RESUMEN
Besides histopathological findings, there are no indicators of increased risk for fibrotic progression in myeloproliferative neoplasms (MPNs). Age-related clonal hematopoiesis (ARCH) or clonal hematopoiesis of indetermined potential (CHIP) are frequent findings in the elderly and combinations with MPN driver mutations (JAK2, MPL, and CALR) have been described. To determine the impact of ARCH/CHIP-related mutations for the development of fibrosis in primary myelofibrosis (PMF), the mutational status of cases with fibrotic progression from grade 0 to grade 2/3 (nâ¯= 77) as evidenced by follow-up bone marrow biopsies (median 6.2 years) was compared to prefibrotic PMF samples without the development of fibrosis (nâ¯= 27; median follow-up 7.3 years). Frequent ARCH/CHIP-associated mutations (TET2, ASXL1, DNMT3A) demonstrable at presentation were not connected with fibrotic progression. However, mutations that are rarely found in ARCH/CHIP (SRSF2, U2AF1, SF3B1, IDH1/2, and EZH2) were present in 24.7% of cases with later development of fibrosis and not detectable in cases staying free from fibrosis (Pâ¯= 0.0028). Determination of tumor mutational burden (TMB) in a subgroup of cases (nâ¯= 32) did not show significant differences (7.68 mutations/MB vs. 6.85 mutations/MB). We conclude that mutations rarely found in ARCH/CHIP provide an independent risk factor for rapid fibrotic progression (median 2.0 years) when already manifest at first presentation.
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Mielofibrosis Primaria , Anciano , Fibrosis , Trasplante de Células Madre Hematopoyéticas , Humanos , Janus Quinasa 2/genética , Mutación , Mielofibrosis Primaria/genéticaRESUMEN
BACKGROUND: Biliary atresia (BA) is a rare disease of the newborn, resulting in liver cirrhosis due to obliterative cholangiopathy. Liver biopsies are commonly performed in order to confirm the diagnosis and in order to stage fibrosis. OBJECTIVES: The present study intended to analyze two established scores for evaluating liver fibrosis focusing on the interobserver variability as well as the prognostic reliability towards the time of liver transplantation. MATERIALS AND METHODS: Liver biopsies of BA patients between 2012 and 2015 were evaluated retrospectively by two pathologists at the Hannover Medical School (MHH) and the RWTH Aachen University Hospital. Fibrosis was measured using Ishak and Chevallier scores. Furthermore, a computerized automatically algorithm-based analyzation (ABAA) was performed. Results were evaluated towards the time point of liver transplantation and hepatoportoenterostomy (HPE). RESULTS: Overall, 34 liver biopsies were analyzed. The Ishak score showed a remarkable interobserver variability (ΚWâ¯= 0.68) while the Chevallier score was proven to have a poor interobserver variability (Fleiss' Κappaâ¯= -0.01). However, both scores were correlated positively, as was the ABAA (pâ¯< 0.001). Regarding prognostic reliability, ROC analyses of the Ishak score revealed the best validity towards an early liver transplantation within 12 months (AUC 0.813, pâ¯= 0.011). In addition, an increased Ishak score ≥4 reduced the survival time with the native liver (hazard ratio 6.6 [95% CI 1.9-23.3]). CONCLUSIONS: The Ishak score was revealed to have the best interobserver variability as well as prognostic validity towards an early liver transplantation in BA patients. Due to its easy applicability, the Ishak score was proven superior in comparison to the Chevallier score and ABAA. Therefore, use of the Ishak score is recommended in daily clinical routine for analyzing liver biopsies in BA patients.
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Atresia Biliar , Cirrosis Hepática , Humanos , Hígado , Portoenterostomía Hepática , Reproducibilidad de los Resultados , Estudios RetrospectivosRESUMEN
BACKGROUND: Chronic viral hepatitis is linked to fibrotic liver injury that can progress to liver cirrhosis with its associated complications. Recent evidence suggests a role of senescence in liver fibrosis, although the senescence regulators contributing to fibrosis progression remain unclear. AIM: To investigate the role of senescence and different senescence markers for fibrosis progression in patients with chronic hepatitis C virus (HCV) infection. METHODS: The expression of the cell cycle inhibitors p21, p27 and p16 as well as the senescence markers p-HP1γ and γ-H2AX was analysed in liver tissue with different fibrosis stages. Senescence-associated chitotriosidase activity was measured in sera of HCV patients (n = 61) and age-matched healthy individuals (n = 22). RESULTS: We found a remarkable up-regulation of the cell cycle inhibitors and senescence markers in chronic HCV infection compared to healthy liver tissue. Liver tissue with relevant fibrosis stages (F2-3) or cirrhosis (F4) revealed a significant increase in senescent cells compared to livers with no or minimal fibrosis (F0-1). In cirrhotic livers, a significantly higher number of p-HP1γ, p21 and p27 positive cells was detected compared to liver tissue with F2-3 fibrosis. Importantly, we identified T-cells as the dominant cell type contributing to increased senescence during fibrosis progression. Compared to healthy individuals, serum chitotriosidase was significantly elevated and correlated with histological fibrosis stages and liver stiffness as assessed by transient elastography. CONCLUSIONS: Senescence of hepatic T-cells is enhanced in chronic viral hepatitis and increases with fibrosis progression. Serological detection of senescence-associated chitotriosidase might allow for the non-invasive detection of relevant fibrosis stages.
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Biomarcadores , Senescencia Celular , Hepatitis C Crónica/diagnóstico , Hepatocitos/patología , Cirrosis Hepática/diagnóstico , Adulto , Biomarcadores/análisis , Biomarcadores/metabolismo , Estudios de Casos y Controles , Senescencia Celular/genética , Progresión de la Enfermedad , Diagnóstico por Imagen de Elasticidad , Femenino , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/patología , Hepatocitos/metabolismo , Hexosaminidasas/análisis , Hexosaminidasas/genética , Hexosaminidasas/metabolismo , Humanos , Hígado/diagnóstico por imagen , Hígado/metabolismo , Hígado/patología , Cirrosis Hepática/etiología , Cirrosis Hepática/patología , Masculino , Persona de Mediana EdadAsunto(s)
Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/diagnóstico , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/genética , Mutación/genética , Receptores del Factor Estimulante de Colonias/genética , Anciano , Humanos , Masculino , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/genéticaAsunto(s)
Calreticulina/genética , Trasplante de Células Madre Hematopoyéticas , Janus Quinasa 2/genética , Proteínas Nucleares/genética , Mielofibrosis Primaria/genética , Receptores de Trombopoyetina/genética , Ribonucleoproteínas/genética , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Mielofibrosis Primaria/terapia , Factores de Empalme Serina-Arginina , Factor de Empalme U2AFRESUMEN
Fine needle aspiration (FNA) is a sensitive and specific method (95%), often helpful in characterizing suspected liver lesions. It is appropriate to distinguish between primary and secondary liver neoplasia. Moreover, in most cases, the use of cell block preparations of small specimens allows immunocytochemical evaluation to determine the nature of the primary tumour. In a retrospective study at Hannover Medical School (MHH) from 1998 to 2012 (14 years), 4,136 sonographically guided FNAs were performed. The patients provided consent and the study protocol was approved by the local ethics committee. There were 39.6% malignant and 57.5% benign lesions in the liver, while 2.8% of the cases were undetermined. FNA was non-representative in 1.1% of the cases. The diagnostic utility of highly differentiated hepatocellular carcinoma (HCC; G1) remains difficult; cell bridges with cell atypia are pathognomonic for diagnosis. Ancillary techniques and immunocytochemical investigations will increase the sensitivity and specificity, particularly by using the cell block technique.
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Neoplasias Hepáticas/diagnóstico , Hígado/patología , Neoplasias de los Conductos Biliares/diagnóstico , Biopsia con Aguja Fina , Humanos , Neoplasias Hepáticas/secundario , Tumores Neuroendocrinos/diagnóstico , Sensibilidad y EspecificidadRESUMEN
Myeloproliferative neoplasms (chronic myeloproliferative disorders according to former nomenclature) comprise chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, primary myelofibrosis, chronic eosinophilic leukemia, chronic neutrophilic leukemia and systemic mastocytosis. All disorders have excessive proliferation of one or more hematopoietic lineages in common and progress with different probability to blast crisis or fibrosis. A further common feature is provided by the activating mutation of tyrosin kinases and associated pathways of signal transduction (BCR-ABL, JAK2(V617F), MPL(W515L/K), KIT(D816V) and FIP1L1-PDGFRA) causative for the abnormal proliferation. With regard to diagnosis and therapy these mutations are of utmost importance because they enable the exclusion of reactive processes, contribute with varying specificity to subtyping of MPN and are at least partly sensitive to targeted therapy. The molecular mechanisms of blastic and fibrotic progression are not yet understood.
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Examen de la Médula Ósea/métodos , Médula Ósea/patología , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Enfermedades Mielodisplásicas-Mieloproliferativas/genética , Enfermedades Mielodisplásicas-Mieloproliferativas/patología , Biomarcadores de Tumor/genética , Crisis Blástica/genética , Crisis Blástica/patología , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Aberraciones Cromosómicas , Análisis Mutacional de ADN , Marcadores Genéticos/genética , Humanos , Inmunohistoquímica , Técnicas de Diagnóstico Molecular , Estadificación de NeoplasiasRESUMEN
Acute cellular rejection (ACR) occurs frequently after liver transplantation and can usually be controlled. Triggering of allospecific immune responses and lack of immunoregulation are currently suggested as a cause of ACR, but there are no investigations of intrahepatic immune responses during ACR. Therefore we prospectively analyzed the intrahepatic T cell infiltration pattern in correlation to the severity of ACR in a cohort of patients with graft hepatitis (n = 151). While CD4(+) cells dominated the portal infiltrates in mild-moderate ACR, CD8(+) cells prevailed in severe ACR. Furthermore portal CD8(+) and not CD4(+) infiltration correlated with serum transaminases and with the likelihood of subsequent ACRs. Surprisingly, the rise of portal effector T cells density during ACR was surpassed by the increase in portal infiltration of regulatory T cells by a factor of two. Thus ACRs rather showed an increase and not a lack of regulation, as was suggested by analysis of peripheral blood mononuclear cells. Despite the pattern of enhanced immunoregulation, patients with severe ACR had a higher risk for subsequent rejections and showed a trend to a reduced survival. Thus, patients with severe rejections might need a modification of their immunosuppression to improve prognosis.
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Linfocitos T CD8-positivos/inmunología , Rechazo de Injerto/inmunología , Leucocitos Mononucleares/inmunología , Trasplante de Hígado/inmunología , Linfocitos T Reguladores/inmunología , Enfermedad Aguda , Adulto , Anciano , Femenino , Humanos , Pruebas de Función Hepática , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Trasplante HomólogoRESUMEN
Chronic courses of hepatitis E virus (HEV) infections have been described in immunosuppressed patients. We aimed to study the role of HEV infections in heart transplant recipients (HTR). 274 HTR were prospectively screened for HEV infection using an anti-HEV-IgG ELISA and HEV-PCR. In addition, 137 patients undergoing cardiac surgery (non-HTR) and 537 healthy subjects were studied cross-sectionally. The anti-HEV-IgG seroprevalence was 11% in HTR, 7% in non-HTR and 2% in healthy controls (HTR vs. healthy controls p<0.0001; non-HTR vs. healthy controls p<0.01). Anti-HEV tested positive in 4.0% in control cohorts of other immunocompromised patients (n = 474). Four HTR (1.5%) were chronically infected with HEV as shown by HEV-PCR and all four patients had liver transaminases of >200 IU/L and histological or clinical evidence of advanced liver disease. In three patients ribavirin treatment was successful with a sustained biochemical and virological response while treatment failed in one cirrhotic patient after ribavirin dose reduction. Heart transplant recipients and patients undergoing cardiac surgery have an increased risk for HEV infections. Chronic hepatitis E may explain elevated liver enzymes in heart transplant recipients. Treatment of HEV infection with ribavirin is effective but the optimal dose and duration of ribavirin therapy remains to be determined.
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Trasplante de Corazón/inmunología , Anticuerpos Antihepatitis/análisis , Virus de la Hepatitis E/inmunología , Hepatitis E/epidemiología , Adolescente , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Biopsia con Aguja , Estudios de Casos y Controles , Enfermedad Crónica , Ensayo de Inmunoadsorción Enzimática , Femenino , Estudios de Seguimiento , Alemania/epidemiología , Trasplante de Corazón/estadística & datos numéricos , Hepatitis E/inmunología , Hepatitis E/patología , Virus de la Hepatitis E/aislamiento & purificación , Humanos , Huésped Inmunocomprometido/inmunología , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Prevalencia , Estudios Prospectivos , ARN Viral/análisis , Medición de Riesgo , Distribución por Sexo , Estadísticas no Paramétricas , Tasa de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: Cases with subcutaneous metastasis of differentiated hepatocellular carcinoma to the abdominal wall without prior seeding as a consequence of local interventions with a negative or normal alpha-fetoprotein level in the serum are extremely rare. CASE REPORT: This is the first report of a case with AFP-negative, differentiated hepatocellular carcinoma metastasis to the abdominal wall within a pre-existing subcutaneous lipoma since childhood after antiandrogen therapy with leuprorelin and buserelin acetate for prostate cancer without seeding. METHODS: Clinical features including histology, immunohistochemistry, clinical course and surgical approach are presented. RESULTS: Histological examination revealed a hepatocellular carcinoma with a trabecular and pseudoglandular growth pattern with moderately atypical hepatocytes with multifocal bile formation within a lipoma. The postoperative course of abdominal wall reconstruction with a monocryl-prolene mesh and a local flap after potentially curative resection was uncomplicated. DISCUSSION AND CONCLUSION: It may be that previous antiandrogen treatment for prostate carcinoma contributed to the fact that our patient developed alpha-fetoprotein-negative and androgen receptor-negative subcutaneous abdominal wall metastasis within a pre-existing lipoma since childhood.
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Neoplasias Abdominales/secundario , Pared Abdominal/patología , Antagonistas de Andrógenos/efectos adversos , Carcinoma Hepatocelular/patología , Diferenciación Celular , Lipoma/inducido químicamente , Neoplasias Hepáticas/patología , alfa-Fetoproteínas/metabolismo , Neoplasias Abdominales/inducido químicamente , Neoplasias Abdominales/metabolismo , Neoplasias Abdominales/cirugía , Pared Abdominal/cirugía , Anciano , Carcinoma Hepatocelular/inducido químicamente , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/cirugía , Niño , Humanos , Lipoma/patología , Lipoma/cirugía , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/cirugía , Masculino , Estadificación de Neoplasias , Pronóstico , Neoplasias de la Próstata/tratamiento farmacológicoRESUMEN
Hepatitis E is an infectious disease caused by the hepatitis E virus (HEV). Hepatitis E is mainly a self-limiting travel-associated disease without chronic evolution. In recent years an increasing number of authochtonous HEV-infections has been described in industrialized countries. HEV-infections frequently take a mild clinical silent course of disease in immunocompetent individuals and thus HEV infection is largely underdiagnosed. Therefore, the anti-HEV-prevalence is much higher than anticipated with 2 - 20% in Western Europe. HEV genotype 3 infections must be considered as zoonotic infections with several animals including swines serving as reservoirs. Cases of HEV-transmissions by blood transfusion were described not only in Asia but also in France and the UK. HEV-infections may take severe courses in pregnant women and patients with chronic liver diseases, sometimes leading to acute liver failure. In addition several centres described cases of progressive chronic HEV-infection in organ transplant recipients and HIV-positive patients during the last two years. In this review we summarize the current state-of-the-art on the knowledge of HEV-infections in industrialised countries.
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Hepatitis E/diagnóstico , Animales , Anticuerpos Antivirales/sangre , Patógenos Transmitidos por la Sangre , Estudios Transversales , Reservorios de Enfermedades/virología , Europa (Continente) , Femenino , Genotipo , Seropositividad para VIH/epidemiología , Seropositividad para VIH/inmunología , Hepatitis E/epidemiología , Hepatitis E/inmunología , Hepatitis E/transmisión , Virus de la Hepatitis E/genética , Virus de la Hepatitis E/inmunología , Hepatitis Crónica/diagnóstico , Hepatitis Crónica/epidemiología , Humanos , Trasplante de Órganos , Embarazo , Pronóstico , Factores de Riesgo , Porcinos/virología , Zoonosis/transmisión , Zoonosis/virologíaRESUMEN
The thrombopoietin receptor gene (MPL) is expressed in megakaryocytes and exhibits the gain of function point mutation W515K/L in approximately 5% of patients with primary myelofibrosis/idiopathic myelofibrosis (PMF) representing one subtype of the chronic myeloproliferative disorders (myeloproliferative neoplasm). A series of primary and secondary acute myeloid leukaemias (AML) with megakaryoblastic phenotype and myelofibrosis unrelated to PMF (n=12) was analysed for the MPL(W515K/L) mutation by pyrosequencing. In three cases (25%), MPL(W515L) was found and in two of these a combination with trisomy 21 or the Philadelphia chromosome occurred. None of the secondary AML cases evolving from pre-existing PMF showed MPL(W515K/L) (n=4). We conclude that MPL(W515L) occurs in a considerable proportion of acute megakaryoblastic leukaemias with myelofibrosis unrelated to PMF.
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Leucemia Megacarioblástica Aguda/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Mutación/genética , Mielofibrosis Primaria/genética , Receptores de Trombopoyetina/genética , Adulto , Anciano , Anciano de 80 o más Años , Crisis Blástica , Células de la Médula Ósea , Niño , Preescolar , Femenino , Humanos , Janus Quinasa 2/genética , Rayos Láser , Masculino , Microdisección , Persona de Mediana EdadRESUMEN
We report a case of a patient who presented with a left sided inguinal swelling. Ultrasound examination clearly revealed a bilateral inguinal lymphoma. In addition, a renal cell carcinoma was diagnosed through ultrasound. The differences in texture between lymph nodes and renal tumour as well as the even concentric swelling of the lymph node sinus permitted a clear cut differentiation between the two entities. CT could not provide this clear distinction. Despite some controversy several case reports as well as a few retrospective studies showed an increased coincidence of renal cell carcinoma and malignant lymphoma. However, a pathophysiological connection has not yet been discovered. This report presents another case of synchronous appearance of renal cell carcinoma and malignant lymphoma and demonstrate the relevance of ultrasound in the discrimination between the two clinical entities. It is essential for physicians performing either sonography and/or CT to be aware of this coincidence to avoid misdiagnosis of lymphadenopathy in patients with renal cell carcinoma as metastasis and, vice versa, renal tumours in lymphoma patients as renal manifestation of the lymphoma.
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Carcinoma de Células Renales/diagnóstico por imagen , Neoplasias Renales/diagnóstico por imagen , Linfoma/complicaciones , Linfoma/diagnóstico por imagen , Neoplasias Primarias Secundarias/diagnóstico por imagen , Carcinoma de Células Renales/complicaciones , Diagnóstico Diferencial , Humanos , Neoplasias Renales/complicaciones , Escisión del Ganglio Linfático , Ganglios Linfáticos/patología , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Rayos X , UltrasonografíaRESUMEN
The diagnosis of chronic eosinophilic leukemia (CEL) is based on the evidence of an autonomous, clonal proliferation of eosinophilic precursors and the exclusion of other myeloid neoplasms with eosinophilia. Histopathological evaluations of bone marrow are rare, and reliable data on the frequency of CEL do not yet exist. A total of 100 cases characterized by eosinophilia >/=1.5x10(9)/l blood for more than 6 months were evaluated. In 87 cases, the eosinophilia turned out to be secondary and a reactive genesis was likely, but not proven in 3 further cases. Idiopathic hypereosinophilic syndrome was diagnosed in three cases. The diagnosis CEL was considered in four out of a total of seven cases with a myeloid neoplasia and all four disorders showed an abnormal karyotype. However, only one of them could be classified as CEL. We conclude that CEL is a rare disease concerning only a minority of cases with chronic eosinophilia.
Asunto(s)
Síndrome Hipereosinofílico/epidemiología , Síndrome Hipereosinofílico/patología , Diagnóstico Diferencial , Humanos , Incidencia , Leucemia Eosinofílica Aguda/patología , Leucemia Mieloide Aguda/patologíaRESUMEN
Staging biopsies of the bone marrow in lymphoma patients are among the most important indications and therefore of substantial practical importance. Occasionally it is the only organ infiltrated, and therefore a bone marrow biopsy is the prime diagnostic choice in cases of leukemic lymphomas. A synoptical diagnostic approach relying on immunophenotypic as well as on molecular biological criteria aside from histomorphology (cytomorphology), is of utmost importance for the subtyping of malignant lymphomas. This too can be done reliably on bone marrow biopsies, as comparative studies have yielded a concordance rate of more than 90% with lymphoma typing on corresponding lymph nodes. Cytology and the pattern of infiltrates, (i.e. diffuse, interstitial, nodular peritrabecular and intrasinusoidal), in combination with immunological phenotyping are the mainstays for subtyping, giving clear-cut decisions in most cases of small B-cell lymphoma, mantle zone as well as marginal cell and follicular lymphomas and hairy cell leukemia. Among the blastic variants the most important are the lymphoblastic lymphomas of either B- or T-cell type which have to be discerned from AML and the so-called blastoid mantle cell lymphomas. T-cell lymphomas are rare compared to B-cell lymphomas. Among the rarely seen T-cell neoplasias the lymphoma of large granular lymphocytes is the dominating lymphoma, which in most cases can only be diagnosed reliably by molecular biological means, followed by T-CLL, Sezary's syndrome and hepatosplenic chi delta lymphoma.
Asunto(s)
Médula Ósea/patología , Leucemia/patología , Linfoma no Hodgkin/patología , Biopsia/métodos , Diagnóstico Diferencial , Humanos , Inmunofenotipificación , Leucemia de Células B/patología , Linfoma no Hodgkin/clasificación , Linfoma no Hodgkin/inmunologíaRESUMEN
Pseudo-Gaucher cells (PGC) are a characteristic finding in Ph-positive CML, and prolongation of survival was observed when PGC were detected within the bone marrow. However, the conspicuous variation in the reported frequencies indicates the necessity for analysis of their natural occurrence in the bone marrow from untreated CML patients. A total of 833 diagnostic bone marrow biopsies from patients with Ph-positive CML were examined for PGC by 7 observers. Proof of PGC was based on systematic examination of Giemsa-stained slides with and without polarization at high magnification. Birefringence within the cytoplasm turned out to be highly specific for PGC. The risk of overlooking PGC was at least 80% when the number of these storing histiocytes was 70 per slide or less, and at least 50% when the total amount per slide was < or = 250. This high risk of failure explained the disagreement among the authors. An intensive investigation by at least two observers is mandatory if results are to be evaluated in research. Under the conditions used in this study, the natural frequency of PGC within the bone marrow from untreated patients with a Ph-positive CML is much higher than assumed to date, amounting to about 70%. On the basis of these findings, the prognostic importance of PGC in CML must be evaluated critically.
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Médula Ósea/patología , Enfermedad de Gaucher/patología , Histiocitos/patología , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Adulto , Biopsia , Distribución de Chi-Cuadrado , Errores Diagnósticos , Humanos , Masculino , Variaciones Dependientes del Observador , Adhesión en Parafina , Adhesión en Plástico , Reproducibilidad de los Resultados , Estudios Retrospectivos , Medición de Riesgo , Sensibilidad y Especificidad , Estadísticas no ParamétricasRESUMEN
OBJECTIVE: A new parametric method is presented, called "square sampling," which speeds up the estimate of the number of cells or particles that are randomly distributed within a tissue. STUDY DESIGN: The principle of square sampling is subdivision of a biopsy into at least 100 squares of the same size using a measuring ocular or computer-based morphometric system and estimating the cell number by counting "positive" squares, squares with at least one cell of interest, assuming a binomial distribution of positive squares, depending on numerical density. RESULTS: The derived estimate yielded almost identical results when compared with the exact count of pseudo-Gaucher cells within bone marrow biopsies from untreated patients with chronic myeloid leukemia (r = .97, examined area = 94 x 2 mm2, with 400 squares/2 mm2), but (1) the total time of investigation could be halved by square sampling (25.1 versus 55.3 hours, P < .00005), and (2) the estimated number of cells did not very more widely around the mean exact count than the cell numbers exactly counted (P > .05). CONCLUSION: Square sampling is an easy, fast and effective alternative to nonparametric approaches in order to quantify the numerical density of cells randomly distributed within a tissue. The method can also be applied to test hypotheses of random distribution as well as to quantify a clustering of cells in cases of nonrandom cell distribution.