Loss of a novel tumor suppressor gene locus at chromosome 8p is associated with leukemic mantle cell lymphoma.

Patients with mantle cell lymphoma (MCL) may present with either nodal or leukemic disease. The molecular determinants underlying this different biologic behavior are not known. This study compared the pattern of genetic abnormalities in patients with nodal and leukemic phases of MCL using comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH) for specific gene loci. Although both leukemic and nodal MCL showed similar genomic patterns of losses (involving 6q, 11q22-q23, 13q14, and 17p13) and gains (affecting 3q and 8q), genomic loss of chromosome 8p occurred more frequently in patients with leukemic disease (79% versus 11%, P <.001). Subsequent CGH analysis confirmed the genomic loss of 8p21-p23 in 6 of 8 MCL cell lines. Interestingly, MYC gene amplification was restricted to cases with 8p deletion. These data indicate the presence of a novel tumor suppressor gene locus on 8p, whose deletion may be associated with leukemic dissemination and poor prognosis in patients with MCL.

Identification of two subgroups of mantle cell leukemia with distinct clinical and biological features.

INTRODUCTION: Mantle cell leukemia (MCLeu) has been considered as a leukemic form of mantle cell lymphoma (MCL). However, the presence of certain features rarely observed in MCL, such as transformation to prolymphocytic leukemia (PLL) or indolent clinical course, suggests that MCLeu may represent a distinct disorder. METHODS: Seven cases of MCLeu with t(11;14)(q13;q32) and BCL1-IGH gene rearrangement were ascertained among 140 newly diagnosed chronic B-cell lymphoproliferative disorders with leukemic expression. Comparative genomic hybridization, FISH for specific gene loci, and immunological studies were preformed in them. RESULTS: In comparison with CLL, MCLeu cases had low immunological scores < or =2 with respect to B-CLL (P<0.0001). Expression of CD38 was absent in 43% of MCLeu and in 44% of B-CLL. Comparative genomic hybridization analysis identified genomic imbalances in 86% of MCLeu with a similar pattern than in MCL: gains of 3q, 8q involving MYC gene and 15q, and losses of 6q, 9p, 13q and 17p affecting P53 gene. Differently from MCL and CLL, genomic loss of 8p was frequently detected in MCLeu (83%). Although clinical presentation of MCLeu was indistinguishable from CLL, all patients but one had disease progression within three years. According to the immunologic and genomic profiles, two distinct subgroups of MCLeu were defined: one related to PLL, showing CD38-, deletion of P53, and MYC amplification and another which corresponds to a leukemic form of classical MCL, presenting with CD38+ and normal P53 and MYC status. CONCLUSION: MCLeu and MCL are closely related disorders, as they show similar genomic and molecular patterns. However, the deletion of the short arm of chromosome 8 may represent a specific marker for MCLeu. Two distinct subgroups of MCLeu may also be distinguished according to the immunologic and genomic cell profiles.

Chromosomal abnormalities in women with breast cancer after autologous stem cell transplantation are infrequent and may not predict development of therapy-related leukemia or myelodysplastic syndrome.

We determined prospectively the incidence of chromosomal abnormalities in patients with high-risk breast cancer (HRBC) after high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT), and correlated the cytogenetic abnormalities with the development of post-transplant myelodysplastic syndrome or acute myeloid leukemia (MDS/AML). From 1990 to 1999, 229 women with HRBC underwent ASCT. Cytogenetic analysis of bone marrow (BM) cells was performed 12-59 months after ASCT in 60 consecutive women uniformly treated with six courses of FAC/FEC followed by HDCT and ASCT. With a median follow-up of 36 months after ASCT, there were no cases of MDS/AML among the 229 patients. In the selected cohort of 60 patients, three (5%) showed clonal chromosomal abnormalities (two single trisomy X and one t(1;6)), whereas two additional patients showed non-clonal reciprocal translocations. Two of the patients with clonal aberrations had blood cytopenias as well as subtle dysplastic pictures in BM which were not classifiable as MDS according to the FAB criteria. Similar dysplastic features were also observed in four patients with normal karyotypes. All cytogenetic aberrations were transient and disappeared, except a +X detected by FISH in a residual cell population in one of the patients. Retrospective cytogenetic and FISH studies of samples obtained after six cycles of FAC/FEC and before transplant demonstrated no chromosomal abnormalities in any of the five patients with post-ASCT karyotypic changes. Early changes in karyotype detected in breast cancer patients following ASCT are transient and do not correlate with or predict development of MDS/AML. As these aberrations were not present before ASCT, they may be related to the HDCT regimen or transplant procedure rather than to the prior adjuvant therapy. Our results suggest that ASCT may be less likely to cause MDS or AML in breast cancer patients as compared to other malignancies. Bone Marrow Transplantation (2000) 25, 1203-1208.

Ciprofibrate effects on carbohydrate and lipid metabolism in type 2 diabetes mellitus subjects.

BACKGROUND AND AIMS: Atherosclerosis is the most common cause of morbidity and mortality in type 2 diabetes mellitus. Hyperglycemia, dyslipoproteinemia, arterial hypertension and coagulation abnormalities are the most important cardiovascular risk factors. Hypertriglyceridemia and low high density lipoprotein-cholesterol (HDLc) seem to be related with insulin resistance. Fibric acid derivates (fibrates) are effective in the treatment of dyslipoproteinemia in diabetes. Our aim was to evaluate the efficacy and safety of ciprofibrate in improving dyslipoproteinemia and its effect on fibrinogen plasma concentrations, carbohydrate metabolism variations and insulin action. METHODS AND RESULTS: 13 subjects with type 2 diabetes mellitus were treated with diet and placebo for 4 weeks and then randomized to one of two treatments: ciprofibrate 100 mg or placebo for four weeks. After a four-week wash-out period they were crossed over as shown in Figure 1. Total cholesterol, triglycerides, low density lipoprotein-cholesterol (LDLc), very low density lipoprotein-cholesterol (VLDLc), HDLc, Apolipoprotein B100, fibrinogen, insulin and Lp(a) were measured. Insulin erythrocytes union was made by the Gambhir method. There was a 15% decrease in total cholesterol (p < 0.05) and 47% decrease in triglycerides (p < 0.01); similar changes were observed in VLDL-cholesterol and VLDL-triglycerides; 17% increase in HDL-cholesterol (p < 0.05). No significant differences were observed in LDL-cholesterol, apolipoprotein B100 and lipoprotein (a). Fibrinogen decreased 10% (p < 0.05). A non-significant 10% decrease in insulin secretion (area under curve) after oral glucose was observed with ciprofibrate. These findings indicate a decrease in receptor affinity. A non-significant decrease in insulin receptor number/cells was also observed. CONCLUSIONS: Ciprofibrate has a potent hypolipidemic effect, especially a decrease in triglycerides, VLDL and fibrinogen, and an increase in HDL-cholesterol, but does not influence glycemic control nor insulin action. Decreased insulin secretion may be due to peripheral use of glucose due to the drug's antilipolytic action.

Variant three-way translocation of inversion 16 in AML-M4Eo confirmed by fluorescence in situ hybridization analysis.

The inv(16) and t(16;16) characterize a subgroup of acute myelomonocytic leukemia (AML) with distinct morphological features and a favorable prognosis. Both cytogenetic abnormalities result in a fusion of CBF beta at 16q22 and MYH11 gene at 16p13, whose detection by PCR and fluorescence in situ hybridization (FISH) is useful for diagnosis and monitoring of the disease. Variant translocations of inv(16)/t(16;16) are very rare and whether they are also associated with a favorable prognosis is unknown. We report a patient presenting with typical AML-M4Eo and a three-way translocation of inv(16) involving 16p13, 16q22, and 3q22. FISH studies on bone marrow (BM) chromosomes using CBFB and MYH11 DNA probes revealed a fusion of CBFB and MYH11 on 16q of the der(16), as well as a signal from MYH11 on 16p but not from CBFB; normal signals for both probes were present on the normal 16. Neither of these labeled probes was on the der(3), but the translocation between the der(3) and der(16) was confirmed by using a chromosome 16 painting probe. Molecular analysis of BM cells using RT-PCR identified a CBFB-MYH11 fusion transcript type D. After achieving complete remission, the patient relapsed. We conclude that FISH and PCR are feasible tools to distinguish cases with variant abnormalities of inv(16) from cases with other chromosome 16 abnormalities. Variant abnormalities of inv(16) may be not associated with favorable prognosis.

Value of CA 15.3 in breast cancer and comparison with CEA and TPA: a study of specificity in disease-free follow-up patients and sensitivity in patients at diagnosis of the first metastasis.

The specificity and sensitivity of a tumor marker (TM) are important in establishing its potential clinical utility for a specific type of neoplasm. CA 15.3 is a TM specific for breast cancer; it is defined by two monoclonal antibodies (DF3 and 115D8), whose specificity, in disease-free follow-up patients, and sensitivity, in patients at diagnosis of first metastasis, have been evaluated in the present study and compared with those of carcinoembryonic antigen (CEA) and tissue polypeptide antigen (TPA). Serum concentrations of all three TMs were quantified in 618 individuals: 80 healthy controls, 421 patients with local breast cancer who became free of disease following locoregional treatment, and 117 patients with disseminated disease at diagnosis of metastasis. Radioimmunoassay (RIA) was the method employed, and the cut-off values obtained were 30 U/ml for CA 15.3, 5 ng/ml for CEA, and 120 U/I for TPA. The results showed CA 15.3 and CEA specificities to be analogous (95.7 and 95.5%, respectively). TPA specificity (81.9%) was lower (p < 0.001). During adjuvant therapy, CA 15.3 serum levels were seen to increase, followed by a normalization of concentration after terminating therapy. On the other hand, CA 15.3 and TPA sensitivities (64.1 and 67.5%, respectively) were greater than for CEA (44.4%, p < 0.01). It is concluded that CA 15.3 is a useful TM for breast cancer, as it offers a greater sensitivity than CEA and a higher specificity than TPA. Combining CA 15.3 and CEA fails to increase CA 15.3 sensitivity, while combining CA 15.3 with TPA increases false-positives and so likewise offers no additional benefit.

CA 15.3, CEA and TPA tumor markers in the early diagnosis of breast cancer relapse.

To evaluate the utility of CA 15.3 in detecting breast cancer relapse before clinical evidence of metastatic disease, serial determinations of CA 15.3 serum levels were made in 444 disease-free patients after surgery, during 36 months of follow-up. The results were compared with carcinoembryonic antigen (CEA) and tissue polypeptide antigen (TPA). The study found CA 15.3 to be more sensitive as an early indicator of relapse than CEA or TPA; moreover, simultaneous determination of the other markers offers no information additional to that obtained by CA 15.3 alone.

Quantitative monoclonal antibody determination of estrogen and progesterone receptors in human breast cancer: correlation with the radioligand method.

To assess the possibility of substituting our routine method (dextran-coated charcoal, DCC) of determining estrogen (ER) and progesterone receptors (PR) for an enzyme immunoassay technique (EIA), we compared the two methods for determination of the two types of receptor in breast cancer specimens. In terms of sample positivity or negativity, the two techniques agreed in 76 of the 82 samples analyzed for ER (92.7%; p < 0.001), and in 65 out of 75 samples assayed for PR (86.6%; p < 0.001). Quantitative analysis of the data showed a significant correlation between DCC and EIA for both ER (r = 0.84; p < 0.0001) and PR (r = 0.77; p < 0.0001). The results suggest the usefulness of EIA in substituting DCC, although further clinical studies are required to fully evaluate this new method.

Intratumoral variation of estrogen and progesterone receptors in breast cancer: relationship with histopathological characteristics of the tumor.

Estrogen (ER) and progesterone (PR) receptors were assayed in the center and the periphery of 24 primary breast cancers and correlated with seven morphological features of the tumors. Quantitative variations in ER and PR contents between center and periphery were not significant, and the major discordance rate of the receptor status was only 8.3% for ER and 12.5% for PR. Among all morphological features studied, only tumor cellularity was correlated with steroid receptors; thus 18 out of 19 ER-positive samples (p less than 0.005) and 15 out of 16 PR-positive samples (p less than 0.025) were tumor cellularity 2-3, and higher ER (p less than 0.003) and PR (p less than 0.007) levels were found in tumor cellularity 2-3. Our results indicate that steroid receptors should be assayed in samples with a high content of tumor cellularity, whether the sample is taken from the center or the periphery of the tumor.