Ibrutinib and R-GemOx in patients with relapsed or refractory diffuse large B-cell lymphoma of non-GCB type: Phase II clinical trial of the Spanish GELTAMO group.

PURPOSE: This phase II clinical trial evaluated the combination of Ibrutinib with rituximab, gemcitabine and oxaliplatin (R-GemOx) in patients with non-germinal centre B-cell-like (non-GCB) diffuse large B-cell lymphoma (DLBCL). PATIENTS AND METHODS: The IBDCL trial (NCT02692248) included patients with histological diagnosis of non-GCB DLBCL with relapsed or refractory disease and non-candidates for stem cell transplantation. Patients received an induction treatment consisting of 6 or 8 cycles of R-GemOx at standard doses every 2 weeks, in combination with ibrutinib (560 mg daily), followed by a maintenance treatment with ibrutinib for a maximum of 2 years. The primary objective was to evaluate the overall response rate (ORR) after 4 cycles. RESULTS: Sixty-four patients were included, 72% of them refractory to the last regimen. The ORR and CR rate after the 4th cycle were 53% (95% confidence interval [CI], 41-65) and 34% (95% CI, 24-46), respectively. Twenty-four (37%) patients started maintenance and 7 (11%) completed the planned 2 years. After a median follow-up of 29.7 months (range: 0.4-48.6), the estimated 2-year PFS and OS were 18% (95% CI, 8 - 28) and 26% (95% CI, 14 - 37), respectively. The most common grade ≥3 treatment-related adverse events (TRAEs) were thrombocytopenia (44%), neutropenia (30%) and anemia (14%). Grade ≥3 infectious and cardiovascular TRAEs were reported in 6 (9%) and 1 (2%) patient, respectively. CONCLUSIONS: Ibrutinib in combination with R-GemOx, followed by ibrutinib maintenance, demonstrated encouraging antitumor activity with durable responses and a manageable toxicity in patients with non-GCB DLBCL.

Effects of the periocular botulinum toxin on the ocular surface and anterior chamber: a prospective study in patients with hemifacial spasm and blepharospasm.

PURPOSE: To analyze using Pentacam®, the corneal and anterior chamber changes following periocular botulinum toxin injection in patients with facial dystonia. METHODS: Prospective study that included patients with facial dystonia that were going to receive a periocular botulinum toxin injection for the first time or six months or more after the previous injection. A Pentacam® examination was carried out in all patients before and 4 weeks after the injection. RESULTS: Thirty-one eyes were included. Twenty-two had a diagnosis of blepharospasm and nine of hemifacial spasm. Analysis of corneal and anterior chamber parameters revealed a significant decrease in iridocorneal angle after botulinum toxin injection (from 35 ± 10º to 33.8 ± 9.7º, p = 0.022). No other corneal or anterior chamber parameters changed significantly after the injection. CONCLUSIONS: Periocular botulinum toxin injection causes narrowing of the iridocorneal angle.

Adolescents and youths' opinions about the factors associated with cannabis use: a qualitative study based on the I-Change model.

BACKGROUND: To learn about the experiences and opinions of adolescent non-consumers and regular cannabis users about cannabis use and the factors that determine its use, using the I-Change explanatory model as a basis. METHODS: Qualitative methodology with a content analysis was used. Focus groups were conducted with adolescents who were non-regular cannabis users (those who had not tried cannabis or had only experimented with it before) and semi-structured interviews were conducted with adolescent and young adult in recovery who were in a detoxification program. A deductive analysis of the audio-recorded and transcribed interviews was performed, using the domains of the I-Change Model as a reference. RESULTS: Personal problems, social problems or family problems can lead to cannabis use. There was a lack of knowledge and low risk perception about consumption of this drug. There are other factors that influence consumption, the perception of advantages, such as the feeling of freedom and the influence of the peer group. The consumption of this substance in girls is changing, becoming more and more equal to that of boys. The family has an important role to play in preventing drug use. CONCLUSION: Knowledge of these factors is of vital importance as a prior step to the development of efficient intervention measures adjusted to the needs identified and the characteristics of the population.

Continuing education programme on vaccines for primary healthcare professionals: mixed-method protocol.

INTRODUCTION: Vaccination is a fundamental intervention in disease prevention; therefore, the advice and recommendations of health professionals have a major influence on the population's decision to be vaccinated or not. Professionals must have sufficient competencies to carry out their work and recommend vaccination with evidence-based knowledge. The aim is to design and validate a strategy to improve professional competencies in vaccination to positively influence adherence and increase vaccination rates in the population. METHODS AND ANALYSIS: Training will be designed based on evidence and previous studies and piloted with healthcare providers. To test changes in knowledge, a pretest and post-test will be conducted. To test feasibility, a think-aloud method will be used with participants and triangulated with focus groups using SWOT (strengths, weaknesses, opportunities and threats) analysis. Transfer will be measured using the questionnaire 'factors for the indirect evaluation of transfer' and an efficacy questionnaire 1½ months later; for satisfaction, an ad hoc questionnaire will be used. A summative approach will be used for the analysis of the focus groups and descriptive and bivariate statistics for the questionnaires. ETHICS AND DISSEMINATION: This study was approved by the Andalusian Research Ethics Committee, Spain (approval number: 0524-N-20). The results will be made available to the public at journal publications and scientific conferences.

Microplastics, bisphenols, phthalates and pesticides in odontocete species in the Macaronesian Region (Eastern North Atlantic).

The gastrointestinal contents of twelve individuals from six odontocete species that stranded between 2018 and 2019 in the Macaronesian Region (Eastern North Atlantic) were examined for the presence of marine debris. In addition, concentrations of eleven organic persistent contaminants (nonylphenols, bisphenols, phthalates and pesticides) were analysed in muscle samples by liquid chromatography. No particles larger than 5 mm were found, except for two plastic labels that were found on the same dolphin. On the contrary, all animals contained microplastics of diverse sizes, most of them being fibres (98.06%, n = 708). The predominant detected pollutants were bisphenols (4-984 ng/g) and DEHP (102-1533 ng/g). Also, except for two individuals, all animals had pesticide levels in their tissues. This work has allowed the establishment of a protocol for the study of microplastic ingestion in cetaceans, and tests the potential of microRaman to improve the understanding of microplastic alteration processes.

Sexual behaviour, human papillomavirus and its vaccine: a qualitative study of adolescents and parents in Andalusia.

BACKGROUND: Human papillomavirus (HPV) is one of the most common sexually transmitted infections and can be prevented by vaccination. The purpose of this study is to gain a better understanding, by analysing interview responses of adolescents and parents, of how adolescent sexual behaviour is approached in families, how widespread knowledge about HPV is in Andalusia, the autonomous region with the lowest vaccination rate in Spain, as well as to learn more about the interviewees' position regarding vaccination. METHODS: A qualitative study by means of 15 focus groups of adolescents (N = 137, aged 14-17 years) and five focus groups of parents with children of those ages (N = 37) was conducted in the provinces of Granada, Seville and Jaén (Andalusia, Spain). The audio data were transcribed verbatim, coded and analysed thematically using NVIVO-10 software. RESULTS: There were three major results: (1) There is a lack of communication between adolescents and parents regarding sexual behaviour; (2) In both groups, scarce knowledge about HPV and vaccination was found; (3) Parents mistrust vaccination due to a lack of qualified and verified information about its benefits. CONCLUSIONS: Healthy adolescent sexual behaviour is aided by communication within the family. Families need more information based on the evidence about HPV and vaccination. Health professionals are a key element in this process.

The 18F phantom clinical trials qualification for 18F-FDG-PET scanning adopted by GELTAMO (Grupo Español de Linfomas/Trasplante Autólogo de Médula Ósea). / Cualificación de fantomas 18F para ensayos clínicos con imagen PET/TC-18F-FDG adoptada por GELTAMO (Grupo Español de Linfomas/Trasplante Autólogo de Médula Ósea).

INTRODUCTION AND OBJECTIVES: Since different PET/CT (Positron Emission Tomography/Computed Tomography) scanners give different qualitative readings, a program for clinical trial qualification (CTQ) is mandatory to guarantee a reliable and reproducible use of PET/CT in prospective multi-centre clinical trials. Within this work we will show the results carried out in performing CTQ in Spain. MATERIALS AND METHODS: We set up, under the auspices of Grupo Español de Linfomas/Trasplante Autólogo de Médula Osea (GELTAMO), a CTQ program consisting of the acquisition and analysis of 18F uniformity and image quality phantoms for the reduction of inter-scanner variability (ISV). The ISV was estimated on background activity concentration (BAC) and sphere to background ratio (SBR) and defined as their 95% confidence level. RESULTS: Twenty-six out of 27 (96%) scanners fulfilled the CTQ requirements. The CTQ was fulfilled at the first round in 27% of the cases, while in 38%, 15% and 20%, two, three or more than three iterations, were required, respectively. The mean CTQ time was (1.8 ± 1.4) months (range: 0.3-4.6). The ISV in BAC and SBR were 20.3% and 67.7%. CONCLUSIONS: The CTQ proven to be a reliable tool to reduce ISV. This enabled to set-up clinical trials in which PET/CT was used to evaluate different clinical endpoints.

Measures to Maintain a SARS-CoV-2 Negative Inpatient Hematological Unit in the Midst of the COVID-19 Pandemic.

The University Hospital of Salamanca, in Spain, had its first COVID-19 case on March 1st and as of May 11th, we had 1,100 positive cases. Based on the vulnerability of patients with blood cancers, on March 9th, the Hematology Department developed a protocol, amended as the new information was available, to maintain the Hematology Unit as a "free COVID-19 island." The protocol included symptom-based surveys and screening tests to patients, caregivers, and healthcare personnel to identify early potential positive cases and prevent its spread. Between March 9 and April 28, 32 asymptomatic patients and caregivers were tested and 68 rT-PCR diagnostic assays have been performed with two positive results. A 106 healthcare workers have been tested (208 rT-PCR) and seven of them were positive. In summary, the implementation of preemptive measures after the first case appeared allowed us to be able to provide treatment to our patients.

A Case of Paraneoplastic Cerebellar Degeneration that Preceded the Diagnosis of Classical Hodgkin's Lymphoma by 16 Months.

BACKGROUND Paraneoplastic cerebellar degeneration (PCD) is a rare condition that can present as an acute or subacute cerebellar syndrome. PCD is most commonly associated with gynecological and breast cancer, small-cell lung cancer, and classical Hodgkin's lymphoma. The symptoms of PCD can arise several months before tumor diagnosis. This report is of a case of a 44-year-old man with PCD that preceded the diagnosis of classical Hodgkin's lymphoma by 16 months. CASE REPORT A 44-year-old man was admitted to hospital with a cerebellar syndrome that was initially diagnosed as vertebrobasilar insufficiency. Eight months later, cerebral magnetic resonance imaging (MRI) findings and serum anti-Tr antibodies supported the diagnosis of PCD, but no underlying malignancy was initially found. At 16 months after the initial diagnosis of PCD, the patient developed an enlarged inguinal lymph node. Histology of the excisional lymph node biopsy confirmed the diagnosis of classic mixed cellularity Hodgkin's lymphoma, Ann Arbor stage IIA. The patient responded to four cycles of adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy. CONCLUSIONS This case illustrates that in patients who present with PCD, an associated malignancy, such as classical Hodgkin's lymphoma, may emerge several months later, which supports long-term follow-up. The presence of anti-Tr antibodies may support a diagnosis of classical Hodgkin's lymphoma in a patient with a history of PCD who develops lymphadenopathy.

Biological Features and Prognostic Impact of Bone Marrow Infiltration in Patients with Diffuse Large B-Cell Lymphoma.

The biology and clinical impact of bone marrow (BM) infiltration in patients with diffuse large B-cell lymphoma (DLBCL) remains unclear in the rituximab era. We retrospectively analyzed 232 patients diagnosed with DLBCL at our center between 1999 and 2014. Concordant-presence of large cells similar to those of the lymph node biopsy- and discordant-infiltration by small cells forming lymphoid aggregates, lacking cytological atypia-BM infiltration was defined by histological criteria and further characterized by flow cytometry (FCM). Cell of origin (COO) was determined using Hans' algorithm. For the clonal relationship between tumor and discordant BM, the VDJH rearrangement was analyzed. Survival analyses were restricted to 189 patients treated with rituximab and chemotherapy. Thirty-six (16%) had concordant, and 37 (16%) discordant BM infiltration. FCM described different indolent lymphomas among discordant cases, clonally related with DLBCL in 10/13 available samples. Median follow-up was 58 months. 5-year-progression-free survival (PFS) for non-infiltrated, discordant and concordant groups was 68%, 65% and 30%, respectively (p < 0.001). Combining COO and BM infiltration, patients with discordant BM and non-germinal center B-cell COO also had decreased 5-year-PFS (41.9%). In multivariate analysis, concordant BM had an independent effect on PFS (HR 2.5, p = 0.01). Five-year cumulative incidence of central nervous system (CNS) relapse was 21%, 4% and 1% in concordant, discordant and non-infiltrated groups, respectively (p < 0.001). In conclusion, concordant BM infiltration represents a subset with poor prognosis, whereas the prognostic impact of discordant BM infiltration could be limited to non-CGB cases.

Response-adapted treatment with rituximab, bendamustine, mitoxantrone, and dexamethasone followed by rituximab maintenance in patients with relapsed or refractory follicular lymphoma after first-line immunochemotherapy: Results of the RBMDGELTAMO08 phase II trial.

BACKGROUND: Consensus is lacking regarding the optimal salvage therapy for patients with follicular lymphoma who relapse after or are refractory to immunochemotherapy. METHODS: This phase II trial evaluated the efficacy and safety of response-adapted therapy with rituximab, bendamustine, mitoxantrone, and dexamethasone (RBMD) in follicular lymphoma patients who relapsed after or were refractory to first-line immunochemotherapy. Sixty patients received three treatment cycles, and depending on their response received an additional one (complete/unconfirmed complete response) or three (partial response) cycles. Patients who responded to induction received rituximab maintenance therapy for 2 years. RESULTS: Thirty-three (55%) and 42 (70%) patients achieved complete/unconfirmed complete response after three cycles and on completing induction therapy (4-6 cycles), respectively (final overall response rate, 88.3%). Median progression-free survival was 56.4 months (median follow-up, 28.3 months; 95% CI, 15.6-51.2). Overall survival was not reached. Progression-free survival did not differ between patients who received four vs six cycles (P = .6665), nor between patients who did/did not receive rituximab maintenance after first-line therapy (P = .5790). Median progression-free survival in the 10 refractory patients was 25.5 months (95% CI, 0.6-N/A) and was longer in patients who had shown progression of disease after 24 months of first-line therapy (median, 56.4 months; 95% CI, 19.8-56.4) than in those who showed early progression (median, 42.31 months; 95% CI, 24.41-NA) (P = .4258). Thirty-six (60%) patients had grade 3/4 neutropenia. Grade 3/4 febrile neutropenia and infection were recorded during induction (4/60 [6.7%] and 5/60 [8.3%] patients, respectively) and maintenance (2/43 [4.5%] and 4/43 [9.1%] patients, respectively). CONCLUSIONS: This response-adapted treatment with RBMD followed by rituximab maintenance is an effective and well-tolerated salvage treatment for relapsed/refractory follicular lymphoma following first-line immunochemotherapy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov # NCT01133158.

Treating anxiety and depression of cancer survivors: Behavioral activation versus acceptance and commitment therapy / Tratamiento de ansiedad y depresión en supervivientes de cáncer: activación conductual versus terapia de aceptación

Background: Behavioral activation (BA) and acceptance and commitment therapy (ACT) are considered particularly useful treatments when dealing with emotional problems of cancer survivors. The efficacy of these two treatments, applied on a group basis, were evaluated and compared. Method: An analysis was carried out of pre-post treatment changes in the emotional state and patterns of activation/avoidance of 52 cancer patients, with anxiety and/or depression, randomly assigned to three groups (BA/ACT/waiting list control). Results: Both therapies were superior to no treatment in all the variables evaluated. Significant differences were found between the two treatments in favor of ACT in social impairment and avoidance/rumination. Conclusions: BA and ACT, applied on a group basis, are efficacious in the treatment of those emotional difficulties most prevalent in cancer survivors. Results suggest that activation and avoidance are the mechanisms responsible for the changes (AU)

Antecedentes: la activación conductual (AC) y la terapia de aceptación y compromiso (ACT) se plantean como tratamientos especialmente útiles para los problemas emocionales de los supervivientes de cáncer. Se evaluó y comparó la eficacia de ambas terapias aplicadas en formato grupal. Método: se analizaron los cambios pre-post tratamiento en el estado emocional y los patrones de activación/evitación de 52 supervivientes de cáncer con ansiedad y/o depresión que se asignaron aleatoriamente a tres grupos (AC/ACT/control de lista de espera). Resultados: ambas terapias fueron superiores al no tratamiento en todas las variables evaluadas. Se encontraron diferencias significativas entre tratamientos a favor de la ACT en deterioro social y evitación/rumia. Conclusiones: la AC y la ACT, en formato grupal, son eficaces para el tratamiento de las dificultades emocionales más prevalentes en supervivientes de cáncer. Los resultados apuntan a la activación y la evitación como mecanismos responsables de los cambios (AU)

Plitidepsin: design, development, and potential place in therapy.

Plitidepsin is a cyclic depsipeptide that was first isolated from a Mediterranean marine tunicate (Aplidium albicans) and, at present, is manufactured by total synthesis and commercialized as Aplidin®. Its antitumor activity, observed in preclinical in vitro and in vivo studies has prompted numerous clinical trials to be conducted over the last 17 years, alone or in combination with other anticancer agents. Single-agent plitidepsin has shown limited antitumor activity and a tolerable safety profile in several malignancies, such as noncutaneous peripheral T-cell lymphoma, melanoma, and multiple myeloma. In patients with relapsed or refractory multiple myeloma, plitidepsin activity seems to be enhanced after addition of dexamethasone while remaining well tolerated, and a Phase III trial comparing plitidepsin plus dexamethasone vs dexamethasone alone is underway. Additional studies are required to better define the role of plitidepsin in combination with other active agents in these indications. Results of plitidepsin activity in other hematological malignancies or solid tumors have been disappointing so far. Further studies analyzing its mechanisms of action and potential biomarkers will help select patients who may benefit most from this drug. In this review, we critically analyze the published studies on plitidepsin in hematological malignancies and solid tumors and discuss its current role and future perspectives in treating these malignancies. We also review its design, pharmaceutical data, and mechanism of action.

The number of tumor infiltrating T-cell subsets in lymph nodes from patients with Hodgkin lymphoma is associated with the outcome after first line ABVD therapy.

Prognostic factors in Hodgkin lymphoma (HL) still fail to accurately identify high-risk patients. Tumor microenvironment in HL is a current focus of research for risk definition but few studies have focused on infiltrating lymphocytes. Here, we analyzed the number of tumor infiltrating lymphocytes by flow cytometry in diagnostic biopsies from 96 HL homogeneously treated patients with ABVD with or without radiotherapy. Most lymph node cells were lymphocytes (90 ± 17), with a median T/B/NK distribution of 74%/26%/0.7%, and CD4+ T-cell predominance. The amount of CD19+ B cells, and NK cells did not show association with disease features. However, high numbers of CD8+ and CD4+ cells were associated with better and poorer outcomes, respectively. Patients with ≥15% cytotoxic CD8+ cells among the total cell population had a longer 10-year freedom from treatment failure (FFTF) (93% vs. 73%, p=.04). In turn, cases with ≥75% of CD4+ infiltrating cells showed a significantly decreased FFTF (73% vs. 96%, p=.021). Consequently, CD4/CD8 ratio ≥5 associated with a poorer 10-year FFTF (69.5% vs. 94%, p=.02). This deleterious effect was particularly prominent in advanced disease (n = 58, p=.01). In multivariate analysis, a CD4/CD8 ratio ≥5 was the only independent variable to predict for treatment failure (HR = 4.5, 95% confidence interval, 1.2-16.8). In conclusion, our study shows that high CD4+ and low CD8+ T-cells infiltrates of tumor specimens associate with poor prognosis in HL patients, and CD4/CD8 ratio might be potentially useful for tailoring therapy.

Management patterns and outcomes in symptomatic venous thromboembolism following allogeneic hematopoietic stem cell transplantation. A 15-years experience at a single center.

BACKGROUND: Experience is limited with regard to antithrombotic therapy in patients with venous thromboembolism (VTE) following allogeneic hematopoietic stem cell transplantation (HSCT). DESIGN AND METHODS: We described a cohort of patients presenting with symptomatic VTE following allogeneic HSCT, including management patterns and outcomes. RESULTS: Twenty-four patients developed a deep vein thrombosis and/or pulmonary embolism unrelated to a catheter. Median time of VTE diagnosis and duration of antithrombotic therapy were 9.5 and 6months. Eleven patients were treated with full-dose low molecular weight heparin (LMWH). Eleven patients with minor bleeding, thrombocytopenia or renal failure received prophylactic dose LMWH. In two patients an inferior vena cava filter was inserted due to thrombocytopenia and bleeding. There were 2 major and 4 life-threatening bleeding episodes, so LMWH was discontinued permanently. Two deaths were directly attributable to bleeding. Ten patients developed a catheter-associated VTE. Median time to diagnosis and duration of anticoagulation was 2.5 and 3months. Catheter was removed in all patients. LMWH was administered at therapeutic-dose in 4 patients, and was reduced by bleeding in 2 of them. LMWH was administered at prophylactic-dose in 6 patients, and was reduced by renal failure in one patient. There were three episodes of minor bleeding. Rate of clot recurrence was 29.4% (n=10). Patients at recurrence were without antithrombotic treatment (n=4), intermediate-dose LMWH (n=2), low-dose LMWH (n=2) or acenocumarol (n=2). Eight patients with recurrence VTE had extensive chronic graft versus host disease (GVHD). CONCLUSIONS: LMWH was used in most HSCT recipients but half of them may not receive full-dose LMWH. Thrombocytopenia, renal impairment and bleeding were the reasons for reducing LMWH. Also, rates of clinically relevant hemorrhage or recurrent VTE were highly significant. The development of GVHD could mainly explain these findings.

Blastic plasmacytoid dendritic cell neoplasm frequently shows occult central nervous system involvement at diagnosis and benefits from intrathecal therapy.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare aggressive myeloid neoplasm which shows a high rate of central nervous system (CNS) recurrence and overall survival (OS) of <1 year. Despite this, screening for CNS involvement is not routinely performed at diagnosis and intrathecal (IT) prophylaxis is not regularly administered in BPDCN. Here, we prospectively evaluated 13 consecutive BPDCN patients for the presence of CNS involvement by flow cytometry. Despite none of the patients presented with neurological symptoms, occult CNS involvement was detected in 6/10 cases evaluated at diagnosis and 3/3 studied at relapse/progression. BPDCN patients evaluated at diagnosis received IT treatment -either CNS prophylaxis (n = 4) or active therapy (n = 6)- and all but one remain alive (median follow-up of 20 months). In contrast, all three patients assessed at relapse/progression died. The potential benefit of IT treatment administered early at diagnosis on OS and CNS recurrence-free survival of BPDCN was further confirmed in a retrospective cohort of another 23 BPDCN patients. Our results show that BPDCN patients studied at diagnosis frequently display occult CNS involvement; moreover, they also indicate that treatment of occult CNS disease might lead to a dramatically improved outcome of BPDCN.