tbuckley/cabot-search huggingface dataset:
Acquired resistance to combination therapy with lapatinib and MEK 1/2 inhibitor GSK1120212 in an in vivo murine model of pancreatic cancer.
Authors: James M. Lindberg, Dustin M Walters, Sara J Adair, Catharine R Cowan, Jayme B Stokes, Cheryl A Borgman, Edward B Stelow, Bryce T Lowrey, Maria E Chopivsky, J Thomas Parsons, Todd W. Bauer
Journal: Journal of Clinical Oncology (2012)

208 Background: Mutations of the oncogene KRAS and activation of cell-surface receptor tyrosine kinases are important and preserved mechanisms of tumorgenicity in pancreatic cancer. Dual inhibition of the downstream KRAS effector MEK 1/2 and tyrosine kinases EGFR and Her2 results in effective inhibition of patient-derived tumor growth in a murine orthotopic transplantation model. Because combinatorial therapies are moving rapidly into clinical trials, we sought to develop a model of acquired tumor resistance to this combination therapy. Methods: Patient-derived pancreatic tumor xenografts MAD 09-366 (KRAS mut), MAD 08-608 (KRAS mut) and MAD 08-738 (KRAS wt) were implanted orthotopically in nude mice and treated with combination lapatinib (EGFR/Her2 inhibitor) and GSK1120212 (MEK1/2 inhibitor) and tumor volume was measured by MRI. Following 4-6wks of treatment, tumors were reimplanted in second and third generation mice and retreated. Tumors were evaluated by phospho-RTK and phospho-MAPKinase array. Results: Acquired resistance developed in all three tumor xenografts. Treated tumors demonstrated a relative volume decrease in the original (F 0 ) generation. All second re-implantation (F 2 ) tumors, demonstrated relative tumor volume increases despite treatment. A comparison of pre-treatment mean tumor volumes showed a significant decrease in tumor size from the F 0 to F 2 generations suggesting selection for slower growing tumors. Array data demonstrated increased activation of FGFR1, VEGFR1/3, GSK-3β, p38, and Akt in resistant tumors as compared to their pre-treatment controls. These may represent mechanisms of tumor resistance and warrant further investigation. Conclusions: Repeated tumor exposure in vivo to combination treatment with GSK1120212 and lapatinib was used to develop a preclinical, orthotopic murine model of acquired drug resistance in patient-derived pancreatic cancers. This model provides the opportunity to define the mechanism of resistance in an appropriate tumor microenvironment and to develop alternative strategies for treating tumors resistant to this and other emerging therapies.
Hepatic Sinusoidal Obstruction Syndrome After Allogenetic Hematopoietic Stem Cell Transplantation in Adult Acquired Aplastic Anemia
Authors: Hawk Kim, Sung-Soo Yoon, Chul Won Jung, Sang Kyun Sohn, Young Don Joo, Byung Soo Kim, Sung Hyun Kim, Sung-Hwa Bae, Ho-Jin Shin, Jong-Ho Won, Deog-Yeon Jo, Jae Hoo Park, Kyoo-Hyung Lee
Journal: Blood (2011)
Mini BEAM with Full-Dose of Melphalan (beaM) As a Conditioning Regimen for High Risk Patients with NHL Undergoing Autologous SCT
Authors: Matko Kalac, Cristine Candland, Lisa Wallace, Elizabeth Gentner, Shreya Shah, Jennifer E Amengual, Changchun Deng, Suzanne Lentzsch, Owen A. O'Connor, Markus Y Mapara
Journal: Blood (2016)
Extracellular proteases in renal cell carcinoma.
Authors: B. Lipe, M. S. Ernstoff, J. Gui, J. D. Seigne, A. Schned, B. Petrella
Journal: Journal of Clinical Oncology (2011)

363 Background: Tumor growth and metastasis relies on extracellular matrix remodeling, which is primarily mediated by the matrix metalloproteinase (MMP) family of enzymes. Extracellular matrix metalloprotease inducer (EMMPRIN, E) is a glycoprotein also implicated in tumor progression and has been shown to function in concert with MMPs. MMPs and E are highly expressed on the surface of many malignant tumors, including renal cell carcinoma (RCC). We investigated whether MMPs and E represent molecular prognostic factors in RCC. Methods: Protein expression was evaluated in 77 patients with immunohistochemical analysis of a tissue microarray (TMA) consisting of two tumor samples and an adjacent normal renal sample from each patient. Tumors represented on the TMA were clear cell (57), chromophobe (9), papillary (4), oncocytomas (3), clear cell with sarcomatoid differentiation (2), and metastatic (2). Protein expression scores were correlated with clinical outcomes to determine prognostic significance by univariate and multivariate analyses. Results: Using univariate analysis of all RCC tumors, membranous E correlated with overall survival (OS), metastasis-free survival (MFS), size, stage and overall 5-yr survival. Cytoplasmic E correlated with OS, MFS, size, grade, stage and 5-yr survival. Membranous MT1-MMP correlated with MFS, and endothelial MMP-2 correlated with grade. In multivariate analysis, membranous E was an independent indicator of stage, whereas cytoplasmic E was an independent indicator for size, stage, grade and MFS. In the clear cell population, membranous MT1-MMP correlated with OS and MFS, and endothelial MMP-2 correlated with grade in univariate analysis. In multivariate analysis, membranous MT1-MMP was an independent indicator for MFS. Conclusions: We identified EMMPRIN as an independent prognostic indicator for size, grade, stage, and MFS in RCC. While MT1-MMP and MMP-2 both significantly correlated with disease outcome in the clear cell RCC population, only MT1-MMP was an independent prognostic factor for MFS. We conclude that MMPs and E mediate important steps in RCC progression. Further investigation is warranted using larger datasets and a prospective study to determine the strength of the prognostic significance of these findings. No significant financial relationships to disclose.
High Levels of Soluble HLA-I in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome: Relevance to Clinical Behavior and b2M Levels.
Authors: Maher Albitar, Marcy Johnson, Kim-Ann Do, Amanda Day, Iman Jilani, Sherry Pierce, Elihu Estey, Hagop Kantarjian, Michael Keating, Srdan Verstovsek, Susan O’Brien, Francis J. Giles
Journal: Blood (2004)
Target Proteins of C/EBPa-p30 in AML: A Critical Role of Ubiquitin-Conjugating Enzyme (Ubc9) in Modulating C/EBPa-p42 Functions.
Authors: M. Geletu, M. Balkhi, A. Peer Zada, A. Trivedi, J. Pulikkan, M. Christopeit, Daniel G. Tenen, G. Behre
Journal: Blood (2006)
Contribution of C-reactive protein to predicting overall survival in patients with advanced urothelial carcinoma: Development of a nomogram and evaluation by decision curve analysis.
Authors: Junichiro Ishioka, Kazutaka Saito, Mizuaki Sakura, Minato Yokoyama, Yoh Matsuoka, Noboru Numao, Fumitaka Koga, Hitoshi Masuda, Kazunori Kihara
Journal: Journal of Clinical Oncology (2012)

280 Background: To accurately estimate the individual survival of patients with advanced urothelial carcinoma (UC), the application of prediction models such as nomograms has been warranted in clinical use. We therefore constructed a nomogram which included C-reactive protein (CRP) as a novel biomarker in order to increase its predictive accuracy. Furthermore, the clinical usefulness of this nomogram was evaluated by decision curve analysis which incorporated the negative consequences of each decision to generate a net benefit (Vickers et al, BMC Med Inform Decis Mak, 2008). Methods: A total of 232 consecutive patients with locally advanced or metastatic urothelial carcinoma (UC) were treated at our institute. Among them, 9 patients with missing data were excluded. The current study cohort was comprised of the remaining 223 patients. A nomogram predicting 6- and 12-month survival probability was developed based on the results of the final multivariate analytic model. To evaluate the efficacy of this nomogram, a quantified concordance-index (c-index) was computed and a decision curve analysis was performed. Results: Overall, 184 patients died of the primary disease and the remaining 39 were censored. The median follow-up period and length of overall survival were 5 and 6 months, respectively. The 6- and 12-month survival rates were 48% and 30% respectively. A nomogram was developed which included the parameters of age, PS, visceral metastasis, hemoglobin and CRP. The c-index of this prediction model was 0.79 compared with 0.75 for that of a model without CRP. The decision curve analysis revealed that a novel nomogram which incorporated CRP had a superior net benefit to that without CRP for most of the examined threshold probabilities. Conclusions: Incorporation of CRP increased the predictive accuracy of a prognostic nomogram for advanced UC. In clinical practice, this nomogram would contribute to the decision making process in the treatment of patients suffering from this form of carcinoma.
Brain metastasis in metastatic renal cell carcinoma: Predictive factors of occurrence and survival with or without antiangiogenic therapy.
Authors: M. Vanhuyse, N. Penel, A. Caty, I. Fumagalli, M. Alt, L. Zini, A. Adenis
Journal: Journal of Clinical Oncology (2011)

394 Background: We analyzed renal cell carcinoma (RCC) brain metastasis (BM) risk factors and compared BM occurrence in advanced RCC treated with or without antiangiogenic agents (AAA). Methods: Data from all consecutive metastatic RCC patients (pts) treated in the Northern France Cancer Center (Centre Oscar Lambret, Lille) between 1995 and 2008 were reviewed. Eligible pts had histologically confirmed advanced RCC without synchronous BM at the time of metastasis diagnosis. Bellini duct and neuroendocrine carcinoma and sarcoma were excluded. AAA were sorafenib, sunitinib, bevacizumab, temsirolimus, and everolimus. Characteristics of the two groups, treated with or without AAA, were compared with a Fisher exact test. Impact of AAA on overall survival (OS) and BM-free survival (BMFS) was explored by Kaplan-Meier method and adjusted to confounders parameters in a Cox model. Results: A total of 199 pts with advanced RCC were identified, 51 treated with AAA and 148 treated without AAA. The median follow-up duration was 40 months. BM occurred in 35 pts. As expected in this retrospective analysis, characteristics between AAA treated and non AAA treated groups were unbalanced for 11 parameters including age, Motzer prognostic factors, performance status and favoring better prognostic factors in the AAA treated group. The median overall survival was 24 months. Overall survival was higher in patients with AAA versus patients without AAA (31 versus 18 months, hazard ratio (HR) 0.67 [0.45–0.97], p=0.038). The AAA were not associated with better BMFS (HR=0.58 [0.26–1.30], p=0.187). The alkaline phosphatase was an independent prognostic factor for BM (p=0.05). In multivariate cox model, AAA treatment improved the OS (adjusted HR 0.60 [0.38–0.94] but not the BMFS (adjusted HR 0.53 [0.22–1.32]. Conclusions: In this retrospective single center study, elevated alkaline phosphatase is a predictive factor for brain metastasis in metastatic RCC. AAA significantly improved overall survival in advanced RCC without any significant impact on brain-metastasis-free survival. No significant financial relationships to disclose.
Use of epirubicin, carboplatin, and 5-fluorouracil (ECarboF) as a second-line treatment in metastatic castration-resistant prostate cancer.
Authors: U. B. McGovern, S. J. Harland
Journal: Journal of Clinical Oncology (2011)

173 Background: ECarboF chemotherapy is an active first line chemotherapy treatment for metastatic prostate cancer. We have now investigated its efficacy and toxicity in patients who have progressed during or after docetaxel chemotherapy. Methods: 37 patients with metastatic prostate cancer who had received ECarboF chemotherapy were retrospectively reviewed from a five year period (2005-2010). All patients had previously received first-line docetaxel chemotherapy and had either progressed following treatment (n=17) or were docetaxel refractory (n=20). Patients received epirubicin 50mg/m 2 iv d1, carboplatin (AUC 5) d1, fluorouracil 440mg/m 2 d1, d15 and folinic acid 20mg/m 2 d1, d15 on a q4w cycle. 20% dose reductions were made for the first cycle in patients with poorer performance status. PSA was measured before each cycle of treatment and all patients were assessed for toxicity. Results: Patients had a median age of 70 years (range 48-77), median baseline PSA of 226.5 ng/mL (range 9.6-1,580) and the median number of ECarboF chemotherapy cycles received was 6 (range 1-10). 65% (n=24) of patients were ECOG 0-1, the remaining 35% (n=13) were ECOG 2-3. 16% (n=6) patients had a ≥ 30% decline in PSA and 16% (n=6) patients had a ≥ 50% decline in PSA. 35% (n=13) of patients experienced grade 3/4 toxicity, most commonly anaemia (13.5%), neutropenia (13.5%) and thrombocytopenia (8.1%) with one treatment related death (neutropenic sepsis) during the five year period analysed. Median time to PSA progression was 5.1 months. Conclusions: ECarboF has activity with acceptable toxicity post docetaxel in the treatment of metastatic castration resistant prostate cancer. Although PSA response rates are modest, the time to progression is comparable to that of more toxic regimens. ECarboF should be considered as an active second-line chemotherapy regimen. No significant financial relationships to disclose.
Transfusion of Stored Autologous Blood Alters Reactive Hyperemia and Circulating Nitrite Levels in Healthy Volunteers
Authors: Lorenzo Berra, Walter Sunny Dzik, Andrea Coppadoro, Kenneth D. Bloch, Binglan Yu, Ester Spagnolli, Andrea U. Steinbicker, Martin Feelisch, Bernadette Fernandez, Christopher Stowell, Shaw H Warren, Tian Lin, Warren M. Zapol
Journal: Blood (2011)
Carcinomatous meningitis related to patients with breast cancer patients: A new approach of an individual treatment regimen with liposomal cytarabine.
Authors: H. Rudnicka, R. Dubianski, D. Larecka, E. Szombara, A. Skrzypczyk
Journal: Journal of Clinical Oncology (2011)

e11532 Background: Carcinomatous meningitis occurs in 5 % of patients with breast cancer. The median survival amounts from 4 to 6 months and only 15% of patients survive more than 1 year. The best result of carcinomatous meningitis treatment is achieved by the use of the combined systemic and intrathecal chemotherapy accompanied by the spinal and whole brain radiotherapy. The patients with carcinomatous meningitis are treated with intrathecal methotrexate as the initial therapy. However the results of methotrexate treatment are not satisfactory. It seems that liposomal cytarabine treatment might be promising for the patients with carcinomatous meningitis. Therefore this therapy was investigated. Methods: In year 2010, 8 patients of Breast Cancer Department in Cancer Center in Warsaw with carcinomatous meningitis received the intrathecal chemotherapy with liposomal cytarabine. The diagnosis was based on the presence of cancer cells in cerebro-spinal fluid and/or cerebrospinal MRI. Liposomal cytarabine was administered in the intrathecal injection of 50 mg, every 2 weeks for 5 cycles followed by 5 cycles of 50 mg every 4 weeks. Results: Generally the liposomal cytarabine therapy was well tolerated. No serious adverse events were observed. The regimen of the treatment was more convenient than weekly administering of methothrexate. Intrathecal liposomal cytarabine treatment results in the rapid cancer cells count decrease in cerebrospinal fluid. It does not seem to correspond with clinical benefits. The progression of the disease was observed in each case after two weeks after drug administration Conclusions: The results suggest that liposomal cytarabine intrathecal chemotherapy is well tolerated. The clarification of cerebrospinal fluid from cancer cells can not to be the factor of the termination of the liposomal cytarabine intrathecal treatment. It seems that the better results could be achieved by the change of the used regimen of treatment, as the every 4 weeks treatment is not efficacious and the progression of disease occurrs after two weeks. The individual timetable of the treatment scheme should be considered in every case according to the clinical status.
Tyrosin Kinase Inhibition Restores the Membrane Localization of FLT3-ITD
Authors: Katrin S. Reiter, Harald Polzer, Christina Krupka, Binje Vick, Andreas Maiser, Marion S. Subklewe, Irmela Jeremias, Heinrich Leonhardt, Karsten Spiekermann, Philipp A. Greif
Journal: Blood (2015)
Use of next-generation deep sequencing to improve FGFR3 mutation detection in the urine of patients with bladder cancer.
Authors: John M. Millholland, Shuqiang Li, Cecilia A. Fernandez, Anthony P. Shuber
Journal: Journal of Clinical Oncology (2012)

289 Background: FGFR3 mutations have been identified in ∼60-70% of low-stage, non-invasive tumors. Our group and others have developed assays to detect FGFR3 mutations in the urine of bladder cancer patients. However, urine-based assays have been limited by the technical ability to detect rare events in a dilute medium where there is a high background of normal DNA. In these assays, FGFR3 mutations are generally found in ∼30% of the urine samples, which is &lt; 50% concordance with the expected detection in tissue. We have now developed an ultra-deep amplicon sequencing technique that increases FGFR3 mutation detection in urine to ∼67%, near the expected detection if every mutation found in tissue could be detected in urine. Methods: Amplicons were designed against FGFR3 exons 7, 10, and 15 using PCR primers containing the adapter sequences for unidirectional sequencing. Taqman probes were used to determine if sufficient DNA was present in each sample. Primary amplification was performed from DNA isolated from 4 ml of urine. The resulting PCR products were used as template for emulsion PCR and these were then sequenced using the Roche 454 GS Junior. Samples were analyzed for total DNA reads per sample and number of mutant sequencing reads to determine percent mutation. Results: Urine samples from 29 patients with stage Ta bladder cancer were analyzed by both our previously described qPCR method and the new ultra-deep sequencing approach. Of the 29 samples, 2 did not have sufficient DNA for analysis by sequencing. Using ultra-deep amplicon sequencing, 18 out of 27 (66.7%) were positive for FGFR3 mutations, while only 3 out of 27 (11.1%) were positive for mutations by qPCR. The urine samples from the 15 newly identified mutations using deep sequencing contained FGFR3 mutations as low as 0.05%. The sensitivity achieved using deep sequencing approximates the FGFR3 mutations observed in tissue. Conclusions: We have developed a highly sensitive non-invasive urine based assay that can detect FGFR3 mutant DNA when present at &lt; 1% of the sample and suggests &gt; 90% concordance with the expected mutations in Ta tumor tissues. To our knowledge, this is the first practical application of next generation sequencing technology for diagnostic use.
MYBL2 Is a Candidate Tumor Suppressor Gene In MDS
Authors: Stefan Heinrichs, Lily Conover, Carlos E. Bueso-Ramos, Outi Kilpivaara, Ross Levine, Kristen Stevenson, Donna Neuberg, Rafael Bejar, Benjamin L. Ebert, Guillermo Garcia-Manero, Hagop M. Kantarjian, A. Thomas Look
Journal: Blood (2010)
siRNA silencing of TFF3 modulates angiogenesis, invasion and proliferation properties of gastric cancer cell line MKN45
Authors: Victor Y. Chan, Michael W. Chan, Ka-Fai To, Francis K. Chan
Journal: Cancer Research (2004)

1448  Intestinal trefoil factor (TFF3) is absent in normal stomach but is over-expressed in both types of gastric cancers. However the role of TFF3 in gastric carcinogenesis is still unknown. Our aim is to examine the effect of silencing of TFF3 by specific small interference RNA (siRNA) on proliferation, invasion and angiogenesis of gastric cancer. siRNA against TFF3 mRNA was generated by in-vitro transcription and transfected into human gastric cancer cell line MKN45 at concentration ranged from 10nM to 600nM. Total RNA was extracted, followed by reverse-transcription polymerase chain reaction (RT-PCR). Under optimal transfection condition, MKN45 transfected with 200nM siRNA (MK200A) for 3 days was chosen for further investigations. Parental cell line incubated with the transfection reagent alone was acted as control (MKCon). We assessed the cell proliferation by MTT and BrdU incorporation-assay. While apoptosis was determined by DNA fragmentation using cell death detection ELISA, and sub-G1 peak on flow-cytometer. The expressions of angiopoietins (Ang1 and Ang2), E-cadherin (ECad), metalloproteinases (MMP9) and its preferential inhibitor, tissue inhibitor of metalloproteinases (TIMP1), and transcription factor Nuclear Factor kappa B (NFκB) mRNA were also determined by quantitative real-time PCR (QRT-PCR). Our result showed that the silencing efficiency was shown to be concentration- and time-dependent. Over 80% of TFF3 expression in MKN45 was silenced by siRNA transfection at concentration of 200nM for 3 days. On the other hand, MK200A cells showed a upregulation of doubling time by 22.5%, while cell proliferation was downregulated by 52% when compared to MKCon. This decrease in cell growth may relate to increase in apoptosis by 2 to 4 folds in MK200A cells as determined by DNA fragmentation assay and appearance of sub G1-peak. Moreover, Ang1, MMP9, and NFκB mRNA expressions of MK200A, compared to MKCon, were downregulated by 65.1%, 41.8%, and 21.0%, respectively. While Ang2, ECad, and TIMP1 mRNA of MK200A were upregulated by 56.4%, 121.2%, and 65.9%, respectively. In conclusion, siRNA induced-silencing of TFF3 gene expression significantly inhibited cell proliferation in MKN45 cells. This anti-proliferation may be mediated through increase in apoptosis. Function of TFF3 may also link to invasion- and angiogenesis-related genes. Taken together, these result suggested that TFF3 may be involved in the modulation of gastric carcinogenesis and is a potential therapeutic target for gastric cancer.
Results of a pilot study of a web-based care plan to meet the communication needs of breast cancer survivors and their primary care physicians.
Authors: R. Haq, F. H. Leung, D. Dastur, N. A. Baker, L. Heus, B. Li, J. A. Parsons
Journal: Journal of Clinical Oncology (2011)

200 Background: Following treatment, breast cancer patients (BCPs) can feel “lost in transition”. Family practitioners (FP) also report feeling ill-equipped to provide follow-up care to breast cancer patients. In this 3-phase qualitative pilot study we designed, implemented and evaluated a multi-faceted care plan (MCP) to address the information/communication needs of BCPs and their FPs. Methods: We first conducted focus groups and interviews with 35 participants from 3 stakeholder groups (BCPs, FPs and oncology team), to identify specific information and communication needs. A MCP was designed based on these findings. The MCP was then evaluated via focus groups and interviews with 26 participants. Interviews and focus groups were audiotaped, transcribed and content analysed for emergent themes and patterns. Results: Pre-implementation, participants identified communication needs pertinent to BCPs and FPs. Patients commented that web-based, paper-based and human resources components are essential to any care plan. Patients did not focus solely on the post-treatment period, but rather spoke of evolving needs throughout their cancer journey. FPs indicated that any tools to support them must distill important information in a readily accessible and easy-to-use format. Based on this needs assessment, a MCP was designed and implemented for BCPs and FPs. This consisted of tailored websites, as well as paper-based care plans and a patient booklet. Patients provided positive feedback about the MCP, indicating that it was effective at addressing many of their needs and commented “I wish I’d had this before”. Suggestions for future improvements to the MCP included greater emphasis on health-and-wellness post-treatment. In addition, some patients voiced resistance to the terms “survivor” and “survivorship” in materials, as they did not self-identify with such terms. Conclusions: This MCP shows promise in addressing the information/communication needs of BCPs and FPs who care for them. Next steps include tool refinement, further evaluation, and planning for more extensive implementation.