PubMed Health⌕ Search

Biomedical subjects

A Mittelman

Publications and source records attributed to A Mittelman.

At least 37 records · Page 2Linked to original sources
PubMed1998

Distinct classes of chaperoned IL-6 in human blood: differential immunological and biological availability.

Transport of IL-6 in blood is fundamental to the biology of this cytokine. In the present study, IL-6 transport, immunological reactivity, and biological availability were investigated in blood from melanoma patients subjected to different active specific immunization regimens (an anti-idiotypic mAb immunization protocol (mAb-keyhole limpet hemocyanin (KLH)-Calmette-Guerin bacillus (BCG), an autologous anti-cancer vaccine protocol (AAAP), or both). Sera were subjected to Sephadex G-200 gel filtration chromatography, and the structure and biological activity of IL-6 complexes in the eluate fractions were probed using five IL-6 ELISAs and two bioassays. Sera from patients administered mAb-KLH+BCG followed by AAAP contained three distinct classes of IL-6 eluting at 30, 200, and 450 kDa, each with its characteristic ELISA reactivity and bioactivity: the 30- and 450-kDa complexes were bioactive in the B9 and Hep3B assays, but the 200-kDa complex was not. The 30- and 450-kDa IL-6 complexes were preferentially reactive in the 7IL6/5IL6 ELISA, the 200-kDa IL-6 complexes were preferentially reactive in the 4IL6/5IL6 ELISA, while the three commercial ELISAs (R&D, Endogen, and Genzyme) detected essentially only the 30-kDa IL-6. In contrast, 1) sera from AAAP patients contained biologically active 30- and 450-kDa IL-6 complexes, while 2) sera from mAb-KLH+BCG patients contained 200-kDa IL-6 complexes inactive in ex vivo bioassays. Both the 450- and 200-kDa complexes included soluble IL-6R, with the 200-kDa complexes additionally containing ligand-occupied anti-IL-6 and anti-soluble IL-6R IgG. The data indicate the existence of specific mechanisms that regulate the transport and function of IL-6 in vivo.

Antibodies, Neoplasm↗
PubMed1998

G1 arrest of U937 cells by onconase is associated with suppression of cyclin D3 expression, induction of p16INK4A, p21WAF1/CIP1 and p27KIP and decreased pRb phosphorylation.

Onconase is a 12 kDa protein homologous to pancreatic RNase A isolated from amphibian oocytes which shows cytostatic and cytotoxic activity in vitro, inhibits growth of tumors in mice and is in phase III clinical trials. The present study was aimed to reveal mechanisms by which onconase perturbs the cell cycle progression. Human histiocytic lymphoma U937 cells were treated with onconase and expression of cyclins D3 and E, as well as of the cyclin-dependent kinase inhibitors (CKIs) p16INK4A, p21WAF1/CIP1 and p27KIP1 (all detected immunocytochemically) was measured by multiparameter flow cytometry, in relation to the cell cycle position. Also monitored was the status of phosphorylation of retinoblastoma protein (pRb) by a novel method utilizing mAb which specifically detects underphosphorylated pRb in individual cells. Cell incubation with 170 nM onconase for 24 h and longer led to their arrest in G1 which was accompanied by a decrease in expression of cyclin D3, no change in cyclin E, and enhanced expression of all three CKIs. pRb was underphosphorylated in the onconase arrested G1 cells but was phosphorylated in the cells that were still progressing through S and G2/M in the presence of onconase. The cytostatic effect of onconase thus appears to be mediated by downregulation of cyclin D3 combined with upregulation of p27KIP1, p16INK4A and p21WAF1/CIP1, the events which may prevent phosphorylation of pRb during G0/1 and result in cell arrest at the restriction point controlled by Cdk4/6 and D type cyclins.

Animals↗
PubMed1997

Treatment of plasma refractory thrombotic thrombocytopenic purpura with protein A immunoabsorption.

The objective of this study was to assess the effect of protein A immunoabsorption in terms of response rate and toxicities in patients with classical thrombotic thrombocytopenic purpura (TTP) refractory to therapeutic plasma exchange. The study included nine females and one male with a diagnosis of classical TTP treated at multiple university hospital centers with protein A immunoabsorption (PAI) after having failed plasma exchange. The 10 patients had an age range 17-62 years. Prior to PAI, the patients had failed to respond to a mean of 15 (range 6-39) therapeutic plasma exchanges. Three patients had previous episodes of TTP. Evaluation for response to PAI included serial measurements of serum creatinine, lactate dehydrogenase (LDH), hemoglobin, hematocrit, and platelet count before, during, and up to 18 months post-PAI treatment. Seven of 10 study patients had resolution of their TTP. Six of the patients required six or fewer therapeutic PAIs and one required 12 treatments. All responding patients had evidence of improvement by the third PAI treatment. Three patients demonstrated no response to PAI, with two patients expiring from complications of TTP and one patient demonstrating a complete response to a subsequent therapy. No significant toxicity was noted with the use of PAI in this setting. Protein A immunoabsorption in patients with classical TTP refractory to plasma exchange can produce durable complete remissions and warrants comparative studies.

Adult↗
PubMed1997

Cell cycle specificity of apoptosis during treatment of leukaemias.

This review summarizes our observations on the mechanism of induction of apoptosis in vitro in leukaemic cell lines and in vivo in patients with leukaemia undergoing chemotherapy, in relation to the cell cycle. Multiparameter flow cytometric methods allowed us to identify apoptotic cells and position them with respect to their cell cycle phase. Several antitumor agents of different classes have been characterized in terms of the cell cycle phase specificity of induction of apoptosis. Three types of apoptosis could be distinguished in relation to the initial damage to the cell vis-a-vis cell cycle position: (1) homo-phase apoptosis where the cells underwent apoptosis during the same phase in which they were initially affected; (2) homo-cycle apoptosis, where the cells underwent apoptosis during the same cell cycle in which they were initially affected, i.e., prior to or during the first mitosis, and (3) post-mitotic apoptosis, where cells underwent apoptosis during the cell cycle(s) subsequent to that in which the cell was initially affected, most likely at the G1 or G2 checkpoints of these cycle(s). Four ranges of drug concentration can be distinguished in vitro for most drugs, where either: (1) no immediate effects; (2) cytostasis or post-mitotic apoptosis; (3) homo-cycle or homo-phase apoptosis; or (4) necrosis are observed. Analysis of cell death of blast cells from peripheral blood or bone marrow of over 250 leukaemia patients (AML, ALL, CML in blast crisis) treated with various drugs during routine chemotherapy reveals that in the case of DNA topoisomerase inhibitors (e.g., mitoxantrone, VP-16) apoptosis is often rapid (peaks at 1-2 days after drug administration) and has features of homo-phase apoptosis. In contrast, cell death observed after administration of paclitaxel (taxol) or cytarabine (cytosine arabinoside) occurs later and has features of post-mitotic apoptosis: the cells divide but die in G1 of the subsequent cycle(s).

Journal Article↗
PubMed1997

Single and double autotransplants for relapsing/refractory Hodgkin's disease: results of two consecutive trials.

To evaluate a strategy of one cycle of dose-intensive chemotherapy for patients with Hodgkin's disease in sensitive relapse and two cycles for those with refractory disease, 122 patients received dose-intensive chemotherapy followed by autotransplant in two consecutive studies. Patients with refractory disease were offered a second transplant with different conditioning in the absence of progression or excessive toxicity. CR was present after treatment in 46% while 16% died in the peritransplant period. Of 41 patients with primary refractory disease and 42 with refractory relapse, 24 and 21 respectively received a second cycle. Of these 45 refractory patients, 12 were in CR and 11 in PR after the first cycle and 10 of these 11 in PR achieved a durable CR with the second transplant. The CR rate is 37% in patients with refractory relapse and 19% in those with primary refractory disease. At a median follow-up of 4 years, median survival is 45 months. Progression-free survival of the refractory patients who could receive a second cycle was similar to that of patients with sensitive disease. A sequential transplant strategy is feasible. A subgroup of patients with refractory disease can achieve long-term survival after sequential BMT.

Adolescent↗
PubMed1997

Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer.

PURPOSE: To determine the cardioprotective effect of dexrazoxane (DZR) used in a doxorubicin-based combination therapy in advanced breast cancer. PATIENTS AND METHODS: Between November 1988 and January 1991, 534 patients with advanced breast cancer were randomized to two multicenter, double-blind studies (088001 and 088006). Patients received fluorouracil, doxorubicin, and cyclophosphamide (FAC) with either DZR (DZR-to-doxorubicin ratio, 10:1) or placebo (PLA) every 3 weeks and were monitored with serial multiplegated acquisition (MUGA) scans. RESULTS: The hazards ratio (HR) of PLA to DZR for a cardiac event, which was predefined ejection fraction changes or congestive heart failure (CHF), was 2.63 (95% confidence interval [CI], 1.61 to 4.27; P < .001) for 088001 and 2.00 (95% CI, 1.01 to 3.96; P = .038) for 088006. The objective response rates for 088001 were 46.8% for DZR and 60.5% for PLA, a difference of 14% (95% CI, -25% to -2%; P = .019), and for 088006 were 53.7% for DZR and 49.3% for PLA, a difference of 4% (95% CI, -13% to 22%; P = .63). Time to progression and survival were not significantly different between treatment arms in either study. Toxicities on the DZR arms included lower granulocyte and platelet counts at nadir (P = .009 and P = .004, respectively) and more pain on injection (P = .001), with no difference in the rates of fever, infection, or hemorrhage. CONCLUSION: DZR had a significant cardioprotective effect as measured by noninvasive testing and clinical CHF. One of the two studies (088001) showed a lower response rate with DZR, but time to progression and survival were not significantly different. DZR is the first agent shown to reduce cardiotoxicity from doxorubicin.

Aged↗
PubMed1996

Phase II study of elsamitrucin (BMY-28090) for the treatment of patients with refractory/relapsed non-Hodgkin's lymphoma.

PURPOSE: To determine the response rate of patients with refractory/relapsed non-Hodgkin's lymphoma to treatment with elsamitrucin and to further characterize the toxic effects of elsamitrucin in this group of patients. PATIENTS AND METHODS: Eligibility required pathologically verified relapsed or refractory non-Hodgkin's lymphoma with no more than two prior chemotherapy regimens for patients with tumors classified by the International Working Formulation (IWF) as A-C and no more than one prior chemotherapy for those with IWF grades D-G. Patients were entered with either normal or impaired bone marrow function, but normal liver function tests were required unless clearly related to lymphomatous involvement of the liver. Elsamitrucin 25 mg/m2 was administered intravenously over 5-10 minutes weekly. RESULTS: Thirty-one patients entered the study and were treated for a median of six weeks (range 1-42). All patients were evaluable for toxicity and 30 for response. Mild nausea and/or vomiting and asthenia were the most frequently reported adverse events. Four (13%, 95% Cl 4.4-31.6%) partial responses were seen along with two (7%) minor responses while 9 (30%) patients had stable disease. CONCLUSION: Elsamitrucin showed modest activity in patients with relapsed or refractory non-Hodgkin's lymphoma. Toxicity was relatively mild, consisted mainly of asthenia, nausea and vomiting and did not include myelosuppression. The activity of elsamitrucin in this group of patients and its lack of myelosuppression suggest utility in this disease especially when combined with other proven agents.

Adult↗
PubMed1996

Clinical pharmacokinetics of amonafide (NSC 308847) in 62 patients.

Amonafide (A) demonstrates dose-related increases in area under the curve (AUC) and Cmax values. Total body clearance for A (ranging from 44.2 to 53.8 L/hr/m2) is relatively constant within the dosing range of this study. The dose-related increase of AUC was also observed for the two identified metabolites, acetylamonafide (AA) and noramonafide (NA). A and NA plasma data could be described by a four-compartmental model (two compartments for A, one compartment each for NA and AA). The fitting for NA was poor owing to its low plasma concentration. The terminal half-lives for A, NA, and AA were in the range of 3-6 hr. No cumulative accumulation of parent compound or metabolites was detected after daily administration, The concentrations of A, NA, and AA 24 hr after dosing were either below or very close to the quantitative limits of the assay. Polymorphic disposition of A was confirmed by a frequency distribution of AUC value versus dose plot.

Adenine↗
PubMed1995

Antiantiidiotypic response and clinical course of the disease in patients with malignant melanoma immunized with mouse antiidiotypic monoclonal antibody MK2-23.

An active specific immunotherapy trial has been implemented in patients with malignant melanoma utilizing the mouse anti-id MAb MK2-23. The latter bears the internal image of the determinant by the anti-HMW-MAA MAb 763.74. The immunogenicity of anti-id MAb MK2-23 is enhanced by conjugation to a carrier and administration with an adjuvant. Anti-id MAb MK2-23 induced humoral anti-HMW-MAA immunity in about 60% of the immunized patients. The latter was associated with a statistically significant survival prolongation. It is suggested that anti-HMW-MAA immunity may have a beneficial effect on the clinical course of the disease by inhibiting the function of HMW-MAA in the biology of melanoma cells.

Animals↗
PubMed1995

Human high molecular weight-melanoma associated antigen mimicry by mouse anti-idiotypic monoclonal antibody MK2-23: modulation of the immunogenicity in patients with malignant melanoma.

The mouse anti-idiotypic (anti-id) mAb MK2-23 bears the mirror image of the antigenic determinant defined by antihuman high molecular weight-melanoma associated antigen (HMW-MAA) mAb 763.74. The purpose of this study was to evaluate the effect of conjugation to a carrier and administration with an adjuvant and cyclophosphamide (CTX) on the immunogenicity of anti-id mAb MK2-23 in patients with malignant melanoma and to analyze the relationship between development of humoral immunity and survival time of patients. Fifty-eight patients were sequentially entered into four immunization protocols which included administration of mAb MK2-23, mAb MK2-23 conjugated to keyhole limpet hemocyanin (KLH) and mixed with Bacillus Calmette-Guérin (BCG), mAb MK2-23 and CTX, and mAb MK2-23 conjugated to KLH and mixed with BCG and CTX. Six patients could not be evaluated since they withdrew from the clinical trial after the first immunization. Sera were tested for the development of anti-anti-id antibodies, including those reacting with HMW-MAA. Testing of sera for development of antimouse Ig antibodies was used to monitor the immune competence of patients. Conjugation to KLH and administration with BCG markedly enhanced the ability of mAb MK2-23 to induce anti-anti-id antibodies, including those reacting with HMW-MAA. In contrast, pretreatment with CTX had no detectable effect on the ability of mAb MK2-23 to elicit a humoral anti-anti-id response. Kaplan-Meier survival analysis showed that the performance status of patients, anti-anti-id antibody level, and development of anti-HMW-MAA antibodies had an effect on survival time. This effect was found when the survival time was calculated both from the day of the first immunization and from 4 weeks after the first immunization to the end of the study. A multivariate analysis by Cox regression showed that the development of anti-HMW-MAA antibodies was the most important variable for predicting survival, and that performance status was the only variable that significantly added to the prediction of survival. These data have to be interpreted with caution because of the retrospective nature of the analysis. Nevertheless, the present study suggests that mAb MK2-23 represents a useful immunogen to implement active, specific immunotherapy in patients with malignant melanoma.

Animals↗
PubMed1994

Sustained high levels of circulating chaperoned interleukin-6 after active specific cancer immunotherapy.

In a phase 1 study of recombinant interleukin-6 (rIL-6) in patients with advanced solid tumors (n = 15), we discovered that the endogenous IL-6 levels, in pretreatment plasma or serum samples, were distributed into two groups. One set of patients (designated "type 1"; n = 9) was characterized by low plasma IL-6 levels (48 to 1,700 pg/mL) as measured using enzyme-linked immunosorbent assays (ELISA) for IL-6. In the second set of patients (designated "type 2"; n = 6), IL-6 ELISAs showed high levels of plasma IL-6 (50 to 600 ng/mL). Neither group had detectable B9 hybridoma cell growth factor activity associated with the IL-6 in their pretreatment plasma or serum. Plasma C-reactive protein (CRP) levels were markedly elevated in type II patients suggesting that the circulating IL-6 was biologically active in vivo. In both groups of patients there was a small but significant increase in B9 activity in the plasma within three hours after rIL-6 administration (n = 5). Gel filtration profiles showed that circulating IL-6 in type 1 patients, 15 to 120 minutes after rIL-6 administration was of approximate mass 20 to 40 kD, whereas in type 2 patients, the IL-6 before and after exogenous rIL-6 administration was indistinguishable and was of an approximate mass of 200 kD. IL-6 immunoaffinity purification of the 200 kD complexes showed these to contain multiple isoforms of IL-6 (14 to 31 kD) and the soluble IL-6 receptor (sIL-6R; 50 to 55 kD). A distinguishing clinical history was that all of the type 2 patients had been actively immunized with an anti-idiotypic monoclonal antibody (MoAb) (MK2-23) 3 to 12 months before initiation of this study for advanced melanoma. An analysis of the plasma IL-6 content in other melanoma patients (n = 16) during antiidiotypic MoAb immunization indicated that marked (up to 600 ng/mL) and sustained (several months) elevations of circulating "chaperoned" IL-6 were induced by active immunization regimens.

Antibodies, Monoclonal↗
PubMed1994

Kinetics of the immune response and regression of metastatic lesions following development of humoral anti-high molecular weight-melanoma associated antigen immunity in three patients with advanced malignant melanoma immunized with mouse antiidiotypic monoclonal antibody MK2-23.

Active specific immunotherapy has been implemented in patients with advanced malignant melanoma, utilizing the mouse antiidiotypic (anti-id) monoclonal antibody (mAb) MK2-23 which bears the internal image of high molecular weight-melanoma associated antigen (HMW-MAA). In a previous study, development of anti-HMW-MAA immunity in patients with advanced malignant melanoma immunized with anti-id mAb MK2-23 was found to be associated with a statistically significant survival prolongation. Since no information is available about the relationship between development of immunity and clinical response in patients immunized with anti-id mAb, the present study has characterized the kinetics of the immune response in three patients with advanced malignant melanoma who experienced regression of metastatic lesions following immunization with the anti-id mAb MK2-23. The three patients developed anti-mouse IgG antibodies, anti-anti-id antibodies and anti-HMW-MAA antibodies. The anti-HMW-MAA antibodies are mainly IgG, suggesting that the immune response elicited by anti-id mAb MK2-23 is T-cell dependent. The development of anti-HMW-MAA immunity preceded the reduction in the size of metastatic lesions. This temporal relationship suggests but does not prove that the anti-HMW-MAA immunity elicited by anti-id mAb MK2-23 has a beneficial effect on the clinical course of the disease in patients with malignant melanoma. This finding in conjunction with minor side effects associated with repeated administrations of mouse anti-id mAb MK2-23 suggest that active specific immunotherapy with anti-id mAb which bear the internal image of melanoma-associated antigen represents a viable therapeutic approach to malignant melanoma.

Aged↗
PubMed1994

Antigens of Lyme disease of spirochaete Borrelia burgdorferi inhibits antigen or mitogen-induced lymphocyte proliferation.

Modulation of cellular immune responses by the spirochaete Borrelia burgdorferi, the bacteria that causes Lyme disease, was demonstrated. When cultured in the presence of sonicated Borrelia preparation (Bb), the mitogen- or antigen-stimulated proliferative responses of normal lymphocytes were consistently lowered. Bb caused the greatest reduction in Concanavalin A (ConA) or antigen-stimulated proliferation, where almost 100% reduction in proliferation could be achieved. Bb also reduced phytohemagglutinin-M (PHA) or pokeweed mitogen (PWM)-stimulated peripheral blood lymphocyte (PBL) proliferation, with the PWM proliferation being the least affected. This regulatory activity was not due to toxicity and was determined to be caused by Bb protein antigens. The degree of the proliferation reduction was directly proportional to both Bb quantity and length of exposure to lymphocytes. IL-2 production was significantly reduced from Bb-exposed lymphocytes. The entry of lymphocytes into the proliferating phases of the cell cycle was also shown to be blocked. These results have demonstrated an immune suppressive mechanism of B. burgdorferi. The magnitude of host immune responses may be dependent on the degree of suppression which is related to the spirochaete quantity and their length of presence in the host.

Antigens, Bacterial↗
PubMed1994

Incidence and treatment of tumor lysis syndrome in patients with acute leukemia.

Tumor lysis syndrome (TLS) is a complication associated with electrolyte abnormalities that is observed in patients with acute leukemia who are receiving intense doses of chemotherapy. Forty-one patients with acute leukemia were treated with high-dose combination chemotherapy and were evaluated for TLS. A grading system developed for the evaluation of these patients was applied. Grade I tumor lysis was observed in 22 patients, grade II TLS in 2 patients and grade III in 1 patient. All patients were treated with intravenous fluids, mannitol, allopurinol and in some patients, aluminum-based antacids. Treatment for TLS prior to intensive chemotherapy reduced morbidity and mortality associated with high-dose chemotherapy for acute leukemias.

Adolescent↗
PubMed1994

Allogeneic marrow transplantation for myelodysplastic syndrome complicating autologous bone marrow transplantation.

A patient with refractory relapsed Hodgkin's disease underwent an autologous bone marrow transplant in July 1987 and achieved remission of Hodgkin's disease. He had complete hematological recovery but developed pancytopenia 3 years post bone marrow transplantation with morphological evidence of myelodysplasia. High-dose cyclophosphamide, 200 mg/kg, chemotherapy followed by an allogeneic bone marrow transplant from a HLA-matched sibling was performed in April 1991 with complete hematological recovery. Allogeneic bone marrow transplantation was thus used successfully to treat a potential complication of autologous bone marrow transplantation.

Adult↗
PubMed1994

Treatment of gancyclovir resistant cytomegalovirus with foscarnet: a report of two cases occurring after bone marrow transplantation.

Cytomegalovirus (CMV) infection is common in patients who undergo allogeneic bone marrow transplantation. Gancyclovir is useful in treating CMV infections. Resistance to gancyclovir is rare and has, thus far, not been reported in the setting of BMT. Two patients with CMV infections unresponsive to gancyclovir were successfully treated with foscarnet. 10-15% of CMV infections are resistant initially or develop resistance to gancyclovir. Both patients had an adequate trial of gancyclovir and resistance developed over time. While we did not document resistance in the laboratory there was dramatic clinical improvement with foscarnet.

Adult↗
PubMed1994

TMJ: a well-tolerated high-dose regimen for the adjuvant chemotherapy of high risk breast cancer.

Following local treatment and doxorubicin-containing standard chemotherapy, 42 patients with surgical Stage II or IIIA breast cancer containing ten or more involved axillary nodes and 13 patients with Stage IIIB disease were treated with high-dose chemotherapy (TMJ) consisting of thiotepa (750 mg/m2), mitoxantrone (40 mg/m2), and carboplatin (1000 mg/m2), with autologous bone marrow (ABM) and peripheral stem cell (PSC) transplant, followed by irradiation and/or hormone therapy. Sargramostim (GM-CSF) support was given to most patients. The median time to transfusion independence was two weeks. Severe non-hematologic toxicity was uncommon, with no intensive care admission or treatment-related death. At a median follow-up of 17 months, eight patients have relapsed and five have died of tumor progression. No statement can yet be made regarding adjuvant efficacy, but this high-dose regimen is very well tolerated.

Adult↗