A phase III trial of docetaxel/carboplatin versus mitomycin C/ifosfamide/ cisplatin (MIC) or mitomycin C/vinblastine/cisplatin (MVP) in patients with advanced non-small-cell lung cancer : a randomised multicentre trial of the British Thoracic Oncology Group (BTOG1)

Background: Phase III studies suggest that non-small-cell lung cancer (NSCLC) patients treated with cisplatin-docetaxel may have higher response rates and better survival compared with other platinum-based regimens. We report the final results of a randomised phase III study of docetaxel and carboplatin versus MIC or MVP in patients with advanced NSCLC. Patients and methods: Patients with biopsy proven stage III-IV NSCLC not suitable for curative surgery or radiotherapy were randomised to receive four cycles of either DCb (docetaxel 75 mg/m 2, carboplatin AUC 6), or MIC/MVP (mitomycin 6 mg/m 2, ifosfamide 3 g/m 2 and cisplatin 50 mg/m 2 or mitomycin 6 mg/ m 2, vinblastine 6 mg/m 2 and cisplatin 50 mg/m 2, respectively), 3 weekly. The primary end point was survival, secondary end points included response rates, toxicity and quality of life. Results: The median follow-up was 17.4 months. Overall response rate was 32% for both arms (partial response = 31%, complete response = 1%); 32% of MIC/MVP and 26% of DCb patients had stable disease. One-year survival was 39% and 35% for DCb and MIC/MVP, respectively. Two-year survival was 13% with both arms. Grade 3/4 neutropenia (74% versus 43%, P < 0.005), infection (18% versus 9%, P = 0.01) and mucositis (5% versus 1%, P = 0.02) were more common with DCb than MIC/MVP. The MIC/MVP arm had significant worsening in overall EORTC score and global health status whereas the DCb arm showed no significant change. Conclusions: The combination of DCb had similar efficacy to MIC/MVP but quality of life was better maintained. © 2006 European Society for Medical Oncology.

Evaluation of the alkaline comet assay and urinary 3-methyladenine excretion for monitoring DNA damage in melanoma patients treated with dacarbazine and tamoxifen

Purpose: To develop, using dacarbazine as a model, reliable techniques for measuring DNA damage and repair as pharmacodynamic endpoints for patients receiving chemotherapy. Methods: A group of 39 patients with malignant melanoma were treated with dacarbazine 1 g/m2 i.v. every 21 days. Tamoxifen 20 mg daily was commenced 24 h after the first infusion and continued until 3 weeks after the last cycle of chemotherapy. DNA strand breaks formed during dacarbazine-induced DNA damage and repair were measured in individual cells by the alkaline comet assay. DNA methyl adducts were quantified by measuring urinary 3-methyladenine (3-MeA) excretion using immunoaffinity ELISA. Venous blood was taken on cycles 1 and 2 for separation of peripheral blood lymphocytes (PBLs) for measurement of DNA strand breaks. Results: Wide interpatient variation in PBL DNA strand breaks occurred following chemotherapy, with a peak at 4 h (median 26.6 h, interquartile range 14.75- 40.5 h) and incomplete repair by 24 h. Similarly, there was a range of 3-MeA excretion with peak levels 4-10 h after chemotherapy (median 33 nmol/h, interquartile range 20.448.65 nmol/h). Peak 3-MeA excretion was positively correlated with DNA strand breaks at 4 h (Spearman's correlation coefficient, r = 0.39, P = 0.036) and 24 h (r = 0.46, P = 0.01). Drug-induced emesis correlated with PBL DNA strand breaks (Mann Whitney U-test, P = 0.03) but not with peak 3-MeA excretion. Conclusions: DNA damage and repair following cytotoxic chemotherapy can be measured in vivo by the alkaline comet assay and by urinary 3-MeA excretion in patients receiving chemotherapy.

Enhancing people capabilities for the promotion of sustainability in facilities management practices

Sustainability has become an important principle to be pursued throughout the life-cycles of project development. Facility managers are in a commanding position to maximise the potential of sustainability. Sustainability endeavours in facility management (FM) practices will not only contribute to reducing energy consumption and waste, but will also help increase organisational productivity, financial returns and standing in the community. At the forefront of sustainable practices, FM professionals can exercise a great deal of influence through operational and strategic management and they should be empowered with the necessary knowledge and capabilities. However, literature studies suggest that there is a gap between the level of awareness and knowledge and the necessary skills required to promote sustainability endeavours in the FM profession. Therefore, it is worthwhile to reflect on people capability issues since it is considered as the key enabler in managing the sustainability agenda as well as being central to the improvement of competency and innovation in an organization. This paper aims to identify the critical factors for enhancing people capabilities in promoting the sustainability agenda in the FM sector. To achieve this objective, a total of 60 factors were identified through a comprehensive literature review and then a questionnaire survey with 52 respondents was conducted to collect the perceived importance of these factors. The survey analysis revealed 23 critical factors as significantly important. These critical factors will serve as the basis for the establishment of a mechanism to equip facility managers with the right knowledge, to continue education and training and to develop new mind-sets to enhance the implementation of sustainability measures in FM practices.

Murray Valley Encephalitis

Outbreaks of an acute, severe, encephalitic illness, clinically similar to Japanese and St. Louis encephalitis, occurred in rural areas of southeastern Australia in 1917, 1918, 1922, 1925, 1951, and 1974[1,9,14-16] and in north and northwestern Australia in 1981, 1993, and 2000.[8,12,41] Approximately 420 cases were reported in these nine outbreaks.[41] They are thought to represent a single entity for which various names (Australian X disease, Murray Valley encephalitis, Australian encephalitis) have been used. Twenty-two cases were diagnosed in the 5 years between 2007 and 2011; three were fatal, and one of the fatalities occurred in a Canadian tourist on return from a holiday in northern Australia. Case-fatality rates, as high as 70 percent in the early years,[9,11] declined to 20 percent in the 1974 outbreak and have remained at about this level since then.[5,10,12] However, significant residual neurologic disability occurs in as many as 50 percent of survivors.[10,12] The presence of this disease in Papua New Guinea was confirmed in 1956.[20] The causative virus was transmitted to experimental animals as early as 1918,[6,11] although those strains could not be maintained. The definitive isolation and characterization of Murray Valley encephalitis virus in 1951[19] led to epidemiologic studies that suggested its survival in bird-mosquito cycles in northern Australia but not in the area of epidemic occurrence in southern Australia.[1] Murray Valley encephalitis is caused by Murray Valley encephalitis virus. In an effort to dissociate a disease from a specific locality, the term Australian encephalitis was proposed by residents of Murray Valley for the disease caused by Murray Valley encephalitis virus. Some researchers subsequently have attempted to expand the term Australian encephalitis to include encephalitis caused by any Australian arbovirus. Because the term Australian encephalitis has no scientific validity and is ambiguous, it should not be used.

Vision in water

The purpose of this study is to determine visual performance in water, including the influence of pupil size. The water en-vironment was simulated by placing a goggle filled with saline in front of eyes, with apertures placed at the front of the goggle. Correction factors were determined for the different magnification under this condition in order to to estimate vision in water. Experiments were conducted on letter visual acuity (7 participants), grating resolution (8 participants), and grating contrast sensitivity (1 participant). For letter acuity, mean loss in vision in water, compared to corrected vision in air, varied between 1.1 log minutes of arc resolution (logMAR) for a 1mm aperture to 2.2 logMAR for a 7mm aperture. The vision in minutes of arc was described well by a linear relationship with pupil size. For grating acuity, mean loss varied between 1.1 logMAR for a 2mm aperture to 1.2 logMAR for a 6mm aperture. Contrast sensitivity for a 2mm aperture dete-riorated as spatial frequency increased, with 2 log unit loss by 3 cycles/degree. Superimposed on this deterioration were depressions (notches) in sensitivity, with the first three notches occurring at 0.45, 0.8 and 1.3 cycles/degree with esti-mates for water of 0.39, 0.70 and 1.13 cycles/degree. In conclusion, vision in water is poor. It becomes worse as pupil size increases, but the effects are much more marked for letter targets than for grating targets.

Effect of text type on near work-induced contrast adaptation in myopic and emmetropic young adults

Purpose Contrast adaptation has been speculated to be an error signal for emmetropization. Myopic children exhibit higher contrast adaptation than emmetropic children. This study aimed to determine whether contrast adaptation varies with the type of text viewed by emmetropic and myopic young adults. Methods Baseline contrast sensitivity was determined in 25 emmetropic and 25 spectacle-corrected myopic young adults for 0.5, 1.2, 2.7, 4.4, and 6.2 cycles per degree (cpd) horizontal sine wave gratings. The adults spent periods looking at a 6.2 cpd high-contrast horizontal grating and reading lines of English and Chinese text (these texts comprised 1.2 cpd row and 6 cpd stroke frequencies). The effects of these near tasks on contrast sensitivity were determined, with decreases in sensitivity indicating contrast adaptation. Results Contrast adaptation was affected by the near task (F2,672 = 43.0; P < 0.001). Adaptation was greater for the grating task (0.13 ± 0.17 log unit, averaged across all frequencies) than reading tasks, but there was no significant difference between the two reading tasks (English 0.05 ± 0.13 log unit versus Chinese 0.04 ± 0.13 log unit). The myopic group showed significantly greater adaptation (by 0.04, 0.04, and 0.05 log units for English, Chinese, and grating tasks, respectively) than the emmetropic group (F1,48 = 5.0; P = 0.03). Conclusions In young adults, reading Chinese text induced similar contrast adaptation as reading English text. Myopes exhibited greater contrast adaptation than emmetropes. Contrast adaptation, independent of text type, might be associated with myopia development.

Phase III trial of gemcitabine and carboplatin versus mitomycin, ifosfamide, and cisplatin or mitomycin, vinblastine, and cisplatin in patients with advanced nonsmall cell lung carcinoma

BACKGROUND. The authors compared gemcitabine and carboplatin (GC) with mitomycin, ifosfamide, and cisplatin (MIC) or mitomycin, vinblastine, and cisplatin (MVP) in patients with advanced nonsmall cell lung carcinoma (NSCLC). The primary objective was survival. Secondary objectives were time to disease progression, response rates, evaluation of toxicity, disease-related symptoms, World Health Organization performance status (PS), and quality of life (QoL). METHODS. Three hundred seventy-two chemotherapy-naïve patients with International Staging System Stage III/IV NSCLC who were ineligible for curative radiotherapy or surgery were randomized to receive either 4 cycles of gemcitabine (1000 mg/m2 on Days 1, 8, and 15) plus carboplatin (area under the serum concentration-time curve, 5; given on Day 1) every 4 weeks (the GC arm) or MIC/MVP every 3 weeks (the MIC/MVP arm). RESULTS. There was no significant difference in median survival (248 days in the MIC/MVP arm vs. 236 days in the GC arm) or time to progression (225 days in the MIC/MVP arm vs. 218 days in the GC arm) between the 2 treatment arms. The 2-year survival rate was 11.8% in the MIC/MVP arm and 6.9% in the GC arm. The 1-year survival rate was 32.5% in the MIC/MVP arm and 33.2% in the GC arm. In the MIC/MVP arm, 33% of patients responded (4 complete responses [CRs] and 57 partial responses [PRs]) whereas in the GC arm, 30% of patients responded (3 CRs and 54 PRs). Nonhematologic toxicity was comparable for patients with Grade 3-4 symptoms, except there was more alopecia among patients in the MIC/MVP arm. GC appeared to produce more hematologic toxicity and necessitated more transfusions. There was no difference in performance status, disease-related symptoms, of QoL between patients in the two treatment arms. Fewer inpatient stays for complications were required with GC. CONCLUSIONS. The results of the current study failed to demonstrate any difference in efficacy between the newer regimen of GC and the older regimens of MIC and MVP. © 2003 American Cancer Society.

Platinum-based chemotherapy in metastatic breast cancer : the Leicester (UK) experience

Aims: After failure of anthracycline- and taxane-based chemotherapy in metastatic breast cancer, treatment options until recently were limited. Until the introduction of capecitabine and vinorelbine, no standard regimen was available. We conducted a retrospective study to determine the efficacy and toxicity of platinum-based chemotherapy in metastatic breast cancer. Materials and methods: Forty-two women with metastatic breast cancer previously treated with anthracyclines (93%) and/or taxanes (36%) received mitomycin-vinblastine-cisplatin (MVP) (n = 23), or cisplatin-etoposide (PE) (n = 19), as first-, second- and third-line treatment at a tertiary referral centre between 1997 and 2002. Chemotherapy was given every 3 weeks as follows: mitomycin-C (8 mg/m 2) (cycles 1, 2, 4, 6), vinblastine (6 mg/m 2), and cisplatin (50 mg/m 2) all on day 1; and cisplatin (75 mg/m 2) and etoposide (100 mg/m 2) on day 1 and (100 mg/m 2) orally twice a day on days 2-3. Results: The response rate for 40 evaluable patients (MVP: n = 23; PE: n = 17) was 18% (95% confidence interval [CI]: 9-32%). The response rate to MVP was 13% (95% CI: 5-32%, one complete and two partial responses) and to PE 24% (10-47%, four partial responses). Disease stabilised in 43% (26-63%) and 47% (26-69%) of women treated with MVP and PE, respectively. After a median follow-up of 18 months, 37 women (MVP: n = 19; PE: n = 18) died from their disease. Median (range) progression-free survival and overall survival were 6 months (0.4-18.7) and 9.9 months (1.3-40.8), respectively. Median progression-free survival for the MVP and PE groups was 5.5 and 6.2 months (Log-rank, P = 0.82), and median overall survival was 10.2 and 9.4 months (Log-rank, P = 0.46), respectively. The main toxicity was myelosuppression. Grades 3-4 neutropenia was more common in women treated with PE than in women treated with MVP (74% vs 30%; P = 0.012), but the incidence of neutropenic sepsis, relative to the number of chemotherapy cycles, was low (7% overall). The toxicity-related hospitalisation rate was 1.2 admissions per six cycles of chemotherapy. No treatment-related deaths occurred. MVP and PE chemotherapy have modest activity and are safe in women with metastatic breast cancer. © 2005 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Vision in water

Purpose: To determine visual performance in water, including the influence of pupil size. Method: The water environment was simulated by placing a goggle filled with saline in front of eyes, with apertures placed at the front of the goggle. Correction factors were determined for the different magnification under this condition to estimate vision in water. Experiments were conducted on letter visual acuity (7 participants), grating resolution (8 participants), and grating contrast sensitivity (1 participant). Results: For letter acuity, mean loss in vision in water, compared to corrected vision in air, varied between 1.1 log minutes of arc resolution (logMAR) for a 1mm aperture to 2.2 logMAR for a 7mm aperture. The vision in minutes of arc was described well by a linear relationship with pupil size. For grating acuity, mean loss varied between 1.1 logMAR for a 2mm aperture to 1.2 logMAR for a 6mm aperture. Contrast sensitivity for a 2mm aperture deteriorated as spatial frequency increased, with 2 log unit loss by 3 cycles/degree. Superimposed on this deterioration were depressions (notches) in sensitivity, with the first three notches occurring at 0.45, 0.8 and 1.3 cycles/degree and with estimates for water of 0.39, 0.70 and 1.13 cycles/degree. Conclusion: Vision in water is poor. It becomes worse as pupil size increases, but the effects are much more marked for letter targets than for grating targets.

Phase II clinical trial of first or second-line treatment with bortezomib in patients with malignant pleural mesothelioma

Based on promising preclinical efficacy of bortezomib in mesothelioma, a single-arm phase II trial (Ireland Cooperative Oncology Research Group 05-10 study), with Simon's two-stage design, was undertaken to assess efficacy of bortezomib monotherapy in the first-line (poor performance status) and second-line settings. The Bcl-2 homology domain 3-only protein Noxa has been implicated as a key inducer of apoptosis by bortezomib. Thus, in a biomarker research substudy, we hypothesized that deficiency in Noxa expression might correlate with resistance. In the second-line setting, 23 patients were enrolled. Partial response was confirmed in one patient (4.8%) who received four cycles of bortezomib. One patient had stable disease; however, progression occurred in the majority of patients within the first two cycles. Median progression-free survival and overall survival were 2.1 and 5.8 months, respectively. In the first-line setting, ten patients were accrued, and there was no evidence of objective response. In the tumor analysis, expression of Noxa was seen in all biopsies. Bortezomib monotherapy exhibits insufficient activity to warrant further investigation in unselected patients with mesothelioma. © 2012 by the International Association for the Study of Lung.

A randomised, concentration-controlled, comparison of standard (5-day) vs. prolonged (15-day) infusions of etoposide phosphate in small-cell lung cancer

Purpose: This randomised trial was designed to investigate the activity and toxicity of continuous infusion etoposide phosphate (EP), targeting a plasma etoposide concentration of either 3 μg/ml for five days (5d) or 1 μg/ml for 15 days (15d), in previously untreated SCLC patients with extensive disease. Patients and methods: EP was used as a single agent. Plasma etoposide concentration was monitored on days 2 and 4 in patients receiving 5d EP and on days 2, 5, 8 and 11 in patients receiving 15d EP, with infusion modification to ensure target concentrations were achieved. Treatment was repeated every 21 days for up to six cycles, with a 25% reduction in target concentration in patients with toxicity. Results: The study has closed early after entry of 29 patients (14 with 5d EP, 15 with 15d EP). Objective responses were seen in seven of 12 (58%, confidence interval (CI): 27%-85%) evaluable patients after 5d EP, and two of 14 (14%, CI: 4%42%) evaluable patients after 15d EP (P = 0.038). Grade 3 or 4 neutropenia or leucopenia during the first cycle of treatment was observed in six of 12 patients after 5d EP and 0/14 patients after 15d EP (P = 0.004), with median nadir WBC count of 2.6 x 109/1 after 5d and 5.0 x 109/1 after 15d EP (P = 0.017). Only one of 49 cycles of 15d EP was associated with grade 3 or worse haematological toxicity, compared to 14 of 61 cycles of 5d EP. Conclusions: Although the number of patients entered into this trial was small, the low activity seen at 1 μg/ml in the 15d arm suggests that this concentration is below the therapeutic window in this setting. Further concentration- controlled studies with prolonged EP infusions are required.

Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment : the M77001 study group

Purpose: This randomized, multicenter trial compared first-line trastuzumab plus docetaxel versus docetaxel alone in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). Patients and Methods: Patients were randomly assigned to six cycles of docetaxel 100 mg/m 2 every 3 weeks, with or without trastuzumab 4 mg/kg loading dose followed by 2 mg/kg weekly until disease progression. Results: A total of 186 patients received at least one dose of the study drug. Trastuzumab plus docetaxel was significantly superior to docetaxel alone in terms of overall response rate (61% v 34%; P = .0002), overall survival (median, 31.2 v 22.7 months; P = .0325), time to disease progression (median, 11.7 v 6.1 months; P = .0001), time to treatment failure (median, 9.8 v 5.3 months; P = .0001), and duration of response (median, 11.7 v 5.7 months; P = .009). There was little difference in the number and severity of adverse events between the arms. Grade 3 to 4 neutropenia was seen more commonly with the combination (32%) than with docetaxel alone (22%), and there was a slightly higher incidence of febrile neutropenia in the combination arm (23% v 17%). One patient in the combination arm experienced symptomatic heart failure (1%). Another patient experienced symptomatic heart failure 5 months after discontinuation of trastuzumab because of disease progression, while being treated with an investigational anthracycline for 4 months. Conclusion: Trastuzumab combined with docetaxel is superior to docetaxel alone as first-line treatment of patients with HER2-positive MBC in terms of overall survival, response rate, response duration, time to progression, and time to treatment failure, with little additional toxicity. © 2005 by American Society of Clinical Oncology.

Thymidylate synthase expression and outcome of patients receiving pemetrexed for advanced nonsquamous non-small-cell lung cancer in a prospective blinded assessment phase II clinical trial

INTRODUCTION In retrospective analyses of patients with nonsquamous non-small-cell lung cancer treated with pemetrexed, low thymidylate synthase (TS) expression is associated with better clinical outcomes. This phase II study explored this association prospectively at the protein and mRNA-expression level. METHODS Treatment-naive patients with nonsquamous non-small-cell lung cancer (stage IIIB/IV) had four cycles of first-line chemotherapy with pemetrexed/cisplatin. Nonprogressing patients continued on pemetrexed maintenance until progression or maximum tolerability. TS expression (nucleus/cytoplasm/total) was assessed in diagnostic tissue samples by immunohistochemistry (IHC; H-scores), and quantitative reverse-transcriptase polymerase chain reaction. Cox regression was used to assess the association between H-scores and progression-free/overall survival (PFS/OS) distribution estimated by the Kaplan-Meier method. Maximal χ analysis identified optimal cutpoints between low TS- and high TS-expression groups, yielding maximal associations with PFS/OS. RESULTS The study enrolled 70 patients; of these 43 (61.4%) started maintenance treatment. In 60 patients with valid H-scores, median (m) PFS was 5.5 (95% confidence interval [CI], 3.9-6.9) months, mOS was 9.6 (95% CI, 7.3-15.7) months. Higher nuclear TS expression was significantly associated with shorter PFS and OS (primary analysis IHC, PFS: p < 0.0001; hazard ratio per 1-unit increase: 1.015; 95%CI, 1.008-1.021). At the optimal cutpoint of nuclear H-score (70), mPFS in the low TS- versus high TS-expression groups was 7.1 (5.7-8.3) versus 2.6 (1.3-4.1) months (p = 0.0015; hazard ratio = 0.28; 95%CI, 0.16-0.52; n = 40/20). Trends were similar for cytoplasm H-scores, quantitative reverse-transcriptase polymerase chain reaction and other clinical endpoints (OS, response, and disease control). CONCLUSIONS The primary endpoint was met; low TS expression was associated with longer PFS. Further randomized studies are needed to explore nuclear TS IHC expression as a potential biomarker of clinical outcomes for pemetrexed treatment in larger patient cohorts. © 2013 by the International Association for the Study of Lung Cancer.

Predicting crack initiation due to ratchetting in rail heads using critical element analysis

This paper presents a strategy to predict the lifetime of rails subjected to large rolling contact loads that induce ratchetting strains in the rail head. A critical element concept is used to calculate the number of loading cycles needed for crack initiation to occur in the rail head surface. In this technique the finite element method (FEM) is used to determine the maximum equivalent ratchetting strain per load cycle, which is calculated by combining longitudinal and shear stains in the critical element. This technique builds on a previously developed critical plane concept that has been used to calculate the number of cycles to crack initiation in rolling contact fatigue under ratchetting failure conditions. The critical element concept simplifies the analytical difficulties of critical plane analysis. Finite element analysis (FEA) is used to identify the critical element in the mesh, and then the strain values of the critical element are used to calculate the ratchetting rate analytically. Finally, a ratchetting criterion is used to calculate the number of cycles to crack initiation from the ratchetting rate calculated.

SRL 172 (killed Mycobacterium vaccae) in addition to standard chemotherapy improves quality of life without affecting survival, in patients with advanced non-small-cell lung cancer : phase III results

Background: This open-label, randomised phase III study was designed to further investigate the clinical activity and safety of SRL172 (killed Mycobacterium vaccae suspension) with chemotherapy in the treatment of non-small-cell lung cancer (NSCLC). Patients and methods: Patients were randomised to receive platinum-based chemotherapy, consisting of up to six cycles of MVP (mitomycin, vinblastine and cisplatin or carboplatin) with (210 patients) or without (209 patients) monthly SRL172. Results: There was no statistical difference between the two groups in overall survival (primary efficacy end point) over the course of the study (median overall survival of 223 days versus 225 days; P = 0.65). However, a higher proportion of patients were alive at the end of the 15-week treatment phase in the chemotherapy plus SRL172 group (90%), than in the chemotherapy alone group (83%) (P = 0.061). At the end of the treatment phase, the response rate was 37% in the combined group and 33% in the chemotherapy alone group. Patients in the chemotherapy alone group had greater deterioration in their Global Health Status score (-14.3) than patients in the chemotherapy plus SRL172 group (-6.6) (P = 0.02). Conclusion: In this non-placebo controlled trial, SRL172 when added to standard cancer chemotherapy significantly improved patient quality of life without affecting overall survival times. © 2004 European Society for Medical Oncology.