Reduced ER-mitochondria connectivity promotes neuroblastoma multidrug resistance.

Most cancer deaths result from progression of therapy resistant disease, yet our understanding of this phenotype is limited. Cancer therapies generate stress signals that act upon mitochondria to initiate apoptosis. Mitochondria isolated from neuroblastoma cells were exposed to tBid or Bim, death effectors activated by therapeutic stress. Multidrug-resistant tumor cells obtained from children at relapse had markedly attenuated Bak and Bax oligomerization and cytochrome c release (surrogates for apoptotic commitment) in comparison with patient-matched tumor cells obtained at diagnosis. Electron microscopy identified reduced ER-mitochondria-associated membranes (MAMs; ER-mitochondria contacts, ERMCs) in therapy-resistant cells, and genetically or biochemically reducing MAMs in therapy-sensitive tumors phenocopied resistance. MAMs serve as platforms to transfer Ca2+ and bioactive lipids to mitochondria. Reduced Ca2+ transfer was found in some but not all resistant cells, and inhibiting transfer did not attenuate apoptotic signaling. In contrast, reduced ceramide synthesis and transfer was common to resistant cells and its inhibition induced stress resistance. We identify ER-mitochondria-associated membranes as physiologic regulators of apoptosis via ceramide transfer and uncover a previously unrecognized mechanism for cancer multidrug resistance.

Rare tumors: Retinoblastoma, nasopharyngeal cancer, and adrenocorticoid tumors.

The role of surgery, chemotherapy, and radiation therapy for retinoblastoma has evolved considerably over the years with the efficacy of intraarterial chemotherapy and the high incidence of secondary malignant neoplasms following radiation therapy. The use of spot scanning intensity-modulated proton therapy may reduce the risk of secondary malignancies. For pediatric nasopharyngeal carcinoma, the current standard of care is induction chemotherapy followed by chemoradiation therapy. For adrenocortical carcinoma, the mainstay of treatment is surgery and chemotherapy. The role of radiation therapy remains to be defined.

Proton therapy for pediatric head and neck malignancies.

PURPOSE: Pediatric head and neck malignancies are managed with intensive multimodality therapy. Proton beam therapy (PBT) may reduce toxicity by limiting exposure of normal tissue to radiation. In this study, we report acute toxicities and early outcomes following PBT for pediatric head and neck malignancies. MATERIALS AND METHODS: Between 2010 and 2016, pediatric patients with nonhematologic malignancies of the head and neck were treated with PBT. Clinical and dosimetric data were abstracted from the medical record and treatment planning system with institutional review board approval. RESULTS: Sixty-nine consecutive pediatric patients were treated with proton-based radiotherapy for head and neck malignancies. Thirty-five were treated for rhabdomyosarcoma to a median dose of 50.4 Gy relative biological effectiveness [RBE]. Ten patients were treated for Ewing sarcoma to a median dose of 55.8 Gy[RBE]. Twenty-four patients were treated for other histologies to a median dose of 63.0 Gy[RBE]. Grade 3 oral mucositis, anorexia, and dysphagia were reported to be 4, 22, and 7%, respectively. Actuarial 1-year freedom from local recurrence was 92% (95% CI 80-97). Actuarial 1-year overall survival was 93% (95% CI 79-98) in the entire cohort. Oral cavity mucositis was significantly correlated with oral cavity dose (D80 and D50 [P < 0.05], where D80 and D50 are dose to 50% of the volume and dose to 80% of the volume, respectively). CONCLUSIONS: In this study, we report low rates of acute toxicity in a cohort of pediatric patients with head and neck malignancies. PBT appears safe for this patient population, with local control rates similar to historical reports. Longer follow-up will be required to evaluate late toxicity and long-term disease control.

Pencil beam scanning proton therapy for treatment of the retroperitoneum after nephrectomy for Wilms tumor: A dosimetric comparison study.

BACKGROUND: Multimodality treatment for patients with Wilms tumor has improved patient survival, but is associated with acute and long-term toxicity, partially due to irradiation. Proton therapy using pencil beam scanning (PBS) is a promising technique to reduce dose to organs at risk (OAR). In this study, we evaluate PBS plans for postoperative irradiation in patients with Wilms tumor. PROCEDURE: Patients were treated with anterior-posterior-posterior-anterior (AP-PA) photon fields encompassing the preoperative tumor volume. Patients requiring whole lung irradiation were treated with AP-PA photon fields covering the bilateral lungs. Prescription doses were generally 1,080 and 1,200 cGy, respectively. Flank PBS plans encompassing the ipsilateral retroperitoneum and para-arotic nodes were generated for dosimetric evaluation. RESULTS: Treatment records and comparison plans of 11 patients were reviewed. Mean dose and median dose to 50% or more of the contralateral kidney (D50) were 135 cGy and 139 cGy with photons and 52 cGy relative biological effectiveness (RBE) (P = 0.009) and 5 cGy RBE (P = 0.000001) with PBS. Mean dose and median D50 to bowel was 639 cGy and 979 cGy with photons and 379 cGy RBE (P = 0.001) and 47 cGy RBE (P = 0.004) with PBS. Mean dose and median D50 to the liver were 755 cGy and 1,013 cGy with photons and 411 cGy RBE (P = 0.02) and 132 cGy RBE (P = 0.02) with PBS. For patients with right-sided tumors, mean liver dose following sequential whole lung irradiation was 1,252 cGy with photons and 845 cGy RBE (P = 0.04) with PBS. DISCUSSIONS: PBS proton therapy is a feasible method for irradiating the retroperitoneum and provides significant sparing of dose to critical OAR. This may translate to improved long-term health outcomes for patients and warrants further clinical investigation.

Risk of major cardiac events following adjuvant proton versus photon radiation therapy for patients with thymic malignancies.

BACKGROUND: While often managed with surgery alone, patients with thymic malignancies with high-risk features may benefit from adjuvant radiation therapy but are at risk for late toxicities. Previously, the risk of major cardiac events (MCEs) was reported to increase by 7% per one Gray (Gy) to the heart. In this study, we compare dose to organs at risk (OARs) with intensity-modulated (IMRT) versus proton beam therapy (PBT). We hypothesize a decrease risk of predicted MCEs with PBT. MATERIAL AND METHODS: Patients requiring adjuvant therapy for thymic malignancies were treated with double scattered proton beam therapy (DS-PBT). Clinical backup IMRT plans were generated. Predicted MCEs were calculated based on median dose to the heart. A Wilcoxon rank sum test was used for statistical comparisons. RESULTS: Twenty-two consecutive patients were evaluated. DS-PBT resulted in statistically significant decreases in dose to the heart, lungs, left ventricle, esophagus, and spinal cord (all p ≤ .01). The increase in risk of MCEs from 0 to ≥20 years was lower with PBT (74% versus 135%, p = .04). DISCUSSION: DS-PBT results in decreased dose to OARs and may reduce the risk of MCEs compared with IMRT. Long-term follow-up is required to assess for clinical benefit from DS-PBT.

N-(Pyridin-2-yl) arylsulfonamide inhibitors of 11ß-hydroxysteroid dehydrogenase type 1: strategies to eliminate reactive metabolites.

N-(Pyridin-2-yl) arylsulfonamides 1 and 2 (PF-915275) were identified as potent inhibitors of 11ß-hydroxysteroid dehydrogenase type 1. A screen for bioactivation revealed that these compounds formed glutathione conjugates. This communication presents the results of a risk benefit analysis carried out to progress 2 (PF-915275) to a clinical study and the strategies used to eliminate reactive metabolites in this series of inhibitors. Based on the proposed mechanism of bioactivation and structure-activity relationships, design efforts led to N-(pyridin-2-yl) arylsulfonamides such as 18 and 20 that maintained potent 11ß-hydroxysteroid dehydrogenase type 1 activity, showed exquisite pharmacokinetic profiles, and were negative in the reactive metabolite assay.

Treatment of pediatric vaginal rhabdomyosarcoma with the use of a real-time tracked custom applicator.

PURPOSE: To describe the development, design, and implementation of a 3D printed MR-compatible pediatric vaginal multichannel brachytherapy cylinder. Safety and quality measures to ensure consistent treatment required innovative identification on MR and CT, and real-time tracking. METHODS AND MATERIALS: A 4-year-old with vaginal botryoides rhabdomyosarcoma underwent MR-simulation with a custom 3D printed biocompatible resin cylinder with four channels to ensure dose optimization capability. A total of four identifier regions were designed into the applicator in order to utilize these for MR-visualization and real-time tracking. A biocompatible 3D printed cylinder was designed to meet dose objectives using an MR and CT compatible material. 3D slicer was required for real-time tracking during treatment. RESULTS: Based on MR simulation, a treatment plan was created with dose differentials in the area of prior surgery versus normal vaginal tissue. Creation of a low dose CT scan on a mobile CT allowed CT visualization of the applicator for verification. Treatment was administered under the use of a real-time optical tracking with rotational and depth adjustments monitored. CONCLUSIONS: This advanced integration of 3D printed MR and CT biocompatible material, with unique design features consistent with a multi-channel vaginal cylinder, and incorporation of real-time optical tracking ensured that no positional changes were required, allowed successful treatment with differential dosing for a post-operative pediatric vaginal rhabdomyosarcoma patient.

Pulmonary Toxicity After Total Body Irradiation - Critical Review of the Literature and Recommendations for Toxicity Reporting.

INTRODUCTION: Total body irradiation is an effective conditioning regimen for allogeneic stem cell transplantation in pediatric and adult patients with high risk or relapsed/refractory leukemia. The most common adverse effect is pulmonary toxicity including idiopathic pneumonia syndrome (IPS). As centers adopt more advanced treatment planning techniques for TBI, total marrow irradiation (TMI), or total marrow and lymphoid irradiation (TMLI) there is a greater need to understand treatment-related risks for IPS for patients treated with conventional TBI. However, definitions of IPS as well as risk factors for IPS remain poorly characterized. In this study, we perform a critical review to further evaluate the literature describing pulmonary outcomes after TBI. MATERIALS AND METHODS: A search of publications from 1960-2020 was undertaken in PubMed, Embase, and Cochrane Library. Search terms included "total body irradiation", "whole body radiation", "radiation pneumonias", "interstitial pneumonia", and "bone marrow transplantation". Demographic and treatment-related data was abstracted and evidence quality supporting risk factors for pulmonary toxicity was evaluated. RESULTS: Of an initial 119,686 publications, 118 met inclusion criteria. Forty-six (39%) studies included a definition for pulmonary toxicity. A grading scale was provided in 20 studies (17%). In 42% of studies the lungs were shielded to a set mean dose of 800cGy. Fourteen (12%) reported toxicity outcomes by patient age. Reported pulmonary toxicity ranged from 0-71% of patients treated with TBI, and IPS ranged from 1-60%. The most common risk factors for IPS were receipt of a TBI containing regimen, increasing dose rate, and lack of pulmonary shielding. Four studies found an increasing risk of pulmonary toxicity with increasing age. CONCLUSIONS: Definitions of IPS as well as demographic and treatment-related risk factors remain poorly characterized in the literature. We recommend routine adoption of the diagnostic workup and the definition of IPS proposed by the American Thoracic Society. Additional study is required to determine differences in clinical and treatment-related risk between pediatric and adult patients. Further study using 3D treatment planning is warranted to enhance dosimetric precision and correlation of dose volume histograms with toxicities.

Predictors of Recurrence and Patterns of Initial Failure in Localized Ewing Sarcoma: A Contemporary 20-Year Experience.

BACKGROUND: The majority of patients with localized Ewing sarcoma will remain disease-free long term, but for those who suffer recurrence, successful treatment remains a challenge. Identification of clinicopathologic factors predictive of recurrence could suggest areas for treatment optimization. We sought to describe our experience regarding predictors of recurrence and patterns of first failure in patients receiving modern systemic therapy for nonmetastatic Ewing sarcoma. METHODS: The medical records of pediatric and adult patients treated for localized Ewing sarcoma between 1999 and 2019 at Johns Hopkins Hospital were retrospectively analyzed. Local control was surgery, radiotherapy, or both. Recurrence-free survival (RFS) was calculated using the Kaplan-Meier method. Univariable and multivariable Cox proportional-hazards modeling was performed to obtain hazard ratios (HR) for recurrence. RESULTS: In 94 patients with initially localized disease, there were 21 recurrences: 4 local, 14 distant, and 3 combined. 5-year and 10-year RFS were 75.6% and 70.5%, respectively. On multivariable analysis including age at diagnosis and tumor size, <95% tumor necrosis following neoadjuvant chemotherapy (NAC; HR 14.3, p = 0.028) and radiological tumor size change during NAC (HR 1.04 per 1% decrease in size change, p = 0.032) were independent predictors of recurrence. Among patients experiencing distant recurrence, pulmonary metastases were present in 82% and were the only identifiable site of disease in 53%. CONCLUSIONS: Poor pathologic or radiologic response to NAC is predictive of recurrence in patients with localized Ewing sarcoma. Suboptimal tumor size reduction following chemotherapy provides a means to risk-stratify patients who do not undergo definitive resection. Isolated pulmonary recurrence was a common event.

Improving the Pediatric Patient Experience During Radiation Therapy-A Children's Oncology Group Study.

PURPOSE: Treatment with radiation therapy (RT) can cause anxiety and distress for pediatric patients and their families. Radiation oncology teams have developed strategies to reduce the negative psychological impact. This survey study aimed to characterize these methods. METHODS AND MATERIALS: A 37-item questionnaire was sent to all radiation oncology members of the Children's Oncology Group to explore strategies to improve the pediatric patient experience. The Wilcoxon rank-sum test was used to assess factors associated with use of anesthesia for older children. RESULTS: Surveys were completed by 106 individuals from 84/210 institutions (40%). Respondents included 89 radiation oncologists and 17 supportive staff. Sixty-one percent of centers treated ≤50 children per year. Respondents described heterogenous interventions. The median age at which most children no longer required anesthesia was 6 years (range: ≤3 years to ≥8 years). Routine anesthesia use at an older age was associated with physicians' lack of awareness of these strategies (P = .04) and <10 years of pediatric radiation oncology experience (P = .04). Fifty-two percent of respondents reported anesthesia use added >45 minutes in the radiation oncology department daily. Twenty-six percent of respondents planned to implement new strategies, with 65% focusing on video-based distraction therapy and/or augmented reality/virtual reality. CONCLUSIONS: Many strategies are used to improve children's experience during RT. Lack of awareness of these interventions is a barrier to their implementation and is associated with increased anesthesia use. This study aims to disseminate these methods with the goal of raising awareness, facilitating implementation, and, ultimately, improving the experience of pediatric cancer patients and their caregivers.

A Multi-institutional Comparative Analysis of Proton and Photon Therapy-Induced Hematologic Toxicity in Patients With Medulloblastoma.

PURPOSE: This multi-institutional retrospective study sought to examine the hematologic effects of craniospinal irradiation (CSI) in pediatric patients with medulloblastoma using proton or photon therapy. METHODS AND MATERIALS: Clinical and treatment characteristics were recorded for 97 pediatric patients with medulloblastoma who received CSI without concurrent chemotherapy or with concurrent single-agent vincristine from 2000 to 2017. Groups of 60 and 37 patients underwent treatment with proton-based and photon-based therapy, respectively. Overall survival was determined by Kaplan-Meier curves with log-rank test. Comparisons of blood counts at each timepoint were conducted using multiple t tests with Bonferroni corrections. Univariate and multivariate analyses of time to grade ≥3 hematologic toxicity were performed with Cox regression analyses. RESULTS: Median age of patients receiving proton and photon CSI was 7.5 years (range, 3.5-22.7 years) and 9.9 years (range, 3.6-19.5 years), respectively. Most patients had a diagnosis of standard risk medulloblastoma, with 86.7% and 89.2% for the proton and photon cohorts, respectively. Median total dose to involved field or whole posterior fossa was 54.0 Gy/Gy relative biological effectiveness (RBE) and median CSI dose was 23.4 Gy/Gy(RBE) (range, 18-36 Gy/Gy[RBE]) for both cohorts. Counts were significantly higher in the proton cohort compared with the photon cohort in weeks 3 to 6 of radiation therapy (RT). Although white blood cell counts did not differ between the 2 cohorts, patients receiving proton RT had significantly higher lymphocyte counts throughout the RT course. Similar results were observed when excluding patients who received vertebral body sparing proton RT or limiting to those receiving 23.4 Gy. Only photon therapy was associated with decreased time to grade ≥3 hematologic toxicity on univariate and multivariable analyses. No difference in overall survival was observed, and lymphopenia did not predict survival. CONCLUSIONS: Patients who receive CSI using proton therapy experience significantly decreased hematologic toxicity compared with those receiving photon therapy.

Predicted Secondary Malignancies following Proton versus Photon Radiation for Oropharyngeal Cancers.

PURPOSE: There has been a recent epidemic of human papillomavirus (HPV)-positive oropharyngeal cancer, accounting for 70% to 80% of diagnosed cases. These patients have an overall favorable prognosis and are typically treated with a combination of surgery, chemotherapy, and radiation. Because these patients live longer, they are at risk of secondary malignant neoplasms (SMNs) associated with radiation therapy. Therefore, we assessed the predicted risk of SMNs after adjuvant radiation therapy with intensity-modulated proton therapy (IMPT) compared with intensity modulated photon radiation therapy (IMRT) in patients with HPV- positive oropharyngeal cancers after complete resection. MATERIALS AND METHODS: Thirteen consecutive patients with HPV-positive oropharyngeal cancers treated with postoperative radiation alone were selected. All patients were treated with pencil beam scanning IMPT to a total dose of 60 Gy in 2 Gy fractions. The IMRT plans were generated for clinical backup and were used for comparative purposes. The SMN risk was calculated based on an organ equivalent dose model for the linear-exponential dose-response curve. RESULTS: Median age of the patient cohort was 63 years (range, 47-73 years). There was no difference in target coverage between IMPT and IMRT plans. We noted significant reductions in mean mandible, contralateral parotid, lung and skin organ equivalent doses with IMPT compared with IMRT plans (P < .001). Additionally, a significant decrease in the risk of SMNs with IMPT was observed for all the evaluated organs. Per our analysis, for patients with oropharyngeal cancers diagnosed at a national median age of 54 years with an average life expectancy of 27 years (per national Social Security data), 4 excess SMNs per 100 patients could be avoided by treating them with IMPT versus IMRT. CONCLUSIONS: Treatment with IMPT can achieve comparable target dose coverage while significantly reducing the dose to healthy organs, which can lead to fewer predicted SMNs compared with IMRT.

A Phenotypic Screen Identifies Calcium Overload as a Key Mechanism of ß-Cell Glucolipotoxicity.

Type 2 diabetes (T2D) is caused by loss of pancreatic ß-cell mass and failure of the remaining ß-cells to deliver sufficient insulin to meet demand. ß-Cell glucolipotoxicity (GLT), which refers to combined, deleterious effects of elevated glucose and fatty acid levels on ß-cell function and survival, contributes to T2D-associated ß-cell failure. Drugs and mechanisms that protect ß-cells from GLT stress could potentially improve metabolic control in patients with T2D. In a phenotypic screen seeking low-molecular-weight compounds that protected ß-cells from GLT, we identified compound A that selectively blocked GLT-induced apoptosis in rat insulinoma cells. Compound A and its optimized analogs also improved viability and function in primary rat and human islets under GLT. We discovered that compound A analogs decreased GLT-induced cytosolic calcium influx in islet cells, and all measured ß-cell-protective effects correlated with this activity. Further studies revealed that the active compound from this series largely reversed GLT-induced global transcriptional changes. Our results suggest that taming cytosolic calcium overload in pancreatic islets can improve ß-cell survival and function under GLT stress and thus could be an effective strategy for T2D treatment.

Radiation Fractionation Schedules Published During the COVID-19 Pandemic: A Systematic Review of the Quality of Evidence and Recommendations for Future Development.

PURPOSE: Numerous publications during the COVID-19 pandemic recommended the use of hypofractionated radiation therapy. This project assessed aggregate changes in the quality of the evidence supporting these schedules to establish a comprehensive evidence base for future reference and highlight aspects for future study. METHODS AND MATERIALS: Based on a systematic review of published recommendations related to dose fractionation during the COVID-19 pandemic, 20 expert panelists assigned to 14 disease groups named and graded the highest quality of evidence schedule(s) used routinely for each condition and also graded all COVID-era recommended schedules. The American Society for Radiation Oncology quality of evidence criteria were used to rank the schedules. Process-related statistics and changes in distributions of quality ratings of the highest-rated versus recommended COVID-19 era schedules were described by disease groups and for specific clinical scenarios. RESULTS: From January to May 2020 there were 54 relevant publications, including 233 recommended COVID-19-adapted dose fractionations. For site-specific curative and site-specific palliative schedules, there was a significant shift from established higher-quality evidence to lower-quality evidence and expert opinions for the recommended schedules (P = .022 and P < .001, respectively). For curative-intent schedules, the distribution of quality scores was essentially reversed (highest levels of evidence "pre-COVID" vs "in-COVID": high quality, 51.4% vs 4.8%; expert opinion, 5.6% vs 49.3%), although there was variation in the magnitude of shifts between disease sites and among specific indications. CONCLUSIONS: A large number of publications recommended hypofractionated radiation therapy schedules across numerous major disease sites during the COVID-19 pandemic, which were supported by a lower quality of evidence than the highest-quality routinely used dose fractionation schedules. This work provides an evidence-based assessment of these potentially practice-changing recommendations and informs individualized decision-making and counseling of patients. These data could also be used to support radiation therapy practices in the event of second waves or surges of the pandemic in new regions of the world.

N-(Pyridin-2-yl) arylsulfonamide inhibitors of 11beta-hydroxysteroid dehydrogenase type 1: Discovery of PF-915275.

N-(Pyridin-2-yl) arylsulfonamides are identified as inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1), an enzyme that catalyzes the reduction of the glucocorticoid cortisone to cortisol. Dysregulation of glucocorticoids has been implicated in the pathogenesis of diabetes and the metabolic syndrome. In this Letter, we present the development of an initial lead to an efficient ligand with improved physiochemical properties using a deletion strategy. This strategy allowed for further optimization of potency leading to the discovery of the clinical candidate PF-915275.

The Promise of Proton Therapy for Central Nervous System Malignancies.

Radiation therapy plays a significant role in management of benign and malignant diseases of the central nervous system. Patients may be at risk of acute and late toxicity from radiation therapy due to dose deposition in critical normal structures. In contrast to conventional photon delivery techniques, proton therapy is characterized by Bragg peak dose deposition which results in decreased exit dose beyond the target and greater sparing of normal structure which may reduce the rate of late toxicities from treatment. Dosimetric studies have demonstrated reduced dose to normal structures using proton therapy as compared to photon therapy. In addition, clinical studies are being reported demonstrating safety, feasibility, and low rates of acute toxicity. Technical challenges in proton therapy remain, including full understanding of depth of proton penetration and the biological activity in the distal Bragg peak. In addition, longer clinical follow-up is required to demonstrate reduction in late toxicities as compared to conventional photon-based radiation techniques. In this review, we summarize the current clinical literature and areas of active investigation in proton therapy for adult central nervous system malignancies.

Prospective assessment of demographic characteristics associated with worse health related quality of life measures following definitive chemoradiation in patients with locally advanced non-small cell lung cancer.

BACKGROUND: The purpose of this study was to evaluate baseline demographic characteristics which may be associated with worse health related quality of life (HRQOL) for patients with locally advanced non-small cell lung cancer (NSCLC) receiving definitive chemoradiation (CRT). MATERIALS: Patients with NSCLC were prospectively enrolled on an Institutional Review Board-approved clinical trial between 2009 and 2012. HRQOL assessments were collected pre-radiation therapy (RT), during RT, and within 3 months post-RT using Euroqol (EQ-5D), MD Anderson Symptom Inventory (MDASI), and Functional Assessment of Cancer Therapy General (FACT-G). HRQOL correlation was assessed with categorical variables by Wilcoxon rank sum tests and with continuous variables by Pearson correlation. P<0.05 was defined as statistically significant. RESULTS: Forty-three consecutive patients received definitive concurrent CRT and completed assessments at one or more time-points. Patients most commonly had stage IIIB disease (72%), were married or with a partner (70%) and Caucasian (91%). Median patient age was 65 (range: 39-79) years and Charlson comorbidity index (CCI) was 0 (range: 0-5). Female gender, African-American ethnicity, age, chemotherapy type, baseline hemoglobin, and CCI were associated with worse post-treatment HRQOL measures. CONCLUSIONS: We have identified novel characteristics associated with worse quality of life following definitive CRT for lung cancer. Patients at risk for worse post-treatment quality of life may benefit from earlier follow-up and greater supportive measures following treatment.

Proton Therapy Reduces Normal Tissue Dose in Extended-Field Pelvic Radiation for Endometrial Cancer.

PURPOSE: We dosimetrically compared pencil beam scanning (PBS) proton therapy and intensity-modulated radiation therapy (IMRT) for pelvic and para-aortic lymph node disease in endometrial carcinoma and present acute toxicities associated with extended-field PBS. PATIENTS AND METHODS: Twenty-five patients with locally advanced endometrial malignancies were enrolled in an image-guided registry study. Seven of these patients were treated with PBS, and 18 patients were treated with IMRT. Organs at risk included pelvic bone marrow (PBM), small bowel (SB), large bowel (LB), rectum, bladder, and kidneys. The IMRT and PBS dosimetric parameters were compared using Wilcoxon rank-sum tests. RESULTS: Compared with IMRT PBM dose-volume histograms, PBS resulted in significantly lower dose volumes from 0 to 26.0 Gy (P < .05) and higher dose volumes from 33.9 to 42.9 Gy (P < .05). Overall, PBS resulted in 22% lower median PBM volume irradiated to 10 Gy (RBE) (PBS 71.3% versus IMRT 93.4%, P < .001) and 14% lower median volume irradiated to 20 Gy (RBE) (PBS 65.1% versus IMRT 79.4%, P < .001). Compared with IMRT, PBS also significantly reduced SB dose volumes from 0 to 27.5 Gy, LB dose volumes from 0 to 31.6 Gy, bladder dose volumes from 0 to 27.3 Gy, and rectal dose volumes from 0 to 7.6 Gy (all P < .05). However, PBS resulted in higher rectal dose volumes compared with IMRT from 26.0 to 48.4 Gy. Grade 3+ hematologic toxicities were present in 2 (11%) IMRT-treated patients and no PBS-treated patients. No grade 3+ gastrointestinal or genitourinary toxicities were present in either treatment group. CONCLUSION: In endometrial carcinoma, extended-field PBS is clinically feasible, resulting in statistically significant dose reduction to PBM as well as SB, LB, and bladder in the lower dose regions.

Prospective study of proton beam radiation therapy for adjuvant and definitive treatment of thymoma and thymic carcinoma: Early response and toxicity assessment.

BACKGROUND AND PURPOSE: Radiation is an important modality in treatment of thymic tumors. However, toxicity may reduce its overall benefit. We hypothesized that double-scattering proton beam therapy (DS-PT) can achieve excellent local control with limited toxicity in patients with thymic malignancies. METHODS AND MATERIALS: Patients with thymoma or thymic carcinoma treated with DS-PT between 2011 and 2015 were prospectively analyzed for toxicity and patterns of failure on an IRB-approved study. RESULTS: Twenty-seven consecutive patients were evaluated. Patients were a median of 56 years and had thymoma (85%). They were treated with definitive (22%), salvage (15%) or adjuvant (63%) DS-PT to a median of 61.2/1.8 Gy [CGE]. No patient experienced grade ⩾3 toxicity. Acute grade 2 toxicities included dermatitis (37%), fatigue (11%), esophagitis (7%), and pneumonitis (4%). Late grade 2 toxicity was limited to a single patient with chronic dyspnea. At a median follow-up of 2 years, 100% local control was achieved. Three-year regional control, distant control, and overall survival rates were 96% (95% CI 76-99%), 74% (95% CI 41-90%), and 94% (95% CI 63-99%), respectively. CONCLUSIONS: This is the first cohort and prospective series of proton therapy to treat thymic tumors, demonstrating low rates of early toxicity and excellent initial outcomes.

Employment of deaf people as influenced by potential employers' perceptions: pathological compared with sociocultural perspectives.

Two basic perspectives contrast how people perceive deafness: the pathological and sociocultural perspectives. The pathological perspective focuses on the medical issues related to hearing impairment. The sociocultural perspective views deafness as a cultural difference. This study investigated whether these perspectives influenced assessments of deaf job candidates in a mock hiring scenario. Undergraduates were given information supporting either the pathological or sociocultural perspectives. They later rated deaf and hearing job candidates who were presented as having identical qualifications. The hypothesis was not supported in this study; the experiment did not significantly alter the views of future prospective employers. Also, education about the deaf culture did not appear to have an impact on deaf and hearing relations.