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Introduced in 1983, Bland-Altman methods is now considered the standard approach for assessment of agreement between two methods of measurement. The method is widely used by researchers in various disciplines so that the Bland-Altman 1986 Lancet paper has been named as the 29th mostly highly cited paper ever, over all fields. However, two papers by Hopkins (2004) and Krouwer (2007) questioned the validity of the Bland-Altman analysis. We review the points of critical papers and provide responses to them. The discussions in the critical papers of the Bland-Altman method are scientifically delusive. Hopkins misused the Bland-Altman methodology for research question of model validation and also incorrectly used least-square regression when there is measurement error in the predictor. The problem with Krouwers' paper is making sweeping generalisation of a very narrow and somewhat unrealistic situation. The method proposed by Bland and Altman should be used when the research question is method comparison.

This interpretivist community participatory study explores carers’ beliefs about the potential usefulness of counselling in relation to the caring role. Twenty semi-structured interviews with carers were transcribed and analysed thematically. All participants thought counselling could potentially be helpful to carers, but their ideas about the ways in which it would help varied according to whether or not they had personal experience of counselling. Only carers with counselling experience had an awareness of counselling as focussing on changing feelings, thoughts, attitudes and behaviours. The implications of the findings for the provision of counselling services are discussed.

Objectives To explore how the concept of randomization is described by clinicians and understood by patients in randomized controlled trials (RCTs) and how it contributes to patient understanding and recruitment. Study Design and Setting Qualitative analysis of 73 audio recordings of recruitment consultations from five, multicenter, UK-based RCTs with identified or anticipated recruitment difficulties. Results One in 10 appointments did not include any mention of randomization. Most included a description of the method or process of allocation. Descriptions often made reference to gambling-related metaphors or similes, or referred to allocation by a computer. Where reference was made to a computer, some patients assumed that they would receive the treatment that was “best for them”. Descriptions of the rationale for randomization were rarely present and often only came about as a consequence of patients questioning the reason for a random allocation. Conclusions The methods and processes of randomization were usually described by recruiters, but often without clarity, which could lead to patient misunderstanding. The rationale for randomization was rarely mentioned. Recruiters should avoid problematic gambling metaphors and illusions of agency in their explanations and instead focus on clearer descriptions of the rationale and method of randomization to ensure patients are better informed about randomization and RCT participation., Highlights • Practices commonly used to describe randomisation in RCT recruitment could confuse patients. • Patients found it difficult to comprehend gambling-related metaphors of randomisation. • Computer-agency descriptions led to patients believing they would receive the best treatment.

Over the last 20 years, there has been an increased interest in community-based participatory research (CBPR) across a range of disciplines. This approach to research focuses on the empowerment of those for whom the research is relevant by ensuring that they or their representatives have the opportunity for full involvement in developing and undertaking studies, and in disseminating the research findings. However, there is little evidence within counselling and psychotherapy of a substantial engagement with research that includes clients, potential clients and their communities as full partners in the research process. This paper describes CBPR and critically explores its potential for developing knowledge in counselling and psychotherapy.

Aims Increases to radiotherapy dose are constrained by normal tissue effects. The relationship between bowel dose volume data and late bowel toxicity in patients with muscle-invasive bladder cancer treated with radical radiotherapy was assessed. Materials and methods The bowel was contoured retrospectively on radiotherapy plans of 47 patients recruited to the BC2001 trial (CRUK/01/004). The relationship between bowel volume at various dose levels and prospectively collected late bowel toxicity was explored. Results Fifteen per cent and 6% of patients experienced grade 1 and grade 2 or more late bowel toxicity, respectively. The mean bowel volume was significantly less at doses ≥50 Gy in those treated with reduced high dose volume radiotherapy compared with standard radiotherapy. The probability of late bowel toxicity increased as bowel volume increased ( P ≤ 0.05 for dose levels 30–50 Gy). No grade 2 or more late bowel toxicity was observed in patients with bowel volumes under the thresholds given in the model that predict for 25% probability of late bowel toxicity. Conclusions There is a dose volume effect for late bowel toxicity in radical bladder radiotherapy. We have modelled the probability of late bowel toxicity from absolute bowel volumes to guide clinicians in assessing radical bladder radiotherapy plans. Thresholds predicting for a 25% probability of late bowel toxicity are proposed as dose volume constraints.

Background The TACT trial (CRUK/01/001) compared adjuvant sequential FEC-docetaxel (FEC-D) chemotherapy with standard anthracycline-based chemotherapy of similar duration in women with early breast cancer. Results at a median of 5years suggested no improvement in disease-free survival with FEC-D. Given differing toxicity profiles of the regimens, the impact on quality of life (QL) was explored. Methods Patients from 44 centres completed standardised QL questionnaires before chemotherapy, after cycles 4 and 8, at 9, 12, 18 and 24months and at 6years follow-up. Patient diaries assessed frequency, associated distress and impact on daily activity of 15 treatment related side effects. Findings 830 patients (415 FEC-D; 415 controls) contributed assessments during 0–24months; 362 of whom participated again at 6years. During chemotherapy, FEC-D impaired global health/QL and depression rates and significantly more QL domains than standard regimens. Novel diary card ratings highlighted significantly more distress and interference with daily activities due to FEC-D side effects compared with standard treatment. In both groups, most QL parameters returned to baseline levels by 2years and were unchanged at 6years. Interpretation Within expected negative effects of chemotherapy on wide ranging QL domains FEC-D patients reported greater toxicity, disruption and distress during treatment with no improvement in disease outcome at 5years than patients receiving standard anthracycline-based chemotherapy. Findings should inform future patients of relative costs and benefits of adjuvant chemotherapy.

Purpose To test whether reducing radiation dose to uninvolved bladder while maintaining dose to the tumor would reduce side effects without impairing local control in the treatment of muscle-invasive bladder cancer. Methods and Materials In this phase III multicenter trial, 219 patients were randomized to standard whole-bladder radiation therapy (sRT) or reduced high-dose volume radiation therapy (RHDVRT) that aimed to deliver full radiation dose to the tumor and 80% of maximum dose to the uninvolved bladder. Participants were also randomly assigned to receive radiation therapy alone or radiation therapy plus chemotherapy in a partial 2 × 2 factorial design. The primary endpoints for the radiation therapy volume comparison were late toxicity and time to locoregional recurrence (with a noninferiority margin of 10% at 2 years). Results Overall incidence of late toxicity was less than predicted, with a cumulative 2-year Radiation Therapy Oncology Group grade 3/4 toxicity rate of 13% (95% confidence interval 8%, 20%) and no statistically significant differences between groups. The difference in 2-year locoregional recurrence free rate (RHDVRT − sRT) was 6.4% (95% confidence interval −7.3%, 16.8%) under an intention to treat analysis and 2.6% (−12.8%, 14.6%) in the "per-protocol" population. Conclusions In this study RHDVRT did not result in a statistically significant reduction in late side effects compared with sRT, and noninferiority of locoregional control could not be concluded formally. However, overall low rates of clinically significant toxicity combined with low rates of invasive bladder cancer relapse confirm that (chemo)radiation therapy is a valid option for the treatment of muscle-invasive bladder cancer.

To assess the value of pretreatment O6-methylguanine-DNA methyltransferase (MGMT) expression in peripheral blood mononuclear cells (PBMCs) in predicting haematological toxicity with O6-alkylating agent chemotherapy, we explored this relationship retrospectively in melanoma patients. Ninety-three patients treated with temozolomide or dacarbazine in four clinical trials were assessed, and a model of the interaction between MGMT expression and haematological toxicity was constructed. Nadir white-cell and platelet counts were related to, and hence could be predicted from, pretreatment MGMT. Leucopenia and thrombocytopenia were more prevalent amongst patients with low pretreatment MGMT, according to the highest grades of toxicity experienced and/or the dose intensity patients could sustain. Addition of interferon to chemotherapy or compression of the temozolomide schedule increased the toxicity. The model also predicts significant myelotoxicity where PBMC MGMT is inactivated, consistent with the experience in the clinic with lomeguatrib and O6-benzylguanine. Determination of MGMT in PBMC can identify patients at greatest risk of toxicity or who are suitable for dose intensification.

Summary We have previously reported presentation serum selenium level to be predictive of outcome in diffuse large B–cell lymphoma. This has now been studied in a further 430 patients, 163 with acute myeloid leukaemia (AML), 156 with Hodgkin Lymphoma (HL), and 111 with Follicular Lymphoma (FL). Serum selenium was below the UK normal reference range in 45% of patients, and correlated with serum albumin (r = 0·24–0·46, P

Norwood M G A, Bailey N, Nanji M, Gillies R S, Nicholson A, Ubhi S, Darnton J J, Steyn R S, Womack C, Hughes A, Hemingway D, Harrison R, Waters R & Jankowski J A (2010) Histopathology 57, 101–111 Cytoplasmic β-catenin accumulation is a good prognostic marker in upper and lower gastrointestinal adenocarcinomas Aims: β-Catenin is an important molecule in cancer biology. Membranous β-catenin enhances cellular differentiation and inhibits invasion by its action on E-cadherin. The aim was to ascertain whether the cellular expression of these molecules in colorectal and oesophageal cancer specimens is associated with survival in patients with gastrointestinal cancer. Methods and results: Tumour samples from 149 patients undergoing resection for colorectal adenocarcinoma and 147 patients undergoing resection for oesophageal adenocarcinoma were retrospectively analysed using immunohistochemical techniques to assess β-catenin expression. Increasing β-catenin expression in the cytoplasm was associated with improved survival for colorectal cancer cases on both univariate (P = 0.003) and multivariate (P = 0.01) analysis. In addition, increased expression in the most recent cohort of oesophageal adenocarcinoma patients was associated with improved TNM staging (P = 0.007). Membrane expression was weakly associated with survival in colorectal cancer on univariate analysis (P = 0.09), but not on multivariate analysis (P = 0.21). Complete absence of β-catenin expression at all three sites was associated with reduced 5-year survival in colorectal cancer. Conclusions: This is one of the largest prognostic studies of β-catenin in gastrointestinal adenocarcinoma. It shows that low levels of cytoplasmic β-catenin expression are associated with reduced survival in patients with colorectal cancer as well as worse TNM staging in oesophageal adenocarcinoma (a recognized surrogate end-point for survival). We believe this is the first time that this has been reported. This finding should be tested prospectively in oncological trials to validate whether the presence of cytoplasmic β-catenin could be used as a prognostic marker for less aggressive disease.

Summary Background Major depressive disorder severely impairs the quality of life of patients with medical disorders such as cancer, but evidence to guide its management is scarce. We aimed to assess the efficacy and cost of a nurse-delivered complex intervention that was designed to treat major depressive disorder in patients who have cancer. Methods We did a randomised trial in a regional cancer centre in Scotland, UK. 200 outpatients who had cancer with a prognosis of greater than 6 months and major depressive disorder (identified by screening) were eligible and agreed to take part. Their mean age was 56·6 (SD 11·9) years, and 141 (71%) were women. We randomly assigned 99 of these participants to usual care, and 101 to usual care plus the intervention, with minimisation for sex, age, diagnosis, and extent of disease. The intervention was delivered by a cancer nurse at the centre over an average of seven sessions. The primary outcome was the difference in mean score on the self-reported Symptom Checklist-20 depression scale (range 0 to 4) at 3 months after randomisation. Analysis was by intention to treat. This trial is registered as ISRCTN84767225. Findings Primary outcome data were missing for four patients. For 196 patients for whom we had data at 3 months, the adjusted difference in mean Symptom Checklist-20 depression score, between those who received the intervention and those who did not, was 0·34 (95% CI 0·13–0·55). This treatment effect was sustained at 6 and 12 months. The intervention also improved anxiety and fatigue but not pain or physical functioning. It cost an additional £5278 (US$10 556) per quality-adjusted life-year gained. Interpretation The intervention—Depression Care for People with Cancer—offers a model for the management of major depressive disorder in patients with cancer and other medical disorders who are attending specialist medical services that is feasible, acceptable, and potentially cost effective. Funding Cancer Research UK.

The study aims to identify knowledge about sexually transmitted infections (STIs) among Latino adolescents, to explore programmatic components that are essential for an effective educational program, and to explore gender differences regarding STI knowledge and essential components.A naturalistic inquiry approach was used.Knowledge of specific STIs was minimal. Themes including humor, fear, empowered decision-making, peer educators, self-protection, knowledge and information on STIs, and consistency of the sexual health education were identified as essential components for STI educational programs.The findings of this study enhance the understanding of STIs, sexual behaviors, and essential components of an effective STI educational program as perceived by Latino adolescents.It is essential for nurses to provide accurate information about STIs and safe sex to help decrease the transmission of STIs.

PURPOSE: Real-time symptom monitoring using a mobile phone is potentially advantageous for patients receiving oral chemotherapy. We therefore conducted a pilot study of patient dose adaptation using mobile phone monitoring of specific symptoms to investigate relative dose intensity of capecitabine, level of toxicity and perceived supportive care. METHODS: Patients with breast or colorectal cancer receiving capecitabine completed a symptom, temperature and dose diary twice a day using a mobile phone application. This information was encrypted and automatically transmitted in real time to a secure server, with moderate levels of toxicity automatically prompting self-care symptom management messages on the screen of the patient's mobile phone or in severe cases, a call from a specialist nurse to advise on care according to an agreed protocol. RESULTS: Patients (n = 26) completed the mobile phone diary on 92.6 % of occasions. Twelve patients had a maximum toxicity grade of 3 (46.2 %). The average dose intensity for all patients as a percentage of standard dose was 90 %. In eight patients, the dose of capecitabine was reduced, and in eight patients, the dose of capecitabine was increased. Patients and healthcare professionals involved felt reassured by the novel monitoring system, in particular, during out of hours. CONCLUSION: It is possible to optimise the individual dose of oral chemotherapy safely including dose increase and to manage chemotherapy side effects effectively using real-time mobile phone monitoring of toxicity parameters entered by the patient.

Radiotherapy is an alternative to cystectomy in patients with muscle-invasive bladder cancer. In other disease sites, synchronous chemoradiotherapy has been associated with increased local control and improved survival, as compared with radiotherapy alone.In this multicenter, phase 3 trial, we randomly assigned 360 patients with muscle-invasive bladder cancer to undergo radiotherapy with or without synchronous chemotherapy. The regimen consisted of fluorouracil (500 mg per square meter of body-surface area per day) during fractions 1 to 5 and 16 to 20 of radiotherapy and mitomycin C (12 mg per square meter) on day 1. Patients were also randomly assigned to undergo either whole-bladder radiotherapy or modified-volume radiotherapy (in which the volume of bladder receiving full-dose radiotherapy was reduced) in a partial 2-by-2 factorial design (results not reported here). The primary end point was survival free of locoregional disease. Secondary end points included overall survival and toxic effects.At 2 years, rates of locoregional disease-free survival were 67% (95% confidence interval [CI], 59 to 74) in the chemoradiotherapy group and 54% (95% CI, 46 to 62) in the radiotherapy group. With a median follow-up of 69.9 months, the hazard ratio in the chemoradiotherapy group was 0.68 (95% CI, 0.48 to 0.96; P=0.03). Five-year rates of overall survival were 48% (95% CI, 40 to 55) in the chemoradiotherapy group and 35% (95% CI, 28 to 43) in the radiotherapy group (hazard ratio, 0.82; 95% CI, 0.63 to 1.09; P=0.16). Grade 3 or 4 adverse events were slightly more common in the chemoradiotherapy group than in the radiotherapy group during treatment (36.0% vs. 27.5%, P=0.07) but not during follow-up (8.3% vs. 15.7%, P=0.07).Synchronous chemotherapy with fluorouracil and mitomycin C combined with radiotherapy significantly improved locoregional control of bladder cancer, as compared with radiotherapy alone, with no significant increase in adverse events. (Funded by Cancer Research U.K.; BC2001 Current Controlled Trials number, ISRCTN68324339.).

We have previously reported presentation serum selenium level to be predictive of outcome in diffuse large B-cell lymphoma. This has now been studied in a further 430 patients, 163 with acute myeloid leukaemia (AML), 156 with Hodgkin Lymphoma (HL), and 111 with Follicular Lymphoma (FL). Serum selenium was below the UK normal reference range in 45% of patients, and correlated with serum albumin (r=0·24-0·46, P0·001-0·003) in all tumour types. Independent predictors of presentation selenium were; French-American-British subtype and albumin (P0·001 for both) in AML, haemoglobin (P=0·002) and B-symptoms (P=0·01) in HL, and albumin (P0·001) in FL. In AML and HL, response to first line therapy was lower in patients with low serum selenium, but selenium was no longer predictive of response when other variables were entered into a multivariate model. Low selenium was also associated with a worse overall survival in FL [Hazard Ratio (HR) 2·3, 95% confidence interval (CI) 1·4, 4·0] and a trend to a worse overall survival in AML (HR 1·43, 95% CI 0·96, 2·13) by univariate Cox regression analysis, but not by multivariate analysis. In conclusion, low serum selenium is associated with a worse outcome in patients with haematological malignancies, but is not independently predictive, suggesting that it reflects other factors.

beta-Catenin is an important molecule in cancer biology. Membranous beta-catenin enhances cellular differentiation and inhibits invasion by its action on E-cadherin. The aim was to ascertain whether the cellular expression of these molecules in colorectal and oesophageal cancer specimens is associated with survival in patients with gastrointestinal cancer.Tumour samples from 149 patients undergoing resection for colorectal adenocarcinoma and 147 patients undergoing resection for oesophageal adenocarcinoma were retrospectively analysed using immunohistochemical techniques to assess beta-catenin expression. Increasing beta-catenin expression in the cytoplasm was associated with improved survival for colorectal cancer cases on both univariate (P = 0.003) and multivariate (P = 0.01) analysis. In addition, increased expression in the most recent cohort of oesophageal adenocarcinoma patients was associated with improved TNM staging (P = 0.007). Membrane expression was weakly associated with survival in colorectal cancer on univariate analysis (P = 0.09), but not on multivariate analysis (P = 0.21). Complete absence of beta-catenin expression at all three sites was associated with reduced 5-year survival in colorectal cancer.This is one of the largest prognostic studies of beta-catenin in gastrointestinal adenocarcinoma. It shows that low levels of cytoplasmic beta-catenin expression are associated with reduced survival in patients with colorectal cancer as well as worse TNM staging in oesophageal adenocarcinoma (a recognized surrogate end-point for survival). We believe this is the first time that this has been reported. This finding should be tested prospectively in oncological trials to validate whether the presence of cytoplasmic beta-catenin could be used as a prognostic marker for less aggressive disease.

Background Development of prognostic models enables identification of variables that are influential in predicting patient outcome and the use of these multiple risk factors in a systematic, reproducible way according to evidence based methods. The reliability of models depends on informed use of statistical methods, in combination with prior knowledge of disease. We reviewed published articles to assess reporting and methods used to develop new prognostic models in cancer. Methods We developed a systematic search string and identified articles from PubMed. Forty-seven articles were included that satisfied the following inclusion criteria: published in 2005; aiming to predict patient outcome; presenting new prognostic models in cancer with outcome time to an event and including a combination of at least two separate variables; and analysing data using multivariable analysis suitable for time to event data. Results In 47 studies, prospective cohort or randomised controlled trial data were used for model development in only 33% (15) of studies. In 30% (14) of the studies insufficient data were available, having fewer than 10 events per variable (EPV) used in model development. EPV could not be calculated in a further 40% (19) of the studies. The coding of candidate variables was only reported in 68% (32) of the studies. Although use of continuous variables was reported in all studies, only one article reported using recommended methods of retaining all these variables as continuous without categorisation. Statistical methods for selection of variables in the multivariate modelling were often flawed. A method that is not recommended, namely, using statistical significance in univariate analysis as a pre-screening test to select variables for inclusion in the multivariate model, was applied in 48% (21) of the studies. Conclusions We found that published prognostic models are often characterised by both use of inappropriate methods for development of multivariable models and poor reporting. In addition, models are limited by the lack of studies based on prospective data of sufficient sample size to avoid overfitting. The use of poor methods compromises the reliability of prognostic models developed to provide objective probability estimates to complement clinical intuition of the physician and guidelines.

Background Appropriate choice and use of prognostic models in clinical practice require the use of good methods for both model development, and for developing prognostic indices and risk groups from the models. In order to assess reliability and generalizability for use, models need to have been validated and measures of model performance reported. We reviewed published articles to assess the methods and reporting used to develop and evaluate performance of prognostic indices and risk groups from prognostic models. Methods We developed a systematic search string and identified articles from PubMed. Forty-seven articles were included that satisfied the following inclusion criteria: published in 2005; aiming to predict patient outcome; presenting new prognostic models in cancer with outcome time to an event and including a combination of at least two separate variables; and analysing data using multivariable analysis suitable for time to event data. Results In 47 studies, Cox models were used in 94% (44), but the coefficients or hazard ratios for the variables in the final model were reported in only 72% (34). The reproducibility of the derived model was assessed in only 11% (5) of the articles. A prognostic index was developed from the model in 81% (38) of the articles, but researchers derived the prognostic index from the final prognostic model in only 34% (13) of the studies; different coefficients or variables from those in the final model were used in 50% (19) of models and the methods used were unclear in 16% (6) of the articles. Methods used to derive prognostic groups were also poor, with researchers not reporting the methods used in 39% (14 of 36) of the studies and data derived methods likely to bias estimates of differences between risk groups being used in 28% (10) of the studies. Validation of their models was reported in only 34% (16) of the studies. In 15 studies validation used data from the same population and in five studies from a different population. Including reports of validation with external data from publications up to four years following model development, external validation was attempted for only 21% (10) of models. Insufficient information was provided on the performance of models in terms of discrimination and calibration. Conclusions Many published prognostic models have been developed using poor methods and many with poor reporting, both of which compromise the reliability and clinical relevance of models, prognostic indices and risk groups derived from them.

Acquired homozygosity in the form of segmental acquired uniparental disomy (aUPD) has been described in follicular lymphoma (FL) and is usually due to mitotic recombination. SNP array analysis was performed with the use of the Affymetrix 10K 2.0 Gene-chip array on DNA from 185 diagnostic FL patients to assess the prognostic relevance of aUPD. Genetic abnormalities were detected in 118 (65%) of 182 patients. Number of abnormalities was predictive of outcome; more than 3 abnormalities was associated with inferior overall survival (OS; P < .03). Sites of recurrent aUPD were detected on 6p (n = 25), 16p (n = 22), 12q (n = 17), 1p36 (n = 14), 10q (n = 8), and 6q (n = 8). On multivariate analysis aUPD on 1p36 correlated with shorter OS (P = .05). aUPD on 16p was predictive of transformation (P = .03) and correlated with poorer progression-free survival (P = .02). aUPD is frequent at diagnosis of FL and affects probability of disease transformation and clinical outcome.

Tumor protein 53 (TP53) is critical to cell cycle control and is the most common mutational target in germinal center lymphomas. However, these mutations occur infrequently at diagnosis ( G substitution at nucleotide 309 of intron one and leads to higher MDM2 mRNA and protein expression with lower apoptotic response. Significantly, homozygosity for the G allele correlates with earlier onset of de novo diffuse large B-cell lymphoma (DLBCL) in females7 Its role in CLL is less clear as two recent studies provide contrasting results.8,9 TP53 Arg72Pro is a non-synonymous SNP involving G>C substitution at nucleotide 466 of exon 4 in TP53 which creates a TP53 protein with reduced potential to induce apoptosis or suppress cell transformation.10 These SNPs are also associated with poor prognosis or increased cancer risk in certain solid malignancies.11,12 We investigated the relationship of the allelic combinations for both SNPs with the following clinical variables in cases of FL: age, gender, stage at diagnosis, response to first line therapy, best response to therapy, progression-free survival, relapse-free survival, overall survival and time to transformation (Details of each variable are available in the Online Supplementary Table S1). A real-time polymerase chain reaction Allelic Discrimination multiplexed endpoint assay protocol using the ABI PRISM™ 7700 Sequence Detector (Applied Biosystems, Foster City, CA, USA) was used to determine the SNP alleles present in DNA of 226 patient samples from bone marrow (n=207), peripheral blood (n=14) or lymph nodes (n=5). (Oligonucleotide sequences used are available on request.) Samples were obtained from the tissue archive at St Bartholomew’s Hospital under Institutional Ethical Approval obtained from the Local Ethics Committee. Reactions were performed in duplicate including homozygous and heterozygous controls for each SNP genotype and a no DNA template control. Positive controls were confirmed by direct sequencing. In this patient cohort, allelic frequencies were similar to previously published results at 44%, 43%, 13% for MDM2 SNP 309 TT, TG, GG and at 46%, 46%, 8% for TP53 Arg72Pro GG, GC, CC respectively (Online Supplementary Table S2) and both polymorphisms satisfied the Hardy-Weinberg equilibrium. Median age at diagnosis was 46 years, which is younger than that previously described for FL, and reflects our status as a tertiary referral center for patients with FL. There was no difference in the median age at diagnosis for each of the 3 allelic combinations of MDM2 SNP 309 (both for the whole study population and for gender in contrast to findings in DLBCL7) and of TP53 Arg53Pro (Online Supplementary Table S2). Relationships between SNP alleles and clinical parameters were studied using χ2 test for stage and gender, analysis of variance (ANOVA) for age and Kruskal-Wallis test for responses to therapy. The 3 allelic combinations for each SNP were informally assessed as well as formally assessing two groups of patient samples consisting of those homozygous for the common allele or those with at least one rare allele, enabling any dominant effects of the MDM2 SNP 309 G or TP53 Arg72Pro C alleles, as described in other malignancies, to be assessed in FL. As MDM2 SNP 309 can lead to earlier onset or more advanced disease6 and TP53 negatively regulates MDM2 expression, we assessed MDM2 SNP 309 alleles in isolation or in combination with TP53 Arg72Pro alleles against these clinical parameters; there was no evidence of any association (illustrated in Table 1 for gender, stage and responses to therapy; p≥0.13). Kaplan-Meier plots and log rank test statistics demonstrated no evidence for associa-ion oft MDM2 SNP 309 or TP53 Arg72Pro allelic variants alone, or in combination, with overall survival (Figure 1A), progression free survival, relapse free survival or time to transformation (Figure 1B) (p≥0.17). Table 1. Assessment of MDM2 SNP 309 and TP53 Arg72Pro against clinical parameters Figure 1. Kaplan-Meier plots and log rank test statistics for overall survival (A) and time to transformation (B) by MDM2 SNP 309 and TP53 Arg72Pro alleles. Illustrated are results for four groups of allelic combinations of the two SNPs. The four groups Neither ... Consequently, whilst genomic lesions targeting the MDM2-TP53 axis are an important feature of FL, MDM2 SNP 309 and TP53 Arg72Pro do not predict clinical outcome. In contrast to other malignancies these polymorphisms are not significant in FL.

Purpose Cancer is associated with an increased risk of suicide and attempted suicide. However, we do not know how many cancer patients have thoughts that they would be better off dead or thoughts of hurting themselves. This study aimed to determine the prevalence of such thoughts in cancer outpatients and which patients are most likely to have them. Patients and Methods A survey of consecutive patients who attended the outpatient clinics of a regional cancer center in Edinburgh, United Kingdom. Patients completed the Patient Health Questionnaire-9 (PHQ-9), which included Item 9 that asks patients if they have had thoughts of being better off dead or of hurting themselves in some way in the previous 2 weeks. Those who reported having had such thoughts for at least several days in this period were labeled as positive responders. Patients also completed the Hospital Anxiety and Depression Scale (HADS) and a pain scale. The participating patients’ cancer diagnoses and treatments were obtained from the cancer center clinical database. Results Data were available on 2,924 patients; 7.8% (229 of 2,924; 95% CI, 6.9% to 8.9%) were positive responders. Clinically significant emotional distress, substantial pain, and—to a lesser extent—older age, were associated with a positive response. There was strong evidence of interactions between these effects, and emotional distress played the most important role. Conclusion A substantial number of cancer outpatients report thoughts that they would be better off dead or thoughts of hurting themselves. Management of emotional distress and pain should be a central aspect of cancer care.

326 Background: Chemotherapy for penis cancer is used to palliate metastatic disease and treat locally-advanced disease. Pathologic similarities to head and neck SCC suggest that adding docetaxel (T) to platinum-based regimens may enhance efficacy. Methods: A single-stage single-arm phase II trial was conducted. Eligible patients had measurable, histologically proven penile SCC staged M1; or T4, any N, M0; or any T, N3/inoperable N2, M0; or any T, N1, M0 with Multi-Disciplinary Team agreement for chemotherapy as first-line therapy. Treatment was three 21-day cycles of TPF (day 1: T 75mg/m2, P 60mg/m2; days 1-5: F 750mg/m2/day). In 26 evaluable patients ≥14 responses were required to conclude a response rate of ≥60% (p0=0.35, p1=0.60, α=0.1, β=0.2; Fleming-A’Hern design). Primary endpoint was overall response rate at completion/discontinuation of trial treatment. Secondary endpoints included safety, tolerability, progression-free survival (PFS) and overall survival (OS). Results: 29 patients (median age 61 years) were recruited from 9 UK centres between Sept 2009 and Dec 2010. 8 patients were M1. 17 patients had performance status (PS) 0, 11 PS1, 1 PS2. 3 patients discontinued treatment early for reasons other than progression. Dose reductions/delays were reported for 13 patients. 28 patients have on-treatment toxicity data: 19 (68%) experienced grade 3/4 toxicity, with neutropenia most common (n=13, 46%). 7 patients (25%) experienced febrile neutropenia and/or neutropenic sepsis. 10/26 patients (38.5%, 95% CI: 20.2% - 59.4%) in the evaluable population responded. Twelve month PFS was 39.1% (95% CI: 20.9% - 56.8%; median PFS (all 29 patients/M1/M0): 7.1/ 3.1/ 9.6- months). Twelve month OS was 54.6% (34.9% - 70.6%; median OS (all patients/M1/M0): 13.7/ 6.9/ not reached yet-months). Conclusions: UK clinicians successfully recruited to a multi-centre trial in penis cancer, establishing a network of centres for future studies. Toxic effects of TPF were common but not unexpected. The trial did not reach its target response rate of ≥60% to justify further investigation although PFS and OS in this cohort compares favourably to reported data in literature.

Abstract 3390 Poster Board III-278 Introduction: While the outcome of children with acute lymphoblastic leukemia (ALL) has steadily improved, the prognosis for those who relapse (rALL) remains poor. Partly this has been due to the lack of a standardised approach to children with rALL. The international collaborative trial ALLR3 stratified patients into standard (SR), intermediate (IR) and high risk (HR) groups based on the time from first diagnosis to relapse, site of relapse and immunophenotype. All patients received 3 blocks of therapy, with a minimal residual disease (MRD) assessment at the end of blocks 1 and 3. Allogeneic stem cell transplantation (allo-SCT) was offered to all HR and those IR who had a MRD of ≥10-4 at week 5. In children in whom MRD was unavailable, allo-SCT was offered to those who relapsed within 24 months of stopping therapy. All other patients continued on chemotherapy for 24 months. A day 1 and 2 randomisation was performed between mitoxantrone and idarubicin. Results: 239 patients were enlisted, of whom 216 were randomised and 109 idarubicin and 103 mitoxantrone patients are analysable. There were non-significant differences between the groups with regards to time to relapse, site of relapse and cytogenetic subtypes.108 (51%) were in CR2 at a median follow up of 36 months (range 1-70) and Progression Free Survival (PFS) at 3 years was 50.3% (95% CI 42.9%, 57.3%). Forty four percent of idarubicin and 40% of mitoxantrone patients had disease levels of ≥10-4 at week 5 (p=0.90) at the end of block 1. The PFS at 3 years for those who received idarubicin was 35.9% (25.9%, 45.9%) and mitoxantrone 64.6% (54.2%, 73.2%) (p=0.0004). Adjusted for differences in risk group, country, age, gender and cytogenetic subtype, this difference continues to be significant (p=0.003). Overall mitoxantrone was better tolerated and less toxic than idarubicin. A competing risks model showed that the difference between the two drugs is primarily related to disease control (p=0.02), rather than toxicity of treatment (p=0.09). In the patients who were transplanted, 35% and 5% of patients who received idarubicin (n = 48) or mitoxantrone (n = 44) respectively have relapsed. Based on the intention to treat analyses, there were non significant differences in patients treated without an allo-SCT in both arms. IR patients who were transplanted did worse (p = 0.01) in the idarubicin group but had comparable results in the mitoxantrone group to those who received chemotherapy. As a result the randomisation in ALLR3 has now been closed, though the study continues to accrue to better answer the MRD stratification question. Conclusions: Mitoxantrone is a well tolerated and highly effective drug for the treatment of children with rALL. While MRD at week 5 failed to predict the differences in outcome for the two randomised groups, it identified that children in the IR group with Disclosures: Off Label Use: Although Idarubicin and Mitoxantrone have been shown to be effective in ALL, they are not licensed for use in children in the UK. .

Summary Background Although survival of children with acute lymphoblastic leukaemia has improved greatly in the past two decades, the outcome of those who relapse has remained static. We investigated the outcome of children with acute lymphoblastic leukaemia who relapsed on present therapeutic regimens. Methods This open-label randomised trial was undertaken in 22 centres in the UK and Ireland and nine in Australia and New Zealand. Patients aged 1–18 years with first relapse of acute lymphoblastic leukaemia were stratified into high-risk, intermediate-risk, and standard-risk groups on the basis of duration of first complete remission, site of relapse, and immunophenotype. All patients were allocated to receive either idarubicin or mitoxantrone in induction by stratified concealed randomisation. Neither patients nor those giving interventions were masked. After three blocks of therapy, all high-risk group patients and those from the intermediate group with postinduction high minimal residual disease (≥10 −4 cells) received an allogenic stem-cell transplant. Standard-risk and intermediate-risk patients with postinduction low minimal residual disease ( −4 cells) continued chemotherapy. The primary outcome was progression-free survival and the method of analysis was intention-to-treat. Randomisation was stopped in December, 2007 because of differences in progression-free and overall survival between the two groups. This trial is registered, reference number ISCRTN45724312. Findings Of 239 registered patients, 216 were randomly assigned to either idarubicin (109 analysed) or mitoxantrone (103 analysed). Estimated 3-year progression-free survival was 35·9% (95% CI 25·9–45·9) in the idarubicin group versus 64·6% (54·2–73·2) in the mitoxantrone group (p=0·0004), and 3-year overall survival was 45·2% (34·5–55·3) versus 69·0% (58·5–77·3; p=0·004). Differences in progression-free survival between groups were mainly related to a decrease in disease events (progression, second relapse, disease-related deaths; HR 0·56, 0·34–0·92, p=0·007) rather than an increase in adverse treatment effects (treatment death, second malignancy; HR 0·52, 0·24–1·11, p=0·11). Interpretation As compared with idarubicin, mitoxantrone conferred a significant benefit in progression-free and overall survival in children with relapsed acute lymphobastic leukaemia, a potentially useful clinical finding that warrants further investigation. Funding Cancer Research UK, Leukaemia and Lymphoma Research, Cancer Council NSW, and Sporting Chance Cancer Foundation.