The molecular landscape of ETMR at diagnosis and relapse.

Embryonal tumours with multilayered rosettes (ETMRs) are aggressive paediatric embryonal brain tumours with a universally poor prognosis1. Here we collected 193 primary ETMRs and 23 matched relapse samples to investigate the genomic landscape of this distinct tumour type. We found that patients with tumours in which the proposed driver C19MC2-4 was not amplified frequently had germline mutations in DICER1 or other microRNA-related aberrations such as somatic amplification of miR-17-92 (also known as MIR17HG). Whole-genome sequencing revealed that tumours had an overall low recurrence of single-nucleotide variants (SNVs), but showed prevalent genomic instability caused by widespread occurrence of R-loop structures. We show that R-loop-associated chromosomal instability can be induced by the loss of DICER1 function. Comparison of primary tumours and matched relapse samples showed a strong conservation of structural variants, but low conservation of SNVs. Moreover, many newly acquired SNVs are associated with a mutational signature related to cisplatin treatment. Finally, we show that targeting R-loops with topoisomerase and PARP inhibitors might be an effective treatment strategy for this deadly disease.

Effectiveness of game-based exercise interventions on modifiable cardiovascular risk factors of individuals with type two diabetes mellitus: A systematic review and meta-analysis.

BACKGROUND: Sedentary lifestyles have been identified as a major risk factor for cardiovascular complications for individuals with type 2 diabetes mellitus (T2DM). Using video-gaming components, game-based exercise interventions can encourage these individuals to engage in regular physical activity (PA), given their favorable interactive interfaces, feedback, and on-demand flow experiences. AIM: To evaluate the effectiveness of game-based exercise interventions, on modifiable cardiovascular risk factors, quality of life, and PA levels among individuals with T2DM. METHODS: Published and unpublished studies were retrieved from eight electronic databases and reference lists of the included studies. Articles included in this study were from the inception of the databases to January 2022. Two reviewers performed screening, quality appraisal, and data extraction independently. Meta-analyses were conducted for the primary and secondary outcomes through RevMan. The protocol was registered on PROSPERO (CRD42022298894). RESULTS: Of the 11 selected studies involving 1045 individuals of both genders with T2DM, 9 were included in the meta-analyses for glycosylated hemoglobin, blood pressure (BP), low-density lipoprotein cholesterol, quality of life, and physical activity levels. The meta-analyses reported very small to large effect sizes favoring game-based exercise interventions. Large effect sizes were reported for systolic BP, diastolic BP, and quality of life measured through SF-12 Mental Component Summary scores. LINKING EVIDENCE TO ACTION: Game-based exercise interventions may improve modifiable cardiovascular risk factors, quality of life, and PA levels among individuals with T2DM. Supervision, PA levels, or motivation can affect the effectiveness of game-based exercise interventions.

Atypical teratoid/rhabdoid tumors (ATRTs) with SMARCA4 mutation are molecularly distinct from SMARCB1-deficient cases.

Atypical teratoid/rhabdoid tumors (ATRTs) are very aggressive childhood malignancies of the central nervous system. The underlying genetic cause are inactivating bi-allelic mutations in SMARCB1 or (rarely) in SMARCA4. ATRT-SMARCA4 have been associated with a higher frequency of germline mutations, younger age, and an inferior prognosis in comparison to SMARCB1 mutated cases. Based on their DNA methylation profiles and transcriptomics, SMARCB1 mutated ATRTs have been divided into three distinct molecular subgroups: ATRT-TYR, ATRT-SHH, and ATRT-MYC. These subgroups differ in terms of age at diagnosis, tumor location, type of SMARCB1 alterations, and overall survival. ATRT-SMARCA4 are, however, less well understood, and it remains unknown, whether they belong to one of the described ATRT subgroups. Here, we examined 14 ATRT-SMARCA4 by global DNA methylation analyses. We show that they form a separate group segregating from SMARCB1 mutated ATRTs and from other SMARCA4-deficient tumors like small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) or SMARCA4 mutated extra-cranial malignant rhabdoid tumors. In contrast, medulloblastoma (MB) samples with heterozygous SMARCA4 mutations do not group separately, but with established MB subgroups. RNA sequencing of ATRT-SMARCA4 confirmed the clustering results based on DNA methylation profiling and displayed an absence of typical signature genes upregulated in SMARCB1 deleted ATRT. In summary, our results suggest that, in line with previous clinical observations, ATRT-SMARCA4 should be regarded as a distinct molecular subgroup.

Pineoblastoma segregates into molecular sub-groups with distinct clinico-pathologic features: a Rare Brain Tumor Consortium registry study.

Pineoblastomas (PBs) are rare, aggressive pediatric brain tumors of the pineal gland with modest overall survival despite intensive therapy. We sought to define the clinical and molecular spectra of PB to inform new treatment approaches for this orphan cancer. Tumor, blood, and clinical data from 91 patients with PB or supratentorial primitive neuroectodermal tumor (sPNETs/CNS-PNETs), and 2 pineal parenchymal tumors of intermediate differentiation (PPTIDs) were collected from 29 centres in the Rare Brain Tumor Consortium. We used global DNA methylation profiling to define a core group of PB from 72/93 cases, which were delineated into five molecular sub-groups. Copy number, whole exome and targeted sequencing, and miRNA expression analyses were used to evaluate the clinico-pathologic significance of each sub-group. Tumors designated as group 1 and 2 almost exclusively exhibited deleterious homozygous loss-of-function alterations in miRNA biogenesis genes (DICER1, DROSHA, and DGCR8) in 62 and 100% of group 1 and 2 tumors, respectively. Recurrent alterations of the oncogenic MYC-miR-17/92-RB1 pathway were observed in the RB and MYC sub-group, respectively, characterized by RB1 loss with gain of miR-17/92, and recurrent gain or amplification of MYC. PB sub-groups exhibited distinct clinical features: group 1-3 arose in older children (median ages 5.2-14.0 years) and had intermediate to excellent survival (5-year OS of 68.0-100%), while Group RB and MYC PB patients were much younger (median age 1.3-1.4 years) with dismal survival (5-year OS 37.5% and 28.6%, respectively). We identified age < 3 years at diagnosis, metastatic disease, omission of upfront radiation, and chr 16q loss as significant negative prognostic factors across all PBs. Our findings demonstrate that PB exhibits substantial molecular heterogeneity with sub-group-associated clinical phenotypes and survival. In addition to revealing novel biology and therapeutics, molecular sub-grouping of PB can be exploited to reduce treatment intensity for patients with favorable biology tumors.

Heterogeneity within the PF-EPN-B ependymoma subgroup.

Posterior fossa ependymoma comprise three distinct molecular variants, termed PF-EPN-A (PFA), PF-EPN-B (PFB), and PF-EPN-SE (subependymoma). Clinically, they are very disparate and PFB tumors are currently being considered for a trial of radiation avoidance. However, to move forward, unraveling the heterogeneity within PFB would be highly desirable. To discern the molecular heterogeneity within PFB, we performed an integrated analysis consisting of DNA methylation profiling, copy-number profiling, gene expression profiling, and clinical correlation across a cohort of 212 primary posterior fossa PFB tumors. Unsupervised spectral clustering and t-SNE analysis of genome-wide methylation data revealed five distinct subtypes of PFB tumors, termed PFB1-5, with distinct demographics, copy-number alterations, and gene expression profiles. All PFB subtypes were distinct from PFA and posterior fossa subependymomas. Of the five subtypes, PFB4 and PFB5 are more discrete, consisting of younger and older patients, respectively, with a strong female-gender enrichment in PFB5 (age: p = 0.011, gender: p = 0.04). Broad copy-number aberrations were common; however, many events such as chromosome 2 loss, 5 gain, and 17 loss were enriched in specific subtypes and 1q gain was enriched in PFB1. Late relapses were common across all five subtypes, but deaths were uncommon and present in only two subtypes (PFB1 and PFB3). Unlike the case in PFA ependymoma, 1q gain was not a robust marker of poor progression-free survival; however, chromosome 13q loss may represent a novel marker for risk stratification across the spectrum of PFB subtypes. Similar to PFA ependymoma, there exists a significant intertumoral heterogeneity within PFB, with distinct molecular subtypes identified. Even when accounting for this heterogeneity, extent of resection remains the strongest predictor of poor outcome. However, this biological heterogeneity must be accounted for in future preclinical modeling and personalized therapies.

Molecular Classification and Management of Rare Pediatric Embryonal Brain Tumors.

PURPOSE OF REVIEW: Malignant embryonal brain tumors (EBTs) of childhood span a wide clinical spectrum but can share remarkably similar morphologic features. This overlap presents significant diagnostic challenges, particularly for tumor entities that are rarely encountered in clinical practice and for which diagnostic criteria were poorly defined. This review will provide an update on the evolving characterization and treatment of rare EBTs. RECENT FINDINGS: Rapid advances in genomic tools have led to the discovery of robust molecular markers, and identification of novel tumor types and subtypes for almost all major categories of pediatric brain tumors. These developments have had significant impact on improving the diagnostic classification of the rare EBTs, particularly for tumors with newly recognized C19MC alterations, central nervous system primitive neuroectodermal tumors (CNS-PNET), and pineoblastoma (PB). These important developments in the clinical and molecular understanding of rare EBTs are paving the way for novel therapeutic strategies and improved clinical management.

Use of Ultrasound-Guided Superficial Cervical Plexus Block for Pain Management in the Emergency Department.

BACKGROUND: Although use of the superficial cervical plexus block (SCPB) by anesthesia for perioperative indications is well described, there is a paucity of research on use of SCPB in the emergency department (ED). OBJECTIVE: This prospective observational study aims to prospectively characterize the feasibility, potential for efficacy, and safety of ultrasound-guided SCPB in a convenience sample of ED patients presenting with painful conditions of the "cape" distribution of the neck and shoulder. METHODS: Data were gathered prospectively on a convenience sample of 27 patients presenting to a community ED with painful conditions involving the distribution of the SCPB: para-cervical muscle spasm/pain (n = 8), clavicle fractures (n = 7), acromioclavicular joint injuries (n = 3), radicular pain (n = 3), and rotator cuff disorders (n = 6). Pre- and post-block 11-point verbal numeric pain scores (VNPS) were recorded, as was the incidence of any immediate complications. A retrospective chart review looked for delayed complications in the 14-day post-block period. RESULTS: The mean 11-point VNPS reduction was 5.4 points (62%). There were no early serious complications and one case each of self-limiting vocal hoarseness and asymptomatic hemi-diaphragmatic paresis. No delayed block-related complications were found. CONCLUSIONS: While limited by the fact that this was a nonrandomized observational experience with no control group, our findings suggest that SCBP may be safe and have potential for efficacy, and warrants further evaluation in a randomized controlled trial.

The erector spinae plane block vs. usual care for treatment of mechanical back pain in the emergency department: a pilot study.

BACKGROUND: The ultrasound-guided erector spinae plane block (ESPB), traditionally utilized for thoracic regional pain control, has been reported as an effective analgesic option for mechanical back pain, renal colic, and rib fractures in the emergency department (ED). This pilot study aims to compare the effectiveness of the ESPB to usual analgesic treatment for patients presenting to the ED with mechanical back pain. METHODS: A prospective, single-blind randomized controlled trial was conducted at a Canadian community hospital from March 2020 to December 2022. Adult patients presenting to the ED with mechanical back pain of at least 7 out of 10 on the Numeric Pain Rating Scale (NPRS) were randomized to receive either the ESPB or usual care. The primary outcome was the difference in NPRS score reduction at ED discharge. Secondary outcomes included ED length of stay, ED opiate use, follow-up NPRS and Brief Pain Inventory (BPI) scores, back pain-related return ED visits, and ongoing opiate use. RESULTS: A total of 30 patients were enrolled, with 19 randomized to the ESPB cohort and 11 to the usual care cohort. The mean NPRS reduction at ED discharge was significantly higher in the ESPB group compared to the usual care group (5.4 vs. 2.2), with a difference of 3.2 (95% confidence interval 1.4-5.1). ED opiate use was lower in the ESPB group. The ESPB also resulted in a significant reduction in ED length of stay (160 min vs. 235 min). There were no reported adverse effects related to the research interventions. CONCLUSION: This pilot study suggests that the ESPB may be an effective opioid-sparing analgesic option for patients presenting to the ED with mechanical back pain. GOV IDENTIFIER: NCT05982483.

RéSUMé: CONTEXTE: Le bloc raboteux spina érectile guidé par ultrasons (ESPB), traditionnellement utilisé pour le contrôle de la douleur régionale thoracique, a été signalé comme une option analgésique efficace pour les maux de dos mécaniques, les coliques rénales et les fractures des côtes au service des urgences (ED). Cette étude pilote vise à comparer l'efficacité de l'ESPB au traitement analgésique habituel pour les patients présentant à l'urgence des douleurs dorsales mécaniques. MéTHODES: Un essai contrôlé randomisé prospectif en aveugle a été mené dans un hôpital communautaire canadien de mars 2020 à décembre 2022. Les patients adultes se présentant à l'urgence avec une douleur dorsale mécanique d'au moins 7 sur 10 sur l'échelle numérique d'évaluation de la douleur (NPRS) ont été randomisés pour recevoir soit la ESPB ou les soins habituels. Le critère de jugement principal était la différence dans la réduction du score NPRS à la sortie de l'urgence. Les critères de jugement secondaires comprenaient la durée du séjour à l'urgence, l'utilisation d'opiacés à l'urgence, les scores de suivi à l'INRP et au Brief Pain Inventory (BPI), les visites de retour à l'urgence liées à la douleur dorsale et l'utilisation continue d'opiacés. RéSULTATS: Au total, 30 patients ont été recrutés, dont 19 randomisés dans la cohorte de la DGPSE et 11 dans la cohorte de soins habituels. La réduction moyenne du NPRS à la sortie de l'urgence était significativement plus élevée dans le groupe ESPB que dans le groupe de soins habituels (5,4 vs. 2,2), avec une différence de 3,2 (intervalle de confiance à 95 % 1,4-5,1). La consommation d'opiacés aux urgences était plus faible dans le groupe ESPB. La ESPB a également entraîné une réduction significative de la durée du séjour aux urgences (160 min contre 235 min). Aucun effet indésirable lié aux interventions de recherche n'a été signalé. CONCLUSION: Cette étude pilote suggère que l'ESPB peut être une option analgésique efficace épargnant les opioïdes pour les patients se présentant à l'urgence avec des douleurs dorsales mécaniques.

Rapid, economical diagnostic classification of ATRT molecular subgroup using NanoString nCounter platform.

Background: Despite genomic simplicity, recent studies have reported at least 3 major atypical teratoid rhabdoid tumor (ATRT) subgroups with distinct molecular and clinical features. Reliable ATRT subgrouping in clinical settings remains challenging due to a lack of suitable biological markers, sample rarity, and the relatively high cost of conventional subgrouping methods. This study aimed to develop a reliable ATRT molecular stratification method to implement in clinical settings. Methods: We have developed an ATRT subgroup predictor assay using a custom genes panel for the NanoString nCounter System and a flexible machine learning classifier package. Seventy-one ATRT primary tumors with matching gene expression array and NanoString data were used to construct a multi-algorithms ensemble classifier. Additional validation was performed using an independent gene expression array against the independently generated dataset. We also analyzed 11 extra-cranial rhabdoid tumors with our classifier and compared our approach against DNA methylation classification to evaluate the result consistency with existing methods. Results: We have demonstrated that our novel ensemble classifier has an overall average of 93.6% accuracy in the validation dataset, and a striking 98.9% accuracy was achieved with the high-prediction score samples. Using our classifier, all analyzed extra-cranial rhabdoid tumors are classified as MYC subgroups. Compared with the DNA methylation classification, the results show high agreement, with 84.5% concordance and up to 95.8% concordance for high-confidence predictions. Conclusions: Here we present a rapid, cost-effective, and accurate ATRT subgrouping assay applicable for clinical use.

A kinome drug screen identifies multi-TKI synergies and ERBB2 signaling as a therapeutic vulnerability in MYC/TYR subgroup atypical teratoid rhabdoid tumors.

BACKGROUND: Atypical teratoid rhabdoid tumor (ATRT) is a rare, devastating, and largely incurable pediatric brain tumor. Although recent studies have uncovered 3 molecular subgroups of ATRTs with distinct disease patterns, and signaling features, the therapeutic profiles of ATRT subgroups remain incompletely elucidated. METHODS: We examined the effect of 465 kinase inhibitors on a panel of ATRT subgroup-specific cell lines. We then applied multiomics analyses to investigate the underlying molecular mechanism of kinase inhibitor efficacy in ATRT subgroups. RESULTS: We observed that ATRT cell lines are broadly sensitive to inhibitors of the PI3K and MAPK signaling pathways, as well as CDKs, AURKA/B kinases, and polo-like kinase 1. We identified 2 classes of multikinase inhibitors predominantly targeting receptor tyrosine kinases including PDGFR and EGFR/ERBB2 in MYC/TYR ATRT cells. The PDGFRB inhibitor, Dasatinib, synergistically affected MYC/TYR ATRT cell growth when combined with broad-acting PI3K and MAPK pathway inhibitors, including Rapamycin and Trametinib. We observed that MYC/TYR ATRT cells were also distinctly sensitive to various inhibitors of ERBB2 signaling. Transcriptional, H3K27Ac ChIPSeq, ATACSeq, and HiChIP analyses of primary MYC/TYR ATRTs revealed ERBB2 expression, which correlated with differential methylation and activation of a distinct enhancer element by DNA looping. Significantly, we show the brain penetrant EGFR/ERBB2 inhibitor, Afatinib, specifically inhibited in vitro and in vivo growth of MYC/TYR ATRT cells. CONCLUSIONS: Taken together, our studies suggest combined treatments with PDGFR and ERBB2-directed TKIs with inhibitors of the PI3K and MAPK pathways as an important new therapeutic strategy for the MYC/TYR subgroup of ATRTs.

Inhibiting EZH2 targets atypical teratoid rhabdoid tumor by triggering viral mimicry via both RNA and DNA sensing pathways.

Inactivating mutations in SMARCB1 confer an oncogenic dependency on EZH2 in atypical teratoid rhabdoid tumors (ATRTs), but the underlying mechanism has not been fully elucidated. We found that the sensitivity of ATRTs to EZH2 inhibition (EZH2i) is associated with the viral mimicry response. Unlike other epigenetic therapies targeting transcriptional repressors, EZH2i-induced viral mimicry is not triggered by cryptic transcription of endogenous retroelements, but rather mediated by increased expression of genes enriched for intronic inverted-repeat Alu (IR-Alu) elements. Interestingly, interferon-stimulated genes (ISGs) are highly enriched for dsRNA-forming intronic IR-Alu elements, suggesting a feedforward loop whereby these activated ISGs may reinforce dsRNA formation and viral mimicry. EZH2i also upregulates the expression of full-length LINE-1s, leading to genomic instability and cGAS/STING signaling in a process dependent on reverse transcriptase activity. Co-depletion of dsRNA sensing and cytoplasmic DNA sensing completely rescues the viral mimicry response to EZH2i in SMARCB1-deficient tumors.

The utility of internal spinal marking for intraoperative localisation: A systematic review.

BACKGROUND: Incorrect level spinal surgery is an avoidable complication, with significant ramifications. Several pre-operative spinal marking techniques have been described to aid intraoperative localisation. METHODS: A systematic search of Ovid MEDLINE, and EMBASE was performed from inception to July 2022. All publications describing cases of internal spinal marking were included for further analysis. 22 articles describing 503 patients satisfied our eligibility criteria. RESULTS: A number of localisation techniques, including endovascular coiling (n = 16), fiducials (n = 177), dye (n = 109), needle/fixed wire (n = 199), cement (n = 4), and gadolinium tubes (n = 1) were described. The highest rates of technical success were observed with endovascular coiling, fiducials, cement and dye (100 %), and complication rates were lowest with endovascular coiling, fiducials and cement (0 %). CONCLUSIONS: Overall, internal spinal marking was effective and safe. When considering practicality and efficacy, fiducial marking appears the optimal technique, as it can be performed in the outpatient setting under local anaesthesia. This review demonstrates the need for more targeted investigation into localisation methods in spinal surgery.

Diagnostic classification of childhood cancer using multiscale transcriptomics.

The causes of pediatric cancers' distinctiveness compared to adult-onset tumors of the same type are not completely clear and not fully explained by their genomes. In this study, we used an optimized multilevel RNA clustering approach to derive molecular definitions for most childhood cancers. Applying this method to 13,313 transcriptomes, we constructed a pediatric cancer atlas to explore age-associated changes. Tumor entities were sometimes unexpectedly grouped due to common lineages, drivers or stemness profiles. Some established entities were divided into subgroups that predicted outcome better than current diagnostic approaches. These definitions account for inter-tumoral and intra-tumoral heterogeneity and have the potential of enabling reproducible, quantifiable diagnostics. As a whole, childhood tumors had more transcriptional diversity than adult tumors, maintaining greater expression flexibility. To apply these insights, we designed an ensemble convolutional neural network classifier. We show that this tool was able to match or clarify the diagnosis for 85% of childhood tumors in a prospective cohort. If further validated, this framework could be extended to derive molecular definitions for all cancer types.

To Volunteer or Not? Perspectives towards Pre-Registered Nursing Students Volunteering Frontline during COVID-19 Pandemic to Ease Healthcare Workforce: A Qualitative Study.

COVID-19 has caused a shortage of healthcare workers and has strained healthcare systems globally. Pre-registered healthcare students with training have a duty of care and can support the healthcare workforce. This study explored factors influencing the willingness of final-year nursing students to volunteer during the COVID-19 pandemic, the role of professional identity in volunteering as healthcare workers, and strategies to improve future volunteering uptakes and processes. A qualitative study using focus-group discussions was conducted. Final-year nursing students who volunteered, students who did not volunteer, and lecturers who supervised student volunteers were recruited. Interviews were conducted online, video-recorded, and transcribed verbatim. A thematic analysis was used. The themes were "wavering thoughts on volunteering", "bringing out 'the nurse' in students through volunteering" and "gearing up to volunteer". Findings suggested the need to look beyond the simplicity of altruism to the role of professional identity, operational, and motivational factors to explain nursing students' decision to volunteer and their volunteer behavior. Providing accommodation, monetary and academic-related incentives, supporting the transitionary phase from students to "professional volunteers", promoting cohesive and positive staff-student volunteer relationships, and establishing a volunteer management team are strategies identified to improve volunteering uptake and operational processes. Our findings advocate strategic partnerships between hospitals/communities and academic institutions in providing various healthcare services during pandemics.

Clinical phenotypes and prognostic features of embryonal tumours with multi-layered rosettes: a Rare Brain Tumor Registry study.

BACKGROUND: Embryonal tumours with multi-layered rosettes (ETMRs) are a newly recognised, rare paediatric brain tumour with alterations of the C19MC microRNA locus. Due to varied diagnostic practices and scarce clinical data, disease features and determinants of outcomes for these tumours are poorly defined. We did an integrated clinicopathological and molecular analysis of primary ETMRs to define clinical phenotypes, and to identify prognostic factors of survival and key treatment modalities for this orphan disease. METHODS: Paediatric patients with primary ETMRs and tissue available for analyses were identified from the Rare Brain Tumor Consortium global registry. The institutional histopathological diagnoses were centrally re-reviewed as per the current WHO CNS tumour guidelines, using histopathological and molecular assays. Only patients with complete clinical, treatment, and survival data on Nov 30, 2019, were included in clinicopathological analyses. Among patients who received primary multi-modal curative regimens, event-free survival and overall survival were determined using Cox proportional hazard and log-rank analyses. Univariate and multivariable Cox proportional hazard regression was used to estimate hazard ratios (HRs) with 95% CIs for clinical, molecular, or treatment-related prognostic factors. FINDINGS: 159 patients had a confirmed molecular diagnosis of primary ETMRs (median age at diagnosis 26 months, IQR 18-36) and were included in our clinicopathological analysis. ETMRs were predominantly non-metastatic (94 [73%] of 128 patients), arising from multiple sites; 84 (55%) of 154 were cerebral tumours and 70 (45%) of 154 arose at sites characteristic of other brain tumours. Hallmark C19MC alterations were seen in 144 (91%) of 159 patients; 15 (9%) were ETMR not otherwise specified. In patients treated with curative intent, event-free survival was 57% (95% CI 47-68) at 6 months and 31% (21-42) at 2 years; overall survival was 29% (20-38) at 2 years and 27% (18-37) at 4 years. Overall survival was associated with non-metastatic disease (HR 0·48, 95% CI 0·28-0·80; p=0·0057) and non-brainstem location (0·42 [0·22-0·81]; p=0·013) on univariate analysis, as well as with gross total resection (0·30, 0·16-0·58; p=0·0014), high-dose chemotherapy (0·35, 0·19-0·67; p=0·0020), and radiotherapy (0·21, 0·10-0·41; p<0·0001) on multivariable analysis. 2-year event-free and overall survival was 0% at 2 years in patients treated with conventional chemotherapy without radiotherapy (regardless of surgery extent), and 21% (95% CI 1-41) and 30% (6-54), respectively, in patients treated with high-dose chemotherapy, and gross total resection without radiotherapy. 2-year event-free survival in patients treated with high-dose chemotherapy and radiotherapy was 66% (95% CI 39-93) for patients with gross total resection and 44% (7-81) for patients with sub-total resection. 2-5-year overall survival was 66% (95% CI 33-99, p=0·038) for patients with gross total resection and 67% (36-98, p=0·0020) for patients with sub-total resection. INTERPRETATION: Prompt molecular diagnosis and post-surgical treatment with intensive multi-modal therapy tailored to patient-specific risk features could improve ETMR survival. FUNDING: Canadian Institute of Health Research, Canada Research Chair Awards, Australian Lions Childhood Cancer Research Foundation, Spanish Society of Pediatrics, Consejería de Salud y Familias de la Junta de Andalucía, Miracle Marnie, Phoebe Rose Rocks, Tali's Funds, Garron Cancer Centre, Grace's Walk, Meagan's Hug, Brainchild, Nelina's Hope, and Jean Martel Foundation.

DNA Polymerase and Mismatch Repair Exert Distinct Microsatellite Instability Signatures in Normal and Malignant Human Cells.

Although replication repair deficiency, either by mismatch repair deficiency (MMRD) and/or loss of DNA polymerase proofreading, can cause hypermutation in cancer, microsatellite instability (MSI) is considered a hallmark of MMRD alone. By genome-wide analysis of tumors with germline and somatic deficiencies in replication repair, we reveal a novel association between loss of polymerase proofreading and MSI, especially when both components are lost. Analysis of indels in microsatellites (MS-indels) identified five distinct signatures (MS-sigs). MMRD MS-sigs are dominated by multibase losses, whereas mutant-polymerase MS-sigs contain primarily single-base gains. MS deletions in MMRD tumors depend on the original size of the MS and converge to a preferred length, providing mechanistic insight. Finally, we demonstrate that MS-sigs can be a powerful clinical tool for managing individuals with germline MMRD and replication repair-deficient cancers, as they can detect the replication repair deficiency in normal cells and predict their response to immunotherapy. SIGNIFICANCE: Exome- and genome-wide MSI analysis reveals novel signatures that are uniquely attributed to mismatch repair and DNA polymerase. This provides new mechanistic insight into MS maintenance and can be applied clinically for diagnosis of replication repair deficiency and immunotherapy response prediction.This article is highlighted in the In This Issue feature, p. 995.

Injuries and illnesses among human remains detection-certified search-and-recovery dogs deployed to northern California in response to the Camp Fire wildfire of November 2018.

OBJECTIVE: To document injuries and illnesses incurred by search-and-recovery (S&R) dogs deployed to northern California in response to the Camp Fire wildfire of November 2018 and identify fire scene-specific hazards. ANIMALS: 30 human remains detection-certified S&R dogs deployed to the Camp Fire scene. PROCEDURES: Handlers of the S&R dogs completed a survey after deployment. Data on illnesses and injuries incurred by the dogs during deployment were summarized, incidence rates were calculated, and fire scene hazards were identified. RESULTS: Dogs were deployed for 161 days in total, representing 121 operational search shifts that totalled 931 hours. Injuries and illnesses (ie, medical issues) were reported for 20 (67%) dogs. Wounds (lacerations and abrasions) were the most common injury, occurring in 13 (43%) dogs for an incidence rate of 34.4 wounds/1,000 h worked. The most common illness-related issues were weight loss and lethargy or fatigue, each reported for 3 (10%) dogs for an incidence rate of 3.2 events/1,000 h worked. Total incidence rate for all medical issue events was 67.7 events/1,000 h worked. Specific to the Camp Fire scene were respiratory hazards of carcinogenic woodland smoke, aerosolized dry ash, and poison oak fumes; and contact hazards of burning ground or roots, unstable sewer covers, prescription medications, unexploded ammunition, congealed vehicle battery acid, and antifreeze, all hidden under layers of ash. CONCLUSIONS AND CLINICAL RELEVANCE: Lacerations, abrasions, weight loss, and lethargy or fatigue were common among the S&R dogs, and ash covering fire scene-specific hazards likely contributed. In addition to safety concerns common to all team personnel, hazards specific to S&R dogs in a postfire environment should be emphasized during hazmat and safety briefings, especially to handlers, search team managers, and medical personnel.

Molecular subgrouping of atypical teratoid/rhabdoid tumors-a reinvestigation and current consensus.

BACKGROUND: Atypical teratoid/rhabdoid tumors (ATRTs) are known to exhibit molecular and clinical heterogeneity even though SMARCB1 inactivation is the sole recurrent genetic event present in nearly all cases. Indeed, recent studies demonstrated 3 molecular subgroups of ATRTs that are genetically, epigenetically, and clinically distinct. As these studies included different numbers of tumors, various subgrouping techniques, and naming, an international working group sought to align previous findings and to reach a consensus on nomenclature and clinicopathological significance of ATRT subgroups. METHODS: We integrated various methods to perform a meta-analysis on published and unpublished DNA methylation and gene expression datasets of ATRTs and associated clinicopathological data. RESULTS: In concordance with previous studies, the analyses identified 3 main molecular subgroups of ATRTs, for which a consensus was reached to name them ATRT-TYR, ATRT-SHH, and ATRT-MYC. The ATRT-SHH subgroup exhibited further heterogeneity, segregating further into 2 subtypes associated with a predominant supratentorial (ATRT-SHH-1) or infratentorial (ATRT-SHH-2) location. For each ATRT subgroup we provide an overview of its main molecular and clinical characteristics, including SMARCB1 alterations and pathway activation. CONCLUSIONS: The introduction of a common classification, characterization, and nomenclature of ATRT subgroups will facilitate future research and serve as a common ground for subgrouping patient samples and ATRT models, which will aid in refining subgroup-based therapies for ATRT patients.

Advancing biology-based therapeutic approaches for atypical teratoid rhabdoid tumors.

Atypical teratoid rhabdoid tumor (ATRT) is a rare, highly malignant central nervous system cancer arising in infants and younger children, historically considered to be homogeneous, monogenic, and incurable. Recent use of intensified therapies has modestly improved survival for ATRT; however, a majority of patients will still succumb to their disease. While ATRTs almost universally exhibit loss of SMARCB1 (BAF47/INI1/SNF5), recent whole genome, transcriptome, and epigenomic analyses of large cohorts reveal previously underappreciated molecular heterogeneity. These discoveries provide novel insights into how SMARCB1 loss drives oncogenesis and confer specific therapeutic vulnerabilities, raising exciting prospects for molecularly stratified treatment for patients with ATRT.