Life expectancy of follicular lymphoma patients in complete response at 30 months is similar to that of the Spanish general population.

The use of immunochemotherapy has improved the outcome of follicular lymphoma (FL). Recently, complete response at 30 months (CR30) has been suggested as a surrogate for progression-free survival. This study aimed to analyse the life expectancy of FL patients according to their status at 30 months from the start of treatment in comparison with the sex and age-matched Spanish general population (relative survival; RS). The training series comprised 263 patients consecutively diagnosed with FL in a 10-year period who needed therapy and were treated with rituximab-containing regimens. An independent cohort of 693 FL patients from the Grupo Español de Linfomas y Trasplante Autólogo de Médula Ósea (GELTAMO) group was used for validation. In the training cohort, 188 patients were in CR30, with a 10-year overall survival (OS) of 53% and 87% for non-CR30 and CR30 patients, respectively. Ten-year RS was 73% and 100%, showing no decrease in life expectancy for CR30 patients. Multivariate analysis indicated that the FL International Prognostic Index was the most important variable predicting OS in the CR30 group. The impact of CR30 status on RS was validated in the independent GELTAMO series. In conclusion, FL patients treated with immunochemotherapy who were in CR at 30 months showed similar survival to a sex- and age-matched Spanish general population.

Bendamustine as part of conditioning of autologous stem cell transplantation in patients with aggressive lymphoma: a phase 2 study from the GELTAMO group.

We conducted a phase 2 trial to evaluate the safety and efficacy of bendamustine instead of BCNU (carmustine) in the BEAM (BCNU, etoposide, cytarabine and melphalan) regimen (BendaEAM) as conditioning for autologous stem-cell transplantation (ASCT) in patients with aggressive lymphomas. The primary endpoint was 3-year progression-free survival (PFS). Sixty patients (median age 55 [28-71] years) were included. All patients (except one who died early) engrafted after a median of 11 (9-72) and 14 (4-53) days to achieve neutrophil and platelet counts of >0.5 × 109 /l and >20 × 109 /l, respectively. Non-relapse mortality at 100 days and 1 year were 3.3% and 6.7%, respectively. With a median follow-up of 67 (40-77) months, the estimated 3-year PFS and overall survival (OS) were 58% and 75%, respectively. Patients in partial response at study entry had significantly worse PFS and OS than patients who underwent ASCT in complete metabolic remission, and this was the only prognostic factor associated with both PFS (Relative risk [RR], 0.27 [95% confidence interval {CI} [0.12-0.56]) and OS (RR, 0.40 [95% CI 0.17-0.97]) in the multivariate analysis. BendaEAM conditioning is therefore a feasible and effective regimen in patients with aggressive lymphomas. However, patients not in complete metabolic remission at the time of transplant had poorer survival and so should be considered for alternative treatment strategies.

Risk of, and survival following, histological transformation in follicular lymphoma in the rituximab era. A retrospective multicentre study by the Spanish GELTAMO group.

The diagnostic criteria for follicular lymphoma (FL) transformation vary among the largest series, which commonly exclude histologically-documented transformation (HT) mandatorily. The aims of this retrospective observational multicentre study by the Spanish Grupo Español de Linfoma y Transplante Autólogo de Médula Ósea, which recruited 1734 patients (800 males/934 females; median age 59 years), diagnosed with FL grades 1-3A, were, (i) the cumulative incidence of HT (CI-HT); (ii) risk factors associated with HT; and (iii) the role of treatment and response on survival following transformation (SFT). With a median follow-up of 6·2 years, 106 patients developed HT. Ten-year CI-HT was 8%. Considering these 106 patients who developed HT, median time to transformation was 2·5 years. High-risk FL International Prognostic Index [Hazard ratio (HR) 2·6, 95% confidence interval (CI): 1·5-4·5] and non-response to first-line therapy (HR 2·9, 95% CI: 1·3-6·8) were associated with HT. Seventy out of the 106 patients died (5-year SFT, 26%). Response to HT first-line therapy (HR 5·3, 95% CI: 2·4-12·0), autologous stem cell transplantation (HR 3·9, 95% CI: 1·5-10·1), and revised International Prognostic Index (HR 2·2, 95% CI: 1·1-4·2) were significantly associated with SFT. Response to treatment and HT were the variables most significantly associated with survival in the rituximab era. Better therapies are needed to improve response. Inclusion of HT in clinical trials with new agents is mandatory.

Long-Term Follow-Up of a Phase II Trial of Six Cycles of Dose-Dense R-CHOP-14 for First-Line Treatment of Diffuse Large B-Cell Lymphoma in Young and Elderly Patients.

BACKGROUND/AIMS: Rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) every 14 days seems to achieve better outcomes than R-CHOP every 21 days in diffuse large B-cell lymphoma (DLBCL) patients. Currently, the standard regimen is R-CHOP every 21 days. METHODS: This is a phase II clinical trial of treatment with 6 cycles of R-CHOP-14 with pegfilgrastim support in 2 populations of previously untreated DLBCL patients aged ≥65 years (n = 73) or <65 years (n = 51) with low-risk International Prognostic Index scores (0-2). RESULTS: With a median follow-up of 63.7 months, the 5-year event-free survival rate was 53.8% in patients aged ≥65 years and 71.0% in patients aged <65 years. The 5-year overall survival rate was 71.4 and 89.8%, respectively. The complete remission rate was 69.9% for older and 80.4% for younger patients. The median relative dose intensity of cytotoxic drugs was 143.2% in the elderly and 149.1% in the young patients. Febrile neutropenia was the most common grade 3-4 adverse event, being higher in elderly patients (21.3 vs. 9.3%). Eight deaths (7 in elderly patients) were considered treatment related. CONCLUSION: In conclusion, the R-CHOP-14 regimen is feasible and very active, though it is more toxic in elderly patients mainly due to an increased incidence of infections. New strategies, such as new monoclonal antibodies or new targeted therapies, are needed to improve the outcomes of DLBCL patients.

Predictive value of interim ¹8F-FDG-PET/CT for event-free survival in patients with diffuse large B-cell lymphoma homogenously treated in a phase II trial with six cycles of R-CHOP-14 plus pegfilgrastim as first-line treatment.

OBJECTIVE: The predictive value of interim PET/computed tomography (I-PET/CT) in diffuse large B-cell lymphoma (DLBCL) is controversial. Our aim was to evaluate the predictive value of I-PET/CT for an event-free survival. PATIENTS AND METHODS: We analyzed patients with DLBCL included in a prospective clinical trial who were treated with six cycles of dose-dense R-CHOP followed by pegfilgrastim and who had undergone an I-PET/CT (after two cycles) and a final PET [F-PET/CT (60 days after the sixth cycle)]. Event was defined as nonresponse, relapse, or death. RESULTS: A total of 69 patients were included. Their median age was 60 years; 54% were male, 25% had bulky disease, and 67% had an International Prognostic Index of 0-2. The median follow-up duration was 28.8 months. I-PET/CT was positive in 34 (49%) patients and F-PET/CT was positive in 12 (17.4%). The 3-year event-free survival was 86% for patients who were I-PET/CT negative as against 64% for those who were I-PET/CT positive (P=0.036). The negative and positive predictive values, sensitivity, and specificity of I-PET/CT for an event were 83, 32, 65, and 56%, respectively. In a multivariate analysis including baseline characteristics, I-PET/CT, and F-PET/CT, F-PET/CT was the only significant predictor (P<0.0005). CONCLUSION: In patients with DLBCL treated with dose-dense R-CHOP plus pegfilgrastim, a negative I-PET/CT is highly predictive of a favorable outcome and a positive I-PET/CT is of limited clinical value. These results do not support treatment intensification after a short course of chemotherapy based solely on a positive I-PET/CT.

Risk stratification for Splenic Marginal Zone Lymphoma based on haemoglobin concentration, platelet count, high lactate dehydrogenase level and extrahilar lymphadenopathy: development and validation on 593 cases.

This international retrospective study of 593 Splenic Marginal Zone Lymphoma (SMZL) patients aimed to identify factors that determine treatment initiation and influence lymphoma-specific survival (LSS). Logistic regression was used to identify the factors associated with treatment. A Cox regression was used to analyse LSS in a derivation cohort of 366 patients. This produced a prognostic index (PI) and enabled the identification of three risk groups. The resulting stratification was validated in another cohort of 227 patients and compared with the Interguppo Italiano Linfomi (IIL) score in the group of 450 patients for whom all the required data were available using an extension of the net reclassification improvement. Haemoglobin concentration (Hb), extrahilar lymphadenopathy and hepatitis C virus status were associated with the initiation of treatment. Hb, platelet count, high lactate dehydrogenase level and extrahilar lymphadenopathy were independently associated with LSS. Three risk groups with significantly different five-year LSS (94%, 78% and 69%, respectively) were identified. This stratification (named HPLL on the basis of determinant factors) had a better discriminative power than the IIL score. This system is useful for stratifying SMZL patients into risk groups and may help in the selection of risk-tailored treatment approaches.

Influence of biologic markers on the outcome of Hodgkin's lymphoma: a study by the Spanish Hodgkin's Lymphoma Study Group.

PURPOSE: Current therapies fail to cure a significant proportion of patients with Hodgkin's lymphoma (HL). Predictive systems for stratification of the disease and selection of treatment based on sets of clinical variables, such as the international prognostic score (IPS), are of relatively small practical value. The predictive use of biologic parameters has so far provided limited and inconsistent results. Here we explore the influence of a set of molecular markers on the outcome of HL. PATIENTS AND METHODS: Forty molecular markers involved in B-cell differentiation and activation, signal transduction, cell cycle, and apoptosis control were analyzed in 259 classic HL patient cases by using tissue microarrays. Univariate analysis was performed to evaluate the influence of markers on favorable outcome (complete remission of > 12 months). Significant variables were included in a multivariate logistic regression analysis, and the probability of favorable outcome was estimated. RESULTS: Univariate analysis revealed four molecular markers that predicted outcome, and the multivariate analysis showed p53, Bcl-X(L), and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling (TUNEL) to have independent significance. The combination of these factors determined two groups of patients (group I, zero to one factor; group II, two to three factors) with a probability of a favorable outcome of.948 and.687, respectively. A multivariate Cox's model shows that these biologic risk groups have special predictive power in low-IPS patients. CONCLUSION: The data from this exploratory study suggest that the accumulation of molecular events seems to influence the outcome of HL, particularly in the low-IPS group.

Activation of human somatostatin receptor 2 promotes apoptosis through a mechanism that is independent from induction of p53.

The ability of both somatostatin (SS) and its stable analogues to inhibit cell growth depends on the stimulation of specific membrane receptors (SSTR1-5), which belong to the G protein-coupled receptor family. Accumulating evidence suggests that the SSTR2 plays a major role in mediating cell cycle arrest, and it is also clear that SHP-1, a cytoplasmic phosphotyrosine phosphatase (PTP), is an essential component of the SSTR2-mediated cytostatic effect. In contrast, the possibility that SSTR2 activation may also lead to increased apoptosis is still beyond debate, despite SHP-1 activation is also able to promote cell death in several cell types. In the present work we have investigated the ability of SSTR2 to induce apoptosis in HL-60 cells. We have found that HL-60 cells uniquely express the SSTR2 subtype, and that stimulation of SSTR2 with the SS analogue SMS 201-995 results in an increased cell death. In all, these findings demonstrate that activation of SSTR2 promotes apoptosis in HL-60 cells. Moreover, in contrast with the proapoptotic mechanism previously reported for SSTR3, cell death induced by activation of SSTR2 is independent from accumulation of p53.

Actividad antitumoral en tumores experimentales: purificación y caracterización parcial de biopolímeros extraídos de fermentados de bacterias marinas / Antitumor activity in experimental tumors, purification and production of biopolymers from marine bacteria strains

Se reporta la separación, caracterización química parcial y actividad antitumoral de dos biopolímeros producidos por cepas de bacterias marinas en un medio a base de glucosa y agua de mar estéril. Los productos 21NM142a y 21NM156 se separaron del sobrenadante del cultivo de las bacterias Micrococcus sp. y Pseudomona sp. Estos compuestos están constituidos por proteínas y carbohidratos, según fue determinado utilizando los métodos de Loubry (método de Dubois), así como Análisis de aminoácidos y cromatografía gas líquido. Los compuestos fueron homogéneos por cromatografía de filtración con gel, resultando 20 kDa como peso molecular aparente. La caracterización parcial hace pensar en la naturaleza glicoproteica de estos compuestos. El biopolímero 21NM142a aumenta el tiempo de supervivencia en ratones inoculados con células tumorales de Sarcoma 180 y Sarcoma 37.

Toxicidad aguda y a dosis repetidas de Bromelina obtenida de tallos de piña (Ananas comosus (L.) Merr.)

La Bromelina (EC3.4.22.32) es una enzima proteolítica aislada y purificada a partir de diferentes órganos dela piña (Ananas Comosus) (L) Merr; tiene múltiples usos en la industria biotecnológoca alimentaria y en el campo de la medicina se destaca por su uso como antinflamatorio, anticuagulante y antitumoral. Con el fin de evaluar las potencialidades terapéuticas de la enzima, obtenida mediante una tecnología cubana (patente C12N 9\50) se concibió el presente trabajo, donde se presenta la evaluación toxicológica. La administración a dosis única no reveló alteracioneshistopatológicas en los órganos de ningún animal, siendo la DL50 de 216.35 mg\Kg, mientras que a dosis repetidas, provocó degeneraciones hidrópicas, turbias y microhemorragias, principalmente en un pulmón, corazó, riñón, bazo e higado y no mostró citotoxicidad para leococitos, sino que produjo un incremento de los mismos, fundamentalemnte de linfocitos; la DL 50 fue 105.91 mg\Kg (AU)

Sinergismo del Cis-Diaminodicloro Platino (II) (CIS-DDP) y el M-Tiocarbamal en el tratamiento de la leucemia L-1210 / Synergism of Cis-Platinum Diamminodichloride (II) (CIS-DDP) and M-Thiocarbamol in the treatment of leukemia L-1210

El M-tiocarbamal (morfolinditiocarbamato de sodio) es un producto sintético con el cual en estos momentos se lleva a cabo el ensayo clínico fase I. Experimentalmente se combinó con el Cis-DDP en el tratamiento de la leucemia L-1210. Los resultados obtenidos evidencian la potenciación de la acción antitumoral del Cis-DDP cuando el M-tiocarbamal se administra simultáneo o después de la administración del citostático

Empleo de la quimioterapia experimental en la caracterización biológica de un carcinoma epidermoide / Use of experimental chemotherapy in the biological characterization of an epidermoid carcinoma

Con el objetivo de identificar la respuesta de un carcinoma epidermoide, quimioinducido en el labio de ratones IBF1 (IOR/Hab x C57BL/6 Hab) mediante aplicaciones tópicas de un condensado de humo de cigarros, ante la quimioterapi oncológica, se les trasplantó dicho tumor a 52 hembras de 4 a 6 semanas de vida y de 20 a 22 gramos de peso corporal. Las drogas empleadas fueron ciclofosfamida (25 mg/kg; metotrexate (1 mg/kg); bleomicin (2 mg/kg); cisdíamino dicloro platino II (1 mg/kg); administradas por vía intraperitoneal durante 5 días consecutivos una vez transcurridas 48 horas del trasplante. La evaluación antineoplásica se realizó sobre la base de la supervivencia y por las medidas del volumen tumoral durante la evaluación del experimento una vez concluidos los tratamiento antitumorales. Entre los 7 y 12 primeros días de evolución después de concluido el ciclo de tratamiento de los diferentes citostáticos el crecimiento volumétrico resultó lento en relación con los controles, y no rebasó en este periódo 0,7 cm3

Efectos del coralan sobre la mucosa gástrica y su relación con la actividad antinflamatoria / Effects of coralan on gastric mucosa and its relation to antiinflamatory activity

El coralán es unpreparado obtenido a partir de una glicoproteina proveniente de un coral blando que presenta cierto efecto inmunomodulador y notable actividad antiinflamatoria experimental, lo que prevé su posible uso en la terapéutica oncológica. Se conocen los efectos adversos de algunos agentes antiinflamatorios sobre la mucosa gástrica. Se demostró que este producto tiene muy baja actividad ulcerogénica, que potencializa la irritabilidad gástrica debida a otros agentes y que su actividad antiinflamatoria se verifica por mecanismos no relacionados con la actividad ulcerogénica

Efecto de la degradación molecular por métodos físicos (sonicador) de la molécula de coralan sobre su actividad inmunomoduladora in vitro / Effect of molecular desintegration by physical methods (sonicator) of coralan molecula on its immunomodulator activity in vitro

El coralán es un polisacárido obtenido de coral, que ha demostrado poseer actividad inmunomoduladora. Esta molécula tiene un peso molecular muy elevado por lo que es dificil su esterilización. Se sometieron soluciones acuosas de esta molécula o desagregación molecular en un sonicador, y se comprobó que mantenía su actividad biológica in vitro

Efecto de la desagregación molecular por métodos físicos (politrón) de la molécula de coralan sobre su actividad inmunomoduladora in vitro / Effects of molecular disintegration by physical methods (politron) of coralan molecule on its immunomodulator activity in vitro

Elcoralan es un polisácarido que ha demostrado inducir en los ratones una alta capacidad de rechazo al trasplante de células del tumor ascítico de Ehrlich. Este producto provoca además un aumento significativo en la proliferación de linfocitos humanos como respuesta a la fitohemaglutinina (PHA). Este producto es de dificil esterilización por lo que se han buscado métodos para desagregar la molécula (Politrón) sin que pierda su actividad biológica

Efecto de la desagregación molecular por métodos físicos (politrón) de la molécula de coralan sobre su actividad inmunomoduladora in vitro / Effects of molecular disintegration by physical methods (politron) of coralan molecule on its immunomodulator activity in vitro

Elcoralan es un polisácarido que ha demostrado inducir en los ratones una alta capacidad de rechazo al trasplante de células del tumor ascítico de Ehrlich. Este producto provoca además un aumento significativo en la proliferación de linfocitos humanos como respuesta a la fitohemaglutinina (PHA). Este producto es de dificil esterilización por lo que se han buscado métodos para desagregar la molécula (Politrón) sin que pierda su actividad biológica

Efecto de la degradación molecular por métodos físicos (sonicador) de la molécula de coralan sobre su actividad inmunomoduladora in vitro / Effect of molecular desintegration by physical methods (sonicator) of coralan molecula on its immunomodulator activity in vitro

El coralán es un polisacárido obtenido de coral, que ha demostrado poseer actividad inmunomoduladora. Esta molécula tiene un peso molecular muy elevado por lo que es dificil su esterilización. Se sometieron soluciones acuosas de esta molécula o desagregación molecular en un sonicador, y se comprobó que mantenía su actividad biológica in vitro

Efectos del coralan sobre la mucosa gástrica y su relación con la actividad antinflamatoria / Effects of coralan on gastric mucosa and its relation to antiinflamatory activity

El coralán es unpreparado obtenido a partir de una glicoproteina proveniente de un coral blando que presenta cierto efecto inmunomodulador y notable actividad antiinflamatoria experimental, lo que prevé su posible uso en la terapéutica oncológica. Se conocen los efectos adversos de algunos agentes antiinflamatorios sobre la mucosa gástrica. Se demostró que este producto tiene muy baja actividad ulcerogénica, que potencializa la irritabilidad gástrica debida a otros agentes y que su actividad antiinflamatoria se verifica por mecanismos no relacionados con la actividad ulcerogénica

Empleo de la quimioterapia experimental en la caracterización biológica de un carcinoma epidermoide / Use of experimental chemotherapy in the biological characterization of an epidermoid carcinoma

Con el objetivo de identificar la respuesta de un carcinoma epidermoide, quimioinducido en el labio de ratones IBF1 (IOR/Hab x C57BL/6 Hab) mediante aplicaciones tópicas de un condensado de humo de cigarros, ante la quimioterapi oncológica, se les trasplantó dicho tumor a 52 hembras de 4 a 6 semanas de vida y de 20 a 22 gramos de peso corporal. Las drogas empleadas fueron ciclofosfamida (25 mg/kg; metotrexate (1 mg/kg); bleomicin (2 mg/kg); cisdíamino dicloro platino II (1 mg/kg); administradas por vía intraperitoneal durante 5 días consecutivos una vez transcurridas 48 horas del trasplante. La evaluación antineoplásica se realizó sobre la base de la supervivencia y por las medidas del volumen tumoral durante la evaluación del experimento una vez concluidos los tratamiento antitumorales. Entre los 7 y 12 primeros días de evolución después de concluido el ciclo de tratamiento de los diferentes citostáticos el crecimiento volumétrico resultó lento en relación con los controles, y no rebasó en este periódo 0,7 cm3

Sinergismo del Cis-Diaminodicloro Platino (II) (CIS-DDP) y el M-Tiocarbamal en el tratamiento de la leucemia L-1210 / Synergism of Cis-Platinum Diamminodichloride (II) (CIS-DDP) and M-Thiocarbamol in the treatment of leukemia L-1210

El M-tiocarbamal (morfolinditiocarbamato de sodio) es un producto sintético con el cual en estos momentos se lleva a cabo el ensayo clínico fase I. Experimentalmente se combinó con el Cis-DDP en el tratamiento de la leucemia L-1210. Los resultados obtenidos evidencian la potenciación de la acción antitumoral del Cis-DDP cuando el M-tiocarbamal se administra simultáneo o después de la administración del citostático