Impact of hormonal status on outcome of ductal carcinoma in situ treated with breast-conserving surgery plus radiotherapy: Long-term experience from two large-institutional series.

BACKGROUND: Ductal carcinoma in situ (DCIS) is a heterogeneous disease, for which the best adjuvant treatment is still uncertain. Many attempts of risk-groups stratification have been made over time, developing prognostic scores to predict risk of local recurrence (LR) on the basis of features such as age, final surgical margins (FSM) status, grade, and tumor size. The aim of our analysis was to evaluate the patterns of recurrence from a two large-institutional retrospective series. PATIENTS AND METHODS: We collected data on 457 patients treated with BCS and adjuvant RT between 1990 and 2012. Final analysis was performed on 278 patients, due to missing data about hormonal status (HS). Patients were treated at the Radiation Oncology Unit of the University of Florence (n = 195), and S. Maria Annunziata Hospital (n = 83) (Florence, Italy). RESULTS: At a median follow up time of 10.8 years (range 3-25), we observed 20 LR (7.2%). The 5-year and 10-year LR rates were 4.9% and 10.2%, respectively. At Cox regression univariate analysis, estrogen receptor (ER) positive status (p = 0.001), HS positive (p = 0.003), and FSM <1 mm (p = 0.0001) significantly impacted on LR. At Cox regression multivariate analysis positive ER status maintained a protective role (p = 0.003), and FSM status <1 mm its negative impact (p = 0.0001) on LR rate. CONCLUSIONS: Our experience confirmed the wide heterogeneity of DCIS. Inadequate FSM and negative ER status negatively influenced LR rates. Tumor biology should be integrated in adjuvant treatment decision-making process.

Prediction of response to bacillus Calmette-Guérin treatment in non-muscle invasive bladder cancer patients through interleukin-6 and interleukin-10 ratio.

This study aimed to evaluate whether the interleukin-6 (IL-6) and interleukin-10 (IL-10) ratio (IL-6/IL-10) can be used as a prognostic marker of recurrence following bacillus Calmette-Guérin (BCG) therapy in patients with high-risk non-muscle invasive bladder cancer (NMIBC). One hundred and twenty-one consecutive urological patients (72 affected by high-risk NMIBC and 49 controls) were selected for this prospective study. Urine samples for dipstick and interleukin analyses were collected from each subject before surgery. All patients underwent transurethral resection of bladder tumours (TUR-BT), followed by six weekly BCG instillations. IL-6 and IL-10 concentrations in urine were determined by solid phase ELISA Quantikine IL-6 and IL-10 Immunoassay. Patients with NMIBC were stratified in accordance with IL-6/IL-10: group A ≤0.09 and group B >0.10. The main outcome measures were time to first recurrence and recurrence rate following BCG therapy. At enrolment, IL-6/IL-10 was not statistically different between patients and controls (p=0.763, degrees of freedom (df)=1, F-test result (F)=0.092). Of the 72 patients with NMIBC, 38 (52.7%) had an IL-6/IL-10 of ≤0.09 (group A), while 34 (47.3%) had an IL-6/IL-10 of >0.10 (group B). A significant difference between IL-6/IL-10 and status at follow-up was found (p=0.016, df=1, χ(2)=5.800). The Kaplan-Meier curves demonstrated that group B patients had a significantly higher probability of being recurrence-free than group A patients [p=0.003; recurrence rate (RR)=3.1]. At multivariate analysis, IL-6/IL-10 (p<0.003) and the number of lesions (p<0.001) were identified as independent predictors of BCG response probability. In conclusion, this study highlights the feasible role of IL-6/IL-10 in predicting recurrence following BCG therapy in high-risk NMIBC.

Clinical importance of lymph node density in predicting outcome of prostate cancer patients.

BACKGROUND: To evaluate the prognostic role of lymph node density (LND) in patients affected by prostate cancer (PCa) and treated with radical prostatectomy (RP), pelvic lymph node dissection (PLND), and adjuvant hormonal blockade. METHODS: A total of 124 consecutive patients with lymph node positive PCa formed the basis of this report. Clinical and pathological parameters were collected. All patients were stratified in two groups according to LND: Group A (LND ≤ 32%) and Group B (LND ≥ 33%). Time to the first biochemical recurrence (BCR) was the main measure of outcome. RESULTS: Mean number of lymph nodes removed was 5.2 (range 1-17). The mean number of positive lymph nodes was 1.6 (range 1-5). At a mean follow-up of 84.3 mo, 22 patients in Group A (43.1%) and 40 in Group B (54.7%) had BCR. The mean overall BCR-free survival was 46.2 mo (range 8-90). No significant correlation was found between the number of positive lymph nodes and BCR-free survival (P = 0.68). In addition, the patients with LND ≥ 33% had a poor prognosis with significantly decreased disease-specific and BCR-free survival rates (hazard ratio: 0.48; 95% CI, 0.28-0.78; P = 0.0039). At multivariate and artificial neural network (ANN) analyses, LND, Gleason score, and stage were identified as independent prognostic factors of BCR-free survival (P = 0.002; P = 0.003; P = 0.003). CONCLUSIONS: The current study highlights the role of LND in predicting BCR-free survival in patients with lymph node positive PCa after prostatectomy. It also reinforces the need for a stratification of patients with nodal metastasis.

Loss of heterozygosis on IFN-alpha locus is a prognostic indicator of bacillus Calmette-Guerin response for nonmuscle invasive bladder cancer.

PURPOSE: We evaluated the role of loss of heterozygosity on the interferon-alpha locus to predict the response to bacillus Calmette-Guerin therapy in patients with nonmuscle invasive bladder cancer. MATERIALS AND METHODS: A total of 117 consecutive patients were selected, including 77 with nonmuscle invasive bladder cancer and 40 controls. Loss of heterozygosity on the interferon-alpha locus (chromosome 9p21) was assessed in blood and urine samples before transurethral resection. All patients underwent transurethral resection and then 6 weekly bacillus Calmette-Guerin instillations. Those with nonmuscle invasive bladder cancer were assigned to groups 1 and 2 with and without loss of heterozygosity on the interferon-alpha locus, respectively. RESULTS: Of the 77 patients with nonmuscle invasive bladder cancer 39 (50.6%) had loss of heterozygosity on the interferon-alpha locus (group 1) and 38 (49.4%) had no alteration (group 2). Only 1 of 40 controls showed loss of heterozygosity on the interferon-alpha locus. At the end of followup 13 patients in group 1 and 27 in group 2 were alive without recurrence. We noted a significant difference between loss of heterozygosity on interferon-alpha and followup status (dF 01, LR 11.252, p = 0.003). Kaplan-Meier analysis revealed a significant difference in recurrence probability (response to bacillus Calmette-Guerin) and loss of heterozygosity on interferon-alpha (p <0.0001). On multivariate analysis loss of heterozygosity (HR 4.09, 95% CI 2.59-6.28, p = 0.002), grade (grade 3 HR 3.31, 95% CI 1.38-3.35, p = 0.03) and the number of lesions (3 or greater HR 2.31, 95% CI 1.38-3.25, p = 0.03) were independent predictors of the bacillus Calmette-Guerin response. CONCLUSIONS: This study highlights the predictive value of loss of heterozygosity analysis on interferon-alpha in patients with nonmuscle invasive bladder cancer treated with bacillus Calmette-Guerin.

In vivo microwave-induced porcine kidney thermoablation: results and perspectives from a pilot study of a new probe.

OBJECTIVE: To test the in vivo effects (toxicity, completeness of necrosis, dimensions of the lesion) of microwave thermoablation on porcine kidneys, using the Amica Probe v3 (Hospital Service SpA, Aprilia, Italy), in a refrigerated 17-G microwave applicator, that can be used to induce a spherical necrotic area. PATIENTS AND METHODS: Six pigs were used; each kidney was treated, with no kidney pedicle clamping, by microwave thermoablation at least in three different zones with different exposure times and power, during open surgery. Twelve kidneys had 32 microwave thermoablations overall. The kidneys were then surgically removed, and necrotic lesions measured and evaluated microscopically. The sphericity index (SI) was also calculated to evaluate lesion reproducibility. Areas of renal tissue that were missed were then microscopically evaluated by NADH in vivo staining. RESULTS: In all, 32 thermoablations were applied; the mean (sd) lesion diameter ranged from 1.2 (0.3) to 4.2 (0.1) cm and changed in relation to both power and time of exposure. The 50-W power particularly induced necrotic renal lesions ranging from 1.9 (0.2) to 4.2 (0.1) cm as a function of the time of exposure and the optimal SI (1.04). Pathological evaluation showed no skipped areas in the context of the lesion, or healthy kidney tissue damage close to necrotic lesions. CONCLUSIONS: Thermoablation with the Amica probe is safe and showed excellent in vivo effects in this porcine model. Increasing the exposure time at 50 W power could be a useful percutaneous minimally invasive treatment for small solid masses (<4.2 cm), avoiding the risk of missing tumour areas or kidney parenchymal damage from microwave treatment.

Non-sentinel lymph node involvement in a patient with an atypical Spitz tumor and a positive sentinel node. Report of a case and review of the literature.

We report a 20-year-old male patient with an atypical Spitz tumor, located in the dorsal aspect of his left hand, and a positive sentinel axillary lymph node. After lymphadenectomy, 1 of 23 non-sentinel lymph nodes excised was found to contain small multiple deposits of large spindle atypical melanocytes. Reviewing the pertinent literature, 5 of 29 patients with atypical Spitz tumors and positive sentinel nodes who had undergone lymphadenectomy have shown non-sentinel node involvement (17.2%), a proportion similar to that reported in melanoma patients. The exact nature of atypical Spitz tumors and the interpretation of cell deposits detected in sentinel nodes are still debated; data regarding the non-sentinel lymph node involvement in patients with atypical Spitz tumors may contribute to better understand the real biological potential of such tumors.

Transperineal microwave thermoablation in patients with obstructive benign prostatic hyperplasia: a phase I clinical study with a new mini-choked microwave applicator.

PURPOSE: To evaluate the tolerability and safety of a newly designed probe for trans-perineal microwave thermoablation (TPMT) of the prostate in patients with benign prostatic hyperplasia (BPH), and the in vivo microwave effects on prostatic tissue. PATIENTS AND METHODS: Nine patients with obstructive BPH who were candidates for open prostatectomy were selected for this study. Under local anesthesia and transrectal ultrasound monitoring, all patients underwent a single standardized application of TPMT. The visual analog scale (VAS) and Short Form-36 health survey (SF-36) questionnaire were administered to each patient prior to, during, and 1 month after TPMT in order to evaluate pain and quality of life. Then the International Index of Erectile Function (IIEF-5) and International Prostate Symptom Score (IPSS) questionnaires were administered to each patient at baseline and 1 month after prostatectomy in order to evaluate sexual and urinary function, respectively. Then all patients were divided into three groups and underwent open prostatectomy 7, 15, and 30 days after TPMT, respectively. The prostatic adenomas were then evaluated by a pathologist. RESULTS: No adverse events from TPMT treatment were noted. In particular, no patients reported local, pelvic, or abdominal pain during the procedure or subsequent alterations of defecation rhythm, ano-rectal/intestinal problems, or hematuria. No differences in quality of life or in sexual function were reported. The diameters of the lesions obtained with TPMT treatment ranged from 16 to 18.1 mm in all patients. Quasi-spheroid lesions with a well-defined area of complete coagulative necrosis were documented in all removed adenomas 7, 15, and 30 days after TMPT. CONCLUSIONS: The AMICA-PROBE is a safe, well-tolerated, and repeatable method to treat BPH with microwave thermotherapy. The spheroid lesions obtained demonstrated the maximal control over the radial and longitudinal coagulative effects of the therapy. Phase II studies are needed to further evaluate the efficacy of this new probe.

Sensitivity and specificity of histological criteria in the diagnosis of conventional cutaneous melanoma.

The efficacy of the histological criteria currently used in the diagnosis of melanoma is still to be defined. We performed a quantitative analysis of 72 conventional (non-Spitzoid, nondesmoplastic) melanomas and 73 conventional melanocytic naevi, used as controls, for 13 histological diagnostic parameters (dimension >6 mm, asymmetry, poor circumscription, irregular and confluent nests, single melanocytes predominating, absence of maturation, suprabasal melanocytes, asymmetrical melanin, melanin in deep cells, cytological atypia, mitoses, necrosis and dermal lymphocytic infiltrate). Differences in the distribution of selected parameters between the two groups were investigated by Fisher's exact test; for each parameter sensitivity and specificity were calculated. Results showed that all parameters, except poor circumscription, seemed to be significantly associated with melanoma (P<0.05). Cytological atypia, dermal lymphocytic infiltrate, asymmetry, dimension >6 mm and absence of maturation showed a high sensitivity (>90%); absence of maturation, mitoses, necrosis, asymmetrical melanin, suprabasal melanocytes and melanin in deep cells showed a high specificity (>90%); irregular-confluent nests and single melanocytes predominating were poorly sensitive and poorly specific. In melanomas < or =2 mm, two additional parameters were sensitive (> or =90%): suprabasal melanocytes and single melanocytes predominating. We conclude that not all parameters showed to have the same diagnostic value. Absence of maturation and, limited to melanomas < or =2 mm, suprabasal melanocytes were the most discriminating (sensitive and specific) histological features. Cytological atypia, dimension >6 mm, suprabasal melanocytes and mitoses were additional reliable diagnostic features, showing a relatively high sensitivity and a relatively high specificity. Other useful features were dermal lymphocytic infiltrate and asymmetry (sensitive) and necrosis, asymmetrical melanin and melanin in deep cells (specific).

Can early single dose instillation of epirubicin improve bacillus Calmette-Guerin efficacy in patients with nonmuscle invasive high risk bladder cancer? Results from a prospective, randomized, double-blind controlled study.

PURPOSE: We evaluated the impact of epirubicin perioperative instillation in improving subsequent bacillus Calmette-Guerin instillation efficacy in high risk patients with nonmuscle invasive bladder cancer. MATERIALS AND METHODS: Between January 2005 and June 2007, 161 patients affected by high risk nonmuscle invasive bladder cancer were enrolled in this prospective, randomized, controlled, double-blind study. A total of 80 patients were assigned to group A (perioperative epirubicin 80 mg/50 ml normal saline) plus delayed bacillus Calmette-Guerin instillations (5 x 108 colony-forming units in 50 ml saline) and 81 to group B (delayed bacillus Calmette-Guerin alone). The main outcome measures were time to first recurrence and recurrence rate. All data obtained from a median followup of 15.3 months in group A and 14.8 months in group B, were analyzed. RESULTS: At the end of followup 46 of 80 patients in group A (57.5%) had no evidence of disease, just like 41 of 81 in group B (50.6%). No statistical difference was observed between the 2 groups in terms of recurrence rate (p = 0.82) or time to first recurrence (p = 0.095). Kaplan-Meier analysis of recurrence showed no significant differences between group A and group B (p = 0.0952). On multivariate analysis the early single dose instillation of epirubicin was not indicated as an independent prognostic factor (HR 0.50, 95% CI 0.32-1.18). CONCLUSIONS: The present study showed no statistically significant differences in terms of disease-free time and recurrence rate between high risk patients with nonmuscle invasive bladder cancer who had undergone perioperative epirubicin instillation plus delayed bacillus Calmette-Guerin and those who had undergone delayed bacillus Calmette-Guerin alone.

Interleukin-6/10 ratio as a prognostic marker of recurrence in patients with intermediate risk urothelial bladder carcinoma.

PURPOSE: Several potential markers have been investigated to improve the noninvasive diagnosis of recurrent superficial bladder carcinoma. We evaluated the role of the interleukin-6/10 ratio as a prognostic marker of recurrence in patients with intermediate risk superficial bladder carcinoma. MATERIALS AND METHODS: A total of 65 consecutive urological patients seen in the office, including 41 with intermediate risk superficial bladder carcinoma and 24 controls, were selected for this prospective study. Five urine samples for urinary cytology and interleukin analyses were collected from each subject at baseline, and 3, 6, 9 and 12 months after surgery, respectively. Interleukin-6 and 10 were determined in urine by the Quantikine solid phase interleukin-6 and 10 enzyme-linked immunosorbent assay, respectively. Sensitivity, specificity, and positive and negative predictive values of the method were calculated. RESULTS: At baseline sample collection the interleukin-6/10 ratio was not statistically different between patients and controls (p = 0.58). Interleukin-6/10 was statistically different between patients with vs without recurrence 3 (0.009 vs 0.408), 6 (0.011 vs 0.268), 9 (0.012 vs 0.288) and 12 months (0.009 vs 0.302) after pre-transurethral bladder tumor resection (each p <0.001). Multivariate analysis indicated that interleukin-6/10 was an independent prognostic factor of recurrence (HR 3.62, 95% CI 2.80-4.92, p <0.001). Test sensitivity and specificity were 0.83% (95% CI 0.57-0.95) and 0.76% (95% CI 0.45-0.93), respectively. CONCLUSIONS: The current study highlights the feasible role of the interleukin-6/10 ratio for predicting intermediate risk superficial bladder carcinoma recurrence. However, clinical trials with a greater number of patients are needed to consider its use in clinical urological practice.

Penile metastasis from a T1b prostate carcinoma.

BACKGROUND: Penile metastasis from incidental prostate carcinoma has not been described to date. CASE REPORT: The case of a 72-year-old man affected by penile metastasis from incidental prostate carcinoma is described. In March 1998, the patient underwent prostate surgery for lower urinary tract symptoms related to benign prostatic obstruction. Histological examination revealed an incidental adenocarcinoma of the prostate. The pre-operative prostate-specific antigen (PSA) value was 3.6 ng/ml. A prostate biopsy in the peripheral prostate lobes was negative. PSA progressively rose to 8 ng/ml. The prostate biopsy was repeated and was still negative. The patient was subjected to radiotherapy, as a result of which his PSA fell to 0.7 ng/ml. 4 years after prostatectomy, the PSA rose again and the patient underwent hormonal therapy. The PSA fell to < 0.001 ng/ml. In May 2004, the patient reported a painful, erythematous nodule on his penis glans. Surgical biopsy showed a metastasis from prostate adenocarcinoma and he underwent partial penectomy. Due to disease progression, the patient underwent medical therapy. PSA and testosterone were always at minimum levels. 20 months later the patient died. CONCLUSION: We underline the uncertainty of the biological behaviour and optimal management of incidentally identified prostate carcinoma. In addition, we highlight that biological and clinical progression could be the consequence of inadequate treatment recommendations.

Sentinel lymph node biopsy in patients with "atypical Spitz tumors." A report on 12 cases.

The distinction between Spitz nevus and melanoma is currently possible, applying a set of definite histological criteria. However, in certain lesions deviating from the stereotypical morphology of classic Spitz nevi ("atypical Spitz tumors"), the differentiation between benign and malignant cases appears problematic because objective criteria for a reliable diagnosis are lacking. We report the clinicopathologic findings of 12 patients with atypical Spitz tumors, who underwent sentinel node biopsy. All the tumors, composed of spindle and/or epithelioid cells, histologically showed features referable to Spitz nevi mixed to features generally found in malignant melanomas. Nine patients were females and three males, ranging in age from 2 to 48 years (mean, 23.2 years). The size of lesions ranged from 5 to 9 mm, the thickness from 1.12 to 5.70 mm. Nodal micrometastases were found in 4 (33.3%) patients. Among the patients with positive sentinel node, two showed minimal nodal involvements; one patient showed additional tumor deposits in one nonsentinel regional node. All patients are alive and free of disease with a follow-up of 2 to 90 months (mean, 26.3 months). Metastasizing and nonmetastasizing cases appeared clinically and histologically indistinguishable. The statistical analysis showed no significant difference between the two groups. Results suggested that all the reported cases may constitute a relatively homogeneous morphological group of lesions with a relevant metastatic potential that may be underdiagnosed.

Digital images for interobserver variability comparison in cervicovaginal cytology.

OBJECTIVE: To assess whether digital images can be useful in evaluating interobserver variability in cervical-vaginal cytology. STUDY DESIGN: In phase 1 of the study, to measure interobserver variability, a set of 160 digital images was submitted to 192 cytologists with experience ranging from 2 to > 30 years. The set was preceded by two days of immersion in lessons and practical exercises with digital images. In phase 2, to compare different procedures of interobserver variability, two different sets of slides and one set of digital images were used. RESULTS: In phase 1, kappa and weighted kappa w values computed against both the consensus and the target diagnosis showed good agreement, with few exceptions. In phase 2, the consensus and target diagnoses obtained on the slide sets and digital set were compared. Mean k and kw values obtained with the digital images in phase 2 were significantly lower as compared to those in phase 1. CONCLUSION: A set of digital images can be a useful tool for evaluating and improving interobserver reproducibility. A two-day course on digital images could be an ideal modality for introducing this new technology.