The effects of managed care and competition on community-based clinical research

BACKGROUND: The National Institutes of Health is developing practice-based clinical research networks (PBRNs) to expedite the pace of scientific discovery and improve care quality. Anecdotal evidence suggests managed care penetration and provider competition negatively affect PBRN clinical research. OBJECTIVE: The objective of this study is to examine the effects of environmental factors on clinical research performance in the National Cancer Institute's Community Clinical Oncology Program (CCOP). RESEARCH DESIGN: This study examined 49 CCOPs in 34 states using longitudinal (1991-2001) generalized least-squares regression including fixed effects, using secondary data from the National Cancer Institute, Group Health Association of America, InterStudy, American Hospital Association, Area Resource Files, and the Current Population Survey. MEASURES: Performance was measured as CCOP-level accrual in treatment trials, cancer prevention and control (CP/C) trials, and all trials combined. HMO penetration served as a proxy for managed care penetration. Competition measures included both hospital competition and physician competition. RESULTS: Managed care penetration was positively associated with accrual in areas of low to moderate penetration and negative in the areas of high penetration. Compared with areas with 5% penetration, areas with 15% penetration had 21% more treatment accrual and 66% more CP/C accrual. Compared with areas with 40% penetration, areas with 50% penetration had 11% lower treatment accrual and 3% lower CP/C accrual. CP/C accrual was more positively affected than treatment accrual. Greater hospital competition was associated with a decline in trial enrollment. CONCLUSIONS: The healthcare environment appears to have a significant effect on accrual into community-based cancer treatment and CP/C clinical trials. Findings for treatment and CP/C accrual suggest each type of accrual is distinct and requires different strategies and administrative methods.     

The effect of the APOE polymorphism on HDL-C concentrations depends on the cholesterol ester transfer protein gene variation in a Southern European population

BACKGROUND: Apolipoprotein E (ApoE) locus has consistently shown a significant association with low-density lipoprotein cholesterol (LDL-C). However, its impact on high-density lipoprotein cholesterol (HDL-C) has been highly controversial suggesting that it may be context-dependent. We examined the gene-gene interaction between the common ApoE and the CETP polymorphisms in determining HDL-C concentrations in men and women from the general population. METHODS: 550 unrelated Caucasian subjects were randomly selected from a Mediterranean Region in Spain. Plasma lipids, anthropometric, clinical and lifestyle variables were measured. Common ApoE and CETP-TaqIB polymorphisms were determined. RESULTS: We have found a gene-gene interaction between and ApoE and the CETP loci in determining HDL-C concentrations. Thus, after adjustment for gender, age, body mass index, tobacco smoking, alcohol consumption, physical exercise and medication, carriers of the E4 allele had lower HDL-C concentrations [mean and (standard error): 40.1 (2.6) mg/dL] than E2 subjects [47.7 (3.2) mg/dL; p=0.019], and even lower than those of the E3 subjects [44.7 (1.4) mg/dL; p=0.042], only if they had the B1B1 genotype. However, mean HDL-C concentrations were higher among those with E4 allele carrying the B2 allele at the CETP gene locus [50.5 (2.3) mg/dL], and lower among E2 subjects carrying the B2 allele [45.5 (2.6) mg/dL]. This interaction was observed in both men and women. This gene-gene interaction remained statistically significant even after additional adjustment for triglycerides. CONCLUSIONS: The effect of the ApoE polymorphism on HDL-C concentrations depends on the CETP polymorphism, explaining some of the controversial results previously reported for this polymorphism.     

The NK-1 receptor antagonist aprepitant as a broad spectrum antitumor drug

Aprepitant is a selective high-affinity antagonist of human substance P (SP)/Neurokinin-1 (NK-1) receptors. Until now this drug has been used as anxiolytic, antidepressant and antiemetic. It has been demonstrated that SP induces cell proliferation and NK-1 receptor antagonists different to aprepitant inhibit growth in several human cancer cell lines, where NK-1 receptors are overexpressed. The purpose of this study is to demonstrate the antitumor action of aprepitant. We performed an in vitro study of the growth inhibition capacity of the NK-1 receptor antagonist aprepitant against glioma, neuroblastoma, retinoblastoma and pancreas, larynx, gastric and colon carcinomas cell lines. Coulter counter was used to determine viable cell numbers followed by application of the MTS colorimetric method. Furthermore, a DAPI method was applied to demonstrate apoptosis. We have demonstrated: aprepitant at (5–70 μM) concentration elicits growth cell inhibition in a concentration dependent manner in all tumor cell line studied. Maximum inhibition (100%) was observed when the aprepitant was administered at a concentration of ≥70 μM in all tumor cell lines studied. The specific antitumor action of aprepitant occurs through the NK-1 receptor and tumor cells death was by apoptosis pathway. These findings reported here for the first time indicate that aprepitant is a new and promising broad spectrum antitumor drug in the treatment of cancer.     

Hyperandrogenism does not predispose patients to photoepilatory treatment failure: a single-center review

Studies have suggested that patients with PCOS tend to be more treatment resistant to light-mediated depilation compared with their non-PCOS counterparts. We conducted a retrospective assessment of 29 hirsute patients treated between January 2006 and February 2007 to assess whether those with unsatisfactory hair clearance after treatment with intense pulsed light (IPL) were predominantly hyperandrogenic. The number of IPL sessions was also recorded for those patients failing to improve on treatment. Seventy-six percent had satisfactory hair clearance where hyperandrogenic patients dominated. All patients required an average of six treatments before discharge. Eighty-eight percent of poor responders were normoandrogenic. Our hyperandrogenic cohort appeared more responsive to IPL than the normoandrogenic patients. From our observations, the presence of hyperandrogenism does not indicate treatment resistance. This standpoint is unique and warrants a randomized trial directly comparing the two groups to investigate whether a positive or negative relationship actually exists.     

Structural reassignment of a marine metabolite from a binaphthalenetetrol to a tetrabrominated diphenyl ether

The structure of a reported natural product isolate has been revised from (S)-2,2'-dimethoxy-[1,1'-binaphthalene]-5,5',6,6'-tetraol to a known tetrabrominated diphenyl ether. After total synthesis of the reported binaphthalenetetrol was accomplished via a key reduction of a binaphtho-ortho-quinone, comparison of the physical properties and NMR spectroscopic data of the synthetic material indicated that the structure of the natural product isolate was incorrect. Evaluation of the authentic natural product suggested the structure is a tetrabrominated diphenyl ether, likely 3,5-dibromo-2-(3,5-dibromo-2-methoxyphenoxy)phenol.     

Development and validation of a GC/IT-MS method for simultaneous quantitation of para and meta-synephrine in biological samples

After the FDA's ban of ephedrine-containing supplements, Citrus aurantium appeared as an alternative to ephedra in herbal weight loss products. Synephrine, the most abundant active component of C. aurantium, exists in three different structural or positional isomeric forms (ortho—o-, meta—m-, and para—p-). Dietary supplements contain m- and p-synephrine, both α-adrenergic agonists,while the m-isoform is the most potent at α₁-adrenoreceptors. In spite of the pharmacokinetic and toxicological interest in the study of these compounds, adequate methods for their quantification in biological samples are yet to be developed. Thus, in the present study, a sensitive gas chromatography–ion trap mass spectrometry (GC/IT-MS) method was developed and validated for the simultaneous quantitation of m- and p-synephrine in a cellular matrix after solid phase extraction (SPE). The validation of the method was performed through the evaluation of the following parameters: selectivity, linearity, specificity, precision, accuracy, limit of detection, limit of quantification, and recovery. The method's applicability was studied in two different biological matrices by evaluating p- and m-synephrine uptake in Caco-2 cells and also in freshly isolated cardiomyocytes from adult rat. The developed GC/IT-MS method was shown to be selective, accurate, precise, and valid for simultaneous determination of p- and m-synephrine in biological samples.     

In vitro susceptibility of Achromobacter spp. isolates: comparison of disk diffusion,Etest and agar dilution methods

In this study, we analysed the antimicrobial susceptibility of 92 strains of Achromobacter spp. isolated from clinical samples to 18 antimicrobial agents. The disk diffusion method and Etest were compared with the agar dilution method, and the breakpoints of susceptibility and resistance for the disk diffusion method for the antimicrobials tested were determined. The most active antibiotics were piperacillin, piperacillin/tazobactam and the carbapenems. By applying the linear least-squares regression method, breakpoints could be established for antibiotics active against this genus such as imipenem, meropenem, ertapenem and trimethoprim/sulfamethoxazole (SXT). Other active antibiotics, such as piperacillin and minocycline, could be tested by the Etest method. The less active antibiotics such as gentamicin, doxycycline and tetracycline could be tested by the disk diffusion method. For the rest of the antimicrobial agents tested, breakpoints could not be established owing to the high percentage of errors and/or the poor linear regression coefficient obtained. Therefore, these antimicrobial agents should be tested by minimal inhibitory concentration determination. In summary, we recommend the following zone diameter breakpoints for resistant and susceptible, respectively: ≤11 mm and ≥22 mm for imipenem; ≤13 mm and ≥24 mm for meropenem; ≤17 mm and ≥24 mm for ertapenem; ≤15 mm and ≥21 mm for gentamicin; ≤27 mm and ≥28 mm for SXT; ≤20 mm and ≥29 mm for tetracycline; and ≤20 mm and ≥24 mm for doxycycline.     

Stathmin expression and its relationship to microtubule-associated protein tau and outcome in breast cancer

BACKGROUND:

Microtubule‐associated proteins (MAPs) endogenously regulate microtubule stability. Here, the prognostic value of stathmin, a destabilizing protein, was assessed in combination with MAP‐tau, a stabilizing protein, in order to evaluate microtubule stabilization as a potential biomarker.

METHODS:

Stathmin and MAP‐tau expression levels were measured in a breast cancer cohort (n = 651) using the tissue microarray format and quantitative immunofluorescence (AQUA) technology, then correlated with clinical and pathological characteristics and disease‐free survival.

RESULTS:

Univariate Cox proportional hazard models indicated that high stathmin expression predicts worse overall survival (hazard ratio [HR] = 1.48; 95% confidence interval [CI] = 1.119‐1.966; P = .0061). Survival analysis showed 10‐year survival of 53.1% for patients with high stathmin expression versus 67% for low expressers (log‐rank, P < .003). Cox multivariate analysis showed high stathmin expression was independent of age, menopausal status, nodal status, nuclear grade, tumor size, and estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression (HR = 1.19; 95% CI = 1.03‐1.37; P = .01). The ratio of MAP‐tau to stathmin expression showed a positive correlation to disease‐free survival (HR = 0.679; 95% CI = 0.517‐0.891; P = .0053) with a 10‐year survival of 65.4% for patients who had a high ratio of MAP‐tau to stathmin versus 52.5% 10‐year survival rate for those with a low ratio (log‐rank, P = .0009). Cox multivariate analysis showed the ratio of MAP‐tau to stathmin was an independent predictor of overall survival (HR = 0.609; 95% CI = 0.422‐0.879; P = .008).

CONCLUSIONS:

Low stathmin and high MAP‐tau are associated with increased microtubule stability and better prognosis in breast cancer. Cancer 2012. © 2012 American Cancer Society.