Neurologic toxicity associated with interferon α therapy for renal cell carcinoma

A 67-year-old man received interferon alpha (IFN alpha) therapy for lung metastases of renal cell carcinoma (RCC). Multiple pulmonary metastases disappeared completely. However, neurological toxicity was detected by magnetic resonance imaging (MRI) as abnormal brain lesions. After discontinuation of IFN alpha therapy, his neurological symptoms and abnormal lesions on MRI disappeared completely. Complete remission of RCC has continued, and results of neurological study have remained normal for 5 years after discontinuation of IFN alpha therapy.     

Dendritic cell therapy in combination with interferon-α for the treatment of metastatic renal cell carcinoma

Objectives:   To evaluate the safety and efficacy of dendritic cell (DC) therapy in combination with interferon-α (IFN-α) in patients with advanced renal cell carcinoma.
Methods:   Seven patients, with progressive disease following IFN-α and interleukin (IL)-2 treatment, were treated with monocyte-derived DC (Mo-DC) and IFN-α between February 2004 and September 2006. They received Mo-DC once a week for 5 weeks and then every 2 weeks either intradermally or intratumorally. IFN-α (5–6 million U) was subcutaneously administered three times a week. Tumor size was evaluated by computed tomography scans before and after the 5th and 10th DC vaccination. A delayed-type hypersensitivity test was performed after the 4th and 5th DC administration for immunological monitoring.
Results:   Five patients had stable disease while the remaining two patients had progressive disease following 4 months of vaccination. In six patients the time to progression was prolonged in comparison with the previous cytokine treatment. Six patients showed delayed-type hypersensitivity after the 4th or 5th immunization. Three patients developed high fever following DC immunization. Treatment was associated with transient flu-like symptoms.
Conclusions:   Our data indicate that DC therapy combined with IFN-α is safe and has the potential for prolonging the time to progression in patients with advanced renal cell carcinoma.     

Case of α-fetoprotein-producing transitional cell carcinoma of the renal pelvis

An alpha-fetoprotein-producing transitional cell carcinoma of the renal pelvis is extremely rare. To our knowledge, this has not been reported previously. We present the first case of an alpha-fetoprotein-producing transitional cell carcinoma of the renal pelvis in a 70-year-old female.     

Interferon therapy for renal cell carcinoma in hemodialysis patients: Report of two patients

The method of interferon therapy has not been clarified in hemodialysis patients with renal cell carcinoma. Two hemodialysis patients with renal cell carcinoma were treated with natural interferon-alpha. The serum levels of interferon-alpha in both patients were measured after 24, 48, 72 and 96 h of injection. In case 1, the serum concentration of interferon-alpha after 24 h of injection at a dose of 3 x 10(6) reached a maximum and decreased gradually. In case 2, the serum concentration of interferon-alpha reached a maximum 24 h after injection at a dose of 3 x 10(6) and decreasing gradually after this. After an injection of interferon-alpha at a concentration of 6 x 10(6) 7 days later, the serum concentration of interferon-alpha reached a maximum 48 h after the injection and decreased gradually thereafter. The serum interferon-alpha concentrations of these cases were higher than normal renal function patients in other literature. It is necessary to modify the interval between injections for hemodialysis patients with renal cell carcinoma.     

Non-myeloablative allogeneic stem cell transplantation for metastatic renal cell carcinoma

Between 1999 and 2004, 11 patients with metastatic renal cell carcinoma (RCC) underwent non-myeloablative stem cell transplantation (NST) with conditioning using fludarabine-based regimens in two institutions of Korea. Among 11 patients, only one patient showed partial response (response rate: 9%), three showed stable disease, and six progressive disease. Three patients developed acute graft-versus-host disease (GVHD), and among them, one developed grade III acute GVHD which caused early death at day 60 after transplantation, and this patient showed partial response at day 30. Six patients developed chronic GVHD, three limited, and three extensive GVHD, respectively. Survival after one yr was 18% in transplanted patients. Median overall survival for entire cohort was 4.3 months. Eight patients died from progressive disease and three (27%) from treatment-related mortality. Only one patient survived 51.2 months after NST with slowly progressive disease. This patient received donor lymphocyte infusion three times after NST and achieved complete donor chimerism. NST does not lead to durable response and prolonged overall survival in the majority of patients with RCC in our series.     

Laparoscopic cytoreductive nephrectomy for metastatic renal cell carcinoma

OBJECTIVE: To critically analyse the results of laparoscopic cytoreductive surgery for renal cell carcinoma (RCC), as phase III evidence supports cytoreductive nephrectomy before immunotherapy, and there is an overall shift towards minimally invasive renal surgery for this disease. PATIENTS AND METHODS: Since October 2000, 22 patients were treated by laparoscopic cytoreductive nephrectomy for metastatic RCC (group 1). All patients had radiological evidence of metastatic disease, with biopsy confirmation in 10. To put the results into perspective, 25 consecutive contemporary patients with large organ-confined nonmetastatic RCC (>7 cm, clinical stage T2) undergoing laparoscopic radical nephrectomy (group 2) were compared retrospectively. The baseline demographics were comparable between the groups. RESULTS: The mean tumour size was 8 cm in group 1 and 9.6 cm in group 2 (P = 0.07). Variables during and after surgery were comparable between the groups, with a mean operative duration of 3.1 vs 3.2 h (P = 0.82), blood loss of 285 vs 308 mL (P = 0.79), complications in two vs eight (P = 0.08), morphine sulphate equivalent requirements of 51.7 vs 44.1 mg (P = 0.1) and a median length of hospital stay of 1.7 vs 1.6 days (P = 0.68). In group 1 the median (range) time to immunotherapy was 35 (13-136) days. CONCLUSIONS: Laparoscopic cytoreductive nephrectomy is safe and effective in selected patients. Currently the procedure is offered to candidates eligible for immunotherapy and with tumours of < or = 15 cm, and no evidence of adjacent organ invasion or inferior vena caval thrombus. Significant perihilar adenopathy and numerous parasitic vessels can increase the complexity of the surgery. Adequate laparoscopic experience is necessary.     

Type-I interferon receptor expression: Its circadian rhythm and downregulation after interferon-α administration in peripheral blood cells from renal cancer patients

Objectives:   To investigate the regulation of interferon-α (IFN-α) receptor expression in metastatic renal cell carcinoma (RCC) after IFN-α administration.
Methods:   Blood sampling was carried out in eight patients with metastatic RCC and six healthy volunteers. Flow-cytometric analysis using a monoclonal antibody against the active subunit of the type-I IFN-α receptor (IFNAR2) was carried out to examine the circadian rhythm of IFNAR2 expression in peripheral blood mononuclear cells (PBMC) as well as its downregulation after IFN-α administration.
Results:   According to its circadian rhythm IFNAR2 in PBMC had a peak expression at night. Once IFN-α is administered, IFNAR2 levels in PBMC showed downregulation within 48 h and recovered within another 48 h.
Conclusions:   Our findings might support the establishment of an optimal schedule for IFN-α administration.     

舒尼替尼对晚期肾癌患者血脂和尿酸代谢的影响及相关因素分析

目的：探讨舒尼替尼治疗晚期肾癌患者过程中血脂硬尿酸代谢的变化，分析其与甲状腺机能减退、血雎及心脏功能异常的相关性。方法：收集2008年7月～2012年12月74例接受舒尼替尼治疗的晚期肾癌患哲的血清甘油三酯、总胆同醇、尿酸的资料，同时监测其甲状腺功能、血压及心脏功能情况。分析血脂及尿酸代谢异常的可能原因及与心血管系统不良反应的相关性。结果：74例患者治疗期间发生高甘油三酯血症30例，高胆固醇血症23例，高尿酸血症21例。甲状腺功能减退30例，高血压38例、心脏功能异常22例。统计学分析显示，舒尼替尼治疗期间出现的血脂及尿酸代谢异常与甲状腺功能减退具有显著相关性。血脂代谢及甲状腺功能减退的发生与心脏功能异常具有显著相关性，而与高血压的发生无显著相关性。尿酸升高与高血压的发生有显著相火性．而与心脏功能异常无显著相关性。通过药物治疗纠正甲状腺功能减退后，大部分患者的血清甘油三酯和总胆阎醇出现降低或恢复正常。结论：舒尼替尼治疗期间引发的甲状腺功能减退可能是血脂及尿酸代谢异常的主要原因，甲状腺功能减退、血脂及尿酸代鲥异常与心脏功能减低的发生具有密切关系，治疗中应首先纠正甲状腺功能减退，     

Serum gamma glutamyl-transferase is a sensitive but unspecific marker of metastatic renal cell carcinoma

OBJECTIVE: To address the role of serum gamma-glutamyl transferase (GGT) as a marker of metastases in patients with renal cell carcinoma. METHODS: Serum alkaline phosphatase and GGT were determined in 156 patients with localized renal cell carcinoma and 60 patients with metastases as proven by echosonography, computerized tomography and bone scan. The control group consisted of 50 healthy subjects matched for sex and age. Sensitivity and specificity of both enzymes as markers of metastatic disease were compared. In metastatic patients, enzyme activities were analyzed according to the site of metastases. RESULTS: Both alkaline phosphatase and GGT activities were normal in majority of patients with localized renal cell carcinoma and increased in most of the patients with metastatic disease (80% and 70%, respectively). GGT did not significantly differ from alkaline phosphatase in terms of sensitivity (70% vs 80%) and specificity (89% vs 92%). Concerning the site of metastases, high frequencies of increased GGT and alkaline phosphatase were found in patients with liver-only metastases (80% and 90%, respectively). All of the patients with both liver and bone metastases exhibited increased activity of both enzymes. Despite the fact that bone cells do not express GGT, increased activity was found in patients with bone metastases-only (45%), suggesting that enzymes might be released from tumor cells. CONCLUSIONS: Our data provided evidence that GGT is a sensitive marker of metastatic renal cell carcinoma. However, findings of abnormal GGT activity cannot specify the site of involvement.     

Phase II trial of weekly intravenous gemcitabine administration with interferon and interleukin-2 immunotherapy for metastatic renal cell cancer

PURPOSE: Since metastatic renal cell carcinoma has a poor prognosis and treatment strategies, including hormone therapy, chemotherapy and immunotherapy, have little impact on the quality of life and global survival statistics, new interest has recently focused on the combination of immuno-chemotherapy using pyrimidine analogues, such as gemcitabine. MATERIALS AND METHODS: In a phase II study 16 patients with metastatic renal cell carcinoma were treated with 1,000 mg./m. gemcitabine intravenously on days 1, 8, 15 and 28 for 6 months, 3 MU (1 MU = 1 x 10(6) IU) interferon (IFN)-alpha intramuscularly 3 times a week and 4.5 million IU interleukin (IL)-2 subcutaneously daily for 5 days a week for 2 consecutive weeks every month for 6 months. Responding and nonprogressing cases were maintained on immunotherapy consisting of IFN-alpha and IL-2 for further 6 months. RESULTS: In 15 evaluable patients overall response rate (1 complete response plus 3 partial response) was 28% while stable disease was achieved in 7 (47%). Median survival duration was 20 months (range, 9 to 26+) and median time to tumor progression was 14 months (6 to 26+). The complete response lasted 24+ months and partial response lasted 16 months. The regimen was well tolerated with only 1 case of neutropenia (WHO grade 3), while anorexia, fatigue and flu-like symptoms were the most common toxicity problems but were never greater than grade 2. CONCLUSIONS: Despite the small sample size, this study demonstrates that gemcitabine combined with standard doses of IFN-alpha and low doses of IL-2 is effective treatment for metastatic renal cell carcinoma. This biotherapy was well tolerated and resulted in an optimum objective response and relatively long-term survival.     

Dendritic cell immunotherapy for patients with metastatic renal cell carcinoma: University of Tokyo experience

BACKGROUND: Dendritic cells (DC) are the most potent antigen-presenting cells and induce host antitumor immunity through the T-cell response. A clinical study of immunotherapy using cultured DC loaded with tumor antigen, for patients with metastatic renal cell carcinoma (RCC) was performed. METHODS: Dendritic cells were generated by culturing monocytes from peripheral blood for 7 days in the presence of granulocyte-macrophage colony-stimulating factor and interleukin-4. On day 6 the DC were pulsed with lysate from autologous tumor as the antigen and with keyhole limpet hemocyanin (KLH) as immunomodulator. The patients were given four doses of lysate-pulsed DC by intradermal injection with a 2-week interval between doses. Clinical effect and immune response were, respectively, evaluated by radiological examination and delayed-type hypersensitivity (DTH) test. RESULTS: Three patients were enrolled and the immunotherapy was well tolerated without significant toxicity. The vaccination induced a positive DTH reaction to tumor lysate in two patients and to KLH in all patients. Clinical responses consisted of one case of no change and two cases of progression of disease. However, we did not see a significant reduction of tumor volume in any case. CONCLUSION: Dendritic cell vaccination can safely induce an immunological response against RCC. Further trials are needed to fully evaluate its efficacy.     

The role of nephron sparing surgery for metastatic (pM1) renal cell carcinoma

PURPOSE: Studies have demonstrated increased time to progression when cytoreductive nephrectomy is performed for metastatic renal cell carcinoma. We evaluated the role of nephron sparing surgery in these patients. MATERIALS AND METHODS: We selected all patients with pM1 renal cell carcinoma treated with nephron sparing surgery or radical nephrectomy, and all patients with pM0 renal cell carcinoma undergoing nephron sparing surgery for solitary kidney from 1970 to 2002 from the Mayo Clinic Nephrectomy Registry. RESULTS: We identified 16 patients who underwent nephron sparing surgery for pM1 renal cell carcinoma. Solitary kidney was present in 12, 3 had bilateral synchronous disease and 1 had elective nephron sparing surgery. Cancer specific survival rates at 1, 3 and 5 years were 81%, 49% and 49%, respectively. We identified 404 patients who underwent radical nephrectomy for pM1 renal cell carcinoma. Cancer specific survival rates at 1, 3 and 5 years were 51%, 21% and 13%, respectively. The pM1 nephron sparing surgery for solitary kidney cases were more likely to have early (33% vs 10%, p = 0.009) or late (50% vs 19%, p = 0.018) complications compared with pM1 radical nephrectomy cases. There were no significant differences in early (p = 0.475) or late (p = 0.350) complications between pM1 nephron sparing surgery cases and 139 pM0 nephron sparing surgery cases. CONCLUSIONS: Cancer specific survival rates in pM1 nephron sparing surgery cases were comparable to pM1 radical nephrectomy cases. Although there were differences in early and late complications between the pM1 nephron sparing surgery and pM1 radical nephrectomy groups, there were no differences when compared with imperative pM0 nephron sparing surgery cases. This study demonstrates that nephron sparing surgery can achieve adequate cytoreductive therapy while preserving renal function, with postoperative complication rates similar to those of pM0 nephron sparing surgery cases.     

Long-term outcome of postoperative interferon-α adjuvant therapy for non-metastatic renal cell carcinoma

AIM: To investigate the long-term efficacy of postoperative interferon-alpha (IFN-alpha) adjuvant therapy in preventing recurrence in non-metastatic renal cell carcinoma treated with radical nephrectomy and to identify related prognostic markers. METHODS: Long-term follow-up was conducted to study rates of survival and non-recurrence in 88 subjects following radical nephrectomy for non-metastatic disease. RESULTS: The overall survival rate was 90% at 5 years and 88% at 10, with corresponding non-recurrence rates of 81% and 74%. Survival rates reviewed by preadministration pT stage showed a falling tendency from T1 through to T3 in line with pathological progression; when cases at stage pT1b or below were compared with those at stage pT2 or above, the latter showed a tendency to lower survival rates (P = 0.0966, Breslow-Gehan-Wilcoxon). Similarly, non-recurrence rates tended to fall in line with pathological progression, with a significant difference found in the comparison of cases at stage pT1b or below with those at stage pT2 or above (P = 0.0265, log-rank, Mantel-Cox). Duration of IFN-alpha administration showed a tendency to positive correlation with long-term survival (P = 0.3765, Breslow-Gehan-Wilcoxon). Non-recurrence rate was not found to differ according to duration of administration. Comparison of groups with normal and abnormal preadministration immunosuppressive acidic protein values showed that the normal group tended to have higher rates of survival and non-recurrence (P = 0.3371, Breslow-Gehan-Wilcoxon). CONCLUSIONS: Immunosuppressive acidic protein values appear to be a useful predictive marker for recurrence. A randomized trial, examining long-term outcome according to tumor stage and variables such as duration of administration, dose, administration time, and dosing schedule is required.     

舒尼替尼在晚期肾细胞癌二线序贯治疗中的临床应用研究

目的:探讨舒尼替尼在晚期肾细胞癌(renal cell carcinoma,RCC)患者二线序贯治疗中的临床效果与安全性。方法:对11例曾接受其他靶向药物治疗的晚期RCC患者在我院行二线舒尼替尼治疗,观察其客观缓解率(ORR)、疾病控制率(DCR)、中位无进展生存期(PFS)及总生存期(OS)等疗效指标及不良反应发生情况。结果:11例患者中2例因不良反应进行药物减量,1例终止治疗。平均接受舒尼替尼治疗时间10.2个月,9例死亡,2例仍存活。DCR 90.9%,中位PFS为7.4个月,中位OS为22.6个月。主要不良反应包括血小板减少症、白细胞减少症、手足皮肤反应、甲状腺功能低下、高血压等。结论:舒尼替尼序贯治疗对于接受过其他靶向药物治疗后进展的晚期RCC患者仍具有良好的疗效和安全性。     

Tumor size predicts synchronous metastatic renal cell carcinoma: implications for surveillance of small renal masses

PURPOSE: Active surveillance of small incidental renal masses is associated with slow radiographic growth and a low risk of metastatic progression. Radiographic tumor size, in the absence of histological data, is the only prognostic indicator available when considering active surveillance. To better define the relationship between tumor size and the metastatic potential of small renal masses, we investigated whether radiographic tumor size predicts for the presence of synchronous metastases in renal cell carcinoma. MATERIALS AND METHODS: We reviewed our institutional tumor registry to identify sporadic pathologically verified renal cell carcinoma treated during an 8-year period. We analyzed data regarding primary tumor size and the presence of biopsy proven synchronous metastatic disease at presentation. All N+M0 and nonpathologically confirmed M+ disease was excluded from analysis. RESULTS: We compared 110 cases of renal cell carcinoma with biopsy proven synchronous metastatic disease at presentation to 250 controls with clinically localized renal cell carcinoma. Tumors associated with synchronous metastasis were significantly larger than localized lesions (median 8.0 cm [range 2.2 to 20.0] vs 4.5 cm [range 0.3 to 17.5], p <0.0001). The probability of synchronous metastasis increased with increasing primary tumor size (p <0.0001). There were no patients with tumors 2 cm or smaller who presented with biopsy confirmed metastatic disease and less than 5% (5 of 110) of all synchronous metastasis occurred in tumors 3.0 cm or smaller. Logistic regression models determined that the odds of synchronous metastasis increased by 22% for each 1 cm increase in tumor size. CONCLUSIONS: Radiographic tumor size is a significant clinical predictor of the presence of biopsy proven synchronous metastatic renal cell carcinoma. In our series the odds of presenting with synchronous, biopsy proven metastatic disease increased by 22% with each 1 cm increase in tumor size. A 100% odds increase, or doubling of the risk of metastasis, occurs with a 3.5 cm increase in primary tumor size. These data have important implications for extent of disease evaluations in patients with large tumors and for the active surveillance of small enhancing renal masses.     

Multifocal metastases of recurrent renal cell carcinoma successfully treated with a combination of low dose interleukin-2, α-interferon and radiotherapy

A 59-year-old man presented with a 2-month history of left flank pain and a possibility of gross hematuria. Left renal cell carcinoma stage II was diagnosed and radical left nephrectomy was performed. Twenty-two months postoperatively, lung metastases were demonstrated and 6 x 10(6) units of alpha-interferon (IFN-alpha) were administered for 9 months, only to keep the sizes of the metastases unchanged. Thirty-four months after the operation, liver metastases and bone metastasis in the left sacroiliac joint were revealed. The combination cytokine therapy was performed with 1.4 x 10(6) U of interleukin-2 (IL-2) and 3 x 10(6) U of IFN-alpha for 16 weeks, and the left sacroiliac joint metastasis was treated with radiation therapy of 4 Gy per day for 7 days. Six months after the 16 weeks of immunotherapy, computed tomography and bone scintigraphy revealed that the metastases of the lung, liver and bone substantially disappeared and this complete response is still kept after 16 months.