Cytoreductive nephrectomy for metastatic renal cell carcinoma: a review of the historical literature and its role in the era of targeted molecular therapy.

Renal cell carcinoma presents with metastatic disease in approximately 30% cases. While surgical intervention remains the standard of care for organ confined disease, its role is limited in the management of metastatic disease. Over the last decade, cytoreductive nephrectomy prior to immunotherapy has demonstrated significant improvement in overall survival for appropriately selected patients. This review summarizes the evidence for the role of cytoreductive nephrectomy in combination with immunotherapy and discusses its potential role in the current era of targeted molecular therapy.

Investigation of sequential mitomycin C and photodynamic therapy in a mitomycin-resistant bladder cancer cell-line model.

OBJECTIVES: To investigate the hypothesis that sequential mitomycin C and 5-aminolaevulinic acid (ALA)-mediated photodynamic therapy (PDT) interact additively in both the J82 bladder cancer cell line and its mitomycin-C-resistant derivative, J82/MMC, and to assess the theoretical basis of this interaction by measuring the relative mitochondrial density of the respective cell lines, on the basis that the mitochondria are the intracellular site where ALA is metabolized to the active photosensitizer, protoporphyrin IX. MATERIALS AND METHODS: Cell survival was assayed in J82 cell line and the J82/MMC derivative after treating them with sequential ALA-mediated PDT and mitomycin C, and with the sequence of treatments reversed. Cell survival was estimated using the tetrazolium assay. The relative mitochondrial density of the two cell lines was estimated using flow cytometry to measure 123rhodamine fluorescence. RESULTS: The effect of sequential mitomycin C followed by ALA-mediated PDT enhanced the effect of PDT in both cell lines. In J82/MMC this effect was marginally supra-additive. When ALA-mediated PDT was administered before mitomycin C, the combined effect was 'sub-additive'. 123Rhodamine fluorescence was > 10 times greater in J82/MMC than J82, suggesting a significantly higher mitochondrial density in the former than the latter. CONCLUSION: Mitomycin C appears to enhance ALA-mediated PDT when administered first. This appears to be particularly so in J82/MMC. This phenomenon may have clinical significance in recurrent superficial bladder cancer.

Contribution of grade, vascular invasion and age to outcome in clinically localized renal cell carcinoma.

OBJECTIVE: To determine the relative prognostic importance of microvascular invasion in apparently localized renal cell carcinoma (RCC). PATIENTS AND METHODS: A retrospective clinical and pathological review was conducted of 176 consecutive patients identified from pathology records who had a nephrectomy for RCC with a median follow-up of 44 months. Vascular invasion was recorded and categorized by the level of microvascular invasion (MVI), renal vein invasion (RVI) and inferior vena cava invasion (IVCI). Tumour type, grade and size were also assessed. These variables were assessed by univariate and multivariate analysis to determine their effect on disease-free survival. RESULTS: In the univariate analysis tumour size, grade, vascular invasion and young age each predicted reduced disease-free survival. On multivariate analysis for all 176 patients, grade, vascular invasion and young age were the significant independent predictors of reduced disease-free survival. In a subgroup of 149 patients from whom those with very high risk determinants were excluded (those with grade 4 tumours and/or IVCI) most of the risk of metastasis could be accounted for by vascular invasion and young age alone (MVI vs no vascular invasion, hazard ratio 3.18, 95% confidence interval 1.29-7.84; RVI vs no vascular invasion 2.41, 0.989-5.89; and age per year 0.963, 0.94-0.992). CONCLUSIONS: Grade, vascular invasion and young age are the main independent predictors of relapse in clinically localized RCC after nephrectomy. For most patients, who do not have very high risk indicators, the main adverse predictors are vascular invasion and young age. These findings are important when selecting patients for trials of adjuvant therapy and have implications for pathological staging.

Quantitative studies of the kinetics of 5-aminolaevulinic acid-induced fluorescence in bladder transitional cell carcinoma.

Photodynamic therapy is a potential treatment for superficial bladder cancer that utilizes photosensitizer drugs, which are activated by light to cause tissue destruction. However, first-generation photosensitizers cause prolonged phototoxicity, have poor tumour specificity and can accumulate within detrusor muscle, resulting in permanent loss of bladder capacity following treatment. A newer drug, called 5-aminolaevulinic acid (ALA), generates a sensitizer called protoporphyrin IX (PpIX) in situ and has been shown, qualitatively, to be more tumour specific. The fluorescence kinetics of ALA-induced PpIX was investigated in patient biopsies of bladder tumour, normal urothelium and detrusor muscle, both in vitro after incubation of specimens in ALA-rich culture medium for various times and in vivo after instillation of intravesical ALA before endoscopic resection. The fluorescence in tumour tissue was twice that of normal urothelium in vitro and up to tenfold in vivo. There was little ALA-induced fluorescence in detrusor muscle, both in vitro and in vivo. Most importantly, no patients experienced phototoxicity or other adverse events following intravesical instillation of ALA.

Out-patient follow-up after routine surgery: a questionnaire study.

A questionnaire was sent to all consultant general surgeons and urologists in Wales to assess current practice in out-patient follow-up after surgery for nine commonly performed procedures. A further questionnaire was sent to a random sample of general practitioners in South Glamorgan to assess the possibility of GPs taking on responsibility for post-operative follow-up. This should, therefore, reduce the number of post-operative patients passing through the out-patient department. Of the 58 (77%) consultants who responded, the percentage who routinely followed up patients with at least one post-operative visit was calculated. Of the 33 (66%) GPs who responded the percentage who were prepared to take responsibility for post-operative follow-up was calculated for patients having the same operations. There was agreement and disagreement between consultants and GPs, but not distinct pattern emerged. A larger study must be performed before the out-patient department is rationalized using protocols based on this study.

Photodynamic therapy of bladder cancer cell lines.

OBJECTIVE: To determine the effect of photodynamic therapy mediated by 5-aminolevulinic acid (ALA) on a range of bladder cancer cell lines, including a squamous cancer cell line and a multi-drug resistant cell line. MATERIALS AND METHODS: Experiments were performed on cells growing in culture: the cell lines studied were the transitional cell cancer lines RT112, T24 and EJ138, the squamous cancer cell line, SCaBER, and the multi-drug resistant transitional cancer cell line, MGH-U1(R), together with its non-resistant parent line, MGH-U1. The kinetics of the ALA-mediated generation of fluorescent photosensitizer were determined using flow cytometry. Photodynamic therapy was performed by incubating cells in ALA followed by exposure to various doses of white light. RESULTS: The response of the various transitional cancer cell lines to photodynamic therapy depended on dose. The squamous cell line was relatively resistant to photodynamic therapy. There was some cross-resistance of the MGH-U1(R) cell line to photodynamic therapy, although the mechanism of cross-resistance appeared not to be necessarily a property of the drug-resistant phenotype. CONCLUSION: This study suggests that ALA-mediated photodynamic therapy may be effective in transitional cell carcinoma of the bladder. Based on these findings, this therapeutic method should be further evaluated clinically.

Is prednisolone as good as flutamide in hormone refractory metastatic carcinoma of the prostate?

PURPOSE: There are no generally accepted rules for the second line treatment of prostate cancer and few prospective studies have attempted to compare 2 therapeutic strategies with different modes of action. MATERIALS AND METHODS: We describe a prospective, randomized study of 40 patients comparing the second line response of flutamide to prednisolone in patients with known hormone refractory stage M1 prostate cancer. RESULTS: The median survival of patients receiving either treatment was 32.9 weeks, with no difference between the 2 groups. In terms of biological response 11 of 20 patients (55%) receiving prednisolone and 10 of 20 (50%) receiving flutamide exhibited prostate specific antigen (PSA) suppression. Average minimum PSA was 54 and 52% of the initial PSA in patients receiving prednisolone and flutamide, respectively. There was no difference between the 2 treatment groups in terms of long-term survival, although 35% of all patients survived beyond 1 year and 3 survived beyond 2 years. CONCLUSIONS: More patients taking prednisolone described better pain relief, although both medications were well tolerated and there was no difference in terms of performance status or analgesic requirements.

Transurethral vaporization of the prostate: a promising new technique.

OBJECTIVE: To evaluate the efficacy and safety of transurethral electrovaporization of the prostate (TUVP), using a grooved roller electrode, for the surgical treatment of symptomatic benign prostatic hypertrophy (BPH). PATIENTS AND METHODS: TUVP was carried out using a grooved roller electrode, pure-cutting diathermy and a standard irrigating resectoscope to rapidly heat prostatic tissue to > 100 degrees C, resulting in vaporization and cavitation of the prostatic adenoma. Over a 10 month period, 116 patients (mean age 69.8 years, range 51-93) with symptomatic BPH (confirmed by a symptom score, urinary flow rate and an ultrasonographic estimate of residual volume) were treated by TUVP. Patients with carcinoma of the prostate, an elevated level of prostate-specific antigen or those in chronic urinary retention were excluded from the study. Each patient was followed up every 4 months during the first post-operative year, assessing their flow rate, residual volume and symptom score. RESULTS: Symptom scores improved by 67% and residual volumes by 72%; the mean maximal flow rate increased from 8.5 mL/s (range 3.5-14) before treatment to 20.5 mL/s (range 4.5-39.0) at the same 4 month review. The procedure was simple and safe, with a mean operative duration of 35 min (range 20-65), and no patients required a blood transfusion. Most patients had their catheters removed within 24 h and were discharged on the second day after treatment. CONCLUSION: The effectiveness of TUVP in improving symptoms and flow rates in patients with BPH was established. With minimal capital expenditure and a reduced in-patient stay. TUVP appears to have several advantages over other surgical treatments for BPH, although continued follow-up is needed to establish the long-term results.

Effect of photodynamic therapy in combination with mitomycin C on a mitomycin-resistant bladder cancer cell line.

Photodynamic therapy is a method for treating cancer using drugs activated by light. A new compound, 5-aminolaevulinic acid (ALA), is a precursor of the active photosensitizer protoporphyrin IX (PpIX) and has fewer side-effects and much more transient phototoxicity than previous photosensitizers. Cell survival of ALA-mediated photodynamic therapy was measured in the J82 bladder cancer cell line, along with its mitomycin C-resistant counterpart J82/MMC. This demonstrated that mitomycin resistance is not cross-resistant to photodynamic therapy. There was also a suggestion that the mitomycin-resistant cells were more susceptible to photodynamic therapy than the parent cell line. Photodynamic therapy appeared to enhance the effect of mitomycin C, when mitomycin C was given first. This phenomenon was apparent for both drug-resistant and drug-sensitive cell lines. This suggests a possible role for combined mitomycin C and photodynamic therapy in superficial bladder tumours that have recurred despite intravesical cytotoxic drug treatment.

Problematic renal calculi presenting during pregnancy.

Urinary tract calculi presenting during pregnancy are rare, with less than 0.1% of pregnancies being associated with stones, the vast majority being asymptomatic and a chance finding. We outline six cases treated over an 8-year period. They presented with combinations of pain, sepsis and obstruction. Intervention was required in four cases: insertion of antegrade nephrostomy, double-J stent, Dormia basket stone extraction, open pyelolithotomy and induction of labour. In each case the pregnancy had a successful outcome. Renal colic can precipitate premature labour. Delayed diagnosis and intervention can result in permanent renal impairment. Ionising radiation and anaesthetic agents may be harmful during pregnancy. The problem is rarely encountered and we therefore present information on the relative risks in each trimester of exposure to the mother and fetus and present a clinical algorithm for the management of these patients.

A prospective randomized study of self-dilatation in the management of urethral strictures.

Over a 3-year period 51 patients with urethral strictures were treated by internal urethrotomy and then either randomly allocated to a course of post-operative dilatation or no dilatation. The patients in the self-intermittent dilatation (SID) group were shown how to pass a 16-F catheter through the stricture but not into the bladder. Complete follow-up was available in 44 patients, 32 of whom had new strictures while 12 had recurrent strictures. Of the patients with new strictures 13 (76%) in the SID group and 12 (80%) in the non-SID group achieved a satisfactory result (a flow rate > 12 ml per second) at one year (chi 2 = 0.18, P = 0.67). In the 12 patients with recurrent strictures 4 (66%) patients in the SID group and 1 (17%) patient in the non-SID group achieved a satisfactory result (chi 2 = 3.09, P = 0.079). In both groups results were not statistically significant. The technique of short-term postoperative self-dilatation does not seem to prevent recurrent strictures in patients treated with internal urethrotomy.

Involvement of the inferior vena cava by renal tumour: surgical excision using hypothermic circulatory arrest.

OBJECTIVE: To evaluate the immediate and long-term results of a radical surgical technique in the treatment of renal tumours with extensive involvement of the inferior vena cava (IVC). PATIENTS AND METHODS: Seven patients with extensive involvement of renal tumours into the IVC were operated upon using a cardiopulmonary by-pass, hypothermia and cardiac arrest to facilitate surgery. Wide exposure of the IVC in a bloodless field permitted complete removal of all visible tumour in each case. Histological sections confirmed renal cell cancer in six patients and Wilms tumour in a 15-year-old girl. RESULTS: All patients recovered well from their surgery with no major complications and spent one or two days in the Intensive Treatment Unit and an average of 13 days in hospital after the operation. Of the seven patients, four are alive and well with no obvious disease after an average follow-up time of 30 months (range 8-54). The other three patients have died from disseminated renal cancer. CONCLUSION: This procedure provides good local control of the tumour and offers the only hope of cure in patients with this disease. In collaboration with the surgical cardiac team it can be safely carried out with acceptable morbidity and mortality.

Use of the rectus abdominis myocutaneous flap in treating advanced carcinomas of the penis.

OBJECTIVE: To examine the methods used to obtain skin closure after radical surgery for carcinomas of the penis, with special reference to the rectus abdominis myocutaneous flap. PATIENTS AND METHODS: Over a 20 year period, 21 patients underwent surgery for carcinomas of the penis. Seven had advanced tumours, requiring radical surgery for complete local tumour control. The resulting wounds were repaired with scrotal skin transfer in three patients and with a rectus abdominis myocutaneous flap in the other four. RESULTS: These methods of repair were a 100% reliable, all wounds being healed within 10 days. CONCLUSIONS: Scrotal skin transfer is a simple and effective method of achieving wound closure. Where removal of the scrotum is required along with curative or palliative surgery, and after ilio-inguinal lymphadenectomy, a rectus abdominis myocutaneous flap is useful for skin closure.

Transforming growth factor beta 1 expression in benign and malignant prostatic tumors.

The expression of transforming growth factor beta 1 (TGF-beta 1) in prostate specimens obtained from patients with benign prostatic hyperplasia (BPH, n = 32) and prostate carcinoma (n = 66) was investigated using Northern blot analysis and immunohistochemistry. Northern blot analysis revealed TGF-beta 1 message (2.5 kb) in virtually all of the samples examined, reflecting the ubiquitous nature of this growth factor. No statistical difference was found between the levels of mRNA detected in benign and malignant tissues due, in part, to the inherent heterogeneity of prostate tissue. Immunohistochemical methods using an antibody to native TGF-beta 1 revealed a novel pattern of immunoreactivity. Staining observed only in certain epithelial cells of benign glands was associated with areas of infection rather than tumorigenesis. Interestingly, intense staining was also seen in polymorphonuclear leukocytes. No correlation was found with the mRNA results, suggesting that this antibody is binding to TGF-beta 1 activated in response to infection rather than detecting sites of synthesis of latent TGF-beta 1.