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Figure S1 shows Tier 1-3 genomic events in INI1-negative tumors

PURPOSE Osteosarcoma risk stratification, on the basis of the presence of metastatic disease at diagnosis and histologic response to chemotherapy, has remained unchanged for four decades, does not include genomic features, and has not facilitated treatment advances. We report on the genomic features of advanced osteosarcoma and provide evidence that genomic alterations can be used for risk stratification. MATERIALS AND METHODS In a primary analytic patient cohort, 113 tumor and 69 normal samples from 92 patients with high-grade osteosarcoma were sequenced with OncoPanel, a targeted next-generation sequencing assay. In this primary cohort, we assessed the genomic landscape of advanced disease and evaluated the correlation between recurrent genomic events and outcome. We assessed whether prognostic associations identified in the primary cohort were maintained in a validation cohort of 86 patients with localized osteosarcoma tested with MSK-IMPACT. RESULTS In the primary cohort, 3-year overall survival (OS) was 65%. Metastatic disease, present in 33% of patients at diagnosis, was associated with poor OS ( P = .04). The most frequently altered genes in the primary cohort were TP 53, RB1, MYC, CCNE1, CCND3, CDKN2A/B, and ATRX. Mutational signature 3 was present in 28% of samples. MYC amplification was associated with a worse 3-year OS in both the primary cohort ( P = .015) and the validation cohort ( P = .012). CONCLUSION The most frequently occurring genomic events in advanced osteosarcoma were similar to those described in prior reports. MYC amplification, detected with clinical targeted next-generation sequencing panel tests, is associated with poorer outcomes in two independent cohorts.

PURPOSE Multiple FGFR inhibitors are currently in clinical trials enrolling adults with different solid tumors, while very few enroll pediatric patients. We determined the types and frequency of FGFR alterations ( FGFR1-4) in pediatric cancers to inform future clinical trial design. METHODS Tumors with FGFR alterations were identified from two large cohorts of pediatric solid tumors subjected to targeted DNA sequencing: The Dana-Farber/Boston Children's Profile Study (n = 888) and the multi-institution GAIN/iCAT2 (Genomic Assessment Improves Novel Therapy) Study (n = 571). Data from the combined patient population of 1,395 cases (64 patients were enrolled in both studies) were reviewed and cases in which an FGFR alteration was identified by OncoPanel sequencing were further assessed. RESULTS We identified 41 patients with tumors harboring an oncogenic FGFR alteration. Median age at diagnosis was 8 years (range, 6 months-26 years). Diagnoses included 11 rhabdomyosarcomas, nine low-grade gliomas, and 17 other tumor types. Alterations included gain-of-function sequence variants (n = 19), amplifications (n = 10), oncogenic fusions ( FGFR3:: TACC3 [n = 3], FGFR1:: TACC1 [n = 1], FGFR1:: EBF2 [n = 1], FGFR1:: CLIP2 [n = 1], and FGFR2:: CTNNA3 [n = 1]), pathogenic-leaning variants of uncertain significance (n = 4), and amplification in combination with a pathogenic-leaning variant of uncertain significance (n = 1). Two novel FGFR1 fusions in two different patients were identified in this cohort, one of whom showed a response to an FGFR inhibitor. CONCLUSION In summary, activating FGFR alterations were found in approximately 3% (41/1,395) of pediatric solid tumors, identifying a population of children with cancer who may be eligible and good candidates for trials evaluating FGFR-targeted therapy. Importantly, the genomic and clinical data from this study can help inform drug development in accordance with the Research to Accelerate Cures and Equity for Children Act.

The spectrum of neoplasms associated with DICER1 variants continues to expand, with the recent addition of primary “DICER1-associated central nervous system sarcoma” (DCS). DCS is a high-grade malignancy predominantly affecting pediatric patients. Six pediatric DCS were identified through a combination of clinical diagnostic studies, archival inquiry, and interinstitutional collaboration. Clinical, histologic, immunohistologic, and molecular features were examined. Genomic findings in the 6 DCS were compared with those in 14 additional DICER1-associated tumors sequenced with the same assay. The six patients presented at ages 3–15 years with CNS tumors located in the temporal (n = 2), parietal (n = 1), fronto-parietal (n = 1), and frontal (n = 2) lobes. All underwent surgical resection. Histologic examination demonstrated high-grade malignant spindle cell tumors with pleuropulmonary blastoma-like embryonic “organoid” features and focal rhabdomyoblastic differentiation; immature cartilage was seen in one case. Immunohistochemically, there was patchy desmin and myogenin staining, and patchy loss of H3K27me3, and within eosinophilic cytoplasmic globules, alfa-fetoprotein staining. Biallelic DICER1 variants were identified in all cases, with germline variants in two of five patients tested. DCS demonstrated genomic alterations enriched for Ras pathway activation and TP53 inactivation. Tumor mutational burden was significantly higher in the 6 DCS tumors than in 14 other DICER1-associated tumors examined (mean 12.9 vs. 6.8 mutations/Mb, p = 0.035). Postoperative care included radiation (n = 5) and chemotherapy (n = 3); at the last follow-up, three patients were alive without DCS, and three had died of disease. Our analysis expands the clinical, histologic, immunohistological, and molecular spectrum of DCS, identifying distinctive features that can aid in the diagnosis, multidisciplinary evaluation, and treatment of DCS.

Aim To determine the effect of CPR delivery surface (e.g. firm mattress, floor, backboard) on patient outcomes and CPR delivery. Methods We searched Medline, Cochrane Library and Web of Science for studies published since 2009 that evaluated the effect of CPR delivery surface in adults and children on patient outcomes and quality of CPR. We included randomised controlled trials only. We identified pre-2010 studies from the 2010 ILCOR evaluation of this topic. Two reviewers independently screened titles/ abstracts and full-text papers, extracted data and assessed risk of bias. Evidence certainty for each outcome was evaluated using GRADE methodology. Where appropriate, we pooled data in a meta-analysis, using a random-effects model. Results Database searches identified 2701 citations. We included seven studies published since 2009. We analysed these studies together with the four studies included in the previous ILCOR review. All included studies were randomised controlled trials in manikins. Certainty of evidence was very low. Increasing mattress stiffness or moving the manikin from the bed to the floor did not improve compression depth. Use of a backboard marginally improved compression depth (mean difference 3 mm (95% CI 1–4). Conclusion The use of a backboard led to a small increase in chest compression depth in manikin trials. Different mattress types or delivery of CPR on the floor did not affect chest compression depth. PROSPERO CRD42019154791.

The burden of malaria in Myanmar has declined rapidly in recent years; cases decreased from 333,871 in 2013 to 85,019 in 2017 (75% decrease). Decline of malaria in the Ayeyarwady Region of Myanmar reflects this trend with an 86% decrease in cases over this period. In this exploratory analysis, quantitative and qualitative information were assessed to explore potential factors responsible for the decline of malaria in Ayeyarwady. Data on malaria incidence, programmatic financing, surveillance, case management, vector control interventions, climate and ecological factors, and policies and guidelines spanning 2013 to 2017 were compiled. Poisson regression models that adjust for correlation were used to analyze the association between annual malaria case numbers with malaria intervention factors at the township level. Between 2013 and 2017, there was a decrease in mean township-level malaria incidence per 1000 from 3.03 (SD 4.59) to 0.34 (SD 0.79); this decline coincided with the implementation of the government’s multi-pronged malaria elimination strategy, an increase of approximately 50.8 million USD in malaria funding nationally, and a period of deforestation in the region. Increased funding in Ayeyarwady was invested in interventions associated with the decline in caseload, and the important roles of surveillance and case management should be maintained while Myanmar works towards malaria elimination.

Somatic gene translocations are key to making an accurate diagnosis in many cancers including many pediatric sarcomas. Currently available molecular diagnostic approaches to identifying somatic pathognomonic translocations have limitations such as minimal multiplexing, high cost, complex computational requirements, or slow turnaround times. We sought to develop a new fusion-detection assay optimized to mitigate these challenges. To accomplish this goal, we developed a highly sensitive multiplexed digital PCR-based approach that can identify the gene partners of multiple somatic fusion transcripts. This assay was validated for specificity with cell lines and synthetized DNA fragments. Assay sensitivity was optimized using a tiered amplification approach for fusion detection from low input and/or degraded RNA. The assay was then tested for the potential application of fusion detection from FFPE tissue and liquid biopsy samples. We found that this multiplexed PCR approach was able to accurately identify the presence of seven different targeted fusion transcripts with a turnaround time of 1 to 2 days. The addition of a tiered amplification step allowed the detection of targeted fusions from as little as 1 pg of RNA input. We also identified fusions from as little as two unstained slides of FFPE tumor biopsy tissue, from circulating tumor cells collected from tumor-bearing mice, and from liquid biopsy samples from patients with known fusion-positive cancers. We also demonstrated that the assay could be easily adapted for additional fusion targets. In summary, this novel assay detects multiple somatic fusion partners in biologic samples with low tumor content and low-quality RNA in less than two days. The assay is inexpensive and could be applied to surgical and liquid biopsies, particularly in places with inadequate resources for more expensive and expertise-dependent assays such as next-generation sequencing.

Background Ayeyarwady Region in Myanmar has made significant progress towards malaria elimination, with cases decreasing from 12,312 in 2015 to 122 in 2019. As transmission declines, malaria becomes increasingly focalized both in geographic hotspots and among population groups sharing certain risk factors. Developing a thorough profile of high-risk activities associated with malaria infections is critical to ensure intervention approaches are evidence-based. Methods A test-negative study was conducted from September 2017 to May 2018 in Ngaputaw, Pathein and Thabaung townships in Ayeyarwady Region. Patients that presented to selected public facilities or community health volunteers with fever answered survey questions on demographic and behavioural risk factors, including exposure to malaria interventions, and were assigned to case and control groups based on the result of a malaria rapid diagnostic test. A random-effects logistic regression model adjusted for clustering at the facility level, as well as any variables along the causal pathway described by a directed acyclic graph, was used to determine odds ratios and association with malaria infections. Results A total of 119 cases and 1744 controls were recruited from 41 public facilities, with a mean age of 31.3 and 63.7% male. Higher risk groups were identified as males (aOR 1.8, 95% CI 1.2–2.9) and those with a worksite located within the forest (aOR 2.8, 95% CI 1.4–5.3), specifically working in the logging (aOR 2.7, 95% CI 1.5–4.6) and rubber plantation (aOR 3.0, 95% CI 1.4–6.8) industries. Additionally, links between forest travel and malaria were observed, with risk factors identified to be sleeping in the forest within the past month (aOR 2.6, 95% CI 1.1–6.3), and extended forest travel with durations from 3 to 14 days (aOR 8.6, 95% CI 3.5–21.4) or longer periods (aOR 8.4, 95% CI 3.2–21.6). Conclusion Malaria transmission is highly focalized in Ayeyarwady, and results illustrate the need to target interventions to the most at-risk populations of working males and forest goers. It will become increasingly necessary to ensure full intervention coverage of at-risk populations active in forested areas as Myanmar moves closer to malaria elimination goals.

Creative works by black diasporan authors have often been viewed as offering a counter-history or “counter-memory” to the received history of slavery. Frequently, the Atlantic Ocean has tak...

Pediatric pan-cancer genome analyses do not capture the full range of diagnoses encountered in clinical practice. To inform basket trial design and real-world precision oncology practice, we classified diagnoses and assessed the landscape of mutations, including trial-matching, in an unselected cohort of pediatric solid tumors. Since 2013 all Dana-Farber/Boston Children’s patients have been offered participation in the Profile study. Participant tumor samples were sequenced with DFCI-OncoPanel, a targeted panel test sequencing exons of up to 447 cancer genes for single nucleotide variants, insertions and deletions and copy number alterations, and introns and exons of up to 60 genes for rearrangements. Patient diagnosis was classified according to ICD-O, version 3.2. Genomic alterations were analyzed for matching to the actionable mutation lists of precision oncology basket trials (NCI-COG Pediatric MATCH, NCI-MATCH, and the ASCO TAPUR Study v.3). Data will be shared with the Childhood Cancer Data Initiative. There were 888 pediatric patients with sequencing enrolled in Profile between January 2013 and March 2019; 512 (58%) with solid tumors and 376 (42%) with CNS tumors. Fifty-five percent (491/888) of patients had one of ten common pediatric cancer diagnoses: neuroblastoma (n=80), low-grade glioma (n=72), Wilms tumor (n=57), medulloblastoma (n=55), pilocytic astrocytoma (n=47), rhabdomyosarcoma (n=44), osteosarcoma (n=42), ependymoma (n=39), Ewing sarcoma (n=28) and glioblastoma (n=27). The remaining 45% (397/888) had one of 85 distinct rare malignancies with less than 25 cases per diagnosis. Most (80/85) of these rare diagnoses are not represented in prior pediatric pan-cancer sequencing studies. Recurrent (>5%) pathogenic alterations were, in common and rare diagnoses, TP53 mutations(m) and deletions(del) and BRAFm and rearrangements(r), in common diagnoses, MYC/MYCN amplification (amp) and EWSR1r and, in rare diagnoses, CTNNB1m, CDKN2A/Bdel and NF1m/del. We found that 31% (n=271/888) of patients had at least 1 variant matching a basket trial treatment arm. Genes with matching alterations include BRAF (10%), NF1 (4%), PI3KCA (3%), NRAS (2%), BRCA2 (2%), ALK (1%), and FGFR1 (1%). Sequencing of pediatric malignancies is increasing. This study highlights opportunities to use the resulting genomic data to inform genome-selected clinical trial design and uncover drivers in pediatric cancers. The proportion of cases in this cohort with genomic alterations meeting eligibility for basket trials is equivalent to that seen in the pediatric MATCH screening study. Due to the low prevalence of the diagnoses in the long tail of cancer types in this study, defining the genomic landscape of ultra-rare cancers will require data sharing. Classifying pediatric cancer diagnoses using the ICD-O standard ontology system is feasible and will facilitate data sharing. Citation Format: Suzanne J. Forrest, Hersh Gupta, Abigail Ward, Yvonne Li, Duong Doan, Alyaa Al-Ibraheemi, Sanda Alexandrescu, Pratiti Bandopadhayay, Suzanne Shusterman, Elizabeth A. Mullen, Natalie Collins, Susan N. Chi, Karen D. Wright, Priti Kumari, Tali Mazor, Keith L. Ligon, Priyanka Shivdasani, Phani Davineni, Monica Manam, Richard L. Schilsky, Suanna S. Bruinooge, Jaime M. Guidry Auvil, Ethan Cerami, Barrett J. Rollins, Matthew L. Meyerson, Neal I. Lindeman, Laura MacConaill, Bruce E. Johnson, Andrew D. Cherniack, Alanna J. Church, Katherine A. Janeway. Sequencing of 888 pediatric solid tumors informs precision oncology trial design and data sharing initiatives in pediatric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3890.

For this 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations, the Education, Implementation, and Teams Task Force applied the population, intervention, comparator, outcome, study design, time frame format and performed 15 systematic reviews, applying the Grading of Recommendations, Assessment, Development, and Evaluation guidance. Furthermore, 4 scoping reviews and 7 evidence updates assessed any new evidence to determine if a change in any existing treatment recommendation was required. The topics covered included training for the treatment of opioid overdose; basic life support, including automated external defibrillator training; measuring implementation and performance in communities, and cardiac arrest centers; advanced life support training, including team and leadership training and rapid response teams; measuring cardiopulmonary resuscitation performance, feedback devices, and debriefing; and the use of social media to improve cardiopulmonary resuscitation application.

Introduction Tissue from pediatric solid tumors is in high demand for use in high-impact research studies, making the allocation of tissue from an anatomic pathology laboratory challenging. We designed, implemented, and assessed an interdepartmental process to optimize tissue allocation of pediatric solid tumors for both clinical care and research. Methods Oncologists, pathologists, surgeons, interventional radiologists, pathology technical staff, and clinical research coordinators participated in the workflow design. Procedures were created to address patient identification and consent, prioritization of protocols, electronic communication of requests, tissue preparation, and distribution. Pathologists were surveyed about the value of the new workflow. Results Over a 5-year period, 644 pediatric solid tumor patients consented to one or more studies requesting archival or fresh tissue. Patients had a variety of tumor types, with many rare and singular diagnoses. Sixty-seven percent of 1768 research requests were fulfilled. Requests for archival tissue were fulfilled at a significantly higher rate than those for fresh tissue (P > .001), and requests from resection specimens were fulfilled at a significantly higher rate than those from biopsies (P > .0001). In an anonymous survey, seven of seven pathologists reported that the process had improved since the introduction of the electronic communication model. Conclusions A collaborative and informed model for tissue allocation is successful in distributing archival and fresh tissue for clinical research studies. Our workflows and policies have gained pathologists' approval and streamlined our processes. As clinical and research programs evolve, a thoughtful tissue allocation process will facilitate ongoing research.

To determine if two encounter conversation aids for early-stage breast cancer surgery increased observed and patient-reported shared decision making (SDM) compared with usual care and if observed and patient-reported SDM were associated.Surgeons in a cluster randomized trial at four cancer centers were randomized to use an Option Grid, Picture Option Grid, or usual care. We used bivariate statistics, linear regression, and multilevel models to evaluate the influence of trial arm, patient socioeconomic status and health literacy on observed SDM (via OPTION-5) and patient-reported SDM (via collaboRATE).From 311 recordings, OPTION-5 scores were 73/100 for Option Grid (n = 40), 56.3/100 for Picture Option Grid (n = 144), and 41.0/100 for usual care (n = 127; p0.0001). Top collaboRATE scores were 81.6 % for Option Grid, 80.0 % for Picture Option Grid, and 56.4 % for usual care (p0.001). Top collaboRATE scores correlated with an 8.60 point (95 %CI 0.66, 13.7) higher OPTION-5 score (p = 0.008) with no correlation in the multilevel analysis. Patients of lower socioeconomic status had lower OPTION-5 scores before accounting for clustering.Both conversation aids led to meaningfully higher observed and patient-reported SDM. Observed and patient-reported SDM were not strongly correlated.Healthcare providers could implement these conversation aids in real-world settings.

For this 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations , the Education, Implementation, and Teams Task Force applied the population, intervention, comparator, outcome, study design, time frame format and performed 15 systematic reviews, applying the Grading of Recommendations, Assessment, Development, and Evaluation guidance. Furthermore, 4 scoping reviews and 7 evidence updates assessed any new evidence to determine if a change in any existing treatment recommendation was required. The topics covered included training for the treatment of opioid overdose; basic life support, including automated external defibrillator training; measuring implementation and performance in communities, and cardiac arrest centers; advanced life support training, including team and leadership training and rapid response teams; measuring cardiopulmonary resuscitation performance, feedback devices, and debriefing; and the use of social media to improve cardiopulmonary resuscitation application.

Objective Liquid biopsies are being rapidly used in adult cancers as new biomarkers of disease. Circulating tumor DNA (ctDNA) levels have been reported to be proportional to disease burden, correlate with treatment response, and predict relapse. However, little is known about how frequently ctDNA is detectable in pediatric patients with solid tumors. Therefore, we developed a next-generation sequencing approach to detect and quantify ctDNA in the blood of patients with the most common pediatric solid tumors. Methods Detection of ctDNA requires assays sensitive to somatic events typically observed in the cancer type being studied. In pediatric solid tumors, structural variants are more common than recurrent point mutations. We adapted an ultralow passage whole-genome sequencing approach to capture copy number variants and a hybrid capture sequencing assay to detect translocations in liquid biopsy samples from pediatric patients. Results Copy number changes seen by ultralow passage whole-genome sequencing enabled detection of ctDNA in patients with osteosarcoma, neuroblastoma, alveolar rhabdomyosarcoma, and Wilms tumor. In Ewing sarcoma, detection of the EWSR1 translocation was a more sensitive approach. For patients with samples collected at multiple time points, changes in ctDNA levels corresponded to treatment response. We also found that disease-specific genomic biomarkers of prognosis were detectable in ctDNA. Conclusion This study demonstrates that liquid biopsy approaches that detect somatic structural variants are well suited to pediatric solid tumors. We show that children with the most common solid tumor malignancies have detectable levels of ctDNA, which may be used to track disease response and identify genomic subclassifiers of disease. Efforts to profile larger collections of clinically annotated specimens are under way to validate the clinical use of these assays.

A short-cut review was carried out to establish whether shared decision making used alongside a decision aid can lead to greater patient satisfaction, lower healthcare resource use and non-inferior clinical outcomes in patients with suspected acute coronary syndromes. Four studies were directly relevant to the question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these papers are tabulated. The clinical bottom line is that the use of shared decision-making tools in the ED for management of patients with low-risk chest pain appears to be beneficial to the patient and the physician. Use of these shared decision-making tools appears to increase patient knowledge and satisfaction, while decreasing decision conflict and resource use, without causing additional negative outcomes for the patient.

Background: Vascular anomalies are diverse entities and can range in severity from self-limiting to life-threatening. Diagnosis and care of these patients is challenging due to overlapping clinical and histologic features. Recently, it has been established that many vascular anomalies arise from somatic mutations in cancer genes (PIK3CA, AKT, NRAS). Use of cancer genomics in patients with vascular anomalies may establish a genetic diagnosis and expand use of targeted medical therapies. We evaluated the utility of targeted next generation sequencing for vascular anomalies patients at a single pediatric center. Methods: Using OncoPanel, a hybrid-capture and massively parallel sequencing assay that surveys DNA sequences of 447 genes implicated in cancer, we analyzed genetic variants in lesional tissue from vascular anomalies patients evaluated at Boston Children's Hospital between 5/2/2017 and 3/23/2020. Results: A total of 276 patients were consented and sequenced under the Dana Farber Cancer Institute Profile protocols DFCI 11-104 (n= 68) and DFCI 17-000 (n= 208). Clinical diagnoses prior to testing were varied and 11 patients (7%) had an unknown diagnosis. Tissue was analyzed for 138 patients. Targeted sequencing resulted in diagnostically significant alterations in 80 of 138 (57%) of patients and therapeutically significant alterations in 58 of 138 (42%) patients. To date, 18 patients in our cohort have been treated with medical therapy informed by their genetic diagnosis. Several more await enrollment on clinical trials. For patients with diagnoses previously categorized as unknown (n=11), sequencing led to identification of a genetic variant in 6 patients (54%). Additionally, 8/138 patients had variants requiring further evaluation for potential germline involvement. Discussion: Next generation sequencing in vascular anomalies patients identified actionable variants in a large proportion of the patients in our cohort. The mTOR inhibitor sirolimus has been used to treat a variety of vascular anomalies, but not all patients respond to this treatment. Targeted therapies based on specific genotypes hold promise as clinical trials in vascular anomalies are emerging. Additionally, sequencing in this cohort identified several variants suggesting a germline cancer predisposition requiring follow-up. Use of next generation sequencing has clinical utility and increased use of this testing may improve diagnosis, prognosis, and treatment for patients with vascular anomalies. Disclosures Adams: Novartis: Consultancy; Venthura: Consultancy. OffLabel Disclosure: Sirolimus is used off-label for the treatment of vascular anomalies.

The spectrum of neoplasms associated with DICER1 variants continues to expand, with the recent addition of primary "DICER1-associated central nervous system sarcoma" (DCS). DCS is a high-grade malignancy predominantly affecting pediatric patients. Six pediatric DCS were identified through a combination of clinical diagnostic studies, archival inquiry, and interinstitutional collaboration. Clinical, histologic, immunohistologic, and molecular features were examined. Genomic findings in the 6 DCS were compared with those in 14 additional DICER1-associated tumors sequenced with the same assay. The six patients presented at ages 3-15 years with CNS tumors located in the temporal (n = 2), parietal (n = 1), fronto-parietal (n = 1), and frontal (n = 2) lobes. All underwent surgical resection. Histologic examination demonstrated high-grade malignant spindle cell tumors with pleuropulmonary blastoma-like embryonic "organoid" features and focal rhabdomyoblastic differentiation; immature cartilage was seen in one case. Immunohistochemically, there was patchy desmin and myogenin staining, and patchy loss of H3K27me3, and within eosinophilic cytoplasmic globules, alfa-fetoprotein staining. Biallelic DICER1 variants were identified in all cases, with germline variants in two of five patients tested. DCS demonstrated genomic alterations enriched for Ras pathway activation and TP53 inactivation. Tumor mutational burden was significantly higher in the 6 DCS tumors than in 14 other DICER1-associated tumors examined (mean 12.9 vs. 6.8 mutations/Mb, p = 0.035). Postoperative care included radiation (n = 5) and chemotherapy (n = 3); at the last follow-up, three patients were alive without DCS, and three had died of disease. Our analysis expands the clinical, histologic, immunohistological, and molecular spectrum of DCS, identifying distinctive features that can aid in the diagnosis, multidisciplinary evaluation, and treatment of DCS.

Purpose:Several aggressive pediatric cancers harbor alterations in SMARCB1, including rhabdoid tumors, epithelioid sarcoma, and chordoma. As tumor profiling has become more routine in clinical care, we investigated the relationship between SMARCB1 genetic variants identified by next-generation sequencing (NGS) and INI1 protein expression. Therapeutic approaches for INI1-deficient tumors are limited. Early reports suggest a potential role for immune checkpoint inhibition in these patients. Thus, we also investigated PD-L1 and CD8 expression in INI1-negative pediatric brain and solid tumors.Experimental Design:We performed immunohistochemistry (IHC) for INI1 and immune markers (PD-L1, CD8, and CD163) and NGS on tumor samples from 43 pediatric patients who had tumors with INI1 loss on previous IHC or SMARCB1 genomic alterations on prior somatic sequencing.Results:SMARCB1 two-copy deletions and inactivating mutations on NGS were associated with loss of INI1 protein expression. Single-copy deletion of SMARCB1 was not predictive of INI1 loss in tumor histologies not known to be INI1-deficient. In the 27 cases with INI1 loss and successful tumor sequencing, 24 (89%) had a SMARCB1 alteration detected. In addition, 47% (14/30) of the patients with INI1-negative tumors had a tumor specimen that was PD-L1 positive and 60% (18/30) had positive or rare CD8 staining. We report on 3 patients with INI1-negative tumors with evidence of disease control on immune checkpoint inhibitors.Conclusions:A significant proportion of the INI1-negative tumors express PD-L1, and PD-L1 positivity was associated with extracranial tumor site. These results suggest that clinical trials of immune checkpoint inhibitors are warranted in INI1-negative pediatric cancers.

Novelist Zadie Smith’s short story ‘The Embassy of Cambodia’, first published in The New Yorker on 11 February 2013, follows the fortunes of a young woman called Fatou, from the Ivory Coast. She is...

Introduction: In pediatric cancer, there is an urgent need for research that can identify and validate new therapeutic modalities for pediatric cancers. Diagnostic biopsy samples remain the ideal tissue samples for research and must be collected from surplus biopsy material, which is often extremely limited. Here we describe our efforts to optimize tissue allocation for clinical care and research as a joint effort between Department of Pathology at Boston Children’s Hospital and the Pediatric Solid Tumor Program at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. Methods: Oncologists, pathologists, surgeons, interventional radiologists, pathology technical staff, and clinical research coordinators participated in the workflow design. The group agreed to develop a formalized procedure to address these five steps: 1) patient identification and consent, 2) prioritization of research objectives, 3) advance communication of tissue requests to the pathology staff, 4) tissue preparation, and 5) tissue distribution. It was unanimously agreed that all tissue must flow through the pathology department. On or before the day of surgery, clinical research teams sent the pathologist a patient-specific electronic communication indicating research consent and detailing the prioritized disease-specific research requests, including the procedure planned, all tissue types and tissue volumes requested, and details of any special preparation needed, such as avoiding decalcification in bone tumors. The communication was optimized to be clear but brief, with the goal of minimizing the impact to the pathologist’s work load. Pathologists were surveyed about the change in process. Results: Over a five-year period (2013-2018), 662 pediatric DFCI/BCH solid tumor patients have consented to one or more trials that request FFPE, frozen, or fresh tissue. Tumor types represent a spectrum of cases, with many rare and singular diagnoses. Of 1,768 research tissue requests, 1,121 (63%) were fulfilled. Clinical study requests from resection specimens were the most likely to be fulfilled (95% of 390 requests fulfilled), while basic research requests from core biopsies were the least likely to be fulfilled (26% of 255 requests fulfilled). In an anonymous survey, 7 of 7 pathologists report that the process had improved since the introduction of the electronic communication. Conclusions: A collaborative and informed model for tissue allocation is successful in distributing tissue for clinical studies and basic research projects. Our workflows and policies have gained pathologist approval and streamlined our processes. As clinical and research programs evolve, a thoughtful tissue allocation process will facilitate ongoing research. Citation Format: R. Seth Pinches, Catherine Clinton, Abigail Ward, Stephanie C Meyer, Alyaa Al-Ibraheemi, Suzanne Forrest, Gianna R. Strand, Hillary Detert, Anne Piche-Schulman, Kristen Gil, Tamara Restrepo, Rosemarie Tavares-Proulx, Jeffrey Goldsmith, Raja Shaikh, Christopher Weldon, Sanda Alexandrescu, Allison F. O’Neill, Monica Hollowell, Marian H. Harris, Katherine A. Janeway, Brian D. Crompton, Alanna Church. Improving tissue allocation for research in pediatric solid tumors [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A67.

Several aggressive cancers impacting children are characterized by alterations in the SWI/SNF complex, including rhabdoid tumors, epithelioid sarcoma, and chordoma. With recent early-phase trials showing responses to EZH2 inhibitors, it is important to understand the optimal approach to identifying INI1-deficient cancers. As tumor profiling is becoming a more routine part of clinical care, this study was designed to determine the relationship between SMARCB1 genetic variants identified by a sequencing panel test and INI1 protein expression. Beyond EZH2 inhibitors, therapeutic approaches for INI1-deficient tumors are limited. Thus, we also sought to investigate PD-L1 expression in a cohort of INI1-deficient pediatric brain and solid malignancies. Patients were identified by two methods: 1) search of our institutional pathology database from 2000-2015 for INI1-deficient tumors and 2) presence of SMARCB1 genomic alteration in a database of 280 cases with somatic panel sequencing results. Patients were included in the study if sufficient archival tumor tissue was available for repeat, confirmatory sequencing and immunohistochemistry (IHC). Somatic next-generation sequencing (NGS) was performed via a panel assay, OncoPanel, which surveys exonic DNA sequences of 447 cancer genes and 191 regions across 60 genes for rearrangement detection. IHC stains for INI1 and PD-L1 were performed according to standardized procedure on Leica Bond automated platforms and expression was assessed by two investigators (AA, JP) who were blinded to sequencing results. The study included 43 patients. IHC was performed on at least one specimen for all patients and repeat, confirmatory NGS was successful in 91% (39/43). Single-copy deletion of SMARCB1 on NGS panel was not predictive of loss of INI1 expression by IHC with only 1/10 (10%) SMARCB1 single-copy deletion cases having INI1 loss. In the 26 cases with INI1 loss by IHC and successful tumor sequencing, 23 (89%) had a genomic alteration in SMARCB1 detected. Five cases (22%) had 1-copy deletion, 12 (52%) had 2-copy deletion, 2 (9%) had nonsense mutations, and 4 (17%) had two inactivating alterations. 40% (12/30) of the patients with INI1-deficient tumors had at least one tumor specimen that was PD-L1 positive (≥1%). PD-L1 status was not associated with timing of tumor sampling or prior treatment. TMB ranged from 0.76 to 9.13 mut/Mb of DNA. We have observed 2 patients with INI1-deficient cancers with evidence of efficacy of immune checkpoint inhibitors. SMARCB1 2-copy deletions and inactivating mutations are associated with loss of INI1 protein expression, but 1-copy deletion of INI1 in histologies other than those already known to be INI1-deficient is not predictive of loss of protein expression. These results, along with two case reports of successful disease control with immune checkpoint inhibitors, suggest that clinical trials of PD-1 or PD-L1 inhibitors, either as single agents or in combination with an EZH2 inhibitor, are warranted in malignancies with INI1 loss. Citation Format: Suzanne J. Forrest, Alyaa Al-Ibraheemi, Abigail Ward, Duong Doan, Catherine Clinton, Juan Putra, R. Seth Pinches, Cigall Kadoch, Susan Chi, Steve G. Dubois, Patrick Leavy, Natalie Collins, Alanna Church, Katherine A. Janeway. Genomic and immunologic characterization of a cohort of INI1-deficient pediatric cancers [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A16.

11530 Background: Survival rates for patients with metastatic and/or recurrent osteosarcoma are poor, and treatment strategies have remained unchanged for more than three decades. Genomic characterization can identify new treatment strategies and improve risk stratification. To date, sequencing studies of osteosarcoma have focused on newly diagnosed patients. We present one of the first reports of osteosarcoma genomics in a high-risk cohort. Methods: 92 samples from 92 patients were sequenced in a CLIA/CAP laboratory with a targeted NGS panel test. Patients were enrolled in one of two studies. The PROFILE study enrolls all patients seen at Dana-Farber Cancer Institute, and the GAIN study enrolls patients with metastatic and/or recurrent cancer at 11 institutions. Sequencing was performed using primary tumor samples at biopsy and/or from sites of metastasis when available. Results: 33 patients were enrolled on the PROFILE study, and 59 were enrolled on GAIN. Diagnostic stage was available for 65 (67%) of patients. 37% had metastatic disease at diagnosis. The 3-year overall survival (OS) was 71% for the entire study population, 56% for patients with metastatic disease at diagnosis, and 81% for patients with initially localized disease. The presence of metastases at diagnosis was significantly associated with poor outcome (p < 0.0087) and was the only independent clinical prognostic factor identified. Genomic analysis revealed frequent alterations in TP53 (37%), RB1 (15%), CDKN2A (13%), MYC (12%), CDKN1A (12%), ATRX (10%), and CCND3 (8%). Patients whose tumors had MYC amplification (defined as ≥ 6 copies) had a 3-year OS of 39% compared with a 3-year OS of 76% in the absence of MYC amplification, a difference with borderline statistical significance (p = 0.051). Conclusions: In the first study to examine genomic alterations detected by targeted gene panel sequencing in a CAP-certified laboratory in a large population of pediatric patients with higher risk osteosarcoma, the most frequently occurring events were similar to those found in prior reports. MYC amplification, reported as a possible poor prognostic factor in other studies, was present in 12% of patients and was associated with a worse OS, though this finding did not reach statistical significance.

Introduction. Breast cancer is the second most common malignancy in women. The Decision Quality Instrument (DQI) measures the extent to which patients are informed and involved in breast surgery decisions and receive treatment that aligns with their preferences. There are limited data on the performance of the DQI in women of lower socioeconomic status (SES). Our aims were to 1) examine (and if necessary adapt) the readability, usability, and acceptability of the DQI and 2) explore whether it captures factors important to breast cancer surgery decisions among women of lower SES (relevance). Methods. We conducted semistructured cognitive interviews with women of lower SES (based on insurance status, income, and education) who had completed early-stage breast cancer treatments at three cancer centers. We used a two-step thematic analysis with dual independent coding. The study team (including Patient Partners and a Community Advisory Board) reviewed and refined suggested changes. The revised DQI was presented in two focus groups of breast cancer survivors. Results. We conducted 39 interviews. Participants found most parts of the DQI to be helpful and easy to understand. We made the following suggested changes: 1) added a glossary of key terms, 2) added two answer choices and an open text question in the goals and concerns subscale, 3) reworded the treatment intention question, and 4) revised the knowledge subscale instructions since several women disliked the wording and were unsure of what was expected. Discussion. The readability, usability, acceptability, and relevance of a measure that was primarily developed and validated in women of higher SES required adaptation for optimal use by women of lower SES. Further research will test these adaptations in lower SES populations.

The concept of shared decision making (SDM) has gained increasing attention across healthcare fields including emergency care, with a focus shift towards patient-centred medicine.With cardiac chest pain accounting for approximately 6% of all emergency department (ED) attendances we aimed to co-design a personalised decision aid based on the established Troponin-only Manchester Acute Coronary Syndromes (T-MACS) prediction model to increase patient involvement in the decision making on serial troponin testing and follow up.The T-MACS Choice decision aid was co-designed with patient and physician involvement in 7 stages using a mixed-methods approach (figure 1) at the Manchester Royal Infirmary (MRI) from March to May 2017. The initial prototype was developed based on a) a literature review of SDM, b) the AHRQ health literacy toolkit and c) the International Patient Decision Aid Standards instrument.Abstract 014 Figure 1T-MACS choice development flowchartIn subsequent stages the prototype was improved based on feedback provided by the PRIMER patient and public involvement group, three SDM expert clinicians, focus groups interviews involving 26 members from patient groups with a history of cardiac problems, questionnaires from 29 emergency physicians and 14 patients presenting to MRI ED with chest pain and admitted for serial troponin testing.The final T-MACS Choice decision aid is personalised for the individual patient, reflecting their distinct risk group with the relevant choice options (figure 2).Abstract 014 Figure 2T-MACS choiceIn the initial development stages the most common themes identified were the importance of a personalised design and the use of clear, understandable language avoiding medical jargon. Both patients and physicians highlighted the importance of including information on heart health and prevention. In the final stages both sides agreed that T-MACS Choice had the right amount of information, was clear and engaging patients in the decision making.Further research on clinical implementation of T-MACS Choice is needed to determine its impact on patient choice and safety.

Background Tanzania has seen a reduction in the fraction of fevers caused by malaria, likely due in part to scale-up of control measures. While national guidelines require parasite-based diagnosis prior to treatment, it is estimated that more than half of suspected malaria treatment-seeking in Tanzania initiates in the private retail sector, where diagnosis by malaria rapid diagnostic test (RDT) or microscopy is illegal. This pilot study investigated whether the introduction of RDTs into Accredited Drug Dispensing Outlets (ADDOs) under realistic market conditions would improve case management practices. Methods Dispensers from ADDOs in two intervention districts in Tanzania were trained to stock and perform RDTs and monitored quarterly. Each district was assigned a different recommended retail price to evaluate the need for a subsidy. Malaria RDT and artemisinin-based combination therapy (ACT) uptake and availability were measured pre-intervention and 1 year post-intervention through structured surveys of ADDO owners and exiting customers in both intervention districts and one contiguous control district. Descriptive analysis and logistic regression were used to compare the three districts and identify predictive variables for testing. Results and discussion A total of 310 dispensers from 262 ADDOs were trained to stock and perform RDTs. RDT availability in intervention ADDOs increased from 1% (n = 172) to 73% (n = 163) during the study; ACT medicines were available in 75% of 260 pre-intervention and 68% of 254 post-intervention ADDOs. Pre-treatment testing performed within the ADDO increased from 0 to 65% of suspected malaria patients who visited a shop (95% CI 60.8–69.6%) with no difference between intervention districts. Overall parasite-based diagnosis increased from 19 to 74% in intervention districts and from 3 to 18% in the control district. Prior knowledge of RDT availability (aOR = 1.9, p = 0.03) and RDT experience (aOR = 1.9, p = 0.01) were predictors for testing. Adherence data indicated that 75% of malaria positives received ACT, while 3% of negatives received ACT. Conclusions Trained and supervised ADDO dispensers in rural Tanzania performed and sold RDTs under real market conditions to two-thirds of suspected malaria patients during this one-year pilot. These results support the hypothesis that introducing RDTs into regulated private retail sector settings can improve malaria testing and treatment practices without an RDT subsidy. Trial registration ISRCTN ISRCTN14115509

BACKGROUND: Many patients with malaria-like symptoms seek treatment in private medicine retail outlets (PMR) that distribute malaria medicines but do not traditionally provide diagnostic services, potentially leading to overtreatment with antimalarial drugs. To achieve universal access to prompt parasite-based diagnosis, many malaria-endemic countries are considering scaling up malaria rapid diagnostic tests (RDTs) in these outlets, an intervention that may require legislative changes and major investments in supporting programs and infrastructures. This review identifies studies that introduced malaria RDTs in PMRs and examines study outcomes and success factors to inform scale up decisions. METHODS: Published and unpublished studies that introduced malaria RDTs in PMRs were systematically identified and reviewed. Literature published before November 2016 was searched in six electronic databases, and unpublished studies were identified through personal contacts and stakeholder meetings. Outcomes were extracted from publications or provided by principal investigators. RESULTS: Six published and six unpublished studies were found. Most studies took place in sub-Saharan Africa and were small-scale pilots of RDT introduction in drug shops or pharmacies. None of the studies assessed large-scale implementation in PMRs. RDT uptake varied widely from 8%-100%. Provision of artemisinin-based combination therapy (ACT) for patients testing positive ranged from 30%-99%, and was more than 85% in five studies. Of those testing negative, provision of antimalarials varied from 2%-83% and was less than 20% in eight studies. Longer provider training, lower RDT retail prices and frequent supervision appeared to have a positive effect on RDT uptake and provider adherence to test results. Performance of RDTs by PMR vendors was generally good, but disposal of medical waste and referral of patients to public facilities were common challenges. CONCLUSIONS: Expanding services of PMRs to include malaria diagnostic services may hold great promise to improve malaria case management and curb overtreatment with antimalarials. However, doing so will require careful planning, investment and additional research to develop and sustain effective training, supervision, waste-management, referral and surveillance programs beyond the public sector.

This paper explores Peggy Mohan’s novel Jahajin (2007), in which she returns imaginatively to the past history of Indian indenture in order to explore its relevance and remembrance in late twentieth-century Trinidad. As Mohan’s unnamed narrator traces her family’s matrilineal involvement in this past, the novel examines the way in which Indian women, in particular, have been edited from official versions of both Trinidadian and Indian migratory histories. Jahajin’s narrator is a translator of Trinidadian Bhojpuri and, despite the difficulties of translation and challenges of accessing the Indian indentured past, this novel attests to the continued importance of oral narratives as counter-histories in facilitating the remembrance of this neglected history. Translation is also used figuratively in Jahajin to think about how Indian indenture could be “translated”, or interpreted, for twenty-first-century readers who otherwise might not have access to stories about this past. In order to examine the relationship between descendants of Indian indentured labourers and the past of indenture, I borrow Marianne Hirsch’s concept of “postmemory”, or the belated “memories” experienced by those who did not directly witness traumatic events. Postmemory is especially useful in thinking about how Mohan, and other contemporary Indian-Caribbean writers sharing an empathetic connection to this past, can explore the remembrance of Indian indenture in the absence of direct experience or its associated trauma.

We study the $\epsilon$-pseudospectra $\sigma_\epsilon(A)$ of square matrices $A \in \mathbb{C}^{N \times N}$. We give a complete characterization of the $\epsilon$-pseudospectrum of any $2 \times 2$ matrix and describe the asymptotic behavior (as $\epsilon \to 0$) of $\sigma_\epsilon(A)$ for any square matrix $A$. We also present explicit upper and lower bounds for the $\epsilon$-pseudospectra of bidiagonal matrices, as well as for finite rank operators., Comment: 22 pages, 6 figures