Urinary excretion of 3 -methylxanthine and related compounds in children

When screening urine of psychomotorically retarded children by 2-dimensional paper chromatography we found large amounts of an unknown product. After isolation this compound was identified as 3-methylxanthine by using multiple-analytical techniques. Ultraviolet spectra and the major mass spectra peaks are reported for the identified compound and also for 1-methylxanthine. The latter substance also occurs in urine, especially at older age. Another urinary compound is 7-methylxanthine. Evidence is presented that 3-methylxanthine and 7-methylxanthine are metabolites from theophylline and theobromine, occurring in stimulants such as tea and chocolate; 1-methylxanthine probably originates from coffee.Some quantitative data concerning high excretory levels of 3-methylxanthine and 1-methylxanthine are given.     

The association between coronary calcification assessed by electron beam computed tomography and measures of extracoronary atherosclerosis: the Rotterdam Coronary Calcification Study

OBJECTIVES: The present study was designed to examine the associations of coronary calcification assessed by electron beam computed tomography (CT) with measures of extracoronary atherosclerosis. BACKGROUND: Although measures of extracoronary atherosclerosis have been used to predict coronary events, it is not yet known to what extent those measures reflect coronary atherosclerosis. METHODS: The Rotterdam Coronary Calcification Study is a population-based study in subjects age 55 years and over. Participants of the study underwent an electron beam CT scan. Coronary calcification was quantified according to the Agatston calcium score. Measures of extracoronary atherosclerosis included common carotid intima media thickness (IMT), carotid plaques, ankle-arm index (AAI) and aortic calcification. We used the first 2,013 participants for the present analyses. Age-adjusted geometric mean calcium scores were computed for categories of extracoronary measures using analyses of variance. RESULTS: Graded associations with coronary calcification were found for the carotid and aortic measures. Associations were strongest for carotid plaques and aortic calcification; coronary calcification increased from the lowest category (no plaques) to the highest category 9-fold and 11-fold in men and 10-fold and 20-fold in women, respectively. A nonlinear association was found for AAI with an increase in coronary calcification only at lower levels of AAI. CONCLUSIONS: In this population-based study, graded associations were found between coronary calcification and common carotid IMT, carotid plaques and aortic calcification. A nonlinear association was found between coronary calcification and the AAI.     

Time interval from primary melanoma to first distant recurrence in relation to patient outcomes in advanced melanoma

Since the introduction of BRAF(/MEK) inhibition and immune checkpoint inhibition (ICI), the prognosis of advanced melanoma has greatly improved. Melanoma is known for its remarkably long time to first distant recurrence (TFDR), which can be decades in some patients and is partly attributed to immune-surveillance. We investigated the relationship between TFDR and patient outcomes after systemic treatment for advanced melanoma. We selected patients undergoing first-line systemic therapy for advanced melanoma from the nationwide Dutch Melanoma Treatment Registry. The association between TFDR and progression-free survival (PFS) and overall survival (OS) was assessed by Cox proportional hazard regression models. The TFDR was modeled categorically, linearly, and flexibly using restricted cubic splines. Patients received anti-PD-1-based treatment (n = 1844) or BRAF(/MEK) inhibition (n = 1618). For ICI-treated patients with a TFDR <2 years, median OS was 25.0 months, compared to 37.3 months for a TFDR >5 years (P = .014). Patients treated with BRAF(/MEK) inhibition with a longer TFDR also had a significantly longer median OS (8.6 months for TFDR <2 years compared to 11.1 months for >5 years, P = .004). The hazard of dying rapidly decreased with increasing TFDR until approximately 5 years (HR 0.87), after which the hazard of dying further decreased with increasing TFDR, but less strongly (HR 0.82 for a TFDR of 10 years and HR 0.79 for a TFDR of 15 years). Results were similar when stratifying for type of treatment. Advanced melanoma patients with longer TFDR have a prolonged PFS and OS, irrespective of being treated with first-line ICI or targeted therapy.     

Coronary computed tomography--present status and future directions

The use of coronary computed tomography angiography (cCTA) is growing rapidly, in large part because of fast-paced technical innovations that have increased diagnostic accuracy while providing new opportunities for radiation dose reduction. cCTA using recent generation CT scanners has been repeatedly shown to have excellent negative predictive value for ruling out significant coronary stenosis in comparison with invasive coronary angiography (ICA) and is now accepted for this use in selected populations. Current work is increasingly focused on evaluating and optimising radiation dose reduction techniques, the cost-effectiveness of cCTA implementation, and the impact of cCTA on patient management and outcomes. In addition, the potential value of emerging applications, such as atherosclerotic plaque characterisation and myocardial perfusion and viability assessment, are undergoing intense investigation.     

Optimisation of volume-doubling time cutoff for fast-growing lung nodules in CT lung cancer screening reduces false-positive referrals

Objective

To retrospectively investigate whether optimisation of volume-doubling time (VDT) cutoff for fast-growing nodules in lung cancer screening can reduce false-positive referrals.

Methods

Screening participants of the NELSON study underwent low-dose CT. For indeterminate nodules (volume 50–500 mm³), follow-up CT was performed 3 months after baseline. A negative baseline screen resulted in a regular second-round examination 1 year later. Subjects referred to a pulmonologist because of a fast-growing (VDT <400 days) solid nodule in the baseline or regular second round were included in this study. Histology was the reference for diagnosis, or stability on subsequent CTs, confirming benignity. Mean follow-up of non-resected nodules was 4.4 years. Optimisation of the false-positive rate was evaluated at maintained sensitivity for lung cancer diagnosis with VDT <400 days as reference.

Results

Sixty-eight fast-growing nodules were included; 40 % were malignant. The optimal VDT cutoff for the 3-month follow-up CT after baseline was 232 days. This cutoff reduced false-positive referrals by 33 % (20 versus 30). For the regular second round, VDTs varied more among malignant nodules, precluding lowering of the VDT cutoff of 400 days.

Conclusion

All malignant fast-growing lung nodules referred after the 3-month follow-up CT in the baseline lung cancer screening round had VDT ≤232 days. Lowering the VDT cutoff may reduce false-positive referrals.

Key Points

? Lung nodules are common in CT lung cancer screening, most being benign ? Short-term follow-up CT can identify fast-growing intermediate-size lung nodules ? Most fast-growing nodules on short-term follow-up CT still prove to be benign ? A new volume-doubling time (VDT) cut-off is proposed for lung screening ? The optimised VDT cutoff may decrease false-positive case referrals for lung cancer     

Erythropoietin doping in cycling: lack of evidence for efficacy and a negative risk–benefit

Imagine a medicine that is expected to have very limited effects based upon knowledge of its pharmacology and (patho)physiology and that is studied in the wrong population, with low-quality studies that use a surrogate end-point that relates to the clinical end-point in a partial manner at most. Such a medicine would surely not be recommended. The use of recombinant human erythropoietin (rHuEPO) to enhance performance in cycling is very common. A qualitative systematic review of the available literature was performed to examine the evidence for the ergogenic properties of this drug, which is normally used to treat anaemia in chronic renal failure patients. The results of this literature search show that there is no scientific basis from which to conclude that rHuEPO has performance-enhancing properties in elite cyclists. The reported studies have many shortcomings regarding translation of the results to professional cycling endurance performance. Additionally, the possibly harmful side-effects have not been adequately researched for this population but appear to be worrying, at least. The use of rHuEPO in cycling is rife but scientifically unsupported by evidence, and its use in sports is medical malpractice. What its use would have been, if the involved team physicians had been trained in clinical pharmacology and had investigated this properly, remains a matter of speculation. A single well-controlled trial in athletes in real-life circumstances would give a better indication of the real advantages and risk factors of rHuEPO use, but it would be an oversimplification to suggest that this would eradicate its use.     

Heredo-ataxia in a large Dutch pedigree M.R.I. findings

One segment of a large Dutch pedigree with heredoataxia is presented. The clinical and genetic features of the disease, together with the M.R.I. findings, indicate the diagnosis of autosomal dominant late onset olivo-ponto-cerebellar atrophy. The clinical picture remained invariant through successive generations.

Emphasis is put on the diagnostic usefulness of M.R.I. technique in the absence of neuropathological data.     

Non-invasive assessment of coronary calcification

Electron-beam tomography (EBT) and multi-detector computed tomography (MDCT) enable the noninvasive assessment of coronary calcification. The amount of coronary calcification, as detected by EBT, has a close relation with the amount of coronary atherosclerosis, which is the substrate for the occurrence of myocardial infarction and sudden cardiac death. Calcification of the coronary arteries can be seen as a cumulative measure of life-time exposure to cardiovascular risk factors. Several studies have shown that the amount of coronary calcification is associated with the risk of coronary heart disease. Therefore, coronary calcification is a promising method for non-invasive detection of asymptomatic subjects at high risk of developing coronary heart disease. Whether measurement of coronary calcification also increases the predictive power of coronary events based on cardiovascular risk factors is topic of current research. Medical Radiology, Diagnostic Imaging Series: Coronary Radiology, ‘Epidemiology of Coronary Calcification’, R. Vliegenthart and H.H.S. Oei, 2004, pp. 215–224.