tbuckley/cabot-search huggingface dataset:
Baseline brain function in the preadolescents of the ABCD Study
Authors: B. Chaarani, S. Hahn, N. Allgaier, S. Adise, M. M. Owens, A. C. Juliano, D. K. Yuan, H. Loso, A. Ivanciu, M. D. Albaugh, J. Dumas, S. Mackey, J. Laurent, M. Ivanova, D. J. Hagler, M. D. Cornejo, S. Hatton, A. Agrawal, L. Aguinaldo, L. Ahonen, W. Aklin, A. P. Anokhin, J. Arroyo, S. Avenevoli, D. Babcock, K. Bagot, F. C. Baker, M. T. Banich, D. M. Barch, H. Bartsch, A. Baskin-Sommers, J. M. Bjork, D. Blachman-Demner, M. Bloch, R. Bogdan, S. Y. Bookheimer, F. Breslin, S. Brown, F. J. Calabro, V. Calhoun, B. J. Casey, L. Chang, D. B. Clark, C. Cloak, R. T. Constable, K. Constable, R. Corley, L. B. Cottler, S. Coxe, R. K. Dagher, A. M. Dale, M. Dapretto, R. Delcarmen-Wiggins, A. S. Dick, E. K. Do, N. U. F. Dosenbach, G. J. Dowling, S. Edwards, T. M. Ernst, D. A. Fair, C. C. Fan, E. Feczko, S. W. Feldstein-Ewing, P. Florsheim, J. J. Foxe, E. G. Freedman, N. P. Friedman, S. Friedman-Hill, B. F. Fuemmeler, A. Galvan, D. G. Gee, J. Giedd, M. Glantz, P. Glaser, J. Godino, M. Gonzalez, R. Gonzalez, S. Grant, K. M. Gray, F. Haist, M. P. Harms, S. Hawes, A. C. Heath, S. Heeringa, M. M. Heitzeg, R. Hermosillo, M. M. Herting, J. M. Hettema, J. K. Hewitt, C. Heyser, E. Hoffman, K. Howlett, R. S. Huber, M. A. Huestis, L. W. Hyde, W. G. Iacono, M. A. Infante, O. Irfanoglu, A. Isaiah, S. Iyengar, J. Jacobus, R. James, B. Jean-Francois, T. Jernigan, N. R. Karcher, A. Kaufman, B. Kelley, B. Kit, A. Ksinan, J. Kuperman, A. R. Laird, C. Larson, K. LeBlanc, C. Lessov-Schlagger, N. Lever, D. A. Lewis, K. Lisdahl, A. R. Little, M. Lopez, M. Luciana, B. Luna, P. A. Madden, H. H. Maes, C. Makowski, A. T. Marshall, M. J. Mason, J. Matochik, B. D. McCandliss, E. McGlade, I. Montoya, G. Morgan, A. Morris, C. Mulford, P. Murray, B. J. Nagel, M. C. Neale, G. Neigh, A. Nencka, A. Noronha, S. J. Nixon, C. E. Palmer, V. Pariyadath, M. P. Paulus, W. E. Pelham, D. Pfefferbaum, C. Pierpaoli, A. Prescot, D. Prouty, L. I. Puttler, N. Rajapaske, K. M. Rapuano, G. Reeves, P. F. Renshaw, M. C. Riedel, P. Rojas, M. de la Rosa, M. D. Rosenberg, M. J. Ross, M. Sanchez, C. Schirda, D. Schloesser, J. Schulenberg, K. J. Sher, C. Sheth, P. D. Shilling, W. K. Simmons, E. R. Sowell, N. Speer, M. Spittel, L. M. Squeglia, C. Sripada, J. Steinberg, C. Striley, M. T. Sutherland, J. Tanabe, S. F. Tapert, W. Thompson, R. L. Tomko, K. A. Uban, S. Vrieze, N. E. Wade, R. Watts, S. Weiss, B. A. Wiens, O. D. Williams, A. Wilbur, D. Wing, D. Wolff-Hughes, R. Yang, D. A. Yurgelun-Todd, R. A. Zucker, A. Potter, H. P. Garavan
Journal: Nature Neuroscience (2021)
Genomic analysis of primary malignant melanoma of the esophagus.
Authors: Jingjing Li, Shi Yan, Wenyan Guan, Xiao Xiao, Bing Liu, Changxi Wang, Zicheng Yu, Yuanyuan Ma, Nan Wu
Journal: Journal of Clinical Oncology (2021)

e21515 Background: Primary malignant melanoma of the esophagus (PMME) is an exceedingly rare disease but behave more aggressively and have a poorer prognosis. No specific histopathological classification and therapy strategies have been established for this type of disease due to lack of both tumor biological and genetics perception to PMME. Methods: We performed whole exome sequencing on 29 dissections including 23 primary tumors and 6 metastatic lymph nodes from 18 PMME patients. The genetic characteristics including somatic mutations and copy number variation (CNV) of PMME were compared to 398 skin cutaneous melanoma (SKCM), 67 mucosal melanoma (MM) and 79 uveal melanoma (UVM). Using multi-region sequencing, we reconstructed the phylogenetic structure and inferred the evolutionary mode. Results: We found that PMME/MM have similar genomic patterns to SKCM but distinct from UVM. Frequently mutated driver genes such as MUC16, BRAF, NRAS, NF1, KMT2C, POLE, PTPRT, RANBP2 appeared in both SKCM and PMME/MM cohorts. Of note, pathway enrichment analysis using identified driver genes revealed that melanoma pathway and MAPK signaling pathway were among the top affected pathways in MM/PMME as well as in SKCM. UVR-associated single base substitution signature 7 (SBS7) was not a dominant signature (median: 0.17, range:0̃0.79) in PMME/MM but 99 percent (89/90) of them do have it. An overall concordant trend in genome instability was found between PMME and SKCM. Significant CNV events at arm level showed the similar changes in PMME and SKCM, including amplification regions of 1q, 6p, 7p, 8q, 15q, 20p and deletion of 10p, 10q, 11p. CDKN2A loss appeared as a shared focal event by PMME and SKCM. To elucidate the evolution trajectory of spatially separated samples, we also performed multi-region sequencing, and the phylogenetic analysis suggested that whole genome doubling (WGD) was an early and clonal event, which preceded the majority of somatic mutations and CNV. Most driver genes such as NF1, RANBP2 and MUC16 mutated after WGD except TP53. Above findings suggested that WGD might be capable of promoting ongoing genome instability and shaping the evolution in PMME. Moreover, parallel evolution of RANBP2 was recurrently observed indicating the existence of constraints and selection. Conclusions: Our data showed that PMME/MM exhibited genetic features very similar to SKCM so it might not be excluded from treatments currently used for common SKCM.
TMOD-03. A NOVEL MB GR3 TRANSGENIC MOUSE MODEL IS GENERATED BY <i>MYCN</i> AND <i>P53</i> DEFECTS IN VENTRICULAR ZONE PROGENITORS.
Authors: Alaide Morcavallo, Karen Barker, Toma Adachi, Jessica K R Boult, Colin Kwok, Patricia Benites Goncalves da Silva, Konstantin Okonechnikov, Luke Hitchen, Simon P Robinson, Steven C Clifford, Stefan M Pfister, Daisuke Kawauchi, Louis Chesler
Journal: Neuro-Oncology (2021)

Abstract Medulloblastoma (MB) represents the most common embryonal tumour of the Central Nervous System in childhood. MB occurs in the cerebellum and molecular features dictate the classification into four subgroups. Although Group3 (Gr3) MB tumours are dominated by primitive progenitor-like cells, the cells of origin remain unidentified. Gr3 MB is associated with relatively common MYC family member amplification and overexpression, often combined with p53 pathway defects at relapse. Molecularly stratified treatment is not yet available, causing Gr3 MB and its subsequent relapse to often represent an unstoppable progressive disease. The limited understanding of Gr3 tumorigenesis and targeted therapy development is also due to the lack of faithful in vivo models and consequently, their use in preclinical studies. We have now developed a new germline genetically engineered mouse model (GEMM), harbouring MYCN amplification in a p53 inactive background (tamoxifen-inducible p53 activation, Trp53ERTAM). The purpose of the GEMM is to investigate the developmental significance of MYC aberration in putative Gr3 MB cells of origin and exploit it in preclinical studies. A LSL-MYCN-Luciferase strain was crossed with mice expressing Cre recombinase under the Blbp promoter and subsequently to Trp53ERTAM inducible mice. As result, the MYCN overexpression alone did not generate tumours, conversely to the combination of MYCN with p53 deregulation. Tumours arise exclusively in the hindbrain of homozygote mice, with a penetrance of 100% and a latency of ~135 days. Pathology report suggests tumours are Gr3 MB with large cell/anaplastic (LCA) histology. Preliminary transcriptional profiling data analysis reveals that tumours share molecular features with human counterparts, clustering with Gr3 MB. Ongoing analysis will explore the tumour cells of origin, followed by tumour progression alteration restoring p53 activity and blood-brain barrier integrity status. In conclusion, we have developed a MYCN/Trp53ERTAM Gr3 MB GEMM arising from ventricular zone progenitor cells and resembling human cancer characteristics.
Development of evidence-based clinical pathways for an outpatient oncology acute care clinic.
Authors: Shayna Simon, Sadaf Charania, Judy Devlin, Edie Brucker, Christine Hong, Angela F. Bazzell, Kavitha Nair, John W. Sweetenham
Journal: Journal of Clinical Oncology (2021)

e18676 Background: Oncology patients frequently experience acute physical symptoms related to cancer and its treatment. Management of symptoms is best accomplished using evidence-based clinical care. When implementing an advanced practice provider (APP)-led oncology acute care clinic, evidence-based clinical pathways were developed to ensure standardization among treating providers. Methods: The top ten emergency department admitting diagnoses for oncology patients identified by the Centers for Medicare and Medicaid Services provided the foundation for development of the clinical pathways. Relevant primary literature, National Comprehensive Cancer Center Network guidelines, and American Society of Clinical Oncology guidelines were reviewed for development of outpatient oncology acute care clinical pathways. The information was cross-referenced with institutional data to confirm applicability to the patient population. A multidisciplinary team including nursing, pharmacy, laboratory services, radiology, information technology, and administrative staff reviewed the workflow to ensure best processes. The pathways were reviewed by oncologists, APPs and pharmacists before finalization. Results: Nine evidence-based clinical pathways were developed by August 1, 2020. From August to December 2020, 165 patient visits took place in the outpatient oncology acute care clinic. Gastrointestinal manifestations (25%), hypovolemia/weakness (25%), and infections (17%) were the most frequently encountered symptoms. Evidence-based clinical pathways were followed for patients with a chief complaint with an associated algorithm (N=124). Conclusions: Implementation of clinical pathways facilitate best practice standardization when ordering labs, tests, and medications while enhancing the acceptance of the new service. The pathways will be reviewed and updated by a multidisciplinary team every 3 months to ensure current evidence-based practices. Semi-annual pathway audits have been implemented to evaluate utilization and optimize patient outcomes, as well as determine areas of improvement and growth. Areas of opportunity identified during the first pathway audit included creating pathways for cardiac disorders, mouth disorders, and infections unrelated to neutropenia. Additionally, order set integration to automate the clinical pathway process in the electronic medical record is in progress.[Table: see text]
MATTERHORN: Efficacy and safety of neoadjuvant-adjuvant durvalumab and FLOT chemotherapy in resectable gastric and gastroesophageal junction cancer—A randomized, double-blind, placebo-controlled, phase 3 study.
Authors: Yelena Y. Janjigian, Eric Van Cutsem, Kei Muro, Zev A. Wainberg, Salah-Eddin Al-Batran, Woo Jin Hyung, Daniela Molena, Brent Evans, Dario Ruscica, Scott H. Robbins, Alejandra Negro, Josep Tabernero
Journal: Journal of Clinical Oncology (2021)

TPS4151 Background: Gastric and gastroesophageal junction cancers (GC, GEJC) are the fifth most common cancer types and the third leading cause of cancer-related deaths globally (Globocan 2020). Standard of care for resectable GC/GEJC includes neoadjuvant-adjuvant FLOT chemotherapy (5-fluorouracil + leucovorin + oxaliplatin + docetaxel) combined with surgery and lymph node dissection for some regions of the world. While treatment advances have improved survival, the 5-year recurrence rate remains high and 5-year overall survival (OS) is poor for patients with resectable disease. Evidence suggests cytotoxic chemotherapy can promote antitumor immunity, thus the combination of immune checkpoint inhibitors, such as durvalumab (an anti–PD-L1 antibody), with cytotoxic chemotherapy may result in increased efficacy (Yu et al. Cancer Lett. 2019; Li et al. Mol Cancer. 2021). MATTERHORN (NCT04592913) is a phase 3, multicenter study evaluating the efficacy and safety of neoadjuvant-adjuvant durvalumab or placebo with FLOT followed by adjuvant durvalumab or placebo in patients with resectable GC/GEJC. Methods: Approximately 900 adult patients will be randomized 1:1 to Arm A or Arm B for 2 neoadjuvant and 2 adjuvant cycles (single cycle defined as durvalumab or placebo every 4 weeks [Q4W] + FLOT [Q2W × 2]); followed by durvalumab or placebo Q4W for 10 cycles. Eligible patients must have histologically confirmed, resectable, stage II or higher GC or GEJC not treated with anticancer therapy, ECOG performance status 0 or 1, and adequate organ function. Complete surgical resection of the primary tumor must be achievable. A tumor tissue sample will be taken at screening or &lt;3 months prior to enrollment. Key exclusion criteria are any prior immune-mediated therapy, peritoneal dissemination or distant metastasis, (adeno)squamous cell carcinoma, or gastrointestinal stromal tumor. The primary endpoint is event-free survival (EFS) assessed by blinded independent central radiology review (BICR) and/or local pathology testing. Secondary endpoints include OS and pathological complete response rate (pCR). Safety and tolerability will be evaluated by adverse events, vital signs, laboratory parameters, and electrocardiogram. Enrollment is ongoing. Funding: AstraZeneca. Clinical trial information: NCT04592913.
Uptake of immunotherapy in patients with advanced cancer: A population-based study using health administrative data from Ontario, Canada.
Authors: Jacques Raphael, Lucie Richard, Melody Lam, Phillip S. Blanchette, Natasha B. Leighl, George Rodrigues, Maureen E. Trudeau, Monika K. Krzyzanowska
Journal: Journal of Clinical Oncology (2021)

6529 Background: The introduction of immunotherapy (IO) in the treatment of patients with cancer has significantly improved clinical outcomes. Herein we report on IO uptake in Ontario, Canada, a publicly funded healthcare system. Methods: We conducted a retrospective cohort study using provincial health administrative data to: 1) assess IO uptake in adult patients with advanced melanoma, bladder, lung, head and neck (HN) and kidney cancers; and 2) identify predictors of IO usage between 2011 (pre-IO funding) and 2019. The datasets were linked using unique encoded identifiers and analyzed at ICES. IO uptake was captured between cancer diagnosis and last follow up and reported as a proportion of the entire cohort and by tumor site and drug type. A competing risk Fine and Gray regression model with death as competing risk was used to identify factors associated with IO use. Results: Among 59,510 patients with one of the five advanced cancers of interest, 7,660 (12.9%) received IO. Details of IO uptake are summarized in Table. IO uptake increased yearly from 2011 (2.7%) to 2019 (34.0%). Uptake was highest in melanoma (48.2%) and lowest in HN cancer (5.8%). The most commonly used drugs used were pembrolizumab (41.1%) and nivolumab (40.5%). In adjusted analysis, predictors of lower IO uptake included older age (hazard ratio (HR) 0.953, 95%CI 0.934-0.972 with every additional 10 years), female sex (HR 0.859, 95%CI 0.819-0.9), lower income quintile (HR 0.893, 95%CI 0.83-0.96), history of hospital admission (HR 0.768, 95%CI 0.734-0.805), female oncologist (HR 0.942, 95%CI 0.892-0.995), and de novo stage 4 cancer (HR 0.918, 95%CI 0.873-0.966). Predictors of higher IO uptake were low Charlson score (HR 1.118, 95%CI 1.01-1.236) and previous radiation therapy (HR 1.438, 95%CI 1.367-1.512). IO uptake was heterogeneous across cancer centres levels (1 to 4) and regions. Conclusions: While the use of IO for advanced cancer has steadily increased over time, uptake is associated with patient and physician characteristics, as well as system level factors. This variation suggests potential inequity in access to these potentially life-prolonging drugs and should be further investigated and addressed.[Table: see text]
CTNND1 to mediate bone metastasis of triple-negative breast cancer via regulating CXCR4.
Authors: Chang Gong, Qun Lin, Xiaolin Fang, Wenguo Jiang, Jun Li, Juanmei Li, Yu Shi, Qing Luo, Zihao Liu, Yinghuan Cen
Journal: Journal of Clinical Oncology (2021)

e13045 Background: Compared to lumial breast cancer, the proporation of triple-negative breast cancer (TNBC) with bone metastases (BMs) is relatively low and few data focusing on the mechanism of the BMs in TNBC are available, Here, we screened that CTNND1 was associated with BMs of TNBC by integrating high-throughput sequencing, and further investigated the role of CTNND1 in BMs of TNBC in vitro. Methods: TNBC tissue samples with only BMs (n = 6) and without any metastasis (n = 10) were tested using high-throughput sequencing and 11 differentially expressed relative genes were identified. We then quantified these 11 genes in normal breast tissue samples (n = 26), TNBC tissue samples with only BMs (n = 10), TNBC tissue samples without any metastasis (n = 88) as well as luminal tissue samples with BMs（n = 10）through qPCR and immunohistochemical staining (IHC). The effects of knocking down CTNND1 on the interaction between TNBC cells and osteoblasts were examined by cell adhesion, transwell migration and matrigel invasion assays. To explorethe role of CTNND1 in mediating bone metastasis in TNBC, we used RNA-sequencing to find out the relative downstream gene CXCR4 and PI3K-AKT-mTOR pathway and verified it in vitro by Western Blotting. Results: Combining our high-throughput sequencing data, qPCR and IHC in clinical tissue samples, we verified that CTNND1 was decreased in TNBC patients with bone metastasis compared to normal tissue and luminal tissue with BMs. Knocking down of CTNND1 in TNBC cells including MDA-MB-231, MDA-MB-468 and BT549 weakened cells adhesion, but facilitated cells migration and invasion. Mechanically, knocking down of CTNND1 upregulated CXCR4 via activating PI3K-AKT-mTOR pathway in TNBC but not luminal and HER2- positive breast cancer cells lines. Conclusions: CTNND1 mediates bone metastasis in triple-negative breast cancer via regulating CXCR4.CTNND1 may serve as a potential predictor of bone metastasis for TNBC patients.
A Generalized Linear modeling approach to bootstrapping multi-frame PET image data
Authors: Finbarr O’Sullivan, Fengyun Gu, Qi Wu, Liam D O’Suilleabhain
Journal: Medical Image Analysis (2021)

PET imaging is an important diagnostic tool for management of patients with cancer and other diseases. Medical decisions based on quantitative PET information could potentially benefit from the availability of tools for evaluation of associated uncertainties. Raw PET data can be viewed as a sample from an inhomogeneous Poisson process so there is the possibility to directly apply bootstrapping to raw projection-domain list-mode data. Unfortunately this is computationally impractical, particularly if data reconstruction is iterative or the acquisition protocol is dynamic. We develop a flexible statistical linear model analysis to be used with multi-frame PET image data to create valid bootstrap samples. The technique is illustrated using data from dynamic PET studies with fluoro-deoxyglucose (FDG) and fluoro-thymidine (FLT) in brain and breast cancer patients. As is often the case with dynamic PET studies, data have been archived without raw list-mode information. Using the bootstrapping technique maps of kinetic parameters and associated uncertainties are obtained. The quantitative performance of the approach is assessed by simulation. The proposed image-domain bootstrap is found to substantially match the projection-domain alternative. Analysis of results points to a close relation between relative uncertainty in voxel-level kinetic parameters and local reconstruction error. This is consistent with statistical theory.
An institutional evaluation of the safety and efficacy of same-day administration of pegfilgrastim in patients receiving chemotherapy for lung cancer.
Authors: Jamie Vraney, Neda AlRawashdh, Briana Choi, Ivo Abraham, Ali McBride
Journal: Journal of Clinical Oncology (2021)

e18591 Background: Pegfilgrastim is recommended to be administered 24 hours after myelosuppressive chemotherapy (CTX) as prophylaxis for chemotherapy-induced (febrile) neutropenia (CIN/FN). Recent studies have yielded equivocal data on same day versus next day administration of pegfilgrastim. There has been limited real world evidence addressing lung cancer (LC) patients and the use of same day pegfilgrastim. We evaluated our own institutional data on the safety of same day pegfilgrastim administration in LC patients. Methods: A retrospective chart review was performed by searching electronic health records using ICD-9 and ICD-10 codes corresponding with a lung cancer diagnosis between November 1, 2013 and August 31, 2018 at The University of Arizona Cancer Center (UACC). Patients included in the study were 18 years of age or older, diagnosed with biopsy-confirmed lung cancer, treated at UACC, and receiving chemotherapy and pegfilgrastim on the same day. The outcomes of interest included FN incidence after the first cycle and across all cycles of CTX, CIN grade 3/4 and CTX dose delays or hospitalizations due to CIN/FN after first cycle and across all cycles of CTX. Results: 1,181 patient records were reviewed and 114 patients met the inclusion criteria; 87 (76%) patients had non-small cell LC and 27 (24%) patients had small cell LC. The median age was 68 years, 52% of patients had cancer stage of 3 to 4, and 63% of patients had 0-1 ECOG status. The FN risk assessment was mild in 72% of patients. The mean (SD) of baseline absolute neutrophil count was 5.68 (3.09). In total 384 CTX cycles were received. The table shows the results of all intended outcomes. One patient experienced FN after the first cycle of CTX of irinotecan and 5 patients developed 6 FN episodes across all cycles; 2 patients were on carboplatin etoposide; 1 patient on cisplatin etoposide; 1 patient on vinorelbine and 1 patient was on pemetrexed and then on irinotecan CTX when the two FN episodes were developed. Conclusions: This study showing that same day administration of pegfilgrastim was as effective as next day administration in LC patients, without warranting any concerns for febrile neutropenia or delayed engraftment. Utilization of same day pegfilgrastim, in light of biosimilars and COVID, provides a unique opportunity for cancer care without concerns for FN as stated in previous studies.[Table: see text]