Combined therapy with dabrafenib and trametinib in BRAF-mutated metastatic melanoma in a real-life setting: the INT Milan experience.

PURPOSE: Combination therapy with dabrafenib and trametinib is safer and more effective than BRAF inhibitor-based monotherapy for metastatic melanoma. METHODS: We retrospectively analyzed BRAF-mutated metastatic melanoma patients treated at our institution with daily oral dabrafenib 300 mg and trametinib 2 mg from November 2013 to April 2016. This clinical record included both untreated and previously treated stage IV melanomas. Physical examination and laboratory examinations were performed monthly and disease re-evaluations were performed every 3 months. RESULTS: A total of 48 patients (24 male, 24 female) with BRAF-mutated metastatic melanoma received dabrafenib and trametinib; median age was 48 years (range 23-75). Median follow-up was 362.5 days (range 72-879). Best overall response rate consisted of 6.2% (3 patients) complete response, 64.6% (31) partial response, and 25% (12) stable disease; median time to best response was 11 weeks (range 5.7-125.5). Progression of disease was seen in 19 patients (39.6%), with median time to progression (TTP) of 26 weeks (range 8-54). A total of 15 patients (31.2%) died due to progression of disease. Median progression-free survival and median overall survival were not reached. To date, 30 patients (62.5%) are still under treatment. A total of 27 (56.2%) patients had at least one adverse event (AE); grade 3-4 AEs were seen in 4 cases (8.3%). The main toxicities were fever (25%), skin rash (14.6%), arthralgias (10.4%), and aspartate aminotransferase/alanine aminotransferase increase (8.3%). Treatment dose was reduced in 7 subjects (14.6%), with only one case of discontinuation due to AE. CONCLUSIONS: Our data, using combined targeted therapy, are in line with the scientific literature in terms of both safety and effectiveness in a real-life setting.

Cutaneous melanoma in children and adolescents: the Italian rare tumors in pediatric age project experience.

OBJECTIVE: To describe a series of cutaneous melanoma in children collected by the Italian Rare Tumors in Pediatric Age project. STUDY DESIGN: From 2000 to 2012, 54 patients younger than 18 years of age were prospectively registered and treated at 12 Italian pediatric centers on the basis of the same diagnostic/therapeutic recommendations and with the same forms to record clinical data. RESULTS: Considering the estimated annual incidence in Italy, the registered cases accounted for 30% of those expected in children and 10% of adolescents. Clinically, 47% of the tumors were amelanotic and 81% were raised, 39% of cases had tumor thickness >2 mm, and 36% had lymph node involvement. For the whole series, 5-year event-free survival and overall survival rates were 75.2% and 84.6%, respectively. Patient survival correlated with tumor stage and ulceration. No relapses were recorded for T1-2 (thickness <2 mm), N0, and stage 0-I-II cases. CONCLUSION: We suggest that the variables influencing survival in children with melanoma are the same as for adults, the clinical approach used in adults is feasible in children, and pediatric cases are more likely to have advanced disease at diagnosis but similar survival. New effective drugs are needed for advanced disease, and biological studies and international cooperative schemes are warranted.

Side effects of Bacillus Calmette-Guérin (BCG) in the treatment of intermediate- and high-risk Ta, T1 papillary carcinoma of the bladder: results of the EORTC genito-urinary cancers group randomised phase 3 study comparing one-third dose with full dose and 1 year with 3 years of maintenance BCG.

BACKGROUND: Although bacillus Calmette-Guérin (BCG) has proven highly effective in non-muscle-invasive bladder cancer (NMIBC), but it can cause severe local and systemic side effects. OBJECTIVES: The objective was to determine whether reducing the dose or duration of BCG was associated with fewer side effects. Efficacy comparisons of one-third dose versus full dose BCG given for 1 yr versus 3 yr have previously been published. DESIGN, SETTING, AND PARTICIPANTS: After transurethral resection, patients with intermediate- and high-risk NMIBC without carcinoma in situ were randomised to one-third dose or full dose BCG and 1 yr or 3 yr of maintenance. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Local and systemic side effects were recorded at every instillation and divided into three time periods: during induction, during the first year after induction, and during the second and third years of maintenance. RESULTS AND LIMITATIONS: Of the 1316 patients who started BCG, 826 (62.8%) reported local side effects, 403 (30.6%) reported systemic side effects, and 914 (69.5%) reported local or systemic side effects. The percentage of patients with at least one side effect was similar in the four treatment arms (p=0.41), both overall and in the different time periods. The most frequent local and systemic side effects were chemical cystitis in 460 (35.0%) patients and general malaise in 204 patients (15.5%); 103 patients (7.8%) stopped treatment because of side effects. No significant difference was seen between treatment groups (p=0.74). In the 653 patients randomised to 3 yr of BCG, 35 (5.4%) stopped during the first year, and 21 (3.2%) stopped in the second or third year. CONCLUSIONS: No significant differences in side effects were detected according to dose or duration of BCG treatment in the four arms. Side effects requiring stoppage of treatment were seen more frequently in the first year, so not all patients are able to receive the 1-3 yr of treatment recommended in current guidelines. This study was registered at ClinicalTrials.gov with identifier NCT00002990 (http://clinicaltrials.gov/ct2/show/record/NCT00002990).

Final results of an EORTC-GU cancers group randomized study of maintenance bacillus Calmette-Guérin in intermediate- and high-risk Ta, T1 papillary carcinoma of the urinary bladder: one-third dose versus full dose and 1 year versus 3 years of maintenance.

BACKGROUND: The optimal dose and duration of intravesical bacillus Calmette-Guérin (BCG) in the treatment of non-muscle-invasive bladder cancer (NMIBC) are controversial. OBJECTIVE: To determine if a one-third dose (1/3D) is not inferior to the full dose (FD), if 1 yr of maintenance is not inferior to 3 yr of maintenance, and if 1/3D and 1 yr of maintenance are associated with less toxicity. DESIGN, SETTING, AND PARTICIPANTS: After transurethral resection, intermediate- and high-risk NMIBC patients were randomized to one of four BCG groups: 1/3D-1 yr, 1/3D-3 yr, FD-1 yr, and FD-3 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The trial was designed as a noninferiority study with the null hypothesis of a 10% decrease in the disease-free rate at 5 yr. Times to events were estimated using cumulative incidence functions and compared using the Cox proportional hazards regression model. RESULTS AND LIMITATIONS: In an intention-to-treat analysis of 1355 patients with a median follow-up of 7.1 yr, there were no significant differences in toxicity between 1/3D and FD. The null hypotheses of inferiority of the disease-free interval for both 1/3D and 1 yr could not be rejected. We found that 1/3D-1 yr is suboptimal compared with FD-3 yr (hazard ratio [HR]: 0.75; 95% confidence interval [CI], 0.59-0.94; p=0.01). Intermediate-risk patients treated with FD do not benefit from an additional 2 yr of BCG. In high-risk patients, 3 yr is associated with a reduction in recurrence (HR: 1.61; 95% CI, 1.13-2.30; p=0.009) but only when given at FD. There were no differences in progression or survival. CONCLUSIONS: There were no differences in toxicity between 1/3D and FD. Intermediate-risk patients should be treated with FD-1 yr. In high-risk patients, FD-3 yr reduces recurrences as compared with FD-1 yr but not progressions or deaths. The benefit of the two additional years of maintenance should be weighed against its added costs and inconvenience. TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov, number NCT00002990; http://clinicaltrials.gov/ct2/show/record/NCT00002990.

Can gemcitabine instillation ablate solitary low-risk non-muscle-invasive bladder cancer? Results of a phase II marker lesion study.

PURPOSE: The purpose of this phase II study was to evaluate whether low-risk non-muscle-invasive bladder cancer can be ablated with intravesical gemcitabine in a marker lesion study. PATIENTS AND METHODS: The study had a Simon II-stage design. Thirteen patients were to be recruited for stage I. In the event of ≥4 responses, another 30 patients were to be recruited. Patients were given gemcitabine 2,000 mg intravesically once per week for 6 weeks and the response was assessed with endoscopic, histological, and urine cytological findings. RESULTS: Fourteen patients evaluated for efficacy completed the study; complete responses were achieved by 2 patients (14.3%), both of these patients had lesions of <1 cm. Eleven patients (78.6%) were non-responders and 1 patient (7.1%) had progressive disease. Since the response rate in stage I was below the minimal pre-defined limit, the study was stopped. CONCLUSIONS: This study shows that intravesical gemcitabine does not merit further study in this patient population. A tumor size of >1 cm may be a critical factor in accounting for the low response rate.

Small nodular melanoma: the beginning of a life-threatening lesion. A clinical study on 11 cases.

AIMS AND BACKGROUND: Because of its high thickness, nodular melanoma often bears a poor prognosis. Thus, an earlier diagnosis of this type of lesion while it is still thin would be an important step in secondary prevention. The principal aim of the present study was to better define the initial clinical features of nodular melanoma to allow an early diagnosis. A secondary aim was to establish the prognosis of this type of lesion. METHODS: We retrospectively studied and illustrated the clinical features of 11 small (< or = 6 mm maximum diameter) cutaneous nodular melanomas seen and treated during a 10-year period. Prognostic characteristics of the various lesions were also described. RESULTS: The results of the study help to describe a small nodular melanoma as a dark and/or pink/red raised lesion, which may be evenly or unevenly colored, with well-defined borders, that often appears de novo. A correct clinical diagnosis was made in 7 of the cases. During a median follow-up of 6 years, none of the patients had local or distant relapses. CONCLUSIONS: Detection of small nodular melanoma is feasible by accurate visual inspection, provided that physicians are aware of this type of lesion and maintain the index of suspicion at a high level to bring about curative surgery.

Immunohistochemical expression and localization of somatostatin receptor subtypes in androgen ablated prostate cancer.

OBJECTIVE: The aim was to examine the expression and localization of the five somatostatin receptors (termed SSTR1 to 5) in radical prostatectomies (RPs) from patients with prostatic adenocarcinoma (PCa) under complete androgen ablation (CAA) before operation. MATERIAL: The five SSTRs were evaluated in the epithelial, smooth muscle and endothelial cells of normal-looking epithelium (Nep), high-grade prostatic intraepithelial neoplasia (HGPIN) and PCa in 20 RPs with clinically detected PCa from patients under CAA. Twenty RPs with clinically detected PCa from hormonally untreated patients were used as control group. RESULTS: Concerning the secretory cells (i) Membrane staining was seen for SSTR3 and SSTR4; the mean percentages of positive cells, higher in SSTR3 than in SSTR4, decreased sharply in HGPIN and PCa compared with Nep; the mean percentages in the androgen ablated group were 30% to 90% lower than in the untreated; (ii) Cytoplasmic staining was seen for all five SSTRs; the mean percentages of positive cells in Nep, HGPIN and PCa of the untreated group were similar, and in general as high as 80% or more; in the treated group, the Nep values were similar to those in the untreated, whereas the values in HGPIN and PCa were lower for SSTR1, three and five, with a decrease of 30% for SSTR1; (iii) Nuclear staining was seen with SSTR4 and SSTR5, the mean percentages for the former being much lower than for the latter; treatment affected both HGPIN and PCa, whose proportions of stained cells were 30% to 55% lower than in the untreated group. Cytoplasmic staining in the basal cells was seen for all five SSTRs, both in Nep and HGPIN. The values in the treated group were lower than in the other, the difference between the two group being in general comprised between 10% and 40%. Treatment did not affect SSTR staining in the smooth muscle and endothelial cells. CONCLUSIONS: The present study expands our knowledge on the expression and localization of the five SSTRs in the prostate following CAA.

A prospective, randomised EORTC intergroup phase 3 study comparing the oncologic outcome of elective nephron-sparing surgery and radical nephrectomy for low-stage renal cell carcinoma.

BACKGROUND: Nephron-sparing surgery (NSS) can safely be performed with slightly higher complication rates than radical nephrectomy (RN), but proof of oncologic effectiveness is lacking. OBJECTIVE: To compare overall survival (OS) and time to progression. DESIGN, SETTING, AND PARTICIPANTS: From March 1992 to January 2003, when the study was prematurely closed because of poor accrual, 541 patients with small (≤5 cm), solitary, T1-T2 N0 M0 (Union Internationale Contre le Cancer [UICC] 1978) tumours suspicious for renal cell carcinoma (RCC) and a normal contralateral kidney were randomised to NSS or RN in European Organisation for Research and Treatment of Cancer Genito-Urinary Group (EORTC-GU) noninferiority phase 3 trial 30904. INTERVENTION: Patients were randomised to NSS (n=268) or RN (n=273) together with limited lymph node dissection (LND). MEASUREMENTS: Time to event end points was compared with log-rank test results. RESULTS AND LIMITATIONS: Median follow-up was 9.3 yr. The intention-to-treat (ITT) analysis showed 10-yr OS rates of 81.1% for RN and 75.7% for NSS. With a hazard ratio (HR) of 1.50 (95% confidence interval [CI], 1.03-2.16), the test for noninferiority is not significant (p=0.77), and test for superiority is significant (p=0.03). In RCC patients and clinically and pathologically eligible patients, the difference is less pronounced (HR=1.43 and HR=1.34, respectively), and the superiority test is no longer significant (p=0.07 and p=0.17, respectively). Only 12 of 117 deaths were the result of renal cancer (four RN and eight NSS). Twenty-one patients progressed (9 after RN and 12 after NSS). Quality of life and renal function outcomes have not been addressed. CONCLUSIONS: Both methods provide excellent oncologic results. In the ITT population, NSS seems to be significantly less effective than RN in terms of OS. However, in the targeted population of RCC patients, the trend in favour of RN is no longer significant. The small number of progressions and deaths from renal cancer cannot explain any possible OS differences between treatment types.

Sequential intravesical chemoimmunotherapy with mitomycin C and bacillus Calmette-Guérin and with bacillus Calmette-Guérin alone in patients with carcinoma in situ of the urinary bladder: results of an EORTC genito-urinary group randomized phase 2 trial (30993).

BACKGROUND: Bacillus Calmette-Guérin (BCG) is the intravesical treatment of choice for carcinoma in situ (CIS). OBJECTIVE: Our aim was to assess if sequential mitomycin C (MMC) plus BCG after transurethral resection (TUR) is worthy of further study in non-muscle-invasive bladder cancer patients with CIS. DESIGN, SETTING, AND PARTICIPANTS: In a noncomparative phase 2 study, 96 patients with primary/secondary/concurrent CIS of the urinary bladder were randomized to sequential MMC plus BCG or to BCG alone after TUR. INTERVENTION: Patients received six weekly instillations of MMC followed by six weekly instillations of BCG or six weekly instillations of BCG, 3 wk rest, and three further weekly instillations of BCG. Complete responders received three weekly maintenance instillations at 6, 12, 18, 24, 30, and 36 mo in accordance with the initial randomization. MEASUREMENTS: End points were complete response (CR) rate at the first control cystoscopy 16-18 wk after start of treatment, disease-free interval, overall survival, and side effects. RESULTS AND LIMITATIONS: Ninety-six patients were randomized, 48 to each treatment group. Ten patients were ineligible, and three did not start treatment. In all randomized patients, CR rates on MMC plus BCG and BCG alone were 70.8% and 66.7%, respectively. In 83 eligible patients who started treatment, CR rates were 75.6% and 73.8%, respectively. Based on a median follow-up of 4.7 yr, 25 patients (52.1%) on MMC plus BCG and 22 patients (45.8%) on BCG alone were disease free. Twelve patients stopped treatment due to toxicity: three during induction (two MMC plus BCG, one BCG) and nine during maintenance (three MMC plus BCG, six BCG). CONCLUSIONS: In the treatment of patients with CIS, sequential chemoimmunotherapy with MMC plus BCG had acceptable toxicity. CR and disease-free rates were similar to those on BCG alone and to previous publications on sequential chemoimmunotherapy. TRIAL REGISTRATION: This study was registered with the US National Cancer Institute clinical trials database (protocol ID: EORTC-30993). http://www.cancer.gov/search/ViewClinicalTrials.aspx?cdrid=68869&version=HealthProfessional&protocolsearchid=7920643.

Somatostatin receptor subtypes in hormone-refractory (castration-resistant) prostatic carcinoma.

The aim of this study was to examine the tissue expression and localisation of the somatostatin receptors (SSTRs) in hormone-refractory (HR) prostate cancer (PCa). Five SSTRs were evaluated immunohistochemically in 20 radical prostatectomies (RPs) with Gleason score (GS) 3+3=6 PCa, in 20 RPs with GS 4+4=8 and 4+5=9 PCa, and 20 transurethral resection of the prostate specimens with HR PCa. The mean values in the cytoplasm (all five SSTRs were expressed), membrane (only SSTR3 and SSTR4 were expressed) and nuclei (only SSTR4 and SSTR5 were expressed) of the glands in HR PCa were 20-70% lower than in the other two groups, the differences being statistically significant. All five SSTRs were expressed in the smooth muscle and endothelial cells of HR PCa, the mean values being lower than in the other two groups. In conclusion, this study expands our knowledge on the expression and localisation of five SSTRs in the various tissue components in the HR PCa compared with hormone-sensitive PCa.

Immunohistochemical expression and localization of somatostatin receptor subtypes in androgen ablated prostate cancer.

OBJECTIVE: The aim was to examine the expression and localization of the five somatostatin receptors (termed SSTR1-5) in radical prostatectomies (RPs) from patients with prostatic adenocarcinoma (PCa) under complete androgen ablation (CAA) before operation. MATERIAL: The five SSTRs were evaluated in the epithelial, smooth muscle and endothelial cells of normal-looking epithelium (Nep), high-grade prostatic intraepithelial neoplasia (HGPIN) and PCa in 20 RPs with clinically detected PCa from patients under CAA. 20 RPs with clinically detected PCa from hormonally untreated patients were used as control group. RESULTS: Concerning the secretory cells (i) membrane staining was seen for SSTR3 and SSTR4; the mean percentages of positive cells, higher in SSTR3 than in SSTR4, decreased sharply in HGPIN and PCa compared with Nep; the mean percentages in the androgen ablated group were 30-90% lower than in the untreated; (ii) cytoplasmic staining was seen for all 5 SSTRs; the mean percentages of positive cells in Nep, HGPIN and PCa of the untreated group were similar, and in general as high as 80% or more; in the treated group, the Nep values were similar to those in the untreated, whereas the values in HGPIN and PCa were lower for SSTR1, 3 and 5, with a decrease of 30% for SSTR1; (iii) nuclear staining was seen with SSTR4 and SSTR5, the mean percentages for the former being much lower than for the latter; treatment affected both HGPIN and PCa, whose proportions of stained cells were 30-55% lower than in the untreated group. Cytoplasmic staining in the basal cells was seen for all 5 SSTRs, both in Nep and HGPIN. The values in the treated group were lower than in the other, the difference between the two group being in general comprised between 10 and 40%. Treatment did not affect SSTR staining in the smooth muscle and endothelial cells. CONCLUSIONS: The present study expands our knowledge on the expression and localization of the five SSTRs in the prostate following CAA.

Sorafenib's inhibition of prostate cancer growth in transgenic adenocarcinoma mouse prostate mice and its differential effects on endothelial and pericyte growth during tumor angiogenesis.

OBJECTIVE: To evaluate Sorafenib's efficacy (60 mg/kg/d per os) in preventing the transformation of high grade prostate intraepithelial neoplasia (HGPIN) into adenocarcinoma (ADC) and in inhibiting the onset and progression of poorly differentiated carcinoma (PDC) in transgenic adenocarcinoma mouse prostate (TRAMP) mice. STUDY DESIGN: Forty-four TRAMP mice were randomly divided into 2 groups of 22 and assigned to daily treatment by gavage with vehicle only or Sorafenib from the 10th to the 26th week of age. At 26 weeks of age the mice were killed, and their genitourinary apparatus was removed and examined by histology, immunohistochemistry and confocal microscopy. RESULTS: Sorafenib reduced HGPIN growth and progression to ADC and was probably also effective in PDC inhibition. The major effect of Sorafenib was on tumor angiogenesis. Interestingly a dissociation between endothelial cells and pericytes was noted in treated PDC since inhibition of pericyte recruitment was less complete than that of endothelial cells. CONCLUSION: Sorafenib's potent antiangiogenic action may be supposed to be exerted primarily by inhibiting endothelial proliferation and sprouting, whereas its inhibition of pericyte recruitment and maturation is less complete. These observations suggest that Sorafenib's effects could be improved by the joint employment of substances capable of interfering with the recruitment and organization of pericytes.

Immunohistochemical expression of somatostatin receptor subtypes in prostate tissue from cystoprostatectomies with incidental prostate cancer.

OBJECTIVE: To examine immunohistochemically the expression of the five somatostatin receptors (SSTRs) in cystoprostatectomies (CyPs) with incidental prostate cancer. MATERIALS AND METHODS: The five SSTRs (SSTR1-5) were evaluated in 'normal-looking' epithelium (NEp), high-grade prostatic intraepithelial neoplasia (HGPIN) and pT2a Gleason score 6 adenocarcinoma in 20 CyP specimens with incidental prostate cancer and 20 radical prostatectomy (RP) specimens with clinically detected prostate cancer. RESULTS: For cytoplasm expression, the mean percentage of positive secretory cells with strong cytoplasmic staining increased from NEp to HGPIN and prostate cancer, being slightly lower in the CyP than in the RP specimens. Both in the CyP and RP specimens SSTR4 was found in the highest percentage of cells. There was membrane staining in the secretory cells for SSTR3 and SSTR4. There was nuclear staining in the secretory cells for SSTR4 and SSTR5. For SSTR1 and SSTR3 the mean proportions of positive basal cells were higher than for the other three subtypes, and greater in NEp than in HGPIN. There were positive smooth muscle and endothelial cells for all five SSTR subtypes, the highest proportions being SSTR1 and the lowest SSTR5. CONCLUSIONS: This immunohistochemical study expands our knowledge of the expression and localization of SSTRs in the various tissue components in the prostate with incidental cancer, compared with clinically detected cancer. Such information might be useful in developing further non-invasive strategies for the prevention and treatment of pre-neoplastic and neoplastic lesions of the prostate.

GnRH receptor expression in human prostate cancer cells is affected by hormones and growth factors.

GnRH receptors (GnRH-R) have been found in various malignancies, including prostate cancer (PCa). They mediate the direct antitumor effects of GnRH analogs. Nevertheless, few reports concern drug-induced modulation of GnRH-R levels. In this study, we investigated GnRH-R expression in androgen-sensitive (LNCaP) and -insensitive (PC-3) PCa cells treated for 4 and 6 days with a GnRH agonist (Leuprorelin acetate, LA, 10(-11) or 10(-6) M), Dihydrotestosterone (DHT, 10(-9) M), Cyproterone acetate (CA, 10(-7) M), and Epidermal growth factor (EGF, 10 ng/ml), either alone or combined. The RT-PCR analysis showed no variation in GnRH-R mRNA levels of both treated LNCaP and PC-3 cells. On the contrary, immunoblotting indicated that in LNCaP and PC-3 cells, LA upregulated membrane GnRH-R expression (up to 92%). In androgen-sensitive cells, DHT induced a GnRH-R increase (up to 119%) always comparable to that occurring in the presence of CA. GnRH-R upregulation by LA/DHT or CA/DHT association was similar to that promoted by the single agents. In PC-3 cells, EGF upregulated GnRH-R (up to 110%). A prolonged treatment (for 12 days) determined a greater EGF-induced increase in GnRH-R levels (142%). Lower (or no) receptor enhancement occurred when LA and EGF were associated. Our findings indicate that LA post-transcriptionally upregulates its own membrane receptor in androgen-sensitive and -insensitive PCa cells, counteracting the receptor enhancement produced by DHT and EGF. The effects, obtained with a relatively long and continuous treatment, may have implications in the choice of therapy modality with GnRH analogs and may render the receptor a novel therapeutic target, particularly in hormone-refractory PCa.

In vivo characterization of melanin in melanocytic lesions: spectroscopic study on 1671 pigmented skin lesions.

The purpose of this study is to determine the role of melanin in the various steps of progression of melanocytic neoplasia. To this aim, we perform a retrospective analysis on 1671 multispectral images of in vivo pigmented skin lesions previously recruited in the framework of a study focused on the computer-assisted diagnosis of melanoma. The series included 288 melanomas in different phases of progression, i.e., in situ, horizontal and vertical growth phase invasive melanomas, 424 dysplastic nevi, and other 957 melanocytic lesions. Analysis of the absorbance spectra in the different groups shows that the levels of eumelanin and pheomelanin increase and decrease, respectively, from dysplastic nevi to invasive melanomas. In both cases, the trend of melanin levels is associated to the progression from dysplastic nevi to vertical growth phase melanomas, reflecting a possible hierarchy in the natural history of the early phases of the disease. Our results suggest that diffuse reflectance spectroscopy used to differentiate eumelanin and pheomelanin in in vivo lesions is a promising technique useful to develop better strategies for the characterization of various melanocytic lesions, for instance, by monitoring melanin in a time-lapse study of a lesion that was supposed to be benign.

Intermittent androgen deprivation for locally advanced and metastatic prostate cancer: results from a randomised phase 3 study of the South European Uroncological Group.

BACKGROUND: Few randomised studies have compared intermittent hormonal therapy (IHT) with continuous therapy for the treatment of advanced prostate cancer (PCa). OBJECTIVE: To determine whether intermittent therapy is associated with a shorter time to progression. DESIGN, SETTING, AND PARTICIPANTS: 766 patients with locally advanced or metastatic PCa received a 3-mo induction treatment. The 626 patients whose prostate-specific antigen (PSA) level decreased to <4 ng/ml or to 80% below the initial value were randomised. INTERVENTION: Patients received cyproterone acetate (CPA) 200mg for 2 wk and then monthly depot injections of a luteinising hormone-releasing hormone (LHRH) analogue plus 200mg of CPA daily during induction. Patients randomised to the intermittent arm ceased treatment, while those randomised to the continuous arm received 200mg of CPA daily plus an LHRH analogue. MEASUREMENTS: Primary outcome measurement was time to subjective or objective progression. Secondary outcomes were survival and quality of life (QoL). Time off therapy in the intermittent arm was also recorded. RESULTS AND LIMITATIONS: 127 patients from the intermittent arm and 107 patients from the continuous arm progressed, with a hazard ratio (HR) of 0.81 (95% confidence interval [CI]: 0.63-1.05, p=0.11). There was no difference in survival, with an HR of 0.99 (95% CI: 0.80-1.23) and 170 deaths in the intermittent arm and 169 deaths in the continuous arm. The greater number of cancer deaths in the intermittent treatment arm (106 vs 84) was balanced by a greater number of cardiovascular deaths in the continuous arm (52 vs 41). Side-effects were more pronounced in the continuous arm. Men treated with intermittent therapy reported better sexual function. Median time off therapy for the intermittent patients was 52 wk (95% CI: 39.4-65.7). CONCLUSIONS: IHT should be considered for use in routine practice because it is associated with no reduction in survival, no clinically meaningful impairment in QoL, better sexual activity, and considerable economic benefit to the individual and the community.

Cutaneous melanoma in childhood and adolescence shows frequent loss of INK4A and gain of KIT.

Childhood cutaneous melanoma is a rare disease with increasing incidence. It is not clear whether it differs from adult melanoma in etiology and clinical evolution. To genetically characterize childhood melanoma, 21 pediatric patients were studied by germ-line analysis of CDKN2A, CDK4, and MC1R genes. In addition, alterations in CDKN2A, c-Kit, BRAF, and NRAS genes were evaluated at the somatic level by direct gene sequencing, fluorescence in situ hybridization analysis, and immunohistochemistry. As a control group of susceptible patients, we studied patients from 23 melanoma-prone families. At the germ-line level, CDKN2A and MC1R gene variants were detected in 2/21 and 12/21 pediatric patients and in 9/23 and 19/22 in familial patients. At the somatic level, most lesions (9/14) from pediatric patients showed CDKN2A locus homozygous deletions and a null p16 immunophenotype, whereas most lesions (5/8) from familial patients were disomic and immunoreactive. A c-Kit low-polysomy profile seems to parallel CDKN2A homozygous deletions in pediatric melanoma whereas the single activating mutation observed segregates with familial patients. Loss of KIT protein expression was frequent (7/14) in pediatric melanomas, where metastatic cases were prevalent. BRAF(V600E) mutation occurred at a similar rate (approximately 50%) in lesions from pediatric and familial patients, whereas no NRAS mutations were detected.

Immunohistochemical detection and localization of somatostatin receptor subtypes in prostate tissue from patients with bladder outlet obstruction.

BACKGROUND AND AIM OF THE STUDY: Scant information on the cellular distribution of the five somatostatin receptor (SSTR) subtypes in the normal prostate and in neoplasms of the prostate has been reported in very few studies in which techniques, such as in situ hybridization histochemistry, autoradiography, and more recently immunohistochemistry, have been applied. The aim of the study was to examine immunohistochemically the distribution and localization of these 5 subtypes in the various tissue components in normal prostate. MATERIALS: The study was conducted in 14 surgical specimens of normal prostate tissue from adenomectomy specimens from patients with bladder outlet obstruction. The distribution and localization of the 5 somatostatin receptor (SSTR) subtypes was investigated with an immunohistochemical technique. Specificity of the antibodies against the 5 receptor subtypes was preliminarily investigated. RESULTS: Close to 90% of secretory cells showed a weak positivity in the cytoplasm, the proportion ranging from 86.3% (SSTR4) to 89.9% (SSTR5). Strong immunoreactivity was seen in a small proportion of cells, ranging from 0.8% (SSTR3) to 3.2% (SSTR1). For the subtypes 1 and 3 the greatest proportion of basal cells showed a moderate intensity (42.5 and 41.4%, respectively), strong immunoreactivity being observed only in 18.1 and 15.8% of cells, respectively. For the subtypes 2, 4 and 5, the majority of cells showed a weak intensity (72.3, 65.7 and 65.1%, respectively). Subtype 1 showed a strong immunoreactivity in the cytoplasm in 60% of the smooth muscle cells. With subtypes 2, 3 and 4 the greatest proportion of cells showed a weak intensity (63.4, 89.8 and 81.7%, respectively). With the subtype 5 the majority of cells (59.8%) were negative. Subtype 1 showed a strong immunoreactivity in the cytoplasm in 98.6% of the endothelial cells. With subtypes 3 and 4 the greatest proportion of cells showed a weak intensity (73.5 and 56.4%, respectively). With the subtype 2 and 5 the majority of cells were negative (59.1 and 50.7%, respectively).

Metamorphosis of melanoma. Trends in size and thickness of cutaneous melanoma over one decade at the Istituto Nazionale Tumori, Milan.

AIMS AND BACKGROUND: Messages about the description of the clinical features of cutaneous melanoma (CM) have remained unchanged since 1985, when the ABCD (Asymmetry, Border irregularity, Color variegation, Diameter >6 mm) rule for melanoma detection was formulated. Given the significant shift to the diagnosis of earlier-stage CMs over the past decades, it is reasonable to think that also the clinical aspects of the disease might have changed. The aim of this study was to examine trends in the presentation of CM over the last decade at our Institution, focusing on two characteristics of the disease: size and thickness. METHODS: A retrospective study was conducted including 1,603 primary invasive CMs seen and treated at the Unit for Melanoma Detection at our Institute between January 1997 and December 2006. RESULTS: The results showed a trend towards smaller CMs, with a difference of 3 mm in median size from the beginning to the end of the period. Detection of small (< or =6 mm) CMs increased at a rate of about 1.5% per year, with a current ratio of 25% with respect to all CMs. Thickness remained substantially unchanged over time. CONCLUSIONS: Physicians must be aware that the characteristics of melanoma have undergone a metamorphosis over the years and the ABCD signs cannot be relied on for adequate sensitivity to further the early detection of CM.