Prognostic Value of Serum Proteomic Test and Comorbidity Index in Diversified Population with Lung Cancer.

BACKGROUND: The usefulness of serum proteomic test (VeriStrat) in African-Americans with non-small cell lung cancer (NSCLC) as well as the relationship between comorbidity and test performance have not been studied. MATERIALS AND METHODS: We reviewed records of patients with NSCLC in our practice for whom VeriStrat was performed to assist with the selection of therapy. We correlated survival with VeriStrat test classification, race, and comorbidity index using SAS software 9.4. RESULTS: We identified 49 qualified patients; 33 with VeriStrat Good (VSG), 16 with VeriStrat Poor (VSP). When stratified by VSG vs. VSP, overall survival (OS) did not differ between African-Americans and Whites [hazard ratio (HR)test (VSG/VSP)=0.78, 95% confidence interval (CI)=0.38-1.61; p=0.51]. OS adjusted for mean Charlson Comorbidity Index (CCI) was not different between erlotinib- and chemotherapy-treated groups in patients with non-squamous NSCLC (adjusted HR=0.91, 95% CI= 0.37-2.23; p=0.84), but was inferior in patients with squamous NSCLC treated with erlotinib (adjusted HR=10.6, 95% CI=1.28-87.8; p=0.029). Cox proportional hazard model for OS effect of VeriStrat test was estimated after adjusting for CCI. In both the VSG and VSP groups, a higher CCI value was associated with lower survival, and at any CCI value, the VSG group had better survival than the VSP group. CONCLUSION: Our study corroborates that race does not influence prognostic and predictive values of VeriStrat; however, comorbidities have a significant impact on survival in each proteomic stratum.

In vitro characterization of oritavancin clearance from human blood by low-flux, high-flux, and continuous renal replacement therapy dialyzers.

BACKGROUND: Oritavancin is an investigational lipoglycopeptide antibiotic under clinical development for the treatment of gram-positive bacterial infections. The impact of hemodialysis on plasma concentrations of oritavancin is unknown and may be important in making dosage adjustments in such patients. The present study sought to determine the clearance of oritavancin from human blood by various commercially available dialyzers in an in vitro hemodialysis model. METHODS: Three types each of low-flux (Dicea 130, F6, and Polyflux 14L) and high-flux (Revaclear, Exeltra 150, and Optiflux F160NR) dialyzers and one type of continuous renal replacement therapy (CRRT) dialyzer (Prismaflex M100) were studied. Heparinized human blood containing oritavancin (200 mg/L) was circulated from a reservoir to the dialyzers and back to the reservoir. Fresh dialysate was pumped through the dialyzers in a countercurrent manner. Blood samples from each side of the dialyzers and contaminated dialysate samples were collected at periodic intervals. Oritavancin levels were analyzed by a liquid chromatography/mass spectrometry method with a limit of quantification of 12.5 ng/mL and plasma clearances of oritavancin were calculated. RESULTS: The mean dialytic clearance of oritavancin was insignificant for each of the low-flux, high-flux and CRRT dialyzers. Clinically significant amounts of oritavancin were not detected in dialysate during any of the experimental dialysis sessions. CONCLUSIONS: The clearance of oritavancin from human blood by the dialyzers used in this study is insignificant. Further clinical studies would be required before making changes in dosage of oritavancin in hemodialysis patients.

Human S-adenosylhomocysteine hydrolase: common gene sequence variation and functional genomic characterization.

S-Adenosylhomocysteine hydrolase (AHCY) is the only mammalian enzyme known to catalyze the hydrolysis of S-adenosylhomocysteine. We have used a genotype-to-phenotype strategy to study this important enzyme by resequencing AHCY in 240 DNA samples from four ethnic groups. Thirty-nine polymorphisms were identified - 28 of which were novel. Functional genomic studies for wild type AHCY and the three variant allozymes identified showed that two variant allozymes had slight, but significant decreases in enzyme activity, but with no significant differences in levels of immunoreactive protein. Luciferase reporter gene assays for common 5'-flanking region haplotypes revealed that one haplotype with a frequency of approximately 2% in Caucasian-American subjects displayed a decreased ability to drive transcription. The variant nucleotide at 5'-flanking region single nucleotide polymorphism (SNP) (-34) in that haplotype altered the DNA-protein binding pattern during electrophoresis mobility shift assay. Finally, an AHCY genotype-phenotype association study for expression in lymphoblastoid cells identified four SNPs that were associated with decreased expression. For the IVS6 (intervening sequence 6, i.e., intron 6) G56 > C SNP among those four, electrophoresis mobility shift assay showed that a C > G nucleotide change resulted in an additional shifted band. These results represent a step toward understanding the functional consequences of common genetic variation in AHCY for the regulation of neurotransmitter, drug and macromolecule methylation.

Dose escalating study of biweekly gemcitabine and carboplatin in patients with advanced cancer.

Combination chemotherapy with gemcitabine and carboplatin administered on a 3-week cycle is used commonly in the treatment of cancer. The purpose of our study was to establish a safe dose of combined gemcitabine and carboplatin when administered on a biweekly schedule to patients with advanced solid tumors. Gemcitabine was given intravenously over 30 minutes followed by carboplatin also given intravenously over 30 minutes once every 2 weeks (one cycle). Five dose levels were examined, ranging from gemcitabine at 1250 mg/m2 to 2000 mg/m2 and carboplatin at an area under the curve of 2.5 to 3.0. Twenty-six patients were studied (18 male and 8 female) with a median age of 57 years (range, 41-83 years); ECOG performance status was 0 or 1 in 22 patients (85%); median number of prior chemotherapy regimens was 2 (range, 0-4); median number of cycles administered per patient was 3 (range, 1-9) with a total of 89 cycles. Two dose-limiting toxicities were observed. Delay in treatment was seen in a total of 8 cycles with 6 of the delays due to myelosuppression. Grade 3 or 4 hematologic toxicity rates were as follows: anemia in one cycle (1%), neutropenia in 13 cycles (15%), and thrombocytopenia in one cycle of chemotherapy (1%). There were no hospitalizations for neutropenic fever. Mild fatigue was the most common nonhematologic toxicity. The median time to progression was 40 days (mean, 49 days; range, 4-133 days). Of the 21 evaluable patients, partial response or stable disease was observed in 11 (42%). The maximum tested dose of gemcitabine at 2000 mg/m2 and carboplatin at area under the curve of 3.0 was well tolerated on a biweekly schedule. Our findings indicate that further investigation of this biweekly regimen is warranted in patients with advanced cancer.

Skin rash and bronchoalveolar histology correlates with clinical benefit in patients treated with gefitinib as a therapy for previously treated advanced or metastatic non-small cell lung cancer.

BACKGROUND: Only 15% of patients with non-small cell lung cancer (NSCLC) treated with oral epidermal growth factor tyrosine kinase inhibitor gefitinib, as a second-line therapy have objective responses. Fifty percent will have improvement of lung cancer related symptoms. It will be critical to identify patients who will benefit clinically from this therapy even when there is no objective response seen on imaging studies. We have performed a retrospective analysis of 76 patients who received gefitinib as a therapy for previously treated metastatic NSCLC at the University of Minnesota Comprehensive Cancer Center in order to describe characteristics of patients who will likely derive benefits from gefitinib therapy. METHODS: All patients treated with gefitinib therapy at the University of Minnesota from September 2001 to January 2004 were entered into the study. The Log-rank Test and Cox proportional hazards regression were used to assess the effect of the number of previous therapy lines, histology subtype, performance status, gender, stage of disease at initial diagnosis, and presence of skin rash on time to disease progression and overall survival (OS). Fisher's Exact Test and multiple logistic regressions were used to assess the effect of these covariates on disease response. RESULTS: Seventy-six patients entered the study, with a median age of 60 years (range 37-82). There were 37 female and 39 male patients; 47 patients had adenocarcinoma, 22 had squamous and 7 had other NSCLC histologies. Six patients had no prior therapy, 23 had one, 32 had two, 8 had three, and 7 had four prior therapies for lung cancer. Fifty-six were current smokers. Median time to disease progression was 3 months (95% CI: 3.0, 6.0). There was no difference in time to disease progression whether patients had one or more prior therapies. Patients with brain metastases (26 patients) benefited from gefitinib therapy at least equally well as those without brain metastatic disease. Patients with adenocarcinoma histology with bronchoalveolar features had superior median time to progression versus other lung cancer histology (14 months versus 3 months, p=0.076), which translated into survival advantage in this group >24 months (95% CI: 0.76, 24+) versus 6.6 months (p=0.0096). Patients with EGFR positive tumors had median survival of 10.2 months (95% CI: 1.45, 16.94) versus 3.7 months (95% CI: 2.66, 4.74) with EGFR negative tumors. Patients who developed any degree of skin rash had prolonged time to disease progression with median of 6 months (95% CI: 2.56, 15.5) versus patients without skin rash median 3 months (95% CI: 1.43, 2.83) (p=0.023). This last factor was the best predictor of improved time to disease progression in multiple regression analysis (p=0.0405). CONCLUSION: A subgroup of patients with NSCLC will benefit from gefitinib therapy. Objective responses will likely be seen in half the patients with mutation of internal domain of EGFR; however, a larger group of patients will also enjoy prolonged disease stabilization and clinical benefit. We suggest that adenocarcinoma with bronchoalveolar features and the presence of skin rash may be used as predictors of gefitinib benefit.