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The high risk of recurrence in superficial transitional cell cancer (TCC) of the bladder prompted evaluation of whether chromosome changes detected at first recurrence were correlated with relapse or with response to fluoroquinolone treatment. Fluorescence in situ hybridization analysis was applied to desquamated cells from bladder washings obtained immediately before surgical resection. Cells were screened for numeric changes in chromosomes 7 and 9. Aberrations were identified in 38/54 patients eligible for evaluation. Although no clear associations were established owing to sample size, the results suggested that risk of progression/relapse was positively associated with loss of chromosome 9 and with polysomy, and negatively associated with gain of chromosome 7, the latter in contrast to published data. A short-term survival advantage was noted anecdotally with gain of chromosome 9.

Chondrosarcomas are the second most common primary malignant tumor of bone. Chemotherapy for conventional chondrosarcomas is generally ineffective. Methylthioadenosine phosphorylase (MTAP) is a ubiquitous enzyme, essential in the salvage pathway of adenine and in methionine synthesis. MTAP-deficient cells are more susceptible than wild-type cells to pharmacologic inhibitors of de novo purine synthesis. Homozygous deletions of MTAP have been reported in hematologic and solid tumor malignancies. Based on these observations, we investigated the frequency of MTAP deletions in conventional, grade II chondrosarcomas by fluorescence in situ hybridization (FISH) analysis: 23 conventional, grade II chondrosarcoma patient samples from the Cleveland Clinic Foundation were analyzed for MTAP deletions. Nuclei were successfully extracted from 14 of 23 samples (61% evaluable) for FISH analysis: 7 of 14 samples (50%) showed either homozygous or hemizygous deletion of the MTAP gene, 6 of 14 (43%) failed to show deletion, and 1 of 14 (7%) was inconclusive. These findings suggest that approximately one-half of conventional, grade II chondrosarcomas may be preferentially sensitive to pharmacologic inhibitors of de novo purine synthesis. The present study led to development by the Intergroup Coalition Against Sarcomas of a phase II trial of pemetrexed, a multitargeted anti-folate, for advanced chondrosarcomas.

Trisomy 15 as the sole karyotypic aberration is an uncommon clonal cytogenetic aberration in hematological malignancies, making its significance unclear. Previous studies have reported relations of trisomy 15 with low-grade myelodysplasia or a benign age-related phenomenon associated with loss of the Y chromosome. To define the significance of trisomy 15, we conducted a retrospective study of all examples of trisomy 15 accessed in our laboratories. Trisomy 15 was observed as a clonal abnormality (> or =2 cells) in 17 cases and nonclonal (single cell) in 9 cases. The majority of cases (14/17 clonal cases) had a minor clone (5-35% of metaphase cells) of trisomy 15. The minority of cases (3/17) had a major clone (80-95% of metaphase cells) of trisomy 15. Two of these 3 cases were diagnosed as having acute myelocytic leukemia. Fluorescence in-situ hybridization (FISH) with the use of a chromosome 15-specific alpha-satellite probe was performed on 3 of 17 clonal cases and on 3 of 9 nonclonal cases. FISH results revealed the presence of a minor clone (from 3 to 5 of 700 interphase cells) in 5 of them, 2 of which had trisomy 15 in 20% of metaphase cells. These results may indicate that the 20% of trisomy 15 are very likely an overrepresentation of a very minor clone that could be transitory. In summary, the analysis of our cytogenetic and FISH results revealed the presence of two types of trisomy 15 clones: a minor clone that could be transitory or indolent and a major clone that could be of a neoplastic nature.

Cytogenetic translocations involving chromosome band 19p13, the site of the E2A gene, have previously been reported in pediatric acute lymphoblastic leukemias (ALL) in association with a precursor-B cell immunophenotype and poor prognosis. We studied the frequency, pathologic findings, and clinical course of adults with leukemia with 19p13 translocations. Six patients with t(1;19) (q23;p13) and one patient with t(17;19)(q21;p13), all with ALL, were identified over an 8-year period from among 183 adult ALL patients (2.7%); t(1;19) was observed in 2.2% and t(17;19) in 0.5% of these patients. The seven patients (four females and three males) ranged from 18 to 59 years of age (median 33). All cases had a precursor-B cell immunophenotype, and a distinctive expression of surface markers (CD10, CD19, TdT, and HLA-Dr positive, usually negative for CD20, CD34, and negative for myeloid-associated antigens CD13, CD14, and CD33). The blast cells in one case expressed CD15. All patients were treated with combination chemotherapy and three patients received allogeneic bone marrow transplantation. All patients had early (range 6-20 months) relapses, and died due to progressive disease 7-29 months after diagnosis. Similar to pediatric patients, adults with 19p13 leukemias usually do not respond to intensive therapy and have short survival. The poor prognosis of this group of adult ALL patients highlights the importance of detecting 19p13 translocations by cytogenetic analysis or molecular studies.

The der(1;7)(q10;p10) aberration is observed in about 1-3% of the myelodysplastic syndromes (MDS) and less commonly in acute myeloid leukemia (AML) and the myeloproliferative disorders. This unbalanced translocation is considered a "variant" of the del(7q)/-7 subgroup and has been assigned a poor risk karyotype score in the MDS International Prognostic Scoring System (IPSS). Recent reports suggest der(1;7) MDS should be considered a discrete MDS subgroup with an intermediate, not poor, karyotype score. At the City of Hope, we compared the clinical-pathologic features of 12 der(1;7) MDS patients to 51 MDS patients with del(7q) (n=10) or -7 (n=41), selected for a similar frequency of secondary aberrations. The der(1;7) patients showed older age at diagnosis, lower platelet counts, less trilineage dysplasia, and lower blast counts. The der(1;7) patients did not differ from del(7q)/-7 patients in subtypes of MDS by World Health Organization, French-American-British classifications, or bone marrow cellularity. Neither the proportion of therapy-related MDS nor the transformation to AML differed significantly among the three subgroups. Five-year survival rates for der(1;7), del(7q), and -7 (44.4, 32.0, and 23.6%, respectively) did not differ significantly (P=0.94). While der(1;7) MDS is associated with some clinically distinctive features, reassignment of risk category based on these data would be premature.

Standard fluorescence in situ hybridization (FISH) easily detects nonrandom karyotypic abnormalities in multiple myeloma (MM) at disease presentation, when tumor burden is high. In contrast, the detection of residual MM using the standard 200 unselected nonmitotic nuclei FISH approach correlates poorly with residual disease detected by morphology, flow cytometry, immunohistochemistry, or reverse-transcription polymerase chain reaction (RT-PCR). We have used sequential May-Grunwald Giemsa stain to identify plasma cell populations, followed by FISH analyses (target FISH or T-FISH) to detect immunoglobulin heavy-chain gene ( IGH ) rearrangements, 13q or 17p deletions, or hyperdiploidy. In this study, 115 samples were collected from 100 patients with MM regardless of treatment status. In this proof-of-principle prospective study, T-FISH detected MM in 52 samples (45%), a percentage similar to that obtained by pathology. Disease detection increased from 5.6% with standard FISH to 48% with T-FISH, and cell culture experiments showed that T-FISH consistently detected a clonal abnormality at dilutions of 10 −3 . In five patients, T-FISH further identified myelodysplastic-associated karyotypic changes restricted to myeloid cells. Our observations suggest that T-FISH identifies cell lineage involvement of cytogenetic abnormalities, improves detection of low-level or residual MM, and may define the coexistence of hematologic karyotypic changes in individual patients.

We identified seven patients with hematologic disorders and trisomy 6 as the sole karyotypic aberration in bone marrow aspirates or unstimulated peripheral blood. Five patients were male and two were female; all were adults with ages ranging from 22 to 74 years. Three of the seven patients presented with manifestations of peripheral cytopenia. Their bone marrows were hypocellular with slight or no dysplastic changes and without an increase in blasts. One of these patients subsequently developed acute myeloid leukemia (AML-M1). The four remaining patients were initially diagnosed with AML--three consistent with French-American-British classification of M1 and M4 in the fourth patient. These results suggest that trisomy 6 is a nonrandom primary numerical anomaly of myeloid disorders. The association of cytopenia and hypoplastic bone marrow with trisomy 6 may constitute a new, distinctive variant among myelodysplastic syndromes.

A case of acute monocytic leukemia (FAB-M5b) expressing natural killer cell-associated antigens containing a t(8;14)(p11;q11.1) is presented. We interpret this translocation to represent a variant of the t(8;16) previously reported in FAB-M5b. These findings support the contention that the 8p11 breakpoint site is the critical junction in the oncogenesis of acute monoblastic leukemia with differentiation.