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J A Fletcher

Publications and source records attributed to J A Fletcher.

At least 127 records · Page 7Linked to original sources
PubMed1992

Trisomy 12 in pediatric granulosa-stromal cell tumors. Demonstration by a modified method of fluorescence in situ hybridization on paraffin-embedded material.

The use of fluorescence in situ hybridization (FISH) to detect chromosomal abnormalities has many applications. Use of FISH on archival, paraffin-embedded material has been limited to microscopic sections. We have carried out FISH on preparations of disaggregated nuclei obtained from paraffin-embedded tissue to evaluate chromosome 12 copy number in granulosa-stromal cell neoplasms occurring in infants, children, and adolescents. Trisomy 12 was detected in the majority of cells from three of four juvenile granulosa cell tumors (three ovarian and one testicular) and one malignant granulosa cell tumor. Tetrasomy 12 was observed in a case of ovarian thecoma.

Cell Nucleus↗
PubMed1991

Diagnostic relevance of clonal cytogenetic aberrations in malignant soft-tissue tumors.

BACKGROUND: Malignant soft-tissue tumors often present substantial diagnostic challenges. Chromosome aberrations that might be diagnostic have been identified in some types of soft-tissue tumors, but the overall frequency and diagnostic relevance of these aberrations have not been established. METHODS: We attempted to determine the karyotypes of a series of 62 consecutive, unselected malignant spindle-cell or small round-cell soft-tissue tumors (from 46 adults and 16 children) after direct harvesting of cells or short-term culture. All tumors were examined independently by immunohistochemical staining in addition to routine light-microscopical evaluation, and all but two tumors were examined by electron microscopy. RESULTS: Metaphases were obtained from 61 of the 62 tumors, and clonal chromosome aberrations were identified in 55 (89 percent). In the six tumors that yielded metaphases but lacked apparent clonal aberrations, the normal metaphases were found to originate from non-neoplastic stromal elements within the tumor specimens. Thus, all tumors in which karyotyping was successful contained clonal chromosome aberrations. Forty of 62 tumors (65 percent) contained clonal chromosome aberrations that either suggested or confirmed a specific diagnosis; in 15 of these tumors (24 percent of all tumors), the aberrations were important in establishing the final diagnosis. Cytogenetic analyses were particularly informative about small round-cell tumors from children: 8 of 14 round-cell tumors contained diagnostically important chromosome aberrations. Using the combined approaches of light and electron microscopy, immunohistochemistry, and cytogenetics, we established an unambiguous diagnosis for 60 of 62 tumors. CONCLUSIONS: Cytogenetic analyses reveal clonal chromosome aberrations in virtually all malignant soft-tissue tumors. These clonal chromosome aberrations, particularly in small round-cell tumors in children, often have diagnostic relevance.

Adult↗
PubMed1991

Translocation (9;22) is associated with extremely poor prognosis in intensively treated children with acute lymphoblastic leukemia.

The prognostic implications of t(9;22)(q34;q11) were assessed at a median follow-up of 3.5 years in 434 children receiving intensive treatment for acute lymphoblastic leukemia (ALL). Four-year event-free and overall survivals were 81% and 88%, respectively, in 419 children lacking t(9;22), but were 0% and 20%, respectively, in 15 children with t(9;22) (P less than .001). Poor outcome for children with t(9;22)-positive ALL was particularly notable because we have reported improved survival in other historically poor prognosis ALL cytogenetic categories when treated with similarly intensive therapy. We recommend that very intensive treatment approaches, including bone marrow transplantation in first remission, be considered for all children with t(9;22)-positive ALL.

Adolescent↗
PubMed1991

Cytogenetic evidence of clonality in a case of pigmented villonodular synovitis.

Pigmented villonodular synovitis is an uncommon benign lesion that is characterized by diffuse synovial proliferation. Based on animal models, this lesion has been conjectured previously to be reactive in nature. In this report, the authors present the histologic and cytogenetic findings for a pigmented villonodular synovitis that was excised from the right knee of a 47-year-old man. Trisomy 7 was observed in 24 of 75 (35%) metaphases obtained from short-term culture of cells from this tumor. These findings suggest that some cases of pigmented villonodular synovitis represent clonal, neoplastic proliferations.

Chromosomes, Human, Pair 7↗
PubMed1991

Consistent cytogenetic aberrations in hepatoblastoma: a common pathway of genetic alterations in embryonal liver and skeletal muscle malignancies?

Cytogenetic analyses of four consecutive hepatoblastomas revealed near-diploid stemline karyotypes with relatively simple chromosome aberrations. Cytogenetic abnormalities shared by each tumor included trisomy for all of part of chromosome 2 and trisomy for chromosome 20. In two cases, partial trisomy for chromosome 2 resulted from direct duplication of long arm material with the shortest region of overlap being 2q23-2q35. In one tumor, each metaphase also contained a variable number of double minute chromosomes found not to derive from NMYC amplification. Interestingly, trisomy for 2q and trisomy 20 are also characteristic events in pediatric embryonal rhabdomyosarcomas. Furthermore, others have reported loss of heterozygosity for the short arm of chromosome 11 in both hepatoblastoma and childhood embryonal rhabdomyosarcoma, and both these malignant diseases are associated with Beckwith-Wiedemann syndrome. These cytogenetic and molecular findings suggest a parallel pathway of genetic steps in the initiation and/or progression of tumors of embryonal liver and skeletal muscle.

Carcinoma, Hepatocellular↗
PubMed1991

HLA-DQA1 and -DQB1 alleles associated with genetic susceptibility to IDDM in a black population.

Transracial analysis provides a method of distinguishing primary associations between insulin-dependent diabetes mellitus (IDDM) and HLA class II alleles from those secondary to linkage disequilibrium. Blacks show DR-DQ relationships that are different from other races and are a useful group in which to investigate HLA-D region associations with IDDM. In this study, the frequencies of HLA-DQA1 and -DQB1 alleles in Afro-Caribbean IDDM and control subjects were compared. Alleles were identified with sequence-specific oligonucleotide probing. The DQA1 allele A3 was positively associated with IDDM (relative risk [RR] = 25.3, corrected P [Pc] less than 7.0 x 10(-6). The DQB1 alleles DQw2 and DQw8 were also positively associated (RR = 4.7, Pc less than 6.5 x 10(-3) and RR = 12.3, Pc = 3.4 x 10(-3), respectively). The A1.2 and DQw6 alleles were negatively associated (RR = 0.16, Pc less than 3.5 x 10(-3) and RR = 0.15, Pc = 2.4 x 10(-2), respectively). These findings were compared to data from other races. The positive associations with A3 and DQw2 are consistent with all racial groups investigated. The negative association with DQw6 is present in all racial groups in which it is a common allele. These findings suggest that DQ alleles, and hence DQ molecules, may directly affect predisposition to IDDM.

Alleles↗
PubMed1991

Lineage-restricted clonality in biphasic solid tumors.

Cytogenetic analysis of two pulmonary chondroid hamartomas and nine breast adenofibromas revealed clonal chromosome aberrations in both hamartomas and in four breast tumors. To determine lineage of the cells with chromosome aberrations, a combined immunohistochemical/cytogenetic approach was developed that enabled simultaneous ascertainment of cytogenetic aberrations and immunohistochemical features in individual cells. Immunohistochemical/cytogenetic evaluation of one hamartoma and two adenofibromas demonstrated that neoplastic proliferation, in each case, was confined to the mesenchymal (stromal) component, whereas epithelial cells appeared to be reactive. Cytogenetically abnormal short-term cultures of the remaining hamartoma and another of the breast adenofibromas were composed entirely of mesenchymal elements, indicating mesenchymal clonality in those tumors as well. Our findings support redesignation of pulmonary chondroid hamartomas as 'pulmonary chondromas' and suggest that carcinomas developing within fibroadenomas arise from reactive epithelial proliferation. Combined immunohistochemical/cytogenetic analysis might be useful in the development of novel therapeutic approaches that selectively target neoplastic populations within solid tumors.

Adenocarcinoma↗
PubMed1991

Laboratory investigation, genetics, and experimental models in sarcomas.

The sarcomas, particularly those of soft-tissue origin, pose substantial diagnostic challenges for the clinician and pathologist. Several small round cell sarcomas, including Ewing's sarcoma, peripheral primitive neuroectodermal tumor, and alveolar rhabdomyosarcoma, can be difficult to distinguish from one another. These same sarcomas can be difficult to distinguish from other small round cell tumors, including non-Hodgkin's lymphoma and neuroblastoma. Spindle cell sarcomas, including malignant peripheral nerve sheath tumor, synovial sarcoma, and leiomyosarcoma, present similar diagnostic challenges. This review discusses 1) recent advances in immunohistochemistry, electron microscopy, and cytogenetics that enable a specific diagnosis in virtually all sarcoma cases; 2) cell biology and oncogenetic implications of novel morphologic and genetic findings in sarcomas; and 3) clinical implications of the recent characterization of several family cancer syndrome genes.

Animals↗
PubMed1991

Ovarian granulosa-stromal cell tumors are characterized by trisomy 12.

Eleven ovarian granulosa-stromal cell tumors including 1 thecoma, 2 fibromas, 6 fibrothecomas, and 2 granulosa cell tumors, were karyotyped after direct harvest and/or short-term tissue culture. Bilateral fibrothecomas from one patient appeared to lack cytogenetic aberrations: the remaining nine tumors were characterized by trisomy for chromosome 12. Cytogenetic aberrations in the two granulosa cell tumors were much less complex than those described previously in undifferentiated carcinomas; accordingly cytogenetic analyses might be useful in distinguishing these categories. The consistent occurrence of trisomy 12 in different varieties of granulosa-stromal cell tumors suggests a common mechanism of oncogenesis within this diverse group of neoplasms. That mechanism probably involves promotion of low-grade, orderly cell proliferation.

Chromosomes, Human, Pair 12↗
PubMed1991

Cytogenetic abnormalities in uterine leiomyomata.

Uterine leiomyomata are thought to be monoclonal tumors; however, the factors involved in the neoplastic proliferation of uterine leiomyomata are unknown. The purpose of the present study was to characterize uterine leiomyomata using cytogenetic techniques. Thirteen leiomyoma specimens were obtained by hysterectomy or myomectomy. Short-term cultures were successfully established for all specimens, and metaphase spreads were prepared by conventional techniques. Clonal chromosome rearrangements were detected in seven leiomyoma specimens (54%). These rearrangements involved chromosome bands 12q14-15 in five specimens, including three tumors with a specific translocation, t(12;14)(q14-15;q23-24). Chromosome rearrangements involving chromosome band 7q22 were identified in two specimens. A normal 46,XX karyotype was observed in six specimens. Myometrial specimens from two patients with abnormal leiomyoma karyotypes were normal cytogenetically. These results suggest that spontaneous chromosome rearrangements may be responsible for the initiation and proliferation of leiomyoma growth.

Adult↗
PubMed1990

Chromosome aberrations in uterine smooth muscle tumors: potential diagnostic relevance of cytogenetic instability.

Cytogenetic studies were carried out on a low-grade metastatic uterine leiomyosarcoma and on a large degenerating uterine leiomyoma. The leiomyosarcoma and leiomyoma were hyperdiploid and hypodiploid, respectively, and both tumors contained multiple consistent chromosome aberrations. In the patient with leiomyosarcoma, flow cytometric studies of proliferative foci from a previously resected uterine leiomyoma revealed near triploidy, suggesting that the leiomyosarcoma was metastatic from an unrecognized malignant uterine primary lesion. The leiomyosarcoma was characterized by extreme cytogenetic instability, whereas the leiomyoma demonstrated cytogenetic stability. The present cases and review of the literature on leiomyosarcomas and leiomyomas reveal cytogenetic instability to be very common in leiomyosarcomas (present in 8 of 10 cases) and uncommon in leiomyomas (present in 1 of 25 cases). A grading system is described which might be useful in evaluating the diagnostic and prognostic relevance of cytogenetic instability in uterine, and other, malignancies.

Aged↗
PubMed1990

Transfer from animal insulins to semisynthetic human insulin: a study in four centres.

The effects of transfer from animal insulin to semisynthetic human insulin on glycaemic control, insulin dose and anti-insulin antibodies were investigated in a total of 108 patients at four centres in a double-blind controlled study of eight months duration. Six months after transfer from porcine to human insulin there was a mean (+/- SE) increase in pre-breakfast blood glucose of 1.1 +/- 0.6 mmol l-1 (vs a reduction of 1.6 +/- 0.7 mmol l-1 in controls) (p less than 0.01), and a mean increase of pre-lunch blood glucose of 0.9 +/- 0.7 mmol l-1 (vs a reduction of 1.14 +/- 0.7 mmol l-1 in controls) (p less than 0.05). Six months after transfer from bovine to human insulin, there were no significant changes in blood glucose. Glycated haemoglobin showed no significant change six months after transfer from either bovine or porcine to human insulin. Hypoglycaemic symptoms, the total daily insulin dose, and the ratio of short- to intermediate-acting insulin did not change significantly after transfer from either bovine or porcine to human insulin. Transfer from bovine to human insulin resulted in a significant decline in anti-human insulin antibodies (mean (range): 50.5(14.8-125)% of initial levels), vs controls (113(43.4-234)% of initial levels; p = 0.034), and a non-significant decline in anti-bovine insulin antibodies (52.2(25.8-111)% vs 81.7(42.5-128)%; p = 0.082).

Adult↗
PubMed1989

Prognostic implications of cytogenetic studies in an intensively treated group of children with acute lymphoblastic leukemia.

We assessed the prognostic significance of leukemia cell cytogenetics by analyzing bone marrow aspirates obtained at time of diagnosis in 165 children on a single protocol for acute lymphoblastic leukemia (ALL). These children were assigned to six mutually exclusive cytogenetic categories as follows: (1) hyperdiploid, with 50 or more chromosomes (n = 35); (2) hyperdiploid, with 47 to 49 chromosomes (n = 11); (3) diploid (n = 42); (4) pseudodiploid (n = 34); (5) hypodiploid (n = 9); and (6) insufficient data (n = 34). At a median follow-up of 5 years, there were no statistically significant differences between any of these cytogenetic categories in either event-free or overall survival. Those children with chromosomal translocations (n = 26) appeared to fare the same as those lacking translocations (n = 105). The absence of karyotypic prognostic significance was observed not only within the overall group, but also when the results were stratified by standard-risk and high-risk status. Of the specific structural chromosome changes that we studied, only the Philadelphia chromosome (Ph) appeared to confer a poor prognosis, although there were too few such cases to achieve statistical significance. Although we did not detect the event-free survival differences that have been described previously in hyperdiploid, hypodiploid, and pseudodiploid childhood ALL, our findings must be viewed as preliminary given the small number of children in some of the cytogenetic categories. We think that the prognostic implications of these cytogenetic features might have been nullified by improvements in therapy.

Adolescent↗
PubMed1989

Complex cytogenetic aberrations in a well-differentiated chondrosarcoma.

The cytogenetic analysis of a well-differentiated (grade I) chondrosarcoma is presented. Despite a low-grade histopathology, metaphase preparations of tumor cells were characterized by numerous structural chromosome aberrations and a striking degree of genetic instability; the t(9;22)(q31;q12) that has been described recently in extraskeletal myxoid chondrosarcoma was not observed. This report suggests that chondrosarcomas may be heterogeneous cytogenetically. In chondrosarcoma, it appears that "high-grade" cytogenetic abnormalities do not necessarily engender a high-grade histology. These findings offer a possible explanation for the clinical aggressiveness of certain low-grade chondrosarcomas.

Aged↗
PubMed1989

Association of trisomy 8 and squamous differentiation in an endometrial adenocarcinoma.

Cytogenetic analysis was performed on a case of endometrial adenocarcinoma in which 10% to 15% of the tumor showed squamous differentiation. Of 26 cells examined, all had trisomy 1q and monosomy 16; four cells (15%) also showed trisomy 8. Trisomy 8 is an unusual finding in endometrial carcinoma, having been reported in only one other case, which was an adenosquamous carcinoma. Our findings suggest that trisomy 8 may be a marker of squamous differentiation in endometrial carcinoma.

Adenocarcinoma↗
PubMed1988

Autoantibodies in Indian-Asians with insulin-dependent diabetes in the UK.

Classical insulin-dependent diabetes mellitus (IDDM) is relatively uncommon in Indian-Asians whether in India or in the UK and this may be related to immunogenetic factors. We have studied the presence or absence of islet cell antibodies and other auto-antibodies in 36 subjects with IDDM and 41 controls, all of Indian origin. Islet cell antibodies (ICA-IgG) were found in 8 subjects with IDDM but in none of the controls. Four of the 8 patients with ICA-IgG also possessed the complement fixing variety (CF-ICA). There was no definite association between possession of ICA and HLA-DR antigens. Thyroid antibodies were commoner in patients (22%) compared with controls (7%) as were parietal cell antibodies (8.3% vs 4.8%). None of the patients or controls had adrenal antibodies. The frequency of organ-specific antibodies in Indian-Asians with IDDM is similar to that of white Caucasians. The overall frequency of ICA is, however, lower than that reported for white Caucasians although the temporal distribution is similar. We conclude that even though the prevalence of IDDM in Indian-Asians is lower than in white Caucasians there is no evidence that different immunological mechanisms are involved in the pathogenesis of IDDM in the two groups.

Adolescent↗