tbuckley/cabot-search huggingface dataset:
Peritoneal carcinomatosis of colorectal origin: Impact of ovarian metastases.
Authors: Laurent Ghouti, Amandine Pinto, Sylvain Kirzin
Journal: Journal of Clinical Oncology (2018)

604 Background: To compare survival and morbidity in women treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) for colorectal peritoneal carcinomatosis with or without ovarian metastases (OM). Methods: A prospectively maintained database was analyzed to identify women treated by CRS- HIPEC between 2009 and 2015. Results: Among 62 included women, 39 had ovarian metastasis (63%) with comparable PCI (10 vs. 7 p=0.15). OM patients experienced more frequent grade III/IV postoperative morbidity (56.4% vs. 30% p=0.04), and postoperative haemoperitoneum (23.1% vs 4.3% p=0.07) leading to more frequent reoperation (36 vs. 21.7% p=0.2). Among OM patients, 20 (52 %) had undergone ovariectomy previously to CRS-HIPEC procedure. Haemoperitoneum (30% vs 15% p=0.4) and reoperation (45% vs. 26% p=0.2) were more frequent if previous OM resection had been performed as compared to synchronous. The 36-month survival (94.7 % vs 61.7 %) was significantly impaired by OM (p=0.007) and 36- month survival without recurrence was better when ovariectomy was performed during CRS- HIPEC (24 % vs. 5.5%, p=0.4). Conclusions: Survival and morbidity of patients with CRS-HIPEC for colorectal peritoneal carcinomatosis were impaired by the presence of OM and previous OM resection.
Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma
Authors: David F. McDermott, Mahrukh A. Huseni, Michael B. Atkins, Robert J. Motzer, Brian I. Rini, Bernard Escudier, Lawrence Fong, Richard W. Joseph, Sumanta K. Pal, James A. Reeves, Mario Sznol, John Hainsworth, W. Kimryn Rathmell, Walter M. Stadler, Thomas Hutson, Martin E. Gore, Alain Ravaud, Sergio Bracarda, Cristina Suárez, Riccardo Danielli, Viktor Gruenwald, Toni K. Choueiri, Dorothee Nickles, Suchit Jhunjhunwala, Elisabeth Piault-Louis, Alpa Thobhani, Jiaheng Qiu, Daniel S. Chen, Priti S. Hegde, Christina Schiff, Gregg D. Fine, Thomas Powles
Journal: Nature Medicine (2018)
Alzheimer’s Disease-Associated β-Amyloid Is Rapidly Seeded by Herpesviridae to Protect against Brain Infection
Authors: William A. Eimer, Deepak Kumar Vijaya Kumar, Nanda Kumar Navalpur Shanmugam, Alex S. Rodriguez, Teryn Mitchell, Kevin J. Washicosky, Bence György, Xandra O. Breakefield, Rudolph E. Tanzi, Robert D. Moir
Journal: Neuron (2018)
Expectations for survivorship care among hematology oncology and primary care providers.
Authors: Damien Mikael Hansra, Jeremy Ramdial, Eugene Ahn, Anthony Perre, Lauren Masar, Alora Brock, Tamara Walters, Kimberly Randolph, Ricardo H. Alvarez
Journal: Journal of Clinical Oncology (2018)

5 Background: Significant controversy exists between hem/onc &amp; primary care providers regarding various aspects of survivorship care. Here we administer a 23 question survey to address these discrepancies. Methods: A 23 question (Q) electronic survey was created on www.surveymonkey.com and sent to providers at Cancer Treatment Centers of America, &amp; The University of Miami Health Network. Survey included provider demographics (7Qs) and practice preference Qs (16Qs). Survey asked: who should be primary responsible for managing cardiotoxicity (CT), cardiovascular risk reduction (CRD), physical activity assessments (PA), nutrition (N), weight (W), anxiety depression panic disorder PTSD (ADPP), cognitive function (CF), fatigue (F), sexual function (SF), lymphedema (L), side effect of hormonal agents (SEH), side effect of targeted agents (SET), side effect of bone modifying agents (SEB), vaccinations (V), cancer screening (CS), sleep disorders (SD)? Answer choices were 1) Hematologist Oncologist (HO), 2) Primary Care Provider (PCP), 3) Both HO + PCP (BO), 4) Other (O). Results: 55 providers enrolled in the survey (92% physician 6% ARNP 2% other). 56% hem/onc, 7% PCP, 37% subspecialty. 56% hospital based, 20% academic, 16% multispecialty practice, 8% other. Survey results: (CT): HO 29%, PCP 5%, BO 60%, 0 6%, (CRD): HO 7%, PCP 49%, BO 36%, 8% O, (PA): HO 5%, PCP 45%, BO 38%, O 12%, (N): HO 5%, PCP 38%, BO 35%, O 12%, (W): 4%, PCP 47%, BO 31%, O 16%, (ADPP): HO 5%, PCP 33%, BO 38%, O 24%, (CF): HO 5%, PCP 33%, BO 45%, O 17%, (F): HO 4%, PCP 36%, BO 53%, O 7%, (SF): HO 5%, PCP 22%, BO 49%, O 24%, (L): HO 31%, PCP 7%, BO 36%, O 26%, (SEH): HO 62%, PCP 4%, BO 27%, O 7%, (SET): HO 69%, PCP 4%, BO 20%, O 7%, (SEB): HO 62%, PCP 4%, PCP 25%, O 9%, (V): HO 16%, PCP 42%, BO 36%, O 6%, (CS): HO 9%, PCP 38%, BO 47% O 6%, (SD): 3% HO, PCP 51%, BO 31%, O 15%. Conclusions: In our study we found that the majority of providers think PCPs should manage: CRD &amp; SD; HO should manage: SEH, SET, SEB; BO should manage: CT, F. A minority of providers favored combined approach (BO) for: CRD, ADPP, CF, SD, L, CS in survivors.
Immunomodulatory innate defence regulator (IDR) peptide alleviates airway inflammation and hyper-responsiveness
Authors: Hadeesha Piyadasa, Mahadevappa Hemshekhar, Anthony Altieri, Sujata Basu, Anne M van der Does, Andrew J Halayko, Pieter S Hiemstra, Neeloffer Mookherjee
Journal: Thorax (2018)

Background Exacerbation in asthma is associated with decreased expression of specific host defence peptides (HDPs) in the lungs. We examined the effects of a synthetic derivative of HDP, innate defence regulator (IDR) peptide IDR-1002, in house dust mite (HDM)-challenged murine model of asthma, in interleukin (IL)-33-challenged mice and in human primary bronchial epithelial cells (PBECs). Methods IDR-1002 (6 mg/kg per mouse) was administered (subcutaneously) in HDM-challenged and/or IL-33-challenged BALB/c mice. Lung function analysis was performed with increasing dose of methacholine by flexi Vent small animal ventilator, cell differentials in bronchoalveolar lavage performed by modified Wright-Giemsa staining, and cytokines monitored by MesoScale Discovery assay and ELISA. PBECs stimulated with tumour necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ), with or without IDR-1002, were analysed by western blots. Results IDR-1002 blunted HDM challenge-induced airway hyper-responsiveness (AHR), and lung leucocyte accumulation including that of eosinophils and neutrophils, in HDM-challenged mice. Concomitantly, IDR-1002 suppressed HDM-induced IL-33 in the lungs. IFN-γ/TNF-α-induced IL-33 production was abrogated by IDR-1002 in PBECs. Administration of IL-33 in HDM-challenged mice, or challenge with IL-33 alone, mitigated the ability of IDR-1002 to control leucocyte accumulation in the lungs, suggesting that the suppression of IL-33 is essential for the anti-inflammatory activity of IDR-1002. In contrast, the peptide significantly reduced either HDM, IL-33 or HDM+IL-33 co-challenge-induced AHR in vivo. Conclusion This study demonstrates that an immunomodulatory IDR peptide controls the pathophysiology of asthma in a murine model. As IL-33 is implicated in steroid-refractory severe asthma, our findings on the effects of IDR-1002 may contribute to the development of novel therapies for steroid-refractory severe asthma.
Chitosan‐based multifunctional nanomedicines and theranostics for targeted therapy of cancer
Authors: Marziyeh Fathi, Sima Majidi, Parham Sahandi Zangabad, Jaleh Barar, Hamid Erfan‐Niya, Yadollah Omidi
Journal: Medicinal Research Reviews (2018)

Abstract Nanotechnology as an emerging field has established inevitable impacts on nano‐biomedicine and treatment of formidable diseases, inflammations, and malignancies. In this regard, substantial advances in the design of systems for delivery of therapeutic agents have emerged magnificent and innovative pathways in biomedical applications. Chitosan (CS) is derived via deacetylation of chitin as the second most abundant polysaccharide. Owing to the unique properties of CS (e.g., biocompatibility, biodegradability, bioactivity, mucoadhesion, cationic nature and functional groups), it is an excellent candidate for diverse biomedical and pharmaceutical applications such as drug/gene delivery, transplantation of encapsulated cells, tissue engineering, wound healing, antimicrobial purposes, etc. In this review, we will document, discuss, and provide some key insights toward design and application of miscellaneous nanoplatforms based on CS. The CS‐based nanosystems (NSs) can be employed as advanced drug delivery systems (DDSs) in large part due to their remarkable physicochemical and biological characteristics. The abundant functional groups of CS allow the facile functionalization in order to engineer multifunctional NSs, which can simultaneously incorporate therapeutic agents, molecular targeting, and diagnostic/imaging capabilities in particular against malignancies. These multimodal NSs can be literally translated into clinical applications such as targeted diagnosis and therapy of cancer because they offer minimal systemic toxicity and maximal cytotoxicity against cancer cells and tumors. The recent developments in the CS‐based NSs functionalized with targeting and imaging agents prove CS as a versatile polymer in targeted imaging and therapy.
Primary care provider-reported participation in breast cancer treatment decision making.
Authors: Lauren P. Wallner, Yun Li, Chandler McLeod, Archana Radhakrishnan, Sarah T. Hawley, Steven J. Katz
Journal: Journal of Clinical Oncology (2018)

78 Background: Surgical treatment decisions for early-stage breast cancer patients are complex and often involve discussions with multiple oncology providers. However, with the increasing adoption of team-based cancer care models, it remains unknown to what extent primary care providers (PCPs) are participating in breast cancer treatment decisions and whether they feel they have enough knowledge to participate in these decisions effectively. Methods: A stratified random sample of PCPs identified by newly diagnosed early-stage breast cancer patients who participated in iCanCare Study (Georgia and Los Angeles SEER registries) were surveyed about their experiences caring for cancer patients (N = 519, 58% current response rate). PCPs were asked how frequently they discussed which surgery a patient should have, how comfortable they were with these discussions, whether they had the necessary knowledge to participate in treatment decision making and their confidence in their ability to help with treatment decision making (5-item likert-type scales). The individual items were then categorized as somewhat/often/always vs. never/rarely for analyses. Results: In this preliminary sample, 62% of PCPs were not comfortable having a discussion about surgery options with a patient newly diagnosed with breast cancer, 41% did not feel that they had the necessary knowledge to participate in treatment decision-making, and 34% were not confident in the ability to help with treatment decision-making. One third (32%) of PCPs reported discussing surgical treatment options with their newly diagnosed breast cancer patients, but 22% of these PCPs also reported that they were not comfortable having these discussions and 16% reported they did not have necessary knowledge to participate in decision-making. Conclusions: A minority of PCPs participate in breast cancer treatment decision-making and there are notable gaps in their self-reported knowledge about decision-making and confidence in their ability to help with these decisions. Efforts to increase PCP knowledge about the specifics of cancer treatments may be warranted, but further research is needed to assess the impact of PCP participation on treatment decision-making outcomes.
Using Digital Health Technology to Better Generate Evidence and Deliver Evidence-Based Care
Authors: Abhinav Sharma, Robert A. Harrington, Mark B. McClellan, Mintu P. Turakhia, Zubin J. Eapen, Steven Steinhubl, James R. Mault, Maulik D. Majmudar, Lothar Roessig, Karen J. Chandross, Eric M. Green, Bakul Patel, Andrew Hamer, Jeffrey Olgin, John S. Rumsfeld, Matthew T. Roe, Eric D. Peterson
Journal: Journal of the American College of Cardiology (2018)
Surveillance of premalignant gastric lesions: a multicentre prospective cohort study from low incidence regions
Authors: Wouter J den Hollander, I Lisanne Holster, Caroline M den Hoed, Lisette G Capelle, Tjon J Tang, Marie-Paule Anten, Ingrid Prytz-Berset, Ellen M Witteman, Frank ter Borg, Gijsbert den Hartog, Marco J Bruno, Maikel Petrus Peppelenbosch, Wilco Lesterhuis, Michael Doukas, Ernst J Kuipers, Manon C W Spaander
Journal: Gut (2018)

Objective International guidelines recommend endoscopic surveillance of premalignant gastric lesions. However, the diagnostic yield and preventive effect require further study. We therefore aimed to assess the incidence of neoplastic progression and to assess the ability of various tests to identify patients most at risk for progression. Design Patients from the Netherlands and Norway with a previous diagnosis of atrophic gastritis (AG), intestinal metaplasia (IM) or dysplasia were offered endoscopic surveillance. All histological specimens were assessed according to the updated Sydney classification and the operative link on gastric intestinal metaplasia (OLGIM) system. In addition, we measured serum pepsinogens (PG) and gastrin-17. Results 279 (mean age 57.9 years, SD 11.4, male/female 137/142) patients were included and underwent at least one surveillance endoscopy during follow-up. The mean follow-up time was 57 months (SD 36). Four subjects (1.4%) were diagnosed with high-grade adenoma/dysplasia or invasive neoplasia (ie, gastric cancer) during follow-up. Two of these patients were successfully treated with endoscopic submucosal dissection, while the other two underwent a total gastrectomy. Compared with patients with extended AG/IM (PGI/II≤3 and/or OGLIM stage III–IV), patients with limited AG/IM (PG I/II&gt;3 and OLGIM stage 0–II) did not develop high-grade adenoma/dysplasia or invasive neoplasia during follow-up (p=0.02). Conclusion In a low gastric cancer incidence area, a surveillance programme can detect gastric cancer at an early curable stage with an overall risk of neoplastic progression of 0.3% per year. Use of serological markers in endoscopic surveillance programmes may improve risk stratification.
Extrathymically Generated Regulatory T Cells Establish a Niche for Intestinal Border-Dwelling Bacteria and Affect Physiologic Metabolite Balance
Authors: Clarissa Campbell, Stanislav Dikiy, Shakti K. Bhattarai, Takatoshi Chinen, Fanny Matheis, Marco Calafiore, Beatrice Hoyos, Alan Hanash, Daniel Mucida, Vanni Bucci, Alexander Y. Rudensky
Journal: Immunity (2018)
The human heart contains distinct macrophage subsets with divergent origins and functions
Authors: Geetika Bajpai, Caralin Schneider, Nicole Wong, Andrea Bredemeyer, Maarten Hulsmans, Matthias Nahrendorf, Slava Epelman, Daniel Kreisel, Yongjian Liu, Akinobu Itoh, Thirupura S. Shankar, Craig H. Selzman, Stavros G. Drakos, Kory J. Lavine
Journal: Nature Medicine (2018)
Abstract 13527: Role of Rotor Activation in Persistent Atrial Fibrillation Perpetuated After Pulmonary Vein isolation: Relation to the Complex Fractionated Electrogram Region
Authors: Hiroshige Yamabe, Hisanori Kanazawa, Miwa Ito, Shozo Kaneko, Yusuke Kanemaru, Takuya Kiyama, Hisao Ogawa
Journal: Circulation (2016)

Background: Complex fractionated electrogram (CFE) region has been suggested as the substrate of random wave propagation perpetuated after pulmonary vein (PV) isolation in patients with persistent atrial fibrillation (AF). While the rotor has also been suggested as the driving sources. But the relation between CFE and rotor remains unclear. Objectives: We elucidated the significance of CFE and rotor for the maintenance of AF perpetuated after PV isolation in persistent AF patients. Methods: Endocardial non-contact mapping of the left atrium was performed in 16 patients with persistent AF perpetuated after PV isolation. To define the role of CFE and rotor for the maintenance of AF, the number of pivoting activation involved in the CFE was compared with that involved in the rotor activation. The location of rotor and pivoting activation were also compared between the CFE and non-CFE region. Presence of rotor activation was defined when the circular activation around the functional block line once completed its whole reentrant activation. Results: Rotor activation was observed in 11 patients (69%) with a mean number of 2.1±2.0 times/sec. Rotor activation continued at the same site more than once in 2 patients, but shifted to the different location or observed intermittently in the remaining 9 patients. All rotors were observed at CFE region (CFE area; 7.7±2.5 cm2). Total number of pivoting activation was 12.8±4.6 times/sec. The number of pivot activation involved in the CFE region was significantly higher than that in the non-CFE region (12.4±4.9 vs. 0.5±1.0 times/sec, p&lt;0.0001). Thus, 99% of pivoting activations were observed within the CFE region. Pivoting activation involved in the rotor activation was significantly lower than that not involved in the rotor activation (3.5±3.2 vs. 8.7±5.0 times/sec, p&lt;0.01) in the CFE region, but was not different in non-CFE region (0.0±0.0 vs. 0.5±1.0 times/sec, p=NS). Conclusions: Rotor activation was observed within the CFE region after PV isolation. However, few rotors sustained at the stable location. Further, most of pivoting activation was not involved in the rotor activation, suggesting that AF was driven by the meandering non-rotor propagation associated with frequent pivoting activation over the CFE region.
A phase II study of cabozantinib (cabo) alone or in combination with trastuzumab (T) in patients (pts) with breast cancer brain metastases (BCBM).
Authors: Jose Pablo Leone, Jiani Hu, William Thomas Barry, Dan G. Duda, Elizabeth Robins Gerstner, Rakesh K. Jain, Sally Tan, Elizabeth S Lawler, Eric P. Winer, Nancy U. Lin, Sara M. Tolaney
Journal: Journal of Clinical Oncology (2018)

1026 Background: BCBM rely on VEGF pathway activation for angiogenesis and dissemination. Activation of MET leads to tumor invasion and resistance to anti-VEGF therapy. The aim of this study was to analyze the efficacy and tolerability of cabo —a small molecule inhibitor of MET and VEGFR2— alone or with T in BCBM pts. Methods: This is a single-arm, two-stage phase II study. Eligible pts had new or progressive measurable BCBM. The study included 3 cohorts: Cohort 1 (HER2+), Cohort 2 (HR+ HER2-) and Cohort 3 (triple negative). Pts received cabo 60 mg daily on a 21-day cycle. Cohort 1 also received standard T every 3 weeks. Pts had restaging scans every 6 weeks for 6 cycles, then every 9 weeks; a research brain MRI was performed at baseline and after 1 cycle. Primary objective was CNS objective response rate (ORR) by RECIST 1.1 in Cohort 1. Target sample size for Cohort 1 was 21 pts; if ≥ 3 pts had CNS ORR the null rate (5%) would be rejected in favor of a 30% rate of activity. Secondary objectives were CNS ORR in Cohorts 2 and 3, progression-free survival (PFS), overall survival (OS), toxicity, and changes in fMRI vascular parameters and plasma biomarkers. Results: 35 pts (Cohort 1 n = 21, Cohort 2 n = 6, Cohort 3 n = 8) were enrolled and this analysis was done with a median follow up of 7.3 months (range 0.8-30.6). Median age was 50 years (range 28-69). Pts had a median of 3 prior lines for metastatic disease (range 1-9). Prior to enrollment, 4 pts underwent craniotomy, 24 pts whole brain radiation and 11 pts stereotactic radiosurgery. Efficacy is shown in the Table. Most common grade 3/4 AE included elevations in lipase (12%), AST (9%), ALT (6%), hyponatremia (9%), thromboembolism (9%), hypertension (6%), fatigue (6%) and vomiting (6%). Ongoing studies are exploring MRI perfusion changes with cabo, and biomarkers of response. Conclusions: Cabo was well tolerated but had insufficient activity in heavily pretreated BCBM. Biomarker changes and their association with outcome will be presented at the meeting. Clinical trial information: NCT02260531. Cohort 1 Cohort 2 Cohort 3 CNS ORR 5% 17% 0% Non-CNS ORR 0% 0% 0% Clinical benefit rate (CR + PR + SD) at 12 weeks 43% 17% 13% Median time on therapy (months) 4.2 0.8 2.5 Median PFS (months) 4.2 0.8 2.5 Median OS (months) 13.9 2.2 5.2
Acute O2 Sensing: Role of Coenzyme QH2/Q Ratio and Mitochondrial ROS Compartmentalization
Authors: Ignacio Arias-Mayenco, Patricia González-Rodríguez, Hortensia Torres-Torrelo, Lin Gao, M. Carmen Fernández-Agüera, Victoria Bonilla-Henao, Patricia Ortega-Sáenz, José López-Barneo
Journal: Cell Metabolism (2018)
Ibrutinib inactivates BMX-STAT3 in glioma stem cells to impair malignant growth and radioresistance
Authors: Yu Shi, Olga A. Guryanova, Wenchao Zhou, Chong Liu, Zhi Huang, Xiaoguang Fang, Xiuxing Wang, Cong Chen, Qiulian Wu, Zhicheng He, Wei Wang, Wei Zhang, Tao Jiang, Qing Liu, Yaping Chen, Wenying Wang, Jingjing Wu, Leo Kim, Ryan C. Gimple, Hua Feng, Hsiang-Fu Kung, Jennifer S. Yu, Jeremy N. Rich, Yi-Fang Ping, Xiu-Wu Bian, Shideng Bao
Journal: Science Translational Medicine (2018)

Glioblastoma (GBM) is the most lethal primary brain tumor and is highly resistant to current treatments. GBM harbors glioma stem cells (GSCs) that not only initiate and maintain malignant growth but also promote therapeutic resistance including radioresistance. Thus, targeting GSCs is critical for overcoming the resistance to improve GBM treatment. Because the bone marrow and X-linked (BMX) nonreceptor tyrosine kinase is preferentially up-regulated in GSCs relative to nonstem tumor cells and the BMX-mediated activation of the signal transducer and activator of transcription 3 (STAT3) is required for maintaining GSC self-renewal and tumorigenic potential, pharmacological inhibition of BMX may suppress GBM growth and reduce therapeutic resistance. We demonstrate that BMX inhibition by ibrutinib potently disrupts GSCs, suppresses GBM malignant growth, and effectively combines with radiotherapy. Ibrutinib markedly disrupts the BMX-mediated STAT3 activation in GSCs but shows minimal effect on neural progenitor cells (NPCs) lacking BMX expression. Mechanistically, BMX bypasses the suppressor of cytokine signaling 3 (SOCS3)-mediated inhibition of Janus kinase 2 (JAK2), whereas NPCs dampen the JAK2-mediated STAT3 activation via the negative regulation by SOCS3, providing a molecular basis for targeting BMX by ibrutinib to specifically eliminate GSCs while preserving NPCs. Our preclinical data suggest that repurposing ibrutinib for targeting GSCs could effectively control GBM tumor growth both as monotherapy and as adjuvant with conventional therapies.
Abstract 17871: Brugada Phenotype in Cardiac-Specific GPD1-L Knockout Mice
Authors: Haider Mehdi, Jin-Young Yoon, Gina M Morgan, Tariq Hameed, Ajit Vikram, Xiaodong Zhu, Robert M Weiss, Barry London
Journal: Circulation (2014)

Introduction: A Brugada syndrome (BrS) mutation (A280V) in Glycerol-3 Phosphate Dehydrogenase-1 Like (GPD1-L) decreases SIRT1 deacetylase activity, surface expression of Nav1.5, and Na+ current (IN...
The antiprotease SPINK7 serves as an inhibitory checkpoint for esophageal epithelial inflammatory responses
Authors: Nurit P. Azouz, Mario A. Ynga-Durand, Julie M. Caldwell, Ayushi Jain, Mark Rochman, Demetria M. Fischesser, Leanne M. Ray, Mary C. Bedard, Melissa K. Mingler, Carmy Forney, Matthew Eilerman, Jonathan T. Kuhl, Hua He, Jocelyn M. Biagini Myers, Vincent A. Mukkada, Philip E. Putnam, Gurjit K. Khurana Hershey, Leah C. Kottyan, Ting Wen, Lisa J. Martin, Marc E. Rothenberg
Journal: Science Translational Medicine (2018)

Loss of esophageal SPINK7 unleashes protease activity, impairs barrier function, and induces proinflammatory responses.