Real-life analysis on safety and efficacy of asciminib for ponatinib pretreated patients with chronic myeloid leukemia.

Failure of second-generation tyrosine kinase inhibitors (2GTKI) is a challenging situation in patients with chronic myeloid leukemia (CML). Asciminib, recently approved by the US Federal Drug Administration, has demonstrated in clinical trials a good efficacy and safety profile after failure of 2GTKI. However, no study has specifically addressed response rates to asciminib in ponatinib pretreated patients (PPT). Here, we present data on responses to asciminib from 52 patients in clinical practice, 20 of them (38%) with prior ponatinib exposure. We analyzed retrospectively responses and toxicities under asciminib and compared results between PPT and non-PPT patients.After a median follow-up of 30 months, 34 patients (65%) switched to asciminib due to intolerance and 18 (35%) due to resistance to prior TKIs. Forty-six patients (88%) had received at least 3 prior TKIs. Regarding responses, complete cytogenetic response was achieved or maintained in 74% and 53% for non-PPT and PPT patients, respectively. Deeper responses such as major molecular response and molecular response 4.5 were achieved in 65% and 19% in non-PPT versus 32% and 11% in PPT, respectively. Two patients (4%) harbored the T315I mutation, both PPT.In terms of toxicities, non-PPT displayed 22% grade 3-4 TEAE versus 20% in PPT. Four patients (20% of PPT) suffered from cross-intolerance with asciminib as they did under ponatinib.Our data supports asciminib as a promising alternative in resistant and intolerant non-PPT patients, as well as in intolerant PPT patients; the resistant PPT subset remains as a challenging group in need of further therapeutic options.

Air particulate matter exacerbates lung response on Sjögren's Syndrome animals.

Epidemiological studies have associated air particulate matter (PM) inhalation with a decline in lung function and increased morbo-mortality due to cardiorespiratory diseases, particularly in susceptible populations. Sjögren's Syndrome (SS) is a chronic autoimmune disease characterized by cellular infiltration in exocrine glands and extraglandular tissue, being the respiratory tract an important target. We evaluated the effect of PM on the airways of NOD mice, which develop SS and BALB/c mice. BALB/c or NOD mice (2-3 months) were randomized in two groups and exposed to intranasal instillation either with saline (control) or ROFA solution (1mg/kg body weight). After 24h, mice were euthanized in order to perform lung histology, or measure total cell number (TCN), differential cell count (DCC) and superoxide anion generation in the bronchoalveolar lavage (BAL) fluid. BALB/c mice showed normal histoarchitecture, while NOD mice showed lymphocytic peribronchial infiltrates. ROFA exposure affected the respiratory tract from both BALB/c and NOD mice, with a significant increase in the TCN (p<0.05) and generation of O2(-) (p<0.05), as well as an imbalance in the DCC (p<0.05). All histological observations correlated with the cellular parameters evaluated. Lesions in NOD mice were more severe than those of BALB/c, showing cellular infiltration in the alveoli and leading to a greater decrease in the alveolar space. We have proved that in this experimental Sjögren's Syndrome animal model (NOD mice); airborne pollution exacerbates pre-existing pulmonary lesions. These findings show experimental evidence on the harmful effects of airborne pollution on the airways of patients with Sjögren's Syndrome.

Regulación del flujo sanguíneo uterino: II. funciones de estrógeno y receptores estrogénicos alfa/beta en acciones genómicas y no-genómicas del endotelio uterino / Regulation of uterine blood flow: II. functions of estrogen and estrogen receptor alpha/beta in genomic and non- genomic actions of the uterine endothelium

El embarazo está marcado por cambios y adaptaciones cardiovasculares que son importantes para el crecimiento y mantenimiento de la placenta y el feto. Durante este periodo, las adaptaciones vasculares uterinas manifiestan cambios clasificados como de corto o largo plazo los cuales están relacionados con adaptaciones vasodilatadoras, angiogénicas o de remodelación. El estrógeno y los receptores estrogénicos clásicos (REs), RE-alfa y RE-beta, han demostrado ser parcialmente responsables por facilitar el incremento dramático en el fluido sanguíneo uterino necesario durante el embarazo. En ésta revisión bibliográfica se discuten la base estructural para la diversidad y selectividad funcional de los REs por el estrógeno, el papel de los REs sobre los efectos genómicos y no-genómicos en células endoteliales de arterias uterinas (CEAU). Estos temas integran el conocimiento científico sobre la regulación molecular de CEAU para mantener el incremento fisiológico en la perfusión útero-placentaria observada durante un embarazo normal.

Pregnancy is marked by changes and cardiovascular adaptations that are important for the maintenance and growth of the placenta and fetus. During this period, the uterine vascular adaptations manifest changes that can be classified as short or long term and they related to adaptations for vasodilation, angiogenic or remodeling. Estrogen and the classical estrogen receptors (ERs), ER-alpha and ER-beta, have been shown to be partially responsible for facilitating this dramatic increase in uterine blood flow needed during pregnancy. This literature review discusses the basis for structural diversity and functional selectivity of ERs by estrogen, the role of ERs on the genomic and non-genomic effects in endothelial cells of uterine arteries (UAEC). These themes integrate scientific knowledge about the molecular regulation of UAEC to maintain the physiological increase in uteroplacental perfusion observed during normal pregnancy.

[Regulation of uterine blood flow. II. Functions of estrogen and estrogen receptor α/ß in genomic and non-genomic actions of the uterine endothelium]. / Regulación del flujo sanguíneo uterino. II. Funciones de estrógeno y receptores estrogénicos α/ß en acciones genómicas y no-genómicas del endotelio uterino.

Pregnancy is marked by changes and cardiovascular adaptations that are important for the maintenance and growth of the placenta and fetus. During this period, the uterine vascular adaptations manifest changes that can be classified as short or long term and they related to adaptations for vasodilation, angiogenic or remodeling. Estrogen and the classical estrogen receptors (ERs), ER-α and ER-ß, have been shown to be partially responsible for facilitating this dramatic increase in uterine blood flow needed during pregnancy. This literature review discusses the basis for structural diversity and functional selectivity of ERs by estrogen, the role of ERs on the genomic and non-genomic effects in endothelial cells of uterine arteries (UAEC). These themes integrate scientific knowledge about the molecular regulation of UAEC to maintain the physiological increase in uteroplacental perfusion observed during normal pregnancy.

[Regulation of uterine blood flow. I. Functions of estrogen and estrogen receptor α/ß in the uterine vascular endothelium during pregnancy]. / Regulación del flujo sanguíneo uterino. I. Funciones de estrógeno y receptores estrogénicos α/ß en el endotelio vascular uterino durante el embarazo.

Estrogen and classical estrogen receptors (ERs), ER-α and ER-ß, have been shown to be partially responsible for short and long term uterine endothelial adaptations during pregnancy. The molecular and structural differences, together with the various effects caused by these receptors in cells and tissues, suggest that their function varies depending upon estrogen and estrogen receptor signaling. In this review, we discuss the role of estrogen and its classic receptors in the cardiovascular adaptations during pregnancy and the expression of ERs in vivo and in vitro in the uterine artery endothelium during the ovarian cycle and pregnancy, while comparing their expression in arterial endothelium from reproductive and non-reproductive tissues. These themes integrate current knowledge of this broad scientific field with various interpretations and hypothesis that related estrogenic effects by either one or both ERs. This review also includes the relationship with vasodilator and angiogenic adaptations required to modulate the dramatic physiological increase to the uteroplacental perfusion observed during normal pregnancy.

Regulación del flujo sanguíneo uterino: I. funciones de estrógeno y receptores estrogénicos alfa/beta en el endotelio vascular uterino durante el embarazo / Regulation of uterine blood flow: I. functions of estrogen and estrogen receptor alpha/beta in the uterine vascular endothelium during pregnancy", "_i": "en

El estrógeno y los receptores estrogénicos clásicos (REs), RE- alfa y RE-beta, han demostrado ser parcialmente responsable por las adaptaciones endoteliales uterinas durante el embarazo al corto y largo plazo. Las diferencias moleculares y estructurales, junto con los diferentes efectos causados por estos receptores en las células y los tejidos, sugieren que su función varía dependiendo de la manera en la cual el estrógeno se comunica con sus receptores. En ésta revisión bibliográfica se discuten la función del estrógeno y sus receptores clásicos en las adaptaciones cardiovasculares durante el embarazo y la expresión de los Res in vivo e in vitro en el endotelio de la arteria uterina durante el ciclo ovárico y el embarazo, a la vez comparado con la expresión en endotelio arterial de tejidos reproductivos y no reproductivos. Estos temas integran el conocimiento actual de este amplio campo científico con interpretaciones e hipótesis diversas relacionadas con los efectos estrogénicos mediados bien sea por uno o los dos REs. Esta revisión también incluye la relación con las adaptaciones vasodilatadoras y angiogénicas requeridas para modular el dramático incremento fisiológico en la perfusión útero-placentaria observada durante un embarazo normal.

Estrogen and classical estrogen receptors (ERs), ER- alpha and ER- beta, have been shown to be partially responsible for short and long term uterine endothelial adaptations during pregnancy. The molecular and structural differences, together with the various effects caused by these receptors in cells and tissues, suggest that their function varies depending upon estrogen and estrogen receptor signaling. In this review, we discuss the role of estrogen and its classic receptors in the cardiovascular adaptations during pregnancy and the expression of ERs in vivo and in vitro in the uterine artery endothelium during the ovarian cycle and pregnancy, while comparing their expression in arterial endothelium from reproductive and non-reproductive tissues. These themes integrate current knowledge of this broad scientific field with various interpretations and hypothesis that related estrogenic effects by either one or both ERs. This review also includes the relationship with vasodilator and angiogenic adaptations required to modulate the dramatic physiological increase to the uteroplacental perfusion observed during normal pregnancy.

Identification of seven novel SMPD1 mutations causing Niemann-Pick disease types A and B.

Niemann-Pick disease (NPD) types A and B are autosomal, recessively inherited, lysosomal storage disorders caused by deficient activity of acid sphingomyelinase (E.C. 3.1.4.12) because of mutations in the sphingomyelin phosphodiesterase-1 (SMPD1) gene. Here, we present the molecular analysis and clinical characteristics of 15 NPD type A and B patients. Sequencing the SMDP1 gene revealed eight previously described mutations and seven novel mutations including four missense [c.682T>C (p.Cys228Arg), c.1159T>C (p.Cys387Arg), c.1474G>A (p.Gly492Ser), and c.1795C>T (p.Leu599Phe)], one frameshift [c.169delG (p.Ala57Leufs*20)] and two splicing (c.316+1G>T and c.1341delG). The most frequent mutations were p.Arg610del (21%) and p.Gly247Ser (12%). Two patients homozygous for p.Arg610del and initially classified as phenotype B showed different clinical manifestations. Patients homozygous for p.Leu599Phe had phenotype B, and those homozygous for c.1341delG or c.316+1G>T presented phenotype A. The present results provide new insight into genotype/phenotype correlations in NPD and emphasize the difficulty of classifying patients into types A and B, supporting the idea of a continuum between these two classic phenotypes.

[Splenic marginal zone B-cell lymphoma with epidermotropic skin involvement]. / Linfoma B esplénico de la zona marginal con afectación cutánea epidermotropa.

Marginal zone B-cell lymphoma (MZL) is subclassified into extranodal MZL of mucosa-associated lymphoid tissue (including cutaneous lymphomas), splenic MZL, and nodal MZL. We report the case of a 68-year-old man with erythematous-violaceous plaques and nodules. Skin biopsy showed an epidermotropic lymphocytic infiltration and cytology and immunohistochemistry were consistent with MZL. The workup revealed disease in the peripheral blood and bone marrow and massive splenomegaly. Splenectomy confirmed the diagnosis of splenic MZL and led to resolution of the skin lesions. Cutaneous recurrence was treated successfully with chemotherapy and rituximab but caused fatal hepatitis due to hepatitis B virus reactivation. Skin involvement by splenic MZL is uncommon; this form of the disease can present epidermotropism, a very rare finding in primary cutaneous MZL. Treatment consists of splenectomy, which may be associated with chemotherapy and/or rituximab; this treatment may lead to reactivation of latent hepatitis B infection and screening for hepatitis should therefore be performed prior to starting therapy.

Evolución y factores de pronóstico en cáncer diferenciado de tiroides / Evolution and prognosis of differentiated thyroid carcinoma

Differentiated thyroid carcinoma has a good prognosis with a 90 percent survival at 10 years. Follicular carcinoma is more aggressive than papillary carcinoma Aim: To study the clinical presentation, evolution and prognosis of differentiated thyroid carcinoma. Material and Methods: The pathological registries of differentiated thyroid cancer processed in a pathology service of a general hospital, between 1984 and 2007, were searched. The clinical records of patients were reviewed. Results: One hundred six pathology registries were identified but only 89 patients had complete medical records. Seventy six patients aged 44 +/- 16 years had a papillary carcinoma and 13 patients aged 42 +/- 15 years had a follicular carcinoma. After a mean follow up of 53 months, 65 patients with papillary and 12 patients with follicular thyroid cancer were alive. Five patients with papillary carcinoma and one with follicular carcinoma had a local or distant relapse. Calculated actuarial survival at 10 years was 84 and 100 percent for papillary and follicular carcinoma, respectively. Ten year survival for stage I, II, III and IV tumors was 100, 92, 68 and 0 percent, respectively. Mortality was associated with the presence of distant metastases, a stage IV tumor, vascular or lymphatic tumor infiltration, tumor size, lymph node involvement, extra capsular invasion and a multi focal lesions. The relative risk for mortality increases between 2.7 and 9 times with the presence of lymph node infiltration and distant metastases. Conclusions: The prognosis of differentiated thyroid cancer is related to lymph node infiltration and the presence of distant metastases.

Los objetivos del presente estudio son identificar la forma de presentación clínica y evolución del cáncer diferenciado de tiroides (CDT); definir la curva de sobrevivencia para ambos tipos histológicos e identificar los factores clínicos e histológicos de mal pronóstico. Se presentan 89 pacientes portadores de cáncer diferenciado (papilar y folicular) de tiroides (75 CP Y 13 CF) tratados en los Hospitales de Coquimbo y La Serena, entre 1984 y 2007. La forma de presentación de ambos tumores fue similar. La mediana de seguimiento fue 53 meses. El 75 por ciento de los pacientes tuvo un seguimiento mínimo de 7 años y el 86,4 por ciento de los pacientes (64 cáncer papilar y 12 cáncer folicular) se encuentran vivos y libres de enfermedad; el intervalo libre de enfermedad fue de 52,7 meses con rango entre 3 meses y 16 años. La sobrevida actuarial a 10 a±os para cáncer papilar es 84 por ciento y, para cáncer folicular 100 por ciento. Por estadios, a los 10 años la sobrevida es de 100 por ciento en estadio I, 92 por ciento en estadio II, 68 por ciento en estadio III y 0 por ciento en estadio IV. El riesgo de muerte se asoció a la presencia de metástasis distantes, T4 e infiltración histológica vascular y/o linfática, p = 0,02. Otros factores no mostraron asociación: tamaño del tumor < T4, compromiso de linfonodos, invasión extracapsular y multifocalidad histológica. Sin embargo, el RR se incrementa 2,7 y 9 veces con invasión linfática o con presencia de metástasis, 1,6 veces con el aumento del tamaño tumoral, y 1,33 con multifocalidad neoplásica en la glándula. La presencia de metástasis linfáticas en cáncer papilar representa un RR de 1,22. Aunque el seguimiento de esta casuística es reducido (mediana 5 años), los resultados sugieren que el mal pronóstico se asocia fundamentalmente a compromiso linfático y metástasis a distancia y, por otra parte, a que el planteamiento terapéutico ha resultado efectivo para el control de la enfermedad en estadio I y II.

Cambios en la expresión inmunohistoquímica del protooncogen Bcl2 y apoptosis por acción de estimulación colinergica en pacientes con síndrome de Sjõgren primario (SSp) / Changes in Bcl2 immunochemical expresión and apoptosis due to cholinergic stimulation from Systemic Lupus Erythematosus (SLE)

El síndrome de Sjõgren es una enfermedad reumática autoinmune, sistémica, que supone la destrucción de la glándula exocrina y órganos internos por medio de grandes infiltraciones mononucleares asociadas con los anticuerpos Ro/SSA, La/SSB y factores reumáticos, ambos síntomas principales de los factores celulares y humorales de la xeroftalmia y la xerostomía. Los infiltrados mononucleares más comunes son los linfocitos CD4, CD8 y B. Los pacientes que sufren de síndrome de Sjõgren corren el riesgo de desarrollar linfoma no Hodgkin. El linfoma folicular es el resultado de una traslocación no homóloga cromosómica 14; 18 produciendo la desregulación de la transcripción y síntesis de la proteína Bcl2. Las proteínas de la familia Bcl2 son reguladores clave de la apoptosis, que estimulan la supervivencia de la célula. Otros grupos de la familia Bcl2 son estimuladores pro-apoptóticos. El comportamiento de las células dependerá de la concentración de los dos miembros de la familia. Objetivos: Los niveles de expresión y apoptosis de Bcl2 en la glándula salival menor pre y pos-tratamiento con agonistas colinérgicos. Pacientes y métodos: Diagnóstico del síndrome de Sjõgren según los criterios europeos. Se eclutaron 10 pacientes, a quienes se estudió durante 5 meses y se los trató con 15 mg de clorhidrato de pilocarpina en cápsulas orales de 5 mg cada 8 horas. Se llevaron a cabo biopsias pre-tratamiento y pos-tratamiento desde el día cero (antes del tratamiento) hasta el quinto mes (después del tratamiento). Antes de ingresar al estudio clínico, los pacientes SSp voluntarios firmaron el consentimiento informado y el estudio se realizó según las normas de buenas prácticas clínicas. Se evaluó la expresión Bcl2 mediante técnicas de inmunohistoquímica y la apoptosis nucleotidil transferasa-peroxidasa mediante técnicas in situ. Diseño del estudio: Abierto, longitudinal, autocontrolado.

Identification of genes involved in imatinib resistance in CML: a gene-expression profiling approach.

The use of the tyrosine kinase inhibitor imatinib, which blocks the enzymatic action of the BCR-ABL fusion protein, has represented a critical advance in chronic myeloid leukemia (CML) treatment. However, a subset of patients initially fails to respond to this treatment. Use of complementary DNA (cDNA) microarray expression profiling allows the identification of genes whose expression is associated with imatinib resistance. Thirty-two CML bone marrow samples, collected before imatinib treatment, were hybridized to a cDNA microarray containing 6500 cancer genes, and analyzed using bootstrap statistics. Patients refractory to interferon-alpha treatment were evaluated for cytogenetic and molecular responses for a minimum of 12 months. A set of 46 genes was differentially expressed in imatinib responders and non-responders. This set includes genes involved in cell adhesion (TNC and SCAM-1), drug metabolism (cyclooxygenase 1), protein tyrosine kinases and phosphatases (BTK and PTPN22). A six-gene prediction model was constructed, which was capable of distinguishing cytogenetic response with an accuracy of 80%. This study identifies a set of genes that may be involved in primary resistance to imatinib, suggesting BCR-ABL-independent mechanisms.

Utilidad clínica del estudio de diseminación inicial en cáncer de mama estadios I y II / Clinical utility of initial dissemination study an patients with stage I or II breast cancer I

Se evalúa el rendimiento y utilidad clínica del estudio inicial de diseminación en nuestra serie de 616 casos de cáncer de mama, centrado especialmente en los estados I y II ( 374 casos ), buscando establecer si existe un subgrupo de mayor riesgo en el cual esté justificado el estudio inicial de diseminación. Se separaron las pacientes en 2 grupos de acuerdo a la palpación de ganglios axilares: sospechosos de metástasis (N1), no sospechosos (N0); comprobando que las pacientes N1 tenían un 5,99 por ciento de metástasis iniciales (13/217) versus un 2,3 por ciento (4/174) en las pacientes N0, (p=0,085); sin embargo durante el seguimiento de la serie (23 años) se comprobó que un porcentaje mayor de pacientes N1 desarrolló metástasis (50/ 204=24,5 por ciento) en relación a las pacientes N0 (25/170=14,7 por ciento) (p=0,0198); aunque no en todos estos casos los estudios iniciales fueron útiles para diagnosticar metástasis. En las pacientes que desarrollaron metástasis durante el seguimiento, los estudios iniciales de diseminación negativos, sirvieron de base comparativa a los estudios posteriores que mostraron metástasis, obteniéndose una utilidad clínica global para dichos estudios de un 24,4 por ciento (53/217) en las pacientes N1 versus un 14,4 por ciento (25/174) en las pacientes N0 (p=0,0154). En el 21 por ciento de las pacientes estado III, el estudio inicial de diseminación demostró metástasis. En 41 de 204 pacientes N1 (20 por ciento) la ecotomografía abdominal demostró colelitiasis, lo que se consideró un beneficio adicional del examen. Se concluye que el estudio inicial de diseminación es de utilidad clínica en pacientes con ganglios axilares palpables.

Validity and reliability of simple nutrition screening tools adapted to the elderly population in healthcare facilities.

This study was conducted to assess the validity and the reliability of simple tools to screen the protein-energy malnutrition (PEM) risk among the elderly population in healthcare facilities. An initial screening tool, made up of nine PEM risk factors, was previously developed to be validated. This tool was quite complex and showed low validity results. A stepwise regression analysis determined significant risk factors (P < or = 0.05) among those included in the initial tool. These were the foundation to develop two simplified screening tools. One included Body Mass Index (BMI) and % weight loss over time. The second included BMI and albumin. Both tools classified subjects in low or high PEM risk levels. In the present study, the simple tools were assessed in a sample of 142 elderly subjects divided into two categories: acute care elderly (ACE, n=72) and long-term care elderly (LTCE, n=70). The simple tools were administered by a dietetic technician and a nurse with the purpose of assessing inter-rater and test-retest reliabilities. The criterion validity of the simple tools were assessed in comparison to in-depth nutritional assessments carried out by a dietitian. The validity results were ranked between 60.5% and 91.7%. The reliability scores showed levels of agreement of 70.8% to 93.1% and kappa coefficients ranking between 0.59(+/-0.07) and 0.79(+/-0.05). Simple tools are now available for efficiently screening the PEM risk among the elderly population on a healthcare facility-wide basis.

Simple nutrition screening tools for healthcare facilities: development and validity assessment.

The purpose of nutrition screening is to identify individuals at high nutritional risk. Given that dietitians cannot always carry out screening in health-care facilities, tools should be simple and based on data obtained from the nursing admission questionnaire. This study was conducted to develop timely and valid tools for screening protein-energy malnutrition (PEM). A dietetic technician administered an initial screening tool to 160 subjects recruited from two settings. This tool comprised nine PEM risk factors. The sample included 54 adults in acute care, 57 elderly adults in acute care, and 49 elderly adults in long-term care. Dietitians performed comprehensive nutritional assessments to determine the validity of this screening tool. Stepwise regression analysis revealed significant risk factors among those included in the initial screening. These risk factors were considered during development of the first simple screening tool, which encompassed body mass index (BMI) and percentage of weight loss, and classified subjects as having low or high PEM risk levels. A second tool using BMI and albumin level was tested in cases where an albumin measurement was available upon admission. These simple tools had validity indices of 75.9% or higher, except in adults in acute care; sensitivity was low in this group. The tools proved helpful in establishing dietitians' priorities for involvement and in initiating early nutritional care.

Is veno-occlusive disease a specific syndrome or the exacerbation of physiopathologic hemostatic changes in hematopoietic stem cell transplantation (HSCT)?

The objective of the present study was to analyze whether veno-occlusive disease (VOD) is based on specific findings or whether this syndrome is the exacerbation of changes in hemostatic parameters that develop following hematopoietic stem cell transplantation (HSCT). 40 patients undergoing HSCT were enrolled (6 allogeneic bone marrow transplantation and 34 peripheral stem cell rescue-2 allogeneic, 32 autologous). Measurements of hemostatic parameters (endothelial, hypercoagulability and fibrinolytic markers) were obtained prior to chemotherapy and weekly thereafter for 3 weeks. The incidence of VOD was 15%. HSCT showed a state of moderate hypercoagulability (increase of thrombin-antithrombin complex and fibrinogen, and decrease of Factor VII, Protein C, and antithrombin-III), probably as a consequence of marked endothelial damage (increase of von Willebrand Factor and tissue plasminogen activator). All these alterations create a potentially prothrombotic state, more pronounced in VOD. The decreasing incidence of VOD and the moderate disease in all patients suggest that increasing improvements in transplant strategies have reduced the risk and severity of a syndrome that at the beginning of the transplantation era was a leading cause of morbidity/mortality.

Autologous peripheral blood progenitor cell transplantation with <2 x 10(6) CD34(+)/kg: an analysis of variables concerning mobilisation and engraftment.

INTRODUCTION: This study analyses the factors affecting mobilisation and engraftment in autologous peripheral blood progenitor cell transplantation according to the number of CD34(+) re-infused. MATERIALS AND METHODS: A total of 190 patients underwent mobilisation with G-CSF alone (n=113) or in combination with chemotherapy (n=77). A total of 116 patients (61%) were autografted with <2 x 10(6) CD34(+) cells/kg and 74 patients were transplanted with >2 x 10(6) CD34(+) cells/kg. Rates of granulocyte and platelet recovery were estimated using the product-limit method of Kaplan-Meier and compared using a log-rank test. The Cox regression model was used for the multivariate analysis of factors influencing engraftment. Differences between cohorts were evaluated by one-way ANOVA or Mann-Whitney tests, and multivariate analysis was performed using a stepwise lineal regression. RESULTS: Neutrophil and platelet engraftment was significantly longer with <2 x 10(6)/CD34(+)/kg (12 vs 10 days, P=0.014 and 16 vs 13 days, P=0.0001 respectively). Platelet recovery was affected by exposure to alkylating agents (P=0.04), refractory disease (P=0.02) and AML (P=0.0001), but only the last two variables remained significant in Cox regression (P<0.01). Granulocyte engraftment was longer in CML (univariate, P=0.04) and in refractory disease (multivariate, P=0.02). In patients re-infused with >2 x 10(6)/CD34(+)/kg, the Cox model did not identify prognostic factors for haematopoietic recovery. CONCLUSION: Although mobilisation schedules and disease status influenced not only the yield of progenitor cells, but also the engraftment kinetics, the number of CD34(+) re-infused was the main predictor of haematopoietic recovery. While engraftment succeeded in most of the cases, the re-infusion of >2 x 10(6)/CD34(+)/kg resulted in significantly shorter recovery times.

Subcutaneous versus intravenous low-dose IL-2 therapy after autologous transplantation: results of a prospective, non-randomized study.

Use of IL-2 therapy after autologous transplantation is currently being explored to reduce relapse rate. Low doses of the cytokine induce significant immunomodulation avoiding the severe side-effects associated with high-dose IL-2 therapy. However, low-dose IL-2 is usually given by continuous infusion through central venous lines with the consequent risks of thrombosis and infections. Twenty-six consecutive patients who received autologous transplants received low-dose IL-2 after stable engraftment had been achieved. The first 13 patients (group A) were scheduled to receive 400,000/IU/m2/day for 3 months by continuous intravenous infusion. Ten of these patients suffered infectious episodes, mainly bacteriemias that often necessitated delaying IL-2 therapy (median delivered dose: 32% of planned). The next 13 patients were then assigned to receive IL-2 (800,000-1,000,000 IU/m2/day for 3 months) subcutaneously (group B). For group B patients, median dose intensity was 84% (P = 0.01 when compared with group A patients). Only one severe infectious episode was observed in these patients. Clinical toxicity in group B patients consisted mainly of s.c. nodules. Immunomodulation, measured as an increase in the absolute number of CD56+ cells and CD56+(bright) cells, was higher in patients who received the cytokine by the subcutaneous route (median peak increase of CD56+ cells: 160 and 220% for group A and B patients respectively; median peak increase of CD56+(bright) cells: 210% and 310% for group A and B respectively, P < 0.05 between groups A and B). No statistically significant increment of T lymphocytes was observed in any group. No hematologic toxicity was observed apart from eosinophilia, which was very marked in group B (P < 0.01). Our results show that low-dose s.c. IL-2 therapy is associated with low clinical and hematologic toxicity after autologous transplantation. The immunomodulation achieved is no less than that achieved with the i.v. approach.