Outcomes following treatment for patients with cranial nerve involvement from nasopharyngeal cancer

Introduction: Patients with locally advanced nasopharyngeal carcinoma (NPC) commonly present with cranial nerve (CN) involvement, which can cause significant morbidity. We aimed to characterise the pattern of involvement and outcomes of these patients, as well as determine if these differed according to the mode of diagnosis. Methods: Patients were included if they had non‐distant metastatic NPC, presented with CN involvement and completed radiotherapy treatment between 2002 and 2008. The clinical response was categorised as complete response, partial response, stable or progressive disease. The radiological response was assessed using the Response Evaluation Criteria in Solid Tumors criteria. The loco‐regional control and disease‐free survival rates were estimated with the Kaplan–Meier method. Results: Forty‐seven patients fulfilled the inclusion criteria. CN lesions were diagnosed on clinical examination in 15% of patients, radiologically in 40% and both clinically and radiologically in 45% of patients. A complete or partial response of the CN lesions was seen clinically in 82% and radiologically in 95% of patients. The 3‐year local relapse free survival was 64.3%, distant metastasis‐free survival was 46.1% and overall survival was 82.8%. There were no differences in outcomes between patients with clinically versus radiologically detected CN lesions. Conclusion: Most of these patients are likely to undergo clinical and/or radiological resolution of the nerve lesions following chemoradiotherapy, but the outcome was not determined by the mode of diagnosis (radiological or clinical).     

Insulinlike Growth Factor-1, Insulinlike Growth Factor Binding Protein-1, and Cognitive Function in Older Men and Women

OBJECTIVES: To assess the association between insulinlike growth factor (IGF)-1 and IGF binding protein (IGFBP)-1 with three cognitive function tests in a healthy elderly population.
DESIGN: Cross-sectional analyses from the Rancho Bernardo Cohort Study.
SETTING: Southern California community of Rancho Bernardo.
PARTICIPANTS: Men (n=636) and women (n=899) from the Rancho Bernardo study (median age 74) were assessed between 1988 and 1992 for cognitive function using the Mini-Mental State Examination (MMSE), Verbal Fluency (VF) test, and Trail-Making Test Part B (Trails B). Blood samples were obtained at the same time for IGF-1 and IGFBP-1 levels. The association between biomarkers and cognitive function tests was assessed by dichotomizing tests at the clinically relevant cutoff using logistic regression and according to tertiles and continuous IGF-1 and IGFBP-1 levels using multivariate linear regression analyses.
RESULTS: The mean MMSE, VF and Trails B scores indicated better cognitive function with higher IGF-1 tertile. Multivariate analyses showed that VF and MMSE were each significantly associated with IGF-1 in a dose-response manner for men ( P for trend=.001), but no cognitive function tests were related to IGF-1 in women. For men, the highest IGFBP-1 tertile was inversely and significantly different from the lowest tertile for the MMSE test only ( P for trend=.02).
CONCLUSION: IGF-1 was independently and positively related to MMSE and VF in men, and IGFBP-1 was inversely associated with MMSE in men. Sex differences in the association should be further investigated.     

Undetected chronic obstructive pulmonary disease and asthma in people over 50 years with persistent cough

Background

Chronic obstructive pulmonary disease (COPD) and asthma are underdiagnosed in primary care.

Aim

To determine how often COPD or asthma are present in middle-aged and older patients who consult their GP for persistent cough.

Design of study

A cross-sectional study in 353 patients older than 50 years, visiting their GP for persistent cough and not known to have COPD or asthma.

Setting

General practice in the Netherlands.

Method

All participants underwent extensive diagnostic work-up, including symptoms, signs, spirometry, and body plethysmography. All results were studied by an expert panel to diagnose or exclude COPD and/or asthma. The reproducibility of the panel diagnosis was assessed by calculation of Cohen''s κ statistic in a sample of 41 participants.

Results

Of the 353 participants, 102 (29%, 95% confidence interval [CI] = 24 to 34%) were diagnosed with COPD. In 14 of these 102 participants, both COPD and asthma were diagnosed (4%, 95% CI = 2 to 7%). Asthma (without COPD) was diagnosed in 23 (7%, 95% CI = 4 to 10%) participants. Mean duration of cough was 93 days (median 40 days). The reproducibility of the expert panel was good (Cohen''s κ = 0.90).

Conclusion

In patients aged over 50 years who consult their GP for persistent cough, undetected COPD or asthma is frequently present.     

Reduced levels of hydroxylated, polyunsaturated ultra long-chain fatty acids in the serum of colorectal cancer patients: implications for early screening and detection

Background

There are currently no accurate serum markers for detecting early risk of colorectal cancer (CRC). We therefore developed a non-targeted metabolomics technology to analyse the serum of pre-treatment CRC patients in order to discover putative metabolic markers associated with CRC. Using tandem-mass spectrometry (MS/MS) high throughput MS technology we evaluated the utility of selected markers and this technology for discriminating between CRC and healthy subjects.

Methods

Biomarker discovery was performed using Fourier transform ion cyclotron resonance mass spectrometry (FTICR-MS). Comprehensive metabolic profiles of CRC patients and controls from three independent populations from different continents (USA and Japan; total n = 222) were obtained and the best inter-study biomarkers determined. The structural characterization of these and related markers was performed using liquid chromatography (LC) MS/MS and nuclear magnetic resonance technologies. Clinical utility evaluations were performed using a targeted high-throughput triple-quadrupole multiple reaction monitoring (TQ-MRM) method for three biomarkers in two further independent populations from the USA and Japan (total n = 220).

Results

Comprehensive metabolomic analyses revealed significantly reduced levels of 28-36 carbon-containing hydroxylated polyunsaturated ultra long-chain fatty-acids in all three independent cohorts of CRC patient samples relative to controls. Structure elucidation studies on the C28 molecules revealed two families harbouring specifically two or three hydroxyl substitutions and varying degrees of unsaturation. The TQ-MRM method successfully validated the FTICR-MS results in two further independent studies. In total, biomarkers in five independent populations across two continental regions were evaluated (three populations by FTICR-MS and two by TQ-MRM). The resultant receiver-operator characteristic curve AUCs ranged from 0.85 to 0.98 (average = 0.91 ± 0.04).

Conclusions

A novel comprehensive metabolomics technology was used to identify a systemic metabolic dysregulation comprising previously unknown hydroxylated polyunsaturated ultra-long chain fatty acid metabolites in CRC patients. These metabolites are easily measurable in serum and a decrease in their concentration appears to be highly sensitive and specific for the presence of CRC, regardless of ethnic or geographic background. The measurement of these metabolites may represent an additional tool for the early detection and screening of CRC.     

Toenail nicotine levels as a biomarker of tobacco smoke exposure.

Currently used biomarkers of tobacco smoke exposure have several disadvantages, including that they reflect short-term exposure and can therefore be affected by day-to-day variations. The aim of this study was to assess the validity of toenail nicotine levels as a biomarker of exposure to tobacco smoke for use in epidemiological studies. Toenails were collected in 1982 from 62,641 women participating in the Nurses' Health Study, whereas questionnaire data at that time provided information on active and passive smoke exposure. A stratified random sample of stored toenails from 106 women were selected according to their reported exposure category. Toenails were analyzed for nicotine levels by high-performance liquid chromatography. Toenail nicotine levels differed significantly according to tobacco smoke exposure (P < 0.0001). Among nonactive smokers, there was a significant difference in toenail nicotine levels between passive smokers (mean = 0.28 ng/mg) and nonexposed women (mean = 0.08 ng/mg; P = 0.0006). Among active smokers, there was also a significant difference (P = 0.04) in mean nicotine levels according to categories of cigarettes smoked (means for smokers of 1-14, 15-24, and 25 or more cigarettes/day were 0.94, 1.81, and 2.40 ng/mg). An overlap of the distribution of nicotine levels among passive and active smokers was found. Among all women, the correlation between nail nicotine levels and smoking exposure categories was r = 0.80 (P < 0.0001). The results of this study indicate that toenail nicotine level measurement is a valid biomarker for assessment of active and passive exposure to tobacco smoke. Nail nicotine levels may reflect aspects of active and passive exposure not captured by standard questionnaires and, thus, have the potential to provide better assessment of associations with health risk.     

A prospective study of self-reported sleep duration and incident diabetes in women

Short-term sleep restriction results in impaired glucose tolerance. To test whether habitually short sleep duration increases the risk of developing diabetes, we studied a cohort of 70,026 women enrolled in the Nurses Health Study, without diabetes at baseline, and who responded to a question about daily sleep duration in 1986. Subjects were followed until 1996 for the diagnosis of diabetes (1,969 cases). Long and short sleep durations were associated with an increased risk of diabetes diagnosis. The relative risks (RRs) for short (slept < or =5 h per day) and long (slept > or =9 h per day) sleepers were 1.57 (95% CI 1.28-1.92) and 1.47 (1.19-1.80), respectively. After adjustment for BMI and a variety of confounders, the RR was not significantly increased for short sleepers (1.18 [0.96-1.44]) but remained modestly increased for long sleepers (1.29 [1.05-1.59]). We then performed a similar analysis using only symptomatic cases (n = 1,187). Adjusted RRs for symptomatic diabetes were modestly elevated in both short (1.34 [1.04-1.72]) and long (1.35 [1.04-1.75]) sleepers. Our data suggest that the association between a reduced self-reported sleep duration and diabetes diagnosis could be due to confounding by BMI, or sleep restriction may mediate its effects on diabetes through weight gain. Sleep restriction may be an independent risk factor for developing symptomatic diabetes.     

Comparative analysis of 8-oxo-2' -deoxyguanosine in DNA by 32P- and 33P- postlabeling and electrochemical detection

8-Oxo-2'-deoxyguanosine (8-oxo-dG) is emerging as a useful marker for oxidative DNA damage. Reported basal levels determined by 32P- postlabeling (PPL) method were 10-fold or more higher than those obtained with HPLC/electrochemical detection (ECD). This discrepancy was investigated. In commercial calf thymus DNA, levels of 4 +/- 1 and 64 +/- 14 8-oxo-dG per 10(6) 2'-deoxynucleosides (dN) were measured by the standard HPLC/ECD and PPL methods, respectively. DNA digestion by micrococcal nuclease/spleen phosphodiesterase and nuclease P1 (as used in the standard PPL method), followed by ECD analysis resulted in a level of 8 +/- 3. In calf thymus DNA spiked with chemically synthesized 8-oxo-dGp to give an increment of 9 8-oxo-dG/10(6) dN, the added standard produced a significant increase with HPLC/ECD but not PPL. After spiking the DNA with 90 8-oxo-dG/10(6) dN, the added 8-oxo-dGp was detectable also with PPL, with a labeling efficiency of 65%. In order to investigate the role of ionizing radiation from 32P for the higher 8-oxo-dG levels in PPL, incubation times and amounts of radioactivity in the phosphorylation reaction with commercial dGp were increased, and external irradiation of commercial dG with 32P was investigated. All modifications resulted in higher values of 8-oxo-dG measured, but the effect was not large enough to fully explain the discrepancy between PPL and HPLC/ECD. Using [gamma-33P]ATP instead of [gamma-32P]ATP or adding [33P]phosphate to a 32P-PPL assay resulted in even higher levels of 8-oxo-dG measured. The increase in 8-oxo-dG levels during the PPL workup is attributed to the presence and oxidation of unmodified dGp in the reaction mixture. For a determination of true basal levels, the PPL method will have to be modified, including the removal of dGp prior to the phosphorylation reaction.      

TGF-alpha sustains clonal expansion by promoter-dependent, chemically initiated rat hepatocytes

A series of promoting and non-promoting barbiturates and hydantoins were examined for their ability to sustain the growth of a phenobarbital (PB)-dependent hepatocyte line in cell culture. The effective liver tumor promoters, pentobarbital, allobarbital and 5- ethyl-5-phenylhydantoin, replaced PB and supported 6/27C1 hepatocyte colony formation in vitro at 52-87% of the level induced by PB. The weak promoters secobarbital and amobarbital supported colony formation at only 11-19% of the PB control. A significant correlation was observed for in vivo and in vitro promotion activities of barbiturates and hydantoins, indicating that clonal expansion by 6/27C1 hepatocytes was promoter-dependent. Cell density also appeared to influence hepatocyte growth in vitro. Hepatocyte colonies acquired the ability to grow in the absence of PB, such that after 10 days incubation with PB, approximately 50% of colonies continued to grow in the absence of promoter. This phenomenon of clone-size-dependent hepatocyte growth suggested the operation of an autocrine growth factor pathway. Addition of the hepatocyte mitogen and autocrine growth factor, transforming growth factor-alpha (TGF-alpha), to culture medium lacking PB induced a dose-dependent increase in 6/27C1 hepatocyte colony formation. At the optimal concentration of 3 ng/ml, TGF-alpha sustained hepatocyte clonal expansion at 84% of the level induced by 2 mM PB. Individual 6/27C1 colonies that grew from single cells in the presence of TGF-alpha were tested for promoter-dependent colony formation. Either PB or TGF-alpha supported colony formation by these cells at similar levels and when combined at optimal concentrations, the response appeared to be saturated. When these factors were tested in combination at suboptimal concentrations, the two compounds were additive for supporting colony formation by the parental 6/27C1 line. The ability of TGF-alpha to replace PB and sustain hepatocyte clonal expansion was confirmed with the tumorigenic 6/15 hepatocyte line. These results suggest that TGF- alpha and PB may promote hepatocarcinogenesis by stimulating a common signal transduction pathway.      

A prospective study of smoking and risk of breast cancer in young adult women.

OBJECTIVES: To investigate the association between smoking and invasive breast cancers characterized by their estrogen receptor status in a large prospective study of mainly premenopausal women. METHODS: 112,844 women aged 25-42 years in 1989 were followed 10 years; questionnaire information on medical illnesses and risk factors was collected biennially and information on diet was collected in 1991 and 1995. During this period of follow-up (1,077,536 person-years), 1009 incident breast cancer cases were documented. RESULTS: In the multivariate-adjusted models, smoking status was not significantly related to overall breast cancer risk: compared with never smokers, the relative risks (RRs) were 1.18 [95% confidence interval (CI) 1.02-1.36] for past smokers and 1.12 (95% CI 0.92-1.37) for current smokers. Increasing duration of smoking before the first pregnancy was associated with a greater risk of breast cancer, although little increase was seen in the highest category: compared with never smokers, RRs were 1.42 (95% CI 1.10-1.83) for 15-19 years of smoking and 1.10 (95% CI 0.80-1.52) for >/=20 years of smoking (P for trend = 0.01). Smoking was related most strongly to the risk of estrogen receptor-positive breast cancers. For women who had smoked for >/=20 years, the RR of estrogen receptor-positive cancer was 1.37 (95% CI 1.07-1.74) and the RR of estrogen receptor-negative cancer was 1.04 (95% CI 0.71-1.53). For smoking before age 15, the RRs were 1.49 (95% CI 1.03-2.17) for estrogen receptor-positive cancer and 1.19 (95% CI 0.69-2.08) for estrogen receptor-negative cancer. CONCLUSIONS: Our results suggest that longer duration of smoking may be related to the risk of estrogen receptor-positive breast cancer but possibly less so for estrogen receptor-negative breast cancer.