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Biomedical subjects

R Alexanian

Publications and source records attributed to R Alexanian.

At least 109 records · Page 6Linked to original sources
PubMed1988

Correlated flow cytometric analysis of H-ras p21 and nuclear DNA in multiple myeloma.

Correlated analysis of the H-ras oncogenes product (p21) and of nuclear DNA content was performed by flow cytometry (FCM) in patients with DNA-aneuploid multiple myeloma (MM). Bone marrow cells from normal donors and MM patients in remission served as controls. Seventy-four percent of 23 patients with active MM had higher p21 fluorescence in aneuploid tumor cells than were observed in normal donor or myeloma remission bone marrows; 39% of the 23 patients also showed high H-ras p21 expression in diploid cells. There was an inverse relationship between p21 levels and the presence of trisomy 11; especially high p21 levels were noted in patient without trisomy 11. The frequent elevation of p21 protein in aneuploid plasma cells suggests the involvement of the H-ras oncogene in the pathophysiology of MM, which is further supported by a shorter survival among patients with high p21 levels.

Antibody Specificity↗
PubMed1988

Prognostic factors with high-dose melphalan for refractory multiple myeloma.

High doses of melphalan (HDM) and dexamethasone were administered to 43 patients with advanced multiple myeloma, 36 of whom were refractory to both standard melphalan-prednisone and vincristine-adriamycin-dexamethasone (VAD). Forty-four percent responded with greater than 75% reduction in calculated tumor mass, including three patients who achieved a complete remission. The response rate to HDM was 56% in 18 relapsing patients and 50% in 12 patients with less than 12 months of primary drug resistance, but it was only 23% among the remaining 13 unresponsive patients. A high early mortality rate of 30% was confined to 26 patients with either poor performance (Zubrod greater than 1) or impaired renal function (creatinine greater than 1.4 mg%). When this toxic treatment was given to the 21 patients with good performance (Zubrod less than 2) whose disease lacked high serum lactic dehydrogenase (less than or equal to 500 U/L) as a recently recognized feature of high-grade myeloma, a superior median survival of 18 months was obtained as opposed to only 3 months for the 22 remaining patients (P less than .001). Thus, when employed in a timely fashion, HDM overcomes resistance to standard chemotherapy and VAD and benefits selected patients with advanced myeloma.

Aged↗
PubMed1988

Alteration and abnormal expression of the c-myc oncogene in human multiple myeloma.

Structural alterations of the c-myc oncogene in human Burkitt's lymphoma and mouse plasmacytoma suggest that this oncogene is involved in several B cell neoplasms. The possibility of c-myc alterations in human myeloma has not been explored, probably because the low proliferative activity characteristic of this tumor impairs the propagation of representative cell lines for the performance of adequate cytogenetic studies. This report describes alterations in the c-myc locus with concomitant elevated expression of mRNA in the tumor cells of two of 37 patients with multiple myeloma. In one case, somatic cell hybrid studies revealed that the cloned rearranged DNA was entirely derived from chromosome 8, thus indicating a novel mechanism of c-myc activation different from that in Burkitt's lymphoma. Seven other patients exhibited five- to 12-fold overexpression of c-myc RNA when compared with normal marrow cells. Elevated mRNA expression in about one fourth of our patients suggests that the c-myc oncogene has a pathogenetic role in the evolution of multiple myeloma.

Animals↗
PubMed1988

Plasma cell karyotype in multiple myeloma.

Karyotypic abnormalities were studied in multiple myeloma and were correlated with clinical features. Among 115 evaluable patients, 46% had an abnormal karyotype. Trisomy 3, 5, 9, and 15 and monosomy 13 and 16 were the most common clonal abnormalities. Translocations described previously in other B cell malignancies occurred in nine patients, including four with t(8;14)(q24;q32) translocations. The association of all t(8;14) abnormalities with IgA protein type suggested a pathogenetic relationship between a specific karyotypic abnormality and myeloma protein type. Hypodiploidy occurred mainly in patients with only Bence Jones protein, was associated with resistance to therapy, and justified the early consideration of investigational therapies.

Chromosome Aberrations↗
PubMed1987

Biology and therapy of multiple myeloma.

Bone marrow plasma cells of patients with myeloma are frequently aneuploid, have a high RNA content and typically show monoclonal immunoglobulin in their cytoplasm. Kappa-lambda co-expression in aneuploid tumor cells was restricted to patients with IgG lambda myeloma. Immunophenotype studies revealed early B cell expression often in association with mature B cell markers. Chromosomal aberrations were complex with a predominance of numeric but also structural lymphoma-type translocations; the latter were most prevalent in IgA myeloma. Specific translocations such as t(8;14) and t(11;14) were accompanied by aberrations of c-myc and bcl-l cellular genes. Effective salvage programs have been developed for melphalan-prednisone refractory myeloma. In comparing high-dose dexamethasone with vincristine-adriamycin + dexamethasone (VAD), VAD was superior particularly for relapsing myeloma (response rate of 60 vs. 23%). For VAD refractory myeloma, high-dose melphalan (HDM) programs were developed; total body irradiation (850 rad) followed by HDM 140 mg/m2 and supported by autologous bone marrow grafts was particularly effective and relatively well tolerated with all 4 patients still in remission from 3 to 15 months.

Antigens, Neoplasm↗
PubMed1987

Characterization of hematologic malignancies by flow cytometry.

The quantitative assessment of cellular DNA and RNA content by flow cytometry to provide useful information for both diagnosis and prognosis of patients with hematologic malignancies is reviewed. While the characterization of cell surface antigens seems to be more germane to questions of the normal cell counterpart (stage) of malignant transformation and the biology of regulation of proliferation and differentiation by cell-cell contact and humoral factors, DNA-derived and RNA-derived parameters were surprisingly sensitive in the distinction of major morphologic groups, drug sensitivity and long-term prognosis. Our findings to date in the study of leukemias, lymphomas and myelomas are summarized.

DNA, Neoplasm↗
PubMed1987

High-dose chemoradiotherapy and autologous bone marrow transplantation for resistant multiple myeloma.

Seven patients with advanced multiple myeloma, refractory to therapy with alkylating agent-VAD (vincristine-adriamycin-dexamethasone), received a regimen combining high-dose melphalan with total body irradiation supported by autologous bone marrow transplantation. Very rapid, usually greater than 90% tumor mass reduction was achieved in six patients, regardless of prior chemotherapy responsiveness and marrow plasmacytosis up to 30%. Despite signs of early relapse in three patients (median remission duration of all patients, 15 months), five remain alive and well without further cytotoxic therapy from 2 to 21 months (median, 9+ months). Two patients died, one from surgical complications after transplantation and a second due to persistent neutropenia with fatal pneumonia. This treatment provides meaningful disease control for selected patients with resistant myeloma and a poor prognosis.

Blood Cells↗
PubMed1986

Biclonal and hypodiploid multiple myeloma.

Plasma cell DNA and RNA content was measured by flow cytometry of acridine orange-stained bone marrow cells from 72 untreated patients with multiple myeloma. Biclonal or hypodiploid DNA stemlines were identified in 10 patients, nine of whom had a low RNA content and did not have response to chemotherapy. Biclonal tumors often showed atypical myeloma protein changes with chemotherapy, suggesting that one clone was reduced whereas the other remained unchanged. These findings suggest a genetic basis for the resistance of low RNA tumors to chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1986

Therapy of primary resistant and relapsed multiple myeloma.

This article reports the efficacy of two salvage programs for primary resistant and relapsed multiple myeloma. Employing high dose dexamethasone alone or combined with continuous infusions of vincristine and adriamycin (VAD) in 83 patients, 1/3 achieved a greater than or equal to 75% tumor cytoreduction. The highest response rate of 65% was observed among previously responding patients receiving VAD compared to approximately 1/4 among those receiving VAD for primary resistant disease or dexamethasone alone regardless of prior response status. Tumor halving times were short with values of 0.5 months for VAD and 1.3 months for dexamethasone alone. The single most important pretreatment variable associated with failure to achieve remission was a low RNA content of myeloma plasma cells in the bone marrow. The second program evaluated high dose melphalan with or without autologous bone marrow transplantation in 23 patients resistant to VAD salvage treatment. Ten of 23 patients responded for at least 2 months, and 4 others had a comparable anti-tumor effect but died between 4-6 weeks from disseminated infection. Unlike the VAD regimen, responses occurred regardless of prior response or plasma cell RNA content, and tumor halving times were extremely short with a median of 0.3 months. With autologous bone marrow support, the higher melphalan dose (140 vs. 100 mg/m2) could be more safely administered to an older patient population (median of 63 vs. 44 years) with 1 of 7 vs 6 of 16 drug-related deaths in the absence of marrow support.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1986

High-dose glucocorticoid treatment of resistant myeloma.

Intermittent, high-dose dexamethasone treatment was given to 49 consecutive patients with refractory multiple myeloma. In patients who were unresponsive to previous treatment, the response rate of 27% was similar to that achieved with the VAD regimen, which combines the same schedule of dexamethasone with vincristine and doxorubicin given by continuous infusion. Among patients with relapses, VAD chemotherapy induced remissions in 11 of 17 patients (65%), whereas dexamethasone alone induced remissions in 4 of 19 (21%). The median survival of all patients responding to either treatment, 22 months, was longer than that from any previous program for treatment of resistant myeloma. These findings indicate the value of frequent dexamethasone administration in patients unresponsive to standard therapy and show the major role of vincristine and doxorubicin given by continuous infusion in patients with relapses. They also suggest different mechanisms for primary and secondary resistance to chemotherapy.

Aged↗
PubMed1986

High-dose melphalan with autologous bone marrow transplantation for multiple myeloma.

A large dose of melphalan was given to 23 patients with advanced multiple myeloma that was refractory to multiple prior treatments. Sixteen patients received a dose of 80 to 100 mg/m2, and seven were given 140 mg/m2 followed by autologous bone marrow infusion. Tumor mass was reduced by more than 75% in 14 patients, including four who died of bone marrow aplasia. Serious infections were prevented in six of seven patients who received autologous bone marrow. The marked cytoreduction in patients with previously refractory disease indicated the apparent drug resistance could be overcome by dose escalation. However, short remission times in most responding patients were consistent with rapid regrowth of primordial tumor cells with high proliferative activity. Although high-dose melphalan was of limited benefit to patients with refractory myeloma, further studies are necessary to clarify its role during earlier phases of disease.

Adult↗
PubMed1986

Treatment of multiple myeloma with recombinant alpha-interferon.

Thirty-two patients with multiple myeloma were treated with recombinant alpha-interferon clone A (rIFN alpha A) daily by intramuscular injection with an initial dose of 12 X 10(6) U/m2. Of 27 patients evaluable for response, tumor responses were obtained in seven of 14 previously untreated patients (50%) and two of 13 who had relapsed or failed prior chemotherapy (15%). In all patients who had tumor response, there was restoration from subnormal levels of serum immunoglobulins, an effect infrequently observed with chemotherapy. The median duration of tumor responses exceeded 14 months (range, 6 to 20). Moderate-to-severe fatigue was the predominant side effect and necessitated dose reductions in all patients. We conclude that treatment of early stages of multiple myeloma with rIFN alpha A is beneficial because of the substantial response rate and the improvement in the synthesis of serum immunoglobulins. rIFN alpha A has a potential role in combination with other agents in the treatment of multiple myeloma.

Female↗
PubMed1985

Beta 2 microglobulin in multiple myeloma.

Serum beta 2 microglobulin levels (B2M) were evaluated before and during chemotherapy in 97 previously untreated patients with multiple myeloma. Pretreatment values were useful in confirming tumor mass grade, and marked reductions following chemotherapy correlated well with the onset of remission. No gain was evident from correcting the B2M for the level of serum creatinine. A pretreatment B2M value greater than 6 mg/L correlated with a low response rate and was the most important variable that predicted a short survival time.

Aged↗
PubMed1985

Cytoplasmic immunoglobulin content in multiple myeloma.

Bone marrow cells of 82 patients with multiple myeloma were subjected to flow cytometric analysis of DNA and cytoplasmic immunoglobulin (CIg) content using propidium iodide and direct immunofluorescence assays. Except for two patients with nonsecretory myeloma, there was conformity in the immunoglobulin type derived from immunoelectrophoresis and plasma cell CIg staining. One patient with nonsecretory myeloma exhibited monotypic CIg staining, while the second showed no reaction. In eight patients with IgG lambda myeloma, the same tumor cells contained both lambda and kappa light chains, suggesting the productive rearrangement of both light chain genes. 14 patients with previously unrecognized plasma cells of low RNA content, all of whom were resistant to chemotherapy, were identified by CIg staining. By revealing previously unrecognized plasma cells with low RNA content, CIg analysis identified more patients with treatment-refractory myeloma.

Bone Marrow Cells↗
PubMed1985

Prognostic implications of tumor cell DNA and RNA content in multiple myeloma.

Flow cytometric studies of bone marrow DNA and RNA content were conducted in 71 previously untreated patients with multiple myeloma. There was a progressive increase in response rate with rising plasma cell RNA content. The DNA-derived ploidy level also affected chemotherapy sensitivity: only one of 11 patients with either hypodiploidy or biclonal DNA stemlines responded. DNA-RNA-defined marrow plasmacytosis was the only tumor mass-related variable adversely affecting remission induction. Survival was longer in patients with low tumor burden and favorable DNA features. The availability of objective and quantitative pretreatment variables associated with both initial response and survival should permit a risk-based selection of patients for novel treatment approaches.

Bone Marrow↗