Quality of life during dendritic cell vaccination against metastatic renal cell carcinoma.

Patients with metastatic renal cell carcinoma (RCC) undergoing cytokine or targeted therapies may show a remarkable decline in quality of life (QoL). We wanted to evaluate QoL in patients with metastatic RCC undergoing therapeutic vaccination with dendritic cells (DCs). In a cross-sectional analysis, QoL was therefore assessed in RCC patients participating in three consecutive clinical trials of DC vaccination. Before the first and after the third vaccination with DCs, patients completed a QoL questionnaire (EORTC QLQ-C30, version 3). Data were transformed into scale scores and analysed using SPSS 12.0 software. Mean values of the resulting scores obtained before and after DC vaccination were compared using students t test and Wilcoxon rank-sum test. P < 0.05 was considered statistically significant. The questionnaire was completed by 55 of 71 patients (compliance rate, 77.5%) who had a median age of 58.7 years (from 30 to 75 years). No significant reductions in functioning scales including physical, emotional and social criteria as well as symptom scores, which assess typical symptoms of tumour therapies, were observed indicating that QoL remained high during DC vaccination. Significant correlations were found between overall survival and functional as well as symptom scores. Our data indicate that DC vaccination, which is a personalised treatment modality, maintains QoL and thus represents an attractive nontoxic treatment option for patients with metastatic RCC. It will be important to identify the most effective conditions of DC vaccination including combinations with other therapeutics to maximise clinical efficacy while still preserving QoL.

Allogeneic dendritic cell vaccination against metastatic renal cell carcinoma with or without cyclophosphamide.

In this phase I/II study, we evaluated the feasibility, safety and efficacy of allogeneic dendritic cells (DCs) with or without cyclophosphamide in the treatment of patients with metastatic renal cell carcinoma (RCC). Immunomagnetic beads were used to isolate CD14(+) monocytes from healthy donor leukapheresis products, and CD83(+) antigen-pulsed monocyte-derived DCs (moDCs) loaded with tumor lysate and keyhole limpet hemocyanin (KLH) were generated. Twelve patients were treated with allogeneic moDCs alone, while ten patients also received cyclophosphamide on days 4 and 3 prior to vaccination. Of the 22 patients enrolled, 20 received full treatment consisting of at least three vaccinations at monthly intervals. Two mixed responses with substantial tumor regression were observed. In 3 patients, disease stabilization occurred, in 13 patients disease progressed and 4 patients were lost to follow-up. Overall, immune responses against KLH and tumor lysate were weak or absent; however, the strongest increases in antigen-independent and KLH-specific responses were observed in the 2 patients with mixed responses. In addition, 1 of them showed a substantial increase in oncofetal antigen (OFA)-specific IFN-gamma production. Importantly, the 2 mixed responders and 1 patient with stable disease belonged to the cyclophosphamide group. Median overall survival in the cyclophosphamide group was 23.2 and 20.3 months in the group that received allogeneic moDCs alone. Allogeneic immunotherapy with moDCs is feasible and well tolerated. However, the immunogenicity of allogeneic moDCs is clearly less pronounced than that of autologous moDC immunotherapy. Cyclophosphamide may have the capacity to augment DC-induced antitumor immunity.

Up-regulation of functional chemokine receptor CCR3 in human renal cell carcinoma.

There is increasing evidence that chemokines and chemokine receptors are causally involved in tumorigenesis by facilitating tumor proliferation and metastasis. Little is known about the possible function of chemokine receptors in the development and progression of renal cell carcinoma (RCC). We, therefore, analyzed the expression of chemokine receptors in tumor specimens and adjacent healthy kidney tissues [normal kidney cell (NKC)] from 10 RCC patients. We also characterized the permanent RCC cell line A-498. CCR6, CXCR2, and CXCR3 were consistently expressed by both malignant cells and NKCs. A-498 displayed additional expression of CXCR4. Importantly, the expression of CCR3 was almost absent on NKCs but clearly enhanced in a substantial proportion of RCC specimens. The primary CCR3 ligand, eotaxin-1/CCL11, induced intracellular Ca2+ mobilization, receptor internalization, and proliferation in A-498 cells confirming signaling competence of RCC-associated CCR3. In addition, we screened tumor tissue sections of 219 patients and found that 28% (62 of 219) expressed the CCR3 receptor. The presence of CCR3 in tumor samples seemed to correlate with the grade of malignancy. Previous work has established that eotaxin-1 expression is induced by tumor necrosis factor-alpha, a cytokine known to be present in RCC tissue. Our data, therefore, supports a scenario in which eotaxin-1 as part of tumor-associated inflammation promotes progression and dissemination of CCR3-positive RCC.

Generation of clinical-grade monocyte-derived dendritic cells using the CliniMACS system.

We describe the generation of monocyte-derived dendritic cells (MoDC) from leukapheresis products using the CliniMACS system from Miltenyi Biotec. In a clinical setting, the method turned out to be feasible for the generation of clinical-grade MoDC from patients with metastatic renal-cell carcinoma. MoDC generated with this system exhibited a fully mature phenotype as well as high migratory and T-cell stimulatory capacity.

Monitoring of CD4+ and CD8+ T-cell responses after dendritic cell-based immunotherapy using CFSE dye dilution analysis.

CFSE dye dilution analysis and [3H] thymidine incorporation were used side by side to assess proliferative responses of peripheral blood mononuclear cells (PBMCs) after vaccination of renal cell carcinoma patients (n=6) with antigen-loaded dendritic cells. Immune responses against the control antigen keyhole limpet hemocyanin (KLH) were induced in all patients. While [3H] thymidine incorporation revealed a 4 to 977-fold increase in KLH-induced proliferation (mean: 209-fold), CFSE-labeling experiments demonstrated that the KLH-responsive population of postvaccination PBMCs represented 7-53% (mean: 23%). Combining CFSE-labeling with T-cell subset analysis confirmed the presence of CD4+ KLH-reactive T cells but also revealed a substantial population of CD8+ KLH-reactive T cells in one patient as well as minor populations of CD8+ KLH-reactive T cells in three other patients. Our data indicate that CFSE dye dilution analysis is a valuable tool for immune monitoring after dendritic cell vaccination.

Long-term results of laparoscopic retroperitoneal lymph node dissection: a single-center 10-year experience.

OBJECTIVES: To evaluate the feasibility, morbidity, and long-term oncologic efficacy of laparoscopic retroperitoneal lymph node dissection (L-RPLND) in patients with nonseminomatous germ cell tumor (NSGCT). METHODS: L-RPLND was performed 188 times in 185 patients; 114 procedures were performed for Stage I NSGCT and 6 procedures for tumor marker-negative clinical Stage IIA disease. In the case of positive lymph nodes, adjuvant cisplatin-based chemotherapy was administered. After chemotherapy, L-RPLND was performed for retroperitoneal Stage IIA (10 patients), IIB (43 patients), and IIC lesions (15 patients). RESULTS: The mean operative time was 256 minutes for Stage I and 243 minutes for Stage II; the conversion rate was 2.6%. The mean blood loss was 159 mL in patients with Stage I and 78 mL in those with Stage II disease. Active tumor was found in 19.5% of patients with Stage I lesions and in 50% of patients with tumor marker-negative clinical Stage IIA disease. After chemotherapy, active tumor was found in 1 patient with Stage IIC disease and mature teratoma in 38.2% of patients. The mean postoperative hospital stay for those with Stage I and II disease was 4.1 and 3.7 days, respectively. Antegrade ejaculation was preserved in 98.4% of patients. The mean follow-up was 53.7 months for those with Stage I and 57.6 months for those with Stage II disease. All but 6 patients have remained free of relapse, and no patient died of tumor progression. CONCLUSIONS: The rate of tumor control after L-RPLND and the diagnostic accuracy of L-RPLND were equal to the open procedure, and the morbidity was significantly lower. Therefore, L-RPLND for Stage I and low-volume retroperitoneal Stage II disease can be performed at centers with experience in urologic laparoscopy and oncology.

Orthotopic bladder reconstruction in women--what we have learned over the last decade.

Approximately 10 years ago protocols for urethra-sparing cystectomy and orthotopic urinary diversion to the urethra in female patients with bladder cancer were initiated at several centers. Long-term data regarding the oncological and functional outcome are the subject of this review. Studies regarding the relationship between primary bladder cancer and secondary urethral tumors in women revealed in most studies a lower risk for women than for men in most studies. In a recent meta-analysis the incidence of urethral tumors was 6.8% in 5657 male and 3.6% in 841 female patients with transitional cell cancer of the bladder. Anatomical and functional studies revealed that smooth musculature can be found in the entire length of the female urethra. The rhabdosphincter which is the important structure for postoperative continence in low pressure intestinal reservoirs is in the midportion of the urethra which will not be touched during urethra-sparing surgery. A recent study looked at the oncological and functional results of 102 women with orthotopic urinary diversion after a follow-up ranging from one and half to 100 months (mean 26, median 24 months). There was no perioperative mortality, and an early and late complication rate requiring secondary intervention in 5 (5%) and 12 (12%) patients. With 88 of 102 patients alive and 83 of 102 patients disease free, a disease specific survival of 74% and a disease free survival of 63% was estimated at 5 years. No pelvic recurrence was seen in 81 patients with TCC. Daytime continence was 82%; nocturnal continence was 72%. Twelve patients (12%) were unable to empty their bladders completely and needed some form of catheterization. Increasing experience in recent years confirms the initial preliminary results showing that sparing the urethra at cystectomy will not compromise oncological outcome and can be satisfactorily used for orthotopic reconstruction of the lower urinary tract. Both diurnal and nocturnal continence and clean intermittent catheterization rates after 6 months justify the use of orthotopic neobladders as the procedure of choice in the majority of female patients with bladder neoplasms.

Frozen section analysis-guided organ-sparing approach in testicular tumors: technique, feasibility, and long-term results.

OBJECTIVES: To evaluate retrospectively the indications, surgical technique, feasibility, and follow-up data of our frozen section analysis-guided organ-sparing approach to small testicular tumors. Removal of a solitary testis or bilateral orchiectomy for testicular neoplasm results in androgen deprivation and infertility. Moreover, removal of a testis for benign lesions is to be avoided. Organ-sparing surgery aims at preserving enough testicular parenchyma to maintain physiologic endocrine function and, if possible, fertility. METHODS: Tumors of 25 mm or less in diameter were managed by an organ-sparing approach. Normal preoperative plasma levels of luteinizing hormone and testosterone were a prerequisite. After localization of the tumor by ultrasonography and accurate staging, organ-sparing surgery was performed under cold ischemia. Frozen section analyses of the tumor and tumor bed biopsies were obtained. In the case of malignant germ cell tumor with a normal contralateral testis, ablation of the tumor-bearing testis was performed. RESULTS: A total of 32 organ-preserving procedures were performed in 30 patients without any complications. Local recurrence was observed in 1 patient who refused to undergo local radiotherapy for concomitant testicular intraepithelial neoplasia; repeat organ-sparing surgery was performed in this patient. After organ-sparing surgery, ablation of the remaining testis was performed in 1 patient because of positive margins on final histologic analysis and in another patient because of endocrine insufficiency. In all other patients, the serum testosterone levels remained within normal limits. No retroperitoneal, pulmonary, or other recurrences were encountered; all patients were free of disease at a mean follow-up of 46.3 months. CONCLUSIONS: The organ-sparing frozen section analysis-guided approach to testicular masses represents a promising treatment alternative to orchiectomy in selected patients with bilateral malignant testicular tumors, tumors in a solitary testis, or unilateral or bilateral benign tumors. The technique is oncologically efficient, lifelong hormonal substitution can be prevented, and, in some patients, even fertility may be preserved, provided certain criteria concerning patient selection and surgical technique are observed.

Photodynamic therapy with intravesical instillation of 5-aminolevulinic acid for patients with recurrent superficial bladder cancer: a single-center study.

OBJECTIVES: Photodynamic therapy (PDT) is an effective treatment option for patients with superficial bladder cancer uncontrolled by transurethral resection and/or intravesical bacille Calmette-Guérin (BCG) immunotherapy alone. We determined the efficacy and side effects of PDT in patients with recurrent superficial bladder cancer. METHODS: Between April 1994 and July 2001, PDT was performed in 31 patients (23 men and 8 women). 5-Aminolevulinic acid (50 mL) in a 3% concentration was instilled intravesically. Patients were instructed to hold the solution as long as possible and were irradiated transurethrally with a mean light dose of 3.9 W using laser light emitting a wavelength of 633 nm for a mean time of 1260 seconds. RESULTS: The mean patient age at the procedure was 70.2 years. At an average follow-up of 23.7 months (range 1 to 73), 16 patients were free of tumor recurrence; 15 patients had developed tumor recurrence after a mean of 8.3 months. Of 10 patients with prior BCG treatment, 4 were free of tumor recurrence. Treatment was well tolerated, with the only side effect being dysuria due to urinary tract infection in 4 patients and hematuria in 7 patients. No phototoxic skin reactions were observed. CONCLUSIONS: PDT represents a safe, effective, and less-invasive treatment for patients with recurrent superficial bladder cancer. Because of the favorable side-effect profile, PDT can also be applied to patients with comorbidity precluding surgical treatment. Furthermore, PDT represents a second-line treatment for patients with tumor recurrence after BCG failure.

Immunotherapy of metastatic renal cell carcinoma with tumor lysate-pulsed autologous dendritic cells.

PURPOSE: We wanted to evaluate feasibility and safety of dendritic cell-based immunotherapy in patients with metastatic renal cell carcinoma (RCC). EXPERIMENTAL DESIGN: Patients with metastatic RCC (n = 35) received vaccinations (i.v. or i.d.) of CD83+ autologous monocyte-derived dendritic cells (moDCs). MoDCs were loaded with lysate of cultured autologous or allogeneic permanent tumor cells (A-498) as well as keyhole limpet hemocyanin as control and helper antigen. Maturation of moDCs was induced by a combination of tumor necrosis factor alpha, interleukin 1 beta, interleukin 6, and prostaglandin E2. RESULTS: Treatment was associated with transient flu-like symptoms. In 2 of 27 evaluable patients, any evidence of disease disappeared (complete response). In both cases, metastatic tissue had been the source of tumor antigen. One patient had an objective partial response. Seven patients had stable disease, the remaining 17 patients had progressive disease. In 11 of 11 patients evaluated, moDCs induced strong immune responses against keyhole limpet hemocyanin. In 5 of 6 patients tested, enhanced immune responses against oncofetal antigen (immature laminin receptor; OFA/LRP) could also be detected. The strongest responses against OFA/LRP were detectable in 2 patients with complete response and partial response, respectively. At the time of submission, mean follow up is 32 months and 8 patients are currently alive. CONCLUSIONS: Our data indicate that moDC-based vaccination is well tolerated and has immunological as well as clinical effects in patients with metastatic RCC. OFA/LRP might be an attractive candidate antigen for DC-based immunotherapy of RCC.

Blunt renal trauma in children: 26 years clinical experience in an alpine region.

OBJECTIVES: From 1975 to 2001, 254 children aged younger than 17 were transferred to our department for renal trauma. We performed a retrospective study to assess causality and kind of the trauma, diagnostic procedures and therapeutic consequences, respectively. METHODS: The 254 children at a mean age of 10.56 years (+/-3.8) ranging from 2 to 17 years were treated for kidney trauma. Among these, 166 presented with a grade I trauma according to the kidney injury scale of the American Association for the Surgery of Trauma without any other accompanying injuries and 88 had a grade II-V lesion, respectively. Diagnostic evaluation included various standard lab tests such as urinalysis and routine blood parameters, ultrasound, IVP and/or CT. RESULTS: Most of the traumatic injuries resulted from skiing accidents. However, 18 children had a severe polytrauma with laceration of other vital organs. Most of the renal injuries could be treated conservatively. Surgical treatment options included immediate exploration, reconstruction, partial resection, or even nephrectomy. No child died. CONCLUSIONS: Due to leisure time activities in our region, skiing accidents often result in isolated laceration of the kidney. About one third presented with a severe kidney trauma, and approximately 20% of all affected children required surgical therapy. However, most of the injured kidneys could be preserved and only four nephrectomies had to be performed.

An Escherichia coli-based oral vaccine against urinary tract infections potently activates human dendritic cells.

OBJECTIVES: To investigate the effects of Uro-Vaxom, an oral vaccine against Escherichia coli urinary tract infections, on human monocyte-derived dendritic cells (moDCs). Dendritic cells (DCs) are important antigen-presenting cells of the immune system. DCs are considered promising cellular adjuvants for inducing immunity against cancer or infectious diseases. METHODS: moDCs were generated in the presence of granulocyte-macrophage colony-stimulating factor and interleukin-4. Flow cytometric phenotyping, as well as the ability to stimulate T cells in an allogeneic mixed leukocyte reaction, was used to assess the effects of Uro-Vaxom on human moDCs. In addition, interferon-gamma and interleukin-4 production by T cells stimulated with Uro-Vaxom-activated moDCs were measured by intracellular fluorescence-activated cell sorter-staining at the single-cell level. RESULTS: Uro-Vaxom induced the terminal maturation of CD83+ moDCs in a dose-dependent manner. Phenotypic analyses revealed that Uro-Vaxom-activated moDCs displayed a phenotype of mature DCs with high levels of MHC molecules and increased levels of co-stimulatory molecules (CD80, CD86). Consistent with these findings, Uro-Vaxom-activated moDCs potently stimulated T-cell proliferation and interferon-gamma production in the allogeneic mixed leukocyte reaction. CONCLUSIONS: In DC-based immunotherapy, Uro-Vaxom could be used as a stimulant of DC maturation, which meets the standards of good manufacturing practice. In future preclinical studies, we will evaluate the effectiveness of a vaccination with Uro-Vaxom-activated moDCs. It could be an attractive treatment option in preventing recurrent E. coli urinary tract infections in predisposed individuals.

Long-term experience with carboplatin monotherapy for clinical stage I seminoma: a retrospective single-center study.

OBJECTIVES: To evaluate the long-term oncologic efficacy and morbidity of carboplatin monotherapy, which was introduced at our department 11 years ago for the treatment of Stage I seminoma. Radiotherapy is the standard treatment of patients with clinical Stage I seminoma. Carboplatin has been advocated as a treatment alternative to avoid the late side effects of radiotherapy and the high recurrence rate of surveillance strategies. METHODS: From February 1990 until August 2001, 108 patients received two adjuvant cycles of single-agent carboplatin (400 mg/m2 body surface on days 1 and 22) 2 weeks after high inguinal orchiectomy. To assess for myelosuppression, complete blood counts were performed at least once a week until the nadir occurred after the second treatment cycle. RESULTS: During a mean follow-up period of 59.8 months (range 6 to 134), 2 patients (1.85%) developed a recurrence (retroperitoneal tumor) within the first year. Both patients received cisplatin-based salvage chemotherapy. At last follow-up, all patients were alive without any evidence of disease. Carboplatin treatment was well tolerated by all patients and was associated with only mild gastrointestinal side effects. Leukopenia was noted in 32 patients (29.6%); 21 (19.4%) of these patients had World Health Organization (WHO) grade 1, 8 (7.4%) had grade 2, 3 (2.8%) had grade 3, and none had grade 4. No patient developed neutropenic fever. Thrombocytopenia was observed in 48 patients (44.4%); of these patients, 38 (35.2%) had WHO grade 1, 5 (4.6%) had grade 2, 2 (1.9%) had grade 3, and 3 (2.8%) had grade 4. CONCLUSIONS: From an oncologic standpoint, two cycles of carboplatin monotherapy was highly effective and very well tolerated by all patients.