Post-treatment bone marrow residual disease > 5% by flow cytometry is highly predictive of short progression-free and overall survival in patients with Waldenström's macroglobulinemia.

To assess the value of bone marrow (BM) assessment by flow cytometry FCM after therapy in the clinical outcome of WM patients, we analyzed 42 WM patients who were evaluated before and after therapy. Patients were studied with a panel that always included the CD19, CD22, CD25, and κ/λ light chain immunoglobulin monoclonal antibodies. The mean of abnormal B-cells in the pre-therapeutic BM was 17.8% ± 12.1%, which decreased was after therapy to 5.4% ± 0.7% (P = .049). A linear correlation was seen between the better quality of response and the reduction in the tumor B-lymphocyte counts at the BM, since the ratio of abnormal B cells between pre and posttherapy BM was 1172.17, 221.64, 3.37, 1.03, and 0.56 for responses complete, partial, minor, stable disease and progression, respectively (P < .001). Intensive and rituximab-containing therapies correlated with deeper tumor cell reductions. Finally, the B-cell decrease correlated with the better overall and progression-free survival.

Comparison of two-step transient evoked otoacoustic emissions (TEOAE) and automated auditory brainstem response (AABR) for universal newborn hearing screening programs.

OBJECTIVE: Both transitory auditory otoemissions (TEOAE) and automated auditory brainstem responses (AABR) are considered adequate methods for universal hearing screening. The goal of this study was to compare the results obtained with each device, applying the same screening procedure. MATERIALS AND METHODS: From 2001 to 2003, all the newborns in our health area (2454 infants) were evaluated with TEOAE (ILO92, otodynamics) and all those born from 2004 to 2006 (3117) were evaluated with AABR (AccuScreen, Fischer-Zoth). The population studied included all well newborns and those admitted to neonatal intensive care units (NICU). The first screening was normally undertaken with well babies during the first 48h of life, before hospital discharge. Infants referred from this first step underwent a second screening after hospital discharge, before they were a month old. RESULTS: The results from each study group were compared and analyzed for significant differences. TEOAE screening yielded 10.2% fail results from the first screening step; AABR gave 2.6%. In the second screening step, 2% of the newborns screened with TEOAE were referred, whereas 0.32% of those screened with AABR were referred. These differences are statistically significant. CONCLUSIONS: Although AABR screening tests involve a slightly higher cost in time and money than TEOAE, the results obtained compensate this difference. AABR gives fewer false positives and a lower referral rate; the percent of infants lost during follow-up is consequently smaller. Therefore, in our environment, universal newborn auditory screening with AABR is more effective than that with TEOAE.

Low expression of ZHX2, but not RCBTB2 or RAN, is associated with poor outcome in multiple myeloma.

RAN, ZHX2 and RCBTB2 (CHC1L) expression was evaluated by quantitative real time reverse transcription polymerase chain reaction in plasma cells from 85 monoclonal gammopathies: 58 symptomatic multiple myeloma (MM) (52 untreated, six relapsed), eight smouldering MM, five monoclonal gammopathy of undetermined significance, four plasma cell leukaemias and 10 myeloid cell lines. ZHX2 was weakly expressed in high-risk/proliferative disease compared to low-risk or indolent disease. High ZHX2 expression was associated with better response and longer survival after high-dose therapy. RCBTB2 expression was weaker in hyperdiploid versus non-hyperdiploid cases while RAN was more expressed in symptomatic MM and cell lines.

Randomized comparison of dexamethasone combined with melphalan versus melphalan with prednisone in the treatment of elderly patients with multiple myeloma.

Melphalan-prednisone (MP) has been the gold standard treatment for more than 30 years in elderly multiple myeloma (MM) patients. In order to assess whether the combination of dexamethasone with melphalan (MD) could improve on the efficacy of MP, we have carried out a randomized trial comparing both treatment approaches. A total of 201 patients >/=70 years old were included in the study. The overall response rate was similar after six cycles (MP: 67.9%versus MD: 64.5%) and after 12 cycles (MP: 49.4%versus MD: 46.1%). However, the proportion of complete responses (CR) was higher in the MD arm, particularly after 12 cycles (MD: 22.4%versus MP: 9.1%; P < 0.05). There was no significant difference in event-free survival (MP: 15.9 months versus MD: 23.3 months). The median overall survival in both arms was almost identical (MP: 29.4 months versus MD: 27.2 months; P = 0.63). No significant differences in haematological toxicity were observed, but non-haematological toxicity was significantly higher in the MD arm. According to these results MP remains as the gold standard for treatment of MM and should be the reference for comparison of new therapeutic approaches involving novel agents.

Proliferative activity of plasma cells is the most relevant prognostic factor in elderly multiple myeloma patients.

Although multiple myeloma (MM) is predominantly a disease of the elderly, few studies have focused on the identification of prognostic factors in this group of patients. Four hundred twenty five MM patients >65 years were uniformly treated with chemotherapy (MP or VCMP/VBAD). Multivariate analysis identified 4 factors with independent unfavorable prognostic influence: high percentage of S-phase bone marrow plasma cells (>2.5%); elevated beta(2) microglobulin (B2M) (>4 mg/L); age >80 years old; and LDH serum levels (above normal limit). The S-phase value was the most powerful independent prognostic factor to discriminate subgroups of patients with different prognosis. Thus, 3 main risk categories could be identified according to S-phase values: 3%, with median survivals of 34, 22 and 12 months, respectively (p < 0.0001). Our study also proved the value for elderly patients of the recently developed International Score System (ISS) based on B2M and albumin. Furthermore, the number of S-phase cells helped to subdivide the ISS III Group identifying a subset of patients with very poor prognosis defined by an additional high S-phase, who displayed a median survival of only 8 months. These results demonstrate that elderly patients can be accurately classified according to prognosis, which may be particularly valuable when comparing the efficacy of new treatment strategies. Moreover, our results underline the high prognostic value of proliferative activity of PC, a parameter that should be considered in routine laboratory investigations of MM.

Hiperbilirrubinemia neonatal. Peculiar debut del déficit de alfa-1-antitripsina / Neonatal hyperbilirrubinemia: a peculiar presentation of alpha-1-antitrypsin deficiency

La deficiencia de alfa-1-antitripsina (AlTT) es una enfermedad hereditaria que predispone a afección hepática en la infancia y a enfisema pulmonar en la edad adulta. Constituye la causa genética más común en el niño y de enfisema en el adulto; también es la que motiva más trasplantes hepáticos en niños y adolescentes. En nuestro medio presenta una prevalencia de 1 / 1.600-4.000 y una incidencia de 1 / 200 nacidos vivos. La A1TT es una glucoproteína inhibidora de proteasas séricas, codificada en el cromosoma 14 y que se hereda de forma autosómica recesiva. El fenotipo normal es el MM, y las mutaciones más frecuentes son las que asocian S y Z. Las manifestaciones clinicas más frecuentes en neonatos son la hiperbilirrubinemia conjugada, la colestasis y la hepatomegalia. Presentamos el caso de un recién nacido del sexo masculino ingresado por prematuridad e hiperbilirrubinemia directa, lo que motiva diferentes supuestos etiopatogénicos. Realizadas las pruebas sistemáticas y el estudio hepático, se determinó descenso de AlTT, y se decidió efectuar un estudio genético, en el que presentó un genotipo SS para el alelo de AlTT. La madre era SS y el padre MS, y ambos eran asintomáticos. En controles posteriores, se confirmó descenso en la cifra de AlTT, asociado a elevaciones puntuales de ésta como reactante de fase aguda, en relación con diversos procesos agudos. El interés de este caso radica en que, compartiendo la alteración genética con familiares de primer grado y, al ser éstos aparentemente asintomáticos, nuestro paciente debutó en el periodo neonatal inmediato; este hecho es peculiar en la bibliografía médica (AU)

[Results of one year's application of a universal protocol for the early detection of hearing loss in neonates]. / Resultados de aplicar durante 1 año un protocolo universal de detección precoz de la hipoacusia en neonatos.

These are the results of the first year of the application of a universal programme for the early detection of neonatal deafness. Our objective is making a diagnosis of all the unilateral or bilateral cases of hearing loss above 35 dB HL, before the age of 6 months. The detection strategy has 2 screening phases with transient evoked otoacoustic emissions (TEOAE) and one diagnostic phase with auditory brain stem response (ABR). The ABR were carried out both on those patients that failed the TEOAE screening and on the neonates with hearing loss risk factors. Of the 1,277 living newborn babies (NB), we evaluated 94%. 3.3% of the NB showed hearing loss risk factors. 90% of the NB passed the first TEOAE in both ears and, after the second TEOAE, only 2.5% of the NB reached the diagnostic phase. We provided early detection and treatment of 0.58% of cases of bilateral severe-deep hearing loss. Finally, the results obtained are examined together with the importance of planning universal hearing screening.

[Results of the application of the protocol for the early detection of hearing loss in high-risk neonates]. / Resultados de la aplicación del protocolo de detección precoz de la hipoacusia en neonatos de alto riesgo.

In coordination with the Paediatrics Department, we drew up a protocol for the "Early Detection of Hearing Loss in High-Risk Neonates" based fundamentally on the sequential application of impedanciometry and the Auditory Brain Stem Response (ABR). These are the results obtained from October 1994 to March 2001. Of the 240 children examined, we found 36 cases (15%) of severe-to-profound bilateral sensorineural hearing loss (> 60 dBs HL). 55% was associated with risk factors. However, we diagnosed only 2 of these cases of hearing loss (5.5%) using the protocol (sent by the neonatology department due to the fact that they showed hearing loss risk factors), since the rest (94.5%) came as a result of suspected hearing loss, which resulted in an average age for diagnosis of 3 years. Although the procedure used is highly sensitive and is diagnostically specific, in the light of these results, we consider it necessary to extend hearing screening to all newborn infants in order to evaluate its effectiveness in the early detection of infant deafness.

Resultados de la aplicación del protocolo de detección precoz / Results of the application of the protocol for the early detection of hearing loss in high-risk neonates

En coordinación con el Servicio de Pediatría, elaboramos un protocolo de "Detección precoz de la hipoacusia en neonatos de alto riesgo" basado fundamentalmente en la aplicación secuencias de la impedanciometría y los potenciales evocados auditivos del tronco cerebral (PEATC). Presentamos los resultados obtenidos desde octubre de 1994 a marzo de 2001. De los 240 niños estudiados, hemos encontrado 36 hipoacusias neurosensoriales severas profundas (<60 dBs HL) bilaterales (15 por ciento). El 55 por ciento se asociaba con factores de riesgo. Sin embargo, sólo diagnosticado 2 de estas hipoacusias (5,5 por ciento) gracias al protocolo (enviados por el Servicio de Neonatología por presentar factores de riesgo de hipoacusia), pues el resto (94,5 por ciento) acudieron por sospecha de hipoacusia, con lo que la edad media de diagnóstico es de 3 años. Aunque el procedimiento utilizado presenta alta sensibilidad y especificidad diagnóstica, a la vista de estos resultados, creemos necesario universalizar la exploración auditiva a todos los recién nacidos, a fin de evaluar su efectividad en la detección precoz de la sordera infantil (AU)

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Corticoides antenatales en la amenaza de parto prematuro / Antenatal corticoids in the threat of premature birth

La prematuridad es uno de los problemas más importantesde la asistencia perinatal actual, y la prevención delparto prematuro y de sus secuelas, su principal reto.La inducción farmacológica de la madurez pulmonarfetal con corticoides es la intervención que más ha cambiado el pronóstico de estos niños, ya que desde su aplicación se ha conseguido disminuir de forma notable la incidencia del síndrome de distrés respiratorio y de la mortalidad perinatal. Aunque la maduración pulmonar fetal (a través de la regulación de distintos sistemas enzimáticos en los neumocitos tipo 2) es el efecto más importante de estos fármacos, poseen también otros efectos extrapulmonares que contribuyen a la maduración de los diferentes órganos y sistemas del recién nacido. Se han utilizado diversos corticoides pero, en base a los últimos estudios, la betametasona parece el más recomendable. Es preferible administrar un ciclo único (dos dosis), ya que la utilización de múltiples ciclos no parece disminuir la morbilidad global y se ha relacionado, en diversos trabajos experimentales, con efectos adversos y restricciones en el crecimiento cerebral. Quedan todavía numerosos aspectos por esclarecer con respecto a la administración prenatal de corticoides, fundamentalmente relacionados con sus efectos a largo plazo, pero, a la luz de los conocimientos actuales, los efectos beneficiosos están fuera de toda duda

Molecular characterization of acute myeloblastic leukemia according to the new WHO classification: a different distribution in Central-West Spain.

BACKGROUND AND OBJECTIVES: Molecular analysis has contributed to the identification of several non-random chromosomal translocations, such as t(15;17), t(8:21), inv(16)/t(16;16) and 11q23 abnormalities, typically associated with acute myeloid leukemia (AML). The identification of these chromosomal abnormalities helps not only to define different AML subtypes with distinct prognoses and treatments but also to monitor the disappearance of malignant cells after treatment. Recent reports suggest that the frequency of these alterations may differ according to geographic distribution. However, most of these reports focus on just one or two genetic alterations, which may lead to some selection bias. Appropriate epidemiological studies should be based on unselected consecutive series of patients in which all relevant genes are simultaneously analyzed. The aim of the present study was to explore whether or not the incidence of genetic lesions in Spanish AML patients differs from that reported in other countries. DESIGN AND METHODS: In a series of 145 consecutive un-selected adult patients with AML we simultaneously analyzed the presence of 4 genetic abnormalities, PML/RARalpha for t(15;17), AML1/ETO for t(8;21), CBFbeta/MYH11 for inv(16)/t(16;16) and rearrangements of the MLL gene for 11q23 abnormalities. AML were classified using the new World Health Organization (WHO) classification for hematologic malignancies. The techniques used were standardized according to the recommendations of the European BIOMED-1 Concerted Action. RESULTS: The PML/RARalpha transcript was present in 34 patients (23.4%) (23 were bcr1, 2 bcr2 and 9 bcr3). The AML1/ETO fusion transcript was detected in only 2 cases (1.4%) both with M2 morphology, but 29 other cases with M2 morphology were negative. CBFbeta/MYH11 transcript was present in 9 cases (6.2%) eight of them displaying M4Eo morphology. Finally, 5 cases (3.5%) showed rearrangements of theMLL gene. Our results differ from those reported from the United States and North/Central Europe, particularly regarding the incidence of t(15;17) and t(8;21) translocations. In Spain the frequency of t(15;17) is higher while that of t(8;21) is lower. INTERPRETATION AND CONCLUSIONS: These data add epidemiological information about geographic heterogeneity of such chromosome aberrations in AML and would contribute to the design of specific screening strategies adapted to the incidence in each country.

p16/INK4a gene inactivation by hypermethylation is associated with aggressive variants of monoclonal gammopathies.

INTRODUCTION: A model of a stepwise malignant transformation has been proposed for the pathogenesis of monoclonal gammopathies. In this model, cell cycle regulators play a central role as a source of genetic events; particularly, p16/INK4a gene acts as a tumoral suppressor gene and, recently, inactivation of this gene through a methylation mechanism, has been observed in multiple myeloma patients. Under the diagnosis of monoclonal gammopathies there is a broad spectrum of disorders with very different outcomes, ranging from indolent courses, such as those of monoclonal gammopathy of undetermined significance, Waldeströn macroglobulinemia and smoldering multiple myeloma, to aggressive diseases such as symptomatic MM and primary plasma cell leukemia. To the best of our knowledge, the activity of p16 gene has not been evaluated and compared in these different subtypes of monoclonal gammopathies. MATERIALS AND METHODS: The methylation status of the p16 gene was analysed in a group of 159 patients with monoclonal gammopathies (40 monoclonal gammopathy of uncertain significance, eight Waldenström Macroglobulinemia, eight smoldering multiple myeloma, 98 symptomatic multiple myeloma and five primary plasma cell leukemia) using three different assays (restriction enzymes and PCR or S-B and modification by sodium bisulphite). RESULTS: Forty-one of 98 MM patients (41.8%) as well as four of the five (80%) primary PCL patients showed methylation of the p16 gene, while none of the patients with monoclonal gammopathy of undetermined significance, Waldenström Macroglobulinemia or smoldering multiple myeloma displayed a methylation status. CONCLUSION: These findings suggest that the methylation of the p16 gene could be a relevant oncogenic event in the monoclonal gammopathies evolution being associated with the most aggressive forms.

Increased conventional chemotherapy does not improve survival in multiple myeloma: long-term results of two PETHEMA trials including 914 patients.

BACKGROUND: Melphalan and prednisone (MP) has been the standard treatment for multiple myeloma (MM) for the last 30 years. Combination chemotherapy at conventional doses has not shown a significant prolongation of survival when compared to MP. There are few data comparing conventional chemotherapy at standard doses with conventional treatment at higher doses. We present the long-term outcome of 914 patients from two randomized trials comparing three different dose intensity regimens. METHODS: From 1 January, 1985 to 31 December, 1989, 487 patients were randomized between MP (melphalan 9 mg/m(2) p.o. and prednisone 60 mg/m(2) days 1-4) and alternating VCMP (vincristine 1 mg i.v. on day 1, cyclophosphamide 500 mg/m(2) i.v. on day 1, melphalan 6 mg/m(2) p.o. on days 1-4, and prednisone 60 mg/m(2) on days 1-4) and VBAP (vincristine 1 mg i.v. on day 1, BCNU and doxorubicin 30 mg/m(2) i.v. each on day 1, and prednisone 60 mg/m(2) on days 1-4). From 1 January, 1990 to 31 May, 1994, 427 patients were randomized between VCMP/VBAP at the above detailed doses (VCMP/VBAP 'SD') and the same regimen increasing the doses of cyclophosphamide and doxorubicin from 500 to 1200 mg/m(2) and from 30 to 50 mg/m(2), respectively (VCMP/VBAP 'HD'). RESULTS: Increasing dose intensity produced a significantly higher partial response rate (31% vs 45% vs 51% for MP, VCMP/VBAP 'SD', and VCMP/VBAP 'HD', respectively; P < 0.01). However, a significantly early death rate was observed in the HD arm (7.7, 7.5 and 12.1% for MP, VCMP/VBAP 'SD', and VCMP/VBAP 'HD', respectively; P = 0.05). Median duration of response (20 vs 18 vs 19 months for MP, VCMP/VBAP 'SD', and VCMP/VBAP 'HD', respectively; P = NS) and median survival (25 vs 31 vs 29 months for MP, VCMP/VBAP 'SD', and VCMP/VBAP 'HD', respectively; P = NS) were similar in the three groups. MP produced a higher degree of thrombocytopenia than combination chemotherapy at standard (P = 0.002) or high dose (P = 0.01), this leading to a significantly higher dose reduction in the MP arm (P < 0.001 and P = 0.003 for VCMP/VBAP 'SD' and VCMP/VBAP 'HD', respectively). CONCLUSION: In these trials the response rate significantly correlated with the regimen intensity. However, no significant differences in response duration and survival were found. This highlights the limited role of conventional chemotherapy in MM and the need for further trials, aimed at determining the impact of new treatment approaches such as high-dose therapy/autotransplantation.

Correlation between cytogenetic abnormalities and disease characteristics in multiple myeloma: monosomy of chromosome 13 and structural abnormalities of 11q are associated with a high percentage of S-phase plasma cells.

BACKGROUND AND OBJECTIVES: Cytogenetic studies in multiple myleoma (MM) are limited by the difficulties in obtaining metaphases that can be investigated and few studies have analyzed the relationship between cytogenetics and clinical disease characteristics. The aim of our study was to analyze the recurrent cytogenetic changes in MM and to correlate them with clinical and biological characteristics including the percentage of S-phase plasma cells (PCs). DESIGN AND METHODS: Chromosomal abnormalities were analyzed in 86 patients with MM. In all patients, two types of cultures (5 d culture with interleukin-4 and unstimulated 72 h culture) were used for cytogenetic analysis. DNA content analysis (ploidy and cell cycle analysis) together with the most relevant clinical and biological disease features were studied. RESULTS: Cytogenetic analysis was successful in 72 of the 86 patients (84%). Forty-seven patients (65%) had an abnormal karyotype. The most frequent trisomies involved chromosomes 3, 5, 9, 11, 15, 19, 22, 1, 7, 17, 18, and 21, and monosomies affected chromosomes 13 and 8, while structural changes involved chromosomes 1, 11, 14q32, 4p16 and 16q22-23. Patients with abnormal karyotype displayed a poor performance status, advanced stage, anemia and a high percentage of bone marrow plasma cells. In addition, MM patients with -13/13q- and 11q abnormalities showed a significantly higher proportion of S-phase PCs (p=0.02). INTERPRETATION AND CONCLUSIONS: In summary, our study shows a relationship between unfavorable cytogenetics (-13/13q-/11q abnormalities) and a high percentage of S-phase PCs, a well-known adverse prognostic factor.

[Early diagnosis of childhood deafness: detection protocol in high-risk neonates]. / Diagnóstico precoz de hipoacusia infantil: protocolo de detección en neonatos de alto riesgo.

The protocol developed at our hospital for auditory assessment of children with risk factors for deafness is presented. The results obtained with tympanometry and auditory brainstem response (ABR) audiometry from October 1994 to March 1998 were analyzed. In 122 children, 17 cases (14%) of severe-to-profound bilateral deafness were found. Only 50% of these cases were associated with risk factors present at birth. The average age at time of diagnosis of deafness was over 3 years. In view of these results, we recommend auditory screening for all newborns as the only effective procedure for early detection of childhood deafness.

Markers of pulmonary inflammation in tracheobronchial fluid of premature infants with respiratory distress syndrome.

To asses the role of pulmonary inflammation in the outcome of preterm neonates with respiratory distress syndrome (RDS) we measured soluble intercellular adhesion molecule-1 (ICAM-1), interleukin-8 (IL-8), eosinophil cationic protein (ECP) and transforming growth factor beta-1 (TGF beta 1) in tracheobronquial lavage (TBL) fluid of 15 preterm infants; 9/15 completely recovered from RDS and 6/15 developed chronic lung disease (CLD). ICAM-1 (p: 0.001) and TGF beta 1 (p: 0.04) levels increased in TBL fluid during the first days of life. The values of ICAM-1 were correlated to the days of 0(2) and mechanical ventilation dependency. At 3 days of age, ICAM-1 levels in TBL fluid were higher in infants who later developed CLD compared to infants without CLD (24.5 vs 8.3 micrograms/ml; p: 0.02). Thereafter no significant differences were found although the CLD group had higher values. IL-8 levels showed a fall, specially from 1 to 3 days of age in children without CLD (77.0 to 41.7 ng/ml) although not significant. No difference in TGF beta 1 values were found between both groups, but the TGF beta 1 levels were lower in patients with CLD and they showed undetectable values in 8 samples. ICAM-1 is a major factor associated with airways inflammation whereas IL-8 is not a good marker during the first days of life to predict the RDS outcome. A defect of TGF beta 1 in the smallest premature infants may delay the lung repair process which occurs after tissue injury. High ICAM-1 levels and low TGF beta 1 levels in lung fluid are related to oxygen dependency at 28 days of age.

Primary plasma cell leukemia: clinical, immunophenotypic, DNA ploidy, and cytogenetic characteristics.

We report on a series of 26 patients diagnosed with primary (de novo) plasma cell (PC) leukemia (PCL) in whom we analyzed the clinicobiologic characteristics of the disease together with the immunophenotype, DNA cell content, proliferative index, and numeric chromosomal aberrations of the neoplastic PC, and compared them with 664 multiple myeloma (MM) patients at diagnosis. The median age, sex ratio, and bone lesion extension were similar, but PCL cases displayed a higher prevalence of clinical stage III, extramedullary involvement, and Bence Jones cases, with fewer IgA cases than for MM patients. In addition, according to several prognostic indicators (beta2-microglobulin serum level, proportion of S-phase PCs, proteinuria, calcium serum level, lactate dehydrogenase [LDH] and renal function), the incidence of adverse prognostic factors was significantly higher in PCL versus MM. Immunophenotypic expression was similar for CD38, CD138, CD2, CD3, CD16, CD10, CD13, and CD15, but PCL differed from MM in the expression of CD56, CD9 HLA-DR, CD117, and CD20 antigens. Twenty-two PCL cases were diploid and one was hypodiploid, while most MM cases (57%) showed DNA hyperdiploidy. With the fluorescent in situ hydridization (FISH) technique, 12 of 13 PCL cases displayed the numeric aberrations, -13 (86%), +/-1 (57%), +18 (43%), and -X in women (25%), but they lacked several numeric aberrations usually found in MM such as +3, +6, +9, +11, and +15. PCL cases had a lower overall response to therapy than MM cases (38% v 63%, P =.01332). Among PCL patients, a trend for a worse response was observed in cases treated with melphalan and prednisone (MP) versus polychemotherapy. Overall survival was significantly worse in PCL versus MM patients (8 v 36 months, P <.0001), but it was significantly better in PCL patients treated with polychemotherapy versus MP (18 v 3 months, P =.0137). By contrast, MM patients did not show significant differences in overall survival according to the treatment used, MP or polychemotherapy. Ten variables seemed to predict survival in PCL patients, but only the beta2-microglobulin level and S-phase PCs retained an independent value in multivariate analysis. In summary, our study illustrates that PCs from PCL display singular phenotypic, DNA cell content, and cytogenetic characteristics that lead to a different disease evolution versus MM.

In vitro growth in acute myeloblastic leukaemia: relationship with other clinico-biological characteristics of the disease.

The in vitro growth characteristics of a large series of acute myeloid leukaemia (AML) patients and their relationship with other clinical and biological disease characteristics were analysed. Patients with AML were studied, 181 with de novo AML and 45 with secondary AML (24 myelodysplastic syndrome, sAML-MDS, 21 myeloproliferative disorder, sAML-MPD). Leukaemic colony forming units (L-CFU) were assayed by plating peripheral blood (PB) blast cells in methyl-cellulose and using LCM-PHA as stimulant. In each case parallel cultures were made with and without stimulating factors. Plating efficiency (PE) was defined as the number of clusters plus colonies/10(5) cells plated. Autonomous growth (AG) was the number of colonies plus clusters growing without stimulant. The autonomous proliferative index (API) was calculated as the number of clusters + colonies without stimulating factor divided by the number of clusters + colonies with stimulating factor. No significant differences in the PE between de novo and secondary AML were found. Autonomous growth was significantly higher in sAML-MPD. The FAB subtype M3 leukaemias displayed a significantly greater PE and a significantly lower API when compared with the other FAB subgroups (P=0.0002). Upon analysing the relationship with the immunophenotype, only CD33 expression showed a significant relationship with the in vitro growth pattern; CD33+ cases displayed a higher PE (P=0.0002) and AG (P=0.0003) than CD33- cases. When patients were grouped according to the level of rh123 efflux (MDR1) it was observed that cases with >30% elimination showed a higher AG and API than those with <30% (P=0.03). Finally we found that patients with higher API (>0.05) displayed a significantly shorter overall survival as compared with patients with API<0.05 (P=0.04). The in vitro study properties of clonogenic cells produces relevant clinical information of leukaemic cell biology in AML patients.

Prognostic value of numerical chromosome aberrations in multiple myeloma: A FISH analysis of 15 different chromosomes.

Recent observations indicate that chromosome aberrations are important prognostic factors in patients with multiple myeloma (MM) treated with high-dose chemotherapy. Nevertheless, the inherent problems of conventional cytogenetics have hampered the systematic evaluation of this parameter in series of patients treated with conventional chemotherapy. Fluorescence in situ hybridization (FISH) analysis is an attractive alternative for evaluation of numerical chromosomal changes. In the present study, we analyze the relationship between aneuploidies of 15 different chromosomes assessed by FISH and prognosis in a series of 63 patients with MM treated with conventional chemotherapy. After a median follow-up of 61 months (range, 6 to 109), 49% of patients are still alive with a median survival of 33 months. The overall incidence of numerical chromosome abnormalities was 70%. This incidence significantly increased when seven or more chromosomes were analyzed (53 patients), reaching 81%. Trisomies of chromosomes 6, 9, and 17 were associated with prolonged survival (P = .033, P = .035, and P = .026, respectively); by contrast, overall survival (OS) was lower in cases with monosomy 13 (as assessed by deletion of Rb gene, P = .0012). From the clinical point of view, loss of Rb gene was associated with a poor performance status; low hemoglobin levels; high creatinine, C-reactive protein, and lactic dehydrogenase serum levels; high percentage of bone marrow plasma cells (BMPC); extensive bone lytic lesions; and advanced clinical stage. Other chromosome abnormalities such as trisomy of chromosome 9 and 17 were associated with good prognostic features including high hemoglobin levels, early clinical stage, beta2microglobulin less than 6 micro/mL, and low percentage of BMPC. A multivariate analysis for OS showed that S-phase PC greater than 3% (P = .010) and beta2microglobulin serum levels greater than 6 micro/mL (P = .024), together with monosomy of chromosome 13 (P = .031) and nontrisomy of chromosome 6 (P = .048) was the best combination of independent parameters for predicting survival in patients with MM. According to these results, chromosomal analysis is of great use in patients with MM at diagnosis to have a correct prognostic evaluation for clinical decision making.