tbuckley/cabot-search huggingface dataset:
Overcoming Antigen Escape with CAR T-cell Therapy
Authors: Hollie J. Jackson, Renier J. Brentjens
Journal: Cancer Discovery (2015)

Abstract Summary: Sotillo and colleagues describe the molecular events associated with apparent loss of target antigen expression following CAR T-cell therapy. We propose that broader immune activation is required to prevent outgrowth of tumor antigen escape variants following targeted therapies. Cancer Discov; 5(12); 1238–40. ©2015 AACR. See related article by Sotillo et al., p. 1282.
Resensitization to Crizotinib by the Lorlatinib<i>ALK</i>Resistance Mutation L1198F
Authors: Alice T. Shaw, Luc Friboulet, Ignaty Leshchiner, Justin F. Gainor, Simon Bergqvist, Alexei Brooun, Benjamin J. Burke, Ya-Li Deng, Wei Liu, Leila Dardaei, Rosa L. Frias, Kate R. Schultz, Jennifer Logan, Leonard P. James, Tod Smeal, Sergei Timofeevski, Ryohei Katayama, A. John Iafrate, Long Le, Michele McTigue, Gad Getz, Ted W. Johnson, Jeffrey A. Engelman
Journal: New England Journal of Medicine (2015)

In a patient who had metastatic anaplastic lymphoma kinase (ALK)-rearranged lung cancer, resistance to crizotinib developed because of a mutation in the ALK kinase domain. This mutation is predicted to result in a substitution of cysteine by tyrosine at amino acid residue 1156 (C1156Y). Her tumor did not respond to a second-generation ALK inhibitor, but it did respond to lorlatinib (PF-06463922), a third-generation inhibitor. When her tumor relapsed, sequencing of the resistant tumor revealed an ALK L1198F mutation in addition to the C1156Y mutation. The L1198F substitution confers resistance to lorlatinib through steric interference with drug binding. However, L1198F paradoxically enhances binding to crizotinib, negating the effect of C1156Y and resensitizing resistant cancers to crizotinib. The patient received crizotinib again, and her cancer-related symptoms and liver failure resolved. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT01970865.).
Minimally invasive genomic and transcriptomic profiling of visceral cancers by next-generation sequencing of circulating exosomes
Authors: F.A. San Lucas, K. Allenson, V. Bernard, J. Castillo, D.U. Kim, K. Ellis, E.A. Ehli, G.E. Davies, J.L. Petersen, D. Li, R. Wolff, M. Katz, G. Varadhachary, I. Wistuba, A. Maitra, H. Alvarez
Journal: Annals of Oncology (2015)

The ability to perform comprehensive profiling of cancers at high resolution is essential for precision medicine. Liquid biopsies using shed exosomes provide high-quality nucleic acids to obtain molecular characterization, which may be especially useful for visceral cancers that are not amenable to routine biopsies.We isolated shed exosomes in biofluids from three patients with pancreaticobiliary cancers (two pancreatic, one ampullary). We performed comprehensive profiling of exoDNA and exoRNA by whole genome, exome and transcriptome sequencing using the Illumina HiSeq 2500 sequencer. We assessed the feasibility of calling copy number events, detecting mutational signatures and identifying potentially actionable mutations in exoDNA sequencing data, as well as expressed point mutations and gene fusions in exoRNA sequencing data.Whole-exome sequencing resulted in 95%-99% of the target regions covered at a mean depth of 133-490×. Genome-wide copy number profiles, and high estimates of tumor fractions (ranging from 56% to 82%), suggest robust representation of the tumor DNA within the shed exosomal compartment. Multiple actionable mutations, including alterations in NOTCH1 and BRCA2, were found in patient exoDNA samples. Further, RNA sequencing of shed exosomes identified the presence of expressed fusion genes, representing an avenue for elucidation of tumor neoantigens.We have demonstrated high-resolution profiling of the genomic and transcriptomic landscapes of visceral cancers. A wide range of cancer-derived biomarkers could be detected within the nucleic acid cargo of shed exosomes, including copy number profiles, point mutations, insertions, deletions, gene fusions and mutational signatures. Liquid biopsies using shed exosomes has the potential to be used as a clinical tool for cancer diagnosis, therapeutic stratification and treatment monitoring, precluding the need for direct tumor sampling.
Protection From Procedural Myocardial Injury by Atorvastatin Is Associated With Lower Levels of Adhesion Molecules After Percutaneous Coronary Intervention
Authors: Giuseppe Patti, Massimo Chello, Vincenzo Pasceri, Diego Colonna, Annunziata Nusca, Marco Miglionico, Andrea D’Ambrosio, Elvio Covino, Germano Di Sciascio
Journal: Journal of the American College of Cardiology (2006)
Increased glucose metabolism in untreated non-Hodgkin's lymphoma: a study with positron emission tomography and fluorine-18- fluorodeoxyglucose
Authors: M Lapela, S Leskinen, HR Minn, P Lindholm, PJ Klemi, KO Soderstrom, J Bergman, M Haaparanta, U Ruotsalainen, O Solin
Journal: Blood (1995)
Clinical results of combined vemurafenib and tumor-infiltrating lymphocyte therapy for metastatic melanoma
Authors: Amod Sarnaik, MacLean Hall, John Mullinax, Erica Royster, Allison Richards, Georgina Crago, Jonathan Zager, Sondak Vernon, Jeffrey Weber, Shari Pilon-Thomas
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts We previously established the feasibility of Tumor-Infiltrating Lymphocyte (TIL) cell therapy for unresectable metastatic melanoma at our institution[[1][1]]. This involves resection of tumor from patients for in vitro TIL generation. Upon satisfactory TIL growth, patients are
PTH-099 Vap-1 is elevated in psc, correlates with clinical outcome and exhibits amine oxidase activity in a substrate-dependent manner
Authors: PJ Trivedi, J Tickle, D Smith, J Vainio, G Hirschfield, C Weston, D Adams
Journal: Gut (2015)

<h3>Introduction</h3> Vascular adhesion protein (VAP)-1 is an adhesion molecule and potent amine-oxidase. Activation on hepatic sinusoidal endothelial cells (HSEC) leads to H<sub>2</sub>O<sub>2 </sub>release, NFκB activation and expression of gut-homing receptor MAdCAM-1, which promotes homing of gut-tropic lymphocytes to the liver. Given the proposed role of this pathway in hepatic disorders complicating inflammatory bowel disease (IBD); we quantified serum (sVAP-1) titre and intrahepatic/colonic enzyme activity in primary sclerosing cholangitis (PSC)/IBD, as well as investigated consequences of activation with variant amine substrates. <h3>Method</h3> sVAP-1 was quantified by ELISA in PSC (n = 105); PBC (90); AIH (99); IBD-alone (50) and healthy controls (21). Correlation with clinical outcome was assessed using Cox proportional hazards assumption/KM-estimates. VAP-1 activity was determined (Amplex red assay) in protein lysates extracted from (a) explanted liver (PSC=9; PBC=10, AIH=5, normal donor, n = 10) and (b) colonic resections (n = 7). Putative VAP-1 substrates were selected based on inclusion in the human metabolome database, and induced kinetic rates measured (Michaelis-Menton analysis). Induction of MAdCAM-1 on HSEC was evaluated quantitatively (cell-ELISA) and functionally (flow-adhesion assays). <h3>Results</h3> PSC patients had higher sVAP-1 concentration (median 517 ng/mL) than those with AIH (475), PBC (472), IBD-alone (413) and healthy controls (425) (p &lt; 0.001). sVAP-1 tires &gt;530 ng/ml in PSC were associated with significantly worse transplant-free survival (unadj. HR:2.94, p = 0.008), and retained independent predictive value when controlling for other significant risk factors (cirrhosis, ascending cholangitis and liver biochemistry; adj. HR:3.85, p = 0.003). Intrahepatic VAP-1 enzyme activity was significantly greater in PSC (227 pmol H<sub>2</sub>O<sub>2</sub>/min/mg protein) compared with PBC (124), AIH (128) and donor liver (109) (p &lt; 0.001), yet comparable to activity in colonic tissue (220; p=n.s.). The substrate associated with highest VAP-1 enzymatic efficiency was cysteamine (k<sub>cat</sub>/K<sub>m</sub>:5.4 × 10<sup>7</sup>); an amine secreted by Escherichia. which induces colitis in mice. Cysteamine+TNFa provision resulted in greater MAdCAM-1 expression by HSEC ELISA than that with other substrates or TNFa alone (p &lt; 0.01), with increased a4b7-dependent adhesion under flow (p &lt; 0.01). <h3>Conclusion</h3> Elevated levels of circulating sVAP-1 exist in PSC and predictive of poor outcome. Intrahepatic VAP-1 enzyme activity is also increased in PSC and akin to that seen in the colon. The ability of VAP-1 to catabolise amine substrates secreted by gut commensals/enteric pathogens, provides a theoretical link between altered colonic microbiota and mucosal immunity in the pathogenesis of PSC. <h3>Disclosure of interest</h3> None Declared.
PTU-180 Predicting outcomes of biofeedback therapy for faecal incontinence – where ‘good’ practice makes perfect
Authors: DH Vasant, K Solanki, RK Sharma, LJ Quest, R George, S Balakrishnan, N Radhakrishnan
Journal: Gut (2015)

<h3>Introduction</h3> Biofeedback therapy is known to be effective in Faecal Incontinence (FI) with reported success rates of around 70%. However, virtually all available data is from tertiary centres. We aimed to evaluate our biofeedback programme based on the Iowa protocol<sup>1</sup>within the constraints of a District General Hospital (DGH) and determine predictive factors for successful outcomes. <h3>Method</h3> We retrospectively reviewed 199 FI patients (mean age 62 ± 1 years, 72% female) enrolled in our Gastroenterologist-led biofeedback programme between 2009–2014. Baseline symptoms, QOL scores, co-morbidities and investigations including lower GI endoscopy (91%) were noted in addition to anorectal manometry findings. Anorectal sphincter technique was graded (good, fair or poor) at each session. Based on symptoms during the last session, patients were classified as responders (complete or partial) or non-responders. The 2 groups were compared statistically for factors including; demographics, symptoms, pelvic dyssynergia, manometry data, sphincter exercises technique/practice and the number and frequency of biofeedback sessions. Data are expressed as the mean (± SEM) unless stated otherwise. P values ≤0.05 were deemed statistically significant. <h3>Results</h3> All 199 patients had auditable outcome measures despite 5% having ongoing therapy and 23% drop out. Patients attended a mean 4 (± 0.1) biofeedback sessions with an interval of 69 (±3) days between visits. Neurotrac stimulator was used adjunctively in 12% of cases. Overall, 148/199 (74%) responded (complete n = 100, partial n = 48) with marked reduction in FI frequency (median before 7/week vs. post-treatment 0.25/week, U = 20,425, P &lt; 0.0001). Whilst male gender was associated with poorer outcome (Chi<sup>2</sup>= 5.4, P = 0.02), documented ‘good’ sphincter exercise technique (Chi<sup>2</sup>= 9.3, P = 0.002) and longer weekly durations of sphincter exercises at home (df = 66.3, P = 0.01) were associated with favourable outcomes. By contrast, age, symptoms, QOL, physical/sexual abuse, depression, lateral sphincterotomy, resting and squeeze pressures, rectal sensitivity, dyssynergia, number and frequency of biofeedback sessions were not associated with outcomes. <h3>Conclusion</h3> To the best of our knowledge this is the largest series from a DGH in the UK. Despite less intensive follow-up schedules we were able to achieve comparable outcomes to studies reported elsewhere with bi-weekly induction followed by periodic reinforcements suggesting our physician-led approach may be just as effective. Our data reinforces the importance of sphincter exercise technique, training and patient self-practice at home, which along with female gender appear to be predictive factors in successful outcomes. <h3>Disclosure of interest</h3> None Declared. <h3>Reference</h3> Ozturk, <i>et al</i><i>.</i><i>APT</i>2004;20(6):667–74
The Deleterious Effects of Hyperglycemia on Platelet Function in Diabetic Patients With Acute Coronary Syndromes
Authors: Matthew I. Worthley, Andrew S. Holmes, Scott R. Willoughby, Angela M. Kucia, Tamila Heresztyn, Simon Stewart, Yuliy Y. Chirkov, Christopher J. Zeitz, John D. Horowitz
Journal: Journal of the American College of Cardiology (2007)
Treating to target in psoriatic arthritis: how to implement in clinical practice
Authors: Laura C Coates, Philip S Helliwell
Journal: Annals of the Rheumatic Diseases (2015)

Treating to target is becoming the standard of care in many medical specialities, including rheumatology. The Tight Control of Psoriatic Arthritis (TICOPA) trial has recently provided evidence of the benefit of treating to target in psoriatic arthritis (PsA), and the revised European League Against Rheumatism (EULAR) recommendations on the management of PsA suggest this approach. However, the question of the optimal measure to use and the practicalities of incorporating this into routine clinical practice remain problematic.
O112 : HBsAg clearance after addition of 48 weeks of pegifn in HBeAg negative CHB patients on nucleos(T)ide therapy with undetectable hbvdna for at least one year: final results from ANRS-HB06 pegan study: multicenter randomized controlled phase III trial
Authors: M. Bourliere, P. Rabiega, N. Ganne-Carrie, L. Serfaty, P. Marcellin, N. Pouget, D. Guyader, C. Hezode, M. Picon, X. Causse, V. Leroy, J.P. Bronowicki, G. Riachi, I. Rosa, P. Attali, J.M. Molina, Y. Bacq, A. Tran, J.D. Grangé, F. Zoulim, H. Fontaine, I. Bertucci, M. Bouvier-Alias, F. Carrat, Y. Benhamou
Journal: Journal of Hepatology (2015)
Lactation and Maternal Cardio-Metabolic Health
Authors: Cria G. Perrine, Jennifer M. Nelson, Jennifer Corbelli, Kelley S. Scanlon
Journal: Annual Review of Nutrition (2016)

Researchers hypothesize that pregnancy and lactation are part of a continuum, with lactation meant to “reset” the adverse metabolic profile that develops as a part of normal pregnancy, and that when lactation does not occur, women maintain an elevated risk of cardio-metabolic diseases. Several large prospective and retrospective studies, mostly from the United States and other industrialized countries, have examined the associations between lactation and cardio-metabolic outcomes. Less evidence exists regarding an association of lactation with maternal postpartum weight status and dyslipidemia, whereas more evidence exists for an association with diabetes, hypertension, and subclinical and clinical cardiovascular disease.
Aberrant metalloprotease expression and activity in bronchoalveolar lavage fluid of bronchiolitis obliterans patients
Authors: Dennie Rozeveld, Sicco van der Heide, Rainer Bischoff, Wim van der Bij, Antoon van Oosterhout, Hilde Heijink, Marco van der Toorn
Journal: European Respiratory Journal (2013)

Long-term success of lung transplantation (LT) is hindered by the development of bronchiolitis obliterans syndrome (BOS). Increased expression of matrix metalloproteases (MMPs) and tissue inhibitors of metallopreoteases (TIMPs) have been observed in BOS patients suggesting a role for proteases and tissue remodeling. However, little is known about the activity state of MMPs and their actual binding to TIMPs.  Therefore, we investigated the levels of different molecular forms of MMPs in lung transplant recipients with unimpaired pulmonary function and early clinically diagnosed BOS.  Cell differentials, cytokine levels (IL-6, IL-8), TIMP (1 – 4), total MMP-1, -2, -3, -7, -8, -9, -12 and -13 levels and activity of these MMPs using an MMP activity assay were measured in bronchoalveolar lavage (BAL) fluid from stable LT patients (n=20) and LT patients with BOS (n=20). The patient9s rejection status was assessed by patho-histology.  The number of BAL lymphocytes and neutrophils as well as the levels of IL-8, TIMP1 and 2 and total MMP-2, -3, -7, -8 and -9 were significantly higher in patients with BOS compared to stable LT patients. Interestingly, while active MMP-7 was significantly lower in BAL of BOS patients compared to stable LT patients, levels of TIMP1- and TIMP2-bound MMP-7, -8 and -9 were significantly increased in patients with BOS.  In conclusion, we demonstrate that development of BOS after lung transplantation is associated with increased levels of TIMP 1 and 2 and total MMP-2, -3, -7, -8 and -9. Furthermore, we show for the first time that levels of TIMP-bound MMPs are associated with BOS which indicates that these enzymes have been active previously.
Generation of anti-tumor responses by primary human T cells through expression of a chimeric NKG2D receptor
Authors: Tong Zhang, Amorette Barber, Charles L. Sentman
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

622 

In order to create more effective CTLs against human tumors, we have designed a strategy to allow T cells to recognize tumor cells using NK cell receptors but retain the effector responses of T lymphocytes. NKG2D is an activating cell-surface receptor expressed on natural killer (NK) cells and some T-cell subsets. Its ligands are primarily expressed on tumor cells. We have shown that by linking mouse NKG2D to the CD3 zeta chain we were able to generate a chimeric NKG2D receptor (chNKG2D) that allowed direct activation of murine T cells upon engagement with NKG2D ligand-positive tumor cells leading to anti-tumor responses in mice. In this study, a human version of the chNKG2D receptor was expressed on human T cells and anti-tumor responses determined. Human PBMC-derived T cells were retrovirally transduced with the human chNKG2D receptor gene. These chNKG2D-bearing human T cells responded to NKG2D ligand-positive tumor cells by producing T-helper 1 (Th1) cytokines, proinflammatory chemokines and significant cellular cytotoxicity. This response was dependent upon NKG2D ligand expression on the target cells but not on expression of MHC molecules, and this response was blocked by anti-NKG2D antibodies. In addition, the activity of chNKG2D-bearing T cells remained unimpaired after exposure to a soluble NKG2D ligand, soluble MICA, at a concentration as high as 150ng/ml. These data indicate the feasibility of developing chimeric NKG2D receptors on human T cells and suggest this approach may be a promising means for cancer immunotherapy.
Phase I trial of thalidomide and capecitabine for treatment of metastatic colorectal cancer
Authors: M. J. Goldstein, J. C. Leighton, A. Chapman, A. Muskett, K. Sharan, J. Sansom, E. P. Mitchell
Journal: Journal of Clinical Oncology (2006)

13552 Background: Survival of patients with metastatic colorectal cancer (CRC) has increased with the advent of new chemotherapeutic and biologic agents. Yet, there remains a need for more effective third- and fourth-line chemotherapy. Thalidomide (Thal) has angiogenic and immunomodulatory properties and antitumor effects have been consistently demonstrated in pts with multiple myeloma and occasionally in pts with advance solid tumors. Capecitabine (Cape) has demonstrated efficacy as a single agent and in combination therapy in pts with metastatic CRC. We conducted a phase I study of Thal/Cape in pts with refractory metastatic CRC previously treated with irinotecan, oxaliplatin and fluoropyrimidines. Methods: Pts with metastatic CRC who had received two or more prior chemotherapy regimens were eligible. Treatment consisted of Cape at 1500 mg/m 2 po daily for 14 days every three weeks with dose levels increasing to 2500mg/m 2 ; Thal dosing was initially 100 mg with escalations individually to 400 mg per day. Toxicity rates, response and overall survival were analyzed. Results: Twenty-five eligible pts were enrolled; median age= 58 (20–79); M/F=13/12; ECOG PS 0/1/2=11/12/2. The median number of Thal/Cape cycles administered was 3 (range 1–9). Treatment was well tolerated; grade 3–4 non-hematologic toxicities included somnolence/syncope (20%), fatigue (20%), constipation (10%), diarrhea (10%), infections (10%) and neuropathy, thrombosis, hypoglycemia, nausea/vomiting each occurred in 5% of pts; grade 3–4 hematological toxicities anemia (15%), neutropenia (5%), prolonged prothrombin time (15%), increased LFTs (10%). Grade 3–4 hand-foot syndrome occurred in 2 pt (8%). There were no radiographic responses, but 6 pts achieved a decline in CEA of 50% or greater and 6 pts achieved stable disease. Conclusion: The MTD is Cape 2500mg/m 2 per day. The combination of Thal/Cape was well tolerated; the recommended dose is thal 200mg and cape 2000mg/m 2 . Despite the lack of radiographic responses, the rate and duration of disease stabilization observed in this heavily pretreated pt population suggest that this regimen may offer some benefit. [Table: see text]
Recurrent venous thromboembolism and abnormal uterine bleeding with anticoagulant and hormone therapy use
Authors: Ida Martinelli, Anthonie W. A. Lensing, Saskia Middeldorp, Marcel Levi, Jan Beyer-Westendorf, Bonno van Bellen, Henri Bounameaux, Timothy A. Brighton, Alexander T. Cohen, Mila Trajanovic, Martin Gebel, Phuong Lam, Philip S. Wells, Martin H. Prins
Journal: Blood (2015)
Phase II clinical trial of intravesical <i>bacillus Calmette-Guerin </i>(BCG) followed by sunitinib for the treatment of high-risk nonmuscle-invasive bladder cancer (NMIBC).
Authors: Alexander M. Helfand, Cheryl T. Lee, Khaled Hafez, Maha Hussain, Monica Liebert, Stephanie Daignault, Jeffrey Scott Montgomery, David Christopher Miller, Linda Drnek, Brent K. Hollenbeck, Alon Z. Weizer
Journal: Journal of Clinical Oncology (2015)

293 Background: We conducted a phase II trial to evaluate combination therapy with intravesical BCG + sunitinib for prevention of recurrence and progression of NMIBC. Methods: Patients with high-grade clinical ≤ T1N0M0 NMIBC without BCG in the past year were eligible and received induction BCG followed 2 weeks later by 28 days of sunitinib (50mg). The primary endpoint was 3 month complete response (CR) by biopsy and cytology. Patients with incomplete response were eligible for a second cycle of BCG + sunitinib. Secondary endpoints included 2-year recurrence and progression-free survival (RFS, PFS). Toxicity was graded according to the NCI CTCAE v.3.0. The Simon Minimax 2-stage study had 80% power with a 5% type I error assuming a 3m CR of 75% with sunitinib + BCG compared to 55% with BCG alone. If ≥ 25/36 evaluable patients achieved a 3m CR, then the treatment would be considered for further study. Binomial proportions, confidence intervals and Kaplan-Meier estimates are reported. Results: Of 36 evaluable patients, median age was 65.9 years (IQR 59-72). Initial stage was T1 (19), Ta (9), and CIS (8). Thirty-six percent completed sunitinib without interruption. Treatment was delayed (median 12 days (IQR 9-16)) and dose was reduced to 37.5 mg in 13 patients. One patient had reduction to 25mg with re-escalation to 37.5mg. One patient completed a 2nd cycle of BCG + sunitinib for incomplete response. BCG maintenance therapy was given to 21 patients. Of 133 adverse events in 34/36 patients, 6 (4.5%) in 5 patients were ≥ grade 3: thrombocytopenia, diarrhea (2), shingles, extremity rash/pain and hand + foot syndrome. CR at 3m included 26/36 (72%, 95% CI[55,86]) reaching the primary endpoint. The patient who completed a 2nd cycle of BCG induction and sunitinib had CR at 6 months. 2y RFS (patients with intact bladder) was 77% (95% CI[58,88]) and 2y PFS was 100%. Conclusions: The primary endpoint of the study of 25 3m CR has been reached. Combined treatment with BCG + sunitinib is associated with low rates of recurrence and progression. Adverse effects were common and frequent but few were serious. BCG + sunitinib may produce outcomes superior to BCG alone. (Study supported by Pfizer, Inc) Clinical trial information: NCT00794950.