tbuckley/cabot-search huggingface dataset:
SCORAD III: Randomized noninferiority phase III trial of single-dose radiotherapy (RT) compared to multifraction RT in patients (pts) with metastatic spinal canal compression (SCC).
Authors: Peter Hoskin, Vivek Misra, Kirsten Hopkins, Tanya Holt, Gillian Brown, Seonaid Arnott, Sharon Shibu Thomas, Krystyna Reczko, Sandy Beare, Andre Lopes, Sharon Forsyth
Journal: Journal of Clinical Oncology (2017)

LBA10004 Background: SCC is a common complication of metastatic cancer. Most pts receive RT to improve neurological function and mobility and to relieve pain. There is no standard schedule (RT ranges from single dose 8Gy to 40Gy in 20 fractions). SCORAD III was conducted to show whether a single fraction is as effective as multifraction RT without compromising patient outcomes. Methods: Pts from 43 UK and 4 Australian sites were randomized (1:1) to receive external beam spinal canal RT as a single dose of 8Gy or 20Gy in 5 fractions; stratified by RT center, ambulatory status (AS), site of primary, and presence or absence of nonskeletal metastases. Eligible pts had spinal cord or cauda equina (C1-S2) compression confirmed by MRI/CT scan, treatable within a single radiation field, life expectancy &gt;8 weeks (wks), no previous RT to the same area. Primary endpoint was AS at wk 8: graded 1 (full function) to 4 (no/flicker motor power). The noninferiority margin was 11% for comparing the proportion of patients with AS 1 or 2 at wk 8 (whether maintained from baseline or improved from AS 3-4). Results: 688 pts were randomized Feb 2008 to Apr 2016 (n=345 single dose, n=343 multifraction). 73% were male; median age 70 years; ambulatory with/without walking aids 66%; 44% prostate, 18% lung, 11% breast, 11% gastrointestinal. Baseline characteristics were balanced. 69.5% (114/164 pts evaluable at wk 8) single dose vs. 73.3% (129/176) multifraction had AS 1-2 at wk 8 (risk difference: -3.78%, 90%CI -11.85 to 4.28). Importantly, overall survival (OS) was very similar: median OS 12.4 wks single dose vs. 13.7 multifraction, (hazard ratio 1.02 [95%CI 0.86-1.21], p=0.81). Proportion of pts with adverse events was similar for grade 3-4 (20.6% single dose vs. 20.4% multifraction), but grade 1-2 events were lower with single dose (51.0% vs. 56.9%). Conclusions: Using a single dose of 8Gy in pts with metastatic SCC was as effective as multiple fractions for AS at 8 wks and OS. We now recommend using single dose RT in this setting, with the major benefit of requiring only a single instead of multiple hospital visits, important when considering the short survival in these pts. Clinical trial information: 97108008.
Abstract 1580: The Current Diagnostic Accuracy Of Cardiac CT For Left Atrial Appendage Thrombus Is Poor
Authors: Ilan Gottlieb, Aurelio Pinheiro, Jeffrey A Brinker, Mary Corretti, Susan A Mayer, David Bluemke, Joao A Lima, Joseph E Marine, Ronald D Berger, Hugh Calkins, Theodore Abraham, Charles A Henrikson
Journal: Circulation (2007)
Kinase-independent functions of RIPK1 regulate hepatocyte survival and liver carcinogenesis
Authors: Trieu-My Van, Apostolos Polykratis, Beate Katharina Straub, Vangelis Kondylis, Nikoletta Papadopoulou, Manolis Pasparakis
Journal: Journal of Clinical Investigation (2017)

The mechanisms that regulate cell death and inflammation play an important role in liver disease and cancer. Receptor-interacting protein kinase 1 (RIPK1) induces apoptosis and necroptosis via kinase-dependent mechanisms and exhibits kinase-independent prosurvival and proinflammatory functions. Here, we have used genetic mouse models to study the role of RIPK1 in liver homeostasis, injury, and cancer. While ablating either RIPK1 or RelA in liver parenchymal cells (LPCs) did not cause spontaneous liver pathology, mice with combined deficiency of RIPK1 and RelA in LPCs showed increased hepatocyte apoptosis and developed spontaneous chronic liver disease and cancer that were independent of TNF receptor 1 (TNFR1) signaling. In contrast, mice with LPC-specific knockout of Ripk1 showed reduced diethylnitrosamine-induced (DEN-induced) liver tumorigenesis that correlated with increased DEN-induced hepatocyte apoptosis. Lack of RIPK1 kinase activity did not inhibit DEN-induced liver tumor formation, showing that kinase-independent functions of RIPK1 promote DEN-induced hepatocarcinogenesis. Moreover, mice lacking both RIPK1 and TNFR1 in LPCs displayed normal tumor formation in response to DEN, demonstrating that RIPK1 deficiency decreases DEN-induced liver tumor formation in a TNFR1-dependent manner. Therefore, these findings indicate that RIPK1 cooperates with NF-κB signaling to prevent TNFR1-independent hepatocyte apoptosis and the development of chronic liver disease and cancer, but acts downstream of TNFR1 signaling to promote DEN-induced liver tumorigenesis.
FOLFOX or CAPOX perioperative chemotherapy versus postoperative chemotherapy for locally advanced colon cancer: OPTICAL study.
Authors: Yanhong Deng, Huabin Hu, Ping Lan, Lei Wang, Meijin Huang, Zhiyang Zhou, Yue Cai, Jianping Wang
Journal: Journal of Clinical Oncology (2016)

TPS3637 Background: In patients with high risk stage II and stage III colon cancer (CC), curative surgery followed by adjuvant chemotherapy with FOLFOX or CAPOX regimens has become a standard treatment. However, 20 to 30 % of these patients will develop distant metastasis, which ultimately result in death. Perioperative chemotherapy is a promising strategy with potential benefits that could be more effective at eradicating micrometastases. Moreover, shrinking tumor before surgery not only facilitate removal of all the tumor by the surgeon but also reduce tumor cell spreading during the procedure. With recent advances in radiology, preoperative computed tomography is a robust method for measuring the depth of tumor invasion and identifying the CC patients with poor prognosis, who may benefit from perioperative chemotherapy. We conducted the present randomized study to explore whether perioperative chemotherapy with FOLFOX or CAPOX regimens compared with postoperative chemotherapy could improve disease-free survival in patients with radiologically staged, locally advanced, but resectable colon cancer. Methods: This trial is a two-arm, multicenter, open labelled, prospective, randomized phase III studies. 738 eligible patients with locally advanced (T4 or T3 with extramural depth≧5 mm) CC patients will be randomly assigned, in a 1:1 ratio, to receive either perioperative (6 cycles of mFOLFOX6 or 4 cycles of CAPOX followed by surgery and a further 6 cycles of mFOLFOX6 or 4 cycles of CAPOX) or postoperative chemotherapy (surgery followed by 12 cycles of mFOLFOX6 or 8 cycles of CAPOX). The primary objective of this study is 3-year disease-free survival. Secondary objectives are efficacy in terms of R0 resection rate, overall survival (OS), relapse-free survival (RFS), down-staging of primary tumors, and tolerability of perioperative therapy and postoperative complications. Clinical trial information: NCT02572141.
Living on the Fat of the Land: The Changing Face of Malnutrition amongst Medical Patients
Authors: A Coss, M Doherty, A Geary, C Keenan, J Mahon, G Courtney, C McGurk
Journal: Endoscopy (2004)

Previous studies have identified that a significant proportion of general medical admissions are malnourished and that this has a negative impact on clinical outcome.
Minimal Residual Disease Monitoring in Acute Myeloid Leukemia (AML) with Translocation t(8;21)(q22;q22): Results of the AML Study Group (AMLSG)
Authors: Mridul Agrawal, Andrea Corbacioglu, Peter Paschka, Daniela Weber, Verena I. Gaidzik, Nikolaus Jahn, Andrea Kündgen, Thomas Kindler, Mohammad Amen Wattad, Michael Lübbert, Walter Fiedler, Katharina Götze, Mark Ringhoffer, Jan Schleicher, Elisabeth Lange, Gerhard Held, Martin Griesshammer, Richard Greil, Heinz Kirchen, Elisabeth Koller, Felicitas Thol, Jürgen Krauter, Michael Heuser, Arnold Ganser, Lars Bullinger, Richard F. Schlenk, Hartmut Döhner, Konstanze Döhner
Journal: Blood (2016)
First-line icotinib in elderly patients with non-small cell lung cancer harboring active EGFR mutation: A multi-center, single-arm study.
Authors: Chunlei Shi, Aiqin Gu, Liwen Xiong, Yuping LI, Xiaohong Cai, Tianqing Chu, Jialin Qian, Rong Li, Baohui Han
Journal: Journal of Clinical Oncology (2016)

e20519 Background: Increasing elderly patients suffer from non-small cell lung cancer (NSCLC) due to aged population, which is associated with more comorbidities and reduced organ function. Here we present a phase 2, single-arm study to evaluate first-line icotinib in elderly NSCLC patients harboring EGFR mutation. Methods: Chemotherapy-naïve patients aged 70 years or older with stage IIIB or IV NSCLC with activating EGFR mutation (exon 19 deletion and L858R mutation in exon 21) were enrolled and treated with oral icotinib (125 mg, three times per day) until disease progression. The primary endpoint was progression-free survival (PFS). This study was registered at ClinicalTrials.gov as NCT01646450. Results: Between October 12, 2012 and February 12, 2014, 35 patients were enrolled and received treatment per protocol at 3 sites in China. The median age was 76.4 years, most patients had stage IV disease (71.4%) with ECOG performance status 0-1 (85.7%). Hypertension was the most common comorbidity (56%), followed by diabetes mellitus (16%). At the cut-off, 27 patients reached endpoints(25 progressive diseases, 2 deaths), the median PFS was 17.2 months (95%CI 12.3-25.1). The objective response rate and disease control rate was 62.9% and 97.1%, respectively. Rash (68.6%) was the most common treatment-related adverse events, followed by diarrhea (48.6%), pruritus (25.7%), and fatigue (14.3%). Grade 3 toxicities were only seen in 3 patients (rash, pruritus and rhagades). Thirty-two patients completed the FACT-LCS questionnaire after 6, 12, and 18 weeks of treatment, with a mean FACT-LCS score of 100.5, 97.1, and 99. 2, respectively. Conclusions: First-line icotinib showed favorable efficacy, safety profile and quality of life in elderly patients harboring EGFR mutation, suggesting it a feasible treatment option for this population. Clinical trial information: NCT01646450.
Phase II trial of the MEK1/2 inhibitor selumetinib (AZD6244) in adults with neurofibromatosis type 1 (NF1) and inoperable plexiform neurofibromas (PNs).
Authors: Diana Bradford, Patricia Whitcomb, Eva Dombi, Alice P. Chen, Andrea Baldwin, Pamela Wolters, Staci Martin, John Glod, Joanne Derdak, Geraldine Helen O'Sullivan Coyne, Edward W. Cowen, Marielle Holmblad, Jane Trepel, Bradford J. Wood, Scott M. Paul, Wade Clapp, Gary L. Johnson, Larry Rubinstein, L. Austin Doyle, Brigitte C. Widemann
Journal: Journal of Clinical Oncology (2016)

TPS2596 Background: PNs in NF1 are a major source of morbidity, causing disfigurement, functional impairment, and pain. Selumetinib is an oral inhibitor of MEK 1/2, which may mediate anti-tumor effects in PNs by inhibiting Ras signaling. Selumetinib is currently undergoing evaluation in adult cancers, pediatric brain tumors and NF1 related PNs. Our phase I trial of selumetinib for children with NF1 and inoperable PNs demonstrated unprecedented activity with objective responses (PN volume decrease ≥ 20% using volumetric MRI analysis) in > 50% of patients (pts) enrolled. However, we have observed slow PN regrowth in several patients who required dose reductions for toxicity. This suggests that a certain selumetinib tissue concentration may be required for target inhibition and anti-tumor activity. Methods: This study will evaluate 1) the objective response rate to selumetinib in pts ≥ 18 years old with NF1 and inoperable, growing or symptomatic PNs, 2) PN and dermal neurofibroma (DN) biopsies prior to and on treatment with selumetinib for mechanisms of response and resistance, 3) the potential clinical benefit of selumetinib with evaluations of PN related pain, quality of life, and function, and 4) steady state pharmacokinetics and pharmacodynamics (cytokines, bone marrow derived precursor cells, and peripheral blood immune subsets). Willingness to undergo PN biopsies is required for eligibility. Pts will receive selumetinib at the adult recommended dose of 75 mg every 12 hours on a continuous dosing schedule (1 cycle = 28 days). PN biopsies will be analyzed for pERK, pAKT, pMEK, tumor kinome and transcriptome, and immune infiltrate. In addition, we will analyze and compare pERK, pAKT in DN. Response will be evaluated with periodic volumetric MRI analysis. Patient-reported outcome and adherence evaluations will be conducted. With a Simon two-stage design targeting a 45% response rate (90% power), if ≥ 5/20 pts in stage 1 respond, enrollment will be expanded to 35 evaluable patients and if ≥ 12/35 patients respond, selumetinib will be considered active. This CTEP-sponsored single site open label phase II study (NCT02644512) is currently enrolling patients. Clinical trial information: NCT02644512.
Soundings: Axel Munthe and The Story of San Michele
Authors: George Dunea
Journal: BMJ (2006)

He loved birds, flowers, and especially dogs, which he thought were easier to understand and to love than men. He travelled widely, from Lapland in his native Sweden to Italy, where he built the villa of San Michele at Anacapri on the ruins of Tiberius's palace. In Naples he witnessed the dying gathered in heaps and thrown into cholera mass graves dead or alive. In Messina he saw people crushed to death during a horrific earthquake. He tended patients dying from typhoid and children suffocating from diphtheria. He often saw young patients with consumption: fever, wasting, “ominous crackles in the top of the lung,” then the fatal haemorrhage. He saw others, some in prominent positions, develop the expansive insanity of the general paretic. But in Paris, and later in Rome, he was incredibly successful with the neurotic or hysterical women who had chronic “appendicitis” or “colitis.” This success he ascribed to his ability to inspire confidence, a gift he thought was granted by birthright to one doctor but denied to another, one so magic that “the doctor who possesses this gift can almost raise the dead.”

In Paris he knew Henry and William James, Guy de Maupassant, Somerset Maugham. He remembers Louis Pasteur, pale and worn, helpless at the bedside of the Russian peasants bitten by rabid wolves. He accompanied the body of a young Swede to Stockholm but then discovered that the caskets had been switched and that he had brought the body of an ancient Russian general.

Not always politically correct, he attributed women's historic lack of achievement in the arts and sciences to intrinsic differences rather than to lack of opportunities. For criminals he favoured short sentences with severe floggings for first offenders, execution for recidivists. He thought doctors should keep aloof of their patients or their prestige would suffer, and so should authors, as shown by the medieval monks who would “think little of a man's writings if they had even once seen him.” Books, including his own, would need successive generations of readers and reviewers to fix their value. But in 1928 he wrote The Story of San Michele, which became a best seller in 25 languages and is still read today.
Failure to Upregulate IL-2/IL-15 in Tumour Bearing Liver May Reflect Defective Effector Mechanisms
Authors: AM Kelly, L Golden-Mason, O Traynor, G McEntee, JE Hegarty, C O'Farrelly
Journal: Endoscopy (2004)

We have previously demonstrated a significant antitumour-Th1 response, evidenced by upregulation of IFN-γ levels, but a failure to upregulate IL-2 production in tumour-bearing liver, which may reflect a defect in the cytotoxic T-cell response, thus promoting tumour tolerance. IL-15 shares many biological properties with IL-2 and also plays a critical role in the development of NK/NKT cells – principal mediators of innate anti-tumour immunity. The relative deficiency of IL-2 in tumour-bearing liver may be balanced by an increase in IL-15 levels. The aim of this study was to localise and quantify IL-15 expression and to enumerate IL-15 responsive lymphocyte populations in normal and tumour-bearing liver. Normal (n=11) and tumour-bearing (n=12) liver, was snap frozen, powdered, protein was extracted and IL-15 levels were quantified using a modified ELISA. IL-15 was localised using immunohistochemistry. CD8+cytotoxic T-lymphocytes and NKT-cells were quantified in hepatic tissue using flow cytometry. IL-15 protein was detected in normal liver at a median concentration of 0.349ng/100mg protein. There was a significant reduction in IL-15 levels in tumour bearing liver (0.22ng/100mg protein, p=0.01). IL-15 was localised to both infiltrating monocytes within portal tracts and to perisinusoidal tissue. Surprisingly, there was no increase in CD8+ T-cells or NKT-cells in tumour-bearing compared to normal liver. These results suggest that, while there is a significant anti-tumour immune response in tumour-bearing liver, the lack of a significant increase in IL-2 and the down regulation of IL-15 levels, may reflect a defect in both cytotoxic T-cell and innate immune responses, thus promoting tumour progression.
Abstract 105: The nitroso-redox-induced SR Ca <sup>2</sup> + leak is temperature-sensitive: Role of Nitric Oxide Synthase 1
Authors: Raul A Dulce, Vera Mayo, Erika B Rangel, Wayne Balkan, Joshua M Hare
Journal: Circulation Research (2013)

Sarcomeric reticulum (SR) Ca 2+ leak contributes to an impaired Ca 2+ cycling and contractile dysfunction of the heart. Leak is thought to be regulated by post-translational modifications of RyR2 associated with nitroso-redox (NO/redox) imbalance. Ca 2+ cycling is affected by both NO signaling and temperature. We hypothesized that NO/redox balance modulates SR Ca 2+ leak in a temperature–dependent manner. We used tetracaine to investigate SR Ca 2+ leak in cardiomyocytes (CMs) using a model of NO/redox imbalance (NOS1 −/− mice) or WT mice. Reactive oxygen species (ROS) were measured by H 2 DCF. The expression of NOS isoforms was assessed by real time PCR. Experiments were carried out at 23°C - 37°C. The SR Ca 2+ leak increased as the temperature decreased from 34°C to 23°C in WT CMs whereas, in NOS1 −/− CMs, the leak suddenly increased when the temperature surpassed 30°C (Fig. A). SR Ca 2+ content in NOS1 −/− CMs was reduced at 37°C compared to 23°C (42.7 mol/L vs. 115.6 mol/L, respectively; p =0.001), whereas it was unaffected in WT CMs. Differences in Ca 2+ leak between WT and NOS1 −/− were magnified according the SR Ca 2+ load increased. Contrarily to WT, there was a trend to rise in ROS production at temperatures over 30°C in NOS1 −/− CMs (Fig. B). There was a linear association between ROS and leak in both strains. The NOS isoforms were unaffected by temperature in WT. Our observations show that Ca 2+ leak increases when the temperature drops below 34°C; however, in the absence of NOS1 activity, the leak rises at temperatures greater than 30°C, and is associated with more ROS production. These results suggest that Ca 2+ leak from the SR is regulated by a temperature-dependent balance between NO and ROS.
Immunomodulatory properties of fluconazole on the activity of PMNs from hemodyalized and renal transplant patients towards C.albicans.
Authors: C. Merlino, F. Giacchino, V. Tullio, A.M. Cuffini, A. Bonino, M.A Aimino, N.A. Carlone
Journal: Journal of the American Society of Nephrology (1996)
Abstract P250: Reversal of Excessive <i>O</i> -GlcNAcylation Restores Myofilament Function in Diabetic Cardiomyopathy: Potential Role of OGT/OGA Enzymes Localization
Authors: Genaro A Ramirez-Correa, Chad Slawson, Wengang Ding, Xiaoxu Shen, Wei D Gao, Gerald W Hart, Anne M Murphy
Journal: Circulation Research (2011)

Diabetes Mellitus impacts the heart contractile apparatus, as well as cellular ion homeostasis, and energy production systems. Diabetic cardiomyopathy is accompanied by extensive changes in protein post-translational modifications (PTMs), including phosphoylation and O- GlcNAcylation. The cellular and molecular mechanisms of diabetic cardiomyopathy are only partially understood. We previously identified 32 total O- GlcNAcylation sites on MHC, Actin, MLC 1, MLC2, and TnI from normal hearts, and showed that exposure of skinned muscles to GlcNAc induces myofilament Ca 2+ desensitization. In addition, Actin O- GlcNAcylation was increased when exposed to GlcNAc in vitro or to hyperglycemia in two models of Diabetes Mellitus (DM) type 1 and type 2. Our hypothesis is that hyperglycemia directly alters the cycling of O -GlcNAcylation on key myofilament regulatory proteins, and that excessive O -GlcNAcylation is responsible for defective myofilament Ca 2+ -activated response, thus contributing to diabetic cardiomyocyte dysfunction. To test this hypothesis, we have identified OGT localization at the Z-disks where other relevant signaling molecules reside, whereas OGA is localized along the M-band. OGT and OGA affinity for myofilament proteins (Actin, Tm, MLC1 and MLC2) is dramatically up-regulated in the diabetic heart, as assessed by co-immunoprecipitation and Western Blot. We also investigated the effect of O -GlcNAc removal from normal and diabetic skinned muscles by an engineered hexosaminidase (CPJ). We found that 1 hour exposure to CPJ restored myofilament Ca 2+ sensitivity exclusively in diabetic cardiac muscles (EC 50 4.17±0.48 µM pre-CPJ vs 2.73±0.22 µM post-CPJ, n =5 vs n =4, p=0.029 ). These results establish a direct link between cardiac protein hyper- O -GlcNAcylation and diabetic altered cardiac myofilament Ca 2+ sensitivity. Furthermore, OGT and OGA are abundant, and located at strategic signaling compartments, such as the Z-Disk. Overall these data suggest that a specific increase of OGT/OGA affinity towards key myofilament regulatory proteins, and subsequent hyper- O -GlcNAcylation may lead to dysfunctional regulation of myocardial contractility.
Antiplatelet therapy and the risk of hepatocellular carcinoma in chronic hepatitis B patients on antiviral treatment
Authors: Minjong Lee, Goh Eun Chung, Jeong‐Hoon Lee, Sohee Oh, Joon Yeul Nam, Young Chang, Hyeki Cho, Hongkeun Ahn, Young Youn Cho, Jeong‐ju Yoo, Yuri Cho, Dong Hyeon Lee, Eun Ju Cho, Su Jong Yu, Dong Ho Lee, Jeong Min Lee, Yoon Jun Kim, Jung‐Hwan Yoon
Journal: Hepatology (2017)

Antiplatelet therapy has shown protective effects against hepatocellular carcinoma (HCC) in preclinical studies. However, it is unclear whether antiplatelet therapy lowers the risk of HCC in patients with chronic hepatitis B. A retrospective analysis was conducted of data from 1,674 chronic hepatitis B patients, enrolled between January 2002 and May 2015, whose serum hepatitis B virus DNA levels were suppressed by antivirals to &lt;2,000 IU/mL. The primary and secondary outcomes were development of HCC and bleeding events, respectively. Risk was compared between patients with antiplatelet treatment (aspirin, clopidogrel, or both; antiplatelet group) and patients who were not treated (non‐antiplatelet group) using a time‐varying Cox proportional hazards model for total population and propensity score–matching analysis. The antiplatelet group included 558 patients, and the non‐antiplatelet group had 1,116 patients. During the study period, 63 patients (3.8%) developed HCC. In time‐varying Cox proportional analyses, the antiplatelet group showed a significantly lower risk of HCC (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.23–0.85; P = 0.01), regardless of antiplatelet agent. In propensity score–matched pairs, antiplatelet therapy significantly reduced the risk of HCC (HR, 0.34; 95% CI, 0.15‐0.77; P = 0.01). However, the overall risk of bleeding was higher in the antiplatelet group (HR, 3.28; 95% CI, 1.98‐5.42; P &lt; 0.001), particularly for clopidogrel with or without aspirin. Treatment with aspirin alone was not associated with a higher bleeding risk (HR, 1.11; 95% CI, 0.48‐2.54; P = 0.81). Conclusion : Antiplatelet therapy reduces the risk of HCC in chronic hepatitis B patients whose hepatitis B virus is effectively suppressed. However, antiplatelet therapy containing clopidogrel may increase the risk of bleeding. (H epatology 2017;66:1556–1569)