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S F Williams

Publications and source records attributed to S F Williams.

88 records · Page 5Linked to original sources
PubMed1989

The role of high-dose therapy and autologous bone marrow reinfusion in the treatment of Hodgkin's disease.

In a significant fraction of patients with Hodgkin's disease, a condition develops that is resistant to conventional chemotherapy. Experience using high-dose chemotherapy, with or without TBI, and ABMR is expanding. In Hodgkin's disease, remissions can be achieved in approximately half of the patients with relapsed advanced disease. High-dose chemoradiotherapy regimens are toxic and require extensive supportive care. Relapse frequently occurs in areas of previous disease, which suggests failure of the conditioning regimen rather than infusion of occult tumor cells in the autologous bone marrow. Thus, the role of marrow purging in this therapy needs to be evaluated further. It is also important to evaluate the effects of more vigorous attempts at cytoreduction of bulky disease prior to high-dose therapy and ABMR. We recommend that high-dose therapy and ABMR in an investigational setting be used in patients with Hodgkin's disease who experience relapse after MOPP and ABVD or equivalent regimens. Toxicity can be decreased and efficacy increased only if therapy is administered to patients who have not been heavily pretreated and who have lower tumor burden and a good performance status. Finally, high-dose therapy with ABMR has a definite role in salvaging patients with refractory Hodgkin's disease. Many issues need to be resolved, including the optimal timing of this approach and the optimal conditioning regimen. In the years to come these questions may be answered by the many studies now under way.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Human plasma pharmacokinetics of thiotepa following administration of high-dose thiotepa and cyclophosphamide.

Thiotepa is an established alkylating agent whose pharmacokinetics in standard doses are well defined. In order to ascertain whether dose-dependent variations in pharmacokinetics occur, we have undertaken an analysis of plasma thiotepa levels in 16 patients entered on a phase I-II study of bialkylator chemotherapy. High-dose thiotepa (1.8 to 7.0 mg/kg) and cyclophosphamide (2.5 g/m2) were administered intravenously (IV) on days -6, -4, and -2 followed by autologous marrow reinfusion on day 0. Plasma and urinary thiotepa was assayed by gas chromatography. Biexponential plasma decay curves were seen in ten patients, with a t 1/2 alpha of 10.0 +/- 6.4 minutes, a t 1/2 beta of 174 +/- 61 minutes and a total body clearance of 379 +/- 153 mL/h/kg (mean +/- SD). Six patients displayed monoexponential plasma decay curves with a terminal t 1/2 of 137 +/- 83 minutes and a total body clearance of 440 +/- 195 mL/h/kg. Although there was a trend toward reduced plasma clearance in the three patients treated at the highest dose level, the available data suggest that metabolic clearance mechanisms for thiotepa were not saturated with the doses used in this study. By stepwise regression analysis, linear functions using only 15-minute and four-hour postinfusion plasma levels were derived that correlated closely with area under the plasma concentration X time curves (AUC) (P less than .002). We conclude that high-dose thiotepa results in similar pharmacokinetic values to conventional doses with no apparent dose-dependent variation. The value of specific time points to predict AUC and clearance will require prospective evaluation.

Chromatography, Gas↗
PubMed1988

The role of high-dose therapy and autologous bone marrow reinfusion in the treatment of malignant lymphomas.

In a significant fraction of patients with NHL or HD, disease develops that is resistant to conventional chemotherapy. Experience using high-dose chemotherapy, with or without TBI, and ABMR is expanding. In HD, remissions can be achieved in approximately half of the patients with relapsed advanced disease. This may also be true in patients with NHL who do not respond to conventional regimens. High-dose chemoradiotherapy regimens are toxic and require extensive supportive care. Relapse frequently occurs in areas of previous disease, suggesting failure of the conditioning regimen rather that an infusion of occult tumor cells in the autologous bone marrow had occurred. Thus, the role of marrow purging in this therapy needs to be further evaluated and compared with findings involving nonpurged marrow reinfusion. It is also important to evaluate the effects of more vigorous attempts at cytoreduction of bulky disease prior to high-dose therapy and ABMR. We recommend that high-dose therapy and ABMR in an investigational setting be used (1) in patients with HD who experience relapse after MOPP/ABVD or equivalent regimens and (2) in patients with intermediate or high-grade NHL whose disease recurs or is resistant to conventional regimens. Potential areas for development include the use of this modality as intensification therapy following conventional therapy in patients with intermediate or high-grade NHL with poor prognostic features. Toxicity can be decreased and efficacy increased only if therapy is administered to patients who have not been heavily pretreated and who have lower tumor burden and a good performance status. The role of high-dose chemotherapy of ABMR in the nodular lymphomas is not known at this point. Finally, high-dose ABMR therapy has a definite role in salvaging patients with malignant lymphomas. Many issues need to be resolved, including (i) the optimal timing of this approach, (ii) the optimal conditioning regimen, and (iii) the need for purging bone marrow prior to reinfusion. The past 10 years have led to significant gains. During the next 10 years, it may be possible to refine this therapy and find solutions to the above issues.

Antineoplastic Agents↗
PubMed1987

Motivational vs. motor effects of striatal and pallidal gabergic projections to subthalamic and entopeduncular nuclei, ventromedial thalamus, and ventral globus pallidus.

Four GABA-terminal sites downstream from the rat corpus striatum were injected bilaterally with either a GABA agonist (muscimol 15-250 ng) or antagonist (picrotoxin 15-300 ng), and the effects on spontaneous locomotor activity or variable-interval hypothalamic self-stimulation were recorded. Significant changes in locomotor activity were produced at all four sites, as in previous studies. Two of the sites tested, the anterior globus pallidus and the thalamic ventromedial nucleus, also receive gabergic projections from the nucleus accumbens or from structures other than the basal ganglia; at these two sites, injection of either muscimol (depressant), or picrotoxin (facilitatory), had the same effect on self-stimulation as on locomotor activity. The two other sites tested, the entopeduncular nucleus and subthalamic nucleus, do not receive projections from the accumbens; in these two structures, muscimol enhanced locomotor activity but abolished self-stimulation; picrotoxin was without significant effect, or was disruptive. These results confirm previous reports that gabergic systems downstream from the striatum can mediate a simple, innate motor sequence (locomotion), but they fail to demonstrate a specific involvement of these pathways in learned behaviour (self-stimulation).

Animals↗
PubMed1987

Physiological and behavioural consequences of seizures induced in the rat by intrahippocampal tetanus toxin.

Injecting tetanus toxin into rat hippocampus induces a syndrome of intermittent generalized seizures which recurs for about one month. Following remission from their seizures, the rats exhibit very persistent impairments of learning and memory. Learning was impaired on a circular platform task and a spatial reference memory task, and evoked responses from the commissural-CA3 pyramidal cell system were depressed for up to 22 weeks after injection. There was no significant loss of pyramidal neurons because antidromic responses, evoked from other parts of the commissural fibre system, were not affected by the toxin treatment. The depression of these pyramidal neurons provides a reasonable physiological explanation for the learning impairment. These results suggest that impairments of neuronal function can be significant factors in the development of interictal behavioural abnormalities.

Animals↗
PubMed1987

A phase I-II study of bialkylator chemotherapy, high-dose thiotepa, and cyclophosphamide with autologous bone marrow reinfusion in patients with advanced cancer.

Twenty patients with disseminated cancer both untreated and previously treated received bialkylator chemotherapy, thiotepa, and cyclophosphamide and reinfusion of cryopreserved autologous bone marrow (ABMR). The cyclophosphamide dose was constant at 7.5 g/m2 over three days, while thiotepa was started at 1.8 mg/kg for three days in escalating dose by a modified Fibonacci schema to 7 mg/kg. The median time to recovery of more than 500 granulocytes and more than 50,000 platelets/microL was 18 and 27 days, respectively. Four patients died as a consequence of severe, overwhelming infections or progressive disease during their period of aplasia. Of the 18 evaluable patients, a complete response (CR) was achieved in three patients and a partial response (PR) in ten patients for an overall response rate of 72%. The median duration of response was 14 weeks. Other nonhematologic toxicities included nausea/vomiting, diarrhea, stomatitis, skin rash, and cardiomyopathy. The maximum tolerated dose (MTD) of thiotepa was 700 mg/m2 or 6 mg/kg for three doses. Although there are substantial toxicities associated with this regimen, high-dose thiotepa and cyclophosphamide produce high response rates in patients with disseminated cancer.

Adult↗
PubMed1987

Sequential hydroxyurea-cytarabine chemotherapy for refractory non-Hodgkin's lymphoma.

In experimental systems, hydroxyurea (HU) and cytarabine (ara-C) produce synergistic cytotoxicity to murine and human leukemia cells due to both cytokinetic and biochemical interactions that tend to enhance the effectiveness of ara-C. Therefore, we began a phase II trial of the combination of HU and ara-C to determine the efficacy and toxicity of this combination in treatment of patients with refractory non-Hodgkin's lymphoma. Chemotherapy began with HU 500 mg administered orally every six hours for four doses. Twelve hours following the fourth HU dose, ara-C 100 mg/m2/d was administered by continuous intravenous (IV) infusion for three days. Concomitantly with the three-day ara-C infusion, patients again received HU 500 mg orally every four hours. Cycles of therapy were repeated every 28 days. Twenty-five patients ranging in age from 26 to 70 years were enrolled in the study. Of 21 patients evaluable for response, nine (43%) obtained complete (CR) or partial remissions (PR). Most responding patients had either large-cell or cutaneous T cell lymphoma, and all but two had a performance status of 0 to 1 at entry in the study. The median survival for all responding patients was 13 months compared with 2.5 months for nonresponders. Patients obtaining a CR had a median survival of 27.5 months, and two of the four CRs remain alive and in remission at 10+ and 30+ months from achievement of CR status. The primary toxic effect of this regimen was bone marrow suppression. The median WBC nadir was 2,200 cells/microL, and the median platelet nadir was 80,000/microL. Other toxicities included mild nausea and vomiting and diffuse maculopapular rash. This biochemically rational approach to enhancing ara-C activity may have significant clinical utility and should be further explored in treatment of patients with large-cell and cutaneous T cell lymphomas.

Adult↗
PubMed1986

Acute myelomonocytic leukemia with abnormal eosinophils and inv(16) or t(16;16) has a favorable prognosis.

Inv(16)(p13q22) and t(16;16)(p13;q22) are recurring chromosomal rearrangements which juxtapose the metallothionein gene cluster at 16q22 with other DNA sequences from 16p13. We have studied 20 men and 13 women who had acute nonlymphocytic leukemia; 27 patients had an inv(16) and six patients had a t(16;16). Eight patients also had trisomy 22, and four had trisomy 8. All but two patients had the unique morphologic features of acute myelomonocytic leukemia with abnormal eosinophils (M4Eo). In one patient with M4 leukemia, abnormal eosinophils were not observed in the marrow. A second patient had acute monocytic leukemia, plus abnormal eosinophils. Eosinophils constituted 1% to 46% (median, 6%) of the bone marrow cells, and in all but a single patient, the eosinophils exhibited distinctly abnormal morphology. Twenty-five patients have had a complete remission (78% of treated patients). Nine patients have remained in remission longer than 24 months. No patient had symptoms of central nervous system (CNS) disease at diagnosis, and none had CNS leukemic mass lesions at any time. Treatment with high-dose cytarabine may have provided prophylactic CNS therapy. Four additional patients with chromosomal rearrangements involving a breakpoint at 16q22 but not at 16p13 have had different morphological features and different clinical courses. Thus, the juxtaposition of genes at 16p13 and 16q22, which occurs both in the inv(16) and the t(16;16), results in a specific subset of acute nonlymphocytic leukemia that has a favorable prognosis.

Chromosome Banding↗
PubMed1986

Perspective on staging approaches in the malignant lymphomas.

The value of staging in malignant lymphomas is underscored by the advances made in therapeutic options. Through the years, it has become clear that combined modality therapy should be avoided if possible because of the increased risk of second malignant diseases. Thus, it is crucial to define those patients who are potentially cured by limited therapy, such as radiotherapy alone, or combination chemotherapy. This means that careful clinical staging with the best roentgenographic techniques currently available is necessary. At institutions, such as the University of Chicago and Stanford University, it is important to determine nodal disease that is potentially cured with radiotherapy (I through III, III1, at the University of Chicago). In non-Hodgkin's lymphoma, such as poorly differentiated lymphoma and diffuse histiocytic lymphoma, only a small percentage of patients in certain centers who have truly localized Stage I disease may benefit from radiotherapy alone. It is these groups of patients who may need surgical staging. Thus, in 1986, only a small percentage of patients with non-Hodgkin's lymphoma will actually benefit in terms of therapeutic options from the staging laparotomy. Perhaps as newer imaging techniques, such as magnetic resonance imaging, become available, the staging laparotomy may become obsolete.

Abdomen↗
PubMed1985

Cancer and pregnancy.

The most common malignancies occurring in women of child-bearing ages include breast, cervical, genital, and GI malignancies, and melanoma, lymphoma, and leukemia. Pregnancy does not appear to adversely affect the outcome of most tumors but may affect those that are known to be hormonally dependent. The approach in general to malignancy during pregnancy needs to be individualized. Therapy, whether by radiation or with cytotoxic drugs, has the greatest potential for fetal risk during the first trimester but more acceptable risk in the second and third trimesters. There are many unanswered questions concerning long-term effects of malignancy and its therapy upon the surviving child.

Adolescent↗
PubMed1984

Contribution of sodium to the mechanism of one-kidney, renal-wrap hypertension.

The early and chronic stages of one-kidney, figure-8 renal-wrap hypertension were studied during low or normal dietary sodium intake in rats. The renal-wrap procedure caused a significant elevation in arterial pressure at 3 and 28 days postwrap with normal sodium diet. Sodium-depleted rats did not experience an increased arterial pressure following renal wrapping. Blockade of angiotensin II receptors with [Sar1-Ala8]angiotensin II caused a greater decrease in arterial pressure in the sodium-depleted, renal-wrapped animals compared with sham-operated rats. In sodium-replete rats, angiotensin receptor blockade did not lower arterial pressure. Total ganglionic blockade decreased arterial pressure significantly more in the wrapped animals than in the sodium-replete sham-operated rats and the wrapped or sham-wrapped, sodium-deplete animals. Thus the early and chronic phases of normal sodium, one-kidney, figure-8 renal hypertension are supported by an increased sympathetic nervous system function. These observations suggest that sodium is necessary for the development of one-kidney, figure-8 renal-wrap hypertension and that the presence of sodium in the diet permits a functional activation of the sympathetic nervous system in response to the renal-wrap procedure.

Angiotensin II↗
PubMed1983

Anti-conflict and depressant effects by GABA agonists and antagonists, benzodiazepines and non-gabergic anticonvulsants on self-stimulation and locomotor activity.

Rats were injected systemically with different classes of gabergic agent in order to investigate gabergic involvement in limbic output. Agonists differed one from another in their effects on variable-interval self-stimulation: clonazepam (in repeatedly-tested rats), chlordiazepoxide and pentobarbitone had a strongly biphasic action, low doses being facilitatory and high doses depressant, whereas other agonists including valproate and 3-APS (homotaurine) were uniformly depressant. The facilitatory effects of the benzodiazepines were dramatically enhanced by GABA antagonists (picrotoxin or pentylenetetrazol) even though antagonists on their own produced a dose-dependent depression that was not reversible by other anticonvulsant drugs. Ventral tegmental electrode placements yielded generally similar results. Depression of self-stimulation observed on initial exposure to clonazepam was reversed by repeated self-stimulation testing in the drugged state but not by repeated daily injections without testing. Locomotor activity (under conflict-free conditions) was unaffected or was depressed both by agonists and by antagonists. Thus, the facilitation of self-stimulation by chlordiazepoxide, pentobarbitone and clonazepam appears to be accounted for in terms of non-gabergic anti-conflict activity by these agents. Self-stimulation and locomotor changes following systemic administration did not disclose facilitatory effects attributable to gabergic efferents from limbic dopamine areas.

Animals↗
PubMed1982

Feeding stimulated by very low doses of d-amphetamine administered systemically or by microinjection into the striatum.

The effects of d-amphetamine over a wide range of doses (0.125-4.0 mg/kg IP) on rat unconditioned behaviour were examined in the presence of food and water (experiment 1), in their absence (experiment 2) and after microinjection (2.0 micrograms in 0.5 microliter) directly into the striatum (experiment 3). In experiment 1 very low doses (0.125 and 0.25 mg/kg) stimulated the intake of food, but not water, and higher doses produced locomotor hyperactivity, rearing, stereotyped sniffing and anorexia. In experiment 2 all doses, including very low doses (0.125 and 0.25 mg/kg), significantly potentiated locomotor activity. In experiment 3, microinjection into the corpus striatum elicited substantial feeding, but not drinking, locomotor activity or stereotyped behaviour. The results suggest that a single graded facilitative mechanism underlies the effects on food intake and other behavioural effects of amphetamine, as implied by a general hypothesis of amphetamine action proposed in the literature, and that these effects may to a large extent be mediated by forebrain dopamine systems.

Animals↗
PubMedDate not supplied

PHA applications: addressing the price performance issue: I. Tissue engineering.

This paper describes the development of medical applications for polyhydroxyalkanoates (PHAs), a class of natural polymers with a wide range of thermoplastic properties. Methods are described for preparing PHAs with high purity, modifying these materials to change their surface and degradation properties, and methods for fabricating them into different forms, including tissue engineering scaffolds. Preliminary reports characterizing their in vivo behavior are given, as well as methods for using the natural polymers in tissue engineering applications.

Biocompatible Materials↗