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Biomedical subjects

A B Deisseroth

Publications and source records attributed to A B Deisseroth.

At least 127 records · Page 7Linked to original sources
PubMed1991

Intensive combination chemotherapy and autologous bone marrow transplantation leads to the reappearance of Philadelphia chromosome-negative cells in chronic myelogenous leukemia.

Fifteen patients with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) who were ineligible for allogeneic bone marrow transplantation (BMT) or alpha-interferon therapy were included in this study. Eight patients were in the first late chronic phase, five were in the second chronic phase, one was in the accelerated phase, and one was in the blastic phase. Autologous bone marrow cells (median, 2.5 x 10(8) nucleated cells/kg) were stored at a median of 30 months after diagnosis. Patients were treated with cyclophosphamide (1.5 g/m2 daily for 4 days), carmustine (BCNU) (300 mg/m2), and etoposide (VP-16) (250 mg/m2 daily for 3 days) (CBV), followed by reinfusion of autologous bone marrow. Hematopoietic recovery was rapid, and toxicity was mild to moderate in 14 patients. One patient died of cytomegalovirus pneumonitis. Eight of 15 patients showed Ph suppression to less than 90% Ph-positive metaphases after autologous BMT. Major cytogenetic responses (Ph suppression to less than 35% Ph-positive metaphases) developed in four patients. Cytogenetic responses were observed in 4 of 11 patients infused with 100% Ph-positive marrows, and in all 4 patients infused with Ph-mosaic marrows (mixture of diploid and Ph-positive cells). Better results were observed when autologous BMT was performed in the chronic phase compared with the advanced phases. The major cytogenetic responses have lasted for 3, 4, 12, and 15+ months, whereas minor cytogenetic responses lasted for only a short time (less than 2 months). Three of seven patients (43%) in the chronic phase with previous resistance to alpha-interferon therapy became sensitive to alpha-interferon therapy after autologous BMT. The authors concluded that intensive chemotherapy followed by autologous BMT produced cytogenetic remissions in patients with Ph-positive CML and reinduced disease sensitivity to alpha-interferon therapy in patients previously resistant to it. This is particularly useful when treatment is given during the chronic phase and stem cells are collected at a time of previous cytogenetic remission.

Adult↗
PubMed1991

Therapeutic effects of genetically engineered toxin (DAB486IL-2) in patient with chronic lymphocytic leukaemia.

In DAB486IL-2 the receptor-binding domain of native diphtheria toxin is replaced by human IL-2 sequences. This recombinant fusion protein is selectively cytotoxic for cells bearing high-affinity IL-2 receptors--eg, leukaemic cells. A patient with chronic lymphocytic leukaemia who did not respond to gamma interferon and conventional antileukaemic drugs has responded to DAB486IL-2.

Diphtheria Toxin↗
PubMed1991

An effective acute graft-vs.-host disease prophylaxis with minidose methotrexate, cyclosporine, and single-dose methylprednisolone.

Cyclosporine and methotrexate at standard doses (15 mg/m2 on day 1 and 10 mg/m2 on days 3, 6, and 11, total 45 mg/m2) are effective in the prophylaxis of acute graft-vs.-host disease. However, the combination has significant early toxicities with delayed engraftment, increased mucositis, and hepatotoxicity. We modified the combination by adding single-dose methylprednisolone and lowered the total dose of methotrexate to 35 mg/m2 (5 mg/m2 on days 1, 3, and 6, and then 10 mg/m2 on days 11 and 18) and then to 20 mg/m2 (5 mg/m2 on days 1, 3, 6, and 11) in an attempt to decrease these side effects in two sequential consecutive groups of patients. We demonstrated that the modified regimens maintained the efficacy with reduced toxicities. The rate of engraftment was comparable to cyclosporine alone and the hepatotoxicity was reduced with reduced doses of methotrexate. Factors such as early immunosuppression of the host, intravenous immunoglobulin, the timing of steroid administration, nucleotide free diet and germ free environment may contribute to the effectiveness of the combination and permit reduction of methotrexate dose.

Bone Marrow Transplantation↗
PubMed1991

Rapidly alternating radiotherapy and high dose cisplatin chemotherapy in stage IIIB non-small cell lung cancer: results of a phase I/II study.

Alternating radiotherapy and chemotherapy increases tumor cure rates in some animal models with reduced normal tissue damage compared to sequential use of these modalities. To test this concept in non-small cell lung cancer, 23 patients with predominantly Stage IIIB disease were treated on a Northern California Oncology Group pilot study of alternating radiotherapy and high dose cisplatin. Radiotherapy consisted of 6000 cGy delivered in three separate 10-day courses of 200 cGy/fraction/day during weeks 1 and 2, 5 and 6, and 9 and 10. High dose cisplatin, 100 mg/m2 in 3% saline, was administered on weeks 3 and 4, 7 and 8, 11 and 12, and 15 and 16. The response rate in 22 eligible patients is 73% (16/22) with four complete responses and 12 partial responses. Feasibility of this approach is demonstrated by 20/22 patients completing radiotherapy and a median of 2.5 courses of chemotherapy administered. Median survival time is 14.2 months (range 2-40+ months). One- and 2-year survival rates are 64% (14/22) and 41% (9/22), respectively. Hematologic, renal, and radiation-related toxicities were significant but manageable. We conclude that rapid alternation of radiotherapy and a high dose intensity cisplatin regimen is feasible in Stage IIIB non-small cell lung cancer, with a high response rate and acceptable toxicity. The long-term impact on local control and survival remains unclear, although preliminary survival data are encouraging in this poor prognosis population. Further studies of this concept are warranted.

Adenocarcinoma↗
PubMed1991

Interleukin-2, cisplatin, and 5-fluorouracil for patients with non-small cell lung and head/neck carcinomas.

The feasibility and efficacy of treating patients with locally recurrent or metastatic non-small cell lung cancer (NSCLC) or head/neck cancer with interleukin-2 (IL-2), cisplatin, and 5-fluorouracil (5-FU) was tested. Treatment was given every 28 days and consisted of cisplatin, 100 mg/m2 on days 1 and 8; 5-FU, 1,000 mg/m2 by continuous infusion on days 1-3; and IL-2, 12 million units/m2 by i.v. bolus on days 15-19. Thirty-four patients (22 NSCLC, 12 head/neck cancer) were registered in the study. The median age was 58 years; 59% had Karnofsky performance status of 70-80% and over one-half received prior therapy. All patients were evaluable for toxicity and 29 (18 NSCLC, 11 head/neck cancer) were evaluable for response. Twenty-five patients experienced at least one grade 3 or 4 toxicity, but these toxicities were transient and, in general, well tolerated. The response rate was 37% for NSCLC (0 complete response, 7 partial response) and 55% for head/neck cancer (2 complete response, 4 partial response). Two patients with head/neck cancer responded to treatment after failing prior therapy with cisplatin/5-FU alone. The combination of IL-2, cisplatin, and 5-FU is tolerable and active for treatment of NSCLC and head/neck carcinoma; the combination may not be cross-resistant with other chemotherapy combinations. Further studies of IL-2 combined with cisplatin/5-FU are warranted to determine the most effective dose and schedule.

Adult↗
PubMed1991

Chromosome 17- and p53 changes in lymphoma.

The clinical course of lymphoma patients in whom rearrangements or deletions of the short arm of chromosome 17 (17p) were evident by cytogenetics was rapidly progressive with a short survival. The gene for the protein designated p53 resides in 17p. We studied four lymphoma cell lines derived from human tumours, and 25 tumour samples of patients with lymphomas, for any evidence of p53 genomic changes by Southern blot technique. The four cell lines and four of the 25 tumour samples showed numerical changes of chromosome 17 or structural abnormalities of 17p (translocations or deletions). Allelic loss of the p53 gene was found in two of the four cell lines, and one of these in addition showed a rearrangement of the 3' end of the gene. Of the four tumours known to have chromosome 17 abnormality, one specimen showed allelic loss of the p53 gene. None of the remaining tumour samples showed any significant change. These studies suggest that acquisition of changes in the short arm of chromosome 17, which may be interrelated with the p53 gene, may carry a poor prognosis in patients with non-Hodgkin's lymphoma.

Adult↗
PubMed1991

Effects of low doses of recombinant human granulocyte-macrophage colony stimulating factor (GM-CSF) in patients with myelodysplastic syndromes.

There has been no previously published experience with granulocyte-macrophage colony stimulating factor (GM-CSF) doses less than 12 micrograms/m2 daily in patients with myelodysplastic syndromes, and most observations have been made at doses greater than or equal to 120 micrograms/m2 daily. We administered 5 micrograms/m2 daily by subcutaneous injection to 29 such patients increasing the dose in patients who did not show a haematologic response. Doses of 5 or 10 micrograms/m2 ('low-dose GM-CSF') produced an increase in neutrophils in 14/29 patients. Response was significantly (P = 0.03) more frequent in patients who had a higher pre-treatment neutrophil count (e.g. 11/16 in patients with greater than or equal to 0.5 x 10(9)/l). A rise in blasts followed administration of low-dose GM-CSF in five patients, all with either refractory anaemia with excess blasts (RAEB) or refractory anaemia with excess blasts in transformation (RAEBT). Platelets decreased in five patients, four of whom had no change in blasts, reverting to baseline when GM-CSF was discontinued. We and others have previously observed similar rises in blasts or decreases in platelets at doses of 120 micrograms/m2 daily. Low-dose GM-CSF produced no constitutional side effects. Our results suggest that low doses of GM-CSF might be initially employed in neutropenic patients with myelodysplastic syndromes who present with pretreatment neutrophil counts greater than 0.5 x 10(9)/l. Increasing the dose, and hence the risk of extramedullary toxicity, only in patients who do not respond to the low dose. Patients who present with lower pre-treatment neutrophil counts might begin treatment at doses above 10 micrograms/m2, but below the 120 micrograms/m2 commonly employed, which may be necessary in relatively few patients.

Aged↗
PubMed1991

Interferon-alpha restores the deficient expression of the cytoadhesion molecule lymphocyte function antigen-3 by chronic myelogenous leukemia progenitor cells.

Hematopoietic cells from the malignant clone in chronic myelogenous leukemia (CML) maintain and expand a proliferative advantage over normal hematopoietic cells within the bone marrow. This advantage is often ameliorated or reversed in vivo by IFN alpha. Based upon earlier studies suggesting decreased adhesiveness of CML progenitor cells, we asked whether CML progenitor cells are deficient in their expression of the cytoadhesion molecule lymphocyte function antigen-3 (LFA-3, CD58) which is normally expressed on hematopoietic progenitors. Progenitor cells from untreated CML patients showed greatly reduced or absent LFA-3 expression, whereas progenitors from patients treated with IFN alpha in vivo or in vitro expressed surface LFA-3 at more normal levels. LFA-3-deficient CML progenitor cells were unable to stimulate normal regulatory proliferative responses in autologous T cells. We hypothesize that IFN alpha-sensitive LFA-3 deficiency reflects a cell surface cytoadhesion defect which may help explain adhesive abnormalities of CML progenitor cells in vitro and clonal proliferation in vivo.

Antigens, Surface↗
PubMed1991

Impact of autologous bone marrow infusion on hematopoietic recovery after high-dose cyclophosphamide, etoposide, and cisplatin.

Because of potential tumor contamination and inadequacy of current purging technique of bone marrow in patients with solid tumors, we investigated an alternative approach to high-dose therapy without autologous bone marrow (ABM) infusion. Three levels of nonmyeloablative doses of cyclophosphamide 4.5 to 5.25 g/m2, etoposide 750 to 1,200 mg/m2, and cisplatin 120 to 165 mg/m2 (CVP) were administered to patients with metastatic solid tumors. Patients were randomized to ABM (n = 46) or no-ABM (NABM) (n = 46) infusion after CVP to study the impact of ABM on hematopoietic recovery, morbidity, and mortality. All patients had ABM harvested, underwent conventional chemotherapy, and then received CVP. Seventy-three patients received two courses of similar doses. The following were the median days to absolute neutrophil count (ANC) of 0.1 x 10(9)/L: for the ABM arm, 19, 21, and 19 and for the NABM arm, 23, 20, and 21 at levels 1, 2, and 3, respectively, during course 1 (P = .01, .80, and .01, respectively). During course 2, ANCs to 0.1 x 10(9)/L and 0.5 x 10(9)/L were attained significantly faster at levels 1 and 3 in the ABM arm. ANC to 1.0 x 10(9)/L was comparable in both arms. Incidence of infection and duration of fever were similar in both arms. Although mortality and the incidence of delayed hematopoietic recovery were more frequent in the NABM arm, this was not statistically significant. Platelet recovery was consistently prolonged in course 2 in both arms, with demonstrable benefit of ABM in course 2 when dose levels were collectively considered. We conclude that (1) ABM enhanced recovery of ANC to 0.1 x 10(9)/L; (2) ABM did not decrease the incidence of infections and the duration of fever; and (3) CVP can be safely given without ABM to carefully selected patients.

Adult↗
PubMed1991

Use of blood and blood products for supportive care in cancer treatment.

Prophylactic platelet transfusion can prevent spontaneous hemorrhage in thrombocytopenic cancer patients undergoing intensive treatment, but it is limited by the development of platelet alloimmunization. Exclusive use of leukocyte-depleted blood products delays or prevents the development of platelet alloimmunization and also decreases the frequency of chill and fever reactions and reduces the transmission of cytomegalovirus and possibly other viral infections. Management of disease refractory to platelet transfusion remains a difficult problem. Intravenous immune globulin reduces the incidence of infection and may modify the severity of gram-negative sepsis, decreases the incidence of acute graft-versus-host disease, and may benefit some patients with platelet refractoriness. All blood products given to severely immunocompromised patients, including those undergoing chemoradiotherapy and high-dose therapies, should be irradiated. In addition, designated donor transfusions from first-degree relatives (even when given to immunocompetent patients) should be irradiated.

Blood Transfusion↗
PubMed1990

Treatment of poor-prognosis, newly diagnosed acute myeloid leukemia with ara-C and recombinant human granulocyte-macrophage colony-stimulating factor.

We administered recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) (120 micrograms/m2/d by continuous intravenous [IV] infusion) to 12 patients with newly diagnosed acute myeloid leukemia (AML) at relatively high risk of early death during remission induction. GM-CSF began 3 days after completion of induction chemotherapy (ara-C 1.5 g/m2 d x 4 days by continuous IV infusion after a 3 g/m2 bolus). Rates of fatal infection (42%), pneumonia and/or sepsis (83%), and CR (50%) did not differ significantly (P less than .05) from those observed after administration of the identical chemotherapy without GM-CSF to 53 historical controls with newly diagnosed AML at similarly high risk of early death. There were no significant differences between the GM-CSF-treated and the historical groups in the time required to reach neutrophil counts of 500 or 1,000/microL after administration of chemotherapy. Four patients died of infection before they could have benefited from the earliest recovery of neutrophil count observed in patients who entered CR. Growth of leukemia after GM-CSF administration was observed in only 1 of the 8 patients who survived long enough for response to induction therapy to be fully evaluated. This observation suggests that it might be safe to undertake larger, randomized studies, perhaps using earlier administration of GM-CSF, to definitively determine the role of GM-CSF added to chemotherapy in patients with newly diagnosed AML.

Adult↗
PubMed1989

Cisplatin dose intensity in non-small cell lung cancer: phase II results of a day 1 and day 8 high-dose regimen.

Between October 1985 and March 1987, 92 patients were registered on a phase II study of the Northern California Oncology Group investigating the importance of dose intensity in the treatment of advanced non-small cell lung cancer (NSCLC). Treatment consisted of high-dose cisplatin in hypertonic saline (200 mg/m2 on a 28-day cycle) given in a divided day 1 and day 8 schedule. The response rate among 76 assessable patients was 36% (27/76), with complete response (CR) in 8% (6/76) and partial response (PR) in 28% (21/76). If all patients receiving any drug therapy were considered, the overall response rate was 31% (27/87), with CR in 7% (6/87) and PR in 24% (21/87). Median survival times for all assessable patients and all patients receiving any therapy were 37 and 35 weeks, respectively. With the use of a protocol design specifying dose delays rather than dose reduction for toxicity, the mean dose intensity delivered was 47.2 mg/m2 per week, or 94% of projected. Compared with other dose-intensive regimens of cisplatin, this day 1 and day 8 schedule was relatively well tolerated, with peripheral neuropathy as the dose-limiting toxicity. The data on response and median survival times among patients receiving this single-agent therapy are encouraging. They support the potential importance of cisplatin dose intensity in the treatment of NSCLC. Whether these results represent a positive dose-response effect in NSCLC will be tested in a randomized comparative trial of high-dose versus standard-dose cisplatin therapy.

Adenocarcinoma↗
PubMed1989

Ras oncogene mutations are rare late stage events in chronic myelogenous leukemia.

DNA from bone marrow and peripheral blood samples of 44 chronic myelogenous leukemia (CML) patients were analyzed for the presence of mutations of codons 12, 13 or 61 of the N-ras, H-ras, or K-ras genes. In seven patients, samples were available from both their chronic phase and blast crisis. A total of 29 samples examined were at chronic phase and 22 were at blast crisis (eight lymphoid, eight myeloid, and six undifferentiated). No mutations were identified in N-ras or H-ras. Two patients in myeloid blast crisis had K-ras mutations, one patient at codon 12, the other at codon 13. In the former patient the mutation was not present and the latter patient was not tested in chronic phase. Our findings indicate ras mutations are an infrequent late stage event in CML that occur in myeloid blast crisis.

Genes, ras↗
PubMed1986

v-abl activates embryonic globin gene expression in mouse erythroleukemia cells.

The Philadelphia chromosome translocation, which is present in 90-95% of chronic myelogenous leukemia patients, involves translocation of the c-abl protooncogene to chromosome 22 and is accompanied by activation of embryonic globin gene expression in the K562 chronic myelogenous leukemia cell line. To test directly if the protein products of the translocated c-abl protooncogene can activate embryonic globin gene expression, we transfected the v-abl oncogene (which shares the property of autophosphorylation with the translocated c-abl protooncogene) into mouse erythroleukemia cells. v-abl-transfected mouse erythroleukemia cells, which contained multiple copies of the v-abl transgenome, exhibited activation of mouse embryonic globin gene expression. These results suggest that the translocated c-abl protooncogene of the Philadelphia chromosome translocation is central to the pathogenesis of chronic myelogenous leukemia and that it may result in the activation of embryonic globin genes in some chronic myelogenous leukemia cell lines.

Abelson murine leukemia virus↗
PubMed1986

Late intensive combined modality therapy followed by autologous bone marrow infusion in extensive-stage small-cell lung cancer.

To attempt to improve the poor prognosis of extensive-stage small-cell lung cancer (SCLC) patients, we tried to administer late intensive combined modality therapy (LICMRX) to patients with good tumor regression after 12 weeks of conventional chemotherapy. Twenty-nine consecutive extensive-stage SCLC patients received 6 weeks of cyclophosphamide, methotrexate, and lomustine (CMC) induction therapy, followed by 6 weeks of vincristine, doxorubicin, and procarbazine (VAP). After restaging for assessment of tumor response, autologous bone marrow (ABM) was collected in patients in good medical condition with complete response (CR) or partial response (PR) and no tumor on marrow examination. LICMRX consisted of irradiation with 2,000 rad in five fractions for five days to sites of initial tumor involvement, followed by cyclophosphamide, 60 mg/kg for 2 days, and etoposide, 200 mg/m2 for 3 days and then by ABM infusion. Prophylactic cranial irradiation (PCI) was administered thereafter, but no further chemotherapy was used. Due to lack of tumor regression or poor medical condition, only ten of the original 29 patients were eligible for LICMRX; two refused, so only eight (28%) received therapy. Three patients who began LICMRX in CR developed recurrence of SCLC after an additional 4, 8, and 15 months. Of five patients with PR, one attained CR but relapsed at 3 months, two remained in PR and progressed at 2 and 4 months, and two died of infection without recovery from LICMRX. Mean time from ABM infusion to recovery of granulocyte count to 500/microL was 15.8 days in the six surviving patients (range, 12-22). The major non-hematologic toxicity of LICMRX was severe esophagitis. Among all 29 patients, there were six CRs (21%) and no 2-year survivors, compared with a CR rate of 36% and 10% 2-year survivors in 78 extensive-stage patients previously treated with CMC plus VAP without LICMRX. We conclude that the LICMRX given in this study can be administered to only a minority of extensive-stage SCLC patients and is very unlikely to yield substantial improvement in the fraction of 2-year survivors (95% confidence limits for 2-year survival 0% to 10%).

Adult↗