tbuckley/cabot-search huggingface dataset:
Abstracts 624-854
Journal: Hepatology (2009)

Background: Cell derinved microparticles (MPs, <1.5 mum) originate from platelet and cell membrane lipid rafts and regulate inflammatory responses and thrombogenesis.In this study we aimed to evaluate the origin and impact of MPs in patients undergoing liver resection.Methods: A total of 30 patients undergoing liver resections were investigated.Plasma samples were collected at various time points up to postoperative day 5 and MPs were isolated via differential centrifugation.The impact of liver regeneration and ischemia and reperfusion injury was assessed by comparing extended versus standard resections and whether a pringle maneuver was used intraoperatively.Endothelial cell (CD31+), platelet (CD41+) and leukocyte (CD11b+) specific surface antigens distinguished the major sources of MPs.Impact of MPs on generation of thrombin was assessed with ELISA and compared to prothrombin time and thormbelastography.Results: Hematologic baseline characteristics between the groups compared were not significantly different.Significant changes in the fractions of MPs were only found during the surgical procedure and not during the postoperative course.Total numbers of CD31+ MPs were significantly elevated after 2 hours of operation compared to baseline values.In patients after extended hepatectomy (n=8) absolute numbers of MPs were significantly elevated for CD31+ MPs by a factor 4.0 (p=0.023), for CD41+ MPs by a factor 2.2 (p=0.016) and for Annexin V by a factor 2.5 (p=0.019)compared to standard and minor liver resections.Conversely CD11b+ MPs were slightly decreased to 0.53 for CD11b+ MPs (p=ns).After inflow occlusion the fraction of platelet derived CD41+ MPs was selectively elevated to 72.3±11% compared to 56.7±17% (p=0.035).MPs pro-coagulant activity was significantly elevated at postoperative day 1by a factor 2.2(p=0.007),compared to preoperative.Conclusion: These findings demonstrate an elevation of endothelial and platelet derived MPs in response to standard and extended liver resection.In patients with short term inflow occlusion the fraction of platelet derived MPs is specifically increased.These plasma MPs potentially represent a specific response to surgical stress and exhibit relevant intra-and postoperative thrombogenic properties.
Randomized trial and pharmacokinetic study of pegfilgrastim vs. filgrastim in children and young adults with newly diagnosed sarcoma treated with dose intensive chemotherapy
Authors: E. Fox, N. Jayaprakash, B. C. Widemann, D. Hawkins, R. Dagher, P. Mansky, C. Mackall, L. J. Helman, S. Steinberg, F. M. Balis
Journal: Journal of Clinical Oncology (2006)

9020 Background: Daily subcutaneous (SC) filgrastim reduces the duration of severe neutropenia in children receiving dose intensive chemotherapy. A single SC dose of pegfilgrastim may be as efficacious. Methods: We conducted a randomized, non-inferiority trial comparing neutrophil recovery, tolerability, and pharmacokinetics of pegfilgrastim (100 mcg/kg SC once/cycle) to filgrastim (5 mcg/kg SC daily until post nadir ANC &gt;10,000) in children and young adults with newly diagnosed sarcoma treated with vincristine, doxorubicin, and cyclophosphamide (VDC) for cycles 1, 2, 5, 9, 11, 13 alternating with etoposide and ifosfamide (IE) for cycles 3, 4, 6–8, 10, 12, 14. Local control with radiation or surgery was initiated after cycle 5. Serum GCSF concentrations were monitored during cycle 1 and measured by ELISA. Complete blood counts were monitored thrice weekly during cycles 1–4. Cycle duration was collected for all cycles. Results: Accrual has been completed. 34 patients (median age 19 y, range 3–25 y) were enrolled, 28 have completed 4 cycles, and 26 have completed therapy. Growth factor associated toxicity included reversible transaminase elevation and arthralgias and was similar on the 2 treatment arms. For filgrastim (n=13) the median (range) GCSF C max was 12 ng/mL (4–16 ng/mL), C ss was 7 ng/mL (2–9 ng/mL) and T max was 6 h (4–8 h). For pegfilgrastim (n=13), the median (range) GCSF C max was 69 ng/mL (11–235 ng/mL), C ss was 43 ng/mL (7–151 ng/mL) and T max was 28 h (4–168 h). Median (range) neutrophil recovery and cycle duration are presented in the table. Conclusion: Pegfilgrastim was well tolerated. Peak and steady state serum GCSF concentrations were higher in patients receiving pegfilgrastim but more variable. The number of days of severe neutropenia and the cycle duration with single dose pegfilgrastim appear to be at least equivalent to daily filgrastim. [Table: see text] No significant financial relationships to disclose.
MGMT promoter methylation status and DNA mismatch repair genes in paired primary and recurrent glioblastoma: A translational study of the German Glioma Network.
Authors: J. Tonn, J. Felsberg, N. Thon, S. Eigenbrod, M. Westphal, G. Schackert, M. Loeffler, F. Kreth, M. Weller, G. Reifenberger
Journal: Journal of Clinical Oncology (2010)

2076 Background: Hypermethylation of the MGMT promoter is strongly associated with longer progression-free and overall survival in glioblastoma patients. We here addressed the question whether glioblastoma relapses are associated with changes in the MGMT promoter methylation status or altered expression of the DNA mismatch repair genes, MLH1, MSH2, MSH6 and PMS2. Methods: MGMT promoter methylation status was analysed in paired primary and recurrent glioblastoma samples containing vital tumor of 80 patients using non-quantitative methylation-specific PCR (MSP). Quantitative promoter methylation analyses using DNA pyrosequencing were performed, too, for MGMT in 48 patients as well as for the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2 in 42 patients. Furthermore, levels of MGMT, MLH1, MSH2, MSH6 and PMS2 proteins were analysed semiquantitatively by immunohistochemistry in 42 patients. Results: MSP revealed MGMT promoter hypermethylation in 28 patients, borderline methylation in 3 patients and no methylation in 49 patients at diagnosis. In 71 of the 80 patients, the MGMT promoter status was retained at recurrence. In 7 patients, loss or reduction of MGMT promoter methylation was detected in the recurrent tumor, in 3 patients this finding was explained by low tumor cell contents in the recurrent tumor specimen. Two patients showed a change from unmethylated to borderline methylation and borderline methylation to hypermethylation, respectively. None of the investigated primary and recurrent glioblastomas showed MLH1, MSH2, MSH6 or PMS2 promoter hypermethylation. Immunohistochemical expression scores for MLH1, MSH2, MSH6 and PMS2 proteins were frequently reduced in the recurrent as compared with the corresponding primary tumor. Conclusions: The MGMT promoter methylation status does not change from the primary to the recurrent tumor in the vast majority of glioblastoma patients. Our results further suggest that glioblastoma recurrences often demonstrate lower MLH1, MSH2, MSH6 and/or PMS2 immunoreactivity scores. However, MLH1, MSH2, MSH6 and PMS2 promoter hypermethylation does not appear to be involved in glioblastoma recurrence. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Essex Pharma, Merck Serono, Roche
Impact of <sup>18</sup>F-flurodeoxyglucose positron emission tomography in the staging and treatment response assessment of extrapulmonary small cell cancer
Authors: S. M. Brennan, D. Gregory, A. Stillie, A. Herschtal, M. P. MacManus, D. L. Ball
Journal: Journal of Clinical Oncology (2009)

e14639 Background: To assess the frequency of use and impact of FDG PET in the management of extrapulmonary small cell carcinoma (EPSCC). Methods: Patients treated for EPSCC who had undergone FDG PET for staging or response assessment between 1985 and 2007 were identified from the institutional database and patient records. The PET result was compared to the conventional staging investigations and management decisions were recorded. Results: 22 patients had staging PET at diagnosis. All known disease was PET avid. Stage migration occurred in one patient. Additional disease without upstaging was noted in 3 patients. PET influenced management in 4/22 (18%) of cases, in one case changing from radical to palliative therapy, and in 3 cases altering radiation target volume. 21 patients had reassessment PET scans. There was disparity with conventional imaging in 8 cases. In 4 cases the PET was found to be correct, in 2 case the PET result was a false positive and 2 cases were not assessable. (Sensitivity 100%, specificity 80%.) PET resulted in a change in management in 25% of patients, in all cases discontinuing radical therapy in patients with persistent disease. Conclusions: PET contributes to both staging and restaging of EPSCC and may influence management in up to 25% of cases. No significant financial relationships to disclose.
Analysis of toxicity in a phase II study of sorafenib in soft tissue sarcoma (STS)
Authors: M. Keohan, D. D'Adamo, L. Qin, M. Saulle, L. Caltieri, S. Schuetze, J. J. Wright, G. Schwartz, R. Maki
Journal: Journal of Clinical Oncology (2007)

10061 Background: Sorafenib (BAY 43–9006) is an oral multi-targeted kinase inhibitor. Sorafenib causes dermatologic toxicity and hypertension, although the mechanisms are poorly understood. We observed significant toxicity requiring dose reductions in our phase II study of sorafenib in STS. Methods: 120 patients (40 M, 80 F; median age, 55 years) were treated between 10/05 and 12/06; accrual continues. All patients initially received sorafenib 400 mg BID. 118/120 registered patients were evaluable for toxicity. Clinical and laboratory variables were analyzed for association with dose reduction, using Kruskal-Wallis rank sum test for continuous variables and Fisher exact test for categorical variables. Variables significant at the p=0.05 level were further analyzed with a multivariate logistic regression model for their effects on dose reduction. Results: 53% of patients (63/118) required dose reductions, 53/63 for grade 2 or greater skin toxicity. Most common grade 3–4 drug-related toxicities included lymphopenia (14%), rash (12%), and hand-foot skin reaction (10%). Sex, height, weight, BSA and serum creatinine (Cr) were significantly associated with dose reduction by univariate analysis. Adjusting for sex and/or low serum Cr, BSA was not significantly associated with dose reduction. Sex and low serum Cr were borderline statistically significant predictors of dose reductions when both variables were included in a multivariate model. Only female sex remained a significant predictor when eliminating one outlier with BSA 2.83 (p=0.04). Conclusions: Female gender appears associated with skin toxicity, requiring dose reductions. Based on this multivariate analysis, a starting dose of 400 mg oral daily in women may limit side effects. Correlation with trough serum sorafenib levels is pending. This study is funded in part by NCI Grant P01-CA47179. No significant financial relationships to disclose.
Protease-Activated Receptor 1 (PAR-1) Is Required and Rate-Limiting for Thrombin-Enhanced Experimental Pulmonary Metastasis
Authors: Mary Lynn Nierodzik, Kui Chen, Kenichi Takeshita, Jian-Jun Li, Yao-Qi Huang, Xue-Sheng Feng, Michael R. D’Andrea, Patricia Andrade-Gordon, Simon Karpatkin
Journal: Blood (1998)
Circulating dendritic cells as a prognostic factor in patients with pancreatic cancer
Authors: H. Yanagimoto, S. Takai, S. Satoi, H. Toyokawa, K. Takahashi, N. Terakawa, K. Tanaka, A.-H. Kwon, Y. Kamiyama
Journal: Journal of Clinical Oncology (2004)

4097 Background.Pancreatic cancer is one of the cancers with very poor prognosis that might be associated with impaired host immune function. The aim of study is to determine whether circulating dendritic cell (CDC) number or function could be decreased in patients with pancreatic cancer, and to evaluate these changes before and after surgical resection or chemoradiotherapy (CRT). Moreover, we prospectively investigated the correlation between prognosis and CDC. Methods.We examined 53 patients with pancreatic cancer including 15 patients who underwent surgical resection, 20 patients who underwent CRT, 18 patients who underwent chemotherapy and 20 healthy control subjects. DC was purified from peripheral blood and analyzed by flow cytometry. DC was classified into two subsets: DC1 (myeloid DC population) and DC2 (lymphoid DC population). DC was tested for their ability to stimulate allogeneic T lymphocytes in a standard mixed leukocyte reaction as an indicator of DC function. The results were expressed as the ratio of the stimulatory index compared to that of healthy controls. CD4/8, NK cell activity, proliferative response of T lymphocytes (PHA) were also analyzed. Results. The number and function of DC1 were significantly reduced in cancer patients in comparison with controls (patients: 5914±3420cell/ml, 0.55±0.38, controls: 8995±6617cell/ml, 1.05±0.70, p<0.05). There were no significant differences in PBMC and lymphocyte subsets between them nor were there significant differences in PHA and NK cell activity. Allostimulatory activity of DC1 after surgical resection or after CRT was significantly increased from the pretreatment levels(0.60±0.32→1.05±0.37, 0.59±0.40→1.54±1.31, p<0.05). The DC1 number before treatment was significantly higher in patients with a survival period longer than 6 months than in patients with a shorter survival period (6110±3767cell/ml vs. 3727±2014cell/ml, p<0.05). Patients with DC1>3600cell/ml had a significantly longer median survival than those of the patients with DC1<3600(26 months vs. 5 months, P<0.05). Conclusion.The reduced number of CDC might be associated with a poor prognosis in patients with pancreatic cancer. No significant financial relationships to disclose.
A phase I/II, pharmacokinetic (PK) and pharmacogenomic (PG) study of weekly irinotecan (CPT-11) therapy for elderly patients with advanced non-small cell lung cancer
Authors: H. Isobe, N. Yamamoto, H. Kunikane, N. Masuda, K. Eguchi, M. Shibuya, Y. Takeda, T. Ogura, A. Yokoyama, M. Harada, K. Watanabe
Journal: Journal of Clinical Oncology (2007)

2539 Background: CPT-11 is commonly used to treat lung cancer, but there is little evidence about its efficacy in elderly patients. The aim of this study was to determine the recommended dose (RD) of CPT-11 for weekly administration to elderly patients, and to assess its efficacy and safety. In addition, a PK and PG study was performed to investigate the influence on the clinical outcome. Methods: CPT-11 was infused intravenously on Days 1 and 8 (every 21 days). In the phase I study, the dosage of CPT-11 was escalated from 60 (Level 1) to 80 (Level 2) and 100 mg/m 2 (Level 3). PK of CPT-11 and SN-38, and UGT1A1 polymorphism were analyzed during the first treatment cycle in the phase II study. Results: In the phase I study, 12 patients were enrolled (level 1/2/3=6/3/3) and the RD was determined to be 100 mg/m 2 . The 37 patients in phase II had the following characteristics: male/female=25/12, median age=77 (71–88), IIIB/IV=10/27, PS 0/1=12/25. The overall response rate and the disease control rate (PR+SD) was 8% and 73%, respectively. The median survival time was 441 days and the 1-year survival rate was 54.0%. Grade 3/4 neutropenia and diarrhea occurred in 27% and 8%, respectively. The AUCs for both CPT-11 and SN-38 were significantly correlated with neutropenia (P=0.0095, P=0.0004). Both the UGT1A1*6 and UGT1A1*28 genotypes were significantly correlated with the AUC ratio, leukopenia, and neutropenia ( Table ). Conclusion: CPT-11 monotherapy is considered to be effective for non-small cell lung cancer in elderly patients because good survival with tolerable adverse events were achieved. The UGT1A1*6 and UGT1A1*28 genotypes might both influence the toxicity of irinotecan in Asians. [Table: see text] [Table: see text]
A phase I study of pegylated liposomal doxorubicin + gemcitabine in a fixed dose-rate infusion for the treatment of patients with recurrent ovarian cancer
Authors: G. Crespo, M. Sierra, R. Losa, N. Villanueva, J. Fra, P. J. Fonseca, Y. Fernández, M. Capelán, J. P. Berros, A. J. Lacave
Journal: Journal of Clinical Oncology (2008)

5579 Background: Pegylated liposomal doxorubicin (PLD) constitutes the reference treatment for platinum-resistant (PR) ovarian cancer (OC). The combination of gemcitabine (G) + PLD seems to have additive activity in OC; however, it also has additive haematological toxicity, precluding administration of optimal dose of both drugs. Fixed dose-rate infusion (FDRI) of G improves haematological tolerance. Methods: We present data of a phase I trial using the combination of these two drugs, including G in this FDRI to ascertain whether we can enhance the therapeutic index of this combination. Inclusion criteria were: recurrent OC with a platinum-free interval <1 year, primary or secondary treatment with platinum, age < 80 years, Karnosky >60 and with normal organ function. The starting dose of G was 1500 mg/m2, 10 mg/m2 minute, q 2 weeks (± 250 mg G titration depending on toxicity) followed by PLD 35 mg/m2 q 4 weeks. Pharmacokinetic analyses were performed on days 1 and 15 of the first cycle. Results: From December 2005 to July 2007, 20 patients (pts) were enrolled. 5 were non-evaluable for toxicity due to early progression. In the first step, 4 (pts) were treated and 2 developed dose-limiting toxicity (DLT) consisting on grade 4 neutropenia and grade 3 stomatitis. In the next step G1250/PLD35, 5 pts have been included, 2 developed late grade 3 stomatitis and dermatitis. Heavily-pretreated pts (>6 cycles) and/or >70 years (frail pts) were treated with G1000/PLD35; to date 1 of 6 has presented grade 3 stomatitis. PLD did not affect the pharmacokinetic of G or its metabolites. Conclusions: In conclusion, the recommended dose for a phase II study in recurrent OC is G1250/PLD35, although dose reduction may be necessary due to late toxicity (being stomatitis and dermatitis the most common DLT). For frail pts, the recommended dose is G1000/PLD35. The study is ongoing in order to have more solid long-term toxicity data. Activity appears to be promising: 30.7% (4/13) objective response in PR OC (platinum-free interval < 6 months) and 85.8% (6/7) in pts with a platinum-free interval between 6–12 months. No significant financial relationships to disclose.
Factors influencing time to initiation of chemotherapy in elderly patients with diffuse large B-cell lymphoma (DLBCL)
Authors: C. Reyes, K. B. Knopf, M. Gleeson, M. Danese
Journal: Journal of Clinical Oncology (2008)

6630 Background: DLBCL is an aggressive lymphoma for which treatment should be initiated quickly. The purpose of this study is to identify factors associated with the time to initiation of chemotherapy and the incremental cost of care. Methods: We analyzed DLBCL patients diagnosed from 1998–2002 with 1 year of non-HMO coverage prior to diagnosis in the SEER-Medicare dataset. Time to initial chemoimmunotherapy (CT) and costs of care were identified through claims for inpatient, outpatient and physician services through 2005. Costs were compared to a random sample of non-cancer Medicare patients using linear regression. Time to CT was assessed using proportional hazards regression with censoring for death and end of coverage. Models were adjusted for age, race, gender, comorbidity score, year of diagnosis, region (cost model) and stage (time model). CT was classified using all claims after diagnosis. Results: There were 4,716 patients identified. The mean age at diagnosis was 77 years, 86% were white, 31% were stage IV and 53% were alive 12 months after diagnosis. The mean monthly cost for the first year after diagnosis was $8,003 higher in DLBCL patients than in typical Medicare patients. Only 7.164% of patients received CT within the follow up period. Median time to first CT was 57 days. The most common initial CT used was CHOP±R (63%). Older age and greater comorbidity burden were associated with longer times to first CT (p<0.01). Black and other race were also associated with a significantly longer time to first CT (p<0.01). Conclusions: DLBCL is associated with an increased incremental cost of care. The time to CT initiation was associated with several patient characteristics including age and race. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech, Inc. Genentech Genentech
Familial Aggregation of Multiple Myeloma and Its Precursor Monoclonal Gammopathy of Undetermined Significance (MGUS): A Population-Based Study in Sweden.
Authors: Sigurdur Y Kristinsson, Magnus Bjorkholm, Lynn R. Goldin, Cecilie Blimark, Ulf-Henrik Mellqvist, Anders Wahlin, Ingemar Turesson, Ola Landgren
Journal: Blood (2008)
Prognostic significance of immunohistochemical markers in non-small cell lung cancer
Authors: D. Renouf, R. Wood-Baker, D. Ionescu, S. Leung, H. Massoudi, B. Gilks, J. Laskin
Journal: Journal of Clinical Oncology (2006)

7211 Background: The purpose of this study is to use a large patient population to identify immunohistochemical (IHC) biomarkers to enable improved prognostication in patients with non-small cell lung cancer (NSCLC). Methods: A tissue microarray was constructed using duplicate 0.6 mm cores of formalin-fixed paraffin embedded tissue blocks from 609 patients with NSCLC. IHC was used to detect 11 biomarkers including EGFR, HER2, HER3, p53, p63, Bcl-1, Bcl-2, TTF-1, CEA, Ch, and SNP. A clinical database was created prospectively at the time of tissue collection. Survival outcomes were obtained from a Provincial Cancer Registry database. Results: Male to female ratio was 400:209; median age 63yrs (range 35–82); median survival 3.5yrs (mean 5.7). All specimens were reviewed: 243 adenocarcinoma (ACA), 272 squamous cell carcinoma (SCC), 35 large cell carcinoma, 32 non-small cell carcinoma NOS, and 6 other (giant cell carcinoma). 21 patients with other histologies were excluded. Survival data for 535 cases was available. As of June 2005, 429 patients (80%) had died; of these 286 (54%) died of lung cancer, 117 (22%) died of other known causes, and for 26 (5%) the cause of death was not available. Bcl-2 (p = 0.007) was the only biomarker to predict better overall survival (OS). Bcl-2 (p = 0.021) and p63 (p = 0.025) were significant for disease specific survival (DSS) in all NSCLC. Analysis of the subgroups indicated that p63 was significant (p = 0.039) for DSS in squamous cell carcinoma (SCC) but not for adenocarcinoma (ACA) (p = 0.81). Bcl-2 was not significant for DSS in either subgroup (p = 0.28 for SCC, p = 0.112 for ACA). EGFR expression was associated with improved DSS in SCC (p = 0.012) but not for ACA. Co-expression of EGFR-HER3 was more likely in SCC then in ACA (p = 0.033). There was no correlation between outcome and any combination or clustering of biomarkers. Conclusions: The biomarkers p63 and Bcl-2 are predictive of DSS in NSCLC. EGFR expression is predictive of DSS in SCC. Sub-classification of NSCLC by histopathology is important as the relevance of some biomarkers (EGFR) would be lost if pooled. p63, Bcl-2, and EGFR may be used as prognostic markers in patients with NSCLC. Co-expression of EGFR-HER3 is more likely in SCC then in ACA. This may help explain the differential response to EGFR inhibitors in SCC versus ACA. No significant financial relationships to disclose.