An integrated prognostic model for diffuse large B-cell lymphoma treated with immunochemotherapy.

Diffuse large B-cell lymphoma (DLBCL), the most frequent non-Hodgkin's lymphoma subtype, is characterized by strong biological, morphological, and clinical heterogeneity, but patients are treated with immunochemotherapy in a relatively homogeneous way. Here, we have used a customized NanoString platform to analyze a series of 197 homogeneously treated DLBCL cases. The platform includes the most relevant genes or signatures known to be useful for predicting response to R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) in DLBCL cases. We generated a risk score that combines the International Prognostic Index with cell of origin and double expression of MYC/BCL2, and stratified the series into three groups, yielding hazard ratios from 0.15 to 5.49 for overall survival, and from 0.17 to 5.04 for progression-free survival. Group differences were highly significant (p < 0.0001), and the scoring system was applicable to younger patients (<60 years of age) and patients with advanced or localized stages of the disease. Results were validated in an independent dataset from 166 DLBCL patients treated in two distinct clinical trials. This risk score combines clinical and biological data in a model that can be used to integrate biological variables into the prognostic models for DLBCL cases.

Ability of final PET/CT to predict response to first-line treatment in real patients with classical Hodgkin lymphoma.

Up to 25% of patients with classical Hodgkin lymphoma (cHL) and a negative interim PET/CT will progress. Unfortunately, there are few published studies on the predictive value of PET/CT performed after finishing treatment. The objective of our study was to assess the role of the final PET/CT (fPET/CT) in predicting progression in a retrospective series of patients treated in the last 10 years with a homogeneous protocol (ABVD + / - radiotherapy). We reviewed a cohort of 227 patients with newly diagnosed cHL. fPET/CT was performed on 212 patients (93%). In patients with a positive fPET, progression-free survival at 60 months was 17% (94% if fPET was negative, p = 0.000). The positive and negative predictive values for the fPET were 76% and 94%, respectively (Fisher's exact test, p = 0.000). In the subgroup of patients with advanced-stage cHL, progression-free survival at 60 months was 91% with negative fPET and 0% with positive fPET (p = 0.000). However, fPET was negative in 19 of the 29 patients with a positive interim PET/CT (only 2 showed progression). In conclusion, fPET is a useful tool to predict treatment failure in patients with newly diagnosed cHL, especially advanced-stage disease.

Avelumab in Combination Regimens for Relapsed/Refractory DLBCL: Results from the Phase Ib JAVELIN DLBCL Study.

BACKGROUND: Relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) is associated with a poor prognosis despite the availability of multiple treatment options. Preliminary evidence suggests that DLBCL may be responsive to programmed death ligand 1 (PD-L1)/programmed death 1 inhibitors. OBJECTIVE: The JAVELIN DLBCL study was conducted to assess whether a combination of agents could augment and sustain the antitumor immunity of avelumab, an anti-PD-L1 antibody, in R/R DLBCL. METHODS: This was a multicenter, randomized, open-label, parallel-arm study with a phase Ib and a phase III component. Reported here are the results from the phase Ib study, wherein 29 adult patients with DLBCL were randomized 1:1:1 to receive avelumab in combination with utomilumab (an immunoglobulin G2 4-1BB agonist) and rituximab (arm A), avelumab in combination with utomilumab and azacitidine (arm B), or avelumab in combination with bendamustine and rituximab (arm C). The primary endpoints were dose-limiting toxicities and objective response as assessed by the investigator per Lugano Response Classification criteria. RESULTS: Of the seven patients in arm A, one (14.3%) experienced two grade 3 dose-limiting toxicities (herpes zoster and ophthalmic herpes zoster); no dose-limiting toxicities were reported in arms B or C. No new safety concerns emerged for avelumab. One partial response was reported in arm A, three complete responses in arm C, and no responses in arm B. Given the insufficient antitumor activity in arms A and B and the infeasibility of expanding arm C, the study was discontinued before initiation of the phase III component. CONCLUSIONS: The low level of clinical activity suggests that PD-L1 inhibitor activity may be limited in R/R DLBCL. CLINICALTRIALS. GOV IDENTIFIER: NCT02951156.

Incidence of COVID-19 in outpatients with cancer receiving active treatment in the context of a pandemic: An Andalusian cohort study.

BACKGROUND: Leading scientific societies have recommended delaying and/or suspending active cancer treatment during the COVID-19 pandemic. Nevertheless, data on this novel infection in patients with a diagnosis of cancer receiving active treatment are scarce and it is unknown if these recommendations could have repercussions on future progress of the disease. The main objective of this study is to learn the COVID-19 incidence rate in outpatients with cancer receiving active treatment. METHODS: This work is a retrospective cohort study that included all patients with a diagnosis of cancer who received active cancer treatment in two Andalusian hospitals between February 26 and May 13, 2020. Variables regarding the patient, tumor, and development of COVID-19 were collected. A descriptive analysis was performed and the cumulative incidence of COVID-19 in these patients was evaluated. RESULTS: A total of 673 patients were included. The median age was 62 years. There was a low rate of comorbidity and 12.1% had an ECOG >2. Breast cancer was the most common cancer (41%), followed by colorectal and lung cancer. Stage IV cancer was reported in 52.7% of patients. The most common treatment was chemotherapy (53.9%). Treatment was delayed or suspended in 6% of patients. Only three patients developed COVID-19. The cumulative incidence was 0.44% and one person died due to infection. CONCLUSIONS: In the present retrospective cohort study we found a low incidence of COVID-19 infection in patients with cancer receiving active treatment in an outpatient setting. The sociodemographic factors of Andalusia may explain why these results differ from those presented by other colleagues in Spain, but raise questions about whether universal recommendations may put the benefits of antineoplastic therapy at risk.

Proposal and validation of a method to classify genetic subtypes of diffuse large B cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease whose prognosis is associated with clinical features, cell-of-origin and genetic aberrations. Recent integrative, multi-omic analyses had led to identifying overlapping genetic DLBCL subtypes. We used targeted massive sequencing to analyze 84 diagnostic samples from a multicenter cohort of patients with DLBCL treated with rituximab-containing therapies and a median follow-up of 6 years. The most frequently mutated genes were IGLL5 (43%), KMT2D (33.3%), CREBBP (28.6%), PIM1 (26.2%), and CARD11 (22.6%). Mutations in CD79B were associated with a higher risk of relapse after treatment, whereas patients with mutations in CD79B, ETS1, and CD58 had a significantly shorter survival. Based on the new genetic DLBCL classifications, we tested and validated a simplified method to classify samples in five genetic subtypes analyzing the mutational status of 26 genes and BCL2 and BCL6 translocations. We propose a two-step genetic DLBCL classifier (2-S), integrating the most significant features from previous algorithms, to classify the samples as N12-S, EZB2-S, MCD2-S, BN22-S, and ST22-S groups. We determined its sensitivity and specificity, compared with the other established algorithms, and evaluated its clinical impact. The results showed that ST22-S is the group with the best clinical outcome and N12-S, the more aggressive one. EZB2-S identified a subgroup with a worse prognosis among GCB-DLBLC cases.

La disfunción de las pequeñas vías aéreas inducida por el tabaco ¿podría ser un marcador precoz de una futura EPOC? / Smoking-Induced Small Airway Dysfunction. An Early Marker of Future Copd?

No disponible

La e-basura: rare earth elements, nuevos tóxicos presentes en los cigarrillos y cigarrillos electrónicos / e-waste: Rare Earth Elements, New Toxic Substances in Cigarettes and Electronic Cigarettes

No disponible

La disfunción de las pequeñas vías aéreas deteriora la calidad de vida de fumadores sin limitación al flujo aéreo / Small Airway Dysfunction Impairs Quality of Life Among Smokers With No Airflow Limitation

Introducción: La disfunción de las pequeñas vías aéreas (DPV) inducida por el tabaco contribuye precozmente a la patogenia de la limitación al flujo aéreo (LFA), aunque resulta poco conocida su repercusión en la percepción de salud. Se pretende evaluar la frecuencia de DPV en fumadores activos sin LFA y comparar la calidad de vida relacionada con la salud (CVRS) de no fumadores, fumadores sin DPV, fumadores con DPV y fumadores con LFA. Métodos: En 53 fumadores activos sin LFA, 20 fumadores con LFA y 20 no fumadores, se utilizaron los cuestionarios SF-36 y EuroQoL y se realizó oscilometría de impulsos, espirometría y determinación de las densidades de atenuación del parénquima pulmonar en inspiración y espiración máximas. Se consideró que existía DPV cuando la resistencia a 5 Hz (R5), la diferencia R5-R20 y el área de reactancia (AX) excedían su límite superior de la normalidad. Resultados: El 35,8% de los fumadores sin LFA tenía DPV. No se detectaron diferencias en los parámetros espirométricos ni la atenuación pulmonar entre los fumadores con o sin DPV y los no fumadores. Sin embargo, los fumadores con DPV presentaban una peor puntuación en los cuestionarios de CVRS que los fumadores sin DPV o los no fumadores, e intermedia a los fumadores con LFA. R5 y X5 fueron identificados como determinantes independientes de la CVRS en los fumadores sin LFA. Conclusiones: La DPV es frecuente en fumadores sin LFA, afectando a un tercio de los mismos, y condicionando de forma independiente su percepción de salud

Introduction: Small airway dysfunction (SAD) caused by smoking contributes to the early onset of airflow limitation (AFL), although its impact on patients’ perception of health is largely unknown. We aimed to evaluate the frequency of SAD in active smokers without AFL, and to compare health-related quality of life (HRQoL) of non-smokers, smokers without SAD, smokers with SAD, and smokers with AFL. Methods: A total of 53 active smokers without AFL, 20 smokers with AFL, and 20 non-smokers completed the SF-36 and EuroQoL questionnaires and performed impulse oscillometry and spirometry. Pulmonary parenchymal attenuation was determined in inspiration and expiration. SAD was determined to exist when resistance at 5Hz (R5), the difference between R5 and R20, and reactance area (AX) exceeded the upper limit of normal. Results: In total, 35.8% of smokers without AFL had SAD. No differences were detected in spirometric parameters or pulmonary attenuation between smokers with or without AFL and non-smokers. However, smokers with SAD had worse scores on HRQoL questionnaires than smokers without SAD or non-smokers, and scores compared to smokers with AFL were intermediate. R5 and X5 were identified as independent determinants of HRQoL in smokers without AFL. Conclusions: SAD is common in smokers without AFL, affecting one third of this population, and independently affecting their perception of health

Safety of switching from intravenous to subcutaneous rituximab during first-line treatment of patients with non-Hodgkin lymphoma: the Spanish population of the MabRella study.

Rituximab is a standard treatment for non-Hodgkin diffuse large B-cell (DLBCL) and follicular (FL) lymphomas. A subcutaneous formulation was developed to improve the resource use of intravenous rituximab, with comparable efficacy and safety profiles except for increased administration-related reactions (ARRs). MabRella was a phase IIIb trial to assess the safety of switching from intravenous to subcutaneous administration of rituximab during first-line induction/maintenance for DLBCL or FL, focusing on ARRs. Efficacy, satisfaction and quality of life were also assessed. Patients received subcutaneous rituximab plus standard induction chemotherapy for DLBCL or FL for 4-7 cycles, and/or every 2 months maintenance monotherapy for FL for 6-12 cycles. The study included 140 patients: DLBCL, n = 29; FL, n = 111. Ninety-five percent of patients experienced adverse events, reaching grade ≥3 in 38·6% and were serious in 30·0%. AARs occurred in 48·6%, mostly (84·9%) at the injection site, with only 2·1% of patients reaching grade 3. The end-of-induction complete/unconfirmed complete response rate was 69·6%. After a median follow-up of 33·5 months, median disease-/event-/progression-free and overall survivals were not attained. The Rituximab Administration Satisfaction Questionnaire showed improvements in overall satisfaction and the EuroQoL-5D a good quality-of-life perception at induction/maintenance end. Therefore, switching to subcutaneous rituximab showed no new safety issues and maintained efficacy with improved satisfaction and quality of life.

Small Airway Dysfunction Impairs Quality of Life Among Smokers With No Airflow Limitation. / La disfunción de las pequeñas vías aéreas deteriora la calidad de vida de fumadores sin limitación al flujo aéreo.

INTRODUCTION: Small airway dysfunction (SAD) caused by smoking contributes to the early onset of airflow limitation (AFL), although its impact on patients' perception of health is largely unknown. We aimed to evaluate the frequency of SAD in active smokers without AFL, and to compare health-related quality of life (HRQoL) of non-smokers, smokers without SAD, smokers with SAD, and smokers with AFL. METHODS: A total of 53 active smokers without AFL, 20 smokers with AFL, and 20 non-smokers completed the SF-36 and EuroQoL questionnaires and performed impulse oscillometry and spirometry. Pulmonary parenchymal attenuation was determined in inspiration and expiration. SAD was determined to exist when resistance at 5Hz (R5), the difference between R5 and R20, and reactance area (AX) exceeded the upper limit of normal. RESULTS: In total, 35.8% of smokers without AFL had SAD. No differences were detected in spirometric parameters or pulmonary attenuation between smokers with or without AFL and non-smokers. However, smokers with SAD had worse scores on HRQoL questionnaires than smokers without SAD or non-smokers, and scores compared to smokers with AFL were intermediate. R5 and X5 were identified as independent determinants of HRQoL in smokers without AFL. CONCLUSIONS: SAD is common in smokers without AFL, affecting one third of this population, and independently affecting their perception of health.

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.

Unraveling transformation of follicular lymphoma to diffuse large B-cell lymphoma.

Follicular lymphoma (FL) is an indolent but largely incurable disease. Some patients suffer histological transformation to a more aggressive subtype with poorer prognosis. This study aimed to improve our understanding of the genetics underlying FL histological transformation, and to identify genetic drivers or promoters of the transformation by elucidating the differences between FL samples from patients who did and did not transform. We conducted targeted massive parallel sequencing of 22 pre-transformed FL/transformed diffuse large B-cell lymphoma pairs and 20 diagnostic samples from non-transformed FL patients. Additionally, 22 matched samples from 11 transformed FL patients (pre-transformed FL and diffuse large B-cell lymphoma) and 9 non-transformed FLs were studied for copy number variation using SNP arrays. We identified recurrently mutated genes that were enriched at transformation, most notably LRP1B, GNA13 and POU2AF1, which have roles in B-cell differentiation, GC architecture and migration. Mutations in POU2AF1 might be associated with lower levels of expression, were more frequent in transformed FLs, and seemed to be specific to transformed- compared with de novo-diffuse large B-cell lymphomas. Pre-transformed FLs carried more mutations per sample and had greater subclonal heterogeneity than non-transformed FLs. Finally, we identified four mutated genes in FL samples that differed between patients who did and did not transform: NOTCH2, DTX1, UBE2A and HIST1H1E. The presence of mutations in these genes was associated with shorter time to transformation when mutated in the FL biopsies. This information might be useful for identifying patients at higher risk of transformation.

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.

Small airway dysfunction in smokers with stable ischemic heart disease.

BACKGROUND: A higher prevalence of airflow limitation (AL) has been described in patients with ischemic heart disease (IHD). Although small airway dysfunction (SAD) is an early feature of AL, there is little information about its occurrence in IHD patients. Our objective was to describe the prevalence of SAD in IHD patients, while comparing patient-related outcomes and future health risk among IHD patients with AL, SAD and normal lung function. METHODS: In 118 consecutive smoking patients with stable IHD, comorbidities, utilization of healthcare resources, current treatment, blood biochemistry and health status were recorded. SAD was evaluated by impulse oscillometry, and pre- and post-bronchodilator spirometry was performed. RESULTS: The prevalence of AL and SAD were 20.3 (95% CI, 13.1-27.6%) and 26.3% (95% CI, 18.3-34.2%), respectively. Compared to the normal lung function group, patients with SAD and without AL had lower spirometric values, poorer quality of life and higher levels of C-reactive protein (CRP), as well as increased cardiovascular risk and more vascular age. In patients with normal spirometry, the presence of SAD was independently associated with pack-years, HDL-cholesterol and CRP levels. CONCLUSION: In patients with IHD, the presence of SAD is common and that it is associated with reduced health status and increased future cardiac risk.

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.

Primary Breast Lymphoma: Analysis of 55 Cases of the Spanish Lymphoma Oncology Group.

INTRODUCTION: Primary breast lymphoma is a rare form of localized extranodal lymphoma, which affects the mammary glands unilaterally or bilaterally, and can also affect the regional lymph nodes. MATERIALS AND METHODS: We reviewed 55 patients, with disease stages IE and IIE, diagnosed in 16 Spanish institutions between 1989 and 2016. A serial of clinical variables and treatment were collected, and overall survival (OS) and progression-free survival (PFS) were calculated. RESULTS: Of the 55 patients, 96.4% were women with an average age of 69 years. A total of 53 patients corresponded to non-Hodgkin lymphoma (NHL), of whom 36.3% had lymph node involvement upon diagnosis. Of the patients, 58.2% were stage IE, and 41.8% were stage IIE. Treatments received included radiotherapy (36.3%), chemotherapy (85.5%), and rituximab (in 38 of the 45 patients with NHL treated with chemotherapy). In all, 82.2% of complete responses were achieved. OS and progression-free survival at 5 years in NHL patients was 76% and 73%, respectively. CONCLUSION: Current treatments (chemotherapy, immunotherapy, and radiotherapy) achieve good control of the disease, with an OS of 5 years in 80% of the patients, although there is no consensus in treatment, given the scarce incidence of these lymphomas.