Axl receptor tyrosine kinase is a potential therapeutic target in renal cell carcinoma.

BACKGROUND: Axl plays multiple roles in tumourigenesis in several cancers. Here we evaluated the expression and biological function of Axl in renal cell carcinoma (RCC). METHODS: Axl expression was analysed in a tissue microarray of 174 RCC samples by immunostaining and a panel of 11 normal tumour pairs of human RCC tissues by western blot, as well as in RCC cell lines by both western blot and quantitative PCR. The effects of Axl knockdown in RCC cells on cell growth and signalling were investigated. The efficacy of a humanised Axl targeting monoclonal antibody hMAb173 was tested in histoculture and tumour xenograft. RESULTS: We have determined by immunohistochemistry (IHC) that Axl is expressed in 59% of RCC array samples with moderate to high in 20% but not expressed in normal kidney tissue. Western blot analysis of 11 pairs of tumour and adjacent normal tissue show high Axl expression in 73% of the tumours but not normal tissue. Axl is also expressed in RCC cell lines in which Axl knockdown reduces cell viability and PI3K/Akt signalling. The Axl antibody hMAb173 significantly induced RCC cell apoptosis in histoculture and inhibited the growth of RCC tumour in vivo by 78%. The hMAb173-treated tumours also had significantly reduced Axl protein levels, inhibited PI3K signalling, decreased proliferation, and induced apoptosis. CONCLUSIONS: Axl is highly expressed in RCC and critical for RCC cell survival. Targeting Axl is a potential approach for RCC treatment.

Feasibility of felt application for renorrhaphy after laparoscopic partial nephrectomy.

AIM: Laparoscopic partial nephrectomy (LPN) has become a well-established treatment for selected renal malignancies. Aim of the study was to explore feasibility of the application of haemostatic felt pledgets during renorrhaphy after Laparoscopic Partial Nephrectomy (LPN) and evaluate its efficacy. METHODS: Between May 2008 and December 2011, 42 patients underwent LPN as a treatment for renal tumors by a single surgeon. Tumor size and location were assessed by contrast enhanced computed tomography (CT) scan. A rolled Tabotamp was placed on the tumor bed; 2/0 Vycril sutures, secured with 5mm Hem-o-lok clips, were used to perform the renorrhaphy. 7.9x7.9 mm (5/16"x5/16") felt pledgets were placed between the hem-o-lok clips and the renal parenchyma on both needle entrance sites. W.i.t., EBL, OR time, post-operative complications and hospital stay were recorded. RESULTS: Mean w.i.t. was 21±5 min, mean OR time 151±52 min, while EBL was 162±56 cc. Surgical complications were recorded in 11/42 (26%; Clavien-Dindo classification: II-III). Three patients experienced postoperative ileus, 3 had a urinary leakage, 1 a wound infection and 4 tumor bed bleeding: of these, 2 required blood transfusions, 1 was managed by embolization and 1 underwent nephrectomy. Mean LOS was 2 days. CONCLUSION: The application of hemostatic felt pledgets during renorrhaphy after LPN is feasible and safe. This technique may reduce cortical bleeding, and could ameliorate surgical outcomes.

Robotic-assisted laparoscopic simple prostatectomy and bladder diverticulectomy with temporary clamping of internal iliac arteries.

The minimally invasive approach for benign prostatic hyperplasia (BPH) is replacing open surgery. Laparoscopic and robotic techniques have benefits in treatment of BPH especially for large prostatic adenoma. We present a case of laparoscopic robotic-assisted simple prostatectomy with bilateral transient occlusion of internal iliac arteries. This could be an optional surgical technique when a significant blood loss is expected, for example in patients with an estimated volume of BPH larger than 100 ml or in patients who cannot suspend antiaggregant therapy. In this case we temporarily occluded the internal iliac arteries bilaterally with Bulldog clamps and the adenoma was enucleated according to Sotelo's laparoscopic robotic-assisted technique. We had optimal results in terms of intraoperative and postoperative outcomes.

Laparoscopic partial nephrectomy: a review.

Surgical treatment of renal cell carcinoma has evolved dramatically in the last 10 years. With the improvement of radiological imaging and minimally invasive nephron sparing techniques, more and more lesions can be managed laparoscopically. Stage migration to earlier lesions has followed the wider use of cross sectional tridimensional imaging. Open partial nephrectomy has been the benchmark to which laparoscopic partial nephrectomy (LPN) has been compared. In this review we focus on the available recent literature data on LPN and we outline the key surgical points.

Complications of radical cystectomy.

Radical cystectomy has become a standard and arguably the best definitive form of therapy for high-grade, invasive bladder cancer. Lower urinary tract reconstruction, particularly orthotopic diversion, has been a major component in enhancing the quality of life of patients requiring cystectomy. As with any major surgery, however, complications do arise. It is important for all surgeons to be familiar with the presentation, prevention and treatment of the major causes of morbidity and mortality associated with radical cystectomy and lower urinary tract reconstruction. The complications discussed are among the most common of the complications seen with cystectomy and urinary-intestinal diversion. There are, in fact, many others that may be encountered, as the published literature testifies, and a thorough understanding as to their presentation, prevention and treatment is equally essential for a successful patient outcome. Adherence to proper surgical technique, familiarization with recent data regarding the most successful treatment methods, and attention to detail in the perioperative period are crucial for minimizing complications in any surgical undertaking. Radical cystectomy with orthotopic neobladder as well as total pelvic exenteration and its modifications need to be considered among the treatment options for patients with muscle invasive bladder cancer or advanced pelvic malignancies. Recent advances in patient selection, surgical technique, and perioperative care have led to decreased morbidity. Despite this, these procedure remain complex with the potential for both short and long-term complications. There is abundant evidence that radical cystectomy for bladder malignancies and pelvic exenteration for primary rectal cancer and cervical cancer can lead to meaningful long-term survival; however, the prognosis after pelvic exenteration for recurrent rectal cancer is not as good. The recent introduction of combined chemoradiotherapy is likely to improve local recurrence rates and may translate into more durable long-term survival. Pelvic exenteration continues to have an important role in the multimodality approach to patients with advanced pelvic malignancies. In conclusion, pelvic exenteration appears to be a safe and effective option for an experienced multi specialty surgical team in the treatment of complex locally advanced pelvic malignancy. The success of pelvic exenteration is highly dependent on good patient selection where an en bloc resection may result in prolonged disease-free survival and long term cure. In recent times the morbidity and mortality of this operation has decreased so that palliative exenteration has a role to help improve quality of life for this difficult group of patients.

EphB4 receptor tyrosine kinase is expressed in bladder cancer and provides signals for cell survival.

We sought to evaluate the biological function of the receptor tyrosine kinase EphB4 in bladder cancer. All of the nine bladder cancer cell lines examined express EphB4 and the receptor could be phosphorylated following stimulation with its cognate ligand, EphrinB2. Out of the 15 fresh bladder cancer specimens examined, 14 expressed EphB4 with a mean sevenfold higher level of expression compared to adjacent normal urothelium. EphB4 expression was regulated by several mechanisms: EPHB4 gene locus was amplified in 27% tumor specimens and 33% cell lines studied; inhibition of EGFR signaling downregulated EphB4 levels; and forced expression of wild-type p53 reduced EphB4 expression. EphB4 knockdown using specific siRNA and antisense oligodeoxynucleotides molecules led to a profound inhibition in cell viability associated with apoptosis via activation of caspase-8 pathway and downregulation of antiapoptotic factor, bcl-xl. Furthermore, EphB4 knockdown significantly inhibited tumor cell migration and invasion. EphB4 knockdown in an in vivo murine tumor xenograft model led to a nearly 80% reduction in tumor volume associated with reduced tumor proliferation, increased apoptosis and reduced tumor microvasculature. EphB4 is thus a potential candidate as a predictor of disease outcome in bladder cancer and as target for novel therapy.

Molecular markers for diagnosis, staging, and prognosis of bladder cancer.

Conventional histopathologic evaluation of bladder cancer, encompassing tumor grade and stage, is inadequate to accurately predict the behavior of most bladder tumors. Intense research efforts are under way to identify and characterize various bladder cancers and their true biological potential more effectively. The need to predict which superficial tumors will recur or progress--and which invasive tumors will metastasize--has led to the identification of a variety of potential prognostic markers for patients with bladder cancer. The molecular changes that occur in transitional cell carcinoma of the bladder are numerous and can be categorized into (1) chromosomal alterations, leading to carcinogenesis; (2) loss of cell-cycle regulation, accounting for cellular proliferation; and (3) growth control events such as angiogenesis, resulting in metastasis. It is becoming apparent that the accumulation of genetic and molecular changes ultimately determines a tumor's phenotype and subsequent clinical behavior. The potential clinical application of new diagnostic techniques (ie, loss-of-heterozygosity analysis to identify tumor suppressor genes) and older, well-established, techniques (ie, immunohistochemistry) combined with improvements in the use of automated and standardized systems are areas of active investigation.

Tube gastrostomy after radical cystectomy and urinary diversion: surgical technique and experience in 709 patients.

We describe our surgical technique of tube gastrostomy and report our experience with 709 patients who underwent cystectomy and urinary diversion with gastrostomy tube placement from January 1988 to December 1997. This modified Stamm technique provides an effective means of gastric decompression without the discomfort associated with nasogastric decompression, is associated with a low complication rate (0.05%), and may be considered as the procedure of choice when gastric drainage is required after radical cystectomy and lower urinary tract reconstruction.

[The role of prostate specific antigen and its derivatives (age-specific PSA, PSA density, velocity, free/total PSA) in the diagnosis of prostate cancer]. / Ruolo dell'antigene prostatico specifico e dei suoi indici derivati (PSA età-specifico, densità-PSAD, velocità-PSAV, PSA libero-f-PSA) nella diagnosi del carcinoma della prostata.

PSA is the most useful tumor marker for the diagnosis and treatment of prostate cancer. Its clinical use, however, still lacks the necessary sensitivity and specificity to be considered as ideal. In fact PSA is not specific for adenocarcinoma of the prostate: an elevated serum level of the marker does not necessarily mean malignant growth and normal levels too often hide an occult and potentially lethal cancer. With the discovery of different molecular PSA forms in the serum, an improved discrimination between benign prostate hyperplasia (BPH) and prostate cancer appears possible. This may be particularly useful in cases with equivocal PSA values and unpalpable prostate neoplasm to reduce the number of unnecessary prostate biopsies and increase the number of biopsies in cases without palpable or ultrasonic visible anomalies. The clinical use of PSA age-referenced levels is discussed. Their use is invaluable in screening programs where the routine adoption of age-specific values can help to pick-up younger patients with potentially curable prostate cancer and older patients with BPH where additional tests would be unnecessary. The role of PSA velocity (PASAV) s also discussed. An elevation rate of PSA of 0.75 ng/ml over 18 months on 3 serial samples appears to be the best cut-off to distinguish BPH from prostate cancer. However, the use of PSAV seems to be less useful in patients with elevated PSA levels and negative biopsy results. Free to total PSA ratio is probably the best parameter to reduce the number of unnecessary biopsies in men with a serum total PSA of 4 to 10 ng/ml. The advantages and limitations for different levels of cut-off are shown. A flow chart illustrating the role of various PSA "derivatives" in screening and subsequent evaluation of men over 50 years of age is also presented.

Relationship among symptom score, prostate volume, and urinary flow rates in 543 patients with and without benign prostatic hyperplasia.

BACKGROUND: Studies on the relationship among symptom score, urinary flow rate, and prostate volume in men with lower urinary tract symptoms (LUTS) continue to be of great interest. METHODS: A total of 2,418 men, aged 30-86 years, agreed to participate in an interview and to complete a questionnaire regarding voiding patterns. All subjects answering positively to one or more of the questions were submitted to a diagnostic assessment, based on the algorithm outlined by the guidelines of the International Consultation on Benign Prostatic Hyperplasia (BPH). Five hundred forty-three out of the 2,418 participants (22.45%) were evaluated. At the end of the diagnostic evaluation, 400 men with LUTS but without concomitant conditions (except BPH) known to interfere with normal voiding were selected. Descriptive statistics were used to characterize age, symptom score (International Prostate Symptom Score), prostate volume, and urinary flow rate distribution in these patients. Correlations among the aforementioned parameters were evaluated by means of a multivariate, multiple linear regression and logistic regression model. RESULTS: As reported in other studies, only weak or modest correlations were found. Moreover, the 400 cases were classified according to four age decades. The decrease in peak and mean flow rate per decade of age was similar (0.5 and 0.4 ml/sec); the increase in prostate volume and in total symptom score per decade was 3.3 cc and 0.6, respectively. In patients less than 50 years old, most of the correlations were stronger than those observed in the entire population of 400 men (age and prostate volume, c.c. 0.2864; age and peak flow rate, c.c. -0.2689; age and mean flow rate, c.c. -0.3034). However, symptom score continued to be weakly correlated with age and prostate volume (c.c. 0.0498 and 0.1966, respectively). In the last part of the study, men were assigned to different treatment strategies. Patients who were assigned to surgical treatment had higher prostate volume and IPSS and lower urinary flow rate than those assigned to nonsurgical treatment. CONCLUSIONS: We believe that the reason for the weak statistical association frequently reported in the literature is mainly the urology clinic-based population from which the patient samples were drawn. Data emerging from this analysis support the hypothesis that age is one of the principal factors influencing the relationship among symptom score, urinary flow rate, and prostate volume.

Surgical enucleation for renal cell carcinoma (RCC). Prognostic significance of tumour stage, grade and DNA ploidy.

This study reviews a total of 26 renal cell carcinoma (RCC) who underwent enucleation of the tumour with functionally and anatomically normal controlateral kidney and no evidence of systemic renal disease. At follow-up, after a mean of 62 months the disease specific survival rate for this series was 88.5%. Survival rates according to the pathologic stage, grading, tumour diameter and ploidy are reported. Local recurrences were documented in 4 of the 26 RCC. All 4 RCC were more than 5 cm in diameter and recurred in the remaining parenchyma. After local recurrence, three tumours with aneuploid DNA content underwent radical nephrectomy, whereas 1 with diploid DNA content was submitted to a new enucleation of the recurrence. To date the diploid case is still alive 3 years after the original resection of the primary tumour whereas the other 3 patients died for metastatic disease. In our experience the ideal candidate for renal sparing surgery in the presence of a normal opposite kidney is an asymptomatic patient that incidentally is brought to our attention with a small size (less than 5 cm in diameter), low stage (T1-T2) tumour, well surrounded by a pseudocapsule. DNA content is a valuable prognostic factor in patients submitted to conservative surgery. Diploid tumours have been seen to have a better prognosis and in case of local recurrence they may be reconsidered for a new enucleation of the recurrence.

DNA ploidy, Gleason score, pathological stage and serum PSA levels as predictors of disease-free survival in C-D1 prostatic cancer patients submitted to radical retropubic prostatectomy.

We report our experience with 85 prostatic cancer patients aged 51-79 years, who underwent radical retropubic prostatectomy from 1989 to December 1994 (mean follow-up 35 months). In order to get a more relevant analysis we chose to describe in detail only pathological C-D1 cases and to subdivide the patients, according to the Gleason sum, into G2-G5 and G6-G10 groups. Means of pre- and postsurgery PSA levels were ranked by DNA ploidy and presence or absence of recurrence: aneuploid patients showed lower levels of PSA production that may be due to cell dedifferentiation. However, in patients who developed recurrence, postsurgery PSA levels were higher (p < 0.005). The influence of DNA ploidy on disease-free survival was evaluated: the cumulative survival proportion was better in diploid (0.3581) than in aneuploid patients (0.2996). Using the Cox proportional hazard model with age, Gleason sum, DNA ploidy and presurgery PSA levels as covariates, we demonstrated that, in our series, only the presurgery PSA level was an important and significant predictor of recurrences (p < 0.005). Considering global recurrences with age, Gleason sum and presurgery PSA levels kept fixed, DNA aneuploidy conferred a relative risk 2.3 times higher than diploidy. When, in the same analysis, we introduced postsurgery PSA levels, only DNA ploidy and the latter variable kept statistical significance with a relative risk of 2.5. Considering only local and distant recurrences (with exclusion of those identified by elevated PSA levels) the relative risk was 3.9 and 3.8, respectively. These data support the critical role of nuclear DNA analysis as predictor of outcome after surgery even in this discussed subset of patients (C-D1).

Is medical therapy an expensive way for delaying surgery in BPH patients?

Nowadays, no medical therapy can be considered as a real and definitive alternative to surgery in the management of BPH patients. We considered pharmacologic approach as a treatment that may delay the need for surgery for BPH. In some cases a delayed therapy may continue for all patient life, excluding the need for TURP. The questions that we propose in the present review are: Is there always a role for a delayed medical therapy in the treatment of BPH patients? In which BPH patients a delayed medical therapy and in which instead an immediate surgery may be chosen? Which factors may influence this decision? A delayed medical therapy cannot be chosen in all BPH cases. Two factors can influence the evolution of the disease and the decision of the therapy: the first, natural history of BPH is related to BPH progression, and the second to patient characteristics. The role of growth factors in the natural history of BPH is investigated. Age of patient, his health condition and the presence of concomitant diseases are characteristics that may influence the therapeutic choice. In a young patient with good health condition and no concomitant diseases, the specific clinical phase of BPH is crucial to determinate the need for surgery of for medical delayed therapy. If there is a worsening health status or concomitant diseases as diabetes and hypertension that can increase the risk related to surgery in the future or can determine a more rapid evolution of BPH, TURP may be immediately recommended in all clinical phases of prostatic hyperplasia. The role of age in this therapeutic decision must be carefully examined.

Is there always a role for radical prostatectomy in the treatment of localized prostate cancer?

The efficacy of radical prostatectomy on localized prostate cancer is well documented. However if a high risk for patients suffering from prostate cancer and effectiveness of treatment would be documented, the advantage of the therapy on the natural history of the disease must be demonstrated. Johansson et al. analyzed the natural history of 223 untreated localized prostate cancer with a mean follow up of 123 months. Only 8.5% of the patients died of prostate cancer. The 10 year disease specific survival rate was 86.8%. The progression free survival rate was 53.1%. Zincke et al. reported that the disease specific survival of the T1 T2 submitted to radical prostatectomy at 15 years was 93% and the survival free of disease was 70%. Our data on localized prostate cancer submitted to radical prostatectomy showed that the disease specific survival and the progression free survival after 5 years of follow-up were 99% and 85.7% respectively. Fleming, focusing on life expectancy, demonstrated that radical prostatectomy provides some benefit compared with watchful waiting for patients younger than 70 years. The greatest marginal benefits of treatment arise when we assume higher metastatic rates and higher treatment efficacy. In fact in this case, radical prostatectomy offers 3.5 years of improvement in quality of life adjusted survival in younger patients with moderately or poorly differentiated tumors. Radical prostatectomy can particularly benefit selected groups of patients with localized prostate cancer. The grade of differentiation has been shown to be the most powerful predictor in several series. DNA ploidy and tumor volume may be other reliable prognostic factors. Among all the parameters considered, the two with greatest effect in determining the outcome of treatment compared to watchful waiting were the rate of progression to metastatic disease in untreated patients and the estimated efficacy of treatment in reducing the metastatic rate.

Cost effectiveness in the management of benign prostatic hyperplasia: Italian data.

Several works in literature demonstrate that in some countries the economic considerations are as important as the clinical aspects of a disease; economic evaluation may be of help for decision making. The exact cost of the diagnosis and treatment of benign prostatic hypertrophy (BPH) patients is difficult to estimate. The total number of males in Italy is 27,982,144 (1991 data). In the last year 2,200,000 patients have been treated for BPH in Italy (surgically and pharmacologically); the overall cost for the therapy of BPH exceeded 46 million dollars per year. Currently surgery represents the standard treatment of BPH. In the USA alone over 350,000 surgical procedures are performed annually. In USA the cost per TURP is 12,000 dollars. In Italy the minimum direct cost is 3681 dollars; in most cases, however, the cost per TURP is over 5000 dollars. It is estimated that about 80% of patients with micturion problems prefer an alternative treatment before surgery. In our country 4,338,000 diagnoses of BPH have been performed in 1991. The number of prescriptions for BPH has been 4,867,000 and the number of drugs per prescription 1.16. It may be of interest to compare costs associated with different pharmacological therapies for BPH. Considering the direct costs, it has been estimated that the cost of 1 year's treatment with finasteride is 1833 dollars, while that of 1 year with plant extracts is 1151 dollars. The existing literature is deficient in defining the cost related to the therapeutical options for BPH.(ABSTRACT TRUNCATED AT 250 WORDS)

Pathology of BPH.

Much research has been conducted to determine which tissue (epithelium or stroma) in the prostate gives rise to benign prostatic hyperplasia (BPH). Considering that BPH displays two structural compartments, stromal and epithelial and that the periurethral and transitional regions are particularly involved, the immunohistochemical and regional evaluation of steroid receptors concentration, 5 alpha reductase, DHT and estrogen activity, may show important data on the role of these factors in BPH development. We started a immunohistochemical study on the epidermal growth factor (EGF) concentrations in the periurethral, central and pericapsular zones of BPH samples, considering the stroma-epithelium ratio; investigations are performed on BPH patients submitted to transvesical prostatectomy. Considering that the periurethral zone is particularly involved in BPH, the presence of high concentration of growth factors in this region, may support the concept of their involvement in BPH.

Plant extracts in BPH.

In Italy plant extracts represent 8.6% of all pharmacological prescriptions for Benign Prostatic Hyperplasia (data from 1991). This review evaluates all the suggested mechanisms of action for plant extracts. Recently we demonstrated an antiestrogenic effect of Serenoa Repens in BPH patients. Clinical trials with plant extracts have yielded conflicting results. In a recent review by Dreikorn and Richter, only five placebo controlled studies were found. Moreover, as opposed to chemically defined drugs, it is possible that for these extracts the active ingredients are not known; consequently pharmacodynamic and pharmacokinetic data are often missing. The International Consultation of Benign Prostatic Hyperplasia (Paris, June 1991) concluded that, to date, phytotherapeutic agents must be considered as a symptomatic treatment. Now more adequate pharmacological and clinical studies, placebo controlled, should determine the exact role of these drugs in the treatment of BPH.

[Pharmacological combinations in the treatment of benign prostatic hypertrophy]. / Associations pharmacologiques dans le traitement de l'hypertrophie prostatique bénigne.

In the development of the obstructive symptomatology of benign prostatic hypertrophy (BPH), two components may be identified, mechanical and dynamic. In the mechanical component, the interaction of a stromal and a epithelial compartment determines prostatic mass growth. The dynamic component involves smooth muscle tone in the prostate and urethra. The consideration that prostatic disease is not only epithelial in origin, but also stromal, leads to the association of an antiandrogen (which acts on the epithelial component) and an antiestrogen (active on the stromal component) in the medical therapy of BPH. In 1985 we carried out a randomized study on 256 BPH patients treated with Cyproterone acetate (CPA) plus Tamoxifen (TAM). Recently, we performed a multicenter double blind study on BPH patients treated with the association CPA plus Serenoa Repens. A statistically significant difference in prostate volume reduction between the groups treated with the combinations and those with the monotherapies was observed. The development of new compounds, such as 5 alpha reductase and aromatase inhibitors, consents to introduce a combination therapy with less side effects. A second pharmacological association may be obtained with drugs acting on the mechanical and others acting on the dynamic (alpha blockers) component of BPH. This combination may associate the early symptomatic effect of alpha blockers with the long term results of a 5 alpha reductase inhibitor, antiestrogen or aromatase inhibitor.