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Purpose: Optimal treatment of retroperitoneal sarcoma (RPS) remains undefined. Here, we report the feasibility of using high-dose boost radiation (3-4 Gy) to the central part of the tumor in patients with unresectable RPS., Methods and Materials: Five patients with unresectable RPS were treated with radiation therapy using a central boost technique with intensity modulated radiation therapy. On average, doses of 25 Gy to 45 Gy were delivered to the outer part of the tumor (planning target volume 1), while the central part of the tumor (planning target volume 2) received a 56 Gy to 75 Gy physical dose, which translates to a 62.67 Gy to 87.5 Gy equivalent dose in 2 Gy fractions (EQD2). To minimize radiation toxicity to the adjacent bowel and other organs, we used sequential, interdigitated, or simultaneous integrated boost (SIB) techniques., Results: In this case series of variable RPS histology, the median survival postradiation therapy was 30 months. Three of the 5 patients had clinically stable local disease on follow-up scans, and none of the patients experienced clinically significant toxicity., Conclusions: In summary, in this small case series of 5 patients, treatment was tolerated well, and excellent local responses were observed regardless of the timing of the central boost. Given the high rates of metastatic disease that developed in responding patients, effective systemic therapy will likely be needed for unresectable RPS treated with aggressive radiation therapy to the central part of the tumor., Competing Interests: David G. Kirsch is a cofounder and stockholder of XRAD Therapeutics, which develops radiosensitizers. David G. Kirsch is a member of the scientific advisory board and owns stock in Lumicell Inc, a company commercializing intraoperative imaging technology. None of these affiliations represent a conflict of interest with respect to the work described in this manuscript. David G. Kirsch is a coinventor on a patent for a handheld imaging device and is a coinventor on a patent for radiosensitizers. XRAD Therapeutics, Merck, Bristol Myers Squibb, and Varian Medical Systems have provided research support to David G. Kirsch, but this did not support the research described in this manuscript. The other authors have no conflicting financial interests., (© 2024 The Authors.)

CIC-rearranged sarcomas comprise a group of exceptionally aggressive round-cell sarcomas. These tumors most commonly demonstrate CIC::DUX4 fusion and show similar histopathology to Ewing sarcomas, though lesions mimicking vascular neoplasms have recently been described. Here, we describe a case of a patient with CIC::DUX4 fusion sarcoma identified using RNA-based molecular testing who was initially diagnosed with an endothelial neoplasm. The tumor showed extensive vasoformative growth, complete WT1 negativity, and global positive staining for ERG, CD31, and DUX4 by immunohistochemistry. Methylation testing of the tumor clustered more closely with angiosarcomas than with CIC-rearranged sarcomas. Our findings suggest that CIC::DUX4 fused neoplasms may demonstrate a more diverse phenotypic range than previously appreciated and offer evidence that both molecular and immunohistochemical studies are needed for accurate diagnosis., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare cancer, and large international cooperative efforts are needed to evaluate the significance of clinical risk factors and immunoarchitectural patterns (IAPs) for all stages of pediatric and adult patients with NLPHL., Methods: Thirty-eight institutions participated in the Global nLPHL One Working Group retrospective study of NLPHL cases from 1992 to 2021. We measured progression-free survival (PFS), overall survival (OS), transformation rate, and lymphoma-specific death rate. We performed uni- and multivariable (MVA) Cox regression stratified by management to select factors for the lymphocyte-predominant international prognostic score (LP-IPS) validated by five-fold cross-validation., Results: We identified 2,243 patients with a median age of 37 years (IQR, 23-51). The median follow-up was 6.3 years (IQR, 3.4-10.8). Most had stage I to II (72.9%) and few B symptoms (9.9%) or splenic involvement (5.4%). IAP was scored for 916 (40.8%). Frontline management included chemotherapy alone (32.4%), combined modality therapy (30.5%), radiotherapy alone (24.0%), observation after excision (4.6%), rituximab alone (4.0%), active surveillance (3.4%), and rituximab and radiotherapy (1.1%). The PFS, OS, transformation, and lymphoma-specific death rates at 10 years were 70.8%, 91.6%, 4.8%, and 3.3%, respectively. On MVA, IAPs were not associated with PFS or OS, but IAP E had higher risk of transformation (hazard ratio [HR], 1.81; P < .05). We developed the LP-IPS with 1 point each for age ≥45 years, stage III-IV, hemoglobin <10.5 g/dL, and splenic involvement. Increasing LP-IPS was significantly associated with worse PFS (HR, 1.52) and OS (HR, 2.31) and increased risk of lymphoma-specific death (HR, 2.63) and transformation (HR, 1.41)., Conclusion: In this comprehensive study of all ages of patients with NLPHL, we develop the LP-IPS to identify high-risk patients and inform upcoming prospective clinical trials evaluating de-escalation of therapy for patients with low LP-IPS scores (<2).

CIC::DUX4 sarcoma (CDS) is a rare but highly aggressive undifferentiated small round cell sarcoma driven by a fusion between the tumor suppressor Capicua (CIC) and DUX4. Currently, there are no effective treatments and efforts to identify and translate better therapies are limited by the scarcity of patient tumor samples and cell lines. To address this limitation, we generated three genetically engineered mouse models of CDS (Ch7CDS, Ai9CDS, and TOPCDS). Remarkably, chimeric mice from all three conditional models developed spontaneous soft tissue tumors and disseminated disease in the absence of Cre-recombinase. The penetrance of spontaneous (Cre-independent) tumor formation was complete irrespective of bi-allelic Cic function and the distance between adjacent loxP sites. Characterization of soft tissue and presumed metastatic tumors showed that they consistently expressed the CIC::DUX4 fusion protein and many downstream markers of the disease credentialing the models as CDS. In addition, tumor-derived cell lines were generated and ChIP-seq was preformed to map fusion-gene specific binding using an N-terminal HA epitope tag. These datasets, along with paired H3K27ac ChIP-sequencing maps, validate CIC::DUX4 as a neomorphic transcriptional activator. Moreover, they are consistent with a model where ETS family transcription factors are cooperative and redundant drivers of the core regulatory circuitry in CDS., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Purpose: The intracranial benefit of offering dual immune-checkpoint inhibition (D-ICPI) with ipilimumab and nivolumab to patients with melanoma or non-small cell lung cancer (NSCLC) receiving stereotactic radiosurgery (SRS) for brain metastases (BMs) is unknown. We hypothesized that D-ICPI improves local control compared with SRS alone., Methods and Materials: Patients with melanoma or NSCLC treated with SRS from 2014 to 2022 were evaluated. Patients were stratified by treatment with D-ICPI, single ICPI (S-ICPI), or SRS alone. Local recurrence, intracranial progression (IP), and overall survival were estimated using competing risk and Kaplan-Meier analyses. IP included both local and distant intracranial recurrence., Results: Two hundred eighty-eight patients (44% melanoma, 56% NSCLC) with 1,704 BMs were included. Fifty-three percent of patients had symptomatic BMs. The median follow-up was 58.8 months. Twelve-month local control rates with D-ICPI, S-ICPI, and SRS alone were 94.73% (95% CI, 91.11%-96.90%), 91.74% (95% CI, 89.30%-93.64%), and 88.26% (95% CI, 84.07%-91.41%). On Kaplan-Meier analysis, only D-ICPI was significantly associated with reduced local recurrence (P = .0032). On multivariate Cox regression, D-ICPI (hazard ratio [HR], 0.4003; 95% CI, 0.1781-0.8728; P = .0239) and planning target volume (HR, 1.022; 95% CI, 1.004-1.035; P = .0059) correlated with local control. One hundred seventy-three (60%) patients developed IP. The 12-month cumulative incidence of IP was 41.27% (95% CI, 30.27%-51.92%), 51.86% (95% CI, 42.78%-60.19%), and 57.15% (95% CI, 44.98%-67.59%) after D-ICPI, S-ICPI, and SRS alone. On competing risk analysis, only D-ICPI was significantly associated with reduced IP (P = .0408). On multivariate Cox regression, D-ICPI (HR, 0.595; 95% CI, 0.373-0.951; P = .0300) and presentation with >10 BMs (HR, 2.492; 95% CI, 1.668-3.725; P < .0001) remained significantly correlated with IP. The median overall survival after D-ICPI, S-ICPI, and SRS alone was 26.1 (95% CI, 15.5-40.7), 21.5 (16.5-29.6), and 17.5 (11.3-23.8) months. S-ICPI, fractionation, and histology were not associated with clinical outcomes. There was no difference in hospitalizations or neurologic adverse events between cohorts., Conclusions: The addition of D-ICPI for patients with melanoma and NSCLC undergoing SRS is associated with improved local and intracranial control. This appears to be an effective strategy, including for patients with symptomatic or multiple BMs., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: To investigate whether TP53 variants may be correlated with overall survival and local control following stereotactic radiosurgery (SRS) for brain metastases (BMs) from non-small cell lung cancer (NSCLC)., Methods: Patients undergoing an initial course of SRS for NSCLC brain metastases between 1/2015 and 12/2020 were retrospectively identified. Overall survival and freedom from local intracranial progression (FFLIP) were estimated via Kaplan-Meier method. Cox models assessed TP53 variant status (pathogenic variant, PV; variant not detected, ND)., Results: 255 patients underwent molecular profiling for TP53, among whom 144 (56%) had a TP53 PV. Median follow-up was 11.6 months. OS was not significantly different across TP53 status. A trend toward superior FFLIP was observed for PV (95% CI 62.9 months-NR) versus ND patients (95% CI 29.4 months-NR; p=0.06). Superior FFLIP was observed for patients with one TP53 variant versus those with TP53 ND., Conclusion: Among NSCLC patients with BMs, the potential association between TP53 status and post-SRS FFLIP warrants further investigation in a larger prospective cohort., Competing Interests: We thank Karen Allen for her assistance maintaining the prospective QA database. Authors’ disclosure of potential conflicts of interest The funding sources for this study (NIH grant R38CA24520401 to DJC, K08CA256045 to ZJR and NIH 5R38CA245204 to EJV and an Office of Physician Scientist Development Technician Award to EJV) had no role in the collection, analysis, or interpretation of the data, the writing of the manuscript, or the decision to submit it for publication. ZJR has intellectual property managed by Duke University that has been licensed to GeneTron Health related to brain tumor genomic profiling tests, and has received honoraria from Eisai Pharmaceuticals and Oakstone Publishing. JK reported receiving grants from Varian Medical Systems and BioMimetix SBR, receiving personal fees from Monteris Medical, and owning ClearSight LLC outside the submitted work. None of the above entities played a role in the collection, analysis, or interpretation of the data, the writing of the manuscript, or the decision to submit it for publication., (© 2024 Old City Publishing, Inc.)

Background and Objectives: The efficacy of our current approach to incorporating intracranial pressure (ICP) data into pediatric severe traumatic brain injury (sTBI) management is incompletely understood, lacking data from multicenter, prospective, randomized studies. The National Institutes of Health-supported Benchmark Evidence from Latin America-Treatment of Raised Intracranial Pressure-Pediatrics trial will compare outcomes from pediatric sTBI of a management protocol based on ICP monitoring vs 1 based on imaging and clinical examination without monitoring. Because no applicable comprehensive management algorithms for either cohort are available, it was necessary to develop them., Methods: A consensus conference involving the 21 intensivists and neurosurgeons from the 8 trial sites used Delphi-based methodology to formulate management algorithms for both study cohorts. We included recommendations from the latest Brain Trauma Foundation pediatric sTBI guidelines and the consensus-based adult algorithms (Seattle International Brain Injury Consensus Conference/Consensus Revised Imaging and Clinical Examination) wherever relevant. We used a consensus threshold of 80%., Results: We developed comprehensive management algorithms for monitored and nonmonitored cohort children with sTBI. We defined suspected intracranial hypertension for the nonmonitored group, set minimum number and timing of computed tomography scans, specified minimal age-adjusted mean arterial pressure and cerebral perfusion pressure targets, defined clinical neuroworsening, described minimal requisites for intensive care unit management, produced tiered management algorithms for both groups, and listed treatments not routinely used., Conclusion: We will study these protocols in the Benchmark Evidence from Latin America-Treatment of Raised Intracranial Pressure-Pediatrics trial in low- and middle-income countries. Second, we present them here for consideration as prototype pediatric sTBI management algorithms in the absence of published alternatives, acknowledging their limited evidentiary status. Therefore, herein, we describe our study design only, not recommended treatment protocols., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

Background and Objectives: Traumatic brain injury (TBI) is a major global public health problem. It is a leading cause of death and disability in children and adolescents worldwide. Although increased intracranial pressure (ICP) is common and associated with death and poor outcome after pediatric TBI, the efficacy of current ICP-based management remains controversial. We intend to provide Class I evidence testing the efficacy of a protocol based on current ICP monitor-based management vs care based on imaging and clinical examination without ICP monitoring in pediatric severe TBI., Methods: A phase III, multicenter, parallel-group, randomized superiority trial performed in intensive care units in Central and South America to determine the impact on 6-month outcome of children aged 1-12 years with severe TBI (age-appropriate Glasgow Coma Scale score ≤8) randomized to ICP-based or non-ICP-based management., Expected Outcomes: Primary outcome is 6-month Pediatric Quality of Life. Secondary outcomes are 3-month Pediatric Quality of Life, mortality, 3-month and 6-month Pediatric extended Glasgow Outcome Score, intensive care unit length of stay, and number of interventions focused on treating measured or suspected intracranial hypertension., Discussion: This is not a study of the value of knowing the ICP in sTBI. This research question is protocol-based. We are investigating the added value of protocolized ICP management to treatment based on imaging and clinical examination in the global population of severe pediatric TBI. Demonstrating efficacy should standardize ICP monitoring in severe pediatric TBI. Alternate results should prompt reassessment of how and in which patients ICP data should be applied in neurotrauma care., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

Background and Objectives: Our Phase-I parallel-cohort study suggested that managing severe traumatic brain injury (sTBI) in the absence of intracranial pressure (ICP) monitoring using an ad hoc Imaging and Clinical Examination (ICE) treatment protocol was associated with superior outcome vs nonprotocolized management but could not differentiate the influence of protocolization from that of the specific protocol. Phase II investigates whether adopting the Consensus REVised Imaging and Clinical Examination (CREVICE) protocol improved outcome directly or indirectly via protocolization., Methods: We performed a Phase-II sequential parallel-cohort study examining adoption of the CREVICE protocol from no protocol vs a previous protocol in patients with sTBI older than 13 years presenting ≤24 hours after injury. Primary outcome was prespecified 6-month recovery. The study was done mostly at public South American centers managing sTBI without ICP monitoring. Fourteen Phase-I nonprotocol centers and 5 Phase-I protocol centers adopted CREVICE. Data were analyzed using generalized estimating equation regression adjusting for demographic imbalances., Results: A total of 501 patients (86% male, mean age 35.4 years) enrolled; 81% had 6 months of follow-up. Adopting CREVICE from no protocol was associated with significantly superior results for overall 6-month extended Glasgow Outcome Score (GOSE) (protocol effect = 0.53 [0.11, 0.95], P = .013), mortality (36% vs 21%, HR = 0.59 [0.46, 0.76], P < .001), and orientation (Galveston Orientation and Amnesia Test discharge protocol effect = 10.9 [6.0, 15.8], P < .001, 6-month protocol effect = 11.4 [4.1, 18.6], P < .005). Adopting CREVICE from ICE was associated with significant benefits to GOSE (protocol effect = 0.51 [0.04, 0.98], P = .033), 6-month mortality (25% vs 18%, HR = 0.55 [0.39, 0.77], P < .001), and orientation (Galveston Orientation and Amnesia Test 6-month protocol effect = 9.2 [3.6, 14.7], P = .004). Comparing both groups using CREVICE, those who had used ICE previously had significantly better GOSE (protocol effect = 1.15 [0.09, 2.20], P = .033)., Conclusion: Centers managing adult sTBI without ICP monitoring should strongly consider protocolization through adopting/adapting the CREVICE protocol. Protocolization is indirectly supported at sTBI centers regardless of resource availability., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

CIC-DUX4 sarcoma (CDS) is a rare but highly aggressive undifferentiated small round cell sarcoma driven by a fusion between the tumor suppressor Capicua (CIC) and DUX4. Currently, there are no effective treatments and efforts to identify and translate better therapies are limited by the scarcity of patient tumor samples and cell lines. To address this limitation, we generated three genetically engineered mouse models of CDS (Ch7CDS, Ai9CDS, and TOPCDS). Remarkably, chimeric mice from all three conditional models developed spontaneous tumors and widespread metastasis in the absence of Cre-recombinase. The penetrance of spontaneous (Cre-independent) tumor formation was complete irrespective of bi-allelic CIC function and the distance between loxP sites. Characterization of primary and metastatic mouse tumors showed that they consistently expressed the CIC-DUX4 fusion protein as well as other downstream markers of the disease credentialing these models as CDS. In addition, tumor-derived cell lines were generated and ChIP-seq was preformed to map fusion-gene specific binding using an N-terminal HA epitope tag. These datasets, along with paired H3K27ac ChIP-seq maps, validate CIC-DUX4 as a neomorphic transcriptional activator. Moreover, they are consistent with a model where ETS family transcription factors are cooperative and redundant drivers of the core regulatory circuitry in CDS., Competing Interests: Additional Declarations: Yes there is potential conflict of interest.

Pooled genetic screens represent a powerful approach to identify vulnerabilities in cancer. Here we used pooled CRISPR/Cas9-based approaches to identify vulnerabilities associated with telomerase reverse transcriptase (TERT) promoter mutations (TPMs) found in >80% of glioblastomas. We first developed a platform to detect perturbations that cause long-term growth defects in a TPM-mutated glioblastoma cell line. However, we could not detect dependencies on either TERT itself or on an E-twenty six transcription (ETS) factor known to activate TPMs. To explore this finding, we cataloged TPM status for 441 cell lines and correlated this with genome-wide screening data. We found that TPM status was not associated with differential dependency on TERT, but that E-twenty six (ETS) transcription factors represent key dependencies in both TPM+ and TPM- lines. Further, we found that TPMs are associated with expression of gene programs regulated by a wide array of ETS-factors in both cell lines and primary glioblastoma tissues. This work contributes a unique TPM cell line reagent, establishes TPM status for many deeply-profiled cell lines, and catalogs TPM-associated vulnerabilities. The results highlight challenges in executing genetic screens to detect TPM-specific vulnerabilities, and suggest redundancy in the genetic network that regulates TPM function with therapeutic implications., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

CIC-DUX4 sarcoma (CDS) is a rare but highly aggressive undifferentiated small round cell sarcoma driven by a fusion between the tumor suppressor Capicua (CIC) and DUX4. Currently, there are no effective treatments and efforts to identify and translate better therapies are limited by the scarcity of tissues and patients. To address this limitation, we generated three genetically engineered mouse models of CDS (Ch7CDS, Ai9CDS, and TOPCDS). Remarkably, chimeric mice from all three conditional models developed spontaneous tumors and widespread metastasis in the absence of Cre-recombinase. The penetrance of spontaneous (Cre-independent) tumor formation was complete irrespective of bi-allelic CIC function and loxP site proximity. Characterization of primary and metastatic mouse tumors showed that they consistently expressed the CIC-DUX4 fusion protein as well as other downstream markers of the disease credentialing these models as CDS. In addition, tumor-derived cell lines were generated and ChIP-seq was preformed to map fusion-gene specific binding using an N-terminal HA epitope tag. These datasets, along with paired H3K27ac ChIP-seq maps, validate CIC-DUX4 as a neomorphic transcriptional activator. Moreover, they are consistent with a model where ETS family transcription factors are cooperative and redundant drivers of the core regulatory circuitry in CDS., Competing Interests: The other authors have no conflicting financial interests.

Purpose: Genetic variants affecting the radiation response protein ataxia-telangiectasia mutated (ATM) have been associated with increased adverse effects of radiation but also with improved local control after conventional radiation therapy. However, it is unknown whether ATM variants affect rates of radionecrosis (RN) and local intracranial progression (LIP) after stereotactic radiosurgery (SRS) for brain metastases., Methods and Materials: Patients undergoing an initial course of SRS for non-small cell lung cancer (NSCLC) brain metastases at a single institution were retrospectively identified. Kaplan-Meier estimates were calculated and Cox proportional hazards testing was performed based on ATM variant status., Results: A total of 541 patients completed SRS for brain metastasis secondary to NSCLC, of whom 260 completed molecular profiling. Variants of ATM were identified in 36 cases (13.8%). Among patients who completed molecular profiling, RN incidence was 4.9% (95% CI, 1.6%-8.2%) at 6 months and 9.9% (95% CI, 4.8%-15.0%) at 12 months. Incidence of RN was not significantly increased among patients with ATM variants, with an RN incidence of 5.3% (95% CI, 0.0%-15.3%) at both 6 and 12 months ( P  = .46). For all patients who completed genomic profiling, LIP was 5.4% (95% CI, 2.4%-8.4%) at 6 months and 9.8% (5.5%-14.1%) at 12 months. A significant improvement in LIP was not detected among patients with ATM variants, with an LIP incidence of 3.1% (0.0%-9.1%) at both 6 and 12 months ( P  = .26). Although differences according to ATM variant type (pathologic variant or variant of unknown significance) did not reach significance, no patients with ATM pathologic variants experienced LIP., Conclusions: We did not detect significant associations between ATM variant status and RN or LIP after SRS for NSCLC brain metastases. The current data set allows estimation of patient cohort sizes needed to power future investigations to identify genetic variants that associate with significant differences in outcomes after SRS., Competing Interests: Eugene Vaios reported receiving research grants from the National Institutes of Health (NIH) and consulting fees from Glasshouse Health, United Kingdom, and having leadership roles in the American Society for Radiation Oncology Finance/Audit Committee. Scott R. Floyd reported receiving research grants from and/or having contracts with the NIH and the American Cancer Society and having a US patent (9,610,332). John P. Kirkpatrick reported having research grants and/or contracts with SBIR Project Funding, Varian Medical Systems, and BioMimetix JV LLC; receiving consulting fees and speaking honoraria from Monteris Medical; and being the owner and president of Clearsight RT LLC. Michelle Green reported receiving a research grant from Bayer Medical Education and receiving royalties from SciMed Solutions. Zachary J. Reitman reported receiving research grants from and/or having contracts with St. Baldrick's Foundation, the Pediatric Brain Tumor Foundation, the Defeat DIPG Foundation, the SoSo Strong Foundation, the ChadTough Foundation, and the National Cancer Institute; receiving royalties from Genetron Health; receiving payment or honoraria for presentations from Oakstone Publishing and Eisai Pharmaceuticals; and having patents (10711310, 11306364, and 8691960) for brain tumor diagnostic technology and biocatalyst technology, managed by the Duke Office of Licensing and Ventures. All other authors declare no conflicts of interest. None of the organizations or institutions had any role in the collection, analysis, or interpretation of the data, the writing of the manuscript, or the decision to submit it for publication., (© 2023 The Authors.)

Background: Most patients with severe traumatic brain injury (sTBI) in low- or-middle-income countries and surprisingly many in high-income countries are managed without intracranial pressure (ICP) monitoring. The impact of the first published protocol (Imaging and Clinical Examination [ICE] protocol) is untested against nonprotocol management., Objective: To determine whether patients treated in intensive care units (ICUs) using the ICE protocol have lower mortality and better neurobehavioral functioning than those treated in ICUs using no protocol., Methods: This study involved nineteen mostly public South American hospitals. This is a prospective cohort study, enrolling patients older than 13 years with sTBI presenting within 24 h of injury (January 2014-July 2015) with 6-mo postinjury follow-up. Five hospitals treated all sTBI cases using the ICE protocol; 14 used no protocol. Primary outcome was prespecified composite of mortality, orientation, functional outcome, and neuropsychological measures., Results: A total of 414 patients (89% male, mean age 34.8 years) enrolled; 81% had 6 months of follow-up. All participants included in composite outcome analysis: average percentile (SD) = 46.8 (24.0) nonprotocol, 56.9 (24.5) protocol. Generalized estimating equation (GEE) used to account for center effects (confounder-adjusted difference [95% CI] = 12.2 [4.6, 19.8], P = .002). Kaplan-Meier 6-month mortality (95% CI) = 36% (30%, 43%) nonprotocol, 25% (19%, 31%) protocol (GEE and confounder-adjusted hazard ratio [95% CI] = .69 [.43, 1.10], P = .118). Six-month Extended Glasgow Outcome Scale for 332 participants: average Extended Glasgow Outcome Scale score (SD) = 3.6 (2.6) nonprotocol, 4.7 (2.8) protocol (GEE and confounder-adjusted and lost to follow-up-adjusted difference [95% CI] = 1.36 [.55, 2.17], P = .001)., Conclusion: ICUs managing patients with sTBI using the ICE protocol had better functional outcome than those not using a protocol. ICUs treating patients with sTBI without ICP monitoring should consider protocolization. The ICE protocol, tested here and previously, is 1 option., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)

In mammalian embryos, proper zygotic genome activation (ZGA) underlies totipotent development. Double homeobox (DUX)-family factors participate in ZGA, and mouse Dux is required for forming cultured two-cell (2C)-like cells. Remarkably, in mouse embryonic stem cells, Dux is activated by the tumor suppressor p53, and Dux expression promotes differentiation into expanded-fate cell types. Long-read sequencing and assembly of the mouse Dux locus reveals its complex chromatin regulation including putative positive and negative feedback loops. We show that the p53-DUX/DUX4 regulatory axis is conserved in humans. Furthermore, we demonstrate that cells derived from patients with facioscapulohumeral muscular dystrophy (FSHD) activate human DUX4 during p53 signaling via a p53-binding site in a primate-specific subtelomeric long terminal repeat (LTR)10C element. In summary, our work shows that p53 activation convergently evolved to couple p53 to Dux/DUX4 activation in embryonic stem cells, embryos and cells from patients with FSHD, potentially uniting the developmental and disease regulation of DUX-family factors and identifying evidence-based therapeutic opportunities for FSHD., (© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Li-Fraumeni Syndrome (LFS) is a rare cancer-predisposing condition caused by germline mutations in TP53. Conventional wisdom and prior work has implied an increased risk of secondary malignancy in LFS patients treated with radiation therapy (RT); however, this risk is not well-characterized. Here we describe the risk of subsequent malignancy and cancer-related death in LFS patients after undergoing RT for a first or second primary cancer., Methods: We reviewed a multi-institutional hereditary cancer registry of patients with germline TP53 mutations who were treated from 2004 to 2017. We assessed the rate of subsequent malignancy and death in the patients who received RT (RT group) as part of their cancer treatment compared to those who did not (non-RT group)., Results: Forty patients with LFS were identified and 14 received RT with curative intent as part of their cancer treatment. The median time to follow-up after RT was 4.5 years. Fifty percent (7/14) of patients in the curative-intent group developed a subsequent malignancy (median time 3.5 years) compared to 46% of patients in the non-RT group (median time 5.0 years). Four of seven subsequent malignancies occurred within a prior radiation field and all shared histology with the primary cancer suggesting recurrence rather than new malignancy., Conclusion: We found that four of14 patients treated with RT developed in-field malignancies. All had the same histology as the primary suggesting local recurrences rather than RT-induced malignancies. We recommend that RT should be considered as part of the treatment algorithm when clinically indicated and after multidisciplinary discussion., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Globally, intracranial pressure (ICP) monitoring use in severe traumatic brain injury (sTBI) is inconsistent and susceptible to resource limitations and clinical philosophies. For situations without monitoring, there is no published comprehensive management algorithm specific to identifying and treating suspected intracranial hypertension (SICH) outside of the one ad hoc Imaging and Clinical Examination (ICE) protocol in the Benchmark Evidence from South American Trials: Treatment of Intracranial Pressure (BEST:TRIP) trial. As part of an ongoing National Institutes of Health (NIH)-supported project, a consensus conference involving 43 experienced Latin American Intensivists and Neurosurgeons who routinely care for sTBI patients without ICP monitoring, refined, revised, and augmented the original BEST:TRIP algorithm. Based on BEST:TRIP trial data and pre-meeting polling, 11 issues were targeted for development. We used Delphi-based methodology to codify individual statements and the final algorithm, using a group agreement threshold of 80%. The resulting CREVICE (Consensus REVised ICE) algorithm defines SICH and addresses both general management and specific treatment. SICH treatment modalities are organized into tiers to guide treatment escalation and tapering. Treatment schedules were developed to facilitate targeted management of disease severity. A decision-support model, based on the group's combined practices, is provided to guide this process. This algorithm provides the first comprehensive management algorithm for treating sTBI patients when ICP monitoring is not available. It is intended to provide a framework to guide clinical care and direct future research toward sTBI management. Because of the dearth of relevant literature, it is explicitly consensus based, and is provided solely as a resource (a "consensus-based curbside consult") to assist in treating sTBI in general intensive care units in resource-limited environments.

Hepatocellular Carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. Current systemic therapies result only in modest benefits and new therapeutic options are critically needed. Some patients show promising clinical responses to immune checkpoint inhibitors, however, additional immunotherapeutic approaches, such as adoptive cell therapies (ACT), need to be developed. This review summarizes recent ACT studies and discusses the promise and obstacles of this approach. We further discuss ways of improving the efficacy of ACT in HCC including the use of combination therapies and locoregional delivery methods., (© 2019 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Objective: While existing guidelines support the treatment of intracranial hypertension in severe traumatic brain injury (TBI), it is unclear when to suspect and initiate treatment for high intracranial pressure (ICP). The objective of this study was to derive a clinical decision rule that accurately predicts intracranial hypertension., Methods: Using Delphi methods, the authors identified a set of potential predictors of intracranial hypertension and a clinical decision rule a priori by consensus among a group of 43 neurosurgeons and intensivists who have extensive experience managing severe TBI without ICP monitoring. To validate these predictors, the authors used data from a Latin American trial (n = 150; BEST TRIP). To report on the performance of the rule, they calculated sensitivity, specificity, and positive and negative predictive values with 95% confidence intervals. In a secondary analysis, the rule was validated using data from a North American trial (n = 131; COBRIT)., Results: The final predictors and the clinical decision rule were approved by 97% of participants in the consensus working group. The predictors are divided into major and minor criteria. High ICP would be considered suspected in the presence of 1 major or ≥ 2 minor criteria. Major criteria are: compressed cisterns (CT classification of Marshall diffuse injury [DI] III), midline shift > 5 mm (Marshall DI IV), or nonevacuated mass lesion. Minor criteria are: Glasgow Coma Scale (GCS) motor score ≤ 4, pupillary asymmetry, abnormal pupillary reactivity, or Marshall DI II. The area under the curve for the logistic regression model that contains all the predictors was 0.86. When high ICP was defined as > 22 mm Hg, the decision rule performed with a sensitivity of 93.9% (95% CI 85.0%-98.3%), a specificity of 42.3% (95% CI 31.7%-53.6%), a positive predictive value of 55.5% (95% CI 50.7%-60.2%), and a negative predictive value of 90% (95% CI 77.1%-96.0%). The sensitivity of the clinical decision rule improved with higher ICP cutoffs up to a sensitivity of 100% when intracranial hypertension was defined as ICP > 30 mm Hg. Similar results were found in the North American cohort., Conclusions: A simple clinical decision rule based on a combination of clinical and imaging findings was found to be highly sensitive in distinguishing patients with severe TBI who would suffer intracranial hypertension. It could be used to identify patients who require ICP monitoring in high-resource settings or start ICP-lowering treatment in environments where resource limitations preclude invasive monitoring.Clinical trial registration no.: NCT02059941 (clinicaltrials.gov).

Background: Severe traumatic brain injury (sTBI) is a significant global health problem disproportionately affecting low- and middle-income countries (LMICs). Management of intracranial hypertension in sTBI is crucial to survival and optimal recovery. Practitioners in high-income countries routinely use intracranial pressure (ICP) monitors although their usefulness has been questioned. ICP monitors are usually unavailable in LMICs. No consensus-based/tested protocols or literature exists for sTBI treatment without ICP monitoring., Methods: Investigators developed serial SurveyMonkey surveys for Latin American neurointensivists and neurosurgeons to determine current practice. These clinicians had extensive routine ongoing experience in sTBI without ICP monitoring. Surveys were administered and analyzed before/during/after a 2015 Buenos Aires consensus conference. Investigators identified areas of convergence blinded from colleagues' responses. A 47-clinician task force, representing 15 countries, who routinely manage patients with sTBI without monitors developed consensus-based treatment guidelines during a 3-day facilitated conference., Results: Elements were added to the protocol at an 80% agreement threshold. Follow-on surveys resolved remaining elements to 97% agreement. The protocol addresses both tapering (on improvement) and neuroworsening. Staged treatment options were identified, plus unique clinical practice issues. This process introduced a research method to a large multidisciplinary group of LMIC clinicians. This report describes the process used to develop an LMIC-specific protocol that is transferable to other diseases/injuries. The protocol is being tested in 5 LMICs., Conclusions: We derived consensus-based guidelines for sTBI treatment without ICP monitoring, and introduced a research method to a large multidisciplinary group of LMIC clinicians naive to such methods., (Copyright © 2017 Elsevier Inc. All rights reserved.)

To better understand transcriptional regulation during human oogenesis and preimplantation development, we defined stage-specific transcription, which highlighted the cleavage stage as being highly distinctive. Here, we present multiple lines of evidence that a eutherian-specific multicopy retrogene, DUX4, encodes a transcription factor that activates hundreds of endogenous genes (for example, ZSCAN4, KDM4E and PRAMEF-family genes) and retroviral elements (MERVL/HERVL family) that define the cleavage-specific transcriptional programs in humans and mice. Remarkably, mouse Dux expression is both necessary and sufficient to convert mouse embryonic stem cells (mESCs) into 2-cell-embryo-like ('2C-like') cells, measured here by the reactivation of '2C' genes and repeat elements, the loss of POU5F1 (also known as OCT4) protein and chromocenters, and the conversion of the chromatin landscape (as assessed by transposase-accessible chromatin using sequencing (ATAC-seq)) to a state strongly resembling that of mouse 2C embryos. Thus, we propose mouse DUX and human DUX4 as major drivers of the cleavage or 2C state.

A new study compares DNA methylation profiles in developing zebrafish, Xenopus tropicalis and mice and suggests roles for Tet proteins in demethylating conserved gene enhancers during the phylotypic period of early development. These findings provide an epigenetic underpinning for the 'hourglass' model.

Objective: To assess the knowledge of youth soccer athletes' parents, coaches, and soccer officials regarding concussion and return-to-play guidelines contained in the Lystedt Law in Washington State., Design: Survey study., Setting: Surveys were distributed via the youth soccer association monthly electronic newsletter in September and October 2010. Links to the survey also were provided via the Washington Youth Soccer Facebook page and Twitter feed., Participants: Respondents were 18 years or older and were associated with Washington Youth Soccer., Main Outcome Measures: The percentage of correct responses to questions regarding the identification and management of concussion symptoms and return to play guidelines as outlined in the Lystedt Law., Results: A total of 391 adults responded; 63% were exclusively parents, 20% were coaches, and 17% were noncoaches (eg, club officers, referees, or volunteers). A total of 96% knew that concussions were a type of traumatic brain injury, 93% identified concussions as serious, and 93% knew that loss of consciousness is not universal. From the responses, 98% identified neurological manifestations of concussions, 90% chose to delay return to play in the presence of neurological symptoms, 85% were aware of the Lystedt Law, and only 73% knew that players must receive written clearance to return to play. A total of 88% were aware that a parent or legal guardian was not allowed to clear an athlete to return to play if a trained professional was not available. Survey respondents were less sure of soccer association guidelines for reporting medical clearance to club officials., Conclusions: These data suggest that, although general knowledge of parents, coaches, and referees in youth soccer in Washington State is high, gaps in knowledge and practice regarding the prevention of concussion in youth soccer athletes still exist., (Copyright © 2012 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.)

An open reading frame (ORF) was found in the mitochondrial genome of the Pan2-16 strain of Didymium iridis that showed high similarity to the NADH dehydrogenase subunit 3 (nad3) gene in other organisms. So far all other typical mitochondrial genes identified in this organism require RNA editing to generate ORFs capable of directing protein synthesis. The D. iridis sequence was compared to the putative nad3 gene in the related myxomycete Physarum polycephalum, which would require editing. Based on this comparison, editing sites could be predicted for the P. polycelphalum gene that would result in the synthesis of a highly conserved ND3 protein between the two organisms. To determine the editing status of the nad3 gene in other D. iridis strains, PCR was used to amplify this region from eight other independent isolates of the A1 Central American interbreeding series. In each case a 378 base pair ORF was detected by PCR amplification and sequencing. Three patterns of sequence variation were observed; however all base substitutions were in the third codon position and silent with respect to the amino acids encoded. The distribution of the sequence variants was mapped geographically. The requirement for RNA editing in all other typical mitochondrial genes of D. iridis and P. polycephalum and the presence of RNA editing in the nad3 gene of P. polycephalum suggest that the D. iridis nad3 gene might have been edited at one time. We propose that the D. iridis nad3 gene may have lost the requirement for RNA editing by reverse transcription of an edited transcript that subsequently was inserted into the genome.

Similarity searches with Didymium iridis mitochondrial genomic DNA identified six possible ribosomal protein-coding regions, however, each region contained stop codons that would need to be removed by RNA editing to produce functional transcripts. RT-PCR was used to amplify these regions from total RNA for cloning and sequencing. Six functional transcripts were verified for the following ribosomal protein genes: rpS12, rpS7, rpL2, rpS19, rpS3, and rpL16. The editing events observed, such as single C and U nucleotide insertions and a dinucleotide insertion, were consistent with previously observed editing patterns seen in D. iridis. Additionally, a new form of insertional editing, a single A insertion, was observed in a conserved region of the rpL16 gene. While the majority of codons created by editing specify hydrophobic amino acids, a greater proportion of the codons created in these hydrophilic ribosomal proteins called for positively charged amino acids in comparison to the previously characterized hydrophobic respiratory protein genes. This first report of edited soluble mitochondrial ribosomal proteins in myxomycetes expands upon the RNA editing patterns previously seen; there was: a greater proportion of created codons specifying positively charged amino acids, a shift in the codon position edited, and the insertion of single A nucleotides.