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An imbalance between cytoproliferation and apoptosis may be relevant in liver carcinogenesis. The aim of this study was to analyse these parameters in patients with chronic liver damage in relation to the aetiology of the disease. Forty-eight patients were studied: 23 had hepatitis C virus (HCV)- and 11 had hepatitis B virus (HBV)-related chronic hepatitis, seven had alcoholic liver disease, and seven had haemochromatosis. The biopsies were used for routine diagnosis, cytoproliferative indexing (MIB1, Ki67 monoclonal antibody), apoptosis (APO, in situ end labelling) and, in part, liver iron and malondialdehyde determination. Apoptosis was similar in all patient subgroups and correlated with hepatitis grading (P = 0.002) and ALT levels (P = 0.004); cytoproliferation (MIB1) levels were higher in HCV patients, both as a whole and in the periportal area (P = 0.02 and P = 0.03). MIB1 correlated with ALT levels (P = 0.0001), hepatitis grading (P = 0.02) and tissue iron (P = 0.04). APO and MIB1 were higher in patients with than in those without cirrhosis (P = 0.0006 and P = 0.03, respectively). APO correlated with MIB1 (P=0.001), overall but not in HCV patients. The MIB1/APO ratio was significantly higher in HCV patients than in the other groups (P = 0.02). In summary, cytoproliferation is more pronounced in chronic HCV-related hepatitis, while APO is not significantly higher than in other types of liver damage, suggesting an imbalance between the two. APO and MIB1 are directly related to the extent of liver damage and, from a biochemical point of view, to tissue iron levels.

AIM: To review benign and malignant paratesticular lesions. MATERIALS AND METHODS: A non-systematic review of the English literature in the National Library of Medicine Database (MEDLINE) was performed using the key words "spermatic cord", "inguinal canal", "neoplasms" (focusing on soft tissue sarcomas). The 74 most significant contributions were selected. RESULTS: Although generally benign (lipoma is the most frequent), paratesticular tumors have a high incidence of malignancy (30%). Ultrasonography, computed tomography and magnetic resonance imaging represent the main tools in the evaluation of a solid paratesticular mass. Most malignant tumors are sarcomas and commonly spread via local invasion to adjacent structures. The definitive diagnosis is made postoperatively. Surgical excision in the form of radical orchiectomy and wide local resection of tumor margins is mandatory and represents the mainstay of treatment options. CONCLUSION: Surgical treatment of paratesticular tumors is fundamental in order to determine the histology so as to define the correct follow-up for each patient.

We have analyzed the composition of the tumor stroma and the expression of cell-matrix and cell-cell adhesion molecules in 11 cases of fibrolamellar carcinoma of the liver (FLC), in comparison with 34 cases of hepatocellular carcinoma and 8 cases of focal nodular hyperplasia. Fibrolamellar carcinoma was characterized by the presence of large amounts of tenascin in tumor stroma and by the scarce expression of basement membrane components at the contact of neoplastic clusters. Like normal hepatocytes, neoplastic cells constantly expressed the alpha1 integrin chain, lacked the beta4 integrin chain, and coexpressed E-cadherin and the hepatocyte N-related cadherin. Abnormalities in the expression of cell adhesion molecules, including altered cadherin expression, alphaV integrin chain induction, and CD44 expression, were detected in the majority of cases. The composition of the tumor stroma and the pattern of expression of cell adhesion molecules in fibrolamellar carcinoma were reminiscent of those observed in grade III and grade IV hepatocellular carcinomas. Our results therefore show that, despite its slow local growth and good prognosis, fibrolamellar carcinoma expresses many characteristics usually associated with clinically aggressive malignancies. Further studies are needed to identify the factors responsible for the apparent dissociation between clinical behavior and biological characteristics in this tumor.

PURPOSE In a randomized clinical trial (European Organization for the Research and Treatment of Cancer [EORTC] no. 40813) on adjuvant chemotherapy in gastric cancer, results obtained after administration of the FAM2 regimen (fluorouracil [5-FU], doxorubicin, and mitomycin) were compared with results obtained after surgery alone to assess the effect of this regimen on overall survival, time to progression, and disease-free interval. PATIENTS AND METHODS Three hundred fourteen patients who had undergone curative resection for stage II or stage III (International Union Against Cancer [UICC] 1978) gastric adenocarcinoma were randomized to receive chemotherapy (treatment arm) or no further treatment (control arm). The chemotherapy schedule was repeated every 43 days for seven cycles. The log-rank test and the Cox model were used for statistical analysis. RESULTS Of 314 patients, 159 comprised the control group and 155 the FAM2 group. Nineteen FAM2 patients never received chemotherapy. The median number of cycles was five. Of the patients started on adjuvant treatment, severe hematologic and nonhematologic toxicity (grades 3 or 4, World Health Organization [WHO] scale) occurred, respectively, in 6% to 9% and in 1% to 29% of cases. The overall 5-year survival rate was 70% for stage II and 32% for stage III patients. No statistically significant difference was found between overall survival of the two treatment arms (P = .295). However, time to progression was significantly delayed in the FAM2 arm (P = .020) and disease-free survival showed borderline significance (P = .068). CONCLUSION FAM2, in view of its high toxicity, cannot be advocated as standard adjuvant treatment for gastric cancer. Large-scale clinical trials using more active, less toxic regimens are required to demonstrate whether adjuvant chemotherapy provides any real benefit.

Several oncogenes involved in prostate carcinogenesis activate mitogen- activated protein (MAP) kinases, which can relay both proliferative (via extracellular regulated kinases (ERK)) and apoptotic signals (via jun N- terminal protein kinases (JNK)) to the nucleus. Mitogen-activated protein kinase phosphatase 1 (MKP-1) is induced by several oncogenes in the ras- dependent pathway and can inactivate both MAP kinase pathways. The role of MKP-1 in proliferation and apoptosis is, however, still controversial. A series of 51 prostate cancers, including a subset (n = 13) that had been previously treated by androgen ablation, was used to examine whether MKP-1 mRNA and protein expression correlated with that of ERK-1, JNK-1, bcl-2, which confers resistance to apoptosis, and apoptotic index measured by in situ end-labeling of fragmented DNA. In a subset of tumors, MKP-1 expression was assessed by semiquantitative RT-PCR and was compared with both ERK-1 and JNK-1 enzymatic activity. In cases not treated by endrogen ablation, MKP-1 was overexpressed in the preinvasive stage of prostate cancer, but its expression decreased with higher histologic grade and advanced disease stage. There was coexpression of MKP-1, ERK-1, and JNK-1 proteins. In addition, MKP- 1 expression was inversely correlated to JNK-1 but not to ERK-1 enzymatic activity. Finally, MKP-1 and bcl-2 were inversely related to apoptotic indices. In cases treated by total androgen ablation, MKP-1 and bcl-2 were both down-regulated, whereas JNK-1 was up-regulated. Subpopulations of cells that did not undergo apoptosis maintained expression of both MKP-1 and bcl- 2. These results suggest that MKP-1 overexpression is associated with the early phases of neoplastic transformation in prostate tissue. The enzymatic data on MKP-1 kinase substrates and the inverse correlation between MKP-1 and parameters of programmed cell death support the hypothesis that MKP-1 inhibits apoptosis in human prostate tumors, perhaps through the JNK pathway.

Undifferentiated (embryonal) sarcoma of the liver is a rare malignant mesenchymal tumor with a poor prognosis. Thirty cases worldwide have been reported over the last 40 years. The absence of specific symptoms, the rapid tumor growth, the normality of the common tumoral markers and the consequential delay in the diagnosis, often allow a significant enlargement of the hepatic mass. Three patients ages 15, 25, and 60 were admitted to our department with such a tumor. In spite of the large dimensions of the neoplasms, all underwent a right hepatectomy without any major surgical complications. Two of them died due to tumor recurrence after 10 and 67 months, respectively. The one case remaining is alive and disease free 62 months postoperatively. The latter one was the only case where a complete tumoral capsule was found in the resected specimen. Surgery is strongly recommended for every case with evidence of a liver-confined tumor even if it is large.

The p27 cyclin-dependent kinase inhibitor is a negative regulator of cell-cycle progression. In many human epithelial malignancies, decreased expression of p27 correlates with high grade, early recurrence, and poor prognosis. To evaluate the prognostic significance of p27 in hepatocellular carcinoma (HCC), we studied 54 HCCs along with corresponding nontumoral tissue. Immunohistochemistry (IHC) and Western blot (WB) analysis before and after immunoprecipitation with Cdk2 were performed on paraffin-embedded tissues and protein homogenates, respectively, to compare localization and expression of the p27 protein and to determine the total and active (Cdk2-bound) fractions of p27. Correlations were analyzed between IHC-assessed levels of p27, survival, and major clinical and pathological variables. IHC revealed no p27 expression in the majority of hepatocytes from normal and cirrhotic liver, whereas 14 HCCs (26%) were high p27 expressers (>50% positive cells), 26 (48%) low expressers (

The expression of the insulin-like growth factor-2 (IGF-2) gene was studied by means of both in situ hybridization and immunohistochemistry in eight cases of Wilms' tumor with different histological features. An anti- sense cRNA IGF-2 probe revealed the presence of abundant IGF-2 mRNAs in all eight tumors examined, localized in the most undifferentiated tumoral cells (blastemal cells): none of the tumors showed immunoreactivity for the anti- IGF-2 antibody. Using a sense cRNA IGF-2 probe, we also detected anti-sense transcripts of the IGF-2 gene in five of eight tumors. These transcripts were exclusively localized in the cells expressing the IGF-2 mRNAs. Although the function of these anti-sense transcripts is unknown, we think that their presence could explain the lack of IGF-2 peptides in Wilms' tumors despite increased expression of IGF-2 mRNAs.

Purpose and Experimental Design: The prognosis for intrahepatic cholangiocarcinoma (ICC) depends mainly on the feasibility of complete surgical resection. In the absence of demonstrated biological predictors of survival, we evaluated the prognostic value of the cyclin-dependent kinase inhibitor p27 by immunohistochemistry in a series of routine specimens from 47 ICC patients, 22 with the hilar and 25 with the peripheral subtype. Proliferation rate was also evaluated in the same cases by the MIB1 index. Tumors were scored as high, low, and negative p27 expressers (≥50%

Background: Surgery is the primary treatment for patients with stage I, II, or IIIA non-small-cell lung cancer (NSCLC). However, long-term survival of NSCLC patients after surgery alone is largely unsatisfactory, and the role of adjuvant chemotherapy in patient survival has not yet been established. Methods: Between January 1994 and January 1999, 1209 patients with stage I, II, or IIIA NSCLC were randomly assigned to receive mitomycin C (8 mg/m 2 on day 1), vindesine (3 mg/m 2 on days 1 and 8), and cisplatin (100 mg/m 2 on day 1) every 3 weeks for three cycles (MVP group; n = 606) or no treatment (control group; n = 603) after complete resection. Randomization was stratified by investigational center, tumor size, lymph-node involvement, and the intention to perform radiotherapy. The primary endpoint was overall survival and secondary endpoints were progression-free survival and toxicity associated with adjuvant treatment. Survival curves were analyzed using the log-rank test. All statistical tests were two-sided. Results: After a median follow-up time of 64.5 months, there was no statistically significant difference between the two patient groups in overall survival (hazard ratio = 0.96, 95% confidence interval = 0.81 to 1.13; P = .589) or progression-free survival (hazard ratio = 0.89, 95% confidence interval = 0.76 to 1.03; P = .128). Only 69% of patients received the three planned cycles of MVP. Grades 3 and 4 neutropenia occurred in 16% and 12%, respectively, of patients in the MVP arm. Radiotherapy was completed by 65% of patients in the MVP arm and by 82% of patients in the control group. In the multivariable analysis, only disease stage and sex were associated with survival. Conclusion: This randomized trial failed to prospectively confirm a statistically significant role for adjuvant chemotherapy in completely resected NSCLC. Given the poor compliance with the MVP regimen used in this study, future studies should explore more effective treatments.

Aims: To investigate the morphological and molecular characteristics of Leydig cell tumours (LCTs) of the testis for the identification of cases that may metastasise. Methods and results: Six parameters for a predictive model of the metastatic risk were evaluated in 37 benign and 14 malignant LCTs of the testis [LCT Scaled Score (LeSS)]. The tumour size (benign LCTs, mean 13.3mm; malignant LCTs, mean 44mm) (P&nbsp

The healthy prostate is a relatively quiescent tissue. Yet, prostate epithelium overgrowth is a common condition during aging, associated with urinary dysfunction and tumorigenesis. For over thirty years, TGF-β ligands have been known to induce cytostasis in a variety of epithelia, but the intracellular pathway mediating this signal in the prostate, and its relevance for quiescence, have remained elusive. Here, using mouse prostate organoids to model epithelial progenitors, we find that intra-epithelial non-canonical Activin A signaling inhibits cell proliferation in a Smad-independent manner. Mechanistically, Activin A triggers Tak1 and p38 ΜAPK activity, leading to p16 and p21 nuclear import. Spontaneous evasion from this quiescent state occurs upon prolonged culture, due to reduced Activin A secretion, a condition associated with DNA replication stress and aneuploidy. Organoids capable to escape quiescence in vitro are also able to implant with increased frequency into immunocompetent mice. This study demonstrates that non-canonical Activin A signaling safeguards epithelial quiescence in the healthy prostate, with potential implications for the understanding of cancer initiation, and the development of therapies targeting quiescent tumor progenitors.

PURPOSE: Nonpalpable tumors of the testis are generally incidental findings on ultrasound examination. Most of these tumors are benign but some turn out to be germinal tumors at histology. Therefore, intraoperative histopathologic analysis of nonpalpable testicular lesions is pivotal for guiding a testis-sparing surgical approach. METHODS: We report clinical and pathologic characteristics of 3 small nodules of the testis with challenging histologic features at intraoperative frozen section examination and peculiar histology. One was a known testicular mass, undertreated for 5 years, whose enlargement worried the patient, while the other 2 were incidental findings during clinical testicular examination for non-neoplastic diseases. CONCLUSIONS: The 3 cases reported are characterized by small size, which limited the accuracy of preoperative ultrasound diagnosis. Intraoperative frozen section examination was able to rule out a diagnosis of germ cell malignancy in all cases, but diagnosis was conclusive only at histology. Knowledge of unexpected rare testicular lesions is of great relevance at the time of frozen section examination in view of conservative surgical strategy.v Nonpalpable tumors of the testis are generally incidental findings on ultrasound examination. Most of these tumors are benign but some turn out to be germinal tumors at histology. Therefore, intraoperative histopathologic analysis of nonpalpable testicular lesions is pivotal for guiding a testis-sparing surgical approach. METHODS: We report clinical and pathologic characteristics of 3 small nodules of the testis with challenging histologic features at intraoperative frozen section examination and peculiar histology. One was a known testicular mass, undertreated for 5 years, whose enlargement worried the patient, while the other 2 were incidental findings during clinical testicular examination for non-neoplastic diseases. CONCLUSIONS: The 3 cases reported are characterized by small size, which limited the accuracy of preoperative ultrasound diagnosis. Intraoperative frozen section examination was able to rule out a diagnosis of germ cell malignancy in all cases, but diagnosis was conclusive only at histology. Knowledge of unexpected rare testicular lesions is of great relevance at the time of frozen section examination in view of conservative surgical strategy.

Background: Circulating tumor cells (CTCs) are a promising source of biological information in cancer. Data correlating PD-L1 expression in CTCs with patients’ response to immune checkpoint inhibitors (ICIs) in non–small-cell lung cancer (NSCLC) are still lacking. Methods: This is a prospective single-center cohort study enrolling patients with advanced NSCLC. CTCs were identified and counted with the CellSearch system. PD-L1 expression on CTCs was assessed with phycoerythrin-conjugated anti-human PD-L1 antibody, clone MIH3 (BioLegend, USA). Primary endpoint was the correlation between the CTCs PD-L1 expression and overall survival (OS). Among secondary objectives, we evaluated the correlation between PD-L1 expression on CTCs and matched tumor tissue and the correlation of CTC number and baseline tumor size (BTS). Results: Thirty-nine patients treated with anti-PD-1/PD-L1 agents as second- or third-line therapy were enrolled. Patients were divided into 3 groups: no CTC detectable (CTCnull, n = 15), PD-L1 positive CTC (CTCpos, n = 13), and PD-L1 negative CTC (CTCneg, n = 11). Median OS in patients with CTCneg was 2.2 months, 95% confidence interval (CI), 0.8-3.6 (reference) versus 3.7 months, 95% CI, 0.1-7.5 (hazard ratio [HR] 0.33; 95% CI, 0.13-0.83; P = .019) in patients with CTCpos versus 16.0 months, 95% CI, 2.2-29.8 (HR 0.17; 95% CI, 0.06-0.45; P< .001) in patients with CTCnull. No correlation was found between PD-L1 expression on CTCs and on tumor tissue. CTC number was correlated with BTS. Conclusion: PD-L1 expression on CTCs is a promising biomarker in patients with NSCLC treated with ICIs. Further validation as predictive biomarker is needed.

Peripheral extracorporeal membrane oxygenation (ECMO) setting remains a valid option to treat cardiogenic shock (CS). We investigated a percutaneous approach to unload the left ventricle (LV) while on veno-arterial (v-a) peripheral ECMO support. Between 2017 and 2018, eight patients (three females, mean age: 49.6 years old, and five males, mean age: 58 years old, respectively) suffered refractory CS due to acute myocardial infarction (n = 4), acute myocarditis (n = 2), acute decompensation on chronic heart failure (n = 1), and primary graft failure after heart transplantation (Htx) (n = 1), respectively. After a multidisciplinary CS team discussion, it was decided to proceed with peripheral v-a ECMO placement and percutaneous LV venting via right internal jugular vein access to drain the pulmonary artery (PA), in the hybrid operating room. In a single postcardiotomy case, the PA trunk was vented centrally. Mean ECMO support time was 8.5 days. Seven (87.5%) patients were successfully weaned from ECMO and one (12.5%) successfully bridged to Htx. All patients were successfully discharged after treatment except for a single case who died due to sepsis. In case of not recommended usage of LV apical venting, the adoption of v-a peripheral ECMO support associated with percutaneous PA drainage enables the rapid onset of extracorporeal life support with an effective biventricular unloading.

Differentiation between penile squamous cell carcinoma patients who can benefit from limited organ-sparing surgery and those at significant risk of lymph node metastasis is based on histopathological prognostic factors including histological grade and tumor histological subtype. We examined levels of interobserver and intraobserver agreement in assessment of histological subtype and grade in 207 patients with penile squamous cell carcinoma. The cases were assessed by seven pathologists from three hospitals located in Sweden and Italy. There was poor to moderate concordance in assessing both histological subtype and grade, with Fleiss kappas of 0.25 (range: 0.02–0.48) and 0.23 (range: 0.07–0.55), respectively. When choosing HPV-associated and non-HPV-associated subtypes, interobserver concordance ranged from poor to good, with a Fleiss kappa value of 0.36 (range: 0.02–0.79). A re-review of the slides by two of the pathologists showed very good intraobserver concordance in assessing histological grade and subtype, with Cohen’s kappa values of 0.94 and 0.91 for grade and 0.95 and 0.84 for subtype. Low interobserver concordance could lead to undertreatment and overtreatment of many patients with penile cancer, and brings into question the utility of tumor histological subtype and tumor grade in determining patient treatment in pT1 tumors.

In the past few years several hormonal agents have been tested in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) leading to an impressive improvement in terms of metastases-free survival (MFS). We performed a meta-analysis aimed to: (1) estimate the pooled effect of new hormonal compounds in terms of MFS, overall survival (OS) in overall and specific subpopulations; and (2) estimate the effect of high-grade toxicities of these drugs. We identified 881 studies published between January 1, 2010 and February 16, 2018 on PubMed/Medline, Cochrane Library, and Scopus. Three randomized placebo controlled clinical trials were selected (PROSPER, SPARTAN, and ARAMIS). Because of the absence of individual data, all of the analyses performed were made on aggregated data provided in selected studies. We used the inverse variance technique for the meta-analysis of the hazard ratios collected for MFS and OS analysis. Fixed and randomized models were used. Relative risk and 95% confidence intervals and risk difference were estimated considering the number of Grade 3 adverse events in treatment and control arms. Administration of new hormonal compounds in nmCRPC patients led to a significant benefit in MFS in the overall population and in all subgroups analyzed. These agents might also improve OS but longer follow-up is needed to confirm this hypothesis. Indeed results of OS analysis should be carefully evaluated because none of the studies selected provided mature OS data. Administration of these agents resulted in a significant increased risk of treatment-related death, high cardiovascular toxicity, hypertension, fractures, and falls. Administration of new hormonal compounds prolongs the time of metastases occurrence and might prolong also survival in patients with nmCRPC. Treatment-related toxicity is an important issue because these agents increase the risk of death, cardiovascular toxicity, hypertension, fractures, and risk of falls.

Introduction Few data are available regarding the trend of IgA anti-transglutaminase antibodies (TGA-IgA) in children with celiac disease (CD) on a gluten-free diet (GFD). Our aim is to examine the normalization time of CD serology in a large pediatric population, and its predictors. Material and methods We retrospectively evaluated the normalization time of TGA-IgA and its predictive factors (age, sex, ethnicity, symptoms, associated diabetes/thyroiditis, Marsh stage, TGA-IgA and endomysial antibody levels at diagnosis, diet adherence), in 1024 children diagnosed from 2000 to 2019 in three pediatric Italian centers, on a GFD. Results TGA-IgA remission was reached in 67,3%, 80,7%, 89,8% and 94,9% after 12, 18, 24 and 36 months from starting a GFD, respectively (median time = 9 months). TGA-IgA >10´upper limit of normal at diagnosis (HR = 0.56), age 7–12 years old (HR = 0.83), poor compliance to diet (HR = 0.69), female sex (HR = 0.82), non-Caucasian ethnicity (HR = 0.75), and comorbidities (HR = 0.72) were independent factors significantly associated with longer time to normalization. Conclusions Our population is the largest in the literature, with the majority of patients normalizing CD serology within 24 months from starting a GFD. We suggest a special attention to patients with comorbidities, language barriers or age 7–12 years for a proper management and follow-up.

Background In recent years, HER2 amplification has been evaluated as a potential prognostic biomarker and therapeutic target in urothelial carcinoma (UC). In this retrospective study, we aimed at exploring the prognostic role of HER2 amplification in UC, measured by chromogenic in situ hybridization (CISH). Methods We retrospectively evaluated the presence of HER2 amplification by using CISH in 31 UC patients followed at a single institution between 2018 and 2020. The primary objective was to assess the frequency of HER2 amplification and to compare clinical outcomes of HER2-amplified patients with non-amplified UCs. Results HER2 amplification was identified in 4 out of 31 patients (12.9 %). After a median follow-up of 28.1 months (95 % Confidence Intervals [CI] 11.2–45.1), median overall survival (OS) in the whole population was 10.9 months (95 % CI 3.5–22.1). Despite not reaching statistical significance, median OS was shorter in HER2-amplified patients (6.8 months, 95 % CI 3.9–9.7) compared to HER2-negative UCs (15.4 months, 95 % CI 7.5–23.3) (p = 0.45). Conclusions Although limited by the small sample size, the results of our study suggest that HER2 amplifications by CISH could represent a prognostic factor for shorter survival in UC patients.

OBJECTIVES A heart transplant (Htx) remains the gold standard treatment for patients with advanced heart failure. Considering the limited availability of organs, donor risk scores might improve organ selection and allocation. The objective of the study was to compare United Network for Organ Sharing, RADIAL and Eurotransplant scoring models in calculating post-Htx outcomes in an Italian Htx population. METHODS Between January 2000 and December 2017, a total of 461 adult patients underwent Htxs. United Network for Organ Sharing, RADIAL and Eurotransplant scores were calculated. Clinical features and donor risk scores were tested to identify preoperative, intraoperative and postoperative risk variables and eventually validate the scores on our population. RESULTS Early graft failure was detected in 16.1% (74/461). Post-Htx extracorporeal life support was used in 11.1% (51/461). Of the donor-related factors, the use of noradrenaline (P = 0.015) negatively influenced early outcomes, whereas an ischaemic time >240 min (P = 0.037) influenced early graft failure occurrence. The Eurotransplant donor score did not impact outcomes; the RADIAL score significantly influenced both early and late mortality; and the United Network for Organ Sharing score influenced only late mortality. On the multivariable analysis, after adjustment of scores per cohort, noradrenaline infusion was the main independent predictor of in-hospital mortality for the donors, whereas age of the recipient [odds ratio (OR) 1.003, 1.003–1.081; P = 0.032] and use of preoperative extracorporeal membrane oxygenation (OR 3.320, 1.124–9.805; P = 0.030) were the main independent predictors for the recipients. CONCLUSIONS None of the validated donor scoring systems fully behave as reliable predictors of transplant outcomes. According to our ‘local only’ graft selection, specific donor and recipient risk variables should be monitored in order to predict early and late outcomes satisfactorily.

BACKGROUND: We aimed to assess the detection rate of overall PCa and csPCa, and the clinical impact of MRI/TRUS fusion targeted biopsy (FUSION-TB) compared to TRUS guided systematic biopsy (SB) in patients with different biopsy settings. METHODS: Three hundred and five patients were submitted to FUSION-TB, divided into three groups: biopsy naïve patients, previous negative biopsies and patients under active surveillance (AS). All patients had a single suspicious index lesion at mpMRI. Within these groups, we enrolled men underwent both to FUSION-TB and SB in the same session. Overall detection rate of PCa and csPCa for the two biopsy methods were compared separately between the three groups of patients. RESULTS: No differences were observed between the three groups concerning clinical and radiological characteristics. We found no differences in terms of overall PCa detection (66% vs. 63.8%, P=0.617) and csPCa detection (56.4% vs. 51.1%; P=0.225) concerning biopsy naïve patients. In patients previously submitted to a negative biopsy, FUSION-TB showed higher detection rate of csPCa compared to SB alone (41,3% vs. 27% respectively, P=0.038). In patients under AS, no differences were observed between FUSION-TB and SB in terms of overall PCa (50% vs. 73.1%) and csPCa (30.8% vs. 26.9%, respectively; P=0.705) detection. CONCLUSIONS: Our results suggest that in men with previously negative biopsy, FUSION-TB showed significantly higher diagnostic performance for clinically significant PCa as compared to SB. Combination of FUSION-TB and SB should be recommended in AS population to offer higher chance of csPCa diagnosis.

Tissue microarrays (TMAs) have been used in thousands of cancer biomarker studies. To what extent batch effects, measurement error in biomarker levels between slides, affects TMA-based studies has not been assessed systematically. We evaluated 20 protein biomarkers on 14 TMAs with prospectively collected tumor tissue from 1448 primary prostate cancers. In half of the biomarkers, more than 10% of biomarker variance was attributable to between-TMA differences (range, 1-48%). We implemented different methods to mitigate batch effects (R packageTo understand cancer, researchers need to know which molecules tumor cells use. These so-called ‘biomarkers’ tag cancer cells as being different from healthy cells, and can be used to predict how aggressive a tumor may be, or how well it might respond to treatment. A popular technique for assessing biomarkers across multiple tumors is to use tissue microarrays. This involves taking samples from different tumors and embedding them in a block of wax, which is then cut into micro-thin slices and stained with reagents that can detect specific biomarkers, such as proteins. Each block contains hundreds of samples, which all experience the same conditions. So, any patterns detected in the staining are likely to represent real variations in the biomarkers present. Many cancer studies, however, often compare samples from multiple tissue microarrays, which may increase the risk of technical artifacts: for example, staining may look stronger in one batch of tissue samples than another, even though the amount of biomarker present in these different arrays is roughly the same. These ‘batch effects’ could potentially bias the results of the experiment and lead to the identification of misleading patterns. To evaluate how batch effects impact tissue microarray studies, Stopsack et al. examined 14 wax blocks which contained tumor samples from 1,448 men with prostate cancer. This revealed that for some biomarkers, but not others, there were noticeable differences between tissue microarrays that were clearly the result of batch effects. Stopsack et al. then tested six different ways of fixing these discrepancies using statistical methods. All six approaches were successful, even if the arrays included tumors with different characteristics, such as tumors that had been diagnosed more or less recently. This work highlights the importance of considering batch effects when using tissue microarrays to study cancer. Stopsack et al. have used their statistical approaches to develop freely available software which can reduce the biases that sometimes arise from these technical artifacts. This could help researchers avoid misleading patterns in their data and make it easier to detect real variations in the biomarkers present between tumor samples.

Purpose: To assess the role of the multiparametric Magnetic Resonance Imaging (mpMRI) in predicting the cribriform pattern in both the peripheral and transition zones (PZ and TZ) clinically significant prostate cancers (csPCas). Material and methods: We retrospectively evaluated 150 patients who underwent radical prostatectomy for csPCa and preoperative mpMRI. Patients with negative (n = 25) and positive (n = 125) mpMRI, stratified according to the presence of prevalent cribriform pattern (PCP, ≥ 50%) and non-PCP (< 50%) at specimen, were included. Difference between the two groups were evaluated. Multivariate logistic regression was used to identify predictors of PCP among mpMRI parameters. The receiver operating characteristic (ROC) analysis was performed to evaluate the area under the curve (AUC) of apparent diffusion coefficient (ADC) and ADC ratio in detecting lesions harboring PCP. Results: Considering 135 positive lesions at the mpMRI, 30 (22.2%) and 105 (77.8%) harbored PCP and non-PCP PCa. The PCP lesions had more frequently nodular morphology (83.3% vs 62.9%; p = 0.04) and significantly lower mean ADC value (0.87 ± 0.16 vs 0.95 ± 0.18; p = 0.03) and ADC ratio (0.52 ± 0.09 vs 0.60 ± 0.14; p = 0.003) when compared with non-PCP lesions. At univariate and multivariate analyses, mean ADC and ADC ratio resulted as independent predictors of the presence of the PCP of the PZ tumors(OR: 0.025; p = 0.03 and OR: 0.001; p = 0.004, respectively). At the ROC analysis, the AUC of mean ADC and ADC ratio to predict the presence of PCP in patients with PZ suspicious lesion at the mpMRI were 0.69 (95% CI 0.56–0.81P, p = 0.003) and 0.72 (95% CI 0.62–0.82P, p = 0.001), respectively. Conclusions: The mpMRI may correctly identify PCP tumors of the PZ and the mean ADC value and ADC ratio can predict the presence of the cribriform pattern in the PCa.

Background: We aim to evaluate the impact of multiparametric magnetic resonance imaging and fusion-target biopsy for early reclassification of patients with low-risk Prostate Cancer in a randomized trial. Materials and methods: Between 2015 and 2018, patients diagnosed with Prostate Cancer after random biopsy fulfilling PRIAS criteria were enrolled and centrally randomized (1:1 ratio) to study group or control group. Patients randomized to study group underwent multiparametric magnetic resonance imaging at 3 months from enrollment: patients with positive findings (PIRADS-v2>2) underwent fusion-target biopsy; patients with negative multiparametric magnetic resonance imaging or confirmed ISUP - Grade Group 1 at fusion-target biopsy were managed according to PRIAS schedule and 12-core random biopsy was performed at 12 months. Patients in control group underwent PRIAS protocol, including a confirmatory 12-core random biopsy at 12 months. Primary endpoint was a reduction of reclassification rate at 12-month random biopsy in study group at least 20% less than controls. Reclassification was defined as biopsy ISUP Grade Group 1 in >2 biopsy cores or disease upgrading. Results: A total of 124 patients were randomized to study group (n = 62) or control group (n = 62). Around 21 of 62 patients (34%) in study group had a positive multiparametric magnetic resonance imaging, and underwent fusion-target biopsy, with 11 (17.7%) reclassifications. Considering the intention-to-treat population, reclassification rate at 12-month random biopsy was 6.5% for study group and 29% for control group, respectively (P < 0.001). Conclusions: The early employment of multiparametric magnetic resonance imaging for active surveillance patients enrolled after random biopsy consents to significantly reduce reclassifications at 12-month random biopsy.

Background The Androgen Receptor Splice Variant 7 (AR-V7) has been associated with poor clinical outcomes in patients with castration-resistant prostate cancer (CRPC). Herein, we performed a meta-analysis aimed at systematically exploring the association between metastatic sites and AR-V7 expression in CRPC patients across prospective clinical trials. Methods We retrieved all the relevant prospective clinical trials through PubMed/Medline, Cochrane library, and EMBASE; additionally, proceedings of the main international oncological meetings were also searched for relevant abstracts. Outcomes of interest included metastatic sites (lymph node metastases, any site metastases, visceral metastases, and bone metastases) in AR-V7 positive and AR-V7 negative CRPC patients. Odds Ratios (ORs) and 95 % confidence intervals (CI) were calculated. Results Overall, 14 eligible prospective studies involving a total of 1944 CRPC patients (AR-V7 positive: 467; AR-V7 negative: 1477) were included in the analysis. According to our results, no differences between AR-V7 positive and AR-V7 negative CRPC patients were observed in terms of lymph node (OR 1.01; 95 % CI 0.49–2.09) and visceral metastases (OR 1.23; 95 % CI 0.89–1.71). Conversely, AR-V7 positive CRPC patients presented higher rate of any site metastases (OR 2.22; 95 % CI 1.58–3.12) and bone metastases (OR 2.03; 95 % CI 1.42–2.9) compared to AR-V7 negative subjects. Conclusions The results of this meta-analysis, the first in literature to be specifically focused on this topic so far, suggest that AR-V7 positivity may be associated with any site metastases and bone metastases; conversely, no association has been highlighted between AR-V7 expression and lymph node or visceral metastases. Although this meta-analysis should be interpreted with caution due to some limitations, our findings confirm that AR-V7 status could designate a unique and peculiar subtype of PC. Further studies aimed at improving and standardizing AR-V7 detection in clinical trials on CRPC patients are warranted.

Purpose: To define the value of clinical and radiological data, using multiparametric magnetic resonance imaging (mpMRI), to predict prostate cancer (PCa) in prostate imaging reporting and data system version 2.1 (PIRADSv2.1) 3 lesions of the peripheral and the transition zones (PZ and TZ). Methods: The mpMRI of patients with PIRADSv2.1 3 lesions who had undergone fusion targeted biopsy was reviewed. Morphological pattern, diffusion parameters and vascularisation were evaluated. The radiological/histopathological data of benign and malignant lesions, between the PZ and TZ were compared. Univariate and multivariate analyses were carried out to identify the clinical and radiological data capable of predicting PCa. Results: One hundred and twenty-three lesions were assessed, 93 (76%) in the PZ and 30 (24%) in the TZ. Of these, 56 (46%) were PCa and 67 (54%) were benign. The majority of the PCas were Grade Group System (GGS) 1 (38%) and GGS 2 (39%); tumours having a GGS ≥ 3 were more frequently in the TZ (p = 0.02). Univariate analysis showed a significant correlation between PCa and prostate volume, prostate-specific antigen (PSA) density, lesion zone and the apparent diffusion coefficient. At multivariate logistic regression PSA density > 0.15ng/ml/ml {Odds ratio [OR] 2.38; p = 0.001} and lesion zone (i.e. TZ OR 7.55) were independent predictors of PCa (all p ≤ 0.04). Conclusion: In solitary PIRADSv2.1 3 lesions, the most important predictive factor was the location zone, with a much greater risk for TZ lesions.

DNA repair genes are commonly altered in metastatic prostate cancer, but BRCA1 mutations are rare. Preliminary studies suggest that higher tumor expression of the BRCA1 protein may be associated with worse prognosis. We undertook a prospective study among men with prostate cancer in the Health Professionals Follow-up Study and evaluated BRCA1 via immunohistochemical staining on tissue microarrays. BRCA1 was expressed in 60 of 589 tumors. Prevalence of BRCA1 positivity was 43% in the 14 men with metastases at diagnosis compared with 9% in non-metastatic tumors [difference, 33 percentage points; 95% confidence interval (CI), 7–59]. BRCA1-positive tumors had 2.16-fold higher Ki-67 proliferative indices (95% CI, 1.18–3.95), higher tumor aneuploidy as predicted from whole-transcriptome profiling, and higher Gleason scores. Among the 575 patients with non-metastatic disease at diagnosis, we evaluated the association between BRCA1 expression and development of lethal disease (metastasis or cancer-specific death, 69 events) during long-term follow-up (median, 18.3 years). A potential weak association of BRCA1 positivity with lethal disease (hazard ratio, 1.61; 95% CI, 0.82–3.15) was attenuated when adjusting for age, Gleason score and clinical stage (hazard ratio, 1.11; 95% CI, 0.54–2.29). In summary, BRCA1 protein expression is a feature of more proliferative and more aneuploid prostate tumors and is more common in metastatic disease. While not well suited as a prognostic biomarker in primary prostate cancer, BRCA1 protein expression may be most relevant in advanced disease.

Background: Augmented reality (AR) is a novel technology adopted in prostatic surgery. Objective: To evaluate the impact of a 3D model with AR (AR-3D model), to guide nerve sparing (NS) during robot-assisted radical prostatectomy (RARP), on surgical planning. Design, Setting, and Participants: Twenty-six consecutive patients with diagnosis of prostate cancer (PCa) and multiparametric magnetic resonance imaging (mpMRI) results available were scheduled for AR-3D NS RARP. Intervention: Segmentation of mpMRI and creation of 3D virtual models were achieved. To develop AR guidance, the surgical DaVinci video stream was sent to an AR-dedicated personal computer, and the 3D virtual model was superimposed and manipulated in real time on the robotic console. Outcome measurements and statistical analysis: The concordance of localisation of the index lesion between the 3D model and the pathological specimen was evaluated using a prostate map of 32 specific areas. A preliminary surgical plan to determinate the extent of the NS approach was recorded based on mpMRI. The final surgical plan was reassessed during surgery by implementation of the AR-3D model guidance. Results and limitations: The positive surgical margin (PSM) rate was 15.4% in the overall patient population; three patients (11.5%) had PSMs at the level of the index lesion. AR-3D technology changed the NS surgical plan in 38.5% of men on patient-based and in 34.6% of sides on side-based analysis, resulting in overall appropriateness of 94.4%. The 3D model revealed 70%, 100%, and 92% of sensitivity, specificity, and accuracy, respectively, at the 32-area map analysis. Conclusions: AR-3D guided surgery is useful for improving the real-time identification of the index lesion and allows changing of the NS approach in approximately one out of three cases, with overall appropriateness of 94.4%. Patient summary: Augmented reality three-dimensional guided robot-assisted radical prostatectomy allows identification of the index prostate cancer during surgery, to tailor the surgical dissection to the index lesion and to change the extent of nerve-sparing dissection. Augmented reality three-dimensional (3D) guided robotic prostatectomy is feasible to improve the real-time identification of index prostate cancer and to modulate the nerve-sparing approach targeted to the index lesion. Augmented reality 3D models revealed good concordance with the whole-mount pathology.

BACKGROUND: To develop a clinical nomogram aimed to predict the achievement of trifecta in patients treated with open, laparoscopic and robotic partial nephrectomy (PN) for localized renal masses ( < cT2). METHODS: We retrospectively evaluated 482 consecutive patients who underwent PN with open (OPN: 243), laparoscopic (LPN: 156) and robotic (RAPN: 83) approach for T1 renal mass at single tertiary center. Trifecta was defined as follows: warm ischemia time (WIT)

Background: The occurrence of early graft failure (EGF) after heart transplantation (Htx) often requires a mechanical circulatory support (MCS) therapy. The aims of our study were to identify risk factors of mechanically supported severe EGF and evaluate their impact on both early and late outcomes. Methods: Between January 2000 and December 2019, 499 consecutive adult patients underwent Htx at our institution. Severe EGF was defined as the need for extracorporeal life support (ECLS) within 24 hours after surgery. All available recipient and donor variables were retrospectively analyzed. Results: Overall, EGF occurred in 58 (11.6%) patients. Post-Htx peripheral or central ECLS was necessary in 32 (6.4%) cases. Independent predictors of severe EGF were, in the recipient group, preoperative transpulmonary gradient (TPG) >12 mm Hg (odds ratio [OR] 4.1, P =. 013), preoperative inotropic score >10 (OR 7.3, P =. 0001), and pre-Htx ECLS support (OR 5.2, P =. 015), while in the donors, a Eurotransplant donor score ≥17 (OR 8.5, P =. 005). The absence of EGF was related with a better survival at 1 year and 5 years (94% and 85%, respectively) compared with EGF requiring ECLS population (36% and 28% at 1 year and 5 years, respectively; P

Background HER2 is a potential target of therapy in urothelial cancer (UC). Pathological case stratification according to HER2 gene amplification or HER2 protein overexpression was critical for patients’ selection in previous unsuccessful clinical trial with HER2 targeting agents. Study design We evaluated the HER2 overexpression by immunohistochemistry (IHC) together with the amplification of the HER2 gene with chromogenic(CISH) and fluorescent (FISH) in situ hybridization in a cohort of 61 patients covering the whole spectrum of bladder UC variants, using a tissue microarray (TMA) approach. Results IHC was available in all the 61 cases while ISH in 37 and FISH in 42. At IHC, 2/61 cases (3%) were scored 3+; 2 (3%) scored 2+; 2 (3%) scored 1+; the remaining 55 (91%) scored 0. At CISH analysis 10/37 cases (27%) were amplified, 6 cases with HER2 amplification showed positive HER2 IHC (3+, 2+, 1+). Seven cases with IHC score 0 were amplified at CISH. FISH analysis revealed an amplification in 5/42 cases (12%). The total number of HER2amplified cases was different between chromogenic and fluorescent ISH with 5 cases amplified using FISH compared to 10 with CISH. Conclusions In clinical trials with HER2 targeting agents the candidate patients should be investigated not only by IHC but also by ISH, independently of the IHC results. Since also usual type UC can overexpress HER2 we recommend to extend the patients’ selection to all the histotypes of bladder cancer other than the micropapillary type.

Background: Primary soft tissue sarcomas arising from the male urinary and genital tract are rare tumors, only accounting for 1% to 2% of all malignancies of the genitourinary tract. Clinical management of advanced disease is lacking in standardized recommendations due to the rarity of the disease. To date, complete and extensive surgery represents the only curative and standardized approach for localized disease, while the impact of retroperitoneal lymphadenectomy and adjuvant treatments on clinical outcomes are still unclear. Similarly, a standardized systemic treatment for advanced metastatic disease is still missing. Cases Presentation: Four out of 274 patients have been identified in our sarcoma population. The mean age was 54 years (range = 45-73). The histotypes showed liposarcoma in 2 cases and leiomyosarcoma in the remaining 2 cases. In all 4 cases, the disease was localized at presentation, patients underwent complete surgery, and no adjuvant treatments were done. Three cases presented a recurrence of disease at a mean follow-up of 86 months (range = 60-106 months), more than 7 years. Two cases were treated with a second surgery and chemotherapy and 1 case only with chemotherapy. Discussion and Conclusions: Sharing data about clinical management of paratesticular mesenchymal tumors is a key issue due to the rarity of this tumor’s subtype. In this article, we report the clinical history of 4 patients affected by paratesticular mesenchymal tumor. In particular, main issues of interest are the decision of postoperative treatment and systemic treatment at time of disease recurrence.

In the last decade, immunotherapy has revolutionized the treatment landscape of several hematological and solid malignancies, reporting unprecedented response rates. Unfortunately, this is not the case for metastatic castration-resistant prostate cancer (mCRPC), as several phase I and II trials assessing programmed death receptor 1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors have shown limited benefits. Moreover, despite sipuleucel-T representing the only cancer vaccine approved by the Food and Drug Administration (FDA) for mCRPC following the results of the IMPACT trial, the use of this agent is relatively limited in everyday clinical practice. The identification of specific histological and molecular biomarkers that could predict response to immunotherapy represents one of the current challenges, with an aim to detect subgroups of mCRPC patients who may benefit from immune checkpoint monoclonal antibodies as monotherapy or in combination with other anticancer agents. Several unanswered questions remain, including the following: is there—or will there ever be—a role for immunotherapy in prostate cancer? In this review, we aim at underlining the failures and promises of immunotherapy in prostate cancer, summarizing the current state of art regarding cancer vaccines and immune checkpoint monoclonal antibodies, and discussing future research directions in this immunologically “cold” malignancy.

Programmed death ligand 1 (PD-L1) is a protein which, when interacting with its receptor programmed death 1, acts as a negative regulator of the antitumor T-cell-mediated immune response. The prognostic value of PD-L1 expression in renal cell carcinoma (RCC) has been controversial. In this study, the prognostic value of PD-L1 expression in RCC was evaluated by analyzing PD-L1 immunoreactivity in tumor cells and tumor-infiltrating immune cells (TIICs) in 346 RCC patients with long-term follow-up. PD-L1 positivity in tumor cells was associated with higher World Health Organization nucleolar grade (P

Background It has been hypothesized that M2 macrophages and regulatory T cells (Tregs) may contribute to tumor progression by suppression of antitumor immunity. Objective To investigate the association between infiltration of CD163+ M2 macrophages and CD4+FOXP3+ Tregs with clinical outcomes in renal cell carcinoma patients. Design, setting, and participants A cohort of 346 patients diagnosed with renal cell carcinoma at Örebro University Hospital between 1986 and 2011 was evaluated for CD163+ M2 macrophage and CD4+FOXP3+ Treg infiltration by immunohistochemistry. Outcome measurements and statistical analysis Associations between clinicopathological features and infiltration of CD163+ M2 macrophages and/or CD4+FOXP3+ Tregs were estimated with chi-square or Fisher's exact tests. For survival analyses, Kaplan-Meier curves with log-rank tests and multivariate Cox proportional hazards regression models were used. Results and limitations We found that infiltration of CD163+ M2 macrophages and CD4+FOXP3+ Tregs were associated with adverse clinical outcomes. Our data further demonstrate that CD163+ M2 macrophages and CD4+FOXP3+ Tregs colocalize in tumor and normal tissue, and that this colocalization may have synergistic effects on tumor aggressiveness. The use of tissue microarrays rather than whole sections may be viewed as a limitation. Conclusions Infiltration of CD163+ M2 macrophages and CD4+FOXP3+ Tregs is associated with recurrence of renal cell carcinoma, and colocalization of these cell types may have an association with clinical outcome. Patient summary The aim of this study was to investigate the association between infiltration of M2 macrophages and regulatory T cells with clinical outcomes in renal cell carcinoma. We demonstrated that renal cell carcinoma patients with high infiltration of both these cell types are at an increased risk of poor clinical outcomes., Take Home Message Regulatory T cells (Tregs) and M2 macrophages have been hypothesized to contribute to tumor progression. We found that M2 macrophages and Tregs are associated with more aggressive renal cell carcinoma, and that they have a synergistic effect on clinical outcome.

Summary Recently cabozantinib, a tyrosine kinase inhibitor with activity against VEGF, MET, AXL, and downregulating cathepsin K in vitro, has been proposed for the treatment of advanced clear and non-clear renal cell carcinomas. Since it is well known that cathepsin K is expressed in the majority of MiT family translocation renal cell carcinomas, we investigated cathepsin K, MET, AXL, and VEGF in a large series of those tumours, looking for possible predictive markers. We collected the clinicopathological features of 34 genetically confirmed MiT family translocation renal cell carcinomas [26 Xp11 and 8 t(6;11) renal cell carcinomas] and studied them using an immunohistochemical panel including PAX8, cathepsin K, HMB45, Melan-A, CD68 (PG-M1), CK7, CA9, MET, AXL and by FISH for VEGFA and MET. Cathepsin K was expressed in 14 of 26, HMB45 in 8 of 25, and Melan-A in 4 of 23 Xp11 renal cell carcinomas, whereas labelling for CK7 and CA9 was minimal. In t(6;11) renal cell carcinoma, cathepsin K and melanogenesis markers were constantly positive, whereas CK7 and CA9 were negative. None of the 34 carcinomas showed CD68 (PG-M1) and AXL expression. One aggressive Xp11 renal cell carcinoma showed increased VEGFA gene copy number (4–5 copies) with concurrent gains of TFE3 and TFEB. None of the 34 carcinomas showed MET gene amplification, whereas staining for MET was found in 7 of 8 t(6;11) and in 16 of 24 Xp11 renal cell carcinomas, and in the latter cases, when the expression was >50%, correlated with aggressiveness (p=0.0049). In Xp11 renal cell carcinomas, the aggressiveness was also correlated with larger tumour size (p=0.0008) and the presence of necrosis (p=0.027) but not nucleolar grading (p=1). Interestingly, in patients with tumours exhibiting two of three parameters (necrosis, larger tumour size and MET immunolabelling >50%) an aggressive clinical behaviour was observed in 88% of cases. In conclusion, cathepsin K, CD68 (PG-M1), CK7, CA9, and PAX8 is a useful panel for the diagnosis. Larger tumour size, the presence of necrosis and MET immunohistochemical expression correlate with aggressive behaviour in Xp11 renal cell carcinomas, especially in combination. VEGF, MET, cathepsin K but not AXL may be potential predictive markers for targeted therapy in MiT family translocation renal cell carcinomas.

Melanoma in giant congenital nevus (M-GCN) is a rare and potentially lethal neoplasm. In children, M-GCN appears as a dermal/deep-seated melanoma (DDM-GCN) with histopathologic features difficult to distinguish from proliferative nodules (PNs-GCN). DDM-GCN in adults is an anecdotal entity and only 8 cases have been described and genetically characterized. We report the first case of DDM-GCN in a 34-year-old man characterized with a large-panel next-generation sequence (NGS) highlighting a TP53 mutation with a UV-signature (C>T substitution) in DDM but not in PNs-GCN and GCN. Curiously, DDM showed an aberrant p16 overexpression without detection of CDKN2A mutation at NGS. In line with previous studies, it supports a different pathway in children and adults: UV-induced mutations may be involved in the latter not only by CDKN2A but also by TP53 mutations, with a potentially confusing overexpression of p16 protein. While these data need to be confirmed in larger cases series, our results show that NGS could be an additional genetic diagnostic tool in DDM-GCN.

Objective A growing number of studies have suggested that non-pathologists can reliably assess the adequacy and malignancy in rapid on-site evaluation (ROSE) smears prepared during endoscopic sampling procedures. However, no study has verified whether they can also consistently estimate the tumour burden, which is critical for the molecular profiling of lung cancer. We aimed to assess the interobserver agreement (IOA) between a pathologist, a pulmonologist (previously trained in lung and lymph node cytopathology) and a molecular pathologist for the tumour burden in ROSE smears. Methods The ROSE smears of consecutive patients with suspected lung cancer undergoing endosonography or guided bronchoscopy were assessed independently by a pathologist, a pulmonologist and a molecular pathologist (gold standard). The IOA for the tumour burden, assessed through k-statistics, was the primary outcome. Results A total of 322 ROSE smears obtained from 162 patients were evaluated. The IOA between the molecular pathologist and pulmonologist was very good (moderate to substantial), although slightly inferior to the IOA between the molecular pathologist and pathologist in the whole slide set (k: 0.707, 95% confidence interval [CI]: 0.677-0.739 vs 0.793, 95% CI: 0.762-0.815), as well as in smears prepared from lymphadenopathy (k: 0.783, 95% CI: 0.760-0.855 vs 0.827, 95% CI: 0.728-0.892) or from pulmonary nodules/masses (k: 0.558, 95% CI: 0.416-0.686 vs 0.715, 95% CI: 0.621-0.767). Conclusions A professionally trained pulmonologist can reliably estimate the tumour burden in bronchoscopically derived ROSE smears, especially in the setting of lymphadenopathy. This can be particularly useful in institutions where a cytopathologist is not available regularly.

BACKGROUND: We report long-term oncologic outcomes in patients with positive surgical margins (PSMs) at radical prostatectomy (RP) and the oncologic impact of different scenarios of PSMs presentation. METHODS: We selected 494 men with at least 3 years follow-up after surgery. PSMs patterns were recorded as: burden (focal vs multifocal), site (apical-anterior vs posterolateral vs base-bladder neck vs multiple) and side (unilateral vs bilateral). Kaplan-Meier curves depicted the clinical recurrence-free survival (CR-FS) rates at 10-year in the overall population, after biochemical recurrence and according to different PSMs patterns. Multivariate Cox-regression analysis was performed to predict CR. RESULTS: Overall, PSMs sites were apical-anterior, postero-lateral, base-bladder neck and multiple in 19.8%, 23.7%, 3.4% and 43.8%, respectively. Out of 494 patients, 278 (56.3%) had a focal margin, while 216 (43.7%) had a multifocal margin. In 268 (54.3%) and 87 (17.6%) men, PSMs were unilateral and bilateral, respectively. Median follow-up was 93 months. No significant differences were found in CR-FS rates after stratifying according to burden and site of PSMs. Men with unilateral PSMs experienced significant higher CR-FS rates compared to those with bilateral PSMs (87.1% vs. 71,3% at 10 years, p

Lymphovascular invasion (LVI) is a relevant prognostic factor in germ cell tumors of the testis (GCTT) and it has been included in the AJCC staging system. Nevertheless, its histological assessment is challenging, with low/moderate interobserver agreement also among expert uropathologists. Few studies focused on the potential role of immunohistochemistry to solve this critical issue; as result, in current guidelines there is no indication for additional staining to detect this histological feature. In the present study, we investigated the detection of LVI invasion in a small cohort of GCTT with double staining for OCT4/CD34. Although our results need to be validated in larger case series with follow-up data, they suggest as OCT4/CD34 could be a useful tool for the histological assessment of these tumors, helping to identify some histological mimickers of LVI and modifying the pT/stage in a significant percentage of patients.

Purpose: Gleason score strongly predicts prostate cancer mortality; however, scoring varies among pathologists, and many men are diagnosed with intermediate-risk Gleason score 7. We previously developed a 157-gene signature for Gleason score using a limited gene panel. Using a new whole-transcriptome expression dataset, we verified the previous signature's performance and developed a new Gleason signature to improve lethal outcome prediction among men with Gleason score 7. Experimental Design: We generated mRNA expression data from prostate tumor tissue from men in the Physicians' Health Study and Health Professionals Follow-Up Study (N = 404) using the Affymetrix Human Gene 1.0 ST microarray. The Prediction Analysis for Microarrays method was used to develop a signature to distinguish high (≥8) versus low (≤6) Gleason score. We evaluated the signature's ability to improve prediction of lethality among men with Gleason score 7, adjusting for 3 + 4/4 + 3 status, by quantifying the area under the receiver operating characteristic (ROC) curve (AUC). Results: We identified a 30-gene signature that best distinguished Gleason score ≤6 from ≥8. The AUC to predict lethal disease among Gleason score 7 men was 0.76 [95% confidence interval (CI), 0.67–0.84] compared with 0.68 (95% CI, 0.59–0.76) using 3 + 4/4 + 3 status alone (P = 0.0001). This signature was a nonsignificant (P = 0.09) improvement over our previous signature (AUC = 0.72). Conclusions: Our new 30-gene signature improved prediction of lethality among men with Gleason score 7. This signature can potentially become a useful prognostic tool for physicians to improve treatment decision making. Clin Cancer Res; 23(1); 81–87. ©2016 AACR. See related commentary by Yin et al., p. 6

Nivolumab is an effective and tolerable treatment for metastatic renal cell carcinoma, showing longer median overall survival than everolimus and achieving a good percentage of objective response, stable disease, and prolonged responses. However, very few cases have been reported in the literature of a complete response to nivolumab in the metastatic pretreated setting. Here, we report a case of complete response to nivolumab in II line following sunitinib in a metastatic clear cell renal cell carcinoma with favorable risk according to the IMDC criteria. This is also an interesting case on the use of immunotherapy following a long period of antiangiogenetic therapy, underlining the importance of the sequence of treatment to achieve the best possible outcome in terms of prolonged overall survival, progression-free survival, and objective response.

Introduction: Preoperative liver and renal dysfunction remain surgical risk factors for both postoperative morbidity and mortality. The Model of End-Stage Liver Disease Excluding INR (international normalized ratio), or MELD-XI, score calculation may help as a predictor in patients with advanced heart failure. We analyzed the impact of progressive elevated MELD-XI values among recipients of heart transplant at our institution. Methods: The data of a total of 425 consecutive adult patients who underwent heart transplantation, between January 2000 and August 2018, have been reviewed and divided into 3 cohorts according to preoperative MELD-XI calculations (MELD-XI < 11; MELD-XI 11-18; and MELD-XI > 18). Early and late outcomes have been analyzed. Results: Patients with a MELD-XI score > 18 had a more critical clinical condition preoperatively and had a higher risk of early mortality (hazard ratio [HR] 1.45 [1.11-1.67], P < .001). They showed high risk for postoperative dialysis (HR 2.8 [1.5-5.3], P < .001), rethoracothomy for bleeding (HR 2.1 [1.2-4.1], P = .001), prolonged time of mechanical ventilation, time of intensive care unit stay (HR 2.2 [1.3-3.8], P = .005), and graft failure requiring mechanical circulatory support (HR 1.9 [1.1-3.3], P = .003). After risk adjustment per MELD-XI cohort, ischemic dilated cardiomyopathy, redo operation, and cold ischemic time > 240 minutes resulted in being the strongest predictors of early mortality (P < .001). The 5-year and 10-year survival for MELD-XI > 18 cohort was 63% and 47% vs 72% and 59% in the control group (MELD-XI < 18) (log-rank, P < .001). Conclusions: Patients with an elevated preoperative MELD-XI profile presented more comorbidities and significantly lower survival. This suggests the MELD-XI score may provide further insight into appropriate recipient and eventual donor selection. Renal insufficiency and congestive hepatopathy should be properly optimized before heart transplantation.

Left ventricular assist device graft protection and its intraoperative orientation continues to be a major concern in bridge-to-transplant strategy. Different techniques have been described, including the adoption of a standard full sternotomy approach. We describe our institutional experience of placement of the with HeartWare HVAD® implantable continuous flow pump, with outflow graft tunnelling through the transverse sinus to prepare patients in need of eventual re-sternotomy. Surgical tips are provided in the tutorial videos both for HVAD® placement, and for explantation at the time of heart transplantation.

Objectives Patients harboring rearrangements of the ROS1 gene are eligible for first-line therapy with Crizotinib, which represents the best available treatment option. Diagnostic criteria, based on break-apart fluorescence in situ hybridization, were mirrored from ALK by analogy and include tumors with 5' deletions. However, the probability of response to Crizotinib in patients with 5' deletion in ROS1 is unknown given the rarity of this condition. Materials and methods We hereby describe clinical outcome of 8 NSCLC patients harboring a 5' deletion at FISH treated with Crizotinib Results Three out of 4 cases whose 5' deletion was confirmed by NGS as a ROS1/EZR fusion displayed an objective response to Crizotinib while a case with ROS1/SDC4 fusion did not. By contrast, among the 4 cases where NGS did not detect ROS1 gene fusions only 2 patients responded to crizotinib therapy with one also harboring a concomitant EML4-ALK rearrangement. Conclusion 5' ROS1 deletions detected by FISH are associated with a high chance of response to Crizotinib in NSCLC, similarly to canonical ROS1 split-apart FISH rearrangements. However, the confirmation of the ROS1 gene fusion with at least another method, such as NGS, seems beneficial in order to define the ROS1 fusion partner and to avoid possible false positive results.

Nowadays, the major limit to the immunohistochemical (IHC) analysis of tissue PD-L1 is the high variability of the monoclonal antibodies commercially available. Aims of the present paper are to assess the best clone and the most suitable scoring for PD-L1 IHC determination on human hepatocellular carcinoma (HCC) among three commercially available clones, and to evaluate which PD-L1 clone is the best in predicting HCC aggressiveness in vivo. We built a tissue microarray (TMA) with 60 retrospective HCC cases, including the correspondent non-tumoral tissue. IHC was automatically performed using the following anti-PD-L1 clones: 28.8, SP142, and SP263. As results, we did not find any immunoreactivity for PD-L1 in both neoplastic and normal hepatocytes included in the TMA using the three antibodies. Positivity for PD-L1 was exclusively seen in inflammatory cells within the HCC tissue and in cirrhotic parenchyma. When a gold standard was assessed, the sensitivity of SP142, 28.8 and SP263 was 46 %, 54 % and 85 % respectively. Using the SP263 clone, the absolute number of PD-L1-positive inflammatory cells in the HCC cores was paired with the number of PD-L1-positive inflammatory cells in the corresponding non-tumoral tissue (P = 0.001). Finally, using SP263, the mean number of PD-L1-positive cells was 11.3 ± 12.6 in HCC from deceased patients, versus 4.7 ± 5.2 in alive patients (p = 0.039). SP263 is the most sensitive clone for PD-L1 IHC tissue determination in HCC, as well as the best antibody for the assessment of its biological behavior.

Systemic metabolic alterations associated with increased consumption of saturated fat and obesity are linked with increased risk of prostate cancer progression and mortality, but the molecular underpinnings of this association are poorly understood. Here, we demonstrate in a murine prostate cancer model, that high-fat diet (HFD) enhances the MYC transcriptional program through metabolic alterations that favour histone H4K20 hypomethylation at the promoter regions of MYC regulated genes, leading to increased cellular proliferation and tumour burden. Saturated fat intake (SFI) is also associated with an enhanced MYC transcriptional signature in prostate cancer patients. The SFI-induced MYC signature independently predicts prostate cancer progression and death. Finally, switching from a high-fat to a low-fat diet, attenuates the MYC transcriptional program in mice. Our findings suggest that in primary prostate cancer, dietary SFI contributes to tumour progression by mimicking MYC over expression, setting the stage for therapeutic approaches involving changes to the diet.

Blockade of inhibitory immune checkpoints is currently arising as a potential immunologic option for tumor therapy. Inhibition of programmed cell death protein 1 and/or its specific ligand programmed death-ligand 1 (PD-L1) was effective in clinical trials in advanced melanoma, non-small cell lung cancer (NSCLC) bladder and kidney cancer. The predictive role of the immunohistochemical (IHC) expression of PD-L1 is highly debated. Different reagents, clones, cutoffs of cell expression and subjective interpretation of PD-L1 immunoreactivity in epithelial cells and lymphocytes are the main issue. In this study we selected 58 consecutive NSCLC surgical specimens that underwent pathologic examination from January 2014 to July 2015. Using a tissue microarray approach we evaluated the IHC expression of PD-L1 in tumor-infiltrating lymphocytes and tumor cells (TCs) and compared the ICH staining with tumor histology, grade and the age of the tissue blocks. The main new finding was the fading of PD-L1 IHC expression in TCs in tissues processed in 2014 compared with 2015. PD-L1 expression in tumor-infiltrating lymphocytes in the 2 years was similar. We also found a significant higher immunoreactivity of TCs in high grade NSCLC and in the squamous carcinoma histotype compared with low grade tumors and the adenocarcinoma histology (P=0.013). We demonstrated that the IHC evaluation of PD-L1 in NSCLC archival tissues is feasible and can be implemented in a routine pathology setting, but it should be carefully assessed in tissue blocks older than 1 year.