tbuckley/cabot-search huggingface dataset:
Efficacy of nilotinib (AMN107) in patients (Pts) with newly diagnosed, previously untreated philadelphia chromosome (Ph)- positive chronic myelogenous leukemia in early chronic phase (CML-CP)
Authors: J. E. Cortes, S. M. O'Brien, A. Ferrajoli, G. Borthakur, J. Burger, W. Wierda, G. Garcia-Manero, L. Letvak, H. M. Kantarjian
Journal: Journal of Clinical Oncology (2008)

7016 Background: Nilotinib is an oral tyrosine kinase inhibitor with increased selectivity against Bcr-Abl approximately 30-fold more potent than imatinib effective in CML after imatinib failure. We initiated a phase II study to evaluate the efficacy of nilotinib as 1st line therapy in pts with newly diagnosed CML-CP. Methods: The primary objective was to estimate the proportion of pts attaining major molecular response at 12 months (mo). Pts with untreated CML-CP were eligible and received nilotinib 400mg twice daily. Results: Thirty-five pts have been treated for a median of 6.5 months (mo). The median age was 47 years (yrs). The rate of complete cytogenetic response [CCyR] at 3, 6 and 12 mo compares favorably to those observed in historical controls treated with imatinib 400mg or 800 mg daily: Major molecular response (MMR) was observed in 13% at 3 mo, 45% at 6 mo, and 45% at 12 mo. Grade 3–4 thrombocytopenia was observed in 6% and neutropenia in 3%. Other grade 3–4 adverse events included elevation of lipase in 9% and bilirubin in 9%. Fifteen (43%) pts had transient treatment interruptions (median 11 days) and 14 had dose reductions. The actual median dose is 800mg daily. Thirty-two patients continue on study. Conclusion: Nilotinib 400 mg twice induces a CCyR in nearly all patients as early as 3 months after the start of therapy with a favorable toxicity profile. Accrual is ongoing. Percent with CCyR (No. evaluable) Months on therapy Percent with CCyR (No. evaluable) P value Nilotinib Imatinib 400mg Imatinib 800mg 3mo 96 (31) 37 (49) 62 (202) < 0.0001 6mo 100 (20) 54 (48) 82 (199) < 0.0001 12mo 100 (11) 65 (48) 86 (197) 0.0007 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Novartis Novartis
Manifestations of cardiovascular toxicity associated with the approved tyrosine kinase inhibitors
Authors: S. L. Verbois, H. Saber, K. A. Benson, D. E. Morse, R. Justice
Journal: Journal of Clinical Oncology (2007)

14152 Background: Since 2001, 5 tyrosine kinase inhibitors (TKi’s; imatinib, erlotinib, sorafenib, sunitinib and dasatinib) have been approved for hematologic and solid tumor indications including, CML, ALL, GIST, RCC, pancreatic and NSCLC. While individual agents are designed to inhibit the TK activity of specific targets, “cross-talk” with non-target TKs (e.g., ABL, EGFR, VEGFRs, KIT, KDR, CSF1R, PDGFRs, RET, the SRC family, EPHA2, RAF, and FLT3) is extensive. The relationship between inhibition of individual kinases and the toxicity profile of each drug is unclear. Methods: Following from the observation of cardiovascular (CV) toxicity in clinical settings (pre- and post- marketing) and from the original non-clinical toxicologic evaluations, a new “class-related” review of non-clinical toxicological findings was conducted. To compare the non-clinical and clinical CV findings, the Adverse Event Reporting System (AERS) was searched for all events, excluding those of non-CV nature and those unlikely to be drug-related (e.g. hemorrhagic events were excluded from the initial analyses). Individual patient reports were not reviewed in full, therefore definitive attribution of disease related events can not be made. Results: While variable in expression, the non-clinical signs of toxicity included cardiac and vascular inflammation, cardiac degeneration and hypertrophy, decreased cardiac function (e.g. LVEF decreases), alterations in blood pressure, and QT prolongation. Clinical reports for the TKi’s have included hypo- and hypertension, conduction abnormalities and arrhythmias, cardiac hypertrophy and changes in cardiac function (LVEF and CHF). Conclusions: It is not possible at this time to relate the CV toxicities associated with the TKi’s to a specific pattern of TK inhibition. CV toxicity has been observed both clinically and non-clinically and warrants further investigation. No significant financial relationships to disclose.
Additive anti-inflammatory effect of glucocorticoids and PDE4 inhibitors on COPD CD8 cells
Authors: Seamus Grundy, Jonathan Plumb, Manminder Kaur, Simon Lea, Dave Singh
Journal: European Respiratory Journal (2014)

Rationale   CD8 cells play a role in COPD pathogenesis. Glucocorticoids (GC) and phosphodiesterase 4 inhibitors (PDE4i) are established anti-inflammatory treatments. We studied the combined effects of GC with PDE4i on COPD CD8 cells.   Methods   CD8 cells were treated with dexamethasone (dex) alone or in combination with roflumilast or GSK256066 prior to stimulation. Interleukin 2 (IL-2) and interferon gamma (IFNγ) release were measured by ELISA.  The combined effects of dex with PDE4i on mRNA levels of the GC inducible genes GILZ, MKP-1 and FKBP5 were measured using qRT-PCR.  The combined effects of dex with PDE4i on nuclear translocation of key transcription factors were studied using immunofluorescence for p65, CREB and NFAT.   Results   Dex inhibited IL-2 and IFNγ release in a concentration dependent manner. The addition of PDE4i significantly enhanced the effect of dex in an additive fashion.  Dex significantly increased transcription of GILZ, MKP-1 and FKBP-5. GSK256066 had no effect on GILZ or FKBP-5 but significantly increased transcription of MKP-1. There was some evidence to suggest that Dex and GSK256066 together synergistically enhanced transcription of MKP-1.  Dex inhibited nuclear translocation of p65. GSK256066 increased CREB nuclear translocation. Neither dex nor GSK256066 affected NFAT nuclear translocation.   Conclusions   The combination of dexamethasone with PDE4 inhibitors results in an additive anti-inflammatory effect. This addition appears to be due to effects on different transcription factors. These findings may translate to enhanced clinical benefits with the combination of inhaled corticosteroids with PDE4i.
Improved outcome for acute lymphoblastic leukemia (ALL) in children and adolescents: Results of the MCP841—A two decades report from a developing country (India)
Authors: T. G. Sagar, A. Chandra, S. Devarajan
Journal: Journal of Clinical Oncology (2006)

6586 Background: In the 1970s, survival rates after treatment for ALL in children and young adults (&lt; 25 years) in India were poor. The introduction of a standard protocol (MCP841) and improvements in supportive care led to an increase in the event-free survival (EFS) from &lt;20% to 45–50% at 4 yrs. Results of treatment with protocol MCP841 between 1983–2002 have been briefly reviewed here. The MCP841 reports the first prospective, nonrandomized trial for ALL, in collaboration with NCI-US. The aim of this study was to classify immunophenotypes, to analyze clinical features and laboratory features, and to assess whether this protocol would improve the survival rate. Methods: From Jan. 1983 to Dec. 2002, 566 patients (0–25 years) were diagnosed with ALL were treated on MCP841 protocol with intensive induction, central nervous system (CNS) directed therapy and maintenance therapy. Results: From 1983–1989, 171 patients were enrolled and achieved a complete remission (CR) of 74.8% with 25.1% induction deaths and 47.6% relapsed after remission. During 1989–2002 with improvement in supportive care 395 patients enrolled. 328 (83%) of the patients achieved CR, 45 failed to respond and 59 (11.9%) had drug or disease related death before completing induction therapy. The overall 5-year EFS rate was 38.3%. The 5-year RFS rate was 44.5%. Relapse was noted in 147 of the 328 patients (44.8%). The cumulative incidence of CNS relapse was low. Age and white blood cell count is strongly associated with outcome in Western series, but was not a risk factor for EFS. At univariate and multivariate analysis the most significant determinant of a positive outcome was the achievement of CR. Comparison of patient characteristics with published series from Western nations indicated that patients had more extensive disease at presentation, as measured by WBC, lymphadenopathy and organomegaly. The proportions of ALLs with precursor T-cell immunophenotypes, were also increased. Conclusions: Our strategy to adapt to our population of patients and was effective in improving the EFS. It cannot be assumed that risk factors defined in Western populations are equally appropriate for patient assignment to risk-adapted therapy groups in less affluent countries. No significant financial relationships to disclose.
Abstract #5381: Impairment of Ras-mediated tumorigenicity through chemical inhibition of PARP-1
Authors: Victor M. Arce, Marcos Seoane, Pablo Iglesias, Jose A. Costoya
Journal: Cancer Research (2009)

AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Gliomas are the most common primary tumors in the brain. We use this tumor type as a paradigm of oncogenic transformation. One common alteration in gliomas of all grades is the abnormal activation of cell growth signaling pathways through overproduction of growth factors such as FGF2, EGFR and PDGF19, and their receptors. Through activate HRas (HRasV12) we can recapitulate mutations in several growth factor receptors activating downstream effectors like Raf/MEK/ERK and PI3K/AKT pathways. We found that in astrocytes, the hyperactivation of growth signaling pathways, mediated by transduction with HRasV12, increases cell proliferation rate in the absence of senescence, facilitating their transformation into tumoral cells. Poly(ADP-ribose) polymerase (PARP-1) facilitates DNA repair by binding to DNA breaks and attracting DNA repair proteins to the site of damage. Despite its important role in the cellular response to genotoxic stress, PARP-1 is not required for survival and Parp1-/- mice are viable and fertile. These mice do not develop early onset tumors and tumor latency is increased in Parp1 knockout mice that are deficient for p53. Unexpectedly, here we observed that Parp1-/- astrocytes transduced with HRasV12 display a marked proliferative decrease when compared with wild type astrocytes that express HRasV12. Given that Parp1-/- astrocytes are less susceptible to HRasV12 induced transformation, the inactivation of PARP-1 with chemical inhibitors is a potential therapeutic approach to restrain the tumor progression. Interestingly, in our model of gliomagenesis PARP-1 chemical inhibition (PJ34) leads to a significant decrease in the proliferative rate in HRasV12 astrocytes comparable to Parp1-/- astrocytes. These findings suggest that PARP inhibition may be useful in combination with other chemotherapeutic agents in the treatment of gliomas. This study was supported by Spanish Ministry of Education and Science (SAF2005-00306) and Xunta de Galicia grants (PGIDIT05PXIB20801PR); Grupos emerxentes 2007/064 to J.A.C.); Xunta de Galicia (PGIDIT05BTF20801PR to V.M.A.), and by Fundacion de Investigacion Medica Mutua Madrilena (J.A.C.). J.A.C. is an Investigator of Ramon y Cajal Programme (Spanish Ministry of Education and Science).

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5381.
A Meta-analysis of Individual Participant Data Reveals an Association between Circulating Levels of IGF-I and Prostate Cancer Risk
Authors: Ruth C. Travis, Paul N. Appleby, Richard M. Martin, Jeff M.P. Holly, Demetrius Albanes, Amanda Black, H. Bas Bueno-de-Mesquita, June M. Chan, Chu Chen, Maria-Dolores Chirlaque, Michael B. Cook, Mélanie Deschasaux, Jenny L. Donovan, Luigi Ferrucci, Pilar Galan, Graham G. Giles, Edward L. Giovannucci, Marc J. Gunter, Laurel A. Habel, Freddie C. Hamdy, Kathy J. Helzlsouer, Serge Hercberg, Robert N. Hoover, Joseph A.M.J.L. Janssen, Rudolf Kaaks, Tatsuhiko Kubo, Loic Le Marchand, E. Jeffrey Metter, Kazuya Mikami, Joan K. Morris, David E. Neal, Marian L. Neuhouser, Kotaro Ozasa, Domenico Palli, Elizabeth A. Platz, Michael N. Pollak, Alison J. Price, Monique J. Roobol, Catherine Schaefer, Jeannette M. Schenk, Gianluca Severi, Meir J. Stampfer, Pär Stattin, Akiko Tamakoshi, Catherine M. Tangen, Mathilde Touvier, Nicholas J. Wald, Noel S. Weiss, Regina G. Ziegler, Timothy J. Key, Naomi E. Allen
Journal: Cancer Research (2016)

The role of insulin-like growth factors (IGF) in prostate cancer development is not fully understood. To investigate the association between circulating concentrations of IGFs (IGF-I, IGF-II, IGFBP-1, IGFBP-2, and IGFBP-3) and prostate cancer risk, we pooled individual participant data from 17 prospective and two cross-sectional studies, including up to 10,554 prostate cancer cases and 13,618 control participants. Conditional logistic regression was used to estimate the ORs for prostate cancer based on the study-specific fifth of each analyte. Overall, IGF-I, IGF-II, IGFBP-2, and IGFBP-3 concentrations were positively associated with prostate cancer risk (Ptrend all ≤ 0.005), and IGFBP-1 was inversely associated weakly with risk (Ptrend = 0.05). However, heterogeneity between the prospective and cross-sectional studies was evident (Pheterogeneity = 0.03), unless the analyses were restricted to prospective studies (with the exception of IGF-II, Pheterogeneity = 0.02). For prospective studies, the OR for men in the highest versus the lowest fifth of each analyte was 1.29 (95% confidence interval, 1.16-1.43) for IGF-I, 0.81 (0.68-0.96) for IGFBP-1, and 1.25 (1.12-1.40) for IGFBP-3. These associations did not differ significantly by time-to-diagnosis or tumor stage or grade. After mutual adjustment for each of the other analytes, only IGF-I remained associated with risk. Our collaborative study represents the largest pooled analysis of the relationship between prostate cancer risk and circulating concentrations of IGF-I, providing strong evidence that IGF-I is highly likely to be involved in prostate cancer development. Cancer Res; 76(8); 2288-300. ©2016 AACR.
The Role of Microenvironment Expression of Pd-1 Ligands and Chemokines in Clinical Outcome of Hodgkin'S Lymphoma
Authors: N. Svergun, N. Khranovska, I. Kriachok, O. Novosad, T. Kadnikova, O. Gorbach, I. Tytorenko, I. Pastushenko, E. Kushchevyy, K. Ulianchenko
Journal: Annals of Oncology (2014)
Intravenous (i.v.) busulfan (Bu) plus melphalan (Mel) is a well-tolerated preparative regimen for stem cell transplantation (SCT) in patients (pts) with advanced lymphoid malignancies
Authors: P. Kebriaei, T. Madden, N. Thapar, E. Shpall, C. Hosing, M. Qazilbash, P. Thall, I. Khouri, R. Champlin, R. Jones, B. Andersson
Journal: Journal of Clinical Oncology (2006)

6548 Background: High dose chemotherapy and SCT is an accepted treatment option for pts with relapsed lymphoid malignancies. However, relapse remains a significant problem. A double alkylating regimen of Bu and Mel has been suggested as an effective and myeloablative pre-transplant conditioning regimen. Historically, oral Bu was used and the combination resulted in considerable mucositis and VOD. An i.v. formulation of Bu has been developed that has less pharmacokinetic variability. We are investigating i.v. Bu-Mel in pts with lymphoid malignancies undergoing auto- or allo-SCT. Patients and Methods: The conditioning regimen consists of i.v. Bu 130 mg/m 2 over 3 hr daily for 4 days, either as a fixed dose per BSA, or to target an average daily AUC of 5,000 μMol-min ± 12% determined by a test dose of i.v. Bu at 32 mg/m 2 given 48 hours prior to the high dose regimen. After the 4 daily Bu doses, there is a rest day, followed by 2 daily doses of Mel at 70mg/m 2 . Stem cells are infused the following day. Dilantin is given for seizure prophylaxis. GVHD prophylaxis is tacrolimus and methotrexate for pts receiving allo-SCT. Results: Patient characteristics, engraftment, and regimen-related toxicities are listed below: Grade I or II mucositis was the most common regimen-related toxicity. There were no cases of VOD; reversible hyperbilirubinemia was observed in 3 pts receiving allo-SCT. No grade IV toxicity was noted, and there were no regimen-related deaths with longest follow-up of 10 months. All allo-SCT pts had 100% donor chimerism by day 30. 27 pts had i.v. Bu delivered per test dose guidance; 6 pts received fixed dose Bu at 130 mg/m 2 . The median daily systemic Bu exposure was 4867 μMol-min. Conclusion: Intravenous Bu-Mel is well tolerated, and enables prompt neutrophil and platelet engraftment. Individualized PK-directed dosing of i.v. Bu is feasible, and likely contributes to the low toxicity profile of this regimen. Longer time is needed to assess disease control. [Table: see text] No significant financial relationships to disclose.
A Metalloproteinase Inhibitor Prevents Lethal Acute Graft-Versus-Host Disease in Mice
Authors: Koichi Hattori, Takao Hirano, Chifuyu Ushiyama, Hiroaki Miyajima, Norifumi Yamakawa, Tomohiko Ebata, Yukihisa Wada, Shoji Ikeda, Kohichiro Yoshino, Masatoshi Tateno, Kazuo Oshimi, Nobuhiko Kayagaki, Hideo Yagita, Ko Okumura
Journal: Blood (1997)
Abstract 11: Early Cardiac Catheterization Is Associated with Improved Survival in Comatose Survivors of Cardiac Arrest Without ST-Segment Elevation Myocardial Infarction
Authors: Ryan D Hollenbeck, Hui Nian, Jeremy S Pollock, Michael E Cash, Michael B Kelley, Carol R Scott, Chad E Wagner, Joseph L Fredi, John A McPherson
Journal: Circulation (2012)

Background: Early cardiac catheterization (CC) is generally accepted in the standard of care in patients with cardiac arrest due to STEMI. The optimum timing of CC following cardiac arrest without ...
(Question: do herpesviruses cause cancer? Answer: of course they do]) (Editorial)a
Authors: Rapp F
Journal: JNCI Journal of the National Cancer Institute (1973)

It is time to give attention to those viruses known to infect both humans and animals and to be multipotential.  Of particular interest would be those viruses with the ability to persist in the body for extended periods coupled with the potential to cause a variety of clinical illnesses 1 of which may be the neoplastic process.  The hyperviruses are a major group of viruses that have such qualities under natural conditions both in animals and in humans.  Attention in this discussion is on the involvement of herpesvirsuses in animal neoplasias multipotential of human herpesviruses the case for Epstein-Barr virus and the case for herpes simplex virus.  The more virulent the virus the less likely that virus-specific products will be easily detected in the transformed cells.  Continued accumulation of circumstantial evidence is required in order to link these viruses to the etiology of the various neoplasms with which they have already been associated.  At this time it is known that the herpesviruses are frequently at the right place at the right time and they seem to have the properties that qualify them as candidates for the role of human cancer viruses.
Identification of the Cell-Intrinsic and -Extrinsic Pathways Downstream of EGFR and IFNγ That Induce PD-L1 Expression in Head and Neck Cancer
Authors: Fernando Concha-Benavente, Raghvendra M. Srivastava, Sumita Trivedi, Yu Lei, Uma Chandran, Raja R. Seethala, Gordon J. Freeman, Robert L. Ferris
Journal: Cancer Research (2015)

Many cancer types, including head and neck cancers (HNC), express programmed death ligand 1 (PD-L1). Interaction between PD-L1 and its receptor, programmed death 1 (PD-1), inhibits the function of activated T cells and results in an immunosuppressive microenvironment, but the stimuli that induce PD-L1 expression are not well characterized. Interferon gamma (IFNγ) and the epidermal growth factor receptor (EGFR) utilize Janus kinase 2 (JAK2) as a common signaling node to transmit tumor cell-mediated extrinsic or intrinsic signals, respectively. In this study, we investigated the mechanism by which these factors upregulate PD-L1 expression in HNC cells in the context of JAK/STAT pathway activation, Th1 inflammation, and HPV status. We found that wild-type, overexpressed EGFR significantly correlated with JAK2 and PD-L1 expression in a large cohort of HNC specimens. Furthermore, PD-L1 expression was induced in an EGFR- and JAK2/STAT1-dependent manner, and specific JAK2 inhibition prevented PD-L1 upregulation in tumor cells and enhanced their immunogenicity. Collectively, our findings suggest a novel role for JAK2/STAT1 in EGFR-mediated immune evasion, and therapies targeting this signaling axis may be beneficial to block PD-L1 upregulation found in a large subset of HNC tumors.
Absence of Malignant Transformation After Weekly Irradiation of a Mouse Spleen Cell Culture
Authors: J C Klein
Journal: JNCI Journal of the National Cancer Institute (1966)

A nonmalignant mouse cell line was developed, which can be used for experiments on carcinogenesis. Special precautions were taken during the entire culture period to avoid the introduction of carcinogenic factors. Irradiation was tested in this in vitro system for its capacity to induce malignant transformations. The fact that exposure of the culture to weekly doses of 100, 200, or 300 rads of X radiation during a culture period of 1½ years, up to total doses exceeding 10,000 rads, did not produce malignant changes suggested that the irradiation had no direct carcinogenic effect on cells in vitro. The absence of a carcinogenic effect of X rays in vitro cannot be attributed to a peculiarity of the cell line, since cells of this line did turn malignant in a parallel experiment after introduction of a known cytotoxic serum.
Abstract 9376: Maximum Dose of N-acetylcysteine and Prevention of Renal Dysfunction in Patients With Chronic Kidney Disease Undergone Surgical Coronary Intervention: A Prospective, Randomized, Double-blind, Controlled Trial
Authors: Jose J De Lima, Eduesley S Santos, Luis Henrique W Gowdak, Fabio Gaiotto, Luiz B Puig, Valeria Costa-Hong, Rodolfo L Arantes, Luiz Antonio M César, Luiz A Bortolotto
Journal: Circulation (2012)

Background: The role of N-acetylcysteine (NAC) for the prevention of renal damage in experimental models and in diverse clinical settings is controversial. Disparate results may be caused by differences in dosing and route administration. Objective: to test the safety and efficacy of maximum IV dose of NAC, as recommended for acetaminophen overdose, on the incidence of renal dysfunction, in 50 patients with GFR &lt;60/≥15 ml/min (64±9 yo, Caucasians 80%, men 74%, diabetics 56%, comorbidities 90%, LVEF 54%±11%, GFR 45±11 ml/min, Euroscore 5.4%) undergone elective surgical coronary intervention (CI). Methods: patients were randomized to receive either IV saline (n=26) or NAC (n= 24) in equal volume of saline (150 mg/Kg followed by 50 mg/kg) during surgery. End-points: renal dysfunction (AKIN criteria), serum NGAL and TBARS during the first 72-h post-operation; need of dialysis and death within 30-days post-operation. Results: NAC was not associated with significant side-effects. There was one death in the NAC group (cardiac arrest) and none among controls and no patient needed dialysis. Base-line age, gender, race, diabetes, dyslipidemia, smoking, comorbidities, GFR, Euroscore, and number of grafts, on-pump surgery, transfusions, vasoactive drugs and diuresis (during and after operation) did not differ between groups. Renal dysfunction was observed in 64% (controls) and 27% (NAC) patients (p= 0.02) and no use of NAC was the only independent predictor of renal dysfunction (OR= 4.86, p=0.02). NGAL and TBARS were higher in patients not receiving NAC (=&lt; 0.05). Conclusion: maximum IV dosing of NAC was well tolerated and was associated with reduction on the incidence of renal dysfunction in patients with CKD undergone surgical coronary intervention. More work is needed to determine the optimal dosing of NAC in this setting.