tbuckley/cabot-search huggingface dataset:
A systematic review of the impact of comorbidity on chemotherapy utilization and outcomes in solid tumors
Authors: L. M. Lee, W. Y. Cheung, M. K. Krzyzanowska
Journal: Journal of Clinical Oncology (2009)

e20646 Background: The management of cancer patients (pts) with comorbidities can be challenging as these individuals are underrepresented in oncology clinical trials. We conducted a systematic literature review to determine the impact of comorbidity on utilization, tolerability, and efficacy of chemotherapy among pts with solid tumors. Methods: Using MEDLINE and EMBASE databases, all English-language articles published from 1990–2008 that explored the association between comorbidity and chemotherapy were identified. MeSH and keyword search terms included “comorbidity,” “chemotherapy” and “cancer.” All abstracts were manually reviewed for eligibility based on inclusion and exclusion criteria. Two reviewers independently abstracted data on the design and results of each eligible study, and rated the quality of the article using the STROBE checklist. Results: Of 1,031 citations retrieved by the search, 29 articles met inclusion criteria. Study designs were too heterogeneous to permit a quantitative summary and the overall quality of articles was poor. Comorbidity was investigated most frequently among pts with lung (41%), breast (17%), or colon cancers (17%). Most studies were retrospective (72%), based on cancer registry data (48%), and assessed the effect of cumulative comorbidity based on an index score (76%). Fourteen studies (41%) investigated access and 26 (90%) addressed survival. For pts with comorbidities, the majority reported decreased access (50%) and inferior survival (65%). Of the 12 articles that included both parameters, 6 showed that comorbidity was independently associated with worse survival while 4 demonstrated that impaired access to treatment, not comorbidity, was the stronger predictor of inferior outcomes. Few studies addressed toxicity (24%), ability to complete chemotherapy (7%) or response rates (7%). Among them, no differences based on comorbidity were noted. Conclusions: The evidence regarding the impact of comorbidity on chemotherapy utilization and outcomes among cancer pts is limited and of poor quality. Further better-designed studies are warranted to determine the relationship between decreased access and inferior outcomes and to better define the tolerability and efficacy of chemotherapy in pts with comorbidities. No significant financial relationships to disclose.
Anarchy or Respect the Hierarchy? The Complexity of Glioblastoma
Authors: Robert F. Koncar, Sameer Agnihotri
Journal: Cancer Research (2020)

Abstract Glioma stem-like cells (GSC) in glioblastoma (GBM) structure tumor cells into a hierarchical organization and are postulated to be recalcitrant to conventional treatments, resulting in fatal relapse of the disease. A better understanding of these cells would be essential for meaningful and lasting treatments. In this issue of Cancer Research, Virolle and colleagues report a fascinating phenotype whereby the extracellular signal-regulated kinase (ERK) pathway regulates a mechanism of dedifferentiation of GBM cells into a stem-like state expressing markers of pluripotency through an EGFR-ERK-EGR1–dependent axis. This aptly termed “toggle switch” may contribute to maintenance of GSCs, promote intratumor heterogeneity, and potentially provide innovative treatment options. See related article by Almairac et al., p. 3236
Abstract IA01: The epigenetics of cancer
Authors: Peter A. Jones
Journal: Clinical Cancer Research (2020)

Abstract Human cancers are initiated and maintained by DNA mutations and also by alterations in the cancer epigenome. The interaction between these processes is underscored by the observation that all human cancers contain DNA methylation aberrations and also frequently harbor mutations in genes that modify the epigenome. These include the enzymes that apply and remove methyl groups to and from cytosine, DNMT3A and TET2. Abnormal DNA cytosine methylation has received the most attention in our understanding of its potential to silence tumor suppressor genes and thus to directly contribute to the malignant phenotype. There are now many drugs that can target the epigenome, and I will focus on those that inhibit DNA methylation. It is important that we understand how these drugs elicit responses in patients, and most of the attention to date has centered on their ability to activate genes that are methylated and altered in a cancer relative to the normal tissue. However, a large percentage of the human genome codes for transposable elements, and these are often silenced by DNA methylation. Activation of these transposable elements can give rise to a state of “viral mimicry” in which a cancer cell behaves as though it is infected by an exogenous virus. I will explore how this activation of transposable elements may contribute to an interferon response that leads to apoptosis of cancer cells and to increased visibility to the immune system. Coupling epigenetic therapies with other approaches may be useful in the future in the treatment of cancers, including bladder cancer. Citation Format: Peter A. Jones. The epigenetics of cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr IA01.
Prognostic and Predictive Impact of Circulating Tumor DNA in Patients with Advanced Cancers Treated with Immune Checkpoint Blockade
Authors: Qu Zhang, Jia Luo, Song Wu, Han Si, Chen Gao, Wenjing Xu, Shaad E. Abdullah, Brandon W. Higgs, Phillip A. Dennis, Michiel S. van der Heijden, Neil H. Segal, Jamie E. Chaft, Todd Hembrough, J. Carl Barrett, Matthew D. Hellmann
Journal: Cancer Discovery (2020)

Abstract The utility of circulating tumor DNA (ctDNA) as a biomarker in patients with advanced cancers receiving immunotherapy is uncertain. We therefore analyzed pretreatment (n = 978) and on-treatment (n = 171) ctDNA samples across 16 advanced-stage tumor types from three phase I/II trials of durvalumab (± the anti-CTLA4 therapy tremelimumab). Higher pretreatment variant allele frequencies (VAF) were associated with poorer overall survival (OS) and other known prognostic factors, but not objective response, suggesting a prognostic role for patient outcomes. On-treatment reductions in VAF and lower on-treatment VAF were independently associated with longer progression-free survival and OS and increased objective response rate, but not prognostic variables, suggesting that on-treatment ctDNA dynamics are predictive of benefit from immune checkpoint blockade. Accordingly, we propose a concept of “molecular response” using ctDNA, incorporating both pretreatment and on-treatment VAF, that predicted long-term survival similarly to initial radiologic response while also permitting early differentiation of responders among patients with initially radiologically stable disease. Significance: In a pan-cancer analysis of immune checkpoint blockade, pretreatment ctDNA levels appeared prognostic and on-treatment dynamics predictive. A “molecular response” metric identified long-term responders and adjudicated benefit among patients with initially radiologically stable disease. Changes in ctDNA may be more dynamic than radiographic changes and could complement existing trial endpoints. This article is highlighted in the In This Issue feature, p. 1775
Reorganization of a Nuclear Medicine Department in Northern Italy During a 2-Month Lockdown for COVID-19 Pandemic
Authors: Anna Margherita Maffione, Sotirios Chondrogiannis, Lucia Rampin, Gaia Grassetto, Maria Cristina Marzola, Alex Bassan, Arianna Massaro, Patrick M. Colletti, Domenico Rubello
Journal: Clinical Nuclear Medicine (2020)

Abstract Coronavirus disease (COVID-19) outbreak has profoundly changed the organization of hospital activities. We present our experience of reorganization of a nuclear medicine service settled in Northern Italy during the pandemic period of March and April 2020 characterized a government-mandated lockdown. Our service remained open during the whole period, performing approximately 80% of the routine practice, while maintaining it COVID-free despite the geographical context characterized by a high risk of infection. Reorganization involved all aspects of a nuclear medicine department, following local, national, and international guidelines for prioritizing patients, telephone and physical triages, deployment of appropriate personal protective equipment, social distancing, and logistic changes for scheduling examinations and disinfection procedures. All staff remained COVID-19–negative despite the unintentional admission of 4 patients who later turned out to be positive for the severe acute respiratory syndrome coronavirus 2. These adopted measures would serve as the basis for safe nuclear medicine services in the post–lockdown phase.
COVID-19 and multisystem inflammatory syndrome in children and adolescents
Authors: Li Jiang, Kun Tang, Mike Levin, Omar Irfan, Shaun K Morris, Karen Wilson, Jonathan D Klein, Zulfiqar A Bhutta
Journal: The Lancet Infectious Diseases (2020)

As severe acute respiratory syndrome coronavirus 2 continues to spread worldwide, there have been increasing reports from Europe, North America, Asia, and Latin America describing children and adolescents with COVID-19-associated multisystem inflammatory conditions. However, the association between multisystem inflammatory syndrome in children and COVID-19 is still unknown. We review the epidemiology, causes, clinical features, and current treatment protocols for multisystem inflammatory syndrome in children and adolescents associated with COVID-19. We also discuss the possible underlying pathophysiological mechanisms for COVID-19-induced inflammatory processes, which can lead to organ damage in paediatric patients who are severely ill. These insights provide evidence for the need to develop a clear case definition and treatment protocol for this new condition and also shed light on future therapeutic interventions and the potential for vaccine development. TRANSLATIONS: For the French, Chinese, Arabic, Spanish and Russian translations of the abstract see Supplementary Materials section.
Abstract 15073: Predictors for Heart Rate in Patients With Atrial Fibrillation
Authors: Giorgio Moschovitis, Steffen Blum, Otmar Pfister, Peter Ammann, Paul Erne, Marcello di Valentino, Dipen Shah, Jürg Schläpfer, Michael Kühne, Christian Sticherling, Stefan Osswald, David Conen
Journal: Circulation (2017)

Introduction: In patients suffering from atrial fibrillation (AF), rate control represents a valid therapy option, but the optimal heart rate (HR) for this patient population is relatively unknown....
Single-cell transcriptomics identifies a distinct luminal progenitor cell type in distal prostate invagination tips
Authors: Wangxin Guo, Lin Li, Juan He, Zhuang Liu, Ming Han, Fei Li, Xinyi Xia, Xiaoyu Zhang, Yao Zhu, Yu Wei, Yunguang Li, Rebiguli Aji, Hao Dai, Hui Wei, Chunfeng Li, Yu Chen, Luonan Chen, Dong Gao
Journal: Nature Genetics (2020)
Feasibility of a standardized ultrasound examination in patients with rheumatoid arthritis: Quality improvement among rheumatologists
Authors: Karen Ellegaard, Søren Tobias Torp-Pedersen, Robin Daniel Kjersgaard Christensen, M. Stoltenberg, Annette Hansen, T. Lorenzen, D. Jensen, Lars Juul, H. Lindegaard, Henrik Røgind, P. Bülow, S. Cheysider, Marcin Ryszard Kowalski, Bente Danneskiold-Samsøe, Henning Bliddal
Journal: Annals of the Rheumatic Diseases (2011)
Abstract 6587: Proteogenomic characterization of colorectal cancer using the IndivuType multiomics database
Authors: Margarita Krawczyk, Jonathan Woodsmith, Marcel Nutsoa, Thomas Corwin, Silvia von der Heyde, Vincent Piras, Mark Whittaker, Alex Hergovich, Peter Frommolt, Hartmut Juhl
Journal: Cancer Research (2020)

Abstract Cancer is a highly heterogeneous disease, both intra- and inter-individually consisting of complex phenotypes and systems biology. Although genomic data has contributed greatly towards the identification of cancer-specific mutations and the progress of precision medicine, genomic alterations are only one of several important biological drivers of cancer. Furthermore, single-layer omics represent only a small piece of the cancer biology puzzle and provide only partial clues to connecting genotype with phenotype. A more integrated approach is urgently needed to unravel the underpinnings of molecular signatures and the phenotypic manifestation of cancer hallmarks. We have developed IndivuType, a knowledge and discovery platform that combines genomics, transcriptomics, and proteomics datasets to identify putative therapeutic targets in a colorectal cancer (CRC) cohort of 500 patients. We identified hundreds of proteins dysregulated in CRC that are dependent on the genetic background of the patient. Further, we characterized these proteins using clinical parameters from the IndivuType database to prioritize targets for precision medicine approaches. This project highlights the utility of moving beyond solely genomics approaches to better understand the molecular mechanisms underpinning cancer. Citation Format: Margarita Krawczyk, Jonathan Woodsmith, Marcel Nutsoa, Thomas Corwin, Silvia von der Heyde, Vincent Piras, Mark Whittaker, Alex Hergovich, Peter Frommolt, Hartmut Juhl. Proteogenomic characterization of colorectal cancer using the IndivuType multiomics database [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6587.
Abstract A11: Generation and characterization of immune-competent syngeneic model of muscle-invasive bladder cancer (MIBC)
Authors: Shruti D. Shah, Bryan Gillard, Ellen Karasik, Michelle Wrobel, Michael T. Moser, Barbara A. Foster
Journal: Clinical Cancer Research (2020)

Abstract Immunologically, MIBC tumors can be divided into inflamed and noninflamed phenotype. Inflamed tumors show high immune cell infiltration. In contrast, noninflamed tumors have little to no immune infiltration. Clinical evidence shows that response to therapy, particularly immune therapy, is associated with the immune phenotype of the tumor. In our preliminary analysis of the TCGA tumor expression data, we observed that patients with high CD8 T-cell infiltration expression signature show an improved overall survival irrespective of treatment. To study the molecular and immunologic drivers of CD8+ T-cell tumor infiltration in MIBC, we have generated immune-competent syngeneic models of bladder cancer. The mouse models were generated by inducing invasive disease by treating C57BL/6 mice with carcinogen N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). The induced tumors were grafted into sex-matched immune-competent syngeneic hosts establishing allograft tumor lines. The models represent different clinical subtypes both molecularly and histologically. Currently we have 8 different models with squamous, sarcamatoid, or a more differentiated phenotype. RNA-seq analysis of the tumor lines was used to classify the models into basal-like and luminal-like tumors using the TCGA classifier system. Using the RNA-seq data, we applied a deconvolution algorithm to identify models that had inflamed or noninflamed immune phenotype. Flow cytometry data indicate that the inflamed tumors have a higher infiltration of the myeloid population. We treated 4/8 models with cisplatin, the current standard of care. The models show variable response to cisplatin, indicating the variability between the different models. In conclusion, we have successfully developed immune-competent syngeneic mouse models of MIBC that can be used to study the molecular and immune-driven processes of the disease. Citation Format: Shruti D. Shah, Bryan Gillard, Ellen Karasik, Michelle Wrobel, Michael T. Moser, Barbara A. Foster. Generation and characterization of immune-competent syngeneic model of muscle-invasive bladder cancer (MIBC) [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr A11.
A DNA Hypomethylating Drug Alters the Tumor Microenvironment and Improves the Effectiveness of Immune Checkpoint Inhibitors in a Mouse Model of Pancreatic Cancer
Authors: Tamas A. Gonda, Jarwei Fang, Martha Salas, Catherine Do, Emily Hsu, Anna Zhukovskaya, Ariel Siegel, Ryota Takahashi, Zoila A. Lopez-Bujanda, Charles G. Drake, Gulam A. Manji, Timothy C. Wang, Kenneth P. Olive, Benjamin Tycko
Journal: Cancer Research (2020)

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer that has proven refractory to immunotherapy. Previously, treatment with the DNA hypomethylating drug decitabine (5-aza-dC; DAC) extended survival in the KPC-Brca1 mouse model of PDAC. Here we investigated the effects of DAC in the original KPC model and tested combination therapy with DAC followed by immune checkpoint inhibitors (ICI). Four protocols were tested: PBS vehicle, DAC, ICI (anti-PD-1 or anti-VISTA), and DAC followed by ICI. For each single-agent and combination treatment, tumor growth was measured by serial ultrasound, tumor-infiltrating lymphoid and myeloid cells were characterized, and overall survival was assessed. Single-agent DAC led to increased CD4+ and CD8+ tumor-infiltrating lymphocytes (TIL), PD1 expression, and tumor necrosis while slowing tumor growth and modestly increasing mouse survival without systemic toxicity. RNA-sequencing of DAC-treated tumors revealed increased expression of Chi3l3 (Ym1), reflecting an increase in a subset of tumor-infiltrating M2-polarized macrophages. While ICI alone had modest effects, DAC followed by either of ICI therapies additively inhibited tumor growth and prolonged mouse survival. The best results were obtained using DAC followed by anti-PD-1, which extended mean survival from 26 to 54 days (P < 0.0001). In summary, low-dose DAC inhibits tumor growth and increases both TILs and a subset of tumor-infiltrating M2-polarized macrophages in the KPC model of PDAC, and DAC followed by anti-PD-1 substantially prolongs survival. Because M2-polarized macrophages are predicted to antagonize antitumor effects, targeting these cells may be important to enhance the efficacy of combination therapy with DAC plus ICI. SIGNIFICANCE: In a pancreatic cancer model, a DNA hypomethylating drug increases tumor-infiltrating effector T cells, increases a subset of M2 macrophages, and significantly prolongs survival in combination with immune checkpoint inhibitors.See related commentary by Nephew, p. 4610.
Dabrafenib plus trametinib in patients with BRAFV600E-mutated biliary tract cancer (ROAR): a phase 2, open-label, single-arm, multicentre basket trial
Authors: Vivek Subbiah, Ulrik Lassen, Elena Élez, Antoine Italiano, Giuseppe Curigliano, Milind Javle, Filippo de Braud, Gerald W Prager, Richard Greil, Alexander Stein, Angelica Fasolo, Jan H M Schellens, Patrick Y Wen, Kert Viele, Aislyn D Boran, Eduard Gasal, Paul Burgess, Palanichamy Ilankumaran, Zev A Wainberg
Journal: The Lancet Oncology (2020)
The role of TDP-43 mislocalization in amyotrophic lateral sclerosis
Authors: Terry R. Suk, Maxime W. C. Rousseaux
Journal: Molecular Neurodegeneration (2020)

Abstract Since its discovery as a primary component in cytoplasmic aggregates in post-mortem tissue of patients with Amyotrophic Lateral Sclerosis (ALS), TAR DNA Binding Protein 43 kDa (TDP-43) has remained a central focus to understand the disease. TDP-43 links both familial and sporadic forms of ALS as mutations are causative for disease and cytoplasmic aggregates are a hallmark of nearly all cases, regardless of TDP-43 mutational status. Research has focused on the formation and consequences of cytosolic protein aggregates as drivers of ALS pathology through both gain- and loss-of-function mechanisms. Not only does aggregation sequester the normal function of TDP-43, but these aggregates also actively block normal cellular processes inevitably leading to cellular demise in a short time span. Although there may be some benefit to therapeutically targeting TDP-43 aggregation, this step may be too late in disease development to have substantial therapeutic benefit. However, TDP-43 pathology appears to be tightly linked with its mislocalization from the nucleus to the cytoplasm, making it difficult to decouple the consequences of nuclear-to-cytoplasmic mislocalization from protein aggregation. Studies focusing on the effects of TDP-43 mislocalization have demonstrated both gain- and loss-of-function consequences including altered splicing regulation, over responsiveness to cellular stressors, increases in DNA damage, and transcriptome-wide changes. Additionally, mutations in TARDBP confer a baseline increase in cytoplasmic TDP-43 thus suggesting that small changes in the subcellular localization of TDP-43 could in fact drive early pathology. In this review, we bring forth the theme of protein mislocalization as a key mechanism underlying ALS, by highlighting the importance of maintaining subcellular proteostasis along with the gain- and loss-of-functional consequences when TDP-43 localization is dysregulated. Additional research, focusing on early events in TDP-43 pathogenesis (i.e. to the protein mislocalization stage) will provide insight into disease mechanisms, therapeutic targets, and novel biomarkers for ALS.
Long-Term Noninvasive Ventilation in Chronic Stable Hypercapnic Chronic Obstructive Pulmonary Disease. An Official American Thoracic Society Clinical Practice Guideline
Authors: Madalina Macrea, Simon Oczkowski, Bram Rochwerg, Richard D. Branson, Bartolome Celli, John M. Coleman, Dean R. Hess, Shandra Lee Knight, Jill A. Ohar, Jeremy E. Orr, Amanda J. Piper, Naresh M. Punjabi, Shilpa Rahangdale, Peter J. Wijkstra, Susie Yim-Yeh, M. Bradley Drummond, Robert L. Owens
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Background: Noninvasive ventilation (NIV) is used for patients with chronic obstructive pulmonary disease (COPD) and chronic hypercapnia. However, evidence for clinical efficacy and optimal management of therapy is limited.Target Audience: Patients with COPD, clinicians who care for them, and policy makers.Methods: We summarized evidence addressing five PICO (patients, intervention, comparator, and outcome) questions. The GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach was used to evaluate the certainty in evidence and generate actionable recommendations. Recommendations were formulated by a panel of pulmonary and sleep physicians, respiratory therapists, and methodologists using the Evidence-to-Decision framework.Recommendations:1) We suggest the use of nocturnal NIV in addition to usual care for patients with chronic stable hypercapnic COPD (conditional recommendation, moderate certainty); 2) we suggest that patients with chronic stable hypercapnic COPD undergo screening for obstructive sleep apnea before initiation of long-term NIV (conditional recommendation, very low certainty); 3) we suggest not initiating long-term NIV during an admission for acute-on-chronic hypercapnic respiratory failure, favoring instead reassessment for NIV at 2-4 weeks after resolution (conditional recommendation, low certainty); 4) we suggest not using an in-laboratory overnight polysomnogram to titrate NIV in patients with chronic stable hypercapnic COPD who are initiating NIV (conditional recommendation, very low certainty); and 5) we suggest NIV with targeted normalization of PaCO2 in patients with hypercapnic COPD on long-term NIV (conditional recommendation, low certainty).Conclusions: This expert panel provides evidence-based recommendations addressing the use of NIV in patients with COPD and chronic stable hypercapnic respiratory failure.