tbuckley/cabot-search huggingface dataset:
Targeted gene expression classifier identifies pediatric T-cell acute lymphoblastic leukemia (T-ALL) patients at high risk for end induction minimal residual disease positivity.
Authors: Lauren K. Meyer, Ritu Roy, Benjamin J. Huang, Cristina Delgado-Martin, Tiffaney L. Vincent, Brent L. Wood, Yu Liu, Jinghui Zhang, Charles Grenfell Mullighan, Terzah M. Horton, Mignon L. Loh, Meenakshi Devidas, Elizabeth A. Raetz, Robert J. Hayashi, Stuart S. Winter, Kimberly P. Dunsmore, Stephen Hunger, David T. Teachey, Adam B. Olshen, Michelle L. Hermiston
Journal: Journal of Clinical Oncology (2021)

10002 Background: The heterogeneity of T-ALL has hindered biomarker identification and limited biology-based risk stratification. Historically, minimal residual disease (MRD) has been the strongest predictor of poor outcomes. However, stratification by MRD does not allow for risk-adapted therapy early in treatment, which may induce deeper remissions and decrease risk of relapse. We hypothesized that gene expression profiling at diagnosis may have prognostic value in identifying high risk patients. Methods: We analyzed RNA-seq data from 189 diagnostic samples from the Children’s Oncology Group (COG) AALL0434 trial. Using leave-one-out cross-validation, we identified a set of genes that optimally differentiated MRD+ and MRD- samples. We then derived a risk score (RS) that indicates a probability of being MRD+ for a given gene expression pattern. Finally, we validated this model in an independent cohort of COG AALL1231 samples. Results: The AALL0434 early T-cell precursor (ETP) samples (n = 19), which have high rates of MRD+, had the highest RS, with an average of 81.3 (SD 18.7), versus 24.9 (SD 22.7) for non-ETPs (n = 146). Intriguingly, non-ETPs with RS &gt; 50 had a gene expression pattern that mirrored ETPs and was distinct from the remaining non-ETPs. In this RS &gt; 50 non-ETP cohort, 80% were MRD+, versus 20% of the &lt; 50 cohort (p &lt; 0.0001). When applied to 31 diagnostic non-ETP samples from COG AALL1231, 57% of the RS &gt; 50 cohort were MRD+, versus 17% of the RS &lt; 50 cohort (p = 0.05). Importantly, AALL0434 used prednisone during induction, while AALL1231 used dexamethasone, indicating that the predictive value is independent of the induction steroid. Finally, we converted our model to the customizable Nanostring nCounter platform by analyzing 96 AALL0434 samples on the Nanostring assay. The Nanostring data closely recapitulated the RNA-seq data, with a tight correlation between the resulting RS (concordance correlation coefficient = 0.91). Conclusions: We have developed a gene expression classifier that differentiates a subset of non-ETP T-ALLs with an ETP-like gene expression pattern and a high risk of MRD+, and have adapted the classifier to a clinically tractable targeted platform. Identification of this high-risk subset at diagnosis has the potential to facilitate risk-adapted trials to evaluate the utility of novel or more intensive therapies aimed at improving clinical outcomes.
Can Intratumoral neutrophil lymphocyte ratio (NLR) be a prognostic biomarker in breast cancer patients?
Authors: Yoshihisa Tokumaru, Masanori Oshi, Vijayashree Murthy, Eriko Katsuta, Nobuhisa Matsuhashi, Manabu Futamura, Kazuhiro Yoshida, Kazuaki Takabe
Journal: Journal of Clinical Oncology (2021)

e12573 Background: In breast cancer patients, it is well known that the elevation of neutrophil lymphocyte ratio (NLR) in the blood are reported to associate with poor prognosis based on the notion that neutrophils represent pro-cancer, and lymphocytes represent anti-cancer immune cells. Tumor immune microenvironment has been demonstrated to play critical roles in the outcome of breast cancer patients. However, there is scarce evidence on the clinical relevance of intratumoral NLR in breast cancer patients. In the current study, we hypothesized that intratumoral NLR high tumors are associated with worse survival particularly in TNBC that is known to have high immune cell infiltration. Methods: A total of 1904 breast cancer patients’ data from METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) and analyzed. NLR was calculated by the gene expressions of CD66b (CEACAM8) and CD8 (CD8A). NLR high and low were divided by the median. Overall Survival (OS) and Disease-Free Survival were calculated utilizing Kaplan Meier method between intratumoral NLR high and low groups. xCell algorithm was used to analyze the infiltrated immune cells within the tumor immune microenvironment as we have previously published. Results: Intratumoral NLR high group was associated with worse OS in whole, ER-positive/HER2-negative, and triple negative (TN) subtypes, in agreement with the previous studies. TN subtype alone demonstrated worse DFS of NLR high group. Surprisingly, gene set enrichment analysis (GSEA) demonstrated no gene set enrichment to NLR high group, which implicates that there is no distinctive mechanism that associate with worse survival. Whereas, immune response-related gene sets significantly enriched to NLR low group in TN subtype. This enrichment was consistent in ER-positive/HER2-negative. Compared with ER-positive/HER2-negative subtype, anti-cancer immune cells such as CD4+ T cells, CD8+ T cells, M1 macrophage, and helper T helper type 1 cells were significantly infiltrated in TN patients (p &lt; 0.001 for all genes), where M2 macrophages and neutrophils were less and regulatory T cells and T helper type 2 cells were more infiltrated in TN subtype. Furthermore, intratumoral NLR was significantly lower in TN compared with ER-positive/HER2-negative subtype (p &lt; 0.001). These results suggest that intratumoral NLR low group is associated with better survival due to favorable tumor immune microenvironment in TN subtype rather than NLR high group has worse survival. Conclusions: Intratumoral NLR low tumor demonstrated more favorable OS and more favorable DFS in TN patients. Intratumoral NLR low breast cancer was associated with enhanced immune response and higher infiltration of anti-cancer immune cells were observed in TN subtype compared to ER-positive/HER2-negative which may contribute to the favorable outcome of in TN breast cancer.
60 Years Young: The Evolving Role of Allogeneic Hematopoietic Stem Cell Transplantation in Cancer Immunotherapy
Authors: Nicoletta Cieri, Katie Maurer, Catherine J. Wu
Journal: Cancer Research (2021)

The year 2020 marked the 30th anniversary of the Nobel Prize in Medicine awarded to E. Donnall Thomas for the development of allogeneic hematopoietic stem cell transplantation (allo-HSCT) to treat hematologic malignancies and other blood disorders. Dr. Thomas, "father of bone marrow transplantation," first developed and reported this technique in 1957, and in the ensuing decades, this seminal study has impacted fundamental work in hematology and cancer research, including advances in hematopoiesis, stem cell biology, tumor immunology, and T-cell biology. As the first example of cancer immunotherapy, understanding the mechanisms of antitumor biology associated with allo-HSCT has given rise to many of the principles used today in the development and implementation of novel transformative immunotherapies. Here we review the historical basis underpinning the development of allo-HSCT as well as advances in knowledge obtained by defining mechanisms of allo-HSCT activity. We review how these principles have been translated to novel immunotherapies currently utilized in clinical practice and describe potential future applications for allo-HSCT in cancer research and development of novel therapeutic strategies.
トロンボポエチン/MPLはPI3K/AKTシグナル伝達を介してRUNX1-ETO急性骨髄性白血病の発生および維持に関与する
Authors: Pulikkan John Anto, Madera Dmitri, Xue Liting, Bradley Paul, Landrette Sean Francis, Kuo Ya-Huei, Abbas Saman, Zhu Lihua Julie, Valk Peter, Castilla Lucio Hernan
Journal: Blood (2012)
FOXR2 Stabilizes MYCN Protein and Identifies Non–<i>MYCN</i>-Amplified Neuroblastoma Patients With Unfavorable Outcome
Authors: Felix Schmitt-Hoffner, Sjoerd van Rijn, Umut H. Toprak, Monika Mauermann, Felix Rosemann, Anke Heit-Mondrzyk, Jens-Martin Hübner, Aylin Camgöz, Sabine Hartlieb, Stefan M. Pfister, Kai-Oliver Henrich, Frank Westermann, Marcel Kool
Journal: Journal of Clinical Oncology (2021)

Clinical outcomes of patients with neuroblastoma range from spontaneous tumor regression to fatality. Hence, understanding the mechanisms that cause tumor progression is crucial for the treatment of patients. In this study, we show that FOXR2 activation identifies a subset of neuroblastoma tumors with unfavorable outcome and we investigate the mechanism how FOXR2 relates to poor outcome in patients.We analyzed three independent transcriptional data sets of in total 1030 primary neuroblastomas with full clinical annotation. We performed immunoprecipitation for FOXR2 and MYCN and silenced FOXR2 expression in two neuroblastoma cell lines to examine the effect on cellular processes, transcriptome, and MYCN protein levels. Tumor samples were analyzed for protein levels of FOXR2 and MYCN.In three combined neuroblastoma data sets, 9% of tumors show expression of FOXR2 but have low levels of MYCN mRNA. FOXR2 expression identifies a group of patients with unfavorable outcome, showing 10-year overall survival rates of 53%-59%, and proves to be an independent prognostic factor compared with established risk factors. Transcriptionally, FOXR2-expressing tumors are very similar to MYCN-amplified tumors, suggesting that they might share a common mechanism of tumor initiation. FOXR2 knockdown in FOXR2-expressing neuroblastoma cell lines resulted in cell cycle arrest, reduced cell growth, cell death, and reduced MYCN protein levels, all indicating that FOXR2 is essential for these tumors. Finally, we show that FOXR2 binds and stabilizes MYCN protein and MYCN protein levels are highly increased in FOXR2-expressing tumors, in several cases comparable with MYCN-amplified samples.The stabilization of MYCN by FOXR2 represents an alternative mechanism to MYCN amplification to increase MYCN protein levels. As such, FOXR2 expression identifies another subset of neuroblastoma patients with unfavorable clinical outcome.
Assessment of cancer-specific microbiome signature of response to immune checkpoint inhibitors.
Authors: Michal Sarfaty, Christopher A. Desjardins, Paul Giardina, Kankana Bardhan, Swarna Pandian, Keith Halley, Elizabeth M. Halvorsen, Margaret K. Callahan, Michael A. Postow, Chung-Han Lee, Ritesh Kotecha, Daniel Kashani, Neha Ratna, Ashley Marie Regazzi, Matthew R. Henn, Matthew D. Hellmann, Gopa Iyer, Christopher B. Ford, Jonathan U. Peled
Journal: Journal of Clinical Oncology (2021)

2574 Background: Clinical and preclinical experiments suggest that the gut microbiome can affect outcome in cancer patients treated with immune checkpoint inhibitors (ICI). Most data to date has been in melanoma, so the relationship of the gut microbiome with treatment outcome in other cancers is poorly understood. Here, we evaluated the microbiome composition in correlation to ICI response in patients with metastatic lung, urothelial, or renal cancer, as well as metastatic melanoma. Methods: Fecal microbiome samples were obtained from patients with metastatic melanoma, lung, urothelial, or renal cancer immediately before ICI therapy was initiated. Bacterial genomic DNA was isolated and profiled by whole metagenome sequencing. Sequence data were analyzed using a custom implementation of MetaPhlAn2. Response to ICI was defined as partial or complete response or remaining on therapy for more than 6 months. Results: Samples were prospectively collected from 94 patients, including metastatic melanoma (n = 17), lung (n = 44), urothelial (n = 23), or renal cancer (n = 10). Treatment included anti-PD(L)1 monotherapy (n = 51), anti-PD1 + anti-CTLA4 combination therapy (n = 17), or a combination of anti-PD1 and chemotherapy (n = 26). Clinical response was observed in 58% of patients, including partial or complete response (45%) and on treatment for more than 6 months (55%, with 31% on treatment for more than 1 year). Although the variance in the composition of pretreatment microbiome samples did not explain response alone (R vs NR, PERMANOVA, p = 0.273), a significant portion of the variance in microbiome composition was explained by the interaction of cancer type and outcome (PERMANOVA, p = 0.014), suggesting a cancer-specific microbiome relationship. Notably, there was some similarity in the signature of NR across three cancer types (lung, urothelial and melanoma). One sample in this NR cluster was from a patient whose metastatic NSCLC was nonresponsive to pembrolizumab and carboplatin/pemetrexed. This microbiome sample was evaluated in vivo using subcutaneous MC38 and CT26 tumor models in germ-free mice. In contrast to mice colonized with stool from a healthy donor, mice colonized with stool from this patient yielded a nonresponsive result upon treatment with anti-PD1 or anti-PD-L1 in combination with anti-CTLA4. Conclusions: Analysis of the fecal microbiome composition from patients with metastatic lung, urothelial, renal cancer, and melanoma identified a cancer-specific signature of R and NR to ICI. Across three cancer types, a consistent signature of NR was identified and corroborated experimentally in preclinical models.
Abstract 426: Factors Contributing to Out-Of-Hospital Cardiac Arrest Mortality Trends in the City of Detroit (2014-2018)
Authors: Shobi Mathew, James H Paxton, Brian Reed, Joseph B Miller, Howard Klausner, Robert Dunne, Brian O’Neil
Journal: Circulation (2019)

Introduction: Survival with good neurologic outcome following out-of-hospital cardiac arrest (OHCA) requires intensive post-ROSC care. In response to a recent decline in OHCA survival rates in Detroit, we conducted an analysis to identify factors contributing to this regression. Methods: CARES data from Detroit EMS transports were analyzed, including adult non-traumatic OHCA patients treated from 2014-2018 at four hospitals. Patient demographics, conditions of the arrest, and post-ROSC interventions including left heart catheterization, (LHC) and targeted temperature management, (TTM), were correlated to survival to hospital discharge and discharge with CPC 1 or 2. We calculated crude and adjusted survival rates across sites. Survival rates were adjusted for Utstein criteria using multilevel multi-variable regression analyses. Results: A total of 5,175 CARES patients were included. There was no difference in Utstein criteria between years, other than a small increase in the rate of witnessed arrest. We noted a steady decrease in LHC, and steady increase in TTM rate over the 5 years. There was a system-wide decrease in survival to hospital discharge during 2018, though the percentage of patients discharged with CPC 1 or 2 was similar. We found a strong, though insignificant, trend for LHC rate and survival: 0.72 (p = 0.1057), R 2 : 0.88, Adjusted R 2 : 0.76; and for survival with CPC 1 or 2: 0.59 (p = 0.5172), R 2 : 0.72, Adjusted R 2 : 0.44. In 2018, the rate of patients with LHC and good CPC nearly doubled. Conclusion: During the study period, we found a steady increase in TTM rate and concomitant decrease in LHC rate. The rate of LHC correlated best with survival to hospital discharge. In 2018, an increase in the proportion of patients with CPC 1 or 2 receiving LHC occurred, despite a decline in the overall rate of LHC.
Patient and provider education on HER2-positive metastatic breast cancer: Defining gaps in clinician practice, patient behaviors, patient-provider alignment, and clinical knowledge.
Authors: Wendy Turell, Tariqa Ackbarali
Journal: Journal of Clinical Oncology (2021)

e23007 Background: Current breast cancer management is driven by inherent heterogeneity of disease. Therapeutic options for later lines of HER2 therapy have expanded, shifting practice patterns to incorporate the latest evidence and guidelines. Health care providers (HCPs) require education to synthesize new evidence in the context of clinical practice including three approved HER2-directed therapies between December 2019 and April 2020. Concurrent patient and caregiver education is imperative to improve collaborative treatment decisions for HER2+ metastatic breast cancer (MBC). Methods: Two, 1-hour online video-based programs were hosted in June, 2020 for HCPs and patients/caregivers, respectively. Practice and knowledge gaps among HCPs, and knowledge, communication and self-efficacy behaviors among patients were assessed. Each activity was interactive, consisting of slides, polling and live questions, and both remain on-demand (and on social media for patients/caregivers) for 12 months. Assessments were administered at 3 time points (pre-, immediate post-, and 2 mos. post-activity). Data from these questions, responses to live polling questions, and learner-submitted questions during live Q&amp;A were analyzed to determine engagement, lessons learned, and continuing education gaps. Results: As of February 2021, 525 HCPs and 9,582 patients (9,449 Facebook Video; 133 CancerCoachLive.com) participated in the ongoing activities. Post education, HCP learners anticipated the education would positively impact practice behavior (77%) and patient clinical outcomes (73%). HCP improvements in pre/post knowledge and competence questions were realized in 3/4 of the questions. Of patients/caregivers, 34% more learners reported confidence in managing their condition post vs. pre-education. They listed “affording therapy” and “understanding treatment options” as their greatest challenges, and reported “self-care strategies” as their most sought information during the COVID-19 pandemic. At 2-mos. follow-up, 83% of patients reported improvements in communication with their HCPs, and 77% of HCPs reported improvements in their clinical practice. Updated data will be shared, including aligned HCP and patient questions pertaining to care challenges and communication goals. Conclusions: CME and patient education can yield gains in clinical practice behaviors, patient healthcare communication and confidence, and treatment knowledge of HER2-postive breast cancer. Together, aligned education directed to HCPs and patients can improve the ability to provide evidence-based treatment for patients.
P2Y12 inhibitor monotherapy or dual antiplatelet therapy after coronary revascularisation: individual patient level meta-analysis of randomised controlled trials
Authors: Marco Valgimigli, Felice Gragnano, Mattia Branca, Anna Franzone, Usman Baber, Yangsoo Jang, Takeshi Kimura, Joo-Yong Hahn, Qiang Zhao, Stephan Windecker, Charles M Gibson, Byeong-Keuk Kim, Hirotoshi Watanabe, Young Bin Song, Yunpeng Zhu, Pascal Vranckx, Shamir Mehta, Sung-Jin Hong, Kenji Ando, Hyeon-Cheol Gwon, Patrick W Serruys, George D Dangas, Eùgene P McFadden, Dominick J Angiolillo, Dik Heg, Peter Jüni, Roxana Mehran
Journal: BMJ (2021)

Abstract Objective To assess the risks and benefits of P2Y 12 inhibitor monotherapy compared with dual antiplatelet therapy (DAPT) and whether these associations are modified by patients’ characteristics. Design Individual patient level meta-analysis of randomised controlled trials. Data sources Searches were conducted in Ovid Medline, Embase, and three websites ( www.tctmd.com , www.escardio.org , www.acc.org/cardiosourceplus ) from inception to 16 July 2020. The primary authors provided individual participant data. Eligibility criteria Randomised controlled trials comparing effects of oral P2Y 12 monotherapy and DAPT on centrally adjudicated endpoints after coronary revascularisation in patients without an indication for oral anticoagulation. Main outcome measures The primary outcome was a composite of all cause death, myocardial infarction, and stroke, tested for non-inferiority against a margin of 1.15 for the hazard ratio. The key safety endpoint was Bleeding Academic Research Consortium (BARC) type 3 or type 5 bleeding. Results The meta-analysis included data from six trials, including 24 096 patients. The primary outcome occurred in 283 (2.95%) patients with P2Y 12 inhibitor monotherapy and 315 (3.27%) with DAPT in the per protocol population (hazard ratio 0.93, 95% confidence interval 0.79 to 1.09; P=0.005 for non-inferiority; P=0.38 for superiority; τ 2 =0.00) and in 303 (2.94%) with P2Y 12 inhibitor monotherapy and 338 (3.36%) with DAPT in the intention to treat population (0.90, 0.77 to 1.05; P=0.18 for superiority; τ 2 =0.00). The treatment effect was consistent across all subgroups, except for sex (P for interaction=0.02), suggesting that P2Y 12 inhibitor monotherapy lowers the risk of the primary ischaemic endpoint in women (hazard ratio 0.64, 0.46 to 0.89) but not in men (1.00, 0.83 to 1.19). The risk of bleeding was lower with P2Y 12 inhibitor monotherapy than with DAPT (97 (0.89%) v 197 (1.83%); hazard ratio 0.49, 0.39 to 0.63; P&lt;0.001; τ 2 =0.03), which was consistent across subgroups, except for type of P2Y 12 inhibitor (P for interaction=0.02), suggesting greater benefit when a newer P2Y 12 inhibitor rather than clopidogrel was part of the DAPT regimen. Conclusions P2Y 12 inhibitor monotherapy was associated with a similar risk of death, myocardial infarction, or stroke, with evidence that this association may be modified by sex, and a lower bleeding risk compared with DAPT. Registration PROSPERO CRD42020176853.