Molecular mechanism underlying the synergistic interaction between trifluorothymidine and the epidermal growth factor receptor inhibitor erlotinib in human colorectal cancer cell lines

The pyrimidine trifluorothymidine (TFT) inhibits thymidylate synthase (TS) and can be incorporated into the DNA. TFT, as part of TAS‐102, is clinically evaluated in phase II studies as an oral chemotherapeutic agent. Erlotinib is a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR) that is often deregulated in colorectal cancer. This study investigated molecular mechanisms underlying the cytotoxic actions of the combination of an EGFR?tyrosine kinase inhibitor with TFT in colorectal cancer cells Caco2, WiDR, Lovo92, and Colo320. Drug interactions were examined by the sulforhodamine B assay and subsequent combination index (CI) analyses, cell cycle effects by FACS analysis of propidium iodide stained cells, Akt, MAPK and EGFR phosphorylation and expression levels by Western blotting and TS activity by the TS in situ assay. All combination schedules were synergistic in wt‐EGFR expressing (but with mutated downstream pathways) WiDR and Lovo92 (CI 0.4–0.8) and very synergistic in Caco2 cells (with wt‐EGFR and functional downstream pathways; CI 0.1–0.3), but in EGFR‐lacking Colo320 cells, no additional activity was found (CI 1.0–1.2). Synergism was mostly related to the induction of cell cycle arrest and an erlotinib‐mediated inhibition of the pro‐survival signaling through Akt and MAPK that was activated (phosphorylated) by TFT. Erlotinib inhibited TS activity in EGFR‐expressing cell lines, probably due to cell cycle arrest in the G₁ phase. TS activity was slightly lower in the combinations, probably due to cell cycle interference. Taken together, the combination of erlotinib with TFT seems to present a potential strategy in the field of molecular therapeutics. (Cancer Sci 2009)     

A general method for elicitation,imputation, and sensitivity analysis for incomplete repeated binary data

We develop and demonstrate methods to perform sensitivity analyses to assess sensitivity to plausible departures from missing at random in incomplete repeated binary outcome data. We use multiple imputation in the not at random fully conditional specification framework, which includes one or more sensitivity parameters (SPs) for each incomplete variable. The use of an online elicitation questionnaire is demonstrated to obtain expert opinion on the SPs, and highest prior density regions are used alongside opinion pooling methods to display credible regions for SPs. We demonstrate that substantive conclusions can be far more sensitive to departures from the missing at random assumption (MAR) when control and intervention nonresponders depart from MAR differently, and show that the correlation of arm specific SPs in expert opinion is particularly important. We illustrate these methods on the iQuit in Practice smoking cessation trial, which compared the impact of a tailored text messaging system versus standard care on smoking cessation. We show that conclusions about the effect of intervention on smoking cessation outcomes at 8 week and 6 months are broadly insensitive to departures from MAR, with conclusions significantly affected only when the differences in behavior between the nonresponders in the two trial arms is larger than expert opinion judges to be realistic.     

Factors associated with completion of bowel cancer screening and the potential effects of simplifying the screening test algorithm

Background:

The primary colorectal cancer screening test in England is a guaiac faecal occult blood test (gFOBt). The NHS Bowel Cancer Screening Programme (BCSP) interprets tests on six samples on up to three test kits to determine a definitive positive or negative result. However, the test algorithm fails to achieve a definitive result for a significant number of participants because they do not comply with the programme requirements. This study identifies factors associated with failed compliance and modifications to the screening algorithm that will improve the clinical effectiveness of the screening programme.

Methods:

The BCSP Southern Hub data for screening episodes started in 2006–2012 were analysed for participants aged 60–69 years. The variables included age, sex, level of deprivation, gFOBt results and clinical outcome.

Results:

The data set included 1 409 335 screening episodes; 95.08% of participants had a definitively normal result on kit 1 (no positive spots). Among participants asked to complete a second or third gFOBt, 5.10% and 4.65%, respectively, failed to return a valid kit. Among participants referred for follow up, 13.80% did not comply. Older age was associated with compliance at repeat testing, but non-compliance at follow up. Increasing levels of deprivation were associated with non-compliance at repeat testing and follow up. Modelling a reduction in the threshold for immediate referral led to a small increase in completion of the screening pathway.

Conclusions:

Reducing the number of positive spots required on the first gFOBt kit for referral for follow-up and targeted measures to improve compliance with follow-up may improve completion of the screening pathway.     

Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized, placebo-controlled trials

BACKGROUND: Pamidronate therapy previously has been shown to reduce skeletal complications effectively for up to 12 months in breast carcinoma patients with bone metastases. The current study data provide further follow-up results regarding the effects of long term (up to 24 months) pamidronate treatment in women with breast carcinoma and osteolytic metastases. METHODS: Follow-up results from two prospective, multicenter, randomized, double-blind, placebo-controlled intervention trials conducted at academic and community oncology centers were combined to provide a large data set with which to evaluate the long term efficacy and safety of pamidronate therapy. Seven hundred fifty-four women with Stage IV breast carcinoma and osteolytic metastases were randomized to the 2 treatment arms of the trial. Three patients were excluded from the intent-to-treat population for the analysis. A total of 751 evaluable patients were randomized to receive either a 90-mg intravenous pamidronate infusion (367 patients) or a placebo infusion (384 patients) every 3-4 weeks. The primary outcome measures were skeletal morbidity rate (events/year), proportion of patients developing a skeletal complication, and time to first skeletal complication. RESULTS: Of the 367 women receiving pamidronate, 115 (31.3%) completed the trial and 81 (22.1%) discontinued the study due to adverse events. Of the 384 women who received placebo, 100 (26.0%) completed the study and 76 (19.8%) discontinued the study due to adverse events. The skeletal morbidity rate was 2.4 in the pamidronate group and 3.7 in the placebo group (P < 0.001). In the pamidronate group, 186 of the 367 patients (51%) had skeletal complications compared with 246 of the 384 patients in the placebo group (64%) (P < 0.001). The median time to first skeletal complication was 12.7 months in the pamidronate group and 7 months in the placebo group (P < 0.001). Six patients treated with pamidronate discontinued treatment due to drug-related adverse events. Pain and analgesic scores were significantly worse in the placebo group compared with those patients in the pamidronate group. CONCLUSIONS: In the current study, monthly infusions of 90 mg of pamidronate as a supplement to antineoplastic therapy were found to be well tolerated and superior to antineoplastic therapy alone in preventing skeletal complications and palliating symptoms for at least 24 months in breast carcinoma patients with osteolytic bone metastases.     

The mechanism of action of docetaxel (Taxotere®) in xenograft models is not limited to bcl-2 phosphorylation

Docetaxel is a new taxoid compound with a broad spectrum of antitumor activity. Previous studies have shown that in vitro treatment of specific human tumor lines with docetaxel is associated with the phosphorylation and inactivation of the bcl-2 protein and the occurrence of apoptosis. The goal of this study was to examine whether bcl-2 expression is truly required for in vivo responsiveness to docetaxel. The expression and state of phosphorylation of bcl-2 was examined in human MX-1 breast or DU-145 prostate tumors explanted from nu/nu mice treated with docetaxel. The MX-1 cells accumulated in the G2/M phase of the cell cycle and exhibited phosphorylation of bcl-2 after treatment with docetaxel. By Western blot analysis DU-145 prostate tumor cells did not express bcl-2 protein before or following in vivo treatment with docetaxel. However, docetaxel was highly active against the DU-145 tumor xenograft model. Thus, docetaxel induces apoptosis and cell death through a different, bcl-2-independent mechanism in the DU-145 human prostate tumor, indicating that bcl-2 may not have prognostic value for treatment with docetaxel.     

The pharmacokinetics and pharmacodynamics of zoledronic acid in cancer patients with varying degrees of renal function

An open-label pharmacokinetic and pharmacodynamic study of zoledronic acid (Zometa) was performed in 19 cancer patients with bone metastases and known, varying levels of renal function. Patients were stratified according to creatinine clearance (CLcr) into different groups of normal (CLcr > 80 mL/min), mildly (CLcr = 50-80 mL/min), or moderately/severely impaired (CLcr = 10-50 mL/min) renal function. Three intravenous infusions of 4 mg zoledronic acid were administered at 1-month intervals between doses. Plasma concentrations and amounts excreted in urine were determined in all subjects, and 4 patients were administered 14C-labeled zoledronic acid to assess excretion and distribution of drug in whole blood. In general, the drug was well tolerated by the patients. Mean area under the plasma concentration versus time curve and mean concentration immediately after cessation of drug infusion were lower, and mean amounts excreted in urine over 24 hours from start of infusion were higher in normal subjects than in those with impaired renal function (36% vs. 28% of excreted dose), although the differences were not significant. Furthermore, with repeated doses, there was no evidence of drug accumulation in plasma or changes in drug exposure in any of the groups, nor was there any evidence of changes in renal function status. Serum levels of markers of bone resorption (serum C-telopeptide and N-telopeptide) were noticeably reduced after each dose of zoledronic acid across all three renal groups. It was concluded that in patients with mildly to moderately reduced renal function, dosage adjustment of zoledronic acid is likely not necessary.     

Combined analysis of two multicenter, randomized, placebo-controlled studies of pamidronate disodium for the palliation of bone pain in men with metastatic prostate cancer.

PURPOSE: Bone metastases occur in approximately 80% of patients with advanced prostate cancer. Pain is common in these patients. The purpose of this study was to evaluate the effect of an intravenous bisphosphonate, pamidronate disodium, on pain control in metastatic prostate cancer patients. PATIENTS AND METHODS: Two multicenter, double-blind, randomized, placebo-controlled trials were conducted in patients with bone pain due to metastatic prostate cancer, with disease progression after first-line hormonal therapy. Intravenous pamidronate disodium (90 mg) or placebo was administered every 3 weeks for 27 weeks. Efficacy was measured via self-reported pain score (Brief Pain Inventory), analgesic use, the proportion of patients with a skeletal-related event (SRE; defined as pathologic fracture, radiation or surgery to bone, spinal cord compression, or hypercalcemia), and a pilot quantitative measurement of mobility. Laboratory evaluations included serum prostate-specific antigen, interleukin-6, bone alkaline phosphatase, and urinary bone resorption markers. RESULTS: Results of the two trials were pooled. There were no sustained significant differences between the pamidronate and placebo groups in self-reported pain measurements, analgesic use, proportion of patients with an SRE, or mobility at week 9 or 27. Urinary bone resorption markers were suppressed in the pamidronate group compared with placebo. CONCLUSION: Pamidronate disodium failed to demonstrate a significant overall treatment benefit compared with placebo in palliation of bone pain or reduction of SREs. Evaluation of more potent bisphosphonates in patients with prostate cancer is warranted.     

Neglected chronic disease: The WHO framework on non-communicable diseases and implications for the global poor

The current global framework on noncommunicable disease (NCD), as exemplified by the WHO Action Plan of 2012, neglects the needs of the global poor. The current framework is rooted in an outdated pseudo-evolutionary theory of epidemiologic transition, which weds NCDs to modernity, and relies on global aggregate data. It is oriented around a simplistic causal model of behaviour, risk and disease, which implicitly locates ‘risk’ within individuals, conveniently drawing attention away from important global drivers of the NCD epidemic. In fact, the epidemiologic realities of the bottom billion reveal a burden of neglected chronic diseases that are associated with ‘alternative’ environmental and infectious risks that are largely structurally determined. In addition, the vertical orientation of the framework fails to centralise health systems and delivery issues that are essential to chronic disease prevention and treatment. A new framework oriented around a global health equity perspective would be able to correct some of the failures of the current model by bringing the needs of the global poor to the forefront, and centralising health systems and delivery. In addition, core social science concepts such as Bordieu's habitus may be useful to re-conceptualising strategies that may address both behavioural and structural determinants of health.     

Sublethal and lethal toxicity of aluminum industry effluents to early developmental stages of the Crassostrea gigas oyster

The toxicity of the effluent from an aluminum plant on Crassostrea gigas oyster embryogenesis (lethal effects) and larval growth (sublethal effects) was tested. Liquid and solid phases of the effluent were separately tested, and effects of mixing during exposure were also evaluated. The effluent was highly toxic, causing abnormal embryogenesis at 0.03 to 1 g 1^–1 and reduced growth at 0.01 to 0.3 g/l. The solid fraction was markedly more toxic than the liquid fraction. Mixing during exposure consistently increased both lethal and sublethal toxicity. Considering the trace metal content of the effluent, Hg is suspected to be primarily responsible for the toxicity, although synergistic effects of Al, Fe, and Cr cannot be discarded. Experimental evidence shows that bioavailable metal species were present not only in the liquid phase as soluble ions, but most importantly, bound to sediment particles. Based on the present data, uncontrolled disposal of aluminum plant effluent may be a major hazard to the environment, involving early life stages and recruitment in marine biota.     

Radiation-induced esophageal carcinoma

Radiation-induced carcinoma of the esophagus is rare and only 8 cases have been reported since 1957. This article presents 2 additional patients in whom esophageal carcinoma developed in segments previously exposed to large therapeutic doses of irradiation. The first patient had received 5,000 rads to her mediastinum and the second patient 3,200 rads to her neck region. The latent intervals were 11 years and 30 years, respectively.