tbuckley/cabot-search huggingface dataset:
A randomized phase II study of everolimus in combination with chemoradiation in newly diagnosed glioblastoma: results of NRG Oncology RTOG 0913
Authors: Prakash Chinnaiyan, Minhee Won, Patrick Y Wen, Amyn M Rojiani, Maria Werner-Wasik, Helen A Shih, Lynn S Ashby, Hsiang-Hsuan Michael Yu, Volker W Stieber, Shawn C Malone, John B Fiveash, Nimish A Mohile, Manmeet S Ahluwalia, Merideth M Wendland, Philip J Stella, Andrew Y Kee, Minesh P Mehta
Journal: Neuro-Oncology (2017)

This phase II study was designed to determine the efficacy of the mammalian target of rapamycin (mTOR) inhibitor everolimus administered daily with conventional radiation therapy and chemotherapy in patients with newly diagnosed glioblastoma.Patients were randomized to radiation therapy with concurrent and adjuvant temozolomide with or without daily everolimus (10 mg). The primary endpoint was progression-free survival (PFS) and the secondary endpoints were overall survival (OS) and treatment-related toxicities.A total of 171 patients were randomized and deemed eligible for this study. Patients randomized to receive everolimus experienced a significant increase in both grade 4 toxicities, including lymphopenia and thrombocytopenia, and treatment-related deaths. There was no significant difference in PFS between patients randomized to everolimus compared with control (median PFS time: 8.2 vs 10.2 mo, respectively; P = 0.79). OS for patients randomized to receive everolimus was inferior to that for control patients (median survival time: 16.5 vs 21.2 mo, respectively; P = 0.008). A similar trend was observed in both O6-methylguanine-DNA-methyltransferase promoter hypermethylated and unmethylated tumors.Combining everolimus with conventional chemoradiation leads to increased treatment-related toxicities and does not improve PFS in patients with newly diagnosed glioblastoma. Although the median survival time in patients receiving everolimus was comparable to contemporary studies, it was inferior to the control in this randomized study.
OC-078 Combined histo-cytological analysis of eus-fna samples from solid lesions using standard fna needles gives better diagnostic yield and accuracy
Authors: AK Banerjee, A Cairns, L Sanni, B Paranandi, M Huggett
Journal: Gut (2017)

Introduction  Diagnostic yield from EUS-FNAC (fine needle aspiration cytology) has improved in the past few years with better tissue acquisition techniques. Core biopsy needles are now available but are more expensive than FNAC needles. We assessed the diagnostic yield and accuracy of FNAC samples processed for both cytology and histology.  Method  EUS-FNA samples of solid lesions (from September 2014 to September 2016) were included in a prospective audit of practice. Between September 2014 and January 2016 the standard practice was to send FNAC samples for cytology only. After this date, FNAC samples were filtered through a cassette. The solid material was sent in formalin to histology and the effluent to cytology for cytospin and cell block as previously. Cellularity was graded as adequate or inadequate. Final diagnosis was obtained from MDT outcomes.  Results  A total of 211 patients (118 male) were included. Samples were sent to cytology (n=135; 107 pancreas, 10 biliary, 7 lymph nodes, 11 other), or cytology and histology (n=76; 56 pancreas, 12 biliary, 5 lymph nodes, 3 other). Sample adequacy was 80.7% and 98.7% (p=0.0004). Diagnostic yield (64.4%, 94.7%) and accuracy (81.3%, 96.1%) was significantly better in the combined (histology and cytology) group (p  Conclusion  Our study confirms significant improvement in diagnostic yield and accuracy when samples were sent for both cytology and histology using standard FNAC needles.  Disclosure of Interest  None Declared
The positive effects of early integrated palliative care on patient coping strategies, quality of life, and depression.
Authors: Jamie M. Jacobs, Joseph Greer, Areej El-Jawahri, Ryan David Nipp, Emily R. Gallagher, William F. Pirl, Elyse Park, Alona Muzikansky, Juliet Jacobsen, Vicki Jackson, Jennifer S. Temel
Journal: Journal of Clinical Oncology (2017)

92 Background: In a recent trial, early integrated palliative care (PC) improved quality of life (QOL) and reduced depressive symptoms in patients with newly-diagnosed incurable lung and gastrointestinal (GI) cancer. The mechanisms by which PC benefits these outcomes are unclear. We examined whether early integrated PC improved patients’ coping strategies and the degree to which changes in coping mediated intervention effects on QOL and depressive symptoms. Methods: From 5/2011 to 7/2015, we enrolled 350 patients with newly diagnosed incurable lung or non-colorectal GI cancer in a randomized trial of early PC integrated with oncology care vs. oncology care alone at Massachusetts General Hospital. Patients completed self-report measures of QOL (Functional Assessment of Cancer Therapy-General), depressive symptoms (Patient Health Questionnaire-9), and use of active and avoidant coping strategies (Brief Cope) at baseline, 12, and 24 weeks. Linear regression was used to assess the effects of the early PC intervention on active and avoidant coping strategies. A multiple mediation regression was modeled to examine whether changes in use of coping strategies mediated intervention effects on QOL and depressive symptoms. Results: Compared to oncology care, early integrated PC improved patients’ use of active coping ( B= 1.09, SE= 0.44, p= .01, 95% CI: 0.23, 1.96) and slightly reduced use of avoidant coping strategies ( B= -0.44, SE= 0.23, p= .06, 95% CI:-0.90, 0.02). Improvements in 24-week QOL in patients assigned to PC were mediated by increased use of active coping strategies (indirect effect = 1.27, 95% CI: 0.31, 2.86), but not by decreased use of avoidant coping. Similarly, PC-related reductions in 24-week depressive symptoms were mediated by increased use of active coping strategies (indirect effect = -0.39, 95% CI:-0.89, -0.08) but not by decreased use of avoidant coping. Conclusions: Patients with newly diagnosed incurable cancer who received early integrated PC showed increased use of active coping strategies, which was associated with improved QOL and depressive symptoms. PC may improve QOL and mood by providing patients with the skills to cope effectively with life-threatening illness. Clinical trial information: NCT01401907.
Different first line EGFR-TKI regimen and the clearance of EGFR sensitive mutation in acquired EGFR-TKI resistant lung adenocarcinoma patients
Authors: W. Zhuang, C. Xu, W. Wang, Z. Song, Y. Zhu, R. Chen, Y. Guan, X. Yi, M. Fang, G. Chen, T. Lv, Y. Song
Journal: Annals of Oncology (2017)
Abstract 20981: Use of Intrathoracic Pressure Regulation Therapy in Breathing Patients for the Treatment of Hypotension Secondary to Trauma
Authors: Victor A Convertino, Brent A Parquette, David A Wampler, Craig A Manifold, David A Lindstrom, Lori L Boland, Nathan Burkhart, Nicolas Segal, Keith G Lurie, Charles J Lick
Journal: Circulation (2017)

Objectives: Intrathoracic pressure regulation therapy (IPRT) has been shown to increase blood pressure in hypotensive patients. The potential value of this therapy in patients with hypotension secondary to trauma with bleeding is not well understood. Hypothesis: We hypothesized that IPRT would non-invasively and safely enhance blood pressure in spontaneously breathing patients with trauma-induced hypotension. Methods: This prospective observational cohort study assessed vital signs from hypotensive patients with a systolic blood pressure (SBP) ≤90 mmHg secondary to trauma treated by pre-hospital emergency medical personnel with IPRT (ResQGARD) in three large US metropolitan areas. Upon determination of hypotension, facemask-based IPRT was initiated as long as bleeding was controlled. Vital signs were recorded before, during, and after IPRT. An increased SBP with IPRT use was the primary study endpoint. Device tolerance and ease of use were also reported. Results: A total of 54 patients with hypotension secondary to trauma were treated from 2009 to 2016. The mean (± SD) SBP increased from 81 ± 12 mmHg to 107 ± 19 with IPRT (p &lt; 0.0001) and mean arterial pressures (MAP) increased from 62 ± 11 mmHg to 82 ± 17 (p &lt; 0.0001). There were no significant changes in mean heart rate or oxygen saturation. Approximately 75% of patients reported moderate to easy tolerance of the device. There were no safety concerns or reported adverse events. Conclusion: In patients with hypotension secondary to trauma IPRT increased blood pressure to levels known to provide near normal or normal vital organ blood flow in the vast majority of patients. Patients were treated safely and not over resuscitated with this intervention. These findings support the use of IPRT to treat trauma-induced hypotension as long as bleeding has been controlled.
Structural and functional analysis of BRCA1 isoforms
Authors: Catherine Lewis, Nurjahan Begum, Anna Maniccia, Tameka Watkins, Jian-Qi Cui, Beric Henderson, E. Shyam Reddy, Veena Rao
Journal: Cancer Research (2007)

4532  BRCA1 is a tumor suppressor gene that is either lost or mutated in families with breast and ovarian cancer. Among sporadic cases of breast cancer, expression of BRCA1 is reduced, suggesting the involvement of this gene in the etiology of breast cancer. Several BRCA1 splice variants are found in different tissues, but their regulation and possible functions are poorly understood at the moment. We have previously isolated and characterized two splice variants of BRCA1 named BRCA1a/1b, which are evolutionary conserved of all the BRCA1 isoforms. BRCA1a/1b differ from BRCA1 due to an in frame deletion of a major portion of the exon 11 sequences (amino acids 263-1365). Further, BRCA1b has an additional deletion of exons 9 and 10. They code for smaller p110/p100 kD proteins, respectively. We have found BRCA1a/1b to be multifunctional proteins that interact with several proteins involved in transcriptional activation/repression, cell cycle regulation, growth suppression, apoptosis, etc. In this study, we have analyzed the structure/function relationships of these isoforms and compared them to the wild type BRCA1 protein using several criteria such as in vivo expression in normal and tumor cell lines by RNase protection assays, subcellular localization using FLAG or GFP tagged vectors by immunofluorescence, transcriptional activation/repression using several biologically relevant promoters and growth suppression in breast cancer cells. Our results suggest that even though both wild type BRCA1 and its isoforms exhibit overlapping as well as distinct transcriptional activation functions they still possess antiproliferative activity in breast cancer cells. These results suggest that the exon 11 sequences (amino acids 263-1365) which contain two nuclear localization signals, p53, Rb, c-myc, γ-tubulin, Stat, Rad 51 and Rad 50 binding domains and an angiopoietin-1 repression domain are not absolutely required for the growth suppressor function of these proteins. It is tempting to speculate that mutations that are present in the patients within these regions may not be functionally significant for the tumor suppressor activity of BRCA1 protein. This work is supported by the Georgia Cancer Coalition Distinguished Cancer Scholar Award, NIH Ovarian Cancer SPORE award, and P60 grant to V. N. Rao. *Contributed equally.
Abstract 20385: Defining the End of the Circulatory Phase in Humans Undergoing Cardiopulmonary Resuscitation
Authors: Guillaume Debaty, Johanna C Moore, Jose Labarere, Nathan Burkhart, Nicolas Segal, Keith G Lurie
Journal: Circulation (2017)

Introduction:  Cardiac arrest has been described using a 3-phase model, the electrical, the circulatory and the metabolic phase. A similar 3-phase construct may exist during cardiac arrest treatment. During prolonged CPR it is unknown when the circulatory phase ends and the metabolic phase begins.   Hypothesis:  We assessed the association between CPR duration and survival to hospital discharge with good neurologic outcome, defined as a modified Rankin scale (MRS) score ≤ 3, with two methods of CPR each known to provide different levels of circulation.   Methods:  Data from the ResQTrial, which prospectively compared survival to hospital discharge with MRS≤ 3 using active compression decompression and impedance threshold device (ACD-ITD) versus standard (S) CPR, were used. All subjects were treated for at least 30 minutes before stopping CPR. A Competing risk regression analysis was performed.   Results:  2470 subjects were included in the analysis and 172 (7 %) patients had a MRS≤3 at hospital discharge. Regardless of the method of CPR, survival with good neurologic outcome curve demonstrated a plateau on the competing risk analysis curve after 24 minutes of CPR in both CPR method study groups (Figure). Only 8/172 patients (4.6%) with MRS≤3 received more than 24 minutes of CPR. Patient characteristics (gender, age, first rhythm, witnessed) were similar among all survivors with MRS ≤ 3 with   15 minutes, an arbitrary cutoff point to enable comparison of 75% of the survivors with early versus 25 % with late ROSC.   Conclusions:  These results highlight that after 24 minutes of CPR the circulatory phase is nearly over, with
Immunotherapy for Unresectable Stage III Non–Small-Cell Lung Cancer
Authors: Naiyer A. Rizvi, Solange Peters
Journal: New England Journal of Medicine (2017)

In this issue of the Journal, Antonia and colleagues report the results of the phase 3 PACIFIC study, which evaluated the role of immune checkpoint blockade in locally advanced, unresectable, stage III non–small-cell lung cancer (NSCLC).1 Eligible patients had disease that had not yet progressed after they had received at least two cycles of platinum-based chemotherapy concurrent with radiotherapy (chemoradiotherapy) at a dose of 54 to 66 Gy. A total of 713 patients were randomly assigned, in a 2:1 ratio, to receive an anti–programmed death ligand 1 (anti–PD-L1) antibody, durvalumab, at a dose of 10 mg per kilogram of body . . .
John Hunter's Health
Authors: A W Beasley
Journal: Journal of the Royal Society of Medicine (2001)

J Rosenberg (May 2000 JRSM, p. 260) refers to Everard Home's claim that poor health was the reason for Hunter's enlisting in the Army, and implies that Home's view is endorsed by me. In fact, my text1 goes on to point out that army service in those days was hardly a healthy exercise, and in my more recent study of the Home family2 I quote Drewry Ottley's rather similar story, probably derived from Home: ‘he was strongly advised to leave London, therefore, and seek a more southerly climate’3 with the comment that Hunter's enlistment ‘took him out of London, certainly, and to a more southerly climate as well, though we would have to wonder just how military service in the eighteenth century rated as a rest cure’.

In fact I am about as sceptical as Rosenberg concerning Hunter's choice of an army career as a cure for his health, though an open-air life may have appealed to him after some years in brother William's anatomy school. But how much ambition influenced him, or friction with William (we know they fell out later) we can only conjecture.

We do need, though, to recognize that Hunter's health in Portugal was less than perfect. In a letter dated 8 September 1762 to Lord Loudon, the British commander-in-chief, the commanding officer of Hunter's hospital, William Young, wrote: ‘Mr Hunter... does not downright say he is sick but that he is almost knocked up. He has had too much to do’.2

That said, Rosenberg's letter still raises a paradox. The syphilitic myth, propounded by Sir D'Arcy Power4 to his lasting discredit (and parroted by biographers such as Kobler, Gloyne and Gray) should have been forestalled by the evidence of Hunter's necropsy which—as Rosenberg mentions—showed evidence of widespread coronary and cerebral vascular disease. And that necropsy was carried out in 1793 by the same Everard Home who, a year later, wrote the biographical sketch which accompanied the posthumous publication of Hunter's final work5 and which Rosenberg inclines to ascribe to Home's ‘nefarious reasons’.

Even when Home misrepresented Hunter's intentions regarding his MSS—thirty years later and after the plagiarism and burning—he did not resort to maligning Hunter in other ways. In 1793-94 he had even more reason not to impugn Hunter, on whom his own somewhat dubious fame would be founded; and he had not yet entered into the friendship with the Prince Regent to which, directly and indirectly, I am inclined to attribute his later truculent alcoholism.
Implementation of an interdisciplinary care team to create individualized care plans for high risk oncology patients: A model to decrease aggressiveness of care at the end of life and improve cost effectiveness of care.
Authors: Girish Chandra Kunapareddy, Joseph Hooley, Leticia Varella, Christa Poole, Helen Tackitt, Stacey Booker, Carolyn Best, Julie Fetto, Ruth Lagman, Alberto J. Montero, Armida Parala
Journal: Journal of Clinical Oncology (2017)

171 Background: Due to complexity of disease and treatments, oncology patients have among the highest hospitalization rate, especially towards End of Life (EOL). In our cancer institute, just 6% of all discharged patients accounted for &gt;40% of unplanned readmissions, and continue to be highest risk of future admissions, ICU stay, ED visits, overuse of chemotherapy and under use of hospice care. We hypothesized that developing individualized care plans (ICP) for this high-utilization group will provide guidance in the complex care they require to reduce unnecessary and aggressive medical services. Methods: An Interdisciplinary Care Team (ICT) was created consisting of palliative medicine and oncology physicians, social workers, care coordinators, and nurses. On a bimonthly basis, patients with at least two unplanned hospital readmissions over the last 60 days were identified. ICPs were created using a team-based approach with parallel input from patient’s primary outpatient providers. Results: A total of 36 patients, 226 hospitalizations, and 163 ED visits were evaluated over a 6-month period, with an average number of hospitalizations of 1.08 per patient month (ppm). After implementation of ICP, hospitalizations decreased to 0.23 ppm, with an average length of stay decrease from 7.17 to 4.06 days per admission. Average ED visits decreased from 0.58 to 0.34 ppm, and the average number of unplanned readmissions decreased from 0.43 to 0.13 ppm. Of the 10 patients expired since creation of ICP, 8 utilized hospice care, while 2 patients died in an ICU. Average time to death from creation of ICP was 72 days among this cohort, while time to death from last exposure to chemotherapy was 58 days. Conclusions: Creation of individualized care plans for high-utilizing cancer patients decreased number of hospitalizations, ED visits, unplanned readmissions, and length of stay. A dedicated focus from a team of experts, beyond disease biology, on a unique patient situation may result in improved patient experience with decreased aggressiveness of care at EOL and overall resource utilization.
MONARCH 2: Abemaciclib in combination with fulvestrant in Asian women with HR+, HER2- advanced breast cancer who progressed on endocrine therapy
Authors: M. Toi, C. Huang, Y-H Im, H. Iwata, J.H. Sohn, H-C Wang, N. Masuda, Y. Lin, S. Sakaguchi, N. Bourayou, A. Llombart, G. Sledge
Journal: Annals of Oncology (2017)
Ligand Activation of PPARγ by Ligustrazine Suppresses Pericyte Functions of Hepatic Stellate Cells via SMRT-Mediated Transrepression of HIF-1α
Authors: Feng Zhang, Shuai Lu, Jianlin He, Huanhuan Jin, Feixia Wang, Li Wu, Jiangjuan Shao, Anping Chen, Shizhong Zheng
Journal: Theranostics (2017)

Rationale: Hepatic stellate cells (HSCs) are liver-specific pericytes regulating vascular remodeling during hepatic fibrosis. Here, we investigated how ligustrazine affects HSC pericyte functions. Methods: Rat HSC-T6 and human HSC-LX2 cells were cultured, and multiple molecular experiments including real-time PCR, Western blot, flow cytometry, immunofluorescence, electrophoretic mobility shift assay and co-immunoprecipitation were used to elucidate the underlying mechanisms. Molecular simulation and site-directed mutagenesis were performed to uncover the target molecule of ligustrazine. Rats were intoxicated with CCl4 for evaluating ligustrazine's effects in vivo. Results: Ligustrazine inhibited angiogenic cytokine production, migration, adhesion and contraction in HSCs, and activated PPARγ. Selective PPARγ inhibitor GW9662 potently abrogated ligustrazine suppression of HSC pericyte functions. Additionally, HIF-1α inhibitor PX-478 repressed HSC pericyte functions, and ligustrazine inhibited the transcription of HIF-1α, which was diminished by GW9662. Moreover, ligustrazine downregulation of HIF-1α was rescued by knockdown of SMRT, and ligustrazine increased PPARγ physical interaction with SMRT, which was abolished by GW9662. These findings collectively indicated that activation of PPARγ by ligustrazine led to transrepression of HIF-1α via a SMRT-dependent mechanism. Furthermore, molecular docking evidence revealed that ligustrazine bound to PPARγ in a unique double-molecule manner via hydrogen bonding with the residues Ser289 and Ser342. Site-directed mutation of Ser289 and/or Ser342 resulted in the loss of ligustrazine transrepression of HIF-1α in HSCs, indicating that interactions with both the residues were indispensable for ligustrazine effects. Finally, ligustrazine improved hepatic injury, angiogenesis and vascular remodeling in CCl4-induced liver fibrosis in rats. Conclusions: We discovered a novel ligand activation pattern for PPARγ transrepression of the target gene with therapeutic implications in HSC pericyte biology and liver fibrosis.
Abstract 24036: Inhibition Of Prolyl-tRNA Synthetase As A Novel Mediator Of Cardiac Fibrosis
Authors: Joon Seok Park, Caroline H Lee, Sungjin Yoon, Jong Hyun Kim, Sunghoon Kim, Bongyong Lee
Journal: Circulation (2017)

Introduction: Prolyl-tRNA synthetase (PRS), a member of aminoacyl tRNA synthetases (ARS), is an enzyme that conjugates amino acid proline to its cognate tRNA to generate prolyl-tRNA to be used in protein synthesis. Since ARS are essential for protein synthesis and viability, dysregulation of ARS has been proposed to many human diseases. Cardiac fibrosis is characterized by excess production and deposition of ECM proteins by activated fibroblast. Although proline is a main component of collagen and ECM proteins, the exact mechanism and involvement of PRS in cardiac fibrosis has not yet been elucidated. Hypothesis: We hypothesized that suppression of PRS would down-regulate collagen synthesis, which could be beneficial in cardiac fibrosis. Results: To validate our hypothesis, we investigated the expression levels of pro-fibrotic markers by overexpression or knockdown of PRS in vitro. We showed that PRS is closely related to the expression of collagen I and α-SMA. Then, we showed that treatment of DWN12088, a novel small molecular selective inhibitor of PRS, reduced expression levels of pro-fibrotic markers in TGFβ-induced fibrotic environments using various cell-lines and primary fibroblasts. Interestingly, we showed that down-regulation of pro-fibrotic markers by DWN12088 is independent of TGFβ signaling pathway, although TGFβ is required for induction of pro-fibrotic markers. In vivo study, we performed transverse aortic constriction in C57BL/6 mice to evaluate the effect of DWN12088 in cardiac fibrosis. TAC results in pressure overload-induced left ventricular hypertrophy and fibrosis, and it is one of the most widely used models to study cardiovascular diseases. 2-week oral treatment of DWN12088 markedly reduced cardiac fibrosis with ED 50 of 0.4 mg/kg, based on histological examinations. In addition, we demonstrated that 2-week oral treatment of DWN12088 showed reduction in infiltration of inflammatory cells, left ventricle thickness and accumulation of collagen fiber. Conclusion: These results suggest that inhibition of PRS attenuates pressure-overloaded cardiac fibrosis and a selective inhibitor of PRS, DWN12088, could serve as a potent anti-fibrotic agent without affecting critical cellular signaling cascade.