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Biomedical subjects

Brian I Rini

Publications and source records attributed to Brian I Rini.

At least 19 recordsLinked to original sources
PubMed2007

Hypothyroidism in patients with metastatic renal cell carcinoma treated with sunitinib.

Sunitinib is an inhibitor of the vascular endothelial growth factor and platelet-derived growth factor receptors, and it has antitumor activity in metastatic renal cell carcinoma and gastrointestinal stromal tumors. To further investigate the fatigue associated with sunitinib therapy, thyroid function tests were performed on patients with metastatic renal cell carcinoma who were receiving sunitinib. Seventy-three patients with metastatic renal cell carcinoma were treated with sunitinib at the Cleveland Clinic Taussig Cancer Center, and 66 of them had thyroid function test results available. Fifty-six (85%) of the 66 patients had one or more abnormality in their thyroid function test results, consistent with hypothyroidism, and 47 (84%) of the 56 patients with abnormal thyroid function tests had signs and/or symptoms possibly related to hypothyroidism. Thyroid hormone replacement was undertaken in 17 patients, and symptoms improved in nine of them. Thyroid function test abnormalities appear to be common in patients with metastatic renal cell carcinoma treated with sunitinib, and routine monitoring is warranted.

Adult↗
PubMed2006

Phase II study of lenalidomide in patients with metastatic renal cell carcinoma.

BACKGROUND: Lenalidomide (LEN) is a structural and functional analogue of thalidomide that has demonstrated enhanced immunomodulatory properties and a more favorable toxicity profile. A Phase II, open-label study of LEN in patients with metastatic renal cell carcinoma (RCC) was conducted to determine its safety and clinical activity. METHODS: Patients with metastatic RCC received LEN orally at a dose of 25 mg daily for the first 21 days of a 28-day cycle. The primary endpoint was the objective response rate. Time to treatment failure, safety, and survival were secondary endpoints. RESULTS: In total, 28 patients participated in the trial and were included in the current analysis. Three of 28 patients (11%) demonstrated partial responses and continued to be progression-free for >15 months. Eleven patients (39%) had stable disease that lasted >3 months, including 8 patients who had tumor shrinkage. In total, 6 patients (21%) remained on the trial, and 5 additional patients continued to be followed for survival. The median follow-up for those 11 patients was 13.5 months (range, 8.3-17.0 months). The median survival had not been reached at the time of the current report. Serious adverse events included fatigue (11%), skin toxicity (11%), and neutropenia (36%). CONCLUSIONS: LEN demonstrated an antitumor effect in metastatic RCC, as evidenced by durable partial responses. LEN toxicities were manageable. Further studies will be required to assess the overall activity of LEN in patients with metastatic RCC.

Administration, Oral↗
PubMed2006

Clinical response to therapy targeted at vascular endothelial growth factor in metastatic renal cell carcinoma: impact of patient characteristics and Von Hippel-Lindau gene status.

OBJECTIVE: To describe the relationship among patient characteristics, Von Hippel-Lindau (VHL) gene status and clinical outcome in metastatic renal cell carcinoma (RCC) in patients receiving vascular endothelial growth factor (VEGF)-targeted therapy. PATIENTS AND METHODS: All patients with metastatic RCC who received therapy with interferon-alpha plus bevacizumab, SU11248 or AG013736 at the authors' institution were considered. Clinical features were collected and activation status of the VHL gene (VHL) was determined from baseline paraffin-embedded tumour samples. Tumour response, time to tumour progression (TTP) and overall survival were recorded. RESULTS: Forty-three patients were evaluable for determination of VHL status and clinical response. There was an objective response in 18 patients (43%; 95% confidence interval 28-59%). The median TTP for the entire cohort was 8.1 months. There was an improved clinical outcome in patients with the following clinical features: male gender, lack of hepatic metastases, no previous radiation therapy and higher baseline haemoglobin level. Twenty-six patients (60%) had evidence of VHL mutation or promoter methylation; such patients had an objective response rate of 48%, vs 35% in patients with no VHL mutation or methylation. Patients with VHL methylation or a mutation predicted to truncate or shift the VHL reading frame had a median TTP of 13.3 months, vs 7.4 months in patients with none of these features (P = 0.06). CONCLUSION: VEGF-targeted therapy is active in metastatic RCC and the response can be associated with certain clinical features. The TTP with VEGF-targeted therapy might be prolonged in patients with VHL methylation or mutations that truncate or shift the VHL reading frame. Further investigation of VHL pathway components is needed to understand the biology of the response to VEGF-targeted agents in metastatic RCC.

Adult↗
PubMed2006

Combination immunotherapy with prostatic acid phosphatase pulsed antigen-presenting cells (provenge) plus bevacizumab in patients with serologic progression of prostate cancer after definitive local therapy.

BACKGROUND: APC8015 (sipuleucel-T) is a cellular prostate cancer vaccine containing autologous antigen-presenting cells (APC) loaded with PA2024, a recombinant prostatic acid phosphatase/granulocyte-macrophage-colony-stimulating factor fusion protein, as the immunogen. Bevacizumab is a recombinant antibody against vascular endothelial growth factor, a proangiogenic protein with inhibitory effects on APC. A clinical trial was conducted to determine the prostate-specific antigen (PSA) and immunomodulatory effects of this combination immunotherapy. METHODS: Patients with androgen-dependent prostate cancer who had received prior definitive therapy with nonmetastatic, recurrent disease as manifested by a rising PSA of between 0.4 ng/mL and 6.0 ng/mL were enrolled. APC8015 was given intravenously(i.v.) on Weeks 0, 2, and 4. Bevacizumab was given at a dose of 10 mg/kg i.v. on Weeks 0, 2, 4, and every 2 weeks thereafter until toxicity or disease progression. PSA changes were recorded and the PSA doubling time (PSADT) was calculated. Immune response versus PA2024 was measured at baseline and after treatment by T-cell proliferation and interferon-gamma enzyme-linked immunospot (ELISPOT) assays. RESULTS: Twenty-two patients were treated. One patient achieved a > or =50% decrease in PSA. Nine patients exhibited some decrease in PSA from baseline, ranging from 6% to 72%, with the PSA of 3 patients decreasing at least 25%. The median pretreatment PSADT for the 20 evaluable patients was 6.9 months and the median posttreatment PSADT was 12.7 months (P = .01). All patients demonstrated induction of an immune response against PA2024. CONCLUSIONS: The combination of APC8015 and bevacizumab induces an immune response and modulates PSA in patients with biochemically recurrent prostate cancer.

Acid Phosphatase↗
PubMed2006

Sunitinib in patients with metastatic renal cell carcinoma.

CONTEXT: Current treatment options for metastatic renal cell carcinoma (RCC) are limited and there is a need to identify novel and effective therapies. Sunitinib malate is an oral multitargeted tyrosine kinase inhibitor, which has shown activity in an initial study of cytokine-refractory metastatic RCC patients. OBJECTIVE: To confirm the antitumor efficacy of sunitinib as second-line treatment in patients with metastatic clear-cell RCC, the predominant cell type of this malignancy. DESIGN, SETTING, AND PATIENTS: Open-label, single-arm, multicenter clinical trial. Patients were enrolled between February and November 2004, with follow-up continuing until disease progression, unacceptable toxicity, or withdrawal of consent. The reported data apply through August 2005. Patients (N = 106) had metastatic clear-cell RCC, which had progressed despite previous cytokine therapy. INTERVENTION: Repeated 6-week cycles of sunitinib, 50 mg per day given orally for 4 consecutive weeks followed by 2 weeks off per treatment cycle. MAIN OUTCOME MEASURES: Assessment of clinical response, degree of tumor regression on imaging studies using the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. Primary end point was overall objective response rate (complete plus partial). Secondary end points were progression-free survival and safety. Response was evaluated by independent third-party core imaging laboratory and by treating physicians (investigator assessment). RESULTS: All 106 patients received sunitinib and were included in the intent-to-treat population for safety analyses. Of these, 105 patients were evaluable for efficacy analyses. The objective response rate according to an independent third-party assessment resulted in 36 patients with partial response (34%; 95% confidence interval, 25%-44%), and a median progression-free survival of 8.3 months (95% confidence interval, 7.8-14.5 months). The most common adverse events experienced by patients were fatigue in 30 (28%) and diarrhea 21 (20%). Neutropenia, elevation of lipase, and anemia were the most common laboratory abnormalities observed in 45 (42%), 30 (28%), and 27 (26%) patients, respectively. CONCLUSION: The results of this trial demonstrate the efficacy and manageable adverse-event profile of sunitinib as a single agent in second-line therapy for patients with cytokine-refractory metastatic clear-cell RCC. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00077974.

Adult↗
PubMed2006

Maximal COX-2 immunostaining and clinical response to celecoxib and interferon alpha therapy in metastatic renal cell carcinoma.

BACKGROUND: Cyclooxygenase-2 (COX-2) plays a major role in the development of cancer through numerous mechanisms. COX-2 is expressed in the majority of renal cell carcinoma (RCC) tumors and correlates with stage, grade, and microvessel density. Based on potential additive or synergistic antitumor effects, interferon-alpha (IFNalpha) and celecoxib, an oral COX-2 inhibitor, were given to metastatic RCC patients in a Phase II trial. METHODS: Patients with untreated, metastatic RCC received IFNalpha 3 million units (MU) daily and celecoxib 400 mg orally (p.o.) twice daily continuously until disease progression or unacceptable toxicity. Pretreatment, paraffin-embedded RCC tumor samples were immunohistochemically stained for COX-2 expression and plasma basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) levels were assayed to determine predictive or prognostic potential. RESULTS: There were three partial responses among 25 patients treated (objective response rate, 12%; 95% confidence interval [CI], 3-31%). The observed median time to disease progression (TTP) for the entire cohort was 3.3 months. A significant association between maximal COX-2 staining and clinical response was observed: all patients who experienced an objective response demonstrated 3+ COX-2 tumor immunostaining (trend test: P=0.03). Therapy was well tolerated without cardiac or other notable toxicity. CONCLUSIONS: The addition of celecoxib to IFNalpha did not increase the objective response rate or TTP of this unselected cohort. Maximal COX-2 tumor immunostaining may identify RCC patents more likely to achieve clinical benefit with COX-2 inhibition in combination with IFNalpha. Further investigation of this combination in 3+ COX-2-overexpressing RCC tumors is warranted.

Administration, Oral↗
PubMed2006

VEGF-targeted therapy in renal cell carcinoma: active drugs and active choices.

Several molecular pathways are implicated in renal cell carcinoma (RCC) pathogenesis, including von Hippel--Lindau (VHL) gene inactivation leading to vascular endothelial growth factor (VEGF) expression. Therapeutic targeting of VEGF and related pathways has been undertaken in metastatic RCC. Substantial clinical activity has been reported for multiple agents, leading to several clinical questions regarding the optimal use of these agents. The biology, clinical results, and future considerations regarding VEGF-targeted agents in RCC are presented in this article.

Angiogenesis Inhibitors↗
PubMed2006

Adoptive immunotherapy by allogeneic stem cell transplantation for metastatic renal cell carcinoma: a CALGB intergroup phase II study.

A graft-versus-tumor effect through nonmyeloablative allogeneic stem cell transplantation (N-SCT) in metastatic renal cell carcinoma (RCC) has been reported. An Intergroup phase II trial was undertaken to define further the feasibility, toxicity and efficacy of this approach in a multi-institutional setting, Patients with cytokine-refractory, metastatic RCC were treated with N-SCT. The conditioning regimen was fludarabine 30 mg . m(-2) . d(-1) on day (d) -7 through d -3 and cyclophosphamide 60 mg . kg(-1) . d(-1) on d -4 and d -3. Patients received 2-8 x 10(6) CD34+ cells/kg of granulocyte colony-stimulating factor mobilized stem cells from a 6/6 HLA-matched sibling donor. Immunosuppression after transplantation included tacrolimus and methotrexate. Twenty-two patients were enrolled at 14 institutions. Greater than 90% donor T-cell chimerism was observed in 17 of 19 evaluable patients (89%) by d +120. No objective response was observed. Acute graft-versus-host disease (GVHD) was observed in 11 patients (50%). Chronic GVHD was reported in 5 patients (23%). There was 1 patient death from liver failure secondary to chronic GVHD. Regimen-related mortality was 2 of 22 (9%; liver failure, sepsis). Median survival time was 5.5 months (95% confidence interval, 3.9-12.0 months) and the median time to progression was 3.0 months (95% confidence interval, 2.3-4.2 months). N-SCT for metastatic RCC is feasible in a multi-institutional setting. Adequate donor T-cell engraftment was achieved in most patients before disease progression. A graft-versus-tumor effect was not observed in this study despite acute and chronic GVHD, thus highlighting the need for further understanding of this approach. Allogeneic SCT remains investigational in RCC.

Adult↗
PubMed2006

Clinical and immunological characteristics of patients with serologic progression of prostate cancer achieving long-term disease control with granulocyte-macrophage colony-stimulating factor.

PURPOSE: We describe the clinical and immunological characteristics of patients with biochemically relapsed prostate cancer who achieved long-term disease control with GM-CSF (Leukine). MATERIALS AND METHODS: A total of 30 patients with prostate cancer and nonmetastatic recurrent disease, as manifested by increasing PSA between 0.4 and 6.0 ng/ml after prior definitive therapy, were enrolled in a phase II trial. Patients received 250 microg/m2 GM-CSF daily subcutaneously on days 1 through 14 of a 28-day cycle until PSA or objective progression. The patient and disease characteristics of patients who remained without evidence of disease progression beyond 4 years were examined. Additionally, flow cytometry was performed in peripheral blood to characterize monocyte and dendritic cells. RESULTS: Seven of 29 evaluable patients (24%) remained free of disease progression at a median of 5.1 years (range 4.5 to 5.6 or greater) from the start of GM-CSF therapy. Patients on long-term GM-CSF tended to have lower initial T stage, Gleason score and pretreatment PSA. An increase in the number of circulating monocytes and dendritic cells was observed after 14 days of GM-CSF treatment. These values returned to baseline during the 14-day off period. CONCLUSIONS: GM-CSF modulates PSA in androgen dependent, biochemically relapsed cases. A substantial proportion of patients achieve long-term disease control. The clinical characteristics described may help select patients for future clinical trials with GM-CSF or other immunomodulators. Additional investigation is required to define the immunological mechanism of GM-CSF in prostate cancer.

Aged↗
PubMed2006

The current role of angiogenesis inhibitors in the treatment of renal cell carcinoma.

Over the last few years, renal cell carcinoma (RCC) has become a model disease for targeted therapeutics based on the growing understanding of the underlying molecular pathways in this disease. Clear cell RCC is characterized by the inactivation of the von Hippel-Lindau (VHL) tumor-suppressor gene, which results in the dysregulation of hypoxia response genes, including an overproduction of vascular endothelial growth factor (VEGF), which promotes tumor angiogenesis, growth, and metastasis. In advanced RCC, substantial clinical activity has been reported with VEGF blockade employing a variety of approaches including antibodies and small-molecule VEGF receptor inhibitors. Many trials are still in progress with the goal of defining the optimal utility of these agents as monotherapy or in combination. This review will describe the current clinical data with VEGF-targeted approaches in RCC and plans for future development.

Angiogenesis Inhibitors↗
PubMed2006

Laparoscopic versus open cytoreductive nephrectomy in advanced renal-cell carcinoma.

BACKGROUND AND PURPOSE: There is growing evidence of the benefit of cytoreductive nephrectomy prior to immunotherapy in patients with advanced renal-cell carcinoma (RCC). We compared the outcomes of patients with metastatic RCC undergoing laparoscopic and open cytoreductive nephrectomy prior to systemic therapy. PATIENTS AND METHODS: We retrospectively analyzed 27 patients undergoing cytoreductive nephrectomy for metastatic RCC between 2000 and 2004, 16 laparoscopically and 11 by an open approach. Patients with inferior vena-caval tumor thrombus were excluded from analysis. The two groups were comparable with regard to tumor size, clinical stage, and performance status. Surgical, pathologic, and perioperative characteristics and outcomes were compared. RESULTS: The laparoscopic technique was associated with reduced blood loss (149 v 1135 mL; P = 0.03), transfusion rate and quantity (13% v 55%; P = 0.03; 0.13 v 2.0 units of packed red blood cells; P = 0.007), shorter time to oral intake (1.2 v 2.7 days; P < 0.001), and shorter hospitalization (3.6 v 6.8 days; P < 0.001) compared with open nephrectomy. No significant differences were observed with respect to pathologic stage, operative time, complications, fraction receiving subsequent systemic therapy, time to systemic therapy, or survival. CONCLUSIONS: Laparoscopic cytoreductive nephrectomy is associated with reduced morbidity and hospital stay compared with open surgery. There was no increase in complications, and the ability to proceed with subsequent systemic therapy was maintained in the majority of patients. The laparoscopic approach can be considered in patients with metastatic RCC as part of a cytoreductive and systemic-therapy regimen.

Carcinoma, Renal Cell↗
PubMed2006

Renal cell carcinoma.

PURPOSE OF REVIEW: In this review we will highlight the recent novel contributions to the treatment of renal cell carcinoma in the fields of anti-angiogenesis, immunotherapeutics, and surgical management. In addition, this review will update recent advances in diagnostic and imaging modalities for renal cell carcinoma and dietary and environmental relationships to the epidemiology of this growing disease. RECENT FINDINGS: Advancements in the use of innovative treatment strategies for the management of localized renal cell carcinoma and the introduction of new targeted therapeutics with benefit in the metastatic setting has produced a major impact on the treatment of this disease. SUMMARY: The management of metastatic renal cell carcinoma has undergone a revolution in the past year with groundbreaking treatment strategies encompassing a broad range of therapeutic modalities. At the other end of the spectrum, emerging data is beginning to change our perspective about the management of small, localized renal tumors that are being discovered with increasing frequency. This review will update recent findings supporting diet and tobacco exposure as etiologic factors in the development of renal cell carcinoma, the molecular concepts that underlie the disease and the targeted therapeutics designed to inhibit specific kinase activities, and emerging use of minimally invasive therapies for localized disease.

Angiogenesis Inhibitors↗
PubMed2006

Current status and future directions of molecular markers in renal cell carcinoma.

PURPOSE OF REVIEW: To describe the existing data regarding the prognostic and/or predictive value of molecular markers in metastatic renal cell carcinoma. RECENT FINDINGS: Several molecular markers have been investigated in metastatic renal cell carcinoma for prognostic and/or predictive potential, many of which relate to pathogenic molecular alterations that are now therapeutic targets. Carbonic anhydrase IX is a von Hippel-Lindau (VHL)-mediated enzyme expressed in the majority of renal cell carcinoma tumors. High (>85%) expression of carbonic anhydrase IX in renal cell carcinoma tumors is a favorable prognostic marker and may predict response to interleukin-2 therapy. B7-H1 is a glycoprotein with inhibitory effects on T cells. B7-H1 expression in renal cell carcinoma tumor cells and/or lymphocytes may confer a worse survival in renal cell carcinoma patients, perhaps through impairment of inherent host of antitumor immunity. VHL pathway elements, including VHL gene status and expression of vascular endothelial growth factor protein and receptor, represent a promising area of investigation to predict responses to vascular endothelial growth factor-targeted agents. Prognostication schemas are beginning to incorporate molecular markers with clinical variables to refine the prediction of patient outcome. SUMMARY: Several molecular markers appear promising to refine prognosis and prediction in metastatic renal cell carcinoma. Further prospective evaluation is needed.

Antigens, CD↗
PubMed2006

Clinical trials in patients with biochemically relapsed prostate cancer.

In this section there is a wide diversity of mini-reviews, covering several areas of interest for readers. Authors from the USA write about clinical trials in patients with biochemically relapsed prostate cancer, again bridging the divide between medical oncologists and urologists who specialise in urological oncological surgery. The second paper is a joint one from Germany and the USA, bringing the reader up to date with advances in the treatment of stress urinary incontinence. Finally there are two papers from Australia describing the use of positron emission tomography in renal cancer and in prostate cancer.

Clinical Trials as Topic↗
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

Sorafenib.

Sorafenib is a small molecule inhibitor of several kinases involved in tumour proliferation and tumour angiogenesis including Raf, VEGFR and platelet derived growth factor receptor. In vivo Raf kinase inhibition has been observed in pharmacodynamic studies. Sorafenib is one of several VEGF-targeting compounds with recently demonstrated substantial anti-tumour effects in metastatic renal cell carcinoma. Delay in time to disease progression has been demonstrated in cytokine-refractory metastatic renal cell carcinoma, and further investigation is ongoing in a wide variety of tumour types. Sorafenib is well tolerated, with common toxicities including rash, diarrhoea, hand-foot skin reaction, fatigue and hypertension, when administered as the standard dose of 400 mg b.i.d.

Animals↗
PubMed2006

Molecularly targeted therapy in renal cell carcinoma: where do we go from here?

The angiogenic phenotype of renal cell carcinoma results from vascular endothelial growth factor pathway activation. Several different strategies targeting various aspects of the pathway have emerged as clinically relevant therapeutics in metastatic renal cell carcinoma. Key clinical data regarding these approaches are presented in this article. Furthermore, there are several considerations as to the further development of these agents and their appropriate application in metastatic renal cell carcinoma, such as timing of therapy, choice of initial therapy, continued role of debulking nephrectomy and toxicity concerns. These issues are discussed in light of current data and strategies for further drug development are presented.

Angiogenesis Inhibitors↗