European Journal of Cancer - Articles in Press

ERG protein expression reflects hormonal treatment response and is associated with Gleason score and prostate cancer specific mortality - Corrected Proof

Tarek A. Bismar, Michael Dolph, Liang-Hong Teng, Shuhong Liu, Bryan Donnelly — 2012-02-03

Abstract: Background: ERG (ETS regulated gene) protein expression has been shown to reflect ERG genomic rearrangements in prostate cancer (PCA). However, ERG protein expression prognostic value has not been yet investigated.Design: ERG protein expression was investigated in a cohort of 312 men with PCA diagnosed in transurethral resection of the prostate.Results: ERG expression was detected in 76/293 (25.9%) of patients. Overall ERG expression was associated with Gleason score (GS) (p<0.0001), tumour volume (p=0.04) and with cancer specific mortality (p=0.15). Low ERG intensity was significantly associated with higher GS (p=0.02) and marginally with cancer specific mortality (p=0.11). The association with caner specific mortality was more significant in patients without any hormonal manipulation (p=0.02). Multivariate Cox model using GS, tumour volume and ERG intensity to predict time to cancer specific death yielded a marginally significant effect for high versus low ERG protein expression (hazard ratio (HR)=0.36; 95% confidence interval (CI): 0.10–1.38; p=0.14) and a non-significant effect for GS >7 (HR=4.85; 95%CI: 0.48, 48.65; p=0.18). Men with ERG expression showed longer free progression time to castration resistant disease compared to men with no ERG expression (mean 11.39 versus 6.1months, p=0.08).Conclusion: We report significant association between ERG protein levels and each of GS, progression to castration resistant and cancer specific mortality. High ERG intensity was associated with lower GS, better overall survival and longer free progression times to castration resistant disease. ERG protein levels may have prognostic and therapeutic role in PCA and should be investigated in future studies.

Is the prognosis of stage 4s neuroblastoma in patients 12months of age and older really excellent? - Corrected Proof

2012-02-03

Abstract: Purpose: In the International Neuroblastoma Risk Group (INRG) classification system, stage 4s was changed into stage MS in children less than 18months of age. Stage MS is defined as a metastatic disease with skin, liver and bone marrow, similar to INSS stage 4s. To evaluate the outcome of stage 4s cases in patients 12months of age and over and to determine the appropriate treatment strategy.Method: We performed a retrospective review of 3834 patients registered with the Japanese Society of Pediatric Oncology and Japanese Society of Pediatric Surgeons between 1980 and 1998.Results: The rates of stage 4s patients were 10.7%, 6.3% and 3.3% in patients of ⩽11months of age, from ⩾12 to ⩽17months of age, ⩾18months of age, respectively. The 5year event-free survival rates were 89.4%, 100% and 53.1%, respectively. The rates of MYCN amplification and unfavourable histology were smaller in stage 4s groups than stage 4 groups in all ages.Conclusion: In the children 12months of age and older, stage 4s cases are markedly different from stage 4 cases in regard to the clinical features and prognosis. The prognosis of stage 4s cases from ⩾12 to ⩽17months of age is excellent. The concept of stage MS appears to be appropriate.

Reply to Professor Mercadante: Stop and go strategy for opioid switching requires flexibility - Corrected Proof

Kristin Moksnes — 2012-02-03

To the Editor: We are grateful for the interest and response from Mercadante. This study was a randomized, phase II study, and we agree that there were obvious limitations, as discussed in the article. No firm conclusions could be made. However, it was more dropouts, three serious adverse events (SAEs) and a trend of more pain in the stop and go (SAG) group, indicating that the stop and go strategy should not replace the more careful 3-days switch (3DS) in such frail patients. No clinically significant difference >2 (11 point scale) in pain intensity or adverse effects were found during the first week after the switch. The protocol was strict during the first five days; however, the patients were allowed to take rescue (morphine/oxycodone) as needed.

Risk of haemorrhagic and ischaemic stroke in patients with cancer: A nationwide follow-up study from Sweden - Corrected Proof

Bengt Zöller, Jianguang Ji, Jan Sundquist, Kristina Sundquist — 2012-02-01

Abstract: Background: Stroke is common in cancer patients, but risk estimates for different cancer sites/types have not been determined. The aim of this nationwide study was to examine whether there is an association between cancer and first hospitalisation for haemorrhagic or ischaemic stroke.Methods: All 820,491 individuals in Sweden with a diagnosis of cancer between 1st January 1987 and 31st December 2008 were followed for first hospitalisation for haemorrhagic or ischaemic stroke. The reference population was the total population of Sweden without cancer. Standardised incidence ratios (SIRs) for haemorrhagic and ischaemic strokes were calculated.Results: Overall risk of haemorrhagic stroke and ischaemic stroke during the first 6months after diagnosis of cancer was 2.2 (95% confidence interval (CI)=2.0–2.3) and 1.6 (CI=1.5–1.6), respectively. For 18 and 20 of the 34 cancers studied, respectively, risk of haemorrhagic and ischaemic strokes was increased. Overall stroke risk decreased rapidly, but remained elevated, even 10+years after diagnosis of cancer 1.2 (CI=1.1–1.3) for haemorrhagic stroke and 1.1 (CI=1.1–1.2) for ischaemic stroke. The risk of stroke was highest during the first 6months after diagnosis of cancer of the nervous system (29 (CI=25–34) for haemorrhagic stroke and 4.1 (CI=3.4–4.8) for ischaemic stroke)) or leukaemia (13 (CI=10–16) for haemorrhagic stroke and 3.0 (CI=2.5–3.7) for ischaemic stroke)). Metastasis was associated with an increased risk of haemorrhagic stroke 2.2 (CI=1.8–2.7) and ischaemic stroke 1.5 (CI=1.3–1.7).Interpretation: Several cancer sites/types are associated with an increased risk of haemorrhagic and ischaemic strokes.

Cediranib monotherapy in patients with advanced renal cell carcinoma: Results of a randomised phase II study - Corrected Proof

2012-01-30

Abstract: Background: Cediranib is a highly potent vascular endothelial growth factor (VEGF) signalling inhibitor with activity against VEGF receptors 1, 2 and 3. This Phase II, randomised, double-blind, parallel-group study compared the efficacy of cediranib with placebo in patients with metastatic or recurrent clear cell renal cell carcinoma who had not previously received a VEGF signalling inhibitor.Methods: Patients were randomised (3:1) to cediranib 45mg/day or placebo. The primary objective was comparison of change from baseline in tumour size after 12weeks of therapy. Secondary objectives included response rate and duration, progression-free survival (PFS) and safety and tolerability. Patients in the placebo group could cross over to open-label cediranib at 12weeks or earlier if their disease had progressed. This study has been completed and is registered with ClinicalTrials.gov, number NCT00423332.Findings: Patients (n=71) were randomised to receive cediranib (n=53) or placebo (n=18). The primary study outcome revealed that, after 12weeks of therapy, there was a significant difference in mean percentage change from baseline in tumour size between the cediranib (–20%) and placebo (+20%) arms (p<0.0001). Eighteen patients (34%) on cediranib achieved a partial response and 25 (47%) experienced stable disease. Cediranib treatment prolonged PFS significantly compared with placebo (hazard ratio (HR)=0.45, 90%confidence interval: 0.26–0.76, p=0.017; median PFS 12.1 versus 2.8months). The most common adverse events in patients receiving cediranib were diarrhoea (74%), hypertension (64%), fatigue (58%) and dysphonia (58%).Interpretation: Cediranib monotherapy demonstrated significant evidence of antitumour activity in patients with advanced renal cell carcinoma. The adverse event profile was consistent with previous studies of cediranib 45mg.

Phase I trial to investigate the safety, pharmacokinetics and efficacy of sorafenib combined with docetaxel in patients with advanced refractory solid tumours - Corrected Proof

2012-01-30

Abstract: Aim: The safety, pharmacokinetics and efficacy of sorafenib plus docetaxel in patients with advanced refractory cancer were investigated in a Phase I, dose-escalation trial.Methods: Twenty-seven patients in four Cohorts received docetaxel on Day 1 (Cohorts 1 and 4: 75mg/m2; Cohorts 2 and 3: 100mg/m2) plus sorafenib on Days 2–19 (Cohorts 1 and 2: 200mg twice-daily (bid); Cohorts 3 and 4: 400mg bid) in 21-day cycles.Results: Most common adverse events (AEs) (Grade 3–5) included neutropenia (89%), leucopaenia (81%), hand–foot skin reaction (30%) and fatigue (30%). The most common drug-related AEs leading to dose reduction/interruption or permanent discontinuation were dermatologic (41%), gastrointestinal (26%) and constitutional (22%). Coadministration of sorafenib altered the pharmacokinetics of docetaxel. On average, docetaxel area under the concentration–time curve (AUC)0–24 increased by 5% (Cohort 1), 54% (Cohort 2), 36% (Cohort 3) and 80% (Cohort 4) with docetaxel plus sorafenib, while Cmax increased by 16–32%, independent of sorafenib/docetaxel doses. Three of 25 evaluable patients (11%) had partial responses; 14 (52%) had stable disease.Conclusion: Dose-limiting dermatologic AEs were more common than expected for either therapy alone. A starting dose of docetaxel 75mg/m2 plus sorafenib 400mg bid (with dose reductions for dermatological toxicities) is proposed for Phase II.

Sham-controlled, randomised, feasibility trial of acupuncture for prevention of radiation-induced xerostomia among patients with nasopharyngeal carcinoma - Corrected Proof

2012-01-30

Abstract: Background: Xerostomia (dry mouth) after head/neck radiation is a common problem among cancer patients. Quality of life (QOL) is impaired, and available treatments are of little benefit. This trial determined the feasibility of conducting a sham-controlled trial of acupuncture and whether acupuncture could prevent xerostomia among head/neck patients undergoing radiotherapy.Methods: A sham controlled, feasibility trial was conducted at Fudan University Shanghai Cancer Center, Shanghai, China among patients with nasopharyngeal carcinoma undergoing radiotherapy.To determine feasibility of a sham procedure, 23 patients were randomised to real acupuncture (N=11) or to sham acupuncture (N=12). Patients were treated three times/week during the course of radiotherapy. Subjective measures were the Xerostomia Questionnaire (XQ) and MD Anderson Symptom Inventory for Head and Neck Cancer (MDASI-HN). Objective measures were unstimulated whole salivary flow rates (UWSFR) and stimulated salivary flow rates (SSFR). Patients were followed for 1 month after radiotherapy.Results: XQ scores for acupuncture were significantly lower than sham controls starting in week 3 and lasted through the 1-month follow-up (all P’s <0.001 except for week 3, which was 0.006), with clinically significant differences as follows: week 6 – RR 0.28 [95% confidence interval, 0.10, 0.79]; week 11 – RR 0.17 [95%CI, 0.03, 1.07]. Similar findings were seen for MDASI-HN scores and MDASI-Intrusion scores. Group differences for UWSFR and SSFR were not found.Conclusions: In this small pilot study, true acupuncture given concurrently with radiotherapy significantly reduced xerostomia symptoms and improved QOL when compared with sham acupuncture. Large-scale, multi-centre, randomised and placebo-controlled trials are now needed.

Predictors of prescription errors involving anticancer chemotherapy agents - Corrected Proof

2012-01-30

Abstract: Aim: The majority of medication errors that harm patients relate to the prescribing process. Our study aimed to identify the predictors of prescription errors involving anticancer chemotherapy agents.Methods: All consecutive antineoplastic prescriptions from June 2006 to May 2008 were analysed, with medication errors being captured. Potential risk factors for medication prescribing errors were defined in relation to the patient, chemotherapy regimen and hospital organisation. The relationship between these risk factors and observed medication errors or dose medication errors was assessed by univariate and multivariate logistic-regression analyses.Results: Among the 17,150 chemotherapy prescriptions, 540 contained at least one error (3.15%). The following independent predictors of risk of medication errors were identified: patients with a body surface area >2m2 (odds ratio (OR): 1.3, 95% confidence interval (CI) 1.01–1.67, p=0.04), protocols with more than three drugs (OR: 1.91, 95%CI 1.59–2.31, p<0.001), protocols involving carboplatin (OR: 2.33, 95%CI 1.85–2.95, p<0.001), protocols requiring at least one modification by the physician (OR: 1.32, 95%CI 1.09–1.61, p=0.005), inpatient care (OR: 1.58, 95%CI 1.28–1.93, p<0.001) and prescriptions by a resident physician (OR: 1.83, 95%CI 1.50–2.22, p<0.001). The risk of medication dose prescribing errors was significantly associated with three independent factors: protocols involving carboplatin (OR: 4.47, 95%CI 3.45–5.79, p<0.001), protocols with more than three drugs (OR: 2.4, 95%CI 1.92–3.00, p<0.001) and protocols requiring at least one modification (OR: 1.33, 95%CI 1.04–1.69, p=0.02).Conclusion: In this epidemiologic study, the independent risk factors identified should be targeted for preventive measures in order to improve anticancer agent prescriptions and reduce the risk of medication errors.

Rapamycin blocks hepatoblastoma growth in vitro and in vivo implicating new treatment options in high-risk patients - Corrected Proof

2012-01-30

Abstract: Activation of the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signalling pathway plays a central role in the formation of hepatoblastoma (HB), the most common liver cancer in childhood. Blocking this pathway with specific mTOR inhibitors such as the immunosuppressant rapamycin is being currently tested for a variety of cancers. Here, we report that rapamycin treatment induced a significant dose-dependent inhibition of cell viability and promoted apoptosis in HB cells in vitro. Moreover, rapamycin inhibited AKT/mTOR signalling by dephosphorylation of the downstream target p70S6 kinase (p70S6K). Most importantly, treating subcutaneous HUH6 xenograft tumour bearing mice orally with 5mg/kg/day rapamycin for three weeks resulted in a striking reduction of tumour growth, as evidenced by reduced volume and weight, and moderately lowered tumour-specific alpha-fetoprotein (AFP) serum levels. The anti-tumourigenic effect was primarily ascribed to a significantly reduced proliferation rate upon p70S6K dephosphorylation, as microvascular density of rapamycin-treated compared to vehicle-treated tumours stayed grossly unchanged. Of uttermost clinical importance, we found no evidence for a feedback-loop activation of AKT in vivo. In conclusion, we demonstrate that rapamycin effectively inhibits HB growth both in vitro and in vivo by blocking AKT/mTOR signalling at the level of p70S6K and that rapamycin should be considered to treat HB patients especially those to be indicated for liver transplantation to benefit from its anti-tumourigenic and immunosuppressive properties.

Adaptive designs at European Organisation for Research and Treatment of Cancer (EORTC) with a focus on adaptive sample size re-estimation based on interim-effect size - Corrected Proof

2012-01-27

Abstract: Given the high failure rates and the increased costs of Phase III trials in oncology and the recent explosion of targeted agents, researchers are looking for better design strategies to try and optimise the use of available patients and financial resources. In this context, adaptive designs are seen as promising tools.We reviewed the different possible adaptations in the design of a clinical trial on the basis of the FDA guidance and summarized these. The pro and cons of adaptive designs are highlighted with a focus on one of the more ‘controversial’ adaptive designs, the sample size reassessment based on interim-effect size as proposed by Mehta and Pocock.While group sequential designs are preferable to such adaptive designs, both are difficult to implement in the case of rapid accrual and long time to event. Adaptive designs may have some potential in less favourable situations. However, the increase in overall power should be carefully weighted as well as the risk of a large negative trial.Adaptive designs need good, sometimes extensive, logistics. Some adaptive designs (e.g. group sequential designs) proved to be very useful and are already a part of the standard repertoire of trial designs used at European Organisation for Research and Treatment of Cancer (EORTC). Adaptive designs need strong measures to prevent bias that could otherwise become uncontrollable, particularly if interim results are leaked. This includes a prospective planning of adaptations.Finally, these studies currently have the potential to induce a heavy workload and cost linked to their regulatory management.

Inhibition of human hepatocellular carcinoma HepG2 by phthalocyanine photosensitiser ZnPcS2P2: ROS production, apoptosis, cell cycle arrest - Corrected Proof

2012-01-24

Abstract: Photodynamic therapy (PDT) has been accepted as an alternative treatment for cancer. The rationale for the development of PDT for cancer is that target specificity can be achieved by controlling the location at which light activates the drug, i.e. photosensitiser. Metal phthalocyanines represent a new class of photosensitisers developed for cancer treatment. In the present study, we focused on exploring molecular mechanisms of the lead photosensitiser ZnPcS2P2 on hepatocellular carcinoma (HCC) HepG2 cells to guide our future development of ZnPcS2P2. Growth inhibition potency of ZnPcS2P2 and its analogues was tested in vitro with and without irradiation at wavelength 670nm. Irradiation shifted the concentration-growth inhibition curves of ZnPcS2P2 to the left and decreased the IC50s of ZnPcS2P2 required to produce equivalent inhibition by 200-fold on various cell lines. The amphipathic ZnPcS2P2 permeated through HepG2 cell membrane and predominately distributed to lysosome and mitochondria, where it significantly reduced mitochondrial membrane potential (ΔΨm) and increased caspase-3 activity in a concentration-dependent manner after irradiation. Early apoptosis of HepG2 occurred followed by necrosis when concentrations of ZnPcS2P2 were increased in the presence of irradiation. Reactive oxygen species (ROS) production was significant following ZnPcS2P2 plus irradiation treatment and cell cycle was mainly arrested at G2/M stage. In conclusion, ZnPcS2P2, once irradiated, induces HepG2 cells into apoptosis via reducing ΔΨm, producing ROS, activating caspase-3, and causing cell arrest at G2/M stage. This study provides important insights into molecular mechanisms of the anti-cancer ZnPcS2P2, which now is in the clinical trials II in China.

Quantifying heterogeneity in human tumours using MRI and PET - Corrected Proof

2012-01-24

Abstract: Most tumours, even those of the same histological type and grade, demonstrate considerable biological heterogeneity. Variations in genomic subtype, growth factor expression and local microenvironmental factors can result in regional variations within individual tumours. For example, localised variations in tumour cell proliferation, cell death, metabolic activity and vascular structure will be accompanied by variations in oxygenation status, pH and drug delivery that may directly affect therapeutic response. Documenting and quantifying regional heterogeneity within the tumour requires histological or imaging techniques. There is increasing evidence that quantitative imaging biomarkers can be used in vivo to provide important, reproducible and repeatable estimates of tumoural heterogeneity.In this article we review the imaging methods available to provide appropriate biomarkers of tumour structure and function. We also discuss the significant technical issues involved in the quantitative estimation of heterogeneity and the range of descriptive metrics that can be derived. Finally, we have reviewed the existing clinical evidence that heterogeneity metrics provide additional useful information in drug discovery and development and in clinical practice.

Radiomics: Extracting more information from medical images using advanced feature analysis - Corrected Proof

2012-01-18

Abstract: Solid cancers are spatially and temporally heterogeneous. This limits the use of invasive biopsy based molecular assays but gives huge potential for medical imaging, which has the ability to capture intra-tumoural heterogeneity in a non-invasive way. During the past decades, medical imaging innovations with new hardware, new imaging agents and standardised protocols, allows the field to move towards quantitative imaging. Therefore, also the development of automated and reproducible analysis methodologies to extract more information from image-based features is a requirement. Radiomics – the high-throughput extraction of large amounts of image features from radiographic images – addresses this problem and is one of the approaches that hold great promises but need further validation in multi-centric settings and in the laboratory.

Combining capecitabine and bevacizumab in metastatic breast cancer: A comprehensive review - Corrected Proof

2012-01-18

Abstract: Both capecitabine and bevacizumab are established agents in the treatment of metastatic breast cancer, but until recently clinical data supporting their use in combination were limited. We review available data on the capecitabine–bevacizumab combination in breast cancer, particularly results from the RIBBON-1 trial in the first-line setting, and we discuss these findings in light of previous studies. We also examine ongoing trials investigating capecitabine–bevacizumab combination therapy.

The antitumour activities induced by pegylated liposomal cytochalasin D in murine models - Corrected Proof

2012-01-18

Abstract: Cytochalasin D targets actin and is ubiquitous in eukaryotic cells. When cytochalasin D is used as a cytotoxic agent in cancer therapy, it causes significant side effects. To prevent this, cytochalasin D can be encapsulated in polyethylene liposomes. In this study, high-performance liquid chromatography observation of the biodistribution of pegylated liposomal cytochalasin D in tumour-bearing mice showed that liposomal cytochalasin D could be conveniently dissolved in water for i.v. injection and that it specifically accumulated in tumour tissues, more than natural cytochalasin D did. The half-time of liposomal cytochalasin D in the plasma was also significantly longer than that of natural cytochalasin D (4h versus 10min). MTT 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that liposomal cytochalasin D treatment could cause significant inhibition of cell proliferation in vitro in a manner similar to that of natural cytochalasin D. The antitumour activities of liposomal cytochalasin D were investigated in B16 melanoma, CT26 colorectal carcinoma and H22 hepatoma models, and the results indicated that liposomal cytochalasin D could significantly inhibit tumour growth and prolong survival in a manner similar to that of cisplatin. TUNEL-based apoptosis assays showed that liposomal cytochalasin D induced significant tumour cell apoptosis. Significant inhibition of tumour angiogenesis was observed in mice treated with liposomal cytochalasin D. In addition, no significant side effects were observed in mice treated with liposomal cytochalasin D. Our results show that liposomal cytochalasin D increases solubility and bioavailability, a lower incidence of side effects and improves antitumour effects, indicating its potential as a chemical agent for cancer therapy.

Trucut biopsy of breast lesions: The first step toward international standards in developing countries - Corrected Proof

2012-01-16

Abstract: The new concept in breast cancer diagnosis and treatment is based on a less invasive, more accurate and effective strategy, with a multidisciplinary approach in a specialised breast unit. When indicated, conservative surgery has replaced mastectomy with sentinel-node biopsy substituting routine axillary dissection. But the key factor in respect of these new standards is to confirm the cancer before going to the operating room. Trucut biopsy is performed instead of incisional or excisional biopsy and frozen section. The technique is reliable, simple, and reproducible, and not at all expensive; it can be adapted even for low-income developing countries.Materials and methods: Between March 2006 and June 2010, 764 patients under clinical suspicion of cancer and/or with BIRADS (Breast Imaging Reporting and Data System) III–V in imaging in one university and one private hospital in Tehran, Iran underwent trucut biopsy (60% palpable and 40% non-palpable lesions). Cancer was found in 30.8% of the cases. In benign pathology, in concordance with clinical and imaging suspicion, surgery was omitted with short-term follow-up. For palpable symptomatic benign lesions surgery was performed to relieve the patient’s symptoms. When the pathology report was not in concordance with clinical/imaging suspicion (1.8%), and in the presence of moderate and severe hyperplasia with or without atypia, in lobular and papillary lesions (4.9%) open biopsy was done to rule out cancer (10 added cancers, 1.3%; total cancers 32.1%). Cancer surgery was done as a single procedure in 89.8% of cases.Conclusion: Trucut biopsy for breast lesion assessment is the first step toward a new concept in breast cancer care. It is simple, reduces the number of surgeries (no surgery for non-symptomatic benign lesions and one surgery for cancer), and avoids diagnostic errors with full respect for the patient’s rights. We insist on its routine use to extend international guidelines while decreasing the total cost of this common disease in all low-resource countries.

Effect of cigarette smoking on quality of life in small cell lung cancer patients - Corrected Proof

2012-01-16

Abstract: Background: Continued cigarette smoking after small cell lung cancer (SCLC) diagnosis has been shown to shorten patients’ survival, but little is known about the impact of smoking and cessation on quality of life (QOL) profile (e.g., overall QOL, pain, fatigue, cough, dyspnea, appetite change, and performance status) in SCLC survivors (who survived at least 6months post initial diagnosis). In this study, we sought to evaluate the relationship between cigarette smoking and QOL profiles in SCLC patients.Methods: A total of 223 survivors were classified into five groups: never smokers, former smokers (quit more than 1year prior to diagnosis), recent quitters (quit within 1year surrounding diagnosis), late quitters (quit after 1year post diagnosis) and never quitters. One hundred and sixty-eight of these survivors were matched with 334 lung-cancer-free controls on age, gender, and smoking status for comparative analysis. QOL scales were scored from 0 (worse) to 100 (best). Conditional logistic regression, linear mixed-effect models, and Wilcoxon signed rank tests were used.Results: SCLC survivors consistently showed a significant deficit in QOL profile; e.g., mean overall QOL in patients was 17.5 points worse than the controls (p<0.0001). Among all smokers, former smokers reported the best QOL profile, while late or never quitters reported the worst. The recent quitters showed an improving trend in QOL profile and lower percent of reduced appetite (an average of 43%) compared to the late or never quitters (58%).Conclusions: Our study confirmed the negative impact of smoking on SCLC survivors’ QOL and found that smoking cessation surrounding the time of diagnosis could improve overall QOL and symptoms. The findings of this study provide evidence for oncologists to recommend smoking cessation to their SCLC patients.

Phase II study of biweekly cetuximab in combination with irinotecan as second-line treatment in patients with platinum-resistant gastro-oesophageal cancer - Corrected Proof

K.R. Schønnemann, M. Yilmaz, J.K. Bjerregaard, K.M. Nielsen, P. Pfeiffer — 2012-01-16

Abstract: Background: The purpose of this phase II trial was to evaluate the efficacy and safety of cetuximab and irinotecan as second-line treatment in patients with gastro-oesophageal adenocarcinoma.Patients and methods: Patients with failure to first-line platinum-based chemotherapy received cetuximab 500mg/m2 and irinotecan 180mg/m2 every second week until disease progression. Toxicity was evaluated according to The Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v. 3.0. Antitumour activity was assessed according to Response Evaluation Criteria in Solid Tumours (RECIST) v. 1.0.Results: Sixty-three patients were enrolled, median age was 60years, median performance status was 1 (0–1), 35 patients had two or more organs involved. The median number of courses was 5 (range 1–25). Response rate was 11% (6 partial response (PR)) and 37% had stable disease. Median progression free survival was 2.8months and overall survival (OS) was 6.1months. Grade 3–4 toxicity included: diarrhoea (6%), fatigue (5%), vomiting (5%) and neutropenia (16%). Two patients developed febrile neutropenia. Forty-six patients (73%) had developed grade 1–2 skin rash. Patients developing skin rash had a prolonged survival with an OS at 7.1months.Conclusions: The combination of cetuximab and irinotecan is active as second-line therapy in patients with gastro-oesophageal cancer. Cetuximab induced skin rash was associated with prolonged survival.

Prognostic stratification for children with hepatoblastoma: The SIOPEL experience - Corrected Proof

2012-01-16

Abstract: Purpose: To identify factors relevant to long-term outcome in newly diagnosed hepatoblastoma, and define subgroups for clinical research on tailoring treatment to the individual patient.Patients and methods: Between 1995 and 2006 the SIOPEL group conducted two clinical trials which established risk-adapted therapy for hepatoblastoma patients. Patients were stratified into high-risk (AFP<100ng/mL and/or PRETEXT IV and/or vascular invasion and/or extra-hepatic intra-abdominal disease (V+/P+/E+) and/or metastases) and standard-risk (all others). The hierarchy of these factors plus multifocality, PRETEXT III, AFP>1,200,000ng/mL, patient age, platelet count and histology were further explored. The outcome measure was event-free survival (EFS).Results: In 541 patients, reduced EFS correlated significantly with AFP<100ng/ml (hazard ratio [HR] 4.09, 95% confidence interval 2.16–7.75), AFP⩾1.2×106ng/mL (2.48, 1.47–4.17), metastatic disease (3.02, 2.05–4.44), PRETEXT IV (2.15, 1.19–3.87), multifocality (1.59, 1.01–2.50), age>5years (2.76, 1.68–4.53); borderline with small cell undifferentiated (SCU) histology (2.29, 95% confidence interval 0.91–5.77); but not with PRETEXT III, age 30–60months, platelet count or V+/P+/E+. By using the significant factors and SCU to stratify the population, we have identified three distinct prognostic groups: PRETEXT I/II/III, and no other factors, have 3year EFS of 90%, PRETEXT IV and/or multifocal tumour and/or age>5years and/or AFP>1.2×106 have 3year EFS of 71% and SCU and/or AFP<100ng/mL and/or metastatic have a 3year EFS of 49%.Conclusion: Prognostic stratification for clinical research on newly diagnosed hepatoblastoma should take into consideration PRETEXT, metastatic disease, AFP, multifocality, age and SCU histology.

Primary treatment and prognostic factors of small cell neuroendocrine carcinoma of the uterine cervix: A Taiwanese Gynecologic Oncology Group study - Corrected Proof

2012-01-16

Abstract: Background: Our aims were to investigate the treatment and clinicopathological variables in relation to prognosis in small cell neuroendocrine cervical carcinoma (SCNECC).Patients and methods: Clinical data of SCNECC patients with International Federation of Gynaecology and Obstetrics (FIGO) stages I–IV treated between 1987 and 2009 at member hospitals of the Taiwanese Gynecologic Oncology Group (TGOG) were retrospectively reviewed.Results: Of the 179 eligible patients, 104 were of FIGO stage I, 19 stage IIA, 23 stage IIB, 9 stage III, and 24 stage IV. The median failure-free survival (FFS) was 16.0months, and the median cancer-specific survival (CSS) was 24.8months. In multivariate analysis, FIGO stage and lymph node metastasis were selected as independent variables in stages I–IV. In stages IIB–IVB, primary treatment containing etoposide and platinum for at least 5 cycles (EP5+) (n=16) was associated with significantly better 5-year FFS (42.9% versus 11.8%, p=0.041) and CSS (45.6% versus 17.1%, p=0.035) compared to other treatments (n=40). Furthermore, concurrent chemoradiation with EP5+ (CCRT-EP5+) was associated with even better 5-year FFS (62.5% versus 13.1%, p=0.025) and CSS (75.0% versus 16.9%, p=0.016).Conclusions: FIGO stage and lymph node metastasis are significant prognostic factors in SCNECC. In stages IIB–IVB, CCRT-EP5+ might be the treatment of choice, which could be also true for earlier stages. Despite limitations of a retrospective study spanning a long time period and heterogeneous managements, the results provide an important basis for designing future prospective studies.

A phase II trial of second-line pemetrexed in adults with advanced/metastatic osteosarcoma - Corrected Proof

2012-01-16

Abstract: Background: Osteosarcoma is the most common primary malignant tumour in young adults. An effective treatment strategy for relapsed patients is still not defined. Pemetrexed is a multitargeted antifolate with a mode of action similar to, and a range of action broader than that of methotrexate. The primary objective of this phase II study was to determine tumour response rate in patients with high-grade, advanced/metastatic osteosarcoma. Secondary end-points included progression-free survival (PFS), overall survival (OS) and safety.Methods: Pemetrexed 500mg/m2 was administered on day 1 of 21-day cycles with folic acid and vitamin B12 supplementation. At least 5 tumour responses in a targeted population of 32 were required to consider further investigation.Results: Thirty-two patients (median age, 43.3years; range, 18.6–76.0) with 1 prior chemotherapy regimen for high-grade advanced/metastatic osteosarcoma were enrolled. Thirty (93.8%) patients had an ECOG performance status ⩽1 and 29 (90.6%) had metastases in the lung. One patient had partial response (3.1%) and 5 (15.6%) had stable disease. Median PFS and OS were 1.4months (95% CI: 1.4–1.7) and 5.5months (95% CI: 2.3–10.5), respectively. The most common drug-related grade 3/4 toxicities were leukopaenia, asthaenia and elevated alanine aminotransferase in 3 (9.4%) patients each. One patient died due to multi-organ failure considered possibly related to the study drug.Conclusions: Pemetrexed 500mg/m2 administered on day 1 of 21-day cycles as second-line treatment to patients with advanced/metastatic high-grade osteosarcoma was generally well tolerated but did not meet minimal response expectations for further investigation in this patient population.

A randomised phase II study of the efficacy, safety and cost-effectiveness of pegfilgrastim and filgrastim after autologous stem cell transplant for lymphoma and myeloma (PALM study) - Corrected Proof

2012-01-16

Abstract: Aim: To evaluate in a multicentre randomised study the effect on duration of febrile neutropenia (FN), the safety and cost-effectiveness of a single subcutaneous pegfilgrastim injection compared with daily injections of filgrastim after peripheral blood stem cell transplantation in patients receiving high dose chemotherapy for myeloma and lymphoma.Methods: Patients were randomly assigned to a single dose of pegfilgrastim at day 5 (D5) or daily filgrastim from D5 to the recovery of absolute neutrophil count (ANC) to 0.5G/L. Duration of FN, of neutrophil and platelet recovery, transfusion and antibiotic requirements were the main end-points of the study. Costs were calculated from D0 until transplant unit discharge. The incremental cost-effectiveness ratio was expressed as the cost per day of FN prevented. Probabilistic sensitivity analysis was performed by non-parametric bootstrap methods.Results: Between October 2008 and September 2009, 10 centres enrolled 151 patients: 80 patients with lymphoma and 71 patients with myeloma. The mean duration of FN was 3.07days (standard deviation (SD) 1.96) in the pegfilgrastin arm and 3.29 (SD 2.54) in the filgrastim one. Mean total costs were 23,256 and 25,448euros for pegfilgrastim and filgrastim patients, respectively. There was a 62% probability that pegfilgrastim strictly dominates filgrastim.Concluding statement: Pegfilgrastim after PBSC transplantation in myeloma and lymphoma is safe, effective when compared with filgrastim and could represent a cost-effective alternative in this setting.

A randomized phase II trial of S-1-oxaliplatin versus capecitabine–oxaliplatin in advanced gastric cancer - Corrected Proof

2012-01-16

Abstract: Purpose: S-1 or capecitabine plus oxaliplatin are considered active and tolerable in gastric cancer patients. We conducted a randomized phase II trial in gastric cancer patients to compare the activity and safety of these combinations.Methods: The patients received S-1 at 80mg/m2 for 14days, followed by a 7-day rest period within a 3-week schedule in the S-1/oxaliplatin (SOX) arm, and capecitabine at 2000mg/m2 for 14days, followed by a 7-day rest period within a 3-week schedule in the capecitabine/oxaliplatin (CAPOX) arm. Oxaliplatin 130mg/m2 was administered every 3weeks in both arms.Results: One hundred twenty-nine patients were randomly assigned to SOX (N=65) or CAPOX (N=64). The median time to progression and the overall survival were 6.2 and 12.4months with SOX, respectively; and 7.2 and 13.3months with CAPOX, respectively. The overall response rates were 40% and 44% for SOX and CAPOX, respectively. The most frequent grade 3 or 4 toxicities were thrombocytopenia (15.4%) for SOX and neutropenia (18.8%) for CAPOX. The median time to 10% deteriorations in global health scores was similar in both arms (SOX, 4.3months, CAPOX, 4.9months).Conclusion: Both the SOX and CAPOX regimens were equally active and well tolerated in advanced gastric cancer patients.

A DNA methylation signature associated with aberrant promoter DNA hypermethylation of DNMT3B in human colorectal cancer - Corrected Proof

2012-01-16

Abstract: Altered promoter DNA methylation, one of the most important molecular alterations in cancer, is proposed to correlate with deregulation of DNA methyltransferases, although the molecular mechanisms implicated are still poorly understood. Here we show that the de novo DNA methyltransferase DNMT3B is frequently repressed in human colorectal cancer cell lines (CCL) and primary tumours by aberrant DNA hypermethylation of its distal promoter. At the epigenome level, DNMT3B promoter hypermethylation was associated with the hypomethylation of gene promoters usually hypermethylated in the healthy colon. Forced DNMT3B overexpression in cancer cells restored the methylation levels of these promoters in the healthy colon. Our results show a new molecular mechanism of aberrant DNMT3B regulation in colon cancer and suggest that its expression is associated with the methylation of constitutively hypermethylated promoters in the healthy colon.

A novel apoptotic mechanism of genetically engineered adenovirus-mediated tumour-specific p53 overexpression through E1A-dependent p21 and MDM2 suppression - Corrected Proof

2012-01-16

Abstract: Oncolytic viruses engineered to replicate in tumour cells but not in normal cells could be used as tumour-specific vectors carrying the therapeutic genes. We previously developed a telomerase-specific oncolytic adenovirus, OBP-301, that causes cell death in human cancer cells with telomerase activities. Here, we further modified OBP-301 to express the wild-type p53 tumour suppressor gene (OBP-702), and investigated whether OBP-702 induces stronger antitumour activity than OBP-301. The antitumour effect of OBP-702 was compared to that of OBP-301 on OBP-301-sensitive (H358 and H460) and OBP-301-resistant (T.Tn and HSC4) human cancer cells. OBP-702 suppressed the viability of both OBP-301-sensitive and OBP-301-resistant cancer cells more efficiently than OBP-301. OBP-702 caused increased apoptosis compared to OBP-301 or a replication-deficient adenovirus expressing the p53 gene (Ad-p53) in H358 and T.Tn cells. Adenovirus E1A-mediated p21 and MDM2 downregulation was involved in the apoptosis caused by OBP-702. Moreover, OBP-702 significantly suppressed tumour growth in subcutaneous tumour xenograft models compared to monotherapy with OBP-301 or Ad-p53. Our data demonstrated that OBP-702 infection expressed adenovirus E1A and then inhibited p21 and MDM2 expression, which in turn efficiently induced apoptotic cell death. This novel apoptotic mechanism suggests that the p53-expressing OBP-702 is a promising antitumour reagent for human cancer and could improve the clinical outcome.

Simultaneous inhibition of Src and Aurora kinases by SU6656 induces therapeutic synergy in human synovial sarcoma growth, invasion and angiogenesis in vivo - Corrected Proof

2012-01-16

Abstract: Synovial sarcoma is an obstinate, high-grade malignancy because of its modest responses to radiotherapy and chemotherapy; the identification of effective therapeutics for this sarcoma is therefore necessary. Inhibition of Src family kinases (SFKs) suppresses the proliferation of synovial sarcoma cells in vitro, as we have previously reported. In this study, to validate the efficacy of Src inhibition in vivo, we employed SU6656, which was originally identified as a specific SFK inhibitor. SU6656 treatment significantly impaired the growth of established, existing tumours formed by synovial sarcoma cells in mice. Tumour cell invasion into the surrounding tissues was also abolished by SU6656. It is noteworthy that SU6656 but not PP2 induced a defect in cleavage furrow formation during cytokinesis, resulting in G2/M accumulation and subsequent apoptosis. Intriguingly, SU6656 abrogated the catalytic activities of Aurora kinases and led to the down-regulation of phosphorylated histone H3 coincidently with p53 accumulation, as did the Aurora kinase inhibitor VX-680. Structural comparison indicated an extensive similarity between the catalytic domains of SFKs and Aurora kinases. The structural analysis also revealed the potential binding mode of SU6656 to the ATP-binding cleft of Aurora B via four hydrogen bonds. SU6656 prevented angiogenesis within the tumours by attenuating vascular endothelial growth factor (VEGF) production by tumour cells and the subsequent chemotaxis of endothelial cells; these effects were the result of the inhibition of SFKs but not Aurora kinases. Based on these results, we hereby report a novel property of SU6656 as a dual inhibitor of SFKs and Aurora kinases, the suppression of both of which effectively abrogates tumour development and the progression of synovial sarcoma in vivo.

Electroporation adopting trains of biphasic pulses enhances in vitro and in vivo the cytotoxic effect of doxorubicin on multidrug resistant colon adenocarcinoma cells (LoVo) - Corrected Proof

2012-01-13

Abstract: Few articles in the literature have focused on electroporation as a strategy to reverse multidrug resistance (MDR) of tumour cells and they are mostly limited to the improved efficacy of bleomycin. We tested the application of trains of biphasic pulses to cell suspensions and to murine xenografts as a strategy to increase the uptake of doxorubicin (DOX) and to enhance its cytotoxicity against chemoresistant cells. The human colon adenocarcinoma cell line LoVo DX, expressing MDR phenotype with high levels of P-glycoprotein (P-gp), has been used. The in vitro and in vivo studies gave the following results: (i) the application of the electric pulses to the cell suspension, immediately before DOX administration, induced a significant increase of drug retention; (ii) confocal microscopy observations showed a remarkable increase of intranuclear accumulation of DOX induced by electroporation; (iii) cell survival assay revealed a decrease of cell viability in the cultures treated with the combination of electroporation and doxorubicin; (iv) scanning electron microscopy observations revealed consistent morphological changes after the combined exposure to electroporation and doxorubicin; (v) in implanted mice the combined treatment induced an evident slowdown on the tumour growth when compared to treatment with DOX alone; (vi) histopathological analysis evidenced tumour destruction and its replacement by scar tissue in the tumours treated with the combination of doxorubicin and electroporation.

First-line treatment of metastatic or locally advanced unresectable soft tissue sarcomas with conatumumab in combination with doxorubicin or doxorubicin alone: A Phase I/II open-label and double-blind study - Corrected Proof

2012-01-13

Abstract: Background: Conatumumab is a fully human monoclonal agonist antibody that binds to death receptor 5 and induces apoptosis in sensitive cells. This study evaluated the safety and efficacy of doxorubicin±conatumumab as first-line systemic therapy for metastatic or locally advanced/unresectable soft-tissue sarcoma.Methods: In Phase I, six patients received doxorubicin (75mg/m2) with conatumumab (15mg/kg) every 3weeks. In Phase II, patients were randomised (2:1) to receive doxorubicin with either double-blind conatumumab 15mg/kg (conatumumab–doxorubicin; n=86) or placebo (placebo–doxorubicin; n=42). Patients who progressed on placebo–doxorubicin could receive open-label conatumumab monotherapy post-chemotherapy (n=21).Findings: The expected histopathologic subtypes (e.g. leiomyosarcoma, liposarcoma, others) were represented in this trial. No unexpected adverse events were noted in either Phase I or II. Median progression-free survival in Phase II was 5.6 and 6.4months in the conatumumab–doxorubicin and placebo–doxorubicin arms, respectively (stratified HR: 1.00; p=0.973), with more early progressions noted in the first 3.5months in the conatumumab–doxorubicin arm. Median overall survival was not reached after 8.6months median follow-up in either arm. Common adverse events were nausea (conatumumab–doxorubicin: 66%; placebo–doxorubicin: 80%), alopecia (55%; 63%), fatigue (60%; 38%) and neutropenia (32%; 50%). Post-chemotherapy results were not notably improved by conatumumab dosing.Interpretation: Addition of conatumumab to doxorubicin appeared to be safe but did not improve disease control in a heterogeneous unselected group of patients with soft tissue sarcomas. The results of this trial are very useful for estimating the outcomes of first-line therapy of sarcoma patients treated with standard doxorubicin.Funding: This study was supported by Amgen Inc.

Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to baseline status: Subset analyses of the phase III Sorafenib Asia–Pacific trial - Corrected Proof

2012-01-12

Abstract: Background: The phase III Sorafenib Asia–Pacific (AP) trial—conducted in China, Taiwan and South Korea – confirmed that sorafenib improves overall survival (OS) and is safe for patients with advanced hepatocellular carcinoma (HCC). We performed a series of exploratory subset analyses to determine whether baseline status affected response to sorafenib.Methods: In the Sorafenib AP trial, 226 patients with well-preserved liver function (>95% Child-Pugh A) were randomised 2:1 to sorafenib 400mg bid or matching placebo. Subanalyses were based on aetiology (hepatitis B virus present/absent); tumour burden (macroscopic vascular invasion and/or extrahepatic spread present/absent); presence or absence of either lung or lymph node metastasis at baseline, Eastern Cooperative Oncology Group performance status (0, 1–2); serum concentrations of alanine aminotransferase/aspartate aminotransferase (normal, mildly elevated, moderately elevated), alpha-fetoprotein (normal/elevated) and total bilirubin (normal/elevated); and whether or not there was a history of hepatectomy or transarterial chemoembolisation/embolisation. Subgroup assessments included OS, time to progression (TTP), disease control rate and safety.Findings: Sorafenib consistently improved both median OS and median TTP, compared with placebo (range of hazard ratios (HR), 0.32–0.87 and 0.31–0.75, respectively). The most common grade 3/4 adverse events were hand-foot skin reaction, diarrhoea and fatigue, the incidence of which was similar between subgroups.Interpretation: The efficacy and safety profiles of sorafenib in the subpopulations described were comparable with those in the overall study population. These exploratory analyses suggest that sorafenib is effective for patients from the AP region with advanced HCC, irrespective of baseline status.

Imaging apoptosis with positron emission tomography: ‘Bench to bedside’ development of the caspase-3/7 specific radiotracer [18F]ICMT-11 - Corrected Proof

2012-01-09

Abstract: The capacity to evade apoptosis has been defined as one of the hallmarks of cancer and, thus, effective anti-cancer therapy often induces apoptosis. A biomarker for imaging apoptosis could assist in monitoring the efficacy of a wide range of current and future therapeutics. Despite the potential, there are limited clinical examples of the use of positron emission tomography for imaging of apoptosis. [18F]ICMT-11 is a novel reagent designed to non-invasively image caspase-3 activation and, hence, drug-induced apoptosis. Radiochemistry development of [18F]ICMT-11 has been undertaken to improve specific radioactivity, reduce content of stable impurities, reduce synthesis time and enable automation for manufacture of multi-patient dose. Due to the promising mechanistic and safety profile of [18F]ICMT-11, the radiotracer is transitioning to clinical development and has been selected as a candidate radiotracer by the QuIC-ConCePT consortium for further evaluation in preclinical models and humans. A successful outcome will allow use of the radiotracer as qualified method for evaluating the pharmaceutical industry’s next generation therapeutics.

Apparent diffusion coefficient from magnetic resonance imaging as a biomarker in oncology drug development - Corrected Proof

2012-01-09

Abstract: Magnetic resonance imaging (MRI) can be made sensitive to diffusion of water molecules in biological tissues: this phenomenon can be quantitated to provide a biomarker, the apparent diffusion coefficient (ADC). Over the past decade, evidence has accumulated from numerous clinical and animal studies that ADC is abnormal in tumours; that elevated ADC reflects an elevated non-cellular fraction; and that acute increases in ADC following therapy can indicate that tumour cells have been killed. However there remain substantial challenges in ensuring robust and valid ADC measurements, particularly in multicentre studies in common sites of metastasis such as lung and liver. Moreover, there is uncertainty about how best to select the timing of observation post-therapy to avoid false-negatives, and how to minimise the confounding factors which could decouple drug-induced ADC increase from drug-induced cell kill. In this review we summarise the physical basis of the biomarker, the evidence that it reflects non-viable fraction, particularly in extracranial tumours, and suggest a roadmap for validation and qualification.

Qualification of imaging biomarkers for oncology drug development - Corrected Proof

John C. Waterton, Liisa Pylkkanen — 2012-01-09

Abstract: Although many imaging biomarkers have been described for cancer research, few are sufficiently robust, reliable and well-characterised to be used as routine tools in clinical cancer research. In particular, biomarkers which show that investigational therapies have reduced tumour cell proliferation, or induced necrotic or apoptotic cell death are not commonly used to support decision-making in drug development, even though such pharmacodynamic effects are common goals of many classes of investigational drugs. Moreover we lack well-qualified biomarkers of propensity to metastasise. The qualification and technical validation of imaging biomarkers poses unique challenges not always encountered when validating biospecimen biomarkers. These include standardisation of acquisition and analysis, imaging-pathology correlation, cross-sectional clinical–biomarker correlations and correlation with outcome. Such work is ideally suited to precompetitive research and public–private partnerships, and this has been recognised within the Innovative Medicines Initiative (IMI), a Joint Undertaking between the European Union and the European Federation of Pharmaceutical Industries and Associations, which has initiated projects in the areas of drug safety, drug efficacy, knowledge management and training.

Subjective assessment by ultrasound is superior to the risk of malignancy index (RMI) or the risk of ovarian malignancy algorithm (ROMA) in discriminating benign from malignant adnexal masses - Corrected Proof

2012-01-09

Abstract: Purpose: The combination of two tumour markers, CA125 and HE4, in the risk of ovarian malignancy assay (ROMA) has been shown to be successful in classifying patients into those who have a high or low risk of epithelial ovarian cancer. In the present study, the diagnostic accuracy of ROMA was assessed and compared to the diagnostic accuracy of the two most widely used ultrasound methods, namely the risk of malignancy index (RMI) and subjective assessment by ultrasound.Methods: From August, 2005 to March, 2009, 432 women with a pelvic mass who were scheduled to have surgery were enrolled in a single-centre prospective cohort study. A preoperative ultrasound was performed and preoperative CA125 and HE4 serum levels were measured. Once the final surgical pathology reports were obtained, the diagnostic accuracy and performance indices of ROMA, RMI and subjective assessment were calculated.Results: Of the 432 eligible patients, 374 could be analysed. Subjective assessment had the highest area under the receiver operator characteristic curve (AUC) (0.968, 95%CI:0.945–0.984), followed by the RMI (0.931, 95%CI:0.901–0.955). The subjective assessment and RMI both had significantly higher AUCs than the ROMA (0.893, 95%CI:0.857–0.922; P<0.0001 and P=0.0030, respectively). The pre- and postmenopausal populations generated similar results.Conclusion: Although new tumour markers models are promising, they do not contribute significantly to the diagnosis of ovarian cancer. Ultrasound, especially subjective assessment by ultrasound, remains superior in discriminating malignant from benign ovarian masses.

Tumour-derived IL-10 within tumour microenvironment represses the antitumour immunity of Socs1-silenced and sustained antigen expressing DCs - Corrected Proof

2012-01-09

Abstract: It has been shown that silencing of suppressor of cytokine signalling 1 (Socs1) or stably expressing transgenic protein Ags in antigen-presenting dentritic cells (DCs) strongly enhances antigen-specific anti-tumour immunity. However, whether the strong and long-lasting T cell responses induced by the modified DCs could modulate the immunosuppressive tumour microenvironment has not been clarified. In this study, we explored the anti-tumour immunity of DCs modified by Socs1-shRNA lentiviral transduction combined with sustained expression of TRP2 in different tumour models. We showed that transfer Socs1-silenced or tumour antigen TRP2 persistent expressed DCs, or DCs modified by combination of Socs1-silencing and sustaining TRP2 expression prior to inoculation of tumour cells delayed B16 tumour cell growth, prolonged mouse survival and increased the ratio of CD8+ T/Treg as well as the CTL activity in tumours. However, there was no significant effect on tumour growth and mouse survival rate upon tumour established. Further, we showed that tumour cell secreted IL-10 counteracted the immunity of modified DCs in established tumour model, injection of Socs1-shRNA and TRP2 antigen modified significantly inhibited growth of the established B16-IL-10–/− tumours. These data indicated that the high level of IL-10 within tumour microenvironment is one of factors that compromise DC vaccine functions.

Allergy-associated symptoms in relation to childhood non-Hodgkin’s as contrasted to Hodgkin’s lymphomas: A case–control study in Greece and meta-analysis - Corrected Proof

2012-01-09

Abstract: An increase of the prevalence of childhood allergic diseases and the incidence of childhood Hodgkin’s (HL) and non-Hodgkin’s lymphoma (NHL) were reported in the late 20th century. Among adults, several studies point to an inverse association with lymphoma; it remains to be confirmed whether allergy is also related to childhood lymphomas and whether the association, if any, is of an aetiologic nature. Between 1996 and 2008, 277 children (aged 0–14years) with HL (N=111) or NHL (N=166) were enrolled in Nationwide Registry for Childhood Hematological Malignancies (NARECHEM), a Greek hospital-based-registry of childhood hematological malignancies. Hospital controls were individually matched to cases on age and sex. Multivariate conditional logistic regression was used to estimate odds ratios (ORs) with 95%confidence intervals (CIs) for associations of allergic diseases and other covariates with childhood HL or NHL risk. Subsequently, we combined our results with those of a French case–control study in a meta-analysis amounting to a total of 330 NHL cases/1478 controls and 239 HL cases/959 controls. After controlling for sociodemographic, perinatal and environmental factors, childhood NHL was less prevalent among children with allergy-associated symptoms overall (OR:0.50, 95%CI:0.27–0.92) or a history of asthma (OR:0.43, 95%CI:0.21–0.88). By contrast, allergy did not seem to be associated with childhood HL risk, although statistical power was limited. Fewer seaside holidays and higher birth weight were also associated with increased childhood NHL risk. The combined OR of the two studies for the association of asthma with NHL risk was: 0.52, 95%CI:0.32–0.84, whereas for HL: 0.86, 95%CI:0.51–1.45. Allergy seems to be strongly and inversely associated with childhood NHL. It remains to be elucidated in future investigations comprising larger populations, focusing on specific disease subtypes and employing more pertinent study-designs, whether this association is genuinely protective.

Epidemiology of glial and non-glial brain tumours in Europe - Corrected Proof

2012-01-09

Abstract: To the central nervous system (CNS) belong a heterogeneous group of glial and non glial rare cancers.The aim of the present study was to estimate the burden (incidence, prevalence, survival and proportion of cured) for the principal CNS cancers in Europe (EU27) and in European regions using population-based data from cancer registries participating in the RARECARE project.We analysed 44,947 rare CNS cancers diagnosed from 1995 to 2002 (with follow up at 31st December 2003): 86.0% astrocytic (24% low grade, 63% high grade and 13% glioma NOS), 6.4% oligodendroglial (74% low grade), 3.6% ependymal (85% low grade), 4.1% Embryonal tumours and 0.1% choroid plexus carcinoma. Incidence rates vary widely across European regions especially for astrocytic tumours ranging from 3/100,000 in Eastern Europe to 5/100,000 in United Kingdom and Ireland. Overall, about 27,700 new rare CNS cancers were estimated every year in EU27, for an annual incidence rate of 4.8 per 100,000 for astrocytic, 0.4 for oligodendroglial, 0.2 for ependymal and embryonal tumours and less than 0.1 for choroid plexus carcinoma.More than 154,000 persons with rare CNS were estimated alive (prevalent cases) in the EU at the beginning of 2008.Five-year relative survival was 14.5% for astrocytic tumours (42.6% for low grade, 4.9% for high grade and 17.5% for glioma NOS), 54.5% for oligodendroglial (64.9% high grade and 29.6% low grade), 74.2% for ependymal (80.4% low grade and 36.6% high grade), 62.8% for choroid plexus carcinomas and 56.8% for embryonal tumours. Survival rates for astrocytic tumours were relatively higher in Northern and Central Europe than in Eastern Europe and in UK and Ireland. The different availability of diagnostic imaging techniques and/or radiation therapy equipment across Europe may contribute to explain the reported survival differences.The estimated proportion of cured patients was 7.9% for the ‘glial’ group to which belong astrocytic tumours.Overall results are strongly influenced by astrocytic tumours that are the most common type.This is the first study to delineate the rare CNS cancer burden in Europe by age, sex and European region.

Mucinous adenocarcinomas: Poor prognosis in metastatic colorectal cancer - Corrected Proof

2012-01-06

Abstract: Purpose: Mucinous histology of metastatic colorectal cancer (CRC) has been associated with poor prognosis, however this has never been assessed in large well-defined study populations treated with the current used systemic agents. We investigated the prognostic value of mucinous histology in two large phase III studies in metastatic CRC.Patients and methods: The study population included 1010 metastatic CRC patients who were treated with chemotherapy and targeted therapies in two phase III studies. Patients were classified according to the histology of the primary tumour in mucinous adenocarcinomas (MC) and non-mucinous adenocarcinomas (AC).Results: Patients with MC (n=99) were older, had more often a normal serum lactate dehydrogenase (LDH), extrahepatic localisation of metastases, larger primary tumour diameter and a higher T classification compared to patients with AC (n=911). A deficient mismatch repair system and BRAF mutations were observed in 17% and 22% of patients with MC, compared to 3% and 7% in patients with AC, respectively. Clinical outcome was investigated in both studies separately, showing a worse overall survival (OS), progression free survival and overall response rate in patients with MC compared to patients with AC. Patients with MC received less cycles of treatment compared to AC, but did not suffer from a higher incidence of grade 3/4 toxicity. In multivariate analysis, mucinous histology was as an independent negative prognostic factor for OS, resulting in a combined hazard ratio of 1.78 (95%confidence interval (CI) 1.35–2.35).Conclusions: Patients with metastatic mucinous CRC have distinct clinicopathological features and poor response to chemotherapy and targeted agents. The strong negative prognostic value of MC warrants the use of this pathological feature as a stratification factor for clinical trials in metastatic CRC.

Fluorescence lifetime imaging of E-combretastatin uptake and distribution in live mammalian cells - Corrected Proof

2012-01-03

Abstract: To investigate within live mammalian cells the uptake and disposition of combretastatins, fluorescence lifetime imaging was used with two-photon excitation (2PE). Combretastatin A4 (CA4) and analogues are potential anticancer drugs due to their ability to inhibit angiogenesis. E(trans)-combretastatins are considerably less active than the Z(cis)-combretastatins proposed for clinical use. However the E-combretastatins exhibit stronger intrinsic fluorescence with quantum yields and lifetimes that depend markedly on solvent polarity and viscosity. It is proposed that 2PE in the red and near-infrared tissue window may allow in situ isomerization of E-combretastatins to the more active Z-isomer, offering spatial and temporal control of drug activation and constitute a novel form of photodynamic therapy. In the present work we have characterised 2PE of E-CA4 and have used fluorescence lifetime imaging with 2PE to study uptake and intracellular disposition of E-CA4 and an analogue. The results show that these molecules accumulate rapidly in cells and are located mainly in lipidic environments such as lipid droplets. Within the droplets the local concentrations may be up to two orders of magnitude higher than that of the drug in the surrounding medium.

[18F]FLT: An imaging biomarker of tumour proliferation for assessment of tumour response to treatment - Corrected Proof

Dmitry Soloviev, David Lewis, Davina Honess, Eric Aboagye — 2012-01-03

Abstract: The paradigm of drug development is shifting towards early use of imaging biomarkers as surrogate end-points in clinical trials. Quantitative Imaging in Cancer: Connecting Cellular Processes (QuIC-ConCePT) is an initiative to qualify complementary imaging biomarkers (IB) of proliferation, cell death and tumour heterogeneity as possible tools in early phase clinical trials to help pharmaceutical developers in ‘go, no-go’ decisions early in the process of drug development. One of the IBs is [18F]3′-deoxy-3′-fluorothymidine with Positron Emission Tomography (FLT–PET). We review results of recent clinical trials using FLT–PET for monitoring tumour response to drug treatment and discuss the potential and the possible pitfalls of using this IB as a surrogate end-point in early phase clinical trials for assessing tumour response to drug treatment. From first human trial results it seems that the degree of FLT accumulation in tumours is governed not only by the tumour proliferation rate but also by other factors. Nevertheless FLT–PET could potentially be used as a negative predictor of tumour response to chemotherapy, and hence evaluation of this IB is granted in multi-centre clinical trials.

Health-related quality of life in patients with high-risk melanoma randomised in the Nordic phase 3 trial with adjuvant intermediate-dose interferon alfa-2b - Corrected Proof

2011-12-26

Abstract: Purpose: To compare health-related quality of life (HRQoL) and side-effects in patients with high-risk melanoma participating in a randomised phase III trial of adjuvant interferon alfa-2b (IFN).Patients and methods: A total of 855 patients with histologically verified resected cutaneous melanoma in AJCC stage IIb (T4 N0 M0) or stage III (Tx N1-3 M0) were randomised to: Arm A: observation only (n=284); Arm B: 1-year treatment: induction: IFN alfa-2b, 10 MU (flat dose), SC, 5days/week, 4weeks, maintenance: IFN alfa-2b, 10 MU (flat dose), SC, 3days/week for 12months (n=285); or Arm C: 2years of same treatment as Arm B. HRQoL was assessed using The European Organisation for Research and Treatment of Cancer Core Questionnaire (EORTC QLQ-C30) before randomisation and at 8 pre-defined time-points during 2years. IFN-related side-effects were assessed by a study-specific questionnaire.Results: >80% of eligible patients returned questionnaires at the different assessment points. Statistically significant interactions between randomisation arm and time after randomisation were found for almost all EORTC QLQ-30 variables. While patients in Arm A improved or remained at baseline levels; patients in Arms B and C reported decreased functioning and quality of life, and an increase in side-effects during their treatment. Patients in Arm B improved after the 12th month assessment, when IFN treatment was scheduled to end, to the 16th month assessment (p<0.001). The same pattern of improvement was found for 5 of 7 interferon-related side-effects.Conclusion: A significant negative impact on HRQoL of IFN treatment was demonstrated, however the impact were reversible when treatment was stopped.

Safety of bevacizumab in metastatic breast cancer patients undergoing surgery - Corrected Proof

2011-12-26

Abstract: Background: Evaluate the safety of surgery in relation to bevacizumab in the first-line treatment of metastatic breast cancer (mBC) in two international trials.Patients and methods: The incidence, type and timing of post-surgical bleeding events and wound-healing complications were assessed in surgical patients in the AVastin And DOcetaxel (AVADO) (NCT00333775) and Avastin THErapy for advaNced breAst cancer (ATHENA) (NCT00448591) trials. Both study protocols followed recommendations to withhold bevacizumab for at least 6weeks before elective surgery and to wait 28days (or until the wound was fully healed) after major surgery before recommencing bevacizumab therapy.Results: In AVADO, 221 surgical procedures (55 major, 166 minor) were performed in 155 patients. In ATHENA, 1190 surgical procedures (435 major, 755 minor) were performed in 672 patients. One bevacizumab-treated AVADO patient (0.9%) who underwent surgery experienced a grade 3 bleeding event. In ATHENA, six patients (0.9%) who underwent surgery experienced grade 3 bleeding events and one patient (0.1%) experienced a grade 4 bleeding event. No grade 5 bleeding events in patients undergoing surgery were reported in either study. One grade 3 wound-healing complication was reported in each of the AVADO arms: placebo (n=46, 2.2%), bevacizumab 7.5mg/kg (n=57, 1.8%) and bevacizumab 15mg/kg (n=52, 1.9%). Incidence of grade 3–4 wound-healing complications in ATHENA was 2.2% and 1.3% in patients undergoing minor or major surgery, respectively.Conclusions: Surgery can be performed on patients with mBC undergoing bevacizumab therapy with a low risk of severe bleeding or wound-healing complications post surgery, if current labelling recommendations are adhered to.

Sexuality and body image in long-term survivors of testicular cancer - Corrected Proof

P. Rossen, A.F. Pedersen, R. Zachariae, H. von der Maase — 2011-12-26

Abstract: Objective: This study explores sexual function and the influence of different treatment modalities on sexual function and body image among long-term survivors of testicular cancer (TCSs).Methods: A long-term follow-up assessment of all testicular cancer patients treated at Aarhus University Hospital, Denmark, from 1990 to 2000 was conducted. A total of 401 survivors (mean age: 46.6years; response rate: 66%) completed questionnaires concerning sexuality and changes in body image. Based on the treatment received, patients were categorised into one of four groups: surveillance, radiotherapy, chemotherapy, or chemotherapy supplemented with retroperitoneal lymph node dissection (RPLND).Results: Sexual dysfunctions were reported: 24% reduced sexual interest, 43% reduced sexual activity, 14% reduced sexual enjoyment, 18% erectile dysfunction, 7% ejaculatory problems and 3% increased sexual discomfort. Seventeen percent of the long-term TCSs reported changes in body image, and this was significantly associated with all six parameters of sexual dysfunction. When comparing treatments, only the RPLND procedure was associated with sexual dysfunction in the form of ejaculatory dysfunction.Conclusion: Apart from RPLND, which was associated with ejaculatory dysfunction, treatment strategies for testicular cancer appeared not to influence sexual dysfunction. The level of erectile dysfunction seen in this sample of TCSs seemed to be higher than the level observed in the general male population and high levels of erectile dysfunction were associated with negative changes in body image. The results suggest that changes in body image are of importance when explaining the variation in sexual dysfunctions, but further prospective studies are needed to clarify this issue.

CXCL5, a promoter of cell proliferation, migration and invasion, is a novel serum prognostic marker in patients with colorectal cancer - Corrected Proof

2011-12-26

Abstract: Purpose: Serum CXCL5 levels in patients with colorectal cancer (CRC) were assessed to evaluate correlation with clinicopathologic features and prognosis. The effects of CXCL5 on CRC cells were also investigated in vitro.Methods: Based on cytokine array analysis, CXCL5 was identified as a novel prognostic serum marker. Serum levels of CXCL5 were assessed in 250 CRC patients and 33 normal volunteers by enzyme-linked immunosorbent assay (ELISA), and their relation to clinicopathologic findings and survival investigated. CXCL5 levels in CRC cell lines were also measured by ELISA, and CXCL5 and CXCR2 expression was evaluated by immunohistochemistry. To investigate the biological role of the CXCL5/CXCR2 axis, recombinant human CXCL5 and CXCR2 neutralisation antibodies were used for proliferation, migration and invasion assays.Results: Preoperative serum CXCL5 was significantly elevated in patients with CRC compared with healthy volunteers (p=0.013). High serum CXCL5 was significantly associated with female sex (p=0.0098) and liver metastasis (p=0.0040). Univariate analysis correlated elevated CXCL5 with poor overall survival (p=0.0002). Multivariate analysis showed that elevated CXCL5 was a significant and independent prognostic factor of survival in all CRC patients (p=0.038). CRC cells secreted CXCL5, and administration of recombinant human CXCL5 promoted proliferation, migration and partial invasion. These effects were generally inhibited by CXCR2 neutralisation antibody.Conclusions: Preoperative serum CXCL5 could serve as a novel predictive marker for prognosis determination of CRC patients. CXCL5/CXCR2 axis might be associated with colorectal cancer progression.

Conditional survival of patients with urothelial carcinoma of the urinary bladder treated with radical cystectomy - Corrected Proof

2011-12-23

Abstract: Aim of study: To examine the impact of survival probability according to duration of survivorship following radical cystectomy (RC) in patients diagnosed with urothelial carcinoma of the urinary bladder (UCUB).Methods: Overall, 4991 UCUB patients who underwent RC were abstracted. The cumulative survival estimates were used to generate conditional survival rates. Cox regression analyses were performed for prediction of cancer-specific mortality (CSM), according to duration of survivorship.Results: The five-year CSM-free survival rate was 63.9% at RC, and increased to 71.0%, 77.5%, 81.7%, 85.9% and 86.3% in patients who survived ⩾1, 2, 3, 4 and 5years, respectively. Patients with pT2–4 disease benefitted from the highest increase in survivorship two years after RC. The same findings were recorded according to patients’ nodal status.Conclusion: The survival of the first two years after RC markedly improves individual patient prognosis. The prognostic gains differ according to patient and tumour characteristics.

Socio-economic implications of cancer survivorship: Results from the PROFILES registry - Corrected Proof

2011-12-23

Abstract: Introduction: The goal of this large population-based study was to examine the socio-economic implications of cancer survivorship.Methods: Individuals alive and diagnosed with colorectal cancer and melanoma between 1998 and 2007 or Hodgkin lymphoma, non-Hodgkin lymphoma or multiple myeloma between 1999 and 2008 as registered in the Eindhoven Cancer Registry received a questionnaire on work changes and problems with obtaining a new (or extended) health care insurance, life insurance or a home loan; 70% (n=2892) responded.Results: Results showed that 28% of all cancer patients experienced changes in their work situation after cancer. Most of them switched to part-time work or stopped working entirely. Patients (3.4%) who tried to obtain a different or upgrade their health care insurance experienced problems and in most cases, these were eventually resolved. Problems with life insurance were somewhat more common with 18% of those who tried to obtain a life insurance experiencing problems. The majority of these patients was rejected by the insurance company (61%) or was accepted at a higher premium (22%). Of the 21% who tried to obtain a home loan, 9% experienced problems. However, 22.2% got accepted eventually, 27.8% got accepted but at a higher mortgage payment and 22.2% got rejected but were eventually accepted by another bank.Conclusions: Almost a third of cancer survivors experienced changes in their work situation after cancer. Problems with obtaining health insurance, life insurance and home loans were also common.

MicroRNA-610 inhibits the migration and invasion of gastric cancer cells by suppressing the expression of vasodilator-stimulated phosphoprotein - Corrected Proof

2011-12-22

Abstract: Vasodilator-stimulated phosphoprotein (VASP) has been implicated in the establishment of cancerous phenotypes. However, the role of VASP in gastric cancer progression and metastasis remains poorly understood. Here, we demonstrated that VASP was upregulated by epidermal growth factor (EGF) and promoted the migration and invasion of gastric cancer cells. Then we explored the regulatory mechanisms responsible for high expression of VASP in gastric cancer. Based on miRNA expression profiling of the paired gastric cancer tissues and their adjacent non-tumour gastric tissues 18 miRNAs were identified including microRNA-610 (miR-610) which were down-regulated in gastric cancer. Next, we observed an inverse correlation between VASP and miR-610 expression levels in gastric cancer cells after EGF stimulation. Then we performed bioinformatics analysis, Western blot and reverse transcription polymerase chain reaction (RT-PCR) analysis and luciferase assay to establish that miR-610 directly targets VASP 3′-UTR and inhibits its expression. Functionally, we demonstrated that miR610-mediated inhibition of VASP expression resulted in a significant reduction in the migration and invasion properties of gastric cancer cells. The identification of miR-610 as a novel miRNA regulated by EGF that targets VASP in gastric cancer cells suggests that EGF-miR610-VASP axis may be exploited for therapeutic intervention to inhibit gastric cancer progression and metastasis.

Five-year quality of life of endometrial cancer patients treated in the randomised Post Operative Radiation Therapy in Endometrial Cancer (PORTEC-2) trial and comparison with norm data - Corrected Proof

2011-12-19

Abstract: Background: The PORTEC-2 trial showed efficacy and reduced side-effects of vaginal brachytherapy (VBT) compared with external beam pelvic radiotherapy (EBRT) for patients with high-intermediate risk endometrial cancer. The current analysis was done to evaluate long-term health related quality of life (HRQL), and compare HRQL of patients to an age-matched norm population.Methods: Patients were randomly allocated to EBRT (n=214) or VBT (n=213). HRQL was assessed using EORTC QLQ-C30 and subscales from PR25 and OV28 (bladder, bowel, sexual symptoms); and compared to norm data.Findings: Median follow-up was 65 months; 348 (81%) patients were evaluable for HRQL (EBRT n=166, VBT n=182). At baseline, patient functioning was at lowest level, increasing during and after radiotherapy to reach a plateau after 12 months, within range of scores of the norm population. VBT patients reported better social functioning (p=0.005) and lower symptom scores for diarrhoea, faecal leakage, need to stay close to a toilet and limitation in daily activities due to bowel symptoms (p⩽0.001), compared to EBRT. There were no differences in sexual functioning or symptoms between the treatment groups; however, sexual functioning was lower and sexual symptoms more frequent in both treatment groups compared to the norm population.Interpretation: Patients who received EBRT reported clinically relevant higher levels of bowel symptoms and related limitations in daily activities with lower social functioning, 5 years after treatment. VBT provides a better HRQL, which remained similar to that of an age-matched norm population, except for sexual symptoms which were more frequent in both treatment groups.

Optimisation of the size variation threshold for imaging evaluation of response in patients with platinum-refractory advanced transitional cell carcinoma of the urothelium treated with vinflunine - Corrected Proof

2011-12-16

Abstract: Background: Vinflunine (VFL) has been approved in the European Union for second-line treatment of advanced transitional cell carcinoma of the urothelial tract (TCCU) in patients who progress after a platinum based regimen. However, very few patients achieve response by response evaluation criteria in solid tumours (RECIST). Therefore, another ‘response’ threshold may be more useful than RECIST 1.0 in this setting.Methods: One hundred and seventy nine patients with advanced TCCU treated with second-line VFL therapy had chest Computed Tomography (CT) and abdominal/pelvic CT or MRI performed at baseline and at first follow-up (6weeks±3days) after therapy initiation. Tumour measurements and response by RECIST 1.0 were correlated with overall survival (OS). Kaplan–Meier and receiver operating characteristic (ROC) analysis were then used to determine the optimal size threshold to define ‘responders’. Impact of adverse prognostic factors including Eastern Cooperative Oncology Group Performance Status (ECOG PS) >0, Hb <10g/dL, and liver metastases was analysed.Results: Tumour response included 13 partial responses (PR) by RECIST 1.0 and 52 patients with ⩾10% decrease in the sum of longest diameters. Responders by RECIST 1.0 did not have a statistically significant improvement in OS, while patients with sum long axis diameter (SLD) reduction of ⩾10% had a longer OS than those with SLD reduction of <10%: 11.3 versus 6.9months (log rank p=0.0224). ROC analysis yielded ⩾10% decrease in SLD as the optimal size change correlating with OS. These results persisted on multivariate analysis.Conclusion: In the study population, a ⩾10% reduction in SLD at first follow-up imaging is a better early predictor of outcome than RECIST.

A multi-institutional phase II trial of consolidation S-1 after concurrent chemoradiotherapy with cisplatin and vinorelbine for locally advanced non-small cell lung cancer - Corrected Proof

2011-12-15

Abstract: Aim: To evaluate the efficacy and feasibility of the consolidation therapy of the oral fluoropyrimidine agent S-1 after concurrent chemoradiotherapy for unresectable stage III non-small cell lung cancer (NSCLC).Methods: Eligible patients had unresectable stage III NSCLC with performance status of 0 or 1. Chemoradiotherapy at a total dose of 60Gy consisted of cisplatin (80mg/m2) on days 1 and 29, vinorelbine (20mg/m2) on days 1, 8, 29 and 36. Sequential consolidation S-1 therapy was commenced at a dose of 80–120mg twice daily on day 57 with two cycles of 4weeks administration and 2weeks withdrawal.Results: Of the 66 patients, 65 were evaluated. Chemoradiotherapy was completed in 57 (87.7%) patients, and S-1 consolidation therapy was administered in 45 (69.2%) and completed in 31 (47.6%). Grade 3 pneumonitis developed in three patients with one dying of it. The response rate was 61.5% (95% confidence interval [CI], 48.6–73.3%). The median progression-free survival was 10.2 (95%CI, 8.6–13.7) months and median survival time 21.8 (95%CI, 15.6–27.6) months. The 1- and 3-year survival rates were 73.9% and 34.0%, respectively.Conclusions: Chemoradiotherapy with cisplatin and vinorelbine followed by S-1 consolidation demonstrated a reasonable overall survival in patients with stage III NSCLC. However, less than half of the patients completed this regimen, and the additional effect of S-1 was marginal compared with historical control.We concluded that chemoradiotherapy alone is still the recommended standard treatment for patients.

Offering self-sampling for human papillomavirus testing to non-attendees of the cervical screening programme: Characteristics of the responders - Corrected Proof

2011-12-15

Abstract: Background: Self-sampling for high-risk human papillomavirus (hrHPV) testing is accepted by up to 30% of non-attendees to the regular cervical screening programme. Here, the yield of cervical intraepithelial neoplasia (CIN)2 or worse (⩾CIN2) and CIN3 or worse (⩾CIN3) of 15, 274 HPV self-sampling responders amongst non-attendees were compared to that of 176, 027 women participating in regular screening in the same period and in the same region. We also analysed which subpopulations amongst non-attendees are targeted by HPV self-sampling, and which characteristics relate to hrHPV prevalence and yield of ⩾CIN2/⩾CIN3.Method: Data from two consecutive self-sampling studies were pooled. ⩾CIN2/⩾CIN3 yields, screening history, age and ethnic status were retrieved from centralised pathology and screening databases, respectively. A logistic regression model was fitted to analyse method of invitation, ethnicity, age group, and screening history as predictors for response rate, hrHPV presence and ⩾CIN2/⩾CIN3 in non-attendees. For screening history analyses, women <34years were excluded since it was the first screening round in their life.Findings: ⩾CIN2/⩾CIN3 yields of HPV self-sampling responders were higher than those of screening participants (⩾CIN2: relative risk (RR)=1.6, 95% confidence interval=1.4–1.9; ⩾CIN3: RR=1.8, 95%CI=1.5–2.1 with relative risk values increasing with age (test of homogeneity: ⩾CIN2: p=0.04; ⩾CIN3: p=0.03).Native Dutch non-attendees responded better than immigrants (32% versus 22%, p<0·001) and those screened in the previous round revealed a higher response than underscreened (i.e. previous smear taken >7years ago) or never screened (34% versus 25%, p<0·001) women. Strikingly, amongst under- and never screened women aged ⩾39years, never screened women responded better (25% versus 23%, p<0·001). ⩾CIN2 rates were higher amongst responding native Dutch women than immigrants (p<0·01), and higher in under-/never screened women than in women screened in the previous round (p<0·01).Interpretation: Offering hrHPV self-sampling increases the efficacy of the screening programme by targeting a substantial portion of non-attendees of all ethnic groups who have not regularly been screened and are at highest risk of ⩾CIN2.