tbuckley/cabot-search huggingface dataset:
Comparison of surgical data and survival outcome of rectal cancer patients that need upfront surgery after chemoradiotherapy versus salvage surgery after watch-and-wait
Authors: P. Bulens, A. Debucquoy, I. Joye, A. Wolthuis, A. D’Hoore, E. Van Cutsem, J. Dekervel, X. Sagaert, R. Dresen, V. Vandecaveye, C. Deroose, K. Haustermans
Journal: Annals of Oncology (2019)
Abstract 3993: Programmed cell death ligand-1 (PD-L1) and CD8 expression profiling identifies an immunologic subtype of pancreatic ductal adenocarcinomas with favorable survival
Authors: Won Jin Ho, Ludmila Danilova, Qingfeng Zhu, Teena Vithayathil, Ana De Jesus-Acosta, Nilo Azad, Daniel Laheru, Elana Fertig, Robert Anders, Elizabeth Jaffee, Mark Yarchoan
Journal: Cancer Research (2019)

Abstract Unselected cases of pancreatic adenocarcinoma (PDAC) have not shown clinical benefit from single agent immune checkpoint therapy, but a subset of PDAC are known to upregulate pathways involved in acquired immune suppression. Further delineation of immunologic subtypes of PDAC is key to smarter trial designs and progress toward improved immunotherapy strategies. To accomplish this, we first employed clinical survival and RNA expression data from 155 patients in The Cancer Genome Atlas (TCGA) to investigate the relationship between immune modulating checkpoints and immune subset marker, CD8A, and their impact on survival in PDAC patients. Among the markers explored, overexpression of PD-L1 (HR=2.55, p=0.001) and IDO1 (HR=2.24, p&amp;lt;0.01) were individually associated with poor survival. PD-L1 expression was not significantly associated with stage or tumor mutational burden of the PDACs. While CD8A expression alone was not correlated with survival, stratifying the analysis based on PD-L1 and CD8 expression identified a subtype characterized by low PD-L1 and high CD8A with favorable survival (p=0.004). Similarly, the combination of low IDO1 and high CD8A expression was associated with favorable survival (p=0.038). We further extended these observations using an independent PDAC cohort of 33 patients from our institution via immunohistochemistry, again observing that low PD-L1 / high CD8 subtype associates with positive prognosis (p=0.021). Although PDAC is regarded as a poorly immunogenic cancer type, these findings infer that baseline T cell infiltration into PDAC is a feature of long term survival and highlights the importance of developing future immunotherapeutic strategies based on data-supported biomarkers to refine patient selection. Citation Format: Won Jin Ho, Ludmila Danilova, Qingfeng Zhu, Teena Vithayathil, Ana De Jesus-Acosta, Nilo Azad, Daniel Laheru, Elana Fertig, Robert Anders, Elizabeth Jaffee, Mark Yarchoan. Programmed cell death ligand-1 (PD-L1) and CD8 expression profiling identifies an immunologic subtype of pancreatic ductal adenocarcinomas with favorable survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3993.
Epidemiology of adult meningitis during antiretroviral therapy scale-up in southern Africa: Results from the Botswana national meningitis survey
Authors: Mark W. Tenforde, Margaret Mokomane, Tshepo Leeme, Nametso Tlhako, Katlego Tsholo, Chandapiwa Ramodimoosi, Bonno Dube, Kelebeletse O. Mokobela, Ephraim Tawanana, Tony Chebani, Tlhagiso Pilatwe, William J. Hurt, Hannah K. Mitchell, Mooketsi Molefi, Paul C. Mullan, Brandon L. Guthrie, Carey Farquhar, Andrew P. Steenhoff, Madisa Mine, Joseph N. Jarvis
Journal: Journal of Infection (2019)
ECOG-ACRIN EAA172: Phase 1/2 study of daratumumab, bortezomib, dexamethasone (DVd) with or without venetoclax in relapsed/refractory multiple myeloma (RRMM) with assessment for t(11;14) status.
Authors: Michael A. Thompson, Susanna J. Jacobus, Shaji Kumar, Murali Janakiram, Sagar Lonial, Matthias Weiss, Natalie Scott Callander, S. Vincent Rajkumar
Journal: Journal of Clinical Oncology (2019)

TPS8052 Background: The most common translocation in multiple myeloma (MM) is t(11;14)(q13;q32), present in approximately 20% of cases. MM cells with t(11;14) usually have a favorable high BCL-2 level and inferior outcomes compared to standard risk MM. Venetoclax (VEN) is a potent, selective, orally available small-molecule BCL-2 inhibitor that induces cell death in MM cell lines and primary samples. VEN has single agent activity in relapsed/refractory MM (RRMM) with an acceptable safety profile, especially in t(11;14) MM; however, non- t(11;14) MM patients may benefit from single agent VEN and VEN incorporated in multi-agent RRMM regimens. Dexamethasone (d) promotes Bcl-2 dependence in MM resulting in sensitivity to VEN and this combination with bortezomib (Vd-VEN) has an acceptable safety profile with high response rates in heavily pre-treated MM. Combination therapy with daratumumab and bortezomib (DVd) has become a standard of care in RRMM. Our hypotheses are that the addition of VEN will improve upon this standard and be most effective in the t(11;14) positive subset. Methods: Eligibility criteria include RRMM with measurable disease, not bortezomib refractory, platelet count &gt; 100K. t(11;14) is an integral biomarker with status (positive or negative) established at registration. After a Ph1 study to determine the recommended phase 2 VEN dose, patients are randomized to DVd +/- VEN [stratified by prior lines of therapy and R-ISS]. The primary Ph2 objectives are to compare 8-cycle minimal residual disease (MRD) negative rate and to inform the role of t(11;14) as a biomarker. The Ph2 design proposed by Freidlin et al. follows a decision algorithm as outlined in the table below. Simulations were run to establish an optimal sample size given various parameters including biomarker prevalence and power to make appropriate decisions for a Ph3 design. Target Ph2 accrual is 240 patients with a 1/3 positive:2/3 negative t(11;14) split. Clinical trial information: NCT03701321. [Table: see text]
Abstract 1326: WSD0922: A BBB penetrable EGFR/EGFRVIII inhibitor for the treatment of GBM and metastatic CNS tumor
Authors: Wei Zhong, Jinqiang Zhang, Ahihua Mu, Claire Sun
Journal: Cancer Research (2019)

Abstract Aberrant activity caused by EGFRm+ (EGFRvIII/Del19/L858R) is implicated in the brain tumors such as GBM and DIPG, and metastatic CNS tumors of NSCLC, and cancer of HNSCC. To date, approved EGFRi has limited efficacy against brain tumors due to insufficient BBB penetration and/or poor activity against EGFRvIII. Moreover, GBM is a whole-brain disease and needs a BBB penetrable therapy for killing tumor cells beyond intact BBB. We report that WSD0922, a novel selective EGFRi, displays potent activity, excellent CNS penetration, good safety profile and preclinical anti-tumor efficacy. The IC50 of WSD0922 against EGFRm+ &amp;lt;10nM and the ex-vivo GI50 in GBM PDX with EGFRvIII is ~20nM. WSD0922 is highly selective over other kinases. WSD0922 treatment resulted in dose dependent inhibition on EGFRvIII phosphorylation and AKT phosphorylation in GBM PDX model and the in vivo PD modulation correlated well with PK and efficacy. WSD0922 treatment significantly prolonged the survival of mice with intracranial tumor of EGFRm+ NSCLC. WSD0922 treatment resulted in tumor regression on cetuximab resistant PDX model of HNSCC. In screening platform of squamous lung cancer PDX models, WSD0922 demonstrated remarkable tumor regression in 3 PDX models (platinum sensitive/insensitive/EGFRm+). WSD0922 is well tolerated in GLP tox at dose ~10x clinical equivalent dose. In addition, WSD0922 is predicted to be CNS penetrable with decent PK in human. The phase 1 clinical trial in US will be initiated in early 2019 with a design of 3+3 basket trial. Taken together, our data provide a good rationale for WSD0922 to be developed toward clinic for the treatment of patients with GBM, HNSCC (EGFR and/or EGFRvIII) and CNS metastasis of NSCLC (EGFRm+). Citation Format: Wei Zhong, Jinqiang Zhang, Ahihua Mu, Claire Sun. WSD0922: A BBB penetrable EGFR/EGFRVIII inhibitor for the treatment of GBM and metastatic CNS tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1326.
Toll‐like receptor 2 stimulation augments esophageal barrier integrity
Authors: Melanie A. Ruffner, Li Song, Kelly Maurer, Lihua Shi, Margaret C. Carroll, Joshua X. Wang, Amanda B. Muir, Jonathan M. Spergel, Kathleen E. Sullivan
Journal: Allergy (2019)

Abstract Background Germline‐encoded innate immune pattern recognition receptors (PRR) are expressed at epithelial surfaces and modulate epithelial defenses. Evidence suggests that stimulation of the Toll‐like receptor (TLR) family of PRR may regulate epithelial barrier integrity by upregulating tight junction (TJ) complex protein expression, but it is not known whether this mechanism is utilized in esophageal epithelial cells. TJ complex proteins maintain intact barrier function and are dysregulated in atopic disorders including eosinophilic esophagitis. Methods Pattern recognition receptors expression was assessed in EoE and control primary esophageal epithelial cells, demonstrating robust expression of TLR2 and TLR3. The three‐dimensional air‐liquid interface culture (ALI) model was used to test whether TLR2 or TLR3 stimulation alters epithelial barrier function using an in vitro model of human epithelium. Transepithelial electrical resistance (TEER) and FITC‐Dextran permeability were evaluated to assess membrane permeability. ALI cultures were evaluated by histology, immunohistochemistry, Western blotting, and chromatin immunoprecipitation (ChIP). Results TLR3 stimulation did not change TEER in the ALI model. TLR2 stimulation increased TEER (1.28‐ to 1.31‐fold) and decreased paracellular permeability to FITC‐Dextran, and this effect was abolished by treatment with anti‐TLR2 blocking antibody. TJ complex proteins claudin‐1 and zonula occludens‐1 were upregulated following TLR2 stimulation, and ChIP assay demonstrated altered histone 4 acetyl binding at the TJP1 enhancer and CLDN1 enhancer and promoter following zymosan treatment, implying the occurrence of durable chromatin changes. Conclusions Our findings implicate the TLR2 pathway as a potential regulator of esophageal epithelial barrier function and suggest that downstream chromatin modifications are associated with this effect.
Performance of differential time to positivity as a routine diagnostic test for catheter-related bloodstream infections: a single-centre experience
Authors: J. Orihuela-Martín, O. Rodríguez-Núñez, L. Morata, C. Cardozo, P. Puerta-Alcalde, M. Hernández-Meneses, J. Ambrosioni, L. Linares, M. Bodro, M. de los Angeles Guerrero-León, A. del Río, C. Garcia-Vidal, M. Almela, C. Pitart, F. Marco, A. Soriano, J.A. Martínez
Journal: Clinical Microbiology and Infection (2019)
HMGB1 expression in SJS/TEN sera and skin
Authors: D.F. Carr, C.‐W. Wang, T. Bellón, L. Ressel, G. Nwikue, V. Shrivastava, W. Bergfeld, A.L. Jorgensen, W.‐H. Chung, M. Pirmohamed
Journal: British Journal of Dermatology (2019)

Stevens Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, severe, skin blistering conditions in which areas of skin die and detach. They actually represent a single disease with a spectrum of severity: less than 10% body surface area detachment in SJS and more than 30% in TEN. It affects around 500 people in the UK each year and is most commonly caused by a reaction to a wide‐range of commonly prescribed drugs. This study brought together researchers and patients from the U.K., Spain, Taiwan and the U.S.A. and aimed to determine levels of a protein called high mobility group box 1 (HMGB1) in the serum (part of the blood), blister fluid and skin biopsy tissue of SJS/TEN patients. HMGB1 is a protein which is known to be a marker (biological sign) of a) tissue/cell injury and b) activation of the immune response, both of which occur in SJS/TEN. The authors detected elevated serum HMGB1 levels in SJS/TEN patients at the time of reaction in three independent patient populations, and also extremely high levels in patients’ blister fluid. Levels of HMGB1 in the epidermal (upper) layer of the skin were considerably decreased in SJS/TEN patients but not healthy control or drug‐induced rash skin. The decrease in HMGB1 levels in the epidermis of the skin appears to occur prior to blistering and may represent an early indicator. In addition, levels of HMGB1 appear to be retained at the junction between the epidermis and the next layer of skin, called the dermis, which may suggest a potential role for HMGB1 in the mechanism by which the layers become detached in SJS/TEN patients. The authors conclude that serum HMGB1 may not represent a good clinical marker of SJS/TEN, but that decreased levels of it in the skin may be a sign of the early onset of skin blistering, and could have a key role in the mechanism by which this occurs.
Adipocyte and lipid metabolism in cancer drug resistance
Authors: Yihai Cao
Journal: Journal of Clinical Investigation (2019)

Development of novel and effective therapeutics for treating various cancers is probably the most congested and challenging enterprise of pharmaceutical companies. Diverse drugs targeting malignant and nonmalignant cells receive clinical approval each year from the FDA. Targeting cancer cells and nonmalignant cells unavoidably changes the tumor microenvironment, and cellular and molecular components relentlessly alter in response to drugs. Cancer cells often reprogram their metabolic pathways to adapt to environmental challenges and facilitate survival, proliferation, and metastasis. While cancer cells' dependence on glycolysis for energy production is well studied, the roles of adipocytes and lipid metabolic reprogramming in supporting cancer growth, metastasis, and drug responses are less understood. This Review focuses on emerging mechanisms involving adipocytes and lipid metabolism in altering the response to cancer treatment. In particular, we discuss mechanisms underlying cancer-associated adipocytes and lipid metabolic reprogramming in cancer drug resistance.
Cardiac, vascular, and hypertension safety of bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia in the BFORE trial.
Authors: Jorge E. Cortes, Tim H. Brümmendorf, Carlo Gambacorti-Passerini, Richard E Clark, Eric Leip, Andrea Viqueira, Vamsi Kota, Michael W.N. Deininger
Journal: Journal of Clinical Oncology (2019)

7051 Background: Tyrosine kinase inhibitor therapy has been linked to cardiac and vascular events. Cardiac, vascular and hypertension treatment-emergent adverse events (TEAEs) with bosutinib or imatinib for newly diagnosed chronic phase chronic myeloid leukemia were analyzed. Methods: Patients (pts) who received ≥1 dose of bosutinib (n = 268) or imatinib (n = 265) 400 mg/d in the phase 3 BFORE trial were included. Prespecified MedDRA terms comprised the clusters of investigator assessed TEAEs. Exposure-adjusted TEAE rate was defined as the number of pts with TEAEs / total pt-yr (pt-yr = sum of total time to first TEAE for pts with TEAEs and treatment duration for pts without TEAEs). Results: After ≥36 mo follow-up, 65% vs 62% of pts in the bosutinib vs imatinib arm were still on treatment. Rates of TEAEs, treatment withdrawals and drug-related TEAEs in the clusters of interest were low in both arms (Table). The most common cardiac, vascular and hypertension TEAEs, respectively, were sinus bradycardia (2%), angina pectoris (3%) and hypertension (7%) vs prolonged QT (3%), peripheral coldness (1%) and hypertension (9%) with bosutinib vs imatinib; corresponding grade 3/4/5 TEAE rates in the respective clusters were 3%, 3% and 4% vs 1%, 0.4% and 4%. Hypertension was the only grade 3/4 TEAE occurring in ≥1% of pts in either arm (4% each); 1 grade 5 TEAE each was noted for bosutinib (cardiac failure) and imatinib (cerebrovascular accident). Exposure-adjusted rates of cardiac, vascular and hypertension TEAEs, respectively, were 0.04, 0.03 and 0.04 vs 0.03, 0.01 and 0.04 (grade 3/4/5 only: 0.01, 0.01 and 0.02 vs 0.01, 0.002 and 0.02) for bosutinib vs imatinib. Conclusions: Cardiac, vascular and hypertension TEAE rates were low with bosutinib and imatinib. A majority of TEAEs were low grade and few led to treatment withdrawal. Clinical trial information: NCT02130557. [Table: see text]
Abstract 1616: Adjuvant supplementation of docosahexaenoic acid with 2-deoxyglucose, metformin, and aspirin on cellular metabolism in breast, lung, and prostate tumor cells
Authors: Irvin V. Ma, Michael Mouradian, Andrew R. Cooper, Erika D. Vicente, Ronald S. Pardini
Journal: Cancer Research (2019)

Abstract A standard treatment for cancer often involves the use of adjuvant supplementation with targeted therapy to maximize tumor suppression. Recent studies have shown that docosahexaenoic acid (DHA; C22:6 n-3), a long chain omega-3 polyunsaturated fatty acid, acts on an array of molecular oncogenes that are often targeted by anti-tumorigenic drugs. After a careful review of DHA’s mechanistic properties, 2-deoxyglucose (2DG), metformin, and aspirin were identified as drugs that share similar molecular targets as DHA. 2DG and metformin both target cellular metabolism by inhibiting intracellular ATP, albeit different mechanisms. 2DG inhibits glycolysis, while metformin targets the mitochondria. Aspirin inhibits inflammation via irreversible acetylation of platelet COX. The current study investigates the effects of DHA in combination with each drug on numerous cancer subtypes to determine if concurrent treatments can synergistically inhibit tumor proliferation. In BT-474 human breast ductal carcinoma, MDA-MB-231 human breast adenocarcinoma, and A549 human lung adenocarcinoma, DHA was shown to enhance the tumor-inhibiting effects of 2DG via intracellular ATP reduction. In contrast, DHA showed no effect with metformin on the same tumor cell lines. With limited studies localizing DHA’s metabolic effects, these results suggest that DHA may have potential selectivity for ATP inhibition via glycolysis. In response to DHA + aspirin, the PC-3 prostate adenocarcinoma and MDA-MB-231 displayed synergistic inhibition of cell viability, while LNCaP prostate carcinoma showed an additive effect. With studies showing DHA’s ability to inhibit endothelial COX, further studies will be done to determine whether the synergistic effects of DHA + aspirin expand to COX expression as well. Moreover, downstream targets of 2DG and metformin will be studied to determine the extent of DHA enhancement on oncogenic targets, such as mTOR, 4EB-P1, and GRB10. The results of this study provide preliminary evidence for the efficacy of adjuvant supplementation with DHA in combination with anti-tumorigenic drugs. With ongoing analysis, the potential for adjuvant nutritional supplementation will allow for additional treatment strategies for future patients. Citation Format: Irvin V. Ma, Michael Mouradian, Andrew R. Cooper, Erika D. Vicente, Ronald S. Pardini. Adjuvant supplementation of docosahexaenoic acid with 2-deoxyglucose, metformin, and aspirin on cellular metabolism in breast, lung, and prostate tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1616.
Abstract 3025: Investigation of AKT3 in the resistance of non-small cell lung cancer to EGFR-TKI
Authors: Shih-Hsiang Huang, Jin-Yuan Shih, Ching-Chow Chen
Journal: Cancer Research (2019)

Abstract Lung cancer is the leading cause of cancer deaths worldwide, and EGFR-TKI is the first-line treatment for non-small cell lung cancer (NSCLC) harboring EGFR activation mutation. However, most patients develop acquired resistance around 12 months. Two resistant cells, HCC827/IR (IRESSA resistance) and H1975/AR (AZD9291 resistance) exhibiting EMT phenotypes were generated to investigate the molecular and cellular characteristics of the EGFR-TKI acquired resistance. The expression and activation of EGFR were reduced in both resistant cells. Upregulation of AXL and FGFR1 were found in HCC827/IR but not H1975/AR cells. HCC827/IR (without T790M) and H1975/AR (without C797S) showed “off target resistance”. Activation of AKT (p-AKT) in both parental cells was more sensitive to EGFR-TKI than that in resistant cells. RNA-seq revealed that AKT3 was upregulated in both resistant cells. High expression of AKT3 was predicted to correlate with the poor survival of lung adenocarcinoma patients. Knockdown of AKT3 in HCC827/IR cells inhibited cell migration and increased the protein expression of E-cadherin, as well as inhibited S phase population to reduce cell proliferation. Knockdown of AKT3 in H1975/AR cells enhanced AZD9291-induced inhibition on AKT activation (p-AKT). Immunoprecipitation of AKT3 in both resistant cells demonstrated its involvement in AKT activation, and AKT3 activation (p-AKT3) was not sensitive to inhibition by gefitinib and AZD9291 in resistant cells. We also found that protein but not mRNA of AKT3 was upregulated in gefitinib-treated HCC827/IR and AZD9291-treated H1975/AR cells. Therefore, AKT3 might serve as a predictive biomarker for EGFR-TKIs therapy, and its upregulation might be one of the mechanisms for EGFR-TKIs acquired resistance. In addition, combination of AZD9291 with AKT inhibitors elicited synergistic inhibition on cell viability of H1975/AR cells. This work was supported by the National Health Research Institutes (NHRI)- NHRI-EX107-10707BI. Citation Format: Shih-Hsiang Huang, Jin-Yuan Shih, Ching-Chow Chen. Investigation of AKT3 in the resistance of non-small cell lung cancer to EGFR-TKI [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3025.