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Biomedical subjects

J P Dutcher

Publications and source records attributed to J P Dutcher.

At least 19 recordsLinked to original sources
PubMed2001

Phase I study of recombinant human CD40 ligand in cancer patients.

PURPOSE: To determine the toxicity, maximum-tolerated dose (MTD), and pharmacokinetics of recombinant human CD40 ligand (rhuCD40L) (Avrend; Immunex Corp, Seattle, WA), suggested in preclinical studies to mediate cytotoxicity against CD40-expressing tumors and immune stimulation. PATIENTS AND METHODS: Patients with advanced solid tumors or intermediate- or high-grade non-Hodgkin's lymphoma (NHL) received rhuCD40L subcutaneously daily for 5 days in a phase I dose-escalation study. Subsequent courses were given until disease progression. RESULTS: Thirty-two patients received rhuCD40L at three dose levels. A total of 65 courses were administered. The MTD was 0.1 mg/kg/d based on dose-related but transient elevations of serum liver transaminases. Grade 3 or 4 transaminase elevations occurred in 14%, 28%, and 57% of patients treated at 0.05, 0.10, and 0.15 mg/kg/d, respectively. Other toxicities were mild to moderate. At the MTD, the half-life of rhuCD40L was calculated at 24.8 +/- 22.8 hours. Two patients (6%) had a partial response on study (one patient with laryngeal carcinoma and one with NHL). For the patient with laryngeal cancer, a partial response was sustained for 12 months before the patient was taken off therapy and observed on no additional therapy. Three months later, the patient was found to have a complete response and remains biopsy-proven free of disease at 24 months. Twelve patients (38%) had stable disease after one course, which was sustained in four patients through four courses. CONCLUSION: The MTD of rhuCD40L when administered subcutaneously daily for 5 days was defined by transient serum elevations in hepatic transaminases. Encouraging antitumor activity, including a long-term complete remission, was observed. Phase II studies are warranted.

Adult↗
PubMed2001

Torsades de pointes in 3 patients with leukemia treated with arsenic trioxide.

Arsenic trioxide is used in clinical trials in the treatment of relapsed and resistant cases of acute promyelocytic leukemia. Adverse effects from arsenic in these studies have been multisystemic. Arsenic is known to cause corrected QT-interval prolongation and T-wave changes, but the potential for serious ventricular arrhythmias is less well understood. Torsades de pointes, a form of ventricular tachycardia, has been reported with arsenic poisoning but not at therapeutic doses used in protocols for hematologic malignancies. We describe 3 patients in whom this arrhythmia developed while they were treated with arsenic trioxide. Early recognition of the arrhythmia or correction of contributory factors is important because arsenic induced ventricular arrhythmias are known to be resistant to most chemical methods and electrical cardioversion.

Adult↗
PubMed2001

Angiogenesis and melanoma.

Angiogenesis is a process that is central to tumor growth and survival. This process is stimulated by a variety of intrinsic growth factors such as vascular endothelial growth factor, basic and acid fibroblast growth factor, and platelet-derived endothelial growth factor, among others. The process of neo-angiogenesis has been shown to be key in the proliferation of melanoma, and primarily believed to be so in the metastatic process. Biologic markers of angiogenesis are being evaluated for correlations with prognosis and biologic behavior of the tumor. These markers may also indicate susceptibility to targeted therapy. Interruption of the tumor-sustaining process of angiogenesis has become a major focus of anticancer drug development. Promising agents are in both preclinical and clinical development. Several may prove to be clinically important.

Angiogenesis Inhibitors↗
PubMed2000

Accelerated and blastic phase of chronic myeloid leukemia.

There is currently no standard treatment for the blastic phase of chronic myeloid leukemia (CML-BC), which is a chemoresistant form of acute leukemia. Current approaches include using standard acute myeloid leukemia (AML) regimens in an effort to induce remission, variations of these approaches with drugs that seem more active in this specific leukemia, and the direct entry of patients into studies of investigational agents. Although the likelihood of achieving remission is small, immediate bone marrow transplantation in remission should be considered because it provides the only opportunity for long-term survival at this time. Allogeneic transplantation is preferred, but autologous transplantation of an early chronic phase marrow may provide benefit. Often, however, the duration of chemotherapy-induced remission of blast crisis is very short and may preclude entry into a transplant program. In addition, the patient may not be a candidate due to donor issues, age, or medical problems. If transplant is not an option, maintenance interferon is often used, although its benefit is uncertain. For patients in the accelerated phase of the disease, which is characterized by a variety of clinical presentations and cytogenetic abnormalities, the possibility of favorably manipulating the disease is greater. Again, there is no standard treatment, and clinical trials are recommended as first-line therapy. Treatment in the accelerated phase includes standard AML chemotherapy regimens, combinations of new agents, and the combination of cytostatic agents with interferon. Patients whose accelerated phase reverts to chronic phase after treatment may become candidates for bone marrow transplantation. However, current new approaches to the chronic phase applied in accelerated phase as well as new approaches directed specifically toward accelerated phase may lead to prolonged stabilization without bone marrow transplantation. In view of a median age of 55 at diagnosis of chronic phase, nontransplant regimens for accelerated phase that produce long-term benefit are urgently needed.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

Immunotherapy: are we making a difference?

There is a 10-20 year history of immunotherapeutic approaches in metastatic renal cell cancer, which have produced a consistent demonstration of anti-tumour effect in a small percentage of patients. Clarification of dose and schedule of current agents continues to be modified. New technologies for immune system activation are attempting to enhance the response rate and improve outcome. Anti-proliferative effects of immunotherapy produce prolongation of stable disease, and new agents are being developed to enhance this approach.

Carcinoma, Renal Cell↗
PubMed2000

Phase II trial of interleukin 2, interferon alpha, and 5-fluorouracil in metastatic renal cell cancer: a cytokine working group study.

The purpose of this study was to evaluate the potential efficacy of alternating two outpatient regimens for the treatment of metastatic renal cell cancer. These regimens consisted of 4 weeks of recombinant interleukin 2 (rIL-2) plus IFN-alpha2B followed by 4 weeks of 5-fluorouracil plus IFN-alpha2B. Fifty patients meeting eligibility criteria of previous Cytokine Working Group studies were treated on an outpatient basis. Patients received s.c. rIL-2 (Proleukin; Chiron, Emeryville, CA) during weeks 1-4 of the 8-week regimen. During weeks 1 and 4, the dosage for rIL-2 was 10 MIU/m2 twice daily on days 3-5, and the dosage for IFN-alpha2B (Intron; Schering Plough, Kenilworth, NJ) was 6 MIU/m2 on day 1. During weeks 2 and 3, the dosage for rIL-2 was 5 MIU/m2 on days 1, 3, and 5, and the dosage for IFN-alpha2B was 6 MIU/m2 on days 1, 3, 5. During weeks 5-8, 5-fluorouracil (750 mg/m2) was administered once weekly by i.v. infusion, and IFN-alpha2B (9 MIU/mZ) was administered as a s.c. injection three times weekly. Throughout the treatment, an assessment of quality of life was made and a symptom-distress scale was evaluated. There were two patients with complete responses (CRs) and seven with partial responses (PRs) for an objective response rate of 18% (95% confidence interval, 10-25). The median response duration was 8 months (range, 3-51+ months). The CRs lasted 5 months and 51+ months and the PRs ranged from 3+ to 18 months. After completing at least one course of treatment, eight patients (three with PR, one with minor response, four with stable disease) became CRs after surgery for remaining metastatic disease. Six remain alive at 43+ to 53+ months, and 5 remain disease-free since surgery. The median survival of the study group is 17.5 months, with a maximal follow-up of 53+ months. The range in survival is 1-53+ months. Toxicity was primarily constitutional. and treatment modifications were designed to maintain toxicity at grade 2/3. The most common toxicities during treatment with IL-2/IFN were fatigue, nausea/vomiting, anorexia, skin reaction, diarrhea, fever, and liver enzyme elevations. One-third had central nervous system toxicity (headache, depression, insomnia). During 5FU/IFN treatment, 49 of 50 patients experienced grade 2/3 myelosuppression during course 1. Eight patients experienced grade 4 toxicities. In conclusion, the activity of this alternating regimen is similar to that of IL-2/IFN alone, given in 4-week cycles. The addition of 5FU/IFN failed to increase the efficacy and added new toxicity (myelosuppression). This report does not confirm the results previously reported for either alternating or simultaneous administration of these three agents. Because 5FU does not appear to add to the antitumor activity of IL-2-based therapy for renal cancer, current efforts are directed toward a Phase III randomized comparison of high-dose i.v. bolus inpatient IL-2 treatment versus treatment with outpatient s.c. injection of IL-2 plus IFN.

Adult↗
PubMed2000

20th-century advances in drug therapy in oncology--Part. II.

Ongoing research in cancer therapy has led to the development of antineoplastic agents which target specific components of the cell cycle. In Part II of this series, we discuss agents which target the mitotic mechanism by inhibiting microtubules. Although many of these agents are being shown to have multiple effects, the Vinca alkaloids and the taxanes are known as antimitotic drugs. They are among the most important anticancer agents currently available, and because of their unique mechanisms, can be combined with a wide variety of other antineoplastic agents in a spectrum of diseases. In addition, in part II, we are discussing agents that target DNA and prevent replication and thus cell growth by inhibiting the enzymes which protect DNA during replication, the topoisomerases. These drugs, too, have unique mechanisms of action and have become major components of combination regimens. The topoisomerase I inhibitors are new drugs derived from an older parent drug, and their full possibilities are still being explored.

Antineoplastic Agents↗
PubMed1999

Novel biologic approaches to hematologic malignancies.

Biologic agents have made a major impact on the treatment of hematologic malignancies and will continue to play a major role as we better understand their function in normal and malignant cell regulation. The examples provided in this chapter are a brief introduction to the potential of these agents. Many have yet to be used in conjunction with current cytotoxic therapy in these diseases, and perhaps combinations will prove even more successful. This possibility provides substantial ground for further investigation and therapy.

Bone Marrow Transplantation↗
PubMed1999

Phase II protocol for the evaluation of new treatments in patients with advanced gastric carcinoma: results of ECOG 5282.

The study was a Phase II randomized study to evaluate the efficacy of new agents for the treatment of advanced gastric carcinoma. Patients were randomized to receive single agent chemotherapy with mitoxantrone, etoposide, aclacinomycin-A or spirogermanium. The patients were stratified by prior use of chemotherapy, prior doxorubicin use and ECOG performance status. Patients with a history of cardiac disease or prior doxorubicin exceeding a dose of 400 mg/m2 were restrictively randomized to sopirogermanium or etoposide only. One hundred and fourteen patients were registered for the study. Among 98 evaluable patients there were only two partial responses (both in the etoposide arm), and one complete response in the mitoxantrone arm. The median survival on the study was 3.3 months. One hundred and six patients were analyzable for toxicity. There were four treatment-related deaths and four life-threatening toxicities. Because of low response rates and relatively high toxicities the studied compounds were not deemed worth further investigation for advanced gastric cancer.

Aclarubicin↗
PubMed1999

A phase II trial of dose-intensive interleukin-2 in metastatic renal cell carcinoma.

PURPOSE: High-dose bolus interleukin-2 (IL-2) is currently the sole agent approved by the Food and Drug Administration for the treatment of advanced renal cell carcinoma. This phase II study was designed to evaluate the clinical activity and toxicity spectrum of a regime consisting of dose-intensive IL-2 in both previously treated and untreated patients with advanced renal cell carcinoma. PATIENTS AND METHODS: Twenty eligible, sequential patients received IL-2 at a dose of 24 mlU m(-2) dose(-1) (1.33 mg m(-2) dose(-1)) every 8 h on days 1-5 and 15 19, for a maximum of 28 boluses. Patients achieving stable disease or a response were treated every 10 weeks for a maximum of five cycles/year. RESULTS: Out of 20 study participants 8 patients (40%; 95% confidence interval, 18.5%-61.4%) demonstrated a response. Three of these responses were complete (CR; 15%) while 5 were partial (PR; 25%) and about 75% of the responses occurred in patients with extensive tumor burdens. All 3 CR continue to respond after 28+ to 30+ months. With a median follow-up time of 26 months, the median overall survival duration for all patients is 18.0 months (95% confidence interval 12-24 months). Response was observed to correlate significantly with the IL-2 dose intensity. A dose intensity below 1440 mlU m(-2) year(-1) and at least 1440 mlU m(-2) year(-1) correlated highly with failure to achieve CR and the successful achieving of CR respectively (P < 0.01). An analysis of the present study database in the context of five previous similar trials demonstrated a significant correlation between IL-2 dose intensity and response rate by regression analysis (r=0.89; P < 0.019). Finally, all toxicities were reversible once the dosing had concluded. CONCLUSIONS: IL-2 dose intensity appears to represent a significant determinant of successful clinical outcomes. This dose-intensive approach led to a high proportion of durable responses. Further evaluation of this regimen is warranted.

Adult↗
PubMed1999

High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993.

PURPOSE: To determine the short- and long-term efficacy and toxicity of the high-dose intravenous bolus interleukin 2 (IL-2) regimen in patients with metastatic melanoma. PATIENTS AND METHODS: Two hundred seventy assessable patients were entered onto eight clinical trials conducted between 1985 and 1993. IL-2 (Proleukin [aldesleukin]; Chiron Corp, Emeryville, CA) 600,000 or 720,000 IU/kg was administered by 15-minute intravenous infusion every 8 hours for up to 14 consecutive doses over 5 days as clinically tolerated with maximum support, including pressors. A second identical treatment cycle was scheduled after 6 to 9 days of rest, and courses could be repeated every 6 to 12 weeks in stable or responding patients. Data were analyzed through fall 1996. RESULTS: The overall objective response rate was 16% (95% confidence interval, 12% to 21%); there were 17 complete responses (CRs) (6%) and 26 partial responses (PRs) (10%). Responses occurred with all sites of disease and in patients with large tumor burdens. The median response duration for patients who achieved a CR has not been reached and was 5.9 months for those who achieved a PR. Twelve (28%) of the responding patients, including 10 (59%) of the patients who achieved a CR, remain progression-free. Disease did not progress in any patient responding for more than 30 months. Baseline performance status and whether patients had received prior systemic therapy were the only predictive prognostic factors for response to IL-2 therapy. Toxicities, although severe, generally reversed rapidly after therapy was completed. Six patients (2%) died from adverse events, all related to sepsis. CONCLUSION: High-dose IL-2 treatment seems to benefit some patients with metastatic melanoma by producing durable CRs or PRs and should be considered for appropriately selected melanoma patients.

Adult↗
PubMed1998

Acquired Glanzmann's thrombasthenia associated with Hodgkin's lymphoma: a case report and review of the literature.

BACKGROUND: Acquired Glanzmann's thrombasthenia is a rare hemorrhagic diathesis resulting from impaired adhesive function of the platelet receptor GPIIb/IIIa (alpha(IIb)beta3). Typically, this disorder develops during adulthood, with patients manifesting fluctuating clinical and laboratory findings. To date, the underlying defect of most if not all cases of acquired Glanzmann's thrombasthenia results from an autoantibody or plasma protein inhibitor directed toward a demonstrably normal GPIIb/IIIa glycoprotein. METHODS: In this report, a patient with a history of treated Hodgkin's lymphoma presented with a severe hemorrhagic diathesis characterized by mild thrombocytopenia, a prolonged bleeding time, and defective platelet aggregation. RESULTS: Examination of the patient's platelet GPIIb/IIIa by Western blot analysis revealed no abnormality. Mixing studies demonstrated a non-immunoglobulin G plasma inhibitory factor, whereas flow cytometry analysis revealed elevated platelet-associated immunoglobulin (Ig) M. After an emergency colectomy for severe hemorrhage, the patient's qualitative and quantitative platelet parameters significantly improved. Pathology of the resected colonic segment demonstrated atypical lymphoid hyperplastic lesions. CONCLUSIONS: To the authors' knowledge, this is the first reported case of acquired Glanzmann's thrombasthenia associated with a putative IgM autoantibody. Furthermore, this report verifies the association of acquired thrombasthenia with lymphoproliferative disease. Although rare, awareness of this hemorrhagic diathesis as a possible sequelae of active or treated lymphoid disorders should encourage clinical vigilance of these patients.

Antibodies, Neoplasm↗
PubMed1998

Impact of histology on the treatment outcome of metastatic or recurrent renal cell carcinoma.

Among 107 renal cell carcinoma (RCC) patients with histopathologic subtype diagnosis who were treated at Albert Einstein Cancer Center with cytokines over a 10-year period, seven patients had sarcomatoid histology, 63 had clear cell carcinoma, and 10 patients had mixed histology (sarcomatoid and clear cell). Regardless of their histology, patients with a disease free interval of 2 years or more had significantly better survival. None of the patients with sarcomatoid histology responded to therapy. However, several patients with mixed and clear cell histology achieved partial or complete responses following high dose Interleukin-2 (IL-2) therapy. The median survival of patients with sarcomatoid histology was the shortest (13.8 months), whilst that of patients with mixed and clear cell histology was much longer (34.8 months and 39.1 months, respectively). This result was statistically significant in both univariate and multivariate survival analysis (P < 0.001 and P < 0.01, respectively). Patients with mixed and clear cell histology had no significant difference in survival, and their median survival combined was significantly longer than that of patients with sarcomatoid histology (P < 0.0001 in univariate analysis, P < 0.01 in multivariate analysis). This study suggests that survival with a diagnosis of RCC is predicted by tumor histology and disease free interval, and this impacts on the ability to respond to standard therapy. Patients with mixed and clear cell histology respond to cytokine therapy. Other therapies should be sought for patients with sarcomatoid RCC.

Adenocarcinoma, Clear Cell↗
PubMed1998

Phase IB trial for malignant melanoma using R24 monoclonal antibody, interleukin-2/alpha-interferon.

The inflammatory tumor lymphocytic infiltrates and spontaneous tumor regressions seen in patients with metastatic malignant melanomas suggest a cellular immune involvement. Enhancement of such responses has been the goal of R24 (GD3 ganglioside-specific) monoclonal antibody trials, alone and in combination with other agents. This study reports the results of 21 patients treated in a phase IB trial employing R24 (0, 5, 25, 50 mg/m2) administered by continuous i.v. infusion on days 1-5 followed by 3 MU each of interleukin-2 (IL-2) and alpha interferon (alpha-IFN) given subcutaneously on days 8-12, 15-19 and 22-26. R24-related toxicities occurred pre-dominantly at the 25 and 50 mg/m2 doses. One patient (50 mg/m2 R24) exhibited a dose-limiting Grade 4 anaphylaxis. Cytokine-related toxicities required IL-2/alpha-IFN dose reduction in two patients and early termination of treatment in five additional patients. Nine of 20 baseline biopsies showed chronic inflammation; six with lymphocytic tumor infiltration and three where inflammation was confined to the perivascular/peritumoral spaces. No day 8 or 29 biopsies in the R24-treated groups demonstrated treatment-induced tumor lymphocytic infiltrates. However, one patient randomized to no R24 treatment, showed a significant inflammatory tumor lymphocytic infiltration at days 8 and 29. Eighteen of 21 treated patients were evaluable for response. One (5%) patient receiving IL-2/alpha-IFN alone had stable disease lasting 1.5 years. Five (28%) R24, IL-2/alpha-IFN-treated patients had stable disease ranging from 6 to 32 weeks, with one patient remaining alive 2.5 years post-treatment. Although this combined treatment program was generally well tolerated, no objective responses were seen and significant R24-induced tumor lymphocytic infiltrates were not demonstrated.

Adult↗
PubMed1998

Phase II study of carboplatin in blast crisis of chronic myeloid leukemia: Eastern Cooperative Oncology Group Study E1992.

This study was a phase II evaluation of the activity of carboplatin in patients with Philadelphia chromosome positive accelerated or blastic phase of CML. Carboplatin, 250 mg/m2/day as an intravenous continuous infusion was given for 5 days, for a total dose of 1250 mg/m2 per course. If necessary, a second induction course could be given, and patients achieving complete remission were to receive an additional consolidation cycle at the same dose. Thirty-six patients were eligible and evaluable. There were five complete and three partial remissions for an overall response rate of 22% (95% CI 10.1-39.1%). The complete remission rate was 13.9% (95% CI 4.7-29.9%). The median remission duration was 3 months (range 1.4-8.94 months) and the median survival on study for all patients was 3.5 months (95% CI, 2.4-11.4 months). The median survival of responders was 12.8 months (95% CI, 3.6-17.2 months). Three eligible patients survived 2.0, 2.5 and 3.5 years following carboplatin therapy. Carboplatin has activity in blast crisis of CML, but responses are brief. Response did allow one patient to proceed to bone marrow transplantation and two other patients to continue therapy for chronic phase disease before returning to blast crisis. Activity in combination regimens should be explored.

Adult↗
PubMed1998

Fulminant metastatic melanoma complicated by a microangiopathic hemolytic anemia.

A 34-year-old male acutely presented with widely disseminated malignant melanoma, a microangiopathic hemolytic anemia, and disseminated intravascular coagulation. Although the patient had a history of intense childhood exposure to ultraviolet light and an occupational exposure to organic dyes, he had no history of a precursor skin lesion. The histopathology of the patient's bone marrow revealed sheets of malignant cells immunoreactive with S-100, HMB-45, and vimentin and also staining positively for melanin. A bone marrow aspirate revealed myeloid precursors filled with melanin-bearing vacuoles. Immunophenotypic analysis of the patient's bone marrow by flow cytometry revealed a paucity of hematopoietic cells. A karyotypic analysis of the patient's tumor cells demonstrated an abnormal hypertriploid composite clone characterized by multiple numerical and structural abnormalities. Although the patient was treated aggressively with transfusional support, heparin, and chemotherapy, he expired 3 weeks after diagnosis. This is the first recognized case of metastatic melanoma occurring in association with a microangiopathic hemolytic anemia.

Adult↗
PubMed1997

A GPIb alpha-related protein is expressed by fresh human breast carcinoma tissue and is regulated by a PKC-sensitive mechanism.

Fresh frozen breast carcinoma tissues were examined for the presence of GPIb alpha by immunohistochemistry. GPIb alpha was detected in six of seven primary invasive intraductal breast carcinoma tissues whereas staining was negative in seven of seven nonmalignant breast specimens. When biotin-labeled, triton-lysed, phorbol-12-myristate 13-acetate (PMA)-incubated breast carcinoma MCF-7 cells were immunoprecipitated with a MoAb directed against the platelet GPIb/IX complex, expression of GPIb was significantly enhanced in comparison to control preparations. Furthermore, incubation of MCF-7 cells for 84 h with 16 nmol/L PMA, but not with its biologically inactive derivative MePMA, induced a three- to fourfold increase in the surface expression of both GPIb alpha and GPIb/IX by flow cytometry. This PMA-enhanced GPIb alpha expression was almost completely abrogated when MCF-7 cells were first preincubated with the specific protein kinase C (PKC) inhibitor, H-7, prior to PMA treatment. Finally, PMA-incubated MCF-7 cells demonstrated a 63% (N = 6; P < 0.001) increase in tumor-induced platelet agglutination when added to platelets in comparison to control tumor cells. This enhancement could be abrogated by H-7. These findings confirm the expression of a protein with homology to platelet GPIb alpha expressed by fresh human breast carcinoma tissues, demonstrate that PMA enhances GPIb membrane expression by MCF-7 cells, and suggest that PKC plays a role in this process.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗