tbuckley/cabot-search huggingface dataset:
Fibroblast activation protein and focal adhesion kinase: novel stromal therapeutic targets in pancreatic adenocarcinoma
Authors: S. J. Cohen, I. Palazzo, N. J. Meropol, A. Rogatko, L. M. Weiner, E. A. Golemis, J. D. Cheng, R. K. Alpaugh
Journal: Journal of Clinical Oncology (2004)

4094 Background: Fibroblast activation protein (FAP) is a serine protease expressed on tumor stromal fibroblasts which results in tumor growth potentiation. Focal adhesion kinase (FAK) is a protein tyrosine kinase which promotes cell growth and migration through the extracellular matrix. Given the extensive desmoplasia characteristic of pancreatic adenocarcinoma, we hypothesized that FAP and FAK would be overexpressed in pancreatic cancer and contribute to poor outcome. Methods: Twenty-nine paraffin-embedded pancreatic adenocarcinoma specimens from patients undergoing curative resection were obtained from the Fox Chase Cancer Center tumor bank. Four samples (2 normal and 2 mucinous borderline tumors) served as controls. FAP and FAK expression was assessed by immunohistochemistry and graded by staining extent (%) and intensity (0–3+). Results: Ninety percent of tumor specimens (26/29) expressed FAP in either fibroblasts surrounding tumor (FST), surrounding stroma (SS), or tumor. The highest expression level by intensity was: 3+ (14), 2+ (9), 1+ (3). A strong correlation was noted between FAP expression in FST and in SS (Pearson correlation coefficient 0.75, p<0.001). In contrast, control samples displayed no FAP expression in SS. FAK was expressed on tumor cells in all 29 samples, with three-quarters having 100% staining. In addition, median FAK expression in SS was 50%. A strong correlation was noted between percent staining of FAP and FAK in SS (Pearson correlation coefficient 0.637 (p<0.001). Conclusions: FAP is overexpressed in 90% of pancreatic adenocarcinoma specimens, with similar expression in both FST and SS. FAK is also overexpressed in SS and correlates with expression of FAP, suggesting that interaction between these proteins may contribute to pancreatic cancer invasiveness. Additional samples are being evaluated and correlation with clinical characteristics is ongoing. As targeting of FAP appears promising in preclinical models, pancreatic cancer is an excellent disease for future clinical development of stromal-directed therapeutics. No significant financial relationships to disclose.
Splenic Irradiation and a Reduced-Intensity Conditioning Regimen Prior to Allogeneic Stem-Cell Transplantation for Myelofibrosis
Authors: Ojas H. Vyas, Esha Kaul, Aaron S. Rosenberg, Gunjan L Shah, Urvi Ajay Shah, Raymond L. Comenzo, Grace Shih-Hui Kao, Andrew M. Evens, Hedy Smith, Andreas K. Klein, Kenneth B. Miller, Kellie A. Sprague
Journal: Blood (2014)
The Humanized Anti PD-1 Antibody, CT-011, Increases Specific CD4+ Effector/Memory and Memory T Lymphocytes in Patients with Diffuse Large B Cell Lymphoma (DLBCL) Following Autologous Stem Cell Transplantation (AuSCT).
Authors: Rinat Rotem-Yehudar, Philippe Armand, Steve Devine, Joseph W. Fay, Chitra Hosing, Markus Y Mapara, Erica Campagnero, Joseph P. Uberti, David Avigan, Karen K Ballen, Jane N. Winter, Arnon Nagler, Leo I. Gordon
Journal: Blood (2009)
Capecitabine in early-stage colon cancer and metastatic colorectal cancer: Results from an Austrian noninterventional trial.
Authors: Wolfgang Eisterer, Bjoern Jagdt, Christa Haeusler, Markus Krenn
Journal: Journal of Clinical Oncology (2012)

e14103 Background: Capecitabine (Cap) is approved for adjuvant therapy in stage III colon cancer and for metastatic colorectal cancer (mCRC) in Austria. Methods: In this open-label, multicenter, single-arm non-interventional trial, Cap-based therapy in patients with early-stage colon cancer and mCRC was observed at 30 sites. Cap was prescribed at the physician’s discretion and according to drug labelling. 409 patients were included between 2008 and 2011. Safety of Cap in routine clinical practice was the primary study endpoint. All adverse events (AEs) were documented in an online CRF by participating investigators. Progression-free survival (PFS), defined as the time from study entry until tumour progression or death, and treatment duration were also assessed. Results: Most of the 409 patients were ≥65 years old (72.6%; n=297). 249 (60.9%) patients were male and 160 (39.1%) were female. 221 (54.0%) patients received Cap as adjuvant therapy; 111 (50.2%) of these received Cap alone, and 110 (49.8%) were treated with Cap plus oxaliplatin. 188 (46.0%) patients were treated for mCRC; 105 (55.9%) received first-line therapy, 48 (25.5%) second-line therapy and 35 (18.6%) third-line or later lines of therapy with different Cap-containing regimens. 163 mCRC patients were eligible for PFS evaluation. The median PFS was 8.1 (range 1.0–28.5) months. Patients who received Cap-based therapy for at least 8 cycles (n=97) had a profound increase in PFS to 9.4 months. The longest treatment duration with Cap was 47 cycles. The median duration of treatment for all patients was 8 cycles (range 1–47) at a median daily dose of 1944 mg/m 2 (range 833–3055 mg/m²) for Cap alone and 1862 mg/m 2 (range 1111–4166 mg/m²) as part of a combination regimen. The most common grade 3/4 AEs included diarrhoea (2.2%), hand-foot syndrome (2.0%), nausea (0.7%), neuropathy (0.7%), and leukopenia (0.2%). Conclusions: Cap therapy is well tolerated in routine clinical practice. The median number of 8 cycles correlates well with the suggested treatment duration. AEs included only known and previously documented safety reactions. Prolonged treatment with Cap in patients with mCRC leads to a meaningful increase in PFS.
Targeted Oligonucleotide Array Assessment of Genomic Copy Number Alterations for Risk Stratification in Chronic Lymphocytic Leukemia
Authors: Jane Houldsworth, Asha Guttapalli, Xiao J. Yan, Charles Ma, Weiyi Chen, Sujata Patil, Kanti R Rai, Nicholas Chiorazzi
Journal: Blood (2011)
Phase I multicenter trial of BMS-690514: Safety, pharmacokinetic profile, biological effects, and early clinical evaluation in patients with advanced solid tumors and non-small cell lung cancer
Authors: R. Bahleda, E. Felip, R. S. Herbst, N. H. Hanna, S. A. Laurie, F. A. Shepherd, J. P. Armand, C. J. Sweeney, E. Calvo-Aller, J. C. Soria
Journal: Journal of Clinical Oncology (2008)

2564 Background: BMS-690514 is an oral selective pan-HER and VEGFR2 inhibitor with activity in a wide range of tumor cell lines dependent on ErbB signaling. Methods: This is a dose-escalation study to define the MTD and to characterize the pharmacokinetics, pharmacodynamics and safety profile of BMS-690514 in patients with advanced tumors. Patients≥ 18 years with advanced or metastatic measurable tumors, refractory to standard therapies, ECOG ≤ 1, and adequate cardiovascular, bone marrow, renal and hepatic functions. Biomarkers of ErbB and VEGFR signaling include tumor tissue for ErbB pathway gene amplification and mutations, single nucleotide polymorphism, skin biopsies, circulating proteins, and DCE-MRI. Dosing initiated at 40 mg/d with dose escalation based on a modified Fibonacci scheme. At the MTD, an expansion cohort (n=60) enrolled patients with erlotinib-naive and erlotinib-resistant NSCLC. Results: The study has treated 65 patients (39 M/ 26 F), median age 56.2 years (range 27–77) between Oct 2006 and Dec 2007. A total of 110 cycles have been given and 19 patients are still on study. BMS-690514 dose cohorts were (no. pts): 40mg (4), 80mg (4), 160mg (4), 200mg (6), 250mg (4), 300mg (6). The dose-limiting toxicities in 2 subjects each at 250 and 300 mg were grade 3/4 diarrhea (2 patients had associated reversible grade 3 renal insufficiency). Other grade 3–4-adverse events possibly related to BMS-690514 included fatigue, rash, angioedema, arterial hypertension, left ventricular dysfunction, and pulmonary embolism. One patient with esophageal cancer experienced an objective response at 300 mg. At or below the MTD of 200 mg, the majority of AEs were mild-moderate and included diarrhea, rash, nausea, vomiting, hypertension, dyspnea, asthenia and renal insufficiency. 37 patients with NSCLC have enrolled into the expansion cohort (14 erlotinib-naie,18 erlotinib- resistant, 5 pending). An objective tumor response has been observed at the MTD in 1 pt as well as SD ≥ 2 months in 14 pts. Conclusions: BMS-690514 has been well tolerated, with mild-moderate, reversible, target-related AEs. The MTD is 200 mg daily. Additional clinical, PK and translational data will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb
Sorafenib (SOR) safety profile in more than 4,600 patients (pts) with renal cell carcinoma (RCC): Assessment at 3-month (mo) intervals using an integrated database of eight company-sponsored studies.
Authors: M. E. Gore, J. Beck, J. J. Knox, T. Eisen, C. Szczylik, S. Negrier, T. E. Hutson, A. Brueckner, J. Kalmus, B. Escudier
Journal: Journal of Clinical Oncology (2010)

4605 Background: With >5 yrs of clinical experience with SOR, a well-defined efficacy and safety profile has been documented. An integrated database was constructed of data from >4,600 pts with RCC treated in company-sponsored clinical studies to provide a collective descriptive assessment of SOR safety. Reported here for the first time is the SOR safety profile during the first 12 mos of treatment from this integrated database. Methods: An integrated database was created using individual patient data from 6 clinical trials and 2 expanded-access studies evaluating SOR monotherapy in RCC. NCI-CTCAE v3 terms were used for the selected drug-related adverse events (DRAEs) and prevalence rates were calculated in 3-mo intervals for up to 12 mos. Results: 4,684 pts (71% male, median age 62 yrs, 20% prior nephrectomy, 52% prior cytokine therapy, 6.3-mo mean duration of SOR) reflect 2,424 pt-years of exposure to SOR. The selected DRAEs were generally mild or moderate at each 3-mo interval, and declined or stabilized over the 3 later 3-mo intervals (Table). The largest mean dose, 692 mg/d, was recorded for 0-3 mos, with an overall mean dose of 676 mg/d; grade ≥3 DRAEs leading to dose reduction/interruption/discontinuation occurred in 15%/13%/4% (0-3 mos), 5%/4%/2% (3-6 mos), 3%/2%/1% (6-9 mos), 4%/3%/1% (9-12 mos) of pts. Conclusions: DRAEs, with the exception of mild/moderate diarrhea, decreased or stabilized over 12 mos of SOR treatment. Grade 3-4 DRAEs and rates of dose reductions and treatment discontinuations generally decreased over time. This integrated SOR safety profile in >4,600 pts confirms that SOR treatment has a consistent and manageable safety profile over time. Mean dose and selected DRAEs by 3-mo intervals during SOR treatment Mo 0-3 (n=4684)* Mo 3-6 (n=2864)* Mo 6-9 (n=1515)* Mo 9-12 (n=993)* Grades, % of pts 1-2 3-4 1-2 3-4 1-2 3-4 1-2 3-4 Hand-foot skin reaction 24 9 30 3 32 2 31 1 Rash/desquamation 24 4 19 0.3 15 0.3 14 0.2 Diarrhea 23 2 34 2 43 3 48 2 Fatigue 17 3 19 2 18 2 18 1 Alopecia 17 <0.1 27 <0.1 26 <0.1 20 0 Hypertension 11 4 10 3 10 3 11 4 Mean SOR dose, mg/d 692 (n=4,419) 655 (n=2,689) 656 (n=1,420) 659 (n=942) * Number of patients entering time interval. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer, French Gustave Roussy Institute AVEO, Bayer, Genentech, GlaxoSmithKline, Novartis, Pfizer, Roche, Wyeth AstraZeneca, Bayer AVEO, Bayer, Genentech, GlaxoSmithKline, Novartis, Pfizer, Roche, Wyeth AVEO, Bayer, Genentech, GlaxoSmithKline, Novartis, Pfizer, Wyeth
Abstract 16522: Structural Insights Into Destabilizing HERG PAS Domain Mutations Linked to Long Qt Syndrome
Authors: Corey L Anderson, Catherine E Kuzmicki, Ryan R Childs, Caleb J Hintz, Craig T January, Ravi C Balijepalli
Journal: Circulation (2015)

Introduction: Hundreds of HERG potassium channel mutations are linked to type 2 Long QT Syndrome (LQT2). Most mutations are trafficking defective but correctable by culturing cells at reduced temperature (27 C) or with the pore blocker E4031. For a few intracellular Per-ARNT-Sim (PAS) domain mutations, trafficking phenotypes have been shown to correlate with PAS domain stability. Since HERG intracellular domains are mutational hotspots containing 1/3 (&gt;100) of all LQT2 mutations, domain destabilization may be a major mechanism underlying LQT2. However, most mutations have not been studied and structural insights are lacking. Results: Using a recombinant PAS domain solubility assay as a proxy for stability, we tested 57 mutations and found a strong correlation between domain solubility and trafficking phenotype (trafficking defective and uncorrectable &lt; temperature correctable &lt; temperature and E4031 correctable &lt; trafficking competent). For buried residues V41 and C64, we used the protein stability prediction tool FoldX and immunoblot to show that domain stability and trafficking phenotype becomes more severe as the side chain becomes larger suggesting overpacking of the PAS domain core as a mechanism for LQT2-V41F and LQT2-C64W. This was further validated by designing second-site suppressor mutations to relieve potential side chain clashes. Immunoblot analysis showed that trafficking of LQT2-V41F is improved at 27 C with C39G or C64G, while C64A improved trafficking at 37 C. Immunoblot and current density analysis showed that trafficking of LQT2-C64W (3.8±0.8 pA/pF, n=4) is improved at 37 C with C39G (37.8±3.5 pA/pF, n=3) or Q61G (69.6±12.7 pA/pF, n=3) and LQT2-I42N (2.2±0.7 pA/pF, n=3) is improved at 37 C with Q61G (41.9±6.3 pA/pF, n=6). Additionally, site-saturation mutagenesis of residue V113 revealed loss of backbone (and not side chain) interactions as the structural basis for LQT2-delV113. Conclusions: This study identifies HERG PAS domain destabilization as a major mechanism underlying LQT2 and demonstrates a novel bioinformatics and structure-based method for analyzing disease-associated HERG mutations. These results are also a proof of concept that strategies to improve HERG domain stability could be a viable therapeutic approach.
Особливості діагностики та лікування кислотозалежної патології у хворих на цукровий діабет
Authors: S.M. Tkach
Journal: GASTROENTEROLOGY (2016)

У статті розглядається проблема поєднаного перебігу кислотозалежної патології шлунково-кишкового тракту та цукрового діабету (ЦД). Акцентовано увагу на тому, що в переважній більшості випадків лікування гастроезофагеальної рефлюксної хвороби і пептичних виразок у хворих на цукровий діабет слід проводити не у вигляді монотерапії інгібітором протонної помпи, а комплексно і диференційовано, з урахуванням етіологічних і патогенетичних особливостей розвитку даної патології. При виборі компонентів схеми потрійної терапії або квадротерапії для ерадикації H.pylori у хворих на ЦД серед групи інгібіторів протонної помпи перевагу бажано віддавати пантопразолу (препарат Зованта). Пантопразол не вступає у конкурентні взаємини з кларитроміцином — основним антибіотиком у складі антихелікобактерної терапії. Антихелікобактерна терапія на основі пантопразолу знижує ймовірність виникнення побічних ефектів і підвищує ефективність лікування.
Acute Upper Abdominal Pain With a Distended Cecum in the Left Upper Quadrant
Authors: Wenliang Chen, David M. Kelly
Journal: JAMA Surgery (2016)

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Analysing data from patient-reported outcome and quality of life endpoints for cancer clinical trials: a start in setting international standards
Authors: Andrew Bottomley, Madeline Pe, Jeff Sloan, Ethan Basch, Franck Bonnetain, Melanie Calvert, Alicyn Campbell, Charles Cleeland, Kim Cocks, Laurence Collette, Amylou C Dueck, Nancy Devlin, Hans-Henning Flechtner, Carolyn Gotay, Eva Greimel, Ingolf Griebsch, Mogens Groenvold, Jean-Francois Hamel, Madeleine King, Paul G Kluetz, Michael Koller, Daniel C Malone, Francesca Martinelli, Sandra A Mitchell, Carol M Moinpour, Jammbe Musoro, Daniel O’Connor, Kathy Oliver, Elisabeth Piault-Louis, Martine Piccart, Francisco L Pimentel, Chantal Quinten, Jaap C Reijneveld, Christoph Schürmann, Ashley Wilder Smith, Katherine M Soltys, Martin J B Taphoorn, Galina Velikova, Corneel Coens
Journal: The Lancet Oncology (2016)
A phase I dose escalation study of sunitinib plus capecitabine in patients with advanced solid tumors
Authors: C. Sweeney, C. Verschraegen, G. Chiorean, F. Lee, S. Jones, L. Tye, A. Bello, R. Chao, H. Burris
Journal: Journal of Clinical Oncology (2007)

3592 Background: Sunitinib malate (SU) is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, and FLT3, approved internationally for the treatment of advanced RCC and imatinib-resistant or -intolerant GIST. This phase I study assesses the safety, tolerability and pharmacokinetics (PK) of SU in combination with capecitabine (C). Methods: Pts with advanced solid tumors not amenable to curative therapy, previously treated with =2 prior chemotherapy regimens, and ECOG PS =1 were eligible. Prior antiangiogenic therapy was not permitted. Three SU schedules were evaluated: 4 wks on treatment followed by 2 wks off in 6-wk cycles (4/2 schedule); 2 wks on followed by 1 wk off in 3-wk cycles (2/1 schedule), and continuous dosing (CD schedule). In all cases C was administered orally bid on days 1–14. SU and C doses were alternately escalated in serial pt cohorts to determine the maximum tolerated dose (MTD) of SU for all schedules using a standard 3 + 3 design. PK and antitumor efficacy were also assessed. Results: A total of 50 pts have been enrolled; 28 pts have been treated on the 4/2 schedule: SU 50 mg + C 1,000 mg/m 2 , and SU 37.5 mg + C 1,250 mg/m 2 were not tolerated. Dose limiting toxicities (DLTs) included: grade 3 myalgia (n=1), grade 3 fatigue (n=2), and grade 3 hand- foot syndrome (n=2). The MTD for the 4/2 schedule was SU 37.5 mg/day + C 1,000 mg/m 2 . No DLTs nor dose reductions were observed among 9 pts treated at the MTD. Preliminary PK data do not indicate drug-drug interactions between SU and C. 3 pts (1 each with breast cancer, neuroendocrine carcinoma, and thyroid carcinoma) achieved confirmed partial responses. On the 2/1 schedule patients are being accrued to SU 37.5 or 50 mg + C 1,000 mg/m 2 and doses of SU 37.5 mg + C 1,000 mg/m 2 or SU 25 mg + C 1,250 mg/m 2 are being explored on the CD schedule. Conclusions: The combination of SU 37.5 mg/day (4/2 schedule) with C 1,000 mg/m 2 in pts with advanced solid tumors appears tolerable. SU may be administered in combination with C with no apparent drug-drug interaction. Subsequent cohorts will define the MTD of SU administered on the 2/1 and CD schedules. Further studies of this combination in breast cancer are warranted. No significant financial relationships to disclose.
Effect of vorinostat use on survival in patients with acute myeloid leukemia (AML) with FLT3 ITD mutations.
Authors: Young Kwang Chae, Anastasios Dimou, Koichi Takahashi, Christopher Brent Benton, Elias Jabbour, Farhad Ravandi, Gautam Borthakur, Jorge E. Cortes, Tapan M. Kadia, Deborah A. Thomas, William G. Wierda, Naval Guastad Daver, Courtney Denton Dinardo, Hagop M. Kantarjian, Guillermo Garcia-Manero
Journal: Journal of Clinical Oncology (2015)

e18019 Background: Novel treatment strategies for patients with AML remain an unmet need. Treatment with vorinostat for three days prior to idarubicin and cytarabine has resulted in high rates of durable responses in patients with FLT3 ITD positive AML in a prospective phase II study. The aim of the current study is to compare the survival of patients with AML treated with or without vorinostat in the FLT3 ITD positive and negative patient groups. Methods: We retrospectively identified patients with AML and known FLT3 ITD mutation status treated at MD Anderson Cancer Center from 2000 to 2012. We compared the survival of patients who received vorinostat as part of their induction chemotherapy with the patients who did not receive vorinostat in the FLT3 ITD mutation positive and negative patient groups. Results: Data on 1043 patients were collected. FLT3 ITD mutation status was known for 817 including 134 patients positive and 683 patients negative for FLT3 ITD mutation. There were 48 patients with known FLT3 ITD status who received vorinostat during induction. There was no difference in survival in the unselected population for the vorinostat and the the non vorinostat group. The vorinostat and non vorinostat groups were balanced in terms of age, gender, cytogenetics, complete response rate and performance status (PS) in both the FLT3 ITD positive and FLT3 ITD negative group. Among patients with FLT3 ITD mutations, 8 patients received vorinostat and 126 patients did not receive vorinostat. There was a survival benefit for the former group (HR 0.26, 95% CI 0.04-0.82, p = 0.04) independent of age and performance status (PS) (Cox proportional model including age and PS; adjusted HR 0.24, 95% CI 0.04-0.79). We did not find a difference in survival for patients with no FLT3 ITD mutation. Conclusions: Vorinostat use was associated with favorable overall survival in patients with FLT3 ITD mutations known to have unfavorable prognosis.
The complex biology and contribution of<i>Staphylococcus aureus</i>in atopic dermatitis, current and future therapies
Authors: L. Hepburn, D.J. Hijnen, B.R. Sellman, T. Mustelin, M.A. Sleeman, R.D. May, I. Strickland
Journal: British Journal of Dermatology (2016)

Atopic dermatitis (AD) is a complex, chronic inflammatory skin disorder affecting more than 10% of U.K. children and is a major cause of occupation‐related disability. A subset of patients, particularly those with severe AD, are persistently colonized with Staphylococcus aureus and exacerbation of disease is commonly associated with this bacterium by virtue of increased inflammation and allergic sensitization, aggravated by skin barrier defects. Understanding the complex biology of S. aureus is an important factor when developing new drugs to combat infection. Staphylococcus aureus generates exoproteins that enable invasion and dissemination within the host skin but can also damage the skin and activate the host immune system. Antibiotics are often used by dermatologists to aid clearance of S. aureus; however, these are becoming less effective and chronic usage is discouraged with the emergence of multiple antibiotic‐resistant strains. New ways to target S. aureus using monoclonal antibodies and vaccines are now being developed. This review will attempt to evaluate the key biology of S. aureus, current treatment of S. aureus infections in AD and recent advances in developing new anti‐S. aureus therapies that have potential in severe AD.