Risk stratification of symptomatic patients suspected of colorectal cancer using faecal and urinary markers.

AIM: Faecal markers, such as the faecal immunochemical test for haemoglobin (FIT) and faecal calprotectin (FCP), have been increasingly used to exclude colorectal cancer (CRC) and colonic inflammation. However, in those with lower gastrointestinal symptoms there are considerable numbers who have cancer but have a negative FIT test (i.e. false negative), which has impeded its use in clinical practice. We undertook a study of diagnostic accuracy CRC using FIT, FCP and urinary volatile organic compounds (VOCs) in patients with lower gastrointestinal symptoms. METHOD: One thousand and sixteen symptomatic patients with suspected CRC referred by family physicians were recruited prospectively in accordance with national referring protocol. A total of 562 patients who completed colonic investigations, in addition to providing stool for FIT and FCP as well as urine samples for urinary VOC measurements, were included in the final outcome measures. RESULTS: The sensitivity and specificity for CRC using FIT was 0.80 [95% confidence interval (CI) 0.66-0.93] and 0.93 (CI 0.91-0.95), respectively. For urinary VOCs, the sensitivity and specificity for CRC was 0.63 (CI 0.46-0.79) and 0.63 (CI 0.59-0.67), respectively. However, for those who were FIT-negative CRC (i.e. false negatives), the addition of urinary VOCs resulted in a sensitivity of 0.97 (CI 0.90-1.0) and specificity of 0.72 (CI 0.68-0.76). CONCLUSIONS: When applied to the FIT-negative group, urinary VOCs improve CRC detection (sensitivity rises from 0.80 to 0.97), thus showing promise as a second-stage test to complement FIT in the detection of CRC.

Diagnostic accuracy of faecal biomarkers in detecting colorectal cancer and adenoma in symptomatic patients.

BACKGROUND: The diagnosis of colorectal cancer (CRC) can be difficult as symptoms are variable with poor specificity. Thus, there is a quest for simple, non-invasive testing that can help streamline those with significant colonic pathology. AIM: To assess using faecal immunochemical test for haemoglobin (FIT) or faecal calprotectin (FCP) to detect CRC and adenoma in symptomatic patients referred from primary care. METHODS: A total of 799 referred for urgent lower gastrointestinal investigations were prospectively recruited. Of these, 430 completed colonic investigations and returned stool samples, and were included in the final statistical analysis. Faecal immunochemical test for haemoglobin was performed on HM-JACKarc analyser (Kyowa Medex, Tokyo, Japan), and FCP by the EliA Calprotectin immunoassay (Thermo Fisher Scientific, Waltham, United States). RESULTS: The negative predictive value (NPV) using FIT alone or both markers (FIT and FCP) in combination was similar at 99% for CRC, with a sensitivity and specificity of 84% and 93%, respectively. FIT measurements were significantly higher in left-sided colonic lesions compared with the right side; 713 vs. 94; P = 0.0203). For adenoma, the NPV using FIT alone, or both markers (FIT and FCP) in combination, was similar at 94% with a sensitivity and specificity of 69% and 56%, respectively. CONCLUSIONS: Undetectable faecal immunochemical test for haemoglobin is sufficiently sensitive to exclude colorectal cancer, with higher values in left-sided lesions. FCP in combination does not appear to provide additional diagnostic information. Further studies to determine the health economic benefits of implementing faecal immunochemical test for haemoglobin in primary care are required.

Utility of faecal calprotectin in inflammatory bowel disease (IBD): what cut-offs should we apply?

BACKGROUND: Faecal calprotectin (FC), a cytosolic protein released by neutrophils (S100 family) in response to inflammation, is a simple, non-invasive test that can be used to differentiate irritable bowel syndrome (IBS) with inflammatory bowel disease (IBD), where there can be considerable symptom overlap. AIMS AND METHODS: The aims of the study were (1) to be able to predict the ability of FC to exclude IBD and determine cut-offs when in remission, (2) to investigate the effects of time and temperature on stability of FC and (3) compare three ELISA kits to measure FC: Buhlmann, PhiCal v1 and PhiCal v2. A total of 311 patients with altered bowel habit were tested for FC; 144 with IBS, 148 with IBD and 19 with other organic causes. RESULTS: Sensitivity and specificity of FC (with PhiCal v2 kit) to distinguish between functional disorder (IBS) and IBD using cut-off 50 µg/g were 88% and 78%, respectively, with a negative predictive value of 87%. Area under the receiver operating curve was 0.84 (CI 0.78 to 0.90). For those with IBD, FC values below 250 µg/g corresponded with remission of disease with a sensitivity and specificity of 90% and 76%, respectively. Area under the receiver operating curve was 0.93 (CI 0.89 to 0.97). FC was stable once extracted and frozen for up to 2.5 months. Pearson correlation was good between Buhlmann assay and PhiCal v2 (r2 = 0.95). CONCLUSIONS: FC has up to 87% negative predictive value to exclude IBD, and cut-offs less than 250 µg/g had 90% sensitivity to determine remission in IBD. Once frozen, FC is stable and the ELISA monoclonal plates were broadly comparable.

Do dermatology outpatients value a copy of the letter sent to their general practitioner? In what way and at what cost?

Dermatology services are largely outpatient based. Time for satisfactory patient communication is limited, with an average of around 15 min per new patient. The amount of new information that can be retained after verbal communication alone is limited during such consultations. One way to reinforce such information is to send patients a copy of the hospital specialist's letter to the general practitioner. Before advocating this unreservedly, it is important to explore the value patients attach to receiving such a letter and to estimate the cost of this practice. In order to explore patients' views of copy letters more fully, all patients attending dermatology outpatients at Queen's Medical Centre, Nottingham during a week in October 2001 were sent copy letters and later interviewed by telephone using a structured questionnaire that gathered information on content, usage, clarity and perceived usefulness. Direct costs were also calculated. Of 70 patients invited to participate, 59 (85%) could be contacted by telephone at the 2-week follow-up period. Of those 59 patients contacted by telephone, surprisingly only 46 (78%) had actually received a copy letter at 14 days post-consultation. Of the 46 patients receiving a copy letter, 45 (98%) thought the information in the letter was consistent with their consultation; the letter was read a mean number of two times; nine patients (20%) understood most and 36 (78%) all of the letter; 25 (54%) found it useful and a further 21 (46%) found it very useful. Patients' views as to the value in receiving the letter included improved communication, recall and a sense of increased involvement in health care decisions. The direct total cost of sending a copy letter was 25.3 pence per patient. Consultants who participated in the exercise did not perceive any additional difficulties in implementing this practice. This small study found that 100% of patients receiving a copy letter found it useful. The fact that around one-fifth of patients did not receive such copy letters within 2 weeks as intended is worrying, and requires further investigation. Sending a copy letter involves a relatively trivial cost for a practice which patients view as a valuable resource.

Scaling evolution in shock-induced transition to turbulence.

In this experimental study, a column of heavy gas (SF6) surrounded by light gas (air) is accelerated by a planar Mach 1.2 shock. Richtmyer-Meshkov instability on the initially diffuse air-SF6 interface determines the repeatable large-scale vortex dynamics of the system after the shock passage. Subsequently secondary instabilities form, with the system eventually transitioning to turbulence. We present highly resolved measurements of two components of the instantaneous velocity fields. With these measurements, we investigate the evolution of velocity statistics over a substantial range of scales in terms of structure functions. The latter evolve to exhibit late-time behavior consistent with the Kolmogorov scaling law for fully developed turbulence, despite the transitional character, anisotropy, and inhomogeneity of our flow. Ensemble averaging and comparison with instantaneous results reveal a trend towards the same scaling manifested much earlier by the structure functions of the fluctuating velocity components.

Apoptosis is induced in post-mitotic rat sympathetic neurons by arabinosides and topoisomerase II inhibitors in the presence of NGF.

Sympathetic neurons depend on nerve growth factor (NGF) for their survival and die by apoptosis when NGF is withdrawn, despite their post-mitotic state. Martin et al. (1990, J. Neurosci. 10, 184-193) showed that cytosine arabinoside, but no other arabinofuranosyl nucleoside, could induce cell death in the presence of NGF and they suggested that it may block a critical step in the NGF-signalling pathway. We show that cytosine arabinoside is not the only nucleoside capable of inducing apoptosis in sympathetic neurons in the presence of NGF. In newly isolated neurons from P0 rat pups cultured in the presence of NGF, all the arabinose nucleosides (adenine, cytosine, guanine and thymine) induce apoptosis at 10 microM when combined with 5-fluorodeoxyuridine treatment. Because 1-beta-arabinofuranosylcytosine is associated with double-strand breaks and chromosomal abberrations, we examined whether topoisomerase II inhibitors, which also cause double-strand breaks by stabilising the enzyme-DNA 'cleavable complex', were capable of promoting apoptosis in these neurons. Although P0 rat neurons are strictly postmitotic, topoisomerase II inhibitors teniposide and mitoxantrone induced them to die by apoptosis in the presence of NGF with the same apparent time-course as arabinose treatment or NGF withdrawal. By contrast, ICRF 193, a catalytic inhibitor of topoisomerase II, reduced the extent of apoptosis induced by mitoxantrone or teniposide by 80% if added simultaneously with the latter but by 2 hours it had no rescue effect, suggesting that topoisomerase II is highly active in these neurons. ICRF 193 also partially reduced the induction of fluorodeoxyuridine-dependent apoptosis by the arabinose nucleosides.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of pemoline in serum by high performance liquid chromatography: clinical application to optimize treatment of hyperactive children.

The analysis of pemoline (2-imino-5-phenyl-4-oxazolidine) by a rapid, sensitive, and specific high performance liquid chromatographic assay using ultraviolet detection is described. Only 100 microliters of plasma or serum is required. Analytical recoveries of 88% for pemoline and 93% for the internal standard (4-methylprimidone) are obtained by this procedure. Between-day precision studies of serum controls containing 10.2, 2.0, and 0.5 mg pemoline/liter produce coefficients of variation of 6.2, 9.4, and 16.2%, respectively. A clinical study of 28 children treated with pemoline demonstrated a linear relationship between drug dose and serum concentrations with an apparent therapeutic range falling between 1.7 and 7.0 mg/liter. These serum concentrations were achieved at drug dosages between 37.5 and 112.5 mg/day.