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The article focuses on project COAL (Communities Organized against Asthma & Lead/ Comunidades organizadas contra la asma y el plomo), which is funded as a factor of the National Institute of Environmental Health Sciences (NIEHS) Environmental Justice: Partnerships for Communication program. It says that the project seeks to teach parents on environmental health hazards, and gather population-based data on prevalence and location of asthma cases and homes with unsafe lead levels. Principal collaborators on the project are also mentioned.

Background: Stroke is among the top contributors to disability and can impact an individual's cognition, physical functioning, and mental health. Since the COVID-19 pandemic, several community-based organizations have started delivering stroke programs virtually. However, participants' experiences in these programs remain understudied, and evidence-based guidelines to inform and optimize virtual stroke program development and delivery are lacking. Thus, this study aimed to describe the perspectives and experiences of individuals with stroke who participated in virtual community-based organization stroke programs, including perceived access and participation facilitators and barriers and suggestions for improving these programs., Methods: A qualitative descriptive design was used to gather participant experiences through semi-structured interviews. Audio-recorded interviews were conducted on Zoom and transcribed verbatim. Adult participants who had experienced a stroke and attended at least one Canadian virtual community-based organization stroke program were recruited. Data were analyzed using inductive thematic analysis., Results: Twelve participants (32-69 years, 2-23 years post-stroke, eight women and four men) participated in this study. Five themes were identified: (1) motives to join virtual community-based organization stroke programs, including gaining peer connections, knowledge and information; (2) perceived barriers to accessing and participating in virtual community-based organization stroke programs, including technology inequities, difficulties navigating technology, and inadequate facilitation; (3) perceived facilitators to accessing and participating in virtual community-based organization stroke programs, including remote access, virtual platform features and program leader characteristics/skills; (4) unmet needs during virtual community-based organization stroke programs, including in-person connection and individualized support; and (5) suggestions and preferences for improving virtual community-based organization stroke programs, including program facilitation, content and format., Conclusions: Study findings highlight opportunities to improve virtual community-based organization stroke programs to optimize participant experiences and outcomes. Addressing the barriers and suggestions identified in this study may improve virtual community-based organization stroke programs' access and quality., (© 2024. The Author(s).)

Purpose: In breast cancer, improved treatment approaches that reduce injury to lung tissue and early diagnosis and intervention for lung toxicity are increasingly important in survivorship. The aims of this study are to (1) compare lung tissue radiographic changes in women treated with conventional photon radiation therapy and those treated with proton therapy (PT), (2) assess the volume of lung irradiated to 5 Gy (V5) and 20 Gy (V20) by treatment modality, and (3) quantify the effects of V5, V20, time, and smoking history on the severity of tissue radiographic changes., Patients and Methods: A prospective observational study of female breast cancer patients was conducted to monitor postradiation subclinical lung tissue radiographic changes. Repeated follow-up x-ray computed tomography scans were acquired through 2 years after treatment. In-house software was used to quantify an internally normalized measure of pulmonary tissue density change over time from the computed tomography scans, emphasizing the 6- and 12-month time points., Results: Compared with photon therapy, PT was associated with significantly lower lung V5 and V20. Lung V20 (but not V5) correlated significantly with increased subclinical lung tissue radiographic changes 6 months after treatment, and neither correlated with lung effects at 12 months. Significant lung tissue density changes were present in photon therapy patients at 6 and 12 months but not in PT patients. Significant lung tissue density change persisted at 12 months in ever-smokers but not in never-smokers., Conclusion: Patients treated with PT had significantly lower radiation exposure to the lungs and less statistically significant tissue density change, suggesting decreased injury and/or improved recovery compared to photon therapy. These findings motivate additional studies in larger, randomized, and more diverse cohorts to further investigate the contributions of treatment modality and smoking regarding the short- and long-term radiographic effects of radiation on lung tissue., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Walter G. O’Dell, PhD reports financial support was provided by Florida Department of Health. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier B.V. on behalf of Particle Therapy Co-operative Group.)

Competing Interests: All authors declare no conflicts of interests.

On December 5, 2022, an indirect drive fusion implosion on the National Ignition Facility (NIF) achieved a target gain G_{target} of 1.5. This is the first laboratory demonstration of exceeding "scientific breakeven" (or G_{target}>1) where 2.05 MJ of 351 nm laser light produced 3.1 MJ of total fusion yield, a result which significantly exceeds the Lawson criterion for fusion ignition as reported in a previous NIF implosion [H. Abu-Shawareb et al. (Indirect Drive ICF Collaboration), Phys. Rev. Lett. 129, 075001 (2022)PRLTAO0031-900710.1103/PhysRevLett.129.075001]. This achievement is the culmination of more than five decades of research and gives proof that laboratory fusion, based on fundamental physics principles, is possible. This Letter reports on the target, laser, design, and experimental advancements that led to this result.

Glycogen storage disorders (GSDs) are inherited disorders of metabolism resulting from the deficiency of individual enzymes involved in the synthesis, transport, and degradation of glycogen. This literature review summarizes the development of gene therapy for the GSDs. The abnormal accumulation of glycogen and deficiency of glucose production in GSDs lead to unique symptoms based upon the enzyme step and tissues involved, such as liver and kidney involvement associated with severe hypoglycemia during fasting and the risk of long-term complications including hepatic adenoma/carcinoma and end stage kidney disease in GSD Ia from glucose-6-phosphatase deficiency, and cardiac/skeletal/smooth muscle involvement associated with myopathy +/- cardiomyopathy and the risk for cardiorespiratory failure in Pompe disease. These symptoms are present to a variable degree in animal models for the GSDs, which have been utilized to evaluate new therapies including gene therapy and genome editing. Gene therapy for Pompe disease and GSD Ia has progressed to Phase I and Phase III clinical trials, respectively, and are evaluating the safety and bioactivity of adeno-associated virus vectors. Clinical research to understand the natural history and progression of the GSDs provides invaluable outcome measures that serve as endpoints to evaluate benefits in clinical trials. While promising, gene therapy and genome editing face challenges with regard to clinical implementation, including immune responses and toxicities that have been revealed during clinical trials of gene therapy that are underway. Gene therapy for the glycogen storage diseases is under development, addressing an unmet need for specific, stable therapy for these conditions., (© 2023 SSIEM.)

Purpose: Obtaining prior authorization (PA) before treatment is becoming increasingly burdensome in oncology, especially in radiation oncology. Here, we describe the impact of a strategic novel operational PA redesign to shorten authorization time and to improve patient access to cancer care at a large United States academic proton therapy center. We ask whether such a redesign may be replicable and adoptable across oncology centers., Materials and Methods: Our PA redesign strategy was based on a 3-tiered approach. Specifically, we (1) held payors accountable to legally backed timelines, (2) leveraged expertise on insurance policies and practices, and (3) updated the submission, appeal writing, and planning procedures for PA. Metrics were compared at the following 3 time points: 6 months before, at phase-in, and at 6 months after intervention., Results: In analyzing the impact of improving PA access to care, the percentage of approvals for commercial proton beam therapy improved by an absolute 30.6% postintervention ( P < .001). The proportion of commercially insured patients treated with proton beam therapy also increased by 6.2%, and the number of new starts rose by 11.7 patients/mo. Overall patient census increased by 13 patients/d. Median authorization time was 1 week, and 90% of surveyed providers reported reduced PA burden and improved patient care., Conclusion: This is the first validated, comprehensive operational strategy to improve access to cancer therapy while reducing the burden of PA. This novel approach may be helpful for addressing barriers to PA in medical and surgical oncology because the redesign is predicated on laws that regulate PA across disciplines., Competing Interests: Conflict of Interest: Nancy P. Mendenhall is the Editor-in-Chief of International Journal of Particle Therapy. All other authors declare no conflict of interest., (©Copyright 2023 The Author(s).)

Purpose: The potential disparities in palliative care delivery for underrepresented minorities with breast cancer are not well known. We sought to determine whether race and ethnicity impact the receipt of palliative care for patients with metastatic breast cancer (MBC)., Methods: We retrospectively reviewed the National Cancer Database for female patients diagnosed with stage IV breast cancer between 2010 and 2017 who received palliative care following diagnosis of MBC to assess the proportion of patients who received palliative care, including non-curative-intent local-regional or systemic therapy. Multivariable logistic regression analysis was performed to identify variables associated with receiving palliative care., Results: 60,685 patients were diagnosed with de novo MBC. Of these, only 21.4% (n = 12,963) received a palliative care service. Overall, there was a positive trend in palliative care receipt from 18.2% in 2010 to 23.0% in 2017 (P < 0.001), which persisted when stratified by race and ethnicity. Relative to non-Hispanic White women, Asian/Pacific Islander women (aOR 0.80, 95% CI 0.71-0.90, P < 0.001), Hispanic women (adjusted odds ratio [aOR] 0.69, 95% CI 0.63-0.76, P < 0.001), and non-Hispanic Black women (aOR 0.94, 95% CI 0.88-0.99, P = 0.03) were less likely to receive palliative care., Conclusions: Fewer than 25% of women with MBC received palliative care between 2010 and 2017. While palliative care has significantly increased for all racial/ethnic groups, Hispanic White, Black, and Asian/Pacific Islander women with MBC still receive significantly less palliative care than non-Hispanic White women. Further research is needed to identify the socioeconomic and cultural barriers to palliative care utilization., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To determine the rib fracture rate in a cohort of patients with breast cancer treated with proton therapy., Patient and Methods: From a prospective database, we identified 225 patients treated with proton therapy between 2012 and 2020 (223 women; 2 men). Clinical and dosimetric data were extracted, the cumulative incidence method assessed rib fracture rate, and Fine-Gray tests assessed prognostic significance of select variables. In-field rib fracture was defined as a fracture that occurred in a rib located within the 10% isodose line. Out-of-field rib fracture was defined as a fracture occurring in a rib location outside of the 10% isodose line., Results: Of the patients, 74% had left-sided breast cancer; 5%, bilateral; and 21%, right-sided. Dual-energy x-ray absorptiometry scans showed normality in 20%, osteopenia in 34%, and osteoporosis in 6% (test not performed in 40%). Additionally, 57% received an aromatase inhibitor. Target volumes were breast ± internal mammary nodes (IMNs) (16%), breast and comprehensive regional lymphatics (32%), chest wall ± IMNs (1%), and chest wall/comprehensive regional lymphatics (51%). Passive-scattered proton therapy was used for 41% of patients, 58% underwent pencil-beam scanning (PBS), and 1% underwent a combination (passive scattering/PBS), with 85% of patients receiving a boost. Median follow-up was 3.1 years, with 97% having >12-month follow-up. The 3-year cumulative in-field rib fracture incidence was 3.7%. Eight patients developed in-field rib fractures (1 symptomatic, 7 imaging identified) for a 0.4% symptomatic rib fracture rate. Median time from radiation completion to rib fracture identification was 1.8 years (fractures were identified within 2.2 years for 7 of 8 patients). No variables were associated with rib fracture on univariate analysis. Three fractures developed outside the radiation field (0.9% cumulative incidence of out-of-field rib fracture)., Conclusion: In this series of patients with breast cancer treated with proton therapy, the 3-year rib fracture rates remain low (in-field 3.7%; symptomatic 0.4%). As in photon therapy, the asymptomatic rate may be underestimated owing to a lack of routine surveillance imaging. However, patients experiencing symptomatic rib fractures after proton therapy for breast cancer are rare., Competing Interests: Conflicts of Interest: Nancy P. Mendenhall, MD, is Editor-in-Chief of the International Journal of Particle Therapy. The authors have no additional conflicts of interest to disclose., (©Copyright 2023 The Author(s).)

Glycogen storage disease type Ia (GSD Ia) is the inherited deficiency of glucose-6-phosphatase (G6Pase), associated with life-threatening hypoglycemia and long-term complications, including hepatocellular carcinoma formation. Gene replacement therapy fails to stably reverse G6Pase deficiency. We attempted genome editing using two adeno-associated virus vectors, one that expressed Staphylococcus aureus Cas9 protein and a second containing a donor transgene encoding G6Pase, in a dog model for GSD Ia. We demonstrated donor transgene integration in the liver of three adult-treated dogs accompanied by stable G6Pase expression and correction of hypoglycemia during fasting. Two puppies with GSD Ia were treated by genome editing that achieved donor transgene integration in the liver. Integration frequency ranged from 0.5% to 1% for all dogs. In adult-treated dogs, anti-SaCas9 antibodies were detected before genome editing, reflecting prior exposure to S. aureus . Nuclease activity was low, as reflected by a low percentage of indel formation at the predicted site of SaCas9 cutting that indicated double-stranded breaks followed by non-homologous end-joining. Thus, genome editing can integrate a therapeutic transgene in the liver of a large animal model, either early or later in life, and further development is warranted to provide a more stable treatment for GSD Ia., Competing Interests: D.D.K., H.R.K., B.A., and B.R.C. have developed the technology that is being used in the study. If the technology is commercially successful in the future, the developers and Duke University may benefit financially. D.D.K. has received research/grant support from Sangamo Therapeutics, Inc. in the past., (© 2023 The Author(s).)

Purpose: Treatment for bilateral breast cancer with radiation therapy is technically challenging. We evaluated the clinical and dosimetric outcomes of a small series of patients with synchronous bilateral breast cancer, including a photon dosimetric comparison, to identify optimal treatment planning approaches., Materials and Methods: We reviewed a registry of patients (simultaneously) diagnosed with synchronous bilateral breast cancers who underwent postoperative definitive adjuvant proton therapy at our institution between 2012 and 2021. All patients were treated with double-scattered proton or pencil-beam scanning therapies. For comparison, intensity-modulated radiation therapy photon plans optimized for organ sparing and coverage were generated after treatment., Results: Six patients were included. The median patient age was 66 years; all were female with no history of breast cancer or radiation therapy. Two (33%) patients received breast/chest wall-only treatments, 1 (17%) required breast plus level I axillary treatment to one side and breast plus regional nodal irradiation (RNI) to the other, and 3 (50%) received bilateral breast/chest plus RNI; dosimetric results are reported for each group's median. Analysis showed clinical target coverage was comparable between proton and photon techniques (V95% of 96.4% with proton, 97.8% with photon). However, protons could deliver superior organ sparing at clinically relevant dose metrics for virtually all structures: a 6.7 Gy absolute reduction in the mean heart dose (7.5 Gy with photons to 0.7 Gy with protons), a 47% to 57% relative reduction in D 0.1cm3 to coronary arteries, a 54% relative reduction in lung V20 Gy, and an absolute 7.6 Gy reduction to the brachial plexus. There was also greater esophagus and spinal cord sparing. The overall survival rate was 100% at 1.5 years of median follow-up (0.5-4.9), and all patients were free of disease. For toxicity, all patients had some form of acute side effects: 66% experienced grade 2 breast/chest pain or soreness; 100% had grade 2 radiation dermatitis or skin induration; 33% had grade 2 fatigue; and 17% had grade 2 esophagitis (per the Common Terminology Criteria for Adverse Events [CTCAE] version 5.0; US National Cancer Institute, Bethesda, Maryland). Subacute toxicity (within 6 months) was observed for 17% of patients with delayed onset of grade 3 dermatitis in the setting of preexisting lupus, 17% with a delayed surgical wound complication, and 17% with grade 2 soft tissue fibrosis. No grade 4 or 5 events were observed., Conclusions: Substantial dose reductions to multiple organs at risk while maintaining target coverage make proton the preferred modality for bilateral breast cancer treatment when available., Competing Interests: Conflicts of Interest: Nancy P. Mendenhall, MD, is Editor-in-Chief of the International Journal of Particle Therapy. The authors have no additional conflicts of interest to disclose., (©Copyright 2023 The Author(s).)

Stereotactic body radiation therapy (SBRT) is commonly used to treat early-stage, node-negative primary lung cancer, but society guidelines provide limited information regarding several technical aspects of SBRT, leading to potential variation in practice. In this report, we present the technical details used by 3 academic institutions when treating a solitary primary lung tumor up to 5 cm in dimension with curative-intent SBRT. We provide specifications outlined in major active or recently completed clinical trials. Among the participating institutions, we discovered multiple divergences in treatment parameters, including, but not limited to, prescription dose and desired degree of heterogeneity within the target volume. It is unclear to what extent these differences in parameters might affect tumor control or toxicity, but updated consensus guidelines addressing the relevant SBRT prescription details may help standardize practice patterns., (Copyright © 2022 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Purpose: There is a lack of level I evidence to guide radiation therapy recommendations for patients receiving neoadjuvant chemotherapy for breast cancer. We used 4 neoadjuvant chemotherapy trials to determine which patients benefit from regional nodal irradiation (RNI)., Methods and Materials: We obtained data from the NSABP (National Surgical Adjuvant Breast and Bowel Project) B-18, B-27, B-40, and B-41 clinical trials. B-40 and B-41 allowed RNI at physician's discretion. We evaluated locoregional recurrence (LRR), distant recurrence, disease-free survival, and overall survival (OS). Kaplan-Meier, Peto-Peto, χ 2 , Fisher exact, and Wilcoxon rank-sum tests were used for survival estimates and comparison., Results: Median follow-up for B-18, B-27, B-40, and B-41 was 13.7, 9.7, 4.5, and 5.1 years, respectively, including 742, 2254, 1154, and 504 patients for analysis. On multivariable analysis, factors significantly associated with RNI included tumor size, ypN status, and tumor subtype; Hispanic patients were less likely to receive RNI. Patients with ypN+HER2+ disease who received RNI had improved OS. B-40 patients with ypN+HR+ disease had improved LRR. On multivariable analysis for the B-40 and B-41 study population, RNI was not associated with significantly improved OS, disease-free survival, distant recurrence, or LRR., Conclusions: RNI was associated with a clinical benefit for patients with ypN+HER2+ and ypN+HR+ disease. RNI was not significantly associated with a clinically beneficial outcome for the entire cohort. Prospective phase 3 clinical trials are needed to establish guidelines for patients who should receive RNI after neoadjuvant treatment, and action is necessary to eliminate the disparity in care delivery shown for Hispanic women., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: Radiation-associated angiosarcoma (RAAS) is a rare complication among patients treated with radiation therapy for breast cancer. Hyperfractionated-accelerated reirradiation (HART) improves local control after surgery. Proton therapy may further improve the therapeutic ratio by mitigating potential toxicity., Materials and Methods: Six patients enrolled in a prospective registry with localized RAAS received HART with proton therapy between 2015 and 2021. HART was delivered twice or thrice daily in fraction sizes of 1.5 or 1.0 Gy, respectively. All patients received 45 Gy to a large elective volume followed by boosts to a median dose of 65 (range, 60-75) Gy. Toxicity was recorded prospectively by using the Common Terminology Criteria for Adverse Events, version 4.0., Results: The median follow-up duration was 1.5 (range, 0.25-2.9) years. The median age at RAAS diagnosis was 73 (range, 60-83) years with a median latency of 8.9 (range, 5-14) years between radiation therapy completion and RAAS diagnosis. The median mean heart dose was 2.2 (range, 0.1-4.96) Gy. HART was delivered postoperatively (n = 1), preoperatively (n = 3), preoperatively for local recurrence after initial management with mastectomy (n = 1), and as definitive treatment (n = 1). All patients had local control of disease throughout follow-up. Three of 4 patients treated preoperatively had a pathologic complete response. The patient treated definitively had a complete metabolic response on her posttreatment PET/CT (positron emission tomography-computed tomography) scan. Two patients developed distant metastatic disease despite local control and died of their disease. Acute grade 3 toxicity occurred in 3 patients: 2 patients undergoing preoperative HART experienced wound dehiscence and 1 postoperatively developed grade 3 wound infection, which resolved., Conclusion: HART with proton therapy appears effective for local control of RAAS with a high rate of pathologic complete response and no local recurrences to date. However, vigilant surveillance for distant metastasis should occur. Toxicity is comparable to that in photon/electron series. Proton therapy for RAAS may maximize normal tissue sparing in this large-volume reirradiation setting., Competing Interests: Conflicts of Interest: Nancy P. Mendenhall, MD, is Editor-in-Chief of the International Journal of Particle Therapy. The authors have no additional conflicts of interest to disclose., (©Copyright 2021 The Author(s).)

Background: Re-irradiation (re-RT) is a technically challenging task for which few standardized approaches exist. This is in part due to the lack of a common platform to assess dose tolerance in relation to toxicity in the re-RT setting. To better address this knowledge gap and provide new tools for studying and developing thresholds for re-RT, we developed a novel algorithm that allows for anatomically accurate three-dimensional mapping of composite biological effective dose (BED) distributions from nominal doses (Gy)., Methods: The algorithm was designed to automatically convert nominal dose from prior treatment plans to corresponding BED value maps (voxel size 2.5 mm 3 and α/β of 3 for normal tissue, BED 3 ). Following the conversion of each plan to a BED 3 dose distribution, deformable registration was used to create a summed composite re-irradiation BED 3 plan for each patient who received two treatments. A proof-of-principle analysis was performed on 38 re-irradiation cases of initial stereotactic ablative radiotherapy (SABR) followed by either re-SABR or chemoradiation for isolated locoregional recurrence of early-stage non-small cell lung cancer., Results: Evaluation of the algorithm-generated maps revealed appropriate conversion of physical dose to BED at each voxel. Of 14 patients receiving repeat SABR, there was one case each of grade 3 chest wall pain (7%), pneumonitis (7%), and dyspnea (7%). Of 24 patients undergoing repeat fractionated radiotherapy, grade 3 events were limited to two cases each of pneumonitis and dyspnea (8%). Composite BED 3 dosimetry for each patient who experienced grade 2-3 events is provided and may help guide development of precise cumulative dose thresholds for organs at risk in the re-RT setting., Conclusions: This novel algorithm successfully created a voxel-by-voxel composite treatment plan using BED values. This approach may be used to more precisely examine dosimetric predictors of toxicities and to establish more accurate normal tissue constraints for re-irradiation., (© 2021. The Author(s).)

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, accounting for 30-40% of all non-Hodgkin lymphoma cases and presenting later in life, most often in the sixth decade. Although DLBCL is curable, long-term remission rates are only 60-80%. The most recent major advance in upfront therapy for DLBCL was the monoclonal anti-CD20 antibody rituximab, which was approved in the late 1990s; now, 25 years later, up to 40% of patients will experience primary refractory or relapsed disease, thereby underscoring the importance of salvage therapy. Radiation therapy can be highly effective in DLBCL, both initially as consolidation therapy and later as salvage therapy and is currently being explored in the context of immune and cellular therapies. The aim of this review is to examine the therapeutic approaches for relapsed or refractory DLBCL, with a focus on whether using radiation therapy as salvage therapy can improve the likelihood of cure.

Purpose: To determine factors that influence insurance approval for definitive proton therapy (PT) for prostate cancer., Materials and Methods: Between 2014 and 2018, 1592 insured patients with localized prostate cancer were evaluated and recommended to undergo definitive PT; 547 patients (34.4%) had commercial insurance, whereas 1045 patients (65.6%) had Medicare/Medicaid. Of those with Medicare, 164 patients (15.7%) had Medicare alone; 677 (64.8%) had supplemental plans; and 204 (19.5%) had secondary commercial insurance. Insurance that "covered" PT for prostate cancer implied that it was an indication designated in the coverage policy. "Not covered" means that the insurance policy did not list prostate cancer as an indication for PT. Of all 1592 patients, 1263 (79.3%) belonged to plans that covered PT per policy. However, approval for PT was still required via medical review for 619 patients (38.9%), comparative dosimetry for 56 patients (3.5%), peer-to-peer discussion for 234 patients (14.7%), and administrative law judge hearings for 3 patients (<0.1%). Multivariate analyses of factors affecting approval were conducted, including risk group (low/intermediate versus high), insurance type (commercial versus Medicare/Medicaid), whether PT was included as a covered benefit under the plan (covered versus not covered), and time period (2014-16 versus 2017 versus 2018)., Results: On multivariate analysis, factors affecting PT approval for prostate treatment included coverage of PT per policy (97.1% had approval with insurance that covered PT versus 48.6% whose insurance did not cover PT; P  < .001); insurance type (32.5% had approval with commercial insurance versus 97.4% with Medicare; P  < .001); and time, with 877/987 patients (88.9%) approved between 2014 and 2016, 255/312 patients (81.7%) approved during 2017, and 255/293 patients (87.0%) approved thereafter ( P  = .02). Clinical factors, including risk group, had no bearing on insurance approval ( P  = .44)., Conclusion: Proton insurance approval for prostate cancer has decreased, is most influenced by the type of insurance a patient belongs to, and is unrelated to clinical factors (risk group) in this study. More work is needed to help navigate appropriate access to care and to assist patients seeking definitive PT for prostate cancer treatment., Competing Interests: Conflicts of Interest: William M. Mendenhall, MD, and Nancy P. Mendenhall, MD, are Operating Editor and Editor-in-Chief of the International Journal of Particle Therapy, respectively. The authors have no other relevant conflicts of interest to disclose., (©Copyright 2021 The Author(s).)

Purpose: Proton beam therapy (PBT) is associated with less toxicity relative to conventional photon radiotherapy for head-and-neck cancer (HNC). Upfront delivery costs are greater, but PBT can provide superior long-term value by minimizing treatment-related complications. Cost-effectiveness models (CEMs) estimate the relative value of novel technologies (such as PBT) as compared with the established standard of care. However, the uncertainties of CEMs can limit interpretation and applicability. This review serves to (1) assess the methodology and quality of pertinent CEMs in the existing literature, (2) evaluate their suitability for guiding clinical and economic strategies, and (3) discuss areas for improvement among future analyses., Materials and Methods: PubMed was queried for CEMs specific to PBT for HNC. General characteristics, modeling information, and methodological approaches were extracted for each identified study. Reporting quality was assessed via the Consolidated Health Economic Evaluation Reporting Standards 24-item checklist, whereas methodologic quality was evaluated via the Philips checklist. The Cooper evidence hierarchy scale was employed to analyze parameter inputs referenced within each model., Results: At the time of study, only 4 formal CEMs specific to PBT for HNC had been published (2005, 2013, 2018, 2020). The parameter inputs among these various Markov cohort models generally referenced older literature, excluding many clinically relevant complications and applying numerous hypothetical assumptions for toxicity states, incorporating inputs from theoretical complication-probability models because of limited availability of direct clinical evidence. Case numbers among study cohorts were low, and the structural design of some models inadequately reflected the natural history of HNC. Furthermore, cost inputs were incomplete and referenced historic figures., Conclusion: Contemporary CEMs are needed to incorporate modern estimates for toxicity risks and costs associated with PBT delivery, to provide a more accurate estimate of value, and to improve their clinical applicability with respect to PBT for HNC., Competing Interests: Conflicts of Interest: Steven J. Frank, MD, is an Associate Editor of the International Journal of Particle Therapy. Outside of the submitted work, Dr Frank reports receiving personal fees as a consultant and advisory board member of Varian Medical Systems, Inc; grants and personal fees as director and founder of C4 Imaging, LLC; grants and honoraria as an advisor for Hitachi; honoraria from Boston Scientific; grants from Eli Lilly; grants from Elekta; honoraria from Augmenix; personal fees as a member of the board of directors of the National Comprehensive Cancer Center (NCCN); and other support as a scientific advisory board member for Breakthrough Chronic Care. Ashish A. Deshmukh PhD, MPH, reports receiving consulting fees from Merck on unrelated projects outside the submitted work. The authors have no additional conflicts of interest to disclose., (©Copyright 2021 The Author(s).)

Purpose: Patient travel time can cause treatment delays when providers and families decide to seek proton therapy. We examined whether travel distance or referral pattern (domestic versus international) affects time to radiation therapy and subsequent disease outcomes in patients with medulloblastoma at a large academic proton center., Patients and Methods: Children with medulloblastoma treated at MD Anderson (MDA) with a protocol of proton beam therapy (PBT) between January 4, 2007, and June 25, 2014, were included in the analysis. The Wilcoxon rank-sum test was used to study the association between time to start of radiation and distance. Classification- and regression-tree analyses were used to explore binary thresholds for continuous covariates (ie, distance). Failure-free survival was defined as the time interval between end of radiation and failure or death., Results: 96 patients were included in the analysis: 17 were international (18%); 19 (20%) were from Houston, Texas; 21 were from other cities inside Texas (21%); and 39 (41%) were from other US states. The median time from surgery to start of radiation was not significantly different for international patients (median = 1.45 months) compared with US patients (median = 1.15 months; P  = .13). However, time from surgery to start of radiation was significantly longer for patients residing > 1716 km (> 1066 miles) from MDA (median = 1.31 months) than for patients residing ≤ 1716 km (≤ 1066 miles) from MDA (median = 1.05 months; P  = .01). This 1- to 2-week delay (median = 7.8 days) did not affect failure-free survival (hazard ratio = 1.34; P  = .43)., Conclusion: We found that short delays in proton access can exist for patients traveling long distances to proton centers. However, in this study, treatment delays did not affect outcomes. This highlights the appropriateness of PBT in the face of travel coordination. Investment by proton centers in a rigorous intake process is justified to offer timely access to curative PBT., Competing Interests: Conflicts of Interest: Steven J. Frank, MD, is an Associate Editor of the International Journal of Particle Therapy. Dr Frank discloses leadership and ownership interests in C4 Imaging and National Comprehensive Cancer Network Stock; honoraria from Boston Scientific, Hitachi, and Varian Medical Systems; research funding from Elekta, Hitachi, and Eli Lilly; a consulting or advisory role with Hitachi, Breakthrough Chronic Care, Varian Medical Systems; and patents developed at the University of Texas MD Anderson Cancer Center, which have been licensed to C4 Imaging. Dr Frank also discloses travel, accommodations, and expenses provided by the National Comprehensive Cancer Network and Boston Scientific. The authors have no other conflicts to disclose., (©Copyright 2020 The Author(s).)

Purpose: Prior authorization (PA) can be a resource-intensive barrier to oncologic care. To improve patient access and reduce delays at our large, academic proton therapy center, we implemented a novel payor-focused strategy to efficiently navigate the PA process while eliminating physician burden and reducing inappropriate denials., Methods: In 2017, business operations were redesigned to better reflect the insurance process: (1) certified medical dosimetrists (CMDs), with their unique treatment expertise, replaced our historical PA team to function as an effective interface among physicians, patients, and payors; (2) a structured, tiered timeline was implemented to hold payors accountable to PA deadlines; and (3) our PA team provided administrative leadership with requisite insurance knowledge. PA outcomes were compared 6 months before and after the intervention., Results: After implementation of this multifaceted strategy, the median time to successful appeal (after initial denial of coverage) decreased from 30 to 18 days ( P < .001), and the total number of overturned denials increased by 56%. Because of the efficiency of the CMDs, full-time equivalents on the PA team actually decreased by 44%, translating to a 34% reduction in team personnel expenses. Internal referrals increased by 29%, attributable to optimized communication and diminished administrative burden for providers. New treatment starts also increased, resulting in a 37% larger patient census on treatment., Conclusion: Incorporating payor-focused strategies can improve patient access in a cost-effective manner while decreasing time and administrative burden associated with the PA process. These operational concepts can be adapted for other oncologic practice settings facing analogous PA-related obstacles.

Purpose: This study aimed to compare and contrast the American Society for Radiation Oncology (ASTRO) model policies (MPs) for intensity modulated radiation therapy (IMRT), stereotactic radiosurgery (SRS), stereotactic ablative radiation therapy (SABR), and proton beam therapy (PBT) with the coverage policies constructed by 5 of the largest publicly available commercial insurers throughout the United States (ie, Aetna, Anthem, Cigna, Humana, and United Healthcare)., Methods and Materials: Appropriate indications for IMRT, SRS, SABR, and PBT by disease site (and particular clinical setting thereof) were extracted from the most recently published ASTRO MPs and published coverage policies (2019 editions) of the 5 carriers. After tabulation, concordance between ASTRO MPs and insurance policies were calculated for each modality., Results: All 5 insurer policies supported IMRT for neoplasms of the central nervous system, head/neck, hepatopancreaticobiliary, anal, and prostate cancers. The least covered diseases were retroperitoneal tumors (n = 0 carriers) and bladder cancer (n = 1). For SRS, all carriers covered benign brain tumors, brain metastases, arteriovenous malformations, and trigeminal neuralgia. None of the insurance carriers covered SRS for medically refractory epilepsy. For SABR, primary liver, lung, and low- or intermediate-risk prostate cancer were covered by all insurers, and none allowed SABR for primary biliary neoplasms. Only one insurance carrier each covered SABR for primary/metastatic adrenal disease and primary renal cancer. All carriers approved PBT for ocular melanoma, skull base tumors, and pediatric malignancies. The ASTRO MPs listed 4 PBT scenarios (ie, spinal disease, retroperitoneal sarcoma, head/neck neoplasms, and patients with genetic radiosensitivity syndromes) not covered by any insurer. Concordance between insurance carriers and ASTRO MPs was 67.8% for IMRT, 72.0% for SRS, 58.4% for SABR, and 41.8% for PBT (P = .005)., Conclusions: Coverage guidelines for IMRT, SRS, SABR, and PBT vary across 5 major insurance providers and may be substantially discordant compared with ASTRO coverage guidelines. There remain several specific areas where ongoing and future dialogues between ASTRO members, payers, and policymakers remain essential., (Copyright © 2019 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Purpose: Management of synchronous early-stage non-small cell lung cancer (NSCLC) remains controversial because resection is not always feasible. This study evaluates efficacy and patterns of failure after SABR for synchronous early-stage NSCLC., Methods and Materials: From 2005 to 2015, patients presenting with ≥2 synchronous NSCLC tumors (T1a-T2b) and receiving SABR to ≥1 lesion were reviewed. The most common prescriptions were 50 Gy in 4 or 70 Gy in 10 fractions. Patients underwent multidisciplinary management with workup including chest computed tomography and positron emission tomography/computed tomography, plus brain imaging and endoscopic bronchial ultrasound for most patients to rule out mediastinal and distant disease. Synchronous lesions were defined as multiple ipsilateral or contralateral intrapulmonary lesions diagnosed within 6 months., Results: Of 912 patients treated with SABR for early-stage NSCLC at our institution, 82 (9%) presented with synchronous disease, with a total of 169 lesions. SABR was delivered to 142 lesions (84%), with 57 patients (69.5%) receiving SABR for all sites. Median overall survival (OS) and progression-free survival (PFS) were 5.1 and 2.7 years, respectively. At a median follow-up of 58 months, OS was 67% and 52% at 3 and 5 years, and corresponding PFS was 47% and 29%. Thirty-nine patients (48%) had progression, with 21 (26%) experiencing distant failure, and intralobar recurrence was among the first failure for 15 patients (18%). Of the 142 SABR-treated sites, these included 6 in-field (4%) and 4 marginal (3%) recurrences. There were no grade ≥3 adverse events. Among patients receiving SABR for all sites, there were no differences in OS (P = .946), PFS (P = .980), local control (P = .683), regional and distant control (P = .656), or toxicity (P = .791). On multivariable analysis, ipsilateral synchronous disease was associated with greater regional and distant failure (hazard ratio, 2.691; P = .025)., Conclusions: Synchronous NSCLC can be managed with definitive local therapy. With high control rates and favorable outcomes, SABR is an effective and feasible treatment for synchronous early-stage NSCLC., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Patterns of local, regional, and distant failure after stereotactic ablative radiotherapy (SABR) for early-stage non-small cell lung cancer (NSCLC) have been widely reported. However, reliable methods for analyzing causes of local failure are lacking. We describe a method for analyzing and reporting patterns of in-field recurrence after SABR, incorporating dosimetric parameters from initial treatment plan as well as geometric information from diagnostic images at recurrence., Material and Methods: Diagnostic CT images at recurrence were registered with initial treatment planning images and radiation dose by deformable image registration. Recurrent gross tumor volume (rGTV) and centroid (geometric center of rGTV) were delineated. In-field failure was classified as centroids originating within the original planning target volume. Dose-volume histograms for each rGTV were used to further classify in-field recurrences as central high-dose (dose to 95% of rGTV [rGTVD95%] ≥95% of dose prescribed to PTV) or peripheral high-dose (rGTVD95% <95% of dose prescribed to PTV)., Results: 634 patients received SABR from 2004 to 2014 with 48 local recurrences. 35 of these had evaluable images with 16 in-field recurrences: 9 central high-dose, 6 peripheral high-dose, and 1 had both. Time to and volume of recurrence were not statistically different between central versus peripheral high-dose recurrences. However mean rGTV dose, mean centroid dose, and rGTVD95% were higher for central versus peripheral high-dose recurrences., Conclusion: We report a standardized method for analysis and classification of in-field recurrence after SABR. There were more central as opposed to peripheral high-dose recurrences, suggesting biological rather than technical issues underlying majority of in-field failures., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Although isolated local (LRs) and regional recurrences (RRs) constitute a minority of post-stereotactic ablative radiotherapy (SABR) relapses, their management is becoming increasingly important as the use of SABR continues to expand. However, few evidence-based strategies are available to guide treatment of these potentially curable recurrences. On behalf of the Advanced Radiation Technology Committee of the International Association for the Study of Lung Cancer, this article was written to address management of recurrent disease. Topics discussed include diagnosis and workup, including the roles of volumetric and functional imaging as well as histopathologic methods; clinical outcomes after salvage therapy; patterns of recurrence after salvage therapy; and management options. Our main conclusions are that survival for patients with adequately salvaged LRs is similar to that for patients after primary SABR without recurrence, and survival for those with salvaged RRs (regardless of nodal burden or location) is similar to that of patients with de novo stage III disease. Although more than half of patients who undergo salvage do not develop a second relapse, the predominant pattern of second failure is distant, especially for RRs. Management requires rigorous multidisciplinary coordination. Isolated LRs can be managed with resection and nodal dissection, repeat SABR, thermal ablation, or systemic therapies. RRs can be treated with combined chemoradiotherapy, radiation or chemotherapy alone, or supportive services. Finally, regular and structured follow-up is recommended after post-SABR salvage therapy., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: Our purpose was to develop predictive nomograms for overall survival (OS), progression-free survival (PFS), and time-to-progression (TTP) at 5 years in patients with early-stage non-small cell lung cancer (ES-NSCLC) treated with stereotactic ablative radiation therapy (SABR)., Methods and Materials: The study cohort included 714 ES-NSCLC patients treated with SABR from 2004-2015 with median follow-up of 59 months, divided into training and testing sets (8:2), with the former used for nomogram development. The least absolute shrinkage and selection operator were initially employed to screen for predictors of OS, PFS, and TTP, and identified predictors were subsequently applied toward Cox proportional hazards regression modeling. Significant predictors (P < .05) on multivariable regression were then used to develop nomograms, which were validated via evaluation of concordance indexes (C-index) and calibration plots. Finally, Kaplan-Meier method and Gray's test were employed to compare and confirm differences in outcomes among various groups and explore prognostic factors associated with local versus distant disease progression., Results: Significant predictors of both OS and PFS at 5 years included age, sex, Charlson comorbidity index, diffusing capacity of carbon monoxide, systemic immune-inflammation index, and tumor size (P ≤ .01 for all). Eastern Cooperative Oncology Group performance status predicted for OS as well (P = .01), and both tumor size (P < .01) and minimum biological equivalent dose to 95% of planning target volume (PTV D95 BED 10 ; P < .01) were predictive of TTP. The C-indexes for the OS, PFS, and TTP nomograms were 0.73, 0.68, and 0.60 in the training data set and 0.72, 0.66, and 0.59 in the testing data set, respectively. Tumor size > 2.45 cm and PTV D95 BED 10 < 113 Gy were significantly associated with both local and distant progression., Conclusions: These prognostic nomograms can accurately predict for OS, PFS, and TTP at 5 years after SABR for ES-NSCLC and may thus help identify high-risk patients who could benefit from additional systemic therapy., (Published by Elsevier Inc.)

Glycogen storage disease type Ia (GSD Ia) is caused by mutations in the glucose-6-phosphatase (G6Pase) catalytic subunit gene ( G6PC ). GSD Ia complications include hepatocellular adenomas (HCA) with a risk for hepatocellular carcinoma (HCC) formation. Genome editing with adeno-associated virus (AAV) vectors containing a zinc-finger nuclease (ZFN) and a G6PC donor transgene was evaluated in adult mice with GSD Ia. Although mouse livers expressed G6Pase, HCA and HCC occurred following AAV vector administration. Interestingly, vector genomes were almost undetectable in the tumors but remained relatively high in adjacent liver (p < 0.01). G6Pase activity was decreased in tumors, in comparison with adjacent liver (p < 0.01). Furthermore, AAV-G6Pase vector-treated dogs with GSD Ia developed HCC with lower G6Pase activity (p < 0.01) in comparison with adjacent liver. AAV integration and tumor marker analysis in mice revealed that tumors arose from the underlying disorder, not from vector administration. Similarly to human GSD Ia-related HCA and HCC, mouse and dog tumors did not express elevated α-fetoprotein. Taken together, these results suggest that AAV-mediated gene therapy not only corrects hepatic G6Pase deficiency, but also has potential to suppress HCA and HCC in the GSD Ia liver., (© 2019 The Authors.)

Objective: To assess right-left differences in ultrasonographic markers of ovarian morphology and determine the impact on the diagnosis of polycystic ovarian morphology (PCOM)., Design: A cross-sectional study of data collected from 2006 to 2018., Setting: Academic clinical research centers., Patient(s): Women with polycystic ovary syndrome (PCOS; n = 87) and controls (n = 67)., Intervention(s): None., Main Outcomes Measure(s): Follicle number per ovary (FNPO), follicle number per cross-section (FNPS), and ovarian volume (OV) were assessed in both ovaries using transvaginal ultrasonography. PCOM was identified based on recent international consensus guidelines or proposed diagnostic thresholds., Result(s): Overall, mean right-left differences were two follicles for FNPO, one follicle for FNPS, and 2 mL for OV. FNPO showed the strongest correlation between ovaries. Its assessment in a single ovary did not impact the diagnosis of PCOM in women with PCOS. However, there were differences in the probability of unilateral versus bilateral PCOM based on FNPS and OV in both groups., Conclusion(s): FNPO is the most reliable unilateral marker of PCOM in light of right-left differences in ovarian morphology. Use of FNPS or OV to define PCOM is discouraged when only one ovary is visualized., (Copyright © 2019 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Proton therapy is an evolving radiotherapy modality with indication for numerous cancer types. With the benefits of reducing dose and sparing normal tissue, protons offer a clear physical and dosimetric advantage over photon radiotherapy for many patients. However, its impact on one type of disease, non-small cell lung cancer (NSCLC), is still not fully understood. Our review aims to highlight the data for using proton therapy in NSCLC, with a focus on the clinical data-or lack thereof-supporting proton treatment for early and advanced stage disease. In evaluating these data, we consider how future directions and advances in proton technology give rise for hope in defining a role for protons in improving NSCLC outcomes. We close with considerations for next steps and the challenges ahead in using proton therapy for this unique patient population., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2019 Translational Lung Cancer Research. All rights reserved.)

Purpose: Long-term neurocognitive sequelae of nonsyndromic craniosynostosis (NSC) patients are just beginning to be clarified. This study uses functional MRI (fMRI) to determine if there is evidence of altered brain functional connectivity in NSC, and whether these aberrations vary by form of synostosis., Methods: Twenty adolescent participants with surgically treated NSC (10 sagittal synostosis, 5 right unilateral coronal synostosis [UCS], 5 metopic synostosis [MSO]) were individually matched to controls by age, gender, and handedness. A subgroup of MSO was classified as severe metopic synostosis (SMS) based on the endocranial bifrontal angle. Resting state fMRI was acquired in a 3T Siemens TIM Trio scanner (Erlangen, Germany), and data were motion corrected and then analyzed with BioImage Suite (Yale School of Medicine). Resulting group-level t-maps were cluster corrected with nonparametric permutation tests. A region of interest analysis was performed based on the left Brodmann's Areas 7, 39, and 40., Results: Sagittal synostosis had decreased whole-brain intrinsic connectivity compared to controls in the superior parietal lobules and the angular gyrus (P = 0.071). Unilateral coronal synostosis had decreased intrinsic connectivity throughout the prefrontal cortex (P = 0.031). The MSO cohort did not have significant findings on intrinsic connectivity, but the SMS subgroup had significantly decreased connectivity among multiple subcortical structures., Conclusion: Sagittal synostosis had decreased connectivity in regions associated with visuomotor integration and attention, while UCS had decreased connectivity in circuits crucial in executive function and cognition. Finally, severity of metopic synostosis may influence the degree of neurocognitive aberration. This study provides data suggestive of long-term sequelae of NSC that varies by suture type, which may underlie different phenotypes of neurocognitive impairment.

Context: Polycystic ovary syndrome (PCOS) is a complex endocrine condition characterized by multiple reproductive and metabolic abnormalities. Because individual reproductive and metabolic abnormalities modulate working memory in the general population, there is growing interest in whether cognitive function is dually and negatively affected in PCOS., Objective: To examine the association of reproductive and metabolic features with cognitive function in women with and without PCOS., Design: An observational, cross-sectional study was conducted at an academic clinical research center in North America between 2006 and 2009. Common tests of working memory ( i.e. , manual dexterity, perceptual speed, and visuospatial ability) were performed by women with PCOS (n = 40) and control subjects (n = 40). Markers of sex steroid hormones, ovulatory function, and cardiometabolic health were also assessed., Results: Reduced visuospatial ability was observed in women with PCOS compared with control subjects ( P < 0.01). Reduced visuospatial ability was linked to higher levels of hemoglobin A1c in the entire study cohort, independent of body mass index or PCOS status. No associations were observed between visuospatial ability and reproductive features, after controlling for confounding variables., Conclusion: Our findings support a role for glycemic control, and not PCOS per se , in cognitive dysfunction in women of reproductive age. Additional studies are needed to understand the short- and long-term effects of dysglycemia on brain health in women with PCOS, given their increased propensity for metabolic comorbidities, compared with control subjects., (Copyright © 2019 Endocrine Society.)

Purpose: Proton therapy is increasingly prescribed for cancer treatment, given its potential for improvements in clinical outcomes and toxicity reduction; however, insurance coverage continues to be a barrier to patient access. This study examined insurance approval and appeal outcomes at a large-volume proton therapy center to clarify the process and identify areas for improvement., Methods and Materials: In 2013 to 2016, 1753 patients with thoracic or head and neck cancer were considered for proton therapy; 903 (553 thoracic, 350 head and neck) entered the insurance process. Rates of and times to approval and successful appeal after initial denial were calculated. Clinical factors were evaluated for association with insurance outcomes via logistic regression., Results: Approval rates by Medicare (n = 538) and private insurance (n = 365) were 91% and 30% on initial request, at a median 3 days and 14 days from inquiry to determination. Of the 306 patients initially denied coverage, 276 appealed the decision, and denial was overturned for 189 patients (68%; median time, 21 days from initial inquiry). On multivariable analysis, Medicare (odds ratio [OR], 14.20; P < .001) was the strongest predictor of initial approval. Approval rates decreased from 2013 to 2014 versus 2015 to 2016 (OR 0.54; P = .001). For patients who appealed denial, multivariable analysis found no associations between approval and trial enrollment or tumor type. Submission of a comparison treatment plan (proton vs photon) indicating dosimetric advantage to normal tissues was associated with decreased likelihood of approval (OR 0.43; P = .006), as was a prescribed dose of ≥66 Gy (OR 0.48; P = .019)., Conclusions: Despite an 87% ultimate approval rate for proton therapy, the insurance process is a resource-intensive barrier to patient access associated with significant time delays to cancer treatment. These findings, plus the lack of clinical correlates with insurance outcomes, highlight a need for increased efficiency, transparency, and collaboration among stakeholders to promote timely patient care and research., (Copyright © 2018. Published by Elsevier Inc.)

Background: Management options for unresected malignant pleural mesothelioma (MPM) are largely limited to palliative chemotherapy and best supportive care. This study sought to delineate subgroups most likely to benefit from chemotherapy., Patients and Methods: The National Cancer Database was queried for newly-diagnosed unresected sarcomatoid, biphasic, and/or metastatic (M1) MPM. Statistics included Kaplan-Meier overall survival (OS) analysis with and without propensity matching, landmark Kaplan-Meier analysis to address immortal time bias, and multivariable Cox proportional hazards modeling in all patients as well as within histologic/M-classification-based subcohorts., Results: Of 4655 patients (48% chemotherapy, 52% best supportive care), 15%, 27%, and 40% had epithelioid, biphasic, and sarcomatoid disease, respectively; 41% had M1 disease. The median OS in the chemotherapy and BSC cohorts was 10.4 versus 4.8 months (P < .001). OS differences persisted following landmark analysis (P = .038) and propensity matching (P < .001). Chemotherapy was associated with higher OS in M1 cases with unknown histology and M1 epithelioid patients (P < .001 for both). For non-epithelioid cases, chemotherapy was associated with higher OS for M0 (P < .001 for sarcomatoid and biphasic) but not M1 (P > .05 for both) disease., Conclusions: Chemotherapy may benefit metastatic epithelioid and non-metastatic non-epithelioid MPM to a greater degree than metastatic non-epithelioid disease. Causation, however, is not implied, and careful patient selection in this population cannot be understated., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Radiotherapy produces immune-promoting effects, which may be blunted by the delivery of corticosteroids (CS). We thus aimed to evaluate the impact of CS use on recurrence and survival outcomes of patients with early stage non-small-cell lung cancer treated with stereotactic ablative radiotherapy (SABR)., Materials and Methods: A prospectively registered database of patients with stage I to II (T1-3N0M0) stage non-small-cell lung cancer treated with SABR from 2004 to 2015 was queried. Concurrent CS administration was defined as receipt of CS within 2 days of the SABR course. Statistics included Kaplan-Meier survival analysis, Cox proportional hazards modeling, and cumulative incidence analysis utilizing death as a competing risk., Results: Of 912 patients, 87 (9.5%) received CS with their SABR course. The most common agent was prednisone (64.4%). Indications for CS use were chronic obstructive pulmonary disease in 53 cases (60.9%), chemotherapy in 7 (8.0%), arthritis in 7 (8.0%), chronic pain in 4 (4.6%), transplant-related in 3 (3.4%), and "others" in 13 (14.9%; pneumonia, asthma, anemia, etc.). The median follow-up time was 59.3 months. Compared with patients who did not receive CS, receipt of CS was associated with poorer overall survival (P = .004). However, CS administration was not associated with worse time to progression (P = .766) or any recurrence when using death as a competing risk (local P = .119, regional P = .449, distant P = .847, and any recurrence P = .708). Toxicity rates were not statistically different between cohorts., Conclusions: These data do not suggest increased recurrence rates when patients undergoing SABR are administered corticosteroids. However, owing to limitations of retrospective analyses, individualized judgment is still recommended., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Considerable interest is being directed toward combining immune-checkpoint inhibition (ICI) with radiotherapy to improve response rates to ICI, which have been disappointingly low at around 15-30% among patients with advanced-stage cancers other than melanoma. Since a case report published in 2012, in which authors described the resolution of metastatic disease after irradiation of a single lesion in a patient who had been receiving ICI, hundreds of clinical trials have been launched with the aim of testing the safety and/or efficacy of radiotherapy in combination with immunotherapy, nearly all of which use this single-site irradiation, or 'abscopal', approach. However, emerging preclinical and clinical evidence suggests that this approach likely produces suboptimal results. In this Perspective, we describe this evidence and provide a biological rationale supporting the abandonment of the single-site abscopal approach. We instead advocate exploring comprehensive irradiation of multiple/all lesions in order to enhance the likelihood of obtaining meaningful clinical outcomes - if such a clinical synergy between radiation and ICI does exist - before the failure of the current, single-site approach leads to the potential premature and inappropriate abandonment of radiotherapy in combination with ICI altogether.

Glucose-6-phosphatase α (G6Pase) deficiency, also known as von Gierke's Disease or Glycogen storage disease type Ia (GSD Ia), is characterized by decreased ability of the liver to convert glucose-6-phosphate to glucose leading to glycogen accumulation and hepatosteatosis. Long-term complications of GSD Ia include hepatic adenomas and carcinomas, in association with the suppression of autophagy in the liver. The G6pc-/- mouse and canine models for GSD Ia were treated with the pan-peroxisomal proliferator-activated receptor agonist, bezafibrate, to determine the drug's effect on liver metabolism and function. Hepatic glycogen and triglyceride concentrations were measured and western blotting was performed to investigate pathways affected by the treatment. Bezafibrate decreased liver triglyceride and glycogen concentrations and partially reversed the autophagy defect previously demonstrated in GSD Ia models. Changes in medium-chain acyl-CoA dehydrogenase expression and acylcarnintine flux suggested that fatty acid oxidation was increased and fatty acid synthase expression associated with lipogenesis was decreased in G6pc-/- mice treated with bezafibrate. In summary, bezafibrate induced autophagy in the liver while increasing fatty acid oxidation and decreasing lipogenesis in G6pc-/- mice. It represents a potential therapy for glycogen overload and hepatosteatosis associated with GSD Ia, with beneficial effects that have implications for non-alcoholic fatty liver disease.