tbuckley/cabot-search huggingface dataset:
K562/GM-CSF vaccination reduces tumor burden, including achieving molecular remissions, in chronic myeloid leukemia (CML) patients (PTS) with residual disease on imatinib mesylate (IM)
Authors: B. Smith, Y. L. Kasamon, C. B. Miller, C. Chia, C. Gocke, J. Kowalski, I. Tartakovsky, B. Biedrzycki, R. J. Jones, K. Hege, H. I. Levitsky
Journal: Journal of Clinical Oncology (2006)

6509 Background: Despite high rates of clinical responses to IM, molecular complete responses are rare. The curative potential of allo transplantation and donor lymphocyte infusions underscores CML’s responsiveness to T cell mediated immunity. K562/GM-CSF is a tumor vaccine derived from a CML cell line that expresses several defined CML associated antigens and has been genetically engineered to produce GM-CSF. A pilot vaccination strategy was developed to determine if K562/GM-CSF immunotherapy in combination with IM could enhance T cell reactivity and clinical responses in pts having persistent, measurable disease despite 1 or more years on IM. Methods: Eligibility required pts to have achieved a major cytogenetic response (&lt;35% Ph+ cells) while on a stable dose of IM. Disease burden was measured serially over 12 wks prior to vaccines. 4 vaccines were administered in 3 wk intervals, each consisting of 1 × 10 8 irradiated K562/GM-CSF cells distributed over 10 sites, with or without topical 5% Aldara (a Toll-like receptor 7 agonist) used as a vaccine adjuvant. Disease burden was measured at 6 wk intervals for 9 mos from the first vaccine and specimens were banked for measurement of immune responses. Results: The trial enrolled 19 pts, all have completed the planned 4 vaccinations and 14 pts have completed all planned disease burden measurements. The median age is 52 (range 28–76) yrs with a median time from dx to enrollment of 57 (range 16–111) mos. Pts were on IM for a median of 37 (13–53) mos prior. 4 of 19 pts had FISH pos as their best previous response (BPR) with 2 becoming FISH neg post-vaccine (1 became PCR neg and 1 achieved a &gt;1 log reduction in disease burden by PCR). Of the 15 pts whose BPR was FISH neg/PCR pos, 4 are now PCR neg post vaccine, 4 experienced a &gt;1 log and 1 had 0.5–0.99 log reduction by PCR. Mean PCR levels for the 19 pts declined btwn pre- and post-vaccine measures (p=0.01). 3 of 5 pts achieving PCR neg remain so beyond 6 months. Only 1 pt progressed having entered the study with a heavy disease burden (30% FISH pos). Conclusions: K562/GM-CSF vaccine appears to improve responses in pts on IM, including achieving complete molecular remissions, despite long durations of previous IM therapy. [Table: see text]
Mismatch in epitope specificities between IFNγ inflamed and uninflamed conditions leads to escape from T lymphocyte killing in melanoma
Authors: Katherine Woods, Ashley J. Knights, Matthew Anaka, Ralf B. Schittenhelm, Anthony W. Purcell, Andreas Behren, Jonathan Cebon
Journal: Journal for ImmunoTherapy of Cancer (2016)

A current focus in cancer treatment is to broaden responses to immunotherapy. One reason these therapies may prove inadequate is that T lymphocytes fail to recognize the tumor due to differences in immunogenic epitopes presented by the cancer cells under inflammatory or non-inflammatory conditions. The antigen processing machinery of the cell, the proteasome, cleaves proteins into peptide epitopes for presentation on MHC complexes. Immunoproteasomes in inflammatory melanomas, and in antigen presenting cells of the immune system, are enzymatically different to standard proteasomes expressed by tumors with no inflammation. This corresponds to alterations in protein cleavage between proteasome subtypes, and a disparate repertoire of MHC-presented epitopes.We assessed steady state and IFNγ-induced immunoproteasome expression in melanoma cells. Using epitope specific T-lymphocyte clones, we studied processing and presentation of three NY-ESO-1 HLA-Cw3 restricted epitopes by melanoma cell lines. Our experimental model allowed comparison of the processing of three distinct epitopes from a single antigen presented on the same HLA complex. We further investigated processing of these epitopes by direct inhibition, or siRNA mediated knockdown, of the immunoproteasome catalytic subunit LMP7.Our data demonstrated a profound difference in the way in which immunogenic T-lymphocyte epitopes are presented by melanoma cells under IFNγ inflammatory versus non-inflammatory conditions. These alterations led to significant changes in the ability of T-lymphocytes to recognize and target melanoma cells.Our results illustrate a little-studied mechanism of immune escape by tumor cells which, with appropriate understanding and treatment, may be reversible. These data have implications for the design of cancer vaccines and adoptive T cell therapies.
Dual inhibition of phosphoinositide 3-kinase and mammalian target of rapamycin as a novel therapeutic approach in human ovarian carcinoma
Authors: Chintda Santiskulvong, Mirela-Rita Fekete, Carol Eng, David Mulholland, Hong Wu, Oliver Dorigo
Journal: Cancer Research (2008)

4970  Mammalian target of rapamycin (mTOR) plays a central role in regulating cell growth and cell cycle progression, and is considered a promising therapeutic target for cancers with phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway activation, including ovarian cancer. However, recent studies have demonstrated that mTOR inhibition can increase levels of phosphorylated Akt (pAkt) due to the stabilization of insulin receptor substrate. This effect can limit the efficacy of mTOR inhibitors due to the growth promoting and anti-apoptotic effects of pAkt. Thus, we hypothesized that concomitant inhibition of PI3K and mTOR would enhance the effect of mTOR inhibition. We tested the effect of the mTOR inhibitor RAD001 (everolimus) and the dual pan-PI3K/mTOR inhibitor NVP-BEZ235 as single agents and in combination on three human ovarian cancer cell lines, SKOV3 and IGR-OV1 with constitutively active PI3K/Akt/mTOR signaling, and OVCAR5 cells with a low level of pathway activation. In SKOV3 cells, treatment with 10 nM RAD001 or 50 nM NVP-BEZ235 as single agents induced only a moderate reduction of cell viability by XTT assay (31% and 38%, respectively). However, combination treatment with RAD001 and NVP-BEZ235 reduced cell viability by 68%. Similar results were found in IGR-OV1 and OVCAR5 cells. The enhanced effects of dual inhibition were confirmed using the inhibitors rapamycin (mTOR) and LY294002 (PI3K). Two-way ANOVA statistical analyses showed that at low concentrations the interaction between RAD001 and NVP-BEZ235 was synergistic. Immunoblotting confirmed that 10 nM RAD001 induced a modest increase in pAkt levels in SKOV3, and up to 3-fold in OVCAR5, but inhibited pAkt in IGR-OV1 cells. NVP-BEZ235 at 50 nM decreased pAkt by up to 75% in SKOV3 and IGROV1 cells. These findings suggest that the cell viability response to dual inhibition of mTOR and PI3K is independent of the activation status of the PI3K/Akt/mTOR pathway and the effect of RAD001 on Akt phosphorylation. In cell cycle distribution assays, treatment of cells with RAD001 and NVP-BEZ235 in combination caused a significantly greater increase in the proportion of cells in G0/G1 compared to single agent treatment. Furthermore, in the LSL-K-Ras G12D/+/PTEN loxP/loxP murine ovarian cancer model that is based on conditional deletion of the tumor suppressor gene PTEN and concomitant expression of constitutively active K-Ras, oral administration of either RAD001 (10 mg/kg) or NVP-BEZ235 (40 mg/kg) resulted in significantly reduced S6 ribosomal protein phosphorylation for RAD001, and decreased Akt phosphorylation for NVP-BEZ235 in tumor tissue of treated mice. In conclusion, our results indicate that the efficacy of mTOR inhibition can be significantly enhanced by concomitant inhibition of Akt phosphorylation. Dual inhibition of mTOR and PI3K could be utilized as a promising new therapeutic strategy in ovarian cancer.
Effect of preoperative concomitant chemoradiotherapy in chemotherapy-refractory breast cancer on feasibility of curative surgery and pathologic tumor response.
Authors: I. Ghorbel, S. Heymann, S. Delaloge, A. Belaid, F. Azoury, C. Mazouni, C. Balleyguier, P. Vielh, H. Marsiglia, C. Bourgier
Journal: Journal of Clinical Oncology (2010)

644 Background: To assess therapeutic response and treatment-related morbidity in patients treated with concomitant chemoradiotherapy for inoperable breast cancer (BC) who had progressed under anthracyclines (A) and/or taxanes (T)-containing primary chemotherapy (CT). Methods: A total of 14 patients (1.8%) with chemotherapy-refractory locally advanced BC (CT-RLABC) from 750 women who received primary CT for between 2000-2009, at Institut Gustave Roussy, Villejuif, France were studied. Patients had T2 (n = 1), T3 (n = 4), T4c (n = 1) and T4d (n = 8) at disease presentation and received either A followed by T (n = 10), or A (n = 3) or T (n = 1) regimens prior to tumor progression. At the time of CT-RLABC, an association of IV vinorelbine 30 mg/m2 day 1 and 8 and either 5-day continuous 5FU (1,000 mg/m2/day) or 14-days capecitabine (2,000 mg/m2/day), 3-weekly regimen, 4 cycles, was given concurrently with radiotherapy (50 Gy) to the breast and regional lymph nodes for 5 weeks followed by a boost of 20 Gy to tumor (n = 10) to all patients. If feasible, radical mastectomy followed radiotherapy. Safety, accessibility to curative surgery and pathologic tumor response were assessed. Results: In 10/14 (71%) patients, grade 2-3 skin acute toxicities were observed during locoregional chemoradiotherapy. Even though all BC were initially inoperable, combined chemoradiotherapy permitted 71% of pts to undergo curative surgery (n = 10) 4-8 weeks after RT completion. Among the 4 remaining pts, 2 had refused surgery despite clinical complete or partial response and 2 developed metastatic progression during loco-regional treatment. Of the 10 patients who had undergone surgery, complete pathologic response was observed in 5 patients (50%). None of them had major peri- or postoperative complications. Conclusions: FUN-based chemoradiotherapy enabled to perform surgery in 71% of A/T-refractory inoperable BC with a pathologic complete response in 50% of operated pts. Combined chemoradiotherapy should be further assessed at a larger scale to take part in BC treatment when refractory to primary CT. No significant financial relationships to disclose.
Postoperative adjuvant gemcitabine plus oxaliplatin (GemOx) chemotherapy followed by chemoradiation in patients with pancreatic carcinoma: A multicenter phase II study
Authors: F. Mornex, T. André, C. Louvet, J. Seitz, M. Ychou, G. Lledo, E. Touboul, C. Partensky, J. Balosso
Journal: Journal of Clinical Oncology (2007)

4520 Background: Gemcitabine (Gem) is an active drug in metastatic pancreatic cancer and a very good radiosensitizer. We evaluated the safety and potential activity of adjuvant GemOx chemotherapy followed by concurrent Gem and irradiation (RT) after curative resection of pancreatic cancer. Methods: Fifty four patients were enrolled from October 2002 to January 2005 in this trial with potentially curative resection of pathologically confirmed adenocarcinoma of the pancreas with negative resection margins (R0). Gem 1000 mg/m 2 (100 min) on d1 then Ox 100 mg/m 2 (120 min) on d2 were given (q2w for 6 cycles) followed 4 weeks after by Gem 100 mg/m 2 (30 min) combined with RT 50 Gy (2Gy fraction) for 5 weeks in patients with no residual toxicity nor recurrence. Results: The treated population (at least 2 induction cycles) included 49 patients (91%). Characteristics at baseline: median age: 59.2 yrs; Karnofsky performance status =80: 96%; stage TX: 10%, T1: 8%, T2: 41%, T3:39%; T4: 2% (TNM classification, 5 th edition); lymph node positive: 43%; median time from surgery to inclusion was 43 days. Forty six patients (85%) received the 6 planned induction cycles and 41 patients (76%) completed chemoradiation. The recurrence free 1-year survival rate is 71% (N=49); (95% CI 0.581–0 845). Forty one patients (98% of the irradiated population) received the total 50 Gy radiation dose. The most common Gr 3/4 toxicities during induction chemotherapy (N=51) were: neutropenia 18%, thrombocytopenia 14%; nausea, vomiting, diarrhea:16%, neurotoxicity (Gr 3 only) 4%. Acute Gr 3/4 toxicities during chemoradiation (N=42): neutropenia 19%, thrombocytopenia 7.0%, neurotoxicity (Gr 3 only) 7%. No toxic death occurred on treatment. Conclusions: GemOX in adjuvant followed by Gem + Radiotherapy have a manageable toxicity profile with a promising 71% 1 year RFS. Data of OS will be communicated during the meeting. No significant financial relationships to disclose.
AB0470 Efficacy of Very low Dose (100MG) Rituximab in Active Rheumatoid Arthritis Despite Combinations Dmards
Authors: M.K. Bavaliya, P. Shenoy
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Rituximab is an anti-CD20 antibody that represents a therapeutic alternative for the patients with rheumatoid arthritis. It has been proven that Rituximab at a dose of 2 gm is very effective in patients with DMARD and antiTNF failures. But the cost of this therapy is high and increases the economic burden. Limited data has shown that B cell is possible even with lower dosage to what is recommended. <h3>Objectives</h3> 1) To assess B cell depletion with very low dose single dose of 100mg Rituximab 2) To assess improvement in disease activity (EULAR response) <h3>Methods</h3> In this open label, prospective, observational study at tertiary care center sero positive RA patients who responded inadequately to combination of DMARDs were given single dose of 100 mg of Rituximab. B cell numbers in the peripheral blood was assessed by Flow cytometry and B cell depletion was defined as B cell numbers &lt;0.01%. Efficacy was evaluated using B cell depletion after 2 weeks and disease activity score in 28 joints (DAS28) on monthly bases. Those patients who did not achieve B cell depletion and/or EULAR moderate response were given second dose of rituximab 500mg. <h3>Results</h3> 15 patients (13 females and 2 males; mean age 47.7±13.95 years) were included in the study. Mean duration of the disease was 7.3±6.01 years. RF was positive in 14 out of 15 and Anti CCP antibody was positive in all patients. At baseline mean DAS score was 6.14±0.84 and mean CD 19% was 10.69±4.35%. After 2 weeks of Rituximab, B cell depletion was achieved in 12 patients (80%) and mean DAS28 was 2.72±0.57 at the end of 24 weeks. Two patients were given second dose of 500mg Rituximab after 8 weeks of first dose. All patients achieved EULAR good response at the end of 24 weeks. <h3>Conclusions</h3> Early results from this study are very promising and show that low dose Rituximab is effective in treating RA patients inadequately responding to DMARDS. <h3>References</h3> Edwards JC, Szczepanski L, Szechinski J et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis.N Engl J Med. 2004 Jun 17;350(25):2572-81; Mease PJ, Revicki DA, Szechinski J et al.;Improved health-related quality of life for patients with active rheumatoid arthritis receiving rituximab: Results of the Dose-Ranging Assessment: International Clinical Evaluation of Rituximab in Rheumatoid Arthritis (DANCER) Trial. J Rheumatol. 2008 Jan;35(1):20-30. Epub 2007 Nov 15. Anolik JH, Barnard J, Cappione A et al. Rituximab improves peripheral B cell abnormalities in human systemic lupus erythematosus;Arthritis Rheum. 2004 Nov;50(11):3580-90; Bruzzese V. et al. Therapeutic effectiveness of minimal doses of rituximab in a patient with rheumatoid arthritis; Int J Immunopathol Pharmacol. 2011 Jan-Mar;24(1):265-7 <h3>Acknowledgements</h3> We acknowledge flowcytometry lab incharge,chairman-ethics committee and medical director of institute. <h3>Disclosure of Interest</h3> None declared
Results from ARQ 197-209: A global randomized placebo-controlled phase II clinical trial of erlotinib plus ARQ 197 versus erlotinib plus placebo in previously treated EGFR inhibitor-naive patients with locally advanced or metastatic non-small cell lung cancer (NSCLC).
Authors: J. H. Schiller, W. L. Akerley, W. Brugger, D. Ferrari, E. G. Garmey, D. E. Gerber, S. V. Orlov, R. Ramlau, J. Von Pawel, L. V. Sequist
Journal: Journal of Clinical Oncology (2010)

LBA7502 Background: Orally administered ARQ197 is a selective, non-ATP competitive inhibitor of c-MET (MET), a receptor TK implicated in cancer cell migration, invasion, and proliferation. Dual EGFR-MET inhibition is a promising strategy for overcoming MET-mediated resistance to EGFR inhibitors. A prior phase I trial demonstrated the safety of ARQ197 plus erlotinib and suggested activity in patients (pts) with advanced NSCLC. Methods: This is a global, randomized, placebo-controlled, double-blind trial comparing erlotinib plus ARQ197 (E+A) versus erlotinib plus placebo (E+P). Archival tissue was collected for all pts for k-RAS, EGFR, and MET analyses. The primary endpoint was PFS; secondary endpoints included safety, ORR, OS, and subgroup analyses. Results: 167 pts were randomized to E+A (84 pts) or E+P (83 pts). Mean age was 63 yrs and baseline characteristics were well balanced for sex (39%/41% F); race (93%/96% white) and smoking history (20%/22% never smoker). Imbalances were seen among treatment arms in NSCLC histology (54%/64% adeno) and predictive molecular genotypes: EGFR mutations (7%/13%) and k-RAS mutations (12%/6%). Final PFS was prolonged with E+A (median = 16.1 wks) vs E+P (9.7 wks) among ITT pts (HR 0.81 [95% CI 0.57, 1.15]; p=0.23). Planned multivariable Cox regression model adjusting for prognostic factors (including histology, genotype) yielded PFS HR 0.68 (95% CI 0.47, 0.98; p&lt;0.05). PFS improvement was particularly prominent among pts with nonsquamous histology, EGFR wild-type status, and k-RAS mutations. Preliminary safety analysis revealed no major differences between arms with AEs (≥10% of pts; all grades) including rash (64%/52%); diarrhea (48%/53%); fatigue (33%/37%); nausea (26%/26%); and anemia (14%/13%). OS, ORR, and final safety data will be analyzed at study conclusion. Conclusions: Combined with erlotinib in the treatment of second/third-line EGFR-inhibitor naïve NSCLC, ARQ-197 is well-tolerated and prolongs PFS. Particular benefit is observed among pts with non-squamous histology, k-RAS mutations, and EGFR wild-type status. [Table: see text]
Screen all adults for high blood pressure, US panel recommends
Authors: Michael McCarthy
Journal: BMJ (2015)

All adults aged 18 and older should be screened for high blood pressure, but before treatment starts the diagnosis should be confirmed by either home blood pressure monitoring or, preferably, ambulatory blood pressure monitoring (ABPM), the US Preventive Services Task Force has concluded.1

The evidence that ABPM was best for diagnosing hypertension was “convincing,” the task force said in recommendations released on 13 October, adding, “Although the criteria for establishing hypertension varied across studies, there was significant discordance between the office diagnosis of hypertension and 12 and 24 hour average blood pressures using ABPM, with significantly fewer patients requiring treatment based on ABPM.”

High blood pressure, which often …
Association Between Plasma Uric Acid Levels and Cardiorenal Function in Adolescents With Type 1 Diabetes
Authors: Yuliya Lytvyn, Farid H. Mahmud, Denis Daneman, Livia Deda, David B. Dunger, John Deanfield, R. Neil Dalton, Yesmino Elia, Ronnie Har, Timothy J. Bradley, Cameron Slorach, Wei Hui, Rahim Moineddin, Heather N. Reich, James W. Scholey, Luc Mertens, Etienne Sochett, David Z.I. Cherney
Journal: Diabetes Care (2016)

OBJECTIVE The relationship between plasma uric acid (PUA) and renal and cardiovascular parameters in adolescents with type 1 diabetes (T1D) is not well understood. Our aims in this exploratory analysis were to study the association between PUA and estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (ACR), blood pressure, endothelial function, and arterial stiffness in T1D adolescents. These associations were also studied in healthy control (HC) subjects. RESEARCH DESIGN AND METHODS We studied 188 T1D subjects recruited to the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT) and 65 HC subjects. Baseline PUA, eGFRcystatin C, ACR, blood pressure, flow-mediated dilation (FMD), and carotid-femoral pulse wave velocity (PWV) were measured. RESULTS PUA was lower in T1D vs. HC subjects (242 ± 55 vs. 306 ± 74 μmol/L, respectively; P &amp;lt; 0.0001). Higher PUA was inversely associated with eGFR in T1D subjects (r = −0.48, P &amp;lt; 0.0001) even after correction for baseline clinical demographic characteristics. PUA was not associated with ACR in T1D after adjustment for potential confounders such as eGFR. For cardiovascular parameters, PUA levels did not associate with systolic blood pressure, FMD, or PWV in T1D or HC subjects. CONCLUSIONS Even within the physiological range, PUA levels were significantly lower in T1D adolescent patients compared with HC subjects. There was an inverse relationship between PUA and eGFR in T1D, likely reflecting an increase in clearance. There were no associations observed with ACR, blood pressure, arterial stiffness, or endothelial function. Thus, in contrast with adults, PUA may not yet be associated with cardiorenal abnormalities in adolescents with T1D.
Abstract 14571: Role of Microwave Radiometry in the Prediction of Multivessel Coronary Artery Disease
Authors: Konstantinos Toutouzas, Georgios Benetos, Maria Drakopoulou, Archontoula Michelongona, Charalampia Nikolaou, Konstantina Masoura, Konstantinos Stathogiannis, Constantina Aggeli, Eleftherios Tsiamis, Elias Siores, Christodoulos Stefanadis
Journal: Circulation (2013)

Background: Intima-media thickness (IMT) of carotid arteries has been used as a surrogate marker for the extent of coronary artery disease (CAD). Nevertheless, IMT does not provide information rega...
Human immunodeficiency virus-1-tat protein induces the cell surface expression of endothelial leukocyte adhesion molecule-1, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1 in human endothelial cells
Authors: Subhash Dhawan, Raj K. Puri, Ashok Kumar, Helen Duplan, Jean Michel Masson, Bharat B. Aggarwal
Journal: Blood (1997)
Spectrum of clinical and genetic features of patients with inherited platelet disorder with suspected predisposition to hematological malignancies: a nationwide survey in Japan
Authors: A. Yoshimi, T. Toya, Y. Nannya, K. Takaoka, K. Kirito, E. Ito, H. Nakajima, Y. Hayashi, T. Takahashi, A. Moriya-Saito, K. Suzuki, H. Harada, N. Komatsu, K. Usuki, M. Ichikawa, M. Kurokawa
Journal: Annals of Oncology (2016)