tbuckley/cabot-search huggingface dataset:
Nucleosome in patients with systemic sclerosis: possible association with immunological abnormalities via abnormal activation of T and B cells
Authors: Ayumi Yoshizaki, Takashi Taniguchi, Ryosuke Saigusa, Takemichi Fukasawa, Satoshi Ebata, Hiroko Numajiri, Kouki Nakamura, Takashi Yamashita, Takehiro Takahashi, Tetsuo Toyama, Yoshihide Asano, Thomas F Tedder, Shinichi Sato
Journal: Annals of the Rheumatic Diseases (2015)

To determine the serum levels of nucleosome in patients with systemic sclerosis (SSc) and relate the results to the clinical features of SSc.Serum nucleosome levels in 91 patients with SSc were examined by ELISA. The expression of Toll-like receptor (TLR) 9 in T and B cells was quantified by flow cytometric intracellular protein analysis. The effects of nucleosomes on lymphocytes were also analysed. Moreover, we assessed the effects of nucleosomes on fibrosis, using wild type and CD19-deficient bleomycin-treated mice, an experimental model for human SSc.Serum nucleosome levels were elevated in SSc compared with healthy controls and correlated positively with the extent of skin and pulmonary fibrosis and immunological abnormalities. The retrospective longitudinal analysis showed the serum nucleosome levels to be attenuated during the follow-up period. TLR9, which can be stimulated by nucleosome expression was upregulated in the affected T and B cells of patients with SSc. Moreover, nucleosome stimulation strongly increased interleukin (IL)-4 and IL-17 expression of T cells, B-cell IgG production and proliferation of lymphocytes in SSc compared with those in healthy controls. In bleomycin-induced SSc model mice, serum nucleosome levels were elevated compared with control mice. Furthermore, nucleosomes increased IgG production and proliferation of mouse B cells. Although TLR9 expression was similar between wild type and CD19-deficient splenic B cells, CD19 deficiency reduced these nucleosome effects.These results suggest that nucleosomes and its signalling in B and T cells contribute to disease development in SSc via TLR9.
Preclinical activity of ABT-869, a novel receptor tyrosine kinase inhibitor, alone or in combination with paclitaxel
Authors: J. A. Stavropoulos, J. A. Meulbroek, A. L. Niquette, J. M. O’Connor, B. Wang, D. H. Albert, Y. Dai, M. R. Michaelides, S. K. Davidsen, C. K. Donawho
Journal: Journal of Clinical Oncology (2005)

3175 Background: ABT-869, a multi-targeted receptor tyrosine kinase inhibitor, has been shown to inhibit of all members of the VEGF and PDGF receptor families (e.g., KDR IC50 value of 4 nM), and have less activity (IC50 values >1 μM) against unrelated receptor tyrosine kinases, soluble tyrosine kinases and serine/threonine kinases. In addition, it exhibits potent anti-proliferative and apoptotic effects on tumor cells dependent on mutant, constitutively active, FLT3 and KIT kinases. Methods: We tested three different staged, human xenografts with oral (PO) ABT-869: a cKIT driven small cell lung carcinoma H526 and two breast carcinomas: the ductal MDA-435-S-LM and the epithelial MDA-231 LC3. Results: The H526 subcutaneous (SC) flank trial used ABT-869 in log doses of 30, 10 and 3 mg/kg/day (mkd) (PO, QD X 21) and resulted in Tumor Growth Inhibition (TGI) of 74%, 55% and 27%, respectively. The MDA-435 LM and MDA-231 LC3 trials were performed both as SC and orthotopic (OT) mammary fat pad injection models. We tested both monotherapy of ABT-869 and paclitaxel in comparison to the combination of the two drugs. The MDA-435 LM SC model involved dosing with ABT-869 at 25 and 12.5 mkd (PO, BID X 21) and resulted in 60% and 39% TGI respectively. Paclitaxel dosed at 25 mkd (IP, Q3D X 3) had monotherapy TGI of 34% and a significant increase of TGI to 84% was observed in the combination treatment groups (ABT-869 at 25 mkd plus paclitaxel at 25 mkd, as above). Similar results were obtained for both breast cancer cell lines done either in SC or OT models, and there was no increased toxicity when paclitaxel and ABT-869 were dosed simultaneously. Further, histological examination of tumors (300 - 400 mm3 in size) treated with ABT-869 for 3.5 days, then evaluated by CD31+ micro vessel density, Ki67 proliferation, and Caspase 3 apoptosis demonstrated specific ABT-869 activity when compared to paclitaxel and vehicle treated controls. Conclusions: These data support the use of ABT-869, dosed in combination with paclitaxel, in treating breast carcinomas. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories
Phase II study combining gefitinib with etoposide in patients with hormone-refractory metastatic prostate cancer (mHRPC) after docetaxel-based therapy.
Authors: R. J. Hauke, F. R. Loberiza, J. E. Elkahwaji, P. M. Townley, G. K. Bascom, M. Lin, S. Batra
Journal: Journal of Clinical Oncology (2010)

e15071 Background: Second-line chemotherapy after docetaxel-based regimens for mHRPC remains undefined. Epithelial growth factor receptor (EGFR) expression is increased in prostate cancer. Clinical trials evaluating EGFR inhibitors as monotherapy have generally rendered little clinical benefit. In vitro studies demonstrated synergy by combining gefitinib with chemotherapy agents in prostate cancer cell lines. Based on these results, we conducted a phase II study with the aim of evaluating the clinical benefit of gefitinib with etoposide in patients with mHRPC after docetaxel-based therapy. Methods: Eligibility requirements included mHRPC with progression after docetaxel-based therapy, ECOG 0/1 and adequate organ function. A 3-week cycle included gefitinib 250 mg/d PO continuous with etoposide 50 mg/m2/d PO (rounded to 50 mg tablet) days 1-14. Toxicity was assessed every cycle and restaging occurred every 2 cycles. Reasons for terminating patient participation included toxicity, disease progression (per PSAWG 1) or voluntary withdrawal. Results: Twenty-four subjects were enrolled. Baseline characteristics are listed in the table. Median cycles per subject: 2 (range, <1–12). There were no PSA or objective responses. Nine patients (37%) were not evaluable for response: voluntary withdrawal (n=7), seizures unrelated to study drug (n=1) and development of a second malignancy (n=1). Stable disease was noted in 4/15 evaluable subjects (27%). The probability of progression free survival and overall survival at 1 year was 26% (10%-45%) and 44% (21%-65%) respectively, with a median survival of 11.3 months (range, 5.6 – 45.2) for all subjects. Grade 3 or 4 toxicities with >10% incidence included anemia (25%) and weakness (13%). Conclusions: Gefitinib with etoposide is well tolerated by patients with mHRPC. Although no responses were observed, the progression free survival and overall survival were better than in single agent gefitinib studies suggesting clinical benefit which merits further study. Characteristic Median Range Age 71.5 yrs 48–81 yrs ECOG PS 0/1 – 9/15 Prior chemotherapy 2 1–6 Gleason 8 4–9 PSA at entry 230 29–4,502 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca
Dose dense gemcitabine/epirubicin (GE) followed sequentially by dose dense docetaxel (Doc) as primary systemic therapy (PST) of patients (pts) with early breast cancer (BC): First results of a phase I/II trial
Authors: A. Schneeweiss, C. Rudlowski, H.-P. Sinn, F. Beldermann, D. Von Fournier, G. Bastert
Journal: Journal of Clinical Oncology (2004)

734 Background/Methods: We have conducted a monocentric phase I/II trial to define maximum tolerated dose, safety and efficacy of five cycles GE administered every two weeks (q2wks) followed by four cycles Doc q2wks as PST in early BC. Pegylated filgrastim was given prophylactically. Results: From 7/03 to 11/03 thirty one pts with biopsy proven primary invasive BC T2–4 N0–2 M0 have been enrolled. Patient and tumor characteristics were [median(range)]: age 47 years (29–64); sonographically assessed tumor size: 4,0 cm (2,1 to >10); N0/N+/not available (na): 16/7/8 pts; grading 1/2/3/na: 1/8/12/10 pts; hormone receptor positive/negative/na: 15/7/9 pts; Her2/neu (Dako™) ≤2+/3+/na: 15/7/9 pts. Pts were treated with G at 1250 mg/m2 in combination with escalating dose levels of E at 90 mg/m2 (n=14) and 100 mg/m2 (n=17), respectively. Only two dose limiting toxicities occured after GE (one grade 3 fatigue at dose level 1, one febrile neutropenia at dose level 2). Median relative dose intensity amounted to 100%. Considering 97 evaluable cycles of GE the only grade 3/4 hematological toxicity was leukopenia which occured in 1%/1% of cycles. Besides alopecia most severe non-hematological toxicities were grade 3 fatigue in 3% and grade 3 stomatitis in 2% of cycles. Among 13 pts evaluable so far for clinical response 7 pts (54%) achieved at least a partial remission after GE as assessed by ultrasound. During the following treatment with Doc 100 mg/m2 q2wks any of the first ten pts required dose reduction after the first or second cycle due to grade 3 fatigue (9 pts) and/or grade 3 skin toxicity (4 pts). Therefore, escalation of epirubicin dose was stopped and Doc dose was reduced to 80 mg/m2. Conclusions: As no further dose reductions were necessary among the following pts so far the recommended schedule for the phase II part of the study was fixed at five cycles GE 1250/100 mg/m2 q2wks followed by four cycles Doc 80 mg/m2 q2wks. The trial is ongoing and updated results on toxicity and response will be presented. No significant financial relationships to disclose.
In Utero Cltc-ALK Fusion In Hematopoietic Progenitor Cells As a First Step Of Leukemogenesis In Blastic Plasmacytoid Dendritic Cell Neoplasm
Authors: Kiriko Tokuda, Minenori Eguchi-Ishimae, Mariko Eguchi, Eiichi Ishii
Journal: Blood (2013)
Abstract 16013: The Estimation of End-Diastolic Pressure by Echocardiography in Transplant Patients
Authors: Kazuaki Negishi, Tomoko Negishi, Andrew D Grant, Thomas H Marwick, Zoran B Popovic
Journal: Circulation (2012)

Background:  American Society of Echocardiography and European Association of Echocardiography (ASE/EAE) have proposed a multiparametric algorithm to predict left ventricular (LV) end-diastolic pressures (EDP). We evaluated the ability of diastolic parameters used in the ASE/EAE algorithm to predict EDP in patients post heart transplantation.   Methods and Results:  We assessed 53 consecutive transplant patients (40 men, age 57±11 yrs, EF 50±33 %) in whom echocardiography and invasive LV systolic (SBP) and EDP measurement were performed within 24 hours. Early diastolic to atrial wave velocity ratio of the mitral inflow (E/A), early diastolic velocity of mitral annulus measured at its septal and lateral side and averaged (e’), isovolumic relaxation time (IVRT), left atrial volume index (LAVI), right ventricular systolic pressure (RVSP), time interval between the onset of early diastolic velocities at mitral annulus and mitral inflow (Tea-Te’), and time constant of isovolumic pressure decay (tau; calculated as IVRT/[ln{SBP]-ln(EDP)] were measured. Ability of parameters to predict EDP was compared using linear regression. Receiver operating characteristic analysis was used to evaluate parameters’ ability to discriminate EDP of ≥20 mmHg. Only E/e’ ratio significantly correlated with EDP (r= 0.56, p   Conclusion:   E/e’ ratio predicts elevated EDP, while lateral and averaged mitral annulus velocities correlate with tau in transplant patients.
Phase II evaluation of cisplatin plus cetuximab in the treatment of recurrent and persistent cancers of the cervix: A limited access phase II study of the Gynecologic Oncology Group
Authors: J. H. Farley, M. Sill, J. L. Walker, R. J. Schilder, J. T. Thigpen, R. L. Coleman, B. E. Miller
Journal: Journal of Clinical Oncology (2009)

5521 Background: A majority of cervical cancer patients overexpress epidermal growth factor receptor (EGFR), which is a poor prognostic factor. Cetuximab (C225) is a murine monoclonal antibody that binds to EGFR and competes with ligand binding and tyrosine kinase activation.Given the evidence of activity in squamous carcinomas of the head and neck, the purpose of this study was to evaluate the safety and efficacy of cisplatin and cetuximab chemotherapy. Methods: Women with advanced, persistent, or recurrent carcinoma of the cervix not amenable to cure were eligible for this study. Only prior chemotherapy (CT) administered in conjunction with primary radiation as a radiosensitizer was allowed. Women could not have received prior anti-EGFR antibody therapy or therapy with a tyrosine kinase inhibitor that targets the EGFR pathway. All women had measurable disease and a GOG performance status ≤ 2. The women received cisplatin at 30 mg/m 2 days 1 and 8. The first dose of C225 was given at 400 mg/m 2 . All subsequent doses of C225 were given at 250 mg/m 2 . C225 was given on days 1, 8, and 15. Each cycle was 21 days. Adverse events were assessed with CTCAE v 3.0. Primary measure of clinical efficacy was the frequency of tumor response. The study was stratified by prior CT. The design required at least 16 responses in a sample of 40 with prior CT and 29 without prior CT before the regimen was considered for phase III testing. Results: Between September 2004 and March 2008, 76 patients were entered onto the study. Of these, 69 were eligible and evaluable. Three patients were on study at the time of the analysis. 56 (81%) patients had received prior radiation. 40 (58%) patients previously received prior CT. There were 8 (12%) responses. The response rate was 8% among patients with prior CT, and 17% among CT naïve patients. One woman had grade 4 anemia. The most common grade 3 toxicities were metabolic (14), dermatologic (8), fatigue (6), and gastrointestinal (6). Conclusions: The combination of cetuximab with cisplatin was adequately tolerated but did not indicate additional benefit beyond cisplatin therapy. Stratification of patients based upon K-ras mutation and/or EGFR status may select a group for which this regimen is most effective. No significant financial relationships to disclose.
Glufosfamide (GLU) plus gemcitabine (GEM) in pancreatic adenocarcinoma: Preliminary results of a phase 2 trial
Authors: E. G. Chiorean, T. Dragovich, J. Hamm, C. H. Barrios, C. F. Gorini, V. K. Langmuir, S. Kroll, G. T. Tidmarsh, A. B. Colowick, P. J. Loehrer
Journal: Journal of Clinical Oncology (2007)

15005 Background: Glufosfamide is glucose linked to isophosphoramide mustard, the active metabolite of ifosfamide. Cancer cells use glucose at a higher rate than normal cells, which may lead to preferential metabolic targeting by GLU. The Phase 1 study established a GLU dose of 4500 mg/m 2 for the GLU + GEM regimen. The objectives of the Phase 2 part of this study are to evaluate the safety and efficacy of GLU+GEM in pts with pancreatic adenocarcinoma. Methods: Eligible pts had metastatic and/or locally advanced pancreatic adenocarcinoma previously untreated with chemotherapy, Karnofsky Performance Status =70, creatinine clearance (CrCL) =60 mL/min and acceptable hematologic and liver function. Pts received GLU 4500 mg/m 2 iv over 4 hours on Day 1 and GEM 1000 mg/m 2 iv over 30 minutes on Days 1, 8 and 15 of every 28-day cycle. CT scans were obtained every 8 weeks. Primary endpoint was response rate. Results: Twenty-nine pts were enrolled. One patient with ineligible histology was excluded from efficacy analyses. The 14 male/15 female pts had a median age of 59 years. Median cycles on treatment was 4 (range 1–10+) and 9 pts completed all 6 cycles. Six of 28 (21%; 95% CI: 8- 41%) pts had a partial response (duration 1.0+ to 5.8+ months), one unconfirmed. Ten of 28 (36%) pts had stable disease (median duration 5.3 months). Median progression-free survival was 3.7 months. Six-month survival was 54% (95% CI: 38–78%). Grade 3/4 neutropenia and thrombocytopenia occurred in 21/29 (72%) and 8/29 (28%) pts. Five pts (18%) had a GLU-related serious adverse event (SAE). Two pts died due to SAE unrelated to GLU. Three pts developed renal failure; two were GLU-related with evidence of renal tubular acidosis (RTA). One pt developed GLU-related SAE of RTA without renal failure. The CrCL fell below 60 mL/min in 7 of 27 (26%) pts with CrCL =60 at baseline. Conclusions: Preliminary data indicate that GLU + GEM may benefit pts with chemotherapy naïve pancreatic adenocarcinoma. [Table: see text]
Development of antibodies to granulocyte-macrophage colony stimulationg factor (GM-CSF) after embolization of the hepatic artery with GM-CSF
Authors: Mizue Terai, Hiroyuki Sakashita, Michael J. Mastrangelo, David Berd, Kevin L. Sullivan, David J. Eschelman, Takami Sato
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

5994 

We have reported that infusion of the hepatic artery with yeast-derived recombinant human GM-CSF (rhGM-CSF, Leukine, Berlex Laboratories) mixed with ethiodized oil, followed by embolization with gelatin sponge particles (immunoembolization) is a feasible and effective treatment for patients with liver tumors (Proc of ASCO 21: 14a, 2002, and 22:723, 2003). In our phase I/II trial, patients with liver tumors were treated with immunoembolization at various dose levels of GM-CSF (25 mcg - 2,000 mcg) every 4 weeks until maximum clinical benefit. During our initial evaluation, it was found that serum levels of exogenous rhGM-CSF decreased after multiple immunoembolizations in several patients. Therefore, development of binding antibody as well as neutralizing antibody was investigated. A solid phase indirect ELISA was used to detect a binding antibody to rhGM-CSF (Leukine). A rabbit polyclonal anti-human GM-CSF antibody was used for the standardization of assay. The levels of serum antibody were expressed as U/ml, in which 1 U/ml of serum anti-human GM-CSF antibody was defined as the absorbance equivalent to 1 ng/ml of rabbit antibody to human GM-CSF. To detect neutralizing antibody, the TF-1 cell line, which proliferates in response to GM-CSF, was used. The presence of neutralizing antibody was defined as blockage of biological activity of E. Coli-derived rhGM-CSF (88/646, NCI) by 50%. Anti-GM-CSF binding antibody levels in pre-treatment sera were 8.3 +/− 7.1 U/ml and therefore an antibody titer greater than 29.6 U/ml (mean + 3SD) was defined as positive. In 33 patients who received immunoembolization, only one patient had a pre-existing anti-GM-CSF antibody (91.5 U/ml). In contrast, a binding antibody was detected in 5 of 30 and 13 of 26 patients after the first and the second immunoembolizations, respectively. Over all, 22 of 32 patients (68.8%) developed a binding antibody to yeast-derived rhGM-CSF (Leukine). Furthermore, 15 of 22 patients who developed a binding antibody subsequently developed a neutralizing antibody to GM-CSF. In patients with neutralizing antibody, some of the systemic effects of intrahepatic GM-CSF (leukocytosis and transient thrombocytopenia) seem to have diminished. None of these patients developed symptoms suggestive of pulmonary proteinosis. Repeated immunoembolization of the hepatic artery with rhGM-CSF could induce the development of binding and neutralizing antibodies to the cytokine. This may reduce the effectiveness of GM-CSF, but paradoxically, could facilitate a local inflammatory response in the liver tumors.
Induction FOLFIRINOX followed by chemoradiation with capecitabine for unresectable locally advanced pancreatic cancer (LAPC): Preliminary data.
Authors: Rafael Ferreira de Carvalho, Erlon Gil, Raphael Brandao Moreira, Renata D'Alpino Peixoto, Marcus Paulo Fernandes Amarante, Pedro Zanuncio, Robson Ferrigno, Paulo Moraes, Fernando C. Maluf, Antonio C. Buzaid, Marcelo Rocha De Sousa Cruz
Journal: Journal of Clinical Oncology (2015)

458 Background: FOLFIRINOX was found to have higher response rates and overall survival (OS) compared to gemcitabine-based regimens in the metastatic setting. However, the contribution of chemoradiotherapy to outcomes after FOLFIRINOX in LAPC remains uncertain. We aim at evaluating our experience with FOLFIRINOX followed by chemoradiation (IMRT) with capecitabine for patients with LAPC. Methods: Patients with unresectable LAPC who received induction FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan and oxaliplatin) followed by chemoradiation with capecitabine at our institution were screened and accrued at the time of radiotherapy and are being followed prospectively. Radiation technique consisted of IMRT with simultaneous integrated boost (SIB) - dose of 45 Gy (1.8Gy/day) to high-risk lymph nodes and 55 Gy (2.2Gy/day) to the primary tumor. Progression-free survival (PFS) and OS were estimated by the Kaplan-Meier method. Results: Fourteen patients (58% female) were included in the analyses. Median age at diagnosis of LAPC was 61 years (range 38-78). Median number of FOLFIRINOX cycles was 11 (range 4-13). With a median follow up fo 11.7 months, 43% of the patients have died. Median PFS and OS were 15.9 (95% CI 6.8 – 25.1) and 16.7 months (95% CI 10.9 – 22.4), respectively. There were no treatment-related deaths. Conclusions: Our data suggest that sequential treatment with FOLFIRINOX followed by chemoradiation with capecitabine is feasible and may offer promising PFS and OS among selected patients with LAPC. Randomized trials are urgently needed to assess the role of sequential treatment in this population.
Cox-2 driven infectivity enhanced CRAds for cancer treatment
Authors: G. J. Bauerschmitz, A. Kanerva, M. Yamamoto, D. Nettelbeck, D. T. Rein, D. Curiel, A. Hemminki, P. Dall
Journal: Journal of Clinical Oncology (2005)

5091 Background: CRAds are a promising strategy for adenoviral gene therapy of cancer. Although preclinical and the first clinical data with CRAds show good results, more specificity of CRAd replication and infectivity enhancement for target cells would be desirable. The aim of our strategy is to investigate whether a more specific or a more active promoter for CRAds is more advantageous and test the concept of specificity enhancement for cancer cells due to delta-mutations. Methods: To this end we constructed a novel generation of CRAds specific for ovarian cancer treatment. Two length variants of the cox-2 promoter were used, a shorter clone being more active in and a longer clone being more specific for ovarian cancer cells. E1A was used as wild type, as delta24-mutation and as delta2-delta24-mutation. Results: The replication was improved in cox-2 positive cells and reduced in cox-2 negative cells compared to wt Ad. In ovarian cancer cells the replication was improved up to 3 logs as result of the combination of specific replication in and infectivity enhancement. In addition, the liver-off phenotype was tested with primary normal liver cells. Whereas wt replicated in and lysed the liver cells, our newly constructed CRAds replicated at least 2 logs less. Further, the cox-2 driven delta24-CRAds showed stronger oncolysis in ovarian tumor cells than an otherwise identical delta24-CRAd without cox2 promoter. In RT-PCR the replicativity of the cox-2 driven CRAds was directly correlated to cox-2 expression levels. Conclusions: Thus these viruses seem to replicate specifically and amplified in ovarian cancer cells while preserving cox-2 negative and especially liver cells. Therefore these viruses could improve the safety and efficacy profile of ad gene therapy strategies for ovarian cancer. No significant financial relationships to disclose.
Side Effects Of Immunosuppressive Therapy(IST) Of Aplastic Anemia In Children
Authors: Malgorzata Salamonowicz, Katarzyna Pawelec, Michal Matysiak, Anna Panasiuk, Jerzy Kowalczyk, Walentyna Balwierz, Ewa Zaleska-Czepko, Alicja Chybicka, Krzysztof Szmyd, Halina Bubala, Tomasz Szczepanski, Mariusz Wysocki, Andrzej Kurylak, Jacek Wachowiak, Dawid Szpecht, Wojciech Mlynarski, Monika Bulas, Maryna Krawczuk-Rybak, Elzbieta Leszczynska, Tomasz Urasinski, Barbara Kaczorowska-Hac, Anna Balcerska, Jaroslaw Peregud-Pogorzelski
Journal: Blood (2013)