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1.
Leukemia ; 20(11): 2008-14, 2006 Nov.
Article in English | MEDLINE | ID: mdl-16990784

ABSTRACT

Somatic mutations of FLT3 resulting in constitutive kinase activation are the most common acquired genomic abnormality found in acute myeloid leukemia (AML). The majority of these mutations are internal tandem duplications (ITD) of the juxtamembrane region (JM). In addition, a minority of cases of AML are associated with mutation of the FLT3 activation loop (AL), typically involving codons D835 and/or I836. We hypothesized that other novel mutations of FLT3 could also contribute to leukemogenesis. We genotyped 109 cases of AML and identified two novel gain-of-function mutations. The first mutation, N841 H, is similar to previously described mutations involving amino-acid substitutions of codon 841. The other novel mutation, FLT3 K663Q, is the first AML-associated gain-of-function mutation located outside the JM and AL domains. Of note, this mutation was potently inhibited by Sunitinib (SU11248), a previously described FLT3 kinase inhibitor. Sunitinib reduced the proliferation and induced apoptosis of transformed Ba/F3 cells expressing FLT3 K663Q. The potency of Sunitinib against FLT3 K663Q was similar to its potency against FLT3 ITD mutations. We conclude that FLT3 mutations in AML can involve novel regions of the TK1. Future studies are needed to define the incidence and prognostic significance of FLT3 mutations outside the well-established JM and AL regions.


Subject(s)
Antineoplastic Agents/pharmacology , Indoles/pharmacology , Leukemia, Myeloid/drug therapy , Leukemia, Myeloid/genetics , Pyrroles/pharmacology , fms-Like Tyrosine Kinase 3/genetics , Acute Disease , Amino Acid Sequence , Amino Acid Substitution , Animals , Apoptosis/drug effects , Base Sequence , Cell Division/drug effects , Cell Line, Tumor , Humans , Leukemia, Myeloid/pathology , Mice , Mice, Inbred BALB C , Mice, Nude , Mutagenesis, Site-Directed , Neoplasm Transplantation , Point Mutation , Sunitinib , fms-Like Tyrosine Kinase 3/metabolism
2.
Leukemia ; 18(4): 864-71, 2004 Apr.
Article in English | MEDLINE | ID: mdl-14973502

ABSTRACT

Mutations of the ABL kinase domain (KD) are common in patients with chronic myelogenous leukemia (CML) who develop resistance to imatinib. We developed an RT-PCR-based denaturing high-performance liquid chromatography (D-HPLC) assay to detect mutations of the ABL KD. Validation experiments using mixtures of wild type and mutant amplicons showed that the D-HPLC assay could detect mutant transcripts when they represented at least 15% of the total, and was thus twice as sensitive as automated sequencing. When D-HPLC was applied to 30 cDNAs from patients with imatinib resistance that had previously been characterized for KD mutations by direct sequencing of BCR-ABL RT-PCR products, there was concordance in 97% of samples. Resequencing confirmed the original mutations in all cases. In addition, sequencing of individual clones detected a mutation in one sample that had been mutation-positive by D-HPLC but wild type by conventional sequencing. In serial samples from the same individuals, D-HPLC detected mutations as early as 260 days before hematological relapse. D-HPLC is suitable for routine clinical monitoring of CML patients for emergence of KD mutations and may be useful for optimizing therapy. Early detection of emerging mutant clones may aid in guiding decisions regarding alternative treatment options.


Subject(s)
Chromatography, High Pressure Liquid/methods , DNA Mutational Analysis/methods , Oncogene Proteins v-abl/genetics , Adult , Aged , Benzamides , Chromatography, High Pressure Liquid/standards , DNA Mutational Analysis/standards , DNA, Neoplasm/genetics , Drug Resistance/genetics , Female , Humans , Imatinib Mesylate , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Male , Middle Aged , Oncogene Proteins v-abl/chemistry , Piperazines/therapeutic use , Protein Structure, Tertiary , Pyrimidines/therapeutic use , Reverse Transcriptase Polymerase Chain Reaction , Sensitivity and Specificity
5.
Mod Pathol ; 12(1): 88-91, 1999 Jan.
Article in English | MEDLINE | ID: mdl-9950168

ABSTRACT

The cytologic and cytogenetic findings of chondroid lipoma, a rare benign tumor of soft tissue, have not been described. This report details the morphologic features of a fine-needle aspiration biopsy specimen and describes a novel cytogenetic finding. The main cytologic features consisted of clustered, variably mature, multivacuolated, hibernoma-like cells enmeshed in a capillary plexus, with a background of chondromyxoid material. Cytogenetic analysis revealed a balanced translocation t (11, 16)(q13;p12-13) distinct from the known translocation involving 16p11 in myxoid and round-cell liposarcoma. The 11q13 breakpoint was previously noted in hibernomas, raising the possibility of a common genetic deregulation.


Subject(s)
Lipoma/genetics , Lipoma/pathology , Soft Tissue Neoplasms/genetics , Soft Tissue Neoplasms/pathology , Biopsy, Needle , Chromosomes, Human, Pair 11 , Chromosomes, Human, Pair 16 , Humans , Karyotyping , Male , Middle Aged , Thigh , Translocation, Genetic/genetics
6.
Urology ; 53(6): 1228, 1999 Jun.
Article in English | MEDLINE | ID: mdl-10754117

ABSTRACT

We report 3 cases of postirradiation sarcoma that arose in the pelvis 8, 15, and 16 years after completion of external beam radiation therapy (RT) for localized adenocarcinoma of the prostate. Although such cases must be regarded as extremely rare, postirradiation sarcoma should be considered as a potential cause of pelvic pain developing after RT.


Subject(s)
Adenocarcinoma/radiotherapy , Neoplasms, Second Primary/etiology , Pelvic Neoplasms/etiology , Prostatic Neoplasms/radiotherapy , Sarcoma/etiology , Aged , Humans , Male , Middle Aged , Neoplasms, Radiation-Induced/etiology , Radiotherapy, High-Energy/adverse effects
7.
J Clin Oncol ; 16(3): 1150-7, 1998 Mar.
Article in English | MEDLINE | ID: mdl-9508202

ABSTRACT

PURPOSE: The Ewing tumor (ET) family of peripheral primitive neuroectodermal tumors (pPNETs) are primitive small round-cell tumors (SRCTs) of the bone and soft tissue that occur predominantly in children and adolescents. However, pPNETs only rarely enter the differential diagnosis of bone and soft tissue SRCTs in adults. Recently, gene fusions between the EWS gene and different members of the ETS transcription factor family have been shown to occur in virtually all pPNETs and thus constitute a pathognomonic marker for this tumor subclass. The aim of the present study was to document EWS/ETS fusion gene expression in suspected pPNETs of adults as objective evidence for the existence of this tumor family in older patients. PATIENTS AND METHODS: The three contributing molecular diagnostic laboratories retrospectively compiled a cohort of all SRCT cases in which EWS/ETS gene fusions had been shown by molecular analysis. This cohort was surveyed for cases that occurred in patients aged 40 years or older, which were then analyzed for their clinical and pathologic features. RESULTS: Nine patients between 40 and 65 years of age were found to have tumors positive for EWS/ETS gene fusions. Standard histopathologic and clinical features of these cases, other than age, were similar to those of childhood pPNETs. Patients were initiated on appropriate therapy after molecular analysis confirmed the diagnosis of pPNET. CONCLUSION: Identification of an EWS/ETS gene fusion is useful in providing objective evidence of the diagnosis of pPNET in patients over the age of 40 years. This diagnosis should be considered in adults who present with bone and soft tissue SRCTs and appropriate biopsy specimens should be collected for molecular analysis at the time of diagnosis.


Subject(s)
Chromosome Aberrations , Neuroectodermal Tumors, Primitive, Peripheral/genetics , Neuroectodermal Tumors, Primitive/genetics , Oncogene Proteins, Fusion/genetics , Transcription Factors/genetics , Adult , Aged , DNA, Neoplasm/analysis , Female , Gene Expression , Humans , Immunohistochemistry , Karyotyping , Male , Middle Aged , Neuroectodermal Tumors, Primitive/pathology , Neuroectodermal Tumors, Primitive, Peripheral/pathology , Polymerase Chain Reaction
8.
Hum Pathol ; 28(10): 1204-6, 1997 Oct.
Article in English | MEDLINE | ID: mdl-9343328

ABSTRACT

The clinical and pathologic features of two cases of solitary fibrous tumor arising from urinary bladder wall are described. To our knowledge, solitary fibrous tumors have not been previously reported at this site. Both tumors showed typical histologic features of solitary fibrous tumor, were CD34 immunostain positive and pursued a benign clinical course on short term follow-up.


Subject(s)
Neoplasms, Fibrous Tissue/pathology , Urinary Bladder Neoplasms/pathology , Diagnosis, Differential , Female , Humans , Male , Middle Aged , Neoplasms, Fibrous Tissue/diagnostic imaging , Pelvis/diagnostic imaging , Ultrasonography , Urinary Bladder Neoplasms/diagnostic imaging
10.
J Immunol Methods ; 205(2): 163-8, 1997 Jul 14.
Article in English | MEDLINE | ID: mdl-9294598

ABSTRACT

The ability to measure successfully the levels of Th1 or Th2 cytokines during an in vitro antigen-driven, polyclonal T-cell response has proven to be more difficult than expected. Here we describe the development of a highly sensitive cell-based ELISA (celELISA) technique for the detection of murine Th1 and Th2 cytokines. The celELISA combines the quantification aspects of the conventional sandwich ELISA with the sensitivity of the ELISPOT assay. The celELISA was particularly useful for the improved detection of IL-2, IL-4, and to a lessor extent, IFN-gamma.


Subject(s)
Bacterial Proteins , Enzyme-Linked Immunosorbent Assay/methods , Lymphokines/analysis , Animals , Antigens/administration & dosage , Cells, Cultured , Chaperonin 60 , Chaperonins/administration & dosage , Chaperonins/immunology , Concanavalin A/administration & dosage , Enzyme-Linked Immunosorbent Assay/statistics & numerical data , Evaluation Studies as Topic , Immunization , Interferon-gamma/analysis , Interferon-gamma/biosynthesis , Interleukin-2/analysis , Interleukin-2/biosynthesis , Interleukin-4/analysis , Interleukin-4/biosynthesis , Lymphocyte Activation , Lymphokines/biosynthesis , Male , Mice , Mice, Inbred CBA , Sensitivity and Specificity , Spleen/cytology , Spleen/immunology , Th1 Cells/immunology , Th2 Cells/immunology
11.
Virchows Arch ; 430(6): 445-53, 1997 Jun.
Article in English | MEDLINE | ID: mdl-9230909

ABSTRACT

The clinicopathological features of 12 extraserosal solitary fibrous tumours (SFT) are described. The age of the patients ranged from 18 to 72 years (mean: 48.2 years; median: 54 years); 5 were female patients. Seven lesions arose in soft tissue (5 in perifascial, and 1 each in subcutaneous and intramuscular tissues). They were situated in the groin (2 cases) and the neck, right buttock, left scapula, upper arm, and anterior abdominal wall (1 case each). One polypoid lesion was seen in in the nasal cavity and 1 in the nasopharynx; 2 neoplasms arose in the urinary bladder and 1 was located in the prostate and periprostatic tissue. Nine lesions were excised; in 1 patient wide excision was performed and in 2 patients, transurethral resection. Limited follow-up of 3 cases revealed a benign clinical course. The size of the neoplasms ranged from 1.7 cm to 20.0 cm (mean: 5.4 cm; median: 3.5 cm). Histologically, the neoplasms were well circumscribed and composed of cytologically bland spindle cells arranged without an obvious pattern; focally storiform or fascicular growth patterns were seen. Tumour cells were separated by thick bands of collagen demonstrating foci of keloid-like hyalinization. Prominent vascularity showing a haemangiopericytoma-like vascular pattern and vessels with thick, hyalinized vessel walls were seen in all cases. Increased mitotic activity was noted in 2 soft tissue cases (4-6 mitoses in 10 high-power fields); the other cases showed fewer than 2 mitotic figures in 10 highpower fields. Immunohistochemically, all cases tested stained positively for vimentin, CD34 and CD99, and 2 cases showed focal myofibroblastic differentiation. Two cases examined ultrastructurally showed a fibroblastic phenotype; focally pinocytic vesicles and microfilaments were identified. SFT represents a distinct neoplasm that should be included in the differential diagnosis of spindle-cell neoplasms in soft tissue, nasal cavity and nasopharynx, urinary bladder, and prostate. Strict diagnostic criteria are necessary to avoid overdiagnosis or confusion with more aggressive neoplasms in these locations.


Subject(s)
Neoplasms, Fibrous Tissue/pathology , Soft Tissue Neoplasms/pathology , Adolescent , Adult , Aged , Diagnosis, Differential , Female , Humans , Male , Middle Aged , Nasopharyngeal Neoplasms/pathology , Nasopharyngeal Neoplasms/surgery , Nasopharyngeal Neoplasms/ultrastructure , Neoplasms, Fibrous Tissue/surgery , Neoplasms, Fibrous Tissue/ultrastructure , Prostatic Neoplasms/pathology , Prostatic Neoplasms/surgery , Prostatic Neoplasms/ultrastructure , Soft Tissue Neoplasms/surgery , Soft Tissue Neoplasms/ultrastructure , Urinary Bladder Neoplasms/pathology , Urinary Bladder Neoplasms/surgery , Urinary Bladder Neoplasms/ultrastructure
12.
Int J Gynecol Pathol ; 16(2): 117-23, 1997 Apr.
Article in English | MEDLINE | ID: mdl-9100064

ABSTRACT

We report six cases of histologically typical nodular fasciitis that each presented as a vulvar soft tissue mass. The diagnosis of nodular fasciitis had not been considered by the referring pathologist in any of the five consultation cases. The patient's ages ranged from 7 to 51 years (mean 34). The lesion was confined to the labia in the four cases in which a specific site was noted. The masses ranged from 1.5 to 3.5 cm (mean 2.2) in maximal dimension. All of them were locally excised, and the resection margins were involved in each case. In addition to the typical features of nodular fasciitis, a noteworthy finding in two of the six cases was the presence of cleftlike spaces lined by plump synovial-like cells. Follow-up ranged from 3 months to 7 years (mean 24 months). A local recurrence developed in one patient at 4 months and was reexcised; there have been no recurrences in any other case. The literature contains only five additional examples of vulvar nodular fasciitis. Although all were pathologically typical, the diagnosis was often not considered, evidently because of the unusual location. Awareness that nodular fasciitis may occur in the vulva and the features that allow its distinction from other mesenchymal "tumors" occurring at this site will facilitate its correct diagnosis.


Subject(s)
Fasciitis/diagnosis , Fasciitis/pathology , Vulvar Diseases/diagnosis , Vulvar Diseases/pathology , Actins/analysis , Adolescent , Adult , Biomarkers/analysis , Child , Female , Humans , Immunohistochemistry , Middle Aged
13.
Can Assoc Radiol J ; 45(6): 469-72, 1994 Dec.
Article in English | MEDLINE | ID: mdl-7982111

ABSTRACT

Tumours of peripheral nerve sheaths are rarely malignant, and even when malignant they are only infrequently associated with extensive destruction of bone. The authors report the computed tomography and magnetic resonance imaging findings for an unusually large sheath tumour that presented with extensive destruction in the lumbar spine.


Subject(s)
Lumbar Vertebrae/diagnostic imaging , Nerve Sheath Neoplasms/diagnostic imaging , Peripheral Nervous System Neoplasms/diagnostic imaging , Aged , Female , Humans , Lumbar Vertebrae/pathology , Nerve Sheath Neoplasms/pathology , Peripheral Nervous System Neoplasms/pathology , Radiography
14.
J Perinatol ; 12(3): 237-9, 1992 Sep.
Article in English | MEDLINE | ID: mdl-1432280

ABSTRACT

This report describes a newborn with respiratory distress, waxing and waning left lung hyperinflation, and pulmonary hemorrhage. This atypical presentation of congenital cystic adenomatoid malformation of the lung has not been previously reported, posed a major diagnostic problem, and delayed potentially lifesaving surgery.


Subject(s)
Cystic Adenomatoid Malformation of Lung, Congenital/diagnosis , Infant, Premature, Diseases/diagnosis , Lung/physiopathology , Cystic Adenomatoid Malformation of Lung, Congenital/complications , Cystic Adenomatoid Malformation of Lung, Congenital/physiopathology , Diagnostic Errors , Hemorrhage/etiology , Humans , Infant, Newborn , Infant, Premature, Diseases/physiopathology , Lung/diagnostic imaging , Lung/pathology , Lung Diseases/etiology , Male , Radiography
15.
J Lab Clin Med ; 114(6): 728-33, 1989 Dec.
Article in English | MEDLINE | ID: mdl-2512365

ABSTRACT

We examined the functional importance of immunoglobulin polypeptide fragments generated by Pseudomonas aeruginosa elastase (Pseudomonas elastase). The purpose of this study was to determine whether the elastase produced by Pseudomonas aeruginosa cleaves human IgG into immune fragments that functionally inhibit opsonophagocytosis. Our results confirm that IgG isolated from patients with cystic fibrosis (CF) incubated with purified pseudomonas elastase results in the generation of two major polypeptide fragments and that, furthermore, these fragments significantly inhibit bacterial uptake by human neutrophils. After 75 minutes bacterial uptake was six times greater when intact IgG was used as an opsonin (uptake 90.2% +/- 18.6% SEM) compared with a IgG was used as an opsonin (uptake 90.2% +/- 18.6% SEM) compared with a mixture of pseudomonas-lipopolysaccharide-reactive Fab and F(ab')2 fragments generated by pseudomonas elastase (uptake 15.4% +/- 0.8% SEM, p less than 0.001). Hydrolyzed CF IgG antibodies consistently resulted in a level of bacterial uptake less than that of normal saline negative controls (NS): (at 10 minutes, NS 26.6% vs CF 16.8%, p less than 0.05; at 75 minutes, NS 28.2% vs CF 15.4%, p less than 0.01. This suggests that the immune polypeptides are active inhibitors of the essential neutrophil phagocyte-bacterial cell interaction. Intact immune IgG reversed the defect in opsonophagocytosis. When intact IgG was mixed with IgG fragments the phagocytic rates increased directly with increasing amounts of intact IgG. We conclude that the elastase exoproduct secreted by Pseudomonas aeruginosa is capable of cleaving IgG into functionally important fragments that inhibit bacterial uptake. Furthermore, this inhibition can be overcome by increasing amounts of a commercially available preparation of intact immune IgG.(ABSTRACT TRUNCATED AT 250 WORDS)


Subject(s)
Cystic Fibrosis/complications , Immunoglobulin Fragments/metabolism , Immunoglobulin G/metabolism , Pancreatic Elastase/metabolism , Pseudomonas Infections/complications , Pseudomonas aeruginosa/enzymology , Respiratory Tract Infections/complications , Antibodies, Bacterial/isolation & purification , Chromatography, Affinity , Cystic Fibrosis/immunology , Humans , Immunoglobulin Fragments/immunology , Immunoglobulin G/immunology , Immunoglobulin G/therapeutic use , Neutrophils/drug effects , Neutrophils/immunology , Opsonin Proteins/metabolism , Phagocytosis/drug effects , Pseudomonas Infections/prevention & control , Respiratory Tract Infections/prevention & control
16.
J Appl Physiol (1985) ; 66(1): 504-8, 1989 Jan.
Article in English | MEDLINE | ID: mdl-2563726

ABSTRACT

To determine whether inositol phosphates are important second messengers in the regulation of Cl- secretion by airway epithelia, we examined the relationship between inositol phosphate accumulation and Cl- secretion in response to adrenergic agonists. We found that epinephrine stimulated Cl- secretion and inositol phosphate accumulation with similar concentration dependence. Although isoproterenol stimulated Cl- secretion, there was no effect of beta-adrenergic receptor activation on inositol phosphate accumulation. In contrast, alpha 1-adrenergic receptor activation stimulated inositol phosphate accumulation but failed to induce Cl- secretion. Another Cl- secretagogue, prostaglandin E1, also failed to stimulate inositol phosphate accumulation. These data suggest that inositol phosphate accumulation is neither sufficient nor required for stimulation of Cl- secretion in cultured canine tracheal epithelial cells.


Subject(s)
Adrenergic alpha-Agonists/pharmacology , Adrenergic beta-Agonists/pharmacology , Inositol Phosphates/metabolism , Sugar Phosphates/metabolism , Trachea/metabolism , Animals , Cells, Cultured , Chlorides/metabolism , Chlorides/pharmacology , Dogs , Epithelial Cells , Epithelium/metabolism , Lithium/pharmacology , Lithium Chloride , Stimulation, Chemical , Trachea/cytology
18.
Lloydia ; 39(2-3): 147-9, 1976.
Article in English | MEDLINE | ID: mdl-1084950

ABSTRACT

Suspension cultures of Catharanthus roseus, Apocynum cannabinum and Conium maculatum were examined for their capacity to transform aniline, anisole, acetanilide, benzoic acid and coumarin. None of the cultures transformed acetanilide but each produced acetanilide when fed aniline. All three cultures converted benzoic acid to its para-hydroxy derivative. Coumarin was selectively hydroxylated at the 7-position by Catharanthus and Conium and anisole was O-demethylated only by older Catharanthus tissue.


Subject(s)
Plants/metabolism , Acetanilides/metabolism , Aniline Compounds/metabolism , Anisoles/metabolism , Benzofurans/metabolism , Biotransformation , Coumarins/metabolism , Culture Techniques , Species Specificity , Time Factors
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