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BACKGROUND: Standard-of-care first-line chemotherapy for epithelial ovarian cancer is carboplatin and paclitaxel administered once every 3 weeks. The JGOG 3016 trial reported significant improvement in progression-free and overall survival with dose-dense weekly paclitaxel and 3-weekly (ie, once every 3 weeks) carboplatin. However, this benefit was not observed in the previously reported progression-free survival results of ICON8. Here, we present the final coprimary outcomes of overall survival and updated progression-free survival analyses of ICON8. METHODS: In this open-label, randomised, controlled, phase 3 trial (ICON8), women aged 18 years or older with newly diagnosed stage IC-IV epithelial ovarian, primary peritoneal, or fallopian tube carcinoma (here collectively termed ovarian cancer, as defined by International Federation of Gynecology and Obstetrics [FIGO] 1988 criteria) and an Eastern Cooperative Oncology Group performance status of 0-2 were recruited from 117 hospitals with oncology departments in the UK, Australia and New Zealand, Mexico, South Korea, and Ireland. Patients could enter the trial after immediate primary surgery (IPS) or with planned delayed primary surgery (DPS) during chemotherapy, or could have no planned surgery. Participants were randomly assigned (1:1:1), using the Medical Research Council Clinical Trials Unit at University College London randomisation line with stratification by Gynecologic Cancer Intergroup group, FIGO disease stage, and outcome and timing of surgery, to either 3-weekly carboplatin area under the curve (AUC)5 or AUC6 and 3-weekly paclitaxel 175 mg/m2 (control; group 1), 3-weekly carboplatin AUC5 or AUC6 and weekly paclitaxel 80 mg/m2 (group 2), or weekly carboplatin AUC2 and weekly paclitaxel 80 mg/m2 (group 3), all administered via intravenous infusion for a total of six 21-day cycles. Coprimary outcomes were progression-free survival and overall survival, with comparisons done between group 2 and group 1, and group 3 and group 1, in the intention-to-treat population. Safety was assessed in all patients who started at least one chemotherapy cycle. The trial is registered on ClinicalTrials.gov, NCT01654146, and ISRCTN registry, ISRCTN10356387, and is closed to accrual. FINDINGS: Between June 6, 2011, and Nov 28, 2014, 1566 patients were randomly assigned to group 1 (n=522), group 2 (n=523), or group 3 (n=521). The median age was 62 years (IQR 54-68), 1073 (69%) of 1566 patients had high-grade serous carcinoma, 1119 (71%) had stage IIIC-IV disease, and 745 (48%) had IPS. As of data cutoff (March 31, 2020), with a median follow-up of 69 months (IQR 61-75), no significant difference in overall survival was observed in either comparison: median overall survival of 47·4 months (95% CI 43·1-54·8) in group 1, 54·8 months (46·6-61·6) in group 2, and 53·4 months (49·2-59·6) in group 3 (group 2 vs group 1: hazard ratio 0·87 [97·5% CI 0·73-1·05]; group 3 vs group 1: 0·91 [0·76-1·09]). No significant difference was observed for progression-free survival in either comparison and evidence of non-proportional hazards was seen (p=0·037), with restricted mean survival time of 23·9 months (97·5% CI 22·1-25·6) in group 1, 25·3 months (23·6-27·1) in group 2, and 24·8 months (23·0-26·5) in group 3. The most common grade 3-4 adverse events were reduced neutrophil count (78 [15%] of 511 patients in group 1, 183 [36%] of 514 in group 2, and 154 [30%] of 513 in group 3), reduced white blood cell count (22 [4%] in group 1, 80 [16%] in group 2, and 71 [14%] in group 3), and anaemia (26 [5%] in group 1, 66 [13%] in group 2, and 24 [5%] in group 3). No new serious adverse events were reported. Seven treatment-related deaths were reported (two in group 1, four in group 2, and one in group 3). INTERPRETATION: In our cohort of predominantly European women with epithelial ovarian cancer, we found that first-line weekly dose-dense chemotherapy did not improve overall or progression-free survival compared with standard 3-weekly chemotherapy and should not be used as part of standard multimodality front-line therapy in this patient group. FUNDING: Cancer Research UK, Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, and Cancer Australia.

Treatment approaches for relapsed ovarian cancer have evolved over the past decade from a calendar-based decision tree to a patient-oriented biologically driven algorithm. Nowadays, platinum-based chemotherapy should be offered to all patients with a reasonable chance of responding to this therapy. The treatment-free interval for platinum is only one of many factors affecting patients' eligibility for platinum re-treatment. Bevacizumab increases the response to chemotherapy irrespective of the cytotoxic regimen and can be valuable in patients with an urgent need for symptom relief (e.g. pleural effusion, ascites). For patients with recurrent high-grade ovarian cancer, which responds to platinum-based treatment, maintenance therapy with a poly(ADP-ribose) polymerase inhibitor can be offered, regardless of the BRCA mutation status. Here we review contemporary decision-making processes in the systemic treatment of relapsed ovarian cancer.

Objective\ud The therapeutic benefits of poly(ADP-ribose) polymerase inhibitors highlight the need to evaluate BRCA1/2 defects in tubal/ovarian cancer (OC). We sought to determine the pattern and disease characteristics associated with tumor BRCA1/2 mutations and BRCA1 methylation in women with OC.\ud Methods\ud We obtained 111 OC specimens from 2 university hospitals and assessed BRCA1/2 mutations and BRCA1 methylation in tumor DNA. The frequency and pattern of BRCA1/2 defects were examined. Associations between patient/disease characteristics and BRCA1/2 defects were ascertained (Fisher’s exact test). Platinum-free interval (PFI), progression-free survival (PFS), and overall survival (OS) based on the underlying BRCA1/2 defect were determined (Kaplan-Meier analysis [log-rank test]).\ud Results\ud We observed a BRCA1/2 dysfunction rate of 40% (28/70) in high-grade serous tubal/ovarian cancer (HGSC), including 14.3% BRCA1 methylation (n=10), 7.1% BRCA1 mutation (n=5), and 18.6% BRCA2 mutation (n=13). Defects in BRCA1/2 genes were associated with stage III/IV HGSC (BRCA1 methylation: P=0.005 [stage III/IV] and P=0.004 [HGSC]; BRCA1/2 mutation: P=0.03 [stage III/IV] and P

Summary Background The ICON8 study reported no significant improvement in progression-free survival (a primary endpoint) with weekly chemotherapy compared with standard 3-weekly treatment among patients with epithelial ovarian cancer. All ICON8 patients were eligible to take part in the accompanying health-related quality-of-life study, which measured the effect of treatment on self-reported wellbeing, reported here. Methods In this open-label, randomised, controlled, phase 3, three-arm, Gynecologic Cancer Intergroup (GCIG) trial done at 117 hospital sites in the UK, Australia, New Zealand, Mexico, South Korea, and Republic of Ireland, women (aged at least 18 years) with newly diagnosed, histologically confirmed International Federation of Gynecology and Obstetrics stage IC–IV ovarian cancer and an Eastern Cooperative Oncology Group performance status of 0–2 were randomly assigned (1:1:1) centrally using minimisation to group 1 (intravenous carboplatin area under the curve [AUC]5 or AUC6 and 175 mg/m2 intravenous paclitaxel every 3 weeks), group 2 (carboplatin AUC5 or AUC6 every 3 weeks and 80 mg/m2 paclitaxel weekly), or group 3 (carboplatin AUC2 weekly and 80 mg/m2 paclitaxel weekly). Randomisation was stratified by GCIG group, disease stage, and outcome and timing of surgery. Patients and clinicians were not masked to treatment assignment. Patients underwent immediate or delayed primary surgery according to clinicians' choice. Patients were asked to complete European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-OV28 questionnaires at enrolment, before each chemotherapy cycle, then 6-weekly up to 9 months, 3-monthly up to 2 years, and 6-monthly up to 5 years. Quality of life was a prespecified secondary outcome of the ICON8 study. Within the quality-of-life study, the co-primary endpoints were QLQ-C30 global health score at 9 months (cross-sectional analysis) and mean QLQ-C30 global health score from randomisation to 9 months (longitudinal analysis). Data analyses were done on an intention-to-treat basis. The trial is registered on ClinicalTrials.gov , NCT01654146 and ISRCTN Registry, ISRCTN10356387, and is currently in long-term follow up. Findings Between June 6, 2011, and Nov 28, 2014, 1566 patients were recruited into ICON8 (522 were included in group 1, 523 in group 2, and 521 in group 3). Baseline quality-of-life questionnaires were completed by 1438 (92%) of 1566 patients and 9-month questionnaires by 882 (69%) of 1280 patients. We observed no significant difference in global health score at 9 months (cross-sectional analysis) between study groups (group 2 vs group 1, difference in mean score 2·3, 95% CI −0·4 to 4·9, p=0·095; group 3 vs group 1, −0·8, −3·8 to 2·2, p=0·61). Using longitudinal analysis, we found lower global health scores for those receiving weekly paclitaxel than for those receiving 3-weekly chemotherapy (group 2 vs group 1, mean difference −1·8, 95% CI −3·6 to −0·1, p=0·043; group 3 vs group 1, −2·9, −4·7 to −1·1, p=0·0018). Interpretation We found no evidence of a difference in global quality of life between treatment groups at 9 months; however, patients receiving weekly treatment reported lower mean quality of life across the 9-month period after randomisation. Taken together with the lack of progression-free survival benefit, these findings do not support routine use of weekly paclitaxel-containing regimens in the management of newly diagnosed ovarian cancer. Funding Cancer Research UK, Medical Research Council, Health Research Board Ireland, Irish Cancer Society, and Cancer Australia.

Background:\ud Carboplatin and paclitaxel administered every 3 weeks is standard-of-care first-line chemotherapy for epithelial ovarian cancer. The Japanese JGOG3016 trial showed a significant improvement in progression-free and overall survival with dose-dense weekly paclitaxel and 3-weekly carboplatin. In this study, we aimed to compare efficacy and safety of two dose-dense weekly regimens to standard 3-weekly chemotherapy in a predominantly European population with epithelial ovarian cancer.\ud Methods:\ud In this phase 3 trial, women with newly diagnosed International Federation of Gynecology and Obstetrics stage IC–IV epithelial ovarian cancer were randomly assigned to group 1 (carboplatin area under the curve [AUC]5 or AUC6 and 175 mg/m2 paclitaxel every 3 weeks), group 2 (carboplatin AUC5 or AUC6 every 3 weeks and 80 mg/m2 paclitaxel weekly), or group 3 (carboplatin AUC2 and 80 mg/m2 paclitaxel weekly). Written informed consent was provided by all women who entered the trial. The protocol had the appropriate national research ethics committee approval for the countries where the study was conducted. Patients entered the trial after immediate primary surgery, or before neoadjuvant chemotherapy with subsequent planned delayed primary surgery. The trial coprimary outcomes were progression-free survival and overall survival. Data analyses were done on an intention-to-treat basis, and were powered to detect a hazard ratio of 0·75 in progression-free survival. The main comparisons were between the control group (group 1) and each of the weekly research groups (groups 2 and 3).\ud Findings:\ud Between June 6, 2011, and Nov 28, 2014, 1566 women were randomly assigned to treatment. 72% (365), completed six protocol-defined treatment cycles in group 1, 60% (305) in group 2, and 63% (322) in group 3, although 90% (454), 89% (454), and 85% (437) completed six platinum-based chemotherapy cycles, respectively. Paclitaxel dose intensification was achieved with weekly treatment (median total paclitaxel dose 1010 mg/m2 in group 1; 1233 mg/m2 in group 2; 1274 mg/m2 in group 3). By February, 2017, 1018 (65%) patients had experienced disease progression. No significant progression-free survival increase was observed with either weekly regimen (restricted mean survival time 24·4 months [97·5% CI 23·0–26·0] in group 1, 24·9 months [24·0–25·9] in group 2, 25·3 months [23·9–26·9] in group 3; median progression-free survival 17·7 months [IQR 10·6–not reached] in group 1, 20·8 months [11·9–59·0] in group 2, 21·0 months [12·0–54·0] in group 3; log-rank p=0·35 for group 2 vs group 1; group 3 vs 1 p=0·51). Although grade 3 or 4 toxic effects increased with weekly treatment, these effects were predominantly uncomplicated. Febrile neutropenia and sensory neuropathy incidences were similar across groups.\ud Interpretation:\ud Weekly dose-dense chemotherapy can be delivered successfully as first-line treatment for epithelial ovarian cancer but does not significantly improve progression-free survival compared with standard 3-weekly chemotherapy in predominantly European populations.\ud Funding:\ud Cancer Research UK, Medical Research Council, Health Research Board in Ireland, Irish Cancer Society, Cancer Australia.

Oncology patients have had to make many changes to minimise their exposure to COVID-19, causing stress. Despite education, some patients still do not recognise potential COVID symptoms.We assessed patient knowledge of COVID, and its impact on their behaviours, concerns, and healthcare experience.A 16-page questionnaire was distributed to 120 oncology patients attending the day unit of a tertiary Irish cancer centre for systemic anti-cancer therapy (May/June 2020). The Irish 7-day COVID incidence during this period ranged from 2 to 11 cases/100,000 people.One hundred and one responses were received, 1% had tested positive for COVID, and 31% had undergone testing. Participant insight into their knowledge about COVID and their own behaviour was limited in some cases. Seventy-five percent reported total compliance with restrictions, but many were not fully compliant. Self-reported confidence in knowledge was high, but did not predict demonstrated knowledge. Sixty percent did not recognise two or more symptoms; 40% did not self-identify as high-risk. Patients reported more health-related worry (72%), loneliness (51%), and lower mood (42%) since the pandemic began. Financial toxicity worsened, with increased financial worry (78%), reductions in household income (40%), and increased costs due to lockdown (62%). Use of facemasks introduced new communications barriers for 67% of those with hearing loss.Despite self-reported confidence in knowledge, some patient's recognition of COVID symptoms and the preventative strategies they should use are not optimal, highlighting the need for further education in this regard. COVID has been a significant stressor for patients and more practical, financial, and psychological supports are needed.

Interactions between circulating tumour cells (CTCs) and platelets are thought to inhibit natural killer(NK)-cell-induced lysis. We attempted to correlate CTC numbers in men with advanced prostate cancer with platelet counts and circulating lymphocyte numbers. Sixty-one ExPeCT trial participants, divided into overweight/obese and normal weight groups on the basis of a BMI ≥ 25 or &lt, 25, were randomized to participate or not in a six-month exercise programme. Blood samples at randomization, and at three and six months, were subjected to ScreenCell filtration, circulating platelet counts were obtained, and flow cytometry was performed on a subset of samples (n = 29). CTC count positively correlated with absolute total lymphocyte count (r2 = 0.1709, p = 0.0258) and NK-cell count (r2 = 0.49, p &lt, 0.0001). There was also a positive correlation between platelet count and CTC count (r2 = 0.094, p = 0.0001). Correlation was also demonstrated within the overweight/obese group (n = 123, p &lt, 0.0001), the non-exercise group (n = 79, p = 0.001) and blood draw samples lacking platelet cloaking (n = 128, p &lt, 0.0001). By flow cytometry, blood samples from the exercise group (n = 15) had a higher proportion of CD3+ T-lymphocytes (p = 0.0003) and lower proportions of B-lymphocytes (p = 0.0264) and NK-cells (p = 0.015) than the non-exercise group (n = 14). These findings suggest that CTCs engage in complex interactions with the coagulation cascade and innate immune system during intravascular transit, and they present an attractive target for directed therapy at a vulnerable stage in metastasis.

Background Circulating tumour cells (CTCs) represent a morphologically distinct subset of cancer cells, which aid the metastatic spread. The ExPeCT trial aimed to examine the effectiveness of a structured exercise programme in modulating levels of CTCs and platelet cloaking in patients with metastatic prostate cancer. Methods Participants (n = 61) were randomised into either standard care (control) or exercise arms. Whole blood was collected for all participants at baseline (T0), three months (T3) and six months (T6), and analysed for the presence of CTCs, CTC clusters and platelet cloaking. CTC data was correlated with clinico-pathological information. Results Changes in CTC number were observed within group over time, however no significant difference in CTC number was observed between groups over time. Platelet cloaking was identified in 29.5% of participants. A positive correlation between CTC number and white cell count (WCC) was observed (p = 0.0001), in addition to a positive relationship between CTC clusters and PSA levels (p = 0.0393). Conclusion The presence of platelet cloaking has been observed in this patient population for the first time, in addition to a significant correlation between CTC number and WCC. Trial registration ClincalTrials.gov identifier NCT02453139.

Cancer clinical trials (CCTs) are critical to translation and development of better therapies to improve outcomes. CCTs require adequate patient involvement but accrual rates are low globally. Several known barriers impede participation and knowing how subpopulations differ in understanding of CCTs can foster targeted approaches to aid accrual and advance cancer treatments. We conducted the first nationwide survey of 1089 patients attending 14 Irish cancer centres, assessing understanding of fundamental concepts in CCT methodology and factors that influence participation, to help tailor patient support for accrual to CCTs. Two-thirds (66%) of patients reported never having been offered a CCT and only 5% of those not offered asked to participate. Misunderstanding of clinical equipoise was prevalent. There were differences in understanding of randomisation of treatment by age (p &lt, 0.0001), ethnicity (p = 0.035) and marital status (p = 0.013), and 58% of patients and 61% previous CCT participants thought that their doctor would ensure better treatment in CCTs. Females were slightly more risk averse. Males indicated a greater willingness to participate in novel drug trials (p = 0.001, p = 0.003). The study identified disparities in several demographics, older, widowed, living in provincial small towns and fewer years-educated patients had generally poorer understanding of CCTs, highlighting requirements for targeted support in these groups.

Introduction “Transgender” and “gender diverse” are umbrella terms encompassing those whose gender identities or expressions differ from those typically associated with the sex they were assigned at birth. There is scant global information on cancer incidence, outcome, and mortality for this cohort. This group may present with advanced cancer, have mistrust in health care services and report anxiety and depression at higher frequencies, a finding often seen in marginalized groups because of minority stress. Materials and Methods Medical oncologists were contacted by secure email to identify patients who self-identify as transgender and gender diverse in three Irish hospitals. Five patients were identified. A retrospective chart review was conducted and a pseudonymized patient survey was distributed. Results All patients included in our chart review (n = 5) were diagnosed with advanced disease on initial diagnosis. Two patients identified as men, two as women, and one as a transwoman. Two of five patients' health record charts reflected a name or gender change. Three patients had gender transitioning treatment postponed. Assessing comorbidities, it was seen that four patients required psychiatry input. Predominant issues noted in our patient survey by the two respondents (n = 2) were “mis-gendering,” lack of a gender-neutral hospital environment, lack of inclusion in cancer groups, and barriers in changing name and/or sex on hospital records. Conclusion Components of care requiring revision include patient accessible pathways to change names and gender on health records, earlier access to psychological support and targeted screening and support groups. Resources for hospital staff to improve awareness of correct terminology and to provide gender neutral facilities are worthwhile. Implications for Practice The implications for practice on an international level include patient-friendly pathways for changing hospital name and gender so that patients may feel comfortable using wristbands. The need for international screening guidelines for transgender patients and national transgender cancer support groups is highlighted. On a day-to-day level for providers, the correct use of pronouns makes a big difference to patients. Asking about preferred pronoun on first visit and noting on patient's file is worthwhile. It is important for providers to know that increased psychological support should be offered early on first clinic visit and engaged with as necessary when patient has a history of anxiety or depression. Providers should discuss openly that some gender transitioning treatment will be postponed because of cancer care and refer to both the physical and psychological sequelae of this. Asking transgender patients which room or bathroom they would prefer when rooms are gendered is essential.

Background:The NCCN Guidelines for Survivorship recommend dedicated sleep assessment. Reported insomnia prevalence in the general Irish population is 6% to 15%. Reported insomnia prevalence internationally among new/recently diagnosed patients with cancer varies from 30.9% to 54.3%. Insomnia prevalence has not been previously quantified in an Irish oncology cohort.Methods:A 40-item questionnaire was prospectively administered to ambulatory patients with cancer aged ≥18 years. Prespecified criteria to define insomnia syndrome combined those of theInternational Classification of Sleep Disorders, version 1, and theDiagnostic and Statistical Manual of Mental Disorders, Fourth Edition(DSM-IV). The Hospital Anxiety and Depression Scale-Depression/Anxiety (HADS-D/A) was used to screen for potential confounding variables.Results:The response rate to the questionnaire was 87% (294/337). The predominant respondent age group was 55 to 64 years (26%; 77/294), 70.7% were female (208/294), and the most common cancer subtypes were breast (37.4%), colorectal (12.9%), and lung (12.2%). A total of 62% (183/294) of patients reported sleep disturbance after diagnosis, 63% (115/183) reported moderate/severe distress related to this disturbance, and 37% (61/183) reported a significant impact on physical function. Although 33% (98/294) met insomnia syndrome criteria, only 34% (33/98) of these patients had a preexisting history of sleep disturbance. Female sex, age P=.01), age P=.03), and alcohol consumption (OR, 2.3;P=.005) as independent predictors of insomnia syndrome.Conclusions:Insomnia syndrome prevalence in this cohort is comparable to that reported previously and supports dedicated sleep assessment. This study identifies potentially modifiable risk factors for insomnia and demonstrates additional utility of the HADS score in identifying patients at risk.

Achieving adequate levels of physical activity (PA) and avoiding sedentary behaviour are particularly important in cancer survivors. eHealth, which includes, but is not limited to, the delivery of health information through Internet and mobile technologies, is an emerging concept in healthcare which may present opportunities to improve PA in cancer survivors. The aim of this systematic review was to explore the effects of eHealth in the promotion of PA among cancer survivors. Suitable articles were searched using PubMed, CINAHL, EMBASE, PsychInfo, Web of Science and SCOPUS databases using a combination of keywords and medical subject headings. Articles were included if they described an eHealth intervention designed to improve PA in cancer survivors. Two reviewers screened studies for inclusion. In total, 1065 articles were considered. Ten studies met eligibility criteria. A variety of platforms designed to increase PA were described in these studies: web application (app) (n = 5), web and mobile application (n = 2), mobile app (n = 1), website only (n = 1), e-mail based (n = 1). All studies measured PA using self-report outcome measures with the exception of one study which measured steps using a Fitbit. Meta-analysis was not performed because of variations in study design and interventions. All studies reported improvements in PA, with 8/10 studies reporting statistically significant changes. The use of eHealth to promote PA in cancer survivors is a relatively new concept, which is supported by the recent emergent evidence described in this review. eHealth shows promise as a means of promoting and increasing daily PA, but further high-quality, longer term studies are needed to establish the feasibility and effectiveness of eHealth platforms aimed at that goal.

The impact of host immunity on outcome in nonsmall cell lung cancer (NSCLC) is controversial. We examined the relationship between lymphoid infiltration patterns in NSCLC and prognosis.Tumour- and stroma-infiltrating CD3+, CD8+ and forkhead box P3 (Foxp3)+ T-lymphocytes were identified using immunohistochemistry and a novel image analysis algorithm to assess total, cytotoxic and regulatory T-lymphocyte counts, respectively, in 196 NSCLC cases. The median cell count was selected as a cut-point to define patient subgroups and the ratio of the corresponding tumour islet:stroma (TI/S) counts was determined.There was a positive association between overall survival and increased CD8+ TI/S ratio (hazard ratio (HR) for death 0.44, p+ TI/S ratio and overall survival (HR 4.86, p+ islet (HR 0.48, p+ stromal (HR 0.23, p+ and CD8+ stromal counts and high Foxp3+ islet infiltration conferred a worse survival (HR 1.55, 2.19 and 3.14, respectively). By multivariate analysis, a high CD8+ TI/S ratio conferred an improved survival (HR 0.48, p=0.002) but a high Foxp3+ TI/S ratio was associated with worse survival (HR 3.91, pMicrolocalisation of infiltrating T-lymphocytes is a powerful predictor of outcome in resected NSCLC.

97 Background: All patients living with cancer, including those with metastatic cancer, are encouraged to be physically active. This paper examines the feasibility of an aerobic exercise intervention for men with metastatic prostate cancer. Methods: ExPeCT (Exercise, Prostate Cancer and Circulating Tumour Cells), was a multi-centre randomised control trial for men living with metastatic prostate cancer. Participants were randomized to either control or exercise arms. Participants in the exercise arm completed six- months of prescribed aerobic exercise. Quality of life assessments were completed at baseline, at 3 months and at 6 months using a standardised questionnaire derived from the Harvard Health Professionals Follow-up study. Physical activity was measured using a self-administered physical activity questionnaire. Exercise adherence data was collected via Polar heart rate monitors, worn by the patient for every exercise session undertaken. Results: A total of 61 patients were included (69.4±7.3 yr, Body Mass Index 29.2±5.8 kg/m2). The median time since diagnosis was 34 months (IQR 7-54). A total of 35 (55%) of participants had >1 region affected by metastatic disease. A total of 54 (81%) of participants completed the 3 month assessment and 52 (78%) of the participants completed the 6 month assessment. Adherence to the supervised sessions was 83% (329 out of 396 sessions attended). Participants were adherent to both the intensity (82%) and duration (83%) of the prescribed exercise programme during class sessions. No adverse events were reported by participants enrolled in this study. There was no significant difference in physical activity levels, sedentary time or quality of life between either group at baseline, 3 months or 6 months. Systolic blood pressure was significantly lower in the exercise group when compared to the control group at 3 months (p=.008) and 6 months (p=.011). Conclusions: The exercise intervention was tolerated well by a group of patients with a high burden of metastatic prostate cancer however did not lead to change in physical activity levels or quality of life. This trial provides proof of principle evidence for future exercise studies involving this patient group. Clinical trial information: NCT02453139.

Background: Prostate cancer (PrCa) is the second most common cancer in Ireland. Many men present with locally advanced or metastatic cancer for whom curative surgery is inappropriate. Advanced cancer patients are encouraged to remain physically active and therefore there is a need to investigate how patients with metastatic disease tolerate physical activity programmes. Physical activity reduces levels of systemic inflammatory mediators and so an aerobic exercise intervention may represent an accessible and cost-effective means of ameliorating the pro-inflammatory effects of obesity and subsequently decrease poor cancer-specific outcomes in this patient population. This study will assess the feasibility and safety of introducing a structured aerobic exercise intervention to an advanced cancer population. This study will also examine if the evasion of immune editing by circulating tumour cells (CTCs) is an exercise-modifiable mechanism in obese men with prostate cancer. Methods: This international multicentre prospective study will recruit men with metastatic prostate cancer. Participants will be recruited from centres in Dublin (Ireland) and London (UK). Participants will be divided into exposed and non-exposed groups based on body mass index (BMI)≥25kg/m2 and randomised to intervention and control groups. The exercise group will undertake a regular supervised aerobic exercise programme, whereas the control group will not. Exercise intensity will be prescribed based on a target heart rate monitored by a polar heart rate monitor. Blood samples will be taken at recruitment and at 3 and 6months to examine the primary endpoint of platelet cloaking of CTCs. Participants will complete a detailed questionnaire to assess quality of life (QoL) and other parameters at each visit. Discussion: The overall aim of the ExPeCT trial is to examine the relationship between PrCa, exercise, obesity, and systemic inflammation, and to improve the overall QoL in men with advanced disease. Results will inform future work in this area examining biological markers of prognosis in advanced prostate cancer. Trial registration: Clinicaltrials.gov NLM identifier: NCT02453139. Registered on 12 May 2015. This document contains excerpts from the ExPeCT trial protocol Version 1.5, 28 July 2016.

Ovarian cancer is the seventh most common cancer in women and the most frequent cause of gynaecological malignancy-related mortality in women. Currently, no standardized reliable screening test exists. MicroRNA profiling has allowed the identification of signatures associated with diagnosis, prognosis and response to treatment of human tumours. The aim of this study was to determine if a microRNA signature could distinguish between malignant and benign ovarian disease. A training set of 5 serous ovarian carcinomas and 5 benign serous cystadenomas were selected for the initial experiments. The validation set included 20 serous ovarian carcinomas and 20 benign serous cystadenomas. The serum/plasma focus microRNA Exiqon panel was used for the training set. For the validation set a pick and mix Exiqon panel, which focuses on microRNAs of interest was used. A panel of 4 microRNAs (let-7i-5p, miR-122, miR-152-5p and miR-25-3p) was significantly down regulated in cancer patients. These microRNAs target WNT signalling, AKT/mTOR and TLR-4/MyD88, which have previously been found to play a role in ovarian carcinogenesis and chemoresistance. let-7i-5p, miR-122, miR-152-5p and miR-25-3p could act as diagnostic biomarkers in ovarian cancer.

It is long established that tumour-initiating cancer stem cells (CSCs) possess chemoresistant properties. However, little is known of the mechanisms involved, particularly with respect to the organisation of CSCs as stem-progenitor-differentiated cell hierarchies. Here we aimed to elucidate the relationship between CSC hierarchies and chemoresistance in an ovarian cancer model. Using a single cell-based approach to CSC discovery and validation, we report a novel, four-component CSC hierarchy based around the markers cluster of differentiation 10 (CD10) and aldehyde dehydrogenase (ALDH). In a change to our understanding of CSC biology, resistance to chemotherapy drug cisplatin was found to be the sole property of CD10−/ALDH− CSCs, while all four CSC types were sensitive to chemotherapy drug paclitaxel. Cisplatin treatment quickly altered the hierarchy, resulting in a three-component hierarchy dominated by the cisplatin-resistant CD10−/ALDH− CSC. This organisation was found to be hard-wired in a long-term cisplatin-adapted model, where again CD10−/ALDH− CSCs were the sole cisplatin-resistant component, and all CSC types remained paclitaxel-sensitive. Molecular analysis indicated that cisplatin resistance is associated with inherent- and adaptive-specific drug efflux and DNA-damage repair mechanisms. Clinically, low CD10 expression was consistent with a specific set of ovarian cancer patient samples. Collectively, these data advance our understanding of the relationship between CSC hierarchies and chemoresistance, which was shown to be CSC- and drug-type specific, and facilitated by specific and synergistic inherent and adaptive mechanisms. Furthermore, our data indicate that primary stage targeting of CD10−/ALDH− CSCs in specific ovarian cancer patients in future may facilitate targeting of recurrent disease, before it ever develops.

Increased physical activity (PA) has been associated with a decreased risk for the occurrence and recurrence of many cancers. PA is an important outcome measure in rehabilitation interventions within cancer and may be used as a proxy measure of recovery or deterioration in health status following treatment and in the palliative care setting. PA is a complex multi-dimensional construct which is challenging to measure accurately. Factors such as technical precision and feasibility influence the choice of PA measurement tool. Laboratory-based methods are precise and mainly used for validation purposes, but their clinical applicability is limited. Self-report methods such as questionnaires are widely used due to their simplicity and reasonable cost; however, accuracy can be questionable. Objective methods such as pedometers measure step count but do not measure intensity, frequency or duration of activity. Accelerometers can measure PA behaviour at both ends of the movement spectrum from sedentary to vigorous levels of activity and can also provide objective data about the frequency, intensity, type and duration of PA. Balancing precision with ease of use, accelerometry may be the best measure of PA in cancer-based studies, but only a small number of studies have incorporated this measurement. This review will provide a background to PA and an overview of accelerometer measurement as well as technical and practical considerations, so this useful tool could be more widely incorporated into clinical trial research within cancer.

IntroductionExercise and physical activity (PA) are established and effective treatment options for various side effects of cancer treatments such as surgery, chemotherapy and radiotherapy. The advent of eHealth brings new opportunities to influence healthy behaviours, using interactive and novel approaches. Influencing PA behaviours in people with cancer presents a potential application of this. The aim of this study is to evaluate the feasibility and preliminary efficacy of an intervention, using eHealth, for increasing PA in cancer survivors.Methods and analysisThis will be a single-arm pre–post feasibility study. We aim to recruit a heterogeneous sample of 60 participants from cancer clinics in St. James’s Hospital, Dublin, Ireland. Eligibility criteria will include patients who have completed chemotherapy and/or radiotherapy with curative intent between 3 and 36 months prior to enrolment. The intervention will include the delivery of a 12-week PA programme. The eHealth aspect of the intervention will involve the provision of a Fitbit activity tracker, which will be used in conjunction with specific PA goals remotely prescribed and monitored by a physiotherapist. Primary outcomes will be feasibility measures related to the study (recruitment capability, data collection procedures, adherence and compliance, evaluation of the resources to implement the study and evaluation of participant responses to the intervention). Secondary measures will evaluate preliminary efficacy of the intervention in terms of clinical outcomes (body composition, PA (objective and self-report), quality of life and aerobic capacity). Primary and secondary outcomes will be assessed at baseline (as appropriate), at conclusion of the intervention and at a 6-month follow-up.Ethics and disseminationEthical approval has been granted by the St. James’s Hospital/AMNCH Joint Ethics Committee (2016/05/02). Results from this study will be submitted for publication in peer-reviewed journals, as well as for presentation and dissemination at conferences in the field of oncology and survivorship.Trial registrationNCT03036436; Pre-results.

Little is known about objectively measured physical activity during the early survivorship period. This study measured physical activity, fatigue, and quality of life (QOL) in breast cancer patients over the first year after completion of chemotherapy and compared results to a matched non-cancer group.Data was obtained from 24 breast cancer subjects (mean ± SD) 50.9 ± 12.8 years at time points of 6 weeks, 6 months and 1 year after completion of adjuvant chemotherapy and from 20 matched women. The following variables were assessed, physical activity (RT3 accelerometer and International Physical Activity Questionnaire), quality-of-life (EORTC QLQ C-30) and fatigue (Brief Fatigue Inventory).At 6 weeks after completion of chemotherapy, high levels of sedentary behaviour were found (6.8 ± 1.9 h sedentary per day), which did not improve, and was no different to the comparison group (6.5 ± 1.4 h). Less light activity was performed in the cancer cohort compared to the comparison group (p = 0.003). Body mass index (BMI) increased significantly in the cancer cohort (p = 0.015) and 1 year after chemotherapy finished only 13% (n = 3) had a BMI25, while the comparable value was 45% (n = 9) in the non-cancer group. The QOL domain of cognitive function improved over the first 6 months (p = 0.034) but physical functioning declined (p = 0.008) over this time period. Fatigue did not change, and at the 1-year time point, 38% of the cancer patients (n = 11) reported high levels of fatigue.This study highlighted the unchanging sedentary behaviour and weight gain of breast cancer survivors during the first year after completion of chemotherapy, which may inform rehabilitation models in this population.

Physical activity is associated with a reduced risk of breast cancer development and recurrence. There are several hypothesised mechanisms for this including positive effects on metabolic and inflammatory biomarkers and favourable changes in anthropometric variables. This pilot study examined the effect of an 8-week aerobic exercise intervention on several of these outcomes, including body composition, the metabolic syndrome, C-reactive protein (CRP) and physical activity, in breast cancer survivors 2-6 months post-chemotherapy.Assessments were completed at baseline, at 8-weeks and 3-months post-intervention. Measures taken following a 12-h fast included body composition (bioimpedance analysis), metabolic syndrome (waist circumference, blood pressure, high-density lipoprotein cholesterol, triglycerides and fasting glucose), insulin resistance (homeostatic model assessment), CRP and physical activity (accelerometry and questionnaire). Participants were randomized to either an 8-week moderate-intensity aerobic exercise group or a usual-care control group. Analysis was completed using repeated-measures analysis of variance (ANOVA) (p = 0.05).Twenty-six breast cancer survivors participated (mean (standard deviation) age 48.1 (8.8) years, exercise group; n = 16, control group; n = 10). At baseline, 13 participants were overweight, 6 were obese and 19 centrally obese. Intention-to-treat analysis revealed no significant differences between the exercise and control groups in any of the outcomes measures; however, analysis of those who adhered to90 % of the supervised exercise class showed a significant decrease in waist circumference (p = 0.05) and a significant increase in subjectively reported "total weekly" (p = 0.005) activity.While this 8-week aerobic exercise pilot intervention did not elicit significant improvements in biomarkers of breast cancer risk, there was some suggestion of improvements in waist circumference and subjectively measured physical activity in participants with90 % adherence to the programme. A trial of longer duration and greater subject numbers is warranted.

Background Gynaecological cancers are associated with high rates of venous thromboembolism (VTE). Studies on ambulatory cancer patients do not support thromboprophylaxis during chemotherapy. Approximately 6–7% of gynaecological cancer patients suffer a postoperative VTE despite Low Molecular Weight Heparin prophylaxis (LMWH). Large cancer studies have shown that Calibrated Automated Thrombogram (CAT) and Microparticles (MP) assays may be useful in predicting VTE but data on gynaecological cancer patients is scarce. Objective Our objective was to identify whether the CAT assay and MP functional assays have potential as biomarkers predictive of VTE in gynaecological cancer patients. Patients and methods Gynaecological cancer patients were investigated before surgery (n = 146) and at 5, 14 and 42 days post-surgery (n = 78). Fourteen additional patients were investigated before chemotherapy and after 3 and 6 cycles of therapy. Thrombin generation was measured before and after addition of thrombomodulin. Results Patients with clear cell cancer (CCC) of the ovary and patients with endometrial cancer had higher ETP and peak thrombin compared with patients with benign disease. Patients who developed VTE (n = 8) following surgery had enhanced thrombin generation prior to surgery which persisted during the post-operative period despite LMWH prophylaxis. Both neoadjuvant and adjuvant chemotherapy showed increased thrombin generation following addition of thrombomodulin. There were no differences in MP levels during the study. Conclusions CAT assay shows potential as a promising biomarker for the prediction of VTE in gynaecological cancer patients. The identification of high risk patients combined with individualised LMWH prophylaxis might reduce VTE in this high risk group.

Receptor tyrosine kinases (RTKs) and their downstream signalling pathways have long been hypothesized to play key roles in melanoma development. A decade ago, evidence was derived largely from animal models, RTK expression studies and detection of activated RAS isoforms in a small fraction of melanomas. Predictions that overexpression of specific RTKs implied increased kinase activity and that some RTKs would show activating mutations in melanoma were largely untested. However, technological advances including rapid gene sequencing, siRNA methods and phospho-RTK arrays now give a more complete picture. Mutated forms of RTK genes including KIT, ERBB4, the EPH and FGFR families and others are known in melanoma. Additional over- or underexpressed RTKs and also protein tyrosine phosphatases (PTPs) have been reported, and activities measured. Complex interactions between RTKs and PTPs are implicated in the abnormal signalling driving aberrant growth and survival in malignant melanocytes, and indeed in normal melanocytic signalling including the response to ultraviolet radiation. Kinases are considered druggable targets, so characterization of global RTK activity in melanoma should assist the rational development of tyrosine kinase inhibitors for clinical use.

The link between chronic immune activation and tumorigenesis is well established. Compelling evidence has accumulated that histologic assessment of infiltration patterns of different host immune response components in non-small cell lung cancer specimens helps identify different prognostic patient subgroups. This review provides an overview of recent insights gained in the understanding of the role played by chronic inflammation in lung carcinogenesis. The usefulness of quantification of different populations of lymphocytes, natural killer cells, macrophages, and mast cells within the tumor microenvironment in non-small cell lung cancer is also discussed. In particular, the importance of assessment of inflammatory cell microlocalization within both the tumor islet and surrounding stromal components is emphasized.

Background: Globally, prostate cancer (PrCa) is the fourth most common cancer type. Obesity and inflammation have been shown to play significant roles in PrCa disease progression. Obesity and a high body mass index (BMI) are associated with increased PrCa-specific mortality in patients with advanced disease. Furthermore, proinflammatory cytokines can aid metastatic potential and promote angiogenesis. The ExPeCT (Exercise, Prostate Cancer and Circulating Tumor Cells) trial seeks to examine the effectiveness of a structured exercise program in modulating inflammatory mediators and obesity in patients with metastatic PrCa. Methods: ExPeCT (CTRIALIE 15-21 (ClincalTrials.gov identifier NCT02453139)) is a multicenter, randomized trial for patients with metastatic PrCa (n=67). Participants were randomized to either control or exercise arms. Participants in the exercise arm completed six months of prescribed aerobic exercise, which was monitored using percentage heart-rate reserve. Serum samples were collected for all participants at baseline (T0), three months (T3), and six months (T6), and assayed for 16 interlinked adipokines and cytokines using the Meso Scale Discovery platform. An interim statistical analysis was performed (n=26) comparing median change in serum analyte levels between control (n=13) and exercise (n=13) arms using non-parametric Wilcoxon rank-sum tests. Results: Among 26 patients included in our interim analysis, mean age at baseline was 71 years, median BMI was 29.1 kg/m2, and median waist circumference (WC) was 107 cm, with no significant differences between arms (all p>0.3). Between T0 and T6, WC decreased by a median of 3.8 cm in the exercise group and 2.6 cm in the control group (p=0.412), with a similar trend for BMI. Interim serum cytokine analysis showed a 3-fold increase in IL-10 levels in the exercise arm at T3 when compared to the control arm (p=0.036). No significant change in IL-10 levels was recorded at T6 between arms (p=0.776). Similarly, CXCL8 (IL-8) levels were increased by 1.8-fold at T3 in the exercise arm in comparison to the control arm (p=0.017), with no significant change reported at T6 (p=0.191). While changes were evident in serum TNFα, IL-6, VEGF, IL-17a, MMP9 and CCL5 (RANTES) levels, these did not reach significance. Differences in levels of adipokines leptin and resistin were also reported. A 1.5-fold increase in resistin expression was observed in the exercise arm at T6; however, it was not significant (p=0.293). A 2-fold decrease in leptin in the control arm relative to the exercise arm at T6 was also detected (p=0.676). Analysis of adiponectin, MMP2, and CCL2 is ongoing. Conclusion: Our interim analysis of ExPeCT trial participants demonstrated a significant increase in serum CXCL8 and IL-10 levels after three months of a supervised exercise intervention. These preliminary data suggest that a structured exercise program has the potential to modify inflammatory status in patients with metastatic PrCa. Citation Format: Lauren Brady, Grainne Sheill, Anne-Marie Baird, Emma H. Allott, Tatjana Vlajnic, John Greene, Orla Casey, Brian Hayes, Emer Guinan, Juliette Hussey, Fidelma Cahill, Mieke Van Hemelrijck, Nicola Peat, Sarah Rudman, Moya Cunningham, Liam Grogan, Thomas Lynch, Rustom P. Manecksha, John McCaffrey, Orla Sheils, Dearbhaile M. O’Donnell, John O’Leary, Ray McDermott, Stephen P. Finn. Examining the link between obesity, inflammation, and exercise in patients with metastatic prostate cancer—An interim analysis from the ExPeCT trial [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A057.

Background: Patients with metastatic prostate cancer live with a considerable disease burden that may have a profound impact on physical activity and quality of life. This patient group may survive for many years after disease onset; however, there is little evidence on their habitual levels of physical activity. The aim of this study was to investigate physical activity levels and associated health-related quality of life in prostate cancer patients with bone metastases. Methods: ExPeCT (Exercise, Prostate Cancer and Circulating Tumour Cells: CTRIAL-IE 15-21) (ClincalTrials.gov identifier NCT02453139) is an ongoing multicenter trial examining the effect of a 6-month structured exercise intervention for patients with metastatic prostate cancer. Participants complete questionnaires examining self-reported health-related quality of life (FACT-P), sleep (Pittsburgh Sleep Index), depression (PHQ-9), and physical activity (Harvard Health Professionals Study Questionnaire) at baseline, three, and six months. Analysis of 3- and 6-month data is ongoing. Result: An interim analysis of the baseline outcome measures of 64 patients with bone metastases was completed (mean age 69.4 (SD 7.35) years and mean BMI 29.2 (SD 5.8) kg/m2). Median time since diagnosis was 34 months (IQR 7-54) and 55% (n=35) of participants had >1 region affected by metastatic disease. Preliminary data demonstrated that 38% (n=24) of participants did not meet the current aerobic exercise guidelines for cancer survivors. In total, 20% (n=13) of participants reported engaging in vigorous activity and 16% (n=11) reported completing resistance exercise. There was no correlation found between physical activity levels and quality of life (r=0.01), sleep (r=0.02), or depression (r=-0.15) scores. The majority of participants (61% (n=41)) had sleep scores of >7, indicative of poor sleep quality. Sleep scores correlated negatively with global quality of life (r =-0.55, p Discussion: Findings highlight the association between reduced quality of life and poor sleep quality among men with metastatic prostate cancer. In addition, data suggest a high prevalence of suboptimal physical activity levels in this population. Patients with metastatic disease may benefit from lifestyle interventions that aim to increase physical activity levels. Citation Format: Gráinne Sheill, Lauren Brady, Emer Guinan, Juliette Hussey, David Hevey, Tatjana Vlajnic, Orla Casey, Anne-Marie Baird, Fidelma Cahill, Mieke Van Hemelrijck, Nicola Peat, Sarah Rudman, Thomas Lynch, Rustom P. Manecksha, Brian Hayes, Moya Cunningham, Liam Grogan, John McCaffrey, Dearbhaile M. O’Donnell, Ray McDermott, John O Leary, Stephen P. Finn. Lifestyle and health-related quality of life in men with metastatic prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr A059.

107 Background: Physical activity (PA) is beneficial in reducing disease and treatment related side‐effects of cancer. However, insufficient PA levels are common among cancer survivors. eHealth may offer an innovative delivery platform to support cancer survivors to increase PA. Few qualitative studies have explored the views of cancer survivors towards eHealth based PA interventions. Our aim was to use cancer survivors’ input to inform the design of a feasibility study of eHealth for PA promotion. Methods: A ten-item scoping questionnaire-based cross-sectional study was administered to 102 cancer survivors. It evaluated their knowledge of PA guidelines, their access to smartphones and interest in eHealth interventions designed to increase PA levels. Questions were refined and evaluated in a follow-up focus group study (7 groups, n=23). Focus groups were audio recorded and transcribed. Transcripts were coded using NVivo software and themes identified by thematic content analysis. Results: In the questionnaire study, only 17.6% (n=18) of participants correctly identified PA guidelines. Sixty-two (60.8%) participants reported having access to a smartphone. Interest in participating in an eHealth intervention was expressed by 56.9% of all participants (n=58) and by 75.8% (n=47) of those with access to a smartphone. Emergent themes from the focus groups included: the physical barriers to PA, the need for PA goals, the importance of both information from healthcare professionals about PA and of a support network (e.g. peer support), the need for technological support and a motivation to improve general health. Conclusions: Very few cancer survivors were aware of the correct PA guidelines. However, over half of our sample was interested in participating in an eHealth intervention for PA, demonstrating that the cancer survivor population is responsive to a PA program delivered using technology. The focus groups have given us insights about the key elements of an effective PA intervention for cancer survivors using eHealth. We are conducting a feasibility study (The IMPETUS study; NCT03036436) of an eHealth intervention targeting PA in cancer survivors; its design was informed by those insights.

The immune response to cancer is critically determined by the way in which tumor cells die. As necrotic, stress-associated death can be associated with activation of antitumor immunity, whole tumor cell antigen loading strategies for dendritic cell (DC)-based vaccination have commonly used freeze-thaw "necrotic" lysates as an immunogenic source of tumor-associated antigens. In this study, the effect of such lysates on the ability of DCs to mature in response to well-established maturation stimuli was examined, and methods to enhance lysate-induced DC activation explored. Freeze-thaw lysates were prepared from murine tumor cell lines and their effects on bone marrow-derived DC maturation and function examined. Unmodified freeze-thaw tumor cell lysates inhibited the toll-like receptor-induced maturation and function of bone marrow-derived DCs, preventing up-regulation of CD40, CD86, and major histocompatibility complex class II, and reducing secretion of inflammatory cytokines [interleukin (IL)-12 p70, tumor necrosis factor-alpha, and IL-6]. Although IL-10 secretion was increased by lysate-pulsed DCs, this was not responsible for the observed suppression of IL-12. Although activation of the nuclear factor-kappaB pathway remained intact, the kinase activity of phosphorylated p38 mitogen-activated protein kinase was inhibited in lysate-pulsed DCs. Lysate-induced DC suppression was partially reversed in vitro by induction of tumor cell stress before lysis, and only DCs loaded with stressed lysates afforded protection against tumor challenge in vivo. These data suggest that ex vivo freeze-thaw of tumor cells does not effectively mimic in vivo immunogenic necrosis, and advocates careful characterization and optimization of tumor cell-derived vaccine sources for cancer immunotherapy.

In vivo, dendritic cells (DC) are programmed to orchestrate innate and adaptive immunity in response to pathogen-derived “danger” signals. Under particular circumstances, DC can also be directly cytotoxic against tumor cells, potentially allowing them to release tumor associated Ags from dying cells and then prime antitumor immunity against them. In this study, we describe the innate characteristics of DC (OK-DC) generated in vitro after exposure of immature human myeloid-derived DC to OK432, a penicillin-inactivated and lyophilized preparation of Streptococcus pyrogenes. OK-DC produced proinflammatory cytokines, stimulated autologous T cell proliferation and IFN-γ secretion, expressed CCR7, and migrated in response to MIP-3β. Moreover, OK-DC displayed strong, specific cytotoxicity toward tumor cell targets. This cytotoxicity was associated with novel, OK432-induced up-regulation of CD40L on the cell surface of OK-DC, and was absolutely dependent on expression of CD40 on the tumor targets. These data demonstrate that maturation of human DC with OK432, an adjuvant suitable for clinical use, induces direct tumor cell killing by DC, and describes a novel CD40/CD40L-mediated mechanism for specific DC antitumor cytotoxicity.

Purpose: Conventional renal cell carcinoma (RCC) has a variable natural history, and determining individual prognosis is important to guide management. We have examined the prognostic significance of a large number of hematologic and biochemical variables, as well as traditional tumor-related factors in patients with RCC. Experimental Design: Patients undergoing nephrectomy for newly diagnosed RCC between September 1998 and March 2005 were invited to participate. Clinical, pathologic, and laboratory data were recorded in each case, and immunophenotyping was carried out on a subset of patients. A planned subset analysis of patients presenting with N0M0 disease was done. Results: Two hundred twelve patients with RCC formed the study population. In addition to tumor-related factors, multivariate analyses revealed preoperative serum sodium concentration to be independently and significantly associated with overall survival and disease-free survival when considered as both a continuous variable and when dichotomized to above and below the median value [139 mmol/L; reference range 135-145 mmol/L, hazard ratio 0.44, 95% confidence interval (95% CI) 0.22-0.88, P = 0.014]. Five-year overall survival estimates for patients above and below the median serum sodium were 67.6% (95% CI 54.2-80.9) and 44.3% (95% CI 32.8-55.8), respectively. These findings persisted in the N0M0 subgroup analysis. Conclusions: We have confirmed the prognostic value of traditional tumor-related factors but, to our knowledge, these are the first data to show that low preoperative sodium concentration may be an important factor associated with reduced survival in patients with RCC, suggesting that serum sodium should be considered with established prognostic variables in modeling survival in RCC.

Dendritic cells (DC) pulsed with MHC class I-restricted tumour associated antigen (TAA) peptides have been widely tested in pre-clinical models and early clinical studies for their ability to prime cytotoxic T cell (CTL) responses. The effect of co-expression of allogeneic MHC antigens on DC immunogenicity has not been addressed, and has implications for the feasibility of clinical applications.This study compared DC from autologous H-2(b) or semi-allogeneic F1 H-2(bxk) mice pulsed with the H-2(b)-restricted model ovalbumin (OVA) peptide SIINFEKL, and compared in vitro and in vivo their ability to (i) activate specific OT1 cells, (ii) prime naïve CTL, and (iii) protect against B16.OVA challenge. Peptide-pulsed autologous and allogeneic DC were also tested in naïve human CTL priming assays.Semi-allogeneic DC expressed higher levels of co-stimulatory molecules. On pulsing with SIINFEKL they triggered greater proliferation of OT1 cells in vitro and in vivo, but were less effective at naïve CTL priming and tumour protection. Autologous human DC were similarly more potent at naïve CTL priming against the melanoma-associated TAA MART-1 in vitro.The expression of allogeneic MHC antigens on peptide-pulsed DC impairs naïve CTL priming and anti-tumour effects, despite effective TAA presentation both in vitro and in vivo.

Malignant pleural mesothelioma (MPM) is an aggressive inflammatory cancer associated with exposure to asbestos. Untreated, MPM has a median survival time of 6 months,and most patients die within two years of diagnosis. There is an urgent need to identify new therapies for treating MPM patients.

The prognosis of epithelial ovarian cancer is poor in part due to the high frequency of chemoresistance. Recent evidence points to the Toll-like receptor-4 (TLR4), and particularly its adaptor protein MyD88, as one potential mediator of this resistance. This study aims to provide further evidence that MyD88 positive cancer cells are clinically significant, stem-like and reproducibly detectable for the purposes of prognostic stratification. Expression of TLR4 and MyD88 was assessed immunohistochemically in 198 paraffin-embedded ovarian tissues and in an embryonal carcinoma model of cancer stemness. In parallel, expression of TLR4 and MyD88 mRNA and regulatory microRNAs (miR-21 and miR-146a) was assessed, as well as in a series of chemosensitive and resistant cancer cells lines. Functional analysis of the pathway was assessed in chemoresistant SKOV-3 ovarian cancer cells. TLR4 and MyD88 expression can be reproducibly assessed via immunohistochemistry using a semi-quantitative scoring system. TLR4 expression was present in all ovarian epithelium (normal and neoplastic), whereas MyD88 was restricted to neoplastic cells, independent of tumour grade and associated with reduced progression-free and overall survival, in an immunohistological specific subset of serous carcinomas, p

Increased exhaled nitric oxide (NO) may reflect respiratory tract inflammation in untreated asthmatics. We compared exhaled NO and bronchoalveolar lavage (BAL) nitrate/nitrite (NO3-/NO2-) in 10 patients who had untreated, active pulmonary sarcoidosis with those of normal control subjects. Exhaled NO concentrations, determined by chemiluminescence, were similar in patients and control subjects (peak NO concentration of patients [mean +/- SD]: 13.6 +/- 5.9 parts per billion [ppb], peak NO concentration of control subjects: 11.2 +/- 5.7 ppb, p = 0.32; mean alveolar NO concentration of patients: 7.8 +/- 4.4 ppb, mean alveolar NO concentration of control subjects: 7.1 +/- 4.2 ppb, p = 0.70; end-tidal NO concentration of patients: 6.9 +/- 4.5 ppb, end-tidal NO concentration of control subjects: 6.6 +/- 4.0 ppb, p = 0.60). BAL NO2- was assayed using a modified Griess reaction after reduction of NO3- to NO2-. There was no significant difference in mean BAL NO2- concentrations, expressed as nanomoles per milliliter of epithelial lining fluid (patients: 544 nmol/ml, control subjects: 579 nmol/ml, p = 0.81) or as nanomoles per milliliter of BAL fluid (patients: 6.7 nmol/ml, control subjects: 5.7 nmol/ml, p = 0.41). These data suggest that excess NO generation does not accompany the respiratory tract inflammation of pulmonary sarcoidosis.