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Biomedical subjects

M S Mitchell

Publications and source records attributed to M S Mitchell.

At least 37 records · Page 2Linked to original sources
PubMed1994

Phase II study of low dose cyclophosphamide and intravenous interleukin-2 in metastatic renal cancer.

Thirteen patients with metastatic renal cancer were treated in a phase II trial with interleukin-2, 21.6 million IU/m2 intravenously daily for five days on two consecutive weeks, starting 3 days after the administration of low dose cyclophosphamide 350 mg/m2 intravenously. Treatment cycles were repeated every 21 days. No responses were seen (95% Confidence Interval: 0-22%). The most common toxicities were fever, fatigue, hypotension, nausea/emesis, and myalgia/arthralgia. There were 11 episodes of Grade III toxicity including Grade III hypotension in 7 patients. Because of the significant toxicity and the lack of observed response, the study was discontinued. Cyclophosphamide and interleukin-2 at the dose and schedule used in this study has considerable toxicity and is unlikely to improve on response rates previously seen with other IL-2 based regimens in metastatic renal cancer.

Adult↗
PubMed1994

Non-fastidious, melanoma-specific CD8+ cytotoxic T lymphocytes from choroidal melanoma patients.

To characterize the anti-melanoma reactivity of CD8+ cytotoxic T lymphocytes (CTL) from choroidal melanoma patients, CTL clones were isolated from the peripheral blood of three patients after mixed lymphocyte/tumor cell culture (MLTC). Clones were derived from lymphocytes stimulated by allogeneic (OCM-1, A24, A28) or autologous (OCM-3, A1, A30) melanoma cells. Their reactivity against a panel of HLA-typed melanoma and nonmelanoma cells was assessed, to determine whether a single CTL clone could recognize and lyse a variety of allogeneic melanoma cell lines. While proportionately more clones derived from autologous MLTC were melanoma-specific than allogeneic MLTC (42% versus 14%), melanoma-specific CTL were recovered from both. Notably, a novel melanoma specificity was identified. These CTL clones were termed non-fastidious because they were capable of lysing melanoma cells with which they had no HLA class I alleles in common. Nonetheless, lysis was mediated by the HLA class I molecule. Since lysis was specific for melanoma cells, these CTL appeared to recognize a shared melanoma peptide(s). Because of their prevalence, we propose that non-fastidious CTL are integral to human anti-melanoma T cell immunity. This reinforces clinical findings that allogeneic melanomas can substitute for autologous tumors in active specific immunotherapy. By circumventing the need for autologous melanoma, it is possible to treat patients after removal of the primary choroidal melanoma in an attempt to prevent metastasis.

Antigens, CD↗
PubMed1994

Sustained regression of a primary choroidal melanoma under the influence of a therapeutic melanoma vaccine.

PURPOSE: To determine whether active specific immunotherapy with lysates of cutaneous melanoma cells, administered with immunologic adjuvant DETOX (Ribi ImmunoChem Research, Inc, Hamilton, MT), is effective in shrinking a primary choroidal melanoma, in an elderly patient already blind in the nontumorous eye. An 81-year-old man was referred with a primary choroidal melanoma of the left eye, with virtual blindness of the right eye due to macular degeneration. He was begun on active specific immunotherapy with an experimental melanoma vaccine (melanoma theraccine) and DETOX on weeks 1, 2, 3, 4, and 6, respected after a hiatus of 2 weeks. After a response was noted, monthly injections were given. RESULTS: The patient had a significant shrinkage of his choroidal melanoma from a height of 4.2 mm to 2.4 mm within 2 months. This was sustained by continual treatment for 21 months until September 1991. After the patient failed to return for 9 months while recuperating from a stroke, the lesion regrew to a height of 3.7 mm and developed an additional lobe. On resumption of monthly treatments, the lesion shrank to 3.4 mm within 3 months, lost the additional lobe, and has since remained stable. No metastases have been found over a period of nearly 4 years on quarterly computed tomographic (CT) scanning of the chest and abdomen, and magnetic resonance imaging of the head. CONCLUSION: Active specific immunotherapy with cutaneous melanoma lysates has caused a clinically useful protracted regression of a primary choroidal melanoma in an elderly patient in whom surgery and radiation therapy were contraindicated. This may represent the first case of a primary choroidal melanoma, and perhaps the only primary tumor, successfully treated with systemic immunotherapy alone. A formal trial of active specific immunotherapy for primary choroidal melanoma in selected patients may be warranted.

Adjuvants, Immunologic↗
PubMed1994

Increased effectiveness of interferon alfa-2b following active specific immunotherapy for melanoma.

PURPOSE: To determine whether interferon alfa-2b (IFN-alfa; intron-A, Schering Corp, Kenilworth, NJ) can induce a remission in patients previously treated with active specific immunotherapy (therapeutic melanoma vaccine) without response. PATIENTS AND METHODS: Eighteen patients with disseminated melanoma who had failed to respond to at least five injections of Melacine therapeutic melanoma vaccine (Ribi ImmunoChem Research, Inc, Hamilton, MT) were then treated IFN-alfa after a 4-week interval. IFN-alfa 5 or 6 x 10(6) U/m2 was self-administered three times a week subcutaneously by melanoma patients for at least 2 months. Computed tomographic (CT) scans of the chest, abdomen, and pelvis and magnetic resonance imaging of the brain were performed within 4 weeks before treatment as a baseline, and then at 2-month intervals during treatment to evaluate response. All 18 patients were HLA-typed before treatment. The frequency of cytolytic T-cell precursors (pCTL) in the blood had been measured weekly in 13 of the patients during treatment with Melacine. RESULTS: Eight of 18 patients (44.4%) had a major objective clinical response induced by IFN-alfa, including site-specific complete remissions in five. Responses lasted a median of 11 months. The median survival duration of the responders has not been reached, and exceeds 32 months. The group as a whole had a median survival duration of 10.1 months, and nonresponders lived 7.3 months. Cytolytic T-cell precursors had been increased by immunization in all five responding patients tested, but also in five of eight nonresponders. There was no association of response to IFN-alfa with specific HLA phenotypes, in contrast to our previous results with melanoma theraccine alone. CONCLUSION: These data suggest an additive effect of active specific immunotherapy and IFN-alfa on the objective response rate, perhaps through upregulation of HLA molecules and tumor-associated antigens on the tumor cell by IFN-alfa, after immunization of the patient by Melacine. This treatment may have improved survival over that expected in metastatic melanoma.

Adult↗
PubMed1994

The management of depression. The place of the new antidepressants. Part 1. General overview.

The introduction of the selective serotonin reuptake inhibitors, moclobemide and mianserin has been a major advance in the treatment of depression, and is already leading to major shifts in the pattern of antidepressants prescribing. These antidepressants are safe, well tolerated and effective, and in conjunction with older agents such as the tricyclics, provide the clinician with a broad range of treatments for this common and disabling disorder. This two-part review will focus on the management of depression in general practice.

Algorithms↗
PubMed1994

The management of depression. Part 2. The place of the new antidepressants.

Four years since the introduction of fluoxetine into Australian clinical practice, and two years since the availability of moclobemide, it is now possible to comment with some degree of certainty about the place of the new antidepressants. There do not appear to be any major complications or adverse effects associated with the recently marked antidepressants. While these medications clearly share their own similar and specific side effects, these problems are less frequent and severe than those experienced with the TCAs. Additionally, it has become obvious that they have fewer cardiac effects and possess a lower toxicity on overdose than the older classes of antidepressants. The differences in adverse effects between the various SSRIs appear to be minimal. Does this mean that the SSRIs, moclobemide and mianserin should be the treatment of first choice for depression? On balance, the evidence presented in this article would suggest rather that the new agents and TCAs should all be considered first-line agents. While discontinuation rates due to adverse effects are clearly less frequent with the new antidepressants, the currently available data do not indicate any difference in drop-out rates when discontinuation due to lack of efficacy is also incorporated into the equation. Irrespective of cost issues, the possible greater effectiveness of the TCAs in melancholic depression must also be taken into account. In conclusion, the advent of the SSRIs, moclobemide and mianserin has clearly been a major advance in the treatment of depression, and is already leading to major shifts in the pattern of antidepressant prescribing.(ABSTRACT TRUNCATED AT 250 WORDS)

Antidepressive Agents↗
PubMed1993

Active specific immunotherapy of melanoma with allogeneic cell lysates. Rationale, results, and possible mechanisms of action.

Since 1985, we have conducted clinical trials with a therapeutic melanoma vaccine (melanoma theraccine). Mechanical lysates of two melanoma cell lines chosen for their complementary characteristics were combined with the adjuvant DETOX and injected subcutaneously on weeks 1, 2, 3, 4, and 6 for one or two courses and then monthly in patients with objective clinical responses. Of 106 patients, 20 had objective clinical regression of tumor masses, 5 with complete responses. The median duration of response was 21 months. Twelve patients lived at least 2 years, with a median survival of nearly 3 years. Two of them are free of disease for > 2 and > 6 years, respectively. However, it was not necessary to achieve complete remissions to cause an increase in survival, and most of the long-surviving patients have one or more (stable) residual nodules. The pace of the disease process was clearly slowed in those individuals. A rise in the level of cytotoxic T-lymphocyte precursors in the blood (pTC) correlated with clinical response. Only those patients who had a rise in pTC had a remission. In addition to "classical" CD8+ Tc, CD4+ Tc were cloned from the blood of immunized patients. Melanoma-specific Tc of both types that killed autologous melanoma but not matched lymphoblastoid cells were detected. Allogeneic melanoma cell lines were also killed, with mainly HLA-A2/28 and HLA-B12/44/45 degenerate restriction. CD4+ Tc were restricted by HLA Class I antigens, as judged by their killing of HLA Class II-negative melanomas and blocking by anti-class I antibodies. Other CD4+ clones were blocked by both anti-HLA Class I or anti-Class II MHC monoclonal antibodies, and only two were blocked only by anti-HLA Class II. Immunohistory revealed CD4+ and CD8+ T cells in lesions under rejection, but the predominant cells were macrophages, suggesting delayed-type hypersensitivity as a possible mechanism. Clinical responses were found most often in patients with HLA-A2/28, -B12/44/45, and -C3, particularly when two or more of those alleles were present. This may have been due either to (1) similarity of MHC antigens between one of the immunizing melanomas and the patient's melanoma or (2) the intrinsic importance of these MHC molecules in presenting melanoma-associated antigens to Tc in vivo. IFN-alpha 2 b salvaged 8 of 18 patients who failed with the theraccine, regardless of MHC phenotype, perhaps through upregulation of MHC and tumor epitopes on the autochthonous tumor.

Antibodies, Neoplasm↗
PubMed1993

Protection against experimental cerebral metastases of murine melanoma B16 by active immunization.

Melanoma patients often develop brain metastases despite effective systemic immunotherapy against melanoma. We have attempted to establish a mouse model to develop strategies to combat this problem. Immunization of C57BL/6 (H-2b) mice with a combination of the syngeneic G3.12/BM2 melanoma (a B16 subclone) and the allogeneic Cloudman-S91 melanoma was effective in preventing the growth of 10,000 viable, s.c. injected G3.12 cells in 93% of the mice. Irradiated whole tumor cells pretreated with gamma-interferon for 2 days were most effective. A nonspecific adjuvant (DETOX) was injected routinely together with the tumor cells. Active immunization with 2 different doses of irradiated melanoma cells (1 x 10(5) or 2.5 x 10(6) cells/injection x 5 injections) protected against intracerebral challenge with 200 live G3.12 cells in 69% of the mice. This challenge caused the death of all control mice within 30 days. T-cell-mediated, tumor-specific cytotoxicity against G3.12 melanoma was demonstrated in the spleen of immunized mice. Histological observations in the brain, 80 days after tumor challenge, indicated complete eradication of the melanoma, but although CD4+ and CD8+ T-cells and macrophages were present, their number was low. Gliosis was present in both immunized and control animals. Thus, in this murine melanoma model syngeneic mice were protected from death by s.c. and intracerebrally inoculated tumor cells if pretreated with a sufficient number of irradiated syngeneic and allogeneic melanoma cells and an immunological adjuvant. Whether this regimen can treat established tumors of the brain, alone or in combination, is uncertain. Yet its success suggests that the "blood-brain barrier" impeding immunity to tumors may not be absolute.

Animals↗
PubMed1993

Clonal analysis of in vivo activated CD8+ cytotoxic T lymphocytes from a melanoma patient responsive to active specific immunotherapy.

To study in vivo activated cytolytic T cells, CD8+ T cells clones were isolated from a melanoma patient (HLA A2, A11) treated with active specific immunotherapy for 5 years. CD8+ T lymphocytes, purified by fluorescence-activated cell sorting, were cloned directly from the peripheral blood without antigen-presenting cells in the presence of irradiated autologous melanoma cells and recombinant interleukin-2 (IL-2) and IL-4. These conditions were inhibitory to de novo in vitro immunization. Of the 28 cytolytic CD8+ T cell clones, 21 lysed the autologous melanoma cell line (M7) but not the autologous lymphoblastoid cell line (LCL-7) nor the two melanoma cell line, M1 (HLA A28) and M2 (HLA A28, A31), used to immunize the patient. The remaining 7 clones were also melanoma-specific, although their reactivities were broader, lysing several melanoma cell lines but not HLA-matched lymphoblastoid cells. Eight clones from the first group, ostensibly self-MHC-restricted, were expanded for further analysis. All expressed cluster determinants characteristic of mature, activated T cells, but not those of thymocytes, naive T cells, B cells or natural killer (NK) cells. They also expressed CD13, a myeloid marker. Of the 8 clones, 3 expressed both CD4 and CD8, but dual expression was not correlated with specificity of lysis. Two CD8+ and 2 CD4+ CD8+ clones were specific for the autologous melanoma cells, the other 4 were also reactive against other HLA-A2-positive melanomas. Cytotoxicity for both singly and doubly positive clones was restricted by HLA class I but not class II antigens. Analysis of the RNA expression of the T cell receptor (TCR) V alpha and V beta gene segments revealed heterogeneous usage by the A2-restricted clones and, perhaps, also by the broadly melanoma-specific clones. Apparent TCR-restricted usage was noted for the self-MHC-restricted clones; 2 of the 4 expressed the V alpha 17/V beta 7 dimer. Since the T cell clones were derived from separate precursors of circulating cytotoxic T lymphocytes (CTL), the V alpha 17/V beta 7 TCR was well represented in the peripheral blood lymphocytes of this patient. In summary, we show that melanoma cells presented their own antigens to stimulate the proliferation of melanoma-reactive CD8+ CTL. CTL with a range of melanoma specificities and different TCR alpha beta dimers were encountered in this patient, perhaps as a result of hyperimmunization.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1993

Detection of melanoma-reactive CD4+ HLA-class I-restricted cytotoxic T cell clones with long-term assay and pretreatment of targets with interferon-gamma.

Twenty-five CD4+ cytotoxic T lymphocyte (CTL) clones were obtained from the peripheral blood or tumor tissues of melanoma patients undergoing active specific immunotherapy. Melanoma-reactive T cells were cloned by limiting dilution using either autologous or allogeneic melanoma cells to stimulate their proliferation. Sixteen of the clones reacted against autologous melanoma cells but not against the autologous lymphoblastoid cell line, which we defined as "melanoma-specific." Optimal demonstration of the lytic activity of CD4+ CTL required a 16-h incubation period and an effector:target cell ratio of 40:1. In addition, a 24-h pre-incubation of the target melanoma cells with 100 U interferon (IFN) gamma consistently augmented lysis by these CD4+ CTL, increasing it from a mean level of 20% to one of 52%. Lysis by 8 of the 11 melanoma-reactive CD4+ T cell clones was exclusively HLA-class-I-restricted, as judged by blocking with monoclonal antibodies (mAb). Five of these HLA class-I-restricted clones were reactive only with the autologous melanoma cells, while the other 3 clones were also reactive with allogeneic melanoma cells. In all cases, the T cells and melanoma targets shared at least one HLA class I allele, usually HLA-A2, HLA-C3 or HLA-B62. Interestingly, lysis by 2 of the 11 clones was inhibited by both anti-HLA-class-I or -HLA-class-II mAb, while lysis by 1 other clone was inhibited by neither. HLA class I molecules and several accessory molecules were maximally expressed by the melanoma target cells, both in terms of distribution and copy number before IFN gamma treatment. Thus, IFN gamma may have acted by increasing the expression of melanoma-associated epitopes as presented by HLA class I (or HLA class II) molecules. A proportion of human CD4+ CTL appeared to recognize melanoma-associated epitopes presented by the HLA class I molecule, although their lytic potency may be less than that of their CD8+ counterparts.

CD4-Positive T-Lymphocytes↗
PubMed1992

Low-dose recombinant interleukin-2 and low-dose cyclophosphamide in metastatic breast cancer.

We undertook a preliminary study to examine the response rate of recombinant interleukin-2 (rIL-2) in patients with advanced measurable breast cancer, in a phase II clinical trial. The regimen we utilized was designed to allow outpatient administration. A treatment cycle consisted of low-dose cyclophosphamide (350 mg/m2) given on day -3 followed by the bolus administration of rIL-2 (3.6 x 10(6) Cetus units/m2) on days 1-5, and 8-12. Toxicity was significant but acceptable. One partial remission was seen in 13 evaluable patients. In 2 additional patients clear evidence of an antitumor response was observed. The study was terminated prematurely owing to a shortage of rIL-2. Additional evaluation of rIL-2 in breast cancer appears warranted.

Adult↗
PubMed1992

Association of HLA phenotype with response to active specific immunotherapy of melanoma.

PURPOSE: Only a proportion of patients with disseminated melanoma who were immunized successfully with a therapeutic melanoma vaccine (theraccine) had a major clinical response. We investigated whether there was a correlation between their HLA phenotypes and the likelihood of a clinical response. PATIENTS AND METHODS: Seventy patients with disseminated melanoma who were treated with melanoma theraccine were HLA-typed serologically. The two melanoma cell lines used in the theraccine also were typed by serology and cDNA probes (for class II). Results were analyzed to see whether any alleles were present or absent in responders consistently. RESULTS: The HLA class I alleles A2 (and the cross-reacting A28), B12 (and its split B44 and B45), and C3 were found to be associated with clinical remission. The effects of these alleles on response were apparent when two or more of the alleles were analyzed together. There was a 38% response rate in those 24 patients with two or three of the alleles compared with 20% in the group as a whole. CONCLUSIONS: These data support two distinct possibilities between which we cannot yet distinguish. Responses may be more likely when there is a close match between the HLA molecules in the theraccine and the patients' own molecules. Alternatively, certain types of HLA class I molecules present in the patients may facilitate rejection of autochthonous melanomas by efficiently presenting melanoma-associated antigens to cytotoxic T cells.

Adult↗
PubMed1992

Atypical decubital fibroplasia. A distinctive fibroblastic pseudotumor occurring in debilitated patients.

We report 28 cases of atypical decubital fibroplasia, a distinctive pseudosarcomatous fibroblastic proliferation occurring primarily but not exclusively in physically debilitated or immobilized patients. The subjects included 16 women and 12 men ranging in age from 15 to 95 years. Peak incidence was in the 8th and 9th decades of life. Anatomic locations included the soft tissues overlying the shoulder (eight cases), posterior chest wall (five cases), sacrum (five cases), greater trochanter (four cases), buttock (two cases), thigh (two cases), and arm (two cases). Symptoms were due to a painless mass of 3 weeks' to 6 months' duration. Most lesions were ill-defined, focally myxoid masses that ranged from 1 to 8 cm. Histologically, they were situated in the deep subcutis and secondarily involved adjacent skeletal muscle (11 cases) and tendon (three cases). Extensive epidermal ulceration was typically absent. Microscopically, the lesions had a lobular configuration. They were characterized by zones of fibrinoid necrosis and a prominent myxoid stroma rimmed by ingrowing, ectatic, thin-walled vascular channels. All cases contained atypical, enlarged, degenerated fibroblasts with abundant basophilic cytoplasm, large hyperchromatic, smudged nuclei, and prominent nucleoli; these features resulted in a superficial resemblance to proliferative fasciitis. The enlarged, atypical fibroblasts stained diffusely and strongly for vimentin (15 of 15 cases) and focally for muscle-specific actin (10 of 15 cases), keratin (one of 15 cases), CD68 (10 of 15 cases), and CD34 (five of nine cases) antigens; none of the cases stained for desmin. A malignant diagnosis was considered in 43% of cases. Follow-up in 21 patients ranged from 2 to 78 months (median, 12 months). Two lesions recurred once, one recurred twice, and none metastasized; no deaths were attributable to the lesions. The clinical, histologic, and immunohistochemical features of atypical decubital fibroplasia indicate it is a unique type of pressure sore displaying degenerative and regenerative features distinct from decubitus ulcer. Its recognition by pathologists and clinicians in elderly and debilitated patients is important to avoid misdiagnosis as a sarcoma and to prevent or minimize the occurrence of decubital fibroplasia in progressively aging patient populations.

Adolescent↗
PubMed1992

Principles of combining biomodulators with cytotoxic agents in vivo.

Biomodulators (biologic response modifiers) can affect the tumor, the tumor-bearing host, or both, and thereby help the host to overcome the tumor. Most of the biomodulators have been stimulators of the immune system, while many chemotherapeutic drugs are immunosuppressive. Paradoxic effects of each on the immune response are described. This article briefly describes principles of tumor immunology and gives examples of the various effects of chemotherapy on the immune response. An understanding of how one type of therapy may affect the activity of the other will permit us to design rational combinations at schedules that are additive or synergistic.

Antibody Formation↗
PubMed1992

Chemotherapy in combination with biomodulation: a 5-year experience with cyclophosphamide and interleukin-2.

There are four classical forms of immunotherapy: active, adoptive, restorative, and passive, and perhaps a fifth form, cytomodulatory, the upregulation of tumor-associated and HLA antigens to make tumors more recognizable by the immune system. Our 5-year experience with low-dose cyclophosphamide (CY) (350 mg/m2) before low-dose interleukin-2 (IL-2) (21.6 million IU/m2/d x 5 d/wk x 2 wk per course by IV bolus) is reviewed as an example of combination chemotherapy and immunotherapy. Twenty-six percent (10 of 39 evaluable patients) of patients with melanoma had major clinical responses; one other patient (2%) has had more than 48 months of response after a 40% regression of all tumors. Median survival was 18 months for responders and 8 months for the group as a whole. Eleven of 41 patients (27%) lived at least 12 months and four (10%) lived at least 2 years. Liver metastases regressed in 4 of 10 cases, with responses in lung, adrenal, skin, and lymph nodes but no bone. Toxicity was tolerable. A correlation between cytolysis of lymphocytes against a natural killer-resistant melanoma cell line (LAK-like activity) was found, but the role of LAK cells in vivo remains uncertain. No effect was noted in 15 patients with renal cancer, but regressions of breast cancer were found in a shortened trial with 13 patients. While the necessity for CY has not been established in these studies, the regimen of CY + IL-2 as it stands appears to have some clinical efficacy in at least two cancers.

Antineoplastic Combined Chemotherapy Protocols↗