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J R Testa

Publications and source records attributed to J R Testa.

At least 163 records · Page 9Linked to original sources
PubMed1990

Hypereosinophilic syndrome with evolution to myeloproliferative disorder: temporal relationship to loss of Y chromosome and c-N-ras activation.

A case of hypereosinophilic syndrome is presented in which the patient was serially observed for 4 years. Transformation to a disorder resembling chronic myeloid leukemic (CML) occurred 36 months after diagnosis; at 42 months, blastic transformation and marrow failure ensued, leading to death. Marrow examination for histopathologic, cytogenetic, and molecular biologic analyses were performed during the eosinophilic, myeloproliferative, and blastic stages. These demonstrated ras activation by virtue of a codon 12 G to C transversion mutation, predicting for substitution of glycine by alanine; in addition, we observed Y chromosome loss late in the natural history of this illness, suggesting that these genetic lesions can play a role in the profound loss of myeloid differentiation characteristic of the accelerated phase commonly observed in myeloproliferative syndromes.

Adult↗
PubMed1990

Clinical and cytogenetic correlations of abnormal megakaryocytopoiesis in patients with acute leukemia and chronic myelogenous leukemia in blast crisis.

It has been suggested that abnormalities of chromosome 3 at bands q21 and q26 are associated with the presence of increased numbers of abnormal megakaryocytes in patients with hematologic malignancies. The pretreatment bone marrows of 287 patients with leukemia (acute myeloid leukemia (AML), 225 patients; acute lymphocytic leukemia (ALL), 36 patients; or chronic myelogenous leukemia in blast crisis (CML-B), 26 patients) were reviewed to identify those with normal or increased numbers of megakaryocytes. Thirty-two patients with AML, one with ALL, and 10 with CML-B had normal or increased numbers of megakaryocytes. Of the 32 patients with AML, 19 patients had significant numbers of mononuclear or binuclear small megakaryocytes as well as megakaryocytes with separated nuclei ("micromegakaryocytes"). Cytogenetic analyses were obtained in 29 of 32 patients with AML and showed inv(3)(q21q26) (one patient); Ph1 (two patients); -5 and/or -7 (seven patients); normal karyotypes (10 patients). No patient with micromegakaryocytes had a chromosomal abnormality associated with a favorable prognosis. Overall, among 225 patients with AML, four had inv(3)(q21q26) or t(3;3)(q21;q26). Only one of these four patients had normal or increased numbers of megakaryocytes, although all four had micromegakaryocytes. One patient with CML-B had inv(3)(q21q26) but had decreased numbers of megakaryocytes and a platelet count of 24 x 10(3)/microliters. All five patients with abnormal chromosome 3 at bands q21 and q26 had additional cytogenetic abnormalities (Ph1 in two patients; -7 in three patients). Mean and median platelet counts were greater than 100,000/microliters for patients with marrow megakaryocytosis regardless of morphology, as well as for the patients with abnormalities involving 3q21 and 3q26. Abnormalities of megakaryocyte morphology, increases in the numbers of megakaryocytes, and normal to increased platelet counts are not uncommon in patients with acute leukemia and CML-B, and are not uniquely associated with changes involving chromosome 3.

Adult↗
PubMed1989

Recurring loss involving chromosomes 1, 3, and 22 in malignant mesothelioma: possible sites of tumor suppressor genes.

Cytogenetic analysis was performed on short-term cultures of primary tumor tissue obtained from five patients with pleural malignant mesothelioma. Clonal karyotypic abnormalities were detected in four patients, none of whom had received cytotoxic therapy prior to karyotypic evaluation. Recurring chromosomal changes included partial deletions of 1p and 3p, and monosomy of 18, 19, and 22. We also reviewed data on 24 previously reported pretreatment patients and determined that alterations of chromosomes 1, 3, and 22 are frequently associated with malignant mesothelioma. Partial loss of chromosome 1 due to deletions or other rearrangements most frequently involve bands 1p11-pter with the shortest region of overlap (SRO) occurring at 1p21-p22 in our patients. Deletions and other structural changes of chromosome 3 usually involve the region 3p14-p25. The SRO of 3p deletions appeared to be at band 3p21. Monosomy 22 represents the most consistent specific whole chromosome loss seen in malignant mesothelioma, being observed in 11 of 28 cases summarized. In addition, structural changes of 22q have been observed in three patients, and a breakpoint at 22q11 was reported in each case. Taken collectively, these data suggest that a cascade of events involving alterations of genes on more than one specific chromosome may play a critical role in the development of malignant mesothelioma. The pattern of recurring chromosomal loss, particularly of 1p, 3p, and 22q, indicates that these regions should be targeted for future molecular investigations into the possible involvement of suppressor genes in this malignancy.

Adult↗
PubMed1989

Chromosome aberrations in nine patients with ovarian cancer.

Cytogenetic analysis was performed on 13 tumor specimens (six solid tissues and seven effusions) from nine patients with various types of ovarian cancer. Eight of these patients had not received cytotoxic therapy prior to the initial karyologic assessment. Extensive and complex numerical and structural alterations were seen in nearly all specimens. Consistent (clonal) abnormalities were found in each case, but karyotypic heterogeneity within a tumor was a consistent finding in this series. Aberrations of chromosomes 1, 3, 6, 7, 10, and 12 were each observed in five or more patients. Although no specific recurring translocations were observed, partial deletions of 3p, 6q, 8p, and 10q were each seen in three different cases. Breakpoints tended to recur at several chromosomal band regions, some of which appear to be near the known loci of certain protooncogenes. Double minute chromosomes were seen in one patient, and a homogeneously staining region was found in another. Karyotypic analysis was performed on one patient both before and after initiating chemotherapy, and the chromosome pattern became more complex after treatment. Overall, our findings indicate that karyotypes in newly diagnosed, untreated patients with ovarian cancer can be extremely complicated, and that the extent of chromosome change may increase with tumor progression. Furthermore, the recurrence of specific regional chromosome losses suggests that these sites contain genes whose loss plays a role in the formation of some ovarian tumors.

Adenocarcinoma↗
PubMed1989

Cancer in relatives of leukemic patients with chromosomal rearrangements at rare (heritable) fragile-site locations in their malignant cells.

The cancer occurrence in relatives (N = 407) of 40 case probands (who had leukemia and rearrangements at the same chromosomal location as at least one of 23 recognized rare [heritable] autosomal fragile sites [Sutherland and Mattei 1987]) was compared both to cancer occurrence in relatives (N = 390) of 40 control probands (who had leukemia or other hematologic illness but no recognized chromosomal rearrangements) and to cancer incidence in the general population of the United States. Fragile-site carrier status was not determined in case or control probands. No significant excess of cancer in case relatives, compared with either control relatives or to general (SEER) population expectancies, was found. Furthermore, there was neither evidence of cancer at younger ages, when cases were compared with control relatives, nor an excess of cancer at multiple sites. Male relatives of cases did, however, show a small excess of cancer, especially in older age groups. There was a slight, but not statistically significant, excess of lung cancer in case relatives, with this deviation occurring almost exclusively in relatives of probands having rearrangements at 11q23 and having lymphoid leukemia. It is possible that heritable tendency to chromosomal rearrangement--and thus to cancer--is expressed in such a small proportion of family members that cancer excess in these families could not be detected with the numbers of relatives analyzed in this study, although there was no significant evidence for a hereditary predisposition to cancer in the families of probands with leukemia and with chromosomal rearrangements at the same apparent chromosomal location as rare fragile sites.

Adolescent↗
PubMed1989

Prognostic impact of cytogenetic abnormalities in patients with de novo acute nonlymphocytic leukemia.

Detailed cytogenetic analyses were performed on specimens from 198 patients with de novo acute nonlymphocytic leukemia (ANLL), including high-resolution banding studies in 79 patients. One hundred ninety-two patients received induction therapy with daunorubicin and cytosine arabinoside (Ara-C) with an overall complete response rate (CR) of 63%. Responding patients received repetitive cycles of Ara-C-based intensification therapy. Clonal abnormalities were detected in 69% of the patients with specimens adequate for cytogenetic analysis. Certain cytogenetic changes were closely associated with French-American-British (FAB) morphology, age, and outcome: t(8;21) (closely associated with FAB M2), t(15;17) (associated with FAB M3), and abn 16q22 (associated with FAB M4EOS) tended to occur in younger patients and were associated with favorable outcomes in terms of both CR rate and long-term disease-free survival. In contrast, 19% of patients who had -5/5q- and or -7/7q- and seven patients with trisomy 8 were older, had a poor prognosis, and usually failed to achieve remission (CR) because of chemotherapy-resistant leukemia. The adverse effect on CR rate and duration in this group of patients was independent of age, and there was no association with particular morphologic subtypes. These data suggest that cytogenetic findings should influence future therapeutic choices. In particular, patients with abnormalities associated with poor responses may be considered for investigational approaches and may also provide insights into mechanisms of drug resistance.

Adolescent↗
PubMed1989

The bcr gene in Philadelphia chromosome positive acute lymphoblastic leukemia.

In chronic myelogenous leukemia (CML) and in a percentage of childhood and adult acute lymphoblastic leukemia (ALL) the Philadelphia (Ph') chromosome is present in the leukemic cells of patients. This chromosome is the result of a reciprocal translocation between chromosomes 9 and 22. In CML the break on chromosome 22 occurs within the major breakpoint cluster region (Mbcr) of the bcr gene. In this study, we report on the examination of DNAs from nine Ph'-chromosome positive ALL patients for rearrangements within the bcr gene using Southern blot analysis. Of nine patients having a karyotypically identifiable Ph'-chromosome, only five exhibited rearrangements of the bcr gene. This could indicate that in ALL, chromosome 22 sequences other than the bcr gene are involved in the Ph'-translocation. Within the group of Ph'-positive ALL patients having a bcr gene breakpoint, a correlation appears to exist between the age of the patient and the location of the breakpoint within the gene: all or the vast majority of pediatric patients analyzed to date do not have a Mbcr breakpoint as found in CML and in adult ALL.

Adolescent↗
PubMed1988

Isolation of highly multidrug-resistant P388 cells from drug-sensitive P388/S cells by flow cytometric cell sorting.

To investigate the spontaneous frequency of occurrence of stable multidrug-resistant cells in a population of drug-sensitive cells, we exposed drug sensitive P388/S cells to daunorubicin (dnr) for 1 h, then used fluorescence-activated cell sorting based on intracellular dnr fluorescence to isolate cells within P388/S having different intracellular content of drug. One of the sort windows chosen (low dnr content sort window) isolated only P388/S cells with intracellular drug content equal to or less than that of the known multidrug-resistant subline P388/adr. This sort window constituted approximately 3% of P388/S cells with lowest dnr content. By such a procedure we were able, on one of seven attempts, to isolate and cultivate stable, highly multidrug-resistant cells (comparable to that of P388/adr) from the P388/S cells obtained from the low dnr-content sort window. Net growth of cells in culture was observed 15-20 days after sorting, indicating that of the P388/S cells collected from the low dnr-content sort window, very few were actually highly drug-resistant. On no occasion could resistant cells be cultivated from cells sorted from P388/S with higher dnr content, as would be expected if mutation to a multidrug-resistant phenotype had occurred as a result of exposure to drug. The resistant cells isolated from P388/S by sorting (called P388/LoSort) displayed low intracellular accumulation of dnr that was enhanced by verapamil, were cross-resistant to vincristine and actinomycin-D, and distinct from P388/S, possessed a 150- to 160-kD membrane species identified by Vinca alkaloid photoaffinity labeling.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

The AKT1 proto-oncogene maps to human chromosome 14, band q32.

The human AKT1 gene is the proto-oncogene of the viral oncogene v-akt. The AKT1 gene has been localized to human chromosome 14, band q32, proximal to the heavy-chain immunoglobulin locus (IGHM), by analysis of human-hamster somatic cell hybrids and by in situ hybridization. Chromosome rearrangements of this band which occur in T-lymphoid malignancies and Hodgkin's disease may affect the AKT1 gene.

Animals↗
PubMed1988

Two rearranged MET alleles in MNNG-HOS cells reveal the orientation of MET on chromosome 7 to other markers tightly linked to the cystic fibrosis locus.

We have found that two alleles of the MET locus are rearranged in the human cell line MNNG-HOS. One allele is the previously characterized TPR-MET oncogene and the other is found on a der(7)t(1;7)(q23;q32) marker chromosome. These data and in situ chromosomal hybridization analysis would indicate that MET and, therefore, the cystic fibrosis locus are located at bands q31-q32 on human chromosome 7. Using somatic cell hybrids, we show that the chromosome containing the TPR-MET oncogene is grossly rearranged and contains both the upstream and downstream portions of the MET protooncogene locus. These results demonstrate that the TPR-MET oncogene rearrangement involving chromosomes 1 and 7 is either due to an insertion of TPR sequences into the MET locus or is more complex. We also show that the upstream MET protooncogene locus is deleted on der(7), while the downstream portion is retained. We cannot exclude that this is due to an interstitial chromosomal deletion or to a more complex rearrangement, but if MET maps at the breakpoint in der(7), then the 3' end of the MET transcription unit should be oriented towards the centromere. We also show that other DNA restriction fragment length polymorphism markers tightly linked with the inheritance of cystic fibrosis are deleted on der(7).

Alleles↗
PubMed1988

Application of ethidium bromide for high-resolution banding analysis of chromosomes from human malignant cells.

Ethidium bromide was added to cultured human leukemic bone marrow and solid tumor cells to evaluate its inhibitory effect on mitotic chromosome condensation and its possible application to high-resolution banding analysis. In most experiments ethidium bromide treatment resulted in a high proportion of mitotic cells having elongated chromosomes, without remarkable reduction in either the mitotic index or quality of metaphase chromosomes. Optimal effect on chromosome length was obtained by adding 10 micrograms/ml of ethidium bromide during the final 2 hr of culture. Because of the simplicity and reproducibility of the technique involved, ethidium bromide can be used routinely to extend the length of chromosomes for fine-banding analysis of malignant cells.

Chromosome Banding↗
PubMed1988

Acute eosinophilic leukemia with a (10;11) chromosomal translocation.

We report a patient with acute eosinophilic leukemia and a translocation (10;11)(p14;q21). Clinically, the disease was characterized by extreme hypereosinophilia with most eosinophils being immature, pronounced marrow infiltration with abnormal eosinophil precursors, skin and lymphoid infiltration with leukemic eosinophils, and only a brief remission from chemotherapy. This is the second report of a patient with this cytogenetic/clinicopathological association. In our patient, t(10;11)(p14;q21) was the sole karyotypic abnormality seen in the bone marrow, both at diagnosis and relapse. Thus, acute eosinophilic leukemia with t(10;11)(p14;q21) appears to be a rare, new clinical/cytogenetic association. Because both patients with this translocation responded only briefly to chemotherapy, this chromosomal abnormality may confer a poor prognosis.

Adult↗
PubMed1987

Philadelphia chromosome-positive acute leukemia: morphologic and clinical correlations.

Twenty-eight adult patients with Philadelphia chromosome positive (Ph+) acute leukemia were studied to determine if additional chromosomal changes were related to specific morphologic and clinical features. Twenty patients had chronic myeloid leukemia in blast crisis (CML-BC), three had Ph+ de novo acute nonlymphocytic leukemia (ANLL), and five had de novo acute lymphoblastic leukemia (ALL). Chromosomal abnormalities in addition to a single Ph were noted in 90% of patients with CML-BC and included a second Ph (five patients), +8 or duplication of part of 8q (five patients), dicentric isochromosome 17 (two patients), and +19 (two patients). Octaploidy with 4 Ph was seen in one patient with megakaryoblastic transformation. One of two patients with a progranulocytic blast crisis had a t(15;17) abnormality. Hypodiploidy was noted in 4 of 20 patients with CML-BC. Each of the four patients had prominent extramedullary manifestations of blast crisis. All had received intensive chemotherapy prior to the detection of hypodiploidy, and the cytogenetic findings were similar to those often seen in patients with therapy-related leukemia. An inv(3)(q21q26) was noted in two patients (one CML-BC, one de novo Ph+ ANLL), one of whom had hypolobulated micromegakaryocytes. Additional cytogenetic abnormalities in de novo Ph+ ANLL (especially +19) were similar to those in CML-BC. In contrast, the additional karyotypic changes in de novo Ph+ ALL (eg, +4, -7, -20, markers) were those commonly seen in ALL without a Ph and were generally different from those seen in CML-BC.

Acute Disease↗
PubMed1987

Cytogenetic studies of a human medullary thyroid carcinoma cell line.

Detailed karyotypic analyses were performed on early and late passages of the TT cell line derived from malignant cells of a patient with the sporadic form of medullary thyroid carcinoma. Most of the cells examined were hypodiploid with a modal chromosome number of 43. The cells have a complex karyotype with ten rearranged chromosomes found in early passages and 12 rearranged chromosomes in late passages. The karyotypic pattern was relatively stable with continued in vitro culture, and consistent alterations involved chromosomes X, #1, #3, #5, #7, #8, #9, #10, #11, #12, and #14. Rearrangements of chromosome #11 are of particular interest, because the gene for calcitonin, the polypeptide hormone marker for medullary thyroid carcinoma resides on this chromosome. In early passages, one #11 contained an insertion within band q13, and this abnormality was retained in late passages. In late passage cells the other #11 homolog developed a deletion of part of the short arm, which involves the calcitonin gene region. We were unable to detect any deletion of chromosome band 20p12, previously reported by other investigators to occur in the germ line of patients with the hereditary form of medullary thyroid carcinoma.

Carcinoma↗
PubMed1987

Amplification of the c-myc oncogene is associated with an abnormally banded region on chromosome 8 or double minute chromosomes in two HL-60 human leukemia sublines.

Two sublines of HL-60 human promyelocytic leukemia cells were examined cytogenetically with banding techniques. The karyotype of one subline was 44,X,-X,-5,-9,-10,-15,-17,+18,8q+,14q-,16q+,16q+,+mar1,+mar2 ,+mar3. The defective chromosome #8 contained an expanded chromosomal segment at the end of the long arm at band q24. The segment appeared to be a homogeneously staining region on the basis of quinacrine fluorescence banding. Using G-banding technique, this segment showed some evidence of indistinct aberrant bands and, thus, was designated an abnormally banded region (ABR). Double minute chromosomes (DM) were not seen in these cells. The second subline showed a similar karyotype; however, these cells lacked the 8q+ marker and contained one to 37 DM in approximately 90% of the cells examined. Because HL-60 cells are known to contain multiple copies of the c-myc oncogene, in situ chromosomal hybridization of a c-myc probe to HL-60 metaphase cells was performed to localize the amplified genes. The hybridization studies revealed localization to the ABR, as well as to DM, which is consistent with amplification of c-myc within these novel interchangeable chromosomal aberrations.

Cell Line↗
PubMed1987

Clinical and cytogenetic features of familial erythroleukaemia.

A family is described in which six members developed acute nonlymphocytic leukaemia (ANLL) over the past 15 years, all morphologically FAB M6. Five affected individuals (ages 54-73) are members of a single sibship, the sixth (age 31) was the son of one of the affected sibs. The family lives in a rural area, and no environmental hazard has been identified. One of the six patients never resided in the same geographic area as the others. Three patients with leukaemia died without chemotherapy, two died shortly after the initiation of chemotherapy and the most recent patient never achieved remission, surviving 10 months. Bone marrow specimens from the two most recent patients were analysed for cytogenetic abnormalities using chromosome banding techniques. In addition, skin fibroblasts were examined in a single patient. The fibroblasts had a normal karyotype. Bone marrow cells from both patients had complex abnormalities. Some similarities were observed, including: hypodiploidy; loss of one chromosome 20; the presence of multiple marker chromosomes. In each case one marker appeared to involve the 'missing' no. 20 with an alteration of the long arm--loss (20q-) in one patient and gain (20q+) in the other. Peripheral blood lymphocytes were grown in folate deficient medium, but no evidence for folate sensitive fragile sites was found. Marrow chromosomes from a third leukaemic sibling were examined without banding techniques in 1976 and the karyotype was 45,XY,-18,-F(19 or 20), +marker. No specific cytogenetic finding was common to the three patients studied except for the loss of an F group chromosome. This family is unique in the literature with six cases of familial leukaemia of the same morphologic subtype, and the cytogenetic findings suggest that loss or rearrangement of part of the long arm of a single chromosome 20 may have occurred in each of the three patients examined.

Adult↗
PubMed1987

Assessment of methods for the cytogenetic analysis of human solid tumors.

A comparative study was undertaken to evaluate the effectiveness of various procedures (e.g., direct harvest vs. short-term culture) for the cytogenetic analysis of human solid tumors. A total of 51 specimens (38 primary tumors, 13 effusions) were examined from 45 patients with tumors of the ovary, lung, breast, colon, and testicles. Sufficient numbers (greater than or equal to 3) of metaphase cells to be useful for karyotypic analysis were obtained in 42 of 51 (82.3%) specimens. More than 10 analyzable metaphases were found in each of 32 specimens (62.7%), but in some cases it was necessary to examine many slide preparations to achieve this number. The rate of successful chromosome preparations was markedly better for short-term cultures than for specimens harvested directly. Short-term cultures generally showed a mitotic peak after about 3 days of growth in vitro. Generally, the quality of metaphase cells was better in specimens disaggregated enzymatically with collagenase than in those dissociated mechanically. Exposure to ethidium bromide (EB) for the final 2 hours of culture yielded more cells with elongated chromosomes than cultures harvested by conventional methods without EB. Overall, the findings indicate that successful karyotypic analysis can be performed in a high percentage of human solid tumors with the use of techniques that can be readily applied in most cytogenetics laboratories. However, further methodological advances in tissue culture are warranted to routinely provide large numbers of mitotic cells for karyotypic analysis.

Breast Neoplasms↗