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Alexa B Schrock,1 Russell Madison,1 Mark Rosenzweig,2 Justin M Allen,2 Rachel L Erlich,2 Siao-Yi Wang,3 Tarek Chidiac,4 Vodur Suresh Reddy,5 Jonathan W Riess,6 Ahmet Ersin Yassa,6 Abdur Shakir,7 Vincent A Miller,1 Brian M Alexander,1 Jeffrey Venstrom,1 Kimberly McGregor,1 Siraj M Ali1 1Foundation Medicine, Department of Clinical Development, Cambridge, MA, USA; 2Foundation Medicine, Department of Translational Oncology and Clinical Reporting, Cambridge, MA, USA; 3Loyola University Medical Cancer, Department of Hematology and Oncology, Maywood, IL, USA; 4Zangmeister Cancer Center, Department of Hematology and Oncology, Columbus, OH, USA; 5Cancer Care Specialists, Department of Hematology and Oncology, Reno, NV, USA; 6UC Davis Comprehensive Cancer Center, Department of Hematology and Oncology Sacramento, CA, USA; 7Sarah Bush Lincoln Health System, Department of Medical Oncology, Mattoon, IL, USACorrespondence: Alexa B SchrockFoundation Medicine, 150 Second Street, Cambridge, MA 02141, USATel +1617-418-2200Email aschrock@foundationmedicine.comBackground: ALK fusions are targetable drivers in non-small-cell lung cancer (NSCLC). However, patients with NSCLC harboring ALK rearrangements without a fusion partner identified in DNA have also been shown to respond to ALK inhibitors. We aimed to characterize complex ALK variants that may predict sensitivity to multiple approved ALK inhibitors.Methods: Comprehensive genomic profiling (CGP) of DNA isolated from formalin‐fixed paraffin‐embedded (FFPE) tumor tissue or blood-based circulating tumor DNA was performed for 39,159 NSCLC patients during routine clinical care. For a subset of cases, RNA sequencing was performed, and prior ALK test results and clinical treatment information were collected from treating physicians.Results: We queried the Foundation Medicine NSCLC database and identified ALK internal inversions, as well as internal deletions, as the sole ALK rearrangements in 6 (0.02%) and 3 (0.01%) of cases, respectively. In cases with ALK internal inversions, RNA testing identified an EML4-ALK fusion in 2/2 cases evaluated, and 3/3 patients treated with ALK inhibitors had durable responses. A single patient with an ALK internal deletion and clinical data available responded to multiple ALK inhibitors. RNA data available for a subset of non-NSCLC cases suggest that ALK internal deletions removing a portion of the N-terminus are drivers themselves and do not result in ALK fusions. Fluorescence in situ hybridization (FISH) results were inconsistent for both classes of DNA events.Conclusion: Rare internal inversions of ALK appear to be indicative of ALK fusions, which can be detected in RNA, and response to ALK inhibitors in patients with NSCLC. In contrast, ALK internal deletions are not associated with ALK fusions in RNA but likely represent targetable drivers themselves. These data suggest that CGP of DNA should be supplemented with immunohistochemistry or RNA-based testing to further resolve these events and match patients to effective therapies.Keywords: ALK rearrangement, inversion, deletion, genomic profiling, targeted therapy

Timothy D Becker,1 Henry C Lin,2 Victoria A Miller3 1Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 2Division of Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 3Division of Adolescent Medicine, Children’s Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Background: Child participation in pediatric medical visits is low. In this pilot study, we sought to better understand relationships between observed communication and child-reported perceptions of communication in a clinical setting. Materials and methods: For this cross-sectional observational study, pediatric gastroenterology appointments (n=39) were videotaped and coded to quantify various adult affective (eg, chit-chat, empathy) and facilitative (eg, asking questions, encouraging responses) behaviors toward the child, interference with child participation (eg, interrupting or ignoring child), and child verbal participation. Post-visit surveys assessed child perceptions of having voice in the clinical encounter, ease of understanding, and satisfaction with communication. Results: Parent and provider chit-chat was associated with child-reported ease of understanding. Provider facilitation was positively associated with child participation, but affective communication strategies were not. Physician interference was negatively associated with ease of understanding but positively associated with perception of voice. Conclusion: Facilitative communication may improve outcomes by enhancing child participation and thus exchange of medical information, whereas chit-chat appears to positively impact children’s perceptions of communication. Keywords: physician–patient communication, partnership, child participation, pediatric patient experience, child satisfaction

Ankur R Parikh,1 Siraj M Ali,2 Alexa B Schrock,2 Lee A Albacker,2 Vincent A Miller,2 Phil J Stephens,2 Pamela Crilley,1 Maurie Markman1 1Eastern Regional Medical Center, Cancer Treatment Centers of America, Philadelphia, PA, USA; 2Foundation Medicine, Inc, Cambridge, MA, USA Abstract: In non-small-cell lung cancer (NSCLC) refractory to standard therapy and which lacks well-known oncogenic drivers, genomic profiling can still identify genomic alterations that may suggest potential sensitivity to targeted therapy. PTEN mutation in NSCLC may be sensitizing to analogs of rapamycin such as everolimus or temsirolimus, but more investigation is needed. We report the case of a patient with metastatic NSCLC harboring a PTEN mutation as well as high tumor mutational burden and PD-L1 positivity with a durable response to temsirolimus, but refractory to a checkpoint inhibitor. Even in the event of failure of treatment with checkpoint inhibitors in the background of a case with a higher tumor mutational burden and PD-L1 positivity, targeting specific genomic alterations may still result in patient benefit. Keywords: genomic profiling, temsirolimus, targeted therapy, immunotherapy

Casey B Williams,1,* Caitlin McMahon,2,* Siraj M Ali,2 Mark Abramovitz,1 Kirstin A Williams,1 Jessica Klein,1 Heidi McKean,1 Roman Yelensky,2 Thomas J George Jr,3 Julia A Elvin,2 Salil Soman,4 Doron Lipson,2 Juliann Chmielecki,2 Deborah Morosini,2 Vincent A Miller,2 Philip J Stephens,2 Jeffrey S Ross,2,5 Brian Leyland-Jones1 1Avera Cancer Institute, Sioux Falls, SD, USA; 2Foundation Medicine, Inc., Cambridge, MA, USA; 3University of Florida College of Medicine, Gainesville, FL, USA; 4Beth Israel Deaconess Medical Center, Boston, MA, USA; 5Albany Medical College, Albany, NY, USA *These authors contributed equally to this work Abstract: The subset of metastatic colorectal adenocarcinomas that harbor BRAF V600E mutations are aggressive tumors with significantly shortened survival and limited treatment options. Here we present a colorectal cancer patient whose disease progressed through standard chemotherapy and who developed liver metastasis. Comprehensive genomic profiling (FoundationOne®) identified a BRAF V600E mutation in the liver lesion, as well as other genomic alterations consistent with colorectal cancers. Combination therapy of dabrafenib and trametinib with standard cytotoxic chemotherapy resulted in a durable major ongoing response for the patient. This report illustrates the utility of comprehensive genomic profiling with personalized targeted therapy for aggressive metastatic colorectal adenocarcinomas. Keywords: oxaliplatin, colorectal adenocarcinoma, combination targeted therapy, BRAF mutations

Rachel M Squillace, Garrett M Frampton, Phil J Stephens, Jeffrey S Ross, Vincent A MillerFoundation Medicine Inc., Cambridge, MA, USAWe read with concern the paper “Evaluation and comparison of two commercially available targeted next-generation sequencing platforms to assist oncology decision- making”.1 The study directly compared results for the Paradigm Cancer Diagnostic test to the FoundationOne test for formalin-fixed, paraffin-embedded specimen pairs from 21 advanced cancer cases. We believe this study is fundamentally flawed, misleading, and potentially dangerous for patient care, for the reasons outlined herein.The paper neglected to address innumerable discordances between a rigorously analytically validated test (FoundationOne) and the experimental assay. It erroneously ascribes categorization of many genomic alterations detected on FoundationOne as “none”, when in fact available drugs have demonstrated activity or mechanism-based clinical trials exist, and it claims high levels of actionability based on the results of RNA-expression profiling of a single gene – TOPO2A.Read the original paper by Weiss et al.

James L Kreindler,1,2 Victoria A Miller1,31The Children’s Hospital of Philadelphia, 2Department of Pediatrics, 3Department of Anesthesiology and Critical Care Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USAAbstract: Survival for patients with cystic fibrosis (CF) increased to nearly 40 years in 2012 from the early childhood years in the 1940s. Therefore, patients are living long enough to require transition from pediatric CF centers to adult CF centers. The goal of transition is for the young adult to be engaged in the adult health care system in ways that optimize health, maximize potential, and increase quality of life. A successful transition promotes autonomy and responsibility with respect to one's own health. Currently, there is an information gap in the literature with respect to psychological models that can help guide informed transition processes. In this review, we establish the framework in which transition exists in CF; we review some of the published literature from the last 20 years of experience with transition in CF centers around the world; and we discuss psychological models of pediatric illness that can help to explain the current state of transition to adult-oriented care from pediatric-oriented care and help to formulate new models of ascertaining readiness for transition. Finally, we look at our current knowledge gaps and opportunities for future research endeavors.Keywords: cystic fibrosis, transition, adolescent, social-ecological model of AYA readiness for transition, SMART

BackgroundTo determine genomic alterations in head and neck squamous cell carcinoma (HNSCC) using formalin-fixed, paraffin-embedded (FFPE) tumors obtained through routine clinical practice, selected cancer-related genes were evaluated and compared with alterations seen in frozen tumors obtained through research studies.Patients and methodsDNA samples obtained from 252 FFPE HNSCC were analyzed using next-generation sequencing-based (NGS) clinical assay to determine sequence and copy number variations in 236 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer. Human papillomavirus (HPV) status was determined by presence of the HPV DNA sequence in all samples and corroborated with high-risk HPV in situ hybridization (ISH) and p16 immunohistochemical (IHC) staining in a subset of tumors. Sequencing data from 399 frozen tumors in The Cancer Genome Atlas and University of Chicago public datasets were analyzed for comparison.ResultsAmong 252 FFPE HNSCC, 84 (33%) were HPV positive and 168 (67%) were HPV negative by sequencing. A subset of 40 tumors with HPV ISH and p16 IHC results showed complete concordance with NGS-derived HPV status. The most common genes with genomic alterations were PIK3CA and PTEN in HPV-positive tumors and TP53 and CDKN2A/B in HPV-negative tumors. In the pathway analysis, the PI3K pathway in HPV-positive tumors and DNA repair-p53 and cell cycle pathways in HPV-negative tumors were frequently altered. The HPV-positive oropharynx and HPV-positive nasal cavity/paranasal sinus carcinoma shared similar mutational profiles.ConclusionThe genomic profile of FFPE HNSCC tumors obtained through routine clinical practice is comparable with frozen tumors studied in research setting, demonstrating the feasibility of comprehensive genomic profiling in a clinical setting. However, the clinical significance of these genomic alterations requires further investigation through application of these genomic profiles as integral biomarkers in clinical trials.

Calreticulin (CRT) was originally identified as a key calcium-binding protein of the endoplasmic reticulum. Subsequently, CRT was shown to possess multiple intracellular functions, including roles in calcium homeostasis and protein folding. Recently, several extracellular functions have been identified for CRT, including roles in cancer cell invasion and phagocytosis of apoptotic and cancer cells by macrophages. In the current report, we uncover a novel function for extracellular CRT and report that CRT functions as a plasminogen-binding receptor that regulates the conversion of plasminogen to plasmin. We show that human recombinant or bovine tissue-derived CRT dramatically stimulated the conversion of plasminogen to plasmin by tissue plasminogen activator or urokinase-type plasminogen activator. Surface plasmon resonance analysis revealed that CRT-bound plasminogen (K D  = 1.8 μM) with moderate affinity. Plasminogen binding and activation by CRT were inhibited by ε-aminocaproic acid, suggesting that an internal lysine residue of CRT interacts with plasminogen. We subsequently show that clinically relevant CRT variants (lacking four or eight lysines in carboxyl-terminal region) exhibited decreased plasminogen activation. Furthermore, CRT-deficient fibroblasts generated 90% less plasmin and CRT-depleted MDA MB 231 cells also demonstrated a significant reduction in plasmin generation. Moreover, treatment of fibroblasts with mitoxantrone dramatically stimulated plasmin generation by WT but not CRT-deficient fibroblasts. Our results suggest that CRT is an important cellular plasminogen regulatory protein. Given that CRT can empower cells with plasmin proteolytic activity, this discovery may provide new mechanistic insight into the established role of CRT in cancer., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Background: Enrolling children in clinical trials typically requires parental or guardian permission and, when appropriate, child assent. Aligning requirements across jurisdictions would facilitate multisite pediatric trials. Guidance from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) is the best candidate for a global standard but would benefit from additional specification., Methods: Ethical analysis of ICH guidance for permission and assent for pediatric trials, with recommendations for clarification., Results: ICH guidance regarding permission and assent would be enhanced by additional detail in the following areas: (1) what information should be provided to parents, guardians, and children considering a trial, and how that information should be provided; (2) the definition of "assent," the criteria for when assent should be required, and the need to include children in discussions even when assent is not mandated; (3) criteria for requiring children's signatures indicating agreement; (4) greater specificity regarding children's right to decline or withdraw; and (5) clarification of when children's wish to decline or withdraw from participation may be overridden and of what the overriding process should entail., Conclusion: ICH guidance provides a global standard for decision making regarding children's participation in trials. Several clarifications would facilitate the conduct of multinational pediatric research., Impact: Enrolling children in clinical trials requires the permission of a parent/guardian ± the assent of the minor. Differing global regulatory requirements for enrolling children complicate the conduct of multicenter and multinational trials. The authors identify points of ambiguity and/or contradiction in the International Council for Harmonization guidelines and offer recommendations for a common ethical platform for conducting global pediatric research., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Importance: Despite high disease morbidity and mortality and complex treatment decisions, little is known about the medical and end-of-life decision-making preferences of adolescents and young adults (AYA) with advanced heart disease. AYA decision-making involvement is associated with important outcomes in other chronic illness groups., Objective: To characterize decision-making preferences of AYAs with advanced heart disease and their parents and determine factors associated with these preferences., Design, Setting, and Participants: Cross-sectional survey between July 2018 and April 2021 at a single-center heart failure/transplant service at a Midwestern US children's hospital. Participants were AYAs aged 12 to 24 years with heart failure, listed for heart transplantation, or posttransplant with life-limiting complications and a parent/caregiver. Data were analyzed from May 2021 to June 2022., Main Outcomes and Measures: Single-item measure of medical decision-making preferences, MyCHATT, and Lyon Family-Centered Advance Care Planning Survey., Results: Fifty-six of 63 eligible patients enrolled in the study (88.9%) with 53 AYA-parent dyads. Median (IQR) patient age was 17.8 (15.8-19.0) years; 34 (64.2%) patients were male, and 40 patients (75.5%) identified as White and 13 patients (24.5%) identified as members of a racial or ethnic minority group or multiracial. The greatest proportion of AYA participants (24 of 53 participants [45.3%]) indicated a preference for active, patient-led decision-making specific to heart disease management, while the greatest proportion of parents (18 of 51 participants [35.3%]) preferred they and physician(s) make shared medical decisions on behalf of their AYA, representing AYA-parent decision-making discordance (χ2 = 11.7; P = .01). Most AYA participants stated a preference to discuss adverse effects or risks of treatment (46 of 53 participants [86.8%]), procedural and/or surgical details (45 of 53 participants [84.9%]), impact of condition on daily activities (48 of 53 participants [90.6%]), and their prognosis (42 of 53 participants [79.2%]). More than half of AYAs preferred to be involved in end-of-life decisions if very ill (30 of 53 participants [56.6%]). Longer time since cardiac diagnosis (r = 0.32; P = .02) and worse functional status (mean [SD] 4.3 [1.4] in New York Heart Association class III or IV vs 2.8 [1.8] in New York Heart Association class I or II; t-value = 2.7; P = .01) were associated with a preference for more active, patient-led decision-making., Conclusions and Relevance: In this survey study, most AYAs with advanced heart disease favored active roles in medical decision-making. Interventions and educational efforts targeting clinicians, AYAs with heart disease, and their caregivers are needed to ensure they are meeting the decision-making and communication preferences of this patient population with complex disease and treatment courses.

Recombinant human growth hormone (rhGH) is prescribed to youth with growth hormone deficiency (GHD) to support normal growth and ensure healthy physical development, and to youth without GHD to address height concerns. Perceptions of youth involvement in rhGH treatment decisions have not been explored. This study aimed to examine perceptions of youth and parent roles in decisions around rhGH treatment. Youth (n = 22, 11.5 ± 2.0 years) who had undergone evaluation for short stature and their parents (n = 22) participated in semi-structured interviews after stimulation test results had been received. Interviews revealed the following themes: 1) parent provided youth with support; 2) parent facilitated youth's decision-making involvement; 3) youth had no role or did not remember their role; and 4) youth did not remember conversations with their parents or providers. Parents facilitated their children's involvement by sharing information and seeking their opinions. Whereas some participants described youth as having a substantial decision-making role, not all youth felt they were involved, and some youth could not recall conversations about rhGH. Parents can bolster youth involvement by having conversations using developmentally appropriate language, which is critical to youth feeling empowered and developing efficacy over their own care., Competing Interests: Conflicts of Interest: A.G. received the 2020 Growth Hormone Research Competitive Grant Award from Pfizer, Inc. and served as consultant for a seminar on growth hormone deficiency for Pfizer medical staff. The other authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Background: Advanced practice providers (APPs) play important roles in enrolling, educating, and caring for patients in clinical trials. However, much remains unknown about the role of APPs in managing adverse events (AEs) in early (phase I to II) clinical trials. In this study, we assessed the outpatient management of grade 3 to 4 AEs by APPs in early trials and characterized the workflow of our APP Phase I to II Fast Track (FT) Clinic., Patients and Methods: We retrospectively reviewed records of patients with advanced or metastatic solid tumors enrolled in phase I to II clinical trials who were seen by APPs from September 2017 to August 2018 in the APP phase I to II FT clinic in the Department of Investigational Cancer Therapeutics., Results: A total of 808 patients enrolled in 159 clinical trials were seen in 2,697 visits (median 3 visits per patient; range 1-28) by 10 APPs. Treatment was interrupted in 6.9% of visits, and grade 3 to 4 AEs were seen in 5.4% of visits; however, patients from 1.4% of visits were sent to the emergency center (EC) and/or admitted. Patients referred to the EC and/or admitted were more likely to have baseline hypoalbuminemia, high lactate dehydrogenase, and poor Eastern Cooperative Oncology Group performance status (i.e., ECOG > 1; p < .001). There were no associations between EC referral and gender, APP years of experience, or type of treatment., Conclusions: The APP Phase I to II FT Clinic has an important role in the management of AEs by APPs in early clinical trials in the outpatient setting, potentially avoiding EC visits and admissions., Competing Interests: The authors have no potential conflicts of interest to disclose. This work was partially supported by the National Institutes of Health through MD Anderson Cancer Center’s Support Grant (P30 CA016672) and the NCI K12 Paul Calabresi Award CA088084., (© 2022 Harborside™.)

Background: The USA is undergoing a suicide epidemic for its youngest Veterans (18-to-34-years-old) as their suicide rate has almost doubled since 2001. Veterans are at the highest risk during their first-year post-discharge, thus creating a "deadly gap." In response, the nation has developed strategies that emphasize a preventive, universal, and public health approach and embrace the value of community interventions. The three-step theory of suicide suggests that community interventions that reduce reintegration difficulties and promote connectedness for Veterans as they transition to civilian life have the greatest likelihood of reducing suicide. Recent research shows that the effectiveness of community interventions can be enhanced when augmented by volunteer and certified sponsors (1-on-1) who actively engage with Veterans, as part of the Veteran Sponsorship Initiative (VSI)., Method/design: The purpose of this randomized hybrid type 2 effectiveness-implementation trial is to evaluate the implementation of the VSI in six cities in Texas in collaboration with the US Departments of Defense, Labor and Veterans Affairs, Texas government, and local stakeholders. Texas is an optimal location for this large-scale implementation as it has the second largest population of these young Veterans and is home to the largest US military installation, Fort Hood. The first aim is to determine the effectiveness of the VSI, as evidenced by measures of reintegration difficulties, health/psychological distress, VA healthcare utilization, connectedness, and suicidal risk. The second aim is to determine the feasibility and potential utility of a stakeholder-engaged plan for implementing the VSI in Texas with the intent of future expansion in more states. The evaluators will use a stepped wedge design with a sequential roll-out to participating cities over time. Participants (n=630) will be enrolled on military installations six months prior to discharge. Implementation efforts will draw upon a bundled implementation strategy that includes strategies such as ongoing training, implementation facilitation, and audit and feedback. Formative and summative evaluations will be guided by the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework and will include interviews with participants and periodic reflections with key stakeholders to longitudinally identify barriers and facilitators to implementation., Discussion: This evaluation will have important implications for the national implementation of community interventions that address the epidemic of Veteran suicide. Aligned with the Evidence Act, it is the first large-scale implementation of an evidence-based practice that conducts a thorough assessment of TSMVs during the "deadly gap.", Trial Registration: ClinicalTrials.gov ID number: NCT05224440 . Registered on 04 February 2022., (© 2022. The Author(s).)

Objective: Continuous glucose monitoring (CGM) has become increasingly popular among youth with type 1 diabetes (T1D). Used with CGM, remote monitoring (RM) gives caregivers real-time access to patients' glucose values. Whereas RM may safeguard against hypo- and hyperglycemic events, little is known about how older children and adolescents, who are striving for independence, and their parents view the RM aspect of CGM. The goal of this study was to describe and explore parent and youth perceptions of RM., Methods: Youth with T1D and their parents participated separately in semi-structured interviews 2 months after starting CGM. Questions focused on decisions to use and experiences with RM., Results: Analysis of 43 parents and 41 youth (13.79 years ± 2.82) interviews revealed four themes, with 10 subthemes. Seven subthemes emerged in parent and youth interviews, and three emerged exclusively in parent interviews. The overarching themes included the impact of RM on (1) peace-of-mind, (2) parental anxiety, (3) communication; and addressed (4) technological limitations that prevented some from using RM. Regardless of youth age, youth and parents found comfort in parental knowledge of glucose values and parental abilities to assist youth (e.g., giving reminders to eat). Whereas RM could lead to conflicts due to excessive communication (e.g., texting), conflicts could be resolved through iterative parent-youth conversations., Conclusion: RM may facilitate youth independence by providing a way for them to stay connected to their support system while acquiring developmentally appropriate skills. However, families should have iterative discussions about boundaries to mitigate parental over-involvement., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The translocation t(15:19) produces the oncogenic BRD4-NUT fusion which is pathognomonic for NUT carcinoma (NC), which is a rare, but extremely aggressive solid tumor. Comprehensive genomic profiling (CGP) by hybrid-capture based next generation sequencing of 186+ genes of a cohort of advanced cancer cases with a variety of initial diagnoses harboring BRD4-NUT may shed further insight into the biology of these tumors and possible options for targeted treatment., Case Presentation: Thirty-one solid tumor cases harboring a BRD4-NUT translocation are described, with only 16% initially diagnosed as NC and the remainder carrying other diagnoses, most commonly NSCLCNOS (22%) and lung squamous cell carcinoma (NSCLC-SCC) (16%). The cohort was all microsatellite stable and harbored a low Tumor Mutational Burden (TMB, mean 1.7 mut/mb, range 0-4). In two index cases, patients treated with immune checkpoint inhibitors (ICPI) had unexpected partial or better responses of varying duration. Notably, four cases - including the two index cases - were negative for PD-L1 expression. Neo-antigen prediction for BRD4-NUT and then affinity modeling of the peptide-MHC (pMHC) complex for an assessable index case predicted very high affinity binding, both on a ranked (99.9%) and absolute (33 nM) basis., Conclusions: CGP identifies BRD4-NUT fusions in advanced solid tumors which carry a broad range of initial diagnoses and which should be re-diagnosed as NC per guidelines. A hypothesized mechanism underlying responses to ICPI in the low TMB, PD-L1 negative index cases is the predicted high affinity of the BRD4-NUT fusion peptide to MHC complexes. Further study of pMHC affinity and response to immune checkpoint inhibitors in patients with NC harboring BRD4-NUT is needed to validate this therapeutic hypothesis., (Copyright © 2021. Published by Elsevier Inc.)

Background: Non-small cell lung cancer (NSCLC) patients bearing targetable oncogene alterations typically derive limited benefit from immune checkpoint blockade (ICB), which has been attributed to low tumor mutation burden (TMB) and/or PD-L1 levels. We investigated oncogene-specific differences in these markers and clinical outcome., Methods: Three cohorts of NSCLC patients with oncogene alterations (n=4189 total) were analyzed. Two clinical cohorts of advanced NSCLC patients treated with ICB monotherapy [MD Anderson (MDACC; n=172) and Flatiron Health-Foundation Medicine Clinico-Genomic Database (CGDB; n=894 patients)] were analyzed for clinical outcome. The FMI biomarker cohort (n=4017) was used to assess the association of oncogene alterations with TMB and PD-L1 expression., Results: High PD-L1 expression (PD-L1 ≥50%) rate was 19%-20% in classic EGFR , EGFR exon 20 and HER2 -mutant tumors, and 34%-55% in tumors with ALK , BRAF V600E, ROS1 , RET , or MET alterations. Compared with KRAS- mutant tumors, BRAF non-V600E group had higher TMB (9.6 vs KRAS 7.8 mutations/Mb, p=0.003), while all other oncogene groups had lower TMB (p<0.001). In the two clinical cohorts treated with ICB, molecular groups with EGFR , HER2 , ALK , ROS1 , RET , or MET alterations had short progression-free survival (PFS; 1.8-3.7 months), while BRAF V600E group was associated with greater clinical benefit from ICB (CGDB cohort: PFS 9.8 months vs KRAS 3.7 months, HR 0.66, p=0.099; MDACC cohort: response rate 62% vs KRAS 24%; PFS 7.4 vs KRAS 2.8 months, HR 0.36, p=0.026). KRAS G12C and non-G12C subgroups had similar clinical benefit from ICB in both cohorts. In a multivariable analysis, BRAF V600E mutation (HR 0.58, p=0.041), PD-L1 expression (HR 0.57, p=0.022), and high TMB (HR 0.66, p<0.001) were associated with longer PFS., Conclusions: High TMB and PD-L1 expression are predictive for benefit from ICB treatment in oncogene-driven NSCLCs. NSCLC harboring BRAF mutations demonstrated superior benefit from ICB that may be attributed to higher TMB and higher PD-L1 expression in these tumors. Meanwhile EGFR and HER2 mutations and ALK , ROS1 , RET , and MET fusions define NSCLC subsets with minimal benefit from ICB despite high PD-L1 expression in NSCLC harboring oncogene fusions. These findings indicate a TMB/PD-L1-independent impact on sensitivity to ICB for certain oncogene alterations., Competing Interests: Competing interests: MVN is a consultant for Mirati and Merck/MSD, and reports funding to the institution from Mirati, Novartis, Pfizer, Ziopharm, AstraZeneca, and Checkmate; MM is an employee of Foundation Medicine, and owns stock in Roche; KS is an employee of Genentech, and owns stock in Roche; IB is an employee of Genentech, owns stock in Roche; VS is an employee of Roche, and owns stock in Roche; HX is an employee of Roche, and owns stock in Roche; HS is an employee of Genentech, and owns stock in Roche; XL is a Consultant for Eli Lilly, AstraZeneca, and EMD Serono; MEG is a former employee of Foundation Medicine; KM is an employee of Foundation Medicine, and owns stock in Roche; JPR reports licensing/royalties from Spectrum Pharmaceuticals; TC has received speaker’s fees from the Society for Immunotherapy of Cancer and Bristol-Myers Squibb, receives consulting fees from MedImmune and Bristol-Myers Squibb, and reports research funding to MD Anderson Cancer Center from Boehringer Ingelheim, MedImmune and Bristol-Myers Squibb; AT reports research grants from Eli Lilly, Millennium, Polaris, Genentech, Merck, Boehringer-Ingelheim, BMS, Ariad, Epizyme, Seattle Genetics, Takeda, and EMD Serono; advisory board member for BMS, Eli Lilly, Genentech, Roche, Novartis, Ariad, EMD Serono, Merck, Seattle Genetics, Astra-Zeneca, Boehringer-Ingelheim, Sellas Life Science, Takeda, Epizyme, and Huron; VP is an employee of Pfizer; DLG reports research grants from AstraZeneca, Jenssen R & D, Takeda, Ribun Therapeutics; and honoraria member of Senofi, AstraZeneca, Ribun Therapeutics; GS is an employee of Foundation Medicine, and owns stock in Roche; VAM is an employee of Foundation Medicine, and owns stock in Roche; BA is an employee of Foundation Medicine, and owns stock in Roche; GF is an employee of Foundation Medicine, and owns stock in Roche; LAA is an employee of Foundation Medicine, and owns stock in Roche; DS is an employee of Genentech, and owns stock in Roche; JZ reports research funding from Merck, Johnson and Johnson, and consultant fees from BMS, Johnson and Johnson, AstraZeneca, Geneplus, OrigMed, Innovent outside the submitted work; JVH reports research grants from NIH/NCI, American Cancer Society, Cancer Prevention & Research Institute of Texas, AACR Johnson & Johnson Lung Cancer, AZ, Spectrum, Checkmate Pharmaceuticals; Advisory Committees – AZ, BMS, GSK, Guardant Health, Kairos Venture Investments, BrightPath Biotherapeutics Hengrui Therapeutics, Eli Lilly, Spectrum, EMD Serono, Roche, Foundation One Medicine; Royalties & Licensing – Spectrum & Bio-Tree Systems, Inc., (© Author(s) (or their employer(s)) 2021. 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Introduction: The objective of this study was to describe interruptions in the pediatric ambulatory setting and to assess their impact on perceived physician communication, patient satisfaction and recall of provided physician instructions., Methods: An observational study was performed at the Children's Hospital of Philadelphia, Pediatric Gastroenterology clinic. Participation consisted of video recording the clinic visit and the caregiver completed post-visit surveys on communication and satisfaction. Video recordings were coded for interruptions, which were divided into 3 main categories: Visit Associated, Pediatric Associated, and Unanticipated. An interruption rate was calculated and correlated with the following outcome variables to assess the impact of interruptions: caregiver satisfaction, caregiver perception on the quality of physician communication, and caregiver instruction recall., Results: There were 675 interruptions noted in the 81 clinic visits, with an average of 7.96 (σ = 7.68) interruptions per visit. Six visits had no interruptions. The Patient was the most frequent interrupter. Significantly higher interruption rates occurred in clinic visits with younger patients (<7 years old) with most of the interruptions being Pediatric Associated interruptions. There was minimal correlation between the clinic visit interruption rate and caregiver satisfaction with the communication, caregiver perception of quality of communication, or caregiver instruction recall rate., Conclusion: The effect of interruptions on the pediatric visit remains unclear. Interruptions may be part of the communication process to ensure alignment of the patient's agenda. Additional studies are needed to help determine the impact of interruptions and guide medical education on patient communication., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Gastric and gastroesophageal adenocarcinomas represent the third leading cause of cancer mortality worldwide. Despite significant therapeutic improvement, the outcome of patients with advanced gastroesophageal adenocarcinoma is poor. Randomized clinical trials failed to show a significant survival benefit in molecularly unselected patients with advanced gastroesophageal adenocarcinoma treated with anti-EGFR agents., Experimental Design: We performed analyses on four cohorts: IRCC (570 patients), Foundation Medicine, Inc. (9,397 patients), COG (214 patients), and the Fondazione IRCCS Istituto Nazionale dei Tumori (206 patients). Preclinical trials were conducted in patient-derived xenografts (PDX)., Results: The analysis of different gastroesophageal adenocarcinoma patient cohorts suggests that EGFR amplification drives aggressive behavior and poor prognosis. We also observed that EGFR inhibitors are active in patients with EGFR copy-number gain and that coamplification of other receptor tyrosine kinases or KRAS is associated with worse response. Preclinical trials performed on EGFR -amplified gastroesophageal adenocarcinoma PDX models revealed that the combination of an EGFR mAb and an EGFR tyrosine kinase inhibitor (TKI) was more effective than each monotherapy and resulted in a deeper and durable response. In a highly EGFR- amplified nonresponding PDX, where resistance to EGFR drugs was due to inactivation of the TSC2 tumor suppressor, cotreatment with the mTOR inhibitor everolimus restored sensitivity to EGFR inhibition., Conclusions: This study underscores EGFR as a potential therapeutic target in gastric cancer and identifies the combination of an EGFR TKI and a mAb as an effective therapeutic approach. Finally, it recognizes mTOR pathway activation as a novel mechanism of primary resistance that can be overcome by the combination of EGFR and mTOR inhibitors. See related commentary by Openshaw et al., p. 2964 ., (©2021 American Association for Cancer Research.)

The tumor microenvironment (TME) is now being widely accepted as the key contributor to a range of processes involved in cancer progression from tumor growth to metastasis and chemoresistance. The extracellular matrix (ECM) and the proteases that mediate the remodeling of the ECM form an integral part of the TME. Plasmin is a broad-spectrum, highly potent, serine protease whose activation from its precursor plasminogen is tightly regulated by the activators (uPA, uPAR, and tPA), the inhibitors (PAI-1, PAI-2), and plasminogen receptors. Collectively, this system is called the plasminogen activation system. The expression of the components of the plasminogen activation system by malignant cells and the surrounding stromal cells modulates the TME resulting in sustained cancer progression signals. In this review, we provide a detailed discussion of the roles of plasminogen activation system in tumor growth, invasion, metastasis, and chemoresistance with specific emphasis on their role in the TME. We particularly review the recent highlights of the plasminogen receptor S100A10 (p11), which is a pivotal component of the plasminogen activation system.

Precision medicine is associated with favorable outcomes in selected patients with cancer. Herein, we report an interim analysis of IMPACT2, an ongoing randomized study evaluating genomic profiling and targeted agents in metastatic cancer. Patients with metastatic cancer underwent tumor genomic profiling (ClinialTrials.gov: NCT02152254), and 69 patients met the criteria for randomization. Tumor board and multidisciplinary review of molecular alterations optimized treatment selection. From 5/2014 to 4/2017, 320 patients (median age, 63 years; men, 47%) had tumor molecular aberrations, and 213 (66.56%) received anticancer therapy. The most frequently mutated genes were TP53 (42%), KRAS (16%), PIK3CA (12%), and CDKN2A (11%). The median OS was 10.9 months (95% CI, 8.8-12.9). OS was shorter in patients with higher tumor mutational burden. Independent factors associated with shorter OS were age ≥60 years, liver metastases, low albumin levels, high LDH levels, and KRAS and TP53 mutations. Outcomes for randomized patients will be reported after completion of the study.