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Reliable classification of two-class cancer data using evolutionary algorithms.

In the area of bioinformatics, the identification of gene subsets responsible for classifying available disease samples to two or more of its variants is an important task. Such problems have been solved in the past by means of unsupervised learning methods (hierarchical clustering, self-organizing maps, k-mean clustering, etc.) and supervised learning methods (weighted voting approach, k-nearest neighbor method, support vector machine method, etc.). Such problems can also be posed as optimization problems of minimizing gene subset size to achieve reliable and accurate classification. The main difficulties in solving the resulting optimization problem are the availability of only a few samples compared to the number of genes in the samples and the exorbitantly large search space of solutions. Although there exist a few applications of evolutionary algorithms (EAs) for this task, here we treat the problem as a multiobjective optimization problem of minimizing the gene subset size and minimizing the number of misclassified samples. Moreover, for a more reliable classification, we consider multiple training sets in evaluating a classifier. Contrary to the past studies, the use of a multiobjective EA (NSGA-II) has enabled us to discover a smaller gene subset size (such as four or five) to correctly classify 100% or near 100% samples for three cancer samples (Leukemia, Lymphoma, and Colon). We have also extended the NSGA-II to obtain multiple non-dominated solutions discovering as much as 352 different three-gene combinations providing a 100% correct classification to the Leukemia data. In order to have further confidence in the identification task, we have also introduced a prediction strength threshold for determining a sample's belonging to one class or the other. All simulation results show consistent gene subset identifications on three disease samples and exhibit the flexibilities and efficacies in using a multiobjective EA for the gene subset identification task.

Algorithms↗

Anaplastic large cell lymphoma arising in bone: report of a case of the monomorphic variant with the t(2;5)(p23;q35) translocation.

Anaplastic large cell lymphoma (ALCL) represents approximately 2% of all non-Hodgkin lymphomas according to the recent Non-Hodgkin Lymphoma Classification Project. As defined in the revised European-American classification of lymphoid neoplasms (REAL), ALCL is a neoplasm of T-cell or null-cell lineage; 20% to 60% of cases are associated with the t(2;5)(p23;q35) translocation. ALCL commonly involves nodal as well as a wide variety of extranodal sites, although primary or secondary involvement of bone is rare. We describe the case of a 71-year-old man with stage IE T-cell ALCL, monomorphic variant, arising in the left anterior fifth rib and involving adjacent soft tissue without other sites of disease. The monomorphic histologic features hindered the initial recognition of this neoplasm as ALCL. However, strong uniform CD30 antigen expression and subsequent demonstration of the t(2;5)(p23;q35) translocation and anaplastic lymphoma kinase (ALK) immunoreactivity led to the correct diagnosis. We identified only 5 reported cases of T-cell and null-cell ALCL arising in bone and only 2 of these cases involved a single bone site. All 5 previously reported cases were ALCL of the classic type. We report a case of ALCL that is unique to our knowledge. This case of monomorphic ALCL was localized to bone and tumor cells contained the t(2;5)(p23;q35) translocation.

Aged↗

[Clinicomorphological variants of gastric cancer].

A complex clinicomorphologic investigation of 136 gastric cancer cases has been done to reveal the applied character of P.Lauren's classification proposed in 1965 and extremely popular at present with an attempt to classify all the above cases into the so-called intestinal and diffuse-type gastric carcinoma. Significant number (37,5%) of heterogenous tumours with compound topographic and morphologic interrelation between glandular and diffuse compartments in the zones of cancerous transformation and progression has been revealed. This author's approach makes it necessary to improve well-known P. Lauren's classification.

Aged↗

[Histologic classification and morphologic prognostic factors in malignant ovarian tumors].

Most cases of death in genital neoplasms of females are caused by ovarian cancer. Prognostic factors are the postoperative tumor, tumor stage (FIGO, pTNM), age, tumors among family, and the reproductive history. On the basis of 710 malignant ovarian tumors we describe the histogenetic classification and compare the morphologic diagnosis with additional prognostic factors by literature to give a practical review of ovarian neoplasms. The morphologic prognostic factors are the histological subtype, tumor grading and perhaps the receptor status. Worse prognosis, despite of tumor grading, show undifferentiated carcinomas, followed by the serous and mucinous subtype. Endometrioid carcinomas have the best prognosis. Malignant Mullerian tumors show a very aggressive behavior. After the introduction of polychemotherapy the sex-cord- and germ cell-tumors show better prognoses. New prognostic factors are DNA-parameters (ploidy, S-phase-fraction), detection of oncogenes and tumor suppressor genes, cellular adhesion molecules (integrins, CD 44-splicing variants), and the proliferation rate of the tumor. Perhaps, these factors show prognostic relevance for individual treatment. A correct histologic classification with consideration of all morphology related prognostic factors and the knowledge about them is necessary for oncologists to choose the optimal individual therapeutic treatment.

Biomarkers, Tumor↗

Characteristics of p53 and Smad4 immunohistochemistry in pancreatic ductal adenocarcinoma and validation by next-generation sequencing.

BACKGROUND: Mutations in four major driver genes -KRAS, CDKN2A, TP53, and SMAD4- are central to the pathogenesis of pancreatic ductal adenocarcinoma (PDAC) and critically inform diagnosis, therapeutic decision-making, and prognostic assessment. Although next-generation sequencing (NGS) is widely regarded as the gold standard for detecting these mutations, its clinical application is often limited by suboptimal analytical efficiency and substantial economic cost. Among these genes, immunohistochemical (IHC) staining for the proteins encoded by TP53 and SMAD4 has been extensively adopted in routine pathology practice. However, standardized IHC pattern classification schemes and rigorous validation of their predictive accuracy for underlying genomic alterations remain lacking in PDAC. METHODS: We retrospectively enrolled 63 PDAC patients and systematically characterized the typical IHC expression patterns of p53 and Smad4. Targeted NGS was subsequently performed on all available tumor specimens, and the resulting mutational profiles were correlated with corresponding IHC findings. Diagnostic performance including sensitivity, specificity and accuracy of p53 IHC for predicting TP53 mutations and of Smad4 IHC for predicting SMAD4 mutations was rigorously evaluated. RESULTS: Among the four canonical driver genes, co-occurring double- or triple-gene mutations were prevalent; within TP53 and SMAD4, missense mutations constituted the most frequent variant type. Using NGS as the reference standard, we validated the diagnostic utility of a three-tiered p53 IHC classification system, particularly in fine-needle biopsy (FNB) specimens. Furthermore, we proposed a novel, refined Smad4 IHC pattern classification that incorporates an "intermediate" category, thereby expanding upon conventional binary interpretation. This new scheme achieved markedly improved mutation prediction accuracy (0.76) compared with traditional approaches (0.57). CONCLUSION: Our study highlights the complementary diagnostic value of p53 and Smad4 IHC relative to molecular testing in PDAC, especially when tissue is limited, as commonly encountered in FNB specimens. The newly established Smad4 IHC classification system, which integrates an intermediate expression category into the conventional two-tier framework, demonstrates superior clinical utility and enhances predictive accuracy for SMAD4 genomic alterations.

Humans↗

Symposium: classification of leukemia. 1. The classification of acute leukemia.

Two main forms of acute leukemia have been recognized by the French-American-British (FAB) group: myeloid (AML) and lymphoblastic (ALL). Some types of AML can be diagnosed on well prepared bone marrow films stained with May-Grünwald-Giemsa. Poorly differentiated types, myeloblastic (M1) and monoblastic (M5PD), need confirmation by positive cytochemical reactions (Sudan Black B, myeloperoxidase and non-specific esterase). There are 2 sub-types of promyelocytic leukemia: M3 typical, hypergranular and M3 variant, microgranular. The M3 variant has a more acute course, higher WBC and may require cytochemistry to demonstrate promyelocytic differentiation. Electron microscopic cytochemistry can also help in the classification of difficult AML cases; the 'platelet-peroxidase' reaction, for example, is essential for the diagnosis of megakaryoblastic leukemia, a disorder often presenting as 'acute' myelosclerosis. Three morphological types are seen in ALL: L1, predominantly in children, L2, more frequently in adults, and the relatively rare L3 or Burkitt type. Immunological and enzyme markers (ALL and la antigens, terminal transferase, etc.) help define the cell phenotype: (1) non-B, non-T ALL with 3 forms (common, null and pre-B), (2) T-ALL, related to but distinct from T-lymphoblastic lymphoma, and (3) B-ALL, usually with L3 morphology, There is growing evidence that the FAB morphological types correlate with prognosis in ALL independently of other factors. The immunologically defined types also correlate with prognosis but not as an independent variable.

Acute Disease↗

Recent progress in lymphoma classification.

In the Revised European-American list of lymphoid neoplasms recently proposed by the hematopathologists of the International Lymphoma Study Group, the disease entities currently recognized in the literature among the B-cell and T/natural killer (NK)-cell lymphomas and leukemias and variants of Hodgkin's disease are collected and defined. This proposal is here to stay. The main challenge for the future is to present the information in this list in a form that facilitates the understanding, learning, and teaching of these disorders. A meaningful classification for clinical use has already been built on the foundation provided by this list, through the agreement of an international group of clinicians. Newer data confirm the clinical validity of many categories in the list. Others suggest the need for additions or possible changes. To be discussed, among the latter, are: a need for a better definition of the new category of lymphoplasmacytic lymphoma; the variants of mantle-cell lymphoma and their correlation with genomic abnormalities; the need for a clarification of the relationship among the variants listed as "marginal zone B-cell" lymphomas; the subclassification of large B-cell lymphomas; and the coming of age of the NK-cell lymphomas.

Humans↗

Normal values for morphological abnormalities in school children.

Clinical morphology has proven to be a strong tool in the delineation of many syndromes and a helpful instrument in molecular studies. Numerous studies have been performed investigating the prevalence of minor anomalies in various disorders; all concluding that minor anomalies can well be utilized as indicators of altered embryonic differentiation. However, for adequate evaluation, normal values for phenotypic abnormalities are essential. So far, only few studies on the frequency of phenotypic abnormalities in the normal population have been done having one thing in common: all were performed in newborn infants. We studied morphological characteristics in a group of 1,007 school children, representative for the Dutch population, through a body surface examination using detailed definitions for all morphological findings. The region of study and distribution of children over various school types was chosen in such a way that it represented the general Dutch population. The median age of the studied children was 11 years (range 8-14 years), sex ratio (M:F) was 0.93. Nine hundred twenty-three children were of Caucasian descent, 84 others of mixed ethnic backgrounds. The reliability of the examinations was tested by independent scoring of 111 children by two observers, showing a kappa score of 0.85. Normal values for the morphological findings are presented together with their age-adjusted classification. These normal values provide a valuable source for validation of classifications of phenotypic abnormalities, especially those that are depending on frequency, that is, minor anomalies and common variants. Furthermore, they will allow a proper evaluation of patterns of phenotypic abnormalities found in patient groups with specific disorders.

Adolescent↗

Genetic analysis of the cultivated potato Solanum tuberosum L. Phureja Group using RAPDs and nuclear SSRs.

The Solanum tuberosum L. Phureja Group consists of potato landraces widely grown in the Andes from western Venezuela to central Bolivia, and forms an important breeding stock due to their excellent culinary properties and other traits for developing modern varieties. They have been distinguished by short-day adaptation, diploid ploidy (2n = 2x = 24), and lack of tuber dormancy. This nuclear simple sequence repeat (nSSR or microsatellite) study complements a prior random amplified polymorphic DNA (RAPD) study to explore the use of these markers to form a core collection of cultivar groups of potatoes. Like this prior RAPD study, we analyzed 128 accessions of the Phureja Group using nuclear microsatellites (nSSR). Twenty-six of the 128 accessions were invariant for 22 nSSR markers assayed. The nSSR data uncovered 25 unexpected triploid and tetraploid accessions. Chromosome counts of the 102 accessions confirmed these nSSR results and highlighted seven more triploids or tetraploids. Thus, these nSSR markers (except 1) are good indicators of ploidy for diploid potatoes in 92% of the cases. The nSSR and RAPD results: (1) were highly discordant for the remaining 70 accessions that were diploid and variable in nSSR, (2) show the utility of nSSRs to effectively uncover many ploidy variants in cultivated potato, (3) support the use of a cultivar-group (rather than a species) classification of cultivated potato, (4) fail to support a relationship between genetic distance and geographic distance, (5) question the use of any single type of molecular marker to construct core collections.

Cell Nucleus↗

Associations of the dopamine D4 receptor gene VNTR polymorphism with drug use in adolescent psychiatric inpatients.

BACKGROUND: The VNTR polymorphism in the Dopamine D4 receptor gene (DRD4) has been associated with differential urge for substances across multiple methodologies ranging from neuroimaging to assessment in the natural environment. It is unclear whether the DRD4 gene is a marker for an underlying propensity for greater urge or whether the DRD4 gene differentially moderates the neuroadaptive effects of extended substance use on urge. Examination of the DRD4 in an adolescent sample may provide evidence of a mechanism of this putative relationship. METHOD: Data from a subset of 77 participants in a larger assessment study characterized adolescents for substance-related behaviors by DRD4 genotype. The psychiatrically admitted adolescents were genotyped for the variable number of tandem repeats polymorphism in the DRD4 gene (L>or=7 [n=25], S=or<7 [n=52]). Associations of the DRD4 with scores on the SASSI, and ADI were examined as well as selected individual items thought to be most related to the intermediate phenotype of urge. RESULTS: The DRD4 gene was not associated with any DSM-IV substance misuse diagnostic classification. Individual items related to urge were also nonsignificantly related to DRD4 status. Carriers of the long variant of the DRD4 polymorphism were more likely to have used hard drugs within the previous 6 months and scored higher on the self-medication subscale of the ADI compared to short variant homozygotes. DISCUSSION: Preliminary results provide little evidence for the DRD4 VNTR polymorphism to be related to urge-related phenomena in hospitalized adolescents on a psychiatric inpatient unit. The association of the DRD4 gene with hard drug use may support literature linking this gene to impulsivity. Subscale findings may suggest a role of negative affect in previous DRD4 urge findings.

Adolescent↗

Telangiectatic focal nodular hyperplasia: a variant of hepatocellular adenoma.

BACKGROUND & AIMS: "Telangiectatic focal nodular hyperplasia" designate atypical lesions considered as variants of focal nodular hyperplasia (FNH). However, because "telangiectatic FNH" share several morphologic patterns with hepatocellular adenomas, classification of such lesions deserve further clarification. Therefore, the aim of the present study was to reconsider the classification of telangiectatic FNH with the help of a molecular approach. METHODS: Ten telangiectatic FNH, 6 typical FNH, and 6 hepatocellular adenomas were studied. DNA, RNA, and protein from each lesion were extracted. Clonality was assessed by the study of the X chromosome inactivation pattern (HUMARA assay). Angiopoietin (ANGPT-1 and ANGPT-2) mRNA, genes the expression of which is typically modified in FNH, were quantified by a real-time RT-PCR procedure. Protein profiles were analyzed by SELDI-TOF PROTEINCHIP (Cyphergen Biosystem, Inc., Fremont, CA) technology. RESULTS: Although all informative cases of FNH (5 of 6) and hepatocellular adenomas (6 of 6) were polyclonal and monoclonal, respectively, clonal analysis showed a nonrandom pattern of X chromosome inactivation consistent with a monoclonal lesion in 6 of 8 cases of telangiectatic FNH. The mean value of the ANGPT-1/ANGPT-2 mRNA ratio was 21.4 in FNH, 2.6 in adenomas, and 2.1 in telangiectatic FNH (P <or = 0.001 in telangiectatic FNH vs. FNH). SELDI-TOF PROTEINCHIP profiling and hierarchical clustering analysis showed that all except 1 telangiectatic FNH clustered within the group of hepatocellular adenomas. CONCLUSIONS: These results show that telangiectatic FNH display a molecular pattern closer to that of hepatocellular adenomas than to FNH and suggest that these lesions should instead be referred to as "telangiectatic hepatocellular adenomas."

Adenoma, Liver Cell↗

The rise and fall of malignant fibrous histiocytoma.

The term malignant fibrous histiocytoma was coined by Stout and associates in the 1960s to encompass pleomorphic soft tissue sarcomas presumably derived from histiocytes that are capable of fibroblastic transformation. The concept was reaffirmed in the following 2 decades and malignant fibrous histiocytoma thus was regarded as the most common soft tissue tumor in older adults. However, recent more critical clinicopathologic, ultrastructural, and immunohistochemical studies have shown that malignant fibrous histiocytomas are not derived from histiocytic "facultative fibroblasts" and many neoplasms so diagnosed actually are pleomorphic subtypes of other sarcomas. Meticulous electron microscopic and immunohistochemical investigations also found that the more common storiform-pleomorphic, myxoid, and perhaps the giant cell subtypes are composed of variable mixtures of fibroblasts and phenotypically modulated fibroblastic cells, notably myofibroblasts and histiofibroblasts. On the basis of these findings, we propose a new classification for the above subtypes of so-called malignant fibrous histiocytoma, the majority of which are variants of pleomorphic fibrosarcoma.

Fibroblasts↗

Ovarian sex cord tumors with annular tubules. An ultrastructural study of three cases.

The ultrastructural features of three ovarian sex cord tumors with annular tubules were analyzed. The cells had deeply indented nuclei, interdigitating plasma membranes joined by abundant desmosomes, and numerous randomly distributed microfilaments that often complexed with desmosomes. Charcot-Bottchner crystalloids were absent. None of the tubular structures had true lumens. The characteristic central hyaline bodies resembled some forms of Call-Exner bodies and were composed of concentric layers of basal lamina, which often were continuous with redundant basal lamina of the peripheral basement membrane. Because of the clinical, histologic, and ultrastructural similarities to granulosa cell tumors and normal preovulatory granulosa cells, classification of the sex cord tumor with annular tubules is proposed as a distinctive annular and membranous variant of granulosa cell tumor.

Adult↗

[Histological and immunohistochemical characteristics of diffuse large cell B-cell lymphomas].

In the REAL classification, diffuse large B-cell non-Hodgkin's lymphomas are grouped together. We investigated histological variants and immunohistochemical profile of diffuse large B-cell lymphomas in 53 patients. Accuracy of the diagnosis was 73.6% without immunohistochemistry. The usefulness of immunophenotyping in making the correct diagnosis depended on a specific histological variant of diffuse large B-cell lymphoma. Variants with polymorphic and anaplastic morphology or massive reactive component have been diagnosed by routine histological methods with poor validity.

Adult↗

[Diagnosis and treatment of postoperative recurrences of varicosity].

The aim of the present work was to study the causes of post-operative recurrences of varicosity and to define approaches to their optimal correction. Duplex scanning (DS) with Color Doppler Imaging of the blood flow was used to examine 126 patients (136 extremities) with recurrences of varicosity. The patients were distributed according to the CEAP clinical classification. Altogether 76 patients (78) extremities with recurrences of varicosity were operated on. 27 persons received different variants of sclerotherapy including echoscleroobliteration. According to the DS data, the most frequently obtained finding in patients with recurrences of varicosity was identification of the perforating veins with valvular insufficiency, namely in 120 (or in 88.2%) extremities. The long stump of the greater saphenous vein (CSV) was discovered in 86 (63.2%) extremities, the long stump of the lesser saphenous vein (LSV) in 6 (4.4%), ectasia of LSV trunk was recognised in 20 (14.5%), incompetence of the valves of the sural veins in 12 (8.8%) extremities. Incompetence of the valves of the deep veins was present in 73 (53.6%) patients. No sources of pathological veno-venous runoff were identified in 12 (8.1%) cases. A good agreement was established between the incidence of valvular incompetence of the deep veins and the disease severity. The indications for surgical correction of valvular insufficiency were worked out. It has been demonstrated that sclero-obliteration is the method of choice in the treatment of the recurrences of varices. The long-term results of operations for recurrences of varicosity were followed up in 62 patients over the period of one to 15 years. Good and satisfactory results were obtained in 60 (96.8%) cases. The authors believe that the majority of varicosity recurrences arise from an inadequate assessment of the status of lower extremity venous bed as well as from technical and methodological faults of the operating surgeon. DS in an indispensable component of preoperative examination of patients with varicosity recurrences.

Adult↗

[Glucose-6-phosphate dehydrogenase deficiency of erythrocytes in the GDR].

34 persons with G-6-PD deficiency were diagnosed, and the pathological enzyme-variants of red blood cells were characterized according to the recommendations of WHO. We conclude from the differing residual G-6-PD-activities in red blood cells of the propositi and the differing reactivity of the enzyme in kinetic and physicochemical characterizations that a multiple variety of rare pathological G-6-PD variants exists in the GDR. Using the estimated enzymeparameters it was not possible in all cases to compare directly the newly demonstrated G-6-PD variants with cases already described in the literature. In addition, the differing combinations of parameters render a classification more difficult.

Electrophoresis↗

[The morphological characteristics of lymphoid hemoblastoses in dogs].

125 autopsy cases of hemoblastoses in dogs are studied, their morphology was adequate to that in humans. Lymph proliferative diseases are more frequent in dogs. New morphological variants of lymphoid hemoblastosis are distinguished, which have not been yet included into the WHO International Histologic Classification of tumours in domestic animals.

Animals↗

[Current concepts concerning the syndrome of early ventricular repolarization].

Electrocardiograms of 1000 patients examined in a polyclinic for various diseases and during prophylactic checkups, were analyzed. The syndrome of early ventricular repolarization (SEVR) was detected in 54 (5.4%) patients. According to the proposed classification scheme of SEVR one could determine its clinical value and the distribution of frequency of its variants and types. The authors put forward present-day ideas as to SEVR assumed genesis with an attempt to verify some of them. Differential-diagnostic pharmacological tests (procainamide, quinidine and propranolol) were recommended for SEVR recognition.

Adolescent↗