tbuckley/cabot-search huggingface dataset:
Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases
Authors: Antonio Cuadrado, Ana I. Rojo, Geoffrey Wells, John D. Hayes, Sharon P. Cousin, William L. Rumsey, Otis C. Attucks, Stephen Franklin, Anna-Liisa Levonen, Thomas W. Kensler, Albena T. Dinkova-Kostova
Journal: Nature Reviews Drug Discovery (2019)
A novel method for identifying downstream signals in tumor-reactive T cells following PD-1 engagement and monitoring endogenous tumor immunity and immunotherapy.
Authors: Haidong Dong, Wei Zhao, Christopher J Krco, Svetomir Markovic, Aaron Scott Mansfield, Kenneth R Olivier, Sean Sunghun Park, Eugene D. Kwon
Journal: Journal of Clinical Oncology (2014)

3049 Background: Therapies targeting programmed cell death 1 (PD-1) or its ligand B7-H1 (aka PD-L1) have yielded promising therapeutic effects in various solid and hematologic malignancies. A reliable method to determine whether PD-1 on T cells has engaged its ligand B7-H1 on tumor cells is highly desirable as it may have significance as a predictive marker for PD-1 targeted therapy. Methods: Endogenous tumor-reactive CD8+ T cells were identified by their high expression of PD-1 and CD11a CD8+ T cells and their expression of Bim, a pro-apoptotic molecule, in the peripheral blood of 26 patients with metastatic melanoma and 11 patients with metastatic prostate cancer or healthy donors using flow cytometry. Soluble PD-L1 in patients’ sera was quantified using ELISA. Results: The target-cell engaged CD8+ T cell population was significantly higher in patients with melanoma and prostate cancer compared to healthy donors, as assessed by CD11a and PD-1 expression. Bim expression was higher in CD8+ T cells in both cancer patients than healthy controls (p<0.01). In patients with advanced melanoma, Bim was significantly higher in the PD-1(+) target cell-engaged CD8+ T cells than the PD-1(-) CD-8+ T cells (P<0.01). Bim levels above the base line levels of healthy donors in the CD8+ T cells correlated with decreased survival in patients with melanoma (8.9 months v. 13.8 months, p<0.05). Our data suggest that the Bim level is dependent on PD-1 expression, and that higher Bim expression may be indicative of PD-1(+) CD8+ T cells which have engaged B7-H1 (PD-L1), either soluble (peripheral blood) or membrane bound (tumor cells), and are susceptible to apoptotic death. Conclusions: PD-1+ CD11a high CD8+ T cells identify a unique population of effector cells responsive to target tumor cells in cancer patients. Elevated Bim expression in CD8+ T cells may indicate the active immune inhibiting effects of PD-1/B7-H1 signaling on endogenous antitumor T cell responses. Bim expression can serve as a signaling biomarker for PD-1 function and may be useful in selecting patients who may benefit from checkpoint blockade therapy.
SLC7A5, SLC7A7, SLC7A8 and TDO2 in basal cell carcinoma
Authors: E. Tina, S. Prosén, S. Lennholm, G. Gasparyan, M. Lindberg, A. Göthlin Eremo
Journal: British Journal of Dermatology (2019)

Basal cell carcinoma (BCC) is the most common non-malignant skin cancer and the number of patients with BCC is increasing worldwide. Despite variations between carcinomas, some tumour-specific changes can be found across all cases. These changes may include expression of tumour specific factors that could help doctors diagnose a BCC or predict its development, which consequently could lead to the development of new target medicines. In our study, we compared gene expressions in basal cell carcinomas with healthy skin. Gene expression is the process by which specific genes are activated to produce a required protein. Essentially, a cell will express certain genes depending on what the role of the cell will be. The authors of this study used microarray, a method allowing analysis of thousands of genes in one single sample. Among the results they found higher expression of genes involved in transport of amino acids (e.g. SLC7A5, SLC7A7 and SLC7A8) and amino acid metabolism (TDO2) to be of further interest. Tumour cells often depend on altered energy usage and need access to building blocks for growth. When comparing the basal cell carcinomas with healthy skin, the genes SLC7A5, SLC7A8 and TDO2 were significantly upregulated (increased) in the carcinomas. The authors could not prove that there was higher gene expression of SLC7A7. Looking at the cellular origin of the four genes, they found that proteins SLC7A5 and SLC7A8 were expressed by the tumour cells while TDO2 was mainly found in the surrounding tissue and in immune cells. The SLC7A7 protein was located in stratum granulosum, which is a thin layer of cells in the outermost layer of skin called the epidermis. SLC7A7 is not likely involved in carcinogenesis (cancer development). In conclusion, the authors identified several proteins with a potential role in BCC that may be potential targets for special drugs, but further research is needed.
Safety and Efficacy of Blinatumomab in Patients with Central Nervous System (CNS) Disease: A Single Institution Experience
Authors: Mansour Alfayez, Hagop M. Kantarjian, Nicholas J Short, Rita Assi, Maria Khouri, Farhad Ravandi, Shilpa Paul, Caitlin R. Rausch, Patrice Nasnas, Gautam Borthakur, Courtney D. DiNardo, Tapan M. Kadia, Naval G. Daver, Guillermo Garcia-Manero, Kiran Naqvi, Prithviraj Bose, Susan M. O'Brien, Jorge E. Cortes, Elias J. Jabbour
Journal: Blood (2018)
Qualitative Study of Factors That Influence Treatment Decision-Making Among Community Oncologists and Older Patients with Acute Myeloid Leukemia
Authors: Kah Poh Loh, Sindhuja Kadambi, Supriya G. Mohile, Jason H. Mendler, Jane L. Liesveld, Kristen M. O'Dwyer, Michael W. Becker, Colin M. McHugh, Marsha Wittink, Wendy Stock, Navneet S. Majhail, Tanya Wildes, Paul Duberstein, Heidi D. Klepin
Journal: Blood (2018)
A phase IB study of ipilimumab with peginterferon alfa-2b for patients with unresectable stages IIIB/C/IV melanoma.
Authors: Ragini Reiney Kudchadkar, Geoffrey Thomas Gibney, Denise Dorman, Stephanie Merek, Howida Ramadan, Ann Chen, Jeffrey S. Weber
Journal: Journal of Clinical Oncology (2014)

9098 Background: Peginterferon alfa-2b (Sylatron) as adjuvant therapy has been shown to benefit patients with resected melanoma and interferon studies have shown that the induction of autoantibodies may correlate with benefit. Ipilimumab (IPI, Yervoy) is an anti-CTLA-4 antibody that induces immune-related toxicity that may correlate with clinical benefit. This abstract is an update of previously presented data. Methods: This studycombined IPI at 3mg/kg every 3 weeks for 4 doses along with concurrent peginterferon alfa-2b at 3 mcg/kg weekly for up to 156 weeks or until disease progression, unacceptable toxicity, or patient decision to discontinue. The study was designed to obtain toxicity, tolerability, and autoimmune antibody data and to define a well-tolerated dose of the combination. Results: 31 patients were treated with13 female and 18 male subjects. Median age was 65. There were 2 CRs, 9 PRs, 3 with stable disease, and 12 with progressive disease in 26 pts evaluable for response thus far. Five pts have not yet completed cycle 1 and therefore are not evaluable for response at the time of this publication but will be presented. Toxicities from peginterferon alfa-2b 3mcg/kg were dose-limiting with 7 pts requiring dose reduction in peginterferon alfa-2b secondary to toxicity. The grade 3 events leading to dose reductions were nausea and vomiting, leucopenia, dehydration, and hyponatremia. Peginterferon alfa-2b was dose reduced to 2 mcg/kg weekly in future pts after these toxicities were noted. In the subsequent patients grade 3 related events included rash (n = 4), pruritis (2), colitis (1), fatigue (2), and hypothyroidism (1). There was no significant change in the presence autoantibodies (ANA, anti-double stranded DNA, antithyroglobulin, antimicrosomal antibodies, and anticardiolipin antibodies) between responders and nonresponders in the evaluable pts. Conclusions: Peginterferon alfa-2b added to IPI results in an excellent response rate of 42.3% in this population. Peginterferon alpha-2b at 2 mcg/kg weekly with IPI at 3 mg/kg every 3 weeks is tolerated well though 20% of patients treated at this dose experienced grade 3 rash. Based on a clinical benefit rate (CR + PR + SD) of 53.8 %, this combination warrants further exploration. Clinical trial information: NCT01496807.
Stearoyl-CoA Desaturase (SCD) Enhances Central Nervous System Leukemia
Authors: Angela Maria Savino, Orianne Olivares, Shani Barel, Lev Yakimov, Ifat Geron, Hila Fishman, Inbal Mor, Ifat Abramovich, Sara Isabel Fernandes, Eyal Gottlieb, Christina Halsey, Shai Izraeli
Journal: Blood (2018)
Estimating the cost burden of adverse effects associated with metastatic melanoma therapies in Italy.
Authors: Ursula Benter, Katja Vouk, Mayur Amonkar, Alessia Marocco
Journal: Journal of Clinical Oncology (2014)

e17532 Background: Targeted therapy (TT), immunotherapy (IT), and chemotherapy (CT), which are commonly used in the treatment of MM, are frequently associated with adverse effects (AEs). This study estimated the per-event cost and overall cost burden associated with managing the most common and/or severe AEs for these 3 treatment categories from the Italian national healthcare system perspective. Methods: A literature review was conducted to evaluate the incidence and types of AEs associated with the 3 treatment categories. A total of 29 AEs (CT:11; TT:11; and IT:7), all-severity grades (Gr) occurring in >20% or Gr 3/4 occurring in >5%, were selected. Medical resource use related to the management of AEs was assessed by conducting 2 blinded Delphi panel cycles with 8 clinicians. The costs per AE were estimated using published unit costs and then combined with AE incidence (assuming 1 occurrence/patient) treatment usage, and 1-year prevalence of MM (498 cases) to estimate the treatment burden in Italy for a single AE occurrence. Results: The Table presents the top 3 cost-intensive AEs within each treatment category. Across all 3 treatment categories, the top 4 AEs with the highest overall burden on a population level were all Gr 3/4, were associated with CT or IT, and included neutropenia/leukopenia (mean total cost of €11,948), thrombocytopenia (€4579), diarrhea (€4514), and immune-related hypophysitis (€4288). Conclusions: In Italy, per-event costs for management of AEs associated with MM therapies can be substantial. The overall cost burden is likely to be underestimated since it does not account for AE recurrence. Treatment category and AEs Cost of each occurrence, € Mean ± SD Range Targeted therapy Rash, Gr 3/4 103.03 ± 67.20 21.88-186.29 Squamous cell carcinoma, Gr 3/4 92.17 ± 110.86 6.82-254.97 Skin papilloma, Gr 1/2 36.04 ± 10.99 21.03-46.99 Immunotherapy Immune-related hypophysitis, Gr 3/4 405.23 ± 140.34 250.54-524.39 Diarrhea, Gr 3/4 331.78 ± 337.99 53.66-707.96 Colitis, Gr 3/4 183.98 ± 109.98 71.54-291.32 Chemotherapy Neutropenia/leukopenia, Gr 3/4 803.82 ± 604.95 105.85-1177.18 Anaphylaxis, Gr 3/4 712.39 ± 456.70 192.17-1047.39 Thrombocytopenia, Gr 3/4 514.52 ± 364.10 132.20-857.15
Abstract 18824: Impact of Diabetes Mellitus on the Pharmacodynamic Effects of Prasugrel and Ticagrelor After Switching From Clopidogrel in Patients With Coronary Artery Disease
Authors: Fabiana Rollini, Jose Rivas, Deepa Nagaraju, Jae Youn Moon, Andrea Rivas, Malhar Agarwal, Megha Kureti, Latonya Been, Siva Suryadevara, Martin M Zenni, Theodore A Bass, Dominick J Angiolillo, Francesco Franchi
Journal: Circulation (2017)

Introduction: Patients with diabetes mellitus (DM) are at increased risk of atherothrombotic events due to their prothrombotic milieu and reduced response to antiplatelet agents, including clopidog...
Randomized trial on thoracic radiotherapy (TRT) in extensive-stage small cell lung cancer.
Authors: Ben J. Slotman, Corinne Faivre-Finn, Harm van Tinteren, John Praag, Joost Knegjens, Sherif El Sharouni, Matthew Hatton, Astrid Keijser, Suresh Senan
Journal: Journal of Clinical Oncology (2014)

7502 Background: Prophylactic cranial irradiation (PCI) reduces the risk of brain metastases and improves survival in ES-SCLC after response to chemotherapy. As a majority of patients have intrathoracic disease after chemotherapy, this randomized study assesses the role of TRT in ES-SCLC. Methods: Patients (WHO 0-2) with confirmed ES-SCLC with a response after 4-6 cycles of standard chemotherapy were randomized to receive TRT (30 Gy/10fx) or no TRT. All received PCI. Primary study endpoint was overall survival. Acute toxicity was graded using CTCAE v3.0. The study had 80% power to detect a hazard ratio of 0.76 at 1 year (2-sided 5% signif.). Accounting for 5% dropout before treatment, 483 patients had to be randomized. Analysis was based on intent to treat. Results: Between Feb’09 and Dec’12, 498 patients were enrolled (249 per arm); Median follow-up was 24 months. 88% had residual intrathoracic disease. Baseline characteristics were well balanced. Mean age was 63 year (range 36-85), 89% had WHO 0-1; 11% WHO2. Mean interval between start of chemotherapy and randomization was 16 weeks. Three patients subsequently withdrew informed consent leaving 247 (TRT) versus 248 patients (control arm). In the TRT arm, 5 patients did not receive TRT due to progression or refusal. No severe toxicities were observed. At the time of analysis (Dec’13), 76 patients were still alive. Progression-free survival was longer in the TRT-arm (HR=0.73, CI 0.61-0.87; p=0.001). Curves for overall survival overlapped during the first 9 months and then diverged in favour of the TRT-arm. The survival difference at 1 year was not statistically significant (33% vs 28%; HR=0.84, CI 0.69-1.01; p=0.066). Survival at 2 years was 13% (CI 9-19) for the TRT and 3% (CI 2-8%) for the control arm (P=0.004). Conclusions: TRT improves progression-free survival. Although TRT did not influence the risk of death in the first year, it led to a significant increase in 2-year survival. TRT should therefore be offered to all ES-SCLC patients with a response to initial chemotherapy. This study was supported by grants from the Dutch Cancer Society (CKTO) and Cancer Research UK and supported by the Dutch Lung Cancer Research Group and The Christie NHS Foundation Trust Clinical Trials Unit. Clinical trial information: NTR1527.
Lymph node biopsy utilization in lymphoma: Analysis of U.S. commercial health care claims data.
Authors: Benjamin Chastek, Stacey DaCosta Byfield, Carolyn Bodnar
Journal: Journal of Clinical Oncology (2014)

e17643 Background: NCCN guidelines recommend pathological assessment of lymphatic tissue to diagnose and manage lymphoma patients. We examined the clinical frequency and lymph node biopsy type in patients diagnosed with lymphoma over 2 years. Methods: Patients with ≥2 claims for Hodgkin (HL) or non-Hodgkin’s (NHL) lymphoma from 1/1/06-12/31/12 were identified from a national US health plan database; the index date was the first lymphoma claim date. Patients were included if continuously enrolled in the health plan at least 12 months before/after the index date, were not diagnosed with lymphoma during the pre-index period and were not diagnosed with another cancer. The type and count of lymph node biopsy (bone marrow excluded) were examined for the study period. Indication of receipt of biopsy was ≥1 claim for lymph node biopsy (core needle, fine needle, complex surgical, simple surgical, other), pathology or tumor excision. Surgical biopsies were considered complex if they required general anesthesia or an inpatient stay ≥1 day. Patients with multiple biopsies (≥3 biopsy claims), a change from the index diagnosis or with a biopsy specimen sent for outside consultation were identified. Results: 20,813 newly diagnosed lymphoma patients met all inclusion criteria. 12,920 (62%) had ≥2 procedures, 8,783 (42%) ≥3 and 5,359 (26%) ≥4. Of patients with evidence of biopsy 13% had fine needle, 13% core needle, 29% simple surgical, 5% complex surgical, 10% other biopsy, 6% excision and 99% pathology (not mutually exclusive so do not add to 100%). 124 patients had a mediastinum and 55 patients had a thoracoscopy. On average, patients with evidence of biopsy had 3.1 procedures. 12% of all 20,813 patients had a change in diagnosis (7% NHL to HL, 42% HL to NHL), and 15% had a biopsy sample sent for outside consult. Conclusions: This claims analysis demonstrates that diagnosing lymphoma patients incurs significant biopsy utilization. A large percent of patients (62% ≥2, 42% ≥3) diagnosed with lymphoma undergo multiple lymph node assessment to obtain diagnosis. 12% of initial diagnoses were changed upon further evaluation. Improved diagnostic and monitoring tools may reduce repeat biopsy, obtain accurate diagnosis earlier and reduce related costs.
Detection of mild cognitive impairment in middle-aged and older adults with obstructive sleep apnoea: does excessive daytime sleepiness play a role?
Authors: Katia Gagnon, Nadia Gosselin
Journal: European Respiratory Journal (2019)

<b>Sleepiness does not affect the prevalence and subtype of mild cognitive impairment, and discriminative ability of cognitive screening tests in detecting mild cognitive impairment</b>http://ow.ly/se9u30mMtYc
Abstract 17750: A CPVT Mutation Confers Gain of Function to the Cardiac Ryanodine Receptor Channel. Characterization Using Cardiomyocytes Derived From Patient-Specific Ips Cells
Authors: Jonathan J Hernández, Todd Herron, José Jalife, Kathleen Maginot, Jianhua Zhang, Timothy Kamp, Héctor H Valdivia
Journal: Circulation (2013)

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a primary electrical myocardial disease characterized by adrenergic-induced ventricular tachycardia in young people. Mutations in the...
Pancreatitis with vascular endothelial growth factor receptor tyrosine kinase inhibitors.
Authors: Pooja Ghatalia, Charity Morgan, Toni K. Choueiri, Pedro Rocha, Gurudatta Naik, Guru Sonpavde
Journal: Journal of Clinical Oncology (2014)

e13547 Background: Vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) are anecdotally reported to cause pancreatitis. In order to quantitate the risk of pancreatitis associated with all of the currently approved VEGFR TKIs, we performed a systematic review and trial-level meta-analysis of publicly available randomized trials of VEGFR TKIs. Methods: MEDLINE, conferences and clinicaltrials.gov databases were searched for articles published from January 1966 to December 2013. Eligible studies included randomized phase II and III trials comparing arms with and without an US FDA-approved VEGFR TKI (sunitinib, sorafenib, pazopanib, axitinib, vandetanib, cabozantinib, ponatinib, regorafenib). Trials listing clinical pancreatitis as an adverse event in any arm were included. Data abstraction was conducted according to the PRISMA statement and the relative risk (RR) and 95% confidence intervals (CI) were calculated using random-effects or fixed-effects models based on heterogeneity. Trial quality was graded by the Jadad score. Results: A total of 10,578 patients from 16 phase III trials and 6 phase II trials were selected. All-grade pancreatitis occurred in 25 of 5569 patients receiving VEGFR TKIs and in 7 of 5009 patients in the non-TKI group. High grade pancreatitis occurred in 22 of 5051 patients receiving VEGFR TKIs and in 6 of 4486 patients in the non-TKI group. The pooled estimate of RR for all and high-grade pancreatitis for the TKI vs. no-TKI arms was 1.95 (p = 0.042, 95% CI: 1.02 to 3.70) and 1.89 (p = 0.069, 95% CI: 0.95 to 373), respectively. Pancreatitis was not reported in randomized trials of 3 newer VEGFR TKIs (regorafenib, ponatinib, cabozantinib). All trials exhibited high quality (Jadad score 3–5). No evidence of publication bias was detected for all grade or high-grade pancreatitis (p > 0.20 for both using the Egger test). Similarly, there was no evidence of heterogeneity in all or high-grade pancreatitis. Conclusions: VEGFR TKIs are associated with an increased overall risk of pancreatitis, although the incidence appears low. Better patient selection and monitoring may mitigate the risk of pancreatitis.
Prevalence of Severe Visual Disability Among Preterm Children With Retinopathy of Prematurity and Association With Adherence to Best Practice Guidelines
Authors: Mikael Norman, Ann Hellström, Boubou Hallberg, Agneta Wallin, Pelle Gustafson, Kristina Tornqvist, Stellan Håkansson, Gerd Holmström
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Retinopathy of prematurity (ROP) can cause severe visual disability even in high-resource settings. A better understanding of the prevalence and processes leading to ROP-induced severe visual impairment may help health care professionals design preventive measures. <h3>Objectives</h3> To determine the prevalence of severe visual disability among children born preterm in Sweden, evaluate adherence to best practice, and determine the health system’s structural capacity. <h3>Design, Setting, and Participants</h3> Population-based, nationwide cohort study of 1 310 227 children born between January 1, 2004, and December 31, 2015, in Sweden, of whom 17 588 (1.3%) were born very preterm (&lt;32 weeks of gestation). Children born preterm with a verified diagnosis of severe visual disability had their medical records reviewed for evaluation of ROP screening, diagnosis, and treatment. In addition, a questionnaire on structural capacity was sent to all ophthalmology departments. <h3>Exposures</h3> Stages 4 and 5 ROP. <h3>Main Outcomes and Measures</h3> The primary outcome was prevalence of severe visual disability (visual acuity ≤20/200 for both eyes) associated with ROP stages 4 and 5. Secondary outcomes included adherence to national ROP guidelines using a predefined protocol with 15 key performance indicators for screening, diagnosis, and treatment; assessment of whether visual disability was deemed avoidable; and examination of structural capacity, including information on equipment and facilities, staffing, and patients. <h3>Results</h3> Seventeen children (10 boys; mean [range] birth weight, 756 [454-1900] g; mean [range] gestational age, 25 [22-33] weeks) became severely visually disabled because of ROP, corresponding to a prevalence of 1 in 1000 very preterm infants (&lt;32 weeks of gestational age) and 1 in 77 000 for all live births. Severe visual impairment was considered potentially avoidable in 11 of 17 affected children (65%) owing to untimely or no screening, missed diagnosis, or untimely and suboptimal treatment. Large variations in infrastructure (facilities, guidelines, staffing, and annual patient numbers) were also identified as potential contributors to these findings. <h3>Conclusions and Relevance</h3> Retinopathy of prematurity still causes severe visual disability in Sweden, resulting in 1 affected infant per 1000 very preterm births. In most of these infants, noncompliance with best practice was identified, indicating that a significant proportion could have been avoided.