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Background: Women are more likely to search for information on behalf of both themselves and others, thus making them a valuable target for health information research. The purpose of this project was to identify and compare the most important medical concerns and sources of health information trusted by women in relationship to demographic differences in two different clinical settings within the same geographic area (Mayo Clinic Department of Family Medicine and Beaches Community Health care?a Sulzbacher Center Clinic). Methods: A novel survey tool was developed to obtain information regarding the age, race, and socioeconomic demographics of patients as well as the patients' personal significant medical concerns and trusted sources of health information. Results: Despite the huge development of health care information delivery through online resources, in our study, the majority of patients from both clinics still used and viewed their primary care provider as the most trusted source of health information. The health concerns most reported by both populations included cardiac health, breast and other cancers, and obesity; meanwhile, mental health was significantly more reported by patients from the free clinic. Conclusions: Education level may be an important factor of the awareness and ultimate treatment and prevention of these prevalent diseases. Furthermore, our study results may help improve patient satisfaction, knowledge, and health outcomes.

Background: The prevalence and characteristics of acetaminophen-associated liver injury in hospitalized patients are not well defined. Methods: We identified patients hospitalized for excessive acetaminophen ingestion at an urban county hospital over a 40-month period (1992 to 1995) and reviewed their medical records to determine the incidence and clinical features of the ingestions and their outcomes. Results: Of the 71 patients studied, 50 were classified as having taken acetaminophen during suicide attempts and 21 as having accidentally poisoned themselves while attempting to relieve pain. The suicidal patients had ingested almost twice as much acetaminophen as those in the accidental-overdose group (median, 20 vs. 12 g; P=0.009). Among the patients for whom data were available, 63 percent of those in the accidental-overdose group and 25 percent of those in the suicidal group had chronic alcohol abuse (P=0.009). The patients in the accidental-overdose group more often had severe liver necrosis (aminotransferase levels, >3500 IU per liter; 52 percent vs. 14 percent; P=0.002), and were more likely to have hepatic coma (33 percent vs. 6 percent, P=0.006). There were four deaths (19 percent) in the accidental-overdose group and one (2 percent) in the suicidal group (P=0.04). Five patients -- three in the accidental-overdose group and two in the suicidal group -- had ingested 4 g of acetaminophen or less. Acetaminophen ingestion accounted for 12 percent of all patients hospitalized with overdoses (71 of 589) and 40 percent of patients with acute liver failure (10 of 25) during the study period. Conclusions: In an urban county hospital, patients hospitalized with acetaminophen toxicity related to accidental misuse had higher rates of morbidity and mortality than those who attempted suicide, even though the latter had taken more acetaminophen. A higher frequency of chronic alcohol abuse among the patients with accidental overdoses may be one explanation. [ABSTRACT FROM AUTHOR]

Background: Despite the urgent need for improved outcomes in patients with metastatic Ewing sarcoma (EWS) and rhabdomyosarcoma (RMS), it is unknown how to best approach metastatic site radiation therapy for these patients and whether such treatment provides a significant oncologic benefit that outweighs the toxicities., Methods: We gathered a panel of pediatric radiation oncologists from academic hospitals to identify and discuss current controversies regarding the role of radiation in the management of metastatic EWS and RMS. The panel reviewed existing clinical data and ongoing trials to address five key questions: 1) the role of whole lung irradiation (WLI) in treating lung metastases 2) number of metastatic sites warranting radiotherapy and the radicality of such an approach; 3) radiation techniques, including stereotactic body radiation therapy (SBRT); 4) the timing of metastatic-site radiation therapy; and 5) the utility of metastatic site radiation therapy for relapsed metastatic disease., Results: After a review of existing data, consensus recommendations were developed to support the decision-making process in metastatic-site irradiation with the goal of improving long-term disease control. Patients with pulmonary metastases should receive WLI. In patients with limited (<8 sites) metastatic disease, a comprehensive approach should be taken to treat all sites of metastatic disease diagnosed at presentation. SBRT should be considered as a preferred treatment technique. The timing of metastatic-site treatment should coincide with the end of systemic therapy. However, if there is a dosimetric advantage or improved compliance, concurrent treatment with the primary site may be preferred., Conclusions: A consensus guideline was established to address several critical questions regarding the role of radiation in the treatment of metastatic EWS and RMS. The study highlights the existing controversies, provides a structured approach, and underscores the need for future studies to further evaluate the therapeutic ratio of metastatic-site directed therapy., Competing Interests: Declaration of competing interest LYL reports travel support from GT Medical Technologies. JB reports leadership role in PTCOG-NA. No other conflicts of interest to disclose., (Copyright © 2024. Published by Elsevier Inc.)

Purpose: Patients with rhabdomyosarcoma with metastatic disease have a poor prognosis despite therapy intensification. The aim of this study was to investigate the efficacy of whole lung irradiation (WLI) in patients with rhabdomyosarcoma and lung metastases., Methods: Patients with rhabdomyosarcoma with lung metastases enrolled on four Children's Oncology Group protocols (D9802, D9803, ARST08P1, ARST0431) were retrospectively reviewed. Event-free survival (EFS) and overall survival (OS) were compared between patients who received and did not receive WLI., Results: In 143 patients with rhabdomyosarcoma with lung metastases, 65 patients (45.5%) received WLI and 78 patients (54.5%) did not receive WLI despite protocol requirements. The 5-year EFS was 38.3% (95% CI, 24.8 to 51.8) in patients who received WLI and 25.2% (95% CI, 13.8 to 36.6) in patients who did not receive WLI ( P = .0496). The 5-year OS was 45.5% (95% CI, 31.8 to 59.3) in patients who received WLI and 32.4% (95% CI, 20.4 to 44.4) in patients who did not receive WLI ( P = .08). In exploratory subgroup analyses, the benefit of WLI on EFS and OS was significant in patients 10 years and older. Other clinical factors associated with EFS on univariable analysis included age, histology FOXO1 fusion status, number of metastatic sites, location of metastatic sites, and Oberlin Score., Conclusion: WLI is associated with improved EFS in patients with rhabdomyosarcoma with lung metastases. These results highlight the potential importance of WLI and need for more stringent protocol compliance for administering WLI.

Purpose: Understanding quality of life (QOL) implications of individual components of breast cancer treatment is important as systemic therapies continue to improve oncologic outcomes. We hypothesized that adjuvant radiation therapy does not significantly impact QOL domains in breast cancer patients undergoing chemotherapy., Methods: Data was drawn from three prospective studies in women with localized breast cancer being treated with chemotherapy from March 2014 to December 2019. Patient-reported measures were collected at baseline (pretreatment) and post-treatment using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) measure, which consists of 5 subscales. Changes in mean QOL scores in patients who received radiotherapy were compared to those who did not using a one-sided noninferiority method. Statistical significance was determined below 0.05 to meet noninferiority., Results: In a sample of 175 patients, 131 were treated with radiation and 44 had no radiation. The sample consisted mostly of stage I-II breast cancer (78%) with hormone receptor positive (59%) disease, receiving either neoadjuvant (36%) or adjuvant chemotherapy (64%). Mean change in QOL for the group treated with radiation compared to no radiation was noninferior with respect to Physical Well-Being (P = .0027), Social/Family Well-Being (P = .0002), Emotional Well-Being (P = .0203), FACIT-Fatigue Subscale (P = .0072), and the Total FACIT-F score (P = .0005); however, mean change in QOL did not meet noninferiority for Functional Well-Being (P = .0594)., Conclusion: Patient-reported QOL from baseline to post-treatment, using the Total FACIT-F score, was noninferior in patients treated with versus without radiation therapy. This finding, in addition to individualized QOL subscales, provides important information in the informed decision-making process when discussing the effects of locoregional radiation on QOL in localized breast cancer patients treated with chemotherapy., Competing Interests: Disclosure The authors have stated that they have no conflicts of interest., (Published by Elsevier Inc.)

Purpose: A Pediatric Normal Tissue Effects in the Clinic (PENTEC) analysis of published investigations of central nervous system (CNS) subsequent neoplasms (SNs), subsequent sarcomas, and subsequent lung cancers in childhood cancer survivors who received radiation therapy (RT) was performed to estimate the effect of RT dose on the risk of SNs and the modification of this risk by host and treatment factors., Methods and Materials: A systematic literature review was performed to identify data published from 1975 to 2022 on SNs after prior RT in childhood cancer survivors. After abstract review, usable quantitative and qualitative data were extracted from 83 studies for CNS SNs, 118 for subsequent sarcomas, and 10 for lung SNs with 4 additional studies (3 for CNS SNs and 1 for lung SNs) later added. The incidences of SNs, RT dose, age, sex, primary cancer diagnosis, chemotherapy exposure, and latent time from primary diagnosis to SNs were extracted to assess the factors influencing risk for SNs. The excess relative ratio (ERR) for developing SNs as a function of dose was analyzed using inverse-variance weighted linear regression, and the ERR/Gy was estimated. Excess absolute risks were also calculated., Results: The ERR/Gy for subsequent meningiomas was estimated at 0.44 (95% CI, 0.19-0.68); for malignant CNS neoplasms, 0.15 (95% CI, 0.11-0.18); for sarcomas, 0.045 (95% CI, 0.023-0.067); and for lung cancer, 0.068 (95% CI, 0.03-0.11). Younger age at time of primary diagnosis was associated with higher risk of subsequent meningioma and sarcoma, whereas no significant effect was observed for age at exposure for risk of malignant CNS neoplasm, and insufficient data were available regarding age for lung cancer. Females had a higher risk of subsequent meningioma (odds ratio, 1.46; 95% CI, 1.22-1.76; P < .0001) relative to males, whereas no statistically significant sex difference was seen in risk of malignant CNS neoplasms, sarcoma SNs, or lung SNs. There was an association between chemotherapy receipt (specifically alkylating agents and anthracyclines) and subsequent sarcoma risk, whereas there was no clear association between specific chemotherapeutic agents and risk of CNS SNs and lung SNs., Conclusions: This PENTEC systematic review shows a significant radiation dose-response relationship for CNS SNs, sarcomas, and lung SNs. Given the linear dose response, improved conformality around the target volume that limits the high dose volume might be a promising strategy for reducing the risk of SNs after RT. Other host- and treatment-related factors such as age and chemotherapy play a significant contributory role in the development of SNs and should be considered when estimating the risk of SNs after RT among childhood cancer survivors., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: To evaluate local failure (LF) and toxicity after intraoperative radiation therapy (IORT) in pediatric solid tumors (ST)., Methods: A single-institution retrospective study of 96 pediatric patients (108 applications) with ST treated from 1995 to 2022 with IORT. LF was calculated via cumulative incidence function and overall survival (OS) by Kaplan-Meier method, both from the day of surgery., Results: Median age at time of IORT was 8 years (range: 0.8-20.9 years). Median follow-up for all patients and surviving patients was 16 months and 3 years, respectively. The most common histologies included rhabdomyosarcoma (n = 42), Ewing sarcoma (n = 10), and Wilms tumor (n = 9). Most (95%) received chemotherapy, 37% had prior external beam radiation therapy to the site of IORT, and 46% had a prior surgery for tumor resection. About half (54%) were treated with upfront IORT to the primary tumor due to difficult circumstances such as very young age or challenging anatomy. The median IORT dose was 12 Gy (range: 4-18 Gy), and median area treated was 24 cm 2 (range: 2-198 cm 2 ). The cumulative incidence of LF was 17% at 2 years and 23% at 5 years. Toxicity from IORT was reasonable, with postoperative complications likely related to IORT seen in 15 (16%) patients., Conclusion: Our study represents the largest and most recent analysis of efficacy and safety of IORT in pediatric patients with ST. Less than one quarter of all patients failed locally with acceptable toxicities. Overall, IORT is an effective and safe technique to achieve local control in patients with challenging circumstances., (© 2024 Wiley Periodicals LLC.)

Purpose: To evaluate outcomes after intraoperative radiation therapy (IORT) in high-risk neuroblastoma (NB), including local control, overall survival, and toxicity., Methods and Materials: This was a single institution retrospective study of 92 pediatric patients with NB treated with IORT from 1995 to 2022. Each IORT application was considered a separate event for a total of 110 sites treated. Local failure was calculated using the cumulative incidence function and survival by Kaplan-Meier method from the day of surgery., Results: All patients had high-risk relapsed or treatment refractory disease. Median age was 6 years (range, 2-34 years). Median follow-up for all patients and surviving patients was 16 months and 4 years, respectively. All patients previously received chemotherapy, 93% had prior external beam radiation therapy to the site of IORT (median dose, 21.6 Gy; range, 10-36 Gy), and 94% had a prior surgery for tumor resection. The median IORT dose was 12 Gy (range, 8-18 Gy) and median area treated was 18 cm 2 (range, 2.5-60 cm 2 ). The cumulative incidence of local failure was 23% at 2 years and 29% at 5 years. The overall survival (OS) was 44% at 2 years and 29% at 5 years. Local failure after IORT was associated with worse OS (hazard ratio, 1.74; 95% CI, 1.07-2.84; P = .0267). Toxicity from IORT was rare, with postoperative complications likely related to IORT seen in 7 (8%) patients., Conclusions: Our study represents the largest, most recent analysis of the efficacy and safety of IORT in patients with relapsed or refractory NB. Less than one-third of patients failed locally at 5 years, and achieving local control affected overall survival. Minimal toxicities directly related to IORT were observed. Overall, IORT is an effective and safe technique to achieve local control in high-risk relapsed or refractory neuroblastoma., Competing Interests: Disclosures Dana Casey reports participating in the EMD Serono advisory board rhabdomyosarcoma meeting. Shakeel Modak reports earnings from YMABs and Innervate, however not research funds. He participates on the Data Safety Monitoring Board or Advisory Board for Kymera, EUSA, and US WorldMeds. Kathryn Tringale reports receiving the Hopper-Belmont Foundation Inspiration Award, RSNA Resident Research Grant (unrelated), NCCN 2023 Fellow Award (unrelated), and the ASH Abstract Achievement Award (unrelated)., (Copyright © 2024 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Importance: Determining the impact of germline cancer-predisposition variants (CPVs) on outcomes could inform novel approaches to testing and treating children with rhabdomyosarcoma., Objective: To assess whether CPVs are associated with outcome among children with rhabdomyosarcoma., Design, Setting, and Participants: In this cohort study, data were obtained for individuals, aged 0.01-23.23 years, newly diagnosed with rhabdomyosarcoma who were treated across 171 Children's Oncology Group sites from March 15, 1999, to December 8, 2017. Data analysis was performed from June 16, 2021, to May 15, 2023., Exposure: The presence of a CPV in 24 rhabdomyosarcoma-associated cancer-predisposition genes (CPGs) or an expanded set of 63 autosomal-dominant CPGs., Main Outcomes and Measures: Overall survival (OS) and event-free survival (EFS) were the main outcomes, using the Kaplan-Meier estimator to assess survival probabilities and the Cox proportional hazards regression model to adjust for clinical covariates. Analyses were stratified by tumor histology and the fusion status of PAX3 or PAX7 to the FOXO1 gene., Results: In this study of 580 individuals with rhabdomyosarcoma, the median patient age was 5.9 years (range, 0.01-23.23 years), and the male-to-female ratio was 1.5 to 1 (351 [60.5%] male). For patients with CPVs in rhabdomyosarcoma-associated CPGs, EFS was 48.4% compared with 57.8% for patients without a CPV (P = .10), and OS was 53.7% compared with 65.3% for patients without a CPV (P = .06). After adjustment, patients with CPVs had significantly worse OS (adjusted hazard ratio [AHR], 2.49 [95% CI, 1.39-4.45]; P = .002), and the outcomes were not better among patients with embryonal histology (EFS: AHR, 2.25 [95% CI, 1.25-4.06]; P = .007]; OS: AHR, 2.83 [95% CI, 1.47-5.43]; P = .002]). These associations were not due to the development of a second malignant neoplasm, and importantly, patients with fusion-negative rhabdomyosarcoma who harbored a CPV had similarly inferior outcomes as patients with fusion-positive rhabdomyosarcoma without CPVs (EFS: AHR, 1.35 [95% CI, 0.71-2.59]; P = .37; OS: AHR, 1.71 [95% CI, 0.84-3.47]; P = .14). There were no significant differences in outcome by CPV status of the 63 CPG set., Conclusions and Relevance: This cohort study identified a group of patients with embryonal rhabdomyosarcoma who had a particularly poor outcome. Other important clinical findings included that individuals with TP53 had poor outcomes independent of second malignant neoplasms and that patients with fusion-negative rhabdomyosarcoma who harbored a CPV had outcomes comparable to patients with fusion-positive rhabdomyosarcoma. These findings suggest that germline CPV testing may aid in clinical prognosis and should be considered in prospective risk-based clinical trials.

Background: As radiation therapy (RT) for Wilms tumor (WT) evolves with more conformal techniques, it is necessary to evaluate patterns of failure and toxicity. We sought to determine the rate of local failure (LF) after abdominal RT in WT, specifically focusing on those with contained rupture treated with whole abdominal and pelvic RT (WAPRT) vs flank RT. Secondary objectives were to determine overall survival (OS), distant failure (DF), and late toxicities., Methods: A single institution retrospective study of 54 pediatric patients with WT treated with abdominal RT between May 2000 and October 2022. LF and DF were calculated through cumulative incidence function and OS by Kaplan-Meier method., Results: The median age was 4.5 years and the median follow-up was 6 years. Most patients (91%) had favorable histology. Only 1 patient experienced LF, 15 months from completion of RT (cumulative incidence 2% at 5 y). All patients who received unilateral flank radiation for contained rupture/spillage (n=13) experienced long-lasting intra-abdominal tumor control. A total of 5 patients experienced a DF at a median of 7 months, all in the lung. No patient relapsed in the lungs after upfront whole lung irradiation (n=16). OS was 96% at 5 years. Among 28 patients who followed through puberty, 4 female patients with prior WAPRT experienced hormonal irregularities/infertility., Conclusions: Unilateral flank radiation may be a viable alternative to WAPRT for contained rupture/spillage and should be further explored prospectively. Our results may also be utilized in the future for outcome and toxicity comparison as conformal radiation techniques evolve., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: There are currently no predictive molecular biomarkers to identify patients with oligometastatic disease (OMD) who will benefit from definitive-intent radiation therapy (RT). We prospectively characterized circulating tumor cell (CTC) kinetics in patients with OMD undergoing definitive-intent RT., Methods: This prospective correlative biomarker study included patients with any solid malignancy ≤5 metastatic sites in ≤3 anatomic organ systems undergoing definitive-intent RT to all disease sites. Circulating tumor cells (CTCs) were captured and enumerated using a biomimetic cell rolling and nanotechnology-based assay functionalized with antibodies against epithelial cell adhesion molecule, against human epidermal growth factor receptor 2, and against epidermal growth factor receptor before and during RT and at follow-up visits up to 2 years post-RT., Results: We enrolled 43 patients with a median follow-up of 14.3 months. The pretreatment CTC level (cells captured/mL) was not associated with the number of disease sites (median one metastatic site/patient, range 1-5) or metastasis location (bone, brain, visceral) on Wilcoxon signed-rank test, P > .05. Post-RT, 56% of patients received systemic therapy, and 72% of patients experienced subsequent local or systemic progression. For 90% of patients, a CTC level <15 within 130 days post-RT corresponded to a durable control of irradiated lesions. Patients with a favorable versus an unfavorable clearance profile experienced significantly longer progression-free survival after RT (median 13 v 4 months, log-rank test, P = .0011). On logistic regression, CTC level >15 at a given time point was associated with clinical disease progression within the subsequent 6 months (odds ratio 3.31, P = .007). In 26% of patients with disease progression, a CTC level >15 preceded radiographic or clinical progression., Conclusion: CTCs may serve as a biomarker for disease control in OMD and may predict disease progression before standard assessments for patients receiving diverse cancer-directed therapies.

Background: In high-risk neuroblastoma, multimodality therapy including craniospinal irradiation (CSI) is effective for central nervous system (CNS) relapse. Management of post-CSI CNS relapse is not clearly defined., Procedure: Pediatric patients with neuroblastoma treated with CSI between 2000 and 2019 were identified. Treatment of initial CNS disease (e.g., CSI, intraventricular compartmental radioimmunotherapy [cRIT] with 131 I-monoclonal antibodies targeting GD2 or B7H3) and management of post-CSI CNS relapse ("second CNS relapse") were characterized. Cox proportional hazards models to evaluate factors associated with third CNS relapse and overall survival (OS) were used., Results: Of 128 patients (65% male, median age 4 years), 19 (15%) received CSI with protons and 115 (90%) had a boost. Most (103, 81%) received cRIT, associated with improved OS (hazard ratio [HR] 0.3, 95% confidence interval [CI]: 0.1-0.5, p < .001). Forty (31%) developed a second CNS relapse, associated with worse OS (1-year OS 32.5%, 95% CI: 19-47; HR 3.8; 95% CI: 2.4-6.0, p < .001), and more likely if the leptomeninges were initially involved (HR 2.5, 95% CI: 1.3-4.9, p = .006). Median time to second CNS relapse was 6.8 months and 51% occurred outside the CSI boost field. Twenty-five (63%) patients underwent reirradiation, most peri-operatively (18, 45%) with focal hypofractionation. Eight (20%) patients with second CNS relapse received cRIT, associated with improved OS (HR 0.1; 95% CI: 0.1-0.4, p < .001)., Conclusions: CNS relapse after CSI for neuroblastoma portends a poor prognosis. Surgery with hypofractionated radiotherapy was the most common treatment. Acknowledging the potential for selection bias, receipt of cRIT both at first and second CNS relapse was associated with improved survival. This finding necessitates further investigation., (© 2022 Wiley Periodicals LLC.)

Background: The RxPONDER trial demonstrated that the 21-gene recurrence score can be used to guide adjuvant systemic therapy decisions in postmenopausal women with pN1 ER+/HER2- breast cancer. As such, a sentinel lymph node biopsy (SLNB) may not provide systemic treatment-altering information for many patients, and omission of SLNB in patients with low probability of pN2/N3 disease could be considered., Methods: Postmenopausal women (aged ≥ 50 years) diagnosed with cN0cM0, ER+/HER- breast cancer from 2013 to 2017 were identified in the National Cancer Database. The primary outcome was the prevalence of pN2/N3 disease., Results: Of 325,692 postmenopausal women with cN0 ER+/HER2- breast cancer, 7106 (2.2%) were pN2/N3. In total, 81.7% had cT1 tumors, 16.8% T2, 1.3% T3, and 0.2% T4. In patients with T1 tumors, the prevalence of pN2/N3 disease was 1.2% compared with 17.2% in patients with T3/T4 tumors. In multivariable models, cT stage was the strongest predictor of pN2/N3 disease (adjusted odds ratio [aOR] 14.9 [12.1-18.4]). Lobular histology (aOR 2.4 [2.3-2.6]), higher grade (aOR 2.9 [2.6-3.1]), and young age (aOR 1.5 [1.3-1.7]) were also associated with increased prevalence of pN2/N3. We created a model using histology, grade, and T stage that stratifies patients with low prevalence of pN2/3 disease (< 1%) and those at high risk (> 20%)., Conclusions: In postmenopausal women with cN0 ER+/HER2- breast cancer, the prevalence of pN2/N3 disease is low, indicating a potential opportunity to use the results of RxPONDER to extend criteria to omit SLNB. Prospective study is needed to determine safety, including risk of nodal recurrence, of omission of SLNB in carefully selected patients., (© 2022. Society of Surgical Oncology.)

The International Soft Tissue Sarcoma Database Consortium (INSTRuCT) consists of a collaboration between the Children's Oncology Group (COG) Soft Tissue Sarcoma Committee, the European pediatric Soft Tissue Sarcoma Study Group (EpSSG), and the Cooperative Weichteilsarkom Studiengruppe (CWS). As part of the larger initiative of INSTRuCT to provide consensus expert opinions for clinical treatment of pediatric soft tissue sarcoma, we sought to provide updated, evidenced-based consensus guidelines for local treatment of parameningeal rhabdomyosarcoma using both existing literature as well as recommendations from the relevant cooperative group clinical trials. Overall, parameningeal rhabdomyosarcoma represents a distinctly challenging disease to treat, given its location near many critical structures in the head and neck, frequently advanced local presentation, and predilection for local failure. Definitive chemoradiation remains the standard treatment approach for parameningeal rhabdomyosarcoma, with surgery often limited to biopsy or salvage therapy for recurrent disease. In this consensus paper, we specifically discuss consensus guidelines and evidence for definitive local management with radiotherapy, with a focus on imaging for radiotherapy planning, dose and timing of radiation, approach for nodal irradiation, various radiation techniques, including proton therapy, and the limited role of surgical resection., (© 2022 Wiley Periodicals LLC.)

Background: It is unclear how intensity-modulated radiation therapy (IMRT) impacts long-term risk of second malignant neoplasms (SMNs) in childhood cancer patients., Procedure: Patients aged ≤21 years treated with IMRT between 1998 and 2009 and who survived ≥5 years after IMRT were included. SMN site in relation to isodose level (IDL) of IMRT was evaluated. Standardized incidence ratios (SIR) and excess absolute risks (EAR) were calculated. Cumulative incidences were estimated with death as a competing risk., Results: Three-hundred twenty-five patients were included with median follow-up of 11.2 years from IMRT (interquartile range: 9.4-14.0) among patients alive at the end of follow-up. Two hundred (62%) patients had ≥10 years of follow-up and 284 (87%) patients were alive at the time of analysis. Fifteen patients developed SMNs (11 solid, four hematologic). Median time from IMRT to solid SMN was 11.0 years (range: 6.8-19.2) with 10- and 15-year cumulative incidences 1.8% (95% CI: 0.7-3.9) and 3.5% (95% CI: 1.4-7.5), respectively; SIR was 13.7 (95% CI: 6.9-24.6) and EAR was 2.8 per 1000 person-years (95% CI: 1.0-4.6). Eight solid SMNs developed within the IMRT field (100% IDL [n = 5], 80% IDL [n = 1], 50% IDL [n = 1], 40% IDL [n = 1]), one within the 70%-80% IDL of a conventional field, one was out-of-field, and one could not be determined., Conclusions: With median follow-up of >10 years, many solid SMNs after IMRT in childhood cancer survivors develop in the high-dose region. These data serve as a foundation for comparison with other modalities of radiation treatment (e.g., proton therapy)., (© 2022 Wiley Periodicals LLC.)

Purpose: Approximately 30% of women who receive postmastectomy radiation therapy in the setting of breast reconstruction suffer from reconstruction complications. This study aims to assess clinical and dosimetric factors associated with the risk of reconstruction complications after postmastectomy radiation therapy, with the ultimate goal of identifying a dosimetric constraint that can be used clinically to limit this risk., Methods and Materials: We retrospectively identified 41 patients who underwent a modified radical or total mastectomy, followed by immediate or delayed reconstruction (autologous or implant-based) and radiation at a single institution between 2014 and 2020. Reconstruction complications were defined as a flap or implant failure, necrosis, capsular contracture, cellulitis/infection, implant rupture, implant malposition, leakage/rupture, unplanned operation, and hematoma/seroma. Clinical and dosimetric variables associated with complications were assessed with univariate analyses., Results: Twelve patients (29%) suffered reconstruction complications, which led to a flap or implant failure in 5 patients. The median time to complication after reconstruction was 8 months. Thirty-two percent of patients with immediate and 20% with delayed reconstruction suffered a complication, respectively. There were no local failures. Smoking (P = .02), use of bolus (P = .03), and the percentage of the chest wall/reconstructed breast target volume that received ≥107% of the prescribed radiation dose (V 107 ) > 11% (P = .03) were associated with increased complication rates. The complication rates were 42% when V 107 > 11% versus 12% when V 107 < 11%; 58% in smokers versus 17% in nonsmokers; and 42% with versus 7% without bolus., Conclusions: Plan heterogeneity appears to be associated with the risk of reconstruction complications. Pending further validation, V 107 < 11% may serve as a reasonable guide to limit this risk. Further consideration should be given to the selective use of bolus in this setting and optimization of clinical factors, such as smoking cessation., (Copyright © 2021 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Radiotherapy plays an important role in managing highly radiosensitive, indolent non-Hodgkin lymphomas, such as follicular lymphoma and marginal zone lymphoma. Although the standard of care for localized indolent non-Hodgkin lymphomas remains 24 Gy, de-escalation to very-low-dose radiotherapy (VLDRT) of 4 Gy further reduces toxicities and duration of treatment. Use of VLDRT outside palliative indications remains controversial; however, we hypothesize that it may be sufficient for most lesions. We present the largest single-institution VLDRT experience of adult patients with follicular lymphoma or marginal zone lymphoma treated between 2005 and 2018 (299 lesions; 250 patients) using modern principles including positron emission tomography staging and involved site radiotherapy. Outcomes include best clinical or radiographic response between 1.5 and 6 months after VLDRT and cumulative incidence of local progression (LP) with death as the only competing risk. After VLDRT, the overall response rate was 90% for all treated sites, with 68% achieving complete response (CR). With a median follow-up of 2.4 years, the 2-year cumulative incidence of LP was 25% for the entire cohort and 9% after first-line treatment with VLDRT for potentially curable, localized disease. Lesion size >6 cm was associated with lower odds of attaining a CR and greater risk of LP. There was no suggestion of inferior outcomes for potentially curable lesions. Given the clinical versatility of VLDRT, we propose to implement a novel, incremental, adaptive involved site radiotherapy strategy in which patients will be treated initially with VLDRT, reserving full-dose treatment for those who are unable to attain a CR., (© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: p53 plays a key role in the DNA repair process and response to ionising radiation. We sought to determine the clinical phenotype of TP53 mutations and p53 pathway alterations in patients with rhabdomyosarcoma (RMS) and Ewing sarcoma (ES) treated with radiation., Methods: Of patients with available genomic sequencing, we identified 109 patients with RMS and ES treated to a total of 286 radiation sites. We compared irradiated tumour control among tumours with TP53 mutations (n = 40) to those that were TP53 wild-type (n = 246). We additionally compared irradiated tumour control among tumours with any p53 pathway alteration (defined as tumours with TP53 mutations or TP53 wild-type tumours identified to have MDM2/4 amplification and/or CDKN2A/B deletion, n = 78) to those without such alterations (n = 208)., Results: The median follow-up was 26 months from radiation. TP53 mutations were associated with worse irradiated tumour control among the entire cohort (hazard ratio, HR = 2.8, P < 0.0001). Tumours with any p53 pathway alteration also had inferior irradiated tumour control (HR = 2.0, P = 0.003). On multivariable analysis, after controlling for tumour histology, intent of radiation, presence of gross disease, and biologically effective dose, TP53 mutations continued to be associated with a radioresistant phenotype (HR = 7.1, P < 0.0001)., Conclusions: Our results show that TP53 mutations are associated with increased radioresistance in RMS and ES. Novel strategies to overcome this radioresistance are important for improved outcomes in p53 disruptive RMS and ES., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: We previously reported that the cumulative risk of femoral fracture in patients treated with intensity-modulated radiation therapy (IMRT) for thigh and groin soft tissue sarcoma (STS) is low. In the current study, we sought to evaluate the effect of radiation dose constraints on the rate of femoral fracture in a more contemporary cohort., Methods: All patients treated with IMRT for STS of the thigh or groin from 2004 to 2016 were included (n = 145). Beginning in 2011, radiation dose was constrained to a mean dose of < 37 Gy, volume of bone receiving ≥ 40 Gy (V40Gy) < 64%, and maximum dose < 59 Gy to limit the dose to the femur., Results: Sixty-one patients were treated before dose constraints were implemented, and 84 patients were treated after. Median follow-up for patients treated before and after constraints were implemented was 6.1 and 5.7 years, respectively, and the two groups were demographically and clinically similar. On univariate analysis, the 5-year cumulative incidence of femoral fracture among patients treated with and without dose constraints was 1.8% (95% confidence interval [CI] 0.3-12.2%) versus 7.4% (95% CI 3.1-17.6%) [p = 0.11, p = non-significant, respectively]. On multivariable analysis, only age  ≥ 60 years was significantly associated with increased risk of fracture., Conclusions: The risk of femoral fracture after IMRT for STS of the thigh/groin is low, and with the implementation of radiation dose constraints, the risk is < 2%. Although longer follow-up is needed, our results support the utilization of extremity sarcoma IMRT-specific dose constraints for fracture prevention.

Intraoperative radiation therapy (IORT) is a specialized form of accelerated partial breast irradiation in which a single dose of radiation is delivered to the tumor bed at the time of breast conserving surgery. With completion of radiation to the tumor bed at the time of surgery, IORT promises improved patient convenience, compliance, and quality of life. In addition, with its potentially skin-sparing properties and ability to deliver a high biologically effective dose to the tumor bed while reducing dose to nontarget tissues, IORT results in different but overall less toxicities compared with other modalities of radiation for breast cancer. However, skepticism over the role of IORT in breast cancer exists, and the 2 randomized trials that have analyzed IORT as the definitive radiation component of breast conservation therapy have shown an increase in local recurrence rates with IORT compared with whole breast irradiation, but similar rates of overall survival. In this review, we discuss the practicalities of IORT, the prospective data supporting and negating the role of IORT in lieu of whole breast irradiation, and the toxicity after IORT in early-stage breast cancer. We also review the role of IORT as a radiation boost and specific strategies for successful implementation of IORT in breast cancer., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Radiation therapy is one of the most commonly used cancer therapeutics but genetic determinants of clinical benefit are poorly characterized. Pathogenic germline variants in ATM are known to cause ataxia-telangiectasia, a rare hereditary syndrome notable for marked radiosensitivity. In contrast, somatic inactivation of ATM is a common event in a wide variety of cancers, but its clinical actionability remains obscure., Methods: We analyzed 20 107 consecutively treated advanced cancer patients who underwent targeted genomic sequencing as part of an institutional genomic profiling initiative and identified 1085 harboring a somatic or germline ATM mutation, including 357 who received radiotherapy (RT). Outcomes of irradiated tumors harboring ATM loss-of-function (LoF) mutations were compared with those harboring variants of unknown significance. All statistical tests were 2-sided., Results: Among 357 pan-cancer patients who received 727 courses of RT, genetic inactivation of ATM was associated with improved radiotherapeutic efficacy. The 2-year cumulative incidence of irradiated tumor progression was 13.2% vs 27.5% for tumors harboring an ATM LoF vs variant of unknown significance allele, respectively (hazard ratio [HR] = 0.51, 95% confidence interval [CI] = 0.34 to 0.77, P = .001). The greatest clinical benefit was seen in tumors harboring biallelic ATM inactivation (HR = 0.19, 95% CI = 0.06 to 0.60, P = .005), with statistically significant benefit also observed in tumors with monoallelic ATM inactivation (HR = 0.57, 95% CI = 0.35 to 0.92, P = .02). Notably, ATM LoF was highly predictive of outcome in TP53 wild-type tumors but not among TP53-mutant tumors., Conclusions: We demonstrate that somatic ATM inactivation is associated with markedly improved tumor control following RT. The identification of a radio-sensitive tumor phenotype across multiple cancer types offers potential clinical opportunities for genomically guided RT., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Most children with intermediate-risk rhabdomyosarcoma (RMS) have gross disease (group III) at the initiation of chemotherapy. Delayed primary excision (DPE) after induction chemotherapy allows for a reduction in adjuvant radiation dose, but with the risk of potential surgical morbidity. The objectives of this study were to compare outcomes in children with group III RMS who did and did not undergo DPE and to assess surgical morbidity., Methods: The study included 369 patients who had clinical group III RMS at sites amenable to DPE from intermediate-risk Children's Oncology Group studies D9803 (encouraged DPE) and ARST0531 (discouraged DPE)., Results: The primary tumor site was bladder/prostate (136 patients; 37%), extremity (97 patients; 26%), trunk (24 patients; 7%), retroperitoneum (91 patients; 25%), or intrathoracic/perineum/perianal (21 patients; 6%). In total, 112 patients (53.9%) underwent DPE in D9803, and 26 patients (16.2%) underwent DPE in ARST0531 (P < .001), with loss of vital organ or function in 30 of 138 patients (22%). DPE allowed for a reduced radiation dose in 110 of 135 patients (81%; 51% were reduced to 36 Gy, and 30% were reduced to 42 Gy). Patients who underwent DPE had improved unadjusted overall survival (P = .013). In adjusted regression analysis, the risk of death (hazard ratio, 0.71; 95% CI 0.43-1.16) was similar for patients who did and did not undergo DPE and was improved for the subset of patients who had tumors of the trunk and retroperitoneum (hazard ratio, 0.44; 95% CI, 0.20-0.97)., Conclusions: Children with group III RMS have equivalent or improved outcomes with DPE and can receive a decreased radiation dose for definitive local control. The choice of local control modality should weigh the potential morbidity of surgery versus that of higher dose irradiation., (© 2020 American Cancer Society.)

Objectives: At the onset of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic in the United States, testing was limited to the Centers for Disease Control and Prevention-developed reverse transcription polymerase chain reaction assay. The urgent and massive demand for testing prompted swift development of assays to detect SARS-CoV-2. The objective of this study was to assess the accuracy of these newly developed tests., Methods: The American Proficiency Institute sent 2 test samples to 346 clinical laboratories in order to assess the accuracy of SARS-CoV-2 assays. The positive sample, containing 5,175 viral copies/mL, was fully extractable with SARS-CoV-2 viral capsid protein and RNA. The negative sample, with 3,951 viral copies/mL, contained recombinant virus particles with sequences for targeting human RNAase P gene sequences., Results: Of the laboratories submitting results, 97.4% (302/310) correctly detected the virus when present and 98.3% (296/301) correctly indicated when the virus was not present. Among incorrect results reported in this proficiency challenge, 76.9% (10/13) were likely related to clerical error. This accounts for 1.6% (10/611) of all reported results., Conclusions: Overall performance in this SARS-CoV-2 RNA detection challenge was excellent, providing confidence in the results of these new molecular tests and assurance for the clinical and public health decisions based on these test results., (© American Society for Clinical Pathology, 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A subset of patients with initially unresected (Clinical Group III) rhabdomyosarcoma achieve less than a complete response (CR) despite multimodal therapy. We assessed outcome based upon tumor response at the completion of all planned therapy. We studied 601 Clinical Group III participants who completed all protocol therapy without developing progressive disease on two Children's Oncology Group studies ARST0531 (n = 285) and D9803 (n = 316). Response was defined by imaging and categorized by response; complete resolution (CR), partial response (PR) or no response (NR). Failure-free survival (FFS) and overall survival (OS) between response groups were compared using the log-rank test. We found that radiographic response was CR in 393 (65.4%) and PR/NR in 208 (34.6%) patients. Achieving CR status was associated with study D9803, nonparameningeal (PM) primary sites, tumors ≤5 cm, noninvasive tumors and alveolar histology/FOXO fusion-positive tumors. The overall 5-year FFS was 75% for those achieving CR and 66.5% in those with PR/NR (adj. p = 0.094). Patients with PM primary site who achieved CR had significantly improved FFS (adj. p = 0.037) while those with non-PM primary sites had similar outcomes (adj. p = 0.47). Radiographic response was not associated with OS (adj. p = 0.21). Resection of the end-of-therapy mass did not improve FFS (p = 0.12) or OS (p = 0.37). In conclusion, CR status at the end of protocol therapy in patients with PM Clinical Group III RMS was associated with improved FFS but not OS. Efforts to understand the biology and treatment response in patients with PM primary site are under investigation., (© 2020 UICC.)

Purpose: Increased availability of next-generation sequencing has allowed for the genomic characterization of a variety of pediatric tumors, although genomic determinants of response to treatment remain largely unknown. We sought to evaluate the genomic landscape and genomic determinants of clinical outcomes in rhabdomyosarcoma (RMS)., Experimental Design: Of 29,067 patients who underwent genomic profiling at our institution using a 468-gene oncopanel with complete records, 87 had RMS, of whom 22 were fusion positive. The 10 most common genetic alterations were associated with locoregional control (LC), disease-free survival (DFS), and overall survival (OS). Tumor mutational burden (TMB), defined as the total number of somatic nonsynonymous mutations normalized to the number of sequenced megabases, was also associated with clinical outcomes., Results: Median age at diagnosis was 16.4 years and median follow-up, 2.1 years. Patients with fusion-negative RMS had more genomic alterations and a higher TMB than those with fusion-positive RMS (mean number of genomic alterations, 6.0 vs. 2.9; P = 0.007 and mean TMB, 2.6 vs. 1.0; P = 0.01). Genetic alterations in TP53 were associated with worse OS ( P = 0.03). High TMB (defined as the top quartile ≥ 2.8) was associated with worse LC ( P = 0.05), DFS ( P = 0.04), and OS ( P = 0.01), with significance retained on multivariable analysis after controlling for risk group, fusion status, and receipt of chemotherapy as per pediatric protocols., Conclusions: High TMB was associated with worse clinical outcomes in patients with RMS. With further validation, TMB and other genomic classifiers may be combined with traditional clinicopathologic risk factors to guide risk stratification and ultimately treatment decisions., (©2019 American Association for Cancer Research.)

Over the last decade, immunotherapy has rapidly changed the therapeutic landscape and prognosis for many hematologic malignancies and adult solid tumors. Despite this success, immunotherapy for pediatric solid tumors remains in the early stages of development, and significant clinical benefit has yet to be realized, with anti-GD2 for neuroblastoma being the exception. The limited neoepitope expression and paucity of T-cell infiltration into the immunosuppressive tumor microenvironment have hampered current established immunotherapies. Emerging approaches to recruit T cells, to convert phenotypically "cold" into "inflamed" tumors, and to vastly improve therapeutic indices hold exceptional promise. Here, we review these approaches, highlighting the role of the tumor microenvironment and novel antibody platforms to maximize the full clinical potential of immunotherapy in pediatric oncology., (©2020 American Association for Cancer Research.)

Background: The objective of this study was to evaluate local control for patients with intermediate-risk rhabdomyosarcoma (RMS) treated on Children's Oncology Group (COG) protocol ARST0531., Methods: This study analyzed 424 patients with intermediate-risk RMS. Patients were randomized to chemotherapy with either vincristine, dactinomycin, and cyclophosphamide (VAC) or VAC alternating with vincristine and irinotecan. With the goal of improving local control, radiation therapy (RT) was delivered early at week 4 and was concurrent with irinotecan in the experimental arm. Individualized local control plans for children 24 months old or younger were allowed. Local failure on ARST0531 was compared with local failure on the preceding COG intermediate-risk study, D9803., Results: For patients with group I/II alveolar RMS (n = 55), the 5-year cumulative incidence of local failure was 13.4%; for group III alveolar RMS (n = 141), it was 20.2%; and for group III embryonal RMS (n = 228), it was 27.9% (P = .03). Among patients with group III disease, local failure did not differ by histology, site, nodal status, RT modality, or treatment arm. Local failure was worse for a tumor size >5 cm (32.3% vs 16.7%; P = .001). Among patients with group III embryonal RMS, local failure was higher on ARST0531 than D9803 (27.9% vs 19.4%; P = .03). After the exclusion of patients 24 months old or younger or patients who did not receive radiation, local failure remained significantly increased on ARST0531 (P = .02). After adjustments for clinical prognostic factors, event-free survival and overall survival were worse on ARST0531 (P = .004 and P = .05, respectively)., Conclusions: Despite interventions designed to enhance local control, local control was inferior on ARST0531 in comparison with D9803. The reason for this is unclear, but it could be the reduced cyclophosphamide dose on ARST0531., (© 2019 American Cancer Society.)

Ewing sarcoma (ES) family of tumors includes bone and soft tissue tumors that are often characterized by a specific translocation between chromosome 11 and 22, resulting in the EWS-FLI1 fusion gene. With the advent of multi-modality treatment including cytotoxic chemotherapy, surgery, and radiation therapy, the prognosis for patients with ES has substantially improved. However, a therapeutic plateau is now reached for both localized and metastatic disease over the last two decades. Burdened by the toxicity limits associated with the current frontline systemic therapy, there is an urgent need for novel targeted therapeutic strategies. In this review, we discuss the current treatment paradigm of ES, and explore preclinical evidence and emerging treatments directed at tumor signaling pathways and immune targets.

Purpose: For patients with high-risk neuroblastoma (HR-NB), a dose of 21 Gy to the primary tumor site after gross total resection (GTR) provides excellent local control. However, no clinical trial has specifically evaluated the optimal dose of radiation therapy (RT), and RT-related long-term toxicities are of increasing concern. We sought to assess local control, survival outcomes, and toxicity after a reduction in dose to the primary site from 21 Gy to 18 Gy., Methods and Materials: After induction chemotherapy and GTR, patients with HR-NB were enrolled and treated on an RT dose-reduction prospective trial with 18 Gy hyperfractionated RT given in twice-daily fractions of 1.5 Gy each., Results: The 25 study subjects were 1.6 to 9.5 (median, 4.3) years old at enrollment and included 23 (92%) with stage IV and II (8%) with MYCN-amplified stage III disease. Eleven (44%) were in complete remission (CR), and 14 (56%) had persistence of osteomedullary disease postinduction. Three patients (12%) received proton therapy, and the rest received intensity modulated photon therapy. After a follow-up of 1.8 to 4.2 (median, 3.5) years from initiation of RT, no failures occurred within the RT field; 3 patients had marginal recurrences. The respective 3-year progression-free and overall survival rates were 54.5% and 90.9% for patients in first CR and 42.9% and 76.2% for patients not in metastatic CR. Acute toxicity was negligible., Conclusions: Reduced-dose RT with 18 Gy did not compromise local control or survival outcomes in our cohort of patients with HR-NB after GTR. These findings support assessing further RT dose reduction and validation on a larger, multi-institutional trial., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: The presence of brain metastases (BM) in patients with non-seminomatous germ cell tumor (NSGCT) is associated with poor prognosis. While radiation therapy (RT) is an important treatment for patients with NSGCT BM, there is a paucity of data on the optimal regimen. We sought to investigate the impact of RT on clinical outcomes in patients with NSGCT BM., Methods: Patients with NSGCT BM who received RT at our institution from 2002 to 2017 were included. Sixty-three consecutive patients were identified. Clinical factors associated with intracranial control (ICC) and overall survival (OS) were evaluated using cox regression analysis and Kaplan Meier method., Results: Median age was 31 years and number of BM was three. Fifteen patients presented with BM at diagnosis, while 48 developed BM at a median time of 8.4 months from diagnosis. At a median follow-up of 3.6 years, ICC and OS were 39.7% and 30.1%. On multivariate analysis, ICC (hazard ratio [HR] = 0.93, p = 0.03) and OS (HR = 0.93, p = 0.005) were both significantly associated with biologically effective dose (BED) of RT. The 4-year OS of patients who received BED < 39Gy, 39 Gy, 40-50 Gy, and ≥ 50 Gy were 0%, 14.7%, 34.1%, and 70.0%, respectively. Patients who achieved ICC after RT were able to achieve long-term survival (4-year OS 68.1% vs. 0%, p < 0.0001)., Conclusions: Our data supports that a higher BED is required for durable ICC, and that ICC is needed for patients with NSGCT to achieve long-term survival. Prospective studies evaluating radiation dose-escalation for the treatment of NSGCT BM should be considered.

Purpose: This study was designed to compare the observed risk of femoral fracture in primary soft-tissue sarcoma (STS) of the thigh/groin treated with intensity-modulated radiation therapy (IMRT) to expected risk calculated using the Princess Margaret Hospital (PMH) nomogram., Methods: Expected femoral fracture risk was calculated by using the PMH nomogram. Cumulative risk of fracture was estimated by using Kaplan-Meier statistics. Prognostic factors were assessed with univariate and multivariate analysis using Cox's stepwise regression., Results: Between February 2002 and December 2010, 92 consecutive eligible patients were assessed. Median follow-up was 73 months (106 months in surviving patients). IMRT was delivered preoperatively (50 Gy) in 13 (14%) patients and postoperatively in 79 (86%) patients (median dose, 63 Gy; range, 59.4-66.6 Gy). The observed crude risk of fractures was 6.5% compared with 25.6% expected risk from the nomogram; the cumulative risk of fracture using IMRT at 5 years was 6.7% (95% CI 2.8-16.0%). The median time to fracture was 23 months (range, 6.9-88.6). Significant predictors of fracture on univariate analysis were age ≥ 60 years (p = 0.03), tumor location in the anterior thigh (p = 0.008), and periosteal stripping to > 20 cm (p < 0.0001). On multivariate analysis, age ≥ 60 years and periosteal stripping > 20 cm retained significance (p = 0.04 and p = 0.009, respectively)., Conclusions: In this study, the cumulative risk of femur fracture in patients treated with IMRT (6.7%) is less than the expected risk using the PMH nomogram (25.6%). Established predictors of femur fracture, such as gender, tumor size, and dose of RT, seem to have less impact on fracture risk when using IMRT.

Purpose: Recent trends, including the use of proton therapy and administration of reduced doses of cyclophosphamide, have been adapted in head and neck (HN) rhabdomyosarcoma (RMS) to reduce late morbidity. Our primary goal was to analyze local control and survival outcomes after photon versus proton irradiation in pediatric patients with HN-RMS, with the secondary goal of analyzing the effect of cyclophosphamide dose on disease outcomes., Methods and Materials: This single-institution cohort study comprised 76 pediatric HN-RMS patients treated with definitive chemoradiation from 2000 to 2018. Fifty-one patients (67%) received intensity modulated photon radiation therapy, and 25 (33%) received proton therapy., Results: Local failure (LF) at 2 years was 12.5% for parameningeal RMS and 0% for orbital RMS and other head and neck sites (P = .24). Patients treated with protons were more likely to have received reduced-dose cyclophosphamide (P < .0001). The 2-year LF was 7.9% in the intensity modulated photon radiation therapy cohort versus 14.6% in the proton cohort (P = .07), with no difference in survival outcomes. Cumulative cyclophosphamide dose was significantly associated with 2-year LF: 0% for cumulative dose of >20 g/m 2 versus 15.3% for ≤20 g/m 2 (P = .04). In parameningeal RMS patients (n = 59), both cumulative cyclophosphamide dose and dose intensity were associated with LF (P = .01). There was a trend toward worse event-free survival for parameningeal RMS patients who received reduced-dose-intensity cyclophosphamide (59.2% vs 70.6%, P = .11)., Conclusions: Both dose-intensity and cumulative cyclophosphamide dose seem to play an important role in achieving local control for HN-RMS patients treated with either protons or photons. Longer follow-up is needed to further assess disease outcomes with proton therapy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Recurrent meningiomas remain therapeutically challenging, often progressive despite multimodality salvage. There are limited data guiding reirradiation (reRT), and proton beam radiation therapy (PBRT) offers a potential advantage owing to lower integral brain dose., Patients and Methods: We retrospectively conducted a review of 16 patients who received PBRT reRT for recurrent meningiomas. Kaplan-Meier and proportional hazards were used to determine post-PBRT progression-free survival (PFS) and overall survival (OS) and to evaluate clinical predictors., Results: At diagnosis, 7 (44%), 8 (50%), and 1 (6%) patient had World Health Organization (WHO) grade I, II and III tumors, respectively. All received prior radiation therapy (RT) to a median of 54 Gy (range 13-65.5). Median time to PBRT reRT after prior RT was 5.8 years (range 0.7-18.7). Median PBRT dose was 60 Gy(RBE) (range 30-66.6), and median planning tumor volume (PTV) was 76 cm 3 (range 8-249). Median follow-up was 18.8 months. At last follow-up, 7 intracranial recurrences (44%) and 3 disease-related deaths (19%) were found. Median cohort PFS was 22.6 months, with 1- and 2-year PFS of 80% and 43%, respectively. Median OS was not achieved, with 1- and 2-year OS of 94% and 73%; all deaths were felt to be related to meningioma. Patients with initially grade I tumors had improved PFS versus higher grade (Hazard Ratio, HR = 0.23, P  = .03) with 1- and 2-year PFS estimates of 100% versus 71% and 75% versus 29%, respectively. Longer interval between prior RT and PBRT also predicted improved PFS ( P  = .03) and OS ( P  = .049). Overall late grade 3+ toxicity rate was 31%. Two patients (13%) developed radionecrosis at 6 and 16 months after PBRT; only 1 was symptomatic., Conclusions: This is the first series specifically analyzing PBRT alone as a reRT strategy for recurrent meningioma. We report fair intracranial control with low rates of radionecrosis at 1 year after reRT. However, strategies to achieve durable outcomes are needed, particularly for high-grade tumors., Competing Interests: Conflicts of Interest: Dr Yamada serves as a speaker for Varian Medical Systems, BrainLab, and Vision RT Institute for Medical Education. He also sits on the medical advisory board of the Chordoma Foundation. All other authors declare that there are no relevant conflicts of interest, financial or personal, that might bias or be seen to bias their work for this submission. All authors contributed substantially to the study and approved the final version of the manuscript. This manuscript, or any part of it, has not been previously published nor submitted concurrently to any other journal., (© Copyright 2019 The Author(s).)

Background: Locoregional failure is common after subtotal resection in high-risk neuroblastoma. Although a dose of 21 Gy radiation therapy (RT) is standard for treatment of high-risk neuroblastoma after gross total resection, the dose needed for local control of patients with gross residual disease at the time of RT is unknown. We sought to evaluate local control after 21-36 Gy RT in patients with high-risk neuroblastoma undergoing subtotal resection., Methods: All patients with high-risk neuroblastoma who received RT to their primary site from 2000 to 2016 were reviewed. Of the 331 patients who received consolidative RT to their primary site, 19 (5.7%) underwent subtotal resection and were included in our analysis. Local failure (LF) was correlated with biologic prognostic factors and dose of RT., Results: Median follow-up among surviving patients was 6.0 years. Median RT dose was 25 Gy (range, 21 Gy-36 Gy). The 5-year cumulative incidence of LF among all patients was 17.2%. LF at 5 years was 30% in those who received <30 Gy versus 0% in those who received 30-36 Gy (P = 0.12). There was a trend towards improved local control in patients with tumor size ≤10 cm at diagnosis (P = 0.12). The 5-year event-free and overall survival were 44.9% and 68.7%, respectively., Conclusion: After subtotal resection, patients who received less than 30 Gy had poor local control. Doses of 30-36 Gy are likely needed for optimal control of gross residual disease at the time of consolidative RT in high-risk neuroblastoma., (© 2018 Wiley Periodicals, Inc.)

Purpose: As part of consolidative therapy in high-risk neuroblastoma, modern protocols recommend radiation therapy (RT) both to the primary site and to sites of metastatic disease that persist after induction chemotherapy. Although there are abundant data showing excellent local control (LC) with 21 Gy directed at the primary site, there are few data describing the feasibility and efficacy of RT directed at metastatic sites of disease as part of consolidation., Methods and Materials: All patients with neuroblastoma who received RT to metastatic sites of disease as a part of consolidative therapy at a single institution between 2000 and 2015 were reviewed. Among 159 patients, 244 metastases were irradiated., Results: The median follow-up period among surviving patients was 7.4 years. Over 85% of the irradiated metastases were treated with 21 Gy (range, 10.5-36 Gy). Tumor recurrence occurred in 43 of 244 irradiated metastases (18%). The 5-year LC rate of treated metastatic sites was 81%. Metastatic sites that cleared with induction chemotherapy had improved LC compared with sites with persistent uptake on metaiodobenzylguanidine scans (LC rate, 92% vs 67%; P < .0001). LC at irradiated metastatic sites did not differ based on total number of sites irradiated or site of disease irradiated (bone vs soft tissue). Patients with bulky, resistant disease who were treated with 30 to 36 Gy had worse LC (P = .02). However, on multivariate analysis, only persistence after induction chemotherapy remained a significant prognostic factor for LC (hazard ratio, 3.7; P < .0001). Patients who had LC at irradiated metastatic sites had improved overall survival compared with those who did not (overall survival rate, 71% vs 50%; P < .0001)., Conclusions: Response to chemotherapy is an important prognostic factor for LC at irradiated metastatic sites in neuroblastoma. Overall, consolidative RT appears to be an effective modality of LC. Long-term disease control can be achieved with such an approach., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Head and neck rhabdomyosarcoma (HNRMS) is a uniquely challenging site to treat given the young patient age and critical anatomy of the head and neck region. We review the characteristics, management, and future directions in the treatment of HNRMS. Most patients who present with HNRMS have unresectable disease due to functional and/or cosmetic constraints. However, surgical resection and brachytherapy serve a critical role in select patients. The treatment paradigm for the majority of patients with HNRMS consists of definitive chemotherapy and radiation therapy. As the incidence of late toxicities increases with improved survival, modern efforts must focus on ways to decrease long-term morbidity. We recommend a multimodal approach emphasizing the preservation of form and function for the treatment of HNRMS.

Purpose: To analyze the renal function outcomes in patients undergoing radiation therapy for neuroblastoma., Methods and Materials: The clinical metrics of renal function were analyzed in patients undergoing radiation therapy for high-risk neuroblastoma from 2000 to 2015. The blood urea nitrogen (BUN) and creatinine values before radiation therapy were compared with last available follow-up values and analyzed with the clinical circumstances, including follow-up length, age at primary irradiation, nephrectomy, and radiation technique. The creatinine clearance was estimated using the Shull method., Results: With a median follow-up period of 3.5 years, none of the 266 patients studied developed a chronic renal insufficiency. For all patients, the creatinine level increased from 0.44 to 0.51 mg/dL and the BUN increased from 10.53 to 15.52 mg/dL. Three patients required antihypertensive medication. The patients who underwent intensity modulated radiation therapy did not experience increased creatinine levels during the follow-up period; however, they had a reduced median follow-up length compared with patients treated with anteroposterior/posteroanterior beams (4.7 vs 3.3 years). A longer follow-up length was associated with an increased creatinine level. The preradiation therapy creatinine level increased with patient age, similar to that of the last follow-up creatinine level, suggesting that the changes in creatinine could likely be explained by physiologic increases associated with aging rather than radiation-induced renal damage. The creatinine clearance did not decrease in any circumstance., Conclusions: The present cohort had excellent renal outcomes after radiation therapy for neuroblastoma. No patient developed chronic renal insufficiency, and the small increases in BUN and creatinine we observed correlated, as expected, with increases in patient age. The results of the present study revealed a possible advantage for intensity modulated radiation therapy in preserving renal function; however, the follow-up length is a recognized confounding variable. The kidneys are vital structures to consider when planning radiation therapy for neuroblastoma patients, and we have found encouraging evidence that modern techniques to spare them in the setting of multiple treatment-related insults have been successful., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: To evaluate local control after 21-Gy radiation therapy (RT) to the primary site in patients with high-risk neuroblastoma., Methods and Materials: After receiving dose-intensive chemotherapy and gross total resection (GTR), 246 patients (aged 1.2-17.9 years, median 4.0 years) with high-risk neuroblastoma underwent RT to the primary site at Memorial Sloan Kettering from 2000 to 2014. Radiation therapy consisted of 21 Gy in twice-daily fractions of 1.5 Gy each. Local failure (LF) was correlated with biologic prognostic factors and clinical findings at the time of diagnosis and start of RT., Results: Median follow-up of surviving patients was 6.4 years. Cumulative incidence of LF was 7.1% at 2 years after RT and 9.8% at 5 years after RT. The isolated LF rate was 3.0%. Eighty-six percent of all local failures were within the RT field. Local control was worse in patients who required more than 1 surgical resection to achieve GTR (22.4% vs 8.3%, P=.01). There was also a trend toward inferior local control with MYCN-amplified tumors or serum lactate dehydrogenase ≥1500 U/L (P=.09 and P=.06, respectively)., Conclusion: After intensive chemotherapy and maximal surgical debulking, hyperfractionated RT with 21 Gy in high-risk neuroblastoma results in excellent local control. Given the young patient age, concern for late effects, and local control >90%, dose reduction may be appropriate for patients without MYCN amplification who achieve GTR., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose/objectives: To examine the late effects of intensity-modulated radiation therapy (IMRT) in pediatric patients with rhabdomyosarcoma of the head and neck., Materials/methods: All 1-year survivors of pediatric head and neck rhabdomyosarcoma treated with IMRT at a single institution from 1999 to 2014 were assessed for long-term complications. Late toxicities were graded according to CTCAE version 4.03., Results: Among 30 patients, median age at IMRT was 7.4 (1.5-20.8) years, median follow-up was 7.7 (1.2-14.4) years, and median IMRT dose was 50.4 (36-50.4) Gy. Tumor subsites included parameningeal (80%), orbit (13%), and other (7%). Common late toxicities were facial disfigurement (n = 23, 77%), growth hormone deficiency (n = 11, 37%), cataract (n = 10, 34%), and dental problems (n = 10, 33%). Twenty-two patients (73%) had ≥2 late toxicities and 14 patients (47%) had ≥3 late toxicities. Seventeen patients (57%) experienced grade 2 toxicity and 10 patients (33%) had grade 3 toxicity. Grade 3 toxicities included visual disturbance, cataract, facial disfigurement, chronic sinusitis/otitis, and hearing loss. Severe facial deformity was noted in nine patients (30%), and three patients underwent cosmetic surgery. Patients with severe facial deformity were treated at younger ages (median 6.0 years vs. 8.1 years for patients with no/nonsevere facial deformity) and more likely to have infratemporal fossa tumors. There were no secondary solid malignancies., Conclusions: Late radiation toxicities are common in survivors of pediatric head and neck rhabdomyosarcoma treated with IMRT. While the majority of late effects are mild-moderate, they can significantly impact quality of life, particularly facial disfigurement., (© 2016 Wiley Periodicals, Inc.)

Background: Extraskeletal osteosarcoma of the hand is rare, and its optimal modality of local control is not currently known., Methods: A literature search was performed to identify studies that describe the treatment and outcomes of extraskeletal osteosarcoma. A second literature search was performed to identify studies that describe the treatment and outcomes of extraskeletal osteosarcoma of the hand specifically., Results: The role of adjuvant radiation for extraskeletal osteosarcoma is not well defined. All cases in the literature describing treatment of extraskeletal osteosarcoma of the hand utilized amputation, and none of the patients described received radiation therapy. However, there are multiple reports showing excellent local control, minimal toxicity, and superior functional outcome with limb conservation and radiation rather than amputation of the hand in pediatric and adult soft tissue sarcoma., Conclusion: For extraskeletal osteosarcoma of the hand, we recommend a treatment approach with the goal of preservation of form and function using limb-sparing surgery and planned postoperative radiation.

Background: The role, optimal dose, and efficacy of radiotherapy (RT) for the treatment of bone metastases in rhabdomyosarcoma (RMS) and Ewing sarcoma (ES) are unclear., Procedure: All patients with ES or RMS who received RT for bone metastases with curative intent during frontline therapy at Memorial Sloan Kettering Cancer Center (MSKCC) between 1995 and 2013 were reviewed. Among the 30 patients (8 RMS and 22 ES), 49 bone metastases were irradiated., Results: Median biologically effective dose (BED) was 42.4 Gy (range, 34.9-59.7) for RMS and 50.7 Gy (range, 31.3-65.8) for ES. Tumor recurrence occurred in six of 49 irradiated bone metastases. Cumulative incidence of local failure at a treated metastatic site was 6.6% at 1 year and 9.0% at 3 years. Dose, fractionation, and RT technique did not impact local control at an irradiated site. The presence of >5 bone metastases was associated with worse local control at an irradiated site (P = 0.07). The 3-year EFS was 33% in RMS and 16% in ES., Conclusions: RT appears to be an effective modality of local control for bone metastases in ES and RMS. Local control at sites of metastatic bone irradiation is similar to local control at the primary site after definitive RT. Doses in the biologic range prescribed for the definitive treatment of primary disease should be used for metastatic sites of disease., Competing Interests: Nothing to declare., (© 2014 Wiley Periodicals, Inc.)

Background: Treatment with radiotherapy (RT) is associated with an increased risk of second malignant neoplasms (SMNs) in childhood cancer survivors; it is unclear how treatment with intensity-modulated radiation therapy (IMRT) impacts this risk. We provide the first report of SMN risk in a cohort of childhood cancer survivors treated with IMRT., Procedure: Retrospective review of patients ≤21 years of age treated with IMRT at Memorial Sloan Kettering Cancer Center between December 1998 and February 2009. Eligible patients survived at least 5 years from IMRT initiation. The risk of SMN was assessed via standardized incidence ratios (SIRs) and excess absolute risk (EAR). The cumulative incidence was estimated using methods for competing risks., Results: Among 242 patients, six developed SMNs: four developed second solid cancers (all within the radiation field), and two developed myelodysplastic syndrome. Median time from IMRT initiation to a second solid cancer was 7.2 years (range, 6.8-9.5), with a 10-year cumulative incidence of 3.3% (95% confidence interval [CI], 1.0-7.8%), SIR of 11.4 (95% CI, 3.1-29.2) and EAR of 1.8 per 1,000 person-years (95% CI, -0.1 to 3.8)., Conclusions: Longer follow-up is required to determine how the risk of SMN after IMRT compares to other modalities of radiation treatment, such as proton therapy. This study provides a preliminary report, which will serve as a baseline for future longitudinal analyses of SMN risk after IMRT. Pediatr Blood Cancer 2015;62:311-316. © 2014 Wiley Periodicals, Inc., (© 2014 Wiley Periodicals, Inc.)

Purpose: To evaluate whether [(18)F]fluorodeoxyglucose positron emission tomography (FDG-PET) response of the primary tumor after induction chemotherapy predicts outcomes in rhabdomyosarcoma (RMS)., Methods and Materials: After excluding those with initial tumor resection, 107 patients who underwent FDG-PET after induction chemotherapy at Memorial Sloan Kettering Cancer Center from 2002 to 2013 were reviewed. Local control (LC), progression-free survival (PFS), and overall survival (OS) were calculated according to FDG-PET response and maximum standardized uptake value (SUV) at baseline (PET1/SUV1), after induction chemotherapy (PET2/SUV2), and after local therapy (PET3/SUV3). Receiver operator characteristic curves were used to determine the optimal cutoff for dichotomization of SUV1 and SUV2 values., Results: The SUV1 (<9.5 vs ≥9.5) was predictive of PFS (P=.02) and OS (P=.02), but not LC. After 12 weeks (median) of induction chemotherapy, 45 patients had negative PET2 scans and 62 had positive scans: 3-year PFS was 72% versus 44%, respectively (P=.01). The SUV2 (<1.5 vs ≥1.5) was similarly predictive of PFS (P=.005) and was associated with LC (P=.02) and OS (P=.03). A positive PET3 scan was predictive of worse PFS (P=.0009), LC (P=.05), and OS (P=.03)., Conclusions: [(18)F]fluorodeoxyglucose positron emission tomography is an early indicator of outcomes in patients with RMS. Future prospective trials may incorporate FDG-PET response data for risk-adapted therapy and early assessment of new treatment regimens., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background and Purpose: To evaluate local control and survival outcomes in adults with Ewing sarcoma (ES) treated with radiotherapy (RT)., Material and Methods: Retrospective review of all 109 patients age ⩾18 treated for ES with RT to the primary site at Memorial Sloan Kettering Cancer Center between 1990 and 2011. RT was used as the definitive local control modality in 44% of patients, preoperatively for 6%, and postoperatively for 50%., Results: Median age at diagnosis was 27years (range, 18-67). The 5-year local failure (LF) was 18%. Differences in LF were not identified when evaluated by modality of local control (RT versus combined surgery and RT), RT dose, fractionation, and RT technique. However, margin status at time of resection significantly predicted LF. The 5-year event-free survival and overall survival rates were 44% and 66% for patients with localized disease, compared with 16% and 26% for metastatic disease (p=0.0005 and 0.0002). Tumor size, histopathologic response to chemotherapy, and treatment on or according to a protocol were also significantly associated with survival., Conclusions: This series of adults treated with modern chemotherapy and RT had prognostic factors and outcomes similar to adolescents with ES. All adults with ES should be treated with an aggressive, multidisciplinary approach., (Copyright © 2014. Published by Elsevier Ireland Ltd.)

Background: Current Children's Oncology Group (COG) guidelines recommend 24 Gy whole abdominopelvic radiation therapy (WAP-RT) for pediatric patients with sarcoma with peritoneal dissemination and/or malignant ascites. However, WAP-RT has never been described for pediatric sarcoma excluding desmoplastic small round-cell tumor (DSRCT). The objective of this study was to evaluate feasibility, outcomes, and toxicity of WAP-RT in children with sarcoma and peritoneal dissemination., Procedure: Detailed records of all 10 pediatric patients with sarcoma (excluding DSRCT) treated with WAP-RT from 2001 to 2013 were reviewed., Results: Median age was 9.9 years (range, 1.7-33.8). Seven patients had rhabdomyosarcoma, 2 embryonal undifferentiated sarcoma of the liver, and 1 Ewing sarcoma. Patients received a median dose of 24 Gy with intensity-modulated radiation therapy (IMRT) to the whole abdomen and pelvis. Two patients did not complete treatment, one due to transfusion-resistant pancytopenia and one due to moderate acute gastrointestinal toxicity. At a median follow-up of 4.0 years, both relapse-free survival and overall survival were 100%. Acute hematologic toxicities were common, with 40% of patients developing a grade 4 hematologic toxicity. Most acute gastrointestinal toxicities were grade 1 and managed appropriately with anti-diarrheals and anti-emetics. Late effects varied, and half of patients are without long-term sequelae., Conclusions: All patients remain free of disease, both locally and distantly. Although WAP-RT was associated with acute and late toxicity, treatment was feasible with supportive care. Given the excellent rates of tumor control, we recommend that all providers give WAP-RT with IMRT to patients with pediatric sarcoma and peritoneal dissemination and/or malignant ascites., (© 2014 Wiley Periodicals, Inc.)

Purpose: To evaluate feasibility and patterns of failure in adult patients with Ewing sarcoma (ES) treated with whole lung irradiation (WLI) for pulmonary metastases., Methods and Materials: Retrospective review of all ES patients treated at age 18 or older with 12-15 Gy WLI for pulmonary metastases at a single institution between 1990 and 2014. Twenty-six patients met the study criteria., Results: The median age at WLI was 23 years (range, 18-40). The median follow-up time of the surviving patients was 3.8 years (range, 1.0-9.6). The 3-year cumulative incidence of pulmonary relapse (PR) was 55%, with a 3-year cumulative incidence of PR as the site of first relapse of 42%. The 3-year event-free survival (EFS) and overall survival (OS) were 38 and 45%, respectively. Patients with exclusively pulmonary metastases had better outcomes than did those with extrapulmonary metastases: the 3-year PR was 45% in those with exclusively lung metastases versus 76% in those with extrapulmonary metastases (P=.01); the 3-year EFS was 49% versus 14% (P=.003); and the 3-year OS was 61% versus 13% (P=.009). Smoking status was a significant prognostic factor for EFS: the 3-year EFS was 61% in nonsmokers versus 11% in smokers (P=.04). Two patients experienced herpes zoster in the radiation field 6 and 12 weeks after radiation. No patients experienced pneumonitis or cardiac toxicity, and no significant acute or late sequelae were observed among the survivors., Conclusion: WLI in adult patients with ES and lung metastases is well tolerated and is associated with freedom from PR of 45% at 3 years. Given its acceptable toxicity and potential therapeutic effect, WLI for pulmonary metastases in ES should be considered for adults, as it is in pediatric patients. All patients should be advised to quit smoking before receiving WLI., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: To analyze prognostic factors and patterns of failure for rhabdomyosarcoma of the perineal and perianal region (PRMS), with an emphasis on radiation therapy for locoregional control., Methods and Materials: Detailed records of all 14 patients treated for PRMS at Memorial Sloan-Kettering Cancer Center between 1998 and 2012 were reviewed. The Kaplan-Meier method was used to assess the event-free survival (EFS) and overall survival (OS), and a competing-risks analysis was used to assess the cumulative incidence of local, regional, and distant failures., Results: Median age was 15.8 years (range, 1.1-31.9 years). High-risk features were identified: 9 of 14 patients (64%) had group 3 disease and 3 of 14 (21%) had group 4; 11 of 14 tumors (78%) were alveolar; 12 of 14 tumors (86%) were ≥5 cm; and 9 of 14 patients (64%) had involved lymph nodes (N1). Of those aged ≥10 years at diagnosis, 9 of 10 (90%) had alveolar histology, all had tumors ≥5 cm, and 8 of 10 (80%) presented with N1 disease. The rates of local, regional, and distant failure at 5 years were 17%, 31%, and 52%, respectively. Although 3 of the 4 patients with regional failure received nodal irradiation, only one of the nodal failures occurred in the radiation therapy field. The 5-year EFS was 33%, and OS was 39%. Age ≥10 years was associated with poor outcomes: EFS was 13% in patients aged ≥10 years, compared with 75% in those aged <10 years (P=.04); the OS was 13% in patients aged ≥10 years, compared with 100% in those aged <10 years (P=.04)., Conclusions: Patients with PRMS, especially those aged ≥10 years, present with poor prognostic features and continue to have poor outcomes. Given the high incidence of regional node recurrence, we recommend prophylactic ilioinguinal lymph node irradiation for all patients aged ≥10 years. For children aged <10 years, nodal evaluation is essential to determine the role for lymph node irradiation., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The tension between scientific openness versus secrecy has existed for centuries (Hull 1985). However, both academics and practitioners have recently argued that openness by private firms has many positive attributes. The purpose of this research effort is to review the extant literature on openness and to develop hypotheses regarding its impact on organizational outcomes. We then use a unique database to test the idea with 87 companies. Our findings are that openness is beneficial to the firm from a science, technological, and financial perspective and, perhaps, to the employees from an ethical viewpoint. The managerial and societal implications are also discussed.

Background: A facial resurfacing regimen combining manual abrasion of the skin and 25% trichloroacetic acid has been reported to produce excellent results, but the histologic depth of injury produced by this technique has not been studied., Objective: To describe our experience with this technique treating patients with extensive actinic damage and to determine the histologic depth of injury produced., Method: We treated 40 patients using manual resurfacing and trichloroacetic acid, primarily for widespread actinic keratoses. Resurfacing tools included silicone carbide sandpaper, drywall screen, electrocautery tip cleaners, abrasive pads, scalpel blades, and curettes. Four patients underwent sequential biopsies to evaluate the depth of wounding using this technique., Results: Manual resurfacing combined with trichloroacetic acid consistently produced excellent cosmetic results and nearly complete eradication of actinic keratoses. Histologically, treated areas showed replacement of the dermal elastotic band by newly formed collagen, a significantly deeper level of wounding than the Jessner's/35% trichloroacetic acid peel. There was no evidence for foreign body granulomas clinically or histologically as a result of the abrasive materials., Conclusions: The deeper level of this peel explains the improved cosmetic outcome and greater eradication of actinic keratoses. This treatment is particularly well suited for patients with extensive photodamage and widespread actinic keratoses.