Processing of bone marrow for transplantation: development of a mononuclear cell enrichment protocol.
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Blood Component Removal↗
Biomedical subjects
S F Williams
Publications and source records attributed to S F Williams.
High-dose chemotherapy with autologous stem cell rescue in women with metastatic breast cancer with involved bone marrow: a role for peripheral blood progenitor transplant.
This retrospective analysis was done to determine the response rate and survival of women with metastatic breast cancer with bone marrow involvement treated with high-dose cyclophosphamide and thiotepa and peripheral progenitor cell rescue. Eligibility criteria included histologically-documented metastatic breast cancer and either stable disease, a partial response or a complete response to conventional dose chemotherapy. Due to bone marrow involvement, all patients received peripheral progenitor cell reinfusion. Purging of the stem cell product was not performed. Cyclophosphamide (CY) 7.5 gm/m2 total dose and thiotepa 675 mg/m2 total dose was used as the intensification regimen. Of 27 treated patients, 4 (14%) died of treatment-related toxicity. Three patients were in complete remission after induction chemotherapy and remained so after high-dose chemotherapy. Three patients converted from a partial response after induction to a complete response after transplant. This yielded a complete remission rate of 21%. Five of these six patients continue in CR at 5, 6, 11, 14, and 26 months post-transplant. Eight patients (29%) are alive with stable disease post transplant. Ten patients developed disease progression. Six patients died shortly after disease progression; however, four patients are alive with disease at 18, 26, 33, and 53 months post-transplant. The median time to treatment failure is 12 months. In women with metastatic breast cancer with bone marrow involvement, durable responses after high-dose chemotherapy are possible utilizing peripheral blood progenitor support rather than marrow purging.
Adult↗
Guillain-Barré syndrome after autologous bone marrow transplantation for breast cancer: report of two cases.
Guillain-Barré syndrome appeared in two patients following autologous bone marrow transplantation for metastatic breast cancer. In one case, the patient responded to plasmapheresis and became ambulatory. In the second case, the patient died of an unrelated complication: intracerebral hemorrhage. Although Guillain-Barré syndrome is associated with hematologic malignancies, it has not been previously reported in patients with solid tumors undergoing autologous bone marrow transplantation. Because both patients were in remission at the time of the autograft, Guillain-Barré syndrome may emerge as a rare complication of altered immune function and/or viral infection after marrow transplantation.
Adenocarcinoma↗
Mitoxantrone, vincristine, and 5-fluorouracil with leucovorin modulation as induction chemotherapy prior to high-dose intensification in metastatic breast cancer.
We treated 39 women with newly diagnosed stage IV breast cancer with a new regimen of mitoxantrone 18 mg/m2 on days 1, 29, 57, vincristine 1.4 mg/m2 (maximum 2.0 mg) on days 1, 8, 15, 22, 29, 36, 43, 50, and 5-fluorouracil 375 mg/m2 on days 15-20, 43-47, 71-75 with leucovorin modulation 500 mg/m2 before each 5FU infusion (MVF). This regimen was utilized as an initial cytoreductive or induction program for these patients prior to high-dose intensification with autologous stem cell rescue. Ten patients (25%) obtained a clinical complete response and six patients (15%) obtained a partial response for an overall response rate of 40%. In addition, 10 patients had evaluable disease that was improved or stable (primarily bone and/or bone marrow metastases) after MVF induction. Thus, 26 patients (65%) were eligible for high-dose intensification with autologous stem cell rescue after MVF induction. Toxicity was primarily a mild mucositis and more commonly peripheral neuropathy. MVF therapy is an active treatment program for metastatic breast cancer but the neurotoxicity makes it difficult to recommend for widespread use.
Adult↗
Application of peripheral blood progenitors to dose-intensive therapy of breast cancer.
Dose-intensive therapy has been used with increasing frequency in the treatment of women with breast carcinoma. This therapy requires chemotherapeutic agents that exhibit a steep dose-response curve and that have myelosuppression as their primary dose-limiting toxicity. To hasten or to rescue hematologic function after dose-intensive therapy, a hematopoietic rescue is used. The source of this rescue has traditionally been autologous bone marrow cells. However, circulating peripheral blood progenitor cells can also reconstitute hematopoiesis after dose-intensive therapy. The only prerequisites are that hematologic recovery is at least comparable and that survival is not adversely affected by the source of the stem cell graft. Peripheral blood progenitors can be procured in sufficient numbers after priming or mobilization with chemotherapy and/or hematopoietic growth factors. Peripheral blood progenitors collected in this fashion have led to complete and sustained hematologic reconstitution in women with metastatic breast cancer involving the marrow. In addition, peripheral blood progenitors can be used to augment autologous bone marrow grafts, further hastening hematologic recovery after dose-intensive therapy. Future studies will examine the role of peripheral blood progenitor support of multiple dose-intensive cycles in women with breast cancer.
Antineoplastic Agents↗
Epileptic focus induced by intrahippocampal cholera toxin in rat: time course and properties in vivo and in vitro.
A small dose (0.5-1.0 micrograms) of cholera toxin injected into rat hippocampus induced an epileptic focus which discharged intermittently for 7-10 days. Epileptic discharges lasting from 70 ms to 2 min were recorded in vivo through implanted electrodes. The longer bursts could generalize to the neocortex, and occasionally caused motor seizures. The epileptic bursts reached a maximum 3-4 days after injection, and then declined to occasional brief interictal discharges by 9 days. Postmortem histology revealed no evidence of gross pathology or neuronal loss. Hippocampal slices prepared from rats < 8 days after injection of cholera toxin, and maintained in vitro, generated brief spontaneous and evoked epileptic bursts, usually lasting < 1 s. Spontaneous bursts always started in subregion CA3c, and propagated through the pyramidal layer at a mean of 0.18 m/s. Intracellular recordings from CA3 pyramidal layer cells always revealed simultaneous paroxysmal depolarization shifts during epileptic bursts. Epileptic activity, both in vivo and in vitro, required the whole toxin molecule. Injections of either the B subunit or the vehicle solution were not epileptogenic. Therefore binding of the toxin to neuronal membranes, which is mediated by the B subunit, was not sufficient for the epileptogenic effects of cholera toxin. This suggested that the activation of Gs which requires the whole molecule, was necessary. Gs activation is known to stimulate cyclic AMP production, but forskolin, which directly stimulates adenyl cyclase, failed to produce epileptic activity, even though it depressed action potential accommodation and afterhyperpolarizations (AHPs). While further work is required to resolve the basic mechanisms of cholera toxin induced epileptic foci, we propose that they require the activation of Gs, which can enhance Ca2+ currents and modify excitatory synaptic transmission directly. Cyclic AMP induced changes in these properties cannot be excluded. However, cyclic AMP induced reductions in action potential accommodation and AHPs, which are found in cholera toxin foci, may contribute to, but are not sufficient for, epileptogenesis. Cholera toxin differs from the commonly used epileptic agents in that its main action is on G proteins and second messenger systems, rather than on synaptic transmission directly. Furthermore it has a prolonged time course, and does not cause gross pathology. These features combine to make it a distinctive model for epilepsy and neuronal synchronization.
Animals↗
Modulation of vinblastine resistance with cyclosporine: a phase I study.
OBJECTIVE: Tumor cell resistance is a major cause of failure to cure advanced malignancies. Multidrug resistance is thought to be an important mechanism of such resistance. Our aims were to identify doses of cyclosporine that would achieve blood levels effective in modulating multidrug resistance to vinblastine and to evaluate the toxicities and maximum tolerated dose of cyclosporine when administered in conjunction with vinblastine. METHODS: We conducted a phase I trial of vinblastine and escalating doses of cyclosporine. Cyclosporine was given by continuous intravenous infusion over 120 hours and vinblastine was administered by continuous infusion from hour 12 to hour 108. Sixty-two patients entered the trial, of whom 60 were evaluable. RESULTS: Cyclosporine was escalated from 1 to 15.6 mg/kg/day. Vinblastine doses were reduced to 1.6 and then 1.2 mg/m2/day because of increasing vinblastine toxicity at higher cyclosporine doses. The maximum tolerated dose of cyclosporine at 1.2 mg/m2/day vinblastine was 12.5 mg/kg/day; at this dose level, mean blood cyclosporine level was 1.25 +/- 0.41 mumol/L. Significant nephrotoxicity was observed at higher cyclosporine doses in two of four patients. Nephrotoxicity was not significant at doses at or lower than this maximum tolerated dose and was not cyclosporine dose dependent. Myelosuppression, neurotoxicity, and transient hyperbilirubinemia were observed and were cyclosporine dose dependent. CONCLUSIONS. Cyclosporine by continuous infusion may be safely given in high doses concurrently with continuous-infusion vinblastine. Plasma levels of cyclosporine > or = 1 mumol/L can be sustained during vinblastine administration. No sustained effect on T-cell subsets was observed. Vinblastine toxicity is enhanced by cyclosporine in a dose-dependent fashion and correlates with cyclosporine-induced hyperbilirubinemia.
Adult↗
Source of stem cell rescue: bone marrow versus peripheral blood progenitors.
Sustained hematopoiesis can be restored after dose-intensive chemotherapy utilizing stem cells from either bone marrow and/or peripheral blood. Numerous reports have demonstrated the effectiveness of peripheral blood progenitors (PBPC) in restoring hematopoiesis. Here, we review data comparing the recovery among patients rescued with various stem cell sources after dose-intensive therapy. PBPC used alone or to augment autologous bone marrow to achieve timely hematopoietic recovery after dose-intensive therapy can result in shortened hospital stays, decreased transfusion requirements, and antibiotic usage. This will lead to increased application of dose-intensive therapy either singly or in multiple courses to treat various malignancies.
Antineoplastic Combined Chemotherapy Protocols↗
Role of high-dose chemotherapy and autologous stem cell support in treatment of breast cancer.
Patients with metastatic breast cancer with chemotherapy-sensitive disease, good performance status, and few sites of metastatic disease are the best candidates for high-dose chemotherapy and autologous stem cell reinfusion. Even in this selected subset of patients with metastatic breast cancer, at best 30% to 40% will maintain a complete remission beyond 2 years. In the high-risk adjuvant setting, high-dose chemotherapy appears efficacious; however, results from ongoing randomized prospective trials will not be available for several years.
Antineoplastic Agents↗
Biosynthetic thiolase from Zoogloea ramigera. Mutagenesis of the putative active-site base Cys-378 to Ser-378 changes the partitioning of the acetyl S-enzyme intermediate.
The proposed active-site base Cys-378 of thiolase, responsible for deprotonation of acetyl-CoA, has been converted to a less acidic residue Ser-378 by mutagenesis. Comparison of the CD spectra and dimethyl suberimidate cross-linking experiments of the wild type, mutant Ser-378, and Gly-378 enzymes indicated that there have been no major conformational changes. The Ser-378 enzyme retains 0.1% of the Vmax of wild type in the direction of acetoacetyl-CoA thiolytic cleavage and 0.07% of the Vmax in the Claisen condensation direction. Analysis of the acetyl S-enzyme intermediate partitioning, that is capture of the acetyl enzyme by 1) the thiolate of coenzyme A relative to 2) the C-2 carbanion of acetyl-CoA, is changed to favor reaction 2 in the case of the Ser-378 mutant enzyme.
Acetyl-CoA C-Acetyltransferase↗
Don't let payment issue diminish importance of home i.v. therapy.
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Length of Stay↗
Increased expression of GAD mRNA during the chronic epileptic syndrome due to intrahippocampal tetanus toxin.
A few mouse minimum lethal doses (MLD) of tetanus toxin injected into rat hippocampus triggers prolonged changes in neuronal function. Spontaneously recurring epileptic discharges arise in both the injected and the contralateral, uninjected hippocampus. The seizures remit after about 6 weeks, to be succeeded by a permanent depression of hippocampal neuronal responses. There is no evidence of any loss of pyramidal cells at this low dose of toxin. Here we studied presumptive inhibitory, GABAergic neurons, using in situ hybridization (ISH) with a probe directed against the mRNA encoding glutamic acid decarboxylase (GAD), at each of 1, 2, 4 and 8 weeks after injection of tetanus toxin. Epileptic activity was recorded from hippocampal slices prepared from both injected and contralateral hippocampi of rats at each time point, unexpectedly persisting until 8 weeks. There were no significant differences in the numbers of neurons containing GAD mRNA between toxin- and vehicle-injected and control rats in any hippocampal subfield, at any survival time, except for an apparently transient loss of hilar signal in vehicle-injected rats at 1 and 2 weeks which we attribute to a significant, transient loss of neuronal GAD mRNA to below the threshold for detection by ISH using this probe. In contrast there was a marked increase in GAD mRNA in the toxin-injected group, which reached a peak at 4 weeks, and returned to control levels by 8 weeks. The changes were bilateral and were most marked in the hilus of the dentate area, but were also significant in CA3 and CA1. Upregulation of GAD mRNA was preceded by an increase in the levels of the mRNA for the alpha subunit of the GTP binding protein, Gs (Gs alpha), at 2 weeks which affected the GABAergic neurons selectively, and not the pyramidal or granule cells. These marked changes in GAD mRNA may contribute to putative adaptive responses within GABAergic neurons, which would help contain epileptic activity in these chronic foci. The changes in GAD expression may be due to mechanisms acting through an increase in mRNA encoding Gs alpha.
Animals↗
Cyclophosphamide mobilization of peripheral blood stem cells for use in autologous transplantation after high-dose chemotherapy: clinical results in patients with contaminated or hypocellular bone marrow.
Peripheral blood stem cells (PBSC) can be used for hematopoietic reconstitution in patients who have received high-dose chemotherapy (HDC). Previously, we reported 18 such patients who had nonmobilized PBSC harvested in steady state. We have now performed PBSC reinfusion in 24 patients with hypocellular or tumor-involved marrow who received cyclophosphamide (Cy) mobilization (4 grams/m2) prior to PBSC collection. The PBSC were collected upon rebound hematopoietic recovery by continuous-flow leukapheresis and subsequently cryoproserved. A median of 3.17 x 10(8) mononuclear cells/kg (range 1.47-3.95 x 10(8)) were collected. Patients underwent a median of 6 apheresis procedures (range 5-12). To date all 24 patients have undergone PBSC reinfusion after HDC. Fourteen patients received post-reinfusion granulocyte/macrophage colony-stimulating factor. Granulocyte recovery (> 500 x 10(6)/ml) has occurred at a median of 13.5 days (range 7-39) and platelet recovery (> 50 x 10(9)/ml without transfusion support) has occurred in 20 patients at a median of 33 days (range 7-121 days). Four other patients have platelet counts of greater than 20K and are transfusion independent, but have still not achieved counts of 50K. PBSC collection after Cy mobilization is feasible and effective for hematopoietic reconstitution after HDC and reinfusion. All 24 patients demonstrated trilineage engraftment. Although neutrophil recovery was not significantly hastened (as compared with our nonmobilized or steady-state data), time to platelet engraftment was foreshortened.
Adult↗
Neuropathology of the chronic epileptic syndrome induced by intrahippocampal tetanus toxin in rat: preservation of pyramidal cells and incidence of dark cells.
A few nanograms of tetanus toxin injected into a rat hippocampus causes a chronic epileptic syndrome characterized by brief seizures that recur intermittently for about 6 weeks. Cognitive and other behavioural impairments persist after the seizures and other epileptic electrographic activity have remitted, and may be permanent. Our previous studies suggested that the behavioural changes following seizure remission were an indication of functional impairment associated with decreased neuronal excitability rather than with neuronal loss. The conclusion that neurons were preserved relied on qualitative histological observations and, indirectly, on electrophysiological measurements of the amplitudes of antidromic population spikes. Recently, gross histopathology has been described in a quantitative histological study of rats 7-10 days after they had received rather higher doses of intrahippocampal tetanus toxin. Here we report a quantitative histological study of hippocampi from rats which had gained remission from seizures induced by low doses of tetanus toxin. Adult Sprague Dawley rats received unilateral injections of 3-4 ng (about 6-8 mouse LD50) tetanus toxin, or vehicle, into the dorsal hippocampus. The first experiment confirmed that postsynaptic evoked responses recorded from pyramidal cells were depressed 10-19 weeks after injection. Unexpectedly, there also was a decrease of 20% in the antidromic response from CA3a contralateral to the injection. However, cell counts in these hippocampi revealed no change in pyramidal cell numbers. The second experiment used rats from two breeding colonies, prepared for histology 7 weeks after injection. Hippocampal pyramidal cell numbers were within the normal range in all but three of the 24 rats that had received tetanus toxin. These three had lesions of the CA1 pyramidal layer contralateral to the injection. The lesions were of the order of 2 mm in diameter, and were associated with glial proliferation. When these three cases were excluded, there remained a small increase in glial density in CA1 of the toxin-injected rats. In addition, toxin-injected rats from one of the colonies were susceptible to a pathology known as acidophylic or dark cell change. These occurred in 11 of 18 toxin-injected rats from this colony, in all divisions of the pyramidal layer, in both the injected and the contralateral hippocampus (where parallel studies revealed independent secondary epileptic foci). We conclude that loss of pyramidal neurons is not necessary for the persistent behavioural changes in this model.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
High-dose consolidation therapy with autologous stem-cell rescue in stage IV breast cancer: follow-up report.
PURPOSE: Fifty-nine patients with newly diagnosed metastatic breast cancer were treated with induction chemotherapy followed by high-dose intensification and autologous stem-cell rescue (ASCR) to determine therapeutic efficacy. PATIENTS AND METHODS: Induction consisted of cyclophosphamide, doxorubicin, vincristine, and methotrexate with leucovorin rescue (LOMAC) in 27 patients, or fluorouracil, cisplatin, doxorubicin, and cyclophosphamide (FCAP) in 32 patients. Intensification after LOMAC was cyclophosphamide and thiotepa (CyTepa) with ASCR, and after FCAP it was cyclophosphamide, thiotepa, and carmustine (BCNU) in all but eight patients who received CyTepa. RESULTS: Median survival from study entry for the entire group was 13.3 months. Median time to progression from reinfusion for the 45 patients who underwent intensification was 7.5 months. After LOMAC and intensification, there were 12 complete responses (CR) (nine partial responses [PRs] after induction converted to CRs). Responses after FCAP and intensification were eight CRs (two PRs after induction converted to CRs). Median time to treatment failure from reinfusion was 5.4 months for LOMAC and intensification, and was 10.5 months for FCAP and intensification. Median survival from study entry was 15.1 months for all 27 LOMAC patients and 9.3 months for all 32 FCAP patients. Median time to treatment failure from reinfusion for 11 patients who were CRs at intensification has not been reached and is more than 13 months compared with a median of 5.5 months for the 23 patients in partial remission at intensification. CONCLUSIONS: High-dose intensification therapy has led to increased CR rates in metastatic breast cancer. The role of such therapy in the treatment of stage IV breast cancer requires further refinement.
Adult↗
A pilot study of prophylactic aerosolized amphotericin B in patients at risk for prolonged neutropenia.
Invasive aspergillosis continues to be a significant cause of morbidity and mortality in patients with prolonged neutropenia. We performed a phase I trial of escalating doses of aerosolized amphotericin B given by a face mask nebulizer system with a disposable bacterial exhale filter. Five, 10, 15, and 20 mg of drug were dissolved in sterile water and inhaled over 10 to 15 minutes twice daily. Tolerance was studied in 26 patients (18 transplant recipients, and 8 leukemia patients). No side effects were observed at any dose level. Prophylactic treatment ended for 14 patients (54%) when intravenous (IV) amphotericin B was begun empirically for antifungal coverage following fevers. Eleven patients (43%) continued inhaled amphotericin B until blood counts recovered. One patient was taken off study when she developed cardiogenic pulmonary edema. No patient developed clinically suspicious or pathologically documented infection with invasive aspergillosis. Prophylactic aerosolized amphotericin B is well tolerated at 5, 10, 15, and 20 mg twice daily dosing. In addition, prophylactic aerosolized amphotericin B does not appear to sensitize patients to the subsequent use of IV amphotericin B. Although this study suggests that prophylactic inhaled amphotericin B is well tolerated and effective, a large scale controlled trial is needed.
Adult↗
Characterization of CD34+ cells mobilized to the peripheral blood during the recovery from cyclophosphamide chemotherapy.
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Antigens, CD↗
Isolated/primary CNS relapse in women in remission after ABMT for metastatic breast cancer.
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Adult↗