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Prognostic factors for prostate cancer include tumor, node, metastases stage, pretreatment prostate-specific antigen, and pathology (via Gleason score [GS] or grade group). Of these, GS yields the largest effect on prostate cancer specific mortality. It was previously determined that those with cores with a mix of higher and lower GS at biopsy (which was termed a "ComboGS") had decreased risk for prostate cancer specific mortality after either surgical or radiation treatment. We validate the effect of ComboGS in an independent cohort of patients with prostate cancer treated with definitive dose-escalated radiation therapy (DE-RT) at 2 institutions.DE-RT was administered to 2539 men, of which 687 men had a ComboGS. To further ascertain the ComboGS effect we employed the modified Cancer of the Prostate Risk Assessment (mCAPRA) score. Rates of biochemical event-free survival and distant metastasis-free survival were compared across CAPRA scores, with and without modification, and the prognostic value of the CAPRA scores was compared using Harrel's concordance index.On univariate analysis in Gleason 7 to 10 patients the presence of ComboGS improved 10-year biochemical event-free survival from 76.6% to 82.4% (hazard ratio [HR], 0.75; confidence interval [CI], 0.59-0.96; P = .021), 10-year distant metastasis-free survival from 89.3% to 93.2% (HR, 0.57; CI, 0.39-0.85; P = .005), 10-year prostate cancer specific survival from 93.9% to 97.4% (HR, 0.39; CI, 0.21-0.7; P = .001), and 10-year overall survival from 65.7% to 75.6% (HR, 0.69; CI, 0.57-0.83; P.001). Multivariable analysis also supported that ComboGS is protective for biochemical failure (HR, 0.64; CI, 0.50-0.83; P.001), distant metastasis (HR, 0.42; CI, 0.28-0.63; P.001), death from prostate cancer (HR, 0.32; CI, 0.17-0.58; P.001), and overall mortality (HR, 0.65; CI, 0.54-0.79; P.001). Additionally, adjusting the mCAPRA score for ComboGS decreased the risk of biochemical failure by nearly 30% (HR, 0.70; 95% CI, 0.55-0.88; P = .003) and by 50% (HR, 0.54; 95% CI, 0.37-0.80; P = .002) for distant metastasis.ComboGS is a useful and readily available independent prognostic factor for all clinical endpoints evaluated. Moreover, the ComboGS can be used in conjunction with the extensively validated CAPRA scoring to better risk stratify patients being treated with definitive DE-RT for GS 7 to 10 disease.

Adoption of hypofractionated whole breast irradiation (HWBI) for patients with early-stage, biologically high-risk breast cancer remains relatively low. We compared clinical outcomes of conventionally fractionated whole breast irradiation (CWBI) versus moderate HWBI in this patient population.We queried a prospectively maintained database for patients with early-stage (T1-2, N0, M0) breast cancer who received whole breast irradiation with either CWBI or moderate HWBI at a single institution. We included only patients with biologically high-risk tumors (defined as either estrogen receptor/progesterone receptor/human epidermal growth factor receptor 2 negative, human epidermal growth factor receptor 2 amplified, and/or patients with a high-risk multigene assay) who received systemic chemotherapy. Inverse probability of treatment weighting was used to compare treatment cohorts and to estimate 5-year time to event endpoints. Hazard ratios (HR) and 95% confidence interval (CI) were determined based on Cox proportional hazards model.We identified 300 patients, of whom 171 received CWBI and 129 received HWBI. There was a statistically significant difference in median age at diagnosis, 59 years for CWBI versus 63 years for HWBI (P = .004), and in median follow-up time, 97 months for CWBI versus 55 months for HWBI (P.001). After accounting for differences in patient and tumor characteristics with inverse probability of treatment weighting, we found similar 5-year freedom from local recurrence (HR, 0.76; 95% CI, 0.14-4.1), freedom from regional recurrence (HR, 3.395% CI 0.15-69), freedom from distant metastasis (HR 3.9, 95% CI 0.86-17), and disease-free survival (HR 0.84; 95% CI, 0.3-2.4), between those treated with CWBI and those treated with HWBI. Results were similar among each of the 3 high-risk subtypes.Our data support the use of moderate HWBI in patients with early-stage, biologically high-risk breast cancer.

Uterine carcinosarcoma (UCS) confers a high recurrence risk following surgery, and adjuvant chemotherapy (CHT) is typically administered in all stages. The benefit of radiation therapy (RT) in UCS, when added to adjuvant CHT, is unknown. We sought to analyze the Surveillance, Epidemiology, and End Results (SEER) database to ascertain whether RT improves overall survival (OS) when added to surgery and CHT for UCS. SEER 18 Custom Data registries (Nov 2018 submission) were queried for uterine (ICD10 C54.1-9, C55.9) carcinosarcoma (ICD-0-3 8980-3). Patients with stage I-III UCS who underwent surgery and CHT ± RT were analyzed with univariate analysis (UVA) and multivariable analysis (MVA) using Kaplan–Meier and Cox proportional hazards regression modeling. Propensity-score matched analysis with inverse probability of treatment weighting (IPTW) was performed to account for indication bias. Furthermore, conditional landmark analysis (minimum three-month follow-up) was performed to minimize immortal time bias. All 1541 patients (1988–2016) underwent surgery and CHT and 54% received RT. On UVA, RT improved median and 5-year OS from 41 to 87 months and 43–55%, respectively (HR 0.65, 95% CI 0.56–0.77) (p

Background Multiple studies have suggested that patients with early-stage SCC of the lung treated with SBRT are more susceptible to local failure compared to other NSCLC histologies. It is unknown if higher BED leads to improved outcomes in this patient population. We evaluated the effect of “high” BED versus “low” BED SBRT on overall survival (OS) in SCC and non-SCC NSCLC patients. Methods The National Cancer Database was used to identify patients with cT1-2N0M0 NSCLC diagnosed between 2006–2016 treated with 3–5 fraction SBRT. Patients were grouped by BEDhigh (>150 Gy) and BEDlow (≤132 Gy). Univariate and multivariable analysis using Kaplan-Meier and Cox proportional hazards regression modeling were performed. Propensity-score matched analysis with inverse probability of treatment (IPTW) weighting was used to account for selection bias. Results We identified 4,717 eligible SCC patients and 8,807 eligible non-SCC NSCLC patients. In SCC patients, BEDhigh was associated with improved OS in both univariate and multivariate analysis (MVA HR 0.84 95% CI 0.76–0.92, p Conclusions Our analysis suggests that in patients with early-stage NSCLC, SBRT regimens with BED > 150 Gy may confer a survival benefit in patients with SCC histology. Histology-based dose modification should be considered, and prospective validation may be warranted.

PURPOSE Computed tomography (CT)-derived ventilation methods compute respiratory induced volume changes as a surrogate for pulmonary ventilation. Currently, there are no known methods to derive perfusion information from noncontrast CT. We introduce a novel CT-Perfusion (CT-P) method for computing the magnitude mass changes apparent on dynamic noncontrast CT as a surrogate for pulmonary perfusion. METHODS CT-Perfusion is based on a mass conservation model which describes the unknown mass change as a linear combination of spatially corresponding inhale and exhale HU estimated voxel densities. CT-P requires a deformable image registration (DIR) between the inhale/exhale lung CT pair, a preprocessing lung volume segmentation, and an estimate for the Jacobian of the DIR transformation. Given this information, the CT-P image, which provides the magnitude mass change for each voxel within the lung volume, is formulated as the solution to a constrained linear least squares problem defined by a series of subregional mean magnitude mass change measurements. Similar to previous robust CT-ventilation methods, the amount of uncertainty in a subregional sample mean measurement is related to measurement resolution and can be characterized with respect to a tolerance parameter τ . Spatial Spearman correlation between single photon emission CT perfusion (SPECT-P) and the proposed CT-P method was assessed in two patient cohorts via a parameter sweep of τ . The first cohort was comprised of 15 patients diagnosed with pulmonary embolism (PE) who had SPECT-P and 4DCT imaging acquired within 24 h of PE diagnosis. The second cohort was comprised of 15 nonsmall cell lung cancer patients who had SPECT-P and 4DCT images acquired prior to radiotherapy. For each test case, CT-P images were computed for 30 different uncertainty parameter values, uniformly sampled from the range [0.01, 0.125], and the Spearman correlation between the SPECT-P and the resulting CT-P images were computed. RESULTS The median correlations between CT-P and SPECT-P taken over all 30 test cases ranged between 0.49 and 0.57 across the parameter sweep. For the optimal tolerance τ = 0.0385, the CT-P and SPECT-P correlations across all 30 test cases ranged between 0.02 and 0.82. A one-sample sign test was applied separately to the PE and lung cancer cohorts. A low Spearmen correlation of 15% was set as the null median value and two-sided alternative was tested. The PE patients showed a median correlation of 0.57 (IQR = 0.305). One-sample sign test was statistically significant with 96.5 % confidence interval: 0.20-0.63, P

Dose to the left anterior descending artery (LAD) may be significant in patients receiving left-sided irradiation for breast cancer. We investigated if prospective contouring and avoidance of the LAD during treatment planning were associated with lower LAD dose.We reviewed dosimetric plans for 323 patients who received left whole breast or chest wall irradiation with or without internal mammary node (IMLN) coverage between 1/2014 and 1/2019 at a single institution. The LAD was contoured prospectively for 155 cases, and techniques were utilized to minimize LAD dose. Dose-volume-histograms from these patients were compared to those of 168 patients for whom the LAD was contoured retrospectively after treatment completion. EQD2 was calculated to account for fractionation differences.Compared to cases where the LAD was contoured retrospectively (n = 126), prospective LAD contouring (n = 124) was associated with lower unadjusted median max and mean LAD doses for 250 patients receiving whole-breast irradiation (WBI) without IMLN coverage: 8.5 Gy vs 5.2 Gy (p0.0001) and 3.6 Gy vs 2.7 Gy (p0.0001), respectively. EQD2 median max and mean LAD doses were also lower with prospective LAD contouring: 5.2 Gy vs 3.0 Gy (p0.0001) and 1.9 Gy vs 1.5 Gy (p0.0001), respectively. Compared to cases where the LAD was contoured retrospectively (n = 42), prospective LAD contouring (n = 31) was associated with lower max LAD doses for 73 patients with IMLN coverage: 20.4 Gy vs 14.3 Gy (p = 0.042). There was a nonsignificant reduction in median mean LAD dose: 6.2 Gy vs 6.1 Gy (p = 0.33). LAD doses were reduced while maintaining IMLN coverage (mean V90%Prospective contouring and avoidance of the LAD were associated with lower max and mean LAD doses in patients receiving WBI and with lower max LAD doses in patients receiving IMLN treatment. Further reduction in LAD dose may require stricter optimization weighting or compromise in IMLN coverage.

Aim To use inhibition of colony-stimulating factor-1 receptor (CSF-1R) to target tumor-associated macrophages (TAMs) and improve the efficacy of radiotherapy in glioblastoma (GBM). Materials and methods The CSF-1R inhibitor BLZ-945 was used to examine the impact of CSF-1R inhibition on M2 polarization in vitro. Using an orthotopic, immunocompetent GBM model, mice were treated with vehicle, RT, BLZ-945, or RT plus BLZ-945. Results BLZ-945 reduced M2 polarization in vitro. BLZ-945 alone did not improve median overall survival (mOS=29 days) compared to control mice (mOS=27 days). RT improved survival (mOS=45 days; p=0.02), while RT plus BLZ-945 led to the longest survival (mOS=not reached; p=0.005). Resected tumors had a relatively large population of M2 TAMs in GBM at baseline, which was increased in response to RT. BLZ-945 reduced RT-induced M2 infiltration. Conclusion Inhibition of CSF-1R improved response to RT in the treatment of GBM and may represent a promising strategy to improve RT-induced antitumor immune responses.

Background The role for postoperative radiation therapy (PORT) for patients with non–small-cell lung cancer (NSCLC) with mediastinal lymph node (LN) involvement (pN2 disease) is controversial. We compared surgery alone with PORT among patients with pN2 NSCLC. We then performed subset analyses to better delineate patients that might benefit from PORT. Patients and Methods We conducted a propensity score (PS)-matched, inverse probability of treatment weighting (IPTW) Surveillance, Epidemiology, and End Results (SEER) analysis of patients with pN2 disease from 1989 to 2016 with surgery alone or PORT. Multiple imputation with chained equations was used for missing LN data. Results A total of 8631 patients were included in this analysis; 4579 underwent surgery alone, and 4052 underwent PORT. Following PS matching and IPTW, there was no difference in overall survival (OS) (hazard ratio [HR], 0.99; P = .76). However, PORT improved OS among a subset of patients with a LN positive to sampled ratio ≥ 50% (HR, 0.90; P = .01). Moreover, there was a trend towards improved OS among this subset, even with chemotherapy (HR, 0.91; P = .09). Conclusion PORT is not associated with an improvement or detriment in OS for all patients with pN2 NSCLC. However, patients with a positive to sampled LN ratio ≥ 50% may benefit, regardless of chemotherapy status. Nevertheless, PORT will remain the standard of care as we await the results of the ongoing LUNG ART trial.

BACKGROUND: There is an alarming rise in incidence among young patients with rectal cancer. The National Cancer Database (NCDB) and Surveillance, Epidemiology, and End Results Analysis (SEER) databases may help identify population level disparities in incidence and cancer-related outcomes. METHODS: A total of 197,178 patients within the SEER 18 registry and 221,886 patients from the NCDB database with rectal cancer were evaluated in this retrospective cohort study. The analyzed cohort consisted of young (

Introduction Malignant pleural mesothelioma (MPM) is a devastating disease with poor survival outcomes for most patients. Optimizing therapeutic approaches is thus vital, but has been hampered by a dearth of randomized trials to guide decision making. We used a population-level database to evaluate the impact of radiotherapy as a component of trimodality therapy on overall survival (OS) in MPM. Methods We retrospectively reviewed the SEER Radiation/Chemotherapy database for patients with MPM who received surgery and chemotherapy, with or without radiotherapy. A propensity score-matched analysis with inverse probability of treatment weighting (IPTW) was performed. Weight-adjusted univariate KM analysis was performed and doubly robust, IPTW-adjusted multivariable cox proportional hazards regression modeling was also performed to quantify the effect of radiotherapy on OS in trimodality therapy for MPM. Results 1015 patients were identified. 678 patients received surgery and chemotherapy, and 337 patients received trimodality therapy. For patients with localized disease, OS was significantly improved with trimodality therapy (HR 0.56, CI 0.4 – 0.8, p = 0.001), which persisted with IPTW adjustment (HR 0.65, CI 0.49 – 0.95, p = 0.0248). No significant benefit was seen for patients with regional or distant disease. On multivariate analysis, positive predictors of survival after IPTW adjustment were female sex, diagnosis after 2005, and left-sided disease. Conclusions These findings support a significant benefit to OS by incorporating radiotherapy as a component of trimodality therapy for patients with localized MPM compared to only surgery and chemotherapy. It does not provide a significant overall survival benefit for patients with regional or metastatic disease.

BackgroundPulsed radiation therapy (PRT) has shown effective tumor control and superior normal-tissue sparing ability compared with standard radiotherapy (SRT) in preclinical models and retrospective clinical series. This is the first prospective trial to investigate PRT in the treatment of patients with newly diagnosed glioblastoma (GBM).MethodsThis is a single-arm, prospective study. Patients with newly diagnosed GBM underwent surgery, followed by 60 Gy of PRT with concurrent temozolomide (TMZ). Each day, a 2-Gy fraction was divided into ten 0.2-Gy pulses, separated by 3-minute intervals. Patients received maintenance TMZ. Neurocognitive function (NCF) and quality of life (QoL) were monitored for 2 years using the Hopkins Verbal Learning Test‒Revised and the European Organisation for Research and Treatment of Cancer QLQ-C30 QoL questionnaire. Change in NCF was evaluated based on a minimal clinically important difference (MCID) threshold of 0.5 standard deviation.ResultsTwenty patients were enrolled with a median follow-up of 21 months. Median age was 60 years. Forty percent underwent subtotal resection, and 60% underwent gross total resection. One patient had an isocitrate dehydrogenase (IDH)–mutated tumor. Median progression-free survival (PFS) and overall survival (OS) were 10.7 and 20.9 months, respectively. In a post-hoc comparison, median OS for the prospective cohort was longer, compared with a matched cohort receiving SRT (20.9 vs 14 mo, P = 0.042). There was no decline in QoL, and changes in NCF scores did not meet the threshold of an MCID.ConclusionsTreatment of newly diagnosed GBM with PRT is feasible and produces promising effectiveness while maintaining neurocognitive function and QoL. Validation of our results in a larger prospective trial warrants consideration.

This study assessed automated quantification of CD44, c-MET, MTOR, EGFR, and GLUT1 protein expression in a tissue microarray of 109 Stage II-IV p16 positive and negative head and neck squamous cell carcinomas (HNSCC) treated with definitive chemoradiation. Immunohistochemistry-based protein expression was quantified in an automated manner using digitally scanned images processed with Definiens Tissue Studio software to generate a histologic score (H-score, range 0-300) which was normalized for each biomarker. Biomarker expression levels were correlated with one another and with p16 status. Effects of biomarker and p16 status on locoregional control, disease-free survival, and overall survival were analyzed using Kaplan Meier and Cox proportional hazard modelling. There was a significant negative correlation between CD44 and p16 expression and significant positive correlations between CD44 and MTOR, CD44 and GLUT1, c-MET and MTOR, and MTOR and GLUT1. When patients were stratified by p16 status, the significant positive correlation between CD44 expression and MTOR remained for both the p16 positive and negative subsets, while correlations between CD44 and GLUT1 and c-MET and MTOR were seen in the p16 negative subset only. A significant correlation between MTOR and GLUT was seen overall and for the p16 positive subset. When the effects of biomarker expression on clinical endpoints were examined, histologic scores below the defined cut-points for CD44 and c-MET were each associated with improved locoregional control. Higher expressions of CD44, c-MET, EGFR, and GLUT1 were associated with inferior disease-free and overall survival. On multivariable analysis, p16 positivity remained independently associated with improved locoregional control, disease-free survival, and overall survival, high CD44 remained independently associated with inferior locoregional control, disease-free survival, and overall survival, and EGFR with inferior disease-free and overall survival. In conclusion, the use of an automated system to quantify IHC expression allowed objective correlation between biomarkers and stratification of patients, revealing that higher expressions of CD44, c-MET, EGFR, and GLUT1 were associated with poorer disease-free and overall survival.

Previously a phase III trial of a hydrogel rectal spacer during prostate radiation therapy found decreased toxicity and a clinically significant improvement in bowel quality of life (QOL) at 3 years by the Expanded Prostate Cancer Index. We performed a secondary analysis to identify men less likely to benefit.Clinical and dosimetric data for the 222 patients enrolled on the SpaceOAR phase III trial were analyzed. The volume of rectum treated to 70 Gy (V70) and the quantitative analysis of normal tissue effects in the clinic (QUANTEC) rectal dose goals were used as surrogates for clinical benefit and plan quality. Mean bowel QOL was assessed at 15 and 36 months posttreatment and the likelihood of 1× (5 points) or 2× (10 points) minimally important difference changes were assessed.Rectal V70 was correlated with physician scored toxicity (P = .033) and was used as a surrogate for plan quality. There was no correlation between prostate volume and rectal V70 (r = 0.077). Rectal V70 pre- and post-hydrogel was 13% and 3% for the smallest prostates (40 mL) and 12% and 2% for the largest (80 mL). The relative reduction in rectal V70 of 78% did not vary by prespacer V70, but the absolute reduction was greater for a higher V70. All spacer plans met the 5 QUANTEC rectal dose constraints, although 92% of control plans met all constraints. At 3 years, those not meeting all QUANTEC goals had a 15.0-point (standard deviation 15.1) decline, control patients meeting QUANTEC goals had a 4.0-point (9.5) decline, and spacer had0.5 (7.6; P.01). Previous surgery was not correlated with QOL (P = .8). Across prognostic groups, including age, body mass index, previous surgery, target volume, or quality of radiation plans, there was no statistically significant heterogeneity in the relative benefit of spacer in decreasing the risk of 1× or 2× the minimally important difference declines.There was little heterogeneity in the likelihood of spacer reducing the risk of declines in bowel QOL across clinical and dosimetric variables. Even for the95% of plans meeting QUANTEC rectal criteria, hydrogel spacer provided potentially meaningful benefits.

OBJECTIVEContrary to the better described obliteration- and hemorrhage-related data after stereotactic radiosurgery (SRS) of brain arteriovenous malformations (AVMs) in pediatric patients, estimates of the rarer complications, including cyst and tumor formation, are limited in the literature. The aim of the present study was to assess the long-term outcomes and risks of SRS for AVMs in pediatric patients (age < 18 years).METHODSThe authors retrospectively analyzed the International Radiosurgery Research Foundation pediatric AVM database for the years 1987 to 2018. AVM obliteration, post-SRS hemorrhage, cyst formation, and tumor formation were assessed. Cumulative probabilities, adjusted for the competing risk of death, were calculated.RESULTSThe study cohort comprised 539 pediatric AVM patients (mean follow-up 85.8 months). AVM obliteration was observed in 64.3% of patients, with cumulative probabilities of 63.6% (95% CI 58.8%–68.0%), 77.1% (95% CI 72.1%–81.3%), and 88.1% (95% CI 82.5%–92.0%) over 5, 10, and 15 years, respectively. Post-SRS hemorrhage was observed in 8.4% of patients, with cumulative probabilities of 4.9% (95% CI 3.1%–7.2%), 9.7% (95% CI 6.4%–13.7%), and 14.5% (95% CI 9.5%–20.5%) over 5, 10, and 15 years, respectively. Cyst formation was observed in 2.1% of patients, with cumulative probabilities of 5.5% (95% CI 2.3%–10.7%) and 6.9% (95% CI 3.1%–12.9%) over 10 and 15 years, respectively. Meningiomas were observed in 2 patients (0.4%) at 10 and 12 years after SRS, with a cumulative probability of 3.1% (95% CI 0.6%–9.7%) over 15 years.CONCLUSIONSAVM obliteration can be expected after SRS in the majority of the pediatric population, with a relatively low risk of hemorrhage during the latency period. Cyst and benign tumor formation after SRS can be observed in 7% and 3% of patients over 15 years, respectively. Longitudinal surveillance for delayed neoplasia is prudent despite its low incidence.

There is limited retrospective evidence addressing the utility of post-mastectomy radiotherapy (PMRT) in patients with T3N0 breast cancer. We performed a retrospective analysis of the National Cancer Database (NCDB) comparing overall survival (OS) in T3N0 patients treated with mastectomy alone (MTX) or with PMRT.We performed a matched-cohort analysis of NCDB breast cancer patients with pT3N0 disease who did not receive NAC, or cT3N0 patients who received NAC treated between 2006 and 2014. Patients were matched for all available baseline characteristics using propensity scores with inverse probability of treatment weighting (IPTW) with stabilized weights.We identified 13,901 eligible patients. In the pT3N0 cohort, median follow-up was 47 months for the MTX group and 50 months for the PMRT group. In the cT3N0 cohort, median follow-up was 44 months for the MTX group and 46 months for the PMRT group. OS was higher in pT3N0 patients treated with PMRT compared to MTX: 7-year OS of 74% vs. 65% (P 0.001). Doubly robust multivariable analysis showed an association between PMRT and improved OS (HR 0.78, 95% CI 0.68-0.89, P 0.001). There was no benefit to PMRT in patients who received adjuvant chemotherapy (AC). In the NAC cohort, PMRT did not change OS, with 7-year OS of 78% with MTX and 79% with PMRT. There was a trend of improved OS with PMRT in patients with residual disease in the breast and lymph nodes (HR 0.70, 95% CI 0.46-1.07).PMRT improves OS in patients with pT3N0 disease, but the benefit appears limited to those who do not receive AC. PMRT does not improve OS in patients with cT3N0 disease who receive NAC, but there might be a benefit in patients with a poor response to chemotherapy. However, longer follow-up may be needed to make a definitive conclusion about the benefit of PMRT in patients who receive chemotherapy.

We investigated whether the use of chemotherapy before whole breast irradiation (WBI) using either conventional fractionation (CWBI) or hypofractionation (HWBI) is associated with increased toxic effects or worse cosmetic outcome compared with WBI alone.We identified 6754 patients who received WBI alone (without a third field covering the superior axillary and supraclavicular nodal regions) with data prospectively collected in a statewide consortium. We reported rates of 4 toxic effects: physician-reported acute moist desquamation, patient-reported acute moderate/severe breast pain, a composite acute toxic effect measure (including moist desquamation and either patient- or physician-reported moderate/significant breast pain), and physician-reported impaired cosmetic outcome at 1 year after WBI. Successive multivariable models were constructed to estimate the effect of chemotherapy on these outcomes.Rates of moist desquamation, patient-reported pain, composite acute toxic effects, and impaired cosmetic outcome were 23%, 34%, 42%, and 10% for 2859 patients receiving CWBI and 13%, 28%, 31%, and 11% for 3895 patients receiving HWBI. Receipt of chemotherapy before CWBI was not associated with higher rates of patient-reported pain, composite acute toxic effects, or impaired cosmetic outcome compared with CWBI without chemotherapy but was associated with more moist desquamation (odds ratio, 1.32 [1.07-1.63]; P = .01). Receipt of chemotherapy before HWBI was not associated with higher rates of any of the 4 toxic effects compared with HWBI alone.In this cohort, use of chemotherapy before WBI was generally well tolerated. CWBI with chemotherapy but not HWBI with chemotherapy was associated with higher rates of moist desquamation. Rates of acute breast pain and impaired cosmetic outcome at 1 year were comparable in patients receiving chemotherapy before either CWBI or HWBI. These data support the use of HWBI after chemotherapy.

Purpose/objective(s) Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous neoplasm traditionally managed with surgical resection followed by radiotherapy (RT). With the recent approval of checkpoint inhibitors, chemotherapy is less commonly utilized. We analyzed the impact of RT and chemotherapy on overall survival (OS) in patients with MCC using Surveillance, Epidemiology, and End Results (SEER), a population-level database. Materials and methods We performed retrospective analyses on SEER 18 Custom Data registries for MCC (ICD-0-3 8247). Data from 1980 to 2016 was queried for analysis, and an initial list of 9,792 patients was populated (ICD: C00, C07.9, C44, C80.9). Selection for cases with chemotherapy and RT status, single primary tumor, primary tumor location and surgery treatment type yielded 5,002 cases for analysis. Baseline characteristics were compared with Chi-square or Mann-Whitney U test. Univariate and multivariable analysis using Kaplan-Meier and Cox proportional hazards regression modeling were performed. Propensity-score matched analysis with inverse probability of treatment weighting (IPTW) was used to account for indication bias. Results Median follow-up time was 178 months (68 to 217 months). Independent prognostic factors positively correlated with increased OS, for both unadjusted Multivariate analysis and IPTW adjusted MVA were age, male sex, year of diagnosis, stage, RT status, and chemotherapy status. On adjusted MVA, use of chemotherapy was associated with worse OS (hazard ratio: 1.22 [95% CI 1.1-1.35], p

BACKGROUND: The standard of care in locally advanced rectal cancer is preoperative chemoradiation followed by surgical resection. However, the optimal treatment paradigm is currently controversial for patients with pathological T3N0 (pT3N0) in the era of total mesorectal excision (TME). Given the paucity of data, we conducted an analysis using the National Cancer Database (NCDB) to identify patterns of care and outcomes. METHODS: We utilized the NCDB to identify 7,836 non-metastatic, pT3N0 rectal cancer patients who did not receive neoadjuvant therapy from 2004–2014. Univariate and multivariable analysis for factors affecting treatment selection were completed using logistic regression. Overall survival (OS) analyses were completed using Cox regression modeling, incorporating propensity scores with inverse probability of treatment weighting (IPTW) and conditional landmark analysis. RESULTS: There was a significant improvement in OS in patients receiving adjuvant chemotherapy (P

Background Long-term data regarding stereotactic radiosurgery (SRS) as a standalone therapy for unruptured pediatric brain arteriovenous malformations (AVMs) are incompletely defined. Objective To evaluate, in a multicenter, retrospective cohort study, the outcomes after SRS for unruptured, intervention-naive pediatric AVMs. Methods To retrospectively analyze the International Radiosurgery Research Foundation pediatric AVM database from 1987 to 2018. Pediatric patients with unruptured, previously untreated AVMs who underwent SRS were included. The primary endpoint was a composite of hemorrhagic stroke, death, or permanently symptomatic radiation-induced changes. Results The study cohort comprised 101 patients (mean follow-up 80.8 mo). The primary endpoint occurred in 14%, comprising hemorrhagic stroke, death, and permanent radiation-induced changes in 6%, 3%, and 8%, respectively. Estimated probabilities of the primary endpoint were 5.2%, 10.8%, and 23.0% at 2, 5, and 10 yr, respectively. Estimated probabilities of AVM obliteration at 5 and 10 yr were 64% and 82%, respectively. Single SRS treatment (P = .007) and higher margin dose (P = .005) were predictors of obliteration. Subgroup analysis of Spetzler-Martin grade I-III AVMs estimated primary endpoint probabilities of 3.7%, 8.4%, and 18.7% at 2, 5, and 10 yr, respectively. Conclusion Treatment of unruptured, intervention-naive AVMs in the pediatric population with SRS carries an approximately 2% annual risk of morbidity and mortality, which appears to plateau after 10 yr. The poorly described natural history of pediatric AVMs renders any comparison of SRS vs conservative management imperfect.

Recent retrospective studies suggest improved overall survival (OS) with breast conserving therapy (BCT), including breast conserving surgery and adjuvant whole breast radiotherapy, compared to mastectomy in the modern era. The patient subset most likely to benefit from BCT remains unclear, and the role of Oncotype DX Recurrence Score (RS) in this context is unknown. We compared BCT to mastectomy in early-stage, node-negative breast cancer. We further explored outcomes after stratification by RS and age.We performed a matched-cohort analysis of National Cancer Database (NCDB) patients with pT1-2, pN0, cM0 breast cancer treated between 2006 and 2014 with BCT or mastectomy. Patients were matched for all available baseline characteristics using propensity scores with inverse probability of treatment weighting (IPTW) with stabilized weights.We identified 144,263 eligible patients treated with BCT and 87,379 patients treated with mastectomy. After IPTW-matching, OS was higher with BCT compared to mastectomy: 5-year OS of 94.4% vs. 91.8% (P 0.001) and 7-year OS of 90% vs. 85.2% (P 0.001). Doubly robust multivariable analysis showed an association between BCT and improved OS (HR 0.66, 95% CI, 0.64-0.69, P 0.001). In a subset analysis, BCT was associated with improved OS in patients with RS25, but not patients with RS ≤25. When stratified by age, only patients50 years had improved OS with BCT.BCT is associated with improved OS compared to mastectomy in women with early-stage, node-negative breast cancer. The improvement in OS with BCT appears to be most pronounced in patients with high RS and50 years of age. Prospective validation of these findings is required.

Tumor thrombosis is a poor prognostic feature and an exceptionally rare occurrence in salivary gland malignancies. We present a case of primary parotid myoepithelial carcinoma (MC) with tumor thrombosis in the external jugular vein (EJV). An 82-year-old man presented with a right-sided facial mass. MRI with and without gadolinium demonstrated a mass of the right parotid gland with a filling defect of the right EJV. The patient underwent right parotidectomy and selective neck dissection. Tumor thrombosis was found intraoperatively within the EJV. Final pathology demonstrated a poorly differentiated MC. Adjuvant radiation therapy without concurrent systemic therapy was administered. Three months later, restaging positron emission tomography (PET) with CT revealed numerous bilateral pulmonary nodules with biopsy, demonstrating poorly differentiated MC without locoregional relapse. Given that primary parotid tumor thrombosis is associated with a poor prognosis, the use of early systemic therapy should be investigated.

Perivascular epithelioid cell neoplasms, also known as PEComas, are a group of rare mesenchymal tumors that have a perivascular distribution and have no known counterpart to normal cells. The PEComa grouping includes angiomyolipomas, lymphangioleiomyomatoses, clear cell (sugar) tumors at extrapulmonary and intrapulmonary sites, clear cell myomelanocytic tumor of the falciform ligament/ligamentum teres among others. These rare tumors most commonly arise in the uterus. Here, we present an unusual case of malignant PEComa arising in the buttock region.

Background: Lung compliance is the ability of the lung to expand with changes in pressure and is one of the earliest physiological measurements to be altered in patients with parenchymal lung disease. Therefore, compliance monitoring could potentially identify patients at risk for disease progression. However, in clinical practice, compliance measurements are prohibitively invasive for use as a routine monitoring tool. Purpose: We propose a novel method for computing dynamic lung compliance imaging (LCI) from non-contrast computed tomography (CT) scans. LCI applies image processing methods to free-breathing 4DCT images, acquired under two different continuous positive airway pressures (CPAP) applied using a full-face mask, in order to compute the lung volume change induced by the pressure change. LCI provides a quantitative volumetric map of lung stiffness. Methods: We compared mean LCI values computed for 10 patients with idiopathic pulmonary fibrosis (IPF) and 7 non-IPF patients who were screened for lung nodules. 4DCTs were acquired for each patient at 5cm and 10 cm H20 CPAP, as the patients were free breathing at functional residual capacity. LCI was computed from the two 4DCTs. Mean LCI intensities, which represent relative voxel volume change induced by the change in CPAP pressure, were computed. Results: The mean LCI values for patients with IPF ranged between [0.0309, 0.1165], whereas the values ranged between [0.0704, 0.2185] for the lung nodule cohort. Two-sided Wilcoxon rank sum test indicated that the difference in medians is statistically significant (p value = 0.009) and that LCI -measured compliance is overall lower in the IPF patient cohort. Conclusion: There is considerable difference in lung compliance scores between patients with IPF compared to controls. Future longitudinal studies should look for LC alterations in areas of lung prior to radiographic detection of fibrosis to further characterize LCI's potential utility as an image marker for disease progression.

Background In this retrospective surveillance, epidemiology, and end results (SEER) registry analysis, we investigated the role of chemotherapy (CT) in the treatment of olfactory neuroblastoma (ON), an exceedingly rare sino‐nasal tumor typically treated with surgery and/or radiation therapy (RT). Methods We analyzed all patients in the SEER registry diagnosed with a single primary malignancy of ON, a primary tumor site within the nasal cavity or surrounding sinuses, sufficient staging information to derive Kadish staging, and >0 days of survival, ensuring follow‐up data. Receipt of CT in the SEER registry was documented as either Yes or No/Unknown. Results Six hundred and thirty‐six patients were identified. One hundred and ninety‐five patients received CT as part of their treatment for ON. Following propensity score matching and inverse probability of treatment weighting, there was inferior overall survival (OS) (HR 1.7, 95% CI: 1.3‐2.2, P = .001) and cancer‐specific survival (CSS) (HR 1.8, 95% CI: 1.3‐2.4, P

Background The optimal management of patients with stage I-II squamous cell carcinoma (SCC) of the anus is controversial. The current study evaluates the efficacy of combined chemotherapy and radiation therapy (CRT) versus radiation therapy (RT) alone in the treatment of these patients using the Surveillance, Epidemiology, and End Results (SEER) registries. Methods SEER 18 Custom Data registries were queried for patients with stage I-II SCC of the anus. Univariate analysis (UVA) and multivariable analysis (MVA) using Kaplan-Meier and Cox proportional hazards regression modeling were performed. Propensity-score matched analysis with inverse probability of treatment weighting (IPTW) was used to account for indication bias. Results A total of 4,288 patients with stage I-II disease were identified, of whom 3,982 (93%) underwent CRT and 306 (7%) underwent RT. Median follow-up was 42 months. Approximately 30.8% had T1 disease and 69.2% had T2-T3 disease. The IPTW-adjusted 5-year overall survival (OS) was 76.7%, with no significant differences between the CRT and RT groups (77% vs. 73.5%, P=0.33). On multivariate IPTW-adjusted analysis, the lack of association between CRT use and OS was upheld (HR, 0.84, 95% CI, 0.65-1.08, P=0.2). On subgroup analyses, 5-year OS was 86% with CRT (n=1,216) and 84.2% with RT (n=103) (P=0.74) in stage I (T1N0) patients, while 5-year OS was 72.8% with CRT (n=2,766) and 66.4% with RT (n=203) (P=0.13) in stage II (T2-3N0) patients. CRT was associated with improved median OS in stage II patients (119 months vs. not reached, P=0.04). Conclusions The current study suggests that omission of concurrent chemotherapy is not associated with inferior OS in patients with stage I SCC of the anus. However, combined chemoradiation was superior to radiation alone in patients with stage II disease. Prospective evidence is needed to optimize clinical decision-making in this patient population.

Hidradenocarcinomas are rare malignant sweat gland tumors that typically arise in the head and neck area. To the best of our knowledge, this is the only reported instance of hidradenocarcinoma of the abdominal wall as well as the first case arising from a region of prior trauma. A 72-year-old female presented with a left abdominal wall lesion, which she had first noticed after an injury to the area. Initially, the lesion remained stable in size, after which it became mildly pruritic, progressive in size, and expressive of a clear, non-odorous discharge. Imaging demonstrated a heterogeneous cystic density. Surgical pathology revealed a malignant dermal adnexal neoplasm composed of pleomorphic polygonal cells and focal intracytoplasmic lumina lined by eosinophilic cuticles, as well as areas of ductal differentiation, apocrine differentiation, and mucinous metaplasia. Surgical excision of the mass was performed, followed by adjuvant external beam radiotherapy (EBRT). The patient had no long-term toxicities or clinical evidence of local disease recurrence as of one year post-surgery and six months post-EBRT. Early diagnosis and treatment are essential to improving outcomes in patients with hidradenocarcinomas. Frequent follow-up is equally important, as these tumors have high recurrence rates.

Uterine carcinosarcoma (UCS) confers a high recurrence risk following surgery, and adjuvant chemotherapy (CHT) is typically administered in all stages. The benefit of radiation therapy (RT) in UCS, when added to adjuvant CHT, is unknown. We sought to analyze the Surveillance, Epidemiology, and End Results (SEER) database to ascertain whether RT improves overall survival (OS) when added to surgery and CHT for UCS.SEER 18 Custom Data registries (Nov 2018 submission) were queried for uterine (ICD10 C54.1-9, C55.9) carcinosarcoma (ICD-0-3 8980-3). Patients with stage I-III UCS who underwent surgery and CHT ± RT were analyzed with univariate analysis (UVA) and multivariable analysis (MVA) using Kaplan-Meier and Cox proportional hazards regression modeling. Propensity-score matched analysis with inverse probability of treatment weighting (IPTW) was performed to account for indication bias. Furthermore, conditional landmark analysis (minimum three-month follow-up) was performed to minimize immortal time bias.All 1541 patients (1988-2016) underwent surgery and CHT and 54% received RT. On UVA, RT improved median and 5-year OS from 41 to 87 months and 43-55%, respectively (HR 0.65, 95% CI 0.56-0.77) (p 0.001). After IPTW adjustment, RT improved median and 5-year OS from 46 to 65 months and 46-53%, respectively (HR 0.74, 95% CI 0.63-0.87) (p 0.001). The benefit of RT remained on unadjusted and adjusted MVA and conditional landmark analysis.In stage I-III UCS treated with surgery and CHT, receipt of RT is associated with OS benefit. Further prospective data are needed to investigate the RT's benefit in UCS.

Purpose.To develop and evaluate the performance of a deep learning model to generate synthetic pulmonary perfusion images from clinical 4DCT images for patients undergoing radiotherapy for lung cancer.Methods. A clinical data set of 58 pre- and post-radiotherapy99mTc-labeled MAA-SPECT perfusion studies (32 patients) each with contemporaneous 4DCT studies was collected. Using the inhale and exhale phases of the 4DCT, a 3D-residual network was trained to create synthetic perfusion images utilizing the MAA-SPECT as ground truth. The training process was repeated for a 50-imaging study, five-fold validation with twenty model instances trained per fold. The highest performing model instance from each fold was selected for inference upon the eight-study test set. A manual lung segmentation was used to compute correlation metrics constrained to the voxels within the lungs. From the pre-treatment test cases (N = 5), 50th percentile contours of well-perfused lung were generated from both the clinical and synthetic perfusion images and the agreement was quantified.Results. Across the hold-out test set, our deep learning model predicted perfusion with a Spearman correlation coefficient of 0.70 (IQR: 0.61-0.76) and a Pearson correlation coefficient of 0.66 (IQR: 0.49-0.73). The agreement of the functional avoidance contour pairs was Dice of 0.803 (IQR: 0.750-0.810) and average surface distance of 5.92 mm (IQR: 5.68-7.55).Conclusion. We demonstrate that from 4DCT alone, a deep learning model can generate synthetic perfusion images with potential application in functional avoidance treatment planning.

Purpose The purpose of this study was to delineate a scoring system to maximize the ethical allocation of proton beam therapy (PBT) and determine what factors are associated with receipt of PBT, including the role of specific insurance providers. Methods and Materials Our scoring system was developed in collaboration with a multidisciplinary panel of experts. Patients submitted for PBT consideration were assigned a score by committee at a weekly peer-reviewed session at a time when our center was operating at capacity. Univariate analysis and multivariable analysis of initial and final insurance response were performed. Results One hundred ninety-seven patients were prospectively reviewed. Ninety-three percent of patients with Medicaid coverage, 88% of patients with Medicare, and 78% of patients with private insurance were ultimately approved for PBT. Median time to final insurance response was 12 days (interquartile range, 9-18 days) for patients who were ultimately denied PBT coverage. Having primary provider C (odds ratio [OR], 14; 95% confidence interval [CI], 1.20-1.96; P = .033) or third party providers A (OR, 4.22; 95% CI, 1.71-10.9; P = .002) or B (OR, 5.28; 95% CI, 1.56-17.2; P = .006) was significantly associated with final insurance denial for PBT on univariate analysis. Total score (OR, 0.79; 95% CI, 0.67-0.90; P = .002) and having coverage through third party provider A (OR, 24.2; 95% CI, 9.51-68.9; P Conclusions Our scoring system was significantly associated with receipt of proton beam therapy. Certain insurance providers are less likely to approve PBT for patients, all else being equal. Such a scoring system could be implemented effectively at other PBT facilities, and additional work is needed in ensuring patients with the most to gain from PBT will be approved by their insurance providers.

Breast cancer is the most commonly diagnosed cancer in women and radiotherapy is a widely used treatment approach. However, there is an increased risk of coronary artery disease and cardiac death in women treated with radiotherapy. The present study was undertaken to clarify the relation between radiotherapy and coronary disease in women with previous breast irradiation using coronary computed tomographic angiography (CCTA). We conducted a retrospective analysis of women with a history of right or left-sided breast cancer (RBC; LBC) treated with radiotherapy who subsequently underwent CCTA. RBC patients who had reduced radiation doses to the myocardium served as controls. Patients (n = 6,593) with a history of nonmetastatic breast cancer treated with radiotherapy were screened for completion of CCTA; 49 LBC and 45 RBC women were identified. Age and risk factor matched patients with LBC had higher rates of coronary disease compared with RBC patients; left anterior descending (LAD) coronary artery (76% vs 31% [p0.001]), left circumflex (33% vs. 6.7% [p = 0.004]), and right coronary artery (37% vs 13% [p = 0.018]). Mean LAD radiation dose and mean heart dose strongly correlated with coronary disease, with a 21% higher incidence of disease in the LAD per Gy for mean LAD dose and a 95% higher incidence of disease in the LAD per Gy for mean heart dose. In conclusion, LBC patients treated with radiotherapy have a significantly higher incidence of coronary disease when compared with a matched group of patients treated for RBC. Radiation doses correlated with the incidence of coronary disease.

This research project is a case study of land-use decision making in Rhode Island. Choices concerning land development effect people within the local and citizenry throughout the state. Land use evolution and its controls have been incremental with various catalysts serving as the shaper and influencer. Historically, land-use planning and decision-making is found at the local level. The perception of individual property rights and land-use controls at the local level are related. Environmental considerations are steeped in inherent societal rights. Rights to private property is a constitutional hallmark. Environmental protection is a legislative mandate. Perceptions of these rights contribute to a planning dilemma: individual rights versus societal rights. Awareness of this fact is one of the underpinnings of citizen participation. Historically comprehensive planning has been developed on a local level (701 program) by officials, directly or indirectly, responsible to a specific constituency. Obstensibly these plans reflect the will of the people through the electoral process and via citizen participation during plan formulation. The mechanisms and apparatus for environmental protection is appropriately found at the state level. Pertinent

The appropriateness of substituting sentinel lymph node dissection (SLND) and regional nodal irradiation (RNI) for axillary lymph node dissection (ALND) in patients with residual lymph node (LN) disease following neoadjuvant chemotherapy (NAC) is unknown. We used the National Cancer Database (NCDB) to compare survival following SLND and ALND in breast cancer patients with residual LN disease. We analyzed NCDB patients, treated between 2006 and 2014, with cT1–3, cN1, cM0 breast cancer and residual disease in 1–3 axillary LNs (ypN1) following NAC. Patients were grouped into those who received SLND (defined as removal of ≤ 4 LNs) and RNI, or ALND and RNI. Patients were matched for all patient, tumor, and treatment characteristics. We identified 1313 eligible patients in the ALND group and 304 patients in the SLND group. For the matched cohorts, SLND was associated with significantly lower survival in both univariate and doubly robust multivariable analyses (MVA) (HR 1.7, 95% CI 1.3–2.2, P

Background/Aim: We tested JP4-039, a GS-nitroxide radiation damage mitigator in proton therapy of Fanconi anemia (FA) mice. Materials and Methods: Fanca(–/–) and Fanca(+/+) bone marrow stromal cells were pre-treated with JP4-039 and irradiated with either protons or photons (0-10 GyRBE) followed by clonogenic survival and β-Galactosidase senescence analysis. Fanca(–/–) and Fanca(+/+) mice were pretreated with JP4-039 for 10 min prior to oropharyngeal irradiation with either protons or photons (0 or 30 GyRBE) followed by sacrifice and measurement of oral cavity ulceration, distant hematopoietic suppression, and real-time polymerase chain reaction analysis. Results: JP4-039 reduced oral cavity ulceration in Fanca(–/–) mice, transcripts Nfkb, Ap1, Sp1, and Nrf2, and proton therapy induced distant marrow suppression. Conclusion: JP4-039 protected Fanca(–/–) and Fanca(+/+) cells and mouse oral cavity from both proton and photon radiation.

Purpose/Objective(s) Accelerated partial breast irradiation (APBI) can reduce treatment time and spare normal breast tissue. Techniques for APBI include applicator-based, external beam radiotherapy (EBRT), intra-operative radiotherapy (IORT), and interstitial implant-based. Data comparing these various APBI modalities and associated outcomes are lacking in the literature. We conducted a single-institution retrospective analysis of patients treated with APBI to compare treatment techniques and report outcomes. Materials/Methods Patients treated with APBI between 1990 and 2019 were included. Baseline patient characteristics, clinical and pathological features, treatment details, and clinical outcomes were retrospectively reviewed using a single-institution database. Outcomes were updated through August 2020. Statistical methods included Kruskal-Wallis test, Fisher's exact test, chi-square test of independence, and Kaplan-Meier analysis. Results A total of 926 APBI cases were analyzed, a majority of which were invasive ductal carcinoma (50.6%). Comparing applicator-based to EBRT, IORT, and implant-based, there was no difference in overall survival, freedom from local recurrence, or freedom from mastectomy (Table 1). 5-, 10-, and 25-year cumulative incidence of ipsilateral breast tumor recurrence (IBTR) was 1.5% (0.87-2.5%), 3.3% (2.3-4.7%), and 5.2% (3.9-6.7%), with no difference between treatment techniques. The median follow-up time was 121.6 months (66-165.7 months). Cosmesis was good/excellent in 91%, 84%, and 93%, for applicator, EBRT, and interstitial techniques, respectively. Late toxicities assessed included pigmentary changes, telangiectasias, induration/fibrosis, and fat necrosis. The majority of late toxicities were none or Grade 1, with less than 10% of patients experiencing Grade 2 or greater toxicity. Conclusion With our 30-year single-institution APBI experience using various treatment techniques, long term outcomes of both disease control and local morbidity demonstrate that the various APBI techniques are equally effective for suitable early-stage breast cancer patients. As evolving radiotherapy paradigms incorporate more shortened time-course treatments, these results affirm that APBI remains a viable alternative for such favorable patients.

Purpose/objective(s) Stereotactic body radiotherapy (SBRT) is standard for early-stage non-small cell lung cancer in patients who are inoperable or refuse surgery. Data are limited regarding definitive hypofractionated radiotherapy (HFRT) regimens for pulmonary carcinoid tumors. The only two published experiences consist of four and ten patients, respectively. We hypothesize that HFRT is safe and effective for definitive treatment of pulmonary carcinoid tumors. Materials/methods Records from a single healthcare system were retrospectively analyzed. Patients were eligible for analysis if they had undergone histologic confirmation of an early-stage (cT1-2, N0) typical or atypical pulmonary carcinoid tumor and had been treated with HFRT (> 2.2 Gy/fraction) for gross disease. Clinical, radiographic, and dosimetric characteristics were recorded. Overall survival (OS) was calculated with the Kaplan-Meier method. Results From 2008-2020, 10 patients (80% female) were treated with HFRT with a median follow-up of 29 months (5.1 - 145.1). Nine patients (90%) had typical histology; one patient with atypical histology remains alive almost six years post-HFRT. Median max tumor dimension was 1.5 cm (0.9 - 3.8). Five patients (50%) had central tumors per RTOG 0813. Five patients (50%) were medically inoperable, while the remaining five refused surgery. Nine patients (90%) underwent SBRT consisting of 4-5 fractions to 47.5-50 Gy (9.5-12 Gy/fraction); one patient underwent 60 Gy in 20 fractions and remains alive > 12 years post-HFRT. Thus, median BED10Gy was 98.2 Gy (78 - 105.6). On CT, three patients (30%) had stable disease, four (40%) had partial response, and the remaining three (30%) had post-treatment changes obscuring treatment response assessment. Of the four patients (40%) with pre- and post-HFRT metabolic imaging available (FDG-PET, 111In-pentetreotide scintigraphy, or 68Ga-DOTATATE PET), three had a reduction in metabolic activity and one had an increase in activity attributed to inflammation. Availability of pre- and post-HFRT laboratory markers (serum chromogranin A or urine 5-hydroxyindoleacetic acid) was too infrequent to allow for meaningful analysis. There were no local, regional, or distant disease progressions or recurrences. Three patients (30%) have died, none from their carcinoid tumors. Five-year OS was 50% (95% CI 22.5-100). Two patients (20%) developed grade 1 pneumonitis. There were no definite grade 3+ toxicities; one patient treated with five-fraction SBRT developed atrial fibrillation two years post-HFRT with a mean and max heart dose of 6.5 Gy and 37.44 Gy, respectively. Conclusion Definitive HFRT appears to be a safe and effective treatment for early-stage pulmonary carcinoid tumors in this limited cohort. Prospective data with larger sample sizes are needed to further validate this approach, along with standardization of staging studies and post-treatment assessment.

Purpose/Objective(s) Shorter courses of breast radiotherapy are offered as an alternative to 4-6 weeks of whole breast irradiation after lumpectomy, including brachytherapy. A prospective phase II multi-institution clinical trial to study 3-fraction accelerated partial breast irradiation (APBI) delivered by brachytherapy was conducted. Materials/Methods The trial treated selected breast cancers after breast-conserving surgery with brachytherapy applicators that delivered 22.5 Gy in 3 fractions of 7.5 Gy. The planning treatment volume was 1 to 2 cm beyond the surgical cavity. Eligible women were age ≥ 45 years with unicentric invasive or in situ tumors ≤ 3 cm excised with negative margins and with positive estrogen or progesterone receptors and no metastases to axillary nodes. Strict dosimetric parameters were required to be met and follow up information was collected from the participating sites. Results A total of 175 patients who were enrolled were followed for a median of 3.63 years. Three-fraction brachytherapy was associated with low chronic toxicity. There was excellent or good cosmesis in 95% of patients. There were no grade 4 toxicities. Grade 3 fibrosis at the treatment site was present in 1.7% and 32% percent had grades 1 or 2 fibrosis at the treatment site. There was 1 rib fracture. Other late toxicities included 7.4% grade 1 hyperpigmentation, 2% grade 1 telangiectasias, 1.7% symptomatic seromas, 1.7% abscessed cavities, and 1.1% symptomatic fat necrosis. There were 2 (1.1%) ipsilateral local recurrences, 2 (1.1%) nodal recurrences and no distant recurrences. Other incidents included one contralateral breast cancer and 2 second malignancies (lung). Conclusion Ultra-short breast brachytherapy is feasible and with acceptable late toxicity and could be an alternative to standard 5-day, 10 fraction APBI in eligible patients. Patients from this prospective trial will continue to be followed to evaluate long term outcomes.

Purpose/Objective(s) There is a paucity of data regarding the use of whole breast irradiation (WBI) as part of breast conserving therapy (BCT) in women diagnosed with breast cancer who had undergone prior breast implant-based augmentation. In this population, we investigated various factors that impact radiation related toxicities, including the need for additional cosmetic surgery. Materials/Methods A retrospective review was performed for a single institution, with queries done on health-system medical records, radiation therapy medical records, radiology mammography studies, and internal radiation therapy and toxicity databases. We included patients with a prior history of breast implant-based augmentation who subsequently underwent BCT and WBI. Patient and treatment characteristics were collected and reported, and univariate analyses comparing factors correlating with toxicity endpoints were performed. Long-term cosmesis was assessed by the patient's radiation oncologist during routine follow-up visits via the Harvard grading criteria. Results 35 patients treated at our institution between 2006 and 2020 were included in our analyses, with a median follow up time of 2.4 years. Of these, 28 were treated with conventionally fractionated WBI (1.8-2 Gy/Fx) and 7 were treated with hypofractionated WBI (2.66 Gy/Fx). Good/excellent long-term cosmesis was observed in 94% of all patients. 44% of patients ultimately needed additional cosmetic surgery at some point after radiation. Indications for additional surgery included capsular contracture (10), wound complications (2), implant rupture (1), volume loss (1), and asymmetry (1). Fourteen patients (50%) treated with conventionally fractionated WBI and one patient (14%) patient treated with hypofractionated WBI required additional surgery, but this difference was not significant on UVA (P = 0.12). Other factors found not to be significantly associated with rates of additional surgery included BMI, stage, the volume of the breast receiving 105% or 110% of the prescription dose, and presence or absence of bolus during treatment. No patients experienced local or regional recurrence. Conclusion Patients with a prior history of breast implantation often experience good long-term cosmesis with a moderate risk of needing additional future surgery. The use of hypofractionated WBI was not associated with worse cosmetic outcome or an increase in need for additional cosmetic surgery.

Purpose/Objective(s) Multiple studies have suggested that patients with early-stage squamous cell carcinoma (SCC) of the lung treated with stereotactic body radiation therapy (SBRT) are more susceptible to local failure when compared to other non-small cell lung cancer (NSCLC) histologies. It is unknown if higher biological equivalent dose (BED) leads to improved outcomes in this patient population. We used the National Cancer Database (NCDB) to compare overall survival (OS) between patients with SCC and non-SCC NSCLC treated with “high” or “low” BED SBRT. Materials/Methods The NCDB was used to identify patients with cT1-2N0M0 NSCLC diagnosed between 2006-2016 and treated with 3-5 fraction SBRT. Patients were grouped by BEDhigh (> 150 Gy) and BEDlow (≤132 Gy). OS was estimated by Kaplan-Meier analysis. Correlation between BED and OS was tested with univariate and doubly-robust multivariable Cox regression analysis (MVA). The MVA included age, sex, Charlson-Deyo score, tumor grade, clinical T stage, and BED group. Propensity-score matched analysis with inverse probability of treatment (IPTW) weighting was used to minimize selection bias. Results We identified 4,717 eligible SCC patients and 8,807 eligible non-SCC NSCLC patients. For the matched SCC cohorts, BEDhigh was associated with improved OS in both univariate and doubly robust multivariate analysis (MVA HR 0.84 95% CI 0.76-0.92, P Conclusion Our analysis suggests that in patients with early-stage NSCLC, SBRT regimens employing the use of BED > 150 Gy may confer a survival benefit in patients with SCC histology. Histology-based dose modification should be considered, and prospective validation may be warranted.

Purpose/Objective(s) Moist desquamation (MD) and breast/chest wall (CW) pain are common, important acute toxicities associated with breast irradiation (RT). In this study, we correlate near-surface dose (NSD) with acute toxicity in patients receiving pencil beam scanning intensity modulated proton breast RT (PBSIMPT). Materials/Methods We reviewed thirty-one patients at a single institution who received PBSIMPT for breast cancer. All patients received PBSIMPT for the initial chest wall or whole breast treatment; all but two patients received regional nodal irradiation. 25 patients were treated to 50 Gy in 25 fractions and 6 patients were treated to 42.56 Gy in 16 fractions. Boosts to the lumpectomy cavity or mastectomy scar were delivered with proton, electron, or photon RT. A near-surface rind volume (SR3), which was bound by the skin surface and 3 mm and limited by the breast or chest wall PTV, was generated to be used prospectively during treatment planning to limit near-surface dose while maintaining appropriate PTV coverage. For this analysis, we retrospectively generated two additional near-surface rind volumes, bound by either the skin surface and 5 mm (SR5), or by 5 mm and 10 mm (SR10) from the skin surface. We determined mean SR doses of each patient's composite plan. Skin rind doses were converted to percent of pre-boost prescription dose to account for differences in prescription dose. The presence of any breast/CW MD, and grade 2/3 ("moderate" or "severe") breast/CW pain during RT and within the first two months of RT were recorded. Mann-Whitney U tests were performed to determine correlations between mean SR doses and toxicity endpoints. Results The mean composite SR3 dose was 4484 cGY (range 4030-5267) for conventionally fractionated patients and 3983 cGY (range 3568-4040) for hypofractionated patients. Five patients (16.1%) experienced MD, and 6 patients (19.3%) experienced grade 2/3 breast/CW pain. Mean composite SR3 dose converted to percent of prescription dose was 94.6% for patients with grade 2 or higher breast or CW pain, compared to 89.6% for those without (P = 0.036). This difference persisted for mean SR5 dose (96.1% versus 91.1%, P = 0.023) and mean SR10 dose (102.4% versus 99.9%, P = 0.012). Patients with MD had a mean SR3 dose of 93.5% versus 91.0% for those without (P = 0.7), and this trend weakened with mean SR5 dose (94.7% versus 92.9%, P = 0.78) and mean SR10 dose (100.7% versus 100.3%, P = 1.0). Conclusion Higher NSD significantly correlated with increased breast/CW pain. Further analysis with a larger sample size is warranted to explore correlations between NSD and other toxicity endpoints. Optimization of NSD may reduce toxicity in patients receiving PBS IMPT for breast cancer.

PURPOSE/OBJECTIVE(S) There is mixed and limited scientific evidence regarding radiotherapy (RT) tolerance in carriers of a pathogenic, germline ATM variant. The ASTRO-ASCO-SSO guidelines on management of hereditary breast cancer suggest offering RT to these patients if clinically indicated. We investigate RT toxicity for carriers of either a pathogenic ATM variant, or variant of unknown significance (VUS), in ATM. MATERIALS/METHODS Patients with a breast cancer history who had hereditary genetic testing and were found to carry either a pathogenic variant or VUS in ATM were identified. For those who received RT at our institution, toxicity metrics were recorded including dermatitis (scored per CTCAE version 4.0), moist desquamation, and cosmetic outcome (scored per Harvard scale). Fisher's exact test for count data was performed to compare toxicity between the two cohorts. Wilcoxon rank-sum testing was performed to assess for differences in cohort patient characteristics. RESULTS Forty-four carriers of a pathogenic ATM variant, and 163 carriers of an ATM VUS, were identified. Fifteen pathogenic and 56 VUS patients, respectively, received RT at our institution and had available toxicity records. The cohorts did not statistically differ in race, medical comorbidities, clinical or pathologic T-stage, hormone receptor status, receipt of chemotherapy, fractionation schedule, or receipt of a boost. No patients had a known collagen vascular disease. 77% of patients (55/71) had breast conservation. 62% received whole breast RT, 7% received chest wall RT, 4.2% received partial breast RT, and 26.8% received whole breast or chest wall RT with regional nodal RT. 58% received conventionally-fractionated RT, and 38% received hypofractionated RT. Median toxicity follow up was 11.6 months. 29% (4/15) of pathogenic carriers and 26.4% (14/56) of VUS carriers developed moist desquamation (P = 0.7). The rates of grade 2+ acute dermatitis were 71% in pathogenic carriers and 57% in VUS carriers (P = 0.4). 100% of pathogenic carriers and 91% of VUS carriers had a good/excellent cosmetic outcome at first follow up (P > 0.9). No patients with a pathogenic variant had a fair or poor cosmetic outcome at last follow up. CONCLUSION RT is well tolerated in carriers of a pathogenic ATM variant, with rates of grade 2+ dermatitis and moist desquamation comparable to a matched VUS cohort. High rates of good or excellent cosmetic outcome were seen following treatment. Further analyses including an ATM wild type cohort and continued detailed toxicity documentation/analysis is on-going to elucidate longer term morbidity.

Purpose/Objective(s) Recent studies suggest improved local control (LC) of early-stage non-small cell lung cancer (NSCLC) treated with SBRT regimens with biologically equivalent dose (BED10) > 150 Gy. It is unclear if this association is histology dependent. Multiple groups have shown lower LC rates after SBRT for squamous cell carcinoma (SCC), compared to non-SCC NSCLC. We compared LC between BEDlow and BEDhigh SBRT schemes, stratified by histology. Materials/Methods As part of an IRB approved collaborative, we retrospectively analyzed 684 patients with cT1-2, cN0, cM0 NSCLC, treated with definitive SBRT to a minimum BED of 100 Gy at five international centers. Patients were grouped into SCC and non-SCC, then divided into BEDhigh (BED10 ≥150 Gy) or BEDlow (BED10 Results Of 684 eligible tumors, 457 were non-SCC and 227 SCC. Median follow-up was 30 months. Of non-SCC patients, 262 (57%) were BEDlow and 195 (43%) BEDhigh. Of SCC patients, 144 (63%) were BEDlow and 83 (37%) BEDhigh. BEDhigh SBRT included those treated with 54 Gy in 3 fractions (54/3). BEDlow included 60/5, 50/5, 48/4, or 60/8. Baseline characteristics, including T-stage and max tumor dimension, were similar between BED groups after matching. MVA including T-stage, tumor grade, and tumor location, showed BEDlow regimens were associated with higher rates of local failure for SCC (HR 9.8, 95% CI 1.9-25.1, P = 0.007), but not for non-SCC (HR 1.2, 95% CI 0.6-2.5, P = 0.6). Three-year LC rates for BEDlow and BEDhigh were 70% and 97%, respectively for SCC, and 91% and 92%, respectively, for non-SCC. Similarly, there were higher rates of failure with BEDlow PTVmean (3 yr LC 94 vs 69%, MVA HR 6.4, 95% CI 1.9-22.2, P = 0.003) and BEDlow GTVmean (3 yr LC 87 vs 68%, MVA HR 7.6, 95% CI 2.7-21.6, P = 0.001) in SCC patients. In non-SCC patients, LC was similar between BED groups for PTVmean (3 yr LC 92% vs 93%, MVA HR 1.1, 95% CI 0.5-2.8, P = 0.8) and GTVmean (3 yr LC 94 vs 90%, MVA HR 0.8, 95% CI 0.3-2.6, P = 0.8). There was a trend of worse survival in BEDlow SCC patients (MVA HR 1.3, 95% CI 0.9-1.9, P = 0.1), but survival was similar in non-SCC patients (MVA HR 1.02, 95% CI 0.8-1.3, P = 0.9). There were no differences in regional recurrence or distant metastases between BED groups in either histology. Conclusion This multi-institutional analysis shows improved LC in early-stage SCC NSCLC treated with SBRT regimens with BED10 > 150 Gy. No difference was observed in LC between BED groups for non-SCC patients. Our results suggest BEDhigh SBRT should be strongly considered for early-stage non-central SCC NSCLC.

Myoepithelial tumors of the soft tissue are a rare tumor displaying myoepithelial elements and lacking obvious ductal differentiation. The rarity of these precludes any evidence-based consensus regarding optimal management. Nevertheless, the current approach to these lesions begins with amputation or complete excision. The efficacy of neoadjuvant or adjuvant radiation therapy or chemotherapy has not been established. Here, we present the first report to the authors' knowledge of neoadjuvant radiation therapy for the treatment of this rare soft tissue neoplasm and review the management and outcomes of published cases of myoepithelial carcinoma. A patient with a soft tissue myoepithelial carcinoma that declined both amputation and chemotherapy was treated with neoadjuvant radiation therapy and wide surgical excision followed by a brachytherapy boost to the resected tumor bed. Neoadjuvant radiation therapy resulted in an excellent response with extensive treatment-related changes consisting predominantly of fibrosis, hyalinization and hemorrhage and only 10% residual viable myoepithelial carcinoma present in the surgical specimen.

Programmed Cell Death-1 (PD-1) is an inhibitory immune receptor, which plays critical roles in T cell co-inhibition and exhaustion upon binding to its ligands PD-L1 and PD-L2. We report the crystal structure of the human PD-1 ectodomain and the mapping of the PD-1 binding interface. Mutagenesis studies confirmed the crystallographic interface, and resulted in mutant PD-1 receptors with altered affinity and ligand-specificity. In particular, a high-affinity mutant PD-1 (HA PD-1) exhibited 45 and 30-fold increase in binding to PD-L1 and PD-L2, respectively, due to slower dissociation rates. This mutant (A132L) was used to engineer a soluble chimeric Ig fusion protein for cell-based and in vivo studies. HA PD-1 Ig showed enhanced binding to human dendritic cells, and increased T cell proliferation and cytokine production in a mixed lymphocyte reaction (MLR) assay. Moreover, in an experimental model of murine Lewis lung carcinoma, HA PD-1 Ig treatment synergized with radiation therapy to decrease local and metastatic tumor burden, as well as in the establishment of immunological memory responses. Our studies highlight the value of structural considerations in guiding the design of a high-affinity chimeric PD-1 Ig fusion protein with robust immune modulatory properties, and underscore the power of combination therapies to selectively manipulate the PD-1 pathway for tumor immunotherapy., Highlights • We report the crystal structure of human PD-1 and the mapping of the PD-1 ligand binding site. • A high-affinity variant was identified and used to engineer a soluble PD-1 Ig fusion protein (HA PD-1 Ig) for immunotherapy. • HA PD-1 Ig enhanced T cell activation and strongly synergized with RT to control tumor growth in a lung carcinoma model. PD-1 is an inhibitory immune receptor that dampens T cell responses. PD-1 blockade is a successful strategy for cancer immunotherapy. We report the crystal structure of human PD-1 and mapping of its ligand binding site. A high-affinity mutant (HA PD-1) was identified and used to engineer a blocking Ig fusion protein, expected to disrupt the endogenous PD-L/PD-1 pathway. HA PD-1 Ig increased lymphocyte proliferation and cytokine production. Moreover, in combination with radiation therapy it enhanced control of tumor growth in a Lewis lung carcinoma model. This study offers an alternative strategy to manipulate the PD-1 pathway for tumor immunotherapy.

BACKGROUND Atypical teratoid/rhabdoid tumors (AT/RTs) are rare aggressive central nervous system tumors. The use of radiation therapy (RT) remains controversial, especially for patients younger than three years of age. The purpose of the current investigation is to robustly analyze the impact of RT among pediatric AT/RT patients using the Surveillance, Epidemiology, and End Results (SEER) database. METHODS SEER 18 Custom Data registries were queried for AT/RT (ICD-0-3 9508/3). A total of 190 pediatric AT/RT patients were identified, of whom 102 underwent surgery + chemotherapy and 88 underwent trimodality therapy. Univariate and multivariable analyses using Kaplan-Meier and Cox proportional hazards regression modeling were performed. Propensity-score matched analysis with inverse probability of treatment weighting was performed to account for indication bias. The landmark method was used to account for immortal time bias. RESULTS The majority of patients were