tbuckley/cabot-search huggingface dataset:
Six-month and 12-month patient outcomes based on inflammatory subphenotypes in sepsis-associated ARDS: secondary analysis of SAILS-ALTOS trial
Authors: Mohamed D Hashem, Ramona O Hopkins, Elizabeth Colantuoni, Victor D Dinglas, Pratik Sinha, Lisa Aronson Friedman, Peter E Morris, James C Jackson, Catherine L Hough, Carolyn S Calfee, Dale M Needham
Journal: Thorax (2021)

Background Prior acute respiratory distress syndrome (ARDS) trials have identified hypoinflammatory and hyperinflammatory subphenotypes, with distinct differences in short-term outcomes. It is unknown if such differences extend beyond 90 days or are associated with physical, mental health or cognitive outcomes. Methods 568 patients in the multicentre Statins for Acutely Injured Lungs from Sepsis trial of rosuvastatin versus placebo were included and assigned a subphenotype. Among 6-month and 12-month survivors (N=232 and 219, respectively, representing 243 unique survivors), subphenotype status was evaluated for association with a range of patient-reported outcomes (eg, mental health symptoms, quality of life). Patient subsets also were evaluated with performance-based tests of physical function (eg, 6 min walk test) and cognition. Findings The hyperinflammatory versus hypoinflammatory subphenotype had lower overall 12-month cumulative survival (58% vs 72%, p&lt;0.01); however, there was no significant difference in survival beyond 90 days (86% vs 89%, p=0.70). Most survivors had impairment across the range of outcomes, with little difference between subphenotypes at 6-month and 12-month assessments. For instance, at 6 months, in comparing the hypoinflammatory versus hyperinflammatory subphenotypes, respectively, the median (IQR) patient-reported SF-36 mental health domain score was 47 (33–56) vs 44 (35–56) (p=0.99), and the per cent predicted 6 min walk distance was 66% (48%, 80%) vs 66% (49%, 79%) (p=0.76). Interpretation Comparing the hyperinflammatory versus hypoinflammatory ARDS subphenotype, there was no significant difference in survival beyond 90 days and no consistent findings of important differences in 6-month or 12-month physical, cognitive and mental health outcomes. These findings, when considered with prior results, suggest that inflammatory subphenotypes largely reflect the acute phase of illness and its short-term impact.
BRMS1L inhibits bone metastasis of breast cancer cells through epigenetic silence of CXCR4.
Authors: Yinghuan Cen, Chang Gong, Jun Li, Gehao Liang, Zihao Liu, Qing Luo, Qun Lin, Yu Shi, Juanmei Li, Xiaolin Fang
Journal: Journal of Clinical Oncology (2021)

e13002 Background: We previously demonstrated that BRMS1L (breast cancer metastasis suppressor 1 like) suppresses breast cancer metastasis through HDAC1 recruitment and histone H3K9 deacetylation at the promoter of FZD10, a receptor for Wnt signaling. It is still unclear whether BRMS1L regulates organ-specific metastases, such as bone metastasis, the most prevalent metastatic site of breast cancer. Methods: Examination of the expression of BRMS1L in primary tumors, bone metastatic and other metastatic tissues from breast cancer patients was implemented using qRT-PCR and immunohistochemistry staining. To investigate the mechanism by which BRMS1L drives breast cancer bone metastasis, we tested the mRNA expression by qRT-PCR of a set of potential bone related genes (BRGs) based on PubMed database in MDA-MB-231 cells over expressing BRMS1L and MCF-7 cells knocking-down BRMS1L, and detected the expression of CXCR4 in these established cells by western blot. Transwell assays were performed to assess the migration abilities of breast cancer cells towards osteoblasts. ChIP (Chromatin Immuno-Precipitation) were employed to test the interaction between BRMS1L and CXCR4. Results: At both mRNA and protein levels, the expression of BRMS1L was significantly lower in bone metastatic sites than that in primary cancer tissues and other metastatic sites of breast cancer patients. CXCR4 was screened out in a set of BRGs and negatively correlated with the expression of BRMS1L in breast cancer cell lines. BRMS1L inhibited the migration of breast cancer cells towards osteoblasts through CXCL12/CXCR4 axis. In the presence of TSA treatment, breast cancer cell lines showed an increased expression of CXCR4 in a TSA concentration-dependent manner. In addition, ChIP assays verified that BRMS1L directly bound to the promoter region of CXCR4 and inhibited its transcription through promoter histone deacetylation. Conclusions: BRMS1L mediates the migration abilities of breast cancer cells to bone microenvironment via targeting CXCR4 and contributes to bone metastasis of breast cancer cells. Thus, BRMS1L may be a potential biomarker for predicting bone metastasis in breast cancer.
Transcriptomic Analysis Reveals the MicroRNAs Responsible for Liver Regeneration Associated With Mortality in Alcohol‐Associated Hepatitis
Authors: Zhihong Yang, Ting Zhang, Praveen Kusumanchi, Qing Tang, Zhaoli Sun, Svetlana Radaeva, Brandon Peiffer, Vijay H. Shah, Patrick Kamath, Greg J. Gores, Arun Sanyal, Naga Chalasani, Yanchao Jiang, Nazmul Huda, Jing Ma, Suthat Liangpunsakul
Journal: Hepatology (2021)

Background and Aims We conducted a comprehensive serum transcriptomic analysis to explore the roles of microRNAs (miRNAs) in alcohol‐associated hepatitis (AH) pathogenesis and their prognostic significance. Approach and Results Serum miRNA profiling was performed in 15 controls, 20 heavy drinkers without liver disease, and 65 patients with AH and compared to publicly available hepatic miRNA profiling in AH patients. Among the top 26 miRNAs, expression of miR‐30b‐5p, miR‐20a‐5p, miR‐146a‐5p, and miR‐26b‐5p were significantly reduced in both serum and liver of AH patients. Pathway analysis of the potential targets of these miRNAs uncovered the genes related to DNA synthesis and cell‐cycle progression pathways, including ribonucleotide reductase regulatory subunit M2 ( RRM2 ), cyclin D1 ( CCND1 ), cyclin D2 ( CCND2 ), MYC proto‐oncogene ( MYC ), and phorbol‐12‐myristate‐13‐acetate‐induced protein 1 ( PMAIP1 ). We found a significant increase in the protein expression of RRM2, CCND1, and CCND2, but not MYC and PMAIP1, in AH patients who underwent liver transplantation; miR‐26b‐5p and miR‐30b‐5p inhibited the 3′‐UTR (untranslated region) luciferase activity of RRM2 and CCND2 , and miR‐20a‐5p reduced the 3′‐UTR luciferase activity of CCND1 and CCND2 . During a median follow‐up of 346 days, 21% of AH patients died; these patients had higher body mass index (BMI), Model for End‐Stage Liver Disease (MELD), and serum miR‐30b‐5p, miR‐20a‐5p, miR‐146a‐5p, and miR‐26b‐5p than those who survived. Cox regression analysis showed that BMI, MELD score, miR‐20a‐5p, miR‐146a‐5p, and miR‐26b‐5p predicted mortality. Conclusions Patients with AH attempt to deal with hepatocyte injury by down‐regulating specific miRNAs and up‐regulating genes responsible for DNA synthesis and cell‐cycle progression. Higher expression of these miRNAs, suggestive of a diminished capacity in liver regeneration, predicts short‐term mortality in AH patients.
Polio eradication at the crossroads
Authors: Konstantin Chumakov, Ellie Ehrenfeld, Vadim I Agol, Eckard Wimmer
Journal: The Lancet Global Health (2021)

The Global Polio Eradication Initiative, launched in 1988 with anticipated completion by 2000, has yet to reach its ultimate goal. The recent surge of polio cases urgently calls for a reassessment of the programme's current strategy and a new design for the way forward. We propose that the sustainable protection of the world population against paralytic polio cannot be achieved simply by stopping the circulation of poliovirus but must also include maintaining high rates of population immunity indefinitely, which can be created and maintained by implementing global immunisation programmes with improved poliovirus vaccines that create comprehensive immunity without spawning new virulent viruses. The proposed new strategic goal of eradicating the disease rather than the virus would lead to a sustainable eradication of poliomyelitis while simultaneously promoting immunisation against other vaccine-preventable diseases.
RARE-08. POTENTIAL NEW THERAPIES FOR DIFFUSE INTRINSIC PONTINE GLIOMAS IDENTIFIED THROUGH HIGH THROUGHPUT DRUG SCREENING
Authors: Dannielle Upton, Santosh Valvi, Jie Liu, Nicole Yeung, Sandra George, Caitlin Ung, Aaminah Khan, Laura Franshaw, Anahid Ehteda, Han Shen, Isabella Orienti, Giovanna Farruggia, Patrick Reynolds, Maria Tsoli, David Ziegler
Journal: Neuro-Oncology (2021)

Abstract Diffuse Intrinsic Pontine Gliomas (DIPGs) are the most devastating of all brain tumors. There are no effective treatments, hence almost all children will die of their tumor within 12-months. There is an urgent need for novel effective therapies for this aggressive tumor. We performed a high-throughput drug screen with over 3,570 biologically active, clinically approved compounds against a panel of neurosphere-forming DIPG cells. We identified 7 compounds - auranofin, fenretinide, ivermectin, lanatoside, parthenolide, SAHA and mefloquine - that were confirmed to have potent anti-tumor activity against a panel of DIPG-neurospheres, with minimal effect on normal cells. Using cytotoxicity and clonogenic assays, we found that these drugs were able to inhibit DIPG-neurosphere proliferation and colony formation in vitro. To determine whether the in vitro efficacy could be replicated in vivo, we tested the activity of each of these compounds in an orthotopic DIPG model. Of the agents tested, fenretinide, auranofin and SAHA were the most active anti-tumor agents, significantly enhancing the survival of tumor bearing animals. Mechanistic studies showed fenretinide enhancing apoptotic cell death of DIPG cells via inhibition of PDGFRa transcription and downregulation of the PI3K/AKT/MTOR pathway. We therefore examined the therapeutic efficacy of fenretinide using a second orthotopic model with PDGFRa amplification. We used two different fenretinide formulations which were found to enhance survival. Fenretinide is clinically available with safety data in children. Validation of the activity of Fenretinide in PDGFRa-amplified or overexpressed DIPGs will lead to the development of a clinical trial, allowing the advancement of fenretinide as potentially the first active therapy for DIPG.
Characteristics and Spatially Defined Immune (micro)landscapes of Early-stage PD-L1–positive Triple-negative Breast Cancer
Authors: Jodi M. Carter, Mei-Yin C. Polley, Roberto A. Leon-Ferre, Jason Sinnwell, Kevin J. Thompson, Xue Wang, Yaohua Ma, David Zahrieh, Jennifer M. Kachergus, Malvika Solanki, Judy C. Boughey, Minetta C. Liu, James N. Ingle, Krishna R. Kalari, Fergus J. Couch, E. Aubrey Thompson, Matthew P. Goetz
Journal: Clinical Cancer Research (2021)

Programmed death ligand 1 [PD-(L)1]-targeted therapies have shown modest survival benefit in triple-negative breast cancer (TNBC). PD-L1+ microenvironments in TNBC are not well characterized and may inform combinatorial immune therapies. Herein, we characterized clinicopathologic features, RNA-based immune signatures, and spatially defined protein-based tumor-immune microenvironments (TIME) in early-stage PD-L1+ and PD-L1- TNBC.From a large cohort of chemotherapy-naïve TNBC, clinicopathologic features, deconvoluted RNA immune signatures, and intraepithelial and stromal TIME (Nanostring GeoMX) were identified in subsets of PD-L1+ and PD-L1- TNBC, as defined by FDA-approved PD-L1 companion assays.228 of 499 (46%) TNBC were PD-L1+ (SP142: ≥1% immune cells-positive). Using PD-L1 22C3, 46% had combined positive score (CPS) ≥ 1 and 16% had CPS ≥10. PD-L1+ TNBC were higher grade with higher tumor-infiltrating lymphocytes (TIL; P < 0.05). PD-L1 was not associated with improved survival following adjustment for TILs and other variables. RNA profiles of PD-L1+ TNBC had increased dendritic cell, macrophage, and T/B cell subset features; and decreased myeloid-derived suppressor cells. PD-L1+ stromal and intraepithelial TIMEs were highly enriched in IDO-1, HLA-DR, CD40, and CD163 compared with PD-L1-TIME, with spatially specific alterations in CTLA-4, Stimulator of Interferon Genes (STING), and fibronectin. Macrophage- and antigen presentation-related proteins correlated most strongly with PD-L1 protein.In this early-stage TNBC cohort, nearly 50% were PD-L1+ (SP142 companion assay) while 16% were PD-L1+ with the 22C3 companion assay. PD-L1+ TNBC had specific myeloid-derived and lymphoid features. Spatially defined PD-L1+ TIME were enriched in several clinically actionable immune proteins. These data may inform future studies on combinatorial immunotherapies for patients with PD-L1+ TNBC.See related commentary by Symmans, p. 5446.
Development and initial validation of a modified Sinclair scale for female pattern hair loss in men
Authors: Karolina L. Kerkemeyer, Janina Eliza Poa, Lara Trindade de Carvalho, Samantha Eisman, Ivan C. Imperial, Rodney D. Sinclair, Bevin Bhoyrul
Journal: Journal of the American Academy of Dermatology (2021)
Patterns of survival in NSCLC with de novo brain metastasis: SRS, WBRT, and no radiotherapy cohorts.
Authors: Diana Saravia, Nadeem Bilani, Leah Elson, Elizabeth Blessing Elimimian, Evan W. Alley, Mihir Naik, Zeina A. Nahleh, Rafael Arteta-Bulos
Journal: Journal of Clinical Oncology (2021)

9122 Background: Prognostic determinants in metastatic non-small cell lung cancer (mNSCLC) include numerous sociodemographic and clinical characteristics. We provide granular, real-world survival data in different cohorts of this heterogeneous population, stratifying by: age, Charlson/Deyo scoring (CDS) of comorbidity, tumor histology, and use of immunotherapy. Methods: This retrospective analysis uses the National Cancer Database (NCDB) to explore patterns of survival in patients diagnosed between 2010-2016 with mNSCLC involving the brain. Kaplan-Meier (KM) modeling was used to evaluate for differences in overall survival (OS) between 3 cohorts of patients: those undergoing 1) stereotactic radiosurgery (SRS), 2) whole-brain radiotherapy (WBRT), and 3) those not undergoing brain radiotherapy (NR) as part of the first course of treatment. As per Table, we ran 8 KM models to generate median OS (mOS) data across stratifications for age (&lt;70 vs. ≥70), CDS (0-1 vs. 2-3), tumor histology (adenocarcinoma vs. squamous), and use of immunotherapy (yes vs. no). We provide a ranked order of these 3 cohorts by mOS (‘survival sequence’, or ‘SS’), as well as differences in mOS (‘ΔmOS’) between NR and WBRT – the two cohorts most comparable in life expectancy. Results: A total of n=38,119 patients were included in this study. Most received WBRT (n=18,052, 47.4%), n=6,562 (17.2%) received SRS, while n=13,505 (35.4%) did not receive brain radiation as part of their first course of treatment. In all subgroups, patients treated with SRS for brain metastasis had the highest mOS. Survival for those receiving WBRT was better or comparable (difference in mOS &lt;0.5 months) to those that did not receive radiotherapy, except in patients aged ≥70 (SS: NR &gt; WBRT; KM p-value &lt;0.05; ΔmOS of 1.6 months), those with Charlson-Deyo comorbidity scores of 2-3 (SS: NR &gt; WBRT; KM p-value &lt;0.05; ΔmOS: 0.6 months), those with squamous carcinoma (SS: NR &gt; WBRT; KM p-value &lt;0.05; ΔmOS: 0.7 months), and those already receiving immunotherapy (SS: NR &gt; WBRT; KM p-value &lt;0.05; ΔmOS: 0.6 months). Conclusions: SRS for de novo brain metastases is associated with improved OS in mNSCLC. In contrast, the burden of WBRT may outweigh the survival benefit it affords in patients ≥70, and those with comorbidities. Squamous cell carcinomas may be associated with more radio-resistance than adenocarcinomas to WBRT. Finally, as previously described in melanoma, the survival benefit afforded by brain radiotherapy may be lower in patients on immunotherapy.[Table: see text]
Prevalence-adjusted trends in U.S. healthcare spending on upper gastrointestinal cancers, 1996 to 2016.
Authors: Igor Stukalin, Newaz Shubidito Ahmed, Adam Michael Fundytus, Siddharth Singh, Christopher Ma
Journal: Journal of Clinical Oncology (2021)

e16064 Background: Upper gastrointestinal cancers are rising in prevalence and associated with high healthcare costs. We estimated trends in the US healthcare spending in patients with esophageal and stomach cancer between 1996 and 2016. Methods: We used data on national healthcare spending developed by the Institute for Health Metrics and Evaluations Disease Expenditure Project. Corresponding prevalence of esophageal and stomach cancer was estimated from the Global Burden of Diseases Study. Prevalence-adjusted, temporal trends in the US healthcare spending in patients with upper gastrointestinal cancer, stratified by age and setting of care (ambulatory, inpatient, emergency department, pharmaceutical prescriptions, nursing care and government administration) were calculated using joinpoint regression, expressed as annual percent change (APC) with 95% confidence intervals. Results: Overall, annual US healthcare spending on esophageal cancer increased from $0.76 billion (95% CI 0.68-0.86) in 1996 to $1.06 billion (95% CI 0.88-1.29) in 2016, although after adjusting for increasing prevalence, there was a significant decrease in per capita spending of -0.4%/year (95% CI -0.7%, -0.1%). Annual US healthcare spending on stomach cancer increased from $1.23 billion (95% CI $1.14 billion - $1.34 billion) in 1996 to $1.49 billion (95% CI $1.20 billion - $2.03 billion) in 2016. Per capita spending increased by 1.8%/year (95% CI 1.4%, 2.1%) between 1996 and 2011, followed by a decrease in gastric cancer-related per capita spending after 2011 (APC -4.4%/year [95% CI -5.8%, -2.9%]). Inpatient care was the largest contributor to total cost of both cancers between 1996-2016: 61.9% for esophageal cancer and 73.1% in gastric cancer in 2016. The rising price and intensity of care (defined as the cost per encounter) was the largest driver of change from 1996-2016 for both cancers, accounting for $0.28 billion (95% CI 0.12-0.41) for esophageal cancer and $0.95 billion (95% CI 0.41-1.39) for stomach cancer. Conclusions: After adjusting for rising prevalence, US per capita healthcare spending on esophageal cancer has decreased significantly since 1996, while per capita spending on gastric cancer has remained stable. Inpatient care was the most significant contributor to costs for both cancers over the time period studied.
Cancer inpatient malnutrition risk, documentation, and ICD-10 coding in an academic medical center.
Authors: Aynur Aktas, Lenna Finch, Danielle Boselli, Declan Walsh, Kunal C. Kadakia, Lauren Dennis Giamberardino, Sally Trufan, Daniel Slaughter, Rupali Bose
Journal: Journal of Clinical Oncology (2021)

12107 Background: Malnutrition (MN) is common in hospitalized cancer patients but often underdiagnosed. We evaluated the prevalence of MN risk, dietitian documented MN (DDMN), and physician coded malnutrition (PCMN) in a consecutive cohort of cancer inpatients in an academic, community-based medical center. Methods: Electronic medical records (EMR) were reviewed for inpatients with a solid tumor diagnosis staged I-IV and admitted to Atrium Health Carolinas Medical Center at least once between 1/1/2016 to 5/21/2019. All data were collected from the first admission EMR encounter closest to the cancer diagnosis date. High MN risk was a score ≥2 on the Malnutrition Screening Tool (MST) completed by an RN at admission. Registered Dietitian (RD) assessments were reviewed for DDMN and grade (mild, moderate, severe). PCMN diagnosis was based on MN ICD-10 codes extracted from the medical coder’s discharge summary. Multivariate logistic regression models identified associations between clinic-demographic factors and the prevalence of DDMN and PCMN with stepwise selection. Results: N=5,143; 48% females. Median age 63 (range 18-102) years. 70% White; 24% Black, 3% Latino. Most common cancers: thoracic 19% and digestive system (14% other, 11% colorectal). 28% had known stage IV disease. The MST was completed in 79%. Among those with MST ≥2 (N=1,005; 25%), DDMN and PCMN prevalence was 30% and 22%, respectively. In the entire cohort, 8% had DDMN; 7% PCMN; 4% both. Prevalence of MN risk, DDMN, and PCMN by cancer site are in the Table. DDMN (N=420) was mild 2%, moderate 16%; severe 66%; unspecified 16%. On discharge, PCMN (N=360) was mild 10%; moderate 0%; severe 69%; unspecified 21%. Male gender (OR 1.27 [1.01, 1.59]), Black race (OR 1.57 [1.25, 1.98]), stage IV disease (v. I-III) (OR 3.08 [2.49, 3.82]), and primary site were all independent predictors of DDMN (all p&lt;0.05); Black race (OR 1.46 [1.14, 1.87]), stage IV disease (OR 2.70 [2.15, 3.39]), and primary site were independent predictors of PCMN (all p&lt;0.05). Conclusions: 25% of cancer inpatients were at high risk for MN. Primary site, disease stage, and race were independent predictors of a greater risk. MN appears to be under-diagnosed compared to population studies. This is the first study to report the prevalence of MN in a large cancer inpatient database with a representative population.[Table: see text]
Phase I study of CCW702, a bispecific small molecule-antibody conjugate targeting PSMA and CD3 in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Mark Christopher Markowski, Deepak Kilari, Mario A. Eisenberger, Rana R. McKay, Robert Dreicer, Mohit Trikha, Elisabeth I. Heath, Jing Li, Pamela D. Garzone, Travis S. Young
Journal: Journal of Clinical Oncology (2021)

TPS5094 Background: CCW702 is a novel bispecific antibody comprised of a small molecule imaging agent ligand (DUPA) with specificity for prostate specific membrane antigen (PSMA) conjugated to an anti-CD3 antibody via an unnatural amino acid. This format has the structure of an antibody drug conjugate with the activity of a CD3-engaging bispecific antibody. The design of CCW702 was leveraged to optimize the structure and function of T cell redirected cytotoxicity against PSMA-positive prostate cancer tumors in preclinical development. Methods: This is a first-in-human, open-label, multi-center phase 1 study evaluating the safety and tolerability of CCW702 when administered via subcutaneous (SC) injection in men with mCPRC. This study will be conducted in two parts: Part I, a dose escalation to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (R2PD); Part II, a dose expansion to determine efficacy at the R2PD. Safety, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and preliminary efficacy will be evaluated. Efficacy will be assessed by change in circulating tumor cells (CTC), PSA 50 response rate, and objective tumor response by RECIST v1.1. Key biomarkers include characterization of CTC, T cell phenotyping in peripheral blood, chemokines and cytokines over time, and evaluation of available tumor biopsies by IHC. Key inclusion criteria include men age ≥ 18 years with histologically or cytologically confirmed adenocarcinoma who, in the metastatic setting, have progressed on at least one novel AR-targeted therapy. Up to 1 prior chemotherapy regimen is allowed. This study will enroll 20-30 patients in Part 1 and approximately 40 patients in Part 2. The study opened in December 2019 and is currently enrolling in the dose escalation phase. Clinical trial information: NCT04077021.