The impact of docetaxel-related toxicities on health-related quality of life in patients with metastatic cancer (QoliTax).

BACKGROUND: Docetaxel is a widely used cytotoxic agent. This study evaluates the impact of docetaxel toxicities on patient's health-related quality of life (QoL). PATIENTS AND METHODS: We conducted a multicenter, prospective, non-interventional trial, in which the QoL was assessed using the EORTC QLQ-C30 questionnaires at baseline and every 4 weeks up to 40 weeks in patients receiving a docetaxel-based chemotherapy for metastatic disease. Treatment-related adverse events were correlated with the corresponding QoL scores. Uni- and multivariate analyses were applied. RESULTS: From January 2008 to June 2011, a total of 2659 patients were included. The majority of patients (48.1%) had prostate cancer, followed by breast (17.1%) and non-small-cell-lung cancer (15.8%). Patients received a median of 5 docetaxel cycles with the median dose of 75 mg/m(2). The presence of grade 3/4 diarrhea showed the strongest effect on global health status/QoL average scores (50.91 versus 33.06), followed by vomiting (50.91 versus 35.17), dyspnea (50.94 versus 35.81), mucositis/stomatitis (50.88 versus 36.41), nausea (50.91 versus 36.68), infection (50.90 versus 37.14), fatigue (50.90 versus 43.82) and anemia (50.91 versus 41.03), P < 0.05 for all comparisons. Grade 3/4 leukopenia/neutropenia, alopecia, constipation, neurotoxicity and nail disorders had no significant impact on the global health status/QoL or other items. CONCLUSION: In this large non-interventional trial, docetaxel-associated grade 3 or 4 toxicities were shown to have a strong detrimental effect on patient's QoL. Notably, diarrhea and vomiting had the strongest negative impact on QoL measures. This has to be kept in mind while making therapeutic decisions and providing optimized supportive treatment measures. CLINICAL TRIALS NUMBER: This study was registered at Deutsches Krebsstudienregister (DKSR, primary registry in the WHO Registry Network) with the ID 527.

Electrophysiological characterization of electrolyte and nutrient transport across the small intestine in horses.

The aim of this study was to characterize the transport mechanisms of electrolytes and nutrients across the jejunum of nine healthy horses electrophysiologically. The stripped mucosa was mounted in Ussing chambers and tissue conductances (G(t)) and short circuit currents (I(sc)) were continuously monitored. After blocking the sodium and potassium channels with amiloride, tetraethylammonium chloride (TEA) and barium, chloride secretion was stimulated by carbachol and forskolin. Subsequently, chloride channels were inhibited by 4,4'-diisothiocyanato-stilbene-2,2'-disulfonic acid, 5-nitro-2-(3-phenylpropylamino)benzoic acid, CFTR(inh)-172, N-(2-naphtalenyl)-(3.5-dibromo-2.4-dihydroxyphenyl)methylene glycine hydrazide (GlyH-101) and glibenclamide and their dose-response effect was investigated. The response to glucose, l-alanine and glycyl-l-glutamine was determined at two different mucosal pH values (pH 7.4 and 5.4 respectively). Mean basal I(sc) was -0.47 +/- 0.31 microEq/cm(2)h and mean G(t) was 22.17 +/- 1.78 mS/cm(2). Amiloride and TEA did not alter the baseline I(sc). Barium, carbachol and forskolin significantly increased I(sc). Irrespective of the dose, none of the chloride inhibitors changed I(sc). All nutrients induced a significant increase in I(sc) with the increase being significantly higher at pH 7.4 than at pH 5.4. In conclusion, there is evidence that chloride secretion in horses may be different from respective transport mechanisms in other species. The glucose absorption is suggestive of a sodium-dependent glucose cotransporter 1. However, a decrease in luminal pH did not stimulate current response to peptides as shown for other mammals.

How safe is non-bronchoscopic bronchoalveolar lavage in critically ill mechanically ventilated children?

OBJECTIVE: To assess the safety of non-bronchoscopic bronchoalveolar lavage (NB-BAL) in critically ill mechanically ventilated children. SETTING: Paediatric intensive care unit in a tertiary children's hospital. METHODS: The data from 60 consecutive critically ill mechanically ventilated children who underwent NB-BAL was reviewed from November 1997 to December 1999. PRISM score prior to NB-BAL, observations at the time of NB-BAL and arterial blood gases, oxygenation index (OI), ventilator settings, haemodynamic variables and temperature taken at 1 h before, and 1 and 6 h after NB-BAL, were retrieved from the archived computerised database. RESULTS: Median age was 7 months (IQR 2.8-43 months) and median weight was 5.5 kg (IQR 4-14 kg). Four (7%) patients exhibited significant immediate complications, requiring escalation of respiratory or haemodynamic support. Forty-two (70%) patients had complete data for calculation of OI; there was no significant change in median OI at 1 and 6 h after NB-BAL. However 5 (12%) of these patients experienced an increase in OI of between 10 and 45 at 1 h post NB-BAL, which returned to baseline at 6 h post NB-BAL. Complications did not correlate with any of the available variables: baseline OI, PRISM score or with deterioration at the time of the procedure, although it was observed that four out of the six patients with baseline OIs of greater than 20 experienced complications. CONCLUSION: Non-bronchoscopic bronchoalveolar lavage in critically ill mechanically ventilated neonates and children is generally a well-tolerated procedure, but for some patients, in whom it was not possible to elucidate predictive factors, complications developed. All patients, particularly those with OIs of greater than 20, require careful monitoring during and after the procedure.

Are sleep studies worth doing?

AIMS: To evaluate a sleep study service for children suspected of having sleep related upper airway obstruction (SRUAO). DESIGN: Prospective survey. SETTING: Paediatric and ear, nose, and throat clinics of the Royal Free Hampstead NHS Trust. SUBJECTS: Consecutively referred children with SRUAO symptoms. MAIN OUTCOME MEASURES: Sleep study data, referring clinician's impression, and completed symptom questionnaires. RESULTS: A total of 120 children (aged 6 months to 15.5 years) were studied. Study scores showed that 24 were classified as normal, 42 as mild, 33 as moderate, and 21 as severe SRUAO. In the 106 cases with matching data between clinician's impression and study score, 71 had good agreement, 18 were underestimated by the clinician, and 17 were over estimated. No cases reported as moderate or severe sleep apnoea by the study were referred by the clinician as normal. There were no important associations between parental symptom scores and sleep study scores. CONCLUSION: In children with suspected SRUAO, sleep studies do contribute to assessing the need for operation, the likelihood of postoperative respiratory failure, or as a baseline or outcome measure in intervention studies.

Unidirectional fluxes of short-chain fatty acids across segments of the large intestine in pig, sheep and pony compared with guinea pig.

Unidirectional fluxes of short-chain fatty acids across pig, sheep and pony caecum, proximal and distal colon were studied under short-circuit current conditions in Ussing chambers. Findings are compared with results from guinea pig. Marked species differences are apparent; highest mucosal-to-serosal fluxes of acetate, propionate and butyrate were seen in guinea pig, lower values in pig and smallest fluxes in sheep and pony. Segmental differences between caecum, proximal and distal colon exist mainly in guinea pig and are less developed in pig, sheep and pony. Inhibition of Na+/H+ exchange by amiloride added to the mucosal solution decreased the mucosal-to-serosal fluxes of short-chain fatty acids clearly in guinea pig caecum and proximal colon, and very little in distal colon. This effect was somewhat less pronounced in pig caecum and distal colon, in caecum and distal colon of sheep and caecum of the pony. In pig, sheep and pony proximal colon and pony distal colon no significant inhibition was observed. Inhibition of the K(+)-H+ ATPase by addition of ouabain to the mucosal solution diminished mucosal-to-serosal fluxes of short-chain fatty acids in the guinea pig distal colon extensively. No comparable inhibition was seen in any of the other segments in the animals studied.

Effects of amiloride and ouabain on short-chain fatty acid transport in guinea-pig large intestine.

1. Effects of H+ secreting mechanisms on unidirectional passage of the short-chain fatty acids (SCFA) acetate, propionate and n-butyrate across isolated guinea-pig caecum, proximal and distal colon were studied under short-circuit current conditions in Ussing chamber isotope flux experiments. 2. In the caecum and the proximal colon the serosal-to-mucosal fluxes (Jsm) were higher than the mucosal-to-serosal fluxes (Jms). Thus a net secretion of SCFA was present in the caecum and proximal colon. The higher Jsm appears to be coupled to the Na+ gradient established by the basolateral membrane Na(+)-K(+)-ATPase, whereas Jms is related to the operation of an apical membrane Na(+)-H+ exchanger. Inhibition of Na(+)-H+ exchange by amiloride (1 mM) added to the mucosal solution decreased Jms of SCFA in caecum and in proximal colon, but had no major effect in distal colon. 3. In distal colon Jms exceeds Jsm and thus a net absorption of SCFA was observed. Jms is Na+ independent and coupled to the activity of the apical membrane K(+)-H(+)-ATPase. Inhibition of the K(+)-H(+)-ATPase by addition of ouabain (0.1 mM) to the mucosal solution diminished Jms in the distal colon; in the caecum and proximal colon ouabain had no effect on Jms. 4. Neither amiloride nor ouabain caused major changes in Jsm in any of the large intestinal segments. 5. In conclusion, absorption of SCFA, e.g. Jms, in all large intestinal segments is related to the presence and activity of H+ secreting systems located in the apical membrane of colonocytes. In the caecum and proximal colon the predominant system appears to be Na(+)-H+ exchange, and in the distal colon K(+)-H(+)-ATPase. Supply of H+ ions allows protonation of SCFA anions and subsequent permeation by non-ionic diffusion across the apical membrane. These mechanisms account for 35, 40-50 and 60-80% of SCFA transport in the caecum, the proximal and the distal colon of guinea-pig, respectively. The nature of the Na(+)-dependent secretory pathway in the caecum and proximal colon remains to be determined.

Functional role of bicarbonate in propionate transport across guinea-pig isolated caecum and proximal colon.

1. Unidirectional fluxes of propionate across isolated epithelia from the guinea-pig caecum and proximal colon were measured under short-circuit current conditions. In the caecum and proximal colon the serosal-to-mucosal propionate flux (JPrsm) was higher than mucosal-to-serosal flux (JPrms), resulting in a net secretory flux of propionate. 2. HCO3(-)-CO2-free solution reduced JPrms in the caecum and proximal colon markedly; JPrsm was not (caecum) or little (proximal colon) affected. The subsequent addition of acetazolamide caused a further decrease in JPrms in the proximal colon, but not in the caecum. 3. In HCO3(-)-containing solutions acetazolamide or ethoxzolamide inhibited JPrms; JPrsm was not affected. A macromolecular carbonic anhydrase inhibitor, prontosil-dextran, had no effect on propionate fluxes, indicating that the intracellular carbonic anhydrase is of importance for short-chain fatty acid transport. 4. Subsequent to carbonic anhydrase inhibition, mucosal addition of amiloride caused a slight further decrease of JPrms in the caecum and proximal colon; JPrsm was not affected. 5. Results support the view that a considerable proportion of short-chain fatty acids (SCFAs) is absorbed via a SCFA(-)-HCO3- exchange.

Transport of propionate across the distal colonic epithelium of guinea pig in the presence and absence of bicarbonate and of chloride.

Short-chain fatty acids (SCFA) are rapidly absorbed in the large intestine. However, the mechanisms involved have not been fully delineated. Findings indicate that absorption of SCFA occurs in the undissociated form as well as by an anion exchange, whereby marked species and segmental differences are present. The guinea pig distal colon has certain peculiarities. Unidirectional fluxes of propionate across guinea pig distal colon were studied under short-circuit current conditions in Ussing chambers. Removal of bicarbonate caused reduction of mucosal-to-serosal fluxes by 30%, serosal-to-mucosal fluxes were little affected. In chloride-free solution unidirectional fluxes were also reduced. However, in the presence of transepithelial chloride-gradients with the Cl(-)-free solution only at the luminal side, no such effects were seen. Findings support the presence of SCFA(-)-HCO3- exchange in guinea pig distal colon. Chloride seems not of major importance for SCFA transport.