Biomedical subjects

Charles J Ryan

Publications and source records attributed to Charles J Ryan.

At least 19 recordsLinked to original sources

PubMed2024

Molecular analysis of primary and metastatic sites in patients with renal cell carcinoma.

BACKGROUNDMetastases are the hallmark of lethal cancer, though underlying mechanisms that drive metastatic spread to specific organs remain poorly understood. Renal cell carcinoma (RCC) is known to have distinct sites of metastases, with lung, bone, liver, and lymph nodes being more common than brain, gastrointestinal tract, and endocrine glands. Previous studies have shown varying clinical behavior and prognosis associated with the site of metastatic spread; however, little is known about the molecular underpinnings that contribute to the differential outcomes observed by the site of metastasis.METHODSWe analyzed primary renal tumors and tumors derived from metastatic sites to comprehensively characterize genomic and transcriptomic features of tumor cells as well as to evaluate the tumor microenvironment at both sites.RESULTSWe included a total of 657 tumor samples (340 from the primary site [kidney] and 317 from various sites of metastasis). We show distinct genomic alterations, transcriptomic signatures, and immune and stromal tumor microenvironments across metastatic sites in a large cohort of patients with RCC.CONCLUSIONWe demonstrate significant heterogeneity among primary tumors and metastatic sites and elucidate the complex interplay between tumor cells and the extrinsic tumor microenvironment that is vital for developing effective anticancer therapies.

Humans↗

PubMed2006

Intermittent chemotherapy for metastatic hormone refractory prostate cancer.

While docetaxel/prednisone chemotherapy has demonstrated a survival advantage in metastatic hormone refractory prostate cancer (HRPC) patients, the optimal duration of chemotherapy has not yet been established. Currently, a standard practice is to treat patients indefinitely until unacceptable toxicity or disease progression. A systematic approach to providing breaks in treatment schedules (intermittent chemotherapy) for patients who experience an initial response to chemotherapy may avoid or delay the development of progressive toxicity. Whether continuous therapy offers an advantage over intermittent therapy, in terms of balancing disease control and overall survival with treatment-related toxicities and quality-of-life (QOL) is yet unanswered. This article will: (1) review the data from prior studies of intermittent versus continuous chemotherapy in other solid tumors, (2) review existing trials of intermittent chemotherapy in prostate cancer, (3) discuss intermittent chemotherapy clinical trial design considerations, and (4) discuss the future role of intermittent chemotherapy for the treatment of prostate cancer.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2006

Secondary hormonal manipulations in prostate cancer.

Targeting AIPC with therapies that affect the mechanisms of androgen receptor signaling despite a castrate testosterone milieu is an active and growing area of clinical research. At present, for patients with AIPC, the data support the maintenance of the castrate state, recognition of the AAWD phenomenon,the sequential use of oral antiandrogens, and a trial of estrogens or adrenal androgen-targeted therapies. Novel agents are being developed that seek to prolong the duration of clinical responses and the overall response rate.

Androgen Antagonists↗

PubMed2006

The case for secondary hormonal therapies in the chemotherapy age.

PURPOSE: Virtually all patients with high risk localized and metastatic prostate cancer who are treated with androgen deprivation therapy eventually have progressive clinical or biochemical disease despite this therapy. Despite this fact numerous therapies are available that target the interaction of androgen and androgen receptor in the castrate testosterone milieu and many clinical investigations are under way in this area. MATERIALS AND METHODS: This literature review focuses on the current clinical literature in support of secondary hormonal therapy. RESULTS: Despite low androgen levels the androgen receptor remains active through the amplification, mutation or alteration of coactivator function. These observations suggest that secondary hormonal therapies remain a reasonable clinical approach. Such approaches can be receptor or ligand directed. Receptor directed approaches to secondary hormonal therapy are antiandrogen withdrawal, sequential use of antiandrogens and estrogenic compounds. Ligand directed therapies are adrenal cortex inhibitors, such as ketoconazole and others in clinical development. Furthermore, in the context of androgen independent tumor growth in patients with metastatic disease clinicians are now faced with the choice of using chemotherapy or secondary hormonal manipulations. Appropriate patient selection is a critical component to the effective use of these agents. CONCLUSIONS: The modest activity of these secondary therapies challenges the notion that advancing prostate cancer uniformly becomes hormone refractory. It offers an alternative to the early use of chemotherapy in patients with androgen independent disease.

Androgen Antagonists↗

PubMed2006

High risk biochemical relapse and the timing of androgen deprivation therapy.

PURPOSE: Although the timing of androgen deprivation therapy in patients with prostate specific antigen-only relapse remains controversial, a large amount of data exists supporting the use of androgen deprivation early in the clinical course in patients with high risk localized prostate cancer as well as in those with metastatic disease. We offer guidance on its use in patients with prostate specific antigen recurrence only. MATERIALS AND METHODS: We reviewed recent data on androgen deprivation for nonmetastatic prostate cancer, including updates from phase III, randomized studies of androgen deprivation in conjunction with radiation therapy or surgery in patients with high risk features. RESULTS: We commented on the extent to which these data on androgen deprivation for nonmetastatic prostate cancer could be extrapolated to the setting of recurrent disease. In addition, we reviewed retrospective analyses of androgen deprivation in patients with prostate specific antigen-only relapse and prognostic data regarding prostate specific antigen doubling time in recurrent disease. Furthermore, consideration was given to rapid prostate specific antigen doubling time as an indication for androgen deprivation. CONCLUSIONS: In patients with nonmetastatic prostate cancer with high risk features as well as in those with serological (prostate specific antigen-only) relapse androgen deprivation before the development of metastatic disease is indirectly supported by long-term outcomes in a series of clinical trials and retrospective data sets. Furthermore, prognostic data suggest that early androgen deprivation may be most beneficial in patients with serological relapse with prostate specific antigen doubling times less than 12 months.

Androgen Antagonists↗

PubMed2006

Persistent prostate-specific antigen expression after neoadjuvant androgen depletion: an early predictor of relapse or incomplete androgen suppression.

OBJECTIVES: To analyze post-androgen depletion (AD) primary tumors to identify markers of treatment failure because AD does not reduce the probability of prostate-specific antigen (PSA) failure after prostatectomy. METHODS: Tumors removed by radical prostatectomy after 3 months of AD from 21 patients were analyzed for gene expression using oligonucleotide arrays. Differences between patients with and without relapse were identified using a conservative significance criteria of a threefold change and delta 0.68, ensuring a false discovery rate of less than 11%. RESULTS: At 50 months of follow-up, 7 of the 18 evaluable patients developed a biochemical recurrence. Gleason grade, pretherapy PSA level, T stage, and margin status were similar between the two groups. Patients with recurrence had greater post-AD PSA levels than those without recurrence (0.87 versus 0.19 ng/mL; P = 0.042). Gene expression analysis revealed 35 probe sets overexpressed in tumors from patients who relapsed. Among the highest ranked probe sets were PSA and other androgen-responsive genes. Serum PSA values during AD revealed similar findings. After 40 days of AD, the PSA level in those without recurrence was 1.21 ng/mL versus 4.5 ng/mL in those with recurrence (P = 0.0034). Immunohistochemistry of post-AD tumors also demonstrated a high PSA staining intensity in many tumors that recurred relative to those that didn't. CONCLUSIONS: The results of our study show that early recurrence is associated with expression of androgen-responsive genes. Surprisingly, these could be identified as early as 3 months after the initiation of AD therapy. Whether this represents a failure to abrogate androgen receptor mediated signaling with androgen depletion or early reactivation of signaling is under study.

Androgen Antagonists↗

PubMed2006

Prostate cancer update: 2005.

PURPOSE OF REVIEW: The purpose of this review is to highlight the most important developments in the diagnosis, prevention, and management of prostate cancer that have been published in the medical literature in the past year. RECENT FINDINGS: Recent research has shown that prostate specific antigen (PSA) velocity can be utilized as a prognostic tool in patients with localized prostate cancer and at the time of serologic relapse. Several novel biomarkers are, however, demonstrating encouraging results in refining or replacing PSA as a screening and prognostic tool. A number of studies have shown that dose and dose intensity of radiation have important ramifications. SUMMARY: Recent data reported in the past year have significant implications in screening and diagnosis of prostate cancer as well as the management of localized prostate cancer with radiation.

Adenocarcinoma↗

PubMed2006

A phase II trial of imatinib mesylate in patients with biochemical relapse of prostate cancer after definitive local therapy.

OBJECTIVE: To determine the biological effects of imatinib mesylate (STI-571, Gleevec; Novartis Pharmaceuticals, Inc., East Hanover, NJ, USA), as measured by prostate-specific antigen (PSA) kinetics in men with biochemical relapse of prostate cancer after definitive local therapy. PATIENTS AND METHODS: Men with prostate cancer, who had had definitive local therapy, with nonmetastatic recurrent disease as manifested by a rising PSA level, were enrolled on this phase II trial. Men received 400 mg of imatinib mesylate orally twice daily and continuously until disease progression or unacceptable toxicity. The PSA level was measured monthly. RESULTS: In all, 20 men with biochemically relapsed prostate cancer were treated. The median pretreatment PSA level was 5.4 ng/mL. Of the 19 evaluable men, one achieved a >or= 50% reduction in PSA level and two had decreases of <50%. For the 16 men in whom the on-treatment PSA doubling time (PSADT) could be calculated (those with increasing PSA level) the median PSADT did not increase significantly (5.8 vs 7.2 months, P = 0.64). Eleven of 20 men discontinued therapy due to toxicity and the trial was stopped early due to toxicity. CONCLUSIONS: Based on the lack of PSA modulation and pronounced toxicities leading to early closure of this trial, further study of single-agent imatinib mesylate at this dose (400 mg twice daily) cannot be recommended in this patient population.

Aged↗

PubMed2006

Phase II evaluations of cilengitide in asymptomatic patients with androgen-independent prostate cancer: scientific rationale and study design.

Two randomized trials demonstrated an improvement in survival with docetaxel-based chemotherapy for patients with metastatic, androgen-independent prostate disease. However, the effect of current therapy is suboptimal in that it is complicated by toxicities and has no curative potential. Cilengitide (EMD121974; NSC 707544), is a potent selective alphavbeta3 and alphavbeta5 integrin antagonist. Integrins are cell surface receptors that mediate a variety of cell activities including endothelial cell proliferation and migration. Blocking the ligation of integrins by antagonists promotes apoptosis of proliferative angiogenic cells, thereby suspending new blood vessel formation, which is essential for the growth of malignant disease. In prostate cancer specifically, integrins are known to be involved in metastases with differential expression on tumor cells. Tumors and vascular endothelial cells produce factors, such as vascular endothelial growth factor and basic fibroblast growth factor, that promote neovascularization, which has been implicated in prostate cancer progression. Cilengitide has been shown to inhibit alphavbeta3- and alphavbeta5-mediated cell adhesion and block in vitro endothelial cell migration. In vivo experiments demonstrated that cilengitide inhibited cytokine-induced basic fibroblast growth factor- and vascular endothelial growth factor-mediated angiogenesis in a dose-dependent manner. Cilengitide also inhibited tumor growth in various in vivo systems. Two Cancer Therapy Evaluation Program-sponsored, multicenter, phase II trials are designed to evaluate the safety and efficacy of this agent in patients with androgen-independent prostate cancer. National Cancer Institute trial 6735 is evaluating cilengitide at 2000 mg in patients with nonmetastatic androgen-independent prostate cancer, and National Cancer Institute trial 6372 is evaluating 2 dose levels of cilengitide, 500 mg or 2000 mg, intravenously twice weekly in patients with metastatic prostate cancer.

Androgens↗

PubMed2005

Chemotherapy for hormone-refractory prostate cancer: now it's a question of "when?".

Recently, data from two randomized phase III studies that compared docetaxel-based chemotherapy to mitoxantrone-based therapy demonstrated that treatment with docetaxel can prolong life in a significant way for patients with hormone-refractory prostate cancer. For many patients who experience disease progression after androgen-deprivation therapy, however, chemotherapy may not be immediately indicated. Such cases include those individuals with hormone-refractory disease in the absence of clinical metastases, and those with asymptomatic metastatic disease, for example. As a result, clinicians treating patients with hormone-refractory disease must weigh the benefits of earlier chemotherapy against its risks, and may consider other therapies such as secondary hormonal approaches before initiating chemotherapy. This decision is further complicated by the fact that a phase III study designed to compare secondary hormonal therapy with chemotherapy has failed due to lack of accrual. Furthermore, the limitations of chemotherapy for prostate cancer are being clarified and include a lack of standard second-line therapy as well as uncertain benefits for those with nonmetastatic disease. In this review, we will highlight some of the issues that impact on the decision of when to start chemotherapy and in whom as well as the potential benefits of secondary hormonal approaches.

Antineoplastic Agents, Hormonal↗

PubMed2005

Early versus delayed androgen deprivation for prostate cancer: new fuel for an old debate.

The purpose of this review is to discuss the recent increase in data supporting the use of androgen ablation early in the clinical course for patients with nonmetastatic prostate cancer. We systematically reviewed recent publications that report on the use of androgen deprivation (AD) in nonmetastatic prostate cancer patients from the 2003 and 2004 proceedings of the American Society of Clinical Oncology, the 2003 and 2004 proceedings of the American Urological Association as well as published literature from 2003 to 2005. Five recently published mature randomized trials of AD plus local therapy were evaluated plus two large data sets on the use of AD for patients with serologic relapse after local therapy. Four mature randomized studies demonstrate an overall survival benefit to the use of AD in conjunction with definitive local therapy (three with radiation and one with surgery). One retrospective analysis suggests that AD administered early after serologic progression improves overall survival, and one retrospective analysis shows a reduction in metastasis-free survival but has not yet shown an overall survival benefit. For patients with nonmetastatic prostate cancer with high-risk features, as well as those for serologic relapse, the use of AD before the development of metastatic disease is supported by long-term outcomes from a series of clinical trials. Consideration of AD is therefore warranted early in the clinical course of high-risk patients.

Androgen Antagonists↗

PubMed2005

Secondary hormonal manipulations in prostate cancer.

Virtually all patients treated with androgen deprivation eventually develop progressive clinical or biochemical disease despite this therapy. Despite low levels of androgen, the androgen receptor remains active, making secondary hormonal therapies a reasonable clinical approach. Considerations for such patients include antiandrogen withdrawal, sequential use of antiandrogens, adrenal cortex inhibitors, and estrogenic compounds. Collectively, the modest activity of these therapies challenges the notion that advancing prostate cancer will uniformly become "hormone refractory."

Androgen Antagonists↗

PubMed2005

Progress in detection and treatment of prostate cancer.

PURPOSE OF REVIEW: The purpose of this review is to highlight the most important developments in the diagnosis, prevention, and management of prostate cancer reported in the past year that have been published in the medical literature. RECENT FINDINGS: Recent research has shown that clinically meaningful prostate cancer can develop in patients with a PSA value <4 ng/dL and has suggested that 'watchful waiting' approaches may not be appropriate for young patients or those with a life expectancy of greater than 15 years. The contribution of obesity to high-grade disease and a higher rate of relapse has also been described. There is now randomized data suggesting that adjuvant hormonal therapy for as little as six month's time confers a survival benefit for those receiving radiation therapy. Secondary hormonal manipulation with ketoconazole is now supported by randomized phase III data. Most importantly, this year the results of two randomized phase III clinical trials of chemotherapy in hormone refractory prostate cancer have shown that survival can be increased by 20% with the use of docetaxel. SUMMARY: Recent data reported in the past year have significant implications for those involved in the management of prostate cancer. The results of the chemotherapy trials have resulted in new standards of care for this disease.

Antineoplastic Agents, Hormonal↗

PubMed2004

Five-year outcomes after neoadjuvant chemotherapy and conformal radiotherapy in patients with high-risk localized prostate cancer.

OBJECTIVES: To describe the 5-year outcomes of patients with high-risk localized prostate cancer treated with neoadjuvant estramustine and vinblastine followed by concurrent chemotherapy and three-dimensional conformal radiotherapy (3D-CRT). METHODS: A total of 23 patients completed therapy consisting of two 8-week cycles of vinblastine, weekly as 4 mg/m2, followed by 8 weeks of concomitant chemotherapy and 3D-CRT. Estramustine was given daily at 10 mg/kg in three divided doses. 3D-CRT consisted of a total dose of 7560 cGy. RESULTS: Assessable patients include 9 with Stage T3 or greater tumors and 5 with lymph node metastasis at diagnosis. All patients had a Gleason score 7 or greater. The median follow-up was 60 months. Of the 23 assessable patients, 15 (65%) experienced biochemical relapse by American Society for Therapeutic Radiology Oncology criteria. The median time to prostate-specific antigen relapse was 12 months (range 7 to 16). Five patients (22%) developed metastases. The median time to metastasis had not been reached by last follow-up. Of the 23 assessable patients, 11 (48%) received no additional therapy and had noncastrate testosterone levels. Six patients had no evidence of disease and 9 patients were receiving androgen blockade. Three patients died (one of prostate cancer and two of other diseases). CONCLUSIONS: A substantial proportion of patients with unfavorable-risk localized prostate cancer achieved long-term disease control with estramustine and vinblastine and concurrent 3D-CRT, no significant long-term toxicities were seen and 48% underwent no further therapy after RT. These long-term findings support the continued study of chemotherapy combined with RT as a potential alternative to prolonged androgen deprivation.

Adenocarcinoma↗

PubMed2004

Advances in prostate cancer.

PURPOSE OF REVIEW: The purpose of this review is to highlight the most important developments in the diagnosis, prevention, and management of prostate cancer reported in the past year that have been published in the medical literature. RECENT FINDINGS: Recent research has yielded important insights into the effects of lowering the serum prostate-specific antigen threshold for prostate biopsy on the incidence of prostate cancer and suggests that a cutoff value of 2.5 ng/mL would double the rate of diagnosis of the disease in young men. Other developments demonstrate that oral finasteride reduces the incidence of the disease but increases the proportion of high-grade tumors. The incidence of mutations of the androgen receptor gene has been shown to be lower than was previously thought. New randomized data suggest that for patients with high-risk localized prostate cancer treated with radiation, 4 months of androgen deprivation in combination with whole pelvis radiotherapy confers a clinical benefit. The clinical benefits associated with chemotherapy and supportive care therapies such as the bone targeting bisphosphonates continue to be refined. SUMMARY: The data reported in the past year have widespread implications for all clinicians involved in the management of prostate cancer, ranging from primary care physicians who screen for and diagnose the disease to those who manage localized as well as systemic disease. Several of the year's findings will result in significant changes in the manner in which the disease is treated.

Humans↗

PubMed2003

Role of secondary hormonal therapy in the management of recurrent prostate cancer.

Androgen ablation remains the cornerstone of the systemic management of prostate cancer. After initial androgen deprivation, clinical outcomes vary considerably. For the patient with progressive disease after androgen deprivation, multiple therapeutic options are available and include antiandrogen withdrawal, chemotherapy, and secondary hormonal agents. Multiple secondary hormonal agents have clinical activity and the sequential use of these agents may lead to prolonged periods of clinical response. In addition to the use of oral antiandrogens, active secondary hormonal therapies include adrenolytic agents such as ketoconazole and aminoglutethimide, corticosteroids and estrogenic compounds. This article reviews the clinical trial data for these various agents and discusses their role in the management of patients with advanced prostate cancer.

Adenocarcinoma↗

PubMed2002

Chemotherapy for good-risk germ-cell tumors.

Patients with good-risk germ-cell tumors have a high likelihood of cure with an approach that integrates cisplatin-based chemotherapy, surgery, radiation, and observation. This article addresses risk group allocation as well as the controversies regarding the composition, number of cycles, and dosages of chemotherapy regimens used in this population. Recent data from randomized trials demonstrate that carboplatin is inferior to cisplatin and that the dose of etoposide should be 500 mg/m(2) per course. Bleomycin remains controversial in good-risk germ-cell tumors, but the literature suggests that both E(500)P for four cycles or BE(500)P for three cycles may be considered standard.

Antibiotics, Antineoplastic↗

PubMedDate not supplied

Reduced incidence of bony metastasis at initial prostate cancer diagnosis: data from CaPSURE.

PURPOSE: Despite stage migration as a result of screening, many individuals are diagnosed each year with metastatic (M+), as opposed to localized (M0), prostate cancer. This study describes features that characterize patients with M+ compared to those diagnosed with M0 disease. MATERIALS AND METHODS: Patients enrolled in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE), a national, longitudinal registry of men with prostate cancer, formed the basis of this study. The prevalence, and changes with time, of patients with M+ and M0 cancer by clinical and sociodemographic characteristics were examined. RESULTS: Of 10,113 patients diagnosed between 1990 and 2003, 266 (2.6%) had M+ disease at diagnosis. From 1990 to 1997, 4.2% of 4020 total patients had M+ versus 1.6% of 6093 total patients diagnosed between 1998 and 2003 (odds ratio 0.34; 95% confidence interval 0.24-0.48; P < 0.0001). In univariate analysis, advanced age, higher prostate-specific antigen, Gleason grade, black race, lower income, and lower educational level were associated with M+ versus M0 disease (P < 0.01). However, in multivariate analysis, only higher serum prostate-specific antigen and higher Gleason grade, and not the sociodemographic variables, remained associated with M+ disease (P < 0.01). Patients with M+ diagnosed between 1998 and 2003 are more likely to harbor high-grade (Gleason > or =8) primary tumors (62% vs. 45%, P = 0.02) than those diagnosed between 1990 and 1997. No changes in age, race, education, insurance status, or income were observed in the early versus late era. CONCLUSIONS: These findings show a reduction in the incidence of metastatic disease at initial prostate cancer diagnosis. Furthermore, biologic, rather than socioeconomic, factors are associated with this type of disease presentation.

Aged↗