High seroprevalence of antibodies to varicella zoster virus in adult women in a tropical climate

OBJECTIVES To determine whether the seroprevalence of antibodies to varicella zoster virus (VZV) in adults is similar to that reported in tropical populations elsewhere. METHODS We measured the seroprevalence of VZV IgG antibodies, using an enzyme immunoassay (EIA) in women attending an antenatal clinic in an urban centre in tropical Australia. RESULTS The overall seroprevalence of VZV antibodies in 298 women was 92% (95% CI 88-95), with no difference between women who spent their childhoods in the tropics and colleagues. None of the overseas-born women was seronegative. CONCLUSION The seroprevalence of VZV antibodies in this tropical population in Australia is as high as that reported from temperate regions, suggesting that social and cultural factors and population mobility are more important determinants of age distribution of VZV immunity than tropical climate.

Usefulness of a self-reported history of chickenpox in adult women in the Top End

Early determination of immune status is essential for the prevention and/or amelioration of disease following exposure to chickenpox. This is of particular significance for pregnant women because of the additional risks to the foetus or newborn.1 To determine the usefulness of a self-reported history of chickenpox in adult women in the Top End, we compared it with serological evidence of immunity.

Surgical resection for non-small cell lung cancer : clinical features and outcomes for a consecutive series at an Irish tertiary referral centre

Background: Few patients diagnosed with lung cancer are still alive 5 years after diagnosis. The aim of the current study was to conduct a 10-year review of a consecutive series of patients undergoing curative-intent surgical resection at the largest tertiary referral centre to identify prognostic factors. Methods: Case records of all patients operated on for lung cancer between 1998 and 2008 were reviewed. The clinical features and outcomes of all patients with non-small cell lung cancer (NSCLC) stage I-IV were recorded. Results: A total of 654 patients underwent surgical resection with curative intent during the study period. Median overall survival for the entire cohort was 37 months. The median age at operation was 66 years, with males accounting for 62.7 %. Squamous cell type was the most common histological subtype, and lobectomies were performed in 76.5 % of surgical resections. Pneumonectomy rates decreased significantly in the latter half of the study (25 vs. 16.3 %), while sub-anatomical resection more than doubled (2 vs. 5 %) (p < 0.005). Clinico-pathological characteristics associated with improved survival by univariate analysis include younger age, female sex, smaller tumour size, smoking status, lobectomy, lower T and N status and less advanced pathological stage. Age, gender, smoking status and tumour size, as well as T and N descriptors have emerged as independent prognostic factors by multivariate analysis. Conclusion: We identified several factors that predicted outcome for NSCLC patients undergoing curative-intent surgical resection. Survival rates in our series are comparable to those reported from other thoracic surgery centres. © 2012 Royal Academy of Medicine in Ireland.

Endothelin-1 is a novel prognostic factor in non-small cell lung cancer

Endothelin-1 (ET-1) is a potent vasoactive peptide and a hypoxia-inducible angiogenic growth factor associated with the development and growth of solid tumours. This study evaluated the expression of big endothelin-1 (big ET-1), a stable precursor of ET-1, and ET-1 in non-small cell lung cancer (NSCLC). Big ET-1 expression was evaluated in paraffin-embedded tissue sections from 10 NSCLC tumours using immunohistochemistry and in situ hybridisation. The production of big ET-1 and ET-1 was studied in six established NSCLC cell lines. The plasma concentrations of big ET-1 were measured in 30 patients with proven NSCLC prior to chemotherapy by means of a sandwich enzyme-linked immunoassay and compared to levels in 20 normal controls. Big ET-1 immunostaining was detected in the cancer cells of all tumours studied. Using in situ hybridisation, tumour cell big ET-1 mRNA expression was demonstrated in all samples. All six NSCLC cell lines expressed ET-1, with big ET-1 being detected in three. The median big ET-1 plasma level in patients with NSCLC was 5.4 pg/mL (range 0-22.7 pg/mL) and was significantly elevated compared to median big ET-1 plasma levels in controls, 2.1 pg/mL (1.2-13.4 pg/mL) (p=0.0001). Furthermore, patients with plasma big ET-1 levels above the normal range (upper tertile) had a worse outcome (p=0.01). In conclusion, big ET-1/ET-1 is expressed by resected NSCLC specimens and tumour cell lines. Plasma big ET-1 levels are elevated in NSCLC patients compared to controls with levels >7.8 pg/mL being associated with a worse outcome. The development of selective ET-1 antagonists such as Atrasentan indicates that ET-1 may be a therapeutic target in NSCLC. © 2004 Wichtig Editore.

Phase III study of matrix metalloproteinase inhibitor prinomastat in non-small-cell lung cancer

Purpose: Matrix metalloproteinases (MMPs) degrade extracellular proteins and facilitate tumor growth, invasion, metastasis, and angiogenesis. This trial was undertaken to determine the effect of prinomastat, an inhibitor of selected MMPs, on the survival of patients with advanced non-small-cell lung cancer (NSCLC), when given in combination with gemcitabine-cisplatin chemotherapy. Patients and Methods: Chemotherapy-naive patients were randomly assigned to receive prinomastat 15 mg or placebo twice daily orally continuously, in combination with gemcitabine 1,250 mg/m2 days 1 and 8 plus cisplatin 75 mg/m2 day 1, every 21 days for up to six cycles. The planned sample size was 420 patients. Results: Study results at an interim analysis and lack of efficacy in another phase III trial prompted early closure of this study. There were 362 patients randomized (181 on prinomastat and 181 on placebo). One hundred thirty-four patients had stage IIIB disease with T4 primary tumor, 193 had stage IV disease, and 34 had recurrent disease (one enrolled patient was ineligible with stage IIIA disease). Overall response rates for the two treatment arms were similar (27% for prinomastat v 26% for placebo; P = .81). There was no difference in overall survival or time to progression; for prinomastat versus placebo patients, the median overall survival times were 11.5 versus 10.8 months (P = .82), 1-year survival rates were 43% v 38% (P = .45), and progression-free survival times were 6.1 v 5.5 months (P = .11), respectively. The toxicities of prinomastat were arthralgia, stiffness, and joint swelling. Treatment interruption was required in 38% of prinomastat patients and 12% of placebo patients. Conclusion: Prinomastat does not improve the outcome of chemotherapy in advanced NSCLC. © 2005 by American Society of Clinical Oncology.

Response to chemotherapy is predictive in relation to longer overall survival in an individual patient combined-analysis with pleural mesothelioma

Background: There is currently no early predictive marker of survival for patients receiving chemotherapy for malignant pleural mesothelioma (MPM). Tumour response may be predictive for overall survival (OS), though this has not been explored. We have thus undertaken a combined-analysis of OS, from a 42 day landmark, of 526 patients receiving systemic therapy for MPM. We also validate published progression-free survival rates (PFSRs) and a progression-free survival (PFS) prognostic-index model. Methods: Analyses included nine MPM clinical trials incorporating six European Organisation for Research and Treatment of Cancer (EORTC) studies. Analysis of OS from landmark (from day 42 post-treatment) was considered regarding tumour response. PFSR analysis data included six non-EORTC MPM clinical trials. Prognostic index validation was performed on one non-EORTC data-set, with available survival data. Results: Median OS, from landmark, of patients with partial response (PR) was 12·8 months, stable disease (SD), 9·4 months and progressive disease (PD), 3·4 months. Both PR and SD were associated with longer OS from landmark compared with disease progression (both p < 0·0001). PFSRs for platinum-based combination therapies were consistent with published significant clinical activity ranges. Effective separation between PFS and OS curves provided a validation of the EORTC prognostic model, based on histology, stage and performance status. Conclusion: Response to chemotherapy is associated with significantly longer OS from landmark in patients with MPM. © 2012 Elsevier Ltd. All rights reserved.

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.

A phase II study of mitomycin C and oral etoposide for advanced adenocarcinoma of the upper gastrointestinal tract

Background: Mitomycin C and etoposide have both demonstrated activity against gastric carcinoma. Etoposide is a topoisomerase II inhibitor with evidence for phase-specific and schedule-dependent activity. Patients and method. Twenty-eight consecutive patients with advanced upper gastrointestinal adenocarcinoma were treated with intravenous (i.v.) bolus mitomycin C 6 mg/m2 on day 1 every 21 days to a maximum of four courses. Oral etoposide capsules 50 mg b.i.d. (or 35 mg b.i.d. liquid) were administered days 1 to 10 extending to 14 days in subsequent courses if absolute neutrophil count >1.5 x 109/l on day 14 of first course, for up to six courses. Results: Twenty-six patients were assessed for response of whom 12 had measurable disease and 14 evaluable disease. Four patients had a documented response (one complete remission, three partial remissions) with an objective response rate of 15% (95% confidence interval (95% CI) 4%-35%). Eight patients had stable disease and 14 progressive disease. The median survival was six months. The schedule was well tolerated with no treatment-related deaths. Nine patients experienced leucopenia (seven grade II and two grade III). Nausea and vomiting (eight grade II, one grade III), fatigue (eight grade II, two grade III) and anaemia (seven grade II, two grade III) were the predominant toxicities. Conclusion: This out-patient schedule is well tolerated and shows modest activity in the treatment of advanced upper gastrointestinal adenocarcinoma. Further studies using protracted schedules of etoposide both orally and as infusional treatment should be developed.

Bioequivalence of two tablet formulations of capecitabine and exploration of age, gender, body surface area, and creatinine clearance as factors influencing systemic exposure in cancer patients

Purpose: The objective of the study was to assess the bioequivalence of two tablet formulations of capecitabine and to explore the effect of age, gender, body surface area and creatinine clearance on the systemic exposure to capecitabine and its metabolites. Methods: The study was designed as an open, randomized two-way crossover trial. A single oral dose of 2000 mg capecitabine was administered on two separate days to 25 patients with solid tumors. On one day, the patients received four 500-mg tablets of formulation B (test formulation) and on the other day, four 500-mg tablets of formulation A (reference formulation). The washout period between the two administrations was between 2 and 8 days. After each administration, serial blood and urine samples were collected for up to 12 and 24 h, respectively. Unchanged capecitabine and its metabolites were determined in plasma using LC/MS-MS and in urine by NMRS. Results: Based on the primary pharmacokinetic parameter, AUC(0-∞) of 5'-DFUR, equivalence was concluded for the two formulations, since the 90% confidence interval of the estimate of formulation B relative to formulation A of 97% to 107% was within the acceptance region 80% to 125%. There was no clinically significant difference between the t(max) for the two formulations (median 2.1 versus 2.0 h). The estimate for C(max) was 111% for formulation B compared to formulation A and the 90% confidence interval of 95% to 136% was within the reference region 70% to 143%. Overall, these results suggest no relevant difference between the two formulations regarding the extent to which 5'-DFUR reached the systemic circulation and the rate at which 5'-DFUR appeared in the systemic circulation. The overall urinary excretions were 86.0% and 86.5% of the dose, respectively, and the proportion recovered as each metabolite was similar for the two formulations. The majority of the dose was excreted as FBAL (61.5% and 60.3%), all other chemical species making a minor contribution. Univariate and multivariate regression analysis to explore the influence of age, gender, body surface area and creatinine clearance on the log-transformed pharmacokinetic parameters AUC(0-∞) and C(max) of capecitabine and its metabolites revealed no clinically significant effects. The only statistically significant results were obtained for AUC(0-∞) and C(max) of intact drug and for C(max) of FBAL, which were higher in females than in males. Conclusion: The bioavailability of 5'-DFUR in the systemic circulation was practically identical after administration of the two tablet formulations. Therefore, the two formulations can be regarded as bioequivalent. The variables investigated (age, gender, body surface area, and creatinine clearance) had no clinically significant effect on the pharmacokinetics of capecitabine or its metabolites.

Examination of thromboxane synthase as a prognostic factor and therapeutic target in non-small cell lung cancer

Background: Thromboxane synthase (TXS) metabolises prostaglandin H2 into thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with a poor prognosis. TXS inhibition induces cell death in-vitro, providing a rationale for therapeutic intervention. We aimed to determine the expression profile of TXS in NSCLC and if it is prognostic and/or a survival factor in the disease. Methods: TXS expression was examined in human NSCLC and matched controls by western analysis and IHC. TXS metabolite (TXB 2) levels were measured by EIA. A 204-patient NSCLC TMA was stained for COX-2 and downstream TXS expression. TXS tissue expression was correlated with clinical parameters, including overall survival. Cell proliferation/survival and invasion was examined in NSCLC cells following both selective TXS inhibition and stable TXS over-expression. Results: TXS was over-expressed in human NSCLC samples, relative to matched normal controls. TXS and TXB 2levels were increased in protein (p < 0.05) and plasma (p < 0.01) NSCLC samples respectively. TXS tissue expression was higher in adenocarcinoma (p < 0.001) and female patients (p < 0.05). No significant correlation with patient survival was observed. Selective TXS inhibition significantly reduced tumour cell growth and increased apoptosis, while TXS over-expression stimulated cell proliferation and invasiveness, and was protective against apoptosis. Conclusion: TXS is over-expressed in NSCLC, particularly in the adenocarcinoma subtype. Inhibition of this enzyme inhibits proliferation and induces apoptosis. Targeting thromboxane synthase alone, or in combination with conventional chemotherapy is a potential therapeutic strategy for NSCLC. © 2011 Cathcart et al; licensee BioMed Central Ltd.

Prostacyclin synthase expression and epigenetic regulation in nonsmall cell lung cancer

BACKGROUND: Prostacyclin synthase (PGIS) metabolizes prostaglandin H(2), into prostacyclin. This study aimed to determine the expression profile of PGIS in nonsmall cell lung cancer (NSCLC) and examine potential mechanisms involved in PGIS regulation. METHODS: PGIS expression was examined in human NSCLC and matched controls by reverse transcriptase polymerase chain reaction (RT-PCR), Western analysis, and immunohistochemistry. A 204-patient NSCLC tissue microarray was stained for PGIS and cyclooxygenase 2 (COX2) expression. Staining intensity was correlated with clinical parameters. Epigenetic mechanisms underpinning PGIS promoter expression were examined using RT-PCR, methylation-specific PCR, and chromatin immunoprecipitation analysis. RESULTS: PGIS expression was reduced/absent in human NSCLC protein samples (P <.0001), but not mRNA relative to matched controls. PGIS tissue expression was higher in squamous cell carcinoma (P =.004) and in male patients (P <.05). No significant correlation of PGIS or COX2 expression with overall patient survival was observed, although COX2 was prognostic for short-term (2-year) survival (P <.001). PGIS mRNA expression was regulated by DNA CpG methylation and histone acetylation in NSCLC cell lines, with chromatin remodeling taking place directly at the PGIS gene. PGIS mRNA expression was increased by both demethylation agents and histone deacetylase inhibitors. Protein levels were unaffected by demethylation agents, whereas PGIS protein stability was negatively affected by histone deacetylase inhibitors. CONCLUSIONS: PGIS protein expression is reduced in NSCLC, and does not correlate with overall patient survival. PGIS expression is regulated through epigenetic mechanisms. Differences in expression patterns between mRNA and protein levels suggest that PGIS expression and protein stability are regulated post-translationally. PGIS protein stability may have an important therapeutic role in NSCLC. © 2011 American Cancer Society.

Sink or Swim? : Revising Ophelia in contemporary young adult fiction

Shakespeare’s Hamlet has in recent years been used by a number of young adult novels to define and authorise representations of gendered adolescent subjectivity. In so doing, these novels attend not only to Shakespeare’s play but also to other adaptations of the play. For example, the long cultural history of Ophelia being used as a template for depicting adolescent femininity as risky or dangerous is as influential as the play itself in early twenty-first century novels. This paper reads such novels for the ways in which codes of gender and of genre circulate in adolescent fiction when linked explicitly with Shakespearean texts and traditions.

A biological staging model for operable non-small cell lung cancer

Background Currently the best prognostic index for operable non-small cell lung cancer (NSCLC) is the TNM staging system. Molecular biology holds the promise of predicting outcome for the individual patient and identifying novel therapeutic targets. Angiogenesis, matrix metalloproteinases (MMP)-2 and -9, and the erb/HER type I tyrosine kinase receptors are all implicated in the pathogenesis of NSCLC. Methods A retrospective analysis of 167 patients with resected stage I-IIIa NSCLC and >60 days postoperative survival with a minimum follow up of 2 years was undertaken. Immunohistochemical analysis was performed on paraffin embedded sections for the microvessel marker CD34, MMP-2 and MMP-9, EGFR, and c-erbB-2 to evaluate the relationships between and impact on survival of these molecular markers. Results Tumour cell MMP-9 (HR 1.91 (1.23-2.97)), a high microvessel count (HR 1.97 (1.28-3.03)), and stage (stage II HR 1.44 (0.87-2.40), stage IIIa HR 2.21 (1.31-3.74)) were independent prognostic factors. Patients with a high microvessel count and tumour cell MMP-9 expression had a worse outcome than cases with only one (HR 1.68 (1.04-2.73)) or neither (HR 4.43 (2.29-8.57)) of these markers. EGFR expression correlated with tumour cell MMP-9 expression (p<0.001). Immunoreactivity for both of these factors within the same tumour was associated with a poor prognosis (HR 2.22 (1.45-3.41)). Conclusion Angiogenesis, EGFR, and MMP-9 expression provide prognostic information independent of TNM stage, allowing a more accurate outcome prediction for the individual patient. The development of novel anti-angiogenic agents, EGFR targeted therapies, and MMP inhibitors suggests that target specific adjuvant treatments may become a therapeutic option in patients with resected NSCLC.

Prognostic significance of platelet and microvessel counts in operable non-small cell lung cancer

Background: Microvessel density, an indirect measure of angiogenesis, has been shown to be an independent prognostic marker in many solid tumours including non-small cell lung cancer (NSCLC). Platelets transport and release angiogenic growth factors. Platelets are increasingly likely to adhere to tumour microvessels due to raised expression of platelet-binding proteins and stasis in blood-flow. Increased vascular permeability in tumour microvessels facilitates platelet extravasation into the extracellular matrix. Adherence and extravasation both lead to platelet activation and release of growth factors capable of instigating the angiogenic process. Methods: A total of 181 patients were identified who underwent resection of stage I-IIIa NSCLC with a post-operative survival >60 days. Patients were followed-up for a minimum of 24 months. Sections from the tumour periphery were stained for the endothelial marker CD34 (Novocastra NCL-END) using standard ABC immunohistochemistry. Chalkley counting was used to assess microvessel density. Results: A pre-operative platelet count greater than the median and above the normal range (>400) was associated with a poor outcome (P = 0.01 and P = 0.04, respectively). Tumours with an above median and high Chalkley count (upper tertile) had a worse prognosis (P = 0.007 and P = 0.0006, respectively). There was no association between platelet count and Chalkley count. Conclusions: Platelet and microvessel counts are both potential prognostic markers for NSCLC. The role of platelets in the angiogenic process needs to be further investigated. (C) 2000 Elsevier Science Ireland Ltd.