PubMed Health⌕ Search

Biomedical subjects

C J Logothetis

Publications and source records attributed to C J Logothetis.

At least 37 records · Page 2Linked to original sources
PubMed1999

Estramustine in combination with vinblastine and mitomycin-C for patients with progressive androgen independent adenocarcinoma of the prostate.

A phase II trial was performed to assess the antitumor activity and toxicity of estramustine in combination with vinblastine and mitomycin-C in 46 consecutive patients with androgen independent prostate cancer. All patients presented with disease progression following castrate serum testosterone levels and were treated for six consecutive weeks with three daily 140 mg doses of oral estramustine, vinblastine at 5 mg/m(2) weekly by intravenous bolus and mitomycin-C at 15 mg/m(2) every six weeks by intravenous bolus. Prostate specific antigen levels decreased by greater than 50% from baseline in 16 (41%; 95% CI 25-58%) and normalized in 11 (28%; 95% CI 14-45%) of 39 evaluable patients. Patients who demonstrated a greater than 50% reduction in PSA had a longer delay in time to disease progression. Non-hematologic toxicity was mild, predominately gastrointestinal. Hematologic toxicity was apparent in five patients with Grade III granulocytopenia and in 21 patients with Grade IV granulocytopenia of 43 evaluable patients for toxicity. Three patients were admitted to the hospital for neutropenic fever. Eight patients had Grade III thrombocytopenia, four patients had Grade IV thrombocytopenia, no bleeding occurred. Estramustine in combination with vinblastine and mitomycin-C is an active regimen. The non-hematologic toxicity was tolerable, while the hematologic toxicity required individual dosage reduction. The combination and the clinical significance of the decline in the PSA warrants further investigation.

Journal Article↗
PubMed1999

Management consideration in nonpulmonary visceral metastatic seminoma of testis.

To develop a more appropriate therapeutic strategy for treatment of nonpulmonary visceral metastatic testicular seminoma based on the International Germ Cell Consensus Classification, we reviewed the medical records of patients with nonpulmonary visceral metastatic testicular seminoma who were treated over a 20-year period. Only 15 (2.2%) of the 686 cases of testicular seminoma were nonpulmonary visceral metastatic seminoma. The median age of patients was 38 years (range, 22-53 years). Ten (67%) of the patients had an initial diagnosis of supradiaphragmatic or visceral metastatic disease. In addition to nonpulmonary visceral metastasis, all patients had lymph node metastasis as well, the majority of which involved the retroperitoneal lymph nodes. The median and mean progression-free survival durations after chemotherapy for advanced disease were 19 months and 63.7 months, respectively. Six patients (40%) survived, five relapsed after radiation therapy and four died of chemorefractory disease not dependent on the specific regimen. Although the number of cases reviewed in this study was small, we conclude that the choice of chemotherapeutic regimen among the current treatments for nonpulmonary visceral metastatic seminoma of testis primary does not present a different outcome. Therefore, multimodality therapies using new strategies or new agents are well indicated.

Adult↗
PubMed1999

Clinical characteristics of metachronous bilateral testicular tumors in the chemotherapeutic era.

We wanted to present the results of our experience with bilateral testis tumor and to suggest the effects of chemotherapy in suppressing the development of second primary testicular tumors. Between 1978 and 1997, 2,345 patients were treated for testicular tumor at The University of Texas M. D. Anderson Cancer Center. Of these, 2,107 had germ cell cancers. There were 22 (0.94%) cases of bilateral testicular tumor in the overall patient population and 21 (1.0%) cases among patients with germ cell cancer. We reviewed the medical records to determine the incidence of the histological subtype, the incidence of metachronous versus synchronous formation of contralateral tumors, and tumor stage in this patient population. We also examined the effect of chemotherapy in treating the first tumor and preventing the occurrence of a second tumor. Finally, we compared the effect of ultrasonography, serum tumor marker elevation, and physical examination in detecting second tumors. Only one contralateral germ cell tumor developed synchronously; all others developed metachronously. Fifty percent of first tumors were seminomas, compared to 55% of second tumors. The histologic concordance rate for first and second tumors was 35%. Tumor stage was higher among first tumors than second tumors. The majority of second tumors in patients who received chemotherapy for first malignancies tended to be metachronous seminomas. Ultrasonography detected 6 of 21 (28.6%) contralateral tumors before they were evident by physical examination or serum tumor marker elevation. Seminomas were more prevalent among patients with bilateral germ cell disease than patients with unilateral disease. Chemotherapy, when used as treatment for first tumors, may have some effect in preventing the development of nonseminomatous germ cell tumors in the contralateral testicle. Close follow-up of the contralateral testis with ultrasonography is essential for early detection of second tumors. The outcome for patients with bilateral testicular germ cell cancer is excellent, secondary to early detection.

Adolescent↗
PubMed1999

p53 mutations in prostate cancer bone metastases suggest that selected p53 mutants in the primary site define foci with metastatic potential.

PURPOSE: This study was undertaken to establish the pattern of specific p53 gene mutations in prostate cancer within primary tumors and distant metastases. MATERIALS AND METHODS: We performed polymerase chain reaction-single-strand conformation polymorphism and sequencing analyses of p53 exons 5-8 in DNA extracted from 22 formalin-fixed, paraffin-embedded tissues from 17 patients. Samples from three patients included specimens from primary and metastatic sites (paired specimens). RESULTS: G:C-to-A:T transitions were the most common point mutations (64%). Six (55%) of 11 G:C-to-A:T transitions occurred at CpG dinucleotides in five hot-spot codons (175, 245, 248, 273, and 282). Sequencing analysis of the paired samples revealed that two of the three pairs had the same mutation in both. Sequencing analysis of DNA from a different area of one of the primary tumors revealed a different mutation in the p53 gene. CONCLUSIONS: Our results suggest that specific p53 mutations participate in the progression of human prostate cancer. These findings support those of others that indicate that the primary cancer is heterogeneous and clonal expansion occurs during the progression of clinically detectable prostate cancer. Our data also imply that p53 mutations at the primary site may be predictive of metastases.

Aged↗
PubMed1998

Prostate carcinoma cell death resulting from inhibition of proteasome activity is independent of functional Bcl-2 and p53.

The ATP/ubiquitin-dependent 26S proteasome is a central regulator of cell cycle progression and stress responses. While investigating the application of peptide aldehyde proteasome inhibitors to block signal-induced IkappaBalpha degradation in human LNCaP prostate carcinoma cells, we observed that persistent inhibition of proteasomal activity signals a potent cell death program. Biochemically, this program included substantial upregulation of PAR-4 (prostate apoptosis response-4), a putative pro-apoptotic effector protein and stabilization of c-jun protein, a potent pro-death effector in certain cells. We also observed modest downregulation of bcl-XL, a pro-survival effector protein. However, in contrast to some recent reports stable, high level, expression of functional bcl-2 protein in prostate carcinoma cells failed to signal protection against cell death induction by proteasome inhibitors. Also in disagreement to a recent report, no evidence was found for activation of the JNK stress kinase pathway. A role for p53, a protein regulated by the proteasome pathway, was ruled out, since comparable cell death induction by proteasome inhibitors occurred in PC-3 cells that do not express functional p53 protein. These data signify that the ubiquitin/proteasome pathway represents a potential therapeutic target for prostate cancers irrespective of bcl-2 expression or p53 mutations.

Aldehydes↗
PubMed1998

Structural alterations of chromosome 5 in twelve human prostate cancer cell lines.

Neoplastic transformation, cancer progression, and metastasis are determined by a series of well-defined changes that take place in target tissue cells. Genetic alterations associated with human prostate carcinogenesis are not well defined. Some chromosomal changes, including gain of chromosomes 7, 12, 17, and X and loss of heterozygosity in chromosomes 8p, 10q, 16q, 17p, and 18q, have been reported. We examined five newly established and eight previously established prostate cancer cell lines before and after subcutis and orthotopic injection into nude mice and observed that structural alterations of chromosome 5 were present in all of the cell lines except the parental LNCaP. The fluorescence in situ hybridization preparations with the use of whole chromosome 5 DNA painting probe confirmed our Giemsa-banding data. Alterations of chromosome 5 consisted of t(1;5)(p36;q15), t(5;?)(p11;?), del(5)(q23q35) in the SP2964(= ARCaP) cell line; t(5;8)(p15;q12), i(5)(p10), t(5;15)(q11;p11) in the SP3031 cell line; t(5;?;15) (q15;?;p11), t(5;7;14)(q31;p11-q32;q11), in the SP3173 and SP3241 cell lines (derived from the same patient); del(5)(q23-33) and t(5;7;14)(q31;p11-q32;q11) in the SP3316 cell line; t(3;5)(q21;q35) in the SP2884 cell line; t(5;5)(p15;q11) in the SP2356 cell line; i(5)(p10),t(5;?)(q23;?) in the DU-145 cell line; and i(5)(p10), t(5;?)(q11;?) and t(2;5)(q15;q15) in the PC-3 cell line. Because, in most cases, alteration of chromosome 5 resulted in the partial or complete loss of 5q, we conjectured that 5q might contain one or more tumor-suppressor genes for human prostate cancer development.

Chromosome Aberrations↗
PubMed1998

Emerging strategies in the treatment of testis cancer.

The state of the art in the study and therapy of germ-cell tumors of the testis is reflected in this year's literature. For the majority of patients with germ-cell tumors, the therapeutic dilemma no longer relates to cure. For such patients with low-volume non-seminomatous germ-cell tumors of the testicle and those with a pure seminoma, therapeutic dilemmas relate more to selection of the appropriate therapy to achieve cure, the toxicity of therapy, and the precise prediction of outcome. However, a high cure rate cannot be anticipated with equal frequency in those patients with high-volume non-seminomatous germ-cell tumors of the testicle.

Journal Article↗
PubMed1998

Phase I study of suramin combined with doxorubicin in the treatment of androgen-independent prostate cancer.

In this study, we determined the maximum tolerated plasma concentration of suramin (within the predetermined study target range) when combined with doxorubicin in the treatment of androgen-independent prostate cancer. Twenty-four patients received suramin dosages based on proportional adjustment of the steady-state plasma suramin concentration to achieve the targeted plasma concentrations of 50-100, 101-150, 151-200, or 201-250 microg/ml. Doxorubicin (20 mg/m2) was administered i.v. over 24 h at weekly intervals. Suramin was given i.v. over 2 h twice weekly. Patients received treatment until dose-limiting toxicity or disease progression. Side effects similar to those reported for suramin and doxorubicin administered as individual agents were observed. Dose-limiting motor neuropathy developed in three patients (13%). Twelve of 24 evaluable patients (50%; 95% confidence interval, 28-71%) and 6 of 10 evaluable patients (60%; 95% confidence interval, 26-88%) had a >50% decrease of prostate-specific antigen and measurable lesions, respectively. The maximum tolerated plasma level of suramin when combined with doxorubicin was 151-200 microg/ml. Future studies on suramin combined with doxorubicin or other agents could be performed using a fixed dosing scheme with a targeted suramin steady-state plasma concentration of 200 microg/ml.

Adult↗
PubMed1998

Biologic foundation of the therapy for advanced germ cell tumors.

An understanding of the elements that have contributed to the remarkable cure rate in patients with germ cell cancers is a useful exercise for clinicians. The prevailing view is that the introduction of chemotherapy was largely responsible for this remarkable success. Although chemotherapy is clearly the required ingredient, there are other important contributing factors that were essential for the high cure rate. These contributing elements include the understanding of the biology of the cancer and the availability markers. The understanding of the clinical biology and ability to assay persistent minimal cancer led to the appropriate integration of systemic and local therapies. The treatment of germ cell cancers is the paradigm of multidisciplinary therapy of cancer because it accommodates many variables into the clinical decision-making process.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Phase II trial of 5-fluorouracil, interferon-alpha and continuous infusion interleukin-2 for patients with metastatic renal cell carcinoma.

BACKGROUND: This study was designed to evaluate the efficacy and toxicity of the combination of 5-fluorouracil, interferon-alpha, and interleukin-2 for patients with metastatic renal cell carcinoma. METHODS: Previously untreated patients with a Zubrod performance status of < or =2; adequate cardiac, pulmonary, and renal function; and absence of brain metastases were eligible. One course of therapy was 28 days. 5-fluorouracil was administered at a dose of 600 mg/m2/day as a continuous infusions on Days 1-5. Interleukin-2 also was administered as a continuous infusion on Days 1-5 at a dose of 2 million Roche U/m2/day. Interferon-alpha was given as a daily subcutaneous injection of 4 million U/m2/day. RESULTS: Fifty-five patients were enrolled in the trial and 52 were evaluable for response. All patients experienced fever and flu-like symptoms. Grade 3 or 4 nonhematologic toxic effects included hypertension (48%), dermatitis (12%), stomatitis (11%), and altered mental status (9%). There was one toxic death. Four complete responses and 12 partial responses were observed for a total response rate of 31% (95% confidence interval, 18-46%). The survival of responding patients was significantly better than that of nonresponding patients. The improvement in survival was even more significant when comparing patients with at least stable disease with those who progressed through treatment. CONCLUSIONS: The three-drug combination described in this study demonstrates activity. However, it appears to be more toxic than other regimens with similar response rates and cannot be recommended for standard practice. Changing the interleukin-2 route to subcutaneous administration may permit more continuous administration with less toxic effects.

Adult↗
PubMed1997

New approaches in the treatment of metastatic transitional-cell cancer of the bladder.

In recent years, chemotherapy of metastatic transitional-cell carcinoma of the bladder has advanced from the use of individual therapeutic agents, which has effected only rare responses, to the development of multi-agent regimens, which have greatly improved both partial and complete response rates, resulting in improved local care, palliation, and; perhaps, survival. However, because of the limited duration of response, frequent recurrences, and the significant proportion of patients with refractory disease, there have been only modest overall gains in long-term disease-free survival. These shortcomings have prompted investigation of alternative approaches to current combination chemotherapy regimens, including the use of hematopoietic growth factors and novel single-agent, multi-agent, and gene therapy protocols.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Expression of bcl-2 oncoprotein and p53 protein accumulation in bone marrow metastases of androgen independent prostate cancer.

PURPOSE: We correlated the expression of bcl-2 with accumulation of p53 protein in bone marrow metastases from patients with androgen independent prostate cancer and a history of hormonal ablation therapy. These results were correlated with clinical parameters, including the extent of bone marrow metastases and patient survival. MATERIALS AND METHODS: All 43 patients studied had evidence of prostate cancer progression following androgen deprivation therapy and histologically confirmed bone marrow metastases. Decalcified tissue sections were used for immunohistochemical evaluation of bcl-2 protein and p53 protein accumulation. RESULTS: We previously established that p53 protein accumulation as detected by immunohistochemistry is a reliable indicator of p53 gene mutation in prostate cancer. Immunoreactivity was demonstrated for p53 protein in 22 of 43 cases and for bcl-2 protein in 14. A total of 28 cases (65%) exhibited immunohistochemical evidence of p53 and/or bcl-2 expression, and 15 (35%) were negative for p53 and bcl-2. The expression of bcl-2 and accumulation of p53 were independent events (p < 0.01). The expression of bcl-2 or accumulation of p53 protein in prostate cancer metastases did not significantly influence patient survival or the extent of metastatic disease. CONCLUSIONS: The presence or absence of p53 protein accumulation and/or bcl-2 expression did not correlate with tumor burden or patient survival in stage D androgen independent prostate cancer bone marrow metastases. The expression of bcl-2 protein occurs independently of and is inversely correlated with p53 mutations in advanced prostate cancer.

Aged↗
PubMed1997

Phase II trial of alternating weekly chemohormonal therapy for patients with androgen-independent prostate cancer.

Two distinct regimens of weekly chemotherapy for hormone-refractory prostate cancer were combined in an alternating schedule and tested in a Phase II trial to determine efficacy and toxic effects. Forty-six patients with hormone-refractory prostate cancer and rising prostate-specific antigen (PSA) levels entered the trial. Therapy consisted of doxorubicin (20 mg/m2/week) plus oral ketoconazole (400 mg three times a day) given at weeks 1, 3, and 5 and vinblastine (5 mg/m2/week) plus oral estramustine (140 mg three times a day) given at weeks 2, 4, and 6. No therapy was given at weeks 7 and 8. Replacement doses of hydrocortisone were administered throughout treatment to counteract potential adrenal insufficiency secondary to the ketoconazole. In 67% of patients (31 of 46), the PSA declined by 50% or greater for a minimum duration of 8 weeks (95% confidence interval, 52-80%). Among the 16 patients with measurable soft tissue disease, there were 12 responses (75%; 95% confidence interval, 47-92%). The median duration of response was 8. 4 months (1.8-14.9). The median survival for the entire group was 19 months. The median survival of PSA responders has not been reached, whereas that of nonresponders was 13 months (P = 0.010). Seventy-six percent of symptomatic patients noted improvement. Hematological toxicity was modest and was managed without growth factors. Peripheral edema (49%) and deep venous thrombosis (18%) were the most common nonhematological toxicities. The alternating weekly regimen of chemohormonal therapy is active for hormone-refractory prostate cancer, providing a high rate of symptom control, soft tissue response, and PSA decline.

Anti-Inflammatory Agents↗
PubMed1997

Establishment of two human prostate cancer cell lines derived from a single bone metastasis.

Human prostate cancer cell lines are particularly difficult to establish, and most existing cell lines do not exhibit features commonly seen in human prostate cancer. Most available models either grow only in vivo as xenografts or are androgen insensitive and fail to express prostate-specific antigen (PSA). The lack of functionally relevant model systems of advanced prostate cancer has limited prostate cancer research and therapy development. Of 30 processed samples derived from patients with prostate cancer, we established two cell lines (MDA PCa 2a and MDA PCa 2b) that express PSA and androgen receptor, grow in vitro, and are androgen sensitive. Cells from these lines produced tumors in nude mice when injected either s. c. or orthotopically (intraprostatic). Both cell lines were established from a bone metastasis of a patient whose cancer was exhibiting androgen-independent growth. Although both were derived from two samples of the same specimen, they have different genetic features (as assessed by karyotype analysis) and different phenotypes (e.g., morphology and growth rate). It is likely that they are distinct clones isolated by the use of different culture procedures and reflect the genetic heterogeneity of the tumor. These new cell lines are the first available derived from a bone metastasis of an androgen-independent prostatic adenocarcinoma that grow both in vivo and in vitro and have retained PSA expression and androgen sensitivity. They therefore constitute important model systems to address critical questions related to the androgen-independent growth of human prostate cancer and to the complex process of bone metastasis.

Androgens↗
PubMed1996

Characterization of patients with androgen-independent prostatic carcinoma whose serum prostate specific antigen decreased following flutamide withdrawal.

PURPOSE: We confirmed the reported rate of prostate specific antigen (PSA) suppression after flutamide withdrawal in patients with metastatic prostatic carcinoma, increasing serum PSA and tumor progression following treatment with total androgen blockade (castration and flutamide). The value of clinical variables in predicting the rate of PSA decrease after flutamide withdrawal was assessed and adrenal androgen metabolism was correlated with the rate of PSA suppression following flutamide withdrawal. MATERIALS AND METHODS: A total of 41 consecutive patients with metastatic prostatic adenocarcinoma and an increasing serum PSA while effectively castrated (plasma testosterone level less than 50 ng./ml.) who were receiving 250 mg. flutamide 3 times daily was evaluated prospectively before cessation of the flutamide. Responses were determined at 6 weeks. Only 2 of the 41 study patients (3%) had stable disease at 6 weeks, that is they had not met objective criteria for response or progression at analysis. RESULTS: Of 39 patients studied 11 (28.2%, 95% confidence internal 14 to 45%) had a PSA decrease (more than 50% from baseline) following flutamide withdrawal and they were treated with initial complete androgen blockade. Median duration of PSA decrease was only 13 weeks (range 7 to 52), and 3 of the 11 patients had continued suppression of serum PSA concentrations at 12+, 13+ and 20+ weeks. The serum PSA decrease was associated with improved clinical symptoms, although objective regression of the disease was found in only 1 to 2 patients with measurable disease. No statistical correlation between endocrine studies or serum bombesin secretion and PSA decrease was found, although patients with a PSA decrease after flutamide withdrawal tended to have a lower dehydroepiandrosterone concentration than those with PSA progression. No correlation between known prognostic variables and decreased serum PSA after flutamide withdrawal was detected. CONCLUSIONS: We confirmed the existence of the reported paradoxical PSA decrease in patients with androgen-independent carcinoma of the prostate, and that the delivery of simultaneous initial flutamide with castration predicts for PSA decrease. Individual patients appear to benefit from flutamide withdrawal although the overall impact was slight. The differences in frequency compared to those reported by others may be accounted for by patient selection and the number of patients receiving sequential castration therapy followed by flutamide.

Adenocarcinoma↗