Stefano Gobbo

Scopus Publications

Forensic value of soft tissue detachments from the hyoid bone in death due to strangulation asphyxia
Giovanna Del Balzo, Guido Pelletti, Dario Raniero, Alessia Farinelli, Andrea Uberti, Elisa Vermiglio, Gabriele Molteni, Riccardo Nocini, Stefano Gobbo, Francesco Taus,et al.
Wroclaw Medical University
BACKGROUND There are no unequivocal histopathological findings for the diagnosis of fatal asphyxia due to neck compression. From the observation of a series of asphyxiation cases, we noted, during microscopic analysis, a high frequency of "detachment" of soft tissues from the hyoid bone. This specifically refers to the presence of an optical space between the surface of the hyoid bone and soft tissues. OBJECTIVES We aimed to evaluate the detachment of soft tissues from the hyoid bone as specific histological evidence of death due to strangulation asphyxia. MATERIAL AND METHODS Ten blocks were taken from deaths due to external mechanical compression of the neck (strangulation asphyxia, group A), 22 blocks were taken from deaths for other causes without trauma to the neck (group B), and 38 blocks were obtained from living subjects that have undergone laryngectomies (group C). The presence/absence of detachments were compared between the 3 groups (A, B and C) using Fisher's exact test. RESULTS The detachment of soft tissues from the hyoid bone was observed in 5 cases (50%) in group A, 6 cases (27.2%) in group B, and 17 cases (44.3%) in group C. The sensitivity and specificity of the presence of the detachment in group A were 0.5 (95% confidence interval (95% CI): 0.38-0.62) and 0.57 (95% CI: 0.45-0.69), respectively. The comparison between the 3 groups and the presence/absence of soft tissue detachment showed no statistically significant differences between the groups (p = 0.329), clarifying that soft tissue detachment is a nonspecific variable for all 3 situations. CONCLUSIONS Detachment of soft tissues has poor value as a single element to favor the diagnosis of asphyxia due to violent compression of the neck and should be interpreted as an artifactual finding, unrelated to the neck injury or injury vitality.

iForensic, multicentric validation of digital whole slide images (WSI) in forensic histopathology setting according to the College of American Pathologists guidelines
Nicola Pigaiani, Antonio Oliva, Vito Cirielli, Simone Grassi, Vincenzo Arena, Luca-Maria Solari, Naomi Tatriele, Dario Raniero, Matteo Brunelli, Stefano Gobbo,et al.
Springer Science and Business Media LLC
Abstract Pathology has benefited from the rapid progress of image-digitizing technology during the last decade. However, the application of digital whole slide images (WSI) in forensic pathology still needs to be improved. WSI validation is crucial to ensure diagnostic performance, at least equivalent to glass slides and light microscopy. The College of American Pathologists Pathology and Laboratory Quality Center recently updated internal digital pathology system validation recommendations. Following these guidelines, this pilot study aimed to validate the performance of a digital approach for forensic histopathological diagnosis. Six independent skilled forensic pathologists from different forensic medicine institutes evaluated 100 glass slides of forensic interest (80 stained with standard hematoxylin and eosin, 20 with special staining), including different organs and tissues, with light microscopy (Olympus BX51, Tokyo, Japan). Glass slides were scanned using the Aperio GT 450 DX Digital Slides Scanner (Leica Biosystems, Nussloch, Germany). After two wash-out weeks, forensic pathologists evaluated WSIs in front of a widescreen using computer devices with dedicated software (O3 viewer, O3 Enterprise, Zucchetti, Trieste, Italy). Side-by-side comparisons between diagnoses performed on tissue glass slides versus WSIs were above the threshold stated in the validation guidelines (mean concordance of 97.8%). CSUQ Version 3 questionnaire showed high satisfaction for all pathologists (mean result: 6.6/7). Our institutional digital forensic pathology system has been validated for practical casework application. This approach opens new scenarios in practical forensic casework investigations, such as sharing live histological ex-glass slides online, as well as educational and research perspectives, with improving impacts on the whole daily workflow.

Atypical suicide by single incising cut to the throat without hesitation marks: Case report and review of the literature
V. Cirielli, G. Cecchetto, M. Narayanasamy, A. Eccher, S. Gobbo, M. Brunelli, and N. Pigaiani
Elsevier BV

Artificial intelligence-based algorithms for the diagnosis of prostate cancer: A systematic review
Stefano Marletta, Albino Eccher, Filippo Maria Martelli, Nicola Santonicco, Ilaria Girolami, Aldo Scarpa, Fabio Pagni, Vincenzo L’Imperio, Liron Pantanowitz, Stefano Gobbo,et al.
Oxford University Press (OUP)
Abstract Objectives The high incidence of prostate cancer causes prostatic samples to significantly affect pathology laboratories workflow and turnaround times (TATs). Whole-slide imaging (WSI) and artificial intelligence (AI) have both gained approval for primary diagnosis in prostate pathology, providing physicians with novel tools for their daily routine. Methods A systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was carried out in electronic databases to gather the available evidence on the application of AI-based algorithms to prostate cancer. Results Of 6290 articles, 80 were included, mostly (59%) dealing with biopsy specimens. Glass slides were digitized to WSI in most studies (89%), roughly two-thirds of which (66%) exploited convolutional neural networks for computational analysis. The algorithms achieved good to excellent results about cancer detection and grading, along with significantly reduced TATs. Furthermore, several studies showed a relevant correlation between AI-identified histologic features and prognostic predictive variables such as biochemical recurrence, extraprostatic extension, perineural invasion, and disease-free survival. Conclusions The published evidence suggests that AI can be reliably used for prostate cancer detection and grading, assisting pathologists in the time-consuming screening of slides. Further technologic improvement would help widening AI’s adoption in prostate pathology, as well as expanding its prognostic predictive potential.

Characterization of two transcriptomic subtypes of marker-null large cell carcinoma of the lung suggests different origin and potential new therapeutic perspectives
Michele Simbolo, Giovanni Centonze, Anastasios Gkountakos, Valentina Monti, Patrick Maisonneuve, Stela Golovco, Giovanna Sabella, Alessandro Del Gobbo, Stefano Gobbo, Stefano Ferrero,et al.
Springer Science and Business Media LLC
AbstractPulmonary large cell carcinoma (LCC) is an undifferentiated neoplasm lacking morphological, histochemical, and immunohistochemical features of small cell lung cancer, adenocarcinoma (ADC), or squamous cell carcinoma (SCC). The available molecular information on this rare disease is limited. This study aimed to provide an integrated molecular overview of 16 cases evaluating the mutational asset of 409 genes and the transcriptomic profiles of 20,815 genes. Our data showed that TP53 was the most frequently inactivated gene (15/16; 93.7%) followed by RB1 (5/16; 31.3%) and KEAP1 (4/16; 25%), while CRKL and MYB genes were each amplified in 4/16 (25%) cases and MYC in 3/16 (18.8%) cases; transcriptomic analysis identified two molecular subtypes including a Pure-LCC and an adenocarcinoma like-LCC (ADLike-LCC) characterized by different activated pathways and cell of origin. In the Pure-LCC group, POU2F3 and FOXI1 were distinctive overexpressed markers. A tuft cell-like profile and the enrichment of a replication stress signature, particularly involving ATR, was related to this profile. Differently, the ADLike-LCC were characterized by an alveolar-cell transcriptomic profile and association with AIM2 inflammasome complex signature. In conclusion, our study split the histological marker-null LCC into two different transcriptomic entities, with POU2F3, FOXI1, and AIM2 genes as differential expression markers that might be probed by immunohistochemistry for the differential diagnosis between Pure-LCC and ADLike-LCC. Finally, the identification of several signatures linked to replication stress in Pure-LCC and inflammasome complex in ADLike-LCC could be useful for designing new potential therapeutic approaches for these subtypes.

TROP-2, NECTIN-4 and predictive biomarkers in sarcomatoid and rhabdoid bladder urothelial carcinoma
Matteo Brunelli, Stefano Gobbo, Giorgio Malpeli, Grazia Sirgiovanni, Claudia Caserta, Enrico Munari, Simona Francesconi, Anna Caliò, Guido Martignoni, Alessia Cimadamore,et al.
Siapec Servizi Srl
Summary Introduction The surface protein TROP-2/TACSTD2 and the cell adhesion protein NECTIN-4/NECTIN4 are responsible for the efficacy of anticancer therapies based on antibody-drug conjugates (ADC) targeting intracellular microtubules. In contrast with common histologic subtypes of bladder urothelial carcinoma (BUC), little is known of TROP-2 and NECTIN-4 expression in sarcomatoid and rhabdoid BUC. Aims In this study, we aimed to analyze TROP-2 and NECTIN-4 expression and additional predictive biomarkers by immunohistochemistry and fluorescence in situ hybridization (FISH) on 35 undifferentiated BUC (28 sarcomatoid and 7 rhabdoid). Wide genomic investigation was also performed on 411 BUC cases of the PanCancer Atlas, focusing on genes related to the microtubule pathways. Results Seven of 35 (20%) undifferentiated BUC showed expression of TROP-2. NECTIN-4 was expressed in 10 cases (29%). Seven cases (20%) co-expressed TROP-2 and NECTIN-4. HER-2 FISH was amplified in 5 cases (14%) while HER-2 immunoexpression was observed in 14 cases (40%). PD-L1 scored positive for combined proportion score (CPS) in 66% of cases and for tumor proportion score (TPS) in 51% of cases. Pan-NTRK1-2/3 was elevated in 9 cases (26%) and FGFR-2/3 was broken in 7 of 35 cases (20%). Of 28 sarcomatoid BUC, 9 (32%) were negative for all (TROP-2, NECTIN-4, PD-L1, HER-2, FGFR and pan-NTRK) biomarkers and 3 (11%) expressed all five biomarkers. Among cases with rhabdoid dedifferentiation, 1 of 7 (14%) showed activation of all biomarkers, whereas 2 of 7 (28%) showed none. The mRNA analysis identified microtubule-related genes and pathways suitable for combined ADC treatments in BUC. Conclusion Sarcomatoid and rhabdoid BUC do harbor positive expression of the ADC targets TROP-2 or NECTIN-4 in a relatively modest subset of cases, whereas the majority do not. Different combinations of other positive biomarkers may help the choice of medical therapies. Overall, these findings have important clinical implications for targeted therapy for BUC.

Galileo—an Artificial Intelligence tool for evaluating pre-implantation kidney biopsies
Albino Eccher, Vincenzo L’Imperio, Liron Pantanowitz, Giorgio Cazzaniga, Fabio Del Carro, Stefano Marletta, Giovanni Gambaro, Antonella Barreca, Jan Ulrich Becker, Stefano Gobbo,et al.
Springer Science and Business Media LLC
Abstract Background Pre-transplant procurement biopsy interpretation is challenging, also because of the low number of renal pathology experts. Artificial intelligence (AI) can assist by aiding pathologists with kidney donor biopsy assessment. Herein we present the “Galileo” AI tool, designed specifically to assist the on-call pathologist with interpreting pre-implantation kidney biopsies. Methods A multicenter cohort of whole slide images acquired from core-needle and wedge biopsies of the kidney was collected. A deep learning algorithm was trained to detect the main findings evaluated in the pre-implantation setting (normal glomeruli, globally sclerosed glomeruli, ischemic glomeruli, arterioles and arteries). The model obtained on the Aiforia Create platform was validated on an external dataset by three independent pathologists to evaluate the performance of the algorithm. Results Galileo demonstrated a precision, sensitivity, F1 score and total area error of 81.96%, 94.39%, 87.74%, 2.81% and 74.05%, 71.03%, 72.5%, 2% in the training and validation sets, respectively. Galileo was significantly faster than pathologists, requiring 2 min overall in the validation phase (vs 25, 22 and 31 min by 3 separate human readers, p < 0.001). Galileo-assisted detection of renal structures and quantitative information was directly integrated in the final report. Conclusions The Galileo AI-assisted tool shows promise in speeding up pre-implantation kidney biopsy interpretation, as well as in reducing inter-observer variability. This tool may represent a starting point for further improvements based on hard endpoints such as graft survival. Graphical Abstract

A rare case of jejunal Vanek’s tumor causing intussusception in an adult: a case report and comprehensive literature overview
Nicolò Fabbri, Francesco Rimi, Valentina Sani, Antonio Pesce, Salvatore Greco, Stefano Gobbo, and Carlo V Feo
Oxford University Press (OUP)
Abstract Inflammatory fibroid polyp, or Vanek's tumor, is an uncommon benign small bowel tumor and a rare cause of intussusception in adults. This case involves a 62-year-old man with persistent abdominal pain, diagnosed with jejunoileal intussusception. A 4 cm inflammatory fibroid polyp was discovered during surgery, leading to distal jejunal resection. Despite the rarity of adult intussusceptions, they should be considered in abdominal pain diagnoses. The optimal management approach, whether en bloc resection or initial reduction with limited resection, remains debated.

mTOR eosinophilic renal cell carcinoma: a distinctive tumor characterized by mTOR mutation, loss of chromosome 1, cathepsin-K expression, and response to target therapy
Anna Caliò, Stefano Marletta, Giulio Settanni, Mimma Rizzo, Stefano Gobbo, Serena Pedron, Lavinia Stefanizzi, Enrico Munari, Matteo Brunelli, Lisa Marcolini,et al.
Springer Science and Business Media LLC
AbstractIn the spectrum of oncocytic renal neoplasms, a subset of tumors with high-grade-appearing histologic features harboring pathogenic mutations in mammalian target of rapamycin (mTOR) and hitherto clinical indolent behavior has been described. Three cases (2F,1 M) with histologically documented metastases (lymph node, skull, and liver) were retrieved and extensively investigated by immunohistochemistry, FISH, and next-generation sequencing. Tumors were composed of eosinophilic cells with prominent nucleoli (G3 by ISUP/WHO) arranged in solid to nested architecture. Additionally, there were larger cells with perinuclear cytoplasmic shrinkage and sparse basophilic Nissl-like granules, superficially resembling the so-called spider cells of cardiac rhabdomyomas. The renal tumors, including the skull and liver metastases, showed immunoexpression PAX8, CK8-18, and cathepsin-K, and negativity for vimentin. NGS identified mTOR genetic alterations in the three cases, including the skull and liver metastases. One patient was then treated with Everolimus (mTOR inhibitors) with clinical response (metastatic tumor shrinkage). We present a distinct renal tumor characterized by high-grade eosinophilic cells, cathepsin-K immunohistochemical expression, and harboring mTOR gene mutations demonstrating a malignant potential and showing responsiveness to mTOR inhibitors.

Validation of real-time prostatic biopsies evaluation with fluorescence laser confocal microscopy
Stefano GOBBO, Albino ECCHER, Sebastian GALLINA, Damiano D’AIETTI, Alessandro PRINCIOTTA, Francesco DITONNO, Alessandro TAFURI, Maria A. CERRUTO, Stefano MARLETTA, Francesca SANGUEDOLCE,et al.
Edizioni Minerva Medica
BACKGROUND Routine processing of prostate biopsies requires conventional steps that usually take a few days. The aim of this study was to validate the use of fluorescence laser confocal microscopy (FCM) for real-time diagnostics. METHODS We prospectively tested images from prostate needle biopsies (75 images were evaluated by FCM and conventional slides). Two pathologists reviewed the images and assessed agreements between FCM versus conventional slides and between pathologists (κ-values). Interpretation was performed on digital images from the VivaScope 2500 confocal microscope (MAVIG GmbH, Munich, Germany; Caliber I.D., Rochester, NY, USA) placed in the urological operating room. Cancerous versus benign tissue was the primary focus, then the application of the grading system. RESULTS Cancer was diagnosed in 24 conventional slides (on 75 images) in which agreement among pathologists was high for both conventional (κ=0.96) and FMC (κ=0.84). 1/24 (4%) was ISUP/WHO grade group I, 12/24 (50%) II, 8/24 (33%) III, 2/24 (8%) IV and 1/24 (4%) grade V. Near perfect agreement was obtained for grades I, IV and V (κ=0.85). Grade III values achieved a moderate agreement (κ=0.55). The mean time for laser scanning was 9 minutes. For the remaining non-tumor images, agreement was nearly perfect (κ=0.81). CONCLUSIONS We validated the use of FCM for real-time cancer detection in prostate biopsies.

Minimally invasive versus open distal pancreatectomy for resectable pancreatic cancer (DIPLOMA): an international randomised non-inferiority trial
Maarten Korrel, Leia R. Jones, Jony van Hilst, Gianpaolo Balzano, Bergthor Björnsson, Ugo Boggi, Svein Olav Bratlie, Olivier R. Busch, Giovanni Butturini, Giovanni Capretti,et al.
Elsevier BV

STING is a prognostic factor related to tumor necrosis, sarcomatoid dedifferentiation, and distant metastasis in clear cell renal cell carcinoma
Stefano Marletta, Anna Caliò, Giuseppe Bogina, Mimma Rizzo, Matteo Brunelli, Serena Pedron, Lisa Marcolini, Lavinia Stefanizzi, Stefano Gobbo, Alessandro Princiotta,et al.
Springer Science and Business Media LLC
AbstractSTING is a molecule involved in immune reactions against double-stranded DNA fragments, released in infective and neoplastic diseases, whose role in the interactions between immune and neoplastic cells in clear cell renal cell carcinoma has not been studied yet. We investigated the immunohistochemical expression of STING in a series of 146 clear-cell renal cell carcinomas and correlated it with the main pathological prognostic factors. Furthermore, tumoral inflammatory infiltrate was evaluated and studied for the subpopulations of lymphocytes. Expression of STING was observed in 36% (53/146) of the samples, more frequently in high-grade (G3–G4) tumors (48%,43/90) and recurrent/metastatic ones (75%, 24/32) than in low grade (G1–G2) and indolent neoplasms (16%, 9/55). STING staining correlated with parameters of aggressive behavior, including coagulative granular necrosis (p = 0.001), stage (p < 0.001), and development of metastases (p < 0.001). Among prognostic parameters, STING immune expression reached an independent statistical significance (p = 0.029) in multivariable analysis, along with the stage and the presence of coagulative granular necrosis. About tumor immune-environment, no significant statistical association has been demonstrated between tumor-infiltrating lymphocytes and STING. Our results provide novel insights regarding the role of STING in aggressive clear cell renal cell carcinomas, suggesting its adoption as a prognostic marker and a potentially targetable molecule for specific immunotherapies.

Digital pathology world tour
Paola Chiara Rizzo, Alessandro Caputo, Eddy Maddalena, Nicolò Caldonazzi, Ilaria Girolami, Angelo Paolo Dei Tos, Aldo Scarpa, Marta Sbaraglia, Matteo Brunelli, Stefano Gobbo,et al.
SAGE Publications
Objective Digital pathology (DP) is currently in the spotlight and is rapidly gaining ground, even though the history of this field spans decades. Despite great technological progress, the adoption of DP for routine clinical diagnostic use remains limited. Methods A systematic search was conducted in the electronic databases Pubmed-MEDLINE and Embase. Inclusion criteria were all published studies that encompassed any application of DP. Results Of 4888 articles retrieved, 4041 were included. Relevant articles were categorized as “diagnostic” (147/4041, 4%) where DP was utilized for routine diagnostic workflow and “non-diagnostic” (3894/4041, 96%) for all other applications. The “non-diagnostic” articles were further categorized according to DP application including “artificial intelligence” (33%), “education” (5%), “narrative” (17%) for reviews and editorials, and “technical” (45%) for pure research publications. Conclusion This manuscript provided temporal and geographical insight into the global adoption of DP by analyzing the published scientific literature.

TFE3 and TFEB-rearranged renal cell carcinomas: an immunohistochemical panel to differentiate from common renal cell neoplasms
Anna Caliò, Stefano Marletta, Matteo Brunelli, Serena Pedron, Sofia Canete Portillo, Diego Segala, Elena Bariani, Stefano Gobbo, George Netto, and Guido Martignoni
Springer Science and Business Media LLC
Abstract TFE3/TFEB-rearranged renal cell carcinomas are characterized by translocations involving TFE3 and TFEB genes. Despite the initial description of typical morphology, their histological spectrum is wide, mimicking common subtypes of renal cell tumors. Thus, the diagnosis is challenging requiring the demonstration of the gene rearrangement, usually by FISH. However, this technique is limited in most laboratories and immunohistochemical TFE3/TFEB analysis is inconsistent. We sought to identify a useful immunohistochemical panel using the most common available markers to recognize those tumors. We performed an immunohistochemical panel comparing 27 TFE3-rearranged and 10 TFEB-rearranged renal cell carcinomas to the most common renal cell tumors (150 clear cell, 100 papillary, 50 chromophobe renal cell carcinomas, 18 clear cell papillary renal cell tumors, and 50 oncocytomas). When dealing with neoplasms characterized by cells with clear cytoplasm, CA9 is a helpful marker to exclude clear cell renal cell carcinoma. GATA3, AMACR, and CK7 are useful to rule out clear cell papillary renal cell tumor. CK7 is negative in TFE3/TFEB-rearranged renal cell carcinoma and positive in papillary renal cell carcinoma, being therefore useful in this setting. Parvalbumin and CK7/S100A1 respectively are of paramount importance when TFE3/TFEB-rearranged renal cell carcinoma resembles oncocytoma and chromophobe renal cell carcinoma. Moreover, in TFEB-rearranged renal cell carcinoma, cathepsin K and melanogenesis markers are constantly positive, whereas TFE3-rearranged renal cell carcinoma stains for cathepsin K in roughly half of the cases, HMB45 in 8% and Melan-A in 22%. In conclusion, since TFE3/TFEB-rearranged renal cell carcinoma may mimic several histotypes, an immunohistochemical panel to differentiate them from common renal cell tumors should include cathepsin K, CA9, CK7, and parvalbumin.

CXCR4-CXCL12-CXCR7 and PD-1/PD-L1 in Pancreatic Cancer: CXCL12 Predicts Survival of Radically Resected Patients
Crescenzo D’Alterio, Alessandro Giardino, Giosuè Scognamiglio, Giovanni Butturini, Luigi Portella, Giuseppe Guardascione, Isabella Frigerio, Marco Montella, Stefano Gobbo, Guido Martignoni,et al.
MDPI AG
Pancreatic ductal adenocarcinoma (PDAC) is currently the most deadly cancer. Although characterized by 5–20% of neoplastic cells in the highly fibrotic stroma, immunotherapy is not a valid option in PDAC treatment. As CXCR4-CXCL12 regulates tumor invasion and T-cell access and PD-1/PD-L1 controls immune tolerance, 76 PDACs were evaluated for CXCR4-CXCL12-CXCR7 and PD-1/PD-L1 in the epithelial and stromal component. Neoplastic CXCR4 and CXCL12 discriminated PDACs for recurrence-free survival (RFS), while CXCL12 and CXCR7 discriminated patients for cancer-specific survival (CSS). Interestingly, among patients with radical resection (R0), high tumor CXCR4 clustered patients with worse RFS, high CXCL12 identified poor prognostic patients for both RFS and CSS, while stromal lymphocytic-monocytic PD-L1 associated with improved RFS and CSS. PD-1 was only sporadically expressed (<1%) in focal lymphocyte infiltrate and does not impact prognosis. In multivariate analysis, tumoral CXCL12, perineural invasion, and AJCC lymph node status were independent prognostic factors for RFS; tumoral CXCL12, AJCC Stage, and vascular invasion were independent prognostic factors for CSS. CXCL12’s poor prognostic meaning was confirmed in an additional perspective-independent 13 fine-needle aspiration cytology advanced stage-PDACs. Thus, CXCR4-CXCL12 evaluation in PDAC identifies prognostic categories and could orient therapeutic approaches.

Validation of a Novel Three-Dimensional (3D Fusion) Gross Sampling Protocol for Clear Cell Renal Cell Carcinoma to Overcome Intratumoral Heterogeneity: The Meet-Uro 18 Study
Matteo Brunelli, Guido Martignoni, Giorgio Malpeli, Alessandro Volpe, Luca Cima, Maria Rosaria Raspollini, Mattia Barbareschi, Alessandro Tafuri, Giulia Masi, Luisa Barzon,et al.
MDPI AG
We aimed to overcome intratumoral heterogeneity in clear cell renal cell carcinoma (clearRCC). One hundred cases of clearRCC were sampled. First, usual standard sampling was applied (1 block/cm of tumor); second, the whole tumor was sampled, and 0.6 mm cores were taken from each block to construct a tissue microarray; third, the residual tissue, mapped by taking pieces 0.5 × 0.5 cm, reconstructed the entire tumor mass. Precisely, six randomly derived pieces of tissues were placed in each cassette, with the number of cassettes being based on the diameter of the tumor (called multisite 3D fusion). Angiogenic and immune markers were tested. Routine 5231 tissue blocks were obtained. Multisite 3D fusion sections showed pattern A, homogeneous high vascular density (10%), pattern B, homogeneous low vascular density (8%) and pattern C, heterogeneous angiogenic signatures (82%). PD-L1 expression was seen as diffuse (7%), low (33%) and absent (60%). Tumor-infiltrating CD8 scored high in 25% (pattern hot), low in 65% (pattern weak) and zero in 10% of cases (pattern desert). Grading was upgraded in 26% of cases (G3–G4), necrosis and sarcomatoid/rhabdoid characters were observed in, respectively, 11 and 7% of cases after 3D fusion (p = 0.03). CD8 and PD-L1 immune expressions were higher in the undifferentiated G4/rhabdoid/sarcomatoid clearRCC subtypes (p = 0.03). Again, 22% of cases were set to intermediate to high risk of clinical recurrence due to new morphological findings of all aggressive G4, sarcomatoid/rhabdoid features by using 3D fusion compared to standard methods (p = 0.04). In conclusion, we propose an easy-to-apply multisite 3D fusion sampling that negates bias due to tumor heterogeneity.

TSC loss is a clonal event in eosinophilic solid and cystic renal cell carcinoma: a multiregional tumor sampling study
Enrico Munari, Giulio Settanni, Anna Caliò, Diego Segala, Sara Lonardi, Silvia Sandrini, Paola Vacca, Nicola Tumino, Marcella Marconi, Matteo Brunelli,et al.
Elsevier BV

Serous Neoplasms
Paola Capelli, Paolo Tinazzi Martini, Giovanni Morana, Riccardo de Robertis, Claudio Luchini, Stefano Gobbo, and Mirko D’Onofrio
Springer International Publishing

Neuroendocrine Neoplasms
Riccardo De Robertis, Mirko D’Onofrio, Paolo Tinazzi Martini, Stefano Gobbo, Maria Gaia Mastrosimini, Lavinia Stefanizzi, Alessandro Beleù, Luca Geraci, Aldo Scarpa, and Paola Capelli
Springer International Publishing

Role of next-generation genomic sequencing in targeted agents repositioning for pancreaticoduodenal cancer patients
Davide Melisi, Alessandro Cavaliere, Stefano Gobbo, Giulia Fasoli, Valentina Allegrini, Francesca Simionato, Marina Gaule, Simona Casalino, Camilla Pesoni, Camilla Zecchetto,et al.
Elsevier BV
BACKGROUND Pancreaticoduodenal cancer (PDC) is a group of malignant tumors arising in the ampullary region, which lack approved targeted therapies for their treatment. METHODS This retrospective, observational study is based on Secondary Data Use (SDU) previously collected during a multicenter collaboration, which were subsequently entered into a predefined database and analyzed. FoundationOne CDx or Liquid, a next-generation DNA sequencing (NGS) service, was used to identify genomic alterations of patients who failed standard treatments. Detected alterations were described according to ESMO Scale of Clinical Actionability for molecular Targets (ESCAT). RESULTS NGS analysis was performed in 68 patients affected by PDC. At least one alteration ranking tier I, II, III, or IV according to ESCAT classification was detected in 8, 1, 9, and 12 patients respectively (44.1%). Ten of them (33.3%) received a matched therapy. Patients with ESCAT tier I to IV were generally younger than the overall population (median = 54, range = 26-71 years), had an EGOG performance status score = 0 (83.3%), and an uncommon histological or clinical presentation. The most common mutations with clinical evidence of actionability (ESCAT tier I-III) involved genes of the RAF (10.3%), BRCA (5.9%) or FGFR pathways (5.9%). We present the activity of the RAF kinases inhibitor sorafenib in patients with RAF-mutated advanced PDC. CONCLUSIONS In advanced PDC, NGS is a feasible and valuable method for enabling precision oncology. This genomic profiling method might be considered after standard treatments failure, especially in young patients maintaining a good performance status, in order to detect potentially actionable mutations and offer molecularly targeted therapeutic approaches.

Stimulator of interferon genes (STING) immunohistochemical expression in the spectrum of perivascular epithelioid cell (PEC) lesions of the kidney
Anna Caliò, Matteo Brunelli, Stefano Gobbo, Serena Pedron, Diego Segala, Pedram Argani, and Guido Martignoni
Elsevier BV

Cathepsin k: A novel diagnostic and predictive biomarker for renal tumors
Anna Caliò, Matteo Brunelli, Stefano Gobbo, Pedram Argani, Enrico Munari, George Netto, and Guido Martignoni
MDPI AG
Cathepsin K is a papain-like cysteine protease with high matrix-degrading activity. Among several cathepsins, cathepsin K is the most potent mammalian collagenase, mainly expressed by osteoclasts. This review summarizes most of the recent findings of cathepsin K expression, highlighting its role in renal tumors for diagnostic purposes and as a potential molecular target. Indeed, cathepsin K is a recognized diagnostic tool for the identification of TFE3/TFEB-rearranged renal cell carcinoma, TFEB-amplified renal cell carcinoma, and pure epithelioid PEComa/epithelioid angiomyolipoma. More recently, its expression has been observed in a subgroup of eosinophilic renal neoplasms molecularly characterized by TSC/mTOR gene mutations. Interestingly, both TSC mutations or TFE3 rearrangement have been reported in pure epithelioid PEComa/epithelioid angiomyolipoma. Therefore, cathepsin K seems to be a downstream marker of TFE3/TFEB rearrangement, TFEB amplification, and mTOR pathway activation. Given the established role of mTOR inhibitors as a pharmacological option in renal cancers, cathepsin K could be of use as a predictive marker of therapy response and as a potential target. In the future, uropathologists may implement the use of cathepsin K to establish a diagnosis among renal tumors with clear cells, papillary architecture, and oncocytic features.

Parvalbumin immunohistochemical expression in the spectrum of perivascular epithelioid cell (PEC) lesions of the kidney
Anna Caliò, Serena Ammendola, Matteo Brunelli, Serena Pedron, Stefano Gobbo, and Guido Martignoni
Springer Science and Business Media LLC

Magnetic resonance (MR) for mural nodule detection studying Intraductal papillary mucinous neoplasms (IPMN) of pancreas: Imaging-pathologic correlation
Mirko D'Onofrio, Giorgia Tedesco, Nicolò Cardobi, Riccardo De Robertis, Alessandro Sarno, Paola Capelli, Paolo Tinazzi Martini, Gabriele Giannotti, Alessandro Beleù, Giovanni Marchegiani,et al.
Elsevier BV

Correlation of MR features and histogram-derived parameters with aggressiveness and outcomes after resection in pancreatic ductal adenocarcinoma
Riccardo De Robertis, Alessandro Beleù, Nicolò Cardobi, Isabella Frigerio, Silvia Ortolani, Stefano Gobbo, Bogdan Maris, Davide Melisi, Stefania Montemezzi, and Mirko D’Onofrio
Springer Science and Business Media LLC

Stefano Gobbo

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Scopus Publications