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Abstract Advances in bladder cancer (BCa) treatment have been hampered by the lack of predictive biomarkers and targeted therapies. Here, we demonstrate that loss of the tumor suppressor NUMB promotes aggressive bladder tumorigenesis and worsens disease outcomes. Retrospective cohort studies show that NUMB-loss correlates with poor prognosis in post-cystectomy muscle-invasive BCa patients and increased risk of muscle invasion progression in non-muscle invasive BCa patients. In mouse models, targeted Numb ablation induces spontaneous tumorigenesis and sensitizes the urothelium to carcinogenic insults, accelerating tumor onset and progression. Integrative transcriptomic and functional analyses in mouse and human BCa models reveal that upregulation of YAP transcriptional activity via a RHOA/ROCK-dependent pathway is a hallmark of NUMB-deficient BCa. Pharmacological or genetic inhibition of this molecular pathway selectively inhibits proliferation and invasion of NUMB-deficient BCa cells in 3D-Matrigel organoids. Thus, NUMB-loss could serve as a biomarker for identifying high-risk patients who may benefit from targeted anti-RHOA/ROCK/YAP therapies.

We present a focal mechanism catalogue of earthquakes that occurred in the southeastern Alps and surrounding areas from 1928 to 2019. The area involved in the process of convergence between the Adria microplate and Eurasia is one of the most seismically active regions in the Alpine Belt. The seismicity is minor, with the Ms= 6.5 Friuli earthquake being the strongest event recorded in the area, but the seismic risk is relevant because it is a highly populated region. For this reason, numerous studies have been carried out over time to investigate the stress field and the geodynamic characteristics of the region using focal mechanisms. To provide a comprehensive set of revised information, which is challenging to build quickly because the data are dispersed over many papers, we collected and revised the focal mechanisms that were previously published in the literature. Additionally, depending on the data quality and availability, we computed new focal mechanisms by first arrival polarity inversion or seismic moment tensor. Finally, we merged all the fault plane solutions to obtain a catalogue for a selection of 772 earthquakes with 1.8≤M≤6.5. For each earthquake, we reported all the available focal mechanisms obtained by different authors. We also suggested a preferred solution for users who need information provided expeditiously. The catalogue (https://doi.org/10.5281/zenodo.4660412; Saraò et al., 2021) is given as the Supplement of this paper and will be updated periodically (https://doi.org/10.5281/zenodo.4284970).

Advances in bladder cancer (BCa) treatment have been hampered by the lack of predictive biomarkers and targeted therapies. Here, we demonstrate that loss of the tumor suppressor NUMB promotes aggressive bladder tumorigenesis and worsens disease outcomes. Retrospective cohort studies show that NUMB-loss correlates with poor prognosis in post-cystectomy muscle-invasive BCa patients and increased risk of muscle invasion progression in non-muscle invasive BCa patients. In mouse models, targeted Numb ablation induces spontaneous tumorigenesis and sensitizes the urothelium to carcinogenic insults, accelerating tumor onset and progression. Integrative transcriptomic and functional analyses in mouse and human BCa models reveal that upregulation of YAP transcriptional activity via a RHOA/ROCK-dependent pathway is a hallmark of NUMB-deficient BCa. Pharmacological or genetic inhibition of this molecular pathway selectively inhibits proliferation and invasion of NUMB-deficient BCa cells in 3D-Matrigel organoids. Thus, NUMB-loss could serve as a biomarker for identifying high-risk patients who may benefit from targeted anti-RHOA/ROCK/YAP therapies., Competing Interests: Competing interests: G. Renne, G. Vago, D. Tosoni and S. Pece are co-inventors of a patent (EP24191940.6) related to this work, pending to the European Institute of Oncology and University of Milan. All the other authors declare no competing interests., (© 2024. The Author(s).)

Objectives: To test the performance of ex vivo fluorescence confocal microscopy (FCM; Vivascope 2500M-G4), as compared to intra-operative frozen section (IFS) analysis, to evaluate surgical margins during robot-assisted radical prostatectomy (RARP), with final pathology as the reference standard., Methods: Overall, 54 margins in 45 patients treated with RARP were analysed with: (1) ex vivo FCM; (2) IFS analysis; and (3) final pathology. FCM margins were evaluated by two different pathologists (experienced [M.I.: 10 years] vs highly experienced [G.R.: >30 years]) as strongly negative, probably negative, doubtful, probably positive, or strongly positive. First, inter-observer agreement (Cohen's κ) between pathologists was tested. Second, we reported the sensitivity, specificity, positive predictive (PPV) and negative predictive value (NPV) of ex vivo FCM. Finally, agreement between ex vivo FCM and IFS analysis (Cohen's κ) was reported. For all analyses, four combinations of FCM results were evaluated., Results: At ex vivo FCM, the inter-observer agreement between pathologists ranged from moderate (κ = 0.74) to almost perfect (κ = 0.90), according to the four categories of results. Indeed, at ex vivo FCM, the highly experienced pathologist reached the best balance between sensitivity (70.5%) specificity (91.8%), PPV (80.0%) and NPV (87.1%). Conversely, on IFS analysis, the sensitivity, specificity, PPV and NPV were, respectively, 88.2% vs 100% vs 100% vs 94.8%. The agreement between the ex vivo FCM and IFS analyses ranged from moderate (κ = 0.62) to strong (κ = 0.86), according to the four categories of results., Conclusion: Evaluation of prostate margins at ex vivo FCM appears to be feasible and reliable. The agreement between readers encourages its widespread use in daily practice. Nevertheless, as of today, the performance of FCM seems to be sub-par when compared to the established standard of care (IFS analysis)., (© 2024 BJU International.)

Neuroendocrine prostate cancer (NEPC) is an aggressive form of prostate cancer that emerges as tumors become resistant to hormone therapies or, rarely, arises de novo in treatment-naïve patients. The urgent need for effective therapies against NEPC is hampered by the limited knowledge of the biology governing this lethal disease. Based on our prior observations in the transgenic adenocarcinoma of the mouse prostate (TRAMP) spontaneous prostate cancer model, in which the genetic depletion of either mast cells (MC) or the matricellular protein osteopontin (OPN) increases NEPC frequency, we tested the hypothesis that MCs can restrain NEPC through OPN production, using in vitro co-cultures between murine or human tumor cell lines and MCs, and in vivo experiments. We unveiled a role for the intracellular isoform of OPN, so far neglected compared with the secreted isoform. Mechanistically, we unraveled that the intracellular isoform of OPN promotes TNFα production in MCs via the TLR2/TLR4-MyD88 axis, specifically triggered by the encounter with NEPC cells. We found that MC-derived TNFα, in turn, hampered the growth of NEPC. We then identified the protein syndecan-1 (SDC1) as the NEPC-specific TLR2/TLR4 ligand that triggered this pathway. Interrogating published single-cell RNA-sequencing data, we validated this mechanism in a different mouse model. Translational relevance of the results was provided by in silico analyses of available human NEPC datasets and by immunofluorescence on patient-derived adenocarcinoma and NEPC lesions. Overall, our results show that MCs actively inhibit NEPC, paving the way for innovative MC-based therapies for this fatal tumor. We also highlight SDC1 as a potential biomarker for incipient NEPC., (©2024 The Authors; Published by the American Association for Cancer Research.)

Purpose: To assess the ability of tumor apparent diffusion coefficient (ADC) values obtained from multiparametric magnetic resonance imaging (mpMRI) to predict the risk of 5-year biochemical recurrence (BCR) after radical prostatectomy (RP)., Materials and Methods: This retrospective analysis included 1207 peripheral and 232 non-peripheral zone prostate cancer (PCa) patients who underwent mpMRI before RP (2012-2015), with the outcome of interest being 5-year BCR. ADC was evaluated as a continuous variable and as categories: low (< 850 µm 2 /s), intermediate (850-1100 µm 2 /s), and high (> 1100 µm 2 /s). Kaplan-Meier curves with log-rank testing of BCR-free survival, multivariable Cox proportional hazard regression models were formed to estimate the risk of BCR., Results: Among the 1439 males with median age 63 (± 7) years, the median follow-up was 59 months, and 306 (25%) patients experienced BCR. Peripheral zone PCa patients with BCR had lower tumor ADC values than those without BCR (874 versus 1025 µm 2 /s, p < 0.001). Five-year BCR-free survival rates were 52.3%, 74.4%, and 87% for patients in the low, intermediate, and high ADC value categories, respectively (p < 0.0001). Lower ADC was associated with BCR, both as continuously coded variable (HR: 5.35; p < 0.001) and as ADC categories (intermediate versus high ADC-HR: 1.56, p = 0.017; low vs. high ADC-HR; 2.36, p < 0.001). In the non-peripheral zone PCa patients, no association between ADC and BCR was observed., Conclusion: Tumor ADC values and categories were found to be predictive of the 5-year BCR risk after RP in patients with peripheral zone PCa and may serve as a prognostic biomarker., (© 2024. Italian Society of Medical Radiology.)

We designed a phase 3, prospective, randomized trial to evaluate the impact of augmented reality and augmented reality frozen section analysis in reducing the rates of positive surgical margins after robot-assisted radical prostatectomy., (© 2024 The Author(s).)

The strategy to anticipate radiotherapy (RT) before surgery, for breast cancer (BC) treatment, has recently generated a renewed interest. Historically, preoperative RT has remained confined either to highly selected patients, in the context of personalized therapy, or to clinical research protocols. Nevertheless, in the recent years, thanks to technological advances and increased tumor biology understanding, RT has undergone great changes that have also impacted the preoperative settings, embracing the modern approach to breast cancer. In particular, the reappraisal of preoperative RT can be viewed within the broader view of personalized and tailored medicine. In fact, preoperative accelerated partial breast irradiation (APBI) allows a more precise target delineation, with less variability in contouring among radiation oncologists, and a smaller treatment volume, possibly leading to lower toxicity and to dose escalation programs. The aim of the present review, which represents a benchmark study for the AIRC IG-23118, is to report available data on different technical aspects of preoperative RT including dosimetric studies, patient's selection and set-up, constraints, target delineation and clinical results. These data, along with the ones that will become available from ongoing studies, may inform the design of the future trials and representing a step toward a tailored APBI approach with the potential to challenge the current treatment paradigm in early-stage BC.Trial registration: The study is registered at clinicaltrials.gov (NCT04679454)., (© 2023. Italian Society of Medical Radiology.)

Objective: to evaluate the feasibility of the intra-operative application of a specimen PET/CT imager in a clinical setting., Materials and Methods: this is a pilot analysis performed in three patients who received an intra-operative administration of 68 Ga-PSMA-11 (n = 2) and 68 Ga-DOTA-TOC (n = 1), respectively. Patients were administrated with PET radiopharmaceuticals to perform radio-guided surgery with a beta-probe detector during radical prostatectomy for prostate cancer (PCa) and salvage lymphadenectomy for recurrent neuroendocrine tumor (NET) of the ileum, respectively. All procedures have been performed within two ongoing clinical trials in our Institute (NCT05596851 and NCT05448157). Pathologic assessment with immunohistochemistry (PSMA-staining and SSA immunoreactivity) was considered as standard of truth. Specimen images were compared with baseline PET/CT images and histopathological analysis., Results: Patients received 1 MBq/Kg of 68 Ga-PSMA-11 (PCa) or 1.2 MBq/Kg of 68 Ga-DOTA-TOC (NET) prior to surgery. Specimens were collected, positioned in the dedicated specimen container, and scanned to obtain high-resolution PET/CT images. In all cases, a perfect match was observed between the findings detected by the specimen imager and histopathology. Overall, the PET spatial resolution was sensibly higher for the specimen images compared to the baseline whole-body PET/CT images. Furthermore, the use of the PET/CT specimen imager did not significantly interfere with any procedures, and the overall length of the surgery was not affected using the PET/CT specimen imager. Finally, the radiation exposure of the operating theater staff was lower than 40 µSv per procedure (range 26-40 μSv)., Conclusions: the image acquisition of specimens obtained by patients who received intra-surgery injections of 68 Ga-PSMA-11 and 68 Ga-DOTA-TOC was feasible and reliable also in a live-experience session and has been easily adapted to surgery daily practice. The high sensitivity, together with the evaluation of intra-lesion tumor heterogeneity, were the most relevant results since the data derived from specimen PET/CT imaging matched perfectly with the histopathological analysis.

Biobanks are key research infrastructures aimed at the collection, storage, processing, and sharing of high-quality human biological samples and associated data for research, diagnosis, and personalized medicine. The Biobank for Translational and Digital Medicine Unit at the European Institute of Oncology (IEO) is a landmark in this field. Biobanks collaborate with clinical divisions, internal and external research groups, and industry, supporting patients' treatment and scientific progress, including innovative diagnostics, biomarker discovery, and clinical trial design. Given the central role of biobanks in modern research, biobanking standard operating procedures (SOPs) should be extremely precise. SOPs and controls by certified specialists ensure the highest quality of samples for the implementation of science-based, diagnostic, prognostic, and therapeutic personalized strategies. However, despite numerous efforts to standardize and harmonize biobanks, these protocols, which follow a strict set of rules, quality controls, and guidelines based on ethical and legal principles, are not easily accessible. This paper presents the biobank standard operating procedures of a large cancer center.

Objective: To compare different stereotactic body techniques-intensity-modulated radiotherapy with photons and protons, applied to radiotherapy of prostatic cancer-with simultaneous integrated boost (SIB) on the dominant intraprostatic lesion (DIL)., Methods: Ten patients were selected for this planning study. Dosimetric results were compared between volumetric modulated arc therapy, intensity-modulated radiation therapy (IMRT), and intensity-modulated proton therapy both with two (IMPT 2F) and five fields (IMPT 5F) planning while applying the prescription schemes of 7.25 Gy/fraction to the prostate gland and 7.5 Gy/fraction to the DIL in 5 fractions., Results: Comparison of the coverages of the planning target volumes showed that small differences exist. The IMPT-2F-5F techniques allowed higher doses in the targets; conformal indexes resulted similar; homogeneity was better in the photon techniques (2%-5%). Regarding the organs at risk, all the techniques were able to maintain the dose well below the prescribed constraints: in the rectum, the IMPT-2F-5F and IMRT were more efficient in lowering the intermediate doses; in the bladder, the median dose was significantly better in the case of IMPT (2F-5F). In the urethra, the best sparing was achieved only by IMPT-5F., Conclusions: Stereotactic radiotherapy with SIB for localized prostate cancer is feasible with all the investigated techniques. Concerning IMPT, the two-beam technique does not seem to have a greater advantage compared to the standard techniques; the 5-beam technique seems more promising also accounting for the range uncertainty.

Background: Breast-conserving surgery (BCS) and whole breast radiation therapy (WBRT) are the standard of care for early-stage breast cancer (BC). Based on the observation that most local recurrences occurred near the tumor bed, accelerated partial breast irradiation (APBI), consisting of a higher dose per fraction to the tumor bed over a reduced treatment time, has been gaining ground as an attractive alternative in selected patients with low-risk BC. Although more widely delivered in postoperative setting, preoperative APBI has also been investigated in a limited, though increasing, and number of studies. The aim of this study is to test the feasibility, safety and efficacy of preoperative radiotherapy (RT) in a single fraction for selected BC patients., Methods: This is a phase I/II, single-arm and open-label single-center clinical trial using CyberKnife. The clinical investigation is supported by a preplanning section which addresses technical and dosimetric issues. The primary endpoint for the phase I study, covering the 1st and 2nd year of the research project, is the identification of the maximum tolerated dose (MTD) which meets a specific target toxicity level (no grade 3-4 toxicity). The primary endpoint for the phase II study (3rd to 5th year) is the evaluation of treatment efficacy measured in terms of pathological complete response rate., Discussion: The study will investigate the response of BC to the preoperative APBI from different perspectives. While preoperative APBI represents a form of anticipated boost, followed by WBRT, different are the implications for the scientific community. The study may help to identify good responders for whom surgery could be omitted. It is especially appealing for patients unfit for surgery due to advanced age or severe co-morbidities, in addition to or instead of systemic therapies, to ensure long-term local control. Moreover, patients with oligometastatic disease synchronous with primary BC may benefit from APBI on the intact tumor in terms of tumor progression free survival. The study of response to RT can provide useful information about BC radiobiology, immunologic reactions, genomic expression, and radiomics features, to be tested on a larger scale., Trial Registration: The study was prospectively registered at clinicaltrials.gov ( NCT04679454 )., (© 2022. The Author(s).)

PTEN deletion and Ki-67 expression are two of the most promising biomarkers in prostate cancer (PCa). In the same manner, multiparametric magnetic resonance imaging (mp-MRI) guided core biopsy is a powerful tool for PCa detection and staging. The aim of the study is to assess whether a correlation can be identified between the pathological stage defined by an mp-MRI-guided core biopsy and Ki-67 expression and PTEN deletion. Such correlation might be useful for staging and treatment personalization in PCa. This investigation was conducted in the context of phase II clinical study "Short-term radiotherapy for early prostate cancer with a concomitant boost to the dominant lesion" (AIRC IG-13218), ClinicalTrials.gov identifier: NCT01913717. Nineteen patients underwent a further in-bore MRI-targeted core biopsy (MRI-TBx) on the dominant intraprostatic lesion (DIL); on this basis, an additional Gleason Score (GS) was determined. PTEN loss and Ki-67 expression on these samples were analyzed and correlated with both risk categories modifications and oncological outcomes (overall survival, biochemical and clinical relapse). GS was upgraded in 5 cases, with 4 patients re-classified as intermediate-risk and 1 patient as high-risk. The latter experienced a clinical local relapse. No correlations between up/down-staging, PTEN deletion, and Ki-67 expression were observed in this cohort. Further investigations are needed towards the identification of a pattern in the tumor aggressiveness-response in PCa treated with ultra-hypofractionated radiotherapy. Moreover, a possible relationship between biomarker analysis and imaging textural features could be explored.

Purpose: To investigate the use of apparent diffusion coefficient (ADC) values and other MRI features for predicting positive surgical margins (PSMs) in patients undergoing radical prostatectomy., Materials and Methods: We retrospectively identified 400 consecutive patients who underwent surgery for prostate cancer between January 2015 and June 2016. ADC values of the index lesion and other preoperative magnetic resonance imaging features, including tumor site, laterality, level, Prostate Imaging Reporting and Data System category, European Society of Urogenital Radiology extracapsular extension score, and prostate volume, were assessed. Univariate and multivariable logistic regression were performed. Performance in predicting the occurrence of PSMs was measured using the area under the curve (AUC). AUC differences were evaluated with the DeLong method. The Youden index was calculated to identify the ADC threshold to best discriminate patients with PSMs., Results: Of the 400 patients, 105 (26.2%) had PSMs after radical prostatectomy. ADC values, Prostate Imaging Reporting and Data System category, extracapsular extension score, tumor site, and laterality were significantly associated with PSMs (P < .001) in univariate analysis. The AUC of the predictive model based on ADC alone was 68.2% (95% confidence interval, 62.2-74.2%) and did not significantly differ from the best multivariable predictive model which combined laterality, and site with ADC to attain an AUC of 70.0% (95% confidence interval, 64.2-75.8%; DeLong P = .318). The ADC threshold that maximized the Youden index was 960.3 µm 2 /s., Conclusion: ADC values and preoperative magnetic resonance imaging features can help estimate the risk of PSMs after radical prostatectomy., Competing Interests: Disclosure Paul Summers declares a relationship with the following companies: QMRI Tech. The remaining authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Fatal neuroendocrine differentiation (NED) of castration-resistant prostate cancer is a recurrent mechanism of resistance to androgen deprivation therapies (ADT) and antiandrogen receptor pathway inhibitors (ARPI) in patients. The design of effective therapies for neuroendocrine prostate cancer (NEPC) is complicated by limited knowledge of the molecular mechanisms governing NED. The paucity of acquired genomic alterations and the deregulation of epigenetic and transcription factors suggest a potential contribution from the microenvironment. In this context, whether ADT/ARPI induces stromal cells to release NED-promoting molecules and the underlying molecular networks are unestablished. Here, we utilized transgenic and transplantable mouse models and coculture experiments to unveil a novel tumor-stroma cross-talk that is able to induce NED under the pressure of androgen deprivation. Castration induced upregulation of GRP78 in tumor cells, which triggers miR29-b -mediated downregulation of the matricellular protein SPARC in the nearby stroma. SPARC downregulation enabled stromal cells to release IL6, a known inducer of NED. A drug that targets GRP78 blocked NED in castrated mice. A public, human NEPC gene expression dataset showed that Hspa5 (encoding for GRP78) positively correlates with hallmarks of NED. Finally, prostate cancer specimens from patients developing local NED after ADT showed GRP78 upregulation in tumor cells and SPARC downregulation in the stroma. These results point to GRP78 as a potential therapeutic target and to SPARC downregulation in stromal cells as a potential early biomarker of tumors undergoing NED. SIGNIFICANCE: Tumor-stroma cross-talk promotes neuroendocrine differentiation in prostate cancer in response to hormone therapy via a GRP78/SPARC/IL6 axis, providing potential therapeutic targets and biomarkers for neuroendocrine prostate cancer., (©2021 The Authors; Published by the American Association for Cancer Research.)

Objectives: Diagnosis of HPV infection is usually performed from cervical liquid-based cytology specimens (LBC), but these often contain a large amount of human papillomavirus (HPV) genotypes, most of which might cause transient infections. The aim of the study was to evaluate the performance of BD Onclarity HPV test genotyping method on formalin-fixed, paraffin-embedded (FFPE) cervical specimens compared with genotyping results from LBC., Materials and Methods: Formalin-fixed, paraffin-embedded specimens from women surgically treated for cervical intraepithelial lesions (CINs) at the European Institute of Oncology, Milan, from September 2012 to June 2013 were retrieved from the archives of the Department of Pathology of the European Institute of Oncology. The FFPE and LBC specimens were genotyped using the same extended genotyping Onclarity assay., Results: We collected 99 samples (26 CIN 1, 30 CIN 2, and 43 CIN 3+), but 15 were excluded from the analysis: these 84 samples show an overall agreement of 89% for HPV status between FFPE Onclarity samples versus LBC samples. The FFPE and LBC samples showed identical genotype in 75% samples, compatible genotype (at least 1 of the genotypes detected in LBC sample was found in the tissue sample) in 14% specimens, and discrepant genotype in 11% samples., Conclusions: Our data demonstrate a very good concordance between HPV genotypes found in cytological and tissue samples, suggesting that the Onclarity method could also be used to detect HPV in tissue samples and that the HPV genotype detected in FFPE samples is one of the HPV detected in cytological samples, supporting the thesis that one lesion is caused by one HPV genotype., Competing Interests: The authors have declared they have no conflicts of interest., (Copyright © 2021, ASCCP.)

In the last few years, ultrasound-guided vacuum-assisted breast biopsy (US-VABB) has replaced surgical biopsy due to higher diagnostic accuracy and lower patient discomfort, and, at present, an even greater possibility is represented by the new wireless ultrasound-guided VAB device (Wi-UVAB). The purpose of our study is to determine the diagnostic accuracy of this new device in a sizeable representative number of patients. From January 2014 to June 2018, 168 biopsies were performed in our institution using the new Wi-UVAB device. We analyzed sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of biopsies obtained with the new device using surgical results as reference point, following patients for at least one year. In our cohort, we obtained a complete sensitivity of 97.5%, an absolute sensitivity of 94.3%, a complete specificity of 98%, and an absolute specificity of 98%. The positive predictive value of the procedure was 97.5% while the negative predictive value was 98%. The diagnostic accuracy was 98%. The Wi-UVAB is a safe procedure with high diagnostic accuracy, comparable to that of the traditional vacuum-assisted breast biopsy and even higher than that of core needle biopsy (CNB). Moreover, the Wi-UVAB is easy to use and shows low costs as core needle biopsy (CNB)., (© 2021 Wiley Periodicals LLC.)

Myoid gonadal stromal tumor represents a rare testicular neoplasm displaying smooth muscular and gonadal stromal differentiation. This entity has very few cases reported in the literature that describe heterogeneous clinical and pathological characteristics. Bayesian statistics provides a useful framework to combine information from diverse sources. We here presented a case series-the largest so far reported-of myoid gonadal stromal tumor (4 cases) with extensive morphologic, immunohistochemical, and molecular characterization, performed a systematic review of the literature (that identified 9 papers), and used a Bayesian data analysis to understand the characteristics of this disease. Our study collectively described 16 cases. This neoplasm is mainly found in adults (mean age about 40 years) and often has a size of about 3 cm. By morphology, the tumor can infiltrate testicular tubules and is composed of spindle cells; few mitoses can be seen (usually 2/10 HPF). Neoplastic cells are diffusely positive with α-smooth muscle actin with a tram-track staining pattern. S100 protein, FOXL2, and SF1 are also characteristically positive. Moreover, this neoplasm can display epithelial differentiation, in about half of the cases. In conclusion, we foresee the use of this statistical approach in pathology: our analysis allowed a more precise description of this rare entity.

Background: circulating levels of lymphocytes, platelets and neutrophils have been identified as factors related to unfavorable clinical outcome for many solid tumors. The aim of this cohort study is to evaluate and validate the use of the Prostatic Systemic Inflammatory Markers (PSIM) score in predicting and improving the detection of clinically significant prostate cancer (csPCa) in men undergoing robotic radical prostatectomy for low-risk prostate cancer who met the inclusion criteria for active surveillance., Methods: we reviewed the medical records of 260 patients who fulfilled the inclusion criteria for active surveillance. We performed a head-to-head comparison between the histological findings of specimens after radical prostatectomy (RP) and prostate biopsies. The PSIM score was calculated on the basis of positivity according to cutoffs (neutrophil-to-lymphocyte ratio (NLR) 2.0, platelets-to-lymphocyte ratio (PLR) 118 and monocyte-to-lymphocyte-ratio (MLR) 5.0), with 1 point assigned for each value exceeding the specified threshold and then summed, yielding a final score ranging from 0 to 3., Results: median NLR was 2.07, median PLR was 114.83, median MLR was 3.69., Conclusion: we found a significantly increase in the rate of pathological International Society of Urological Pathology (ISUP) ≥ 2 with the increase of PSIM. At the multivariate logistic regression analysis adjusted for age, prostate specific antigen (PSA), PSA density, prostate volume and PSIM, the latter was found the sole independent prognostic variable influencing probability of adverse pathology.

Background : Considering highly selected patients with ductal carcinoma in situ (DCIS), active surveillance is a valid alternative to surgery. Our study aimed to show the reliability of post-biopsy complete lesion removal, documented by mammogram, as additional criterion to select these patients. Methods : A total of 2173 vacuum-assisted breast biopsies (VABBs) documented as DCIS were reviewed. Surgery was performed in all cases. We retrospectively collected the reports of post-VABB complete lesion removal and the histological results of the biopsy and surgery. We calculated the rate of upgrade of DCIS identified on VABB upon excision for patients with post-biopsy complete lesion removal and for those showing residual lesion. Results : We observed 2173 cases of DCIS: 408 classified as low-grade, 1262 as intermediate-grade, and 503 as high-grade. The overall upgrading rate to invasive carcinoma was 15.2% (330/2173). The upgrade rate was 8.2% in patients showing mammographically documented complete removal of the lesion and 19% in patients without complete removal. Conclusion : The absence of mammographically documented residual lesion following VABB was found to be associated with a lower upgrading rate of DCIS to invasive carcinoma on surgical excision and should be considered when deciding the proper management DCIS diagnosis.

Purpose: To compare the efficacy of contrast-enhanced spectral mammography, with ultrasound, full field digital mammography and magnetic resonance imaging in detection and size estimation of histologically proven breast tumors., Methods: This open-label, single center, prospective study, included 160 dense breast women with at least one suspicious mammary lesion evaluated by ultrasound, full field digital mammography and magnetic resonance imaging in whom a mammary tumor was histologically proven after surgery performed at the European Institute of Oncology between January 2013 and December 2015. Following the complete diagnostic procedure, the patients were further investigated by contrast-enhanced spectral mammography prior to surgery., Results: Overall, the detection rate of malignant breast lesions (in situ and invasive) was 93.8% (165/176) for contrast-enhanced spectral mammography, 94.4% (168/178) for ultrasound, 85.5 (147/172) for full field digital mammography and 97.7% (173/177) for magnetic resonance imaging. Radiological measurements were concordant with the post-surgical pathological measurements of the invasive tumor (i.e., within 5 mm) in: 64.6% for contrast-enhanced spectral mammography, 62.0% for ultrasound, 45.2% for full field digital mammography (p < 0.0001) and 69.9% for magnetic resonance imaging (p = 0.28); underestimated in: 17.4% for contrast-enhanced spectral mammography, 19.6% for ultrasound, 24.2% for full field digital mammography (p = 0.03) and 6.7% for magnetic resonance imaging (p = 0.0005); and overestimated in: 16.2% for contrast-enhanced spectral mammography, 16.6% for ultrasound, 16.6% for full field digital mammography and 22.7% for magnetic resonance imaging (p = 0.02)., Conclusions: Our data suggest that contrast-enhanced spectral mammography improves on full field digital mammography and is comparable to ultrasound and magnetic resonance imaging in terms of detection sensitivity and size estimation of malignant lesions in dense breasts.

Objectives: To test international society of urological pathology grade group (ISUP GG) concordance rates between multiparametric magnetic resonance imaging (mpMRI) targeted biopsies (TB) vs. standard systematic biopsies (SB) and radical prostatectomy (RP) specimens, in biopsy naïve patients., Materials and Methods: This retrospective single center study included 80 vs. 500 biopsy naïve patients diagnosed with TB vs. SB and treated with RP between 2015 and 2018. First, we compared ISUP GG concordance rates and the percentages of undetected clinically significant prostate cancer (csPCa: ISUP GG  ≥ 3), between TB vs. SB and RP. Second, multivariable logistic regression models tested predictors of concordance rates before and after 1:3 propensity score (PS) matching. Third, among TB patients, univariable logistic regression models tested variables associated with ISUP GG concordance at RP., Results: Overall, ISUP GG concordance rates were, respectively, 55 vs. 41.4% for TB vs. SB (P = 0.02). However, no differences in concordance rates were observed in patients with biopsy ISUP GG1 (31 vs. 33.9% for TB vs. SB; P = 0.8). Moreover, 15 vs. 18.8% csPCa were missed by TB vs. SB, respectively (P = 0.4). In multivariable logistic regression models, TB were associated with higher concordance rates before (odds ratio [OR]: 1.13; P = 0.04) and after 1:3 PS matching (OR: 1.15; P 0.03), compared to SB. In TB patients, age (OR: 0.98; P = 0.04), maximum cancer core involvement (MCCI; OR: 1.02; P = 0.02) and maximum cancer core length (MCCL; OR: 1.01; P = 0.07) were associated with ISUP GG concordance. Moreover, a trend for lower concordance rates was observed with higher PSA-D (OR: 0.77; P = 0.1). Finally, intermediate lesion location at mpMRI was associated with lowest concordance rates (44%)., Conclusion: In biopsy naïve patients treated with RP, TB achieved higher rates of ISUP GG concordance, but same percentages of csPCa missed, compared to SB. Moreover, only patients with ISUP GG ≥2, but not patients with ISUP GG1, exhibited higher concordance rates. Finally, age, MCCI, MCCL, PSA-D, and lesion location were associated with concordance between TB and RP., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Soft tissue sarcomas (STS) are uncommon, heterogeneous malignant tumors of mesodermal origin. Other than conservative surgery (CS), neoadjuvant or adjuvant radiotherapy (RT) is recommended when the risk of local recurrence is high. The aim of this study is to present our Institutional experience in adjuvant RT for treatment of STS of extremities and trunk (with either brachytherapy (BRT), external beam RT (EBRT), or both) and to provide an insight of toxicity and oncological outcomes for each RT modality. According to the RT treatment approach, patients were divided into three categories: 1) BRT alone; 2) EBRT alone; 3) combined BRT+EBRT. Differences among the three groups were assessed by the Chi-squared test. Patients' follow-up was performed every 6 months for the first two years after the end of RT and then once a year. Data from 90 patients were analyzed. The overall 3-year distant relapse-free survival (DRFS), progression-free survival (PFS), and overall survival (OS) were 84%, 80%, and 97%, respectively. Acute erythema was the most frequent side effect, although severe grade 3 toxicity was present in 5 patients. Chronic toxicity of any grade was reported in 14 patients. The incidence of chronic toxicity did not show any association with treatment modality. Multivariate analysis suggested a significant correlation between acute toxicity and tumor size, RT modality, and RT dose. In conclusion, good local control and toxicity profile were observed, despite negative patients' selection at baseline. Further investigation on wider series is warranted in order to define the optimal combination with systemic therapy.

Background: The METastasis Reporting and Data System for Prostate Cancer (MET-RADS-P) guidelines are designed to enable reproducible assessment in detecting and quantifying metastatic disease response using whole-body magnetic resonance imaging (WB-MRI) in patients with advanced prostate cancer (APC). The purpose of our study was to evaluate the inter-observer agreement of WB-MRI examination reports produced by readers of different expertise when using the MET-RADS-P guidelines., Methods: Fifty consecutive paired WB-MRI examinations, performed from December 2016 to February 2018 on 31 patients, were retrospectively examined to compare reports by a Senior Radiologist (9 years of experience in WB-MRI) and Resident Radiologist (after a 6-months training) using MET-RADS-P guidelines, for detection and for primary/dominant and secondary response assessment categories (RAC) scores assigned to metastatic disease in 14 body regions. Inter-observer agreement regarding RAC score was evaluated for each region by using weighted-Cohen's Kappa statistics (K)., Results: The number of metastatic regions reported by the Senior Radiologist (249) and Resident Radiologist (251) was comparable. For the primary/dominant RAC pattern, the agreement between readers was excellent for the metastatic findings in cervical, dorsal, and lumbosacral spine, pelvis, limbs, lungs and other sites (K:0.81-1.0), substantial for thorax, retroperitoneal nodes, other nodes and liver (K:0.61-0.80), moderate for pelvic nodes (K:0.56), fair for primary soft tissue and not assessable for skull due to the absence of findings. For the secondary RAC pattern, agreement between readers was excellent for the metastatic findings in cervical spine (K:0.93) and retroperitoneal nodes (K:0.89), substantial for those in dorsal spine, pelvis, thorax, limbs and pelvic nodes (K:0.61-0.80), and moderate for lumbosacral spine (K:0.44)., Conclusions: We found inter-observer agreement between two readers of different expertise levels to be excellent in bone, but mixed in other body regions. Considering the importance of bone metastases in patients with APC, our results favor the use of MET-RADS-P in response to the growing clinical need for monitoring of metastasis in these patients.

Objectives: To develop a novel nomogram to identify candidates for active surveillance (AS) that combines clinical, biopsy and multiparametric magnetic resonance imaging (mpMRI) findings; and to compare its predictive accuracy to, respectively: (i) Prostate Cancer Research International: Active Surveillance (PRIAS) criteria, (ii) Johns Hopkins (JH) criteria, (iii) European Association of Urology (EAU) low-risk classification, and (iv) EAU low-risk or low-volume with International Society of Urological Pathology (ISUP) Grade Group (GG) 2 classification., Patients and Methods: We selected 1837 patients with ISUP GG1 or GG2 prostate cancer (PCa), treated with radical prostatectomy (RP) between 2012 and 2018. The outcome of interest was the presence of unfavourable disease (i.e., clinically significant PCa [csPCa]) at RP, defined as: ISUP GG ≥ 3 and/or pathological T stage (pT) ≥3a and/or pathological N stage (pN) 1. First, logistic regression models including PRIAS, JH, EAU low-risk, and EAU low-risk or low-volume ISUP GG2 binary classifications (not eligible vs eligible) were used. Second, a multivariable logistic regression model including age, prostate-specific antigen density (PSA-D), ISUP GG, and the percentage of positive cores (Model 1) was fitted. Third, Prostate Imaging-Reporting and Data System (PI-RADS) score (Model 2), extracapsular extension (ECE) score (Model 3) and PI-RADS + ECE score (Model 4) were added to Model 1. Only variables associated with higher csPCa rates in Model 4 were retained in the final simplified Model 5. The area under the receiver operating characteristic curve (AUC), calibration plots and decision curve analyses were used., Results: Of the 1837 patients, 775 (42.2%) had csPCa at RP. Overall, 837 (47.5%), 986 (53.7%), 348 (18.9%), and 209 (11.4%) patients were eligible for AS according to, respectively, the EAU low-risk, EAU low-risk or low-volume ISUP GG2, PRIAS, and JH criteria. The proportion of csPCa amongst the EAU low-risk, EAU low-risk or low-volume ISUP GG2, PRIAS and JH candidates was, respectively 28.5%, 29.3%, 25.6% and 17.2%. Model 4 and Model 5 (in which only PSA-D, ISUP GG, PI-RADS and ECE score were retained) had a greater AUC (0.84), compared to the four proposed AS criteria (all P < 0.001). The adoption of a 25% nomogram threshold increased the proportion of AS-eligible patients from 18.9% (PRIAS) and 11.4% (JH) to 44.4%. Moreover, the same 25% nomogram threshold resulted in significantly lower estimated risks of csPCa (11.3%), compared to PRIAS (Δ: -14.3%), JH (Δ: -5.9%), EAU low-risk (Δ: -17.2%), and EAU low-risk or low-volume ISUP GG2 classifications (Δ: -18.0%)., Conclusion: The novel nomogram combining clinical, biopsy and mpMRI findings was able to increase by ~25% and 35% the absolute frequency of patients suitable for AS, compared to, respectively, the PRIAS or JH criteria. Moreover, this nomogram significantly reduced the estimated frequency of csPCa that would be recommended for AS compared to, respectively, the PRIAS, JH, EAU low-risk, and EAU low-risk or low-volume ISUP GG2 classifications., (© 2020 The Authors BJU International © 2020 BJU International Published by John Wiley & Sons Ltd.)

Background: To understand the value of multiparametric magnetic resonance imaging (mpMRI) and targeted biopsies at recruitment on active surveillance (AS) outcomes., Materials and Methods: This retrospective single-center study enrolled two cohorts of 206 and 310 patients in AS. The latter group was submitted to mpMRI and targeted biopsies at recruitment. Kaplan-meier curves quantified progression-free survival (PFS) and Bioptic-PFS (B-PFS: no upgrading or >3 positive cores) in the two cohorts. Cox-regression analyses tested independent predictors of PFS and B-PFS. In patients submitted to radical prostatectomy (RP) after AS, significant cancer (csPCa) was defined as: GS ≥ 4 + 3 and/or pT ≥ 3a and/or pN+ . Logistic-regression analyses predicted csPCa at RP., Results and Limitations: Median time follow-up and median time of persistence in AS were 46 (24-70) and 36 (23-58) months, respectively. Patients submitted to mpMRI at AS begin, showed greater PFS at 1- (98% vs. 91%), 3- (80% vs. 57%), and 5-years (70% vs. 35%) follow-up, respectively (all p < 0.01). At Cox-regression analysis only confirmatory mpMRI± targeted biopsy (HR: 0.3; 95% CI 0.2-0.5; p < 0.01) at AS begin was an independent predictor of PFS. Globally, 50 (16%) vs. 128 (62%) and 26 (8.5%) vs. 64 (31%) [all p < 0.01] men in the two groups experienced any-cause and bioptic AS discontinuation, respectively. Patients submitted to confirmatory mpMRI experienced greater 1-(98% vs. 93%), 3-(90% vs. 75%), and 5-years (83% vs. 56%) B-PFS, respectively (all p < 0.01). At Cox-regression analysis, mpMRI±-targeted biopsy at AS begin was associated with B-PFS (HR: 0.3; 95% CI 0.2-0.6; p < 0.01). No differences were recorded in csPCa rates between the two groups (22% vs. 28%; p = 0.47). Limitations of the study are the single-center retrospective nature and the absence of long-term follow-up., Conclusions: Confirmatory mpMRI±-targeted biopsies are associated with higher PFS and B-PFS during AS. However, a non-negligible percentage of patients experience csPCa after switching to active treatment.

Objectives: To evaluate whether low PI-RADS v2 assessment categories are effective at excluding extraprostatic extension (EPE) of prostate cancer (≥pT3a PCa)., Methods: The local institutional ethics committee approved this retrospective analysis of 301 consecutive PCa patients. Patients were classified as low- or intermediate/high-risk based on clinical parameters and underwent pre-surgical multiparametric magnetic resonance imaging. A PI-RADS v2 assessment category and ESUR EPE score were assigned for each lesion by two readers working in consensus. Histopathologic analysis of the whole-mount radical prostatectomy specimen was the reference standard. Univariate and multivariate analyses were performed to evaluate the association of PI-RADS v2 assessment category with final histology ≥pT3a PCa., Results: For a PI-RADS v2 assessment category threshold of 3, the overall performance for ruling out (sensitivity, negative predictive value, negative likelihood ratio) ≥pT3a PCa was 99%/98%/0.04 and was similar in both the low-risk (96%/97%/0.12; N = 137) and the intermediate/high-risk groups (100%/100%/0.0; N = 164). In univariate analysis, all clinical and tumor characteristics except age were significantly associated with ≥pT3a PCa. In multivariate analysis, PI-RADS v2 assessment categories ≤ 3 had a protective effect relative to categories 4 and 5. The inclusion of ESUR EPE score improved the AUC of ≥pT3a PCa prediction (from 0.73 to 0.86, p = 0.04 in the overall cohort). The impact of PI-RADS v2 assessment category is reflected in a nomogram derived on the basis of our cohort., Conclusions: In our cohort, low PI-RADS v2 assessment categories of 3 or less confidently ruled out the presence of ≥pT3a PCa irrespective of clinical risk group., Key Points: • Our analysis of 301 mp-MRI and RARP specimens showed that the addition of PI-RADS v2 assessment categories to clinical parameters improves the exclusion of ≥pT3a (extraprostatic) prostate cancer. • PI-RADS v2 assessment categories of 1 to 3 are useful for excluding ≥pT3a prostate cancer with a NPV of 98%; such patients can be considered as candidates for less invasive approaches. • The ability to exclude ≥pT3a prostate cancer may improve confidence in choosing nerve-sparing surgery or in avoiding pelvic nodal dissections, and similarly for patients undergoing radiotherapy, in adopting short-course adjuvant hormonal therapy or foregoing prophylactic nodal irradiation.

Background: Nowadays, there is a debate about which surgical treatment should be best for clinical T1 renal tumors. If the oncological outcomes are considered, there are many open and laparoscopic series published. As far as robotic series are concerned, only a few of them report 5-yr oncological outcomes., Objective: The aim of this study was to analyze robot-assisted partial nephrectomy (RAPN) midterm oncological outcomes achieved in a tertiary robotic reference center., Design, Setting, and Participants: Between April 2009 and September 2013, 123 consecutive patients with clinical T1-stage renal masses underwent RAPN in our tertiary cancer center. Inclusion criteria were as follows: pathologically confirmed renal cell carcinomas (RCCs) and follow-up for >12 mo. Eighteen patients were excluded due to follow-up of <12 mo and 15 due to benign final pathology. Median follow-up was 59 mo (interquartile range 44-73 mo). Patients were followed according to guideline recommendations and institutional protocol., Outcome Measurements and Statistical Analysis: Outcomes were measured by time to disease progression, overall survival, or time to cancer-specific death. Kaplan-Meier method was used to estimate survival; log-rank tests were applied for pair-wise comparison of survival., Results and Limitations: From the 90 patients included, 66 (73.3%) had T1a, 12 (13.3%) T1b, three (3.3%) T2a, and nine (10%) T3a tumors. Predominant histological type was clear cell carcinoma: 67 (74.5%). Fuhrmann grade 1 and 2 was found in 73.3% of all malignant tumors. Two patients (2.2%) had positive surgical margins, and complication rate was 17.8%. Relapse rate was 7.7%, including two cases (2.2%) of local recurrences and five (5.5%) distant metastasis. Five-year disease-free survival was 90.9%, 5-yr cancer-specific survival was 97.5%, and 5-yr overall survival was 95.1%., Conclusions: Midterm oncological outcomes after RAPN for localized RCCs (predominantly T1a tumors of low anatomic complexity) were shown to be good, adding significant evidence to support the oncological efficacy and safety of RAPN for the treatment of this type of tumors., Patient Summary: Robot-assisted partial nephrectomy seems to be the most promising minimally invasive approach in the treatment of renal masses suitable for organ-sparing surgery as midterm (5 yr) oncological outcomes are excellent., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: The evaluation of the surgical margin in breast conservative surgery is a matter of general interest as such treatments are subject to the critical issue of margin status as positive surgical margins can undermine the effectiveness of the procedure. The relatively unexplored ability of millimeter-wave (mm-wave) spectroscopy to provide insight into the dielectric properties of breast tissues was investigated as a precursor to their possible use in assessment of surgical margins., Methods: We assessed the ability of a mm-wave system with a roughly hemispherical sensitive volume of ∼3 mm radius to distinguish malignant breast lesions in prospectively and consecutively collected tumoral and non-tumoral ex-vivo breast tissue samples from 91 patients. We characterized the dielectric properties of 346 sites in these samples, encompassing malignant, fibrocystic disease and normal breast tissues. An expert pathologist subsequently evaluated all measurement sites., Results: At multivariate analysis, mm-wave dielectric properties were significantly correlated to histologic diagnosis and fat content. Further, using 5-fold cross-validation in a Bayesian logistic mixed model that considered the patient as a random effect, the mm-wave dielectric properties of neoplastic tissues were significantly different from normal breast tissues, but not from fibrocystic tissue., Conclusion: Reliable discrimination of malignant from normal, fat-rich breast tissue to a depth compatible with surgical margin assessment requirements was achieved with mm-wave spectroscopy., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The aim of this study was to assess the long-term oncologic and functional outcomes in elderly patients having undergone robot-assisted partial nephrectomy (RAPN) for renal cancer (RC)., Methods: Sixty-one patients out of 323 who underwent RAPN for localized RC between July 2009 and March 2016 in our high-volume robotic surgery center (>800 procedures/year), had 70 years or more. Inclusion criteria of the study were age ≥70 years; pathological confirmed RCC and ASA Score ≤3. All patients were stratified according to PADUA classification system in three groups: <7 points, 8-9 points, >10 points. Trifecta was defined as a warm ischemia time (WIT) less then 25 min, negative surgical margins and no perioperative complications., Results: A total of 52 patients were included; median follow-up was 47 months. Median age was 74 yrs. (IQR 72-76.5). Complication rate was 15.4%. Trifecta failure was associated to PADUA Score (P=0.02), and tumor diameter (P=0.04). Renal function was altered in 10 (19.2%) patients before surgery and at last follow-up in 11 (21.1%) patients (CKD stage>2) The DFS, OS and CSS were 89.33%, 90.06% and 94.4%, respectively., Conclusions: In a high-volume center, robot-assisted approach is feasible and safe in surgical fit elderly patients with good long-term oncologic outcomes.

Background: Ultrasound-guided vacuum-assisted breast biopsy (US-VABB) has recently replaced surgical biopsy as a result of its high diagnostic accuracy and low patient discomfort, and at present it relies mainly on 2 devices, Mammotome and, more recently, Mammotome Elite (Elite). Our purpose was to compare the efficacy of these 2 bioptical devices., Patients and Methods: We performed US-VABB on 195 patients with Mammotome 8G or 11G in 130 patients and Elite 13G in 65 patients. Of these 195 patients, 95 were submitted to surgery for lumpectomy or mastectomy in case of malignant lesions or of lesions of uncertain malignant potential (B5 and B3), while the remaining 100 were strictly monitored clinically and radiologically for 12 to 24 months., Results: Both the devices showed high absolute sensitivity (96.2% for Mammotome and 83.3% for Elite), complete sensitivity (98.1% for Mammotome and 90.0% for Elite), specificity (92.3% for Mammotome and 94.3% for Elite), and diagnostic accuracy (99.1% for Mammotome and 95% for Elite), thus fulfilling criteria suggested by the European guidelines. Total underestimation rate seemed to be higher in the Elite cohort (14.2%) than in the Mammotome cohort (3.4%) (P = .02). However, none of the patients with a benign diagnosis (B2) presented any event during the follow-up period., Conclusion: US-VABB is an accurate method for sampling breast lesions. Our study did not show large, statistically significant differences in diagnostic accuracy between the Elite and Mammotome systems, except for a slight increase in diagnostic underestimation of benign pathologies when using the Elite., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To report preliminary results of a cutting edge extreme hypofractionated treatment with concomitant boost to the dominant lesion for patients with early stage prostate cancer (PCa)., Methods: AIRC-IG-13218 is a prospective Phase II trial started in June 2015. Patients with low and intermediate risk PCa who met the inclusion criteria underwent extreme hypofractionated radiotherapy to the prostate (36.25 Gy in 5 fractions) and a simultaneous integrated boost to the dominant intraprostatic lesion (DIL) to 37.5 Gy. The DIL was identified by a multiparamentric MRI (mpMRI) co-registered with planning CT. Toxicity was assessed according to CTCAE v4.0 and RTOG/EORTC criteria. The preliminary evaluation of the first 13 patients was required to confirm the feasibility of the treatment before completing the enrollment of 65 patients., Results: The first 13 patients completed the treatment between June 2015 and February 2016. With a median clinical follow-up of 17 months (range 11-26), no Grade 3 or 4 early toxicity was reported., Conclusions: Our preliminary data about early toxicity of an extreme hypofractionated schedule with concomitant boost on the DIL are encouraging. The higher number of patients expected for the trial and a longer follow-up are needed to confirm these results. Advances in knowledge: The use of mpMRI to identify and boost the DIL is an innovative and interesting approach to PCa. Our preliminary findings suggest that dose escalation using DIL boost and extremely hypofractionated radiotherapy regimens might be a safe approach, allowing for short and effective treatment of organ-confined PCa.

Purpose: To evaluate the oncological and functional outcomes of patients diagnosed with penile cancer undergoing conservative treatment through thulium-yttrium-aluminium-garnet (Tm:YAG) laser ablation., Methods: Twenty-six patients with a penile lesion underwent ablation with a RevoLix 200 W continuous-wave laser. The procedure was carried out with a pen-like laser hand piece, using a 360 μm laser fiber and 15-20 W of power. Median (IQR) follow-up time was 24 (15-30) months. Recurrence rate and post-operative sexual function were assessed., Results: Median age at surgery was 61 years. Median (inter quartile range) size of the lesions was 15 [10-20] mm. Overall, 11 (47.8%) and 12 (52.2%) at the final pathology presented in situ and invasive squamous cell carcinoma (SCC), respectively. The final pathological stage was pTis, pT1a, pT2, and pT3 in 11 (47.8%), 7 (30.4%), 3 (13.0%), and 2 (8.7%) patients, respectively. Moreover, four (17.4%) patients had a recurrence of which three (13.0%) and one (4.3%) patients developed an invasive or in situ recurrence, respectively. After treatment 6 (26.1%) patients reported a conserved penile sensitivity, while 13 (56.5%) and 4 (17.4%) patients experienced a better or worse sensitivity after ablation, respectively. Post-treatment sexual activity was achieved within the first month after laser ablation in 82.6% of the patients., Conclusion: Early stage penile carcinomas can be effectively treated with an organ preservation strategy. Tm:YAG conservative laser treatment is easy, safe and offers good functional outcome, with a minor impact on patient's quality of life.

Background: Frozen section examination (FSE) for testicular masses is gaining popularity because of the possibility of performing testis-sparing surgery (TSS) on the basis of the FSE results. The aim of our study was to investigate the reliability of FSE in the diagnosis of testicular masses., Patients and Methods: From 1999 to 2016, 144 of 692 patients who underwent surgery in our tertiary center for testicular masses had FSE. The indications for FSE were: masses < 1 cm, nonpalpable, multiple, or with unusual presentation. Mean follow-up for patients was 25.5 months. The algorithm of surgery determined by FSE was: orchiectomy if malignant or nonconclusive pathology; TSS if benign or nontumor pathology. FSE data were analyzed retrospectively. Specificity and sensitivity of the method was calculated for benign, malignant, seminoma, and nonseminoma tumors., Results: Intraoperative FSE was conducted on 21% of candidates for surgery on testicular masses. The sensitivity and specificity of FSE were 93% and 98%, respectively, for malignant tumors, and 90% and 99%, respectively, for benign tumors. The κ agreement coefficient between FSE and final histopathology was statistically significant (0.76). TSS was performed in 57 (40%) patients, including 6 of 23 monorchid patients., Conclusion: FSE correlates well with final histopathological diagnosis of testicular masses. Thus, it reliably identifies patients who might benefit from TSS. FSE should be considered always in small, nonpalpable, multiple, or uncommonly presenting masses in solitary testis or both testes., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The aim of this study was to assess the ability of pre-and intraoperative parameters, to predict the risk of perioperative complications after robot-assisted laparoscopic simple enucleation (RASE) of renal masses, and to evaluate the rate of trifecta achievement of this approach stratifying the cohort according to the use of ischemia during the enucleation.From April 2009 to June 2016, 129 patients underwent RASE at our Institution. We stratified the procedures in 2 groups: clamping and clamp-less RASE. After RASE, all specimens were retrospectively reviewed to assess the surface-intermediate-base (SIB) scoring system. Patients were followed-up according to the European Association of Urology guidelines recommendations. All pre-, intra-, and postoperative outcomes were prospectively collected in a customized database and retrospectively analyzed.A total of 112 (86.8%) patients underwent a pure RASE and 17 (13.2%) had a hybrid according to SIB classification system. The mean age was 61.17 years. In 21 patients (16.3%), complications occurred, 13 (61.9%) were Clavien 1 and 2, while 8 were Clavien 3a and b complications. Statistical significant association with complications was found in patients with American Society of Anestesiology (ASA) score 3 (44.5%, P = .04), longer mean operative time (OT) 195 versus 161.36 minutes (P =.03), mean postoperative hemoglobin (Hb) 10.1 versus 11.8 (P <.001), and mean ΔHb 3.59 versus 2.18 (P <.001). In multivariate logistic regression, only longer OT and ΔHb were statistical significant predictive factors for complications. In sub-group analysis, clamp-less RASE was safe in terms of complications (14.1%), positive surgical margins (1.3%), and mid-term local recurrence (1.3%). Although in this approach there is higher EBL (P = .01), this had no impact on ΔHb (P = .28). A clamp-less approach was associated with a higher rate of SIB 0 (71.8% vs 51%, P = .02), higher trifecta achievement (84.6% vs 62.7%, P = .004), and better impact on serum creatinine (mean 0.83 vs 0.91, P = .01).RASE of renal tumors is a safe technique with very good postoperative outcomes. Complication rate is low and associated with ASA score >3, longer OT, and ΔHb. RASE is suitable for the clamp-less approach, which allows to perform easier the pure enucleation (SIB 0) and to obtain higher rates of trifecta outcomes.

Objective: To assess whether cell-cycle progression (CCP)-score (Prolaris) can improve the current risk assessment in newly diagnosed prostate cancer (PCa) patients. CCP-score is a well-validated prognostic assay predictive of PCa death, biochemical recurrence, and progression., Methods: We evaluated CCP-score at biopsy in 52 patients newly diagnosed with PCa who underwent radical prostatectomy. CCP-score was calculated as average RNA expression of 31 CCP genes, normalized to 15 housekeeping genes. The predictive ability of CCP-score was assessed in univariate and multivariate analyses, and compared to that of Ki-67 levels and traditional clinical variables including prostate-specific antigen, Gleason score, stage, and percentage of positive cores at biopsy., Results: In spite of an overall good accuracy in attributing the correct risk class, 7 high-risk and 13 intermediate-risk patients were misclassified by the Prolaris test. On analysis of variance, mean CCP-score significantly differed across different risk classes based on pathologic results (-1.2 in low risk, -0.444 in intermediate risk, 0.208 in high risk). CCP-score was a significant predictor of high-risk PCa both on univariate and multivariate analyses, after adjusting for clinical variables. Combining CCP-score and the European Association of Urology clinical risk assessment improved the accuracy of risk attribution by around 10%, up to 87.8%. CCP-score was a significant predictor of biochemical recurrence, but only on univariate analysis., Conclusion: The CCP-score might provide important new information to risk assessment of newly diagnosed PCa in addition to traditional clinical variables. A correct risk attribution is essential to tailor the best treatment for each patient., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Most patients who initially respond to treatment with the multi-tyrosine kinase inhibitor sunitinib eventually relapse. Therefore, developing a deeper understanding of the contribution of sunitinib's numerous targets to the clinical response or to resistance is crucial. Here, we have shown that cancer cells respond to clinically relevant doses of sunitinib by enhancing the stability of the antiapoptotic protein MCL-1 and inducing mTORC1 signaling, thus evoking little cytotoxicity. Inhibition of MCL-1 or mTORC1 signaling sensitized cells to clinically relevant doses of sunitinib in vitro and was synergistic with sunitinib in impairing tumor growth in vivo, indicating that these responses are triggered as prosurvival mechanisms that enable cells to tolerate the cytotoxic effects of sunitinib. Furthermore, higher doses of sunitinib were cytotoxic, triggered a decline in MCL-1 levels, and inhibited mTORC1 signaling. Mechanistically, we determined that sunitinib modulates MCL-1 stability by affecting its proteasomal degradation. Dual modulation of MCL-1 stability at different dose ranges of sunitinib was due to differential effects on ERK and GSK3β activity, and the latter also accounted for dual modulation of mTORC1 activity. Finally, comparison of patient samples prior to and following sunitinib treatment suggested that increases in MCL-1 levels and mTORC1 activity correlate with resistance to sunitinib in patients., Competing Interests: The authors have declared that no conflict of interest exists.

To evaluate the role of multiparametric magnetic resonance imaging (mpMRI) in predicting upgrading, upstaging, and extraprostatic extension in patients with low-risk prostate cancer (PCa). MpMRI may reduce positive surgical margins (PSM) and improve nerve-sparing during robotic-assisted radical prostatectomy (RARP) for localized prostate cancer PCa.This was a retrospective, monocentric, observational study. We retrieved the records of patients undergoing RARP from January 2012 to December 2013 at our Institution. Inclusion criteria were: PSA <10 ng/mL; clinical stage

Background: Several clinical trials have reported that therapies targeting programmed death-1 (PD1) and its ligand (PD-L1) improve patient outcomes, while tumor response has been related to PD-L1 expression., Objective: To investigate the prognostic role of PD-L1 expression in patients affected by renal cell carcinoma (RCC)., Methods: MEDLINE/PubMed, the Cochrane Library, and ASCO University were searched for studies investigating the prognostic role of PD-L1 expression in RCC. Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement., Results: Six studies and 1323 cases were included in the final analysis. PD-L1 was expressed in 24.2 % of clear cell tumors compared to 10.9 % of non-clear cell tumors (p = 0.002). In the overall population, a higher level of PD-L1 expression increased the risk of death by 81 % (HR; 1.81, 95 % CI 1.31-2.49; p < 0.001). When the analysis was restricted to cases evaluated by immunohistochemistry alone, the higher expression of PD-L1 more than doubled the risk of death (HR; 2.05, 95 % CI 1.38-3.05; p < 0.001). In clear cell histology, higher PD-L1 expression increased the risk of death by 53 % (HR; 1.53, 95 % CI 1.27-1.84; p < 0.001), while in metastatic patients, the evaluation of PD-L1 expression on primary tumors revealed that it retains its prognostic role (HR; 1.45, 95 % CI 1.08-1.93; p = 0.01)., Limitations: Significant heterogeneity has been identified among the included studies. As a consequence, cautious interpretation of the results is recommended., Conclusion: This meta-analysis indicates that a higher level of PD-L1 expression is a negative prognostic factor in RCC. Its validation as an independent prognostic factor compared to other traditionally used clinical parameters in localized or advanced disease is recommended.

Background: Fluorouracil-based adjuvant chemotherapy in gastric cancer has been reported to be effective by several meta-analyses. Perioperative chemotherapy in locally advanced resectable gastric cancer (RGC) has been reported improving survival by two large randomized trials and recent meta-analyses but the role of neoadjuvant chemotherapy and optimal regimen remains to be determined. We compared a neoadjuvant with adjuvant docetaxel-based regimen in a prospective randomized phase III trial, of which we present the 10-year follow-up data., Patients and Methods: Patients with cT3-4 anyN M0 or anyT cN1-3 M0 gastric carcinoma, staged with endoscopic ultrasound, computed tomography, bone scan, and laparoscopy, were assigned to receive four 21-day/cycles of docetaxel 75 mg/m(2) day 1, cisplatin 75 mg/m(2) day 1, and fluorouracil 300 mg/m(2)/day over days 1-14, either before (arm A) or after (arm B) gastrectomy. Event-free survival was the primary end point, whereas secondary end points included overall survival, toxicity, down-staging, pathological response, quality of life, and feasibility of adjuvant chemotherapy., Results: This trial was activated in November 1999 and closed in November 2005 due to insufficient accrual. Of the 70 enrolled patients, 69 were randomized, 34 to arm A and 35 to arm B. No difference in EFS (2.5 years in both arms) or OS (4.3 versus 3.7 years, in arms A and B, respectively) was found. A higher dose intensity of chemotherapy was observed in arm A and more frequent chemotherapy-related serious adverse events occurred in arm B. Surgery was safe after preoperative chemotherapy. A 12% pathological complete response was observed in arm A., Conclusion: Docetaxel/cisplatin/fluorouracil chemotherapy is promising in preoperative setting of locally advanced RGC. The early stopping could mask the real effectiveness of neoadjuvant treatment. However, the complete pathological tumour responses, feasibility, and safe surgery warrant further investigation of a taxane-based regimen in the preoperative setting., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Chronic stress induces signalling from the sympathetic nervous system (SNS) and drives cancer progression, although the pathways of tumour cell dissemination are unclear. Here we show that chronic stress restructures lymphatic networks within and around tumours to provide pathways for tumour cell escape. We show that VEGFC derived from tumour cells is required for stress to induce lymphatic remodelling and that this depends on COX2 inflammatory signalling from macrophages. Pharmacological inhibition of SNS signalling blocks the effect of chronic stress on lymphatic remodelling in vivo and reduces lymphatic metastasis in preclinical cancer models and in patients with breast cancer. These findings reveal unanticipated communication between stress-induced neural signalling and inflammation, which regulates tumour lymphatic architecture and lymphogenous tumour cell dissemination. These findings suggest that limiting the effects of SNS signalling to prevent tumour cell dissemination through lymphatic routes may provide a strategy to improve cancer outcomes.

Purpose: The aim of this study was to investigate the prognostic performance of multiparametric magnetic resonance imaging (mpMRI) and Prostate Imaging Reporting and Data System (PIRADS) score in predicting pathologic features in a cohort of patients eligible for active surveillance who underwent radical prostatectomy., Methods: A total of 223 patients who fulfilled the criteria for "Prostate Cancer Research International: Active Surveillance", were included. Mp-1.5 Tesla MRI examination staging with endorectal coil was performed at least 6-8 weeks after TRUS-guided biopsy. In all patients, the likelihood of the presence of cancer was assigned using PIRADS score between 1 and 5. Outcomes of interest were: Gleason score upgrading, extra capsular extension (ECE), unfavorable prognosis (occurrence of both upgrading and ECE), large tumor volume (≥ 0.5 ml), and seminal vesicle invasion (SVI). Receiver Operating Characteristic (ROC) curves and Decision Curve Analyses (DCA) were performed for models with and without inclusion of PIRADS score., Results: Multivariate analysis demonstrated the association of PIRADS score with upgrading (P < 0.0001), ECE (P < 0.0001), unfavorable prognosis (P < 0.0001), and large tumor volume (P = 0.002). ROC curves and DCA showed that models including PIRADS score resulted in greater net benefit for almost all the outcomes of interest, with the only exception of SVI., Conclusions: mpMRI and PIRADS scoring are feasible tools in clinical setting and could be used as decision-support systems for a more accurate selection of patients eligible for AS.

Bone involvement has been reported in 1-13% of patients with sarcoidosis. Both 18F-fluorodeoxyglucose ((18)F-FDG) Positron Emission Tomography/Computed Tomography (PET/CT) and conventional magnetic resonance imaging (MRI) are sensitive in detecting sarcoidosis bone lesions, but are not always reliable in differentiating sarcoidosis bone lesions from metastatic disease, thus often requiring bone biopsy. We describe the use of diffusion whole-body MRI for bone assessment in a patient with breast cancer and sarcoidosis, presenting with bone marrow lesions mimicking metastatic disease at (18)F-FDG PET/CT. In our case, diffusion whole-body MRI represented a useful tool for bone assessment and overcame the limitation of (18)F-FDG PET/CT in discriminating inflammatory bone marrow involvement from metastatic disease.

Background: Obesity is associated with an increased risk of high-grade prostate cancer (PCa). The effect of body mass index (BMI) as a predictor of progression in men with low-risk PCa has been only poorly assessed. In this study, we evaluated the association of BMI with progression in patients with low-risk PCa who met the inclusion criteria for the active surveillance (AS) protocol., Methods: We assessed 311 patients who underwent radical prostatectomy and were eligible for AS according to the following criteria: clinical stage T2a or less, prostate-specific antigen level < 10 ng/ml, 2 or fewer cores involved with cancer, Gleason score ≤ 6 grade, and prostate-specific antigen density < 0.2 ng/ml/cc. Reclassification was defined as upstaged (pathological stage > pT2) and upgraded (Gleason score ≥ 7; primary Gleason pattern 4) disease. Seminal vesicle invasion, positive lymph nodes, and tumor volume ≥ 0.5 ml were also recorded., Results: We found that high BMI was significantly associated with upgrading, upstaging, and seminal vesicle invasion, whereas it was not associated with positive lymph nodes or large tumor volume. At multivariate analysis, 1 unit increase of BMI significantly increased the risk of upgrading, upstaging, seminal vesicle invasion, and any outcome by 21%, 23%, 27%, and 20%, respectively. The differences between areas under the receiver operating characteristics curves comparing models with and without BMI were statistically significant for upgrading (P = 0.0002), upstaging (P = 0.0007), and any outcome (P = 0.0001)., Conclusions: BMI should be a selection criterion for inclusion of patients with low-risk PCa in AS programs. Our results support the idea that obesity is associated with worse prognosis and suggest that a close AS program is an appropriate treatment option for obese subjects., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: To investigate whether use of multiparametric magnetic resonance (MR) imaging-directed intraoperative frozen-section (IFS) analysis during nerve-sparing robot-assisted radical prostatectomy reduces the rate of positive surgical margins., Materials and Methods: This retrospective analysis of prospectively acquired data was approved by an institutional ethics committee, and the requirement for informed consent was waived. Data were reviewed for 134 patients who underwent preoperative multiparametric MR imaging (T2 weighted, diffusion weighted, and dynamic contrast-material enhanced) and nerve-sparing robot-assisted radical prostatectomy, during which IFS analysis was used, and secondary resections were performed when IFS results were positive for cancer. Control patients (n = 134) matched for age, prostate-specific antigen level, and stage were selected from a pool of 322 patients who underwent nerve-sparing robot-assisted radical prostatectomy without multiparametric MR imaging and IFS analysis. Rates of positive surgical margins were compared by means of the McNemar test, and a multivariate conditional logistic regression model was used to estimate the odds ratio of positive surgical margins for patients who underwent MR imaging and IFS analysis compared with control subjects., Results: Eighteen patients who underwent MR imaging and IFS analysis underwent secondary resections, and 13 of these patients were found to have negative surgical margins at final pathologic examination. Positive surgical margins were found less frequently in the patients who underwent MR imaging and IFS analysis than in control patients (7.5% vs 18.7%, P = .01). When the differences in risk factors are taken into account, patients who underwent MR imaging and IFS had one-seventh the risk of having positive surgical margins relative to control patients (adjusted odds ratio: 0.15; 95% confidence interval: 0.04, 0.61)., Conclusion: The significantly lower rate of positive surgical margins compared with that in control patients provides preliminary evidence of the positive clinical effect of multiparametric MR imaging-directed IFS analysis for patients who undergo prostatectomy., (© RSNA, 2014.)