Citations

Abstract Background: Enzymatic creatinine assays are routinely used in clinical laboratories to provide more accurate estimated glomerular filtration rates and to avoid a perceived lack of analytical specificity associated with picrate (Jaffe) methods. Negative interferences with the enzymatic creatinine assay, which we noted in several patients on dopamine or dobutamine, prompted our further investigation into interference of catecholamines with enzymatic methods. Methods: Spiked solutions of dopamine, dobutamine, epinephrine, and norepinephrine were added to pooled sera at catecholamine concentrations consistent with clinically relevant dosing. Creatinine was measured enzymatically on the Roche P-Modular, Ortho Clinical Diagnostics Vitros 350, and Abbott i-STAT. Jaffe methods were performed on the Roche P-Modular and Siemens Dimension RxL. In 10 patients receiving dopamine and/or dobutamine via a venous or arterial line we evaluated and compared the extent of in vivo creatinine interference in paired serum samples obtained by venipuncture and from indwelling catheters. Results: All catecholamines caused significant negative interference with the Roche enzymatic creatinine assay, most pronounced for dopamine and dobutamine. The Vitros enzymatic assay demonstrated slight negative interferences, and i-STAT enzymatic and Jaffe methods were unaffected by the presence of catecholamines. Significant (P < 0.001) differences in creatinine concentrations by Roche enzymatic vs Jaffe methods were observed in venipuncture specimens compared with arterial or venous catheter specimens, suggesting dopamine and dobutamine reversibly adhere to the catheter lumen. Conclusions: Negative interferences were pronounced for Roche enzymatic results in blood samples obtained from indwelling catheters, a phenomenon not observed in peripheral draws. Physicians and laboratorians should be alert to the possibility of a falsely low creatinine result and reevaluate questionable samples using a method unaffected by catecholamines.

AbstractPurpose: This study aimed to investigate the expression of the ErbB family of receptor tyrosine kinases in pulmonary typical carcinoid and atypical carcinoid tumors and to understand the role of epidermal growth factor receptor (EGFR) signaling in pulmonary carcinoid tumor proliferation.Experimental Design: Surgically resected typical carcinoid (n = 24) and atypical carcinoid (n = 7) tumor tissues were analyzed by immunohistochemical staining for EGFR, ErbB2, ErbB3, and ErbB4. Sequencing of tumor DNA of exons 18 to 21 of the EGFR gene and the KRAS gene was carried out. Biochemical analysis of lung carcinoid cell lines was used to investigate EGFR signal transduction and response to erlotinib inhibition.Results: The analysis showed that 45.8% of typical carcinoid and 28.6% of atypical carcinoid tumors express EGFR, 100% of the tumors lack expression of ErbB2, and 100% have moderate to intense staining for ErbB3 and ErbB4. Sequencing of tumor DNA of exons 18 to 21 of the EGFR gene revealed the absence of tyrosine kinase domain mutations in these tumors. Instead, 80.6% tumors harbored a synonymous single nucleotide polymorphism in exon 20. Because EGFR and KRAS mutations tend not to be present at the same time, we sequenced the KRAS gene from pulmonary carcinoid tumor DNA and found that 100% were wild-type. Using a lung carcinoid cell line that expresses EGFR, we found that erlotinib reduced proliferation by inhibiting EGFR signal transduction.Conclusions: Our findings suggest clinical potential for the use of EGFR inhibitors in the treatment of patients with pulmonary carcinoid tumors, particularly for patients with EGFR-positive pulmonary carcinoid tumors not amenable to surgical resection.

Purpose To determine the maximum-tolerated radiation-absorbed dose (RAD) to critical organs delivered by yttrium-90 (90Y) ibritumomab tiuxetan in combination with high-dose carmustine, etoposide, cytarabine, and melphalan (BEAM) chemotherapy with autologous transplantation. Patients and Methods Eligible patients had relapsed or refractory CD20+ non-Hodgkin's lymphoma (NHL). Individualized 90Y activities were based on dosimetry and were calculated to deliver cohort-defined RAD (1 to 17 Gy) to critical organs with three to six patients per cohort. The therapeutic dose of 90Y ibritumomab tiuxetan was followed by high-dose BEAM and autologous transplantation. Results Forty-four patients were treated. Thirty percent of patients had achieved less than a partial remission to their most recent therapy and would not have been eligible for autologous transplantation at most centers. The toxicity profile was similar to that associated with high-dose BEAM chemotherapy. Two dose-limiting toxicities occurred at the 17 Gy dose level, which made 15 Gy the recommended maximum-tolerated RAD. Although eight patients received at least twice the conventional dose of 0.4 mCi/kg, a weight-based strategy at 0.8 mCi/kg would have resulted in a wide range of RAD; nearly 25% of patient cases would have received 17 Gy or more, and many would have received less than 10 Gy. With a median follow-up of 33 months for all patients, the estimated 3-year progression-free and overall survivals were 43% and 60%, respectively. Conclusion Dose-escalated 90Y ibritumomab tiuxetan may be safely combined with high-dose BEAM with autologous transplantation and has the potential to be more effective than standard-dose radioimmunotherapy. Careful dosimetry is required to avoid toxicity and undertreatment.

Abstract Radiation has been shown to up-regulate gene expression from adenoviral vectors in previous studies. In the current study, we show that radiation-induced dsDNA breaks and subsequent signaling through the mitogen-activated protein kinase (MAPK) pathway are responsible, at least in part, for this enhancement of transgene expression both in vitro and in vivo. Inhibitors of ataxia-telangiectasia–mutated, poly(ADP-ribose) polymerase–mutated, and DNA-dependent protein kinase (DNA-PK)–mediated DNA repair were shown to maintain dsDNA breaks (γH2AX foci) by fluorescence-activated cell sorting and microscopy. Inhibition of DNA repair was associated with increased green fluorescent protein (GFP) expression from a replication-defective adenoviral vector (Ad-CMV-GFP). Radiation-induced up-regulation of gene expression was abrogated by inhibitors of MAPK (PD980059 and U0126) and phosphatidylinositol 3-kinase (LY294002) but not by p38 MAPK inhibition. A reporter plasmid assay in which GFP was under the transcriptional control of artificial Egr-1 or cytomegalovirus promoters showed that the DNA repair inhibitors increased GFP expression only in the context of the Egr-1 promoter. In vivo administration of a water-soluble DNA-PK inhibitor (KU0060648) was shown to maintain luciferase expression in HCT116 xenografts after intratumoral delivery of Ad-RSV-Luc. These data have important implications for therapeutic strategies involving multimodality use of radiation, targeted drugs, and adenoviral gene delivery and provide a framework for evaluating potential advantageous combinatorial effects. [Cancer Res 2008;68(23):9771–8]

Abstract Background: The International Lung Cancer Consortium was established in 2004. To clarify the role of DNA repair genes in lung cancer susceptibility, we conducted a pooled analysis of genetic variants in DNA repair pathways, whose associations have been investigated by at least 3 individual studies. Methods: Data from 14 studies were pooled for 18 sequence variants in 12 DNA repair genes, including APEX1, OGG1, XRCC1, XRCC2, XRCC3, ERCC1, XPD, XPF, XPG, XPA, MGMT, and TP53. The total number of subjects included in the analysis for each variant ranged from 2,073 to 13,955 subjects. Results: Four of the variants were found to be weakly associated with lung cancer risk with borderline significance: these were XRCC3 T241M [heterozygote odds ratio (OR), 0.89; 95% confidence interval (95% CI), 0.79-0.99 and homozygote OR, 0.84; 95% CI, 0.71-1.00] based on 3,467 cases and 5,021 controls from 8 studies, XPD K751Q (heterozygote OR, 0.99; 95% CI, 0.89-1.10 and homozygote OR, 1.19; 95% CI, 1.02-1.39) based on 6,463 cases and 6,603 controls from 9 studies, and TP53 R72P (heterozygote OR, 1.14; 95% CI, 1.00-1.29 and homozygote OR, 1.20; 95% CI, 1.02-1.42) based on 3,610 cases and 5,293 controls from 6 studies. OGG1 S326C homozygote was suggested to be associated with lung cancer risk in Caucasians (homozygote OR, 1.34; 95% CI, 1.01-1.79) based on 2,569 cases and 4,178 controls from 4 studies but not in Asians. The other 14 variants did not exhibit main effects on lung cancer risk. Discussion: In addition to data pooling, future priorities of International Lung Cancer Consortium include coordinated genotyping and multistage validation for ongoing genome-wide association studies. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3081–9)