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Biomedical subjects

S Einhorn

Publications and source records attributed to S Einhorn.

At least 19 recordsLinked to original sources
PubMed1995

Response to interferon therapy in patients with multiple myeloma correlates with expression of the Bcl-2 oncoprotein.

The expression of the Bcl-2 oncoprotein was studied in pre-treatment bone-marrow samples from 63 patients with multiple myeloma, using an immunohistochemistry technique. A variable expression of the Bcl-2 protein was found in myeloma cells. 43% of the patients had strong expression of the Bcl-2 protein in the malignant cells. Forty patients received alpha-interferon, whereas 23 patients received melphalan/prednisone therapy. A significant association (p = 0.012) was found between high levels of Bcl-2 expression in myeloma cells and resistance to interferon therapy. No such correlation was found in the melphalan/prednisone treated patients. The data indicate that over-expression of Bcl-2 may be a cause for resistance to interferon therapy in myeloma and that staining for Bcl-2 expression in myeloma cells may have a predictive value for this treatment.

Antineoplastic Agents, Alkylating↗
PubMed1995

Non-Hodgkin's lymphoma and skin malignancies--shared etiology?

The Stockholm-Gotland Cancer Register was used to evaluate the clinical observation that patients with non-Hodgkin's lymphoma (NHL) had an increased risk of malignant melanoma or squamous-cell carcinoma of the skin (SCCS) and vice versa. During 1958-1992, NHL was diagnosed in a total of 6,176 patients. Of these patients, 504 developed a second primary cancer of any type except NHL, compared to 301.9 expected, giving a standardized incidence ratio (SIR) of 1.7 [95% confidence interval (CI) 1.5-1.8]. The risk of SCCS and malignant melanoma in patients with NHL was 4.8 (95% CI 3.6-6.2; n = 54) and 1.7 (95% CI 0.8-3.1; n = 10), respectively. The hazard risk for a second malignancy was relatively constant over time, whereas the skin malignancies revealed the highest risks 3-10 years after initial diagnosis. Similarly, the risk of a secondary NHL was studied in patients with malignant melanoma and SCCS during the same period and found to be 1.3 (95% CI 0.8-2.1; n = 17) and 1.8 (95% CI 1.2-2.5; n = 34), respectively. The highest risk for NHL following malignant melanoma was seen 3-10 years after first diagnosis, while the highest risk following SCCS was observed 0-2 years after initial diagnosis. One of several possible explanations or the development of NHL and a skin malignancy in the same patient is an immunological defect caused by sun exposure.

Aged↗
PubMed1995

13q deletions in lymphoid malignancies.

Previous studies have indicated that a candidate tumor suppressor gene resides telomeric of the RB1 gene at 13q14, a region that is commonly deleted in B-cell chronic lymphocytic leukemia (B-CLL). In this study, we have evaluated the frequency and minimal region of overlap for 13q deletions in malignant cells from various lymphoid neoplasms. We observed losses at 13q14 in 33/75 (44%) B-CLL cases, four of 16 (25%) non-Hodgkin's lymphoma (NHL) cases, eight of 29 (28%) patients with acute lymphocytic leukemia (ALL), and one of 15 T-cell lines. In some ALL cases, inactivation of the RB1 gene is suggested as the important event in the 13q deletions. The most commonly deleted marker in CLL and NHL was D13S319, between RBkpt and the D13S25 loci. Homozygous deletions of this marker were observed in 10 of 75 B-CLL cases, in six of which the homozygous deletions included only the D13S319 locus. Our data suggest that 13q deletions are common in lymphoid neoplasms, and that deletion of a candidate tumor suppressor gene(s) in the vicinity of the D13S319 marker is a tumorigenic event in these diseases.

Base Sequence↗
PubMed1995

p15ink4B and p16ink4 gene inactivation in acute lymphocytic leukemia.

Malignant cells from 52 children with acute lymphocytic leukemia (ALL) were investigated for inactivation of the p15ink4B and p16ink4 genes and other genetic alterations on chromosome 9p21. Homozygous deletions of the p15ink4B and/or the p16ink4 genes were detected in 16 cases and a further 9 cases showed evidence of allelic loss either by hemizygous deletion or loss of heterozygosity (LOH) for 9p21 markers. Most cases had loss of both genes, but 5 patients had lost only p16ink4 and 2 cases had homozygous loss of p15ink4B only. Sequence analysis of all exons of p15ink4B and p16ink4 was performed in patients with hemizygous deletions or LOH for 9p21 markers. A frame shift mutation of p16ink4 exon 1 was shown in 1 case, whereas all other clones carried the wild-type sequence of p15ink4B and p16ink4 in the remaining allele. The data suggest that both the p15ink4B and p16ink4 genes can be inactivated in ALL. The existence of a hitherto undefined tumor-suppressor gene on chromosome 9p cannot be ruled out.

Base Sequence↗
PubMed1995

Sequence variability of a prolonged tetranucleotide repeat.

A tetranucleotide repeat located in intron 20 of the RB gene consists of 16-26 CTTT(+/- T) repeats in 99% of the alleles. In the remaining 1% of alleles the segment is extended to a length of > 60 repeats. Sequence analysis revealed that the prolonged alleles either consisted of perfect CTTT(+/- T) repeats or irregular repeat sequences with variable combinations of C and T. The data provide clues to the mechanisms causing unstable expansions of repeats.

Alleles↗
PubMed1995

Increased risk of second primary malignancies in patients with gynecological cancer. A Swedish record-linkage study.

The Stockholm-Gotland Cancer Register was used to study the risk of developing second primary malignancies (SPM) in women diagnosed with cancer of the uterine cervix, uterine corpus and ovaries during the period 1958-1992. Among 5,325 patients with uterine cervix cancer, 619 developed SPM. Standardized incidence ratio (SIR) was 1.29 (95% confidence interval (CI) 1.19-1.39). Significantly increased risks were observed for cancer of the colon, rectum, lung, vulva, kidney and bladder. A total of 4,815 women with uterine corpus cancer were followed and 660 SPM were found. The overall SIR was 1.21 (95% CI 1.12-1.30) with significantly increased risk for cancer of the colon, ovary, vulva and bladder. The incidence of leukemia was also significantly elevated (SIR = 3.03; 95% CI 1.70-5.00). Among 5,060 patients with ovarian cancer, 379 SPM were found (SIR 1.49; 95% CI 1.34-1.64). Increased risks of cancer of the colon, rectum, breast, uterine corpus, bladder and leukemia were observed. All three primary sites showed elevated risks of cancer of the colon and bladder. For patients with a primary cancer of the corpus and ovary an elevated risk of leukemia was also noted. The conclusion from these findings is that SPM to some extent can be explained by previously known factors, i.e. treatment and common risk factors. However, further studies concerning the role of common etiology, for instance hereditary and hormonal factors, are needed to increase the knowledge on the etiology of second primary malignancies.

Adolescent↗
PubMed1994

Multiple genetic events involving RB1 gene deletion and amplification of chromosome 21 in a case of acute lymphocytic leukemia.

A patient with acute lymphocytic leukemia was found to have a hyperdiploid karyotype, characterized by hexasomy 21 and del(7)(p15). It was shown that the four extra copies of chromosome 21 were all derived from only one of the homologous chromosomes. Molecular analysis showed that the patient had a deletion of both alleles of the retinoblastoma (RBI) gene. These results suggest that multiple events, including loss of RBI gene function and amplification of a key gene(s) on chromosome 21, have contributed to the leukemic transformation.

Alleles↗
PubMed1994

Gamma-IFN induced cell adhesion in chronic myelogenous leukemia cells.

Both gamma- and alpha-interferons (IFNs) have been shown to induce clinical responses in chronic myelogenous leukemia (CML). The mechanisms behind these effects are not known. In chronic phase CML, granulocytic progenitors normally found in the bone marrow only, are found extramedullary. A defect in the adhesion of CML cells, that may be responsible for this finding, has been described earlier. In this study, we have investigated whether IFN can restore the defect in CML cell adhesion. It was found that gamma-, but not alpha-IFN, strongly induced the adhesion of CML cells to other cells and to plastic in a majority of the patients. In parallel, an induction in the expression of the adhesion molecules ICAM-1 and LFA-1 was found, and blocking of these molecules by antibodies abolished the effect. The ability of gamma-IFN to restore the adhesive property of CML cells may add to the antitumor effects observed with gamma-IFN therapy in CML.

2',5'-Oligoadenylate Synthetase↗
PubMed1993

Interferon treatment of human malignancies--a short review.

Interferon (IFN) therapy can induce remissions in human malignancies and has been established as a treatment of choice in several diseases. The clinical effects of IFNs are especially obvious in the treatment of hematological malignancies and virus-associated tumor diseases. Most other types of malignant solid tumors are less likely to respond to IFN as monotherapy and optimal therapeutic schedules are yet to be developed. It is of special interest that combinations of IFNs with other treatment modalities have yielded an increased response rate in several diseases. Several studies on the use of IFN as adjuvant therapy are under way. It is possible, if not likely, that the antitumor effects of IFNs are mediated by different cellular effects in cooperation. These may differ between different malignancies. Mainly based on studies comparing in vitro sensitivity of malignant cells to clinical effects on the same tumor, we suggest that the direct effects of IFNs on the malignant cell are of major importance for the antitumor action of IFN. A deepened insight into the cellular aspects of the antitumor action of these cytokines is a prerequisite for the optimal use of IFNs in the treatment of tumors in man.

Humans↗
PubMed1993

Cytotoxic effect of interferon on primary malignant tumour cells. Studies in various malignancies.

It is a well established fact that interferon (IFN) can inhibit cell growth, but only recently has it been found that IFN can exert a direct cytotoxic effect on primary tumour cells. This was shown in malignant cells from patients with multiple myeloma. In this study the influence of IFN on the viability of primary malignant cells from patients with different malignancies was studied. As previously described a direct cytotoxic effect of IFN on multiple myeloma cells was observed. No major effects on cell viability could be found in malignant cells from patients with lymphoma, chronic lymphocytic leukaemia, hairy cell leukaemia, chronic myelogenous leukaemia and carcinoma. This indicates that the direct cytotoxic effect of IFN in multiple myeloma may be relatively specific for this malignancy. It could be due to a specific differentiation stage in the myeloma cells, specific genetic alterations and/or abrogation of an autocrine/paracrine loop.

Cell Count↗
PubMed1993

Chromosome 9 short arm deletions in malignant diseases.

Deletions of 9p21-22, that frequently include the alpha-, beta- and omega-IFN gene cluster, are common in malignant diseases such as acute lymphocytic leukemia, malignant melanoma and malignant glioma. There is also evidence to support the role of a gene(s) on chromosome 9p21 in predisposition for familial malignant melanoma. Although initial studies implicated that the IFN genes could serve as tumor suppressor genes, there is now data, mainly based on estimations of minimum region of overlap for the deletions, indicating that the relevant tumor suppressor gene is located centromeric of the alpha-, beta-, omega-IFN gene cluster.

Chromosome Deletion↗
PubMed1992

Interferon system in primary acute lymphocytic leukemia cells with or without deletions of the alpha-/beta-interferon genes.

Various aspects of the interferon (IFN) system were studied in malignant cells from 37 unselected patients with acute lymphocytic leukemia (ALL). It was found that leukemic cells from two of 37 patients had a complete loss of alpha- and beta-IFN genes, whereas cells from four of 37 had lost one of the alpha-/beta-IFN alleles. In 25 cases, viable cells were also available for functional studies. Cell clones with loss of one of the alpha-/beta-IFN alleles produced low amounts of IFN after virus induction in vitro. Some clones with an apparently normal set of IFN genes were unable to produce detectable amounts of IFN. All clones studied were found to carry high-affinity alpha-IFN receptors. In clones carrying deletions of IFN genes, the cells were sensitive to IFN in vitro as measured by alpha-IFN-induced enhancement of 2',5'-oligoadenylate synthetase (2',5'-A synthetase). Cells from four patients with an apparently normal set of IFN genes were insensitive to this effect of IFN. We conclude that of the 17 patients in which IFN genes, IFN production, alpha-IFN receptors, and IFN-induced enhancement of 2',5'-A synthetase were studied, nine (53%) showed some abnormality in their IFN system. This finding may add some support to the hypothesis that defects in the IFN system could be a step on the path to malignant transformation in ALL. Moreover, patients whose malignant cells carry IFN gene deletions or other defects in their IFN-producing capacity, but are still sensitive to exogenous IFN, could represent a subgroup of ALL with a greater likelihood of responding to IFN therapy.

2',5'-Oligoadenylate Synthetase↗
PubMed1992

Retinoblastoma gene deletions in B-cell chronic lymphocytic leukemia.

Approximately 10% of B-cell chronic lymphocyte leukemia (B-CLL) cases have structural chromosomal aberrations involving band 13q14. To evaluate a possible role of RBl gene deletions in B-CLL we investigated the malignant cells of 27 patients by molecular genetic and cytogenetic techniques. Four of the cases had chromosomal aberrations that involved 13q14 (including one case with a 13q14 deletion that was observed in a single metaphase cell), and 11 had other chromosomal abnormalities, whereas the malignant cells of 12 patients were either cytogenetically normal or failed to divided in vitro. Eight patients (30%) were found to have hemizygous deletions of the RBl gene. These cases included all four patients with chromosomal changes at 13q14, but also three patients without chromosome abnormalities and one case with a chromosomal aberration not involving 13q. The deletions were interstitial in all cases but one, as defined by probes located centromeric and telomeric of the RBl locus. Inactivation of RBl may thus be a significant event in the development of some B-CLL clones.

Autoradiography↗
PubMed1992

Measurement of interferon sensitivity in tumour cells from fine-needle aspirations.

Previous studies have shown significant correlations between interferon (IFN) induced enhancement of the enzyme 2',5'-oligoadenylate (2',5'-A) synthetase in vitro and response to IFN therapy. A limitation of this and other predictive tests is the availability of malignant cells for culture. Malignant cells can be obtained from most palpable solid tumours by fine-needle aspiration. We investigated whether malignant cells from such aspirations can be used in a 2',5'-A synthetase assay. In 23/27 (85%) of the cases sufficient amounts of viable cells were obtained, containing a high proportion (greater than or equal to 90%) of tumour cells. In 13/23 tumour samples (57%) IFN-alpha significantly enhanced the 2',5'-A synthetase levels. The use of cells from the fine-needle aspirations for prediction of IFN sensitivity, makes the 2',5'-A synthetase test applicable in a wide range of tumours at a variety of disease stages.

2',5'-Oligoadenylate Synthetase↗
PubMed1992

Treatment with alpha-interferon versus alpha-interferon in combination with streptozocin and doxorubicin in patients with malignant carcinoid tumors: a randomized trial.

An open randomized trial was performed to compare the effect of recombinant interferon-alpha 2a (rIFN-alpha 2a) (group A, n = 12) versus rIFN-alpha 2a in combination with chemotherapy (group B, n = 11) in patients with malignant carcinoid tumors. Both groups received rIFN-alpha 2a at a dose of 3 MU/m2 s.c. three times weekly during the first 6 months. IFN was discontinued every third week in group B, followed by an i.v. injection of 2 g streptozocin and 40 mg/m2 doxorubicin. After 6 months group A showed one complete biochemical response (CR), 9 patients with stable disease (SD) and 2 who progressed (PD). Two patients had a partial reduction (PR) of tumor size, 9 showed SD and one PD. All patients in group B demonstrated SD. Chemotherapy was withdrawn after 6 months and all patients continued with rIFN-alpha 2a at an increased dose of 3 MU/m2 five days/week for a further 6 months. After 12 months 6 patients showed PR, 12 SD and one PD biochemically. Tumor size showed SD in 18 patients and PD in one. One patient died from cardiomyopathy, probably induced by doxorubicin. Antibodies against rIFN-alpha 2a developed in 41% of the patients. In conclusion, we detected no difference in response rates between the two treatment groups. Adverse reactions from the combination were considerable. The frequent development of IFN antibodies might have interfered with the therapeutic results.

Aged↗
PubMed1991

Influence of interferon on antibody production and viability of malignant cells from patients with multiple myeloma.

The influence of interferon (IFN) on antibody production and viability of malignant cells from patients with multiple myeloma was evaluated. Following incubation of bone marrow cells with IFN-alpha (5000 units/ml) for 7 days) a decreased production of monoclonal immunoglobin (mlg) was detected in all experiments except one. IFN induced a greater than 50% decrease in myeloma cell viability in 11 patients and a greater than or equal to 25% decrease in 4 patients, whereas in myeloma cells from 8 patients IFN had no or only minor effects. The observed effect was not due to an inhibition of proliferation since less than 5% of the myeloma cells were labeled with [3H]-thymidine during 7 d of culture. There was no statistically significant correlation between decreases in myeloma cell viability and effects on mlg production, exemplified by the fact that mlg production was decreased also in patients showing no sensitivity to IFN's cytotoxic action. Depletion of autologous T-cells, NK-cells and/or monocytes did not abrogate the effects observed. We conclude that IFN can reduce the viability of myeloma cells and the production of Ig from these cells and that the latter can be exerted without an antitumor effect.

Antibody Formation↗
PubMed1990

Deletion of alpha-, beta-, and omega-interferon genes in malignant cells from children with acute lymphocytic leukemia.

Scanning densitometry and restriction fragment length polymorphism analysis were used to study the alpha-, beta-, gamma-, and omega-interferon (IFN) genes in malignant cells from 11 children with acute lymphocytic leukemia and in one cell line of T-cell origin. In the malignant cells of one patient there was a complete loss of alpha-, beta-, and omega-IFN genes, whereas in another patient one of the alleles of these genes had been deleted. Cytogenetic analysis revealed a deletion of the short arm of chromosome 9, i.e., the region containing the alpha-, beta-, and omega-IFN genes, in the latter patient. The normal cells of the patients with IFN gene deletions had two alleles of the alpha-, beta-, and omega-IFN genes. In cells from none of the patients could deletions or rearrangements of the gamma-IFN genes be detected. We conclude that in 2 of 11 patients with acute lymphocytic leukemia the malignant transformation is accompanied by loss of material on one or both chromosomes 9 and that the alpha-, beta-, and omega-IFN genes are included in these deletions.

Adolescent↗