% CI: 74.5-91.0), 95.6% (95% CI: 86.9-98.6), and 87.5% (95% CI: 77.2-93.3) respectively. On univariate analysis, there was a trend towards higher necrosis or treatment response rates in patients who received concurrent chemotherapy, 84.7% (95% CI: 75.9-93.4) and 69.5% (95% CI: 55.1-83.8), p=0.061. Tumor size was associated with inferior disease-free and overall survival. Hazard ratio for disease-free survival is 1.08 (per cm) (95% CI: 1.01-1.16), p=0.019. CONCLUSIONS: Myxoid liposarcoma exhibits histological response to chemotherapy and radiation therapy. Tumor size appears to be greatest predictor of long-term disease control and overall survival. We were not able to show that chemotherapy provides a clinical benefit with regard to local control, disease-free survival, or overall survival. However, it is important to note that the selected usage of chemotherapy in the highest risk patients confounds this analysis. Further investigation is needed to help better determine the optimal use of chemotherapy in this group of patients.

Quality improvement program in radiation oncology: understanding patient hospitalizations, treatment breaks, and weight loss in patients receiving radiotherapy.

INTRODUCTION: The reporting of adverse effects is an integral aspect of a hospital quality improvement (QI) program with the goal of improving care for current and future patients. We report the results of our experience tracking patient hospitalizations, treatment breaks, and weight loss in patients receiving radiotherapy as part of a departmental QI program. METHODS: In 2014, the Center for Cancer Care at Exeter hospital developed a departmental quality initiative to track adverse outcomes in a population of patients receiving radiation therapy. Criteria for inclusion in this initiative included: treatment break ≥3 days, hospitalization either while on treatment of within 2 weeks of treatment, death within 2 weeks of treatment, or weight loss of ≥10%. Patients included on this registry were reviewed at regularly scheduled departmental QI meetings, where solutions for improvement were discussed. RESULTS: Ninety-one patients were identified as having an event that meet the above-mentioned criteria. Forty-three patients were receiving concurrent chemotherapy (47.2%) Fifty-four (54.9%) patients had toxicity directly attributable to their treatment. Sixty-five patients (71.4%) were treated with curative intent. Nineteen patients (21.1%) died either during the course of radiotherapy, or within two weeks of completion of treatment. Advanced age was significantly associated with inferior overall and disease free survival in this analysis, HR 1.030 (1.006-1.054) p = 0.0125, and HR 1.034 (1.008-1.061) p = 0.010 respectively. CONCLUSION: We believe that this protocol to track events has been helpful in making practice changes in our department. Our results suggest that elderly patients who experience qualifying event are at increased risk of death, and providers should be cognizant of this finding. Future QI projects can seek to better understand how such changes have resulted in improvements in patient care.