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D H Vesole

Publications and source records attributed to D H Vesole.

At least 55 records · Page 3Linked to original sources
PubMed1996

Safety of autotransplants with high-dose melphalan in renal failure: a pharmacokinetic and toxicity study.

Melphalan (MEL) is probably the most effective chemotherapeutic agent in multiple myeloma (MM) with a clear dose-response effect. It can be escalated without excessive toxicity to 200 mg/m2, a myeloablative dose requiring hematopoietic stem cell support. Patients with marked renal insufficiency, not an infrequent finding in MM, have either received reduced doses or have been excluded from therapy with high-dose MEL. A prospective study was performed to evaluate the relationship between MEL pharmacokinetics and renal function in 20 patients with MM. Six patients had severe renal insufficiency (creatinine clearance, <40 ml/min), including five on chronic hemodialysis. Three patients with severe renal impairment first received a low test dose of MEL (16 mg/m2) for pharmacokinetic studies. All patients received 200 mg/m2 MEL divided into two equal doses of 100 mg/m2 i.v. on 2 consecutive days, followed by the administration of peripheral blood stem cells. MEL pharmacokinetics, performed after the first dose of 100 mg/m2, was not adversely affected by impaired renal function. The median half-life (t1/2), area under the concentration curve, and clearance of MEL were 1.1 h, 5.5 mg h/liter, and 27.5 liter/h, respectively, in patients with a creatinine clearance of <40 ml/min compared to 1.9, 7.9, and 23.6 for the others. Renal insufficiency also had no apparent negative impact on the quality of peripheral blood stem cell collections and did not adversely affect posttransplant engraftment, transfusion requirements, incidence of severe mucositis, or overall survival. However, it was associated with longer durations of fever (P = 0. 0005) and hospitalization (P = 0.004). No transplant-related deaths were observed. Plasma t1/2 and area under the concentration curve differed by a factor of 10 and MEL clearance by a factor of 5 between patients with the lowest and highest values. These large variations in MEL elimination could not be explained by patient or disease characteristics. We conclude that renal failure does not require dose reduction of MEL in autologous transplant. Due to marked interindividual variation in MEL elimination, pharmacokinetically guided dosing as well as cellular pharmacology studies may be helpful in achieving a more uniform antitumor effect.

Adult↗
PubMed1995

Poor prognosis in multiple myeloma is associated only with partial or complete deletions of chromosome 13 or abnormalities involving 11q and not with other karyotype abnormalities.

Chromosomal abnormalities have major biologic and prognostic implications in leukemias. Cytogenetic information in typically hypoproliferative multiple myeloma (MM) is limited because of difficulties in obtaining analyzable metaphases. In this study, karyotypes and other known prognostic factors were analyzed in 155 newly diagnosed MM patients, entered on an intensive treatment program with two autotransplants. Complete remission (CR), event-free (EFS) and overall survival (OS) were analyzed using standard statistical methods. Abnormal cytogenetics were found in 39% of patients and were associated with a significantly lower CR rate (27% v 48%; P = .008). EFS and OS were inferior in patients with either partial or complete deletion of chromosome 13 or 11q abnormalities ("unfavorable" karyotype) when compared with the remaining patients (P < .001) who, as a group, had a similar prognosis irrespective of cytogenetic findings, ie, inevaluable, normal, or abnormal but without an "unfavorable" karyotype. The patients with abnormalities of both chromosomes 11 and 13 had a dismal prognosis with median EFS and OS of only 11 and 12 months, respectively. Significant associations were noted between an "unfavorable" karyotype and IgA isotype, elevated levels of beta-2 microglobulin (B2M, > or = 3 mg/L) and age > 60 years. On multivariate regression analysis, the absence of an "unfavorable" karyotype was the most significant variable associated with prolonged EFS and OS (P = .0001 and .0002, respectively). Other independent favorable variables were age less than 60 years, C-reactive protein (CRP) < or = 0.4 mg/dL and bone marrow plasmacytosis < or = 50% before treatment. On a multivariate analysis without cytogenetics, these same three standard parameters were identified as the only favorable variables. Patients not having all three standard favorable variables had a significantly lower CR rate (P = .03), EFS (P = .0001), and OS (P = .002) if an unfavorable karyotype was detected. We conclude that, in this program of uniformly treated MM patients, a poor prognosis was associated predominantly with abnormalities of chromosomes 11 and 13.

Chromosome Aberrations↗
PubMed1995

Purified CD34+ Lin- Thy+ stem cells do not contain clonal myeloma cells.

High-dose therapy with autologous marrow or peripheral blood stem cell (PBSC) rescue has been extensively applied in the treatment of multiple myeloma (MM) patients during the past 10 years resulting in improved event-free and overall survival when compared with standard chemotherapy. However, relapses are common and cure is unlikely in the majority of patients. Because both bone marrow and PBSCs are contaminated with myeloma cells it is conceivable that relapse after autotransplantation originates at least in part from autografted tumor cells. In this study, mobilized PBSCs were examined for the presence of myeloma cells based on immunophenotyping and sensitive polymerase chain reaction (PCR)-based techniques. In addition, CD34+ Lin- Thy+ stem cells were purified from mobilized PBSC harvests of 10 MM patients by sequentially using counterflow elutriation centrifugation, treatment with phenylalanine methylester, and flow sorting, using 5-parameter gating (propidium iodide, forward scatter, side scatter, CD34+ v Lin- and CD34+ v Thy+). Virtually all mobilized unsorted PBSC preparations contained myeloma cells in sufficient quantities (range, < 0.01 to > 10%) potentially causing a disease relapse. Stem cell purification led to an overall enrichment by about 50-fold in all 10 patients; approximately 90% of the final cell population expressed CD34+ Lin- Thy+ with no evidence of myeloma cell contamination based on flow cytometric analysis of CD38bright cells (< 0.1%). Quantitative PCR amplification of patient-specific complementarity determining region III (CDRIII) DNA sequences showed depletion of clonal B cells by 2.7 to 7.3 logs, with the highest log reduction noted in the samples initially containing the most tumor cells. Our results show that purification of CD34+ Lin- Thy+ cells depletes myeloma cells to undetectable levels from up to 10% present in unsorted PBSCs, thus offering a tool to investigate whether MM relapse after autotransplantation can be reduced markedly.

ADP-ribosyl Cyclase↗
PubMed1995

Relapse of multiple myeloma after autologous transplantation: survival after salvage therapy.

Owing to lack of progress with standard chemotherapy and the presence of a dose response effect for alkylating agents, autotransplantation is performed with increasing frequency for multiple myeloma (MM). However, sustained relapse-free survival is still infrequent. We studied 94 patients who had relapsed following autotransplantation, in order to evaluate the efficacy of further therapy. Post-transplant salvage treatment consisted of either standard dose therapy (53) or transplantation with an intensive preparative regimen (with autograft support in 31 and allogeneic transplantation in 10). Complete remission (CR) rate, event-free and overall survival were assessed and prognostic variables identified in a multivariate regression analysis. With a median follow-up of 11 months, the projected overall survival at 18 months for all patients is 59%. A multivariate analysis identified pre-salvage beta-2-microglobulin (B2M) < or = 2.5 mg/l (P = 0.0002) and late relapse after the preceding transplant ( > 12 months; (P = 0.02) as independent significant favorable variables for overall survival. By combining pre-salvage B2M and the time to relapse, 2 risk groups of patients could be identified with significantly different overall survival: those with at least one favorable variable had a projected survival at 18 months of 79%, compared to 38% for patients with no favorable variable. Transplantation performed as primary salvage therapy was associated with a significantly prolonged survival (P = 0.009), although this may be more a reflection of the way salvage therapy was selected.

Follow-Up Studies↗
PubMed1994

High-dose therapy for refractory multiple myeloma: improved prognosis with better supportive care and double transplants.

One hundred and thirty-five patients with advanced and refractory myeloma received one of three high-dose therapy regimens: melphalan at doses of 90 to 100 mg/m2 (MEL 100; 47 patients) without autotransplant; total body irradiation (TBI; 850 cGy) with either melphalan 140 mg/m2 or thiotepa 750 mg/m2 and autologous bone marrow transplant (ABMT) (< or = 30% plasma cells; 21 patients); melphalan 200 mg/m2 (MEL 200) supported by both peripheral blood stem cells (PBSC) and ABMT plus GM-CSF intended as a double-transplant program (67 patients; 42 have completed and 3 are still awaiting a second autotransplant; 5 additional patients received an allograft for their second transplant). Mortality within 2 months of therapy was 20% to 25% with MEL 100 and TBI regimens, but less than 1% with MEL 200, mainly because severe neutropenia (< 500/microL) was shortened to less than 1 week due to infusion of PBSC and use of growth factor therapy. Low beta 2-microglobulin (beta 2M) levels < or = 2.5 mg/L and MEL 200 therapy were identified as the two most important independent favorable variables associated with prolonged event-free survival (EFS) and overall survival (OS). On the basis of these two parameters, three risk groups were defined: 29 good-risk patients with low beta 2M receiving MEL 200 had the best outcome, with median durations of EFS of 37 months and projected OS of > or = 43 months; 54 intermediate-risk patients displaying one of the two favorable parameters had EFS and OS durations of 16 and 36 months, respectively; and 52 poor-risk patients with high beta 2M not receiving MEL 200 had a dismal prognosis, with EFS of 3 months and OS of 5 months (all P < .0001). Further analysis that excluded treatment as a variable identified high beta 2M and resistant relapse as the two major adverse prognostic factors, one of which was present in 80% of the 135 patients. Among these 108 high-risk patients, prognosis was improved markedly with MEL 200 because of both better supportive care (PBSC and hematopoietic growth factors) and more intensive therapy using the double-transplant approach. This study supports the concept that safer and potentially more-effective therapies can be developed in the setting of advanced and resistant disease.

Age Factors↗
PubMed1994

Effect of low-dose granulocyte-macrophage colony-stimulating factor (LD-GM-CSF) on platelet transfusion-dependent thrombocytopenia.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a hematopoietic growth factor known to promote the proliferation and differentiation of precursors of granulocytes and monocytes. GM-CSF at standard doses (125-500 micrograms/m2) alleviates neutropenia secondary to cytotoxic chemotherapy, myelodysplastic syndromes, and aplastic anemia, but has minimal effect on anemia or thrombocytopenia. GM-CSF at doses < 30 micrograms/m2 has been reported to improve platelet counts in some patients exhibiting cytopenia related to hematologic disorders such as aplastic anemia and myelodysplastic syndrome. Low-dose GM-CSF (10-20 micrograms/m2) was evaluated in 20 patients with transfusion-dependent thrombocytopenia persisting after myeloablative cytotoxic chemotherapy or with disease-related cytopenia. Seven patients (35%) responded as defined by a reduction in the platelet transfusion requirements by at least 75%. Low-dose GM-CSF did not significantly increase neutrophil counts or decrease red blood cell transfusion requirements. These results indicate that low-dose GM-CSF has a thrombopoietic effect in about one-third of patients with platelet transfusion-dependent thrombocytopenia which has not been observed at higher doses.

Blood Platelets↗
PubMed1994

Toxoplasma pneumonia: cytologic diagnosis by bronchoalveolar lavage.

Two cases of toxoplasma pneumonia in immunocompromised hosts are reported. The diagnoses were made by the identification of trophozoites in bronchoalveolar lavage material. The organisms were more readily identified in the air-dried Diff-Quik-stained smears. Cytologic findings and correlation with postmortem examination material in one case are described. A high index of suspicion for this pathogen, as well as screening cytologic preparations at medium to high magnification may increase the diagnostic rate for this uncommon but treatable disease.

AIDS-Related Opportunistic Infections↗
PubMed1994

Salvage therapy for multiple myeloma: the University of Arkansas experience.

OBJECTIVE: To summarize a spectrum of salvage regimens for multiple myeloma (MM) developed during the past decade. DESIGN: We reviewed the experience at the University of Arkansas in the management of patients with MM who failed to achieve remission ("primary unresponsive") or had a relapse despite myelosuppressive doses of chemotherapy ("resistant relapse"). MATERIAL AND METHODS: Results with use of the various chemotherapeutic protocols are presented, and multivariate regression analysis was applied to determine the independent contributions of certain factors toward event-free and overall survival. RESULTS: The VAD regimen (vincristine sulfate, Adriamycin [doxorubicin hydrochloride], and dexamethasone) yielded responses in 29% of previously unresponsive and 46% of relapsed cases of MM, in comparison with 25% and 21%, respectively, with use of dexamethasone only. Responses occurred more frequently when tumor cell RNA content was high, tumor burden was low, and duration of drug resistance was less than 1 year. The duration of survival in patients who received high doses of melphalan was decreased in those with increased serum levels of lactate dehydrogenase. EDAP (etoposide, dexamethasone, ara-C, and cisplatin) produced 75% or more tumor cytoreduction in 8 of 20 patients. Overall in patients with an increasing number of adverse factors, response rates and survival decreased progressively with less intensive therapy but were unaffected when more intensive therapy was used. In the multivariate analysis, the most important features for extended survival were a low beta 2-microglobulin level before transplantation and application of two bone marrow transplants within 6 months. CONCLUSION: Variables relative to the patient's overall medical condition, prior treatment, characteristics of MM at diagnosis, and response history should be carefully assessed to determine a plan for salvage therapy that will maximize the opportunity for sustained remission and survival.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1994

Hemopoietic stem cell transplants for multiple myeloma.

Recently, high-dose therapy has been evaluated in patients with multiple myeloma, mainly with autologous transplant support. As a result of rapid hemopoietic engraftment with peripheral blood stem cells collected after chemotherapy and/or hemopoietic growth factor priming, procedure-related mortality has dropped to below 5%. When applied within 12 months from initial therapy, autologous transplants effect complete remissions in up to 50% of patients, with median event-free and overall survival durations on the order of 2.5 and 4 to 5 years, respectively. Complete response rates with allogeneic transplantation range from 30% to 50%, and procedure-related mortality is approximately 40%. Although the median durations of event-free and overall survival are shorter with allogeneic transplants, approximately 35% to 40% of patients survive with minimal disease for at least 5 to 6 years. Direct comparisons of standard therapy and autologous transplants have just begun.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

Autotransplantation in multiple myeloma.

High-dose chemotherapy with autologous hematopoietic stem cell reconstitution is efficacious in the treatment of multiple myeloma. The various preparative regimens, sources of hematopoietic stem cells, and post-transplant immunomodulation are discussed. Tandem autotransplantation following intravenous melphalan chemotherapy has low morbidity and mortality even in patients with refractory disease. The most encouraging results are observed in patients undergoing high-dose chemotherapy with less prior treatment, lower tumor mass, and sensitive disease.

Adjuvants, Immunologic↗
PubMed1992

Low-risk intensive therapy for multiple myeloma with combined autologous bone marrow and blood stem cell support.

To improve the safety of autotransplantation for myeloma, peripheral blood stem cell (PBSC) collection was attempted in 75 previously treated patients after the administration of high-dose cyclophosphamide (HD-CTX; 6 g/m2) with or without granulocyte-macrophage colony-stimulating factor (GM-CSF). Sixty patients subsequently received melphalan 200 mg/m2 (57 patients) or melphalan 140 mg/m2 and total body irradiation (850 cGy) (3 patients) supported by both autologous bone marrow and PBSC; 38 patients received GM-CSF posttransplantation. Among 72 patients undergoing PBSC apheresis, "good" mobilization (greater than 50 colony-forming units granulocyte-macrophage [CFU-GM] per 10(5) mononuclear cells) was achieved when prior chemotherapy did not exceed 1 year and when GM-CSF was used post-HD-CTX; similarly, rapid platelet recovery to 50,000/microL within 2 weeks was associated with "good" PBSC mobilization. These same variables also predicted for rapid engraftment after autotransplantation, so that hematologic recovery (granulocytes greater than 500/microL and platelets greater than 50,000/microL) proceeded within 2 weeks among the 37 patients with "good" PBSC collection. As a result of rapid neutrophil recovery (greater than 500/microL) within a median of 2 weeks, infectious complications both post-HD-CTX and posttransplant were readily manageable, resulting in only one treatment-related death post-HD-CTX. The cumulative response rate (greater than or equal to 75% cytoreduction) for all 75 patients was 68%, with 12-month event-free and overall survival projections of about 85%. Using both bone marrow and PBSC together with GM-CSF, autotransplants are safe and appear effective in myeloma, especially when prior therapy had been limited to less than 1 year. More than 80% of transplanted patients achieved complete hematologic recovery within a median of 1 month posttransplant (granulocytes greater than 1,500/microL; platelets greater than 100,000/microL; hemoglobin greater than 10 g%), thus providing sufficient hematopoietic reserve for further chemotherapy in the event of posttransplant relapse.

Bone Marrow Transplantation↗
PubMed1990

Transactivation of a human cytomegalovirus early promoter by gene products from the immediate-early gene IE2 and augmentation by IE1: mutational analysis of the viral proteins.

Expression from a human cytomegalovirus early promoter (E1.7) has been shown to be activated in trans by the IE2 gene products (C.-P. Chang, C. L. Malone, and M. F. Stinski, J. Virol. 63:281-290, 1989). Using wild-type and mutant viral proteins, we have defined the protein regions required for transactivation of the E1.7 promoter in IE2 and for augmentation of transactivation in the IE1 protein. Two regions of the IE2 proteins were found to be essential for transactivation. One near the amino terminus is within 52 amino acids encoded by exon 3. The second comprises the carboxyl-terminal 85 amino acids encoded by exon 5. The IE2 protein encoded by an mRNA which lacks the intron within exon 5 and the IE2 protein encoded by exon 5 had no activity for transactivation of the E1.7 promoter. Although the IE1 gene product alone had no effect on this early viral promoter, maximal early promoter activity was detected when both IE1 and IE2 gene products were present. The IE1 protein positively regulated its enhancer-containing promoter-regulatory region. The IE1 protein alone increased the steady-state level of IE2 mRNA; therefore, IE1 and IE2 are synergistic for expression from the E1.7 promoter. Like the IE2 proteins, the IE1 protein requires for activity 52 amino acids encoded by exon 3. IE1 also requires amino acids encoded by exon 4. Since the IE1 and IE2 proteins have 85 amino acids in common at the amino-terminal end encoded by exons 2 and 3, the difference between these specific transactivators resides in their carboxyl-terminal amino acids encoded by exons 4 and 5, respectively.

Amino Acid Sequence↗
PubMed1989

Identification and expression of a human cytomegalovirus early glycoprotein.

A human cytomegalovirus early gene which possesses three temporally regulated promoters is located in the large unique component of the viral genome between 0.054 and 0.064 map units (C.-P. Chang, C.L. Malone, and M.F. Stinski, J. Virol. 63:281-290, 1989). This gene contains a major open reading frame (ORF) located 233 bases downstream of the cap site of an early unspliced RNA. The major ORF predicts a polypeptide of 17 kilodaltons (kDa) which contains a glycoproteinlike signal and anchor domains as well as potential N-glycosylation sites. Antisera were prepared against synthetic peptides derived from amino acid sequences within the major ORF. The antisera detected a viral glycoprotein of 48 kDa in infected cells and recognized the in vitro-translated 17-kDa protein early-gene product. The viral glycoprotein, designated gp48, was modified by N-linked glycans and possibly O-linked glycans. The synthesis of gp48 occurred in the absence of viral DNA replication but accumulated to the highest levels at late times after infection. Since gp48 was found in the virion, it is considered an early structural glycoprotein.

Amino Acid Sequence↗
PubMed1987

Diffuse large-cell lymphoma in an adult with Schönlein-Henoch purpura.

Schönlein-Henoch purpura is an IgA-mediated immune complex vasculitis of unknown cause which is characterized by nonthrombocytopenic purpura, arthralgias, abdominal pain, angioedema, and glomerulonephritis. It most commonly occurs in children and usually follows a benign course. Associated malignancies are rarely reported. A number of treatment regimens have been used, including corticosteroids and immunosuppressive agents. This is a case report of lymphoma in an adult with Schönlein-Henoch purpura in the absence of renal involvement.

Chronic Disease↗
PubMed1982

Rejection of stable cultured allografts by active or passive (adoptive) immunization.

Injection of live lymphoid cells of donor strain or immune cells of recipient strain resulted in rejection of previously stable cultured mouse thyroid allografts. The results are interpreted to indicate that a cultured graft is relatively ineffective in activating recipient lymphocytes but is capable of maintaining them in an activated state and serving as a target for them once they are activated.

Animals↗
PubMed1980

The induction of human peripheral blood lymphoid colonies by conditioned media from human tumour cell lines.

Conditioned medium (CM) from 29 human tumour cell lines and 3 malignant pleural fluids were tested for their ability to stimulate lymphoid colony formation in semi-solid agar; 9 of 14 malignant melanomas, 3 of 6 colonic carcinomas, 2 of 5 ovarian carcinomas, 3 of 4 breast carcinomas and 1 of 3 pleural fluids from breast cancer patients contained colony-stimulating activity (CSA) for human peripheral blood lymphoid cells (PBL) in semi-solid agar. Conditioned media also stimulated PBL proliferation in liquid medium; these effects were dose dependent. With the exception of one pleural fluid, extensive dialysis of CM did not significantly increase colony formation; CM from two tumour cell lines demonstrated a significant decrease in the induction of colony formation after dialysis.

B-Lymphocytes↗