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Acquired chromosome abnormalities in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are among the most valuable determinants of diagnosis and prognosis. In search of new recurrent balanced translocations, we reviewed the Cancer and Leukemia Group B (CALGB) cytogenetics database containing pretreatment and relapse karyotypes of 4,701 adults with AML and 565 with MDS who were treated on CALGB trials. We identified all cases with balanced structural rearrangements occurring as a sole abnormality or in addition to one other abnormality, excluded abnormalities known to be recurrent, and then reviewed the literature to determine whether any of what we considered unique, previously unknown abnormalities had been reported. As a result, we identified seven new recurrent balanced translocations in AML or MDS: t(7;11)(q22;p15.5), t(10;11)(q23;p15), t(2;12)(p13;p13), t(12;17)(p13;q12), t(2;3)(p21;p21), t(5;21)(q31;q22), and t(8;14)(q24.1;q32.2), and additionally, t(10;12)(p11;q15), a new translocation in AML previously reported in a case of acute lymphoblastic leukemia. Herein, we report hematologic and clinical characteristics and treatment outcomes of patients with these newly recognized recurrent translocations. We also report 52 unique balanced translocations, together with the clinical data of patients harboring them, which to our knowledge have not been previously published. We hope that once the awareness of their existence is increased, some of these translocations may become recognized as novel recurring abnormalities. Identification of additional cases with both the new recurrent and the unique balanced translocations will enable determination of their prognostic significance and help to provide insights into the mechanisms of disease pathogenesis in patients with these rare abnormalities., (Copyright © 2012 Wiley Periodicals, Inc.)

To assess the prevalence of mutations in the CEBPA gene, which encodes the myeloid transcription factor CEBPA in specific cytogenetic subgroups, we initially studied 125 patients with acute myeloid leukemia (AML). Five of the eight patients with del(9q) as the sole aberration or in combination with a single additional abnormality other than t(8;21) had CEBPA mutations associated with loss of CEBPA function. Consequently, 41 additional del(9q) cases were analyzed; nine had CEBPA loss-of-function mutations. The overall prevalence of CEBPA loss-of-function mutations in cases with del(9q) in a noncomplex karyotype was 41% (14 of 34 patients), whereas none of the patients who had a del(9q) in a complex karyotype (n = 7) or together with a t(8;21) (n = 10) demonstrated mutant CEBPA. We have shown for the first time that AML with del(9q) in the context of a noncomplex karyotype is strongly associated with CEBPA loss-of-function mutations. Loss of a critical segment of 9q, most likely in 9q22, and disruption of CEBPA function possibly cooperate in the pathogenesis of del(9q) AML., ((c) 2005 Wiley-Liss, Inc.)

The KG-1 cell line, established from bone marrow cells of a patient with erythroleukemia evolving to acute myelogenous leukemia, and its less differentiated variant, KG-1a, are widely used in research worldwide. However, to our knowledge, neither cell line was studied by use of molecular-cytogenetic techniques such as spectral karyotyping (SKY) and fluorescence in situ hybridization (FISH). Our G-banding, SKY, and FISH analyses revealed a complex karyotype with a pseudodiploid modal chromosome number in both the KG-1 and KG-1a cell lines. The lines shared several identical structural aberrations, including der(4)t(4;8), del(7q), der(8)t(8;12), idic(8)(p11), der(17)t(5;17), and der(20)t(12;20), but also differed with regard to other chromosome rearrangements. In contrast to KG-1, the KG-1a line lost one of the two copies of idic(8)(p11) present in KG-1 cells and gained a der(8;22)(q24;q13), an i(11)(q10), and a der(19)t(14;19)(q13;q13.4). Notably, we have shown that the KG-1 cells harbor a partial hexasomy of the long arm of chromosome 8, which may explain in part the previously reported significantly higher rate of formation of the AML1-ETO fusion gene in KG-1 cells subjected to high-dose gamma irradiation compared with the rates of formation of the BCR-ABL or the DEK-CAN fusion gene. Our detailed description of chromosome rearrangements in KG-1 and KG-1a will be useful for the cytogenetic authentication of the lines, and provide clues as to the regions of the genome that could be studied further to explain the differences in phenotypic properties between KG-1 and KG-1a cells., (Copyright 2003 Wiley-Liss, Inc.)

We used spectral karyotyping (SKY) to study 29 adults with acute myeloid leukemia and a complex karyotype containing one to nine abnormalities that were not fully identifiable by G-banding. SKY showed the origin of rings and unidentified material in unbalanced translocations in all cases and the origin of markers in most, allowing reinterpretation of 136 aberrations and discovery of three aberrations hidden in normal chromosomes. SKY confirmed 10 and refined the interpretation of three balanced aberrations recognized by G-banding and identified another nine balanced aberrations, including a novel translocation involving the RUNX1 gene. Eleven of 32 deletions found by G-banding were shown to be cryptic translocations or insertions, including three of four chromosome 3 deletions, two of three del(7q), and two of 12 del(5q). Of the 92 chromosomes deemed lost entirely by G-banding, 63 (68%) were shown to be involved in structural aberrations. This was especially true for -21 (eight of eight patients), -5 (five of six patients), -20 (seven of nine patients), and -18 (six of 12 patients). Unexpectedly, SKY uncovered a hidden overrepresentation of segments from at least one chromosome in 21 patients. The most frequently overrepresented was 21q, found in eight patients, including four with high-level 21q amplification. Fluorescence in situ hybridization showed that the RUNX1 gene was not the target of amplification in seven of these patients. Also frequently gained were 11q (in seven patients, including three with high-level MLL gene amplification) and 22q (in seven patients). We conclude that SKY considerably enhances the accuracy of karyotype interpretation, and that amplification of chromosomal material may play a greater role in leukemogenesis than has been recognized., (Copyright 2002 Wiley-Liss, Inc.)

The presence of an extra ring chromosome containing material from 17q and 22q, or, less frequently, a t(17;22)(q22;q13), is a cytogenetic hallmark of dermatofibrosarcoma protuberans (DFSP). However, occasionally tumors with other, atypical karyotypes are encountered. We describe a case of recurrent DFSP without a ring chromosome or a t(17;22) on standard cytogenetic analysis. In all cells analyzed by G-banding, an additional, large marker chromosome was present as a sole abnormality. This chromosome apparently included chromosome 8 or the 8q arm, but the origin of its remaining part could not be determined with certainty. To characterize further the abnormal chromosome, we applied spectral karyotyping (SKY). SKY confirmed the presence of an extra chromosome 8 or arm 8q in the marker and showed that its remaining part was composed of segments from chromosomes 7, 17, 21, and 22, with two copies of a 17;22 fusion. Our results and the literature data suggest that, in addition to a specific 17;22 fusion, amplification of material from chromosomes 17, 22, 8, 5, 7, and 21 may play a role in DFSP development and/or progression. Furthermore, our case demonstrates the usefulness of SKY in detection of a diagnostically relevant 17;22 fusion in DFSP patients who have unusual karyotypic features., (Copyright 2001 Wiley-Liss, Inc.)

Cytogenetic study of a short-term culture from a hibernoma, a very rare benign proliferation of the brown fat, demonstrated a four-break translocation t(5;7;11;17)(p14;q11.23;q13.1-13.3;p11.2) as the sole abnormality in all analyzed cells. Complex translocation involving band 11q13 have also been detected in the two other published cases of hibernoma. The consistent finding of 11q13 rearrangements appears to distinguish hibernoma from other benign adipose tissue tumors cytogenetically and suggests that 11q13 changes may play an important role in hibernoma pathogenesis.

Cytogenetic analysis of a short-term culture from a clear cell sarcoma revealed a complex karyotype with the mainline of 49,XY,t(7;18)(p11.2;q21.3), +der(7)t(7;18)(p11.2;q21.3), +8, +der (8;17)(q10;q10),t(12;22)(q13;q12.2-12.3),add(13)(p13). An apparently identical translocation t(12;22) has been described recently in four clear cell sarcomas, indicating that this constitutes a primary cytogenetic change specific for this type of tumor. In our case, the breakpoint on chromosome 22 could be assigned to band 22q12.2 or 22q12.3. Together with the present case, trisomy or tetrasomy 8 has been found in six of nine clear cell sarcomas, suggesting that, as in Ewing's sarcoma and myxoid liposarcoma, trisomy/tetrasomy 8 represents a nonrandom secondary aberration. We conclude that the finding of the specific translocation t(12;22) may prove to be an important marker in the differential diagnosis of clear cell sarcoma from some other soft tissue sarcomas and malignant melanoma.

Cytogenetic analysis was performed on lymph nodes or other tumor masses from 33 patients with Hodgkin's disease. Metaphase cells were obtained in 25 of the 33 cases. Analyzable abnormal clones were found in nine cases. Characteristic abnormalities included polyploidy and complex structural rearrangements nonrandomly involving certain chromosomal regions. Chromosomes most commonly gained were 2, 9, 11, 19, and 20, and those most often lost were 10, 13, 15, 16, 21, and Y. Translocation breakpoints clustered in bands 1p11-1p13, 1p36, 4q35, 14q11, and 15p11. In five patients, breakpoints were in bands to which T-cell receptor genes have been mapped. No specific, recurring translocation was identified. There was, however, recurring loss of chromosomal material from 1q, 4q, 6q, and 17p. Loss or deletions of chromosomes 4 and 6 were found in five and six patients, respectively. Deletions overlapped; the smallest overlapping segments included bands 4q25-4q27 and 6q21-6q23. The data suggest that loss of specific chromosomal regions may be important in the pathogenesis of Hodgkin's disease. With respect to tumor specificity, deletions of 4q are of particular interest because these have not been previously reported to occur nonrandomly in other human malignancies.

Nosocomial septicemias that occurred over a 32-month period on an inpatient medical oncology service were reviewed. One hundred four episodes of septicemia occurred in 84 patients, 33% with solid tumors and 67% with leukemia or lymphoma. Sixty were primary septicemias, with the remainder being secondary. Of the 118 isolates recovered, 42% were Gram-positive organisms, 45% Gram-negative organisms, and 13% were fungi. Coagulase-negative staphylococci and Escherichia coli were the most common Gram-positive and Gram-negative isolates, respectively. The effect of the type of malignancy, neutropenic status, and presence of a central venous access device (CVAD) on the isolate(s) recovered was studied. Coagulase-negative staphylococci were more commonly isolated from leukemia-lymphoma patients (26% vs. 3%, P less than .01), while Gram-negative isolates (63% vs. 36%, P = .01), specifically Klebsiella species (21% vs. 5%, P = .02), were more common in solid tumor patients. Staphylococcus aureus was isolated more frequently from non-neutropenic patients than from those with neutropenia (19% vs. 4%, P = .02). Gram-positive isolates were more commonly found in patients with a CVAD (51% vs. 29%, P = .03), in particular coagulase-negative staphylococci (29% vs. 2%, P less than .001). In contrast, Gram-negative isolates (62% vs. 34%, especially Klebsiella species (22% vs. 3%, P less than .01) and S. aureus (18% vs. 5%, P = .07) were more commonly isolated from patients with no CVAD. Neither neutropenia nor the presence of a CVAD predisposed to early mortality. Our data suggest that empiric antimicrobial coverage for presumed nosocomial septicemia in the febrile cancer patient should include vancomycin for patients with a CVAD to cover coagulase-negative staphylococci and a cephalosporin for patients with solid tumors, especially those without a CVAD, to cover Klebsiella species.

Prognostic factors for long-term survival of 312 patients with diffuse large cell or immunoblastic non-Hodgkin's lymphoma are presented based on analysis of the multiinstitution clinicopathologic study sponsored by the National Cancer Institute. At the time of analysis, 75% of the patients had died and the median follow-up for patients still alive was 11 years. The distribution of Ann Arbor stages was 21% stage I, 32% stage II, 17% stage III, and 30% stage IV. Factors of prognostic significance for survival included age, stage, histologic subtype, presence of B symptoms, size of the largest lesion, number of extra-lymphoid organs involved, and extent of lymphatic involvement. Recursive partitioning analysis suggested a prognostic classification system based on stage, age, size of the largest lesion, and presence of mediastinal involvement. Stage I patient less than 50 years of age had a 10 year survival rate of 65% compared to 36% for older stage I patients. Stage II patients less than 65 years old without bulky lesions or mediastinal involvement had a 10 year survival rate of 45% compared to 10% for the poorer risk stage II patients. Although statistically significant prognostic factors were identified for the stage III/IV patients, they were not strong discriminants of 5-10 year survival rate. Because of the correlation among potential prognostic factors, there is no uniquely best classification system. Reasons for discrepancies among reported prognostic factor analyses are discussed, and a prognostic grouping that synthesizes our results with those of others is proposed.

Neoplastic tumor masses from 47 adults with B cell malignant lymphomas were examined for glucocorticoid receptors and in vitro sensitivity to glucocorticoids. The patients were then treated with dexamethasone as a single agent for 5-14 days. Forty-seven percent of patients achieved at least a partial remission; 40% had no significant tumor response. Lymphoma cells from patients who responded had significantly more glucocorticoid receptor sites per cell and greater in vitro sensitivity as measured by glucocorticoid inhibition of incorporation of thymidine than did tumor cells from non-responders. Using a receptor level of 3000 sites/cell, response could accurately be predicted in 82% of patients. Our data suggest that study of tumor glucocorticoid receptors and glucocorticoid sensitivity in vitro may allow selection of those patients with lymphoma who should receive glucocorticoids as part of combination chemotherapy.

The treatment of refractory acute nonlymphocytic leukemia remains a major clinical problem in leukemia therapy. VP 16-213 is an investigational agent that may have specificity for monocytic blasts, and the combination of VP 16-213 and cyclophosphamide is synergistic in experimental leukemia. Seven patients with highly refractory acute nonlymphocytic leukemia, which demonstrated monocytic features, were treated with a combination of VP 16-213 and cyclophosphamide after they had failed to respond to multiple courses of intensive induction regimens. Three complete remissions and one partial remission were achieved. The times to complete remission were 21, 23, and 34 days. The durations of complete remission were 5, 9, and 12+ months. Myelosuppression was the most common side effect; one patient experienced nausea and stomatitis. There were no documented infections or hemorrhage, and no one died as a result of therapy. This combination is both well tolerated and effective in the treatment of refractory leukemia with monocytic features.

It is clear that a substantial percentage of both children and adults with ALL are currently being cured with appropriate treatment. Certain clinical characteristics and the morphology and biologic features of the lymphoblast at diagnosis can be used to identify those patients who are likely to be long-term disease-free survivors with current therapy and those who need new therapeutic approaches (Table VIII). It is hoped that continued studies, such as described in this review, will allow even better separation of good and poor responders. Such identification and separation will, it is hoped, allow the good responders to be cured with minimal toxicity and the poor responders to benefit from new therapies that may allow them too to be cured.

Clonal chromosome changes can now be detected in most cases of acute leukemia when appropriate methods of study are applied. In both acute nonlymphoblastic leukemia (ANLL) and acute lymphoblastic leukemia (ALL) identification of these chromosome abnormalities is increasingly becoming important clinically for diagnosis and prognosis, and as a result selection of therapy. This paper first briefly reviews the recurring chromosome changes now recognized in ANLL and ALL. The prognostic utility of classification of acute leukemia according to karyotype is then discussed.

Among 31 consecutive patients who developed acute nonlymphocytic leukemia following treatment with chemotherapy or radiation therapy, 17 were treated with intensive chemotherapy aimed at inducing a complete remission. Seven of these 17 patients (41%) obtained a complete remission that ranged in duration from 2 to 11 (median 3) months. Two additional patients who failed to develop normal peripheral blood counts despite postinduction bone marrows that were normocellular and free of leukemia were classified as nonresponders. The median time to complete remission and median duration of leukopenia (WBC less than 1,000/mu 1) were 34 days and 23 days, respectively. Induction chemotherapy was complicated by fever in all patients, documented infection in six patients, and death secondary to sepsis in three. Survival of the 17 patients ranged from less than 1 to 39 (median 4) months. Patients achieving a complete remission had a median survival time of 10 months compared to 2 months for the nonresponders. The other 14 patients received only supportive care and had a median survival of 2 months. These findings indicate that therapy-associated acute nonlymphocytic leukemia (t-ANLL) can frequently respond to chemotherapy and that achieving a complete remission is associated with longer survival. Although these results are encouraging, patients with t-ANLL still have a relatively poor prognosis and efforts directed at improving treatment outcome need to be continued.

Seventy-eight individuals previously treated with chemotherapy for non-Hodgkin's lymphoma were enrolled in a phase II pilot study employing methotrexate 100 mg/M2 iv (day 1), calcium leucovorin 10 mg/M2 iv and/or po q6h (days 2-4), VM-26 (teniposide) 100 mg/M2 iv (days 2 and 9), procarbazine 100 mg/M2 po (days 2-15), and dexamethasone 15 mg/M2po (days 2-8) (MV26PD). Thirty percent of the 78 patients treated had a response to therapy (8% complete, 22% partial). Twenty-four percent of patients with diffuse histiocytic (large cell) lymphoma had a response (12% complete, 12% partial). The estimated failure-free survival was 41% at 3 months and the median survival (death from any cause) was 4.5 months for the entire cohort. Two individuals, including one individual with diffuse histiocytic lymphoma, remain in a complete response for over 900 days. Significant hematologic toxicity and infectious complications were seen in this heavily pretreated group of patients. MV26PD represents an active combination of agents for the treatment of non-Hodgkin's lymphoma. The optimal dosing for MV26PD remains to be determined.

Six adults with refractory acute lymphocytic leukemia (ALL) were treated with high-dose methotrexate, citrovorum factor, and vincristine. All patients had previously received extensive treatment with standard therapeutic agents, including vincristine, and all but one had received prior methotrexate. Two patients achieved complete remission and one achieved partial remission. Responses were seen at 3--6 gm/m2 of methotrexate. The durations of remission were 7--10 weeks. High-dose methotrexate with citrovorum factor is effective in the treatment of advanced ALL and should be considered for inclusion in initial combination chemotherapeutic regimens for adult ALL.