tbuckley/cabot-search huggingface dataset:
Efficacy of L-asparaginase loaded red blood cells combined with gemcitabine on pancreatic cancer.
Authors: E. Dufour, K. Aguera, P. Lorenzi, F. Gay, F. Horand, Y. Godfrin
Journal: Journal of Clinical Oncology (2010)

e14666 Background: Tumor cells deficient in asparagine synthetase (ASNS) are unable to synthesize enough L-asparagine (Asn) to meet metabolic demands and, therefore, depend upon circulating Asn in the plasma for survival. L-asparaginase, which depletes Asn, has been used in the treatment of acute lymphoblastic leukemia (ALL) for over 30 years, since the majority of such tumors are deficient in ASNS. Recent evidence suggests that a subset of pancreatic tumors are deficient in ASNS, providing rationale for testing L-asparaginase against such tumors. However, L-asparaginase is associated with high immunogenicity and severe side effects. Therefore, it has been shown in patients with ALL, that L-asparaginase loaded into red blood cells (GRASPA) allows to strongly reduce side effects and to improve L-asparaginase pharmacokinetics. Methods: In this study, we first evaluated the in vitro cytotoxicity of L-asparaginase and gemcitabine, alone or combined, on 4 human pancreatic cell lines: AsPC-1, BxPC-3, MIA-PaCa-2 and PANC-1. Two of those lines were selected for follow-up in vivo studies: PANC-1 cell viability was synergistically reduced by pre-incubation of gemcitabine for 24 hours before addition of L-asparaginase, and BxPC- 3 cells did not proliferate in a free L-asparagine medium. In a second step, using a metastasis mouse model, luciferase-labeled PANC-1 or BxPC-3 cells were injected into nude mice intraperitoneally. Four days later, mice received either a single IV injection of GRASPA (200 IU/kg), three IV injections of gemcitabine (3 × 100 mg/kg) at 7 day intervals, or a combination of both drugs on the latter treatment schedule. Control mice received only vehicle(s). Tumor cell spreading was determined by bioluminescence imaging up to 63 days. Results: Preliminary results showed that combination treatment (GRASPA + gemcitabine) delayed metastasis development in PANC-1 and BxPC-3 models when compared to gemcitabine alone. Conclusions: RBC-loaded L-asparaginase in combination with gemcitabine is a promising treatment for pancreatic cancer. A phase I clinical trial to evaluate the safety of GRASPA is under enrollment and a biomarker assay for ASNS expression is being developed for patient stratification. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration ERYtech Pharma M. D. Anderson Cancer Center ERYtech Pharma
HDL causes mesangial cell mitogenesis through a tyrosine kinase-dependent receptor mechanism.
Authors: N I Neverov, G A Kaysen, R Nuccitelli, R H Weiss
Journal: Journal of the American Society of Nephrology (1997)

Hypercholesterolemia and mesangial cell proliferation have been proposed to play a role in the progression of glomerulosclerosis in diabetic nephropathy and other renal diseases. Although LDL is mitogenic for and cytotoxic to mesangial cells, the effect of HDL on these cells is unknown. HDL stimulates fibroblast mitogenesis and is the principal cholesterol-bearing lipoprotein in the rat, the experimental model for studying the effect of hyperlipidemia on renal disease. Insulin is mitogenic in several cell systems, and its levels are increased in serum in non-insulin-dependent diabetes mellitus. This study investigates whether HDL acts as a growth factor in mesangial cells and whether it functions in parallel with insulin. It was found that HDL at protein concentrations between 10 and 500 microg/ml, both alone and in the presence of 100 nM insulin, increased DNA synthesis in mesangial cells (129 to 165% of control for HDL alone; 140 to 235% for HDL plus insulin), whereas HDL at 1000 microg/ml and greater inhibited mesangial cell proliferation. Insulin alone at 100 nM stimulated [3H]thymidine incorporation in the same cell system (145% of control); the mitogenic effect of insulin was additive to that of HDL. Purified apo A-I had a similar effect, but at significantly lower concentrations. Specific binding of HDL to mesangial cells was demonstrated (B(max) [binding constant] of 5.19 +/- 0.70 x 10(-7) micromol of HDL bound/mg cell protein and K(b) of 2.83 +/- 0.22 nM). Tetranitromethane alters apo A-I, preventing binding to its cognate receptor. Tetranitromethane-modified HDL did not bind to mesangial cells and had no effect on [3H]thymidine incorporation. Addition of HDL to mesangial cells caused an immediate transient increase in free intracellular calcium in several representative mesangial cells, similar to the response seen with platelet-derived growth factor. The mitogenic effect of HDL was not altered after attenuation of cellular protein kinase C activity, but the stimulatory effect of HDL alone and in combination with insulin on DNA synthesis was completely eliminated after inhibition of cellular tyrosine kinases by 24-h pretreatment with 0.25 microM herbimycin A. Thus, HDL binds to a specific apo A-I-dependent receptor, promotes DNA synthesis, and initiates second-messenger events by a tyrosine kinase-dependent and protein kinase C-independent mechanism.
The Cryptic inv(2)(p23q35) Defines a New Molecular Genetic Subtype of ALK-Positive Anaplastic Large-Cell Lymphoma
Authors: Iwona Wlodarska, Chris De Wolf-Peeters, Brunangelo Falini, Gregor Verhoef, Stephan W. Morris, Anne Hagemeijer, Herman Van denBerghe
Journal: Blood (1998)
Predictors of clinical outcomes of weekly docetaxel in patients with advanced cancer
Authors: K. Charles, L. P. Rivory, M. Stockler, P. Beale, J. Beith, M. Boyer, S. Clarke
Journal: Journal of Clinical Oncology (2004)

2105 Background: Weekly administration of docetaxel is increasingly favoured because of a preferable toxicity profile. The pharmacokinetics of three weekly docetaxel predict the clinical outcomes of this regimen. However, to date there has been no investigation of such predictive factors with weekly docetaxel. Methods: Patients with advanced cancer suitable for palliative chemotherapy with weekly docetaxel were enrolled. All patients received 40mg/m2 docetaxel for 6 weekly doses in an 8-week cycle, or 3 weekly doses in 4 weeks. Pre-treatment clinical history, nutritional assessment and erythromycin breath test were conducted and blood collected for measurement of biochemistry and acute phase protein concentrations. Limited blood sampling for pharmacokinetic analysis was performed. Toxicities were graded according to NCI Common Toxicity Criteria. Overall survival was calculated from the start of treatment to death. Correlations were explored using multivariate Cox proportional hazard analysis. Results: From 2000 - 2003, 68 patients (M:F 29:39) were enrolled. The median age was 63 years and 64% of patients had ECOG PS 0–1. 27 patients (40%) experienced Grade 3/4 toxicity during cycle 1. Decreased docetaxel clearance (5% weight loss, p<0.001 HR: 3.75, 95%CI: 1.95–7.21) and increased alkaline phosphatase (p=0.002, HR:4.04, 95%CI: 1.67–9.75) were predictive of decreased survival. Conclusion: In patients treated with weekly docetaxel, decreased docetaxel clearance predicts patients with the highest risk of haematological toxicity. Evidence of acute inflammation, malnutrition or widely metastatic disease were predictive of poorer survival. Pre-treatment identification of these factors may enhance treatment outcomes. No significant financial relationships to disclose.
A phase I study of erlotinib and bevacizumab for recurrent or metastatic squamous cell carcinoma of the head and neck (HNC)
Authors: E. E. Vokes, E. E. W. Cohen, A. M. Mauer, T. G. Karrison, S. J. Wong, L. J. Skoog-Sluman, M. F. Kozloff, J. Dancey, A. Dekker
Journal: Journal of Clinical Oncology (2005)

5504 Background: We previously reported single agent activity for gefitinib in HNC (Cohen, JCO, 2003). EGFR activation can upregulate vascular endothelial growth factor (VEGF) which has been correlated with resistance to anti-EGFR agents. Therefore, we conducted a phase I-II study of the oral EGFR tyrosine kinase inhibitor (TKI), erlotinib with the monoclonal VEGF antibody, bevacizumab. Methods: Phase I trial at fixed dose of erlotinib 150 mg orally PO daily with escalation of bevacizumab to a maximum of 15 mg/kg q 3 weeks (Mauer, PASCO, 2003). During phase II, a two-stage accrual design was applied. Eligible pts had metastatic and/or recurrent incurable HNC with up to 1 prior chemotherapy regimen for recurrent disease, no prior EGFR or VEGF-based therapy, performance status > 60%, and normal organ and bone marrow function. Pts were excluded for tumors close to or encasing a major vessel, and a history of bleeding diathesis. Pts were randomized to receive the initial bevacizumab dose on either day 15 or day 1 of a daily schedule of erlotinib administration. Subsequent doses of bevacizumab were administered every 21 days. Results: Between 3/03 and 11/04, a total of 51 pts were entered; male, 76%, median age 58 (39–81), performance status 0: 14 pts, 1: 34 pts, and 2: 3 pts. 86% of pts had received prior chemotherapy. No dose limiting toxicities were observed during phase I. A total of 45 pts were treated at the phase II dose of erlotinib 150 mg PO daily and bevacizumab 15 mg/kg q 3 weeks. Cycle number ranged from 1–10. Toxicities include skin rash in 28 of 44 currently evaluated pts (grade 1: 18, grade 2: 10), diarrhea in 15 pts (grade 1: 10, grade 2: 3, grade 3: 2 pts); fatigue in 21 pts, and grade 4 hemorrhage in 1 pt. Best response is CR: 2 pt; PR: 3 pts; SD: 31 pts; PD: 11 pts, and too early: 4 pts. At the time of this analysis, a total of 30 pts have progressed or died. Median progression-free survival is 127 days (95% CI: 85 - 151 days); overall survival is 226 days. Conclusions: The combination of erlotinib and bevacizumab is well tolerated at the doses utilized in this study. The observed response/stable disease rate is encouraging. Mature data on TTP and OS will be available. (supported by NIH N01 CM-17102–01) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, Genentech/OSI Genentech Genentech/OSI NCI
Single/tandem autologous hematopoietic progenitor cell transplantation in high-risk de novo multiple myeloma patients: A retrospective analysis.
Authors: M. V. Martino, R. Fedele, G. Console, G. Irrera, G. Messina, C. Stelitano, M. Brugiatelli, C. Musolino, S. Molica, P. Iacopino
Journal: Journal of Clinical Oncology (2010)

8145 Background: High-dose melphalan (HDM) followed by autologous hematopoitic progenitor cell (HPC) support is widely used as intensification treatment in patients with multiple myeloma (MM) responsive to the initial chemotherapy. However, there is growing evidence that only the subset of patients who achieve complete remission (CR) actually benefit from this approach. Methods: In our bone marrow unit, in the last 12 years, 152 patients with Durie-Salmon stage II-III MM, were intended to undergo two sequential cycles of myeloablative chemotherapy with autologous hemopoietic stem cells (HPC) transplantation after response to primary chemotherapy. Treatment program based on 3 cycles VAD followed by cyclophosphamide 3-4 gr/mq for HPC collection. The preparative regimen was high-dose melphalan (HDM) 200 mg/mq for the first and second transplant with a three-four months interval. 63 patients uderwant a single HDM and 89 a tandem HDM. Results: The median follow up is 34 months (range 1-136). The overall survival (OS) and progression-free survival was 51 and 38 months, respectively. PFS and OS at 8 years was 32% and 45%, respectively. On an intent-to-treat basis, the OS and PFS was significantly higher in patients that underwant a tandem transplant (P = 0.0014 and P = 0.0001, respectively) and with a better response (compete remission/near complete remission) after the first transplant (P = 0.002, P = 0.02, respectively). The Cox analysis confirmed a significant association among the best response and clinical results. Conclusions: Our retrospective analysis show that that CR/nCR achievement is crucial for long-lasting response and prolonged survival after HDM and transplant. The use of the second HDM in the patients in CR/nCR remains of doubtful utility. No significant financial relationships to disclose.
Differential oxidative stress responses during 2-methoxyestradiol (2ME2) and dexamthasone (Dex)-induced apoptosis in multiple myeloma (MM) cells.
Authors: D Chauhan, GL Li, M Sattler, L Catley, R LeBlanc, N Mitsiades, C Mitsiades, N Munshi, P Richardson, T Hideshima, KC Anderson
Journal: Blood (2002)
Quality-of-life (QOL) evaluation for advanced non-small cell lung cancer (NSCLC): Comparison between vinorelbine and gemcitabine followed by docetaxel (VGD), and paclitaxel and carboplatin (PC) regimen on protocol JMTO LC00–03 (BRI LC03- 01)
Authors: H. Tada, A. Tokoro, R. Ishiwata, S. Teramukai, M. Fukushima, K. Kubota, M. Kawahara, K. Furuse
Journal: Journal of Clinical Oncology (2007)

18043 Background: JMTO LC00–03, a randomized trial of VGD versus PC in patients with advanced NSCLC, showed differences between the two treatment groups in response rate (25 vs 37.1%) and regimens’ specific toxicities including taxane-related toxicities such as numbness (0 vs 16.2%) and neuropathy (0.5 vs 9.6%), but not in overall survival (MST, 13.6 vs 14.1 mos) and progression-free survival (MST, 5.5 vs 5.8 mos). (Kawahara et al, # 7013, ASCO, 2006). Methods: Patients with advanced NSCLC were randomly assigned to VGD or PC. The patients were assessed with Functional Assessment of Cancer Therapy- FACT-L and FACT-Taxane score in baseline, and at 6-, 12-, 18-weeks after the treatment. The longitudinal analysis was used to compare mean changes of the QOL score over the two treatment groups. Results: Sixty-eight patients from the trial (VGD: 34, PC: 34) who submitted both baseline questionnaire and at least one questionnaire over the course of the treatment were subjects of the study. The table presents the estimated changes in mean scores in treatment arms over the time period. The longitudinal analysis showed significant difference in FACT-Taxane (p&lt;0.001) in the treatment over time, but no significant difference in the FACT-L score (p=0.261). The analysis assuming non-random missing mechanism resulted in slightly larger differences in the mean change. Conclusions: There was no statistically significant difference in FACT-L between the two groups, but VGD group was numerically better than PC group at any point from baseline. The significant difference in FACT-Taxane score favoring VGD would be due to the difference in frequency of neuropathy with docetaxel than with paclitaxel. [Table: see text] [Table: see text]
Phase I/II trial of carbon-ion therapy for patients with locally recurrent rectal cancer
Authors: S. Yamada, T. Kamada, S. Yasuda, H. Tsujii, T. Ochiai, K. Koda
Journal: Journal of Clinical Oncology (2005)

3638 Background: The rate of local recurrence(LR) for rectal cancer ranges from 10 to 40%. Most patients are referred for radiotherapy. Radiotherapy is generally considered palliative treatment. The purpose of this study is to evaluate the tolerance for and effectiveness of carbon ion radiotherapy in patients locally recurrent rectal cancer. Methods: Between April 2001 and September 2003, 33 lesions at 32 patients were enrolled onto this study. Criteria for trial eligibility were confirmation of locally recurrent rectal cancers without distant metastases by CT, MRI and PET findings and ECOG performance score 0,1,2. Contraindications for trial entry included pelvic bone destruction or infiltration into the bladder. Carbon beams of 290, 350 and 400 MeV/nucleon energy were generated in the HIMAC synchrotron. The dose was determined as 67.2GyE and escalated to 70.4GyE,73.6GyE. Of the 32 eligible patients, 16 were male and 16 female. Median age was 62.8 years. The predominant sites of relapse were 13 presacral, 11 lymph nodes. Toxicity on organs were assessed according to the NCI-CTC and RTOG/EOTRC classification. Tumor response was defined by the RESIST scoring system. Local recurrence was defined in terms of lesions occurring in the tumor bed. Survival curves were estimated by the Kaplan and Meier method. Results: Ten patients received radiation dose at 67.2GyE, fourteen at 70.4GyE and nine at 73.6GyE. All toxicities in the 33 lesions at 32 patients were relatively few and mild in these patients. No grade 3 to 5 acute and late toxicity was observed. Tumor response was evaluated in 33 lesions patients. CR was observed in 5 lesions and PR in 11. The local control rates in 33 lesions are 84.9% at one year and 81.5% at two years. Local control rates at one year were 70% at 67.2GyE, 85% at 70.4GyE and 100% at 73.6GyE. The one and two year overall survival rate were 90.3% and 72.0% respectively. In the literature, the reported two-year survival rates for locally recurrent rectal cancer treated with radiation were 20 to 40%. Conclusions: : Carbon ion radiotherapy seems to be a safe and effective modality in the management of locally recurrent rectal cancer, providing good local control and offering a survival advantage without acceptable morbidity. No significant financial relationships to disclose.
MGMT methylation testing in RTOG 0525: A phase III trial of newly diagnosed glioblastoma
Authors: K. D. Aldape, G. Jones, M. Wang, M. Hegi, R. C. Janzer, R. Stupp, M. P. Mehta, M. R. Gilbert
Journal: Journal of Clinical Oncology (2009)

2051 Background: MGMT promoter methylation has been described as a prognostic marker in glioblastoma (GBM) and may be associated with chemosensitivity to alkylating agents. This study determined the feasibility of real-time determination of MGMT promoter methylation testing in a large international phase III clinical trial. Methods: Paraffin tumor blocks were obtained from patients registered onto RTOG 0525 then distributed to one of two central pathology labs: MD Anderson (Houston TX, K. Aldape) or CHUV (Lausanne, CH, R. Janzer). After histologic confirmation of GBM, unstained slides (40 microns of tumor tissue) were sent to the testing laboratories. Results were used for randomization into a treatment arm. MGMT methylation was assessed using methylation specific real-time PCR (MSP). The assay determined the number of copies of both methylated MGMT and of beta-actin (ACTB) in the sample. The ACTB copy number was used to assess the quality and quantity of the sample DNA. Results: Results were available for 995 samples. Following MSP samples were categorized into one of five possible results: failed (2, 0.2%), methylated (302, 30.2%), non-methylated (602, 60.2%), indeterminate (62, 6.2%), and invalid (27, 2.7%). Among cases that were evaluable as either methylated or unmethylated (n = 904) the MGMT promoter methylation rate in newly diagnosed GBM was approximately 1/3 (33.4%), a rate that is somewhat lower than prior reports. The average time from receipt of sample at the central pathology laboratory to reporting of results was 9.3 days. The time required decreased over the course of the clinical trial. This was due, in part, to training of the sites to deliver samples just before the start of runs. Conclusions: The results demonstrate the feasibility of performing real-time MGMT methylation testing, a tumor based assay, as a stratification factor in a multinational clinical trial. This study confirms that treatment decisions based on the molecular characteristics of the tumor are feasible, thereby providing opportunities to develop more molecularly-based tumor stratification or selection, a major advance in developing personalized treatment regimens. No significant financial relationships to disclose.
What type of feedback to clinicians best improves conformance to supportive care quality measures?
Authors: Arif Kamal, Amy Pickar Abernethy, Janet Bull, Jonathan Nicolla, Joseph Kelly, Charles Steven Stinson, Martha Adams
Journal: Journal of Clinical Oncology (2013)

102 Background: Supportive care is under-addressed in oncology and an important area for quality improvement. Regular, directed feedback is an important component of effective quality management. What type of feedback yields the highest conformance to supportive care measures? Methods: Within the Carolinas Palliative Care Consortium, we conducted a series of three PDSA cycles, each one month-long, to evaluate various types of clinician-directed feedback on conformance to two supportive care measures. We collected data using a web-based, mobile health platform called QDACT-PC (Quality Data Collection Tool for Palliative Care). Every four weeks, feedback to clinicians on performance was changed in a stepwise fashion, from “no feedback” to “personal feedback” to “comparative feedback” (personal conformance compared to the rest of the Consortium). We monitored weekly changes to conformance to two quality measures: documentation of timely management of constipation and dyspnea. To meet the measures, symptoms with intensity of &gt;3/10 on the Edmonton Symptom Assessment Scale required documentation of intervention within 24 hours. Conformance rates were calculated and compared to a historical baseline. Results: 23 providers participated in this quality improvement project, which spanned 465 patient encounters across 104 unique patients. Baseline data generated from 3/2008-10/2011 demonstrated baseline conformance to the dyspnea and constipation measures at 6% (27/457) and 4% (14/398), respectively. After addition of an electronic, prospective quality monitoring system alone (QDACT-PC), conformance increased to 93% (42/45) and 92% (23/25), respectively. With personalized, weekly feedback, these rates increased to 94% for dyspnea and 100% for constipation. Feedback comparing personal performance to the average of the rest of the Consortium further increased this to 100% for both. Conclusions: Regular, weekly feedback on performance increases conformance to supportive care quality measures. Adding comparative feedback versus other peers solidifies this effect. Duration of the effect is being evaluated.