Synthesis and summary of patient-reported outcome measures to inform the development of a core outcome set in colorectal cancer surgery.

AIM: Patient-reported outcome (PRO) measures (PROMs) are standard measures in the assessment of colorectal cancer (CRC) treatment, but the range and complexity of available PROMs may be hindering the synthesis of evidence. This systematic review aimed to: (i) summarize PROMs in studies of CRC surgery and (ii) categorize PRO content to inform the future development of an agreed minimum 'core' outcome set to be measured in all trials. METHOD: All PROMs were identified from a systematic review of prospective CRC surgical studies. The type and frequency of PROMs in each study were summarized, and the number of items documented. All items were extracted and independently categorized by content by two researchers into 'health domains', and discrepancies were discussed with a patient and expert. Domain popularity and the distribution of items were summarized. RESULTS: Fifty-eight different PROMs were identified from the 104 included studies. There were 23 generic, four cancer-specific, 11 disease-specific and 16 symptom-specific questionnaires, and three ad hoc measures. The most frequently used PROM was the EORTC QLQ-C30 (50 studies), and most PROMs (n = 40, 69%) were used in only one study. Detailed examination of the 50 available measures identified 917 items, which were categorized into 51 domains. The domains comprising the most items were 'anxiety' (n = 85, 9.2%), 'fatigue' (n = 67, 7.3%) and 'physical function' (n = 63, 6.9%). No domains were included in all PROMs. CONCLUSION: There is major heterogeneity of PRO measurement and a wide variation in content assessed in the PROMs available for CRC. A core outcome set will improve PRO outcome measurement and reporting in CRC trials.

A systematic review of outcome reporting in colorectal cancer surgery.

AIM: Evaluation of surgery for colorectal cancer (CRC) is necessary to inform clinical decision-making and healthcare policy. The standards of outcome reporting after CRC surgery have not previously been considered. METHOD: Systematic literature searches identified randomized and nonrandomized prospective studies reporting clinical outcomes of CRC surgery. Outcomes were listed verbatim, categorized into broad groups (outcome domains) and examined for a definition (an appropriate textual explanation or a supporting citation). Outcome reporting was considered inconsistent if results of the outcome specified in the methods were not reported. Outcome reporting was compared between randomized and nonrandomized studies. RESULTS: Of 5644 abstracts, 194 articles (34 randomized and 160 nonrandomized studies) were included reporting 766 different clinical outcomes, categorized into seven domains. A mean of 14 ± 8 individual outcomes were reported per study. 'Anastomotic leak', 'overall survival' and 'wound infection' were the three most frequently reported outcomes in 72, 60 and 44 (37.1%, 30.9% and 22.7%) studies, respectively, and no single outcome was reported in every publication. Outcome definitions were significantly more often provided in randomized studies than in nonrandomized studies (19.0% vs 14.9%, P = 0.015). One-hundred and twenty-seven (65.5%) papers reported results of all outcomes specified in the methods (randomized studies, n = 21, 61.5%; nonrandomized studies, n = 106, 66.2%; P = 0.617). CONCLUSION: Outcome reporting in CRC surgery lacks consistency and method. Improved standards of outcome measurement are recommended to permit data synthesis and transparent cross-study comparisons.

Research ethics committees and paternalism.

In this paper the authors argue that research ethics committees (RECs) should not be paternalistic by rejecting research that poses risk to people competent to decide for themselves. However it is important they help to ensure valid consent is sought from potential recruits and protect vulnerable people who cannot look after their own best interests. The authors first describe the tragic deaths of Jesse Gelsinger and Ellen Roche. They then discuss the following claims to support their case: (1) competent individuals are epistemologically and ethically in the best position to say which risks are reasonable for them, so RECs should be no more restrictive than the "normal" constraints on people taking risks with themselves; (2) RECs do not judge individual competence (that is for researchers and psychiatrists); (3) individual liberty is mostly limited by what serves the public interest, and RECs do not determine public interest; (4) RECs may have a paternalistic role in preventing exploitation of competent people vulnerable to the use of incentives, and in protecting the interests of incompetent people; however, (5) the moral and political authority of RECs has not been established in this respect.

The Court of Appeal and conjoined twins: condemning the unworthy life?

The recent decision of the Court of Appeal authorising separation of the conjoined twins 'J' and 'M' appears susceptible to attack on the basis of various inconsistencies. Most fundamentally, the leading judgment of Ward LJ in Re A (Children) (2000) appears to involve a relative devaluation of M's life in consequentialist terms. One life is better than no life appears to be the message, an evaluation apparently reached by reference to 'Quality' of life considerations. But in his speech Ward LJ explicitly rejects such an approach.

Disturbances of amino acids from temporal lobe synaptosomes in human complex partial epilepsy.

We have studied the levels of neuroactive amino acids in synaptosomes (P2 fraction) isolated from brain tissue of ten patients with medically intractable epilepsy who were undergoing temporal lobectomy. First, lateral temporal tissue (nonfocal) was removed followed by medial temporal tissue (focal). A synaptosomal fraction (P2) was immediately prepared from each tissue and analyzed for free amino acid concentrations. Statistically significant reductions were seen in glutamine and GABA concentrations in focal tissue compared to nonfocal tissue. The ratio of excitatory amino acids (aspartate and glutamate) to inhibitory amino acids (taurine and GABA) was significantly higher in focal tissue compared to nonfocal. The glutamine/glutamate ratio was significantly reduced. These data support the hypothesis that alterations in the balance between excitatory and inhibitory amino acids may be involved in the expression of epilepsy.

The relationship between reactivity of metabolites of pyrrolizidine alkaloids and extrahepatic toxicity.

Pyrrolizidine alkaloids (PAs) are a large group of structurally similar toxins. In animals, including man, they are hepatotoxic and in some cases pneumo- and neurotoxic. PAs are metabolized by the liver P450 system to reactive dehydroalkaloid (DHA) intermediates. PA toxicity is a result of alkylation of macromolecules by DHAs. We have measured the relative reactivity of a series of semi-synthetic DHAs by recording the rate at which they alkylate a model nucleophile, 4-(p-nitrobenzyl)pyridine. Rate data fit mono- or biexponential equations. Rank order of reactivity for the macrocyclic and open ester DHAs was the same as those measured for DHA hydrolysis. The reaction with 4-(p-nitrobenzyl)pyridine was easier to follow, however, as rates of reaction can easily be controlled by temperature or level of acid catalysis, and the final product can be measured colorimetrically. DHAs of the primarily hepatotoxic alkaloids, retrorsine and seneciphylline, were more reactive than DHAs of monocrotaline and trichodesmine, which additionally produce pneumo- and neurotoxicity, respectively. This suggests that DHAs with greater stability (longer half-lives) are able to survive long enough to reach target organs downstream form the liver. We believe that differences in PA metabolism and the nature of toxicity ultimately produced are in part related to differences in reactivity of the primary toxic intermediate, the DHA.

Chronic administration of taurine to aged rats improves the electrical and contractile properties of skeletal muscle fibers.

A reduction of resting chloride conductance (GCl) and a decrease of the voltage threshold for contraction are observed during aging in rat skeletal muscle. The above alterations are also observed in muscle of adult rat after taurine depletion. As lower levels of taurine were found by others in aged rats compared to young rats, we tested the hypothesis that a depletion of taurine may contribute to the alteration of the electrical and contractile properties we found in skeletal muscle during aging. This was accomplished by evaluating the potential benefit of a pharmacological treatment with the amino acid. To this aim 25-mo-old Wistar rats were chronically treated (2-3 mo) with taurine (1 g/kg p.o. daily) and the effects of such a treatment were evaluated in vitro on the passive and active membrane electrical properties of extensor digitorum longus muscle fibers by means of current-clamp intracellular microelectrode technique. Excitation-contraction coupling was also evaluated by measuring the voltage threshold for contraction with the intracellular microelectrode "point" voltage clamp method. In parallel muscle and blood taurine contents were determined by high-performance liquid chromatography. Taurine supplementation significantly raised taurine content in muscle toward that found in adult rats. Supplementation also significantly increased GCl vs. the adult value, in parallel the excitability characteristics (threshold current and latency) related to this parameter were ameliorated. The increase of GCl induced by taurine was accompanied by a restoration of the pharmacological sensitivity to the R(+) enantiomer of 2-(p-chlorophenoxy) propionic acid, a specific chloride channel ligand. In parallel also the protein kinase C-mediated modulation of the channel was restored; in fact the potency of 4-beta-phorbol 12, 13-dibutyrate in reducing GCl was lower in taurine-treated muscles vs. untreated aged, being rather similar to that observed in adult. The treatment also improved the mechanical threshold for contraction of striated fibers which in aged rats is shifted toward more negative potentials, moving it toward the adult values. Our results suggest that the reduction of taurine content could play a role in the alteration of electrical and contractile properties observed during aging. These findings may indicate a potential application of taurine in ensuring normal muscle function in the elderly.