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Biomedical subjects

C L Vogel

Publications and source records attributed to C L Vogel.

At least 55 records · Page 3Linked to original sources
PubMed1985

Phase I trial of misonidazole (NSC#261037) plus cyclophosphamide in solid tumors.

Misonidazole, a hypoxic cell sensitizer, enhances the antitumor effects of cyclophosphamide in preclinical studies. Several studies also showed increased cytotoxicity for normal tissues. We undertook a phase I study of this combination. The regimen consisted of oral administration of misonidazole at one of two dose levels, 1 g/m2 and 2 g/m2, followed by an intravenous (IV) injection of cyclophosphamide four hours later. The cycle was repeated every twenty-one days. The dose of misonidazole remained constant for each regimen, but the dose of cyclophosphamide ranged from 0.4 g/m2 to 1.3 g/m2. Thirty-eight trials in 35 patients with advanced solid tumors were considered evaluable. Dose-limiting toxicity was granulocytopenia at 1 g/m2 of cyclophosphamide without significant thrombocytopenia or anemia. Peripheral neuropathy was negligible. Two patients received cumulative doses of 8 and 16 g/m2 of misonidazole without neurotoxicity. One patient developed hemorrhagic cystitis. Nausea and vomiting was mild to moderate. Possible evidence of tumor stabilization was seen in three patients, and one patient had a mixed response. The mean serum half-life for misonidazole was 11.3 hours (range, 8.4 to 20.0) and for cyclophosphamide 8.3 hours (range, 3.2 to 15.5), both within the previously reported ranges. In conclusion, it appears that this combination is well tolerated and that misonidazole does not significantly potentiate myelotoxicity caused by cyclophosphamide or alter its pharmacokinetics. The recommended starting doses for misonidazole and cyclophosphamide in phase II trials using this schedule of administration should be 2 g/m2 and 1 g/m2, respectively, with escalation for cyclophosphamide to individual tolerance.

Adult↗
PubMed1984

Value of 8S/4S fractionation of estrogen receptors (ER) for prediction of response to hormonal manipulation in metastatic breast cancer.

Using sucrose gradient centrifugation, human breast cancer estrogen receptors appear in two molecular forms sedimenting at either 8S or 4S fractions. The sum of these two fractions has been valuable clinically in helping to predict response to hormonal therapies. It has been suggested that the 4S receptor may not be of predictive value and that the practice of using only dextran-coated charcoal methodology might thus overestimate the number of patients whose tumors might be hormonally dependent. The present study correlates clinical response to hormonal manipulations with 8S and 4S receptors as determined by sucrose density gradient centrifugation. Patients with only 4S positive receptors had a 56% response rate to hormonal manipulation compared with a 52% response rate in patients with positive 8S alone or with both 8S and 4S receptors. Although patient numbers are small in this and the other three published series addressing this question, our data do not confirm two previously published studies suggesting clinical importance of 8S/4S fractionation.

Adult↗
PubMed1984

Randomized trial of cyclophosphamide, doxorubicin, and 5-fluorouracil alone or alternating with a "cycle active" non-cross-resistant combination in women with visceral metastatic breast cancer: a Southeastern Cancer Study Group project.

Patients with visceral patterns of metastatic breast cancer were stratified according to dominant metastatic site and performance status and then randomized to therapy with cyclophosphamide, doxorubicin, and 5-fluorouracil (CAF) or CAF alternating with a "cell-cycle active" regimen including cytosine arabinoside, methotrexate with leucovorin rescue, and oncovin ( CAMELEON ). One hundred eighty-seven patients were randomized; response rate for CAF was 44% and for CAF + CAMELEON , 40%. Durations of disease control and survival were not significantly different. Toxicity of CAF was as anticipated with predominant granulocytopenia, vomiting, and alopecia. Toxicity of CAMELEON was less severe than that of CAF, and CAF toxicity was not worsened by preceding courses of CAMELEON ; however, the CAF- CAMELEON regimen was cumbersome and complex leading to both physician and patient noncompliance. Contrary to the preliminary results of a pilot study, and preliminary reports of the present trial suggesting benefit for the CAF- CAMELEON regimen the present randomized trial does not confirm any significant benefit of CAF- CAMELEON over CAF alone in patients with visceral metastatic breast cancer although this conclusion must be viewed in light of the high inevaluability rate due to patient and physician noncompliance.

Agranulocytosis↗
PubMed1984

Management of locally advanced breast cancer (stage III): a review.

Patients classified as having locally advanced breast cancer constitute a heterogeneous population of patients with variable prognoses among subgroups. Analysis of reported series has been complicated by the use of a wide variety of staging classifications and the inclusion by some (and not by others) of inflammatory carcinoma in reporting of end results. In spite of difficulties in this literature review, certain conclusions are possible: The 1983 AJCC-UICC staging system would appear to be a reasonable system for assuring comparability of results in future clinical trials. Although the precise frequency of LABC among series cannot be determined with certainty, this presentation probably constitutes less than 20% of series in the Western world. Recognizing that axillary lymph node status is the single most important prognostic variable in primary breast cancer, it has been reported that LABC with large local tumors are associated with neoplastic involvement of axillary lymph nodes in 65-80% of cases, thus connoting a poor prognosis. Patients with T3N0 lesions may constitute a subgroup of patients with relatively indolent (possibly receptor-positive) disease who might have a reasonably good prognosis compared with other variants of LABC, with approximately 75% to 82% of patients surviving five years with surgery alone. Surgery alone for the overall category of LABC is associated with a 20-31% ten-year survival rate, with local control varying from 50-75% in two reported series. Most radiation therapy (XRT) series deal with patients considered inoperable; hence five-year survival statistics in most series range between 10-20%. Selected radiation therapy series may yield results comparable to surgical series. Where reported, XRT has been associated with median survivals in the range of 25 months. Local control with XRT is likely a function of radiation dose, and the use of external beam or iridium implant boosts to the primary tumor mass for increased local control is worthy of continued study. The combination of XRT and mastectomy appears to be superior to either modality alone in terms of local control and survival, although this conclusion is based on analysis of retrospective studies. Combined modality therapy with systemic therapeutic modalities (hormonal and/or chemotherapy) plus the local modalities of surgery and radiation therapy appear promising. Prospective controlled trials using a uniformly accepted staging classification coupled with gathering of useful biological data (such as cytokinetic perturbation data, receptor information, marker studies, etc) should lead to improved treatment approaches in the future.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1983

Postmastectomy adjuvant chemotherapy with or without radiation therapy in women with operable breast cancer and positive axillary lymph nodes: the Southeastern Cancer Study Group experience.

Between September 1976 and June 1982, 308 patients with operable breast cancer with 1-3 involved axillary nodes were stratified according to institution, type of mastectomy, and time from surgery to protocol entry, and then randomized to receive either six or 12 months of adjuvant chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). With a median time of follow-up of 33 months, relapse rates among 181 reviewed and evaluable patients are 20/85 (23.5%) for pre- and 23/96 (24%) for postmenopausal patients. Results for premenopausal women, while better than historical controls at a similar time interval, appear inferior to other published adjuvant studies (e.g., NSABP and Milan). Although total relapse rates were 23/100 (23%) for six months and 20/81 (25%) for 12 months of therapy, suggestive differences were encountered by menopausal status with early trends favoring 12 months of treatment for premenopausal patients and six months of treatment for postmenopausal patients. During this same period, 283 patients with four or more involved axillary nodes were randomized to 1-3 treatment arms: six months of CMF, six months of CMF preceded by local-regional x-ray therapy (XRT), or 12 months of CMF. The latter arm was closed in February 1980 while the two six-month chemotherapy arms remain open as of January 1983. Relapse rates for 174 reviewed and evaluable patients on the three arms include: 27/76 (36%) for six months CMF, 15/54 (28%) for XRT and CMF, and 24/44 (45%) for 12 months CMF. Local-regional relapse rates were 12/120 (10%) for the combined two non-XRT arms and 3/54 (6%) for the XRT treatment arm (p = 0.34). Thus, at this early stage of follow-up there are still no statistically significant differences between six or 12 months of adjuvant CMF therapy and neither definite beneficial nor detrimental effects of prechemotherapy adjuvant radiation therapy. Longer follow-up will be needed to provide definitive conclusions.

Adenocarcinoma↗
PubMed1982

Maximizing differences in the concanavalin A-induced blastogenic responses of lymphocytes from breast cancer patients and controls by the use of alpha-methyl-D-mannoside.

In an attempt to magnify differences in the immune responses of potentially immunosuppressed cancer patients and normal controls, an assessment was made on the effects of the competitive inhibitor alpha-methyl-D-mannoside on the concanavalin A (Con A)-induced blastogenic responses of lymphocytes from each of these populations. Lymphocytes from breast cancer patients with metastatic disease were significantly deficient in their capability to undergo blast transformation regardless of whether the monosaccharide inhibitor was added to the assay cultures. In contrast, lymphocytes from breast cancer patients who did not display metastatic disease were capable of normal blastogenic responses to Con A. The addition of alpha-methyl-D-mannoside to lymphocyte cultures caused a significantly greater inhibition of the blastogenic responses of these patients' cells as compared to cells of normal controls. Thus the monosaccharide seems to serve as a useful reagent for optimizing differences between lymphocyte blastogenic responses of normal donors and those of immunodepressed donors. The results suggest that lymphocytes from breast cancer patients without clinically evident metastases possess some modification of their cell membrane. One possibility discussed was that the number or distribution of receptors for Con A on the membrane of lymphocytes of these patients is deficient.

Binding, Competitive↗
PubMed1982

Mitogen-induced blastogenesis and receptor mobility inhibition by breast cancer serum with elevated orosomucoid (alpha 1-acid glycoprotein) levels.

Sera from cancer patients have been shown to suppress normal lymphoid cell responsiveness in vitro. In the present study, sera from breast cancer patients were demonstrated to be inhibitory to the concanavalin A (Con A)-, Proteus vulgaris-derived phytohemagglutinin-, and pokeweed mitogen-induced blastogenic responses of normal lymphoid cells. Orosomucoid (OR) (alpha 1-acid glycoprotein), an acute-phase reactant, was elevated in these sera, and a positive correlation existed between the OR level in the sera and its immunosuppressive capacity. When normal lymphoid cells were reached in fluorescein isothiocyanate-labeled Con A, cells that had been preincubated in breast cancer sera known to contain an elevated level of OR showed a significant decrease in Con A receptor mobility as compared to the receptor mobility of the same lymphoid cells preincubated in normal sera. Thus a component(s) from the sera of the breast cancer patients had the capacity to inhibit lymphocyte activation. This inhibition might have resulted from an interaction of OR with the membrane.

Breast Neoplasms↗
PubMed1980

Mechanisms of levamisole-induced granulocytopenia in breast cancer patients.

Five of 39 (13%) women treated with adjuvant combination chemotherapy plus levamisole immunotherapy after mastectomy for Stage II or III breast cancer developed levamisole-induced granulocytopenia. This complication occurred in each of the women between six and ten weeks after the completion of six months of combination chemoimmunotherapy when they were taking levamisole alone. Although none of the patients had an HLA B-27 locus and leukoagglutinins could not be demonstrated, complement-dependent, IgM mediated, peripheral destruction of granulocytes was documented using a microgranulocytotoxicity assay. In addition, a factor(s) present in serum from patients developing levamisole-induced granulocytopenia caused suppression of bone marrow granulocyte progenitor cells (CFU-C). The possible relationships between levamisole-induced peripheral granulocyte destruction and bone marrow CFU-C suppression are discussed.

Acute Disease↗
PubMed1980

Studies on levamisole--induced agranulocytosis.

Widespread clinical trials of leavo-tetramisole (levamisole) as an immunopotentiating agent in rheumatoid arthritis, metastatic carcinoma, and immunodeficiency states have been complicated by agranulocytosis (AGC) in 2.5%-13% of patients. Other than a relationship with prolonged high dosage, very little is known regarding the pathogenesis of levamisole-induced AGC. Whereas leukoagglutination was negative, fluorochromatic microgranulocytotoxicity (GCY) tests were positive with serum from 10 of 10 acutely neutropenic patients. The antibody was IgM, reacted with 100% of unrelated granulocytes, but not with T or B lymphocytes. Some sera also reacted with monocytes and the myeloid cell line, K-562. Tests for antigen-antibody complexes or cold autoantibodies were negative. Although clinical evidence strongly suggests a haptene (drug) mechanism, in vitro mixing experiments were also negative. An alternative choice parallels the model of aldomet-induced Coombs'-positive hemolytic anemia. Finally, GCY first became positive 2-3 mo prior to the onset of AGC on two patients, suggesting the possibility of identifying those at risk well before the onset of neutropenia.

Agranulocytosis↗