tbuckley/cabot-search huggingface dataset:
Long term cardiac tolerability of trastuzumab in HER-2-overexpressing metastatic breast cancer (MBC)
Authors: V. Guarneri, D. J. Lenihan, V. Valero, J. Durand, K. Broglio, L. Boehnke-Michaud, A. M. Gonzalez-Angulo, G. N. Hortobagyi, F. J. Esteva
Journal: Journal of Clinical Oncology (2006)

629 Background: The use of trastuzumab is associated with an increased risk of cardiotoxic events such as congestive hearth failure (CHF) and decline in the left ventricular ejection fraction (LVEF). Our objectives were to evaluate the incidence of cardiac dysfunction, to identify risk factors and to evaluate the outcome of patients with MBC treated with trastuzumab for one year or longer. Methods: Among 218 MBC patients treated with trastuzumab-based therapy for at least one year, 173 patients were evaluable for cardiac toxicity. Cardiac events (CE) were defined as follows: 1) asymptomatic drop of LVEF below 50%; 2) drop of 20 percentage points in LVEF compared to the baseline; 3) signs or symptoms of CHF. The cardiac toxicity was graded according the NCI-CTCAE, version 3.0. Results: Median age at the start of trastuzumab therapy was 50 years (range, 26–79), median cumulative time on trastuzumab was 21.3 months (range, 11.6–77.6), and median follow-up was 32.2 months (range, 9.7–79.0). Eighty-five percent of patients received prior anthracyclines (median cumulative doxorubicin dose: 300 mg/m 2 ). Forty-nine patients (28%) experienced a CE: 3 patients (1.7%) had an asymptomatic drop in the LVEF of 20 percentage points; 27 patients (15.6%) experienced grade 2 cardiac toxicity; and 18 patients (10.4%) experienced grade 3 cardiac toxicity. There was one cardiac related death (0.5%). Cardiac event-free survival was 87.3% at 1 year. All but four patients had improved LVEF or symptoms of CHF after stopping trastuzumab or with appropriate therapy. After complete recovery, 26 patients were re treated with trastuzumab; 16 patients did not experience further CE. Concomitant taxane use was the only factor significantly associated with a CE (HR: 4.37, 95%CI 1.06–17.98, p:0.04).Prior anthracycline exposure was not associated with increased risk of CE. Conclusions: The risk of cardiac toxicity of long-term trastuzumab-based therapy is acceptable in this population, and this toxicity is reversible in the majority of the patients. In patients who have experienced a CE, additional treatment with trastuzumab can be considered after recovery of cardiac function. The increased risk of cardiotoxicity associated with taxane administration needs to be further investigated. No significant financial relationships to disclose.
Methionine Dependence in Skin Fibroblasts of Humans Affected With Familial Colon Cancer or Gardner's Syndrome2
Authors: Yves B. Mikol, Martin Lipkin
Journal: JNCI Journal of the National Cancer Institute (1984)

Reduced growth in methionine-deficient, homocysteine-folic acid-, and vitamin B12-supplemented medium, a characteristic of tumor and transformed cell lines, was investigated in skin fibroblasts of patients affected with hereditary colon neoplasms. The presence or absence of this phenotype was studied in 37 cell lines from either low-risk subjects or members of families with Gardner's syndrome (GS) or familial colon cancer (FCC). Growth constants of skin fibroblasts of the low-risk group were not significantly different in the presence of methionine (Kme) or absence of methionine (Kho) (0.106±0.011 and 0.098±0.011, respectively). However, growth constants of skin fibroblasts of both GS and FCC were significantly reduced in the absence of methionine. In GS, Kho=0.086±0.006 and Kme=0.120±0.006 (P<.01). In FCC, Kho=0.048± 0.007 and Kme=0.084±0.009 (P<.01 ). Thus the growth of skin fibroblasts from both GS and FCC was methionine dependent. This phenotype was expressed in skin fibroblasts of an individual several years before any clinical manifestation of GS. In all populations studied the phenotype was independent of the age or sex of the individuals, aging of the cell lines, low serum concentration, and acute carcinogen treatment. In addition, there is a significant correlation (r=−0.85, P<.001) between the disorganization of actin cables of the skin fibroblasts and the ratio of the growth constants. These data constitute the first report demonstrating methionine dependence in cell lines that are not derived from transformed cells, tumor cells, or fetal cells but are derived from skin fibroblasts of patients with hereditary colonic neoplasms. Inasmuch as these cells are not target cells related to colon cancer, the phenotype appears to be the expression of an inherited autosomal dominant genotype related to the oncogenic transformation.
Optimized preclinical models for human pancreatic adenocarcinoma therapy research
Authors: N. Carbó, S. Pérez-Torras, A. Vidal-Pla, R. Miquel, V. Almendro, L. Fernández-Cruz, J. Maurel, S. Navarro, P. Gascón, A. Mazo
Journal: Journal of Clinical Oncology (2007)

15019 Background: Efforts to find new therapies for human pancreatic ductal adenocarcinoma (PDAC) have not resulted in clear improvements on patient survival. Better knowledge of resistance mechanisms and redefiniton of molecular targets is essential to design more efficient therapies. The multifactorial origin of PDAC points to combined strategies as the therapy of choice, though the effective development of such strategies is hampered by the lack of optimal preclinical models. We have generated and validated optimized human PDAC models by direct implantation of fresh tumoral tissue into the pancreas of athymic mice. Methods: Thirteen pancreatic adenocarcinoma specimens from PDAC patients were obtained by surgical resection. From each specimen, several 10 mg-fragments were used to generate the corresponding intrapancreatic xenografted tumours. Eleven human PDAC orthotopic models have been successfully generated and perpetuated by succesive passages (up to 4). Histological and molecular analyses of both primary and xenografted tumors have been performed by tissue- array, western-blot and DNA sequentiation. Results: Initial engraftment rate ranged from 20 to 100% (mean 59%) and it improved with succesive passages (mean 76% at second and 90% at third generation). Ki67 expression and degree of differentiation in primary tumors correlated with xenograft growth kinetics. Furthermore, their spontaneous metastatic behaviour fairly reproduced the original patient dissemination patterns. Xenografted tumors kept the original architecture and expression patterns of common PDAC markers. Efficacy of several agents was tested on different xenografted tumors, validating this model and underlining its utility to define future therapeutic strategies for drug development and clinical trials. Conclusions: The orthotopic models described here are, probably, the closest resemblance to a patient clinical setting since they preserve human pancreatic structures, genotypic features and biological behaviour. From their use, biological relevant data could be drawn for future clinical trials and for testing new agents and new drug combinations since they represent, very likely, the most reliable animal models at present. No significant financial relationships to disclose.
Abstract 12580: Intensive Lipid Lowering with Atorvastatin in Patients with Treatment Resistant Hypertension: An Analysis from the Treating to New Targets (TNT) Trial
Authors: Sripal Bangalore, Rana Fayyad, Rachel Laskey, David Demicco, Prakash Deedwania, John B Kostis, Franz Messerli
Journal: Circulation (2012)

Background: Patients with resistant hypertension (defined as blood pressure >140 mm Hg despite 3 antihypertensive agents or <140 mm Hg on 4 or more agents) are at high risk for adverse cardiovascular events. New therapies including catheter based radiofrequency ablation of the renal sympathetic nerves are being tested for this condition. However, if intensive lipid lowering is beneficial in this high risk cohort is not known. Methods: We evaluated 10,001 patients, with CAD and a LDL cholesterol level <130 mg/dL, randomized to atorvastatin (AT) 80 mg (intensive) vs. 10 mg (standard), enrolled in the TNT trial. Subjects were followed up at 12 weeks, 6, 9 and 12 months and every 6 months thereafter for a median duration of 4.9 years. Primary outcome was major cardiovascular events (composite of nonfatal MI, fatal CHD, resuscitated cardiac arrest, and stroke). Between treatment differences were assessed using a Cox Proportional Hazards model. Results: Among the 10,001 patients in the trial, 1112 (11.1%) patie...
Titanium dioxide nanoparticles exacerbate DSS-induced colitis: role of the NLRP3 inflammasome
Authors: Pedro A Ruiz, Belen Morón, Helen M Becker, Silvia Lang, Kirstin Atrott, Marianne R Spalinger, Michael Scharl, Kacper A Wojtal, Anne Fischbeck-Terhalle, Isabelle Frey-Wagner, Martin Hausmann, Thomas Kraemer, Gerhard Rogler
Journal: Gut (2016)

Objective Western lifestyle and diet are major environmental factors playing a role in the development of IBD. Titanium dioxide (TiO 2 ) nanoparticles are widely used as food additives or in pharmaceutical formulations and are consumed by millions of people on a daily basis. We investigated the effects of TiO 2 in the development of colitis and the role of the nucleotide-binding oligomerisation domain receptor, pyrin domain containing (NLRP)3 inflammasome. Design Wild-type and NLRP3-deficient mice with dextran sodium sulfate-induced colitis were orally administered with TiO 2 nanoparticles. The proinflammatory effects of TiO 2 particles in cultured human intestinal epithelial cells (IECs) and macrophages were also studied, as well as the ability of TiO 2 crystals to traverse IEC monolayers and accumulate in the blood of patients with IBD using inductively coupled plasma mass spectrometry. Results Oral administration of TiO 2 nanoparticles worsened acute colitis through a mechanism involving the NLRP3 inflammasome. Importantly, crystals were found to accumulate in spleen of TiO 2 -administered mice. In vitro, TiO 2 particles were taken up by IECs and macrophages and triggered NLRP3-ASC-caspase-1 assembly, caspase-1 cleavage and the release of NLRP3-associated interleukin (IL)-1β and IL-18. TiO 2 also induced reactive oxygen species generation and increased epithelial permeability in IEC monolayers. Increased levels of titanium were found in blood of patients with UC having active disease. Conclusion These findings indicate that individuals with a defective intestinal barrier function and pre-existing inflammatory condition, such as IBD, might be negatively impacted by the use of TiO 2 nanoparticles.
High-dose IL-2 in patients with metastatic melanoma after progression on biochemotherapy (BioCT). The experience of the Hospital Sírio-Libanês, Brazil
Authors: R. A. Schmerling, W. N. William, F. A. Belfort, A. C. Buzaid
Journal: Journal of Clinical Oncology (2006)

8038 Background: There are limited data on systemic therapy after progression following BioCT (cisplatin, vinblastine, dacarbazine, interferon-alfa and IL-2) in patients with stage IV melanoma. High-dose IL-2 has a 16% response-rate as first-line therapy, with approximately 5% of the pts achieving long-term survival. Methods: We retrospectively reviewed our experience with high-dose IL-2 in pts who had metastatic melanoma and had progressed during or after BioCT from 1/2000 to 1/2005. One treatment course consisted of IL-2, 600.000 IU/kg IVP q8h for a maximum of 14 doses per cycle, followed by an identical cycle after a one week of rest. Responding patients received 2 additional courses after 6 weeks of rest between courses. All pts were treated in a regular ward setting under the assistance of specialized and trained nurses on high-dose IL-2 therapy. Results: A total of 23 pts (15 male, 8 female); median age 46 (range 21–68) were treated with high-dose IL-2. Two pts received only 1 cycle of therapy due to PD and 1 treatment-related death. The remaining 21 pts received at least 1 full course (2 cycles) of therapy. Median number of cycles was 2 and median number of IL-2 doses/cycle was 10. Response rates using RECIST were as follows: CR, 1 pt (5%); PR, 6 pts (27%). Duration of response was 1, 3, 8, 9, 10, 12, and 18 months. There were no long-term disease-free survivors. Among the 9 patients with a previous response to BioCT, 1 pt had CR and 3 pts had PR to high-dose IL-2. Among the 8 pts whose disease previously progressed on BioCT, 2 pts still achieved a PR. After a median follow-up of 36 months, all pts have presented disease progression and 20 pts have died. Median time to progression and overall survival were 2.5 mo and 9.5 mo, respectively. Conclusions: High-dose IL-2 has modest but definite activity in pts previously treated with BioCT, regardless of the response to the latter treatment, and may be an option in selected pts. No significant financial relationships to disclose.
A randomized trial of cisplatin versus cisplatin plus methotrexate in advanced cancer of the urothelial tract.
Authors: B L Hillcoat, D Raghavan, J Matthews, R Kefford, K Yuen, R Woods, I Olver, J Bishop, B Pearson, G Coorey
Journal: Journal of Clinical Oncology (1989)

One hundred eight patients with recurrent or metastatic transitional cell carcinoma of the urothelial tract were randomized to receive cisplatin (C) 80 mg/m2 on day 1 every 4 weeks, or methotrexate (M) 50 mg/m2 on days 1 and 15 plus C 80 mg/m2 on day 2 every 4 weeks (C + M). Fifty-three eligible patients were randomized to C + M and 55 to C. In the C + M arm, 45% of patients responded (complete response [CR], 9%) and 31% (CR, 9%) in the C arm (P = .18). In the C arm, 20 patients failing or relapsing after C received M. Two patients responded, and four with progressive disease (PD) and one with a previous partial response (PR) showed no change. The median survival was 8.7 months (C + M arm) and 7.2 months (C arm), P = .7. Relapse-free survival was not significantly different, but C + M was associated with a significantly increased time to disease progression (median, 5.0 months, v 2.8 months for C arm). The response of untreated patients (37%) was not different from those with prior treatment (39%). On the C + M arm, 92% of patients and 96% of patients on the C arm received 85% or more of the scheduled C dose. Significantly more grade 3 or 4 hematological toxicity (27% v 2%; P = .01) and mucositis (20% v 0%; P = .0005) occurred in patients on the C + M arm. Although the initial response rates seen on the combination arm look superior, and the time to disease progression is increased, these effects have not translated into a clinically important increase in the duration of survival and were associated with increased toxicity.
Role of selectins in the pathogenesis of multiple myeloma
Authors: A. Azab, F. Azab, J. Runnels, A. M. Roccaro, J. L. Magnani, A. Sarkar, K. C. Anderson, C. P. Lin, I. M. Ghobrial
Journal: Journal of Clinical Oncology (2009)

11103 Background: Multiple myeloma (MM) is characterized by the disseminated involvement of the bone-marrow (BM), and its progression involves a continuous circulation of the MM cells (MMCs) in the peripheral blood and homing back to the BM. Selectins are adhesion molecules involved in the primary interaction of lymphocytes with the endothelial cells (ECs) of blood vessels. In this study we studied the role selectins in the pathogenesis of MM. Methods: We have characterized the expression of E, L and P-selectins and their ligands on MM cell lines, patient sample and plasma cells from normal subjects (NPCs). We have tested the effect of blockade of each of the selectins and selectin-ligands on the interaction of MMCs with ECs. Moreover, we tested the effect of a pan selectin inhibitor on MMCs adhesion to ECs, and trans-well (through filter) and trans-endothelial SDF1-induced migration in vitro, and characterized its effect on cytoskeletal signaling induced by the interaction of MMCs and ECs. Moreover, we have tested the effect of the inhibitor on homing of MMCs to the BM in mice using in vivo flow cytometry to detect the number of circulating cells, and in vivo confocal microscopy to directly visualize the homing. Results: All MM cell lines and patient samples had low expression of all selectins and high expression of L and P, but not E, selectin ligands. While NPCs showed low expression of all selectins and ligands. Blockade of L and P-selectin ligands reduced the interaction of MMCs with ECs in vitro, while blockade of E-selectin ligand or any of selectins did not show any effect. The pan-selectin inhibitor reduced the interaction of MMCs with ECs in vitro, did not alter their SDF1-induced migration through filter, but reduced significantly the migration through ECs. The inhibitor inhibited the activation of FAK and ERK induced by interaction of MMCs and ECs. Moreover, the selectin inhibitor extending the circulation time of MM cells in mice, and reduced the homing of MMCs. Conclusions: We found that L and P selectin ligands are highly expressed in MMCs compared to NPCs, and that those play a major role in homing of MMCs to the BM. Moreover, the pan-selectin inhibitor prevented the homing of MMCs to the BM. This provides a basis for testing the effect of the inhibitor on MM tumor progression and initiation. No significant financial relationships to disclose.
Improving cancer care and research through the reuse of standardized electronic data
Authors: J. Speakman, D. Reeves
Journal: Journal of Clinical Oncology (2008)

17556 The inability to routinely capture oncology patient data electronically at the point of care and re-use this data in other settings (such as follow-up care or in a clinical trial) is a key impediment to improving cancer care and research. The same data collected in the oncology practice are often rekeyed multiple times as a patient moves through treatment and continues into routine follow up care. Even during the course of a single trial, data are rekeyed as the data move between trial site, trial sponsor and regulatory body. The National Cancer Institute (NCI) is collaborating with multiple organizations on multiple standardization and automation initiatives to standardize treatment summaries, electronic case report forms (eCRFs), and data elements associated with cancer care and research so that data can move directly, and in both directions, between clinical systems at the point of care and clinical trials databases, and back again. Standardized electronic data are also necessary to develop systems providing for decision support and quality reporting and analysis. Among the areas where work is complete, or nearly complete, are treatment summaries for colon and breast cancer as well as eCRFs for demography, patient identification, patient enrollment, patient baseline assessment, adverse events and protocol deviations. Discussions are underway among the collaborating organizations to begin work to standardize vocabularies for additional high priority areas such as clinical staging and medications. As the collection of these common vocabularies and data standards grows within the NCI's Cancer Data Standards Repository (caDSR), they can be reused to create new forms and tools. For example, many of the data elements for treatment summaries already existed in the caDSR, lessening the time and effort to complete the summaries. This presentation will describe completed, current and planned work to develop common standards and terminology for treatment summaries, standardized electronic case report forms (eCRFs) and electronic message formats for data transfer during the course of a clinical trial. No significant financial relationships to disclose.
Cdc7 inhibition as a novel approach for pancreas cancer therapy.
Authors: Mark G. Frattini, Lucia Regales, Ruth Santos, Diana Carrillo
Journal: Journal of Clinical Oncology (2013)

e15059 Background: Pancreatic cancer is the fourth leading cause of cancer death in the USA. In 2012, 43,920 people will be diagnosed and 37,390 people will die of this disease. 95% of tumors reveal loss of the p16 protein, a regulator of the G1 to S phase transition. Cdc7 is a conserved kinase required for the initiation of DNA replication, is a target of the S-phase checkpoint, and has a role in controlling the DNA damage response. Downregulation of Cdc7 kinase activity resulted in slowing of S-phase and cell cycle arrest followed by accumulation of DNA damage. Cdc7 has been shown to be over-expressed in many different tumors including the majority of solid and liquid tumors. In our laboratory a novel natural product small molecule inhibitor (MSK-777) has been identified, developed and shown to be efficacious in cell based cytotoxicity assays and multiple animal models of cancer. Methods: We have examined the efficacy of Cdc7 kinase inhibition as a therapeutic approach for pancreatic cancer by examining the sensitivity of MSK-777 in Capan-1, BxPC3, and PANC-1 cell lines. These cells were treated with MSK-777, control (DMSO), or hydroxyurea and collected for viable cell counts, fluorescence-activated cell sorting (FACS), and western blotting. Results: Cell viability analyses revealed that MSK-777 had a dramatic effect after 24 hours, reducing cell viability to less then 20% in BxPC3 cells. FACS results demonstrated that MSK-777 exposure resulted in cell cycle arrest at G1/S in Capan-1 and PANC-1 cells by 48 hours while BxPC3 cells showed a significant sub-G1 population by 24 hours, indicating apoptotic cell death. Western blotting showed that in BxPC3 cells phosphorylation of the mini-chromosome maintenance 2 protein (Mcm2) disappeared by 24 hours, indicating inactivation of the helicase that unwinds the strands of DNA during replication. Western blots of Capan-1 and PANC-1 cells showed lower levels of phosphorylated Mcm2 by 48 hours. Conclusions: We are currently examining the efficacy of MSK-777 in mouse models of orthotopically injected pancreatic cancer cells. Based on these collective results, inhibition of Cdc7 kinase activity with MSK-777 represents a novel and promising therapy for this deadly disease.