Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Summary Background High-dose methotrexate is the standard of care for patients with newly diagnosed primary CNS lymphoma. The role of whole brain radiotherapy is controversial because delayed neurotoxicity limits its acceptance as a standard of care. We aimed to investigate whether first-line chemotherapy based on high-dose methotrexate was non-inferior to the same chemotherapy regimen followed by whole brain radiotherapy for overall survival. Methods Immunocompetent patients with newly diagnosed primary CNS lymphoma were enrolled from 75 centres and treated between May, 2000, and May, 2009. Patients were allocated by computer-generated block randomisation to receive first-line chemotherapy based on high-dose methotrexate with or without subsequent whole brain radiotherapy, with stratification by age ( vs ≥60 years) and institution (Berlin vs Tubingen vs all other sites). The biostatistics centre assigned patients to treatment groups and informed local centres by fax; physicians and patients were not masked to treatment group after assignment. Patients enrolled between May, 2000, and August, 2006, received high-dose methotrexate (4 g/m 2 ) on day 1 of six 14-day cycles; thereafter, patients received high-dose methotrexate plus ifosfamide (1·5 g/m 2 ) on days 3–5 of six 14-day cycles. In those assigned to receive first-line chemotherapy followed by radiotherapy, whole brain radiotherapy was given to a total dose of 45 Gy, in 30 fractions of 1·5 Gy given daily on weekdays. Patients allocated to first-line chemotherapy without whole brain radiotherapy who had not achieved complete response were given high-dose cytarabine. The primary endpoint was overall survival, and analysis was per protocol. Our hypothesis was that the omission of whole brain radiotherapy does not compromise overall survival, with a non-inferiority margin of 0·9. This trial is registered with ClinicalTrials.gov, number NCT00153530. Findings 551 patients (median age 63 years, IQR 55–69) were enrolled and randomised, of whom 318 were treated per protocol. In the per-protocol population, median overall survival was 32·4 months (95% CI 25·8–39·0) in patients receiving whole brain radiotherapy (n=154), and 37·1 months (27·5–46·7) in those not receiving whole brain radiotherapy (n=164), hazard ratio 1·06 (95% CI 0·80–1·40; p=0·71). Thus our primary hypothesis was not proven. Median progression-free survival was 18·3 months (95% CI 11·6–25·0) in patients receiving whole brain radiotherapy, and 11·9 months (7·3–16·5; p=0·14) in those not receiving whole brain radiotherapy. Treatment-related neurotoxicity in patients with sustained complete response was more common in patients receiving whole brain radiotherapy (22/45, 49% by clinical assessment; 35/49, 71% by neuroradiology) than in those who did not (9/34, 26%; 16/35, 46%). Interpretation No significant difference in overall survival was recorded when whole brain radiotherapy was omitted from first-line chemotherapy in patients with newly diagnosed primary CNS lymphoma, but our primary hypothesis was not proven. The progression-free survival benefit afforded by whole brain radiotherapy has to be weighed against the increased risk of neurotoxicity in long-term survivors. Funding German Cancer Aid.

/pdf/high-dose-methotrexate-with-or-without-whole-brain-1oi8qk4vqq.pdf

High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial

https://thelancet.com/pdfs/journals/lanhae/PIIS2352-3026(16)00036-3.pdf

Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: results of the first randomisation of the International Extranodal Lymphoma Study Group-32 (IELSG32) phase 2 trial.

Purpose Concerns regarding neurocognitive toxicity of whole-brain radiotherapy (WBRT) have motivated development of alternative, dose-intensive chemotherapeutic strategies as consolidation in primary CNS lymphoma (PCNSL). We performed a multicenter study of high-dose consolidation, without WBRT, in PCNSL. Objectives were to determine: one, rate of complete response (CR) after remission induction therapy with methotrexate, temozolomide, and rituximab (MT-R); two, feasibility of a two-step approach using high-dose consolidation with etoposide plus cytarabine (EA); three, progression-free survival (PFS); and four, correlation between clinical and molecular prognostic factors and outcome. Patients and Methods Forty-four patients with newly diagnosed PCNSL were treated with induction MT-R, and patients who achieved CR received EA consolidation. We performed a prospective analysis of molecular prognostic biomarkers in PCNSL in the setting of a clinical trial. Results The rate of CR to MT-R was 66%. The overall 2-year PFS was 0.57, with median follow-up of 4.9 years. The 2-year time to progression was 0.59, and for patients who completed consolidation, it was 0.77. Patients age 60 years did as well as younger patients, and the most significant clinical prognostic variable was treatment delay. High BCL6 expression correlated with shorter survival. Conclusion CALGB 50202 demonstrates for the first time to our knowledge that dose-intensive consolidation for PCNSL is feasible in the multicenter setting and yields rates of PFS and OS at least comparable to those of regimens involving WBRT. On the basis of these encouraging results, an intergroup study has been activated comparing EA consolidation with myeloablative chemotherapy in this randomized trial in PCNSL, in which neither arm involves WBRT. J Clin Oncol 31:3061-3068. © 2013 by American Society of Clinical Oncology

/pdf/intensive-chemotherapy-and-immunotherapy-in-patients-with-3wgy2uswe6.pdf

Intensive Chemotherapy and Immunotherapy in Patients With Newly Diagnosed Primary CNS Lymphoma: CALGB 50202 (Alliance 50202)

Purpose A multicenter phase II study was conducted to assess the efficacy of rituximab, methotrexate, procarbazine, and vincristine (R-MPV) followed by consolidation reduced-dose whole-brain radiotherapy (rdWBRT) and cytarabine in primary CNS lymphoma. Patients and Methods Patients received induction chemotherapy with R-MPV (five to seven cycles); those achieving a complete response (CR) received rdWBRT (23.4 Gy), and otherwise, standard WBRT was offered (45 Gy). Consolidation cytarabine was given after the radiotherapy. The primary end point was 2-year progression-free survival (PFS) in patients receiving rdWBRT. Exploratory end points included prospective neuropsychological evaluation, analysis of magnetic resonance imaging (MRI) white matter changes using the Fazekas scale, and evaluation of the apparent diffusion coefficient (ADC) as a prognostic factor. Results Fifty-two patients were enrolled, with median age of 60 years (range, 30 to 79 years) and median Karnofsky performance score of 70 (range, 50...

Rituximab, Methotrexate, Procarbazine, and Vincristine Followed by Consolidation Reduced-Dose Whole-Brain Radiotherapy and Cytarabine in Newly Diagnosed Primary CNS Lymphoma: Final Results and Long-Term Outcome

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(09)61416-1.pdf

High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial.

Twenty three strains of bacteria were isolated from the hemolymph of Argopecten purpuratus.
Our results point out to the predominance of asporogenous Gram-negative rods. We suggest that the presence of these bacteria in the hemolymph is a natural phenomenon.

/pdf/bacterias-en-la-hemolinfa-de-argopecten-purpuratus-lamark-3e74z33p4s.pdf

Bacterias en la hemolinfa de Argopecten purpuratus (Lamark, 1819) (Bivalvia: Pectinidae)

https://dialnet.unirioja.es/descarga/articulo/4700186.pdf

La descripción de la traça de Juan de Arfe en la Biblioteca de la Universidad de La Laguna (Tenerife)

espanolEn la presente entrevista examinamos la teoria y praxis de la cultura digital y sus relaciones educativas con Carlos Escano. El es realizador audiovisual, doctor en Bellas Artes y profesor de Educacion Artistica Visual en la Universidad de Sevilla (Espana). Nos ocupamos de cuestiones relativas a la educacion vinculada con valores propios de la cultura libre en la Web, asi como otras que atanen a las practicas creativas bajo premisas colaborativas y hackers. EnglishIn this interview we examine the theory and praxis of digital culture and educational relation with Carlos Escano. He is a filmmaker, Ph.D. in Fine Arts and Professor of Visual Art Education in the University of Seville (Spain). We deal with issues relating to education linked with values of free culture on the Web, as well as others involving creative practices under collaborative premises and hackers.

https://dialnet.unirioja.es/descarga/articulo/5634815.pdf

Cultura libre y educación hacker: Entrevista a Carlos Escaño

Twenty three strains of bacteria were isolated from the hemolymph of Argopecten purpuratus. Our results point out to the predominance of asporogenous Gram-negative rods. We suggest that the presence of these bacteria in the hemolymph is a natural phenomenon.

Bacterias en la hemolinfa de Argopecten purpuratus (Lamark, 1819) (Bivalvia: Pectinidae) Bacteria in the hemolymph of Argopecten purpuratus (Lamark 1819) (Bivalvia: Pectinidae)

José Luis Crespo Fajardo

Papers

High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial.

Bacterias en la hemolinfa de Argopecten purpuratus (Lamark, 1819) (Bivalvia: Pectinidae)

La descripción de la traça de Juan de Arfe en la Biblioteca de la Universidad de La Laguna (Tenerife)

Cultura libre y educación hacker: Entrevista a Carlos Escaño

Bacterias en la hemolinfa de Argopecten purpuratus (Lamark, 1819) (Bivalvia: Pectinidae) Bacteria in the hemolymph of Argopecten purpuratus (Lamark 1819) (Bivalvia: Pectinidae)