The uptake of tritium-labelled thymidine in bone marrow mononuclear cells from 22 untreated patients with Rai stage 0-II chronic B-lymphocytic leukaemia was analysed in 4-d in vitro cultures. The ...thymidine uptakes showed a great interindividual variability; the counts per min ranged from 1100 to 80 000 (mean 26 360 +/- 21 800 cpm). Bone marrow cells from patients who needed treatment within 1 yr from diagnosis had a lower thymidine uptake than those from patients who were untreated for more than 2 yr (7 820 +/- 7 420 and 34 300 +/- 23 200 cpm, respectively, p less than 0.001). Patients with low uptake cells had poorer prognosis than those with high uptake cells, both regarding survival (5-yr probability: 0.6 and 1.0, respectively; p less than 0.03) and therapy-free survival (5-yr probability: 0.36 and 1.0, respectively; p less than 0.02).
Chromosome analysis of B-cell mitogen-activated cells from patients with B-cell chronic lymphocytic leukemia (CLL) show clonal abnormalities in approximately one half of the cases. Among the most ...frequent aberrations are trisomy 12 and t(11;14). In the other half, no clonal chromosomal abnormalities are found. We wished to determine whether these CLL clones are cytogenetically normal or whether the apparently normal karyotype results from an inability of the malignant cells to enter metaphase in vitro, leaving only the few remaining normal cells to be karyotypically studied. Probes that can detect restriction fragment length polymorphisms (RFLPs) on chromosome 12, which makes it possible to determine the copy number of this chromosome, as well as bcl-1 probes that can detect t(11;14) were used. Of 13 CLL cases with normal karyotypes, none showed evidence for either trisomy 12 or t(11;14). This finding indicates that CLL cases with an apparently normal karyotype do not have two of the most common clonal chromosomal aberrations and may be karyotypically normal. The study also shows that Southern blot analyses, using probes that can detect RFLPs on chromosome 12, can be used for rapid and simple detection of trisomy 12 in CLL patients.
Recent advances in clarifying the activation mechanisms of the normal immune system have provided the basis for successful experiments concerning the activation of malignant lymphocytes. Such studies ...with malignant cells, freshly sampled from patients with lymphoproliferative diseases, can be used for pathophysiological considerations, analysis of tumor evolution, classification of malignant subsets, and karyotyping. Of particular interest is the possibility of abrogating the maturation arrest in some clonally-restricted cells. This might lead to therapeutical implications, since the differentiation blockage plays a fundamental role in the clonal expansion and pathogenesis of tumors. Recently, it has been shown that interferon (IFN) can be a potent inducer of various degrees of transformation, differentiation and even proliferation in different subsets of normal and malignant B cells. This may be important in explaining the divergent results of IFN treatment in various malignant B-cell disorders.
Fifty-nine patients with a leukaemic B-lymphocytic malignancy ("CLL") were studied. According to the Kiel classification, 29 patients had chronic lymphocytic leukaemia (CLL) and 30 had immunocytoma ...(IC). Cell surface immunoglobulin staining showed mu heavy chain phenotype in 14 patients, mu in 35, gamma in 7; in cells from 3 patients the staining was too weak to permit identification. The light chain phenotype was kappa in 39 patients, lambda in 17, and unidentified in 3. The immunoglobulin isotypes differed between the diagnoses. The gamma chain phenotype was found only in IC patients (p less than 0.02), and more CLL than IC patients showed a lambda chain phenotype (p less than 0.04). Blood lymphocytes from IC patients contained more T cells than CLL cell samples (p less than 0.002). No prognostic difference was found between the CLL and IC group. Compared to the lambda phenotype, the kappa phenotype was associated with a poorer prognosis in the IC group, but with a better prognosis in the CLL group. IC patients with mu phenotype had a poorer prognosis than those with gamma phenotype. Low relative T cell numbers were associated with a poor survival (p less than 0.01).
A 45-year-old woman with chronic lymphocytic leukemia developed fever followed by decreasing liver function. Her clinical condition rapidly deteriorated, acute liver necrosis developed, and the ...patient died of hepatic and renal failure. Adenovirus type 1 was isolated before death from blood, urine and throat and found in liver and lung at autopsy. Serologic studies showed that the infection was primary and that the patient was unable to mount an antibody response to the infection. Adenovirus type 1 is an uncommon cause of lethal infections in immunocompromised patients.
A 45-year-old woman with chronic lymphocytic leukemia developed fever followed by decreasing liver function. Her clinical condition rapidly deteriorated, acute liver necrosis developed, and the ...patient died of hepatic and renal failure. Adenovirus type 1 was isolated before death from blood, urine and throat and found in liver and lung at autopsy. Serologic studies showed that the infection was primary and that the patient was unable to mount an antibody response to the infection. Adenovirus type 1 is an uncommon cause of lethal infections in immunocompromised patients.
Cytogenetic analysis was performed on the leukemic cells from two patients with B-prolymphocytic leukemia. Both patients had del(3)(p13) chromosomal abnormality, as well as other clonal aberrations. ...Del(3p) was previously reported in one case of B-cell prolymphocytic leukemia, and is known to be a specific aberration in small-cell carcinoma of the lung. In B-cell prolymphocytic leukemia, as in other B-lymphocytic leukemias/lymphomas, the karyotype often involves chromosomes #3, #6, #11, and #12. All of these chromosomes are suggested sites for the c-ras oncogene family.
Hormone reference intervals in pediatric endocrinology are traditionally partitioned by age and lack the framework for benchmarking individual blood test results as normalized z-scores and plotting ...sequential measurements onto a chart. Reference curve modeling is applicable to endocrine variables and represents a standardized method to account for variation with gender and age.
We aimed to establish gender-specific biomarker reference curves for clinical use and benchmark associations between hormones, pubertal phenotype, and body mass index (BMI).
Using cross-sectional population sample data from 2139 healthy Norwegian children and adolescents, we analyzed the pubertal status, ultrasound measures of glandular breast tissue (girls) and testicular volume (boys), BMI, and laboratory measurements of 17 clinical biomarkers modeled using the established "LMS" growth chart algorithm in R.
Reference curves for puberty hormones and pertinent biomarkers were modeled to adjust for age and gender. Z-score equivalents of biomarker levels and anthropometric measurements were compiled in a comprehensive beta coefficient matrix for each gender. Excerpted from this analysis and independently of age, BMI was positively associated with female glandular breast volume (β = 0.5, P < 0.001) and leptin (β = 0.6, P < 0.001), and inversely correlated with serum levels of sex hormone-binding globulin (SHBG) (β = -0.4, P < 0.001). Biomarker z-score profiles differed significantly between cohort subgroups stratified by puberty phenotype and BMI weight class.
Biomarker reference curves and corresponding z-scores provide an intuitive framework for clinical implementation in pediatric endocrinology and facilitate the application of machine learning classification and covariate precision medicine for pediatric patients.
Abstract
Context
Application of ultrasound (US) to evaluate attainment and morphology of glandular tissue provides a new rationale for evaluating onset and progression of female puberty, but ...currently no hormone references complement this method. Furthermore, previous studies have not explored the predictive value of endocrine profiling to determine female puberty onset.
Objective
To integrate US breast staging with hypothalamic-pituitary-gonadal hormone references and test the predictive value of an endocrine profile to determine thelarche.
Design Setting and Participants
Cross-sectional sample of 601 healthy Norwegian girls, ages 6 to 16 years.
Main Outcome Measures
Clinical and ultrasound breast evaluations were performed for all included girls. Blood samples were analyzed by immunoassay and ultrasensitive liquid chromatography–tandem mass spectrometry (LC-MS/MS) to quantify estradiol (E2) and estrone (E1) from the subpicomolar range.
Results
References for E2, E1, luteinizing hormone, follicle-stimulating hormone, and sex hormone–binding globulin were constructed in relation to chronological age, Tanner stages, and US breast stages. An endocrine profile index score derived from principal component analysis of these analytes was a better marker of puberty onset than age or any individual hormone, with receiver-operating characteristic area under the curve 0.91 (P < 0.001). Ultrasound detection of nonpalpable glandular tissue in 14 out of 264 (5.3%) girls with clinically prepubertal presentation was associated with significantly higher median serum levels of E2 (12.5 vs 4.9 pmol/L; P < 0.05) and a distinct endocrine profile (arbitrary units; P < 0.001).
Conclusions
We provide the first hormone references for use with US breast staging and demonstrate the application of endocrine profiling to improve detection of female puberty onset.
Bone area is one measure of bone size that is easily derived from dual-energy X-ray absorptiometry (DXA) scans. In a GWA study of DXA bone area of the hip and lumbar spine (N ≥ 28,954), we find ...thirteen independent association signals at twelve loci that replicate in samples of European and East Asian descent (N = 13,608 - 21,277). Eight DXA area loci associate with osteoarthritis, including rs143384 in GDF5 and a missense variant in COL11A1 (rs3753841). The strongest DXA area association is with rs11614913T in the microRNA MIR196A2 gene that associates with lumbar spine area (P = 2.3 × 10
, β = -0.090) and confers risk of hip fracture (P = 1.0 × 10
, OR = 1.11). We demonstrate that the risk allele is less efficient in repressing miR-196a-5p target genes. We also show that the DXA area measure contributes to the risk of hip fracture independent of bone density.
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