Biomedical subjects

R T Silver

Publications and source records attributed to R T Silver.

At least 19 recordsLinked to original sources

PubMed1992

Hodgkin disease survivors at increased risk for problems in psychosocial adaptation. The Cancer and Leukemia Group B.

BACKGROUND: The long-term psychosocial adaptations of 273 survivors of advanced Hodgkin disease were assessed to determine the nature and extent of problems experienced and to identify those at high risk for maladaptation. METHODS: Hodgkin disease survivors were identified who initially had been treated in clinical trials within the Cancer and Leukemia Group B from 1966 to 1986, were currently disease free, and had completed treatment for a minimum of 1 year. All survivors had advanced Hodgkin disease (with disease diagnosed at a mean age of 28 years). Survivors were at a mean age of 37 years at the time of interview (6.3 years after treatment completion), and 60% were male. Survivors were interviewed over the telephone 7-10 days after questionnaires were mailed to them concerning their psychological, social, vocational, and sexual functioning. RESULTS: Psychological distress was found to be elevated by one standard deviation (SD) above that of healthy subjects on the Brief Symptom Inventory, and 22% met the criterion suggested for a psychiatric diagnosis. In addition, the following problems were reported by survivors to be a consequence of having had Hodgkin disease: denial of life (31%) and health (22%) insurance, sexual problems (37%), conditioned nausea in response to reminders of chemotherapy (39%), and a negative socioeconomic effect (36%). Survivors found to be at high risk for maladaptation were: men earning less than $15,000 per year or who were currently unemployed; unmarried individuals; those with serious illnesses since treatment completion; and those who were less educated. CONCLUSIONS: These findings suggest that including a routine assessment of these factors would help to target survivors in need of additional evaluation and treatment.

Adaptation, Psychological↗

PubMed1992

Disappearance of a highly unusual clone, 46,XY,del(7)(p12),t(9;22)(q34;q11) in chronic myeloid leukemia after treatment with recombinant interferon and cytosine arabinoside.

A patient with the typical features of the stable phase of chronic myeloid leukemia (CML) displayed two karyotypically related subclones. In addition to the t(9;22), cells from one clone contained a deletion of the short arm of chromosome 7, del(7)(p12), [46,XY,del(7)(p12),t(9;22)(q34;q11)]; the other contained only the standard translocation [46,XY,t(9;22)(q34;q11)]. Cells with a deletion of the short arm of chromosome 7 at band p12 as the only additional abnormality have not been observed previously in CML. Conventional chemotherapy with hydroxyurea and then with recombinant interferon-alpha (rIFN-alpha) did not reduce the population of either subclone. However, after treatment with a combination of rIFN-alpha and low-dose cytosine arabinoside (LoDac) continuously infused subcutaneously (s.c.), cells from the clone with the deleted chromosome 7 disappeared and normal metaphases were demonstrable.

Adult↗

PubMed1992

Chronic myeloid leukemia.

Chronic myeloid leukemia is an enigma in origin and a source of frustration in treatment because until recently no real progress had been made in altering its natural history. Nevertheless, recent advances in cell biology and molecular genetics, and a plethora of morphologic, biochemical, and cytogenetic data of potential clinical relevance have yielded new data regarding this disease. The use of marrow transplantation and recombinant interferon have been of significant clinical importance, although their roles in the overall treatment of the disease remain to be determined.

Bone Marrow Transplantation↗

PubMed1992

Attempted prevention of blast crisis in chronic myeloid leukemia by the use of pulsed doses of cytarabine and lomustine. A Cancer and Leukemia Group B study.

An attempt to prevent the blast crisis in chronic myeloid leukemia by the use of pulsed doses of (cytarabine cytosine arabinoside) and lomustine was attempted as a cooperative group study by Cancer and Leukemia Group B. The basis for this study was to delay the development of blast crisis by pulsing dose of drugs known to be effective against emerging "blast" cells. The experimental arm which consisted of cytarabine and lomustine did not produce overall results superior to conventional treatment with busulfan. This was related to the non-hematologic effects of the combination which produced significant gastrointestinal toxicity leading to relatively early discontinuation of the combination. Nevertheless, the trial design allowed relatively prompt discontinuation of experimental arm and cross-over to conventional treatment with either hydrea or busulfan. No evidence existed that the use of new drug combinations in CML prejudiced the patient's chance to response to conventional chemotherapy. Thus, a role model for future trials in this disease was developed. With the development of the interferons and other experimental forms of therapy this conceptual development may be of significance.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1992

Lymphomatoid papulosis: case report of a patient managed with radiation therapy and review of the literature.

Lymphomatoid papulosis is an elusive and very rare skin disorder. It is clinically benign but histologically "atypical," and about 20% of affected patients go on to develop a lymphoreticular malignancy, usually Hodgkin's disease, or mycosis fungoides. A wide variety of treatments to prevent recurrence and improve local control have been suggested, but the results have been poor. We report on a patient with two nonhealing lymphomatoid papulosis lesions treated successfully with electron beam therapy and describe our technique. The need for close follow-up of all patients with this condition cannot be overemphasized.

Humans↗

PubMed1991

The effects of postinduction intensification treatment with cytarabine and daunorubicin in adult acute lymphocytic leukemia: a prospective randomized clinical trial by Cancer and Leukemia Group B.

Cancer and Leukemia Group B undertook a randomized trial of intensification treatment in adults aged 15 to 79 years with acute lymphocytic leukemia (ALL) in complete remission (CR). Daunorubicin (DNR), prednisone, vincristine (VCR), intrathecal (IT) methotrexate (MTX), and asparaginase produced 177 CRs in 277 patients. One hundred fifty-one patients were randomly assigned to receive treatment as follows: 74 received intensive cytarabine and DNR, and 77 received cycles of mercaptopurine (6-MP) and MTX, followed by 6MP, MTX, VCR, and prednisone for 3 years in all. One hundred twelve patients received CNS prophylaxis. Intensification produced major myelosuppression but did not improve remission duration (median, 21 months). Of the 151 patients with CRs who entered the intensification phase, 29% remain in continuous CR (43 to 117 months); in 19 patients, CRs have lasted for longer than 7 years. No relapses occurred after 60 months. Median survival from the time of randomization was 30 months. Those under 30 years of age responded more frequently, with longer CR and survival. While 53% of those aged 15 to 19 years remain in continuous CR, 92% of patients over 59 years have relapsed. The presence of a myeloid antigen on the leukemic cells was adversely prognostic for CR achievement and for survival. Pretreatment WBC and platelet levels independently affected CR duration and survival. Early M1 marrow development presaged longer remissions. CNS relapse occurred in 47 of 256 patients with normal CSF before treatment, in 29 before CNS prophylaxis. CNS disease occurred after CNS prophylaxis in 18 patients: 13 of 61 who had received standard premaintenance and five of 51 who received intensification. No advantage in CR duration or survival resulted from intensive treatment with DNR and cytarabine following induction of CR.

Adolescent↗

PubMed1991

Multicenter clinical trial of mitoxantrone in non-Hodgkin's lymphoma and Hodgkin's disease.

In this phase II multicenter trial, the efficacy and safety of mitoxantrone (Novantrone; Lederle Laboratories, Wayne, NJ) were evaluated in the treatment of 206 patients with relapsed non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD) previously treated with other agents. Sixty-nine percent of the patients had received prior therapy with doxorubicin. The patients received 14 mg/m2 of mitoxantrone every 3 weeks. Nineteen (12%) of the NHL patients and two (7%) of the HD patients had complete responses (CRs). The combined CR and partial response (PR) rates were 37% (60 of 163) for NHL patients and 36% (10 of 28) for HD patients; the median duration of response was 323 days for NHL patients and 209 days for HD patients. The median survival times were 337 days for patients with NHL and 469 days for patients with HD. The median survival time for patients with low-grade NHL was 589 days compared with 298 days for patients with intermediate-grade NHL and 167 days for patients with high-grade NHL. The median time to treatment failure was 73 days for NHL patients and 98 days for HD patients. The major toxicity was myelosuppression, which was moderate and reversible. Nausea, vomiting, and alopecia were mild. There were two cases of congestive heart failure (CHF) considered related to treatment; both patients had received prior treatment with doxorubicin. In this group of heavily pretreated patients, mitoxantrone was effective and well tolerated. Responses were seen with mitoxantrone in patients who had relapsed after prior therapy with doxorubicin and in patients who had failed to respond to prior therapy with doxorubicin. Mitoxantrone should be evaluated in less heavily pretreated patients and should be considered for incorporation into combination chemotherapeutic regimens for the treatment of malignant lymphoma.

Drug Evaluation↗

PubMed1991

A loading dose/continuous infusion schedule of fludarabine phosphate in chronic lymphocytic leukemia.

Using a loading dose/continuous infusion schedule, fludarabine phosphate was administered to 51 patients with previously treated chronic lymphocytic leukemia (CLL). All patients had evidence of active disease, and the majority had advanced Rai stages. Of the 42 patients assessable for response, 22 (52%) achieved a partial response, five (12%) had stable disease, and 15 (36%) progressed. Thirteen of the 22 responders improved their Rai stages with fludarabine therapy, including six patients who achieved stage 0. Response rates for pretreatment stages III and IV were 60% and 53%, respectively. Patients with final Rai stages 0 to II had better survival than those with stages III and IV. Patients who had undergone splenectomy before starting therapy were more likely to respond. Myelosuppression was the primary toxicity and did not appear to be cumulative. Severe leukopenia and thrombocytopenia, although infrequent, were associated with several deaths in the early cycles of treatment. Nonhematologic toxicity was mild with no serious neurotoxicity noted. Infections were common with 22 minor, 18 major, and 10 fatal episodes. Fludarabine phosphate by this alternative dosing schedule is effective in refractory advanced CLL and is well tolerated by the majority of patients.

Adult↗

PubMed1991

Densitometric analysis of Southern blot autoradiographs and its application to monitoring patients with chronic myeloid leukemia.

The characteristic genetic exchange in chronic myeloid leukemia (CML) is the fusion of the ABL proto-oncogene and a specific part of the BCR or phl gene. Detection of this exchange by cytogenetic or Southern blot analysis is highly diagnostic for CML. The latter approach has not previously been used to quantify the relative proportions of leukemic and non-leukemic cells. We have assessed the feasibility of estimating the relative proportion of leukemic cells present in a sample by densitometric analysis of autoradiographs of Southern blots. In dilution experiments of CML cells with normal cells, a linear relationship could be demonstrated between the relative intensity of the autoradiograph band corresponding bcr rearrangement and the proportion of leukemic cells present. This relationship was found to be largely independent of autoradiograph exposure time. Six patients receiving various therapies have been evaluated for as long as 4.5 years by repeated densitometric and cytogenetic analysis. In general, a declining proportion of Philadelphia (Ph) chromosome positive cells was paralleled by decreasing intensity of the autoradiograph band representing bcr rearrangement. Densitometric changes were often seen prior to the detection of Ph negative cells. This analysis appears to provide a sensitive method for monitoring patients with CML.

Autoradiography↗

PubMed1990

A new treatment for polycythemia vera: recombinant interferon alfa.

Recombinant interferon alfa, a natural product with growth inhibitory capabilities, has been demonstrated for the first time to have significant therapeutic efficacy in controlling the red cell mass in patients with the myeloproliferative disease polycythemia vera. The starting dose was 3.0 X 10(6) U three times a week, subcutaneously (SC). In three patients the dose required was 5.0 X 10(6), U five times a week, SC. Side effects were easily tolerated. The striking advantage in the use of this drug is its presumed absence of antileukemic effect. Further evaluation is necessary, but the initial responses are encouraging.

Dose-Response Relationship, Drug↗

PubMed1990

Recombinant gamma-interferon has activity in chronic myeloid leukemia.

We demonstrated the clinical effectiveness of recombinant interferon-gamma (rIFN gamma) (Biogen) in 18 patients with Philadelphia-positive chronic myeloid leukemia. Sequential cytogenetic studies and molecular analyses of the breakpoint cluster region and for immunoglobulin and T cell rearrangements were performed every 3-4 months. In 13 patients who received treatment for a minimum of 3 months, the majority were treated with 1.5 mg/m2, t.i.w., i.v. Nonhematologic effects--particularly chills, rigors, myalgia, fatigue, headaches, and nausea--were significant. Complete or partial hematologic responses were observed in six patients, two of whom had approximately 20% normal metaphases after an average of 74 weeks of treatment. However, reversion to 100% Ph+ cells occurred 30 weeks later. In these two patients, in whom normal metaphases were found, no changes were observed in the presence of rearrangements of the breakpoint cluster region. In addition, the marrows remained hypercellular, and the leukocyte alkaline phosphatase score and B12 levels remained abnormal. No immunoglobulin or T cell beta-chain gene rearrangements were found. These data indicate the clinical effectiveness of rIFN gamma in some patients with chronic myeloid leukemia, although the fundamental nature of the disease is unaltered by this form of treatment.

Bone Marrow↗

PubMed1990

Quality of life assessment of Hodgkin's disease survivors: a model for cooperative clinical trials.

With the growing number of patients surviving cancer, there has been an increasing concern with their long-term adaptation. Given the large number of Hodgkin's disease survivors, it was possible to conduct a study of their psychosocial adaptation. Two hundred seventy-three survivors of advanced Hodgkin's disease were interviewed over the telephone concerning the impact of cancer upon their lives, in terms of their psychological, social, and sexual functioning. The level of psychological distress was elevated by one standard deviation above normal on the Brief Symptom Inventory (BSI), for both men and women. Survivors in greater distress reported more problems in other areas of functioning, including sexual, social, vocational, and persistent conditioned nausea.

Adaptation, Psychological↗

PubMed1990

Interferon in the treatment of myeloproliferative diseases.

Interferon alfa has been used in the treatment of myeloproliferative disorders, particularly chronic myeloid leukemia, polycythemia vera, and idiopathic thrombocythemia. The effectiveness of interferon alfa in agnogenic myeloid metaplasia needs additional evaluation, although preliminary evidence suggests that it may be more efficacious when used in the cellular (ie, proliferative) phase than when the marrow is fibrotic or osteosclerotic. Cytogenetic and molecular changes after interferon alfa therapy are apparent in patients with chronic myeloid leukemia, as manifested by change in the Philadelphia chromosome and BCR-ABL gene, respectively. The exact role of interferon in prolonging the life of chronic myeloid leukemia patients, however, remains to be determined in larger studies of longer duration. Interferon treatment seems to be well tolerated, and the frequency of treatment-limiting toxicity is low. Data to date suggest that interferon alfa may be a new and effective drug for the treatment of the myeloproliferative disorders.

Humans↗

PubMed1990

Chronic myeloid leukemia. A perspective of the clinical and biologic issues of the chronic phase.

Although chronic myeloid leukemia is an incurable disease for the majority of patients, striking advances in our understanding of cell biology, molecular genetics, and new treatment programs involving interferon and bone marrow transplantation have led to clinical improvement for a small number of patients afflicted with this disease. Nevertheless, hope exists that such basic and clinical information will be expanded to a larger number of patients in the near future.

Blast Crisis↗

PubMed1990

Blastic phase of chronic myeloid leukemia (blCML): a proposal for standardization of diagnostic and response criteria.

The selection of optimal treatment among the alternatives that are available is especially difficult in blastic phase of chronic myeloid leukemia (blCML) because of the absence of universally agreed upon criteria for the diagnosis of this phase and the absence of definitions of response. Variable response rates, from less than 10 to greater than 90% have been reported, but the highest response rates, in general, have not been reproducible. The application of strict morphologic, cytogenetic, and molecular biologic studies should provide the means for selection of optimal treatment among the new therapies that will be introduced in the future.

Blast Crisis↗

PubMed1989

A phase II clinical trial of adoptive immunotherapy for advanced renal cell carcinoma using mitogen-activated autologous leukocytes and continuous infusion interleukin-2.

Forty patients with metastatic, recurrent, or unresectable renal cell carcinoma were entered into a study of the therapeutic efficacy of adoptive immunotherapy using periodate (IO4-) and interleukin-2 (IL2)-activated autologous leukocytes and continuous infusion low-dose IL2. Patient survival was also examined. The first 15 consecutive patients were enrolled in protocol A without an IL2 priming phase and the following 25 patients were entered in protocol B where a 5-day priming phase was initiated before leukapheresis. A maintenance regimen consisted of either 3 x 10(6) units of recombinant interferon-alpha (rIFN-alpha), three times per week only or together with leukapheresis and infusion of IO4-/IL2-activated cells and 2 days of continuous infusion IL2 per month. Thirty-four patients completed the protocol treatment. Four patients were removed from the study owing to rapid tumor progression and two patients died while receiving treatment. The clinical response rate was 22%: two patients had a complete response and five patients had a partial response. Among the 25 patients who had no clinical response, 11 patients had either a mixed response or stabilization. Neither response, response duration, nor site response correlated with the total dose of IL2 administered or the number of activated killer cells infused. Patients who received maintenance therapy had longer survival times than patients who did not receive such therapy. All toxicity and side effects associated with IL2 treatment were transient and resolved after discontinuation of the drug. Patients on maintenance therapy tolerated both rIFN-alpha and monthly infusions of activated killer cells and IL2 well. This study confirms the concept of adoptive immunotherapy as a new treatment approach for advanced renal cell carcinoma and suggests that maintenance therapy may prolong survival time.

Adult↗

PubMed1989

Fine mapping of chromosome 22 breakpoints within the breakpoint cluster region (bcr) implies a role for bcr exon 3 in determining disease duration in chronic myeloid leukemia.

The chromosomal translocation that fuses the phl gene with the c-abl proto-oncogene appears to be a pivotal step in the pathogenesis of some leukemias. In chronic myeloid leukemia (CML) the breakage within the phl gene is largely confined to a 5.8-kb segment referred to as the breakpoint cluster region (bcr). To determine whether the presence of specific bcr exons on the Philadelphia chromosome has any clinical significance, we have analyzed the bcr breakpoints in 134 patients with CML. As many as five probes were used in this analysis, including a synthetic oligonucleotide probe homologous to the bcr exon 3 (phl exon 14) region. The distribution of breakpoints indicates that, in fact, breakage is largely confined to a 3.1-kb segment lying between bcr exon 2 and exon 4 (phl exons 13-15). In 61 CML patients analyzed within 1 year of diagnosis, the distribution of breakpoints appeared to be random within the 3.1-kb region. However, a significant excess of 5' breakpoints was observed in the total population studied, consistent with previous data showing that patients with 3' breakpoints have shorter disease durations. Analysis using the bcr exon 3 sequence probe indicated it was probably the presence or absence of bcr exon 3 on the Philadelphia chromosome that accounts for some of the variability in disease duration seen in CML. The data suggest that the phl/abl protein product may influence the timing of the onset of blast crisis and imply a continuing role for this protein during the evolution of the disease.

Blotting, Southern↗

PubMed1988

The karyotype of Philadelphia chromosome-negative, bcr rearrangement-positive chronic myeloid leukemia.

Philadelphia (Ph) chromosome negative chronic myeloid leukemia (CML) can be distinguished from clinically similar disorders on the basis of the presence of rearrangement of the breakpoint cluster region (bcr) of chromosome 22. We have identified six patients with Ph-negative CML, each with bcr rearrangement. Apparently normal karyotypes were observed in two cases, and a third contained a rearrangement that did not appear to involve chromosomes 9 or 22. The other three cases had translocations involving chromosome band 9q34 but no case contained the common derivative chromosome 9pter----9q34::22q11----22qter. One case appeared to contain either a deletion of an unrearranged bcr locus in approximately 50% of cells or duplication of rearranged bcr, both 5' and 3' of the chromosome 22 breakpoint. Considerable complexity exists in the types of genetic changes that can juxtapose bcr and the c-abl oncogene in CML. Based on the molecular and cytogenetic analyses of these and other cases described in the literature, we conclude that most cases of true Ph-negative CML arise from submicroscopic genetic exchanges rather than masking of simple t(9;22)(q34;q11) translocations by secondary rearrangements.

Adult↗