RESUMEN
BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare, life-threatening disease due to high serum low-density lipoprotein (LDL) cholesterol levels. LDL cholesterol-lowering interventions are fundamental for patients with HoFH. OBJECTIVE: It was aimed to investigate the association between the mental status of patients with HoFH and healthy lifestyle behaviors. METHODS: This subgroup analysis of the A-HIT1 population included the data of patients aged ≥18 years with a clinical diagnosis of HoFH undergoing therapeutic LDL apheresis. Besides the demographic and clinical characteristics of patients, healthy lifestyle behaviors were assessed, and psychiatric symptoms were screened by Symptom Check List (SCL-90-R). RESULTS: The highest percentage for pathology was observed in dimensions of obsessive-compulsive, somatization, interpersonal sensitivity, and depression in SCL-90-R. Patients with any cardiovascular condition have more psychiatric symptoms in different fields of SCL-90-R. The outcomes of the correlative analysis indicated that lower the age of the first coronary event better the psychiatric status, probably denoting a better adaptation to disease and its treatment. Among 68 patients, 36 patients were not exercising regularly. Patients with regular physical activity had significantly lower scores in most dimensions of SCL-90-R and there was no association between regular physical activity and other investigated variables. The strongest predictor of regular exercising was global severity index of SCL-90-R. CONCLUSION: In the HoFH population, there was a high prevalence of mental disturbances. Better psychiatric status was associated with regular exercising. Therefore, assessing the mental status of patients with HoFH and referring patients in need, to a psychiatrist, may improve the outcome of patients.
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Ejercicio Físico , Homocigoto , Hiperlipoproteinemia Tipo II/fisiopatología , Hiperlipoproteinemia Tipo II/psicología , Salud Mental , Sistema de Registros , Encuestas y Cuestionarios , Adulto , Anticolesterolemiantes/uso terapéutico , LDL-Colesterol/sangre , Femenino , Humanos , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Masculino , Persona de Mediana Edad , FenotipoRESUMEN
BACKGROUND: Homozygous familial hypercholesterolemia (HoFH) is a rare, life-threatening inherited disease leading to early-onset atherosclerosis and associated morbidity. Because of its rarity, longitudinal data on the management of HoFH in the real world are lacking, particularly on the impact the condition has on quality of life (QoL), including the impact of the extracorporeal lipid removal procedure apheresis (LA). METHODS: The A-HIT1 study included 88 patients with HoFH aged ≥12 years receiving regular LA in 19 centers in Turkey. Demographic and disease characteristics data were obtained. For patients aged ≥18 years, additional data on psychosocial status were obtained via the SF-36 score, the Hospital Anxiety and Depression Scale, and a HoFH-specific questionnaire. RESULTS: There was no standardized approach to therapy between centers. Mean (±SD) frequency of LA sessions was every 19.9 (±14) days, with only 11.6% receiving LA weekly, and 85% of patients were not willing to increase LA frequency. The most common concerns of patients were disease prognosis (31%), and physical, aesthetic, and psychological problems (27.5%, 15.9%, and 11.6%, respectively). Lower age at diagnosis was associated with better QoL, lower anxiety, improved functioning, and greater emotional well-being compared to later diagnosis. CONCLUSIONS: These findings demonstrate that adult patients with HoFH undergoing LA, experience significant impairment of QoL with an increased risk of depression. From patients' point of view, LA is time-consuming, uncomfortable, and difficult to cope with. The speed of diagnosis and referral has a considerable impact on patient well-being.
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Eliminación de Componentes Sanguíneos , LDL-Colesterol/sangre , Homocigoto , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/terapia , Calidad de Vida , Encuestas y Cuestionarios , Adolescente , Adulto , Femenino , Humanos , Hiperlipoproteinemia Tipo II/genética , Masculino , Persona de Mediana Edad , Sistema de Registros , Turquía , Adulto JovenRESUMEN
Hereditary spherocytosis (HS) is characterized by the morphological transformation of erythrocytes into a spherical shape due to a hereditary defect in cell membrane proteins (ghosts) associated with disruption of erythrocyte skeletal structures. Contrary to the literature, pores were detected in the erythrocytes of a patient with HS. The aim of the present study was to determine the affected proteins and genes that were responsible for the pores. Ghost isolation was performed to determine the proteins responsible for the pores observed on the erythrocytes of the patient. Erythrocyte membrane proteins were visualized using SDSPAGE. Exome and matrixassisted laser desorption/ionization timeofflight mass spectrometry (MALDI TOF MS) analyses were used to identify the genes and proteins responsible for the observed defect. Quantitative protein assessments were performed using MALDI TOF MS. A difference was detected in the components of the erythrocyte membrane proteins. Band 3 and protein 4.2, which serve a particular role in membrane structure, decreased 4.573 and 4.106 fold, respectively. Through proteomic analyses, a nonsynonymous exonic mutation region was identified in the Golgi membrane protein 1 (GOLM1) gene (Chr9 rs142242230). Sorting Intolerant From Tolerant and Polymorphism Phenotyping Scores, Likelihood Ratio Tests and MutationTaster revealed that the mutation was deleterious. The pores observed in the morphology of the erythrocytes may have developed due to the decrease in these proteins, which reside in the erythrocyte membrane structure. Furthermore, genetic profiling of the patient with HS and her family was conducted in the present study. Nextgeneration sequencing was used, and the genetic source of HS was identified as a GOLM1 gene mutation. The assessment of specific molecular defects is often not performed as the majority of mutations are unique to a family. However, molecular analyses should be performed in severe cases where prenatal diagnosis is required, or for unique HS phenotypes to aid scientific investigation.
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Biomarcadores/análisis , Membrana Eritrocítica/patología , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Proteínas de la Membrana/genética , Mutación , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Esferocitosis Hereditaria/patología , Adulto , Anciano , Estudios de Casos y Controles , Niño , Membrana Eritrocítica/genética , Membrana Eritrocítica/metabolismo , Femenino , Humanos , Masculino , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Linaje , Fenotipo , Esferocitosis Hereditaria/genética , Esferocitosis Hereditaria/metabolismoRESUMEN
BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is a common genetic disease of high-level cholesterol leading to premature atherosclerosis. One of the key aspects to overcome FH burden is the generation of large-scale reliable data in terms of registries. This manuscript underlines the important results of nation-wide Turkish FH registries (A-HIT1 and A-HIT2). METHODS: A-HIT1 is a survey of homozygous FH patients undergoing low density lipoprotein (LDL) apheresis (LA). A-HIT2 is a registry of adult FH patients (homozygous and heterozygous) admitted to outpatient clinics. Both registries used clinical diagnosis of FH. RESULTS: A-HIT1 evaluated 88 patients (27⯱â¯11 years, 41 women) in 19 centers. All patients were receiving regular LA. There was a 7.37⯱â¯7.1-year delay between diagnosis and initiation of LA. LDL-cholesterol levels reached the target only in 5 cases. Mean frequency of apheresis sessions was 19⯱â¯13 days. None of the centers had a standardized approach for LA. Mean frequency of apheresis sessions was every 19⯱â¯13 (7-90) days. Only 2 centers were aware of the target LDL levels. A-HIT2 enrolled 1071 FH patients (53⯱â¯8 years, 606 women) from 31 outpatients clinics specialized in cardiology (27), internal medicine (1), and endocrinology (3); 96.4% were heterozygous. 459 patients were on statin treatment. LDL targets were attained in 23 patients (2.1% of the whole population, 5% receiving statin) on treatment. However, 66% of statin-receiving patients were on intense doses of statins. Awareness of FH was 9.5% in the whole patient population. CONCLUSIONS: The first nationwide FH registries revealed that FH is still undertreated even in specialized centers in Turkey. Additional effective treatment regiments are urgently needed.
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Eliminación de Componentes Sanguíneos , LDL-Colesterol/sangre , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hiperlipoproteinemia Tipo II/terapia , Adolescente , Adulto , Biomarcadores/sangre , Eliminación de Componentes Sanguíneos/efectos adversos , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/prevención & control , Regulación hacia Abajo , Femenino , Predisposición Genética a la Enfermedad , Herencia , Heterocigoto , Homocigoto , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/epidemiología , Hiperlipoproteinemia Tipo II/genética , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Pautas de la Práctica en Medicina , Prevalencia , Sistema de Registros , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Turquía/epidemiología , Adulto JovenRESUMEN
The safety of obinutuzumab, alone or with chemotherapy, was studied in a non-randomized, open-label, non-comparative, phase IIIb study (GREEN) in previously untreated or relapsed/refractory chronic lymphocytic leukemia. Patients received obinutuzumab 1000 mg alone or with chemotherapy (investigator's choice of fludarabine-cyclophosphamide for fit patients, chlorambucil for unfit patients, or bendamustine for any patient) on days 1, 8 and 15 of cycle 1, and day 1 of cycles 2-6 (28-day cycles), with the cycle 1/day 1 dose administered over two days. The primary end point was safety/tolerability. Between October 2013 and March 2016, 972 patients were enrolled and 971 treated (126 with obinutuzumab monotherapy, 193 with obinutuzumab-fludarabine-cyclophosphamide, 114 with obinutuzumab-chlorambucil, and 538 with obinutuzumab-bendamustine). Grade ≥3 adverse events occurred in 80.3% of patients, and included neutropenia (49.9%), thrombocytopenia (16.4%), anemia (9.6%), and pneumonia (9.0%); rates were similar in first-line and relapsed/refractory patients, and in first-line fit and unfit patients. Using expanded definitions, infusion-related reactions were observed in 65.4% of patients (grade ≥3, 19.9%; mainly seen during the first obinutuzumab infusion), tumor lysis syndrome in 6.4% [clinical and laboratory; highest incidence with obinutuzumab-bendamustine (9.3%)], and infections in 53.7% (grade ≥3, 20.1%). Serious and fatal adverse events were seen in 53.1% and 7.3% of patients, respectively. In first-line patients, overall response rates at three months post treatment exceeded 80% for all obinutuzumab-chemotherapy combinations. In the largest trial of obinutuzumab to date, toxicities were generally manageable in this broad patient population. Safety data were consistent with previous reports, and response rates were high. (clinicaltrials.gov identifier: 01905943).
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Clorhidrato de Bendamustina/administración & dosificación , Clorhidrato de Bendamustina/efectos adversos , Clorambucilo/administración & dosificación , Clorambucilo/efectos adversos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Persona de Mediana Edad , Vidarabina/administración & dosificación , Vidarabina/efectos adversos , Vidarabina/análogos & derivadosRESUMEN
MABLE investigated the efficacy and safety of rituximab plus bendamustine or rituximab plus chlorambucil in fludarabine-ineligible patients with chronic lymphocytic leukemia. Patients received rituximab plus bendamustine or rituximab plus chlorambucil every four weeks for six cycles. Rituximab plus chlorambucil-treated patients without a complete response after Cycle 6 received chlorambucil monotherapy for at least six additional cycles or until complete response. The primary endpoint was complete response rate (confirmed by bone marrow biopsy) after Cycle 6 in first-line patients. Secondary endpoints included progression-free survival, overall survival, minimal residual disease, and safety. Overall, 357 patients were randomized (rituximab plus bendamustine, n=178; rituximab plus chlorambucil, n=179; intent-to-treat population), including 241 first-line patients (n=121 and n=120, respectively); 355 patients received treatment (n=177 and n=178, respectively; safety population). In first-line patients, complete response rate after Cycle 6 (rituximab plus bendamustine, 24%; rituximab plus chlorambucil, 9%; P=0.002) and median progression-free survival (rituximab plus bendamustine, 40 months; rituximab plus chlorambucil, 30 months; P=0.003) were higher with rituximab plus bendamustine than rituximab plus chlorambucil. Overall response rate and overall survival were not different. In first-line patients with a complete response, minimal residual disease-negativity was higher with rituximab plus bendamustine than rituximab plus chlorambucil (66% vs 36%). Overall adverse event incidence was similar (rituximab plus bendamustine, 98%; rituximab plus chlorambucil, 97%). Rituximab plus bendamustine may be a valuable first-line option for fludarabine-ineligible patients with chronic lymphocytic leukemia.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Clorhidrato de Bendamustina/administración & dosificación , Clorambucilo/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Inducción de Remisión , Rituximab/administración & dosificación , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND AND AIMS: Homozygous familial hypercholesterolemia (HoFH) is a genetic condition characterized by lethally high levels of low-density lipoprotein cholesterol (LDL-C) from birth, and requires rapid and aggressive intervention to prevent death due to coronary heart disease and/or atherosclerosis. Where available, lipoprotein apheresis (LA) is the mainstay of treatment to promote survival. METHODS: A-HIT1 registry was conducted with the aim of providing insight to the real-life management of HoFH patients undergoing LA in Turkey, where LA procedures are fully reimbursed and widely available. Participating centers provided patient information, including family history, treatment patterns and relevant laboratory values, via a standard questionnaire. RESULTS: The study evaluated 88 patients (mean age: 27⯱â¯11 years, 41 women) in 19 centers. All patients were receiving regular LA with a clinical diagnosis of HoFH. Mean age at first symptom disease was 10⯱â¯10 years, and at diagnosis it was 12⯱â¯11 years; 74.7% were diagnosed before age 15 years; and only 31% before the age of 7. First referral of most patients was to pediatricians. Early onset coronary artery disease was present in 57.8% of patients. Mean age at first LA was 21⯱â¯12 years. Only 11 (12.5%) patients were undergoing LA weekly. Mean frequency of apheresis sessions was 19⯱â¯13 days. For the last four LA sessions, LDL-C levels reached the target in only in 5.7% of patients. CONCLUSIONS: Diagnosis of HoFH is delayed, and LDL targets are not reached. LA frequencies are not optimal. Urgent attention is needed to support the survival of patients with HoFH.
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Eliminación de Componentes Sanguíneos , LDL-Colesterol/sangre , Homocigoto , Hiperlipoproteinemia Tipo II/terapia , Mutación , Receptores de LDL/genética , Adolescente , Adulto , Edad de Inicio , Biomarcadores/sangre , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/prevención & control , Niño , Estudios Transversales , Femenino , Predisposición Genética a la Enfermedad , Humanos , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/epidemiología , Hiperlipoproteinemia Tipo II/genética , Masculino , Persona de Mediana Edad , Fenotipo , Factores de Riesgo , Factores de Tiempo , Resultado del Tratamiento , Turquía/epidemiología , Adulto JovenRESUMEN
Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries. Cytogenetic lesions such as del13q14, del11q22.3, and del17p13 are identified in 50-60% of patients. Activation-induced cytidine deaminase (AID) plays a central role in somatic hyper mutation (SHM) and class switch recombination (CSR) and functions on Ig genes, but also target non-Ig genes, and over-expression of AID can lead to point mutations or translocations in non-Ig genes such as IgH/Myc translocation. Dicer and Drosha, which have a role in activation process of miRNA, also act in a double-strand DNA break (DSB) repair mechanism. In this study, whether the changes of AID, Dicer and Drosha expressions may be associated with both deletions and clinical outcomes in patients with CLL were investigated. AID expressions were increased in patients with CLL. However, cell lysate AID protein levels were only increased in patients with del17p or del11q who have poor prognosis. Decreased Dicer expressions were found in patients with deletion, whereas increased Drosha expressions were found in patients without deletion and with del13q. According to Rai and Binet staging systems, advanced-stage patients showed increased AID protein levels, decreased Dicer and Drosha expressions. Our findings may suggest that high AID expression and lower Dicer expression were observed in patients with CLL especially del17p and del11q and might associated with deletions such as del17p and del11q. AID, Dicer, and Drosha expressions might be used as an indicator of prognosis for CLL.
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Deleción Cromosómica , Citidina Desaminasa/genética , ARN Helicasas DEAD-box/genética , Regulación Leucémica de la Expresión Génica , Leucemia Linfocítica Crónica de Células B/diagnóstico , Ribonucleasa III/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Cromosomas Humanos Par 11 , Cromosomas Humanos Par 13 , Cromosomas Humanos Par 17 , Citidina Desaminasa/metabolismo , ARN Helicasas DEAD-box/metabolismo , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/patología , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/patología , Masculino , MicroARNs/genética , MicroARNs/metabolismo , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Ribonucleasa III/metabolismoRESUMEN
OBJECTIVE: Chronic lymphocytic leukemia (CLL) is a disease of nonproliferating and mature-appearing B lymphocytes. Insulin-like growth factor-1 (IGF-1) is a small peptide hormone and has mitogenic and antiapoptotic effects, and insulin-like growth factor binding protein-3 (IGFBP-3) has antiproliferative effects on cells. In this study, we investigated plasma levels of both IGF-1 and IGFBP-3 in patients with CLL compared with controls, and we compared these plasma levels according to prognostic factors. MATERIALS AND METHODS: Patients with newly diagnosed CLL who were being followed at the Haseki Training and Research Hospital, Istanbul, Turkey, and volunteers were included in this study. Patients were stratified according to the Rai staging system. Statistical analysis was conducted using SPSS 17.0 for Windows. RESULTS: Forty-three patients [16 women (37%) and 27 men (63%)] were enrolled in this study. Twenty-one volunteers (11 women, 10 men) were included in the control group. The median age of the patients was 65±9 years (range: 18-63 years), and subjects in the control group were 68±8 years old (range: 18-63 years). Even though the plasma levels of IGF-1 were higher and those of IGFBP-3 were lower and the ratio of IGF-I/IGFBP-3 was higher in comparison with the control group, these differences were not statistically significant (p>0.05). In the study group, IGF-1 levels appeared to be increased in parallel to more advanced Rai stages. There were no significant differences between the other groups (p=0.105). CONCLUSION: Plasma IGF-I levels were found higher in patients than in the control group and plasma IGFBP-3 levels were lower; however, neither result was statistically significant. Plasma IGF level increment was observed in concordance with Rai staging. These results prompted us to think that plasma IGF-1 levels in CLL patients are correlated with tumor burden and Rai staging and therefore could be a valuable prognostic factor. Further comprehensive studies are required to support our results.
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Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/sangre , Factor I del Crecimiento Similar a la Insulina , Leucemia Linfocítica Crónica de Células B/sangre , Adolescente , Adulto , Biomarcadores , Femenino , Expresión Génica , Humanos , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/genética , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/genética , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Carga Tumoral , Adulto JovenRESUMEN
OBJECTIVE: Chronic lymphocytic leukemia (CLL) is a disease that shows varying clinical progression, and expression of the protein tyrosine kinase ZAP70 has been described as a very valuable prognostic factor. Patients with ZAP70 positivity are characterized by worse clinical course and significantly shorter progression-free and overall survival. In this study, intracytoplasmic interferon gamma (IFN-γ) and interleukin-4 (IL-4) content of T, B, and CLL cells in CLL patients and their correlations with Rai staging and ZAP70 positivity were investigated. MATERIALS AND METHODS: CLL patients newly diagnosed or in follow-up at the Istanbul University Istanbul Medical Faculty Hematology Department were included in this study. These patients were classified according to Rai staging and ZAP70 expression. IL-4, IFN-γ, and ZAP70 expressions in peripheral blood T, B, and CLL cells were measured by four-color flow cytometry. RESULTS: There was a statistically significant correlation between advanced disease and ZAP70 positivity. IL-4-secreting T cells were significantly increased; however, IFN-γ secretion was significantly decreased in CLL patients compared to healthy individuals, whereas IL-4-secreting B cells were significantly diminished in contrast to T cells. CONCLUSION: These findings suggest damage in the cellular immunity and that IL-4 might lead to many complications and may be important in disease progression.
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Citocinas/metabolismo , Leucemia Linfocítica Crónica de Células B/metabolismo , Proteína Tirosina Quinasa ZAP-70/biosíntesis , Femenino , Citometría de Flujo , Humanos , Leucemia Linfocítica Crónica de Células B/diagnóstico , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Clozapine remains the antipsychotic of choice for refractory schizophrenia. Given the particular side effects of clozapine including neutropenia and myelosuppression, safety and efficacy of add-on chemotherapy for patients who are already under clozapine treatment remain unknown. OBJECTIVE: We present evidence from a patient with a diagnosis of refractory schizophrenia on clozapine medication, who required essential chemotherapy for chronic lymphocytic leukemia (CLL). We have also reviewed literature regarding this challenging clinical dilemma. METHOD: We report details about a patient with treatment-resistant schizophrenia who was given chemotherapy (fludarabine, cyclophosphamide and rituximab) for CLL in the course of concomitant treatment with clozapine and granulocyte-colony stimulating factor (G-CSFs). In addition, we have reviewed literature using the PUBMED data base. RESULTS: Current evidence remains insufficient to provide authoritative guide to clinicians regarding the efficacy and safety of the combined use of clozapine and chemotherapy. However, general conclusion from our case and of the published evidence is that a combination of clozapine use and chemotherapeutic agents do not cause additional hematological worsening with no decreasing efficacy concerns raised. CONCLUSION: Continuing with clozapine in the course of chemotherapy may be relatively safer for patients who responded well to clozapine concomitant with G-CSF treatment.
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Long non-coding RNAs (lncRNA) which are longer than 200 base pairs in length, play an important role in cellular machinery. Chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) are neoplasms of B-cells. In our study we aimed to investigate circulating lncRNA levels of CLL and MM patients. For this purpose we selected 5 candidate lncRNAs (TUG1, LincRNA-p21, MALAT1, HOTAIR, and GAS5) where the first two are regulated by p53. Analyses were performed by real-time PCR using cDNA synthesized from plasma RNAs. In both disease groups differential levels of plasma lncRNAs were observed. LincRNA-p21 was the only molecule displaying significant changes in the CLL group while all remaining lncRNAs showed significant differences in the MM group. In the MM group only TUG1 showed higher levels than the healthy volunteers. In conclusion, the expression levels of the candidate lncRNA molecules display a general trend for tissue- and disease-specific expression which can provide important potential biomarkers specific to the particular disease type. However, further studies are necessary to elucidate their involvement in disease development and progression.
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Linfocitos B/química , ARN Largo no Codificante/análisis , Linfocitos B/metabolismo , Cartilla de ADN , ADN Complementario/química , ADN Complementario/genética , Progresión de la Enfermedad , Humanos , Linfoma de Células B/sangre , Linfoma de Células B/metabolismo , Mieloma Múltiple/sangre , Mieloma Múltiple/metabolismo , Reacción en Cadena de la Polimerasa , ARN Largo no Codificante/sangreRESUMEN
Activation induced cytidine deaminase (AID) enzyme, which converts cytosine into uracil and is expressed only by activated B lymphocytes, plays a role in B cells in both the mechanisms of somatic hypermutation (SHM) and class switch recombination (CSR). There are studies showing that AID can cause numerous translocations in different lymphoproliferative diseases. Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of monoclonal B cells in bone marrow and peripheral blood. The predictability and clinical status of B-CLL are difficult to determine. About 30-50% of patients have chromosomal abnormalities. AID, which is thought to create fraction segments for translocations, might also cause deletions in DNA regions of 17p13, 11q22.3, 13q14 and 13q34 that are associated with prognostic implications in patients with CLL. In this study, the AID gene expression in patients with CLL with and without deletions was investigated. When compared to healthy subjects and patients without deletions, increased levels of AID expression in patients with deletions of 17p13, 11q22.3 or 13q14 were found, but not for the 13q34 region. Our results show that AID expression may be associated with deletions in patients with CLL.
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Deleción Cromosómica , Citidina Desaminasa/genética , Leucemia Linfocítica Crónica de Células B/genética , ARN Mensajero/genética , Adulto , Anciano , Cromosomas Humanos Par 11/genética , Cromosomas Humanos Par 13/genética , Cromosomas Humanos Par 17/genética , Análisis Citogenético , Femenino , Regulación Enzimológica de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
INTRODUCTION: Therapy-related acute myeloid leukemia occurs as a complication of treatment with chemotherapy, radiotherapy, immunosuppressive agents or exposure to environmental carcinogens. CASE PRESENTATION: We report a case of therapy-related acute myeloid leukemia in a 37-year-old Turkish woman in complete remission from breast cancer. Our patient presented to our facility with fatigue, fever, sore throat, peripheral lymphadenopathy, and moderate hepatosplenomegaly. On peripheral blood and bone marrow aspirate smears, monoblasts were present. Immunophenotypic analysis of the bone marrow showed expression of CD11b, CD13, CD14, CD15, CD33, CD34, CD45 and human leukocyte antigen-DR, findings compatible with the diagnosis of acute monoblastic leukemia (French-American-British classification M5a). Therapy-related acute myeloid leukemia developed three years after adjuvant chemotherapy consisting of an alkylating agent, cyclophosphamide and DNA topoisomerase II inhibitor, doxorubicin and adjuvant radiotherapy. Cytogenetic analysis revealed a 46, XX, deletion 7 (q22q34), deletion 20 (q11.2q13.1) karyotype in five out of 20 metaphases and inversion 16 was detected by fluorescence in situhybridization. There was no response to chemotherapy (cytarabine and idarubicin, FLAG-IDA protocol, azacitidine) and our patient died in the 11th month after diagnosis. CONCLUSIONS: The median survival in therapy-related acute myeloid leukemia is shorter compared to de novoacute myeloid leukemia. Also, the response to therapy is poor. In therapy-related acute myeloid leukemia, complex karyotypes have been associated with abnormalities of chromosome 5, rather than 7. To the best of our knowledge, this is the first case of therapy-related acute myeloid leukemia showing the co-presence of deletion 7q, 20q and the inversion 16 signal.
RESUMEN
Rai and Binet staging systems that have been used as a standard method for evaluating the prognosis of chronic lymphocytic leukemia (CLL) have some restrictions in distinguishing the early stage CLL patients that will progress rapidly. To solve this shortcoming, prognostic parameters other than staging have become important in the recent years. Intracellular upregulation of Fc mu receptor (FCMR, FAIM3/TOSO) gene in the leukemic lymphocytes of the patients with CLL may be an important parameter in predicting the progression of the disease. In this study, FCMR mRNA expression levels were evaluated in 50 CLL patients and in 50 healthy controls. FCMR mRNA expression was found to be significantly higher in CLL patients than in healthy controls. We, then, evaluated FCMR mRNA levels according to the stages of CLL. Rai stage 0, I, II cases were compared with stage III and IV, and Binet A was compared with Binet B and C according to FCMR mRNA levels. In cases with higher risks, Rai stage III, IV and Binet stage B and C, FCMR mRNA levels were also significantly higher. In addition, overexpression of the FCMR seems to be promoting the chromosomal abnormalities. As a result, we found that the mRNA levels of FCMR in the CLL patients are 23-fold higher than that of the control group and this may suggest that it can be associated with the disease progression and survival. For this reason and because of the simplicity of analyzing with Q-PCR, it can be a useful clinical parameter, after its importance has been shown in larger and multi-variate studies.
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Proteínas Reguladoras de la Apoptosis/genética , Aberraciones Cromosómicas , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/patología , Proteínas de la Membrana/genética , Anciano , Estudios de Casos y Controles , Cartilla de ADN/química , Cartilla de ADN/genética , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Linfocitos/metabolismo , Linfocitos/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
The p53 tumor suppressor gene plays an important role in preventing tumor development. The p53 protein interacts with other p53 signal pathway members to control cell proliferation. In this study, expression of the p53, Human homolog of murine Double Minute 2 (HDM2), p14Alternating Reading Frame (ARF), Zinc Finger and BTB domain containing 7A (ZBTB7A), and B-Cell Lymphoma 6 (BCL6) genes was quantitatively investigated by real-time polymerase chain reaction (PCR) in the peripheral blood of patients with chronic lymphocytic leukemia (CLL) and healthy controls. Plasma fibronectin levels were determined by enzyme-linked immunosorbent assay. Expression of the p53, p14, and HDM2 genes were significantly higher in the patients. However, ZBTB7A and BCL6 gene expression was not detectable in both groups. A positive correlation between p14ARF and HDM2 expression and a negative correlation between p53 and p14ARF expression was observed. Expression of the p14ARF and HDM2 genes were inversely correlated in the control group. Neither HDM2 nor p14ARF gene expression was correlated with p53 expression. The p53 gene was also analyzed for the presence of mutations. A splice-site mutation was found in a single patient. Our findings indicate that expression of the p53, p14ARF, and HDM2 genes are associated with CLL. Elucidation of the mutual interactions at the protein level warrants further studies.
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Leucemia Linfocítica Crónica de Células B/genética , Polimorfismo Genético/genética , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteína p14ARF Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/genética , Estudios de Casos y Controles , ADN/genética , Femenino , Fibronectinas/sangre , Genotipo , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Reacción en Cadena de la Polimerasa , Pronóstico , Factores de RiesgoRESUMEN
Polymorphisms of the x-ray repair cross-complementing group 1 (XRCC1) gene have been reported to be associated with various forms of cancer. We evaluated the possible effects of the Arg194Trp and the Arg399Gln polymorphisms on the risk for chronic lymphocytic leukemia (CLL) in 73 patients and 50 controls. We also analyzed their relation to frequency of sister chromatid exchange (SCE). With respect to codon 194, the allelic frequency of the Arg194Trp polymorphism did not significantly differ between the 2 groups. The proportion of individuals carrying the Arg194Trp polymorphism was not different in the 2 groups. With respect to codon 399, the proportion of the individuals carrying the Arg399Gln allele (90% vs 62%; p=0.000; odds ratio [OR], 5.779; 95% confidence interval [CI], 2.2-15.183) and the allelic frequency of the Arg399Gln polymorphism (56% vs 36%; p=0.002; OR, 2.278; 95% CI, 1.350-3.843) was significantly higher in the patient group. The frequency of the Arg/Gln genotype was significantly higher in the patient group (68.50% vs 52%; p=0.049; OR, 2.007; 95% CI, 0.955-4.217). The mean SCE frequency in the patient group was significantly higher (9.2±4 vs 7.5±2; p=0.02). When different compound genotypes were compared, the coexistence of Arg/Arg genotype in codon 194 with Arg/Arg genotype in codon 399 was significantly more frequent in the control group (30% vs 9%; p=0.004; OR, 0.247; 95% CI, 0.092-0.664). Within the patient group, SCE frequency did not differ between patients with various genotypes. The Arg399Gln polymorphism may be etiologically associated with CLL; however, it does not seem to increase SCE frequency.
Asunto(s)
Proteínas de Unión al ADN/genética , Leucemia Linfocítica Crónica de Células B/genética , Polimorfismo Genético/genética , Intercambio de Cromátides Hermanas/genética , Anciano , Codón/genética , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos XRESUMEN
The Rai and Binet staging systems, which are used as standard methods for evaluating the prognosis of chronic lymphocytic leukemia (CLL), have some restrictions in identifying patients with early-stage CLL who will progress rapidly. To solve this defect, other prognostic parameters have become important in recent years. Intracellular up-regulation of the AID gene in the leukemic lymphocytes of patients with CLL may be an important parameter for predicting the progression of CLL. In this study, AID mRNA expression levels were evaluated in 50 patients with CLL and 50 healthy controls. AID mRNA expression was significantly higher in patients than in controls. We then evaluated AID mRNA levels according to the stages of CLL. Regarding AID mRNA levels, patients with Rai stages 0, I, and II were compared with patients with stages III and IV, whereas patients with Binet stage A were compared with patients with Binet stages B and C. In patients with higher-risk Rai stages III and IV and Binet stages B and C, activation-induced cytidine deaminase (AID) mRNA levels were also significantly higher. Additionally, we found that the mRNA levels of patients with AID in CLL were eight-fold higher than those in control patients, suggesting that AID overexpression promotes chromosomal abnormalities and is associated with CLL progression and survival. For this reason, and because of the simplicity of quantitative real-time PCR analysis, AID might be a useful clinical parameter after its importance is confirmed in larger and multivariate studies.
Asunto(s)
Aberraciones Cromosómicas , Citidina Desaminasa/genética , Leucemia Linfocítica Crónica de Células B/genética , ARN Mensajero/genética , Anciano , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Humanos , Leucemia Linfocítica Crónica de Células B/enzimología , Leucemia Linfocítica Crónica de Células B/patología , Linfocitos/enzimología , Linfocitos/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , ARN Neoplásico/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tasa de SupervivenciaRESUMEN
Psychogenic purpura (Gardner-Diamond syndrome) is the occurrence and spontaneous recurrence of painful ecchymosis following emotional stress and minor trauma. Although the exact mechanism of this syndrome remains unknown, apart from skin lesions, different types of hemorrhaging have been reported, such as epistaxis, gastrointestinal bleeding, and bleeding from the ear canals and eyes. We report a psychogenic purpura case that presented with hematuria in addition to skin lesions. Based on the psychiatric evaluation she was diagnosed with major depressive disorder, generalized anxiety disorder, and obsessive-compulsive disorder. Additionally, sexual pain disorder accompanied these disorders. With the help of antidepressant and supportive psychotherapy, the patient's ecchymosis and bleeding disappeared. During 8 months of follow-up the symptoms did not return. Vaginismus has not been reported in patients with psychogenic purpura. The presence of vaginismus, which is seen more frequently in eastern cultures and is thought to be related to sociocultural determinants, suggests that some cultural factors may be common to both psychogenic purpura and vaginismus. The aim of this case report was to call attention to a syndrome that is rarely seen and diagnosed, and to discuss its relationship to psychosocial factors. This syndrome should be considered in the differential diagnosis of not only ecchymotic lesions, but also various types of bleeding, including hematuria. Despite the fact that its etiology and treatment are not clearly understood, it should be noted that psychological factors play a role in this disease and therefore, psychopharmacological and psychotherapeutic approaches can be effective.
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Antipsicóticos/uso terapéutico , Hematuria/etiología , Trastornos Psicofisiológicos/psicología , Púrpura/psicología , Vaginismo/psicología , Adulto , Equimosis/etiología , Equimosis/patología , Femenino , Humanos , Trastornos Psicofisiológicos/complicaciones , Trastornos Psicofisiológicos/tratamiento farmacológico , Púrpura/complicaciones , Púrpura/tratamiento farmacológico , Síndrome , Resultado del Tratamiento , Vaginismo/complicaciones , Vaginismo/tratamiento farmacológicoRESUMEN
Fifty-six adult patients with newly diagnosed acquired severe aplastic anemia (SAA) received horse antilymphocyte globulin (ALG), cyclosporin A (CyA), methylprednisolone (Mpred), granulocyte colony-stimulating factor (G-CSF) as first-line therapy. The median age was 34 (range, 17-72) and median neutrophil count 0.280 x 10(9)/L. Trilineage hematologic recovery (at a median interval of 105 days from treatment) was seen in 46 patients (37 complete, 9 partial) after one (n = 38) or two (n = 8) courses of ALG. Cytogenetic abnormalities were observed in three unresponders, clonal hematologic disease in three complete responders, and relapse of marrow aplasia in four complete responders. Median follow up for surviving patients was 1,668 days (range, 237-4,012). The actuarial survival at 5 years was 82%, falling to 77.1% at 7 years and was stationary at 7 and 8 years. Survival was not influenced by the neutrophil count (72% vs. 87%, for neutrophils less than vs. greater than 0.2 x 10(9)/L; P = 0.54). Immunosuppressive treatment of SAA with the 4-drug combination appears to be effective. The significant prognostic effect of an enduring increase of the white blood cell (WBC) count during G-CSF treatment may suggest complete and partial response to therapy. In nonresponders, the WBC count either did not change or elevated values gradually returned to nearly their initial levels while the patients were still under G-CSF treatment. In patients not responsive to treatment but living under CyA and G-CSF, the possibility of developing cytogenetic abnormalities does not seem to be low, despite the absence of findings attributable to manifest myelodysplastic syndrome.