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Biomedical subjects

P Kantoff

Publications and source records attributed to P Kantoff.

At least 19 recordsLinked to original sources
PubMed2001

CML66, a broadly immunogenic tumor antigen, elicits a humoral immune response associated with remission of chronic myelogenous leukemia.

This report describes a tumor-associated antigen, termed CML66, initially cloned from a chronic myelogenous leukemia (CML) cDNA expression library. CML66 encodes a 583-aa protein with a molecular mass of 66 kDa and no significant homology to other known genes. CML66 gene is localized to human chromosome 8q23, but the function of this gene is unknown. CML66 is expressed in leukemias and a variety of solid tumor cell lines. When examined by Northern blot, expression in normal tissues was restricted to testis and heart, and no expression was found in hematopoietic tissues. When examined by quantitative reverse transcription-PCR, expression in CML cells was 1.5-fold higher than in normal peripheral blood mononuclear cells. The presence of CML66-specific antibody in patient serum was confirmed by Western blot and the development of high titer IgG antibody specific for CML66 correlated with immune induced remission of CML in a patient who received infusion of normal donor lymphocytes for treatment of relapse. CML66 antibody also was found in sera from 18-38% of patients with lung cancer, melanoma, and prostate cancer. These findings suggest that CML66 may be immunogenic in a wide variety of malignancies and may be a target for antigen-specific immunotherapy.

Amino Acid Substitution↗
PubMed2001

Vascular endothelial growth factor and basic fibroblast growth factor urine levels as predictors of outcome in hormone-refractory prostate cancer patients: a cancer and leukemia group B study.

Better prognostic markers are needed for hormone-refractory prostate cancer (HRPC) patients. No single biochemical or clinical parameter can reliably predict patient response to therapy or rapidity of disease progression. Peptide factors involved in major cancer growth pathways, such as tumor angiogenesis, are attractive candidates as markers of low- and high-risk HRPC patients. We analyzed prospectively collected urine specimens from 100 of 390 HRPC patients undergoing therapy with the growth factor antagonist suramin as part of CALGB 9480. Levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were assessed from day 1 of therapy (D1) and day 29 (D29) urine samples from this subset of 100 randomly selected patients. Growth factor levels were determined by standardized ELISA microtiter plate assays from a commercial (bFGF) or proprietary (VEGF) source. Pretreatment urine VEGF levels were predictive of survival. In univariate analysis, patients whose baseline urine VEGF level was < or =28 pg/ml (the median level) had an average survival of 17 months; those with baseline VEGF >28 pg/ml had a significantly shorter survival of 10 months (P = 0.024). This difference corresponded to a 60% increased risk of dying for the higher urine VEGF patients (hazard ratio, 1.62; P = 0.03) and remained significant in multivariate analysis (hazard ratio, 1.72, P = 0.02). No significant correlations between urine bFGF level or change in bFGF levels and survival were found. These results support the notion that certain peptide growth factor-mediated, mitogenic pathways are important in HRPC and that their levels can predict outcome.

Aged↗
PubMed2001

Paclitaxel, estramustine phosphate, and carboplatin in patients with advanced prostate cancer.

PURPOSE: To determine the safety and activity of weekly paclitaxel in combination with estramustine and carboplatin (TEC) in patients with advanced prostate cancer. PATIENTS AND METHODS: In a dose-escalation study, patients with advanced prostate cancer were administered paclitaxel (weekly 1-hour infusions of 60 to 100 mg/m(2)), oral estramustine (10 mg/kg), and carboplatin (area under the curve, 6 mg/mL-min every 4 weeks). Paclitaxel levels were determined 0, 30, 60, 90, and 120 minutes and 18 hours after infusion, and a concentration-time curve was estimated. Once a safe dose was established, a multi-institutional phase II trial was conducted in patients with progressive androgen-independent disease. RESULTS: Fifty-six patients with progressive androgen-independent disease were treated for a median of four cycles. The dose of paclitaxel was escalated from 60 to 100 mg/m(2) without the occurrence of DLT. Posttherapy decreases in serum prostate-specific antigen levels of 50%, 80%, and 90% were seen in 67%, 48%, and 39% (95% confidence interval, 55% to 79%, 35% to 61%, 26% to 52%) of the patients, respectively. Of the 33 patients with measurable disease, two (6%) had a complete response and 13 (39%) had a partial response. The overall median time to progression was 21 weeks, and the median survival time for all patients was 19.9 months. Major grade 3 or 4 adverse effects were thromboembolic disease (in 25% of patients), hyperglycemia (in 38%), and hypophosphatemia (in 42%). Significant leukopenia, thrombocytopenia, and peripheral neuropathy were not observed. CONCLUSION: TEC has significant antitumor activity and is well tolerated in patients with progressive androgen-independent prostate cancer.

Aged↗
PubMed2000

Her-2-neu expression and progression toward androgen independence in human prostate cancer.

BACKGROUND: Human prostate cancers are initially androgen dependent but ultimately become androgen independent. Overexpression of the Her-2-neu receptor tyrosine kinase has been associated with the progression to androgen independence in prostate cancer cells. We examined the expression of Her-2-neu in normal and cancerous prostate tissues to assess its role in the progression to androgen independence. METHODS: Prostate cancer tissue sections were obtained from 67 patients treated by surgery alone (UNT tumors), 34 patients treated with total androgen ablation therapy before surgery (TAA tumors), and 18 patients in whom total androgen ablation therapy failed and who developed bone metastases (androgen-independent [AI] disease). The sections were immunostained for Her-2-neu, androgen receptor (AR), prostate-specific antigen (PSA), and Ki-67 (a marker of cell proliferation) protein expression. Messenger RNA (mRNA) levels and gene amplification of Her-2-neu were examined by RNA in situ hybridization and fluorescent in situ hybridization(FISH), respectively, in a subset of 27 tumors (nine UNT, 11 TAA, and seven AI). All statistical tests were two-sided. RESULTS: Her-2-neu protein expression was statistically significantly higher in TAA tumors than in UNT tumors with the use of two different scoring methods (P =.008 and P =.002). The proportion of Her-2-neu-positive tumors increased from the UNT group (17 of 67) to the TAA group (20 of 34) to the AI group (14 of 18) (P<.001). When compared with UNT tumors, tumor cell proliferation was higher in AI tumors (P =.014) and lower in TAA tumors (P<.001). All tumors expressed AR and PSA proteins. Although Her-2-neu mRNA expression was high in TAA and AI tumors, no Her-2-neu gene amplification was detected by FISH in any of the tumor types. CONCLUSIONS: Her-2-neu expression appears to increase with progression to androgen independence. Thus, therapeutic targeting of this tyrosine kinase in prostate cancer may be warranted.

Androgens↗
PubMed2000

NCCN Practice Guidelines for Prostate Cancer.

Systemic therapies for prostate cancer are likely to improve, and as they do, they will have enormous impact on the treatment of high-risk and locally advanced cancers. Further technical improvements in radiotherapy and alternative local modalities, such as cryoablation, are also likely, and will bring even more options for local control. It is certain these guidelines will continue to evolve.

Evidence-Based Medicine↗
PubMed1999

Antiandrogens in prostate cancer.

Antiandrogens competitively inhibit ligand binding to the androgen receptor (AR), and are used therapeutically in prostate cancer patients. The AR functions as a ligand dependent transcription factor that transduces androgen binding into increased transcription of androgen dependent genes. AR blockade induces programmed cell death in the vast majority of malignant and benign prostate cancer cells that have not previously been exposed to androgen ablation. The antiandrogens are divided structurally into the steroidal and non steroidal agents. The biological effects of the steroidal versus nonsteroidal agents are distinguished by differences in their effects on serum testosterone levels, and by their activity at receptors other than the androgen receptor. There is extensive clinical experience in the palliative and curative therapy of prostate cancer using antiandrogens as monotherapy or antiandrogens in combination with luteinizing hormone agonists or surgical castration. Prolonged therapy with antiandrogens selects for mutations in the AR that change the AR ligand specificity and permits stimulation by ligands that are usually inhibitory. These mutations give insight into one of the means by which prostate cancer progresses despite antiandrogen therapy, and also helps to explain the antiandrogen withdrawal syndrome. Areas of active research that may affect the future use of antiandrogens include the ongoing evaluation of antiandrogens in combination with 5 alpha reductase inhibitors to achieve AR blockade without inducing castrate testosterone levels. There is also interest in developing selective androgen receptor modulators (SARM) that can achieve AR blockade without causing the increased testosterone levels produced by the nonsteroidal antiandrogens currently in use.

Androgen Antagonists↗
PubMed1998

Assessment of prostate cancer volume using endorectal coil magnetic resonance imaging: a new predictor of tumor response to neoadjuvant androgen suppression therapy.

OBJECTIVES: A clinical tool that can reliably assess prostate cancer response to androgen suppression is lacking. This pilot study was designed to identify the potential clinical factor(s) that correlate with tumor response after neoadjuvant therapy. METHODS: Twenty-one patients managed with definitive local therapy and neoadjuvant androgen suppression (median 3 months [range 2 to 7]) between 1995 and 1997 comprise the study population. Fisher's exact test was used to test the significance of the proportion of patients with a given clinical factor and the outcome of pathologic organ-confined disease. The clinical factors tested included preoperative prostate-specific antigen, biopsy Gleason score, clinical stage, months of total androgen suppression, the change in the endorectal magnetic resonance imaging (erMRI)-defined stage, the change in erMRI-defined tumor, and the change in the erMRI-defined prostate volume during neoadjuvant androgen suppression. RESULTS: All 21 patients had a decrease in the erMRI-determined prostate volume and prostate-specific antigen during androgen suppression, whereas only 10 of 21 (48%) had a reduction in the erMRI-determined tumor volume. There was a statistically significant increased proportion of patients with a decrease in the erMRI-determined tumor volume (P = 0.008) who had pathologic organ-confined disease. CONCLUSIONS: The results of this pilot study suggest that the changes in the erMRI-determined tumor volume occurring during androgen suppression may be predictive of the tumor response. Validation in a larger prospective study is currently underway.

Androgen Antagonists↗
PubMed1998

The epidemic of prostate cancer and the medical literature: a causal association?

The diagnosis of prostate cancer has undergone an unprecedented recent increase, while mortality has increased much more slowly. We examined new prostate cancer diagnoses from 1987-1992 in a nationwide prospective cohort study of 51 529 men enrolled in the Health Professionals Follow-up Study, a population likely to be medically sophisticated and thus early to adopt medical innovations. The age-adjusted incidence of prostate cancer rose approximately 2(1/2) fold during the study period. Nearly all of the increase occurred among organ-confined tumors, with a smaller increase for regionally-advanced tumors and none for metastatic tumors. Using a Poisson regression model of newly-diagnosed cancers, we found organ-confined cancers rose abruptly by 86% (95% CI: 36-256%; P=0.0001) and regionally-advanced tumors by 73% (95% CI:12-267%; P=0.01) after March, 1991, when a study advocating screening using the prostate specific antigen (PSA) was published in the New England Journal of Medicine. The recent increase in the incidence of prostate cancer is probably due to the increased PSA screening of asymptomatic men, resulting in the diagnosis of large numbers of men with early-stage disease from 1990 onward. Despite ongoing debate over the value of PSA screening, the rate of diagnosis accelerated sharply after the publication of a well-publicized but inconclusive study advocating screening. In a context of growing disease awareness, well-publicized research reports may result in unexpectedly amplified acceptance into medical practice.

Journal Article↗
PubMed1997

Finasteride and flutamide as potency-sparing androgen-ablative therapy for advanced adenocarcinoma of the prostate.

OBJECTIVES: Androgen ablation with luteinizing hormone-releasing hormone (LHRH) agonists, orchiectomy, or oral estrogens has significant untoward sexual side effects. We evaluated a combination of finasteride and flutamide as potency-sparing androgen ablative therapy (AAT) for advanced adenocarcinoma of the prostate. In addition, we evaluated whether finasteride provided additional intraprostatic androgen blockade to flutamide. METHODS: Twenty men with advanced prostate cancer were given flutamide, 250 mg orally three times daily. Serum prostate-specific antigen (PSA) values were measured weekly. At a nadir PSA value, finasteride, 5 mg orally every day, was added. PSA values were then measured weekly until a second nadir PSA value was achieved. Sexual function was evaluated at baseline, at the second nadir PSA value, and every 3 months thereafter. Testosterone, dihydrotestosterone (DHT), and dehydroepiandrostenedione (DHEA) levels were measured at baseline and at the first and second nadir PSA values. RESULTS: The median follow-up period was 16.9 months. Therapy failed in 1 patient with Stage D2 disease at 12 months, but an additional response to subsequent LHRH agonist therapy was observed. One patient developed National Cancer Institute grade 3 diarrhea and was withdrawn from the study. Seven of 20 men developed mild gynecomastia, and 3 of 20 developed mild transient liver function test elevations. Mean PSA levels were 94.6 +/- 38.2 ng/mL at baseline and 7.8 +/- 2.7 and 4.7 +/- 2.2 ng/mL at the first and second PSA nadir values, respectively (P = 0.034). Mean percent decline in PSA value from baseline was 87.0 +/- 3.1% with flutamide alone and 94.0 +/- 1.9% with both flutamide and finasteride (P = 0.001). Eleven of 20 men were potent at baseline. At the second nadir PSA value, 9 (82%) of 11 were potent, whereas 2 (18%) of 11 were impotent. With longer follow-up (median 16.4 months), 6 (55%) of 11 men were potent, 2 (18%) of 11 were partially potent, and 3 (27%) of 11 were impotent. With flutamide alone, testosterone rose a mean of 77 +/- 14.7% of baseline (P = 0.0001), DHEA fell a mean of 32.4 +/- 4.6% (P = 0.0001), and DHT was unchanged. With the addition of finasteride, testosterone rose another 14 +/- 6% (P = 0.06, not significant), DHEA was unchanged, and DHT fell a mean of 34.8 +/- 4.7% (P = 0.0009). CONCLUSIONS: Finasteride and flutamide were safe and well tolerated as AAT for advanced prostate cancer. Finasteride provided additional intraprostatic androgen blockade to flutamide, as measured by additional PSA suppression. Sexual potency was preserved initially in most patients, although there was a reduction in potency and libido in some patients on longer follow-up. Further evaluation of this therapy is needed.

Adenocarcinoma↗
PubMed1995

Nonpalpable intratesticular masses detected sonographically.

PURPOSE: There is controversy concerning the implications of impalpable testicular masses. We examine the sonographic findings and pathology of such tumors. MATERIALS AND METHODS: Between 1985 and 1994, 3,019 scrotal ultrasound studies were performed for various indications and 15 impalpable masses were discovered. RESULTS: Pathological study revealed 5 seminomas, 6 nonseminomas, 2 "burned-out" tumors, 1 lipoma and 1 granuloma. CONCLUSIONS: Impalpable intratesticular masses are likely to be malignant. Any young man with retroperitoneal or visceral masses should undergo scrotal ultrasound. A testicular mass is likely to be the primary cancer but it may be regressed. Persistent scrotal pain may be a presentation of malignancy and should be evaluated with ultrasound.

Adult↗
PubMed1993

Surgical and medical management of germ cell tumors of the chest.

Germ cell tumors are highly curable when treated appropriately. The majority of germ cell tumors arise in the testes, with a proportion having pulmonary parenchymal or mediastinal metastases. For patients who have such tumors, prompt diagnosis and treatment with chemotherapy are essential. A subset of these patients will have persistent radiographic abnormalities after chemotherapy and will benefit from post-chemotherapy resection of residual masses. These patients need to be distinguished from those who should be observed and those who require further chemotherapy. A small proportion of patients with germ cell tumors will present with tumors arising in the mediastinum. Prompt diagnosis, with adequate tissue for histopathologic and immunohistochemical staining, is essential. Primary therapy for such patients should be chemotherapy, except for some patients with mediastinal seminomas in whom radiotherapy is preferable. Mediastinal nonseminomatous germ cell tumors have a poor prognosis due, in part, to their bulk and relative chemosensitivity, but also due in part to their association with non-germ cell elements and acute leukemia. Proper coordination of the different modalities is essential in optimizing the cure rate of patients with these tumors.

Adult↗