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2.  NCCAM/NCI Phase 1 Study of Mistletoe Extract and Gemcitabine in Patients with Advanced Solid Tumors 
Purpose. European Mistletoe (Viscum album L.) extracts (mistletoe) are commonly used for cancer treatment in Europe. This phase I study of gemcitabine (GEM) and mistletoe in advanced solid cancers (ASC) evaluated: (1) safety, toxicity, and maximum tolerated dose (MTD), (2) absolute neutrophil count (ANC) recovery, (3) formation of mistletoe lectin antibodies (ML ab), (4) cytokine plasma concentrations, (5) clinical response, and (6) pharmacokinetics of GEM. Methods. Design: increasing mistletoe and fixed GEM dose in stage I and increasing doses of GEM with a fixed dose of mistletoe in stage II. Dose limiting toxicities (DLT) were grade (G) 3 nonhematologic and G4 hematologic events; MTD was reached with 2 DLTs in one dosage level. Response in stage IV ASC was assessed with descriptive statistics. Statistical analyses examined clinical response/survival and ANC recovery. Results. DLTs were G4 neutropenia, G4 thrombocytopenia, G4 acute renal failure, and G3 cellulitis, attributed to mistletoe. GEM 1380 mg/m2 and mistletoe 250 mg combined were the MTD. Of 44 patients, 24 developed nonneutropenic fever and flu-like syndrome. GEM pharmacokinetics were unaffected by mistletoe. All patients developed ML3 IgG antibodies. ANC showed a trend to increase between baseline and cycle 2 in stage I dose escalation. 6% of patients showed partial response, 42% stable disease. Median survival was 200 days. Compliance with mistletoe injections was high. Conclusion. GEM plus mistletoe is well tolerated. No botanical/drug interactions were observed. Clinical response is similar to GEM alone.
doi:10.1155/2013/964592
PMCID: PMC3826324  PMID: 24285980
3.  Aryl hydrocarbon receptor expression is associated with a family history of upper gastrointestinal cancer in a high risk population exposed to aromatic hydrocarbons 
Background
Polycyclic aromatic hydrocarbon (PAH) exposure is a risk factor for esophageal squamous cell carcinoma (ESCC), and PAHs are ligands of the aryl hydrocarbon receptor (AhR). This study measured the expression of AhR and related genes in frozen esophageal cell samples from patients exposed to different levels of indoor air pollution, who did or did not have high-grade squamous dysplasia (HGD), and who did or did not have a family history (FH) of upper gastrointestinal cancer (UGI Ca).
Methods
147 samples were evaluated, including 23 (16%) from patients with HGD and 48 (33%) from patients without DYS who heated their homes with coal, without a chimney (a “high” indoor air pollution group), and 27 (18%) from patients with HGD and 49 (33%) from patients without DYS who did not heat their homes at all (a “low” indoor air pollution group). Nearly half (64 (44%)) had a FH of UGI Ca. RNA was extracted and Quantitative-PCR analysis was performed.
Results
AhR gene expression was detectable in 85 (58%) of the samples, and was more than 9-fold higher in those with a FH of UGI Ca (median expression (IQR) -1964 (-18000, -610) versus -18000 (-18000, -1036) Wilcoxon P = 0.02). Heating status, dysplasia category, age, gender, and smoking were not associated with AhR expression (linear regression, all P-values ≥0.1).
Conclusion
AhR expression was higher in patients with a FH of UGI Ca. Such individuals may be more susceptible to the deleterious effects of PAH exposure, including PAH-induced cancer.
doi:10.1158/1055-9965.EPI-08-1098
PMCID: PMC2796959  PMID: 19690180
Gastrointestinal tract cancer; Esophagus; Aryl hydrocarbon receptor; family history of cancer; gene expression; polycyclic aromatic hydrocarbons
4.  Total and Cancer Mortality After Supplementation With Vitamins and Minerals: Follow-up of the Linxian General Population Nutrition Intervention Trial 
Background
The General Population Nutrition Intervention Trial was a randomized primary esophageal and gastric cancer prevention trial conducted from 1985 to 1991, in which 29 584 adult participants in Linxian, China, were given daily vitamin and mineral supplements. Treatment with “factor D,” a combination of 50 μg selenium, 30 mg vitamin E, and 15 mg beta-carotene, led to decreased mortality from all causes, cancer overall, and gastric cancer. Here, we present 10-year follow-up after the end of active intervention.
Methods
Participants were assessed by periodic data collection, monthly visits by village health workers, and quarterly review of the Linxian Cancer Registry. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the cumulative effects of four vitamin and mineral supplementation regimens were calculated using adjusted proportional hazards models.
Results
Through May 31, 2001, 276 participants were lost to follow-up; 9727 died, including 3242 from cancer (1515 from esophageal cancer and 1199 from gastric cancer). Participants who received factor D had lower overall mortality (HR = 0.95, 95% CI = 0.91 to 0.99; P = .009; reduction in cumulative mortality from 33.62% to 32.19%) and gastric cancer mortality (HR = 0.89, 95% CI = 0.79 to 1.00; P = .043; reduction in cumulative gastric cancer mortality from 4.28% to 3.84%) than subjects who did not receive factor D. Reductions were mostly attributable to benefits to subjects younger than 55 years. Esophageal cancer deaths between those who did and did not receive factor D were not different overall; however, decreased 17% among participants younger than 55 (HR = 0.83, 95% CI = 0.71 to 0.98; P = .025) but increased 14% among those aged 55 years or older (HR = 1.14, 95% CI = 1.00 to 1.30; P = .47). Vitamin A and zinc supplementation was associated with increased total and stroke mortality; vitamin C and molybdenum supplementation, with decreased stroke mortality.
Conclusion
The beneficial effects of selenium, vitamin E, and beta-carotene on mortality were still evident up to 10 years after the cessation of supplementation and were consistently greater in younger participants. Late effects of other supplementation regimens were also observed.
doi:10.1093/jnci/djp037
PMCID: PMC2664089  PMID: 19318634
5.  Over-Expression of CDC25B and LAMC2 mRNA and Protein in Esophageal Squamous Cell Carcinomas and Pre-Malignant Lesions in Subjects from a High-Risk Population in China 
Molecular events associated with the initiation and progression of esophageal squamous cell carcinoma (ESCC) remain poorly understood, but likely hold the key to effective early detection approaches for this almost invariably fatal cancer. CDC25B and LAMC2 are two promising early detection candidates emerging from new molecular studies of ESCC. To further elucidate the role of these two genes in esophageal carcinogenesis, we performed a series of studies to: (i) confirm RNA over-expression; (ii) establish the prevalence of protein over-expression; (iii) relate protein over-expression to survival; and (iv) explore their potential as early detection biomarkers. Results of these studies indicated that CDC25B mRNA was over-expressed (≥2-fold over-expression in tumor compared to normal) in 64% of the 73 ESCC cases evaluated, while LAMC2 mRNA was over-expressed in 89% of cases. CDC25B protein expression was categorized as positive in 59% (144/243) of ESCC cases on a tumor tissue microarray, and non-negative LAMC2 patterns of protein expression were observed in 82% (225/275) of cases. Multivariate-adjusted proportional hazard regression models showed no association between CDC25B protein expression score and risk of death (Hazard Ratio [HR] for each unit increase in expression score = 1.00, P=0.90), however, several of the LAMC2 protein expression patterns strongly predicted survival. Using the cytoplasmic pattern as the reference (the pattern with the lowest mortality), cases with a diffuse pattern had a 254% increased risk of death (HR=3.52, P=0.007), cases with no LAMC2 expression had a 169% increased risk of death (HR=2.69, P=0.009), and cases with a peripheral pattern had a 130% greater risk of death (HR=2.30, P=0.02). CDC25B protein expression scores in subjects with esophageal biopsies diagnosed as normal (n=35), dysplastic (n=23), or ESCC (n=32) increased significantly with morphologic progression. For LAMC2, all normal and dysplastic patients had a continuous pattern of protein expression, while all ESCCs showed alternative, non-continuous patterns. This series of studies showed that both CDC25B and LAMC2 over-express RNA and protein in a significant majority of ESCC cases. The strong relation of LAMC2 pattern of protein expression to survival suggests a role in prognosis, while CDC25B’s association with morphologic progression indicates a potential role as an early detection marker.
doi:10.1158/1055-9965.EPI-06-0666
PMCID: PMC2729558  PMID: 18559558
esophageal cancer; quantitative RT-PCR; tissue microarray; survival; early detection; CDC25B; LAMC2

Results 1-5 (5)