Ibrutinib in Combination With Rituximab for Indolent Clinical Forms of Mantle Cell Lymphoma (IMCL-2015): A Multicenter, Open-Label, Single-Arm, Phase II Trial.

PURPOSE: The need for an individualized management of indolent clinical forms in mantle cell lymphoma (MCL) is increasingly recognized. We hypothesized that a tailored treatment with ibrutinib in combination with rituximab (IR) could obtain significant responses in these patients. METHODS: This is a multicenter single-arm, open-label, phase II study with a two-stage design conducted in 12 Spanish GELTAMO sites (ClinicalTrials.gov identifier: NCT02682641). Previously untreated MCL patients with indolent clinical forms defined by the following criteria were eligible: no disease-related symptoms, nonblastoid variants, Ki-67 < 30%, and largest tumor diameter ≤ 3 cm. Both leukemic non-nodal and nodal subtypes were recruited. Patients received ibrutinib 560 mg once daily and a total of eight doses of rituximab 375 mg/m2. Ibrutinib could be discontinued after 2 years in the case of sustained undetectable minimal residual disease (MRD). The primary end point was the complete response (CR) rate achieved after 12 cycles according to Lugano criteria. RESULTS: Fifty patients with MCL (male 66%; median age 65 years) were enrolled. After 12 cycles of treatment, 42 (84%; 95% CI, 74 to 94) patients had an overall response, including 40 (80%; 95% CI, 69 to 91) with CR. Moreover, undetectable MRD in peripheral blood was achieved in 87% (95% CI, 77 to 97) of cases. At 2 years, 24 of 35 evaluable patients (69%) could discontinue ibrutinib because of undetectable MRD. Four patients had disease progression; three were non-nodal MCL and carried high genomic complexity and TP53 mutations at enrollment. No unexpected toxicity was seen except one patient with severe aplastic anemia. CONCLUSION: Frontline IR combination achieves a high rate of CRs and undetectable MRD in indolent clinical forms of MCL. Discontinuation seems appropriate in cases with undetectable MRD, except for TP53-mutated cases.

Effect of Prior Therapy and Disease Refractoriness on the Efficacy and Safety of Oral Selinexor in Patients with Diffuse Large B-cell Lymphoma (DLBCL): A Post-hoc Analysis of the SADAL Study.

BACKGROUND: Despite a number of treatment options, patients with diffuse large B-cell lymphoma (DLBCL) whose disease has become refractory to treatment have a poor prognosis. Selinexor is a novel, oral drug that is approved to treat patients with relapsed/refractory DLBCL. In this post hoc analysis of the SADAL study, a multinational, open-label study, we evaluated subpopulations to determine if response to single agent selinexor is impacted by number of lines of prior treatment, autologous stem cell transplant (ASCT), response to first and most recent therapies, and time to progressive disease. PATIENTS: Patients (n = 134) with DLBCL after 2-5 prior therapies were enrolled in SADAL and received 60mg selinexor twice weekly. RESULTS: The median overall survival was 9.0 months and median progression free survival was 2.6 months. Patients who had the best overall response rate (ORR) and disease control rate were those who had prior ASCT (42.5% and 50.0%) or responded to last line of therapy (35.9% and 43.5%). Patients with primary refractory DLBCL also showed responses (ORR 21.8%). Adverse events between subgroups were similar to the overall study population, the most common being thrombocytopenia (29.1%), fatigue (7.5%), and nausea (6.0%). CONCLUSION: Regardless of prior therapy and disease refractory status, selinexor treatment demonstrated results consistent with its novel mechanism of action and lack of cross-resistance. Thus, single agent oral selinexor can induce deep, durable, and tolerable responses in patients with DLBCL who have recurrent disease after several chemoimmunotherapy combination regimens.

Tartrazina induce genotoxicidad en linfocitos de BALB/c Mus musculus / Tartrazine induces genotoxicity in BALB/c Mus musculus lymphocytes

RESUMEN Objetivos. Determinar el efecto genotóxico de la tartrazina en linfocitos de sangre periférica de Mus musculus BALB/c. Materiales y métodos. Se realizó un estudio experimental, a través de cinco grupos, con cinco ratones en cada uno. Se les registró el peso durante 17 semanas y, en la semana 15 se les administró suero fisiológico (control negativo), dicromato de potasio 25 mg/kg de peso corporal (pc) (control positivo) y tartrazina a dosis de 0,75 mg/kg pc, 7,5 mg/kg pc y 75 mg/kg pc, durante siete días, a excepción del control positivo que fue en dosis única. Luego, cada 24 h se obtuvo una muestra de sangre periférica de la cola y se realizó el frotis, secado y coloración. Posteriormente, se realizó el conteo de 1000 linfocitos por muestra de cada ratón, en todos los tratamientos. Resultados. Los tres tratamientos con tartrazina no causaron diferencias significativas en el peso de ratones a la semana 15, pero sí produjeron diferencias significativas en la frecuencia de linfocitos micronucleados, siendo el tratamiento con tartrazina de 75 mg/kg pc el de mayor efecto genotóxico, induciendo un promedio de 1,63 ± 0,08 linfocitos micronucleados, comparado con el control positivo que generó un promedio de 1,42 ± 0,08 linfocitos micronucleados. Conclusiones. La tartrazina produjo un efecto genotóxico, incrementando el número de linfocitos micronucleados, a dosis de 0,75; 7,5 y 75 mg/kg pc y no afecta el peso corporal durante siete días de administración en M. musculus BALB/c.

ABSTRACT Objectives. To determine the genotoxic effect of tartrazine on peripheral blood lymphocytes of BALB/c Mus musculus. Materials and methods. An experimental study was carried out using five groups, with five mice in each group. Their weight was registered for 17 weeks, and at week 15 they were administered physiological saline solution (negative control), potassium dichromate at 25 mg/kg body weight (bw) (positive control) and tartrazine at doses of 0.75 mg/kg bw, 7.5 mg/kg bw and 75 mg/kg bw, for seven days, with the exception of the positive control which was a single dose. Then, every 24 hours, a peripheral blood sample was obtained from the tail, which was then smeared, dried and stained. Subsequently, 1000 lymphocytes were counted for each sample from each mouse, for all treatment groups. Results. The three tartrazine treatments did not cause significant differences in the weight of mice at week 15, but did produce significant differences in the frequency of micronucleated lymphocytes, with the 75 mg/kg bw tartrazine treatment having the greatest genotoxic effect, inducing an average of 1.63 ± 0.08 micronucleated lymphocytes, compared to the positive control which obtained an average of 1.42 ± 0.08 micronucleated lymphocytes. Conclusions. Tartrazine produced a genotoxic effect, increasing the number of micronucleated lymphocytes, at doses of 0.75; 7.5 and 75 mg/kg bw and did not affect body weight during seven days of administration to BALB/c M. musculus.

Survival among patients with relapsed/refractory diffuse large B cell lymphoma treated with single-agent selinexor in the SADAL study.

Patients with RR DLBCL who have received ≥ 2 lines of therapy have limited treatment options and an expected overall survival (OS) of < 6 months. The SADAL study evaluated single-agent oral selinexor in patients with RR DLBCL and demonstrated an overall response rate (ORR) of 29.1% with median duration of response (DOR) of 9.3 months. The analyses described here evaluated a number of subpopulations in order to understand how response correlates with survival outcomes in order to identify patients who could most optimally benefit from selinexor treatment. Median age was 67 years; 44.8% of patients were ≥ 70 years of age. The median OS was 9.0 months (95% CI 6.2, 13.7) at a median follow-up of 14.8 months. The median OS was not reached in patients with a CR or PR, while patients who did not respond have a median OS of 4.9 months (p < 0.0001). Patients < 70 years had an OS of 11.1 months compared with 7.8 months in patients ≥ 70 years. Among patients with or without prior ASCT, the median OS was 10.9 and 7.8 months, respectively. Among patients with disease refractory to the most recent DLBCL treatment regimen, the median OS was 7.0 months compared with 11.1 months for disease not refractory to the most recent treatment. In a patient population in which survival is expected to be < 6 months, treatment with single-agent oral selinexor was associated with a median survival of 9 months. Increased median OS observed in patients responding to selinexor was consistent across subgroups regardless of age, prior ASCT therapy, or refractory status. Randomized studies of selinexor in combination with a variety of other anti-DLBCL agents are planned. This trial was registered at ClinicalTrials.gov (NCT02227251) on August 28, 2014. https://clinicaltrials.gov/ct2/show/NCT02227251 .

Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial.

BACKGROUND: Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer with a median overall survival of less than 6 months. We aimed to assess the response to single-agent selinexor, an oral selective inhibitor of nuclear export, in patients with relapsed or refractory DLBCL who had no therapeutic options of potential clinical benefit. METHODS: SADAL was a multicentre, multinational, open-label, phase 2b study done in 59 sites in 19 countries. Patients aged 18 years or older with pathologically confirmed diffuse large B-cell lymphoma, an Eastern Cooperative Oncology Group performance status of 2 or less, who had received two to five lines of previous therapies, and progressed after or were not candidates for autologous stem-cell transplantation were enrolled. Germinal centre B-cell or non-germinal centre B-cell tumour subtype and double or triple expressor status were determined by immunohistochemistry and double or triple hit status was determined by cytogenetics. Patients received 60 mg selinexor orally on days 1 and 3 weekly until disease progression or unacceptable toxicity. The study was initially designed to evaluate both 60 mg and 100 mg twice-weekly doses of selinexor; however, the 100 mg dose was discontinued in the protocol (version 7.0) on March 29, 2017, when an improved therapeutic window was observed at 60 mg. Primary outcome was overall response rate. The primary outcome and safety were assessed in all patients who received 60 mg selinexor under protocol version 6.0, or enrolled under protocol versions 7.0 or higher and received at least one dose of selinexor. This trial is registered at ClinicalTrials.gov, NCT02227251 (active but not enrolling). FINDINGS: Between Oct 21, 2015, and Nov 2, 2019, 267 patients were randomly assigned, with 175 allocated to the 60 mg group and 92 to the discontinued 100 mg group. 48 patients assigned to the 60 mg group were excluded due to enrolment before version 6.0 of the protocol; the remaining 127 patients received selinexor 60 mg and were included in analyses of primary outcome and safety. The overall response rate was 28% (36/127; 95% CI 20·7-37·0); 15 (12%) achieved a complete response and 21 (17%) a partial response. The most common grade 3-4 adverse events were thrombocytopenia (n=58), neutropenia (n=31), anaemia (n=28), fatigue (n=14), hyponatraemia (n=10), and nausea (n=8). The most common serious adverse events were pyrexia (n=9), pneumonia (n=6), and sepsis (n=6). There were no deaths judged as related to treatment with selinexor. INTERPRETATION: Single-drug oral selinexor induced durable responses and had a manageable adverse events profile in patients with relapsed or refractory DLBCL who received at least two lines of previous chemoimmunotherapy. Selinexor could be considered a new oral, non-cytotoxic treatment option in this setting. FUNDING: Karyopharm Therapeutics Inc.

Evaluation of the MD Anderson tumor score for diffuse large B-cell lymphoma in the rituximab era.

OBJECTIVES: Diffuse large B-cell lymphoma (DLBCL) is an aggressive heterogeneous lymphoma with standard treatment. However, 30%-40% of patients still fail, so we should know which patients are candidates for alternative therapies. IPI is the main prognostic score but, in the rituximab era, it cannot identify a very high-risk (HR) subset. The MD Anderson Cancer Center reported a score in the prerituximab era exclusively considering tumor-related variables: Tumor Score (TS). We aim to validate TS in the rituximab era and to analyze its current potential role. METHODS: From GELTAMO DLBCL registry, we selected those patients homogeneously treated with R-CHOP (n = 1327). RESULTS: Five-years PFS and OS were 62% and 74%. All variables retained an independent prognostic role in the revised TS (R-TS), identifying four different risk groups, with 5-years PFS of 86%, 71%, 50%, and very HR (28%). With a further categorization of three variables of the original TS (Ann Arbor Stage, LDH and B2M), we generated a new index that allowed an improvement in HR assessment. CONCLUSIONS: (a) All variables of the original TS retain an independent prognostic role, and R-TS remains predictive in the rituximab era; (b) R-TS and additional categorization of LDH, B2M, and AA stage (enhanced TS) increased the ability to identify HR subsets.

A new prognostic model identifies patients aged 80 years and older with diffuse large B-cell lymphoma who may benefit from curative treatment: A multicenter, retrospective analysis by the Spanish GELTAMO group.

The means of optimally managing very elderly patients with diffuse large B-cell lymphoma (DLBCL) has not been established. We retrospectively analyzed 252 patients aged 80-100 years, diagnosed with DLBCL or grade 3B follicular lymphoma, treated in 19 hospitals from the GELTAMO group. Primary objective was to analyze the influence of the type of treatment and comorbidity scales on progression-free survival (PFS) and overall survival (OS). One hundred sixty-three patients (63%) were treated with chemotherapy that included anthracyclines and/or rituximab, whereas 15% received no chemotherapeutic treatment. With a median follow-up of 44 months, median PFS and OS were 9.5 and 12.5 months, respectively. In an analysis restricted to the 205 patients treated with any kind of chemotherapy, comorbidity scales did not influence the choice of treatment type significantly. Independent factors associated with better PFS and OS were: age < 86 years, cumulative illness rating scale (CIRS) score < 6, intermediate risk (1-2) R-IPI, and treatment with R-CHOP at full or reduced doses. We developed a prognostic model based on the multivariate analysis of the 108 patients treated with R-CHOP-like: median OS was 45 vs. 12 months (P = .001), respectively, for patients with 0-1 vs. 2-3 risk factors (age > 85 years, R-IPI 3-5 or CIRS > 5). In conclusion, treatment with R-CHOP-like is associated with good survival in a significant proportion of patients. We have developed a simple prognostic model that may aid the selection patients who could benefit from a curative treatment, although it needs to be validated in larger series.

Bone marrow biopsy superiority over PET/CT in predicting progression-free survival in a homogeneously-treated cohort of diffuse large B-cell lymphoma.

Several studies have reported uneven results when evaluating the prognostic value of bone marrow biopsy (BMB) and PET/CT as part of the staging of diffuse large B-cell lymphoma (DLBCL). The heterogeneity of the inclusion criteria and not taking into account selection and collinearity biases in the analysis models might explain part of these discrepancies. To address this issue we have carried a retrospective multicenter study including 268 DLBCL patients with a BMB and a PET/CT available at diagnosis where we estimated both the prognosis impact and the diagnostic accuracy of each technique. Only patients treated with R-CHOP/21 as first line (n = 203) were included in the survival analysis. With a median follow-up of 25 months the estimated 3-year progression-free survival (PFS) and overall survival (OS) were 76.3% and 82.7% respectively. In a multivariate analysis designed to avoid a collinearity bias with IPI categories, BMB-BMI [bone marrow involvement](+) (HR: 3.6) and ECOG PS > 1 (HR: 2.9) were independently associated with a shorter PFS and three factors, age >60 years old (HR: 2.4), ECOG PS >1 (HR: 2.4), and abnormally elevated B2-microglobulin levels (HR: 2.2) were independently associated with a shorter OS. In our DLBCL cohort, treated with a uniform first-line chemotherapy regimen, BMI by BMB complemented performance status in predicting those patients with a higher risk for relapse or progression. In this cohort BMI by PET/CT could not independently predict a shorter PFS and/or OS.

Characteristics and management of primary and other immune thrombocytopenias: Spanish registry study.

BACKGROUND: The natural history and its modulation by treatments administered for immune thrombocytopenia (ITP) in the clinical practice remains unknown. In addition, little information is available on the characteristics and management of ITP in Spain. METHODS: We conducted an observational, multicenter, registry in 70 Hematology Services from Spain between 2009 and 2011, which included children from 2 months of age and adults with primary ITP or another ITP diagnosed within the last 6 months (platelet count [PC] < 100 × 109/l). Patients were followed-up at 6 and 12 months. RESULTS: 484 patients were included (median [Q1, Q3] age 52 [29,74] years, 87.6% adults), 56% women, 10.5% with secondary ITP. Median (Q1, Q3) PC at diagnosis was 12 × 109/l (4, 32); 72% of patients had bleeding symptoms (62% cutaneous bleeding, 29% oral cavity bleeding, 18% epistaxis). 81% of patients with primary ITP received first-line treatment, mainly with corticosteroids (>6 weeks in 59% of cases), either alone (41%) or associated with intravenous immunoglobulin (33%). The response (≥30 × 109/L) to first-line treatment was 92%. A total of 19% of patients received second-line treatment and 6% additional treatments. At 12 months, 74% of primary ITP patients maintained a PC ≥ 100 × 109/L in absence of treatment (10% still had hemorrhagic manifestations). CONCLUSIONS: Characteristics of Spanish ITP patients are comparable to those from other countries. Although a high response rate to first-line treatments is observed, at 1 year, the disease persists in around one quarter of patients. Overall therapeutic management in Spain conforms to current recommendations, except for an excessive duration of corticosteroids therapy.

Prácticas y creencias sobre estilos de vida asociadas alíndice de masa corporal en enfermeros / Practices and beliefs about lifestyle associated with the body mass index in nurses

Identificar las prácticas y creencias sobre estilos de vida asociadas al índice de masacorporal en el personal de enfermería.MetodologíaEstudio descriptivo, comparativo, correlacional realizado en 136 enfermeros(as)trabajadores en un hospital público de Zacatecas, México, seleccionados a través de unmuestreo aleatorio estratificado por turno laboral. Se aplicó el instrumento de Prácticasy creencias sobre estilos de vida y una cédula para identificar datos personales. Se tomópeso y talla de cada participante. Los datos fueron analizados en el programa SPSS versión18.0ResultadosEl 65,54% del personal de enfermería presentó estilos de vida poco saludables, siendo lapráctica de actividad física el mayor problema, mientras que el autocuidado y cuidadomédico (=64,55) fueron los componentes con mejores resultados. Las creencias mejorevaluadas fueron las asociadas con la actividad física y deporte (=77,45). Un 40,4%presentó sobrepeso y 35,3% algún grado de obesidad. El aumento de índice de masacorporal se asoció con la alimentación no saludable y el sedentarismo (p<.01). Seencontraron diferencias significativas en las prácticas y creencias sobre estilos de vidasegún el turno de trabajo, nivel educativo y estado civil (p< .05).ConclusionesSon las prácticas, específicamente la alimentación y actividad física, y no las creenciassobre el estilo de vida, las que se asocian al exceso de peso en personal de enfermería. Noexiste coherencia entre las creencias y comportamientos en estos profesionales de la salud...

To identify practices and beliefs about lifestyle associated with the body mass index innursing personnel.MethodologyThis is a descriptive, comparative and correlational study, carried out on 136 nurses,workers of a general hospital in Zacatecas, Mexico. The participants were selected througha random stratified sampling by work shift. We applied an instrument for practices andbeliefs about Lifestyle and a document to identify personal data. The weight and size ofevery participant were taken into account. Data were analyzed in SPSS Statistics version18.ResultsMost of the nursing personnel considered presented lifestyles somehow unhealthy (65,54%).Their major problem was physical activity practices, while self-care and medical-carewere the best evaluated lifestyle components ( =64,55). The most positive beliefs wereassociated with sports and physical activity ( =77,45). 40,4% presented overweight, and35,3% showed some degree of obesity. The increase in body mass index was associatedwith unhealthy diet and sedentary lifestyle (p<.01). We found meaningful differences inthe practices and beliefs about lifestyle in relation to the work shift, level of education andcivil status (p< .05).ConclusionsThe practices, specifically feeding and physical activity, and not the beliefs about lifestyle,are the ones associated with the excess of weight in nurses. There is not consistency betweenbeliefs and behaviors in these health professionals...

Intermediate doses of cytarabine plus granulocyte-colony-stimulating factor as an effective and safe regimen for hematopoietic stem cell collection in lymphoma patients with prior mobilization failure.

BACKGROUND: High-dose chemotherapy supported by autologous stem cell transplantation (ASCT) is an effective treatment for patients with lymphomas. However, failure to reach the minimum threshold of hematopoietic stem cells to proceed to ASCT may occur, even with the most effective strategies currently available. STUDY DESIGN AND METHODS: We report on 33 patients diagnosed with lymphoma who had at least one prior mobilization failure and received cytarabine at a dose of 400 mg/m(2) /day intravenously × 3 days plus granulocyte-colony-stimulating factor (G-CSF) 10 to 12 µg/kg/day as mobilization regimen. The median number of previous lines of chemotherapy was three. RESULTS: Thirty-two of 33 patients (96.8%) reached the target CD34+ cell dose (>2 × 10(6) /kg). The mean (range) number of apheresis procedures was 1.8 (1-3) with 4.69 × 10(6) (1.5 × 10(6) -6.8 × 10(6) )/kg CD34+ cells obtained. All but one patient received chemomobilization in the outpatient department. Severe infections or treatment-related mortality were not observed. All patients that received ASCT (31/33) engrafted without requiring G-CSF during the posttransplant period. CONCLUSION: This study shows that cytarabine at intermediate doses plus G-CSF in patients diagnosed with lymphoma who had a prior mobilization failure is a feasible and effective mobilization regimen.

HLA specificities are related to development and prognosis of diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease influenced by genetic and environmental factors. The role of the HLA system in tumor antigen presentation could be involved in susceptibility and disease control. We analyzed the phenotypic frequencies of HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 in 250 DLBCLs, comparing them with 1940 healthy individuals. We also evaluated the influence of HLA polymorphisms on survival in those patients treated with curative intention using cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)-like regimen without (n = 64, 26%) or with (n = 153, 61%) rituximab. DLBCL patients have a higher phenotypic frequency of HLA-DRB1*01 (29% vs 19.5%, P = .0008, Pc = .0104) and a lower frequency of HLA-C*03 (6.4% vs 17.9%, P < .0005, Pc = .007) compared with healthy individuals. Irrespective of the age-adjusted International Prognostic Index, those patients receiving a CHOP-like plus rituximab regimen and carrying the HLA-B44 supertype had worse 5-year progression-free (54% vs 71%, P = .019) and 5-year overall (71% vs 92%, P = .001) survival compared with patients without this supertype. Our data suggest that some HLA polymorphisms influence the development and outcome of DLBCL, allowing the identification of an extremely good-risk prognostic subgroup. However, these results are preliminary and need to be validated in order to exclude a possible population effect.

Rituximab, used alone or in combination, is superior to other treatment modalities in splenic marginal zone lymphoma.

Splenic marginal zone lymphoma (SMZL) is a rare B-cell malignancy, with no standard treatment other than splenectomy. Rituximab has shown encouraging results. We therefore retrospectively assessed 43 patients from two centres, who received rituximab, either alone or with chemotherapy. All patients responded, 34/43 (79%) achieving a complete response (CR), compared with 3/10 (30%) after chemotherapy without rituximab (P = 0·005). Of these 10 patients, 9 (90%) subsequently achieved a CR after rituximab (P = 0·02). Rituximab monotherapy appeared equally as effective as rituximab combination therapy (90% vs. 79% CR, P = 0·7) with significantly less toxicity (12·5% vs. 83%, P = 0·002). Splenectomized patients were more likely to obtain a CR with rituximab (16/16, 100%) than unsplenectomized patients (18/27, 67%, P = 0·008). Disease-free survival (DFS) at 3 years was better after rituximab than after splenectomy alone [79% (95% confidence interval 60-89) vs. 29% (8-54), Hazard ratio (HR) 0·28 (0·12-0·68), P = 0·003] and better than after chemotherapy without rituximab [25% (4-55), HR 0·21 (0·08-0·51), P = 0·0004]. Survival at 3 years after rituximab was 98%. In summary, the CR and DFS rates after rituximab, given alone or with chemotherapy, were significantly better than after chemotherapy without rituximab in the same patients, with manageable toxicity. Rituximab, with or without splenectomy, should be considered for the treatment of SMZL.

Universal antifungal therapy is not needed in persistent febrile neutropenia: a tailored diagnostic and therapeutic approach.

BACKGROUND: Giving antifungal therapy exclusively to selected patients with persistent febrile neutropenia may avoid over-treatment without increasing mortality. The aim of this study was to validate an innovative diagnostic and therapeutic approach based on assessing patients' risk profile and clinical criteria in order to select those patients requiring antifungal therapy. The efficacy of this approach was compared to that of universal empirical antifungal therapy. DESIGN AND METHODS: This was a prospective study which included all consecutive adult hematology patients with neutropenia and fever refractory to 5 days of empirical antibacterial therapy admitted to a teaching hospital in Spain over a 2-year period. A diagnostic and therapeutic approach based on clinical criteria and risk profile was applied in order to select patients for antifungal therapy. The sensitivity, specificity and negative predictive value of this approach and also the overall success rate, according to the same criteria of efficacy described in classical clinical trials, were analyzed. RESULTS: Eighty-five episodes were included, 35 of them (41.2%) in patients at high risk of invasive fungal infections. Antifungal therapy was not indicated in 33 episodes (38.8%). The overall incidence of proven and probable invasive fungal infections was 14.1%, all of which occurred in patients who had received empirical antifungal therapy. The 30-day crude mortality rate was 15.3% and the invasive fungal infection-related mortality rate was 2.8% (2/72). The overall success rate following the diagnostic and therapeutic approach was 36.5% compared with 33.9% and 33.7% obtained in the trial by Walsh et al. The sensitivity, specificity and negative predictive value of the study approach were 100%, 52.4% and 100%, respectively. CONCLUSIONS: Based on the high negative predictive value of this diagnostic and therapeutic approach in persistent febrile neutropenia patients with hematologic malignancies or patients who have received a hematopoietic stem cell transplant, the approach is useful for identifying patients who are not likely to develop invasive fungal infection and do not, therefore, require antifungal therapy. The effectiveness of the strategy is similar to that of universal empirical antifungal therapy reported in controlled trials.

Caracterización isoenzimatica de seis poblaciones de Annona cherimola Mill. de la Región La Libertad, Perú / Isoenzymic characterization of six populations of Annona cherimola Mill. from La Libertad Region, Peru

La presente investigación tuvo por objetivo caracterizar isoenzimáticamente a seis poblaciones de Annona cherimola de la Región La Libertad. Muestras de hojas tiernas de árboles con al menos dos fructificaciones fueron colectadas de las localidades de La Cuesta, Paday, Samne, Cascas, Poroto y Trujillo. Los perfiles electroforéticos de las enzimas PGI, APCH, MDH y ME fueron analizadas y procesadas. Encontramos polimorfismo sólo para los loci Pgi-1 y Me con siete y dos alelos respectivamente; valores promedio para polimorfismo de 0,40 y heterocigosidad media entre 0,206 (La Cuesta) y 0,285 (Poroto). Los resultados indican que existe una alta variabilidad fenotípica y genotípica en las seis poblaciones de Annona cherimola de la Región La Libertad.

The aim of this study was to determinate the isozymic characteristic of six Annona cherimola populations from La Libertad Region. Leaves of trees with at least two fructifications were collected in six localities: La Cuesta, Paday, Samne, Cascas, Poroto and Trujillo. The samples were processed and the electrophoretic profiles of the enzymes PGI, APCH, MDH and ME were analyzed. We found polymorphism for the loci PGI-1 and ME, with seven and two alleles respectively, average values of 0,40 for polymorphism and mean heterozygosity between 0,206 (La Cuesta) and 0,285 (Poroto). There is high phenotypic and genotypic variability in six Annona cherimola populations in La Libertad Region.