Immunohistochemical expression and localization of somatostatin receptor subtypes in prostate cancer with neuroendocrine differentiation.

The aim of the study is to examine the tissue expression and localization of the somatostatin receptors (SSTRs) in prostate cancer (PCa) with neuroendocrine (NE) differentiation. The five SSTR subtypes (SSTR1 to 5) were evaluated immunohistochemically in the secretory cells of normal-looking epithelium (Nep), high-grade prostatic intraepithelial neoplasia (HGPIN) and PCa in 20 radical prostatectomies (RPs) with Gleason score 3+3=6 acinar PCa; 20 RPs with GS 4+4=8 and 4+5=9 PCa; and 20 RPs with PCa with NE differentiation. The basal cells were evaluated in Nep and HGPIN. In all groups the stromal smooth muscle and endothelial cells were also analyzed. Concerning the secretory cells, (i) the greatest mean proportions of cells with strong cytoplasmic staining in PCa were seen for SSTR2, mainly in the group of RP with NE differentiation, and for SSTR4 in all three groups; the mean values in HGPIN were intermediate between Nep and PCa; (ii) Membrane staining was seen for SSTR3 and SSTR4; the mean percentages of positive cells, higher in SSTR3 than in SSTR4, decreased from Nep to HGPIN and PCa in all three RP groups; in the latter two, the mean percentages were similar; and (iii) Nuclear staining was seen with SSTR4 and SSTR5; for SSTR4, the mean percentages in the PCa of the three groups were higher than in HGPIN and Nep, the highest proportion being with PCa with NE differentiation. Concerning the basal cells, in Nep the mean proportions of cells with strong staining intensity were greater for SSTR1 and SSTR3 than for the other subtypes, the lowest being with SSTR2; in HGPIN the highest mean propositions of positive cells was with SSTR3, the proportions in the three RP groups being similar. Concerning the stromal smooth muscle and endothelial cells, the highest mean values being in SSTR1 and the lowest in SSTR5; for the former subtype the highest proportion of endothelial cells with strong intensity was seen in the RP NE group. In conclusion, this immunohistochemical study expands our knowledge on the expression and localization of five SSTRs in the various tissue components in the prostate with PCa with NE differentiation, compared with conventional PCa. Typing somatostatin receptor expression in NE tumours could be of relevance to target somatostatin analogue-based diagnostic approach and treatment.

[Validation of a screening method for occupational bladder cancer]. / Neoplasie transizionali della vescica di origine professionale: valutazione della accuratezza di un metodo di screening basato su intervista strutturata.

BACKGROUND: Transitional bladder cancer is the most frequent malignant urinary neoplasm. Occupational exposure to aromatic amines and to polycyclic aromatic hydrocarbons are the main risk factors, in addition to cigarette smoking, recurrent inflammatory diseases of the urinary tract, consumption of certain drugs and a positive family history. Nevertheless cases of work-related bladder cancer are poorly identified in Italy. OBJECTIVE: The aim of this study is to assess the screening accuracy of a short structured interview to detect suspected cases of occupational bladder cancer, which may be confirmed in a second step assessment by an occupational physician. METHODS: The study sample consisted of 94 transitional bladder cancer patients, first hospitalised in 2004 and 2005 at the Department of Urology of the Ospedale di Circolo - Fondazione Macchi, in Varese, Italy. Based on data collected through a simple structured interview, it was possible to estimate two occupational exposure indices: one taking into account only the length of employment in industrial settings (DS Index) and the other considering job title in addition (DSM Index). For all cases a second-step assessment by an occupational physician (gold standard) made it possible to establish the occupational origin of cancer and to assess accuracy. RESULTS: Satisfactory values of the area under the ROC curve were found for both indices (AUC 0,81 for DS and 0,87 for DSM). In particular at the same level of sensitivity (90%), the DSM Index showed a better specificity (72%) in comparison to the DS Index (64%). CONCLUSIONS: The short structured interview proposed here proved to be a valuable tool for general practitioners and urologists to detect cases of bladder cancer of suspected occupational aetiology, which can be referred to an occupational physician for further investigations.

Differential diagnosis and evaluation of the clinical course of transurethrally resected T1G3 urothelial carcinoma of the bladder by DNA image cytometry.

The value of DNA image cytometry in the differential diagnosis of 106 T1G3 urothelial carcinomas of the bladder and the long-term prognosis (recurrence-free interval, survival) of the patients was tested in comparison with Ta/T1G1 (n=30) and Ta/T1G2 carcinoma (n=54). Monolayer smears were prepared from three 50-microm-thick sections by a cell separation technique and were stained according to Feulgen. The DNA content of 250 epithelial cells, chosen at random, was determined using a TV-image analysis system CM-1 (Hund, Wetzlar, Germany). The DNA content of 30 lymphocytes served as an internal standard for the normal diploid value in every individual case. Different DNA cytometric parameters and the mean nuclear area were calculated. In comparison with G1- and G2-cases, the mean values of all DNA cytometric variables were markedly increased in the group of T1G3 cases, most obviously for the 5cEE, the mean ploidy and the ploidy imbalance (0.0006 > or = p > or = 0.0001). However, a remarkable overlay of the data distribution had to be considered. An aneuploid DNA stemline ploidy was highly characteristic for T1G3 urothelial carcinoma (sensitivity: 92%), but not sufficiently specific (57%). However, if increased values for the mean ploidy, the 2cDI, the 5cEE or the 9cEE (specificity: 86%-89%) were present additionally, the diagnosis of a T1G3 urothelial carcinoma could be made cytometrically. Follow-up data for survival (recurrence) analysis was available for 90 (82) patients of the T1G3 group. Using the median value as threshold, significant differences in survival were found for the mean ploidy only (p=0.0353). The length of the recurrence-free interval was significantly different for the entropy (p=0.0205), the 2cDI (p=0.0309) and the mean ploidy (p=0.0442). In conclusion, DNA single cell cytometry represents a highly relevant tool in the objective identification of T1G3 urothelial carcinoma of the bladder, with a sufficient sensitivity and specificity. Further, this method enables prediction of tumor recurrence if suitable variables are chosen. The long-term survival of patients with T1G3 urothelial carcinoma can be estimated by DNA cytometry only in a limited manner, possibly due to the fact that the causes of death in the mostly elderly patients will be independent from the limited tumor disease.

[Effectiveness and tolerance of tramadol in cancer pain. A comparative study with respect to buprenorphine]. / Efficacité et tolérance du tramadol dans les douleurs néoplasiques. Etude comparative par rapport à la buprénorphine.

Opioid analgesics represent one of the most important tools in a sequential pharmacological approach to oncological pain relief. They are recommended by the WHO when nonsteroidal anti-inflammatory drugs (NSAIDs) no longer provide adequate analgesia. However, the use of opioids is limited because of their numerous and often severe adverse effects. This aspect of opioids has motivated continuous research projects aimed at discovering drugs that can provide maximum pain relief but with improved tolerability. Tramadol is a new, centrally acting analgesic with a dual mechanism of action. It shows a selective interaction with mu receptors, which are responsible for nociception, and has weak pharmacodynamic activity on other opioid receptors. At the same time, it acts synergistically on neuroamine transmission by inhibiting synaptic noradrenaline (norepinephrine) reuptake and inducing intrasynaptic serotonin (5-hydroxytryptamine; 5-HT) release. From a pharmacokinetic standpoint, tramadol offers high bioavailability, with similar patterns after oral or parenteral administration (half-life 5 to 7 hours, time to peak plasma concentration 3.1 hours, and approximately 20% plasma protein binding). Although the efficacy of tramadol is comparable to that of other drugs with similar modes of action, the incidence of side effects such as constipation and respiratory depression is lower. The frequency of euphoria and dysphoria is negligible, resulting in little risk of abuse or dependence. It therefore seemed appropriate to further investigate the efficacy and tolerability of tramadol, defined as having only weak potency, in comparison with a widely used opioid, in oncological pain. Buprenorphine was selected as an opioid with a potency equivalent to half that of morphine, but with tolerability that is partially limited by the fact that it frequently gives rise to adverse reactions considered typical of stronger opioids. To compare the analgesic effect and tolerability of tramadol and buprenorphine, 60 patients (44 men, 16 women; average age 61.4 years), all presenting with advanced tumours, were treated orally in a controlled crossover trial with randomised sequences. Patients took both drugs, each for a week, with a 24-hour washout period between treatments. Tramadol was prescribed at the daily dose of 300mg, orally, and buprenorphine at 0.6 mg/day, as a sublingual preparation. Assessments were made of Karnofsky performance status and severity of pain before and during the 4 hours after taking the 2 drugs. Each patient also completed a daily diary recording the severity of pain 1 hour after the dose, the evolution of pain during the day and its severity compared with that on the previous day. They also assessed the duration and quality of sleep. The Karnofsky index changed little with either treatment, but all other variables showed worthwhile improvement, indicating the significant analgesic effect of both drugs. Buprenorphine and tramadol had a similar analgesic effect, although the improvement with the test drug was significant within 1 hour of administration (p < 0.05 compared with baseline) and more marked (p < 0.05 on day 2 compared with buprenorpine). At the end of tramadol treatment, sleep had also improved, both quantitatively and qualitatively (both p < 0.05). The final assessment was significantly in favour of tramadol as regards efficacy (p < 0.05) and patient acceptability (p < 0.01). Thus, tramadol was better tolerated than buprenorphine, and caused fewer and milder adverse reactions. Only 1 patient discontinued tramadol, compared with 18 using reference therapy. Tramadol, although theoretically less potent, nevertheless brought about as much pain relief as the comparator opioid. In conclusion, for this class of drug, tramadol provides an excellent balance between efficacy and tolerability, confirming preliminary studies.

Clonal chromosome changes in renal carcinoma do not correlate with clinical stages and histopathologic grades.

We analyzed the correlations between chromosome abnormalities and clinical and histopathologic characteristics in 77 cases of renal cell carcinoma (RCC). Chromosome changes such as +5,+7,+8,+10,+18,+X,+Y, and -Y have been excluded from the analysis because they also occur in nonneoplastic kidney tissue and cytogenetic analysis indicates that these anomalies are not involved in tumor progression. The most frequent specific chromosome abnormalities in this sample were 3p rearrangements, trisomy 17, and hyperdiploidy and were not related to tumor stage or grade or to development of distant metastases.

Clonal chromosome changes in non-neoplastic ureters.

Cytogenetic analysis was performed on 23 samples from non-neoplastic ureters. Clonal chromosome abnormalities were found in eight. They were: loss of Y chromosome, as a single abnormality (five cases) or associated with trisomy 10 and 20 (one case) or with trisomy 2 (one case); and duplication of Y chromosome (one case). Different numerical and structural sporadic abnormalities were found in nine cases. Immunohistochemical analysis and direct observation using the inverted microscope showed that the cells were mainly of the fibroblastic type. FISH analysis with chromosome 7 alpha-satellite probes failed to detect the presence of trisomy 7 in three epithelial cases tested.

Results of transurethral resection and intravesical doxorubicin prophylaxis in patients with T1G3 bladder cancer.

OBJECTIVES: This retrospective study evaluates the outcome of patients with T1G3 bladder cancer treated by transurethral resection (TUR) and intravesical doxorubicin prophylaxis and identifies clinically useful prognostic factors. METHODS: One hundred twenty-eight consecutive patients with primary T1G3 bladder cancer were treated by TUR followed by 1-year intravesical prophylaxis with doxorubicin. Sex, age, number, size, and morphology of the tumors, exfoliative cytology, presence of dysplasia at first observation, pathologic findings of the first recurrence, and number of recurrences were the parameters considered in a multivariate analysis whose object was to identify specific risk factors for recurrence and progression. RESULTS: The recurrence rate was 56.3% and progression of disease was seen in 23.4% of cases with a disease-specific mortality rate of 7.8%. The disease-free survival in patients who had cystectomy was 37.7 months and the disease-specific mortality rate for this group was 35.7%. The recurrence rate was found to be significantly higher for multiple tumors, solid morphology, size greater than 3 cm, positive exfoliative cytology, and concurrent dysplasia. The reappearance of Stage 1, grade 3 tumor on first recurrence was the only factor found to be correlated with progression. CONCLUSIONS: Up front therapy consisting of TUR and intravesical doxorubicin prophylaxis is appropriate for T1G3 bladder cancer. Patients with unfavorable prognostic factors should be kept under strict control; and if a T1G3 tumor is identified on first recurrence, immediate cystectomy should be considered.

Recombinant alpha interferon in metastatic renal cell carcinoma. A cooperative phase II study.

A total of 61 evaluable patients with advanced renal cell carcinoma have been treated with 3 x 10(6) IU per square meter of body surface with recombinant alpha 2b interferon three times a week within a Cooperative Phase II Study. Toxic death for terminal renal failure occurred in 1 patient (1.63%), and toxicities greater than WHO grade 2 were present in 10 cases (16%). The overall response rate after six months of treatment was 13.1% (partial response 4, minor response 4). Two complete responses were obtained at nine and fifteen months (3.3%). Long-lasting stabilization of disease was 13.1 percent.

Microvessel density in prostate carcinoma.

The objective of this work was to assess the correlation between microvessel density (MVD), pathological stage and disease recurrence in a series of patients who underwent radical prostatectomy for prostate cancer. Pathological material from 75 consecutive radical prostatectomies performed before 1994 without neo-adjuvant treatment, in which sufficient follow-up data were available, was re-examined. Paraffin embedded material was re-cut and hematoxylin and eosin (H&E) stained. Areas of maximal angiogenesis within tumor were identified. Expression of CD34 was investigated by using the monoclonal antibody MY 10. Within the areas of maximal angiogenesis, microvessels expressing CD34 were counted and specimens were divided into two groups, one showing a count of less than 90 microvessels per microscopic field at 200 x magnification (MVD<90), the second more than 90 microvessels (MVD>90). The MVD was then related to pathological stage, Gleason score (GS) and outcome of the disease. Mean follow-up was 84 months. Clinical or biochemical progression was observed in 38.6% of patients. In low GS cases, MVD was always <90, whereas in GS 5-6, half had MVD <90 and half were >90. In high GS MVD was always >90. MVD was positively associated with a higher pathological stage. Progression of the disease was observed in 20% of MVD <90 and in 51% in MVD >90 (P=0.006). Mantel-Haensz test showed a correlation between MVD and time to progression (P<0.05). Although problems exist in methods of counting and in the cut-off number of vessels, which can discriminate the risk categories, it may be concluded that microvessel counts, using CD34 monoclonal antibody, can accurately predict the outcome of radical prostatectomy.

Surgical pathology examination of radical prostatectomy specimens. Updated protocol based on the Italian TAP study.

Between January 1996 and June 2000, 192 men with prostate cancer underwent radical retropubic prostatectomy (RP) and bilateral pelvic node dissection in 26 centers participating in the Italian randomized prospective TAP study. The reviewing pathologist evaluated 145 RP specimens. Seventy-five cases had not been treated with total androgen ablation before RP was performed, whereas 70 had been treated for three months. Whole-mount sectioning of the complete radical prostatectomy specimens was adopted in each center for accurately evaluating the pathological stage of prostate cancer and resection limit status. The results of this study suggest that total androgen ablation before RP is beneficial in men with clinical stage T2 because of the significant pathological down-staging and decrease in the number of positive margins in the RP specimens. On the basis of the experience acquired through the Italian TAP study and recent publications on prognostic factors in prostate cancer, the original practice protocol for examination of RP specimens removed from patients with carcinoma of the prostate glands was updated.

Tissue polypeptide-specific antigen (TPS) immunoassay in the diagnosis and clinical staging of prostatic carcinoma. Comparison with prostate-specific antigen (PSA).

UNLABELLED: This experimental study investigated the potential role of Tissue Polypeptide-Specific Antigen (TPS) in comparison with Prostate-Specific Antigen (PSA) in the diagnosis and the clinical and pathological staging of prostate cancer. Serum TPS and PSA levels were determined in 128 patients (pts) with benign prostatic hypertrophy (BPH; Group 1) and in 92 pts with prostate cancer (Group 2). TPS was also measured in a control group of 100 healthy subjects. Normal cutoff values of 85 U/l for TPS and 4 ng/ml for PSA were determined on the basis of ROC curve analysis. The sensitivity, specificity and accuracy in the diagnosis of prostate cancer were 49%, 95% and 76% for TPS, and 84%, 90% and 87% for PSA. The combination of the two markers provided a higher accuracy (88%), improving the sensitivity of PSA, since 47% of patients with normal PSA had pathological levels of TPS. TPS showed an increase in sensitivity from low to higher stages of disease and, in patients with skeletal involvement, from small to larger numbers of bone metastases (Kruskal Wallis p < 0.0001). Nevertheless, TPS serum levels are not useful in the clinical staging of prostate cancer as they have a poorer performance than PSA. TPS was ineffective (ROC curve area = 0.68) in predicting extraprostatic disease and demonstrated a reduced ability (area = 0.78) to identify skeletal involvement. Moreover, the combination of the two markers did not significantly improve the performance of PSA alone. The serum concentration of TPS in patients with localized tumors was not related to the degree of tumor cell differentiation evaluated by the Gleason score. CONCLUSION: Our preliminary experience suggests that TPS in association with PSA may be useful at the time of diagnosis of prostate cancer. However, these preliminary data have to be confirmed by larger clinical trials and the role of this association in the clinical setting needs to be analyzed with an adequate evaluation of the cost-effectiveness ratio.

Effect of total androgen ablation on pathologic stage and resection limit status of prostate cancer. Initial results of the Italian PROSIT study.

The likelihood of finding organ-confined untreated prostate cancer (PCa) by pathological examination at the time of radical prostatectomy (RP) is only 50% in patients with clinically organ-confined disease. In addition, tumour is present at the resection margin in approximately 30% of clinical T2 (clinical stage B) cases. The issue of clinical "understaging" and of resection limit positivity have led to the development of novel management practices, including "neoadjuvant" hormonal therapy (NHT). The optimal duration of NHT is unknown. We undertook the present analysis to evaluate the effect of NHT on pathologic stage of PCa and resection limit status in patients with prostate cancer and treated with total androgen ablation either for three or six months before RP. Between January 1996 and February 1998, 259 men with prostate cancer underwent radical retropubic prostatectomy and bilateral pelvic node dissection in the 26 centres participating in the Italian randomised prospective PROSIT study. Whole mount sectioning of the complete RP specimens was adopted in each centre for accurately evaluating the pathologic stage and resection limit status. By February 1998, haematoxylin and eosin stained sections from 155 RP specimens had been received and evaluated by the reviewing pathologist (RM). 64 cases had not been treated with total androgen ablation (e.g. NHT) before RP was performed, whereas 58 and 33 had been treated for three and six months, respectively. 114 patients were clinical stage B whereas 41 were clinical stage C. After three months of total androgen ablation, pathological stage B was more prevalent among patients with clinical B tumours, compared with untreated patients (57% in treated patients vs. 36% in untreated). The percentage of cancers with negative margins was statistically significantly greater in patients treated with neoadjuvant therapy than those treated with immediate surgery alone (69% vs. 42%, respectively). After six months of NHT therapy the proportion of patients with pathological stage B (67% vs. 36%, respectively) and negative margins was greater than after 3 months (92% vs. 42%, respectively). For clinical C tumours, the prevalence of pathological stage B and negative margins in the patients treated for either 3 or 6 months was not as high as in the clinical B tumours, when compared with the untreated group (pathological stage B: 31% and 33% vs. 6% in the clinical C cases, respectively. Negative margins: 56% and 67% vs. 31%, respectively). The initial results of this study suggest that total androgen ablation before RP is beneficial in men with clinical stage B because of the significant pathological downstaging and decrease in the number of positive margins in the RP specimens. These two effects are more pronounced after six months of NHT than after three months of therapy. The same degree of beneficial effects are not observed in clinical C tumours.

The anti-inflammatory action of flurbiprofen suppositories in paediatric urology in comparison with co-trimoxazole.

Fifty male children, aged between 3 and 10 years, were treated for a 12-day period with either trimethoprim (80-160 mg) plus sulphamethoxazole (400-800 mg) daily (co-trimoxazole) or 50-125 mg/day flurbiprofen rectally. The patients had been treated surgically for criptorchidism. Flurbiprofen showed good effectivity in controlling post-operative inflammation in urology. It is concluded that antimicrobial agents such as cotrimoxazole, because of their potential risks of damage at the cell's level, should be used only in presence of a bacterial infection.

Prostatic cancer--survey of hormonal treatment in Europe.

Prostatic cancer is often locally advanced or metastatic when diagnosed, making surgical removal and radiotherapy ineffective treatments. Alternative therapy involves androgen deprivation because prostatic cancer is known to be androgen-dependent. Orchidectomy has proved effective but other methods of reducing androgen concentrations have also been developed. Oestrogens have proved effective, as have progestogens, and both steriodal and non-steroidal anti-androgens have been extensively studied. Another possible treatment is the use of inhibitors of androgen metabolism (aromatase and 5 alpha-reductase). Luteinizing hormone releasing hormone analogues, which act as antagonists or agonists, have been shown to have efficacies comparable to those of other therapies. Adrenal suppression has provided a useful alternative to adrenalectomy, particularly because of the high morbidity rate of surgery in elderly patients. Complete androgen withdrawal using an anti-androgen in association with surgical or chemical castration may be a more superior treatment. Another possible approach is the use of somatostatin analogues, which have been shown to inhibit the growth of animal prostatic cancer cells.

Hemostatic efficacy and safety of TachoComb in surgery. Ready to use and rapid hemostatic agent.

TachoComb is a new, ready-to-use hemostatic agent consisting of a collagen sheet coated on one side with human fibrinogen, bovine thrombin, and bovine aprotinin. The product was used in 125 surgical operations (vascular, hepatic, urological and ENT) in which secondary hemostasis was required. It was placed over the cut surface or over the edges of the wound. The investigating surgeons expressed their opinion on the intra- and postoperative hemostatic efficacy, and routine laboratory tests were done postoperatively. TachoComb had good hemostatic efficacy in 67.2% of cases, and very good in 22.4%. No noteworthy systemic changes were observed. As an adjuvant to obtain complete hemostasis in surgery, TachoComb is effective, practical and quick to use, and is very well tolerated.

Effects of castration on the development of prostate adenocarcinoma from its precursor HGPIN and on the occurrence of androgen-independent, poorly differentiated carcinoma in TRAMP mice.

Androgen ablation is thought to exert selective pressure for the development of androgen-independent forms of prostate cancer. This study was set up to investigate the effects of surgical castration on the development of prostate adenocarcinoma (ADC) from its precursor (high-grade prostate intraepithelial neoplasia (HGPIN)) and on the occurrence of androgen-independent, poorly differentiated carcinoma (PDC) in (C57Bl/6 transgenic adenocarcinoma of mouse prostate) TRAMP mice. It was found that castration cures HGPIN and ADC and prevents their further occurrence and growth, but has no effect on PDC. This indicates that in this model, PDC is not the progression of ADC favoured by androgen ablation and that its initiating cells are different from those of HGPIN and ADC.

[Notes on the tumorigenesis of bladder urothelioma].

Bladder urothelioma is a common and increasingly frequent tumor, which most of the times involves initially the bladder mucosa only. Urotheliomas can be superficial, with low malignant potential despite their high relapsing activity, and highly aggressive ab initio. A series of events are known to influence urothelioma genesis, growth, cell interactions and apoptosis. Some initial constant changes involving chromosome 9 occur in the urothelium, whereas the 20-30 % of cases also show an alteration on chromosome 20, which is likely to result in marked biological aggressiveness. The transformation of normal urothelium into hyperplastic, and then neoplastic, urothelium is secondary to a wide range of molecular changes, which are here summarized.

Intraoperative frozen section diagnosis in urological oncology.

The intraoperative frozen sections are indicated if the pathological findings change the surgical procedure. In urological oncology is not recommended, as a general attitude, in the tumor diagnosis/staging during the surgery. The assessment of the surgical margins is recommended in partial surgical resections but the literature discourages its systematic use in the radical surgical resections. The assessment of the lymph nodes is specially indicated in the penile cancer with intermediate or high risk and non-palpable nodes, and is debated its utility in non-palpable lymph nodes of cystectomies and prostatectomies.