Asunto(s)
Eritema Pernio/terapia , Trasplante de Células Madre Hematopoyéticas , Inmunosupresores/uso terapéutico , Leucemia Mieloide Aguda/terapia , Lupus Eritematoso Discoide/terapia , Pancitopenia/terapia , Eritema Pernio/etiología , Preescolar , Glucocorticoides/uso terapéutico , Humanos , Leucemia Mieloide Aguda/complicaciones , Lupus Eritematoso Discoide/complicaciones , Masculino , Pancitopenia/etiología , Trasplante HomólogoRESUMEN
We conducted a cytogenetic analysis of 642 children with de novo acute myeloid leukemia (AML) treated on the AML-Berlin-Frankfurt-Münster (BFM) 04 protocol to determine the prognostic value of specific chromosomal aberrations including monosomal (MK+), complex (CK+) and hypodiploid (HK+) karyotypes, individually and in combination. Multivariate regression analysis identified in particular MK+ (n=22) as a new independent risk factor for poor event-free survival (EFS 23±9% vs 53±2% for all other patients, P=0.0003), even after exclusion of four patients with monosomy 7 (EFS 28±11%, P=0.0081). CK+ patients without MK had a better prognosis (n=47, EFS 47±8%, P=0.46) than those with MK+ (n=12, EFS 25±13%, P=0.024). HK+ (n=37, EFS 44±8% for total cohort, P=0.3) influenced outcome only when t(8;21) patients were excluded (remaining n=16, EFS 9±8%, P<0.0001). An extremely poor outcome was observed for MK+/HK+ patients (n=10, EFS 10±10%, P<0.0001). Finally, isolated trisomy 8 was also associated with low EFS (n=16, EFS 25±11%, P=0.0091). In conclusion, monosomal karyotype is a strong and independent predictor for high-risk pediatric AML. In addition, isolated trisomy 8 and hypodiploidy without t(8;21) coincide with dismal outcome. These results have important implications for risk stratification and should be further validated in independent pediatric cohorts.
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Variación Genética , Genotipo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Aberraciones Cromosómicas , Cromosomas Humanos Par 7 , Ensayos Clínicos como Asunto , Femenino , Humanos , Cariotipo , Leucemia Mieloide Aguda/diagnóstico , Masculino , Monosomía , Mutación , Pronóstico , Análisis de SupervivenciaAsunto(s)
Resistencia a Antineoplásicos , Eosinofilia/complicaciones , Trastornos Mieloproliferativos/tratamiento farmacológico , Proteínas de Fusión Oncogénica/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/genética , Animales , Proteínas Portadoras/genética , Línea Celular , Humanos , Lactante , Ratones , Mutación , Trastornos Mieloproliferativos/complicaciones , Trastornos Mieloproliferativos/genética , Conformación Proteica , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Receptor beta de Factor de Crecimiento Derivado de Plaquetas/química , Análisis de Secuencia de ADN , Transducción GenéticaRESUMEN
Children with P2RY8-CRLF2-positive acute lymphoblastic leukemia have an increased relapse risk. Their mutational and transcriptional landscape, as well as the respective patterns at relapse remain largely elusive. We, therefore, performed an integrated analysis of whole-exome and RNA sequencing in 41 major clone fusion-positive cases including 19 matched diagnosis/relapse pairs. We detected a variety of frequently subclonal and highly instable JAK/STAT but also RTK/Ras pathway-activating mutations in 76% of cases at diagnosis and virtually all relapses. Unlike P2RY8-CRLF2 that was lost in 32% of relapses, all other genomic alterations affecting lymphoid development (58%) and cell cycle (39%) remained stable. Only IKZF1 alterations predominated in relapsing cases (P=0.001) and increased from initially 36 to 58% in matched cases. IKZF1's critical role is further corroborated by its specific transcriptional signature comprising stem cell features with signs of impaired lymphoid differentiation, enhanced focal adhesion, activated hypoxia pathway, deregulated cell cycle and increased drug resistance. Our findings support the notion that P2RY8-CRLF2 is dispensable for relapse development and instead highlight the prominent rank of IKZF1 for relapse development by mediating self-renewal and homing to the bone marrow niche. Consequently, reverting aberrant IKAROS signaling or its disparate programs emerges as an attractive potential treatment option in these leukemias.
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Fusión Génica , Genómica , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Receptores de Citocinas/genética , Receptores Purinérgicos P2Y/genética , Transcripción Genética , Adolescente , Niño , Preescolar , Dosificación de Gen , Genes Supresores de Tumor , Humanos , Factor de Transcripción Ikaros/genética , Factor de Transcripción Ikaros/fisiología , Lactante , Quinasas Janus/fisiología , Polimorfismo de Nucleótido Simple , Factores de Transcripción STAT/fisiologíaAsunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Lectina de Unión a Manosa/deficiencia , Polimorfismo de Nucleótido Simple , Enfermedad Aguda , Adolescente , Aloinjertos , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Enfermedad Injerto contra Huésped/sangre , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/mortalidad , Humanos , Masculino , Tasa de SupervivenciaRESUMEN
High hyperdiploidy defines the largest genetic entity of childhood acute lymphoblastic leukemia (ALL). Despite its relatively low recurrence risk, this subgroup generates a high proportion of relapses. The cause and origin of these relapses remains obscure. We therefore explored the mutational landscape in high hyperdiploid (HD) ALL with whole-exome (n=19) and subsequent targeted deep sequencing of 60 genes in 100 relapsing and 51 non-relapsing cases. We identified multiple clones at diagnosis that were primarily defined by a variety of mutations in receptor tyrosine kinase (RTK)/Ras pathway and chromatin-modifying genes. The relapse clones consisted of reappearing as well as new mutations, and overall contained more mutations. Although RTK/Ras pathway mutations were similarly frequent between diagnosis and relapse, both intergenic and intragenic heterogeneity was essentially lost at relapse. CREBBP mutations, however, increased from initially 18-30% at relapse, then commonly co-occurred with KRAS mutations (P<0.001) and these relapses appeared primarily early (P=0.012). Our results confirm the exceptional susceptibility of HD ALL to RTK/Ras pathway and CREBBP mutations, but, more importantly, suggest that mutant KRAS and CREBBP might cooperate and equip cells with the necessary capacity to evolve into a relapse-generating clone.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Proteína de Unión a CREB/genética , Diploidia , Mutación/genética , Recurrencia Local de Neoplasia/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Proto-Oncogénicas/genética , Proteínas ras/genética , Adolescente , Estudios de Casos y Controles , Niño , Evolución Clonal , Femenino , Estudios de Seguimiento , Humanos , Masculino , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pronóstico , Proteínas Proto-Oncogénicas p21(ras) , Tasa de SupervivenciaRESUMEN
BACKGROUND: Recently, the UK CCLG and COG reported that an intrachromosomal amplification of chromosome 21 (iAMP21) in acute lymphoblastic leukemia (ALL) loses its adverse prognostic impact with intensified therapy. PATIENT AND METHODS: We evaluated the prognosis of iAMP21 among patients from the ALL-BFM (Berlin-Frankfurt-Münster) 2000 trial with 46 of 2 637 (2%) patients iAMP21+. RESULTS: 8-year event-free-survival (EFS, 64 ± 8% vs. 81 ± 1%, p=0.0026) and cumulative incidence of relapse (CIR, 29 ± 8% vs. 14 ± 1%, p=0.008) of the iAMP21 cases were significantly worse compared with non-iAMP21 patients. Within the MRD low-risk group, iAMP21 cases (n=14) had an inferior 8-year EFS (76 ± 12% vs. 92 ± 1%, p=0.0081), but no increased CIR (10 ± 10% vs. 6 ± 1%, p=0.624). Within the MRD intermediate-risk group, iAMP21 cases (n=27) had a worse 8-year EFS (56 ± 11% vs. 78 ± 2%, p=0.0077) and CIR (44 ± 11% vs. 20 ± 2%, p=0.003) with 6/10 relapses occurring after 2 years. CONCLUSIONS: Conclusively, we believe that there is no necessity for enrolling all iAMP21 patients into the high-risk arm of ongoing ALL-BFM trials because MRD low-risk patients have a moderate relapse risk under current therapy. Whether the increased relapse risk in MRD intermediate-risk patients can be avoided by late treatment intensification remains to be answered by the AIEOP-BFM ALL 2009 trial randomly using protracted pegylated L-asparaginase during delayed intensification and early maintenance.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cromosomas Humanos Par 21/genética , Amplificación de Genes/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Adolescente , Niño , Preescolar , Estudios de Cohortes , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Neoplasia Residual/tratamiento farmacológico , Neoplasia Residual/genética , Neoplasia Residual/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidad , Proteínas Proto-Oncogénicas c-ets/genética , Recurrencia , Proteínas Represoras/genética , Proteína ETS de Variante de Translocación 6RESUMEN
Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct cytogenetic subgroup of childhood B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). To date, fluorescence in situ hybridisation (FISH), with probes specific for the RUNX1 gene, provides the only reliable detection method (five or more RUNX1 signals per cell). Patients with iAMP21 are older (median age 9 years) with a low white cell count. Previously, we demonstrated a high relapse risk when these patients were treated as standard risk. Recent studies have shown improved outcome on intensive therapy. In view of these treatment implications, accurate identification is essential. Here we have studied the cytogenetics and outcome of 530 iAMP21 patients that highlighted the association of specific secondary chromosomal and genetic changes with iAMP21 to assist in diagnosis, including the gain of chromosome X, loss or deletion of chromosome 7, ETV6 and RB1 deletions. These iAMP21 patients when treated as high risk showed the same improved outcome as those in trial-based studies regardless of the backbone chemotherapy regimen given. This study reinforces the importance of intensified treatment to reduce the risk of relapse in iAMP21 patients. This now well-defined patient subgroup should be recognised by World Health Organisation (WHO) as a distinct entity of BCP-ALL.
Asunto(s)
Cromosomas Humanos Par 21 , Análisis Citogenético , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Adulto , Niño , Preescolar , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Femenino , Humanos , Hibridación Fluorescente in Situ , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Resultado del Tratamiento , Adulto JovenRESUMEN
ETV6/RUNX1 (E/R) is the most common fusion gene in childhood acute lymphoblastic leukemia. It is responsible for the initiation of leukemia but also indispensable for disease maintenance and propagation, although its function in these latter processes is less clear. We therefore investigated the effects of the perceived p53 pathway alterations in model cell lines and primary leukemias and, in particular, how E/R upregulates MDM2, the predominant negative regulator of p53. We found that E/R transactivates MDM2 in both p53(+/+) and p53(-/-) HCT116 cells by binding to promoter-inherent RUNX1 motifs, which indicates that this activation occurs in a direct and p53-independent manner. Treatment of E/R-positive leukemic cell lines with Nutlin-3, a small molecule that inhibits the MDM2/p53 interaction, arrests their cell cycle and induces apoptosis. These phenomena concur with a p53-induced expression of p21, pro-apoptotic BAX and PUMA, as well as caspase 3 activation and poly ADP-ribose polymerase cleavage. The addition of DNA-damaging and p53-activating chemotherapeutic drugs intensifies apoptosis. Moreover, Nutlin-3 exposure leads to an analogous p53 accumulation and apoptotic surge in E/R-positive primary leukemic cells. Our findings clarify the role of p53 signaling in E/R-positive leukemias and outline the potential basis for its therapeutic exploitation in this setting.
Asunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Imidazoles/farmacología , Piperazinas/farmacología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Proto-Oncogénicas c-ets/genética , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteínas Represoras/genética , Transducción de Señal , Proteína p53 Supresora de Tumor/metabolismo , Apoptosis/efectos de los fármacos , Niño , Inmunoprecipitación de Cromatina , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Reacción en Cadena en Tiempo Real de la Polimerasa , Transcripción Genética , Proteína p53 Supresora de Tumor/genética , Proteína ETS de Variante de Translocación 6RESUMEN
Despite their apparently good prognosis â¼15% of high hyperdiploid (HD) childhood acute lymphoblastic leukemia (ALL) cases relapse. To search for responsible risk factors we determined copy number aberrations as well as copy neutral loss of heterozygosity (LOH) in 13 matched diagnosis and relapse samples and added the data of the only three available cases from the literature. Deletions and copy neutral LOH in 3 and 2 of the 16 cases directed us to the histone-modifying CREB-binding protein (CREBBP) gene, whose functional impairment is implicated in drug resistance. We therefore screened all samples for mutations in this gene and discovered 9 acquired sequence mutations in 7/16 cases, leading to an overall frequency of somatic CREBBP aberrations in HD ALL relapse cases of 63% that is considerably higher than that of the reported, mainly non-HD ALL (18.3%). Moreover, mutations in HD cases occur almost exclusively in the HAT domain (8/9; 89%). Hot spot mutations are present at diagnosis in 18.8% of relapsing HD ALL cases but in none of 40 respective cases remaining in long-term remission. Thus, the particular high incidence of CREBBP mutations in relapse-prone HD ALL cases could eventually be exploited for refined risk stratification and customized treatment in this genetic subgroup.
Asunto(s)
Proteína de Unión a CREB/genética , Mutación , Ploidias , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Secuencia de Bases , Niño , Preescolar , Variaciones en el Número de Copia de ADN , Femenino , Humanos , Pérdida de Heterocigocidad , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Estructura Terciaria de Proteína/genética , Recurrencia , Resultado del TratamientoRESUMEN
CLTA4 is relevant for FOXP3(+)Treg cells, and the link between skewed X chromosome inactivation (XCI) and autoimmunity is recognized. The observation of immune dysregulation polyendocrinopathy enteropathy X-linked syndrome and multiorgan endocrine autoimmune phenomena in various members of one family, associated with a CTLA4 polymorphism and skewed XCI, provides an in vivo model of how mechanisms of immune dysregulation may cooperate.
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Enfermedades Autoinmunes/genética , Antígeno CTLA-4/genética , Factores de Transcripción Forkhead/genética , Predisposición Genética a la Enfermedad , Inactivación del Cromosoma X/genética , Adulto , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Humanos , Masculino , Mutación , LinajeRESUMEN
The ETV6/RUNX1 (E/R) gene fusion is generated by the t(12;21) and found in approximately 25% of childhood B-cell precursor acute lymphoblastic leukemia. In contrast to the overwhelming evidence that E/R is critical for the initiation of leukemia, its relevance for the maintenance of overt disease is less clear. To investigate this issue, we suppressed the endogenous E/R fusion protein with lentivirally transduced short hairpin RNA in the leukemia cell lines REH and AT-2, and found a distinct reduction of proliferation and cell survival. In line with the observed concurrent inactivation of the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, pharmacological inhibition diminished the phosphorylation of AKT and ribosomal protein S6, and significantly increased the apoptosis rate in E/R-positive leukemias. Moreover, PI3K/mTOR inhibitors sensitized glucocorticoid-resistant REH cells to prednisolone, an observation of potential relevance for improving treatment of drug-resistant relapses. Of note, knockdown of the E/R fusion gene also severely impaired the repopulation capacity of REH cells in non-obese deficient/severe combined immunodeficient mice. Collectively, these data demonstrate that the E/R fusion protein activates the PI3K/AKT/mTOR pathway and is indispensible for disease maintenance. Importantly, these results provide a first rationale and justification for targeting the fusion gene and the PI3K/AKT/mTOR pathway therapeutically.
Asunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Silenciador del Gen , Fosfatidilinositol 3-Quinasas/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-ets/genética , Proteínas Represoras/genética , Transducción de Señal , Serina-Treonina Quinasas TOR/metabolismo , Animales , Línea Celular Tumoral , Humanos , Ratones , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Interferencia de ARN , Reacción en Cadena en Tiempo Real de la Polimerasa , Trasplante Heterólogo , Proteína ETS de Variante de Translocación 6RESUMEN
Approximately 25% of childhood B-cell precursor acute lymphoblastic leukemia have an ETV6/RUNX1 (E/R) gene fusion that results from a t(12;21). This genetic subgroup of leukemia is associated with near-triploidy, near-tetraploidy, and trisomy 21 as rather specific types of secondary changes. Here, we show that, unlike various controls, E/R-expressing Ba/F3 clones acquire a tetraploid karyotype on prolonged culture, corroborating the assumption that E/R may attenuate the mitotic checkpoint (MC). Consistent with this notion, E/R-expressing diploid murine and human cell lines have decreased proportions of cells with 4N DNA content and a lower mitotic index when treated with spindle toxins. Moreover, both RUNX1 and E/R regulate mitotic arrest-deficient 2 L1 (MAD2L1), an essential MC component, by binding to promoter-inherent RUNX1 sites, which results in down-regulation of MAD2L1 mRNA and protein in E/R-expressing cells. Forced expression of E/R also abolishes RUNX1-induced reporter activation, whereas E/R with a mutant DNA-binding site leads to only minor effects. Our data link for the first time E/R, MC, and MAD2L1 and provide new insights into the function of the E/R fusion gene product. Although tetraploidy is an almost exclusive feature of E/R-positive leukemias, its rarity within this particular subgroup implies that further yet unknown factors are required for its manifestation.
Asunto(s)
Proteínas de Unión al Calcio/genética , Proteínas de Ciclo Celular/genética , Mitosis/genética , Proteínas de Fusión Oncogénica/genética , Proteínas Represoras/genética , Línea Celular Tumoral , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Fusión Génica , Reordenamiento Génico , Humanos , Cariotipificación , Proteínas Mad2 , Regiones Promotoras GenéticasRESUMEN
In the management of the childhood acute lymphoblastic leukemia (ALL), 5% of failures are due to induction death and treatment-related deaths in first complete remission. We retrospectively analyzed the incidence, pattern and causes of death and its risk factors for 896 children with ALL enrolled into five Austrian (A) Berlin-Frankfurt-Münster (BFM) trials between 1981 and 1999. The estimated 10-year cumulative incidence of death significantly decreased from 6+/-1% (n=16/268) in trials ALL-BFM-A 81 and ALL-A 84 to 2+/-1% (n=15/628) in trials ALL-BFM-A 86, 90 and 95 (P=0.006). A significant reduction of death was evident during induction therapy (2.2% in trials ALL-BFM-A 81 and ALL-A 84 and 0.2% in trials ALL-BFM-A 86, 90 and 95, P=0.001). Of 31 patients, 21 (68%) patients died from infectious and 10 (32%) from noninfectious complications. Treatment in trial ALL-BFM-A 81, infant age and female gender were independent predictors of an enhanced risk for death. Conclusively, we found a progressive reduction of death rates that may be explained by the increasing experience in specialized hemato-oncologic centers and improved supportive and intensive care. We also identified a distinct subset of patients who are especially prone to death and may need a special focus when receiving intense chemotherapy.
Asunto(s)
Antineoplásicos/toxicidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Inducción de Remisión , Causas de Muerte , Niño , Femenino , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológicoRESUMEN
Childhood B-cell precursor acute lymphoblastic leukemia (BCP ALL) is generally a clonal disease in which the number of IGH rearrangements per cell does not exceed the number of the IGH alleles on chromosome 14. Consequently, monoclonal high hyperdiploid (HeH) cases with a trisomy 14 can harbor three rearrangements, a pattern that otherwise may be misinterpreted to be oligoclonal. Oligoclonal IGH rearrangements, on the other hand, may be instable at relapse and should therefore not be used for minimal residual disease analysis. We thus investigated the association between IGH allele copy numbers and the IGH rearrangement patterns in 90 HeH BCP ALL with either two (13%) or three copies (87%) of chromosome 14. HeH cases (44%) had an oligoclonal IGH rearrangement pattern, but true oligoclonality--after correction for the respective copy number of IGH alleles--was only 16%. Monoclonal and oligoclonal HeH cases had predominantly V(H) to preexisting DJ(H) recombinations, a finding that contrasts with oligoclonal cases of other major genetic BCP ALL subgroups in which V(H) replacements prevail. We conclude that for the precise assessment and correct interpretation of clonality patterns in BCP ALL, the IGH allele copy number has to be taken into consideration.
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Cromosomas Humanos Par 14/genética , Dosificación de Gen/genética , Reordenamiento Génico , Cadenas Pesadas de Inmunoglobulina/genética , Neoplasia Residual/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Southern Blotting , Niño , Diploidia , Humanos , Hibridación Fluorescente in Situ , Neoplasia Residual/genética , TrisomíaRESUMEN
PAX5, a master regulator of B-cell development, was recently shown to be involved in several leukemia-associated rearrangements, which result in fusion genes encoding chimeric proteins that antagonize PAX5 transcriptional activity. In a population-based fluorescence in situ hybridization screening study of 446 childhood acute lymphoblastic leukemia (ALL) patients, we now show that PAX5 rearrangements occur at an incidence of about 2.5% of B-cell precursor ALL. Identification of several novel PAX5 partner genes, including POM121, BRD1, DACH1, HIPK1 and JAK2 brings the number of distinct PAX5 in-frame fusions to at least 12. Our data show that these not only comprise transcription factors but also structural proteins and genes involved in signal transduction, which at least in part have not been implicated in tumorigenesis.
Asunto(s)
Proteínas de Fusión Oncogénica/genética , Factor de Transcripción PAX5/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Niño , Preescolar , Humanos , Lactante , Transducción de Señal/genética , Factores de Transcripción/genética , Transcripción Genética , Adulto JovenRESUMEN
'Calcitonin screening' is not accepted as the standard of care in daily practice. The clinical and surgical consequences of 'calcitonin screening' in a series of patients with mildly elevated basal calcitonin and pentagastrin stimulated calcitonin levels are presented. 260 patients with elevated basal (>10 pg/ml) and stimulated calcitonin levels (>100 pg/ml) were enrolled in this prospective study. None of the patients was member of a known medullary thyroid carcinoma family. Thyroidectomy and bilateral central and lateral neck dissections were performed. Testing for the presence of germ-line mutations was performed in all patients. Histological and immunohistochemical findings were compared with basal and stimulated calcitonin levels. All patients were subsequently followed biochemically. C-cell hyperplasia (CCH) was found in 126 (49%) and medullary thyroid cancer was found in 134 (51%) patients. RET proto-oncogen mutations were documented in 22 (8%) patients (medullary thyroid cancer:18, CCH:4). In 56 (46%) of 122 patients, sporadic CCH was classified neoplastic ('carcinoma in situ'). Of 97 (72%; 10 with hereditary medullary thyroid cancer) had pT1 (International Union against Cancer recommendations 2002) and 33 (25%) had pT2 or pT3 and 4 (3%) pT4 tumors. Of 39 (29.1%) had lymph node metastases. 106 (79.1%; 15 (38.5%) with lymph node metastases) patients were cured. Evaluation of basal and stimulated calcitonin levels enables the prediction of medullary thyroid cancer. All patients with basal calcitonin >64 pg/ml and stimulated calcitonin >560 pg/ml have medullary thyroid cancer. Medullary thyroid cancer was documented in 20% of patients with basal calcitonin >10 pg/ml but <64 pg/ml and stimulated calcitonin >100 pg/ml but <560 pg/ml.
Asunto(s)
Biomarcadores de Tumor/sangre , Calcitonina/sangre , Carcinoma Medular/sangre , Carcinoma Medular/diagnóstico , Neoplasias de la Tiroides/sangre , Neoplasias de la Tiroides/diagnóstico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma Medular/genética , Carcinoma Medular/cirugía , Femenino , Estudios de Seguimiento , Mutación de Línea Germinal , Humanos , Masculino , Persona de Mediana Edad , Pentagastrina , Estudios Prospectivos , Proteínas Proto-Oncogénicas c-ret/genética , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/cirugía , Tiroidectomía , Resultado del TratamientoRESUMEN
BACKGROUND: Recent data suggest that, among other factors, comorbidity may be an important prognostic variable in patients with myelodysplastic syndromes (MDS) who are eligible for haematopoietic stem cell transplantation (SCT). PATIENTS AND METHODS: We examined the overall survival (OS) and underlying risk factors in 45 adult patients with MDS (n = 38), chronic myelomonocytic leukaemia (n = 1), or secondary acute myeloid leukaemia (AML) arising from MDS (n = 6), who underwent allogeneic SCT at our Institution. RESULTS: With a median follow-up of 37 months, OS for all patients was 23%, post-transplant relapse occurred in 11 patients, and 10 patients died from treatment-related complications. The overall outcome and survival was independent of cytogenetic abnormalities and International Prognostic Scoring System (IPSS). However, we identified comorbidity as defined by the haematopoietic cell transplantation specific comorbidity index (HCT-CI), as a significant adverse prognostic variable in our MDS patients. CONCLUSIONS: Based on these data and similar published data we recommend selecting patients with MDS or secondary AML for SCT according to the presence of comorbidities.
Asunto(s)
Supervivencia sin Enfermedad , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/mortalidad , Leucemia Mielomonocítica Crónica/mortalidad , Neoplasias Primarias Secundarias/mortalidad , Adolescente , Adulto , Anciano , Austria/epidemiología , Comorbilidad , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide Aguda/epidemiología , Leucemia Mieloide Aguda/terapia , Leucemia Mielomonocítica Crónica/epidemiología , Leucemia Mielomonocítica Crónica/terapia , Masculino , Persona de Mediana Edad , Neoplasias Primarias Secundarias/terapia , Pronóstico , Recurrencia , Factores de Riesgo , Acondicionamiento Pretrasplante , Trasplante Homólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Recent data suggest that the mammalian target of rapamycin (mTOR) is involved in the regulation of growth of neoplastic cells in chronic myeloid leukaemia (CML). PATIENTS AND METHODS: We treated six patients with imatinib-resistant CML in haematological relapse (leukocytes > 20,000 microL(-1)) with rapamycin at 2 mg per os daily for 14 consecutive days, with dose-adjustment allowed to reach a target rapamycin serum concentration of 10-20 pg mL(-1). RESULTS: A major leukocyte response with decrease to less than 10,000 microL(-1) was obtained in two patients, and a minor transient response was seen in two other patients. In responding patients, we also observed a decrease in vascular endothelial growth factor (VEGF) mRNA levels in circulating leukaemic cells. Side effects during rapamycin treatment were mild in most patients. In one patient, pneumonia developed. Rapamycin was also found to counteract growth of CML cells in vitro as determined by (3)H-thymidine incorporation. Moreover, rapamycin inhibited the growth of Ba/F3 cells exhibiting various imatinib-resistant mutants of BCR/ABL, including the T315I variant that exhibits resistance against most currently available BCR/ABL kinase inhibitors. CONCLUSIONS: Rapamycin shows antileukaemic effects in imatinib-resistant CML in vitro and in vivo. Larger trials with rapamycin or rapamycin-derivatives in combination with other targeted drugs are warranted to further determine clinical efficacy in CML.