Real-world treatment sequencing and survival in previously treated advanced renal cell carcinoma patients receiving nivolumab monotherapy: a UK retrospective cohort study.

BACKGROUND: The CheckMate 025 trial established nivolumab monotherapy as one of the standards of care in previously treated advanced or metastatic renal cell carcinoma (aRCC). However, supporting real-world data is lacking. This study investigated characteristics, treatment sequences and clinical outcomes of patients who received nivolumab monotherapy for previously treated aRCC in the UK. METHODS: This was a retrospective cohort study of aRCC patients treated with nivolumab at second line or later (2L +) at 4 UK oncology centres. Eligible patients commenced nivolumab (index date) between 01 March 2016 and 30 June 2018 (index period). Study data were extracted from medical records using an electronic case report form. Data cut-off (end of follow-up) was 31 May 2019. RESULTS: In total, 151 patients were included with median follow-up of 15.2 months. Mean age was 66.9 years, male preponderance (72.2%), and mostly Eastern Cooperative Oncology Group performance status grade 0-1 (71.5%). Amongst 112 patients with a known International Metastatic RCC Database Consortium score, distribution between favourable, intermediate, and poor risk categories was 20.5%, 53.6%, and 25.9% respectively. The majority of patients (n = 109; 72.2%) received nivolumab at 2L, and these patients had a median overall survival (OS) of 23.0 months [95% confidence interval: 17.2, not reached]. All patients who received nivolumab at 2L had received TKIs at 1L. Amongst the 42 patients (27.8%) who received nivolumab in third line or later (3L +) the median OS was 12.4 months [95% CI: 8.8, 23.2]. The most common reasons for nivolumab discontinuation were disease progression (2L: 61.2%; 3L: 68.8%) and adverse events (2L: 34.7%; 3L: 28.1%). CONCLUSION: This study provides real-world evidence on the characteristics, treatment sequences, and outcomes of aRCC patients who received 2L + nivolumab monotherapy in the UK. Nivolumab-specific survival outcomes were similar to those achieved in the CheckMate 025 trial.

Bronchiectasis is associated with delayed diagnosis and adverse outcomes in the New Zealand Common Variable Immunodeficiency Disorders cohort study.

Common variable immunodeficiency disorders (CVID) are multi-system disorders where target organ damage is mediated by infective, autoimmune and inflammatory processes. Bronchiectasis is probably the most common disabling complication of CVID. The risk factors for bronchiectasis in CVID patients are incompletely understood. The New Zealand CVID study (NZCS) is a nationwide longitudinal observational study of adults, which commenced in 2006. In this analysis, the prevalence and risk factors for bronchiectasis were examined in the NZCS. After informed consent, clinical and demographic data were obtained with an interviewer-assisted questionnaire. Linked electronic clinical records and laboratory results were also reviewed. Statistical methods were applied to determine if variables such as early-onset disease, delay in diagnosis and increased numbers of infections were associated with greater risk of bronchiectasis. One hundred and seven adult patients with a diagnosis of CVID are currently enrolled in the NZCS, comprising approximately 70% of patients known to have CVID in New Zealand. Fifty patients (46·7%) had radiologically proven bronchiectasis. This study has shown that patients with compared to those without bronchiectasis have an increased mortality at a younger age. CVID patients with bronchiectasis had a greater number of severe infections consequent to early-onset disease and delayed diagnosis. Indigenous Maori have a high prevalence of CVID and a much greater burden of bronchiectasis compared to New Zealand Europeans. Diagnostic latency has not improved during the study period. Exposure to large numbers of infections because of early-onset disease and delayed diagnosis was associated with an increased risk of bronchiectasis. Earlier diagnosis and treatment of CVID may reduce the risk of bronchiectasis and premature death in some patients.

Comparison of 3-day and 7-day recall periods for food consumption reference values in foodborne disease outbreak investigations.

Investigations into an outbreak of foodborne disease attempt to identify the source of illness as quickly as possible. Population-based reference values for food consumption can assist in investigation by providing comparison data for hypothesis generation and also strengthening the evidence associated with a food product through hypothesis testing. In 2014-2015 a national phone survey was conducted in Canada to collect data on food consumption patterns using a 3- or 7-day recall period. The resulting food consumption values over the two recall periods were compared. The majority of food products did not show a significant difference in the consumption over 3 days and 7 days. However, comparison of reference values from the 3-day recall period to data from an investigation into a Salmonella Infantis outbreak was shown to support the conclusion that chicken was the source of the outbreak whereas the reference values from a 7-day recall did not support this finding. Reference values from multiple recall periods can assist in the hypothesis generation and hypothesis testing phase of foodborne outbreak investigations.

Boron-Doped C24 Fullerenes for Alkyl Functionalization or Potential Polymerization.

Replacing a single carbon atom in C24 with a boron atom allows the functionalization of one additional carbon atom. Such a process involves little energy cost with regard to the structure of the fullerene. Two such replacements are required if the fullerenes are to act as "pearls on a string". This work shows trends for increasingly higher levels of carbon replacement with boron as well as hydrogenation, methylation, and ethylation of a subsequent carbon atom in such a boron-doped small fullerene. Additionally, dimers are shown to be stable, and the linking ethyl groups actually stabilize the overall structure more than when the ethyl groups are on the surface of the structure and are not serving as linkers. Such stringed fullerenes would certainly have applications to materials science if polymers could be made from these stringed pearls and would be suitable for neutron radiation shielding in spacecraft or spacesuits.

Structure and gene cluster of a tyvelose-containing O-polysaccharide of an entomopathogenic bacterium Yersinia entomophaga MH96T related to Yersinia pseudotuberculosis.

An O-polysaccharide was isolated from the lipopolysaccharide of an entomopathogenic bacterium Yersinia entomophaga MH96T by mild acid hydrolysis and studied by 2D NMR spectroscopy. The following structure of the branched tetrasaccharide repeating unit of the polysaccharide was established: where Tyv indicates 3,6-dideoxy-d-arabino-hexose (tyvelose). The structure established is consistent with the gene content of the O-antigen gene cluster. The O-polysaccharide structure and gene cluster of Y. entomophaga are related to those of some Y. pseudotuberculosis serotypes.

Association of US Centers for Medicare and Medicaid Services Hospital 30-Day Risk-Standardized Readmission Metric With Care Quality and Outcomes After Acute Myocardial Infarction: Findings From the National Cardiovascular Data Registry/Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With the Guidelines.

Importance: The US Centers for Medicare and Medicaid Services Hospital Readmissions Reduction Program penalizes hospitals with higher-than-expected risk-adjusted 30-day readmission rates (excess readmission ratio [ERR] > 1) after acute myocardial infarction (MI). However, the association of ERR with MI care processes and outcomes are not well established. Objective: To evaluate the association between ERR for MI with in-hospital process of care measures and 1-year clinical outcomes. Design, Setting, and Participants: Observational analysis of hospitalized patients with MI from National Cardiovascular Data Registry/Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With the Guidelines centers subject to the first cycle of the Hospital Readmissions Reduction Program between July 1, 2008, and June 30, 2011. Exposures: The ERR for MI (MI-ERR) in 2011. Main Outcomes and Measures: Adherence to process of care measures during index hospitalization in the overall study population and risk of the composite outcome of mortality or all-cause readmission within 1 year of discharge and its individual components among participants with available Centers for Medicare and Medicaid Services-linked data. Results: The median ages of patients in the MI-ERR greater than 1 and tertiles 1, 2, and 3 of the MI-ERR greater than 1 groups were 64, 63, 64, and 63 years, respectively. Among 380 hospitals that treated a total of 176 644 patients with MI during the study period, 43% had MI-ERR greater than 1. The proportions of patients of black race, those with heart failure signs at admission, and bleeding complications increased with higher MI-ERR. There was no significant association between adherence to MI performance measures and MI-ERR (adjusted odds ratio, 0.94; 95% CI, 0.81-1.08, per 0.1-unit increase in MI-ERR for overall defect-free care). Among the 51 453 patients with 1-year outcomes data available, higher MI-ERR was associated with higher adjusted risk of the composite outcome and all-cause readmission within 1 year of discharge. This association was largely driven by readmissions early after discharge and was not significant in landmark analyses beginning 30 days after discharge. The MI-ERR was not associated with risk for mortality within 1 year of discharge in the overall and 30-day landmark analyses. Conclusions and Relevance: During the first cycle of the Hospital Readmissions Reduction Program, participating hospitals' risk-adjusted 30-day readmission rates following MI were not associated with in-hospital quality of MI care or clinical outcomes occurring after the first 30 days after discharge.

Contemporary patterns of discharge aspirin dosing after acute myocardial infarction in the United States: results from the National Cardiovascular Data Registry (NCDR).

BACKGROUND: Accumulated data suggest that low-dose aspirin after myocardial infarction (MI) may offer similar efficacy to higher dose aspirin with reduced risk of bleeding. Few data are available on contemporary aspirin dosing patterns after MI in the United States METHODS AND RESULTS: Aspirin dosing from 221 199 patients with MI (40.2% ST-segment-elevation MI) from 525 US hospitals enrolled in the National Cardiovascular Data Registry's (NCDR's) Acute Coronary Treatment and Intervention Outcomes Network Registry-Get with the Guidelines were described, overall and in clinically relevant subgroups. High-dose aspirin was defined as 325 mg and low dose as 81 mg. Between January 2007 and March 2011, 60.9% of patients with acute MI were discharged on high-dose aspirin, 35.6% on low-dose aspirin, and 3.5% on other doses. High-dose aspirin was prescribed at discharge to 73.0% of patients treated with percutaneous coronary intervention and 44.6% of patients managed medically. Among 9075 patients discharged on aspirin, thienopyridine, and warfarin, 44.0% were prescribed high-dose aspirin. Patients with an in-hospital major bleeding event were also frequently discharged on high-dose aspirin (56.7%). A 25-fold variation in the proportion prescribed high-dose aspirin at discharge was observed across participating centers. CONCLUSIONS: Most US patients with MI continue to be discharged on high-dose aspirin. Although aspirin dosing after percutaneous coronary intervention largely reflected prevailing guidelines before 2012, high-dose aspirin was prescribed with similar frequency in medically managed patients and to those in categories expected to be at high risk for bleeding. Wide variability in the proportional use of high-dose aspirin across centers suggests significant influence from local practice habits and uncertainty about appropriate aspirin dosing.

Evaluation of the QBC Star centrifugal three-part differential haematology system.

The QBC Star haematology system includes the QBC Star centrifugal analytical analyser and the QBC Star tube system. Together, they are capable of producing a haematology profile on venous or capillary whole blood. The aim of this study is to compare full blood count (FBC) including differential white cell count performance between the QBC Star analyser and a gold standard Sysmex XE-2100 haematology analyser. The FBC performance was evaluated according to the National Committee for Clinical Laboratory Standards (NCCLS) document H20-A. Imprecision, correlation and linearity studies all showed excellent results. Overall, the haemoglobin, haematocrit, white cell count (WCC) and platelet count parameters showed excellent correlation. Mean corpuscular haemoglobin concentration (MCHC) results showed poor comparability. The white cell differential parameters showed good correlation within certain clinically significant limits. Imprecision for haemoglobin, haematocrit, WCC, MCHC and platelet count was considered acceptable. The re-read function was found to be stable over the five-hour testing period under the authors' laboratory environmental conditions. The subjective assessment by biomedical scientist staff demonstrated that the system was user friendly, required little maintenance, and no user calibration was required. Staff considered the user manual to be excellent. Overall, the QBC Star appears to be an excellent point-of-care (POC) dry haematology analyser that delivers clinically significant nine-parameter complete blood count and will make a good POC analyser for use in field hospitals, research, screening programmes, GP surgeries as well as in emergency and intensive care units. It is a health and safety-friendly analyser considering the fact that it uses dry haematology reagents instead of the bulky wet reagents that are often associated with liquid biohazard waste.

Serratia entomophila bet gene induction and the impact of glycine betaine accumulation on desiccation tolerance.

AIMS: The genes involved in choline transport and oxidation to glycine betaine in the biopesticidal bacterium Serratia entomophila were characterized, and the potential of osmoprotectants, coupled with increased NaCl concentrations, to improve the desiccation tolerance of this species was investigated. METHODS AND RESULTS: Serratia entomophila carries sequences similar to the Escherichia coli betTIBA genes encoding a choline transporter and dehydrogenase, a betaine aldehyde dehydrogenase and a regulatory protein. Disruption of betA abolished the ability of Ser. entomophila to utilize choline as a carbon source. Quantitative reverse-transcriptase PCR analysis revealed that betA transcription was reduced compared to that of the upstream genes in the operon, and that NaCl and choline induced bet gene expression. Glycine betaine and choline increased the NaCl tolerance of Ser. entomophila, and osmotically preconditioned cultures survived better than control cultures following desiccation and immediately after application to agricultural soil. CONCLUSIONS: Addition of glycine betaine and NaCl to growth medium can greatly enhance the desiccation survival of Ser. entomophila, and its initial survival in soil. SIGNIFICANCE AND IMPACT OF THE STUDY: Serratia entomophila is sensitive to desiccation and does not persist under low soil moisture conditions. Techniques described here for enhancing the desiccation survival of Ser. entomophila can be used to improve formulations of this bacterium, and allow its application under a wider range of environmental conditions.

Variability of clopidogrel response in patients with type 2 diabetes mellitus.

The global prevalence of diabetes mellitus (DM) continues to climb, and is accompanied by an increase in DM associated complications, most often manifesting as coronary heart disease. Platelet dysfunction has been implicated as a central contributor to the increased risk of coronary artery disease in patients with DM, and it is not surprising that the anti-platelet agent, clopidogrel, has been shown to have efficacy in both short and long term outcomes in patients with acute coronary syndrome and those undergoing percutaneous coronary intervention. However, accumulating data suggest a clinically relevant sub-optimal clopidogrel response in some patients with DM. The exact mechanism of these observations is not yet fully understood, but appears to be related to reduced concentrations of circulating clopidogrel active metabolite, with less variability in pharmacodynamic and clinical response suggested by the evaluation of newer P2Y(12) antagonists, such as prasugrel and ticagrelor. More research is needed to better understand both the pharmacology and clinical consequences of these observations.

Incidence of hypoglycemia with tight glycemic control protocols: a comparative study.

BACKGROUND: Comparison of hypoglycemia incidence among tight glycemic control (TGC) protocols is a crucial aspect that has not been done in previous trials. This study compared the incidence of hypoglycemia using three TGC protocols in critically ill patients. METHODOLOGY: This was a prospective study of 420 patients over 18 months. Patients were divided into three groups by TGC protocol: A (modified Leuven protocol), B (Georgia Hospital Association protocol, target blood glucose [BG] 80-110 mg/dL), and C (modified Georgia Hospital Association protocol, target BG 90-140 mg/dL). End points included differences in the incidence of first-degree hypoglycemia (BG or= 180 mg/dL). RESULTS: A total of 34,497 BG samples were analyzed: group A, 11,202 (32.47%); group B, 9,627 (27.91%); and group C, 13,668 (39.62%). First-degree hypoglycemia was more frequent in group A (348 episodes [3.11%]) compared to group B (209 episodes [2.17%] [odds ratio (OR) 1.45, 95% confidence interval (CI) 1.25-1.172, P = 0.001]) and group C (266 episodes [1.95%] [OR 1.66, 95% CI 1.37-1.89, P = 0.001]). Second-degree hypoglycemia was more frequent in group A (131 episodes [1.17%]) compared to group B (62 episodes [0.64%] [OR 1.83, 95% CI 1.22-1.72, P = 0.001]) and group C (58 episodes [0.42%] [OR 2.77, 95% CI 2.04-3.79, P = 0.001]). No significant difference was found when groups B and C were compared (P = 0.10 and P = 0.06, respectively). Hyperglycemia was significantly more common in group A (2,175 episodes [19.42%]) compared to group B (1,333 episodes [13.83%] [OR 1.49, 95% CI 1.39-1.62, P = 0.001], but there was no significant difference compared to group C (2,560 episodes [18.73%] [P = 0.17]). CONCLUSIONS: TGC protocols vary in their risk of inducing hypoglycemia. Whether this translates into differences in clinical outcomes such as mortality and adverse effects is still to be determined by future studies.

Phenotypic changes and the fate of digestive enzymes during induction of amber disease in larvae of the New Zealand grass grub (Costelytra zealandica).

Amber disease of the New Zealand grass grub Costelytra zealandica (Coleoptera: Scarabaeidae) is caused by ingestion of pADAP plasmid carrying isolates of Serratia entomophila or Serratia proteamaculans (Enterobacteriaceae) and causes infected larvae to cease feeding and clear their midgut to a pale amber colour where midgut serine protease activities are virtually eliminated. Using bacterial strains and mutants expressing combinations of the anti-feeding (afp) and gut clearance (sep) gene clusters from pADAP, we manipulated the disease phenotype and demonstrated directly the relationship between gene clusters, phenotype and loss of enzyme activity. Treatment with afp-expressing strains caused cessation of feeding without gut clearance where midgut protease activity was maintained at levels similar to that of healthy larvae. Treatment with strains expressing sep-genes caused gut clearance followed by a virtual elimination of trypsin and chymotrypsin titre in the midgut indicating both the loss of pre-existing enzyme from the lumen and a failure to replenish enzyme levels in this region by secretion from the epithelium. Monitoring of enzymatic activity through the alimentary tract during expression of disease showed that loss of serine protease activity in the midgut was matched by a surge of protease activity in the hindgut and frass pellets, indicating a flushing and elimination of the midgut contents. The blocking of enzyme secretion through amber disease appears to be selective as leucine aminopeptidase and alpha-amylase were still detected in the midgut of diseased larvae.

Serine proteases identified from a Costelytra zealandica (White) (Coleoptera: Scarabaeidae) midgut EST library and their expression through insect development.

Costelytra zealandica larvae are pests of New Zealand pastures causing damage by feeding on the roots of grasses and clovers. The major larval protein digestive enzymes are serine proteases (SPs), which are targets for disruption in pest control. An expressed sequence tag (EST) library from healthy, third instar larval midgut tissue was constructed and analysed to determine the composition and regulation of proteases in the C. zealandica larval midgut. Gene mining identified three trypsin-like and 11 chymotrypsin-like SPs spread among four major subgroups. Representative SPs were examined by quantitative PCR and enzyme activity assayed across developmental stages. The serine protease genes examined were expressed throughout feeding stages and downregulated in nonfeeding stages. The study will improve targeting of protease inhibitors and bacterial disruptors of SP synthesis.

Immunomodulation of the hepatic egg granuloma in Schistosoma japonicum-infected pigs.

Immunomodulation of perioval granulomas is a well-known phenomenon in schistosome-infected mice, but only little is known about granuloma modulation in other animal models of human schistosomiasis. In the present study, we explored immunomodulation of egg granulomas in the liver in a pig model of schistosomiasis japonica. Granuloma size was measured and T cells, B cells and IgG(+) plasma cells in granulomas were quantified in pigs at 9, 12 and 21 weeks post infection (wpi) with Schistosoma japonicum. Granulomas were largest at 9 wpi, had decreased significantly in size at 12 wpi and remained small at 21 wpi (9 vs. 12 and 21 wpi: P < 0.05). The size of granulomas containing mature and immature eggs, respectively, did not differ significantly. The density of T (CD3epsilon(+)) cells and IgG(+) plasma cells in granulomas was the same, irrespective of granuloma size and time points. B (CD79alpha(+)) cells were rare in granulomas. The results indicate that in pigs, S. japonicum egg granulomas in the liver are immunomodulated at an early stage of infection, and that not only mature but also immature eggs induce a marked granulomatous reaction in this species.

Effect of an exercise training program on endothelial dysfunction in diabetic and non-diabetic patients with severe chronic heart failure.

BACKGROUND: Endothelial dysfunction is found both in patients with chronic heart failure and in patients with insulin-treated type 2 diabetes mellitus. This endothelial dysfunction leads to a significant reduction in endothelium-derived vasodilation. Physical exercise can have a positive effect on endothelial dysfunction in patients with coronary artery disease, chronic heart failure and diabetes mellitus. It is not clear, however, whether an exercise program influences endothelial function in diabetics with chronic heart failure. Our study was thus aimed at investigating whether a special exercise program would affect endothelial function. Comparisons were made with insulin-treated type 2 diabetics and with non-diabetics suffering from chronic heart failure. METHODS: 42 patients with severe chronic heart failure (LVEF < or = 30%), insulin-dependent diabetics (n=20, mean age 67+/-6 yrs, 16 male, 4 female), non-diabetics (n=22, mean age 68+/-10 yrs, 20 male, 2 female) participated in a 4-week exercise program consisting of ergometer and special muscle strength training. Before (T1) and at the end (T2) of the training program endothelium-dependent and endothelium-independent vasodilatory capacity were assessed by brachial artery diameter measurement. RESULTS: At the end of the training program, there were no significant results within the two groups. The endothelium-dependent vasodilation changed between T1 and T2 as follows: In the diabetic group, the endothelium-dependent vasodilation at T1 and T2 was 5.1+/-3.6 and 4.9+/-2.5%, respectively. For the non-diabetics, the endothelium-dependent vasodilation was 6.8+/-4.5 and 7.6+/-4.0% at T1 and T2, respectively. The endothelium-independent vasodilation in the diabetics was 10.5+/-5.6 at T1 and dropped to 8.7+/-4.1% at T2. The results for the non-diabetics were 13.2+/-5.8 and 12.3+/-6.3% at T1 and T2, respectively. The LVEF in the diabetics was 24.2+/-3.4% at T1, increasing to 27.8+/-5.8% at T2. In the non-diabetics, the LVEF was 22.9+/-3.8 at T1 vs. 28.6+/-6.9% at T2. In the groups of diabetics, the maximum oxygen uptake (VO2-max) was 10.3+/-3.9 at T1 vs. 11.4+/-2.8 ml/kg/min at T2 and in the group of non-diabetics 10.0+/-3.1 vs. 13.5+/-5.0 ml/kg/min. No correlations were found between the change in endothelium-dependent vasodilation and the increase in oxygen uptake. CONCLUSION: In our study, a program of physical exercise had no influence on endothelium-dependent or endothelium-independent vasodilation in insulin-treated type 2 diabetics or in non-diabetics with considerably reduced ejection fraction. In both groups, however, an exercise-related influence on medical parameters and physical performance could be observed.

Diastolic dysfunction and abnormality of the Na+/Ca2+ exchanger in single uremic cardiac myocytes.

Cardiovascular disease is the most common cause of death in patients with end-stage renal disease, possibly due to a specific "uremic cardiomyopathy". This study investigated the function of the Na(+)/Ca(2+) exchanger in single cardiac myocytes from a model of early renal impairment. Mild uremia was induced by partial (5/6) nephrectomy in male Wistar rats. After 4 weeks, ventricular myocytes were isolated, loaded with the fluorescent Ca(2+) indicator indo-1, and contractile function and calcium transients recorded following electrical pacing at 0.2 Hz. Relaxation from rapid cooling contractures (RCCs) was also studied. Cells from uremic animals (U) were hypertrophied compared with controls (C), with a significant increase in width (14%; P<0.02) and cross-sectional area (13%; P<0.03). There was a significant increase in diastolic intracellular Ca(2+) ratio in the uremic cells (C, 0.33+/-0.00 vs U, 0.37+/-0.02; P<0.02), although the amount of calcium released per twitch was similar. Uremic cells were slower to relax following RCCs, however when Na(+)/Ca(2+) exchange was inhibited using a Na(+)-free/Ca(2+)-free solution, this difference was abolished. Under these conditions, there was little difference in the relaxation rate of control cells, indicating that the Na(+)/Ca(2+) exchanger plays only a minor role in relaxation in normal rat myocytes. However in uremia, the data indicate that the Na(+)/Ca(2+) exchanger actively interfered with relaxation, possibly by working in reverse rather than forward mode. These results indicate that myocyte relaxation and Ca(2+) handling are abnormal in early uremia and may provide further evidence for the existence of a specific "uremic cardiomyopathy".

Leptospira in slaughtered fattening pigs in southern Vietnam: presence of the bacteria in the kidneys and association with morphological findings.

One kidney was collected from each of 32 fattening pigs at an abattoir in southern Vietnam in 2001 in order to demonstrate infecting Leptospira serovar and to associate renal macro- and microscopic findings with the presence of renal leptospires. Leptospires were demonstrated in 22 (69%) of the investigated kidneys by immunofluorescence. Multifocal interstitial nephritis (MFIN) and gross renal lesions (white spots) were each demonstrated in 24 (75%) kidneys. Leptospira interrogans serovar bratislava was isolated from one kidney. There was no association between presence of leptospires and MFIN (P=0.19), respectively and white spots (P=0.98), respectively. These data suggest that Leptospira infection is common among fattening pigs in the study area and that these animals may be considered as an occupational human health hazard. It is also suggested that the presence of white spots is an unreliable indicator of the presence of renal leptospires.

Paclitaxel: a pharmacoeconomic review of its use in non-small cell lung cancer.

UNLABELLED: A number of first-line chemotherapy options for patients with advanced non-small cell lung cancer (NSCLC) are advocated in treatment guidelines and/or by various clinical investigators. Platinum-based chemotherapy has clearly demonstrated efficacy in patients with advanced NSCLC and is generally recommended as first-line therapy, although there is increasing interest in the use of non-platinum chemotherapy regimens. Among the platinum-based combinations currently used in clinical practice are regimens such as cisplatin or carboplatin combined with paclitaxel, vinorelbine, gemcitabine, docetaxel or irinotecan. The particular combinations employed may vary between institutions and geographical regions. Several pharmacoeconomic analyses have been conducted on paclitaxel in NSCLC and most have focused on its use in combination with cisplatin. In terms of clinical efficacy, paclitaxel-cisplatin combinations achieved significantly higher response rates than teniposide plus cisplatin or etoposide plus cisplatin (previously thought to be among the more effective regimens available) in two large randomised trials. One of these studies showed a survival advantage for paclitaxel plus cisplatin [with or without a granulocyte colony-stimulating factor (G-CSF)] compared with etoposide plus cisplatin. A Canadian cost-effectiveness analysis incorporated data from one of the large randomised comparative trials and showed that the incremental cost per life-year saved for outpatient administration of paclitaxel plus cisplatin versus etoposide plus cisplatin was $US 22181 (30619 Canadian dollars; $Can) [1997 costs]. A European analysis incorporated data from the other large randomised study and showed slightly higher costs per responder for paclitaxel plus cisplatin than for teniposide plus cisplatin in The Netherlands ($US 30769 vs $US 29592) and Spain ($US 19 923 vs $US 19724) but lower costs per responder in Belgium ($US 22852 vs $US 25000) and France ($US28 080 vs $US 34747) [1995/96 costs]. In other cost-effectiveness analyses, paclitaxel plus cisplatin was associated with a cost per life-year saved relative to best supportive care of approximately $US 10000 in a US study (year of costing not reported) or $US 11200 in a Canadian analysis ($Can 15400; 1995 costs). Results were less favourable when combining paclitaxel with carboplatin instead of cisplatin and particularly when G-CSF was added to paclitaxel plus cisplatin. The Canadian study incorporated the concept of extended dominance in a threshold analysis and ranked paclitaxel plus cisplatin first among several comparator regimens (including vinorelbine plus cisplatin) when the threshold level was $Can 75000 ($US 54526) per life-year saved or per quality-adjusted life-year gained (1995 values). CONCLUSION: Current treatment guidelines for advanced NSCLC recognise paclitaxel-platinum combinations as one of the first-line chemotherapy treatment options. In two large head-to-head comparative clinical trials, paclitaxel plus cisplatin was associated with significantly greater response rates than cisplatin in combination with either teniposide or etoposide, and a survival advantage was shown for paclitaxel plus cisplatin (with or without G-CSF) over etoposide plus cisplatin. There are limitations to the currently available pharmacoeconomic data and further economic analyses of paclitaxel-carboplatin regimens are warranted, as this combination is widely used in NSCLC and appears to have some clinical advantages over paclitaxel plus cisplatin in terms of ease of administration and tolerability profile. Nevertheless, results of various cost-effectiveness studies support the use of paclitaxel-platinum combinations, particularly paclitaxel plus cisplatin, as a first-line chemotherapy treatment option in patients with advanced NSCLC.