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BackgroundTo evaluate multiparametric magnetic resonance imaging (mpMRI) parameters, such as TransPA (transverse prostate maximum sectional area), TransCGA (transverse central gland sectional area), TransPZA (transverse peripheral zone sectional area), and TransPAI (TransPZA/TransCGA ratio) in predicting prostate cancer (PCa) in prostate imaging reporting and data system (PI-RADS) 3 lesions.MethodsSensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV), the area under the receiver operating characteristic curve (AUC), and the best cut-off, were calculated. Univariate and multivariate analyses were carried out to evaluate the capability to predict PCa.ResultsOut of 120 PI-RADS 3 lesions, 54 (45.0%) were PCa with 34 (28.3%) csPCas. Median TransPA, TransCGA, TransPZA and TransPAI were 15.4cm2, 9.1cm2, 5.5cm2 and 0.57, respectively. At multivariate analysis, location in the transition zone (OR=7.92, 95% CI: 2.70-23.29, PConclusionsIn PI-RADS 3 lesions, the TransPA could be useful in selecting patients requiring biopsy.

The most common somatic event in primary prostate cancer is a fusion between the androgen-related TMPRSS2 gene and the ERG oncogene. Tumors with these fusions, which occur early in carcinogenesis, have a distinctive etiology. A smaller subset of other tumors harbor fusions between TMPRSS2 and members of the ETS transcription factor family other than ERG. To assess the genomic similarity of tumors with non-ERG ETS fusions and those with fusions involving ERG, this study derived a transcriptomic signature of non-ERG ETS fusions and assessed this signature and ERG-related gene expression in 1,050 men with primary prostate cancer from three independent population-based and hospital-based studies. Although non-ERG ETS fusions involving ETV1, ETV4, ETV5, or FLI1 were individually rare, they jointly accounted for one in seven prostate tumors. Genes differentially regulated between non-ERG ETS tumors and tumors without ETS fusions showed similar differential expression when ERG tumors and tumors without ETS fusions were compared (differences explained: R2 = 69-77%), including ETS-related androgen receptor (AR) target genes. Differences appeared to result from similarities among ETS tumors rather than similarities among non-ETS tumors. Gene sets associated with ERG fusions were consistent with gene sets associated with non-ERG ETS fusions, including fatty acid and amino acid metabolism, an observation that was robust across cohorts.ImplicationsConsidering ETS fusions jointly may be useful for etiologic studies on prostate cancer, given that the transcriptome is profoundly impacted by ERG and non-ERG ETS fusions in a largely similar fashion, most notably genes regulating metabolic pathways.

Additional file 1: Appendix I.

Background We report on a female patient who underwent primary radical resection for a stage 2B Her-2-positive Barrett’s-type esophageal adenocarcinoma (EAC). Despite Her-2 targeted therapy, her disease recurred and required repeated metastectomies. Case presentation Digital cell sorting and targeted sequencing of cancer sub-clones from EAC and metastases revealed a completely mutated TP53, whereas the sorted stromal cells were wild-type. Her-2 amplification was significantly lower in the metastases when the patient became therapy-resistant. Conclusions The mechanism of therapy resistance illustrated by this case could only be detected through accurate analysis of tumor sub-populations. Investigating tumor sub-populations of recurrent disease is important for adjusting therapy in recurrent EAC. Electronic supplementary material The online version of this article (10.1186/s12885-018-4789-4) contains supplementary material, which is available to authorized users.

Hairy cell leukemia (HCL) is an uncommon B-cell chronic lymphoproliferative disorder whose pathogenesis and recurrence are strictly dependent on the presence of the BRAF V600E mutant. A 65-year-old male presented a monomorphic epitheliotropic intestinal T-cell lymphoma (formerly enteropathy-associated T-cell lymphoma, type II) with HCL not responding to first-line induction with cladribine. The intestinal lymphoma bears the BRAF V600E mutant, which is the molecular hallmark of HCL, being implicated in its pathogenesis. The case is of interest, as it provides the first description of a BRAF V600E-positive intestinal T-cell lymphoma, along with immunohistochemical and molecular demonstration, occurring in concomitance with HCL. A novel digital PCR-base method for HCL disease assessment is also suggested.

Alessandro Broccoli,1 Clara Bertuzzi,2 Michelangelo Fiorentino,3 Alice Morigi,1 Vittorio Stefoni,1 Claudio Agostinelli,2 Lisa Argnani,1 Michele Cavo,1 Pier Luigi Zinzani11Institute of Hematology “L. e A. Seràgnoli”, University of Bologna, Bologna, Italy; 2Hematopathology Unit, Institute of Hematology “L. e A. Seràgnoli”, University of Bologna, Bologna, Italy; 3Pathology Unit, “S.Orsola-Malpighi” Hospital, University of Bologna, Bologna, ItalyAbstract: Hairy cell leukemia (HCL) is an uncommon B-cell chronic lymphoproliferative disorder whose pathogenesis and recurrence are strictly dependent on the presence of the BRAF V600E mutant. A 65-year-old male presented a monomorphic epitheliotropic intestinal T-cell lymphoma (formerly enteropathy-associated T-cell lymphoma, type II) with HCL not responding to first-line induction with cladribine. The intestinal lymphoma bears the BRAF V600E mutant, which is the molecular hallmark of HCL, being implicated in its pathogenesis. The case is of interest, as it provides the first description of a BRAF V600E-positive intestinal T-cell lymphoma, along with immunohistochemical and molecular demonstration, occurring in concomitance with HCL. A novel digital PCR-base method for HCL disease assessment is also suggested.Keywords: hairy-cell leukemia, BRAF V600E mutant, monomorphic epitheliotropic intestinal T-cell lymphoma, cladribine

Supplemental material, Supplementary_table_1 for KRAS and ERBB-family genetic alterations affect response to PD-1 inhibitors in metastatic nonsquamous NSCLC by Marika Cinausero, Noemi Laprovitera, Giovanna De Maglio, Lorenzo Gerratana, Mattia Riefolo, Marianna Macerelli, Michelangelo Fiorentino, Elisa Porcellini, Vanessa Buoro, Francesco Gelsomino, Anna Squadrilli, Gianpiero Fasola, Massimo Negrini, Marcello Tiseo, Manuela Ferracin and Andrea Ardizzoni in Therapeutic Advances in Medical Oncology

Circulating insulin-like growth factor-1 (IGF-1) is consistently associated with prostate cancer risk. IGF-1 binds to IGF-1 receptor (IGF1R) and insulin receptor (IR), activating cancer hallmark pathways. Experimental evidence suggests that TMPRSS2:ERG may interact with IGF/insulin signaling to influence progression. We investigated IGF1R and IR expression and its association with lethal prostate cancer among 769 men. Protein expression of IGF1R, IR and ERG (i.e. a surrogate of ERG fusion genes) were assayed by immunohistochemistry. Cox models estimated hazard ratios (HR) and 95% confidence intervals (CI) adjusted for clinical characteristics. Among patients, 29% had strong tumor IGF1R expression and 10% had strong IR expression. During a mean follow-up of 13.2 years through 2012, 80 men (11%) developed lethal disease. Tumors with strong IGF1R or IR expression showed increased cell proliferation, decreased apoptosis and a higher prevalence of ERG. In multivariable models, strong IGF1R was associated with a borderline increased risk of lethal prostate cancer (HR 1.7; 95% CI 0.9-3.1). The association appeared greater in ERG-positive tumors (HR 2.8; 95% CI 0.9-8.4) than in ERG-negative tumors (HR 1.3; 95% CI 0.6-3.0, p-heterogeneity 0.08). There was no association between IR and lethal prostate cancer (HR 0.8; 95% CI 0.4-1.9). These results suggest that tumor IGF1R expression may play a role in prostate cancer progression to a lethal phenotype and that ERG-positive tumors may be more sensitive to IGF signaling. These data may improve our understanding of IGF signaling in prostate cancer and suggest therapeutic options for disease subtypes.

Figure S1. Plots of Copy Number Analysis and phylogenetic tree using WES data. A 18 Mb region on chromosome 6 (q21-22.33) is indicated (red box), where CNV analysis identified a copy gain in PT (A) and M1 (B), as reported in Additional file 1: Table S2. (C) In the second chest metastasis (M2) a focal amplification was detected in the 6q22.33 region, spanning RNF146 and ECHDC1 genes (black arrowhead). (D) SNPhylo analysis results, showing the genetic distance between the three tumor samples. Numbers indicate the branch length from central node. The distance between two tumors is equal to the sum of their branch length. Analysis was performed according to [6]. (PDF 137 kb)

Supplementary methods and metarials. (DOCX 79 kb)

BACKGROUND: Few studies have considered etiological differences across molecular subtypes of prostate cancer, despite potential to improve opportunities for precision prevention of a disease for which modifiable risk factors have remained elusive. Factors that lead to DNA double-strand breaks, such as oxidative stress, may promote the formation of the TMPRSS2:ERG gene fusion in prostate cancer. We tested the hypothesis that increasing levels of pre-diagnostic circulating antioxidants, which may reduce oxidative stress, are associated with lower risk of developing TMPRSS2:ERG positive prostate cancer. METHODS: We conducted a nested case-control study, including 370 cases and 2,470 controls, to evaluate associations between pre-diagnostic α- and β-carotene, α- and γ-tocopherol, β-cryptoxanthin, lutein, lycopene, retinol, and selenium with the risk of prostate cancer by ERG protein expression status (a marker of TMPRSS2:ERG). Multivariable unconditional polytomous logistic regression was used to calculate odds ratios and 95% confidence intervals. RESULTS: We did not find any of the antioxidants to be significantly associated with the risk of prostate cancer according to ERG status. CONCLUSIONS: The results do not support the hypothesis that circulating pre-diagnostic antioxidant levels protect against developing TMPRSS2:ERG positive prostate cancer. Additional studies are needed to explore mechanisms for the development of TMPRSS2:ERG positive disease. Prostate 77: 647–653, 2017. © 2017 Wiley Periodicals, Inc.

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Can we consider eligible for active surveillance prostate cancer patients with biopsy Gleason 3+4 in only one core? Results of single center study after extensive central revision of histological specimens and mid-term follow-up

BackgroundThere is limited evidence that supports etiologically distinct molecular subtypes of prostate cancer, the identification of which may improve prevention. Given their antioxidant properties, we hypothesized that lycopene and tomato sauce may be especially protective against diseases harboring the common gene fusion transmembrane protease, serine 2 (TMPRSS2):v-ets avian erythroblastosis virus E26 oncogene homolog (ERG).ObjectiveWe aimed to examine associations between estimated lycopene and tomato sauce intake and the risk of prostate cancer defined by ERG protein expression subtype.DesignOur study population consisted of a prospective cohort of 46,719 men from the Health Professionals Follow-Up Study. TMPRSS2:ERG was assessed by ERG immunohistochemistry on tumor tissue microarrays constructed from radical prostatectomy specimens. We used multivariable competing risk models to calculate HRs and 95% CIs for the risk of ERG-positive and, separately, ERG-negative disease. We implemented inverse probability weighting to account for evaluating ERG status only in surgically treated cases.ResultsDuring 23 y of follow-up, 5543 men were diagnosed with prostate cancer, among whom 884 were assayed for ERG (426 ERG-positive). With inclusion of only the latter cases, increasing cumulative average tomato sauce intake was associated with a decreased risk of prostate cancer overall (≥2 servings/wk compared with

There is limited evidence that supports etiologically distinct molecular subtypes of prostate cancer, the identification of which may improve prevention. Given their antioxidant properties, we hypothesized that lycopene and tomato sauce may be especially protective against diseases harboring the common gene fusion transmembrane protease, serine 2 (TMPRSS2):v-ets avian erythroblastosis virus E26 oncogene homolog (ERG).We aimed to examine associations between estimated lycopene and tomato sauce intake and the risk of prostate cancer defined by ERG protein expression subtype.Our study population consisted of a prospective cohort of 46,719 men from the Health Professionals Follow-Up Study. TMPRSS2:ERG was assessed by ERG immunohistochemistry on tumor tissue microarrays constructed from radical prostatectomy specimens. We used multivariable competing risk models to calculate HRs and 95% CIs for the risk of ERG-positive and, separately, ERG-negative disease. We implemented inverse probability weighting to account for evaluating ERG status only in surgically treated cases.During 23 y of follow-up, 5543 men were diagnosed with prostate cancer, among whom 884 were assayed for ERG (426 ERG-positive). With inclusion of only the latter cases, increasing cumulative average tomato sauce intake was associated with a decreased risk of prostate cancer overall (≥2 servings/wk compared with1 serving/mo; multivariable HR: 0.70; 95% CI: 0.52, 0.95; P-trend = 0.002). With respect to molecular subtypes, cumulative average tomato sauce intake was associated with a decreased risk of ERG-positive disease (HR: 0.54; 95% CI: 0.37, 0.81; P-trend = 0.004) but not with ERG-negative disease (HR: 0.96; 95% CI: 0.62, 1.50; P-trend = 0.10) (P-heterogeneity = 0.04). Increasing quintiles of lycopene intake were associated with a decreased risk of both subtypes (P-heterogeneity = 0.79). Inverse probability weighting did not materially change the results.Our results lend some support to the hypothesis that prostate cancers that harbor TMPRSS2:ERG may be etiologically distinct from fusion-negative cancers. In particular, tomato sauce consumption may play a role in reducing TMPRSS2:ERG-positive disease.

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We found association between prognosis of prostate cancer patients and positive staining for the BRCA2 protein in diagnostic cancer tissue. Positive staining at the cell membrane was associated with improved survival whereas staining in the cytoplasm predicted adverse outcome.Prostate cancer patients with inherited BRCA2 mutations have a survival disadvantage. However, it is unknown whether progression is associated with BRCA2 protein expression in diagnostic prostate cancer tissue, among men without inherited mutations. We conducted a nested case-control study within the Swedish Watchful Waiting cohort. The case group included all 71 patients who died from prostate cancer within 5 years from diagnosis and controls were all patients (n = 165) who lived at least 7 years after diagnosis. Tissue microarrays were stained using antibodies for C- and N-terminal domains of the BRCA2 protein. Location (nuclear, cytoplasmic and membranous) and magnitude (intensity and percentage) of expression were assessed. Logistic regression models produced odds ratios (OR) and 95% confidence intervals (CI) adjusted for age, year of diagnosis and Gleason score. Positive BRCA2 staining at the cell membrane was associated with reduced risk of death within 5 years (N-terminal: OR = 0.47, 95% CI = 0.21-1.04, P = 0.06; C-terminal: OR = 0.41, 95% CI = 0.18-0.91, P = 0.03) and low Gleason scores (P = 0.006). Positive cytoplasmic C-terminal staining was associated with higher Gleason scores and increased lethality (OR = 3.61, 95% CI = 1.61-8.07, P = 0.002). BRCA2 protein expression at the cell membrane and lack of C-terminal expression in the cytoplasm were associated with a reduced risk of rapidly fatal prostate cancer. BRCA2 protein expression in prostate cancer tissue may have independent prognostic value. The potential biological significance of BRCA2 expression at the cell membrane warrants further investigation.

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BACKGROUND: We describe the results of the application of the Italian donor cancer screening protocol to all the 7608 candidate multiorgan donors presented in Italy in 2002-2005. METHODS: All suspect findings raised in the two presurgical and surgical phases of the protocol were investigated by extemporary pathologic evaluation. Donors were classified as standard risk (no transmissible risk); nonstandard risk (low-risk of transmission, eligibility restricted to certified clinical emergencies pending informed consent); and unacceptable risk (unconditional exclusion because of high-risk pathologies). RESULTS: The protocol was successfully implemented for all 7608 candidates. In addition to 8 (0.1%) independent exclusions, clinical suspicion of cancer was raised for 337 (4.6%) donors. According to pathological examination 198 donors (2.6%) were judged at unacceptable risk of tumor transmission; 80 (1%) were included in the "standard risk". Used standard risk and nonstandard risk donors provided a total of 241 organs in 231 recipients. Although no suspect was raised after implementation of the protocol, a malignant tumor was discovered after organ transplantation in 14 (0.2%) donors. All the recipients transplanted with organs from ascertained nonstandard risk donors or from neoplastic donors who donated by accident have been carefully followed. At the time of most recent follow-up no donor/recipient tumor transmission has been reported. CONCLUSIONS: Implementation of the multiorgan cancer screening protocol is feasible at a national level in Italy. In view of the increasing demand for organs our protocol provides a useful tool for rationalization of the use of organs from neoplastic marginal donors.

BACKGROUND: In the United States, half of men with prostate cancer harbor the androgen-regulated gene fusion TMPRSS2:ERG. We hypothesized that men with TMPRSS2:ERG positive tumors are more responsive to androgen deprivation therapy (ADT). METHODS: We studied a cohort of 239 men with prostate cancer from the Physicians' Health Study and Health Professionals Follow-up Study who received ADT during their disease course. Fusion status was assessed on available tumor tissue by immunohistochemistry for ERG protein expression. We used Cox models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for assessment of prostate cancer-specific mortality after ADT initiation. RESULTS: Roughly half of the men had stage T3 or higher tumors at diagnosis and 39% had Gleason 8-10 tumors. During an average follow up of 10.2 years, 42 men died from prostate cancer. There was a non-significant inverse association between positive fusion status and time to death from prostate cancer after ADT (multivariable HR: 0.76; 95% CI: 0.40-1.45). Harboring the TMPRSS2:ERG fusion was associated with a statistically significant lower risk of prostate cancer mortality among men who were treated with orchiectomy (multivariable HR: 0.13; 95% CI: 0.03-0.62), based on 15 events. CONCLUSIONS: Our results, combined with those from earlier studies, provide suggestive evidence that men with TMPRSS2:ERG positive tumors may have longer prostate cancer survival after ADT. Larger cohorts are needed for more robust results and to assess whether men with tumors harboring the fusion benefit from treatment with ADT in the (neo) adjuvant or metastatic setting specifically.

PCR analysis of miR-31*/-126*/-506/-508-3p/-514. Quantitative “miRNA-targeted” real-time PCR of five miRNA aberrantly expressed in the proband’s PEAC according to the microarray results showed that the microarray data were validated by PCR data as well as that the pattern of modulation of expression of these miRNA was similar in the proband’s brother. Columns and bars, average levels ± SD, compared using the 2-ΔΔCt method to a pool of normal lung tissues, dashed line. (PPTX 158 kb)

Analyses of EGFR, KRAS, ALK and MSI. Detailed methods used for the analyses of EGFR, KRAS mutation, ALK rearrangement, MSI, and miRNA-PCR. (DOC 108 kb)

BACKGROUND: We aimed to determine the prognostic role of tumor size in patients with stage pT3a renal cell carcinoma (RCC). PATIENTS AND METHODS: We analyzed our database of patients who underwent radical nephrectomy for RCC between July 2000 and December 2013. Clinical and pathologic data were obtained for each patient. Patients with stage pT3a disease were divided into 2 subgroups according to the most informative threshold for pathologic tumor dimension that was able to predict survival outcomes (group 1, ≤ 8 cm; group 2, > 8 cm). RESULTS: Globally, 185 consecutive patients were evaluated. The median (interquartile range [IQR]) follow-up was 32 months (18-62 months). The median (IQR) pathologic tumor size was 7.5 cm (5.7-10 cm). Seventy (34.3%) patients died of RCC during the follow-up period. Patients in group 2 experienced worse cancer-specific survival (CSS) rates compared with those in group 1, (5- and 10- year CSS, 52% and 40% vs. 67% and 63%, respectively; P = .001). Overall survival (OS) rates were significantly lower for patients included in group 2 compared with patients in group 1 (5- and 10- year OS rates, 46% and 38% vs. 60% and 57%, respectively; P = .01). Subgroup stratification (hazard ratio [HR], 3.65; P < .001), presence of positive surgical margins (HR, 3.86; P = .22), high Fuhrman grade (HR, 4.33; P < .001), and the presence of sarcomatoid cells (HR, 2.61; P = .02) were found to be independent predictors of CSS. CONCLUSION: Worse oncologic outcomes are observed in patients with stage pT3a RCC tumors > 8 cm. The current TNM classification still does not precisely correlate with CSS. Tumor size should be taken into account in a future revision of the TNM staging system.

Immunohistochemical analyses in the cytological sample of the proband’s brother. The stainings for TTF1, CK7, CDX-2, and CK20, summarized in the table, showed patterns of protein expression similar to the expression levels observed in the PEAC component of the proband’s sample. Left column (original magnification ×20); right column (original magnification ×40). (PPTX 32,747 kb)

Comment on: "Pediatric-type" gastrointestinal stromal tumors in adults: distinctive histology predicts genotype and clinical behavior. Rege TA, Wagner AJ, Corless CL, Heinrich MC, Hornick JL. Am J Surg Pathol. 2011 Apr; 35(4):495-504.

La Patologia di Rubin, un classico della letteratura medica anglosassone, è un testo che permette agli studenti e agli studiosi di Patologia di affrontare in modo organico lo studio della materia sia nella sua parte “generale”, sia in quella “sistemica”, integrate tra di loro con grande equilibrio. Il testo presenta caratteristiche di impostazione e di rappresentazione dei concetti per molti aspetti innovative. È stata posta grande attenzione alla chiarezza espositiva e alla finalità didattica: evento del tutto eccezionale, a questo scopo il testo è stato sottoposto al vaglio di un gruppo scelto di studenti-revisori, in modo da tener conto anche della opinione dei lettori più direttamente interessati. Un gran numero di schemi e diagrammi permette di focalizzare con immediatezza e comprendere gli aspetti più complessi della materia, unitamente all’uso delle evidenziazioni e degli elenchi puntati o numerati. L’ impostazione molto moderna, con grande attenzione al livello molecolare delle informazioni più aggiornate, e l’organizzazione in sezioni distinte – epidemiologia, patogenesi, morfologia, caratteristiche cliniche – delle specifiche malattie, sono altri notevoli pregi della Patologia di Rubin.

Loss of PTEN has been shown to be associated with aggressive behavior of prostate cancer. It is less clear that loss of PTEN also increases the risk of cancer mortality. We investigated the association between PTEN expression and prostate cancer mortality and the potential effect modification by IGF-IR, a direct activator of the phosphoinositide-3-kinase (PI3K) pathway.Protein expression in tumor was evaluated using tumor tissues obtained from 805 participants of the Physicians' Health and the Health Professionals Follow-up studies who were diagnosed with prostate cancer and underwent radical prostatectomy. Proportional hazard models were used to assess PTEN expression and its interaction with IGF-IR, in relation to lethal prostate cancer (cancer-specific death or distant metastases).Low PTEN expression was associated with an increased risk of lethal prostate cancer [HR, 1.7; 95% confidence interval (CI), 0.98-3.2; Ptrend = 0.04]. The association was attenuated after adjustment for Gleason grade, tumor stage, and prostate-specific antigen (PSA) at diagnosis. A significant negative interaction between PTEN and IGF-IR was found (Pinteraction = 0.03). Either reduction in PTEN or increase in IGF-IR expression was sufficient to worsen prognosis. Models including PTEN and IGF-IR expression offer additional predicting power to prostate cancer survival, compared to those only including demographic and clinical factors.Low PTEN protein expression significantly increases the risk of lethal prostate cancer, particularly when the IGF-IR expression remains at normal level.PTEN and IGF-IR expression in tumor are promising candidates for independent prognostic factors to predict lethal prostate cancer.

OBJECTIVES: One-third of patients with positive surgical margins after radical prostatectomy develop recurrent disease. The distinction between pT2 with positive margins and pT3a can be difficult. Aim of the present study was to assess the impact of positive surgical margins on biochemical relapse after radical prostatectomy, adjusted for pathological stage and Gleason score. METHODS: We retrospectively evaluated 837 consecutive patients who underwent radical prostatectomy for organ-confined or locally-advanced prostate cancer. Exclusion criteria were: presence of node or distant metastases, neo-adjuvant or adjuvant therapy, and unavailability of full data regarding pathological stage and margin status. A single dedicated genitourinary pathologist evaluated all the specimens. The Kaplan-Meier method and univariable and multivariable Cox regressions were applied for survival analyses. RESULTS: The median follow up was 54.0 ± 35.0 months. Margin status, prostate-specific antigen and Gleason score significantly predicted biochemical relapse in the pT2 group at multivariable analysis, whereas only pathological stage and pathological Gleason score were significant predictors of recurrence in pT3a patients. There were no significant differences in biochemical disease-free survival among pT2 with positive margins patients and pT3a patients (with or without positive surgical margins). Pathological Gleason score was the only significant predictor of biochemical relapse in patients with negative and positive margins, regardless of the pathological stage. CONCLUSIONS: pT2 patients with positive surgical margins and pT3a (with or without positive margins) seem to have similar biochemical disease-free survival. Positive margins and pathological stage might be insufficient clinical predictors. Gleason score remains the most reliable prognostic factor.

OBJECTIVES: To evaluate the outcomes in patients with node-positive prostate cancer (PCa) after radical prostatectomy (RP) and pelvic lymph node dissection (PLND) according to the number of positive lymph nodes (LNs). To identify different risk groups among patients with node-positive PCa. PATIENTS AND METHODS: We evaluated 98 consecutive patients with pN1M0 PCa who underwent RP between November 1995 and May 2011. Kaplan-Meier and Cox proportional univariable and multivariable regression models were used to analyse the survival rates. Patients were divided into two groups according to number of positive LNs using the most informative positive LN theshold for predicting survival, then into three different risk groups according to number of positive LNs and pathological Gleason score (GS). RESULTS: Mean (range) follow-up was 68.4 (10-192) months. Patients with 1-3 positive LNs (n = 75; 76.5%) had significantly better cancer-specific survival (CSS) and overall survival (OS) compared with those with >3 positive nodes (n = 23; 23.4%; P < 0.01). Patients with 1-3 positive LNs and pathological GS ≤7 (Group 1) had significantly better CSS than those with >3 positive LNs or GS 8-10 (Group 2 [P = 0.015]). Group 2 patients, moreover, had significantly better CSS (P = 0.019) and OS (P = 0.021) than those with >3 positive LNs and GS 8-10 (Group 3). CONCLUSIONS: Patients with 1-3 positive LNs have higher CSS and OS rates than those with >3 metastatic LNs. Taking into account the pathological GS, as well as the number of positive nodes, three risk group categories with considerable differences in terms of survival can be found. Patients with LN-positive PCa should be stratified into different groups according to these two measures, to obtain a better prediction of oncological outcomes.

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in Western countries. Although the aberrant expression of several microRNAs (oncomiRs) is associated with CRC progression, the molecular mechanisms of this phenomenon are still under investigation. Here we show that miR-101 expression is differentially impaired in CRC specimens, depending on tumour grade. miR-101 re-expression suppresses cell growth in 3D, hypoxic survival and invasive potential in CRC cells showing low levels of miR-101. Additionally, we provide molecular evidence of a bidirectional regulatory mechanism between miR-101 expression and important CRC pro-malignant features, such as inflammation, activation of the Wnt/β-catenin signalling pathway and epithelial–mesenchymal transition (EMT). We then propose that up-regulated miR-101 may function as a tumour suppressor in CRC and that its pharmacological restoration might hamper the aggressive ehaviour of CRC in vivo. MiR-101 expression may also represent a cancer biomarker for CRC diagnosis and prognosis.

Detection of nodal micrometastases with serial section, immunoistochemistry and real time polymerase chian reaction in intermediate and high risk prostate cancer patients submitted to radical prostatectomy with extended pelvic lymph node dissection: a perspective study.

The following sections are included: INTRODUCTION EPIDEMIOLOGY AND RISK STRATIFICATION GERMLINE GENETIC VARIATIONS AND PCa SOMATIC EVENTS ALTERED PATHWAYS IN PCa Androgen Receptor (AR) Signaling MYC PTEN/PI3K/AKT/mTOR Pathway LIPOGENESIS AND METABOLIC ALTERATIONS Fatty Acid Synthase (FASN) MOUSE MODELS OF PCa TRansgenic Adenocarcinoma Mouse Prostate (TRAMP) Model Androgen Receptor (AR) Transgenics MYC Transgenics NKX3.1 Knockout p27/PTEN Knockouts AKT Transgenics FASN Transgenics TISSUE BIOMARKERS CONCLUSIONS

Objective: Prostate carcinoma (PCa) is one of the most frequent neoplasms, with more than 110.000 new cases/year in Europe. As PCa is not clearly demonstrable at transrectal ultrasound (TRUS), guidelines on TRUS guided biopsy suggest to perform a random tissue sampling (at least 8-12 “cores” depending on gland volume). Although accuracy grows with core number, patient discomfort and adverse event probability grow as well. Thus it would be worth to aim to reduce the number of prostate biopsy cores without loss of diagnostic accuracy. Materials and Methods: A retrospective study was performed to evaluate the feasibility of an improved version of a rtCAB tool developed at DEIS (University of Bologna) for the reduction of prostate biopsy cores. rtCAB is an innovative processing technique which enhances TRUS video stream by a live false color overlay image that helps the physician to perform the biopsy by guiding the sampling into target zones. In order to train rtCAB, a monocentric, single operator prostate gland adenocarcinoma database has been built. The database enlists 81 patients, for a total of 743 prostate byoptic (PBx) cores and 14860 ROI. For each patient we collected age, PSA levels, digital rectal examination (DRE) findings, presence or absence of focal lesions, and prostate volume. During TRUS, raw ultrasound data were acquired and associated to each PBx core. For each core we collected both the radio frequency (RF) signal and the histological outcome. Results: The whole system was optimized for reducing the number of false positives while preserving an acceptable number of false negatives. Comparing to a classical PBx approach (8-12 cores), the estimated positive predictive value ( PPV) of our method increased from 25% to 40%, with an overall sensitivity of 85%. Conclusions: Preliminary results show that the proposed tool can provide real-time feedback to the operator during TRUS. Sensitivity and PPV values suggest that a reduction of almost 50% the number of biopsy cores without losing in diagnostic accuracy is feasible. A prospective study is needed to further confirm these preliminary retrospective results.

Prostate cancer (PCa) is one of the most frequent neoplasia: it can be accurately detected only by prostate biopsy (PBx) and is not clearly visible at TRUS and other diagnostic methods such as PSA levels. For this reason, guidelines for PCa diagnosis suggest to perform a random tissue sampling when suspects arise from standard diagnostic methods. The sampling procedure is TRUS guided and roughly costs 20€/core, including the cost of the following histological analysis. Even if accuracy grows with cores’ number, costs, patient discomfort and adverse event probability grow as well. It is thus desirable to reduce the number of PBx cores without negative impact on diagnostic accuracy. This work describes the follow-up of a retrospective study aimed to the evaluation of the feasibility of a reduction in cores number through the application of a real time too. The studied technique enhances TRUS video streams with a live false color overlay image. Relative organ to transducer movements are tracked and compensated in order to provide a stable classification map which is useful to guide the physician during tissue sampling. The recorded signal is split into Regions of Interest (ROI) and statistical parameters are estimated with optimized algorithm. Finally, a nonlinear supervised classification model discriminates between PCa risk levels and results are superimposed to the TRUS image. The whole system was optimized for reducing the number of false positives while preserving an acceptable number of false negatives. Motion tracking improved the stability of the classification between frames. The proposed algorithm, thanks to its real-time image processing capabilities, may increase detection rate and could be helpful in finding region where cancer is represented.

Prostate cancer (CaP) represents the most prevalent malignancy in men more than 60-year-old, posing a problem in organ procurement from elderly subjects. However, most of the currently diagnosed CaP are low-grade and intraprostatic, with low metastatic risk, and there is recent evidence that most patients are overdiagnosed. The Italian National guidelines about organ acceptance from neoplastic donors changed in March 2005, extending the pool of potential candidates with CaP and introducing the function of a second opinion expert. Between 2001 and February 2005, 40 candidate donors with total PSA>/=10 and/or positive digital rectal examination underwent histopathological analysis of the prostate: 15 (37.5%) donors harboured CaP, and 25 (62%) were judged at 'standard risk'. After the introduction of the new guidelines in 2005, the second opinion expert judged at 'standard risk' 48 of 65 donors, while 17 of 65 needed histopathological analysis. Four (6.2%) donors harboured CaP, and 61 (94%) where judged at 'standard risk', with a significant increase of donated and actually transplanted organs. The application of the new guidelines and the introduction of a second opinion expert allowed a significant extension of the 'standard risk' category also to CaP patients, decreasing the histopathological examinations and expanding the donor pool.

Histological quality assessment of donated livers is a key factor for extending the cadaveric donor pool for liver transplantation. We retrospectively compared frozen-section analysis with routine histological permanent slides and the outcomes of grafts in liver biopsies from 294 candidate donors. The kappa concordance coefficient of agreement between frozen-section analysis and routine histological analysis was very good for macrosteatosis (kappa = 0.934), microsteatosis (kappa = 0.828), and total steatosis (kappa = 0.814). The correlation between the mean amounts of macrosteatosis, microsteatosis, and total steatosis in frozen and permanent sections was also significant (P < 0.001, Spearman's test). Macrosteatosis and microsteatosis were overestimated to >30% in 4 of 32 cases (12.5%) and in 23 of 62 cases (37.1%), respectively. The only 2 histological parameters of frozen sections able to predict graft dysfunction within 7 days of transplantation were macrosteatosis and total steatosis (P = 0.018 and P = 0.015, respectively, Mann-Whitney test). None of the other histopathological features evaluated in frozen sections, including portal inflammation, lobular necrosis, myointimal thickening, biliocyte regression, cholestasis, hepatocellular polymorphism, lipofuscin storage, and fibrous septa, were significantly correlated with the graft outcome. The frozen-section histological evaluation of biopsies from cadaveric liver donors is an accurate, time-effective, and predictive method for the assessment of graft suitability.

11- C – CHOLINE PET/CT IMAGING FOR LOCALIZATION OF RECURRENT PROSTATE CANCER

VALORE DIAGNOSTICO DEL DNA PLASMATICO LIBERO E DELLE CELLULE TUMORALI CIRCOLANTI: UN AIUTO PER LA PREDIZIONE DEL GRADO ISTOLOGICO DEL CARCINOMA PROSTATICO

TOMOGRAFIA AD EMISSIONE DI POSITRONI CON 11- C-CHOLINA INTEGRATO A UN SISTEMA TC ( 11-C- CHOLINE PET/TC) NELLA DIAGNOSI DI NEOPLASIA PROSTATICA