tbuckley/cabot-search huggingface dataset:
Comparing accuracy of lipoarabinomannan urine tests for diagnosis of pulmonary tuberculosis in children from four African countries: a cross-sectional study
Authors: Esin Nkereuwem, Toyin Togun, Marie P Gomez, Rita Székely, Aurélien Macé, Dawda Jobe, Samuel G Schumacher, Beate Kampmann, Claudia M Denkinger, Ishaya Ibrahim Abok, Joshua Tsoukan Angyu, Aziz Diakité, Bassirou Diarra, Augustine Odo Ebonyi, Uzochukwu Egere, Marie P. Gomez, Musa Jallow, Dawda Jobe, Beate Kampmann, Bakary Konate, Gonen Mato Lakda, Hellen Mahiga, Esin Nkereuwem, Nyanda Elias Ntinginya, Willyhelmina Olomi, Issa Sabi, Binta Saidy, Moumine Sanogo, Abdou K. Sillah, Mariam Sylla, Toyin Togun
Journal: The Lancet Infectious Diseases (2020)
MBCL-33. RARE PULMONARY TOXICITY IN THREE MEDULLOBLASTOMA PATIENTS UNDERGOING ANTIANGIOGENIC METRONOMIC COMBINATION THERAPY
Authors: Alicia Lenzen, Daniel Gryzlo, Irene McKenzie, Stewart Goldman, Natasha Pillay-Smiley
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Metronomic and targeted anti-angiogenesis therapy (MEMMAT) has emerged as a promising treatment for recurrent/progressive medulloblastoma. This treatment includes bevacizumab, oral agents (thalidomide, celecoxib, fenofibrate, etoposide &amp; cyclophosphamide) and intrathecal chemotherapy (etoposide &amp; cytarabine). Common toxicities include myelosuppression, nausea, and infection. Mild respiratory toxicities can occur. We report three cases with significant respiratory toxicity. METHODS An IRB approved chart review was performed of three children with recurrent medulloblastoma on MEMMAT treatment and meaningful pulmonary toxicity. Literature review found no reports of similar findings. RESULTS Patient ages ranged from 3 to 11 years old. Patients completed a mean of 6.33 months on treatment. There was no history of chronic respiratory disease prior to starting MEMMAT. Patient #1 developed chronic cough requiring multiple respiratory and anti-infective treatments; CT scan demonstrated airspace opacities concerning for chronic inflammatory change. Each new viral infection led to significant respiratory distress. He eventually died from respiratory failure with large cystic lesions noted on CT. Patient #2 developed a chronic cough not responsive to antibiotics or respiratory treatments. Images reported airspace disease, bronchiectasis, and chronic inflammatory state. Patient #3 developed chronic cough without improvement despite antibiotics and inhaled respiratory treatments; images were suggestive of small airway disease. All three patients required numerous hospitalizations and additional treatment. CONCLUSION With MEMMAT, many side effects are expected though respiratory symptoms have rarely been reported. Our cases highlight the possible important correlation of pulmonary toxicity while being treated on MEMMAT, and its impact on patients’ overall health and quality of life.
Characteristics and challenges of the clinical pipeline of digital therapeutics
Authors: Nisarg A. Patel, Atul J. Butte
Journal: npj Digital Medicine (2020)

In this Comment, we characterize the current pipeline of digital therapeutics and offer a clinical perspective into the advantages, challenges, and barriers to implementation of this treatment modality for patient care, which we hope will inform future regulatory policy, prescribing decisions, and scope of real-world evidence collection.
Abstract 14966: Social Determinants of Health and Health System Utilization for Hypertension and Diabetes on Chicago’s South Side
Authors: Marynia Kolak, Rhys Chua, Stephanie A Besser, Emeka Anyanwu, James K Liao, Elizabeth L Tung, Luc Anselin, Corey E Tabit
Journal: Circulation (2018)

Introduction: Social determinants of health (SDOH) can critically impact healthcare access and outcomes. However, few studies have examined geospatial relationships between SDOH and healthcare util...
Increased rates of immunosuppressive treatment and hospitalization after checkpoint inhibitor therapy in cancer patients with autoimmune disease
Authors: David Andrew Bender, Samuel P Heilbroner, Tony J C Wang, Catherine A Shu, Brigham Hyde, Catherine Spina, Simon K Cheng
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Immune checkpoint inhibitors (ICIs) are important new therapeutic options for the treatment of malignancy. Existing data on the relative safety of ICI treatment in patients with pre-existing autoimmune disease (AID) are limited. Methods In this retrospective study utilizing an oncology medical claims database, we determined the rates of treatment with immunosuppressive agents and hospitalization within 180 days of treatment with ICIs (pembrolizumab, nivolumab, and ipilimumab) in patients both with and without AID. Patients had diagnoses of either malignant melanoma or lung cancer. Immunosuppressive agents evaluated included oral prednisone and intravenous methylprednisolone. Results 124 cancer patients with AID and 1896 cancer patients without AID met inclusion criteria for oral prednisone analysis, while 284 patients with AID and 3230 patients without AID met inclusion criteria for all other analyzes. Following treatment with PD-1 inhibitors, rates of treatment with both oral prednisone and intravenous methylprednisolone within 180 days of ICI treatment were significantly increased in the AID group relative to the control group (oral prednisone: 16.7% treatment in AID vs 8.3% in non-AID, p=0.0048; intravenous methylprednisolone: 8.4% treatment in AID vs 3.7% in non-AID, p=0.0012). Rates of hospitalization were significantly increased in melanoma patients with AID relative to melanoma patients without AID following treatment with PD-1 inhibitors (24.1% in AID vs 5.8% in non-AID, p&lt;0.0001). Conclusion Cancer patients with AID have higher rates of hospitalization and treatment with immunosuppressive agents following treatment with ICI therapy compared with patients with no AID. This suggests that patients with AID may have increased toxicity risk while being treated with checkpoint inhibitor therapy. Further prospective clinical trials are needed to determine safety.
Large nuclear size correlated with better overall survival, Merkel cell polyomavirus positivity, and terminal deoxynucleotidyl transferase expression in Merkel cell carcinoma
Authors: Jakob M.T. Moran, Przemyslaw Biecek, Piotr Donizy, Cheng-Lin Wu, Janusz Kopczynski, Malgorzata Pieniazek, Janusz Ryś, Mai P. Hoang
Journal: Journal of the American Academy of Dermatology (2020)
Peripheral Neuropathy and All-Cause and Cardiovascular Mortality in U.S. Adults
Authors: Caitlin W. Hicks, Dan Wang, Kunihiro Matsushita, B. Gwen Windham, Elizabeth Selvin
Journal: Annals of Internal Medicine (2020)

Background: Growing evidence indicates that peripheral neuropathy (PN) is common even in the absence of diabetes. However, the clinical sequelae of PN have not been quantified in the general population. Objective: To assess the associations of PN with all-cause and cardiovascular mortality in the general adult population of the United States. Design: Prospective cohort study. Setting: NHANES (National Health and Nutrition Examination Survey), 1999 to 2004. Participants: 7116 adults aged 40 years or older who had standardized monofilament testing for PN. Measurements: Cox regression to evaluate the associations of PN with all-cause and cardiovascular mortality after adjustment for demographic and cardiovascular risk factors, overall and stratified by diabetes status. Results: The overall prevalence of PN (±SE) was 13.5% ± 0.5% (27.0% ± 1.4% in adults with diabetes and 11.6% ± 0.5% in adults without diabetes). During a median follow-up of 13 years, 2128 participants died, including 488 of cardiovascular causes. Incidence rates (per 1000 person-years) of all-cause mortality were 57.6 (95% CI, 48.4 to 68.7) in adults with diabetes and PN, 34.3 (CI, 30.3 to 38.8) in adults with PN but no diabetes, 27.1 (CI, 23.4 to 31.5) in adults with diabetes but no PN, and 13.0 (CI, 12.1 to 14.0) in adults with no diabetes and no PN. In adjusted models, PN was significantly associated with all-cause mortality (hazard ratio [HR], 1.49 [CI, 1.15 to 1.94]) and cardiovascular mortality (HR, 1.66 [CI, 1.07 to 2.57]) in participants with diabetes. In those without diabetes, PN was significantly associated with all-cause mortality (HR, 1.31 [CI, 1.15 to 1.50]), but the association between PN and cardiovascular mortality was not statistically significant after adjustment (HR, 1.27 [CI, 0.98 to 1.66]). Limitation: Prevalent cardiovascular disease was self-reported, and PN was defined by monofilament testing only. Conclusion: Peripheral neuropathy was common and was independently associated with mortality in the U.S. population, even in the absence of diabetes. These findings suggest that decreased sensation in the foot may be an underrecognized risk factor for death in the general population. Primary Funding Source: National Institute of Diabetes and Digestive and Kidney Diseases and National Heart, Lung, and Blood Institute of the National Institutes of Health.
Variation in Biosimilar Uptake in Europe—Reply
Authors: Alice J. Chen, Karen Van Nuys
Journal: JAMA Internal Medicine (2020)

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MODL-31. RADIATION-DERIVED TREATMENT-RESISTANT PDX AND CELL CULTURE MODELS RECAPITULATE THE CHARACTERISTICS OF MATCHED PRIMARY/RECURRENT PEDIATRIC HIGH-GRADE GLIOMA
Authors: Aaron J Knox, Patrick Flannery, Anjali Zukosky, John DeSisto, Bridget Sanford, Benjamin van Court, Andrew Donson, Rakeb Lemma, Hannah Chatwin, Sana D Karam, Rajeev Vibhakar, Ken Jones, Adam L Green
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Pediatric high-grade glioma (pHGG) is the most common cause of childhood cancer death. Recurrence after therapy is a major challenge, since recurrent pHGG proliferates aggressively and resists therapy. We developed and validated preclinical models of matched primary and recurrent tumors, providing a method to study recurrence and potential therapies. METHODS We irradiated H3K27M thalamic pHGG cells (BT245) (8 Gy/week,2Gy fractions x3 weeks) and propagated the surviving cells (BT245R). We developed a murine recurrence model by orthotopically implanting BT245 cells, irradiating the resultant tumors (4 Gy/day x2d) and propagating irradiated (BT245RM) or control (BT245CM) tumor cells at endpoint. We performed phenotypic analyses, RNA-Seq, and drug testing. RESULTS BT245R cells were more stemlike than BT245, with an 8-fold greater rate of neurosphere formation (p&amp;lt;0.03). Geneset enrichment analysis showed similar molecular changes in BT245RM cells and primary/recurrent H3K27M pHGG patient sample pair, including relaxation of the G2/M cell cycle checkpoint (Hallmark_G2M_Checkpoint: BT245RM NES=-5.95, FDR=0.0; patient NES=-5.86, FDR=0.0), downregulation of MYC targets (Hallmark_MYC_Targets_V1: BT245RM NES=-7.43, FDR=0.0; patient NES=-5.86, FDR=0.0), and decreased differentiation (Go_Regulation_of_Stem_Cell_Differentiation: BT245RM NES=-3.35, FDR=0.0; patient NES=-3.15, FDR=0.0). Enrichment of the protein_kinase_C_signaling in BT245RM (NES=2.18,FDR=0.03) suggested response to MAPK pathway inhibition. BT245R cells were twice as sensitive as BT245 cells to the MEK inhibitor trametinib (p&amp;lt;0.05). CONCLUSIONS Our neurosphere and murine orthotopic patient-derived xenograft models recapitulate gene expression changes of matched primary/recurrent pHGG. RNA-Seq analysis validated the model against patient samples and identified trametinib as potentially effective in recurrent pHGG.
ETMR-14. TREATMENT OF EMBRYONAL TUMOURS WITH MULTILAYERED ROSETTES (ETMR) WITH CARBOPLATIN-ETOPOSIDE INDUCTION AND TANDEM HIGH-DOSE CHEMOTHERAPY WITHIN THE PROSPECTIVE HIT-TRIALS AND REGISTRIES
Authors: Björn-Ole Juhnke, Marco Gessi, Nicolas Ulrich Gerber, Carsten Friedrich, Christine Haberler, Martin Mynarek, Brigitte Bison, Rolf-Dieter Kortmann, Monika Warmuth-Metz, Ulrich Schüller, Stefan Michael Pfister, Torsten Pietsch, Marcel Kool, Stefan Rutkowski, Katja von Hoff
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Embryonal tumours with multilayered rosettes (ETMR) are highly aggressive tumors, mostly occurring in infants. Published clinical data refer to retrospective cohorts of inhomogeneously treated patients. Here, we describe the outcome of patients, who were prospectively treated within the P-HIT2000-trial, the subsequent HIT2000-interim-registry and earlier HIT-trials. PATIENTS AND METHODS Nineteen patients from the P-HIT2000-trial (2001–2011), 12 patients from the subsequent HIT2000-interim-registry (2012–2014) and 4 patients from earlier HIT-trials with centrally reviewed neuropathological and molecularly-confirmed diagnosis of ETMR were included. Outcome of 18 patients treated with carboplatin-etoposide-induction followed by tandem-high-dose chemotherapy (“CARBO-ETO+HDCT”) with stage-stratified radiotherapy administered in case of persistant disease, relapse or progression were compared to patients treated with HIT-SKK chemotherapy ± radiotherapy (n=9) or other regimens (n=8). RESULTS Median age at diagnosis was 2.9(1.0–5.3) years. Metastases at diagnosis were detected in 9 patients (26%). For the entire cohort of n=35, 5-year overall survival (OS) was 26.7%, and progression-free survival (PFS) was 18.5%. Five-year OS for patients with CARBO-ETO+HDCT, SKK chemotherapy or other regimens was 44.4%, 13.0% and 0%, respectively (p=0.006). Five-year PFS was 33.3%, 0% and 0%, respectively (p=0.119). Of 10 survivors, n=8 were treated with CARBO-ETO+HDCT; n=4 had craniospinal, n=2 local and n=4 no radiotherapy. Impact of initial gross-total-resection (p=0.231) and non-metastatic disease (p=0.097) was limited. CONCLUSIONS We show improved survival with carboplatin-etoposide-induction followed by tandem-high-dose chemotherapy, indicating that a cure is possible for some patients. However, despite intensive treatment, outcome is unsatisfactory and innovative therapies urgently need to be included in an upfront setting.
NCOG-17. PREDICTORS OF SURVIVAL IN ELDERLY PATIENTS UNDERGOING SURGERY FOR GBM
Authors: Mathew Voisin, Gelareh Zadeh
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Despite the median age of diagnosis of GBM being 64 years old, there is only a paucity of studies on elderly patients with GBM. Furthermore, the majority of these studies examine treatment paradigms, and there is limited research on clinical and hospital factors on overall survival. The purpose of this study is to determine predictors of survival in elderly patients undergoing surgery for GBM. METHODS We searched our hospital brain tumour biobank database for all consecutive patients over a 14-year period from 2005 to 2018. All patients 65 years of age or older at time of surgery with a pathological diagnosis of de novo primary GBM were included. Kaplan-Meier survival curve and Cox proportional hazards model were constructed for overall survival vs age, sex, KPS, medical co-morbidities, extent of resection by surgeon, length of stay, postop complications, and discharge destination. RESULTS A total of 150 patients were included. The median age at time of surgery was 74 years old (range: 65-94). Median overall survival was 9.4 months (95% CI: 7.8-12.2). Variables associated with worse survival included longer length of stay (HR: 1.15, 95% CI: 1.02-1.30, p = 0.02), discharge destination other than home (HR: 1.91, 95% CI: 1.01-3.6, p = 0.04), and any postop complication (HR: 3.7, 95% CI: 1.87-7.3, p = &amp;lt; 0.001). The presence of any or multiple medical comorbidities was not associated with worse survival (p = 0.93 and 0.19, respectively). CONCLUSIONS The presence of medical comorbidities is not associated with worse survival in elderly patients undergoing surgery for GBM. In order to maximize survival in these patients, avoidance of postoperative complications is paramount, along with a short hospital stay and attempt to discharge these patients to their home.
Two Faces of Neutrophils in Liver Disease Development and Progression
Authors: Yeonhee Cho, Gyongyi Szabo
Journal: Hepatology (2020)

Neutrophils, the most abundant type of leukocyte in human blood, play a major role in host defense against invading pathogens and in sterile injury. Neutrophil infiltration is characteristic of inflammation because of its antimicrobial and cytotoxic activities. Neutrophils also actively participate in the resolution of inflammation and subsequent tissue repair by acting as a critical mediator between the inflammation and resolution phases of tissue damage. However, neutrophils that are consistently exposed to inflammatory conditions lose their self‐resolving capabilities and maintain an inflammatory phenotype, further exacerbating tissue damage. The current review describes how neutrophils interact with tissue microenvironments and acquire disease‐specific phenotypes under chronic inflammatory conditions. Here, we aim to provide a better understanding of neutrophil‐mediated pathogenesis of various liver diseases.
MBRS-39. MAP4K4 CONTROLS PRO-INVASIVE SIGNALING IN MEDULLOBLASTOMA CELLS
Authors: Jessica Migliavacca, Charles Capdeville, Buket Seçkin, Michael Grotzer, Martin Baumgartner
Journal: Neuro-Oncology (2020)

Abstract The molecular mechanisms contributing to distant dissemination and local recurrence of medulloblastoma, the most common malignant brain tumor in childhood, are poorly understood and no targeted anti-invasion therapies exist till date. We explored regulators and effectors of MAP4K4, a pro-invasive kinase overexpressed in MB and associated with metastatic progression in different solid malignancies. MAP4K4 is upregulated both at mRNA and protein levels in primary pediatric brain tumors compared to normal cerebellum. MAP4K4 is required for growth factor- and irradiation-induced migration and invasion of medulloblastoma cells. It furthermore promotes turnover and activation of the receptor tyrosine kinase c-Met and of the ß1 integrin adhesion receptor 1. To characterize these clinically relevant consequences and to identify druggable targets of MAP4K4 function, we profiled the interactome of MAP4K4 in starved and growth factor stimulated medulloblastoma cells. To systematically address MAP4K4 impact on receptor expression and turnover, we determined the MAP4K4-dependent surface proteome in medulloblastoma cells. We found that MAP4K4 is part of the striatin-interacting phosphatase and kinase (STRIPAK) complex and that STRIPAK component striatin 4 is controlling cell motility and invasiveness in medulloblastoma cells. Invasiveness of medulloblastoma cells is abrogated by a truncation mutant of MAP4K4 lacking the striatin 4 interaction domain. We furthermore found that MAP4K4 mediates growth factor-induced surface expression of solute carriers and immunomodulatory proteins involved in chemoresistance and immune evasion. Thus, our study identified MAP4K4 as a missing link between pro-tumorigenic growth factor signaling and tumor cell functions relevant for disease progression. It may help identifying druggable vulnerabilities in medulloblastoma cells to restrict tumor growth and dissemination. 1. Tripolitsioti, D. et al., Oncotarget9, 23220–23236 (2018).
MBRS-57. IDENTIFICATION OF <i>MYC</i>-DEPENDENT THERAPEUTIC VULNERABILITIES FOR TARGETING GROUP 3 MEDULLOBLASTOMA
Authors: Gemma Llargués-Sistac, Janet Lindsey, Shanel Swartz, Matthew Selby, Alaide Morcavallo, Simon Bailey, Louis Chesler, Christopher J Lord, Daniel Williamson, Steven C Clifford
Journal: Neuro-Oncology (2020)

Abstract Group 3 medulloblastoma (MBGroup3) is a highly aggressive tumour characterised by MYC amplification and elevated expression (17% of MBGroup3). MYC amplification in MBGroup3 confers a dismal prognosis using standard therapies, and there is an urgent unmet need for novel therapeutic approaches. The identification and targeting of MYC’s biological dependencies thus represents a promising strategy to treat MYC-MBGroup3 tumours. Three independent isogenic MYC-regulable MBGroup3 human cell-based models, in which elevated MYC expression can be directly down-regulated by doxycycline-inducible shRNAs, were developed and used initially to establish MYC-dependent growth of each model. Our novel models were then used to investigate MYC-dependent drug sensitivity, by characterising responses to a panel of candidate cancer therapeutics and small molecule inhibitors, including a high-throughput compound screen of &amp;gt;500 established/clinically-relevant small molecule inhibitors. This approach identified several specific, consistently observed, druggable MYC-dependencies (e.g. cell cycle regulators, DNA-damage response controllers, mitotic control machinery) with potential for the development of treatments against MYC-MBGroup3 tumours. PLK1, CHK1 and AURK were identified as prime candidate targets with consistent MYC-dependent response profiles. Subsequent validation of each candidate, by genetic and pharmacological target inhibition, confirmed their MYC-dependent effects, associated with downregulation of MYC and established target-dependent pharmacodynamic biomarkers/pathways. Results were consistent across all of our MBGroup3 models. In summary, our novel models reveal druggable MYC-associated dependencies as a feature of MBGroup3. Our findings support the development of PLK1, CHK1 and AURK inhibition as therapeutic approaches against MYC-dependent MBGroup3. Future work is now essential to validate our findings in vivo, to support the design of future clinical trials.