Massive intrasplenic arterial thrombosis in a patient with chronic ITP during the development of an Evans syndrome.

Long-term safety and efficacy of eltrombopag in adults with persitent/chronic primary immune thrombocytopenia (ITP) evaluated in EXTEND study, showed a high response rate (80%) but, in the clinical safety study, it was observed that 6% of the patients presented venous and arterial thrombotic events. In addition, in the course of the disease, autoimmune hemolytic anemia (Evans syndrome, ES) may occur and could increase the risk of thrombosis. We report an interesting case of splenic rupture due to massive intrasplenic arterial thrombosis in the course of ES in a patient with chronic ITP treated with eltrombopag. The purpose of this case report is to highlight the potential increase in thrombotic risk that may involve the use of eltrombopag in hemolysis situations in patients with ITP.

Results of R-ESHAP as salvage therapy in refractory/relapsed follicular lymphoma: a real-world experience on behalf of GELCAB group.

There is no standard treatment for relapsed follicular lymphoma (FL). Although platinum-based combinations are one of the most used treatments, few data have been reported in this setting. Our aim was to analyse R-ESHAP efficacy in relapsed FL patients. We retrospectively analysed 80 FL patients treated with R-ESHAP in the first or successive relapses. Responding patients received a stem cell transplantation following R-ESHAP. Seventeen histologically transformed patients were included. Median age was 50 years. At R-ESHAP initiation, 85% of the patients were in an advanced stage, 28% had a bulky disease and 40% had increased LDH. There were no statistically significant differences between POD24 and non-POD24 patients in terms of response to R-ESHAP (ORR 72% vs. 93%, p = 0.109). When analyzing R-ESHAP efficacy according to the response to the immediately previous line, patients achieving CR or PR had better CR rates to R-ESHAP than those who did not respond (CR of 57% vs. 15%, respectively, p = 0.009), as well as differences in OS (7.2 vs. 1.4 years, p < 0.0001) and in PFS (2.1 vs. 0.3 years, p < 0.0001). R-ESHAP is an effective treatment in relapsed FL patients who respond to the previous line and has to be considered as an adequate alternative for some patients.

Brentuximab vedotin and ESHAP is highly effective as second-line therapy for Hodgkin lymphoma patients (long-term results of a trial by the Spanish GELTAMO Group).

BACKGROUND: In this work, we assessed the efficacy and safety of brentuximab vedotin (BV) plus ESHAP (BRESHAP) as second-line therapy for Relapsed/Refractory Hodgkin lymphoma (RRHL) to improve the results before autologous stem-cell transplantation (ASCT). PATIENTS AND METHODS: This was a multicenter, open-label, phase I-II trial of patients with RRHL after first-line chemotherapy. Treatment had three 21-day cycles of etoposide, solumedrol, high-dose AraC, and cisplatin. BV was administered at three dose levels (0.9, 1.2, and 1.8 mg/kg) intravenous on day ‒1 to 3 + 3 cohorts of patients. Final BV dose was 1.8 mg/kg. Responding patients proceeded to ASCT, followed by three BV courses (1.8 mg/kg, every 21 days). Main end points for evaluation were maximum tolerable dose and overall and complete response (CR) before ASCT. RESULTS: A total of 66 patients were recruited (median age 36 years; range 18-66): 40 were primary refractory, 16 early relapse and 10 late relapse. There were 39 severe adverse events were reported in 22 patients, most frequently fever (n = 25, 35% neutropenic), including 3 deaths. Grade 3-4 hematological toxicity presented in 28 cases: neutropenia (n = 21), thrombocytopenia (n = 14), and anemia (n = 7). Grade ≥3-4 extrahematological adverse events (≥5%) were non-neutropenic fever (n = 13) and hypomagnesaemia (n = 3). Sixty-four patients underwent stem-cell mobilization; all collected >2×10e6/kg CD34+ cells (median 5.75; range 2.12-33.4). Overall response before transplant was 91% (CI 84% to 98%), including 70% (CRs 95% CI 59% to 81%). 60 patients were transplanted with no failure engraftments. Post-transplant response was CR in 49 patients (82% CI 73% to 91%) and partial responses in six (10% CI 5% to 15%). After a mean follow-up of 27 months, the 30-month time to treatment to failure was 74% (95% CI 68% to 80%), progression-free survival 71% (95% CI 65% to 77%), and overall survival 91% (CI 84% to 98%). CONCLUSION: BRESHAP looks a safe and effective pre-transplant induction regimen, does not jeopardize transplant and allows long-term remissions and survival.

The landscape of fear: Why some free-ranging rodents choose repeated live-trapping over predation risk and how it is associated with the physiological stress response.

Live trapping is an essential element of field ecological studies. However, the act of trapping provides two types of conditional benefits (food from the bait when hungry, and refuge from a predator when threatened) against one type of drawback (confinement). Our understanding of how animals assess the two benefits against the lone risk determines how we interpret classic field studies in chemical ecology and wildlife management. Here, we studied wood mice responses to these risks and rewards of field trapping by examining experience through recapture and faecal corticosterone metabolites (FCM) as a physiological response indicator. Wood mice were live-trapped in two different plots subjected to two distinct phases: phase 1, absence of predator cues, and phase 2, in which traps were treated with red fox faeces. During phase 1, the recapture percentage was lower indicating that mice avoided traps while FCM levels in recaptured mice were higher. On the contrary, during phase 2, despite the total number of captures was lower we found an increase in the recapture percentage and FCM levels did not increase in recaptured mice. Our results suggest that under increased risk perception traps could be likely considered as a suitable shelter and thus, for some individuals the benefits of traps may outweigh their risks. In addition, we discovered that the effects of combining two stressors do not result in the addition of the response originated by each factor separately.

Posttransplant monomorphic Burkitt's lymphoma: clinical characteristics and outcome of a multicenter series.

Burkitt's monomorphic posttransplant lymphoproliferative disorder (B-PTLD) is an uncommon subtype of PTLD. Owing to the paucity of this complication, clinical characteristics and outcome has not been fully described. Clinical characteristics and outcomes of 20 patients diagnosed with B-PTLD from 10 transplant centers belonging to the GEL/TAMO group were reviewed. Median time from transplant to B-PTLD was 7.2 years. All the cases fulfill the morphologic and genetic criteria of B-PTLD, whereas Epstein-Barr virus (EBV) was detected in 70% of cases. Patients were treated with different chemotherapy combinations, and three patients received upfront rituximab monotherapy. The great majority of patients receiving CHOP-like regimens attained a complete response (CR) (73%), similar to that obtained with dose-intensive chemotherapy (83% CR). In contrast, patients receiving upfront rituximab monotherapy required subsequent chemotherapy. Two patients (10%) died during treatment due to infection. The median progression-free survival and overall survival (OS) were 16 months and 139 months, respectively. When analyzing variables predicting for OS, we found that patients with bone marrow involvement had an adverse prognosis, with a median OS of 6 months (p = 0.008). In conclusion, B-PTLD is an uncommon complication usually associated with EBV infection and with an aggressive clinical course, particularly in patients with bone marrow involvement. High-dose chemoimmunotherapy obtained similar responses to R-CHOP, suggesting that R-CHOP could be an adequate alternative for these patients. In contrast, rituximab monotherapy does not seem to be effective enough to control the disease.

Real-life management of primary immune thrombocytopenia (ITP) in adult patients and adherence to practice guidelines.

Very few data exist on the management of adult patients diagnosed with primary immune thrombocytopenia (ITP). The objectives of this study were to describe the diagnostic and treatment patterns for ITP and to compare the findings to recent ITP guidelines. We retrospectively analyzed the medical records of adult ITP patients diagnosed with primary ITP between January 2011 and June 2012 and examined whether management strategies were consistent or not with eight recent guideline-recommended practices. Overall, median age at the diagnosis of the disease (n = 101) was 58 years and median platelet count 12 × 10(9)/L with 75.2 % of patients having symptoms of ITP. The study perceived two major shortcomings in the diagnostic approach: (1) failure to perform peripheral blood film examination in 22.8 % of patients, a test that is mandatory by all guidelines, and (2) ordinary bone marrow assessment in more than half of the patients at diagnosis (50.5 %), a test not routinely recommended by guidelines. Low appropriateness in therapeutic management of patients included (1) unjustified use of intravenous immunoglobulin in the absence of bleeding in 54.8 % of patients and (2) splenectomy not being deferred until 6-12 months from diagnosis (median 161 days). Data also reflect a trend towards the early use of thrombopoietin receptor agonists in the treatment of patients who are refractory to any first-line therapy. We have recognized important areas of inapropriateness in the diagnostic and therapeutic management of adult ITP patients. Compliance with established guidelines should be encouraged in order to improve patient outcomes.

Bendamustine as salvage treatment for patients with relapsed or refractory mantle cell lymphoma patients: a retrospective study of the Spanish experience.

Patients with mantle cell lymphoma (MCL) have an adverse outcome after relapse. Bendamustine has demonstrated a good efficacy and toxicity profile in previously reported trials. In this study, we present a retrospective analysis of the Spanish experience in relapsed/refractory MCL treated with bendamustine in combination or alone with the objective of knowing the efficacy and toxicity profile of this treatment in our current clinical practice. Fifty eight patients were registered: 67 % male with median age of 71 years, and 2 is the median number of previous lines. The most frequent bendamustine regimen was bendamustine plus rituximab (83 %). The median number of cycles was 5 (range 1-8). The overall response rate was 84 % with 53 % of complete response/unconfirmed complete response (CR/uCR). Median progression-free survival (PFS) was 16 months (95 % confidence interval (CI) 13.3-18.8), and for patients who achieved CR/uCR, it was 33 months (95 % CI 11.1-54.2). Median overall survival (OS) was 30 months (95 % CI 25.6-34.9). For PFS, only blastoid histology and not achieving CR after bendamustine had a significant negative impact on the univariate and multivariate analyses (p < 0.05). Nevertheless, for OS, only an elevated lactate dehydrogenase (LDH) had negative impact on both, univariate and multivariate analyses (p < 0.05). Only one case of treatment-related mortality in a 79-year-old patient with very bad performance status was reported. In 280 cycles, 12 (4 %) hospitalizations for febrile neutropenia were reported. In our population, bendamustine has been a good salvage treatment with a favorable toxicity profile in a non selected and heavily pretreated population of patients with MCL.

Primary lymphoma of the colon.

BACKGROUND: primary colorectal lymphoma is a very rare disease, representing less than 0.5 % of all primary colorectal neoplasms. The gastrointestinal tract is the most frequently involved site of all extranodal lymphomas, the most common type of that is non-Hodgkin s lymphoma. Early diagnosis is often difficult because of unspecific symptoms. Therapeutic approaches have classically included radical resection, chemotherapy and radiotherapy. MATERIALS AND METHODS: we present our experience in the management of primary colorectal lymphomas over a 17-year period (1994-20011). RESULTS: in this period 7 cases of primary colorectal lymphoma were diagnosed in our institution. Abdominal pain and change in bowel habit were the most frequent symptoms. Five patients underwent emergency surgery because of bleeding or bowel obstruction. All primary intestinal lymphomas studied were of the Bcell phenotype. Patients were followed up for a median of 59 months (range 1-180). Three of them are alive with no evidence of recurrence. CONCLUSION: combination treatment with chemotherapy and surgery can obtain good remission rate. Surgery can resolve complications such bleeding or intestinal perforation that are implicated in lymphoma mortality.

Aberrant DNA methylation of the Src kinase Hck, but not of Lyn, in Philadelphia chromosome negative acute lymphocytic leukemia.

Hck and Lyn are required in Philadelphia chromosome (Ph) positive acute lymphocytic leukemia (ALL). Here, we present evidence that the promoter CpG island of Hck, but not of Lyn, is aberrantly methylated in leukemia. Hck promoter DNA methylation was detected in 13 out of 23 (56.5%) hematopoietic and eight out of 10 (80%) non-hematopoietic cell lines, but not in normal controls. Treatment with 5-aza-2'-deoxycytidine induced demethylation and restoration of Hck mRNA and protein expression. Hck methylation (> or =15%) was detected in nine out of 44 (20%) patients with Ph negative ALL, and in one out 16 (6%) patients with Ph positive ALL, but not in patients with AML or chronic myelogenous leukemia. In this subset of patients, low levels of Hck methylation (10-15%) were observed in 26-30% of patients. Lyn methylation was observed in three out of 28 (10.7%) cell lines, but only in one out of 71 (1.4%) patients. Patients with Ph negative ALL and Hck methylation had a poorer prognosis. These data indicate that Hck may have tumor suppressor properties in BCR-ABL negative leukemia.

Differential tumor suppressor properties and transforming growth factor-beta responsiveness of p57KIP2 in leukemia cells with aberrant p57KIP2 promoter DNA methylation.

To investigate if the tumor suppressor properties of p57KIP2 are dependent on its DNA methylation status, we studied the impact of several stress stimuli in leukemic cell lines with different p57KIP2 promoter DNA methylation levels. p57KIP2 reactivation was observed after stimulation with transforming growth factor-beta, other cytokines, high-density culture or serum withdrawal in p57KIP2 promoter unmethylated cells but not in methylated cells. In these cells, p57KIP2 reactivation required the use of a hypomethylating agent or a histone deacetylase inhibitor. Overexpression of p57KIP2 in p57KIP2 promoter methylated leukemic cell lines resulted in cell growth arrest and the induction of apoptosis. In contrast, overexpression of p57KIP2 in partially methylated cells only resulted in a moderate inhibition of cell growth and had no impact on apoptosis. Transduction of unmethylated cells expressing high levels of p57KIP2 with p57KIP2 short hairpin RNA resulted in increased cell proliferation. These results suggest that the tumor suppressive properties of p57KIP2 in leukemia may depend on the intrinsic promoter DNA methylation status of the gene.