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Arie S Belldegrun

Publications and source records attributed to Arie S Belldegrun.

At least 19 recordsLinked to original sources
PubMed2007

p21 is a prognostic marker for renal cell carcinoma: implications for novel therapeutic approaches.

PURPOSE: Kidney cancer, although relatively rare compared to other malignancies, is the most lethal of the common urological malignancies. Current treatments are inadequate as evidenced by a poor 5-year survival of patients with metastatic disease. Since there exists a significant disparity in the survival of patients with localized vs metastatic disease, efforts are under way to identify molecular markers of progression as well as targets for novel therapeutic approaches. The apoptosis and cell cycle regulatory protein, p21(waf1/cip1), has been investigated as a possible target in other cancers since it is involved in the repair and apoptotic response of normal and malignant cells to DNA damage. MATERIALS AND METHODS: We performed immunohistochemical analysis of a tissue array of 366 patients for which we have data on grade, stage and survival. We found that nuclear p21 is most highly expressed in collecting duct carcinoma and lowest in oncocytoma. Cytosolic p21 staining was highest in oncocytoma. RESULTS: In clear cell renal cell carcinoma p21 has prognostic value, which is a function of whether patients have localized or metastatic disease at diagnosis, suggesting the existence of 2 discrete classes of this disease. In localized disease higher levels of nuclear p21 were associated with a better prognosis, but in patients with metastatic disease at diagnosis higher levels of nuclear and cytosolic p21 were associated with worse survival. CONCLUSIONS: Based on our findings p21 may be useful in prognostication, and it may have a role in the differing biological behaviors of localized and metastatic renal cell carcinoma.

Biomarkers, Tumor↗
PubMed2006

Evolving principles of surgical management and prognostic factors for outcome in renal cell carcinoma.

The generally accepted principles for the surgical management of renal cell carcinoma (RCC) were first described more than 30 years ago. Since then, much has changed in the understanding of the basic biology and genetics of kidney cancer. Improvements in cross-sectional imaging has allowed for more accurate preoperative clinical staging of renal tumors, and the necessity of completing all the components of the radical nephrectomy have been questioned. Surgical techniques have also evolved, and technology has advanced to make possible new methods of managing renal tumors. The TNM staging system is currently the most extensively used system to provide prognostic information for RCC. However, data published in the last few years has led to significant controversies as to whether further revisions are needed and whether improvements can be made with the introduction of new, more accurate and predictive prognostic factors. Furthermore, the recent discovery of molecular tumor markers are expected to revolutionize the staging of RCC and lead to the development of new therapies based on molecular targeting. This review will examine the evolving principles in the surgical management of RCC as well as provide an update on current staging modalities and prognostic factors.

Carcinoma, Renal Cell↗
PubMed2006

RENCA/carbonic anhydrase-IX: a murine model of a carbonic anhydrase-IX-expressing renal cell carcinoma.

OBJECTIVES: Carbonic anhydrase-IX (CA-IX) is a cell surface tumor-associated antigen expressed by most clear cell renal cell carcinomas (RCCs). The specificity and the prognostic value of CA-IX provide impetus to create a mouse model of CA-IX-expressing RCC for testing CA-IX-targeted therapies against RCC. METHODS: A retrovirus encoding the human CA-IX gene was used to transduce the murine RCC line, RENCA. In vivo growth kinetics and CA-IX expression were compared between RENCA and RENCA/CA-IX using heterotopic, metastatic, and orthotopic models. RESULTS: Transduction of RENCA created the RENCA/CA-IX line with nearly 100% CA-IX surface expression. In the heterotopic model, subcutaneous injection of 500,000 and 50,000 cells led to tumor formation at 2 to 2.5 weeks after injection, with similar growth kinetics between the two cell lines at either cell number. In the pulmonary metastatic model, a similar number of metastases was noted after inoculation of RENCA and RENCA/CA-IX. In the orthotopic model, autopsy revealed a CA-IX-expressing renal tumor, as well as CA-IX-expressing metastases to the lungs, liver, contralateral kidney, intestines, and lymph nodes. In all the above models, the RENCA/CA-IX tumors retained expression of CA-IX, as demonstrated by immunohistochemistry staining. CONCLUSIONS: RENCA/CA-IX is the first tumor model that manifests in immunocompetent Balb/c mice and stably expresses a defined kidney cancer-associated antigen. It maintains antigen expression, forms metastases, and produces reliable tumor growth kinetics equivalent to that of its parental cell line.

Animals↗
PubMed2006

Dendritic cell surface calreticulin is a receptor for NY-ESO-1: direct interactions between tumor-associated antigen and the innate immune system.

How the immune system recognizes endogenously arising tumors and elicits adaptive immune responses against nonmutated tumor-associated Ags is poorly understood. In search of intrinsic factors contributing to the immunogenicity of the tumor-associated Ag NY-ESO-1, we found that the NY-ESO-1 protein binds to the surface of immature dendritic cells (DC), macrophages, and monocytes, but not to that of B cells or T cells. Using immunoprecipitation coupled with tandem mass spectrometry, we isolated DC surface calreticulin as the receptor for NY-ESO-1. Calreticulin Abs blocked NY-ESO-1 binding on immature DC and its cross-presentation to CD8+ T cells in vitro. Calreticulin/NY-ESO-1 interactions provide a direct link between NY-ESO-1, the innate immune system, and, potentially, the adaptive immune response against NY-ESO-1.

Antigens, Neoplasm↗
PubMed2006

Long-term outcomes of the surgical management of renal cell carcinoma.

It has been 35 years since the radical nephrectomy was standardized by the work of Robson et al. (J Urol 101:297-301, 1969). Despite being based on a retrospective review of only 88 cases operated upon over a span of 15 years, this publication was an important milestone in the attempt to create uniformity in the staging of Renal cell carcinoma (RCC), and the measurement of surgical outcomes for RCC. Although this manuscript forms the basis for our contemporary measurement of the long-term results of RCC surgery and set the standard to which the entire subsequent literature was compared, contemporary research subsequently has questioned many of Robson's conclusions regarding RCC. In Robson's era, the majority of patients presented with large, symptomatic tumors, pre-operative staging was imprecise, and many patients had locally advanced disease at the time of surgery: of the 88 patients in Robson's series, 75% were managed through a thoracoabdominal incision. Since that time, advances in renal imaging and clinical staging have led to the increased detection of incidental, lower stage, organ-confined tumors more amendable to expanded surgical options. Surgical techniques have evolved and technological advances have made possible new methods of managing renal tumors in situ that have emphasized a transition from radical to less extirpative approaches. In addition, understanding of the basic biology and genetics of kidney cancer has led to improved prognostication and the development of effective immunotherapies for advanced disease. The current concepts and long-term outcomes of the surgical management of RCC will be reviewed to help elucidate some of these changes, from the evolution of open to laparoscopic to percutaneous, from radical to partial to ablative approaches.

Adrenalectomy↗
PubMed2006

Open partial nephrectomy for the treatment of renal cell carcinoma.

Open partial nephrectomy, or nephron-sparing surgery (NSS), is now considered the standard of care for the treatment of small renal tumors. The oncologic efficacy and safety of NSS for the treatment of stage-T1a renal tumors has been repeatedly demonstrated to be equivalent to radical nephrectomy. NSS initially was reserved for patients with solitary kidneys, impaired renal function, hereditary tumor syndromes, bilateral renal tumors, and those with significant comorbidities predisposing to future renal failure. The indications have expanded recently to allow elective partial nephrectomy in the setting of a normal contralateral kidney. Furthermore, recent data demonstrate that partial nephrectomy for larger tumors (T1b), which have been historically treated with radical nephrectomy, is a viable option when surgical margins can safely be achieved. In the era of minimally invasive techniques, laparoscopic NSS is technically feasible, yet long-term studies are still needed to assess oncologic efficacy. New NSS ablative technologies, such as cryoablation and radiofrequency ablation, are on the horizon. In this article, we discuss the role of open NSS and surgical technique in the contemporary management of renal tumors.

Biopsy↗
PubMed2006

Secondary hormonal therapy for advanced prostate cancer.

PURPOSE: Androgen ablation remains the cornerstone of management for advanced prostate cancer. Therapeutic options in patients with progressive disease following androgen deprivation include antiandrogen withdrawal, secondary hormonal agents and chemotherapy. Multiple secondary hormonal agents have clinical activity and the sequential use of these agents may lead to prolonged periods of clinical response. We provide a state-of-the-art review of the various agents currently used for secondary hormonal manipulation and discusses their role in the systemic treatment of patients with prostate cancer. MATERIALS AND METHODS: A comprehensive review of the peer reviewed literature was performed on the topic of secondary hormonal therapies, including oral antiandrogens, adrenal androgen inhibitors, corticosteroids, estrogenic compounds, gonadotropin-releasing hormone antagonists and alternative hormonal therapies for advanced prostate cancer. RESULTS: Secondary hormonal therapies can provide a safe and effective treatment option in patients with AIPC. The use of steroids and adrenolytics, such as ketoconazole and aminoglutethimide, has resulted in symptomatic improvement and a greater than 50% prostate specific antigen decrease in a substantial percent of patients with AIPC. A similar clinical benefit has been demonstrated with estrogen based therapies. Furthermore, these therapies have demonstrated a decrease in metastatic disease burden. Other novel hormonal therapies are currently under investigation and they may also show promise as secondary hormonal therapies. Finally, guidelines from the United States Food and Drug Administration Prostate Cancer Endpoints Workshop were reviewed in the context of developing new agents. CONCLUSIONS: Secondary hormonal therapy serves as an excellent therapeutic option in patients with AIPC in whom primary hormonal therapy has failed. Practicing urologists should familiarize themselves with these oral medications, their indications and their potential side effects.

Androgen Antagonists↗
PubMed2006

Mammalian target of rapamycin inhibitors in renal cell carcinoma: current status and future applications.

Significant achievements in the basic sciences have led to a greater knowledge of the underlying signaling pathways in renal cell cancer (RCC), including the mammalian target of rapamycin (mTOR) pathway (phosphoinositide 3-kinase/Akt pathway). The mTOR pathway has a central role in the regulation of cell growth and increasing evidence suggests its dysregulation in cancer. Receiving input from multiple signals, including growth factors, hormones, nutrients, and other stimulants or mitogens, the pathway stimulates protein synthesis by phosphorylating key translation regulators such as ribosomal S6 kinase. The mTOR pathway also contributes to many other critical cellular functions, including protein degradation and angiogenesis. Hence, use of inhibitors of the pathway represents a new strategy for the targeted treatment of RCC, and mTOR inhibitors have already shown promising clinical efficacy and low toxicity profiles in unselected patients with metastatic RCC. As with other new, targeted cancer agents, the future use of mTOR inhibitors will benefit from reproducible biomarkers that can be used in the clinic to identify patients most likely to respond and to document modulation of the drug target in addition to clinical response.

Carcinoma, Renal Cell↗
PubMed2006

Prognostic factors in renal cell carcinoma.

The identification of prognostic factors in patients with renal cell carcinoma (RCC) represents an area of increasing interest. The tumor, node, metastasis (TNM) staging system is currently the most extensively used tool for providing prognostic information for RCC. Data published in the last few years have led to significant controversies as to whether further revisions are needed in current staging systems and whether improvements can be made with the introduction of new, more accurate and predictive prognostic factors not currently included in traditional staging systems. While integrated staging systems have improved the staging of RCC, the recent discovery of molecular tumor markers is expected to revolutionize the staging of RCC in the future and lead to the development of new therapies based on molecular targeting. The aim of the current review is to highlight such controversies and provide an update on current staging modalities and prognostic factors for RCC.

Biomarkers, Tumor↗
PubMed2006

Flap endonuclease 1 is overexpressed in prostate cancer and is associated with a high Gleason score.

OBJECTIVE: To investigate the expression and potential clinical usefulness of structure-specific flap endonuclease 1 (FEN-1) in human primary prostate cancer using tissue microarray technology, as FEN-1 was recently identified to be overexpressed in CL1.1, the most aggressive clone generated from the hormone-refractory prostate cancer cell line CL1. MATERIALS AND METHODS: Immunohistochemistry was performed on tissue microarrays constructed from paraffin-embedded specimens of primary prostate cancer from 246 patients who had had a radical prostatectomy. Prostatic intraepithelial neoplasia (PIN), benign prostatic hyperplasia (BPH) and normal prostate epithelium were represented on the array. FEN-1 nuclear expression was scored based on the percentage of target cells staining positively, and correlated with Gleason score, preoperative prostate-specific antigen (PSA) level and pathological stage. The time to PSA recurrence was also analysed. RESULTS: The mean expression of FEN-1 was significantly higher in cancer (36.7%) than in normal (13.2%), BPH (4.5%) and PIN (15.4%) specimens (P < 0.001). FEN-1 expression was significantly correlated with Gleason score (ó = 0.23, P = 0.002). A higher preoperative serum PSA level (P = 0.015), Gleason score > or = 7 (P < 0.001), seminal vesicle invasion (P < 0.001) and capsular involvement (P = 0.004) were associated with PSA recurrence, whereas FEN-1 expression was not. In a multivariate analysis, only Gleason score > or = 7 (P < 0.001), seminal vesicle invasion (P = 0.005) and capsular involvement (P = 0.009) were retained as independent predictors for PSA recurrence. CONCLUSIONS: FEN-1 is overexpressed in prostate cancer compared with matched normal prostate, and its expression increases with tumour dedifferentiation, as shown by increasing Gleason score. These results suggest that FEN-1 might be a potential marker for selecting patients at high risk, and a potential target for prostate cancer diagnosis and therapy.

Aged↗
PubMed2006

Adjuvant treatment for renal cell carcinoma.

Despite significant advances in the diagnosis, staging and treatment of patients with renal cell carcinoma, recurrence rates following surgical resection of locally aggressive tumours remain high. In an effort to delay disease progression and improve survival, the concept of adjuvant therapy has been proposed. Optimal adjuvant therapy for surgically resected renal cell carcinoma remains to be defined and the evaluation of adjuvant therapies will require properly controlled and adequately powered randomised trials. Promising preliminary results have been seen with active immunotherapies and agents that target critical signalling pathways, and there are several Phase III trials of these novel treatment options that are underway. In addition, classification of patients into high- and low-risk subgroups on the basis of a prognosis profile will serve as a useful means to guide clinicians in improving the selection of patients who are likely to derive benefit from adjuvant therapy. This will lead to a future area of investigation, which will be the identification of patients within the target population that should respond to a given treatment. This review will discuss the role and current status of adjuvant therapies for renal cell carcinoma.

Adjuvants, Pharmaceutic↗
PubMed2006

Surveillance strategies for renal cell carcinoma patients following nephrectomy.

Renal cell carcinoma (RCC) is the most lethal of urologic malignancies, accounting for an estimated 36,000 new cases of carcinoma and 12,000 deaths in 2005. Nephrectomy is the usual treatment; however, after nephrectomy, RCC recurs in 20% to 40% of patients with clinically localized disease. A consensus surveillance protocol does not exist for follow-up of RCC after nephrectomy. In this article, available protocols are reviewed with a goal of developing an evidence-based system including the prognostic factors for recurrent disease, chronology and sites of recurrence, available treatment options if recurrent disease is found, and modalities of diagnostic testing available to urologists. New surveillance recommendations are presented based on prognostic factors as well as the University of California, Los Angeles Integrated Staging System for RCC.

Journal Article↗
PubMed2005

Prevention of bladder cancer: a review.

INTRODUCTION: Bladder cancer represents an ideal tumor model to test and apply cancer prevention strategies. In addition to reviewing the epidemiology of transitional cell carcinoma (TCC), we review the current status and the future directions of bladder cancer prevention. MATERIALS AND METHODS: A literature review of peer-reviewed articles which address bladder cancer prevention was performed. RESULTS: Pre-clinical and limited clinical data suggest that bladder cancer is responsive to efforts to delay or prevent its development in at-risk patients, and in reducing the risk of recurrence in patients with established disease. Many epidemiologic studies, however, investigating natural products, such as vitamins and herbal compounds, lack conclusive evidence of their chemopreventive effects. CONCLUSIONS: While many agents hold promise in the prevention of bladder cancer, none currently can be recommended as proven chemoprevention strategies. Improving the accuracy of patient risk assessment and identification of surrogate endpoint biomarkers are crucial to the testing of these strategies. Efficient study design will ensure rapid and substantial advances in the chemoprevention of bladder cancer.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2005

Clinicopathologic and molecular correlations of necrosis in the primary tumor of patients with renal cell carcinoma.

BACKGROUND: The presence of histologic necrosis in the primary tumor of patients with renal cell carcinoma (RCC) has been suggested to be an important predictor of survival. The authors investigated the relation of tumor necrosis to other clinicopathologic factors known to be important prognostic indicators for patients with RCC. METHODS: The records of 311 patients undergoing treatment for RCC were evaluated for basic clinicopathologic information including TNM classification, nuclear grade, Eastern Cooperative Oncology Group (ECOG) performance status (PS), disease recurrence, and survival. The presence and extent of histologic necrosis of the primary tumors was recorded and correlated with clinicopathologic factors, carbonic anhydrase IX and Ki-67 expression, disease recurrence, and survival. RESULTS: The presence of necrosis in the primary tumor of patients with RCC compared with patients with RCC without necrosis was associated with higher T classification (P < 0.0001), the presence of lymph node disease (P = 0.009), the presence of metastases (P < 0.0001), higher grade (P < 0.0001), greater mean tumor size (P < 0.0001), an ECOG PS score > or = 1 (P = 0.007), higher University of California-Los Angeles Integrated Staging System (UISS) category (P < 0.0001), and higher Ki-67 expression (P < 0.0001). The extent of necrosis in the primary tumor was associated with the presence of lymph node disease (P = 0.009) and the presence of metastases (P < 0.0001), and correlated with higher T classification (sigma = 0.31, P < 0.0001), poorer ECOG PS (sigma = 0.18, P = 0.002), higher grade (sigma = 0.33, P < 0.0001), greater tumor size (sigma = 0.40, P < 0.0001), higher UISS category (sigma = 0.37, P < 0.0001), and higher Ki-67 staining (sigma = 0.32, P < 0.0001). Patients with the presence of necrosis in the primary tumor demonstrated a lower 5-year disease-specific survival compared with patients without necrosis in the primary tumor (36% vs. 75%; P < 0.0001). Multivariate analysis demonstrated that T classification (P < 0.0001), distant metastases (P < 0.0001), and ECOG PS (P < 0.0001) were independent predictors of DSS, whereas the presence of necrosis was not (P = 0.1100). Substratification into localized and metastatic disease demonstrated that the presence of necrosis was an independent predictor of survival in patients with localized (P = 0.025), but not metastatic (P = 0.44), disease. The extent of necrosis was not an independent predictor of survival (P > 0.05). Patients with the presence of necrosis in the primary tumor had a lower 5-year disease recurrence-free rate compared with patients without the presence of necrosis (62% vs. 92%, P < 0.0001). CONCLUSIONS: The presence of necrosis in the primary tumor was associated with adverse prognostic factors such as high T classification, presence of lymph node disease and metastases, high grade, large tumor size, and poor ECOG PS. The extent of necrosis was found to be associated with the presence of lymph node disease and metastases and correlated with higher T classification, higher grade, greater tumor size, poorer ECOG PS, and higher UISS category. The presence of this histologic variant was an independent predictor of poor survival in patients with localized, but not metastatic, disease. In addition, Ki-67 expression served as a valuable surrogate marker for the presence of histologic tumor necrosis.

Adenocarcinoma, Clear Cell↗
PubMed2005

Prognostic value of histologic subtypes in renal cell carcinoma: a multicenter experience.

PURPOSE: To analyze to what extent histologic subtype is of prognostic importance in renal cell carcinoma based on a large, international, multicenter experience. PATIENTS AND METHODS: Four thousand sixty-three patients from eight international centers were included in this retrospective study. Histologic subtype (1997 International Union Against Cancer [UICC] criteria of tumor response), age, sex, TNM stage, Fuhrman grade, tumor size, Eastern Cooperative Oncology Goup performance status (ECOG PS), and overall survival were determined in all cases. The prognostic values of clear cell, papillary, and chromophobe histologic features were assessed by uni- and multivariate analysis using the Kaplan-Meier method and Cox model, respectively. RESULTS: Clear cell, papillary, and chromophobe carcinomas accounted for 3,564 (87.7%), 396 (9.7%) and 103 (2.5%) cases, respectively. In univariate analysis, a trend toward a better survival was observed when clear cell, papillary, and chromophobe histologies were considered prognostic categories (log-rank P = .0007). However, in multivariate analysis, TNM stage, Fuhrman grade and ECOG PS, but not histology, were retained as independent prognostic variables (P < .001). CONCLUSION: The stratification in three main renal cell carcinoma histologic subtypes as defined by the 1997 UICC-American Joint Committee on Cancer consensus should not be considered a major prognostic variable comparable to TNM stage, Fuhrman grade and ECOG PS.

Adolescent↗
PubMed2005

Novel approaches in the therapy of metastatic renal cell carcinoma.

Renal cell carcinoma (RCC) is the most lethal of the common urologic malignancies, with approximately 40% of patients eventually dying of cancer progression. Approximately one third of patients present with metastatic disease, and up to 40% treated for localized disease have a recurrence. Recent advances in the understanding of the pathogenesis, behavior, and molecular biology of RCC have paved the way for developments that may enhance early diagnosis, better predict tumor prognosis, and improve survival for RCC patients. The recent discovery of molecular tumor markers is expected to revolutionize the staging of RCC in the future and lead to the development of new therapies based on molecular targeting. Cytokine-based immunotherapy can be considered standard therapy in the treatment of metastatic RCC today. However, new therapies such as tumor vaccines, anti-angiogenesis agents, and small molecule inhibitors are being developed to improve efficacy and treat those patients who are unable to tolerate or are resistant to systemic immunotherapy. The aim of this review is to provide an update on current therapeutic approaches and targeted molecular therapy for metastatic RCC.

Carcinoma, Renal Cell↗
PubMed2005

Dominant B cell epitope from NY-ESO-1 recognized by sera from a wide spectrum of cancer patients: implications as a potential biomarker.

Monitoring the spontaneous antibody (Ab) response against a panel of relevant tumor-associated antigens (TAA) in cancer patients may provide useful information regarding the clinical status of cancer. However, current Ab detection approaches require the purification of recombinant proteins, which is often difficult to achieve. In order to bypass the purification of recombinant proteins, we identified a dominant B-cell epitope from a shared tumor antigen NY-ESO-1. A synthetic peptide of the epitope, ESO:1-40, was as sensitive as the recombinant protein for detecting Ab against NY-ESO-1 in most patients. NY-ESO-1 specific Ab present in the sera of patients with melanoma, prostate cancer, nonsmall cell lung cancer, esophageal cancer, gastric cancer and hepatocellular carcinoma reacted with the dominant peptide at a similar frequency as the recombinant protein. To our knowledge, ESO:1-40 is the first peptide epitope recognized by sera from a wide spectrum of cancer patients but not healthy donors. This simple and straightforward approach may allow the investigation of the clinical significance of spontaneous Ab responses against multiple TAA and their correlation with the clinical course of malignant diseases in the future.

Amino Acid Sequence↗