tbuckley/cabot-search huggingface dataset:
BPI19-015: Reduction of Inappropriate Prophylactic Pegylated Granulocyte Colony-Stimulating Factor (pGCSF) Use for Lung Cancer Patients: Five-Year Follow Up of a Quality Improvement (QI) Initiative at the Cleveland Clinic Taussig Cancer Institute (TCI)
Authors: Anne K. Hubben, Nathan Pennell, Marc Shapiro, Craig Savage, James P. Stevenson
Journal: Journal of the National Comprehensive Cancer Network (2019)

Purpose: National guidelines do not include routine pGCSF as primary prophylaxis (PP) for patients receiving chemotherapy associated with a low risk for febrile neutropenia (FN). Inappropriate pGCSF can increase patient morbidity, financial burden, and overall health care costs. In 2013, an interdisciplinary group at TCI implemented a QI project to reduce inappropriate PP pGCSF in patients with lung cancer; this included prescriber education and modification of chemotherapy orders by risk of FN in the electronic medical record (EMR). Inappropriate pGCSF was reduced from 28% to 4%. In this 5-year follow up study we analyzed pGCSF use in lung cancer patients. Methods: We conducted a review of lung cancer patients who received pGCSF with chemotherapy initiated between January 2016 and August 2018. PP pGCSF use was appropriate if prescribed with chemotherapy regimens with a high risk (&gt;20%) for FN, or intermediate risk (10%–20%) if other accepted FN risk factors were present. PP use with FN low-risk (&lt;10%) chemotherapy was considered inappropriate. Treating physicians were anonymously surveyed about their practices. Results: 294 patients with lung cancer received 1,353 doses of pGCSF during the study period. 58 (20%) were treated at TCI by subspecialty thoracic oncologists and 236 (80%) were treated at regional network sites. 100/294 (34%) patients received low-risk regimens. 62/100 (62%) patients treated with low-risk regimens received 311 doses of PP pGCSF (inappropriate use). 5/62 (8%) of inappropriate use occurred at TCI; 57/62 (92%) at network sites. Of 130 patients who received an intermediate risk regimen, 99 (76%) received PP pGCSF. At least one risk factor for FN was identified in 80/99 (80%) of these patients; age &gt;65 and prior chemotherapy or radiation were the top-cited factors. 33/294 (11%) patients were hospitalized for FN during the study period; 7/100 (7%) received low-risk regimens, 15/130 (11.5%) intermediate-risk, and 11/46 (24%) high-risk regimens. All physicians responding to the survey indicated awareness of guidelines and EMR risk identification. Conclusion: After initial success at our center, we found that guideline-based alignment of pGCSF prescribing in lung cancer patients was not sustained. Despite reported familiarity with guidelines for PP pGCSF use, this analysis suggests an opportunity for re-education and further EMR modification. Based on July 2018 CMS average sales price, reduction in inappropriate use presents a potential cost savings of $1.5 million during the study.
A Structural Change in Butyrophilin upon Phosphoantigen Binding Underlies Phosphoantigen-Mediated Vγ9Vδ2 T Cell Activation
Authors: Yunyun Yang, Liping Li, Linjie Yuan, Xiaoying Zhou, Jianxin Duan, Hongying Xiao, Ningning Cai, Shuai Han, Xianqiang Ma, Weidong Liu, Chun-Chi Chen, Lingle Wang, Xin Li, Jiahuan Chen, Ning Kang, Jing Chen, Zhixun Shen, Satish R. Malwal, Wanli Liu, Yan Shi, Eric Oldfield, Rey-Ting Guo, Yonghui Zhang
Journal: Immunity (2019)
Abstract 18235: Treatment of Small Vessel Disease (<2.5mm) With a Placlitaxel Eluting Balloon: 6 Months Outcomes of the Spanish Multicenter Registry
Authors: Beatriz Vaquerizo, Antonio Serra, Faustino Miranda-Guardiola, Vanesa Martínez, Josep Antoni Gomez-Hosp, Angel Cequier, Andres Iñiguez, Jose Antonio Baz, Guillermo Bastos, Eduard Fernandez, Oriol Rodriguez, Josepa Mauri, Mario Sabada, Jose Antonio Rumoro, Antonio Subinas, Rafael Garcia-Borbolla, Antonio Gomez, Jesus Oneto, Antonio Martinez, Francisco Bossa, Sara Rodriguez, Raul Moreno, Alejandro Saez, Eduardo Pinar, Mariano Valdes, Inmanol Oategui, Bruno Garcia, Juan Angel
Journal: Circulation (2010)

Backgroung: Independently of the type of percutaneous coronary intervention (balloon angioplasty and/or stenting with BMS/DES): coronary vessel size (small) is a strong predictor for restenosis fol...
Evolutionary Trajectories of IDHWT Glioblastomas Reveal a Common Path of Early Tumorigenesis Instigated Years ahead of Initial Diagnosis
Authors: Verena Körber, Jing Yang, Pankaj Barah, Yonghe Wu, Damian Stichel, Zuguang Gu, Michael Nai Chung Fletcher, David Jones, Bettina Hentschel, Katrin Lamszus, Jörg Christian Tonn, Gabriele Schackert, Michael Sabel, Jörg Felsberg, Angela Zacher, Kerstin Kaulich, Daniel Hübschmann, Christel Herold-Mende, Andreas von Deimling, Michael Weller, Bernhard Radlwimmer, Matthias Schlesner, Guido Reifenberger, Thomas Höfer, Peter Lichter
Journal: Cancer Cell (2019)
A Global Dialogue on Withholding and Withdrawal of Medical Care: An East Asian Perspective
Authors: Eisuke Nakazawa, Keiichiro Yamamoto, Reina Ozeki-Hayashi, Akira Akabayashi
Journal: The American Journal of Bioethics (2019)

This article refers to:Withholding and Withdrawing Life-Sustaining Treatment: Ethically Equivalent?Withdrawal Aversion and the Equivalence Test
Pulmonary Arteriovenous Malformations
Authors: Peter B. Terry, Robert I. White, Klemens H. Barth, Stephen L. Kaufman, Sally E. Mitchell
Journal: New England Journal of Medicine (1983)

Pulmonary arteriovenous malformations can result in severe hypoxemia and dyspnea. We measured pulmonary function, arterial blood gases, and hemodynamics in 10 patients with such malformations. Pulmonary-function tests were normal, but hypoxemia was associated with chronic hyperventilation at rest (mean, 12 liters per minute; mean carbon dioxide tension, 28 mm Hg). With exercise, ventilation increased more than expected for the level of carbon dioxide production. Balloon embolization of 58 of the 71 visible vascular malformations in the 10 patients resulted in an increase in arterial oxygen tension (43 vs. 64 mm Hg; P less than 0.001) and hemoglobin saturation (79 vs. 92 per cent; P less than 0.001). Nine patients had improved exercise tolerance. Forty-eight to 72 hours after correction of the hypoxemia, resting ventilation had decreased but was still above normal (mean, 9.3 liters per minutes; mean carbon dioxide tension, 29 mm Hg). We conclude that ventilatory responses in these patients are similar to those of people from sea-level areas who are acclimated to high altitudes and that dyspnea is due to inappropriately high levels of ventilation for a given workload under hypoxic conditions.
Identifying Biological Predictors of Early Saphenous Vein Graft Failure: A Meta-Analysis of 5134 Patients With Angiographic Follow Up in SAFINOUS-CABG Collaborative Group
Authors: Evangelos K Oikonomou, Ayodele Odutayo, Ioannis Akoumianakis, Alexios Antonopoulos, Sheena Thomas, Laura Herdman, Marialena Trivella, Gary Collins, Mario Petrou, Keith Channon, Charalambos Antoniades
Journal: Circulation (2016)

Introduction: Early failure of saphenous vein grafts (SVG) used in coronary artery bypass grafting (CABG) is often attributed to technical factors. We explore the contribution of biological factors...
CLO19-047: Jeopardizing the Oncological Safety: Transurethral Resection of Bladder Tumor May Induce Measurable Hematogenous Seeding of Cancer Cells
Authors: Sumit Saini, Rishi Nayyar, Alpana Sharma, Prem Nath Dogra
Journal: Journal of the National Comprehensive Cancer Network (2019)

Objectives: Transurethral resection of bladder tumour (TURBT) is a standard procedure for both diagnosis and management of bladder cancer. Intravesical seeding of cells shed during TURBT supposedly plays an important role in tumor recurrences. This may be due to the inherent nature of the procedure, which refutes the basic oncological principle and demands for piecemeal resection. Additionally, high pressure of irrigation fluid during TURBT has the treacherous potential for systemic absorption of tumor cells into circulation and metastatic tumor seeding. By measuring circulating tumor cells (CTC) before and after TURBT, it may be possible to ascertain whether TURBT induces measurable seeding of cancer cells into the circulation. Methods: All consecutive patients undergoing TURBT for newly diagnosed bladder mass were enrolled. Cases with resection time less than 10 min, prior intravesical or radiation therapy, chronic cystitis, neurogenic bladder, metastatic disease at presentation, and final histology other than transitional cell carcinoma were excluded. Peripheral venous blood samples were drawn before and after (within 2 hours) of TURBT, and analyzed using flow-cytometry to ascertain the number of CTC. The peripheral blood mononuclear cells were separated, suspended in FACSTM buffer, stained with specific antibodies to CD-45, EpCam, Cytokeratin 18 &amp; 19, and immediately acquired on a FACSCantoTM II cytometer (BD Biosciences, 4-2 configuration). A cell positive for cytokeratins 18, 19 &amp; EpCam and negative for expression of CD45 was defined as a CTC. The number of CTC in pre and postoperative samples were compared and correlated to the final histopathology. Results: 32 patients were studied. No perforations were encountered. 4/32 (12.5%) patients had raised CTC count following TURBT. All 4 of these patients had high grade and at least T2 (ie, muscle invasive) disease. Overall, rise in CTC count was seen in 4/8 patients (50%) with muscle invasion and 4/13 cases (30.79%) with high-grade disease. There was no significant difference in the average resection time between the group showing rise in CTC versus the other (34 vs 32 .5 minutes, respectively; P =.43). Conclusions: This study provides objective evidence that tumor cells are released into the circulation during TURBT and are detectable in peripheral venous circulation. This occurs predominantly in patients with higher grade and higher stage disease.
YIA19-005: Immunotherapy for Prostate Cancer Combining CAR-Engineered T Cells with Targeted Immune Checkpoint Inhibition
Authors: Saul J. Priceman, Stephen J. Forman
Journal: Journal of the National Comprehensive Cancer Network (2019)

Repairing defects in antitumor immunity has been a longstanding challenge in prostate cancer, and in recent years cellular immunotherapy has emerged as a promising approach for controlling advanced disease. To date, therapies including tumor vaccine and adoptive T-cell immunotherapy have made remarkable headway in solid cancers. Several validated prostate-specific tumor antigens are available as targets for T-cell therapy, including prostate stem cell antigen (PSCA), which is overexpressed in metastatic disease. We are in late-stage preclinical development of PSCA-specific chimeric antigen receptor (CAR)-engineered T cells with plans to initiate a clinical trial early 2019 for the treatment of metastatic castration-resistant prostate cancer. Immune checkpoint pathways, including the programmed cell death protein-1 (PD-1) and the cytotoxic T lymphocyte-associated protein-4 (CTLA4), have emerged as critical drivers of immunosuppression in solid cancers, by limiting both adaptive antitumor immunity as well as adoptive T-cell therapies. Unfortunately in prostate cancer, checkpoint inhibition has led to underwhelming responses, likely due to the low mutational load and immunologically “cold” tumor microenvironment. We hypothesize that antitumor activity of PSCA-CAR T cells will elicit checkpoint pathways that dampen antitumor immune responses and reduce overall clinical outcomes. Herein, we utilize an shRNA approach to knockdown checkpoint receptors as a rational combinatorial strategy that targets checkpoint pathways to improve overall therapy with PSCA-CAR T cells for metastatic prostate cancer. We have successfully developed a multiple shRNA knockdown approach to simultaneously disrupt 3 pathways that may hamper CAR T-cell activity in the tumor. These CAR T cells with shRNA knockdown of checkpoint receptors will be directly compared with checkpoint pathway inhibitor antibody therapies in xenograft models of prostate cancer, with the hope that next generation CARs will resist this break on the immune system in solid tumors.
RhoBTB1 protects against hypertension and arterial stiffness by restraining phosphodiesterase 5 activity
Authors: Masashi Mukohda, Shi Fang, Jing Wu, Larry N. Agbor, Anand R. Nair, Stella-Rita C. Ibeawuchi, Chunyan Hu, Xuebo Liu, Ko-Ting Lu, Deng-Fu Guo, Deborah R. Davis, Henry L. Keen, Frederick W. Quelle, Curt D. Sigmund
Journal: Journal of Clinical Investigation (2019)

Mice selectively expressing PPARγ dominant negative mutation in vascular smooth muscle exhibit RhoBTB1-deficiency and hypertension. Our rationale was to employ genetic complementation to uncover the mechanism of action of RhoBTB1 in vascular smooth muscle. Inducible smooth muscle-specific restoration of RhoBTB1 fully corrected the hypertension and arterial stiffness by improving vasodilator function. Notably, the cardiovascular protection occurred despite preservation of increased agonist-mediated contraction and RhoA/Rho kinase activity, suggesting RhoBTB1 selectively controls vasodilation. RhoBTB1 augmented the cGMP response to nitric oxide by restraining the activity of phosphodiesterase 5 (PDE5) by acting as a substrate adaptor delivering PDE5 to the Cullin-3 E3 Ring ubiquitin ligase complex for ubiquitination inhibiting PDE5. Angiotensin-II infusion also caused RhoBTB1-deficiency and hypertension which was prevented by smooth muscle specific RhoBTB1 restoration. We conclude that RhoBTB1 protected from hypertension, vascular smooth muscle dysfunction, and arterial stiffness in at least two models of hypertension.
The Critical Role of RNA m6A Methylation in Cancer
Authors: Qing Lan, Pei Y. Liu, Jacob Haase, Jessica L. Bell, Stefan Hüttelmaier, Tao Liu
Journal: Cancer Research (2019)

Since the identification of the first RNA demethylase and the establishment of methylated RNA immunoprecipitation-sequencing methodology 6 to 7 years ago, RNA methylation has emerged as a widespread phenomenon and a critical regulator of transcript expression. This new layer of regulation is termed "epitranscriptomics." The most prevalent RNA methylation, N6-methyladenosine (m6A), occurs in approximately 25% of transcripts at the genome-wide level and is enriched around stop codons, in 5'- and 3'-untranslated regions, and within long internal exons. RNA m6A modification regulates RNA splicing, translocation, stability, and translation into protein. m6A is catalyzed by the RNA methyltransferases METTL3, METTL14, and METTL16 (writers), is removed by the demethylases FTO and ALKBH5 (erasers), and interacts with m6A-binding proteins, such as YTHDF1 and IGF2BP1 (readers). RNA methyltransferases, demethylases, and m6A-binding proteins are frequently upregulated in human cancer tissues from a variety of organ origins, increasing onco-transcript and oncoprotein expression, cancer cell proliferation, survival, tumor initiation, progression, and metastasis. Although RNA methyltransferase inhibitors are not available yet, FTO inhibitors have shown promising anticancer effects in vitro and in animal models of cancer. Further screening for selective and potent RNA methyltransferase, demethylase, or m6A-binding protein inhibitors may lead to compounds suitable for future clinical trials in cancer patients.
YIA19-003: Size Matters: Larger Size CD19-Positive Extracellular Vesicles in Chronic Lymphocytic Leukemia (CLL) Inhibit Chimeric Antigen Receptor T-Cell Function
Authors: Saad S. Kenderian, Michelle Cox, Reona Sakemura, Fabrice Lucien-Matteoni, Nan Yang, Sutapa Sinha, Cynthia Forsman, Mehrdad Hefazi, Kendall Schick, Justin Boysen, Sameer A. Parikh, Neil E. Kay
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: Unprecedented clinical outcomes were reported after CD19 chimeric antigen receptor T-cell (CART19) therapy. However, the complete response rate in chronic lymphocytic leukemia (CLL) is much lower, at approximately 20%–30%. Several immune defects have been identified in CLL that result from the complex interaction between CLL cells and the microenvironment. This leukemic microenvironment is rich with extracellular vesicles (EVs) secreted by B-CLL cells. Here, we aimed to investigate the role of EVs play in the diminished CART response seen in some CLL patients. Methods: EVs were isolated from peripheral blood of 16 patients with untreated CLL at different Rai stages and risk profile by FISH. Cytometry was used to determine size, number of particles per μl, and CD19 expression. To investigate the impact of EVs on CAR T-cell functions, CART19 cells were stimulated with either CLL B cells or the CD19-positive cell line JEKO and different effector functions were analyzed. Results: Two patterns of EVs in CLL patients were identified; a single versus 2 distinct EV populations, characterized by size (small [EVssmall] and large [EVslarge], Fig 1A). In 25% of patients, EVs were CD19 positive (EVCD19+). CD19 positivity was detected only in patients with the EVslarge (Fig 1B). The EVs concentration, CD19 expression (EVsCD19+ vs EVsCD19-), or the size (EVssmall vs EVslarge) did not correlate with disease stage (early vs advanced Rai stage) or risk profile of CLL (low vs high risk). To investigate our hypothesis that EVs could modulate CART19 function, CART19 cell effector functions were examined in the presence of EVsCD19+, EVsCD19-, EVssmall, or EVslarge. EVs alone were insufficient to stimulate CART19 cells. However when CART19 cells were stimulated with the CD19-positive cell line JEKO, their effector functions were reduced only in the presence of EVsCD19+ but not EVsCD19-. This included a significant reduction in CART-specific killing (Fig 1C) and a reduction in cytokine production. The impairment of CART cell functions was independent of the size of EVs, ie, there was no impairment of CART functions with large or small size EVCD19- in co-culture. Conclusion: We identify CD19-positive large size EVs from patients with CLL and demonstrate that these EVs play a role in the leukemic microenvironment by reducing CAR T-cell activity. Studies are ongoing to define the mechanism(s).
Tolerability of rifapentine-based regimens in latent tuberculosis infection treatment in the elderly
Authors: Pei-Chun Chan, Pin-Hui Lee, Min-Ju Lu, You-Chieh Huang, Teng-Yi Feng, Wen-Wen Chen, Chia-Chi Lee, Yen-Fang Huang, Chen-Yuan Chiang
Journal: European Respiratory Journal (2019)

<b>Our experience has shown that with proper support and medical care under programmatic conditions, it is feasible to achieve a high completion rate of 3HP even among the elderly</b>http://ow.ly/o3ED30nQfRx
Uncommon Penio-Scrotal Metastases of Prostate Cancer Detected on 68Ga PSMA PET/CT
Authors: Nikhil Seniaray, Ritu Verma, Sudhir Khanna, Ethel Belho, Dharmender Malik
Journal: Clinical Nuclear Medicine (2019)

A 68-year-old man, a known case of carcinoma prostate (Gleason score 4 + 4), status post transurethral resection of prostate cancer and radiotherapy, on hormonal treatment with rising prostate-specific antigen 9.0 ng/mL and penile swelling underwent Ga-PSMA PET/CT scan for metastatic workup and restaging. The study revealed abnormal tracer uptake in the prostatic bed region, the pelvic and inguinal lymph nodes, and metastases to the glans of penis and scrotum. The penile and scrotal lesion was proved to be metastatic adenocarcinoma from prostate on fine-needle aspiration cytology.
Aging and the Male Reproductive System
Authors: Jean-Marc Kaufman, Bruno Lapauw, Ahmed Mahmoud, Guy T’Sjoen, Ilpo Tapani Huhtaniemi
Journal: Endocrine Reviews (2019)

This narrative review presents an overview of current knowledge on fertility and reproductive hormone changes in aging men, the factors driving and modulating these changes, their clinical consequences, and the benefits and risks of testosterone (T) therapy. Aging is accompanied by moderate decline of gamete quality and fertility. Population mean levels show a mild total T decline, an SHBG increase, a steeper free T decline, and a moderate LH increase with important contribution of comorbidities (e.g., obesity) to these changes. Sexual symptoms and lower hematocrit are associated with low T and are partly responsive to T therapy. The relationship of serum T with body composition and metabolic health is bidirectional; limited beneficial effects of T therapy on body composition have only marginal effects on metabolic health and physical function. Skeletal changes are associated primarily with estradiol and SHBG. Cognitive decline is not consistently linked to low T and is not improved by T therapy. Although limited evidence links moderate androgen decline with depressive symptoms, T therapy has small beneficial effects on mood, depressive symptoms, and vitality in elderly patients with low T. Suboptimal T (and/or DHT) has been associated with increased risk of stroke, but not of ischemic heart disease, whereas an association with mortality probably reflects that low T is a marker of poor health. Globally, neither severity of clinical consequences attributable to low T nor the nature and magnitude of beneficial treatment effects justify the concept of some broadly applied “T replacement therapy” in older men with low T. Moreover, long-term safety of T therapy is not established.
Pain mechanisms in hereditary palmoplantar keratodermas
Authors: R.L. Weinberg, P.A. Coulombe, M. Polydefkis, M.J. Caterina
Journal: British Journal of Dermatology (2019)

Palmoplantar keratodermas (PPKs) are a heterogeneous group of skin disorders characterized by thickening of the epidermis on the palms of the hands and soles of the feet. Individuals with PPKs report varying degrees of palmoplantar pain that can severely affect quality of life.To provide an overview of the scope of pain in hereditary PPKs and highlight candidate mechanisms underlying this pain.In this review, we discuss several forms of hereditary PPKs, with a focus on the incidence, nature, candidate underlying mechanisms and treatment of pain in these conditions. We also synthesize this information with current understanding of the mechanisms contributing to pathological pain in other conditions.Pain is a major problem for many, but not all individuals with hereditary PPK. This pain remains poorly understood, inconsistently reported and inadequately treated. The heterogeneity of pain prevalence and presentations across the many forms of PPK suggests that there may exist corresponding heterogeneity in the cellular and molecular mechanisms that drive and shape PPK-associated pain. Some candidate mechanisms include structural (e.g. fissures and blisters), infectious and immune/inflammatory processes. However, a growing body of evidence also supports the occurrence of localized neuropathic alterations in the affected skin of individuals with PPK, which might contribute to their pain.Greater understanding of these diverse mechanisms may provide a rational basis for the development of improved and targeted approaches to prevention and treatment of pain in individuals with PPK. What's already known about this topic? Pain is a prominent symptom in hereditary palmoplantar keratodermas (PPKs). Pain in patients with PPK can be difficult to treat. Pain mechanisms in PPKs are poorly understood. What does this study add? This study defines multiple potential sources of pain in PPK, including both structural lesions (fissures, blisters) and specific cell types. This review highlights the variability of pain among several forms of hereditary PPK. This study provides mechanistic insights into how neuropathic and inflammatory mechanisms might contribute to pain in some forms of PPK.