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Abstract Lymphoma is one of the most common cancers in adolescents and young adults, but historically, this population has had lower clinical trial enrollment and improvements in overall survival as compared to other age populations. There are multiple challenges that are unique to this population that have affected drug development and clinical trial enrollment. Our panel of experts have identified barriers, and in this review, we discuss current methods to address these barriers as well as potential solutions moving forward.

AbstractSleep inertia is the brief period of impaired alertness and performance experienced immediately after waking. Little is known about the neural mechanisms underlying this phenomenon. A better understanding of the neural processes during sleep inertia may offer insight into the awakening process. We observed brain activity every 15 min for 1 hr following abrupt awakening from slow wave sleep during the biological night. Using 32-channel electroencephalography, a network science approach, and a within-subject design, we evaluated power, clustering coefficient, and path length across frequency bands under both a control and a polychromatic short-wavelength-enriched light intervention condition. We found that under control conditions, the awakening brain is typified by an immediate reduction in global theta, alpha, and beta power. Simultaneously, we observed a decrease in the clustering coefficient and an increase in path length within the delta band. Exposure to light immediately after awakening ameliorated changes in clustering. Our results suggest that long-range network communication within the brain is crucial to the awakening process and that the brain may prioritize these long-range connections during this transitional state. Our study highlights a novel neurophysiological signature of the awakening brain and provides a potential mechanism by which light improves performance after waking.

A complete simulation chain for the laser-based generation of a microfocus-size gamma ray beam of multi-MeV energy range able to produce radiographic images has been developed. The major interactions needed to obtain such a beam are treated individually. Particle-in-cell is used to study the generation of the electron beam through laser wake-field acceleration (LWFA), and Geant4 is employed for the Bremsstrahlung photon emission and for testing the imaging capabilities of the generated gamma beam. The paper presents detailed discussions about the implementation of each simulation, along with the results obtained. The structure of the article walks through the LWFA of up to 100 MeV electron beam, followed by its attenuation through a tantalum foil generating a 300 μ m spot size photon beam, later used for imaging of a thick lead test-object, assessing a 100 μ m resolution, and confirming the simulated imaging setup suitability for non-destructive testing applications of thick high-density objects. An analysis of the quality control parameters for the generated image along with discussions of possible improvements is also included. [ABSTRACT FROM AUTHOR]

Improvements in outcome have been seen in children and adolescents with cancer. Nevertheless, challenges remain in trying to improve the outcomes for all children diagnosed with cancer, particularly in patients with metastatic disease or with cancers that are resistant or recur after standard treatment. Precision medicine trials using individualized tumor molecular profiling for selection of targeted therapies are ongoing in adult malignancies. Similar approaches are being applied to children and adolescents with cancer. This article describes how precision medicine is being applied to pediatric oncology and the unique challenges being faced with these efforts.

Our paper describes the design and delivery of an online interdisciplinary social science research methods course (ISRM) for graduate students in sociology, education, social work, and public administration. Collaborative activities and learning took place in two types of computer-mediated learning environments: a closed Blackboard course management system and a public facing "openly-networked connected learning" environment designed to facilitate cross-discipline connections, student engagement, and digital fluency. A course formative assessment based on student feedback and instructors' reflections informed the lessons learned about the design and delivery of the course. Our assessment suggests that many of the connected learning goals can be met through the closed course management system rather than through the open platform.

PurposeIn National Wilms Tumor Study 5 (NWTS-5), tumor-specific combined loss of heterozygosity of chromosomes 1p and 16q (LOH1p/16q) was associated with adverse outcomes in patients with favorable histology Wilms tumor. The AREN0533/AREN0532 studies assessed whether augmenting therapy improved event-free survival (EFS) for these patients. Patients with stage I/II disease received regimen DD4A (vincristine, dactinomycin and doxorubicin) but no radiation therapy. Patients with stage III/IV disease received regimen M (vincristine, dactinomycin, and doxorubicin alternating with cyclophosphamide and etoposide) and radiation therapy.MethodsPatients were enrolled through the AREN03B2 Biology study between October 2006 and October 2013; all underwent central review of pathology, surgical reports, and imaging. Tumors were evaluated for LOH1p/16q by microsatellite testing. EFS and overall survival were compared using the log-rank test between NWTS-5 and current studies.ResultsLOH1p/16q was detected in 49 of 1,147 evaluable patients with stage I/II disease (4.27%) enrolled in AREN03B2; 32 enrolled in AREN0532. LOH1p/16q was detected in 82 of 1,364 evaluable patients with stage III/IV disease (6.01%) in AREN03B2; 51 enrolled in AREN0533. Median follow-up for 83 eligible patients enrolled in AREN0532/0533 was 5.73 years (range, 2.84 to 9.63 years). The 4-year EFS for patients with stage I/II and stage III/IV disease with LOH1p/16 was 87.3% (95% CI, 75.1% to 99.5%) and 90.2% (95% CI, 81.8% to 98.6%), respectively. These results are improved compared with the NWTS-5 updated 4-year EFS of 68.8% for patients with stage I/II disease (P = .042), and 61.3% for patients with stage III/IV disease (P = .001), with trends toward improved 4-year overall survival. The most common grade 3 or higher nonhematologic toxicities with regimen M were febrile neutropenia (39.2%) and infections (21.6%).ConclusionAugmentation of therapy improved EFS for patients with favorable histology Wilms tumor and LOH1p/16q compared with the historical NWTS-5 comparison group, with an expected toxicity profile.

Purpose The National Wilms Tumor Study (NWTS) treatment of favorable histology Wilms tumor with lung metastases was vincristine/dactinomycin/doxorubicin (DD4A) and lung radiation therapy (RT). The AREN0533 study applied a new risk stratification and treatment strategy to improve event-free survival (EFS) while reducing exposure to lung RT. Methods Patients with favorable histology Wilms tumor and isolated lung metastases showing complete lung nodule response (CR) after 6 weeks of DD4A continued receiving chemotherapy without lung RT. Patients with incomplete response (IR) or loss of heterozygosity at chromosomes 1p/16q received lung RT and four cycles of cyclophosphamide/etoposide in addition to DD4A drugs (Regimen M). AREN0533 was designed to preserve a 4-year EFS of 85% for lung nodule CR and improve 4-year EFS from 75% to 85% for lung nodule IR. Results Among 292 assessable patients, 133 had CR and 159 had IR. For patients with CR, 4-year EFS and overall survival (OS) estimates were 79.5% (95% CI, 71.2% to 87.8%) and 96.1% (95% CI, 92.1% to 100%), respectively. Expected versus observed event rates were 15% and 20.2% ( P = .052), respectively. For patients with IR, 4-year EFS and OS estimates were 88.5% (95% CI, 81.8% to 95.3%) and 95.4% (95% CI, 90.9% to 99.8%), respectively. Expected versus observed event rates were 25% and 12.2% ( P < .001), respectively. Overall, 4-year EFS and OS were 85.4% (95% CI, 80.5% to 90.2%) and 95.6% (95% CI, 92.8% to 98.4%) compared with 72.5% (95% CI, 66.9% to 78.1%; P < .001) and 84.0% (95% CI, 79.4% to 88.6%; P < .001), respectively, in the predecessor NWTS-5 study. Conclusion Excellent OS was achieved after omission of primary lung RT in patients with lung nodule CR, although there were more events than expected. EFS was significantly improved, with excellent OS, in patients with lung nodule IR using four cycles of cyclophosphamide/etoposide in addition to DD4A drugs. The overall AREN0533 treatment strategy yielded EFS and OS estimates that were superior to previous studies.

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Background: On the fifth National Wilms Tumor Study, treatment for clear cell sarcoma of the kidney (CCSK) included combined vincristine, doxorubicin, cyclophosphamide, and etoposide (regimen I) plus radiation therapy (RT), yielding 5‐year event‐free survival (EFS) rates of 100%, 88%, 73%, and 29% for patients who had with stage I, II, III, and IV disease, respectively. In the Children's Oncology Group study AREN0321 of risk‐adapted therapy, RT was omitted for stage I disease if lymph nodes were sampled, and carboplatin was added for stage IV disease (regimen UH‐1). Patients who had stage II/III disease received regimen I with RT. Methods: Four‐year EFS was analyzed for patients enrolled on AREN0321 and on those enrolled on AREN03B2 who received AREN0321 stage‐appropriate chemotherapy. Results: Eighty‐two patients with CCSK enrolled on AREN0321, 50 enrolled on AREN03B2 only. The 4‐year EFS rate was 82.7% (95% confidence interval [CI], 74.8%–91.4%) for AREN0321 and 89.6% (95% CI, 81.3%–98.7%) for AREN03B2 only (p =.28). When combining studies, the 4‐year EFS rates for patients who had stage I (n = 10), II (n = 47), III (n = 65), and IV (n = 10) disease were 90% (95% CI, 73.2%–100.0%), 93.4% (95% CI, 86.4%–100.0%), 82.8% (95% CI, 74.1%–92.6%), and 58.3% (95% CI, 34%–100.0%), respectively. There were no local recurrences among seven patients with stage I disease who were treated without RT. One stage I recurrence occurred in the brain, which was the most common site of relapse overall. Among patients with local stage III tumors, neither initial procedure type, margin status, nor lymph node involvement were prognostic. Conclusions: Patients with stage I CCSK had excellent outcomes without local recurrences when treated without RT. Patients with stage IV disease appeared to benefit from a carboplatin‐containing regimen, although their outcomes remained unsatisfactory. Further research is needed to improve outcomes for patients with advanced‐stage disease (ClinicalTrials.gov identifiers NCT00335556 and NCT00898365). The results of this study indicate that treatment of clear cell sarcoma of the kidney can be risk‐adapted based on disease stage, radiotherapy should be omitted for patients with stage I disease if lymph nodes are sampled, and patients with stage IV disease appear to benefit from a carboplatin‐containing regimen. With treatment according to the Children's Oncology Group AREN0321 study, most relapses occurred within 3 years, and the most common sites of recurrence were in the central nervous system. [ABSTRACT FROM AUTHOR]

PurposeStagnant outcomes for adolescents and young adults (AYAs; 15 to 39 years old) with cancer are partly attributed to poor enrollment onto clinical trials. The National Cancer Institute (NCI) Community Clinical Oncology Program (CCOP) was developed to improve clinical trial participation in the community setting, where AYAs are most often treated. Further, many CCOP sites had pediatric and medical oncologists with collaborative potential for AYA recruitment and care. For these reasons, we hypothesized that CCOP sites enrolled proportionately more AYAs than non-CCOP sites onto Children's Oncology Group (COG) trials.MethodsFor the 10-year period 2004 through 2013, the NCI Division of Cancer Prevention database was queried to evaluate enrollments into relevant COG studies. The proportional enrollment of AYAs at CCOP and non-CCOP sites was compared and the change in AYA enrollment patterns assessed. All sites were COG member institutions.ResultsAlthough CCOP sites enrolled a higher proportion of patients in cancer control studies than non-CCOP sites (3.5% v 1.8%; P < .001), they enrolled a lower proportion of AYAs (24.1% v 28.2%, respectively; P < .001). Proportional AYA enrollment at CCOP sites decreased during the intervals 2004 through 2008 and 2009 through 2013 (26.7% v 21.7%; P < .001).ConclusionDespite oncology practice settings that might be expected to achieve otherwise, CCOP sites did not enroll a larger proportion of AYAs in clinical trials than traditional COG institutions. Our findings suggest that the CCOP (now the NCI Community Oncology Research Program) can be leveraged for developing targeted interventions for overcoming AYA enrollment barriers.

Cancer is the leading disease-related cause of death in adolescents and young adults (AYAs). This population faces many short- and long-term health and psychosocial consequences of cancer diagnosis and treatment, but many programs for cancer treatment, survivorship care, and psychosocial support do not focus on the specific needs of AYA cancer patients. Recognizing this health care disparity, the National Cancer Policy Forum of the Institute of Medicine convened a public workshop to examine the needs of AYA patients with cancer. Workshop participants identified many gaps and challenges in the care of AYA cancer patients and discussed potential strategies to address these needs. Suggestions included ways to improve access to care for AYAs, to deliver cancer care that better meets the medical and psychosocial needs of AYAs, to develop educational programs for providers who care for AYA cancer survivors, and to enhance the evidence base for AYAs with cancer by facilitating participation in research.

There has been little improvement in the survival of adolescent and young adult (AYA) cancer patients aged 15 to 39 years relative to other age groups, raising the question of whether such patients receive appropriate initial treatment. We examined receipt of initial cancer treatment for a population-based sample of 504 AYAs diagnosed in 2007-2008 with acute lymphoblastic leukemia (ALL), Hodgkin's or non-Hodgkin's lymphoma, germ cell cancer, or sarcoma. Registry data, patient surveys, and detailed medical record reviews were used to evaluate the association of patient demographic, socioeconomic, and health care setting characteristics with receipt of appropriate initial treatment, which was defined by clinical specialists in AYA oncology based on adult guidelines and published literature available before 2009 and analyzed with multivariable logistic regression. All statistical tests were two-sided. Approximately 75% of AYA cancer patients in our sample received appropriate treatment, 68% after excluding stage I male germ cell patients who all received appropriate treatment. After this exclusion, appropriate treatment ranged from 79% of sarcoma patients to 56% of ALL patients. Cancer type (P < .01) and clinical trial participation (P = .04) were statistically significantly associated with appropriate treatment in multivariable analyses. Patients enrolled in clinical trials were more likely to receive appropriate therapy relative to those not enrolled (78% vs 67%, adjusted odds ratio = 2.6, 95% confidence interval = 1.1 to 6.4). Except for those with early stage male germ cell tumors, approximately 30% (or 3 in 10) AYA cancer patients did not receive appropriate therapy. Further investigation is required to understand the reasons for this potential shortfall in care delivery.

Despite successful primary tumor treatment, the development of pulmonary metastasis continues to be the most common cause of mortality in patients with osteosarcoma. A conventional drug development path requiring drugs to induce regression of established lesions has not led to improvements for patients with osteosarcoma in more than 30 years. On the basis of our growing understanding of metastasis biology, it is now reasonable and essential that we focus on developing therapeutics that target metastatic progression. To advance this agenda, a meeting of key opinion leaders and experts in the metastasis and osteosarcoma communities was convened in Bethesda, Maryland. The goal of this meeting was to provide a "Perspective" that would establish a preclinical translational path that could support the early evaluation of potential therapeutic agents that uniquely target the metastatic phenotype. Although focused on osteosarcoma, the need for this perspective is shared among many cancer types. The consensus achieved from the meeting included the following: the biology of metastatic progression is associated with metastasis-specific targets/processes that may not influence grossly detectable lesions; targeting of metastasis-specific processes is feasible; rigorous preclinical data are needed to support translation of metastasis-specific agents into human trials where regression of measurable disease is not an expected outcome; preclinical data should include an understanding of mechanism of action, validation of pharmacodynamic markers of effective exposure and response, the use of several murine models of effectiveness, and where feasible the inclusion of the dog with naturally occurring osteosarcoma to define the activity of new drugs in the micrometastatic disease setting.

Objective: The aim of this study was to describe the clinical, confocal microscopic, histologic, and virologic features of horses with macrodendritic ulcerative keratitis and conjunctival lymphoid hyperplasia associated with equine herpesvirus‐2 and equine herpesvirus‐5 infection. Animal Studied: Four foals with bilateral ocular disease. Procedures: Complete ophthalmic examination was performed for each horse, and corneal samples were collected for cytology and microbiologic evaluation, including virus isolation and molecular diagnostics for the equine herpesviruses. In vivo confocal microscopy examination of the cornea was performed in two horses. Conjunctival biopsies for histopathology were collected from two horses with nodular conjunctival thickening. Results: Each horse had bilateral, large, superficial dendritic corneal ulcerations that covered extensive regions of the corneal surface. Corneal in vivo confocal microscopy examination in two horses detected inflammatory cells and populations of morphologically abnormal corneal epithelial cells adjacent to the ulcerations. The abnormal epithelial cells included round, relatively small, hyperreflective cells intermixed with elongated, enlarged, hyperreflective cells. Equine herpesvirus‐2 was isolated from corneal samples of 2 horses and detected by PCR assay in the other two horses. Equine herpesvirus‐5 was also detected by PCR assay in three of the horses. Conjunctival histopathology identified predominantly lymphocytic infiltrates. The macrodendrites and conjunctival masses resolved with topical antiviral therapy (cidofovir or idoxuridine) in all horses and did not recur. Conclusions and Clinical Relevance: The equine gammaherpesviruses may be associated with the development of macrodendritic ulcerative keratitis and conjunctival lymphocytic masses in foals. In vivo confocal microscopy of horses with macrodendrites revealed similar findings to other host species with herpetic dendritic keratitis. [ABSTRACT FROM AUTHOR]

Background: Patients with stage IV favorable histology Wilms tumor (FHWT) with extrapulmonary metastases (EPM) constitute a small subset of patients with FHWT. Because of their rarity and heterogeneity, optimal FHWT treatment is not well understood. Children's Oncology Group protocol AREN0533 assigned patients with FHWT and EPM to intensified chemotherapy, regimen M, after initial DD‐4A chemotherapy. To improve understanding of prognostic factors and best therapies, experiences of patients with EPM on AREN0533, as well as on protocols AREN03B2 and NWTS‐5, were reviewed. Methods: Combined outcomes for patients with EPM from NWTS‐5, AREN0533, and AREN03B2 were determined. Those treated on AREN0533 were compared with those treated on NWTS‐5. Prognostic factors were explored in the pooled cohort. Results: Forty‐seven patients with FHWT with EPM enrolled on AREN0533, 37 enrolled on NWTS‐5, and 64 were followed only on AREN03B2. The pooled cohort of all 148 patients demonstrated a 4‐year event‐free survival (EFS) of 77.3% (95% CI, 70.8–84.4) and 4‐year overall survival of 88.9% (95% CI, 83.9–94.2). Four‐year EFS of patients with EPM treated on AREN0533 was 76.0% (95% CI, 64.6–89.4) vs 64.9% (95% CI, 51.7–82.2) on NWTS‐5; hazard ratio, 0.64, p =.26; no difference in overall survival was observed. Increasing linear age and slow incomplete lung response were associated with worse EFS in a pooled cohort. Conclusions: Outcomes for patients with EPM are among the lowest for children with FHWT. Further trials with standardized surgical and radiation treatment to metastatic sites, and prospectively collected biologic and treatment details are needed. Clinical trial registration: Clinical Trials.gov identifiers: NCT00379340, NCT00898365, and NCT00002611. Pooled outcomes across three studies of patients with favorable histology Wilms tumor and extrapulmonary metastases revealed 4‐year event‐free survival of 77.3% and overall survival of 88.9%, with no statistical differences seen between patients on AREN0533 compared with those on NWTS‐5. Missing details on local management of metastatic sites informs a critical need for better data capture in future studies to optimize local control strategies and chemotherapy regimens for this higher‐risk favorable histology Wilms tumor patient group. [ABSTRACT FROM AUTHOR]