Prostatectomy restores the maturation competence of blood dendritic cell precursors and reverses the abnormal expansion of regulatory T lymphocytes.

OBJECTIVE: To verify the presence of deviated dendritic cell (DC) precursors and of suppressor lymphocytes (Treg) in tumor bearing prostate cancer (PCa) patients and to monitor the corrective effect of tumor ablation. METHODS: Monocytes isolated from the blood of patients before and 1 month after prostatectomy were allowed to reach complete maturation (mDC) ex vivo in a clinical grade two-step process. T-regulatory cells were identified in the lymphocyte cell fraction by the CD4(+)CD25(high)FoxP3(+)/CD4(+)CD25(high)CD127(low/-) phenotype. RESULTS: Despite loss of the monocytes marker CD14, cytokine-matured DCs of tumor bearing patients expressed lower levels of the costimulatory molecule CD80 and of the maturation markers CD83 and CCR7 compared to mDC of normal subjects (NS, P = 0.001, 0.001, and 0.008, respectively). Prostatectomy restored CD80, CD83, and CCR7 expression to values not different from those of NS (P = 0.15, 0.60, and 0.71) and significantly higher than those of the pre-surgery state (CD83, P = 0.0003 and CCR7, P = 0.002). The frequency of Tregs, identified as either CD4 + CD25(high)FoxP3(+) or CD4(+)CD25(high)CD127(low/-), was significantly higher in pre-surgery patients than in NS (P = 0.0001 and 0.0003) and significant recovery of the CD4(+)CD25(high)CD127(low/-) (P = 0.0005) was observed after surgery. CONCLUSIONS: The presence of defective DC precursors and suppressor lymphocytes in the tumor-bearing, but not tumor-free stage, positions the latter as the ideal setting for clinical success of PCa vaccine therapy.

Identification of a tumor-initiating stem cell population in human renal carcinomas.

The purpose of the present study was to search for the presence of a tumor-initiating stem cell population in renal carcinomas. Based on the recent identification of mesenchymal stem cells in normal kidneys, we sorted cells expressing the mesenchymal stem cell marker CD105 from 5 human renal carcinomas. Because the CD105(+) but not the CD105(-) population showed enhanced tumorigenicity when injected in severely compromised immunodeficient (SCID) mice, we cloned and characterized CD105(+) cells and evaluated their stemness, differentiative ability, and serial tumor generation. Characterization of the phenotype of CD105(+) clones revealed several stem cell properties: 1) clonogenic ability, 2) expression of nestin, Nanog, Oct4 stem cell markers, and lack of differentiative epithelial markers, 3) ability to grow in nonadhesive spheroids, 4) in vitro differentiation into epithelial and endothelial cell types, and 5) generation in vivo of serially transplantable carcinomas containing an undifferentiated CD105(+) tumorigenic and a differentiated CD105(-) nontumorigenic population. In addition, some vessels present in carcinomas generated from CD105(+) clones were of human origin, suggesting the capability of tumor-initiating stem cells to in vivo differentiate also in endothelial cells. In conclusion, we demonstrate that CD105(+) cells and clones derived from renal carcinomas were enriched in tumor-initiating cells with stem characteristics.

Activity of weekly paclitaxel in advanced hormone-refractory prostate cancer.

OBJECTIVE: We evaluated efficacy and toxicity of weekly paclitaxel in metastatic hormone-refractory prostate cancer (HRPC). MATERIALS AND METHODS: Patients received weekly paclitaxel 80 mg/m2 by 1-hour intravenous infusion. A course of therapy consisted of 6 weekly treatments and 2 weeks rest. PSA response was defined as a PSA decrease not less than 50%, maintained for 4 weeks with stable or improved performance status. RESULTS: The study enrolled 43 patients with metastatic HRPC diagnosed a median of 10.5 months before. Median age was 69 years (range, 58-86 years). Five had previous radioisotopes treatment for bone pain, 15 had previous treatment of metastatic hormone-refractory disease, mainly estramustine. The median number of weeks of therapy delivered each patient was 8 (range, 1-24 weeks; cumulative, 369 weeks). PSA response was registered in 13 patients of 36 evaluable for PSA response (36.1%; 95% confidence interval [CI], 20.8-53.8), with a median duration of 4.2 months. Among 16 patients evaluable for objective response, 5 partial responses (31.2%; 95% CI, 11.0-58.7) and 9 stable diseases were registered. Eleven (42.3%) of 26 patients presenting with cancer-related symptoms had improvement. Median survival time was 12.8 months (95% CI, 10.1-15.5) Therapy was associated with acceptable hematological toxicity (anemia grade 3, 16%; neutropenia grade 3-4, 12%) and moderate nonhematologic toxicities (thrombosis/embolism 10%; fatigue all grades, 60%). CONCLUSION: Docetaxel every 3 weeks is the standard of care for metastatic HRPC, but our results suggest some activity and an acceptable toxicity of weekly paclitaxel.

Quality of life in patients undergone oncopreventive intravesical treatment for superficial bladder cancer.

OBJECTIVES: Adjuvant intravesical therapy after TURB for superficial bladder cancer forces the patients to follow prolonged protocols of treatment. In our study we considered the quality of life of these patients. MATERIALS AND METHODS: We created a questionnaire of 52 items in order to analyse free time, working activity, sexual-relational activity, compliance and self esteem of patients undergone intravesical adjuvant therapy. We gave the questionnaires to 63 patients and, on the basis of results, we proposed a psychosexual support therapy according to alteration of Quality of Life (Q.o.L). After the therapy we reproposed the same questionnaires in order to establish the utility of this integrated treatment. RESULTS: We found that quality of life was greatly altered by oncopreventive intravesical therapy. We showed results of questionnaires before and after the multidisciplinary therapy. CONCLUSIONS: The analysis of our data confirme the importance of multidisciplinary approach in adjuvant treatment of superficial bladder cancer. The therapy proposed helps the patients to face neoplastic disease.

CD133+ renal progenitor cells contribute to tumor angiogenesis.

In the present study, we tested the hypothesis that resident progenitor cells may contribute to tumor vascularization and growth. CD133+ cells were isolated from 30 human renal carcinomas and characterized as renal resident progenitor cells on the basis of the expression of renal embryonic and mesenchymal stem cell markers. CD133+ progenitors differentiated into endothelial and epithelial cells as the normal CD133+ counterpart present in renal tissue. In the presence of tumor-derived growth factors, these cells were committed to differentiate into endothelial cells able to form vessels in vivo in SCID mice. Undifferentiated CD133+ progenitors were unable to form tumors when transplanted alone in SCID mice. When co-transplanted with renal carcinoma cells, CD133+ progenitors significantly enhanced tumor development and growth. This effect was not attributable to the tumorigenic nature of CD133+ progenitor cells because the same results were obtained with CD133+ cells from normal kidney. CD133+ progenitors contributed to tumor vascularization as the majority of neoformed vessels present within the transplanted tumors were of human origin and derived from the co-transplanted CD133+ progenitors. In conclusion, these results indicate the presence of a renal progenitor cell population in renal carcinomas that may differentiate in endothelial cells and favor vascularization and tumor growth.

Experiences in US-guided percutaneous radiofrequency ablation of 44 renal tumors in 31 patients: analysis of predictors for complications and technical success.

PURPOSE: Preliminary clinical studies have shown the feasibility, safety, and efficacy of radiofrequency thermal ablation (RFA) of renal tumors, but only a few have analyzed the prognostic factors for technical success and there are no long-term results. Our objective was to statistically evaluate our mid-term results of percutaneous US-guided RFA in order to define predictors for complications and technical success. METHODS: We selected for treatment 44 tumors in 31 patients (24 with renal cell carcinoma, 7 with hereditary tumors, 15 with a solitary kidney), up to 5 cm in diameter. RESULTS: Eight adverse events occurred; 3 (6.8%) were major complications, successfully treated with interventional radiology procedures in 2 cases. Exophytic extension of the tumor was protective against complications (p = 0.040). Technical success was obtained in 38 lesions after one RFA session and in 39 (89%) after one more session, when possible. At the end of treatment, central extension was the only negative predictor for technical success (p = 0.007), while neither size >3 cm (p = 0.091) nor other prognostic factors were statistically significant. CONCLUSION: US-guided percutaneous RFA can be proposed for non-central renal tumors up to 5 cm, also in patients without surgical contraindications, thanks to a low incidence of complications and a high success rate. Randomized controlled trials versus surgery are now needed to investigate long-term comparative results.

Multicenter study on the use of gemcitabine to prevent recurrence of multiple-recurring superficial bladder tumors following intravesical antiblastic agents and/or BCG: evaluation of tolerance.

OBJECTIVES: The treatment of choice for superficial bladder TCC is endoscopic resection, followed or not by intravesical immuno/chemotherapy. Some patients are not responders to common intravesical therapy and are more exposed to disease progression. In this case the suitable treatment is radical cystectomy. Because gemcitabine is effective against advanced bladder cancer, we have initiated a study to evaluate the efficacy of its intravesical use to prevent relapse and disease progression, and tolerance and safety of this drug in patients with multi-treated bladders. In this preliminary study, we cite only data on tolerance. MATERIALS AND METHODS: 64 patients were selected, and 61 were evaluable (age range 39-84 years), with multiple-recurrent bladder TCC. All patients were previously treated with intravesical chemotherapy and/or immunotherapy. The protocol provided for intravesical instillation of gemcitabine (2000 mg) once per week for 8 weeks. We collected data regarding problems noted by the patients (both local and systemic). RESULTS: 53 patients out of 61 (86.9%) completed the cycle. Side effects appeared in 14 patients, 8 of these had to suspend the treatment. Severe side effects were systemic in 4 patients (1 systemic edema, 1 malaise and dysgeusia, 1 hyperthermia and severe strangury, 1 elevated transaminases and asthenia), and local in 4 patients (1 severe urinary urgency, 1 hematuria, 1 urinary incontinence, and 1 case of pelvic pain). In 6 patients we observed pelvic pain, hematuria, strangury and UTI of medium magnitude that did not require treatment interruption. CONCLUSIONS: We believe that the severe side effects requiring treatment interruption are attributable primarily to increased sensitivity in patients with multi-treated bladders. In our experience, the side effects responsible for suspension occurred at the start of treatment in 7 cases out of 8. Our study demonstrates the safety of intravesical gemcitabine in patients with recurrent and multi-treated superficial TCC of the bladder.

Kidney rupture: an unusual and oligosymptomatic complication in a dialysis patient with acquired cystic disease.

Acquired cystic kidney disease (ACKD) is a complication of end-stage renal disease, the prevalence of which is related to dialysis duration; incidence of ACKD and associated conditions (neoplasia, hemorrhage) have decreased with improvements in renal transplantation and with the ageing of the dialysis population. This report regards spontaneous kidney rupture in a 57-year old patient, on home hemodialysis for 11 years, with ACKD for 5 years. At the end of a dialysis session, the patient reported sudden onset of colicky flank pain, followed by macrohematuria. Pain remitted with low doses of pain relievers, leaving dull flank discomfort. The patient self diagnosed a renal colic, and called the hospital two days later. At referral, two large hemorrhagic renal masses (7 and 2.8 cm) were found at ultrasound and CT scan. At surgery, kidney rupture was diagnosed. This case highlights the life threatening complications associated with ACKD, and underlines that massive renal hemorrhage may occur with relatively minor symptoms.

Expression of CD154 on renal cell carcinomas and effect on cell proliferation, motility and platelet-activating factor synthesis.

CD40 activation by CD154 may trigger diverse cellular responses, ranging from proliferation and differentiation to growth suppression and cell death, in normal and malignant cells. However, the pathophysiologic role of CD154 expressed by tumor cells remains unclear. We have investigated the expression of the CD40-CD154 system in 24 primary cultures derived from renal cell carcinomas, its correlation with tumor stage and its potential functional significance. We found coexpression of CD40 and CD154 in most of the renal carcinoma cell lines. CD154, but not CD40 expression, significantly correlated with tumor stage. Moreover, renal carcinoma cell lines also released the soluble form of CD154 into the supernatant. CD40 engagement by CD154 did not affect apoptosis or survival. On the contrary, CD154 stimulated cell proliferation, motility and production of PAF, a phospholipid mediator of inflammation with angiogenic properties. Furthermore, the renal carcinoma cell lines expressed PAF-R. Blockade of PAF-R by WEB-2170, a PAF-R antagonist, abolished the CD154-dependent motility, indicating a role for PAF synthesized after CD154 stimulation in renal carcinoma cell motility. In conclusion, this study identifies new functional properties for CD154, which are potentially relevant for the growth and dissemination of renal carcinoma cells.