Bland-Altman methods for comparing methods of measurement and response to criticisms.

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.

Latino Adolescent Perspectives Toward Sexually Transmitted Infection Educational Programs.

PURPOSE: 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. METHODS: A naturalistic inquiry approach was used. FINDINGS: 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. CONCLUSION: 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. IMPLICATIONS FOR NURSING PRACTICE: It is essential for nurses to provide accurate information about STIs and safe sex to help decrease the transmission of STIs.

A pilot study: dose adaptation of capecitabine using mobile phone toxicity monitoring - supporting patients in their homes.

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.

Validation and reliability testing of the EORTC QLQ-NMIBC24 questionnaire module to assess patient-reported outcomes in non-muscle-invasive bladder cancer.

BACKGROUND: Well-developed and well-tested patient-reported outcome measures for non-muscle-invasive bladder cancer (NMIBC) are required. OBJECTIVE: To test and adapt the scale structure and explore the psychometric properties of the European Organisation for Research and Treatment of Cancer (EORTC) questionnaire for NMIBC. DESIGN, SETTING, AND PARTICIPANTS: A total of 433 patients in the Bladder COX-2 Inhibition Trial (BOXIT) completed the EORTC QLQ-C30 and NMIBC questionnaires. BOXIT is evaluating the addition of celecoxib to standard treatment in high- and intermediate-risk NMIBC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multitrait scaling investigated and adapted the questionnaire scale structure and evaluated the reliability and validity of the revised scales, as well as responsiveness to change. RESULTS AND LIMITATIONS: A total of 410 patients (94.7%) (79.3% men, 74.6% high risk) returned baseline forms, and the questionnaire response rate was 88.2%. Multitrait scaling confirmed six scales and five single items. Scales and items demonstrated significant differences between patients with good and poor performance status scores (p<0.001). Men reported better sexual function than women (p<0.001). Scale and single-item module scores were not highly correlated with QLQ-C30 scores (evidence of discriminant validity), and the module was responsive to changes in health over time. International and test-retest data are required. CONCLUSIONS: This study demonstrates the evidence-driven adapted scale structure and psychometric data of the EORTC QLQ-NMIBC24 module to use in clinical trials of patients with high- or intermediate-risk bladder cancer.

Randomized noninferiority trial of reduced high-dose volume versus standard volume radiation therapy for muscle-invasive bladder cancer: results of the BC2001 trial (CRUK/01/004).

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.

Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer.

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.).

Serum selenium concentration at diagnosis and outcome in patients with haematological malignancies.

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<0·001-0·003) in all tumour types. Independent predictors of presentation selenium were; French-American-British subtype and albumin (P<0·001 for both) in AML, haemoglobin (P=0·002) and B-symptoms (P=0·01) in HL, and albumin (P<0·001) 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.

Predicting the myelotoxicity of chemotherapy: the use of pretreatment O6-methylguanine-DNA methyltransferase determination in peripheral blood mononuclear cells.

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.

Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial.

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 (<10(-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.

Cytoplasmic beta-catenin accumulation is a good prognostic marker in upper and lower gastrointestinal adenocarcinomas.

AIMS: 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. 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 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. CONCLUSIONS: 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.

Reporting methods in studies developing prognostic models in cancer: a review.

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.

Reporting performance of prognostic models in cancer: a review.

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.

Regions of acquired uniparental disomy at diagnosis of follicular lymphoma are associated with both overall survival and risk of transformation.

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.

Better off dead: suicidal thoughts in cancer patients.

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.

Management of depression for people with cancer (SMaRT oncology 1): a randomised trial.

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 pound sterling 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.

The presence of TP53 mutation at diagnosis of follicular lymphoma identifies a high-risk group of patients with shortened time to disease progression and poorer overall survival.

The International Prognostic Index and the Follicular Lymphoma International Prognostic Index are widely used for the risk assessment of follicular lymphoma (FL). Although molecular studies have provided insight into the biology of FL, no molecular marker has impacted on treatment stratification. Because TP53 mutations are associated with poor prognosis in hematologic malignancies, we investigated the prognostic value of TP53 mutation at diagnosis in FL. Heterozygous TP53 mutation was detected in 12 of 185 (6%) analyzed cases. Mutation was associated with older age (P = .02) and higher International Prognostic Index score (P = .04). On multivariate analysis, TP53 mutation correlated with shorter progression-free survival (P < .001) and overall survival (P = .009). TP53 mutation was associated with low expression of the immune-response 1 gene expression signature (P = .016) and with an unfavorable gene expression-based survival predictor score (P < .001), demonstrating for the first time that molecular features of the malignant cell may correlate with the nature of the immune response in FL.

Risk and clinical implications of transformation of follicular lymphoma to diffuse large B-cell lymphoma.

PURPOSE: To study the clinical significance of transformation to diffuse large B-cell lymphoma (DLBCL) in patients with follicular lymphoma (FL). PATIENTS AND METHODS: From 1972 to 1999, 325 patients were diagnosed with FL at St Bartholomew's Hospital (London, United Kingdom). With a median follow-up of 15 years, progression occurred in 186 patients and biopsy-proven transformation in 88 of the 325. The overall repeat biopsy rate was 70%. RESULTS: The risk of histologic transformation (HT) by 10 years was 28%, HT not yet having been observed after 16.2 years. The risk was higher in patients with advanced stage (P = .02), high-risk Follicular Lymphoma International Prognostic Index (FLIPI; P = .01), and International Prognostic Index (IPI; P = .04) scores at diagnosis. Expectant management (as opposed to treatment being initiated at diagnosis) also predicted for a higher risk of HT (P = .008). Older age (P = .005), low hemoglobin level (P = .03), high lactate dehydrogenase (P < .0001), and high-risk FLIPI (P = .01) or IPI (P = .003) score at the time of first recurrence were associated with the diagnosis of HT in a biopsy performed at that time. The median survival from transformation was 1.2 years. Patients with HT had a shorter overall survival (P < .0001) and a shorter survival from progression (P < .0001) than did those in whom it was not diagnosed. CONCLUSION: Advanced stage and high-risk FLIPI and IPI scores at diagnosis correlate with an increased risk of HT. This event strongly influences the outcome of patients with FL by shortening their survival. There may be a subgroup of patients in whom HT does not occur.