Transformed follicular lymphoma in the rituximab era: A report from the Spanish Lymphoma Oncology Group.

Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma (NHL) subtype. The histological transformation (HT) of FL is an event considered frequent in the natural history of this tumor. We studied the transformation rates, predictive factors, and treatment characteristics that may impact in the survival of patients with FL and HT. A total of 1074 patients diagnosed with FL were prospectively enrolled from 1990 to 2016 in a Spanish registry. Sixty-four HTs were recorded based on clinical criteria (55%) or histological confirmation (45%). The cumulative incidence rate of transformation at 5 years is 7.3%. The 5-year overall survival (OS) without HT was 85% (95% confidence interval [CI], 70%-90%) vs 66% (95% CI, 51%-76%; P = 0.0012) with HT. Factors associated with HT were elevated lactate dehydrogenase (LDH) (odds ratio [OR] 1.83), intermediate-high Follicular lymphoma international prognostic index (FLIPI) (OR 2.16-OR 3.21), B symptoms (OR 2.46), or Eastern Cooperative Oncology Group (ECOG) 1 (OR 2.35). Treatment options related to HT were "watch and wait" or no rituximab or anthracyclines initially. A 5-year OS for patients treated with chemotherapy before HT was 55% (95% CI, 38%-69%) versus 81% (95% CI, 53%-93%; P = 0.009) for those who had not received it. The HT rate has decreased after the introduction of rituximab, as has been previously described. The timing of this treatment had an impact on the survival of these patients.

mRNA in exosomas as a liquid biopsy in non-Hodgkin Lymphoma: a multicentric study by the Spanish Lymphoma Oncology Group.

PURPOSE: To determine the feasibility of mRNAs (C-MYC, BCL-XL, BCL-6, NF-κß, PTEN and AKT) in exosomes of plasma as a liquid biopsy method for monitoring and prognostic evolution in B-cell lymphomas. PATIENTS AND METHODS: Exosomes were isolated from 98 patients with B-cell Lymphoma and 68 healthy controls. mRNAs were analyzed by quantitative PCR. An additional 31 post-treatment samples were also studied. RESULTS: In the general and follicular lymphoma series, the presence of AKT mRNA was associated with poor response to rituximab-based treatment. Patients with first relapse or disease progression showed a lower percentage of PTEN and BCL-XL mRNA. The presence of BCL-6 mRNA was associated with a high death rate. The absence of PTEN mRNA in the general series, and presence of C-MYC mRNA in follicular lymphomas, were associated with short progression-free survival. BCL-6 and C-MYC mRNA were independent prognostic variables of overall survival. C-MYC mRNA may provide prognostic information with respect to overall survival. BCL-XL mRNA and increase of BCL-6 mRNA in post-treatment samples could serve as molecular monitoring markers. CONCLUSIONS: This is the first large study to evaluate the prognostic and predictive values of pretreatment tumor-associated mRNA in exosomes. BCL-6 and C-MYC mRNA positivity in pretreatment samples were predictors of worse PFS compared to patients with mRNA negativity. C-MYC mRNA positivity was also a statistically significant predictor of inability to obtain complete response with first-line therapy.

Prognostic value of event-free survival at 12 and 24 months and long-term mortality for non-Hodgkin follicular lymphoma patients: A study report from the Spanish Lymphoma Oncology Group.

BACKGROUND: Relatively few studies have analyzed the mortality of follicular lymphoma (FL) patients in comparison with a sex- and age-matched general population. This study analyzed the overall survival (OS) of patients with FL and compared their survival with the expected survival of a general population. METHODS: Patients diagnosed with FL were prospectively enrolled from 1980 to 2013. Standardized mortality ratios (SMRs) were obtained from yearly sex- and age-specific mortality rates in Spain, and OS was compared with age- and sex-matched general population data. RESULTS: A total of 1074 patients with newly diagnosed FL were enrolled. The median OS was 231 months (95% confidence interval [CI], 195-267 months). Event-free survival at 12 months (EFS12) and event-free survival at 24 months (EFS24) were associated with an increased probability of early death, with an SMR of 10.27 (95% CI, 8.26-12.77) for EFS12. The overall SMR, including all causes of death, was 2.55 (95% CI, 2.23-2.92), and it was higher for women (SMR, 3.02; 95% CI, 2.48-3.67) and young adults (SMR, 6.01; 95% CI, 3.13-11.55). More than 10 years after the diagnosis, mortality rates for FL patients were lower than those for the general population (SMR, 0.47; 95% CI, 0.28-0.78). When FL was excluded as a cause of death, the overall SMR was 1.35 (95% CI, 1.11-1.65) without a statistically significant mortality increase in the >60-year-old group in comparison with age- and sex-matched general population data. More than 15% of the patients included in the study (n = 158) had more than 10 years of follow-up. CONCLUSIONS: EFS12 and EFS24 predict an early increase in mortality. The long-term SMR, over the course of 10 years of follow-up, shows that patients with FL have a risk of dying similar to that of a sex- and age-matched general population. Cancer 2017;123:3709-3716. © 2017 American Cancer Society.

Impact of treatment in long-term survival patients with follicular lymphoma: A Spanish Lymphoma Oncology Group registry.

BACKGROUND: Follicular lymphoma is the second most common non-Hodgkin lymphoma in the United States and Europe. However, most of the prospective randomized studies have very little follow-up compared to the long natural history of the disease. The primary aim of this study was to investigate the long-term survival of our series of patients with follicular lymphoma. PATIENTS AND METHODS: A total of 1074 patients with newly diagnosed FL were enrolled. Patients diagnosed were prospectively enrolled from 1980 to 2013. RESULTS: Median follow-up was 54.9 months and median overall survival is over 20 years in our series. We analyzed the patients who are still alive beyond 10 years from diagnosis in order to fully assess the prognostic factors that condition this group. Out of 166 patients who are still alive after more than 10 years of follow-up, 118 of them (73%) are free of evident clinical disease. Variables significantly associated with survival at 10 years were stage < II (p <0.03), age < 60 years (p <0.0001), low FLIPI (p <0.002), normal ß2 microglobulin (p <0.005), no B symptoms upon diagnosis (p <0.02), Performance Status 0-1 (p <0.03) and treatment with anthracyclines and rituximab (p <0.001), or rituximab (p <0.0001). CONCLUSIONS: A longer follow-up and a large series demonstrated a substantial population of patients with follicular lymphoma free of disease for more than 10 years.

Impact of parenteral nutrition standardization on costs and quality in adult patients.

BACKGROUND: Parenteral nutrition (PN) is a costly therapy that can also be associated with serious complications. Therefore, efforts are focusing on reducing rate of complications, and costs related to PN. OBJECTIVE: The aim was to analyze the effect of the implementation of PN standardization on costs and quality criteria. Secondary aim was to assess the use of individualized PN based on patient's clinical condition. METHODS: We compare the use of PN before and after the implementation of PN standardization. Demographic, clinical and PN characteristics were collected. Costs analysis was performed to study the costs associated to the two different periods. Quality criteria included were: 1) PN administration; 2) nutrition assessment (energy intake between 20-35 kcal/kg/day; protein contribution according to nitrogen balance); 3) safety and complications (hyperglycemia, hypertriglyceridemia, hepatic complications, catheter-related infection); 4) global efficacy (as serum albumin increase). Chi-square test was used to compare percentages; logistic regression analysis was performed to evaluate the use of customized PN. RESULTS: 296 patients were included with a total of 3,167 PN compounded. During the first period standardized PN use was 47.5% vs 85.7% within the second period (p < 0.05). No differences were found in the quality criteria tested. Use of individualized PN was related to critical care patients, hypertriglyceridemia, renal damage, and long-term PN. Mean costs of the PN decreased a 19.5%. Annual costs savings would be € 86,700. CONCLUSIONS: The use of customized or standard PN has shown to be efficient and flexible to specific demands; however customized PN was significantly more expensive.

Introducción: La nutrición parenteral (NP) es una terapia costosa asociada a serias complicaciones. De manera que muchos de los esfuerzos se centran en reducir éstas complicaciones, así como los costes asociados. Objetivos: Analizar el efecto de la estandarización de la NP en los costes y en indicadores de calidad. El objetivo secundario es estudiar la utilización de NP individualizadas en función de las condiciones clínicas de los pacientes. Métodos: Se compara la utilización de NP antes y después de la estandarización de la NP. Se recogen los datos demográficos, clínicos y características de la NP. Se realiza un análisis de costes asociados a los dos periodos de estudio. Se incluyen los siguientes indicadores de calidad: 1) Administración de NP; 2) Valoración nutricional (aporte calórico 20-35 kcal/kg/día; aporte proteico en función del balance nitrogenado); 3) seguridad y complicaciones (hiperglicemia, hipertrigliceridemia, complicaciones hepáticas, infección de catéter); eficacia global (aumento albúmina sérica). Se utiliza test de chi-cuadrado para comparación de porcentajes, y regresión logística para evaluar la utilización de NP individualizada. Resultados: Se incluyeron 296 pacientes para un total de 3,167 NP. Durante el primer período el uso de NP estandarizada fue del 47,5% frente 85,7% en el segundo (p < 0,05). No se encontraron diferencias en los indicadores de calidad estudiados. La utilización de NP individualizada fue relacionada con pacientes críticos, hipertrigliceridemia y NP de larga duración. El coste medio de NP disminuyó en un 19,5%; pudiendo resultar un ahorro anual de 86,700 . Conclusiones: La utilización de NP individualizadas o estándar ha mostrado ser eficiente y flexible; aunque el coste de la individualizada fue significativamente mayor.

Impact of parenteral nutrition standardization on costs and quality in adult patients / Impacto de la estandarización de la nutrición parenteral en costes y calidad en pacientes adultos

Background: Parenteral nutrition (PN) is a costly therapy that can also be associated with serious complications. Therefore, efforts are focusing on reducing rate of complications, and costs related to PN. Objective: The aim was to analyze the effect of the implementation of PN standardization on costs and quality criteria. Secondary aim was to assess the use of individualized PN based on patient’s clinical condition. Methods: We compare the use of PN before and after the implementation of PN standardization. Demographic, clinical and PN characteristics were collected. Costs analysis was performed to study the costs associated to the two different periods. Quality criteria included were: 1) PN administration; 2) nutrition assessment (energy intake between 20-35 kcal/kg/day; protein contribution according to nitrogen balance); 3) safety and complications (hyperglycemia, hypertriglyceridemia, hepatic complications, catheter-related infection); 4) global efficacy (as serum albumin increase). Chi-square test was used to compare percentages; logistic regression analysis was performed to evaluate the use of customized PN. Results: 296 patients were included with a total of 3,167 PN compounded. During the first period standardized PN use was 47.5% vs 85.7% within the second period (p < 0.05). No differences were found in the quality criteria tested. Use of individualized PN was related to critical care patients, hypertriglyceridemia, renal damage, and long-term PN. Mean costs of the PN decreased a 19.5%. Annual costs savings would be Euros 86,700. Conclusions: The use of customized or standard PN has shown to be efficient and flexible to specific demands; however customized PN was significantly more expensive (AU)

Introducción: La nutrición parenteral (NP) es una terapia costosa asociada a serias complicaciones. De manera que muchos de los esfuerzos se centran en reducir éstas complicaciones, así como los costes asociados. Objetivos: Analizar el efecto de la estandarización de la NP en los costes y en indicadores de calidad. El objetivo secundario es estudiar la utilización de NP individualizadas en función de las condiciones clínicas de los pacientes. Métodos: Se compara la utilización de NP antes y después de la estandarización de la NP. Se recogen los datos demográficos, clínicos y características de la NP. Se realiza un análisis de costes asociados a los dos periodos de estudio. Se incluyen los siguientes indicadores de calidad: 1) Administración de NP; 2) Valoración nutricional (aporte calórico 20-35 kcal/kg/día; aporte proteico en función del balance nitrogenado); 3) seguridad y complicaciones (hiperglicemia, hipertrigliceridemia, complicaciones hepáticas, infección de catéter); eficacia global (aumento albúmina sérica). Se utiliza test de chi-cuadrado para comparación de porcentajes, y regresión logística para evaluar la utilización de NP individualizada. Resultados: Se incluyeron 296 pacientes para un total de 3,167 NP. Durante el primer período el uso de NP estandarizada fue del 47,5% frente 85,7% en el segundo (p < 0,05). No se encontraron diferencias en los indicadores de calidad estudiados. La utilización de NP individualizada fue relacionada con pacientes críticos, hipertrigliceridemia y NP de larga duración. El coste medio de NP disminuyó en un 19,5%; pudiendo resultar un ahorro anual de 86,700 Euros. Conclusiones: La utilización de NP individualizadas o estándar ha mostrado ser eficiente y flexible; aunque el coste de la individualizada fue significativamente mayor (AU)

Cost analysis of adult parenteral nutrition systems; three-compartment bag versus customized / Análisis de costes de los sistemas de nutrición parental; bolsa tricompartimental versus individualizada

BACKGROUND: Parenteral nutrition (PN) is a costly technology used widely to provide nutrition to patients who have an inaccessible or non-functioning intestine. Two all-in-one systems currently being used are customized formulations and three-compartment bags. OBJECTIVE: To provide a systematic cost comparison of the two all-in-one PN systems: individualized (made from nutrient solutions) versus commercialized (made from three-compartment bag), both prepared in hospital pharmacies. SETTING: This study was conducted in three public Spanish hospitals. METHOD: We conducted a cost-minimization study to analyze prospectively the total cost of PN bags, accounting for all of the processes involved in preparing and delivering PN bags (cost of manpower, nutrition solutions, medical supplies and quality controls) in three different healthcare settings. To compare therapeutic alternatives of equivalent nutritional value, the study was performed for the most frequently employed formulation and similar to commercial preparations. A univariate sensitivity analysis was performed to evaluate the impact of different rates of use of three-compartment PN bag. RESULTS: 157 routine acts of PN bag preparation (65 customized and 92 three-compartment) were observed and timed over 9 days. Total costs of the 157 PN bags were included in the study. Mean costs of customized bags were higher than three-compartment bags, 51.16 ± 5.63 € versus 39.69 ± 3.00 € respectively (p < 0.01). Manpower costs were responsible for the majority of the differences found (70%). The time to complete an adult bag for the hospital compounded system was a mean of 25.9 minutes longer than the three-compartment system. In scenarios using a three-compartment system for 30%, 70% and 90% of PN provision, a cost savings of 4.3%, 10.1% and 12.9% respectively could be achieved. Greatest rates of changing from customized bags (70% and 90%), in a hospital with 1,800 PN bags/year, might reduce the annual budget by 9306 € and 11,964.8 €, respectively. Meanwhile, in a large facility the savings for 8,000 TPN days would be 64,248 € and 82,605 €, respectively. CONCLUSIONS: Since seeking cost-reduction of effective treatments is needed, the use of three-compartment bags for standard adult PN could lead to cost savings. Our data should be helpful for health care providers to calculate their own cost of administer

ANTECEDENTES: La nutrición parenteral (NP) es una tecnología costosa que se usa ampliamente para proporcionar nutrición a los pacientes que tienen un intestino inaccesible o no funcional. Los dos sistemas todo en uno que se utilizan en la actualidad son las formulaciones individualizadas y las bolsas tri-compartimentales. OBJETIVO: Proporcionar una comparación de costes sistemática entre los dos sistemas todo en uno: los sistemas individualizados (preparados a partir de soluciones de nutrientes) frente a los comerciales (hechos a partir de una bolsa tri-compartimental). Contexto: Este estudio se realizó en tres hospitales públicos españoles. MÉTODO: Realizamos un estudio de minimización de costes para analizar prospectivamente el coste total de las bolsas de NP, considerando todos los procesos implicados en la preparación y suministro de las bolsas (coste de personal, soluciones de nutrición, material fungible y controles de calidad) en tres centros hospitalarios distintos. Para comparar alternativas terapéuticas de valor nutricional equivalente, el estudio se realizó con la formulación que se empleaba con mayor frecuencia y similar a los preparados comerciales. Se realizó un análisis de sensibilidad uni-variaante para evaluar el impacto de las diferentes tasas de uso de la bolsa de NP tri-compartimental. RESULTADOS: Se analizaron 157 elaboraciones de bolsas de NP (65 individualizada y 92 tri-compartimentales) programadas durante 9 días. Los costes totales de las 157 bolsas de NP se incluyeron en el estudio. Los costes medios de las bolsas individualizadas fueron superiores a los costes de las bolsas tri-compartimentales, 51,16 ± 5,63 € frente a 39,69 ± 3,00 €, respectivamente (p < 0,01). Los costes de personal fueron los responsables de la mayor parte de las diferencias encontradas (70%). El tiempo para completar una bolsa de formulación individualizada fue en promedio 25,9 minutos superior que para el sistema tri-compartimental. En los supuestos en que se utilizase el sistema tri-compartimental un 30%, 70% y 90% del total de NP, se producirían unos ahorros del 4,3%, 10,1% y 12,9%, respectivamente. Con mayores tasas de cambio (70% y 90%), en un hospital con 1.800 bolsas de NP/año, se podría obtener un ahorro en el presupuesto anual de 9.306 € y 11.964.8 €, respectivamente. A su vez, en un centro hospitalario mayor, el ahorro para 8.000 bolsas de NP sería de 64.248 € y 82.605 €, respectivamente. CONCLUSIONES: Dada la necesidad de buscar una reducción de costes de tratamientos efectivos, el uso de las bolsas tri-compartimentales para la NP estándar del adulto podría conllevar una reducción de costes. Nuestros datos pueden ayudar a los gestores sanitarios a calcular su propio coste de administración de la NPT

MicroRNA signatures and treatment response in patients with advanced classical Hodgkin lymphoma.

Although specific microRNA (miRNA) signatures in classical Hodgkin lymphoma (cHL) have been proposed, their relationship with clinical outcome remains unclear. Despite treatment advances, a substantial subset of patients with advanced cHL are refractory to standard therapies based on adriamycin and its variants. Global miRNA expression data of 29 advanced cHL patients and five cHL-derived cell lines were used to identify profiles from Hodgkin-Reed-Sternberg (HRS) cells and their non-tumoural microenvironment. A cHL-miRNA signature was identified with 234 miRNAs differentially expressed. A subset of these miRNAs was associated with outcome and selected for study in an independent set of 168 cHL samples using quantitative reverse transcription polymerase chain reaction. Multivariate Cox regression analyses including cross-validation with failure-free survival (FFS) as clinical endpoint revealed a miRNA signature with MIR21, MIR30E, MIR30D and MIR92B* that identified two risk-groups with significant differences in 5-year FFS (81% vs. 35.7%; P < 0.001). Additionally, functional silencing of MIR21 and MIR30D in L428 cells showed increased sensitivity to doxorubicin-induced apoptosis, pointing towards abnormalities of mitochondrial intrinsic and TP53-CDKN1A pathways as related to miRNA deregulation in cHL. These results suggest that clinical outcome in cHL is associated with a specific miRNA signature. Moreover, functional analyses suggest a role for MIR21 and MIR30D in cHL pathogenesis and therapeutic resistance.

Cost analysis of adult parenteral nutrition systems: three-compartment bag versus customized.

BACKGROUND: Parenteral nutrition (PN) is a costly technology used widely to provide nutrition to patients who have an inaccessible or non-functioning intestine. Two all-in-one systems currently being used are customized formulations and three-compartment bags. OBJECTIVE: To provide a systematic cost comparison of the two all-in-one PN systems: individualized (made from nutrient solutions) versus commercialized (made from three-compartment bag), both prepared in hospital pharmacies. SETTING: This study was conducted in three public Spanish hospitals. METHOD: We conducted a cost-minimization study to analyze prospectively the total cost of PN bags, accounting for all of the processes involved in preparing and delivering PN bags (cost of manpower, nutrition solutions, medical supplies and quality controls) in three different healthcare settings. To compare therapeutic alternatives of equivalent nutritional value, the study was performed for the most frequently employed formulation and similar to commercial preparations. A univariate sensitivity analysis was performed to evaluate the impact of different rates of use of three-compartment PN bag. RESULTS: 157 routine acts of PN bag preparation (65 customized and 92 three-compartment) were observed and timed over 9 days. Total costs of the 157 PN bags were included in the study. Mean costs of customized bags were higher than three-compartment bags, 51.16 ± 5.63 € versus 39.69 ± 3.00 € respectively (p < 0.01). Manpower costs were responsible for the majority of the differences found (70%). The time to complete an adult bag for the hospital compounded system was a mean of 25.9 minutes longer than the three-compartment system. In scenarios using a three-compartment system for 30%, 70% and 90% of PN provision, a cost savings of 4.3%, 10.1% and 12.9% respectively could be achieved. Greatest rates of changing from customized bags (70% and 90%), in a hospital with 1,800 PN bags/year, might reduce the annual budget by 9306 € and 11,964.8 €, respectively. Meanwhile, in a large facility the savings for 8,000 TPN days would be 64,248 € and 82,605 €, respectively. CONCLUSIONS: Since seeking cost-reduction of effective treatments is needed, the use of three-compartment bags for standard adult PN could lead to cost savings. Our data should be helpful for health care providers to calculate their own cost of administer.

Background Parenteral nutrition (PN) is a costly technology used widely to provide nutrition to patients who have an inaccessible or non-functioning intestine. Two all-in-one systems currently being used are customized formulations and three-compartment bags. Objective To provide a systematic cost comparison of the two all-in-one PN systems: individualized (made from nutrient solutions) versus commercialized (made from three-compartment bag), both prepared in hospital pharmacies. Setting This study was conducted in three public Spanish hospitals. Method We conducted a cost-minimization study to analyze prospectively the total cost of PN bags, accounting for all of the processes involved in preparing and delivering PN bags (cost of manpower, nutrition solutions, medical supplies and quality controls) in three different healthcare settings. To compare therapeutic alternatives of equivalent nutritional value, the study was performed for the most frequently employed formulation and similar to commercial preparations. A univariate sensitivity analysis was performed to evaluate the impact of different rates of use of three-compartment PN bag. Results 157 routine acts of PN bag preparation (65 customized and 92 three-compartment) were observed and timed over 9 days. Total costs of the 157 PN bags were included in the study. Mean costs of customized bags were higher than three-compartment bags, 51.16±5.63€ versus 39.69±3.00€ respectively (p.

Are there any significant variations in the clinical or histological presentation of lymphoid pathologies over the course of time in Spain?

INTRODUCTION: Little data is available concerning variations in the clinical characteristics of lymphoid neoplasms at presentation. We decided to investigate whether any variations in these characteristics had occurred in Spain during the last few years. MATERIALS AND METHODS: The GOTEL group database is an archive of all new lymphoma cases, regardless of their histological subtype, diagnosed in the hospitals within the group. An analysis was made of all the records between 1 January 1999 and 1 January 2009. Though the number of hospitals submitting data has changed over the course of time, data were provided by 26 hospitals from 16 Spanish provinces. RESULTS: A total of 3651 cases of lymphoma were recorded during this period. Grouped by clinical features, 42.8% (1561 patients) had low-grade lymphoma, 30.4% (1110 patients) intermediate-grade lymphoma and 15.2% (556 patients) Hodgkin's lymphoma; 208 patients had T lymphoma (5.7%), 111 patients high-grade lymphoma (3%) and 105 patients (2.9%) suffered lymphomas that were difficult to classify. A total of 6.3% of the diagnoses (231 patients) were made prior to 1999, 29.5% between 2000 and 2001, 25.7% between 2002 and 2003, 19.7% between 2004 and 2005, 11.2% between 2006 and 2007, and there were 200 entries from 2008 to the close of the study period, corresponding to 1.5% of the complete database. The median age at diagnosis was 60 (range 7-105 years), by percentiles: 25 corresponded to 44 years old, 50 to 60 years old and 75 to 71. Distribution by gender was 53.1% male and 46.9% female. An analysis was made of all the clinical variables collected, comparing their behaviour during the different diagnostic periods. The periods, gender, ECOG, stage, LDH, ß2 microglobulin, Hodgkin's or non- Hodgkin's type neoplasm, B lymphoma vs. Hodgkin's, NK or T, nodal or extra-nodal origin, median age at diagnosis and histological type by region of origin did not show any statistically significant differences in their distribution over the course of time. CONCLUSION: In our experience, there are no significant variations in clinical presentation or histological type in lymphomas diagnosed over the course of time in Spain.

Stage IV and age over 45 years are the only prognostic factors of the International Prognostic Score for the outcome of advanced Hodgkin lymphoma in the Spanish Hodgkin Lymphoma Study Group series.

The International Prognostic Score (IPS) is the most widely used system to date for identifying risk groups for the outcome of patients with advanced Hodgkin lymphoma, although important limitations have been recognized. We analyzed the value of the IPS in a series of 311 patients with advanced classical Hodgkin lymphoma (cHL) (Ann Arbor stage III, IV or stage II with B symptoms and/or bulky masses) treated with first-line chemotherapy including adriamycin (adriamycin, bleomycin, vinblastine, dacarbazine [ABVD] or equivalent variants). In univariate and multivariate analyses, stage IV disease and age ≥ 45 years were the only factors with independent predictive significance for overall survival (OS) (p = 0.002 and p < 0.001, respectively). Stage IV was still significant for freedom from progression (FFP) (p = 0.001) and age ≥ 45 years was borderline significant (p = 0.058). IPS separates prognostic groups, as in the original publication, but this is mainly due to the high statistical significance of stage IV and age ≥ 45 years. Moreover, the combination of these two factors enables a simpler system to be constructed that separates groups with different FFP and OS. In conclusion, in our series, stage IV and age ≥ 45 years are the key prognostic factors for the outcome of advanced cHL.

Effects of an omega-3 fatty acid-enriched lipid emulsion on eicosanoid synthesis in acute respiratory distress syndrome (ARDS): A prospective, randomized, double-blind, parallel group study.

BACKGROUND: The use of lipid emulsions has been associated with changes in lung function and gas exchange which may be mediated by biologically active metabolites derived from arachidonic acid. The type and quantity of the lipid emulsions used could modulate this response, which is mediated by the eicosanoids. This study investigates the use of omega-3 fatty acid-enriched lipid emulsions in ARDS patients and their effects on eicosanoid values. METHODS: Prospective, randomized, double-blind, parallel group study carried out at the Intensive Medicine Department of Vall d'Hebron University Hospital (Barcelona-Spain). We studied 16 consecutive patients with ARDS and intolerance to enteral nutrition (14 men; age: 58 ± 13 years; APACHE II score 17.8 ± 2.3; Lung Injury Score: 3.1 ± 0.5; baseline PaO2/FiO2 ratio: 149 ± 40). Patients were randomized into two groups: Group A (n = 8) received the study emulsion Lipoplus® 20%, B. Braun Medical (50% MCT, 40% LCT, 10% fish oil (FO)); Group B (n = 8) received the control emulsion Intralipid® Fresenius Kabi (100% LCT). Lipid emulsions were administered for 12 h at a dose of 0.12 g/kg/h. We measured LTB4, TXB2, and 6-keto prostaglandin F1α values at baseline [immediately before the administration of the lipid emulsions (T-0)], at the end of the administration (T-12) and 24 hours after the beginning of the infusion (T 24) in arterial and mixed venous blood samples. RESULTS: In group A (FO) LTB4, TXB2, 6-keto prostaglandin F1α levels fell during omega-3 administration (T12). After discontinuation (T24), levels of inflammatory markers (both systemic and pulmonary) behaved erratically. In group B (LCT) all systemic and pulmonary mediators increased during lipid administration and returned to baseline levels after discontinuation, but the differences did not reach statistical significance. There was a clear interaction between the treatment in group A (fish oil) and changes in LTB4 over time. CONCLUSIONS: Infusion of lipids enriched with omega-3 fatty acids produces significant short- term changes in eicosanoid values, which may be accompanied by an immunomodulatory effect. TRIAL REGISTRATION: ISRCTN63673813.

A molecular risk score based on 4 functional pathways for advanced classical Hodgkin lymphoma.

Despite improvement in the treatment of advanced classical Hodgkin lymphoma, approximately 30% of patients relapse or die as result of the disease. Current predictive systems, determined by clinical and analytical parameters, fail to identify these high-risk patients accurately. We took a multistep approach to design a quantitative reverse-transcription polymerase chain reaction assay to be applied to routine formalin-fixed paraffin-embedded samples, integrating genes expressed by the tumor cells and their microenvironment. The significance of 30 genes chosen on the basis of previously published data was evaluated in 282 samples (divided into estimation and validation sets) to build a molecular risk score to predict failure. Adequate reverse-transcription polymerase chain reaction profiles were obtained from 262 of 282 cases (92.9%). Best predictor genes were integrated into an 11-gene model, including 4 functional pathways (cell cycle, apoptosis, macrophage activation, and interferon regulatory factor 4) able to identify low- and high-risk patients with different rates of 5-year failure-free survival: 74% versus 44.1% in the estimation set (P < .001) and 67.5% versus 45.0% in the validation set (P = .022). This model can be combined with stage IV into a final predictive model able to identify a group of patients with very bad outcome (5-year failure-free survival probability, 25.2%).

Extracellular tumor-related mRNA in plasma of lymphoma patients and survival implications.

BACKGROUND: We studied anomalous extracellular mRNAs in plasma from patients with diffuse large B-cell lymphoma (DLBCL) and their survival implications. mRNAs studied have been reported in the literature as markers of poor (BCL2, CCND2, MYC) and favorable outcome (LMO2, BCL6, FN1) in tumors. These markers were also analyzed in lymphoma tissues to test possible associations with their presence in plasma. METHODOLOGY/PRINCIPAL FINDINGS: mRNA from 42 plasma samples and 12 tumors from patients with DLBCL was analyzed by real-time PCR. Samples post-treatment were studied. The immunohistochemistry of BCL2 and BCL6 was defined. Presence of circulating tumor cells was determined by analyzing the clonality of the immunoglobulin heavy-chain genes by PCR. In DLBCL, MYC mRNA was associated with short overall survival. mRNA targets with unfavorable outcome in tumors were associated with characteristics indicative of poor prognosis, with partial treatment response and with short progression-free survival in patients with complete response. In patients with low IPI score, unfavorable mRNA targets were related to shorter overall survival, partial response, high LDH levels and death. mRNA disappeared in post-treatment samples of patients with complete response, and persisted in those with partial response or death. No associations were found between circulating tumor cells and plasma mRNA. Absence of BCL6 protein in tumors was associated with presence of unfavorable plasma mRNA. CONCLUSIONS/SIGNIFICANCE: Through a non-invasive procedure, tumor-derived mRNAs can be obtained in plasma. mRNA detected in plasma did not proceed from circulating tumor cells. In our study, unfavorable targets in plasma were associated with poor prognosis in B-cell lymphomas, mainly MYC mRNA. Moreover, the unfavorable targets in plasma could help us to classify patients with poor outcome within the good prognosis group according to IPI.

Effects on hemodynamics and gas exchange of omega-3 fatty acid-enriched lipid emulsion in acute respiratory distress syndrome (ARDS): a prospective, randomized, double-blind, parallel group study.

INTRODUCTION: We investigated the effects on hemodynamics and gas exchange of a lipid emulsion enriched with omega-3 fatty acids in patients with ARDS. METHODS: The design was a prospective, randomized, double-blind, parallel group study in our Intensive Medicine Department of Vall d'Hebron University Hospital (Barcelona-Spain). We studied 16 consecutive patients with ARDS and intolerance to enteral nutrition (14 men and 2 women; mean age: 58 +/- 13 years; APACHE II score: 17.8 +/- 2.3; Lung Injury Score: 3.1 +/- 0.5; baseline PaO2/FiO2 ratio: 149 +/- 40). Patients were randomized into 2 groups: Group A (n = 8) received the study emulsion Lipoplus 20%, B.Braun Medical (50% MCT, 40% LCT, 10% omega-3); Group B (n = 8) received the control emulsion Intralipid Fresenius Kabi (100% LCT). Lipid emulsions were administered during 12 h at a dose of 0.12 g/kg/h. Measurements of the main hemodynamic and gas exchange parameters were made at baseline (immediately before administration of the lipid emulsions), every hour during the lipid infusion, at the end of administration, and six hours after the end of administration lipid infusion. RESULTS: No statistically significant changes were observed in the different hemodynamic values analyzed. Likewise, the gas exchange parameters did not show statistically significant differences during the study. No adverse effect attributable to the lipid emulsions was seen in the patients analyzed. CONCLUSION: The lipid emulsion enriched with omega-3 fatty acids was safe and well tolerated in short-term administration to patients with ARDS. It did not cause any significant changes in hemodynamic and gas exchange parameters. TRIAL REGISTRATION: ISRCTN63673813.

Analysis of competing risks of causes of death and their variation over different time periods in Hodgkin's disease.

PURPOSE: Hodgkin's disease is considered a model of curable illness. However, long-term studies show excessive mortality in relation to the general population. We studied the various causes of death by use of competing risks and their evolution over the years. EXPERIMENTAL DESIGN: All patients diagnosed with Hodgkin's disease at our institution between 1967 and 2003 were included. The competing risks of causes of death and their vital situation were examined in three time periods: cohort A with patients treated before 1980, cohort B with patients treated from 1981 to 1986, and cohort C with patients treated from 1986 onwards. RESULTS: We studied 534 patients, with a median follow-up time of 9.1 years for the whole cohort. The 5-year, 15-year, and 20-year Kaplan-Meier survival estimates for all patients were 81%, 72%, and 65%, respectively. At the close of the study, 337 (63.1%) were alive and 170 (31.8%) patients had died. The most common cause of death was the progression of Hodgkin's disease, followed by deaths due to a second tumor. Survival was significantly worse in the first period than in the other two (P < 0.001), and in the three periods, the main cause of death was tumor progression. CONCLUSIONS: The progression of Hodgkin's disease is the main cause of death. Over time, a reduction in death related to infection and the acute toxicity of treatment was seen. A lot of patients still die for reasons linked to delayed side effects of radiotherapy, such as second tumors and heart disease, which is important to plan preventive activities and clinical research.

Frequency of BCL2 and BCL6 translocations in follicular lymphoma: relation with histological and clinical features.

Follicular lymphomas (FLs) usually carry BCL2 translocations although BCL6 translocations are also present. We explored relationships between translocations status and clinical or histological parameters at diagnosis in 182 patients stratified in four groups: BCL2-/BCL6-, BCL2+/BCL6-, BCL2-/BCL6+ and BCL2+/BCL6+. BCL2-/BCL6- and BCL2+/BCL6-. Double negative cases were ascribed to lower histological grades. In contrast, BCL2-/BCL6+ cases corresponded to higher grades. However, a majority of BCL2+/BCL6+ tumours were classified as lower grades. These results were reinforced by the finding that double positive patients had lower LDH levels and PS than those with solitary BCL6 rearrangements. Bone marrow involvement was more frequent in BCL2+/BCL6+ compared with BCL2-/BCL6+ tumours. Our data confirm the presence of a relationship between histological grade and translocation status, suggesting that FLs carrying BCL6 translocations probably constitute a special biological subtype. Clinical and histological differences between BCL2-/BCL6+ and BCL2+/BCL6+ tumours could reflect an interplay between both translocations.

R-CHOP-14 in patients with diffuse large B-cell lymphoma younger than 70 years: a multicentre, prospective study.

Several studies have shown that adding rituximab to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) or reducing the interval between chemotherapy cycles from 3 weeks to 2 weeks improves survival in patients with diffuse large B-cell lymphoma (DLBCL). These studies prompted our group (GOTEL) to evaluate prospectively in a pilot study the feasibility and efficacy of R-CHOP-14 in patients with DLBCL. Patients (<70 years) with stage II bulky or stage III or IV DLBCL and no significant comorbidities were included in the study. Rituximab was administered on day 1 before chemotherapy. R-CHOP was given every 14 days. All patients received filgrastim (5 microg/kg) from days 4 to 10. From May 2002 to August 2004, 80 patients were recruited. Median age was 53 years and 58 patients were <60 years. According to the age-adjusted international prognostic index (aaIPI), 13 patients (16%) had low-risk disease, 31 (39%) low-to-intermediate risk, 27 (34%) high-to-intermediate risk and 9 (11%) high-risk disease. Grade 3-4 neutropenia was observed in 15 patients (17.5%) and grade 3-4 infections in 13 patients (16%). After therapy, 58 patients (73%) achieved CR-CRu (95% CI: 55-90%). With a median follow-up of 26 months, progression-free survival (PFS) and overall survival (OS) at 30 months were 72% and 86%, respectively. Administration of R-CHOP-14 is feasible and effective in patients <70 years.

Possible prognostic value of leukotriene B(4) in acute respiratory distress syndrome.

OBJECTIVE: To study the major eicosanoids implicated in the pathophysiology of acute respiratory distress syndrome (ARDS) in order to estimate their relative prognostic values. METHODS: We conducted a prospective study in a consecutive series of patients with ARDS admitted to a university hospital intensive care unit. We measured the plasma concentrations of 3 inflammatory mediators (thromboxane B(2), 6-keto prostaglandin F(1alpha), and leukotriene B(4)) in peripheral arterial and mixed venous plasma samples. RESULTS: We studied 16 patients with ARDS, who had a mean alpha SD baseline ratio of P(aO(2)) to fraction of inspired oxygen (P(aO(2))/F(IO(2))) of 147 +/- 37 mm Hg and a mean +/- SD baseline lung injury score of 2.9 +/- 0.37. The plasma concentrations of thromboxane B(2), 6-keto prostaglandin F(1alpha), and leukotriene B(4) were greater than the general-population reference levels in both arterial and mixed venous plasma, but only leukotriene B(4) was higher in arterial plasma than in mixed venous plasma (401 +/- 297 pg/mL vs 316 +/- 206 pg/mL, p = 0.04). When we correlated the eicosanoid concentrations with specific indicators of clinical severity, we found correlations only between the baseline P((aO2))/F(IO(2)) and the arterial thromboxane B(2) level (r = -0.57, p = 0.02), the arterial leukotriene B(4) level (r = -0.59, p = 0.01), and the transpulmonary gradient of leukotriene B(4) level (r = -0.59, p = 0.01). We also found a correlation between the transpulmonary gradient of leukotriene B(4) and the lung injury score (r = 0.51, p = 0.04). The thromboxane B(2) concentration in arterial plasma and the leukotriene B(4) concentration in both arterial and mixed venous plasma were the only baseline plasma eicosanoid concentrations that predicted significant differences in outcome. When looking at the transpulmonary gradient of the eicosanoids studied, we found that only the gradient of leukotriene B(4) showed significant differences of clinical interest. Among survivors we observed practically no gradient (-4.9%), whereas among nonsurvivors we found a substantial positive gradient of 41.6% for the elevated arterial (post-pulmonary) values, compared with the pulmonary-artery (pre-pulmonary) values, and this difference was statistically significant (p = 0.02). CONCLUSIONS: The pro-inflammatory eicosanoid leukotriene B(4) showed the best correlation with lung-injury severity and outcome in patients with ARDS.