Bcl-3/IgH translocation (14;19)(q32;q13) in non-Hodgkin's lymphomas.

The recurrent cytogenetic (CG) abnormality t(14;19)(q32;q13) involving the oncogene BCL3 is described in patients with atypical chronic lymphocytic leukemia (CLL). We report four patients with non-Hodgkin's lymphoma (NHL) bearing t(14;19). All cases were female and their age ranged from 62 to 91. Histologically, there were two cases of small lymphocytic lymphoma (SLL), both CD11c positive with atypical morphology, one case of Burkitt like lymphoma (BLL), and one case of diffuse large cell lymphoma (DLC-L). One SLL patient showed t(14;19) as the sole abnormality and experienced a benign course for 8 years. The other three cases showed secondary CG progression, including tetraploidy, del(6q), t(8;22) and del(13q). These cases were aggressive in clinical behavior, including an SLL case which transformed to DLC lymphoma in 4 months. Southern analysis and long distance PCR confirmed BCL3/IgH Calpha translocation in one case. We propose that NHLs with t(14;19) may have evolved from the same spectrum of disease as atypical CLL. The poor prognosis of t(14;19) disease is associated with the occurrence of recurrent secondary CG changes, commonly found in B cell lymphoproliferative diseases.

Rational approaches to design of therapeutics targeting molecular markers.

This paper introduces novel therapeutic strategies focusing on a molecular marker relevant to a particular hematologic malignancy. Four different approaches targeting specific molecules in unique pathways will be presented. The common theme will be rational target selection in a strategy that has reached the early phase of human clinical trial in one malignancy, but with a much broader potential applicability to the technology. In Section I Dr. Richard Klasa presents preclinical data on the use of antisense oligonucleotides directed at the bcl-2 gene message to specifically downregulate Bcl-2 protein expression in non-Hodgkin's lymphomas and render the cells more susceptible to the induction of apoptosis. In Section II Dr. Alan List reviews the targeting of vascular endothelial growth factor (VEGF) and its receptor in anti-angiogenesis strategies for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). In Section III Dr. Bruce Cheson describes recent progress in inhibiting cell cycle progression by selectively disrupting cyclin D1 with structurally unique compounds such as flavopiridol in mantle cell lymphoma as well as describing a new class of agents that affect proteasome degradation pathways.

Eradication of human non-Hodgkin's lymphoma in SCID mice by BCL-2 antisense oligonucleotides combined with low-dose cyclophosphamide.

Cancers overexpressing Bcl-2 protein, which prevents programmed cell death (apoptosis), are less sensitive to stresses that produce cellular damage, including chemotherapy. If the level of Bcl-2 protein can be reduced sufficiently using antisense oligonucleotides (ASOs) targeting the gene message, then cytotoxic agents may be rendered more effective in eliminating disease and increasing cure rate. Preclinical studies in SCID mice bearing Bcl-2 overexpressing systemic human B-cell lymphoma (DoHH2) were undertaken to support development of a clinical trial. These data confirm that a combination of an ASO (5 mg/kg) targeting bcl-2 and a low dose of cyclophosphamide (35 mg/kg) was an effective strategy, leading to the eradication of the DoHH2 cells in vivo and cure of the animals. When mice deficient in natural killer cell activity were treated with an ASO, similar results were observed, suggesting that ASO stimulation of the host immune system was not a significant factor in elimination of lymphoma cells. These studies indicate that therapeutic strategies involving the use of an ASO targeting bcl-2 in combination with a cytotoxic agent may improve clinical outcomes.

Incidence of second neoplasms in patients with MALT lymphoma: no increase in risk above the background population.

BACKGROUND: Lymphomas of mucosa associated lymphoid tissue (MALT) are a special type of extranodal lymphoma, possibly related to chronic antigenic stimulation. Increased cancer susceptibility may also contribute to the development of MALT lymphoma (MALToma). It has been suggested that patients with MALToma have an increased incidence of other malignancies. PATIENTS AND METHODS: We retrospectively reviewed the histology and clinical records of 147 patients with MALToma, including 51 cases of gastric MALToma. The incidence of any second malignancy was confirmed with a provincial registry. The relative rates of cancer, excluding MALToma, were calculated relative to the background population of the same age group and secular year. RESULTS: A total of 41 tumors occurred in 32 patients (21%), including 22 solid tumors. The incidence of solid tumors in the gastric MALToma group was 15%. Seven patients had two or more second malignancies. Cancer occurred before diagnosis of MALToma in 29 cases, concurrent with MALToma in three, and after MALToma in nine. Follow-up of the surviving patients is short (median 17.6 months). The relative rate from birth of a second malignancy was 0.86 in the whole group (90% confidence interval (CI): 0.62-1.16) and 0.95 (90% CI: 0.55-1.54) in the gastric MALToma group. The rates were roughly the same if skin cancers were excluded. CONCLUSIONS: The incidence of second cancers in this series is similar to previous reports. However, when compared to an age-matched population followed for the same period of time, MALToma patients do not appear to have a statistically significant increased rate of cancers.

Concurrent chromosomal alterations at 3q27, 8q24 and 18q21 in B-cell lymphomas.

Recurrent chromosomal translocations in malignant lymphomas most commonly involve 18q21(bcl-2), 8q24 (c-myc) and 3q27 (bcl-6), with an incidence of 27%, 11% and 6%, respectively. Individual cases concurrently harbouring two of these three rearrangements have been previously reported. This report describes four patients with cytogenetic alterations affecting all three loci, which was confirmed by molecular analysis in one case. Clinically, each patient had aggressive B-cell lymphoma with disseminated disease often involving the central nervous system, poor response to chemotherapy and short survival. Activation of c-myc in association with deregulation of bcl-2, bcl-6 or both confers high-grade disease with a poor prognosis.

Second malignancies in patients with hairy cell leukemia in british columbia: a 20-year experience.

The purpose of this study was to compare the relative risk of second malignancies in a cohort of patients with hairy cell leukemia (HCL) against the normal population. Potential effects of type of treatment and duration of follow-up and the site distribution of cancer were also examined. Between 1976 and 1996, 117 patients were diagnosed with HCL in British Columbia who were referred to the British Columbia Cancer Agency (BCCA) for treatment. All additional malignancies were traced using a provincial population-based cancer registry and follow-up records from the BCCA. There were 90 men and 27 women. Median age at diagnosis was 53 years. The median follow-up time was 68 months. Twenty-three patients underwent primary splenectomy, 65 received interferon alpha, 24 deoxycoformycin, and 67 cladribine (2-chlorodeoxyadenosine). Thirty-six patients had an additional malignancy (30.7%) with a total of 44 tumors. Six patients (5.1%) had two or more malignancies. Twenty-five patients had malignancies diagnosed after HCL (21.3%), three concurrent with HCL (2.6%), and 12 preceding HCL (10.2%). Second tumors (n = 28 tumors) occurred at a median of 40 months after HCL (range, 3 to 167). The relative rate (RR) of second malignancy among men and women was 2.91 (P < .001) and 1.65 (P = .23), respectively, compared with age and secular trend-matched controls. There were eight prostate cancers, nine nonmelanoma skin cancers, two lung cancers, and four gastrointestinal adenocarcinomas. The RR (90% confidence interval [CI]) in the various treatment groups were: splenectomy (RR = 0.21 to 3.81), purine analogues (RR = 0.60 to 5.69), interferon then purine analogues (RR = 1.60 to 4.31), interferon alone (RR = 1. 57 to 8.40). Cancer risk peaked at 2 years after HCL (RR = 4.13) and fell steadily afterwards, reaching a RR of 1.82 at 6 years. Twenty patients died, six due to HCL, 10 due to second malignancies, and four of unrelated causes. HCL patients appear to be inherently prone to malignancies. This appears to be more related to HCL tumor burden than to genetic predisposition or treatment effect. RR tends to fall with time after effective treatment. However, close monitoring for and vigorous prevention of cancer in HCL patients is advisable.

Mantle cell lymphoma: a clinicopathologic study of 80 cases.

Mantle cell lymphoma (MCL) is a relatively uncommon yet distinct type of malignant lymphoma whose clinical and pathological characterization has been limited by the small numbers of cases published to date. We studied 80 cases of MCL seen at a single institution over 7 years to determine both clinical and pathological prognostic factors. The patients in this study were predominantly male (70%) and older (mean age, 63 years) and presented with advanced-stage disease (88%). Extranodal involvement was common. Median overall survival (OS) was 43 months. Except for performance status, prognosis was not significantly influenced by clinical prognostic factors. Histologically, MCL architecture was classified as diffuse (78%), nodular (16%), or mantle zone (6%); the OS among these groups was identical. Increased mitotic activity (>20 mitotic figures per 10 high power fields), blastic transformation, and peripheral blood involvement at diagnosis also predicted for a worse outcome, but bone marrow involvement did not. The presence or absence of a translocation t(11; 14) by cytogenetic analysis or a bcl-1 rearrangement by Southern analysis did not significantly predict outcome. In summary, this study of 80 cases of MCL highlights its distinctive clinicopathologic features and shows that increased mitotic activity, blastic morphology, and peripheral blood involvement at diagnosis are prognostically important factors.

High-dose cyclophosphamide, carmustine (BCNU), and etoposide (VP16-213) with or without cisplatin (CBV +/- P) and autologous transplantation for patients with Hodgkin's disease who fail to enter a complete remission after combination chemotherapy.

Patients with Hodgkin's disease (HD) who fail to enter a complete remission after an initial course of combination chemotherapy are usually considered to have an induction failure (IF); this subset of patients has an extremely poor outcome with further conventional therapy. Since 1985, we have entered 30 IF patients into protocols using conditioning with high-dose cyclophosphamide, carmustine (BCNU), and etoposide (VP16-213) with or without cisplatin (CBV +/- P) followed by autologous stem cell transplantation (ASCT) with bone marrow (19 patients), peripheral blood stem cells (PBSCs; 8 patients), or both (3 patients). All except 2 patients had previously received chemotherapy regimens for HD that contained at least 7 drugs, and 9 had received prior radiotherapy (RT). After documentation of IF, the majority of patients received some cytoreductive therapy as specified by protocol (local RT in 9, two cycles of conventional chemotherapy in 2, both modalities in 2, or high-dose cyclophosphamide to enhance PBSC collection in 11) before CBV +/- P. Five treatment-related deaths occurred, all before day 150 posttransplant. Eleven patients have had progressive HD at a median of 6 months (range, 0.1 to 45 months) after ASCT. The actuarial progression-free survival (PFS) at a median follow-up of 3.6 years (range, 0.2 to 8.2 years) is 42% (95% confidence intervals, 21% to 61%). The statistical analysis identified only prior clinical bleomycin lung toxicity as an adverse risk factor for PFS, mainly because of the increased nonrelapse mortality seen in these patients. CBV +/- P and ASCT can produce durable remission in a substantial proportion of IF HD patients who otherwise have a poor survival, and we believed ASCT approaches represent the best therapy currently available for these patients. Additional measures are needed to reduce the primary problem of disease progression despite high-dose chemotherapy and stem cell transplantation.

Dose-intensity meta-analysis of chemotherapy regimens in small-cell carcinoma of the lung.

To determine if chemotherapy dose intensity (DI) influences treatment outcome, 60 published studies in limited- and extensive-stage small-cell carcinoma of the lung (SCCL) were retrospectively analyzed for relationship between intended DI and response (complete response [CR] or partial response [PR]) or median survival (MS). Agents used in the regimens included cyclophosphamide (C), doxorubicin (A), vincristine (V), etoposide (E), and cisplatin (P). Relative DI (RDI) of each study regimen was calculated against a reference regimen, and weighted regression analysis was used. Additionally, analysis of individual drug RDI within combinations was performed. For CAV, increasing RDI of the regimen showed no correlation with outcome. For the individual drugs, C RDI correlated positively, while A RDI correlated negatively with attainment of CR in limited disease, but both only after unduly influential observations were eliminated. In extensive-stage disease, A RDI correlated positively with CR+, PR but only in randomized trials, and this correlation lost statistical significance after unduly influential observations were eliminated. For CAE and CAVE, the RDI of the regimens correlated positively with MS in extensive-stage disease as did the C RDI. In limited disease, the C RDI correlated negatively with MS. For EP, no significant correlations were seen. We conclude that DI-outcome correlations are not consistent for these chemotherapy regimens in SCCL. Meta-analysis of retrospective data can generate hypotheses for testing in prospective clinical trials, but study sample and method of analysis can appreciably affect conclusions.

In vivo induction of lymphokine-activated killer cells by interleukin-2 splenic artery perfusion in advanced malignancy.

In an effort to stimulate in vivo LAK cell activity at relatively nontoxic doses, 20 patients with advanced metastatic malignancy (13 renal cell carcinoma, 6 melanoma, 1 lymphoma) were treated with recombinant human interleukin-2 (IL-2) by continuous 5-day splenic artery perfusion using the femoral approach. Two treatment cycles were administered 3 weeks apart; IL-2 doses ranged from 1.5-4 x 10(4) Cetus units/kg/day. Peripheral blood lymphocyte cytotoxicity in a 4-h 51Cr release assay was measured using as tumor cell targets K562 for natural killer (NK) activity, Daudi for LAK, and Daudi plus in vitro IL-2 for inducible LAK (I-LAK). For the 20 patients, an increase in mean peak percent cytotoxicity from pretreatment levels was seen for NK (36% to 53%), LAK (8% to 37%) and I-LAK (20% to 53%) activity, all significant at P = 0.001. On day 43, 16 days after completing the second cycle of treatment, NK activity remained elevated at 47% and I-LAK at 40% (P = 0.008 and 0.01, respectively). Lymphocyte phenotype analysis by flow cytometry demonstrated increases from pretreatment levels in Leu 11+ (13 to 23%), Leu 19+ (10 to 21%), Leu 11+ 19+ (7 to 17%), IL-2r+ (4 to 17%), and HLA-DR+ (12 to 25%) subsets, all significant at P less than or equal to 0.01. Dose effect was studied at 3 dose levels: 1.5, 3, and 4 x 10(4) Cetus units/kg/day. At the higher doses mean peak NK (57%) and I-LAK (57%) activity were greater than at the low dose (42 and 31%, respectively), both significant at P less than 0.05. A trend to positive dose effect was seen in LAK activity (P = 0.08). Splenic artery perfusion with IL-2 can result in significant in vivo peripheral LAK cell generation as well as enhancement of I-LAK and NK activity that persists at least 16 days after the cessation of treatment. Such sustained activity would not be expected with conventional high dose i.v. therapy.

Goodpasture's syndrome: recurrence after a five-year remission. Case report and review of the literature.

Herein is reported the case of a man who has had a recurrence of Goodpasture's syndrome following a five-year remission. The patient presented initially in 1977 at the age of 28 with Goodpasture's syndrome manifested by pulmonary hemorrhage without clinical evidence of renal disease, and positive antiglomerular basement membrane antibody. Following treatment with corticosteroids, remission occurred and the serum antiglomerular basement membrane antibody became negative. In 1983, he experienced a relapse with the reappearance of serum antiglomerular basement membrane antibody, the development of severe life-threatening intrapulmonary hemorrhage, and hematuria. This case illustrates that life-threatening relapse may occur in Goodpasture's syndrome despite a prolonged remission and the disappearance of detectable antiglomerular basement membrane antibody in the circulation.