tbuckley/cabot-search huggingface dataset:
Mutant<i> PIK3CA</i>-mediated pancreatic tumorigenesis and the response to PI3K pathway inhibition.
Authors: Susan Payne, Molly Maher, Nguyen Tran, Dana Van DeHey, Foley Tyler, Alexander Yeuh, Alyssa A. Leystra, Cheri Pasch, Linda Clipson, Kristina Matkowskyj, Dustin A. Deming
Journal: Journal of Clinical Oncology (2015)

e15273 Background: Pancreatic ductal adenocarcinoma (PDA) remains a leading cause of cancer related mortality despite recent treatment advances. The majority of PDAs are initiated secondary to KRAS mutations, which result in resistance to targeted therapies. Subsets of pancreatic cancers possess PIK3CA mutations, which lead to oncogenic activation of the PI3K pathway. Here we examined the ability of PIK3CA mutations to initiate pancreatic tumorigenesis and the response of PIK3CA-mutant PDAs to dual PI3K/mTOR inhibition. Methods: Genetically engineered murine models were generated expressing a constitutively active PI3K within the pancreas, including the PIK3CA H1047R hotspot mutation. A time course was examined to understand tumorigenesis in these models. Mice with PIK3CA mutant pancreatic cancer were treated with a dual PI3K/mTOR inhibitor, NVP-BEZ235 (35mg/kg body weight/day dissolved in 1 volume N-methyl-2-pyrrolidone and 9 volumes PEG300), or a vehicle-only control. Results: A constitutively active PI3K within the pancreas resulted in acinar-to-ductal metaplasia, pancreatic intraepithelial neoplasia (PanIN), and PDAs. In a model with a gene encoding a fusion protein which results in a dominant active PI3K; invasive cancer was detected at just 20 days of age and these mice became moribund at a median of 53 days secondary to large pancreatic tumors. In the H1047R model, PanIN lesions were detected at 150 days of age and PDAs at 250 days. Activation of the PI3K pathway was demonstrated in these lesions. Interestingly, activation of MAPK was also identified. Treatment with NVP-BEZ235 resulted in decreased phosphorylation of AKT and RPS6. Phosphorylation of MAPK was also suppressed with NVP-BEZ235 treatment. Histological analysis demonstrated a profound treatment response with a dramatic decrease in the epithelial component such that the remaining fibrous tumor bed made up the majority of the pancreatic mass Conclusions: PIK3CA mutations can initiate pancreatic tumorigenesis and these cancers are highly sensitive to dual PI3K/mTOR inhibition. These results warrant future studies of PI3K pathway inhibitors for patients with PIK3CA-mutant pancreatic cancers.
California considers plan to replace Obamacare
Authors: Michael McCarthy
Journal: BMJ (2017)

Two California state senators have introduced legislation to establish a universal, single payer healthcare insurance program that would cover all of the state’s residents—including immigrants without documentation—in response to moves by president Donald Trump to repeal the Affordable Care Act.

“With Republicans on the brink of rolling back healthcare it’s time for California to lead,” said state senator Ricardo Lara, a Democrat from a district in Los Angeles County who introduced the bill on 17 February with senator Toni G Atkins, a Democrat from San Diego. The sponsors said that the …
DNA-thioguanine nucleotide concentration and relapse-free survival during maintenance therapy of childhood acute lymphoblastic leukaemia (NOPHO ALL2008): a prospective substudy of a phase 3 trial
Authors: Stine Nygaard Nielsen, Kathrine Grell, Jacob Nersting, Jonas Abrahamsson, Bendik Lund, Jukka Kanerva, Ólafur Gísli Jónsson, Goda Vaitkeviciene, Kaie Pruunsild, Lisa Lyngsie Hjalgrim, Kjeld Schmiegelow
Journal: The Lancet Oncology (2017)
Acceleration of Dabigatran Elimination by Activated Charcoal Perfusion and Hemodialysis in a Pig Model.
Authors: Jessica Lange, Christian Thiel, Karolin Thiel, Wilfried Klingert, Kathrin Klingert, Alfred Königsrainer, Stephan Formella, Andreas Clemens, Joanne van Ryn, Martin Schenk
Journal: Blood (2012)
Response by Meneveau and Ecarnot to Letter Regarding Article, “Optical Coherence Tomography to Optimize Results of Percutaneous Coronary Intervention in Patients With Non-ST-Elevation Acute Coronary Syndrome: Results of the Multicenter, Randomized DOCTORS Study (Does Optical Coherence Tomography Optimize Results of Stenting)”
Authors: Nicolas Meneveau, Fiona Ecarnot
Journal: Circulation (2017)
Phase 1b Study of Pembrolizumab in Patients with Relapsed/Refractory Primary Mediastinal Large B-Cell Lymphoma: Results from the Ongoing Keynote-013 Trial
Authors: Pier Luigi Zinzani, Vincent Ribrag, Craig H. Moskowitz, Jean-Marie Michot, John Kuruvilla, Arun Balakumaran, Yayan Zhang, Patricia Marinello, Sabine Chlosta, Eric Gustafson, Margaret A. Shipp, Philippe Armand
Journal: Blood (2016)
Influence of Matched Sibling Donor's Availability and Stem Cell Transplantation on Treatment Outcome for Acute Lymphoblastic Leukemia; Study on 294 Patients
Authors: Feras Alfraih, Wahiba Chebbo, Dennis Dong Hwan Kim, Ghuzayel Aldawsari, Fahad Z. Alsharif, Hazza A Alzahrani, Said Y Mohamed, Walid Rasheed, Amr Hanbali, Syed Osman Ahmed, Marwan Shaheen, Naeem A. Chaudhri, Fahad Al Mohareb, Mahmoud Aljurf
Journal: Blood (2015)
Erratum: Acetylcholine receptor M3 domain: stereochemical and volume contributions to channel gating
Authors: Hai-Long Wang, Margherita Milone, Kinji Ohno, Xing-Ming Shen, Akira Tsujino, Anna Paola Batocchi, Pietro Tonali, Joan Brengman, Andrew G. Engel, Steven M. Sine
Journal: Nature Neuroscience (1999)
An updated safety analysis of OCEANS, a randomized, double-blind, phase III trial of gemcitabine (G) and carboplatin (C) with bevacizumab (BV) or placebo (PL) followed by BV or PL to disease progression (PD) in patients with platinum-sensitive (Plat-S) recurrent ovarian cancer.
Authors: Carol Aghajanian, Stephanie V. Blank, Barbara Ann Goff, Patricia Lynn Judson, Lawrence R. Nycum, Mika A. Sovak, Jing Yi, Amreen Husain
Journal: Journal of Clinical Oncology (2012)

5054 Background: OCEANS met its primary end point with a statistically significant and clinically meaningful hazard ratio for progression-free survival (PFS) of 0.484. Secondary end points included objective response rate, overall survival, and safety. Eleven additional months of safety data were collected after the data cut-off date for the final PFS analysis event and updated safety analyses were performed. Methods: Eligible patients (pts) were randomized to arm A: GC (G [1000 mg/m 2 days 1 and 8] and C [AUC 4, day 1], q21d for 6–10 cycles) + concurrent PL (q21d), followed by PL until PD or unacceptable toxicity; or arm B: GC + concurrent BV (15 mg/kg q21d), followed by BV until PD or unacceptable toxicity. All adverse events (AE) were recorded and graded per NCI-CTCAE v3.0. Results: The incidence of any grade AE was 100% in both arms and of SAEs was 25.3% (PL arm) and 35.6% (BV arm). The rates of proteinuria, hypertension (HTN), reversible posterior leukoencephalopathy syndrome (RPLS), thrombocytopenia and epistaxis were higher in the BV arm. More pts in the BV arm (20.6%) than in the PL arm (4.7%) experienced an AE that led to discontinuation of study drug, in the BV arm most commonly due to HTN (4%), proteinuria (2.8%), epistaxis (1.2%), thrombocytopenia (1.6%) and RPLS (0.8%). Median number of BV cycles in pts with G ≥3 proteinuria was 22.5 and the AE resolved in 91.7% of pts. Among the pts with G ≥3 HTN, the median number of BV cycles was 16.5 and the AE resolved in 72.7% of pts. Conclusions: The overall safety profile was similar to that seen at the time of the final PFS analysis. Higher incidences of proteinuria and HTN were possibly related to longer BV treatment duration and resolved in the majority of pts. [Table: see text]
Mutations within BCR-ABL1 295–312 Define a Novel Region Associated with Poor Prognosis in Patients with Chronic Myelogenous Leukemia (CML) Resistant to Imatinib.
Authors: Alfonso Quintás-Cardama, Don L. Gibbons, Hagop Kantarjian, Moshe Talpaz, Jorge Cortes, Nicholas Donato
Journal: Blood (2007)
Final Results of a Multicenter Prospective Phase II Trial of Allogeneic Transplantation for Relapsed/Refractory CD20+ B-Cell Lymphomas: Effect of Rituximab on Graft-Versus-Host Disease-Free/Relapse-Free Survival (GRFS)
Authors: Anna Dodero, Francesca Patriarca, Giuseppe Milone, Barbara Sarina, Rosalba Miceli, Anna Paola Iori, Francesco Barretta, Elisabetta Terruzzi, Alberto Mussetti, Massimo Pini, Alberto Bosi, Alida Dominietto, Nicola Cascavilla, Francesco Onida, Franco Narni, Lucia Farina, Alessandro Rambaldi, Paolo Corradini
Journal: Blood (2016)
ME-143, a novel inhibitor of tumor-specific NADH oxidase (tNOX): Results from a first-in-human phase I study.
Authors: Carla Kurkjian, Shubham Pant, Howard A. Burris, Johanna C. Bendell, Suzanne Fields Jones, Kathleen N. Moore, Ofir Moreno, Robert D. Mass, Jeffrey R. Infante
Journal: Journal of Clinical Oncology (2012)

3067 Background: ME-143, a second generation isoflavone-derived compound, specifically binds tNOX, shifting the ceramide-S1P equilibrium and resulting in prompt apoptosis via pleotrophic caspase activation. A first generation compound, phenoxodiol (PXD), showed promising phase II activity with cisplatin in ovarian cancer. ME-143 is broadly active against human cancers in both in vitro and in vivo models, with IC 50 ’s 1-2 logs lower than PXD. Toxicology studies up to 140mg/kg (human dose equivalent ~23mg/kg) showed no STD level. The only significant findings were dose dependent hypospermia and testicular atrophy in rats. We report clinical and PK results from the first-in-human phase I study. Methods: A 3+3 dose escalation design was used with 4 dose cohorts: 2.5, 5, 10, and 20mg/kg IV over 30 minutes weekly times 3, followed by a 1 week break, and then continuous weekly dosing in patients with advanced solid tumors. Dense PK sampling was performed at 0, 5, 10, 20, 30, 60, 90, 120, 180, 240, 300, 360 minutes, and 24 hours post-infusion day 1 and 15 of the first treatment cycle. Results: To date, 9 patients have been enrolled, 3 in each of the first 3 cohorts. Median time on treatment is 56 days (range 6 to 62). Five patients have discontinued protocol therapy, all due to PD. No DLT’s have been observed. Related AE’s include grade 1: myalgia (1), anorexia (1), fatigue (2), headache (1), diarrhea (1), vomiting (1) and grade 2: fatigue (1). Preliminary PK analyses in the first 2 cohorts is shown in table below. Conclusions: ME-143 appears to be well tolerated when administered IV. Preliminary PK data suggest that drug levels achieve target concentration extrapolated from pre-clinical studies (AUC 0-t ~10mg*hr/mL) and exceed levels obtained with IV PXD in the phase II study (AUC 0-t ~2mg*hr/mL) . Updated clinical data from all planned dose cohorts, including the final pharmacokinetic analysis and planned phase II dose, will be presented. [Table: see text]
Community acquired pneumonia in children
Authors: Iram J Haq, Alexandra C Battersby, Katherine Eastham, Michael McKean
Journal: BMJ (2017)

Correspondence to: I J Haq iram.haq@newcastle.ac.uk

#### What you need to know

In 2015, community acquired pneumonia (CAP) accounted for 15% of deaths in children under 5 years old globally and 922 000 deaths globally in children of all ages.1 It is defined as a clinical diagnosis of pneumonia caused by a community acquired infection in a previously healthy child.2 Clinical assessment can be challenging; symptoms vary with age and can be non-specific in young children, and aetiology is often unknown at presentation.

This article will provide an update on CAP management in otherwise healthy children outside the neonatal period and summarises recommendations from the British Thoracic Society guidelines for UK practice.2 Similar international guidelines, including the World Health Organisation and Infectious Diseases Society of America guidelines, have some treatment variations, probably dependent on drug availability, cost, and antibiotic resistance patterns.34

Around 14.4 per 10 000 children aged over 5 years and 33.8 per 10 000 under 5 years are diagnosed with CAP annually in European hospitals.56 CAP is more common in the developing world, estimated at 0.28 episodes per child per year and accounting for 95% of all cases.7 Incidence data varies and may be explained by variation in diagnostic criteria. A bias exists towards hospital based studies, which potentially underestimates overall incidence. Children aged …
Association between financial relationships with commercial interests and research merit at the ASCO Annual Meeting (AM).
Authors: Beverly Moy, Angela R. Bradbury, Paul R. Helft, Moktar Sheikh-Salah, Brian Egleston, Colleen B. Sands, Courtney D. Storm, Jeffrey M. Peppercorn
Journal: Journal of Clinical Oncology (2012)

6095 Background: Financial relationships with commercial interests (COI) are common in cancer research. There are few data examining the correlation between COI and research merit. Meeting placement prominence (MP) and peer review score (PRS) are indicators of research merit. We examined the association between ASCO AM abstracts whose authors disclose COI and both MP and PRS. Methods: We reviewed abstracts presented at the ASCO AM in 2006 and 2008-2011. We evaluated associations between COI disclosed by any author and PRS and MP (order of prominence: plenary session (PS), clinical science symposium (CSS), oral presentation (OP), poster discussion session (PDS), vs. general poster session (GPS)). Chi-square tests, T-tests, and logistic regressions of COI were used to assess associations with MP, PRS, and year. Results: Of 12,446 total abstracts accepted for presentation, 78% of PS, 59% of CSS, 54% of OP, 52% of PDS, and 39% of GPS report at least one COI. Abstracts selected for PS, CSS, OP, and PDS had more COI compared to those selected for GPS (p &lt; 0.05). Stock ownership COI were more frequently disclosed in PS (30%), CSS (30%), OP (22%), and PDS (22%) compared to GPS (16%) (p &lt; 0.05). Employment COI were more frequently reported among abstracts presented at PS (39%), CSS (37%), OP (27%), and PDS (27%) compared to GPS (21%) (p &lt; 0.05). Consultant COI were more likely to have higher MP than GPS placement (OR for PS=5.5; CSS=2.4; OP=2.2; PDS=1.9). Similarly, honoraria COI were more likely to have higher MP than GPS placement (OR for PS=3.9; CSS=1.8; OP=2.1; PDS=1.7). Better PRS was associated with COI (OR 0.17; p &lt; 0.05). The relationship of better PRS with any COI strengthened over time from 2006, 2008-2011 (PRS times year interaction OR=0.65, p&lt;0.001). Conclusions: ASCO abstracts whose authors report COI have higher merit as measured by MP and PRS. This suggests a dependence on industry relationships for access to important data that will lead to prominent cancer research. These relationships will require further investigation and ongoing management. To our knowledge, this is the first study examining the scientific merit of research with relation to COI.
How to diagnose IgG4-related disease
Authors: Hisanori Umehara, Kazuichi Okazaki, Mitsuhiro Kawano, Tsuneyo Mimori, Tsutomu Chiba
Journal: Annals of the Rheumatic Diseases (2017)

How to diagnose IgG4-related diseaseWe read with great interest the editorial by Fox and Fox 1 describing the use of serum immunoglobulin G4 (IgG4) concentrations as a marker for IgG4-related disease (IgG4-RD).IgG4-RD is a fascinating clinical entity including a wide variety of diseases, formerly diagnosed as Mikulicz's disease, autoimmune pancreatitis (AIP), interstitial nephritis, prostatitis and retroperitoneal fibrosis. 2 3However, universal criteria for IgG4-RD have not yet been established at present, making its diagnosis in some patients ambiguous leading to many IgG4-RD mimickers.A 3-year investigation by the Japanese IgG4 team, organised by the Ministry of Health, Labour and Welfare (MHLW) of Japan, has reached a consensus, in that IgG4-RD can occur in various organs, with clinical symptoms depending on lesion location.Characteristics common to all forms of IgG4-RD include elevated serum IgG4 concentration and tissue infiltration by IgG4-positive plasma cells, accompanied by tissue fibrosis and sclerosis. 2In 2011, the Japanese IgG4 team published comprehensive diagnostic (CD) criteria for IgG4-RD, 4 with the major characteristics being serum IgG4 concentration >135 mg/dL, the infiltration of >10 IgG4+ cells per highpowered field (HPF) and an IgG4+/IgG+ cell ratio >40%.The cut-off of 135 mg/dL was based on receiver operating characteristic curves and its validity was confirmed in patients with AIP. 5 6 Since then, serum IgG4 levels have been widely used as a reliable criterion for the diagnosis of IgG4-RD. 4 6 However, Dr Fox mentioned drawbacks of using serum IgG4 levels in diagnosing IgG4-RD, citing studies reporting that the IgG4 cut-off >135 mg/dL had a low sensitivity and specificity for the diagnosis of IgG4-RD. 7 8As increased serum concentrations of IgG4 have been observed in several diseases with aberrant immunological condition unrelated to IgG4-RD, such as malignant tumours, autoimmune diseases especially rheumatoid arthritis and allergic diseases, 9 10 increased IgG4 concentration is not a specific marker for IgG4-RD.In contrast, recent large cohort studies from the UK, Taiwan and Japan showed that serum IgG4 concentration >135 mg/dL had overall sensitivities of 82.8%, 86% and 88%, respectively, in diagnosing 1 of 2
Pediatric Contact Dermatitis Registry Data on Contact Allergy in Children With Atopic Dermatitis
Authors: Sharon E. Jacob, Maria McGowan, Nanette B. Silverberg, Janice L. Pelletier, Luz Fonacier, Nico Mousdicas, Doug Powell, Andrew Scheman, Alina Goldenberg
Journal: JAMA Dermatology (2017)

Atopic dermatitis (AD) and allergic contact dermatitis (ACD) have a dynamic relationship not yet fully understood. Investigation has been limited thus far by a paucity of data on the overlap of these disorders in pediatric patients.
Abstract P6-11-17: Mutations in PIK3R1 activate multiple pathways in breast cancer
Authors: AM Abukhdeir, SB Turturro, MS Najor, SS Brar, MA Cobleigh
Journal: Cancer Research (2017)

Abstract It has been estimated that by the end of this year, 270,000 American women will be newly diagnosed with breast cancer, while 40,000 women that already have breast cancer will succumb to the disease. Considerable attention has been given to the PI3K signaling cascade following the discovery that PIK3CA is the most frequently mutated oncogene in breast cancer.However, few studies have explored the function of PIK3R1, which is the regulatory domain of the PI3K complex, despite being mutated in ~3% of all breast cancers. Several studies have demonstrated that expression of PIK3R1 is downregulated in human cancers. Decreased expression of the PIK3R1 protein leads to tumor formation, suggesting its role as a tumor suppressor gene and a potential prognostic marker in breast cancer. However, PIK3R1 is a gene with little pre-clinical evidence to recommend experimental therapies. Despite this lack of evidence, commercial services that perform molecular analyses of tumors suggest the use of an mTOR inhibitor for patients whose breast cancers carry mutant PIK3R1. In order to determine if mTOR inhibitors were indeed effective in mutant PIK3R1 tumors, we created and characterized a model for mutant PIK3R1 in the non-tumorigenic, human breast epithelial cell line, MCF-10A. Surprisingly, we observed that mTOR inhibitors were ineffective in these cells. However, in searching for other classes of small molecule inhibitors that were effective, we observed that mutations in PIK3R1 sensitized cells to MAPK inhibitors. Herein, we present the first evidence for the use of targeted therapies in breast cancers carrying mutant PIK3R1. We provide evidence against the use of mTOR inhibitors and provide a rationale for the use of MAPK inhibitors. Citation Format: Abukhdeir AM, Turturro SB, Najor MS, Brar SS, Cobleigh MA. Mutations in PIK3R1 activate multiple pathways in breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-11-17.
Recurrent Chromosome Abnormalities Define Non-Overlapping, Unique Subgroups of Tumors in Chronic Lymphocytic Leukemia Patients with Known Karyotypic Abnormalities
Authors: Victor H Jimenez-Zepeda, Wee Joo Chng, Esteban Braggio, Neil Kay, Jose Leis, Rafael Fonseca
Journal: Blood (2008)
Polymorphisms of CTLA-4 Are Associated with Treatment Outcome in Multiple Myeloma Patients Receiving Bortezomib-Based Regimens
Authors: Xiao-Ying Qin, Jin Lu, Guo-Xuan Li, Lei Wen, Lan-Ping Xu, Ying-Jun Chang, Kai-Yan Liu, Zheng-Fan Jiang, Xiao-Jun Huang
Journal: Blood (2016)
The long-term use of calcium channel blockers and the risk of breast cancer.
Authors: Sara V. Soldera, Nathaniel Bouganim, Jamil Asselah, Hui Yin, Ralph Maroun, Laurent Azoulay
Journal: Journal of Clinical Oncology (2015)

1588 Background: The association between calcium channel blockers (CCBs) and the risk of breast cancer is controversial. The objective of this study was to determine whether the use of CCBs is associated with an increased risk of breast cancer overall, and to assess whether this risk varies with cumulative duration of use. Methods: A cohort of 273,152 women newly treated with antihypertensive drugs between January 1, 1995 and December 31, 2009, followed until December 31, 2010, was identified using the UK Clinical Practice Research Datalink. CCB use was treated as a time-varying variable, with exposure lagged by one year for latency considerations and to minimize reverse causality. Time-dependent Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) of incident breast cancer associated with the use of CCBs. A secondary analysis was conducted to assess whether the risk varied with cumulative duration of use. All models were adjusted for a number of potential confounders, including age, smoking status, body mass index, alcohol consumption and use of hormone replacement therapy or other prescription drugs. Results: During 1,567,104 person-years of follow-up, 4520 women were newly diagnosed with breast cancer (incidence rate: 2.9 per 1000 per year). Compared with other antihypertensive drugs, the use of CCBs was not associated with an increased risk of breast cancer (2.8 vs. 3.1 per 1000 per year, respectively; HR: 0.98, 95% CI: 0.92-1.04). In a secondary analysis, the risk did not vary according to cumulative duration of use ( < 5 years, HR: 0.97, 95%: 0.90-1.03; 5-10 years, HR: 1.08, 95% CI: 0.94-1.25; ≥ 10 years, HR: 0.69, 95% CI: 0.36-1.33). Conclusions: The results of this large population-based study indicate that the long-term use of CCBs is not associated with an increased risk of breast cancer.
In-Situ Proliferation May Explain the Persistence of Host Derived Langerhans Cells Following Allogeneic Hematopoietic Stem Cell Transplantation with Reduced Intensity Conditioning.
Authors: Julie Richards, Laurence Pearce, Piers E.M. Patten, Andrea G.S. Buggins, Aloyisius Y. Ho, Anthony Pagliuca, Ghulam J. Mufti, Stephen Devereux
Journal: Blood (2007)