Targeted radiotherapy for early-stage, low-risk pediatric Hodgkin lymphoma slow early responders: a COG AHOD0431 analysis.

Children's Oncology Group (COG) trial AHOD0431 reduced systemic therapy and used response-adapted involved-field radiotherapy (IFRT) in early-stage pediatric classic Hodgkin lymphoma. We investigated the impact of positron emission tomographic response after 1 cycle (PET1) and on IFRT outcomes and pattern of relapse. Patients in AHOD0431 underwent PET1 response assessment after AVPC (doxorubicin, vincristine, prednisone, and cyclophosphamide). "Rapid early responders" (RERs) had a negative PET1 (PET1-); "slow early responders" (SERs) had a positive PET1 (PET1+). Patients with a partial response by computed tomographic and functional imaging after 3 chemotherapy cycles received 21-Gy IFRT, whereas complete responders had no IFRT. Progression-free survival (PFS) was evaluated for RERs and SERs treated with or without IFRT. Recurrence sites were initial, new, or both. Relapses involving initial sites were characterized as "within the PET1+ site" or "initially involved but outside the PET1+ site." Median follow-up was 118 months. The 10-year PFS rate among RERs was 96.6% with IFRT and 84.1% without IFRT (P = .10), whereas SERs were 80.9% with IFRT and 64.0% without IFRT (P = .03). Among 90 RERs who did not receive IFRT, all 14 relapses included an initial site. Among 45 SERs receiving no IFRT, 14 of 16 relapses were in the initial site (9 PET1+ site only). Among 58 patients receiving IFRT, 5 of 10 relapses were in the PET1+ site. After 3 cycles of AVPC alone, RERs showed favorable results. Conversely, SERs had unfavorable outcomes with AVPC alone, although they improved with 21-Gy IFRT. RT remains an important component of treatment for SERs. This trial was registered at www.clinicaltrials.gov as #NCT00302003.

Pulmonary dose tolerance in hemithorax radiotherapy for Ewing sarcoma of the chest wall: Are we overestimating the risk of radiation pneumonitis?

BACKGROUND: Children with chest wall Ewing sarcoma with malignant pulmonary effusion or pleural stranding require hemithorax radiation, often with plans that exceed lung constraints. We investigated disease control and pneumonitis in children requiring hemithorax radiation. PROCEDURE: Eleven children (median age 13 years) received hemithorax radiotherapy. Symptomatic radiation pneumonitis was considered National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) grade 1+ with respiratory symptoms. Mean lung dose (MLD), volume of lung exposed to a dose ≥5 Gy (V5), ≥20 Gy (V20), and ≥35 Gy (V35) were recorded. Adult and pediatric lung constraints were obtained from Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) guidelines and Children's Oncology Group (COG) protocols, respectively. RESULTS: Median hemithorax dose was 15 Gy (1.5 Gy/fraction). Median total dose was 51 Gy (1.8 Gy/fraction). Most plans delivered both protons and photons. The ipsilateral MLD, V5, and V20 were 27.2 Gy, 100%, and 48.3%; the bilateral MLD, V20, and V35 were 14.1 Gy, 22.8%, and 14.3%, respectively. One hundred percent, 36%, and 91% of treatments exceeded recommended adult ipsilateral lung constraints of V5 <65%, V20 <52%, and MLD of 22 Gy; 64%, 45%, and 82% exceeded COG bilateral lung constraints of V20 <20%, MLD <15 Gy, and MLD <12 Gy, respectively; 82% of treatments exceeded the COG ipsilateral lung constraint of V20 <30%. At a median 36 months (range 12-129), the symptomatic radiation pneumonitis incidence was 0%. Two patients progressed with nonpulmonary metastatic disease and died at a median 12 months following radiotherapy. CONCLUSIONS: Existing guidelines may overestimate pneumonitis risk, even among young children receiving multiagent chemotherapy. For children with chest wall Ewing sarcoma and other thoracic malignancies, more data are needed to refine pediatric dose-effect models for pulmonary toxicity.

In Vivo Delivery and Therapeutic Effects of a MicroRNA on Colorectal Liver Metastases.

Multiple therapeutic agents are typically used in concert to effectively control metastatic tumors. Recently, we described microRNAs that are associated with the oligometastatic state, in which a limited number of metastatic tumors progress to more favorable outcomes. Here, we report the effective delivery of an oligometastatic microRNA (miR-655-3p) to colorectal liver metastases using nanoscale coordination polymers (NCPs). The NCPs demonstrated a targeted and prolonged distribution of microRNAs to metastatic liver tumors. Tumor-targeted microRNA miR-655-3p suppressed tumor growth when co-delivered with oxaliplatin, suggesting additive or synergistic interactions between microRNAs and platinum drugs. This is the first known example of systemically administered nanoparticles delivering an oligometastatic microRNA to advanced metastatic liver tumors and demonstrating tumor-suppressive effects. Our results suggest a potential therapeutic strategy for metastatic liver disease by the co-delivery of microRNAs and conventional cytotoxic agents using tumor-specific NCPs.

Regional Radiation Therapy Impacts Outcome for Node-Positive Cutaneous Melanoma.

Background: Regional radiation therapy (RT) has been shown to reduce the risk of regional recurrence with node-positive cutaneous melanoma. However, risk factors for regional recurrence, especially in the era of sentinel lymph node biopsy (SLNB), are less clear. Our goals were to identify risk factors associated with regional recurrence and to determine whether a radiosensitivity index (RSI) gene expression signature (GES) could identify patients who experience a survival benefit with regional RT. Methods: A single-institution, Institutional Review Board-approved study was performed including 410 patients treated with either SLNB with or without completion lymph node dissection (LND; n=270) or therapeutic LND (n=91). Postoperative regional RT was delivered to the involved nodal basin in 83 cases (20.2%), to a median dose of 54 Gy (range, 30-60 Gy) in 27 fractions (range, 5-30). Primary outcomes were regional control and overall survival by RSI GES status. Results: Median follow-up was 69 months (range, 13-180). Postoperative regional RT was associated with a reduced risk of regional recurrence among all patients on univariate (5-year estimate: 95.0% vs 83.3%; P=.036) and multivariate analysis (hazard ratio[HR], 0.15; 95% CI, 0.05-0.43; P<.001). Among higher-risk subgroups, regional RT was associated with a lower risk of regional recurrence among patients with clinically detected lymph nodes (n=175; 5-year regional control: 94.1% vs 69.5%; P=.003) and extracapsular extension (ECE) present (n=138; 5-year regional control: 96.7% vs 62.2%; P<.001). Among a subset of radiated patients with gene expression data available, a low RSI GES (radiosensitive) tumor status was associated with improved survival compared with a high RSI GES (5-year: 75% vs 0%; HR, 10.68; 95% CI, 1.24-92.14). Conclusions: Regional RT was associated with a reduced risk of regional recurrence among patients with ECE and clinically detected nodal disease. Gene expression data show promise for better predicting radiocurable patients in the future. In the era of increasingly effective systemic therapies, the value of improved regional control potentially takes on greater significance.

RIG-I-like receptor LGP2 protects tumor cells from ionizing radiation.

An siRNA screen targeting 89 IFN stimulated genes in 14 different cancer cell lines pointed to the RIG-I (retinoic acid inducible gene I)-like receptor Laboratory of Genetics and Physiology 2 (LGP2) as playing a key role in conferring tumor cell survival following cytotoxic stress induced by ionizing radiation (IR). Studies on the role of LGP2 revealed the following: (i) Depletion of LGP2 in three cancer cell lines resulted in a significant increase in cell death following IR, (ii) ectopic expression of LGP2 in cells increased resistance to IR, and (iii) IR enhanced LGP2 expression in three cell lines tested. Studies designed to define the mechanism by which LGP2 acts point to its role in regulation of IFNß. Specifically (i) suppression of LGP2 leads to enhanced IFNß, (ii) cytotoxic effects following IR correlated with expression of IFNß inasmuch as inhibition of IFNß by neutralizing antibody conferred resistance to cell death, and (iii) mouse embryonic fibroblasts from IFN receptor 1 knockout mice are radioresistant compared with wild-type mouse embryonic fibroblasts. The role of LGP2 in cancer may be inferred from cumulative data showing elevated levels of LGP2 in cancer cells are associated with more adverse clinical outcomes. Our results indicate that cytotoxic stress exemplified by IR induces IFNß and enhances the expression of LGP2. Enhanced expression of LGP2 suppresses the IFN stimulated genes associated with cytotoxic stress by turning off the expression of IFNß.

Predictors of an Academic Career in Radiation Oncology 5 to 10 Years After Residency.

OBJECTIVE: To report the percentage of resident graduates in the modern era who establish careers in academic radiation oncology 5 to 10 years after residency. MATERIALS AND METHODS: The study population included 1147 radiation oncologists who completed residency between 2011 and 2017 and were practicing radiation oncologists in 2021. RESULTS: The percentage of 2011-2017 graduates with an academic career in 2021 (5 to 10 y after residency): Holman Pathway resident: Yes, 74% versus No, 43% ( P <0.05); PhD degree before residency: Yes, 67% versus No, 38% ( P <0.05), Doximity top-10 ranked residency program: Yes, 66% versus No, 37% ( P <0.05).Logistic regression multivariate analysis confirmed PhD and Doximity top-10 as strong independent predictors for all endpoints.Regarding gender, no significant differences were observed for all 4 endpoints in the percentage of women versus men establishing academic careers at the 5-year to 10-year post-residency time point. CONCLUSION: Since 2011, at least one-third (~35%) of radiation oncology residents have gone into academic medicine and are academically productive 5 to 10 years after residency. Holman Pathway, PhD degree, or Doximity top-10 residency program approximately doubles the probability of an academic career. Moreover, radiation oncology is on track to achieve gender equity in academic medicine.

Geographic access to brachytherapy services in the United States.

PURPOSE: Disparities in geographic access to medical care exist in nearly all fields of medicine including radiation oncology. We aim to update knowledge of the geographic distribution of radiation oncologists in the United States. METHODS AND MATERIALS: We used the Physician and Other Supplier Public Use File (PUF) from the Centers for Medicare & Medicaid Services (CMS) as well as the International Atomic Energy Agency (IAEA) Directory of Radiotherapy Centers (DIRAC) database to identify practices that either coded for or are marked as having access to brachytherapy services. Geographic analysis was performed on several levels including United States (US) Census region, Dartmouth Atlas Healthcare Referral Region, and the county level. RESULTS: We identified 327 providers that billed for a brachytherapy code during the calendar year 2018 and 564 facilities providing brachytherapy. Within the 306 HRRs in the US, 149 have access to brachytherapy. This represents 247.5 million people based on 2018 estimates of population from the US Census Bureau. This implies that 76.7% of people within the US live in an HRR with access to brachytherapy, and, conversely, that 75.3 million people (23.3%) do not. Numerically, counties in metropolitan areas were more likely to have access to brachytherapy than those outside of a metropolitan area. CONCLUSIONS: Geographic disparities exist in access to brachytherapy; metropolitan counties are more likely to have access than non-metropolitan counties. We support continued development of databases of brachytherapy providers and programs that may support travel and lodging costs to minimize these disparities.

Proton radiotherapy for infant rhabdomyosarcoma: Rethinking young age as an adverse prognostic factor.

BACKGROUND & PURPOSE: In infants with rhabdomyosarcoma, young age is considered an adverse prognostic factor and treatment is often attenuated to reduce side effects. Proton therapy may improve the therapeutic ratio in these patients. We report outcomes in infants with rhabdomyosarcoma treated with proton therapy. MATERIALS & METHODS: Between 2009 and 2019, 37 infants <24 months old with non-metastatic rhabdomyosarcoma received proton therapy. Local control (LC), progression-free survival (PFS), and overall survival (OS) were estimated using the Kaplan-Meier product limit. The log-rank test assessed significance between selected prognostic factors. Toxicity was graded per CTCAEv5.0. RESULTS: Median follow-up was 5.1 years. Overall, 76% of patients had an unfavorable primary site. Median dose was 50.4GyRBE. At 5 years, LC, PFS, and OS rates were 83%, 78%, and 83%. On univariate analysis, 5-year LC and OS were inferior for favorable versus unfavorable disease sites (67% vs 89%, 67% vs 89%, respectively; p < .05) and 5-year OS was superior in stage 3 versus stage 1-2 disease (91% vs 69%; p = .05), owing to inclusion of nasal ala patients among stage 1. Of 9 recurrences, 7 were in-field, 4 occurring in infants with nasal ala primaries. Recategorizing nasal ala as an unfavorable site resulted in 100% 5-year LC and OS for favorable sites. Six infants experienced late grade 3 toxicity. None developed grade 4 or 5 late toxicity. CONCLUSIONS: Young age alone may not be an adverse prognostic factor provided infants receive local therapy similar to older children. Consideration should be given to classifying nasal ala primaries as an unfavorable site.

The Geography of Employment Outcomes for Radiation Oncology Graduates in 2019.

PURPOSE: The geographic distribution of practicing radiation oncologists is of concern for multiple stakeholders within the field. Employment outcomes of graduating residents can affect that distribution, and they are of major concern to current residents. Data investigating employment outcomes of recent graduates are sparse. We aimed to analyze the employment outcomes of the radiation oncology residency class of 2019. METHODS AND MATERIALS: Using publicly available information, we identified the employment of 179 of 183 graduating residents in the class of 2019. For each, the place of employment, residency program, and medical school were geocoded using Google Maps. We used the rural-urban continuum code (RUCC) published by the United States Department of Agriculture to determine the rurality of each location and compared employment outcomes by RUCC and program size. RESULTS: Two thirds of graduates (66%) took a position in a county within a metropolitan area with a population greater than 1,000,000 people; only 3.4% took a position in a county outside of a metropolitan area. Graduates of smaller programs (≤6 residents) and those in smaller metropolitan areas were more likely to take positions in smaller metropolitan areas or nonmetropolitan areas. The geographic distance between location of employment and residency program did not significantly vary by program size or size of metropolitan area where a residency program was located. CONCLUSIONS: Among the class of 2019, a small proportion took positions in nonmetropolitan areas. Smaller programs and those in smaller metropolitan areas may be more likely to produce graduates that practice in similar settings, but those graduates might not do so locally. We advocate for a centralized, prospective data collection of employment outcomes for graduating residents to refine these analyses and to reduce employment prospect information asymmetry for trainees.

Neoadjuvant or Adjuvant Chemotherapy for Breast Cancer in Sub-Saharan Africa: A Retrospective Analysis of Recurrence and Survival in Women Treated for Breast Cancer at the Korle Bu Teaching Hospital in Ghana.

PURPOSE: It is established that addition of systemic therapy to locoregional treatment for breast cancer improves survival. However, reliable data are lacking about the outcomes of such treatment in women with breast cancer in low middle-income countries. We compared the outcomes of treatment in patients who had received neoadjuvant chemotherapy (NACT) or adjuvant chemotherapy and examined the factors associated with breast cancer recurrence and survival at the National Radiotherapy Oncology and Nuclear Medicine Centre, Korle Bu Teaching Hospital, Ghana. METHODS: This was a retrospective cohort study. The medical charts of women with breast cancer managed at the National Radiotherapy Oncology and Nuclear Medicine Centre from 2005 to 2014 were reviewed. A total of 388 patients with a median follow-up of 48 months were included in the study. Logistic regression was used to estimate the risk of recurrence. Survival was estimated using cox proportional hazards model. All models were adjusted with clinicopathologic variables. A P value of < .05 was considered statistically significant. RESULTS: Fifty-nine percent received adjuvant chemotherapy. In an adjusted logistic model, no difference was observed in locoregional recurrence between patients receiving NACT compared with those receiving adjuvant chemotherapy (odds ratio = 1.05; 95% CI, 0.44 to 2.47). However, NACT recipients had a higher likelihood of distant recurrence (odds ratio = 1.97; 95% CI, 1.24 to 3.15). In a multivariable analysis, no differences were observed in overall survival between the two chemotherapy groups (hazard ratio = 1.43; 95% CI, 0.91 to 2.26). CONCLUSION: NACT yields similar outcomes compared with adjuvant chemotherapy; however, recipients of NACT with advanced disease may have more distant failures. Early detection in a resource-limited setting is therefore crucial to optimal outcomes, significantly limiting recurrence and improving survival.

Why an Increasing Number of Unmatched Residency Positions in Radiation Oncology? A Survey of Fourth-Year Medical Students.

PURPOSE: The number of US fourth-year medical students applying to radiation oncology has decreased during the past few years. We conducted a survey of fourth-year medical students to examine factors that may be influencing the decision to pursue radiation oncology. METHODS AND MATERIALS: An anonymous online survey was sent to medical students at 9 participating US medical schools. RESULTS: A total of 232 medical students completed the survey. Of the 153 students who stated they were never interested in radiation oncology, 77 (50%) reported never having been exposed to the specialty as their reason for not pursuing radiation oncology. The job market was the most commonly cited factor among students who said they were once interested in but ultimately chose not to pursue radiation oncology. Conversely, the recent low pass rates for board examinations and a perception of a lack of diversity within radiation oncology had the least influence. CONCLUSIONS: Despite discussion of potential measures to address this disquieting trend, there have been minimal formal attempts to characterize and address potential causes of a decreasing interest in radiation oncology. This study's data are consistent with previous research regarding the trend of decreased medical student interest in radiation oncology and may be used as part of ongoing introspective assessment to inform future change within radiation oncology.

Geographic Distribution of Radiation Oncologists in the United States.

PURPOSE: The geographic distribution of radiation oncologists determines access to care for patients and job opportunities for practicing physicians, yet available data on practicing radiation oncologists are outdated or use large geographic unit definitions precluding granular analysis. We present an updated county-level analysis of the American radiation oncology workforce. METHODS AND MATERIALS: We used the Area Health Resource File published by the Health Resources and Services Administration of the U.S. Department of Health and Human Services to determine the number of radiation oncologists per 100,000 people in every or equivalent area in the United States as of 2017 (the most recently published data). We then analyzed geographic distribution per U.S. Census Bureau-defined regions, subregions, and combined statistical areas. RESULTS: The Area Health Resource File reports 5338 practicing radiation oncologists for an estimated American population of 326.1 million people as of 2017, resulting in a nationwide average of 1.64 radiation oncologists per 100,000 people. Counties located outside of a metropolitan area had a lower density of radiation oncologists than those within a metropolitan area. Among combined statistical areas (representing most large cities) the variations in density of radiation oncologists are small, with the highest-density areas located in smaller communities with academic medical centers. There was no relationship between population of combined statistical areas and density of radiation oncologists. CONCLUSIONS: The geographic distribution of American radiation oncologists varies widely; the primary variation exists along the urban/rural continuum, with rural areas having fewer practitioners than urban areas. This analysis informs future work in understanding how to optimize the delivery of radiation oncology services throughout the United States.

Nonclinical Time in U.S. Radiation Oncology Residency Programs: Number of Months and Resident Opinion of Value.

PURPOSE: Data regarding the amount and use of nonclinical time (NCT) in radiation oncology residency programs are scarce. We surveyed every U.S. radiation oncology residency program to obtain benchmark data to inform decisions about optimal program structure. METHODS AND MATERIALS: An anonymous, web-based survey was distributed to postgraduate year 5 residents at Accreditation Council for Graduate Medical Education-accredited radiation oncology training programs. The survey included 33 yes/no, Likert-scale, and free-response questions. Program data were analyzed for all programs, including those considered "top 10" per Doximity and those "not top 10." Likert-scale responses were dichotomized as "not as satisfied" (1, 2, 3) or "very satisfied" (4, 5). RESULTS: One hundred twenty-six residents (69%) completed the survey. Program-specific data were obtained for 100% of programs (n = 82). Almost all training programs (98%) provide residents with protected NCT. Including programs with no NCT, the median NCT is 10 months in all programs. The median NCT is 12 months in "top 10" programs and 9 months in "not top 10" programs (P < .01). Most programs (68%) reported >6 months of NCT. The proportion of residents wanting more NCT decreased as the amount of NCT increased (73%, 52%, and 19% for 4-6, 7-9, and 10-12 months, respectively; P < .01). The proportion of residents who were very satisfied with NCT flexibility increased with more NCT (64%, 79%, and 94% for 4-6, 7-9, and 10-12 months, respectively; P < .01), as did the proportion of residents who were very satisfied with accomplishments during NCT (35%, 53%, and 72% for 4-6, 7-9, and 10-12 months, respectively; P < .01). When asked whether residents would theoretically give up some NCT to shorten residency, the proportion of residents willing to shorten their residencies decreased as the amount of NCT increased (65%, 47%, and 33% for 4-6, 7-9, and 10-12 months respectively; P = .04). CONCLUSIONS: Programs should maintain an emphasis on NCT and implement measures to ensure meaningful resident experiences.

Long-term Tumor Control With Radiotherapy for Symptomatic Hemangioma of a Vertebral Body.

STUDY DESIGN: Retrospective outcomes review. OBJECTIVE: To analyze and report long-term outcomes in a cohort of patients treated with radiotherapy (RT) for symptomatic hemangioma of a vertebral body. SUMMARY OF BACKGROUND DATA: Data are scarce on the rate of tumor control with long-term (>5 yr) follow-up after RT for symptomatic hemangioma of a vertebral body. METHODS: We retrospectively reviewed the medical records of patients treated at our institution between 1971 and 2008 for symptomatic hemangioma of a vertebral body, updated their follow-up, analyzed complications, and calculated the tumor control rate. Tumor control by imaging was defined as no increase in tumor size on computed tomography (CT) or magnetic resonance (MR) scan. Clinical tumor control was defined as no symptoms of recurrent tumor. RESULTS: Ten patients were eligible for analysis. All patients had pain from visible hemangioma at the time of radiotherapy for which surgical resection or interventional radiology procedures were likely to result in high morbidity. Tumors were located in the lumbar (40%), thoracic (50%), or cervical (10%) areas of the spine. The mean radiotherapy dose delivered was 47 Gy.Mean imaging follow-up after completion of radiotherapy was 8.1 years; mean clinical follow-up was 21.2 years. The tumor control rate was 90% (9/10). One patient who may have developed a tumor recurrence had radiographic and clinical evidence of tumor progression 30 years after radiotherapy. The actuarial rate of tumor control was 100% at 5, 10, 20, and 25 years. There was no grade more than or equal to three treatment toxicities, no evidence of malignant transformation, and no evidence of second tumors in treatment area (with the possible exception of the one tumor recurrence). CONCLUSION: RT for symptomatic hemangioma of the spine provides long-term tumor control with a low risk of serious complications. Radiotherapy is a good option when surgery or an interventional radiology procedure is high-risk. Our preferred dose is 45 Gy at 1.8 Gy/fraction. LEVEL OF EVIDENCE: 4.

STING Promotes Homeostasis via Regulation of Cell Proliferation and Chromosomal Stability.

Given the integral role of stimulator of interferon genes (STING, TMEM173) in the innate immune response, its loss or impairment in cancer is thought to primarily affect antitumor immunity. Here we demonstrate a role for STING in the maintenance of cellular homeostasis through regulation of the cell cycle. Depletion of STING in human and murine cancer cells and tumors resulted in increased proliferation compared with wild-type controls. Microarray analysis revealed genes involved in cell-cycle regulation are differentially expressed in STINGko compared with WT MEFs. STING-mediated regulation of the cell cycle converged on NFκB- and p53-driven activation of p21. The absence of STING led to premature activation of cyclin-dependent kinase 1 (CDK1), early onset to S-phase and mitosis, and increased chromosome instability, which was enhanced by ionizing radiation. These results suggest a pivotal role for STING in maintaining cellular homeostasis and response to genotoxic stress. SIGNIFICANCE: These findings provide clear mechanistic understanding of the role of STING in cell-cycle regulation, which may be exploited in cancer therapy because most normal cells express STING, while many tumor cells do not.See related commentary by Gius and Zhu, p. 1295.

Late toxicity after post-prostatectomy intensity modulated radiation therapy: Evaluating normal-tissue sparing guidelines.

PURPOSE: Dose-volume histogram (DVH) toxicity relationships are poorly defined in men who receive radiation after radical prostatectomy (RP). We evaluated Radiation Therapy Oncology Group (RTOG) study 0534 and institutional intact normal-tissue sparing guidelines, as well as dose to bladder trigone, for ability to minimize late toxicity. METHODS AND MATERIALS: 164 men received intensity modulated radiation therapy (RT) to a median prostate bed dose of 66.6 Gy at a median of 22 months after RP. 46% of men were prescribed androgen deprivation therapy and pelvic lymph node irradiation to a median dose of 50.4 Gy. DVH relationships for the rectum, bladder, trigone, and bladder excluding the clinical target volume (bladder-CTV) were analyzed against the Common Terminology Criteria for Adverse Events late grade 2 + (G2+) gastrointestinal (GI) and genitourinary (GU) toxicity by log-rank test. RTOG 0534 (rectum V65, 40 Gy ≤35, 55%, and bladder-CTV V65, 40 ≤50, 70%) and intact prostate RT institutional guidelines (rectum V70, 65, 40 ≤20, 40, 80% and bladder V70, 65, 40 ≤30, 60, 80%, respectively) guidelines were evaluated. RESULTS: With a median follow-up time of of 33 months, the 4-year freedom from G2 + GI and GU toxicity were both 91%. G2 + GI (n = 12) and GU (n = 15) toxicity included 4% diarrhea (n = 6), 4% hemorrhage (n = 6), 1% proctitis (n = 1), and 4% urinary frequency (n = 7), 1% obstructive (n = 2), 2% cystitis (n = 3), and 3% incontinence (n = 5), respectively. RTOG 0534 rectum and bladder goals were not achieved in 65% and 41% of cases, while the institutional intact prostate goals were not achieved in 21% and 25% of cases, respectively. Neither dose to the bladder trigone nor any of the proposed normal tissue goals were associated with late toxicity (P > .1). In the univariate analysis, age, pelvic RT, RT dose, anticoagulation use, androgen deprivation therapy, time from RP to RT, and tobacco history were not associated with toxicity. CONCLUSIONS: More than 90% of men were free from late G2 + toxicity 4 years after post-RP intensity modulated RT. No tested parameters were associated with late toxicity. In the absence of established normal-tissue DVH guidelines in the postoperative setting, the use of intact guidelines is reasonable.

Introductory Radiation Oncology Curriculum: Report of a National Needs Assessment and Multi-institutional Pilot Implementation.

PURPOSE: To assess the optimal structure of an introductory curriculum (IC) for radiation oncology residents, including the perceived utility of a 2-day off-site "boot camp," and evaluate the success of a pilot introductory radiation oncology curriculum (IROC) based on these initial data. METHODS AND MATERIALS: In the first phase, anonymous, web-based surveys were sent to US radiation oncology program directors and residents. Likert-type scores (1, not at all; 5, extremely) are reported as the median and interquartile range. Using the phase 1 results, IROC was developed, piloted, and evaluated. RESULTS: Of the 89 program directors and 697 residents, 47 (53%) and 165 (24%) responded, respectively. Of the 89 program directors, 37 (79%) reported offering a formal IC. However, only 83 residents (50%) reported having a formal IC. Program directors reported resident preparation for clinical training as "moderate" (median 3, interquartile range 2-3) on entering residency and "moderate" (median 3, interquartile range 3-4) after IC completion (P = .03). However, residents only believed they were "slightly" prepared (median 2, interquartile range 1-2) on entering residency and "moderately" (median 3, interquartile range 2-3) prepared after IC completion (P < .01). Program directors believed an off-site boot camp would be of "moderate" utility (median 3, interquartile range 3-4) with participation limited by funding (57%). Residents without an IC reported that having an IC would be "quite" beneficial (median 4, interquartile range 3-5). Residents preferred instruction before the clinical training (49%) and over 1 week (40%). Both program directors and residents rated lectures on radiation emergencies and simulation highly. Using these data, IROC was developed and piloted with incoming residents at 4 institutions. After IROC, residents reported improvement in overall preparedness for clinical training (before: median 1, interquartile range 1-2; vs after: median 3, interquartile range 2-3; P < .01) and among specific practice domains. CONCLUSIONS: Beginning radiation oncology residents frequently lack structured introductory curricula but desire instruction before the clinical training with a focus on practical aspects (emergency management, contouring). Program directors recognize the value of both off-site and on-site boot camps. An on-site IC could mitigate funding barriers. A standardized IC, IROC, piloted at 4 programs, showed promising outcomes.

JAK2 Inhibitor SAR302503 Abrogates PD-L1 Expression and Targets Therapy-Resistant Non-small Cell Lung Cancers.

Lung cancer is the leading cause of cancer-related deaths worldwide. Approximately 85% of all lung cancers are non-small cell histology [non-small cell lung cancer (NSCLC)]. Modern treatment strategies for NSCLC target driver oncogenes and immune checkpoints. However, less than 15% of patients survive beyond 5 years. Here, we investigated the effects of SAR302503 (SAR), a selective JAK2 inhibitor, on NSCLC cell lines and tumors. We show that SAR is cytotoxic to NSCLC cells, which exhibit resistance to genotoxic therapies, such as ionizing radiation, cisplatin, and etoposide. We demonstrate that constitutive IFN-stimulated gene expression, including an IFN-related DNA damage resistance signature, predicts for sensitivity to SAR. Importantly, tumor cell-intrinsic expression of PD-L1 is IFN-inducible and abrogated by SAR. Taken together, these findings suggest potential dual roles for JAK2 inhibitors, both as a novel monotherapy in NSCLCs resistant to genotoxic therapies, and in tandem with immune checkpoint inhibition. Mol Cancer Ther; 17(4); 732-9. ©2018 AACR.

Cancer therapies activate RIG-I-like receptor pathway through endogenous non-coding RNAs.

Emerging evidence indicates that ionizing radiation (IR) and chemotherapy activate Type I interferon (IFN) signaling in tumor and host cells. However, the mechanism of induction is poorly understood. We identified a novel radioprotective role for the DEXH box RNA helicase LGP2 (DHX58) through its suppression of IR-induced cytotoxic IFN-beta [1]. LGP2 inhibits activation of the RIG-I-like receptor (RLR) pathway upon binding of viral RNA to the cytoplasmic sensors RIG-I (DDX58) and MDA5 (IFIH1) and subsequent IFN signaling via the mitochondrial adaptor protein MAVS (IPS1). Here we show that MAVS is necessary for IFN-beta induction and interferon-stimulated gene expression in the response to IR. Suppression of MAVS conferred radioresistance in normal and cancer cells. Germline deletion of RIG-I, but not MDA5, protected mice from death following total body irradiation, while deletion of LGP2 accelerated the death of irradiated animals. In human tumors depletion of RIG-I conferred resistance to IR and different classes of chemotherapy drugs. Mechanistically, IR stimulated the binding of cytoplasmic RIG-I with small endogenous non-coding RNAs (sncRNAs), which triggered IFN-beta activity. We demonstrate that the small nuclear RNAs U1 and U2 translocate to the cytoplasm after IR treatment, thus stimulating the formation of RIG-I: RNA complexes and initiating downstream signaling events. Taken together, these findings suggest that the physiologic responses to radio-/chemo-therapy converge on an antiviral program in recruitment of the RLR pathway by a sncRNA-dependent activation of RIG-I which commences cytotoxic IFN signaling. Importantly, activation of interferon genes by radiation or chemotherapy is associated with a favorable outcome in patients undergoing treatment for cancer. To our knowledge, this is the first demonstration of a cell-intrinsic response to clinically relevant genotoxic treatments mediated by an RNA-dependent mechanism.