tbuckley/cabot-search huggingface dataset:
Treatment with rAD001 improves the efficacy of siRNA mediated down-regulation of survivin/BIRC5 in pancreatic carcinoma cell lines
Authors: L. Maute, W. Glienke, E. Milz, N. Bauer, L. Bergmann
Journal: Journal of Clinical Oncology (2007)

15146 The rapamycin derived mTOR inhibitor RAD001 (everolimus) is cytotoxic to a number of cell lines. Because survivin, an important mediator of apoptosis and cell survival, is one of the targets down-regulated by RAD001, we tested the ability of a combination of RAD001 and siRNA mediated inhibition of survivin to enhance the cytotoxic effects. We have used four pancreatic cancer cell lines, MiaPaCa-2, BxPC-3, AsPC-1 and Panc-1. We found that the cytotoxic effect was enhanced in all cell lines after treatment with RAD001 and survivin siRNA. An efficient way of treatment was the initial down-regulation of survivin with RAD001 and a subsequent incubation with survivin siRNA. We conclude, that the transformation efficiency of siRNA, still a limiting factor in using this method, is more sufficiently combining both ways to down-regulate survivin. Our data indicate that a combination of mTOR inhibitors like RAD001 and survivin-targeted down-regulation with siRNA may improve the efficacy of therapy in pancreatic cancer. No significant financial relationships to disclose.
Evaluation of oxaliplatin, fludarabine, cytarabine, and rituximab (OFAR) combination therapy in aggressive chronic lymphocytic leukemia (CLL) and Richter's syndrome (RS).
Authors: A. M. Tsimberidou, W. G. Wierda, X. Badoux, S. Wen, W. Plunkett, S. M. O'Brien, T. J. Kipps, J. A. Jones, H. Kantarjian, M. J. Keating
Journal: Journal of Clinical Oncology (2010)

6521 Background: To improve on outcomes achieved with OFAR1 in CLL/RS (Tsimberidou et al J Clin Oncol 26:196), we designed OFAR2 (phase I/II). Methods: OFAR2 consisted of oxaliplatin 30 mg/m2 D1-4; fludarabine 30 mg/m2; Ara- C 0.5 g/m2; rituximab 375 mg/m2 D3; and pelfigrastim 6 mg D6. Fludarabine and Ara-C were given on D2-3 (level 1), D2-4 (level 2), or D2-5 (level 3) (phase I) every 4 wks. Tumor lysis, DNA virus, and PCP prophylaxis were given. Results: Overall, 94 pts (CLL, 67; RS, 27) were treated. DLT occurred in 2/3 of pts at level 3 (G4 diarrhea and G4 sepsis); level 2 was the MTD; 82 pts (CLL, 60; RS, 22) were treated in phase II (age > 60 yrs, 65%; 17p del, 38%; 11q del, 13%; 13q del, 16%; +12, 21%; normal, 12%; unmutated IgVH, 80%; ZAP70(+), 75%; CD38(+) > 30%, 58%). Response rates in phase II were: RS (n = 18), 39% (CR, 6%); CLL (n = 54), 54% (CR, 4%); and 17p and 11q del, 36% and 50%, respectively. With a median follow-up of 15 months, the median survival was 20 months (95%CI 13-27+) and the median PFS 7 months (95% CI 5-20+); 12 pts underwent SCT after OFAR2 (post-remission, 10). Overall, 216 cycles were administered. G3-4 neutropenia, thrombocytopenia and anemia were noted in 67%, 74% and 44% of pts (51%, 64% and 25% of cycles) and G3-4 infections in 19% of pts. In multivariate analyses (MVA) of pts with cytogenetics (n=293) treated on protocols OFAR2, FCR or CFAR, independent factors associated with (a) response were higher Hgb level (p < 0.0001), no 17p del (p = 0.0001), fewer prior therapies (p = 0.01); (b) longer PFS were no 17p del (p < 0.0001), lower β2-microglobulin level (p = 0.0002), no refractoriness to fludarabine (p=.0008), fewer prior therapies (p = 0.04); and (c) survival were no 17p del (p < 0.0001), no refractoriness to fludarabine (p = 0.0007), fewer prior therapies (p = 0.01), higher Hgb level (p = 0.02), lower LDH level (p = 0.04), younger age (p = 0.04). In MVA type of therapy was not significant for response (CFAR vs. FCR, p = 0.94; OFAR2 vs. FCR, p = 0.88), PFS (CFAR vs. FCR, p = 0.63; OFAR2 vs. FCR, p = 0.74) or survival (CFAR vs. FCR, p = 0.11; OFAR2 vs. FCR, p = 0.98). Conclusions: The OFAR2 regimen had antileukemic activity in pts with 17p del and was equivalent to the CFAR and FCR salvage programs. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories, Celgene, Genentech, GlaxoSmithKline, Igenica, Ligand, MedImmune, Trubion Genentech, NMCR, Physicians' Education Resource PER Abbott Laboratories, ASCO CDA, Bristol-Myers Squibb, Celgene, Genentech, Genmab, GlaxoSmithKline, Novartis, sanofi-aventis, Wyeth Celgene, Genzyme
Safety and efficacy of pegfilgrastim administration on the same day as myelosuppressive chemotherapy (CT) in women with ovarian or primary peritoneal cancer
Authors: S. I. Schuman, N. Lambrou, K. Robson, S. Glück, N. Myriounis, J. Pearson, E. Alvarez, M. P. Crisp, L. B. Twiggs, J. A. Lucci
Journal: Journal of Clinical Oncology (2007)

16009 Background: According to prescribing information, pegfilgrastim should not be administered within 14 days prior to, or within 24 hours after, the administration of cytotoxic CT. However, little data exist to support this recommendation. The purpose of the current study is to determine the safety and efficacy of administering pegfilgrastim on the same day as myelosuppressive CT in patients with ovarian or primary peritoneal carcinoma. Methods: A retrospective review was conducted of all ovarian and primary peritoneal cancer patients that received prophylactic pegfilgrastim on the same day as CT from May 2003 to June 2006. Results: Forty-six patients (mean age: 57, range: 21–82) were treated for the following malignancies: 35 (76%) epithelial ovarian, 6 (13%) primary peritoneal, and 5 (11.0%) ovarian germ cell or stromal cell carcinoma. Twenty-six patients (56%) had primary cancers and 20 (44 %) had recurrent disease. All patients met the ASCO or NCCN recommendations of using colony-stimulating factors for prophylaxis against febrile neutropenia (FN) (Risk of FN &gt; 20%). A total of 269 cycles of CT were administered including 125 cycles (46.5%) docetaxel + carboplatin, 39 cycles (14.5%) gemcitabine + platinum, 30 cycles (11.1%) intravenous paclitaxel + carboplatin, 28 cycles (10.4%) liposomal doxorubicin, 19 cycles (7.1%) paclitaxel + intraperitoneal platinum, 6 cycles (2.2%) docetaxel, 6 cycles (2.2%) liposomal doxorubicin + cisplatin, 5 cycles (2%) bleomycin + etoposide + cisplatin, 4 cycles (1.5%) topotecan, 3 cycles (1.1%) of paclitaxel, 2 cycles (0.7%) vincristine + actinomycin-D + cyclophosphamide, and 2 cycles (0.7%) docetaxel + gemcitabine. All patients received pegfilgrastim within one hour of the completion of CT administration. Grade 1 or 2 neutropenia developed in 10 cycles (3.7%) out of the 269 cycles, mean absolute neutrophil count = 4926 (range, 1293 -24300). No patients had FN episodes, hospitalizations or antibiotic use secondary to neutropenia, or dose-reductions and CT delays due to neutropenia. Conclusions: Administration of pegfilgrastim on the same day as CT in ovarian and primary peritoneal cancer patients is more convenient to the patient and appears safe and effective. No significant financial relationships to disclose.
Two Measles Outbreaks After Importation — Utah, March–June 2011
Authors: Mary Hill, Ilene Risk, Cindy Burnett, Wendy Garcia, Amy Carter, Lisa Guerra, Leona Goodsell, LaPriel Clark, Edward Redd, Shauna Nelson, Valoree Vernon, Karyn Leniek, Louise Saw, Jane F. Seward, Preeta K. Kutty, Greg Wallace, William J. Bellini, Paul A. Rota, Jennifer Rota, William A. Lanier
Journal: MMWR Morbidity and Mortality Weekly Report (2013)
The Effectiveness Of Cidofovir In Disseminated Adenovirus Infections After Pediatric HSCT Is Closely Related To Lymphocyte Reconstitution
Authors: Gertjan Lugthart, Marloes A. Oomen, Cornelia M. Jol-van der Zijde, Lynne M. Ball, Dorine Bresters, Wouter J.W. Kollen, Frans J. Smiers, Clementien L. Vermont, Robbert G.M. Bredius, Marco W. Schilham, Maarten J.D. van Tol, Arjan C. Lankester
Journal: Blood (2013)
A phase I trial of sorafenib (BAY 43–9006) for patients with recurrent or progressive malignant glioma (NABTT 0401)
Authors: L. B. Nabors, M. Rosenfeld, M. Chamberlain, S. Phuphanich, T. Batchelor, J. Supko, S. Desideri, Y. Xiaobu, J. Wright, S. Grossman
Journal: Journal of Clinical Oncology (2007)

2058 Background: Sorafenib (BAY 43–9006) is a small molecule inhibitor of multiple kinases to include raf, VEGF receptors, and PDGF receptors. The molecule has demonstrated anti-proliferative and anti-angiogenic activity in a number of in vitro and in vivo model systems. Methods: In this multi-institutional trial, we have conducted a phase I dose-escalation study to determine the maximum tolerated dose (MTD) of sorafenib in patients with recurrent malignant glioma. Cohorts of 3 patients, stratified based on the use of enzyme inducing anticonvulsants (EIAC) or not (non-EIAC), have completed enrollment through the following dose levels: 200 mg, 400 mg, 600 mg, and 800 mg. Therapy has been given as a twice daily oral administration with cycles of 28 day duration. Results: A total of 35 patients have been enrolled and are evaluable for toxicity. Treatment related dose-limiting toxicity (DLT) was defined as any grade 3 or 4 non-hematological toxicity, and grade 4 hematological toxicity (platlets and ANC) or febrile neutropenia of any duration. The following DLTs were observed: one grade 3 hand-foot-syndrome at the 400 mg BID (EIAC), one grade 3 puritis 400 mg BID (non-EIAC) dose level, grade 3 hand/foot syndrome 800 mg BID (EIAC and non-EIAC arms), grade 3 hypophosphatemia 800 mg BID (EIAC), and grade 3 joint pain 800 mg BID (EIAC). A MTD of 600 mg BID has been defined for the EIAC arm with 3/6 DLTs at 800 mg BID. A MTD has not been defined and enrollment has been completed through the 800 mg BID dose level for the non-EIAC. Of the enrolled patients, 20 are with glioblastoma multiforme (GBM), 8 with anaplastic astrocytoma (AA), and 7 with anaplastic oligodendroglioma (AO). Conclusions: The MTD for sorafenib is 600 mg BID for patients on EIAC. Sorafenib is well tolerated with limited toxicities to doses of 800 mg twice daily in patients with recurrent malignant glioma not on EIAC (non-EIAC arm). No significant financial relationships to disclose.
IER3 Expression in Childhood Myelodysplastic Syndrome,
Authors: Andrica de Vries, Christian M. Zwaan, Astrid Danen- van Oorschot, Valerie de Haas, Henrik Hasle, Franco Locatelli, Barbara De Moerloose, Sophia Polychronopoulou, Jan Stary, Markus Schmugge, Michael Dworzak, Marco Zecca, H. Berna Beverloo, Charlotte M Niemeyer, Rob Pieters, Marry M. van den Heuvel
Journal: Blood (2011)
Novel TRAIL variants for targeted cancer therapy.
Authors: B. Schneider, J. Gerspach-Joner, H. Wajant, K. Pfizenmaier
Journal: Journal of Clinical Oncology (2010)

e13592 Background: Targeting the apoptotic machinery of malignant cells is one attractive concept for the treatment of cancer, which is currently exploited for TRAIL at various stages of preclinical and clinical development. Methods: In an attempt to improve TRAIL's tumor selective activity a variant was designed, where TRAIL is expressed as a single polypeptide chain (scTRAIL). Further, by genetic fusion with a single-chain antibody fragment (scFv) recognizing the extracellular domain of ErbB2 we generated an ErbB2-specific fusion protein for tumor targeting. Apoptotic activity of scTRAIL is equivalent to a homotrimeric TRAIL molecule. We studied tumor targeting and apoptosis induction of scFv-scTRAIL in comparison to non-targeted scTRAIL. Results: Importantly, the tumor antigen targeted scTRAIL fusion protein showed highest apoptotic activity in vitro, with a predominant action via TRAILR2 signaling on Colo205 colon carcinoma cells. Pharmakokinetic studies revealed increased plasma half life of the targeted scTRAIL fusion protein compared to scTRAIL. In vivo studies in a mouse tumor model with xenotransplanted Colo205 cells confirm greater response to the tumor targeted ErbB2 specific scTRAIL fusion protein. Systemic treatment resulted in a significantly enhanced antitumoral effect compared to non-targeted scTRAIL.The underlying mechanisms of this difference in apoptotic and anti tumoral activity will be discussed. Conclusions: Together, in vitro and in vivo data are proof of concept of superior antitumoral activity of scFv-scTRAIL molecules, likely via enforced apoptosis induction. Further, we envisage that through targeting of scTRAIL, potential side effects should be minimized. We propose that design concept of single chain TRAIL fusion proteins with tumor targeting capability represents a promising strategy to improve TRAIL's antitumoral action and to minimize potential unwanted actions on normal tissues. No significant financial relationships to disclose.
Short course of EGF receptor tyrosine kinase inhibitor erlotinib (OSI-774) reduces tumor cell proliferation and active MAP kinase <i>in situ</i> in untreated operable breast cancers: A strategy for patient selection into phase II trials with signaling inhibitors
Authors: M. Guix, M. S. Kelley, M. L. Reyzer, J. Zhang, Y. Shyr, B. K. McLaren, K. Newsome-Johnson, W. Lipscomb, T. C. Dugger, C. L. Arteaga
Journal: Journal of Clinical Oncology (2005)

3008 Background: EGFR TKIs may be active only in a subpopulation of breast cancer patients (pts) but currently there are no known predictors of response. This study was designed: 1) to determine the cellular activity of erlotinib (Tarceva) against breast tumors, and 2) to identify a profile suggestive of EGFR dependence. Methods: Newly diagnosed pts are treated with 150mg/day erlotinib for 7–14 days until surgery. The activity of the drug is measured by changes in tumor cell proliferation [by Ki67 immunohistochemistry (IHC)] and apoptosis (by TUNEL) in the initial versus surgical tumor samples. Two methods are used to identify surrogate markers of response: 1) IHC for total EGFR, P-EGFR, HER2, P-HER2, Akt, P-Akt, MAPK, P-MAPK; and 2) protein profiling of whole tissue frozen sections using matrix-assisted laser desorption/ionization mass spectrometry. Results: Overall, treatment was well tolerated with no delays in surgery. Two pts stopped treatment due to grade 2 skin rash. 5/14 pts exhibited a ≥75% inhibition of Ki67 (p=0.008, paired T-test). P-MAPK was reduced ≥85% in 8/14 pts (p=0.0002, paired T-test). EGFR protein was detected in 4/14 specimens with no correlation with changes in Ki67. Erlotinib did not induce apoptosis and levels of total and/or nuclear P-Akt did not change significantly, suggesting that in breast cancers and different to MAPK, Akt is not under regulation by the EGFR pathway. Cluster analysis of the protein profiles identified a subset of m/z signals that classified pts according to their change in Ki67. Conclusions: This trial represents a novel exploratory approach to define a molecular signature in a cohort of breast cancers in which EGFR inhibitors may have clinical activity. This profile could be then used to identify candidates for enrollment into phase II clinical trials with EGFR or other signaling inhibitors. More importantly, this strategy may allow for the exclusion of pts in which novel drugs are unlikely to exhibit an anti-cancer effect and, in turn, potentially accelerate drug approval. No significant financial relationships to disclose.
Vaccination with DC/RCC fusions following cytoreductive nephrectomy.
Authors: D. Avigan, J. Rosenblatt, B. Vasir, M. B. Atkins, D. F. McDermott, P. Somaiya, H. Mills, D. Fitzgerald, D. Dombagoda, D. W. Kufe
Journal: Journal of Clinical Oncology (2010)

2511 Background: We have developed a cancer vaccine in which patient (pt) derived tumor cells are fused with autologous dendritic cells (DCs). In pts with metastatic renal cell carcinoma (mRCC), cytoreductive nephrectomy (CRN) has been associated with improved overall survival, potentially due to the reduction of tumor-mediated immunosuppression, and may therefore be a setting in which response to vaccination is enhanced. Methods: We conducted a phase I trial in which pts with mRCC undergo vaccination with autologous DC/RCC fusions following CRN. An initial cohort underwent vaccination with DC/RCC fusions alone and a subsequent cohort underwent vaccination in conjunction with GM- CSF. RCC were isolated from CRN specimens and were cryopreserved. DCs were generated from adherent mononuclear cells isolated from leukapheresis collections cultured for 5 days with GM-CSF and IL-4 and matured with TNFa for 48-72 hours. Vaccine was provided via sq injection at 3 wk intervals with tumor assessment via RECIST at wk 12. Results: 29 patients have been enrolled and 16 vaccinated. The mean yield of DCs was 164 × 106 with a mean viability of 81%. At time of fusion, mean RCC yield was 95 × 106 cells with a mean viability of 80%. Fusion cells were quantified by determining the percentage of cells that coexpressed unique DC and RCC antigens following coculture of RCC and DCs with polyethylene glycol. Mean fusion efficiency, viability, and vaccine dose was 26%, 81%, and 3.1 × 106 fusion cells, respectively. DC/RCC fusions potently stimulated allogeneic T cell proliferation ex vivo (mean stimulation indexes of 94, 44, and 10 for the DC, fusion and RCCs, respectively). Adverse events related to vaccination were largely restricted to injection site reactions. All pts in the initial cohort undergoing evaluation demonstrated vaccine induced anti-tumor immunity as defined by a 2 fold increase in IFNg expression by CD4 and/or CD8 T cells in response to ex vivo exposure to autologous tumor lysate. 3 pts demonstrated a partial response, and 4 have stable disease lasting 5, 8, 11, and 18 months following initiation of vaccination. Conclusions: Vaccination with DC/RCC fusions following nephrectomy is feasible, well tolerated, and associated with immunologic and clinical responses. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genzyme
Biological profile of oestrogen receptor alpha positive (ERalpha+) primary breast cancers in the elderly and their response to primary endocrine therapy
Authors: G. Okunade, A. R. Green, M. Ying, A. Agrawal, E. C. Paish, L. Winterbottom, K. Hassell, D. A. Morgan, I. O. Ellis, K. Cheung
Journal: Journal of Clinical Oncology (2009)

e20622 Background: Aromatase inhibitors (AIs) have been shown to be superior to tamoxifen in several settings. However, it is unclear whether this superiority extends to its use as primary endocrine therapy in elderly patients with early operable primary breast cancer. Biological characteristics of the tumours may aid in selecting the most suitable agent. Methods: Primary endocrine therapy with one of the AIs (anastrozole) in 64 women &gt;70 years with ERα+ breast cancer was compared to that in 84 treated with tamoxifen during the same period. Their selection was entirely based on contraindications e.g. thromboembolic risks. Needle core biopsies were assessed, by immunohistochemistry, for expression of biomarkers as described below. Results: There was no significant difference between the two groups (anastrozole vs tamoxifen) in terms of response at 6 months (clinical benefit (objective response + stable disease) rates = 97 vs 100%, p=0.099) or progression free survival (median = 16.5 vs 22.5 months, p=0.376). There were no withdrawals due to side effects from anastrozole, compared to four with tamoxifen. For all patients progesterone receptor (PgR), ERβ2, human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR) and Ki-67 were over-expressed in 48%, 99%, 8%, 4% and 64% respectively. HER2 (18 vs 21 months, p=0.003) and Ki-67 (17.5 vs 23 months, p=0.042) over-expression were significantly associated with shorter progression free survival. Conclusions: These results thus far show that primary endocrine therapy with anastrozole in elderly patients with early operable ERα+ breast cancer is similar to tamoxifen in terms of efficacy, but may be better tolerated. In this population, ERα+ breast cancer also appears to have a less aggressive biological profile favouring better hormone sensitivity. [Table: see text]
Patients’ transport in the hospital: An underestimated cause of pain and discomfort for cancer patients
Authors: M. Di Palma, J. M. Nebbak, D. Mathivon
Journal: Journal of Clinical Oncology (2008)

20515 Background: During their stay in the hospital, cancer patients are submitted to a lot of transports from their room to different destinations: consultations, radiotherapy sessions, or various radiological examinations. In a previous small survey many patients complained with transport conditions. In order to better evaluate this problem we decided to conduct a prospective study. Methods: Patients were asked to fill a self questionnaire before and after the transport process, reporting pain level (visual analogical scale from 0 to 10) before and during the transport, pain treatments, way of transport (own bed, stretcher trolley, wheel chair), and conditions of this transport. Results: 223 patients were included, with a median age of 59 years, 53% were female, 64% were going to radiology. 65% of patients reported some pain before transport, 71% of them receiving chronic pain treatment. Only 1/3 of painful patients get some pain treatment to specifically prevent pain related to transport. We found no relation between the mode of transport and the level of pain before transport. More than 50% of patients complained from significant pain during the transport, in most of the cases these patients were painful before transport. The same proportion of patients reported pain due to transport itself and to manipulations (ie to bring the patient from the stretcher trolley to the radiotherapy table for example). This study is the first to address the problem of patients’ transport in a cancer center. It demonstrates that this is painful for many of them. Ways to improve this situation include the following: give patients extra pain medications before transport, according to basal pain level and expected pain during transport; adapt transport modalities to each patient: painful patients should be transported in their own beds; improve quality and comfort of stretcher trolleys and wheel chairs; give stretcher bearers a specific teaching about pain evaluation. We are implementing specific measures to improve each one of these points. Conclusions: Patients transport is a significant cause of pain for many of them. Identification and prevention of this problem is a way to improve quality of care of cancer patients during their hospital stay. No significant financial relationships to disclose.