Hepatotoxicity as dose-limiting toxicity of the combination of bosutinib and atezolizumab in patients with chronic myeloid leukemia. Results of the ZEROLMC study.

In the field of chronic myeloid leukemia (CML), new strategies are needed to increase the rate of successful treatment discontinuations, a crucial goal in this disease. Anti-PD-L1 checkpoint inhibitors are a promising therapeutic approach in CML after the demonstration of an increase of these inhibitory molecules in patients with CML. A phase Ib/II (NCT04793399, registration date March 11, 2021) open-label exploratory trial has been conducted to evaluate the safety of atezolizumab, a humanized anti-PD-L1 antibody, in combination with bosutinib in patients with newly diagnosed chronic phase CML. A total of 36 patients were planned to be enrolled, but the study had to be prematurely terminated due to safety concerns. Nine patients were included in the study, and only 8 went on to receive the combination with atezolizumab. There were a total of 44 adverse events (AEs) during the study period. The most frequent were gastrointestinal (50%), mostly mild (86% grade 1-2). The most serious AEs were hepatic. There were 17 hepatic AEs in 5 patients. Of the hepatic AEs 5 were during the bosutinib monotherapy phase and 12 during the combination phase (AST increase x4, ALT increase x4, blood bilirubin increase x1, alkaline phosphatase elevation x2, GGT increase x2), most of them grade 3-4. There were 2 patients who presented a dose-limiting toxicity; a grade 3 elevation of transaminases, that led to premature termination of the study. The combination of atezolizumab with bosutinib presents hepatotoxicity as a dose-limiting effect and therefore we do not recommend to explore this combination in future studies.

Comprehensive Custom NGS Panel Validation for the Improvement of the Stratification of B-Acute Lymphoblastic Leukemia Patients.

BACKGROUND: B-acute lymphoblastic leukemia (B-ALL) is a hematological neoplasm of the stem lymphoid cell of the B lineage, characterized by the presence of genetic alterations closely related to the course of the disease. The number of alterations identified in these patients grows as studies of the disease progress, but in clinical practice, the conventional techniques frequently used are only capable of detecting the most common alterations. However, techniques, such as next-generation sequencing (NGS), are being implemented to detect a wide spectrum of new alterations that also include point mutations. METHODS: In this study, we designed and validated a comprehensive custom NGS panel to detect the main genetic alterations present in the disease in a single step. For this purpose, 75 B-ALL diagnosis samples from patients previously characterized by standard-of-care diagnostic techniques were sequenced. RESULTS: The use of the custom NGS panel allowed the correct detection of the main genetic alterations present in B-ALL patients, including the presence of an aneuploid clone in 14 of the samples and some of the recurrent fusion genes in 35 of the samples. The panel was also able to successfully detect a number of secondary alterations, such as single nucleotide variants (SNVs) and copy number variations (CNVs) in 66 and 46 of the samples analyzed, respectively, allowing for further refinement of the stratification of patients. The custom NGS panel could also detect alterations with a high level of sensitivity and reproducibility when the findings obtained by NGS were compared with those obtained from other conventional techniques. CONCLUSIONS: The use of this custom NGS panel allows us to quickly and efficiently detect the main genetic alterations present in B-ALL patients in a single assay (SNVs and insertions/deletions (INDELs), recurrent fusion genes, CNVs, aneuploidies, and single nucleotide polymorphisms (SNPs) associated with pharmacogenetics). The application of this panel would thus allow us to speed up and simplify the molecular diagnosis of patients, helping patient stratification and management.

Chronic lymphocytic leukemia patients with IGH translocations are characterized by a distinct genetic landscape with prognostic implications.

Chromosome 14q32 rearrangements/translocations involving the immunoglobulin heavy chain (IGH) are rarely detected in chronic lymphocytic leukemia (CLL). The prognostic significance of the IGH translocation is controversial and its mutational profile remains unknown. Here, we present for the first time a comprehensive next-generation sequencing (NGS) analysis of 46 CLL patients with IGH rearrangement (IGHR-CLLs) and we demonstrate that IGHR-CLLs have a distinct mutational profile with recurrent mutations in NOTCH1, IGLL5, POT1, BCL2, FBXW7, ZMYM3, MGA, BRAF and HIST1H1E genes. Interestingly, BCL2 and FBXW7 mutations were significantly associated with this subgroup and almost half of BCL2, IGLL5 and HISTH1E mutations reported were previously identified in non-Hodgkin lymphomas. Notably, IGH/BCL2 rearrangements were associated with a lower mutation frequency and carried BCL2 and IGLL5 mutations, while the other IGHR-CLLs had mutations in genes related to poor prognosis (NOTCH1, SF3B1 and TP53) and shorter time to first treatment (TFT). Moreover, IGHR-CLLs patients showed a shorter TFT than CLL patients carrying 13q-, normal fluorescence in situ hybridization (FISH) and +12 CLL, being this prognosis particularly poor when NOTCH1, SF3B1, TP53, BIRC3 and BRAF were also mutated. The presence of these mutations not only was an independent risk factor within IGHR-CLLs, but also refined the prognosis of low-risk cytogenetic patients (13q-/normal FISH). Hence, our study demonstrates that IGHR-CLLs have a distinct mutational profile from the majority of CLLs and highlights the relevance of incorporating NGS and the status of IGH by FISH analysis to refine the risk-stratification CLL model.

Treatment of Frail Older Adults and Elderly Patients With Philadelphia Chromosome-negative Acute Lymphoblastic Leukemia: Results of a Prospective Trial With Minimal Chemotherapy.

BACKGROUND: The treatment of acute lymphoblastic leukemia (ALL) in older adults and elderly patients is a challenge, and modern protocols include targeted therapy and immunotherapy in combination with attenuated or minimal chemotherapy. However, frail patients are excluded from these trials, and reports on the outcome of this subgroup of patients are scarce. Our objective was to analyze the outcome of unfit older adults and elderly patients with Philadelphia chromosome-negative ALL included in a prospective trial (ALL-07FRAIL). PATIENTS AND METHODS: Older adults and elderly patients with Charlson Comorbidity Index (CCI) ≥ 4 were included. Induction therapy consisted of vincristine and dexamethasone, and maintenance therapy with mercaptopurine and methotrexate for 2 years. RESULTS: Seventy-two patients with a median age of 67 years (range, 57-89 years) and a median CCI of 5 (range, 4-12) were included. The rates of early withdrawal, early death, resistance, and complete response (CR) were 5%, 10%, 31%, and 54%, respectively. Six patients with CR abandoned the study, 5 died in CR, and 23 relapsed (cumulative relapse incidence 75%). The medians of disease-free and overall survival (OS) were 6.9 months (95% confidence interval [CI], 0.3-13.5 months) and 7.6 months (95% CI, 6.3-8.9 months), respectively. The most frequent toxic events were hematologic (neutropenia 77% and thrombocytopenia 54%, of grade III-IV in all cases). Eastern Cooperative Oncology Group score but not the CCI had significant impact on OS. CONCLUSION: Complete remission with very attenuated chemotherapy can be attained in one-half of older or elderly infirm patients with ALL. These results suggest that some of these patients could benefit from the concomitant or subsequent use of immunotherapy and/or targeted therapy.

Next-generation sequencing and FISH studies reveal the appearance of gene mutations and chromosomal abnormalities in hematopoietic progenitors in chronic lymphocytic leukemia.

BACKGROUND: Chronic lymphocytic leukemia (CLL) is a highly genetically heterogeneous disease. Although CLL has been traditionally considered as a mature B cell leukemia, few independent studies have shown that the genetic alterations may appear in CD34+ hematopoietic progenitors. However, the presence of both chromosomal aberrations and gene mutations in CD34+ cells from the same patients has not been explored. METHODS: Amplicon-based deep next-generation sequencing (NGS) studies were carried out in magnetically activated-cell-sorting separated CD19+ mature B lymphocytes and CD34+ hematopoietic progenitors (n = 56) to study the mutational status of TP53, NOTCH1, SF3B1, FBXW7, MYD88, and XPO1 genes. In addition, ultra-deep NGS was performed in a subset of seven patients to determine the presence of mutations in flow-sorted CD34+CD19- early hematopoietic progenitors. Fluorescence in situ hybridization (FISH) studies were performed in the CD34+ cells from nine patients of the cohort to examine the presence of cytogenetic abnormalities. RESULTS: NGS studies revealed a total of 28 mutations in 24 CLL patients. Interestingly, 15 of them also showed the same mutations in their corresponding whole population of CD34+ progenitors. The majority of NOTCH1 (7/9) and XPO1 (4/4) mutations presented a similar mutational burden in both cell fractions; by contrast, mutations of TP53 (2/2), FBXW7 (2/2), and SF3B1 (3/4) showed lower mutational allele frequencies, or even none, in the CD34+ cells compared with the CD19+ population. Ultra-deep NGS confirmed the presence of FBXW7, MYD88, NOTCH1, and XPO1 mutations in the subpopulation of CD34+CD19- early hematopoietic progenitors (6/7). Furthermore, FISH studies showed the presence of 11q and 13q deletions (2/2 and 3/5, respectively) in CD34+ progenitors but the absence of IGH cytogenetic alterations (0/2) in the CD34+ cells. Combining all the results from NGS and FISH, a model of the appearance and expansion of genetic alterations in CLL was derived, suggesting that most of the genetic events appear on the hematopoietic progenitors, although these mutations could induce the beginning of tumoral cell expansion at different stage of B cell differentiation. CONCLUSIONS: Our study showed the presence of both gene mutations and chromosomal abnormalities in early hematopoietic progenitor cells from CLL patients.

La soledad en el cibermundo: el suelo digital en la adolescencia / Lonelilness in the cyber-world: the digital dream and adolescents

Este trabajo reflexiona sobre los nuevos medios tecnológicos. El cibermundo está caracterizado por la inmediatez, la velocidad y una información desbordante, pero también mediatizado por la exhibición y la pérdida de la intimidad. Entre las variables que se abordan está el uso de las realidades virtuales frente a las dificultades en la representación psíquica motivada por los traumatismos de la primera infancia. Indaga este trabajo en los vínculos reflectantes, definidos por su dependencia extrema y retroalimentación narcisista constante. Estos vínculos se establecen como defensa frente al vacío y al dolor. También se investiga en la tecnocultura como medio para satisfacer la pulsión inmediata y para anular el contacto con las fantasías del mundo interno. En esta investigación se observa el proceso psicoanalítico de una adolescente en tratamiento durante cuatro años y se exponen secuencialmente los procesos transfero-contratransferenciales. Finalmente se muestra el uso del cibermundo al servicio de la elaboración psíquica como una actividad transicional asociada a la creatividad (AU)

The purpose of this work is to examine the technological resources available today. The cyber-world is characterised by its immediacy, speed and the overwhelming amount of information it provides; however, it is also known for allowing personal exposure and loss of privacy. Among its several variables, we examine how virtual reality is used to handle the difficulties entailed in the psychical representation of early childhood trauma. This work also addresses the reflective links, defined by heavy dependence and constant narcissist feedback. These links are established as a defence against emptiness and pain. We also deal with techno-culture as a means to fulfil immediate drive and to eliminate contact with the fantasies of the inner world. This review analyses the psychoanalytical process of an adolescent who has been undergone treatment for four years, and transference and counter-transference processes are sequentially presented. Finally, the paper shows the use of the cyber-world at the service of psychical elaboration, as a transitional activity linked to creativity (AU)

Genome-Wide DNA Copy Number Analysis of Acute Lymphoblastic Leukemia Identifies New Genetic Markers Associated with Clinical Outcome.

UNLABELLED: Identifying additional genetic alterations associated with poor prognosis in acute lymphoblastic leukemia (ALL) is still a challenge. AIMS: To characterize the presence of additional DNA copy number alterations (CNAs) in children and adults with ALL by whole-genome oligonucleotide array (aCGH) analysis, and to identify their associations with clinical features and outcome. Array-CGH was carried out in 265 newly diagnosed ALLs (142 children and 123 adults). The NimbleGen CGH 12x135K array (Roche) was used to analyze genetic gains and losses. CNAs were analyzed with GISTIC and aCGHweb software. Clinical and biological variables were analyzed. Three of the patients showed chromothripsis (cth6, cth14q and cth15q). CNAs were associated with age, phenotype, genetic subtype and overall survival (OS). In the whole cohort of children, the losses on 14q32.33 (p = 0.019) and 15q13.2 (p = 0.04) were related to shorter OS. In the group of children without good- or poor-risk cytogenetics, the gain on 1p36.11 was a prognostic marker independently associated with shorter OS. In adults, the gains on 19q13.2 (p = 0.001) and Xp21.1 (p = 0.029), and the loss of 17p (p = 0.014) were independent markers of poor prognosis with respect to OS. In summary, CNAs are frequent in ALL and are associated with clinical parameters and survival. Genome-wide DNA copy number analysis allows the identification of genetic markers that predict clinical outcome, suggesting that detection of these genetic lesions will be useful in the management of patients newly diagnosed with ALL.

Estudio de incidencia de las neoplasias hematopoyéticas en Castilla y León / Incidence of haematological neoplasms in Castilla y León, Spain

Fundamento y objetivo: Conocer la incidencia de las neoplasias hematopoyéticas (NH) en Castilla y León, una región de 2,5 millones de habitantes, y su distribución en función de la edad, el sexo y el subtipo histológico. Pacientes y método: Se ha analizado el perfil epidemiológico en función de las variables descritas de las 10.943 NH diagnosticadas durante un período de 10 años, comparándolo con el de otros estudios. Resultados: La incidencia ajustada por edad alcanzó 29,4 casos/105 habitantes-año, con ciertas variaciones geográficas. La edad media fue de 67,3 años, con un punto de inflexión entre la sexta y séptima décadas de la vida, a partir del cual se produjo un aumento muy importante de la incidencia. A medida que avanzaba la edad, ocurrieron de forma paralela otros 2 hechos relevantes: una disminución de la incidencia de los procesos linfoides y el aumento de la de las neoplasias de bajo grado de agresividad. Los procesos linfoides de bajo grado representaron la mitad de los casos del registro, mostraron una mayor preferencia por el sexo masculino y alcanzaron la moda antes que el resto de las NH. La incidencia de neoplasias mieloides (9,5) fue superior a la descrita en otros registros europeos, especialmente en los países del sur de Europa, contrariamente a lo observado con las neoplasias linfoides (20,0). Conclusiones: Se observó una mayor incidencia de neoplasias mieloides y menor de linfoides de lo esperado. El punto de inflexión de incidencia se situó entre la sexta y séptima décadas de la vida, con predominio del sexo masculino, que se reduce con el aumento de la edad. La mayor incidencia de NH se observó en la zona donde se concentra una mayor densidad de industrias potencialmente contaminantes (AU)

Background and objective: We aimed to assess the incidence of haematological neoplasms (HNs) in Castilla y León (2,5 million inhabitants) and its distribution by age, gender and histological type. Patients and method: The epidemiological profile based on the described variables of the 10,943 HNs diagnosed during a 10-years period was analyzed, compared with other studies. Results: The overall age-adjusted incidence was 29.4 cases/105 inhabitants-year, with some geographical differences. The mean age was 67.3 years, with a turning point between the 6th-7th decades of life from which there was a very significant increase of incidence. Two relevant facts where simultaneous with advancing age: decreased lymphoid neoplasms incidence and increased low degree neoplasms incidence. Lymphoid low degree neoplasms accounted for half of the registered processes, showed the greatest preference for male and reached the mode before the rest of neoplasms. Myeloid neoplasms incidence (9.5) was higher than that reported in other European registries, specially compared to southern European countries, opposite to lymphoid neoplasms incidence (20.0). Conclusions: A higher myeloid neoplasms incidence and lower lymphoid one than expected was observed. The turning point of incidence is between the 6th-7th decades of life, with a preference for male that decreases with age. There is an increased incidence of HNs in the area where a higher density of potentially polluting facilities is concentrated (AU)

The cellular origin and malignant transformation of Waldenström macroglobulinemia.

Although information about the molecular pathogenesis of Waldenström macroglobulinemia (WM) has significantly advanced, the precise cell of origin and the mechanisms behind WM transformation from immunoglobulin-M (IgM) monoclonal gammopathy of undetermined significance (MGUS) remain undetermined. Here, we undertook an integrative phenotypic, molecular, and genomic approach to study clonal B cells from newly diagnosed patients with IgM MGUS (n = 22), smoldering (n = 16), and symptomatic WM (n = 11). Through principal component analysis of multidimensional flow cytometry data, we demonstrated highly overlapping phenotypic profiles for clonal B cells from IgM MGUS, smoldering, and symptomatic WM patients. Similarly, virtually no genes were significantly deregulated between fluorescence-activated cell sorter-sorted clonal B cells from the 3 disease groups. Interestingly, the transcriptome of the Waldenström B-cell clone was highly different than that of normal CD25(-)CD22(+) B cells, whereas significantly less genes were differentially expressed and specific WM pathways normalized once the transcriptome of the Waldenström B-cell clone was compared with its normal phenotypic (CD25(+)CD22(+low)) B-cell counterpart. The frequency of specific copy number abnormalities [+4, del(6q23.3-6q25.3), +12, and +18q11-18q23] progressively increased from IgM MGUS and smoldering WM vs symptomatic WM (18% vs 20% and 73%, respectively; P = .008), suggesting a multistep transformation of clonal B cells that, albeit benign (ie, IgM MGUS and smoldering WM), already harbor the phenotypic and molecular signatures of the malignant Waldenström clone.

[Incidence of haematological neoplasms in Castilla y León, Spain]. / Estudio de incidencia de las neoplasias hematopoyéticas en Castilla y León.

BACKGROUND AND OBJECTIVE: We aimed to assess the incidence of haematological neoplasms (HNs) in Castilla y León (2,5 million inhabitants) and its distribution by age, gender and histological type. PATIENTS AND METHOD: The epidemiological profile based on the described variables of the 10,943 HNs diagnosed during a 10-years period was analyzed, compared with other studies. RESULTS: The overall age-adjusted incidence was 29.4 cases/10(5) inhabitants-year, with some geographical differences. The mean age was 67.3 years, with a turning point between the 6th-7th decades of life from which there was a very significant increase of incidence. Two relevant facts where simultaneous with advancing age: decreased lymphoid neoplasms incidence and increased low degree neoplasms incidence. Lymphoid low degree neoplasms accounted for half of the registered processes, showed the greatest preference for male and reached the mode before the rest of neoplasms. Myeloid neoplasms incidence (9.5) was higher than that reported in other European registries, specially compared to southern European countries, opposite to lymphoid neoplasms incidence (20.0). CONCLUSIONS: A higher myeloid neoplasms incidence and lower lymphoid one than expected was observed. The turning point of incidence is between the 6th-7th decades of life, with a preference for male that decreases with age. There is an increased incidence of HNs in the area where a higher density of potentially polluting facilities is concentrated.

Safety and efficacy of splenectomy in over 65-yrs-old patients with immune thrombocytopenia.

AIM: Few studies specifically focus on elderly splenectomized immune thrombocytopenia (ITP) patients. Older patients with ITP and excellent health are often excluded from surgery splenectomy. We aimed to compare the safety and efficacy of splenectomy in elderly and non-elderly ITP patients and to examine the effect of age on therapeutic response. MATERIAL AND METHODS: We carried out a retrospective analysis of a series of 218 patients who had undergone splenectomy for ITP. We compared the data from the elderly group (≥65 yrs, 57 patients) with the young group (<65 yrs, 162 patients). RESULTS: Surgical technique (laparoscopy or open laparotomy splenectomy) was comparable between the two age groups. The adjusted risk of major bleeding following splenectomy for elderly patients was three times that for young patients (OR 3.05, 95% CI: 1.44-6.52). The median duration of postoperative hospital stay was longer for elderly than for young patients (8 d vs. 4 d, P < 0.001). However, we identified a subgroup of elderly ITP patients, those aged between 65 and 70 yrs who had undergone laparoscopic splenectomy, with a low risk of postoperative complications. Of the 218 patients, 89% achieved a favorable response to splenectomy. A favorable response was significantly less common in elderly than in young people (79% vs. 92%, P = 0.005). However, we observed an acceptable long-term control of ITP in the elderly group, in which the probability of maintaining response for 14 yrs after splenectomy was 56%. CONCLUSIONS: Patients aged ≥65 yrs experienced negative effects on safety and efficacy outcomes of splenectomy for ITP, but further studies are needed to identify predictors of postsplenectomy outcomes in this group.

The clinical utility and prognostic value of multiparameter flow cytometry immunophenotyping in light-chain amyloidosis.

The clinical value of multiparameter flow cytometry (MFC) immunophenotyping in primary or light chain amyloidosis (AL) remains unknown. We studied 44 consecutive bone marrow samples from newly diagnosed patients with amyloidosis; 35 patients with AL and 9 with other forms of amyloidosis. Monoclonal plasma cells (PCs) were identifiable by MFC immunophenotyping in 34 of 35 (97%) patients with AL, whereas it was absent from all but 1 of the 9 (11%) patients with other forms of amyloidosis. Quantification of bone marrow plasma cells (BMPCs) by MFC immunophenotyping was a significant prognostic factor for overall survival (OS) (≤ 1% vs > 1% BMPC cutoff; 2-year OS rates of 90% vs 44%, P = .02). Moreover, detecting persistent normal PCs at diagnosis identifies a subgroup of patients with AL with prolonged OS (> 5% vs ≤ 5% normal PC within all BMPC cutoff, 2-year rates of 88% vs 37%, P = .01). MFC immunophenotyping could be clinically useful for the demonstration of PC clonality in AL and for the prognostication of patients with AL.

La función integradora de un sueño repetitivo y su vinculación con el masoquismo / The integrative frunction of a repetitive dream and its relationship with masochism

El artículo estudia en dos niveles la elaboración de un sueño repetitivo desde la adolescencia. Un primer nivel, de origen narcisista, está relacionado con las dificultades de separación y con la simbolización en la piel. En otro plano más evolucionado se analizan los aspectos conectados a una problemática de un marcado carácter edípico. Este último enfoque investiga en los sentimientos de culpa inconscientes asociados a los fracasos y a los problemas del masoquismo. En la exposición se analizan los obstáculos con pacientes que presentan en momentos de la cura dificultades de representación y su efecto en la contratransferencia. Por último, hay una reflexión sobre los conflictos intergeneracionales y su vinculación con la organización pub eral de los adultos (AU)

The elaboration of a recurring dream which appears in adolescence is analysed in this article at two different stafes. A first stage, of a narcissistic origin, is concected with the difficulties derived from detachment and also from skin symbolization. A further more envolved stage analyses elements connected to a distinctly oedipal setting. This latter perspective dives into the unconscious feelings of guilt associated with failure and with problems of masochism. The obstacles set by patients who during their recovering process show mentalistaion difficulties, and the effect of such problems on counter-transference are analysed in this paper. Finally a consideration aboy intergenerational conflicts and their relationship with puberal adult organization is made (AU)

Consideraciones psicoanalíticas sobre el universo cinematográfico de Pedro Almodóvar (volver al origen) / Psychoanalytical reflections on Pedro Amodóvar´s cinematographic universe

El artículo hace una reflexión sobre algunos temas recurrentes del director de cine español Pedro Almodóvar. El problema de la muerte y de los duelos, es enfocado primeramente desde un plano cultural dadas las míticas relaciones de La Mancha con estos rituales. Se analizan posteriormente los fundamentos psicoanalíticos de algunos autores que han investigado en los duelos enquistado s e irresolubles. Estas patologías ilustran las fantasías inconscientes sobre los muertos-vivos que han inspirado a lo largo de la historia a tantas proyecciones cinematográficas. Se indaga también en las tragedias familiares que por generaciones son transmitidas inconscientemente siguiendo una ley de silencio basada en un tabú. Siguiendo el hilo conductor de su obra y tomando como núcleo de la reflexión la película Volver se analizan los orígenes del director y las influencias en su infancia del mundo femenino y masculino y el reflejo de estas vivencias en su cine. Finalmente se abordan los procesos de elaboración de los duelos en el trayecto de la vida por medio de la creación de una obra (AU)

This paper deals with some of the reoccurring subjects in the films of Pedro Almodóvar, the Spanish film director. The subject of death and mourning is at first approached from a cultural point of view due to the mythical relationship found in these rituals in the Spanish region La Mancha. Subsequently, the psychoanalytical foundations of several authors are analysed, especially those who have researched deeply entrenched and unressolved mourning. These pathologies illustrate the unconscious fantasies related to the walking dead that has inspired so many films throught the history of film-making. Family tragedies are also analysed, and are unconsciously transmitted from generation to generation, following an unspoken law based on taboo. Following the threas of his works and using as a core for reflection his film Volver (2006), we delve into the directors origins, his influences derived from both the feminine and masculine world of his childhood and the reflection of these experiences in his films. Finally, through the creation of a piece of art, the elaboration of the mourning process throughout our lives is approached (AU)

The association of increased p14ARF/p16INK4a and p15INK4a gene expression with proliferative activity and the clinical course of multiple myeloma.

p14/p16 and p15 gene expression was assessed by quantitative polymerase chain reaction in purified plasma cells (PC) from 52 patients with symptomatic multiple myeloma (MM) and seven with smoldering MM in order to clarify the impact of these genes on the proliferative activity of tumor cells and patients' outcome. p15 expression was lower in symptomatic MM than in smoldering SMM (-1.80 vs.1.51,p=0.026); similar results were observed for p14/p16. MM patients whose PC displayed high p15 and/or p14/p16 expression had a lower percentage of S-phase PC than the remaining cases (1.79%+/-1.35 vs. 3.04%+/-1.42, p=0.028), favorable prognostic factors and longer survival (100% vs. 49%at 2.5 years; p=0.007).

Geographic differences in the incidence of cytogenetic abnormalities of acute myelogenous leukemia (AML) in Spain.

The incidence of chromosomal abnormalities in acute myeloid leukemia (AML) differs according to geographical regions in Spain. We analyse 1,271 consecutive patients diagnosed of AML between 1995 and 2002 in three different regions of Spain: northern, central and southern. There were 624 males (55%) and 505 females (45%). Age ranged between 1 month and 94 years with a median of 61 years. Abnormal karyotypes were observed in 64% of cases. Numerical abnormalities as sole cytogenetic changes were detected in 15% of patients, while structural aberrations were present in 28% of cases, and both abnormalities were found in 22% of patients. A significantly higher proportion of t(15;17) was observed in the south of Spain (21.6%) than in the central (17%) or northern regions (12.6%) (p=0.03). By contrast, patients from the south of Spain showed lower incidence of t(8;21) (0%, compared to 1.6% and 3.6% in central and northern areas, respectively, p=0.04). These differences were maintained in the age-adjusted analysis. Trisomy 8 showed similar incidence in southern and central areas, while the incidence in the northern area was lower (14% and 10%, respectively, p=0.04). Other chromosomal abnormalities, such as inv(16) or 11q23 rearrangements, were found at similar frequencies in the three regions.

Hematological, immunophenotypic, and cytogenetic characteristics of acute myeloblastic leukemia with trisomy 11.

We evaluated the incidence of trisomy 11 in acute myeloblastic leukemia (AML) and its correlation with the most relevant clinical, biological, and immunophenotypic disease characteristics in a total of 399 consecutive AML patients. Trisomy 11 was found in 15 patients (3.8%), in 3 of them as the sole abnormality. Median age was 68 years (range 48-87); 87% of patients were older than 60 years. Seven patients displayed multilineage dysplasia. Cytogenetics showed an association with trisomy 8 in six patients, and in five cases with a del(5q); nine patients had complex karyotypes. In all cases, in situ hybridization studies revealed three copies of the MLL gene, but no rearrangements or tandem duplications of MLL. Immunophenotypic analysis of blast cells showed a constant immature immunophenotypic profile with CD34 or CD117 expression (or both) in all cases analyzed. The complete remission rate was 43%; median survival time was only 2 months.