Browsing by Author "Malleo, Giuseppe"

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    Comprehensive characterisation of pancreatic ductal adenocarcinoma with microsatellite instability: histology, molecular pathology and clinical implications
    (BMJ Publishing Group, 2020-04-29) Luchini, Claudio; Brosens, Lodewijk A. A.; Wood, Laura D.; Chatterjee, Deyali; Shin, Jae Il; Sciammarella, Concetta; Fiadone, Giulia; Malleo, Giuseppe; Salvia, Roberto; Kryklyva, Valentyna; Piredda, Maria L.; Cheng, Liang; Lawlor, Rita T.; Adsay, Volkan; Scarpa, Aldo; Pathology and Laboratory Medicine, School of Medicine
    Objective Recently, tumours with microsatellite instability (MSI)/defective DNA mismatch repair (dMMR) have gained considerable interest due to the success of immunotherapy in this molecular setting. Here, we aim to clarify clinical-pathological and/or molecular features of this tumour subgroup through a systematic review coupled with a comparative analysis with existing databases, also providing indications for a correct approach to the clinical identification of MSI/dMMR pancreatic ductal adenocarcinoma (PDAC). Design PubMed, SCOPUS and Embase were searched for studies reporting data on MSI/dMMR in PDAC up to 30 November 2019. Histological and molecular data of MSI/dMMR PDAC were compared with non-MSI/dMMR PDAC and with PDAC reference cohorts (including SEER database and The Cancer Genome Atlas Research Network - TCGA project). Results Overall, 34 studies with 8323 patients with PDAC were included in the systematic review. MSI/dMMR demonstrated a very low prevalence in PDAC (around 1%–2%). Compared with conventional PDAC, MSI/dMMR PDAC resulted strongly associated with medullary and mucinous/colloid histology (p<0.01) and with a KRAS/TP53 wild-type molecular background (p<0.01), with more common JAK genes mutations. Data on survival are still unclear. Conclusion PDAC showing typical medullary or mucinous/colloid histology should be routinely examined for MSI/dMMR status using specific tests (immunohistochemistry, followed by MSI-PCR in cases with doubtful results). Next-generation sequencing (NGS) should be adopted either where there is limited tissue or as part of NGS tumour profiling in the context of precision oncology, acknowledging that conventional histology of PDAC may rarely harbour MSI/dMMR.
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    PD-1, PD-L1 and CD163 in pancreatic undifferentiated carcinoma with osteoclast-like giant cells: expression patterns and clinical implications
    (Elsevier, 2018) Luchini, Claudio; Cros, Jerome; Pea, Antonio; Pilati, Camilla; Veronese, Nicola; Rusev, Borislav; Capelli, Paola; Mafficini, Andrea; Nottegar, Alessia; Brosens, Lodewijk A. A.; Noë, Michaël; Offerhaus, G. Johan A.; Chianchiano, Peter; Riva, Giulio; Piccoli, Paola; Parolini, Claudia; Malleo, Giuseppe; Lawlor, Rita T.; Vincenzo, Corbo; Sperandio, Nicola; Barbareschi, Mattia; Fassan, Matteo; Cheng, Liang; Wood, Laura D.; Scarpa, Aldo; Pathology and Laboratory Medicine, School of Medicine
    Undifferentiated carcinoma with osteoclast-like giant cells (UCOGC), a variant of pancreatic ductal adenocarcinoma (PDAC), has striking genetic similarity to PDAC but a significantly improved overall survival. We hypothesize that this difference could be due to the immune response to the tumor, and as such, we investigated the expression of PD-1, PD-L1 and CD163 in a series of UCOGC. To this aim, 27 pancreatic UCOGCs (11 pure and 16 PDAC-associated), 5 extra-pancreatic tumors with osteoclast-like giant cells and 10 pancreatic anaplastic carcinomas (ACs) were immunostained using antibodies against PD-1, PD-L1 and CD163. In pancreatic UCOGCs, PD-L1 was expressed in neoplastic cells of 17/27 (63%) cases, more often in cases with an associated PDAC (P = .04). Expression of PD-L1 was associated with poor prognosis, confirmed by multivariate analysis: patients with PD-L1-positive UCOGCs had a risk of all-cause mortality that was 3 times higher than patients with PD-L1-negative UCOGCs (HR: 3.397, 95%CI: 1.023–18.375, P = .034). PD-L1 expression on tumor cells was also associated with aberrant P53 expression (P = .035). PD-1 was expressed on rare lymphocytes in 12 UCOGCs (44.4%), mainly located at the tumor periphery. CD163 was expressed on histiocytes, with a diffuse and strong staining pattern in all UCOGCs. Extra-pancreatic tumors with osteoclast-like giant cells showed very similar staining patterns for the same proteins. ACs have some similarities to UCOGCs, but PD-L1 has no prognostic roles. Our results may have important implications for immunotherapeutic strategies in UCOGCs; these tumors may also represent a model for future therapeutic approaches against PDAC.
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    Prognostic Role of High-Grade Tumor Budding in Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-Analysis with a Focus on Epithelial to Mesenchymal Transition
    (MDPI, 2019-01-19) Lawlor, Rita T.; Veronese, Nicola; Nottegar, Alessia; Malleo, Giuseppe; Smith, Lee; Demurtas, Jacopo; Cheng, Liang; Wood, Laura D.; Silvestris, Nicola; Salvia, Roberto; Scarpa, Aldo; Luchini, Claudio; Pathology and Laboratory Medicine, School of Medicine
    This study aims at clarifying the prognostic role of high-grade tumor budding (TB) in pancreatic ductal adenocarcinoma (PDAC) with the first systematic review and meta-analysis on this topic. Furthermore, we analyzed with a systematic review the relationship between TB and a recently suggested TB-associated mechanism: the epithelial to mesenchymal transition (EMT). Analyzing a total of 613 patients, 251 of them (40.9%) with high grade-TB, we found an increased risk of all-cause mortality (RR, 1.46; 95% CI, 1.13⁻1.88, p = 0.004; HR, 2.65; 95% CI, 1.79⁻3.91; p < 0.0001) and of recurrence (RR, 1.61; 95% CI, 1.05⁻2.47, p = 0.03) for PDAC patients with high-grade TB. Moreover, we found that EMT is a central process in determining the presence of TB in PDAC. Thanks to this meta-analysis, we demonstrate the potential clinical significance of high-grade TB for prognostic stratification of PDAC. TB also shows a clear association with the process of EMT. Based on the results of the present study, TB should be conveyed in pathology reports and taken into account by future oncologic staging systems.
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    REDISCOVER International Guidelines on the Perioperative Care of Surgical Patients With Borderline-resectable and Locally Advanced Pancreatic Cancer
    (Wolters Kluwer, 2024) Boggi, Ugo; Kauffmann, Emanuele; Napoli, Niccolò; Barreto, George; Besselink, Marc G.; Fusai, Giuseppe K.; Hackert, Thilo; Hilal, Mohammad Abu; Marchegiani, Giovanni; Salvia, Roberto; Shrikhande, Shailesh V.; Truty, Mark; Werner, Jens; Wolfgang, Christopher L.; Bannone, Elisa; Capretti, Giovanni; Cattelani, Alice; Coppola, Alessandro; Cucchetti, Alessandro; De Sio, Davide; Di Dato, Armando; Di Meo, Giovanna; Fiorillo, Claudio; Gianfaldoni, Cesare; Ginesini, Michael; Hidalgo Salinas, Camila; Lai, Quirino; Miccoli, Mario; Montorsi, Roberto; Pagnanelli, Michele; Poli, Andrea; Ricci, Claudio; Sucameli, Francesco; Tamburrino, Domenico; Viti, Virginia; Addeo, Pietro F.; Alfieri, Sergio; Bachellier, Philippe; Baiocchi, Gian Luca; Balzano, Gianpaolo; Barbarello, Linda; Brolese, Alberto; Busquets, Juli; Butturini, Giovanni; Caniglia, Fabio; Caputo, Damiano; Casadei, Riccardo; Chunhua, Xi; Colangelo, Ettore; Coratti, Andrea; Costa, Francesca; Crafa, Francesco; Dalla Valle, Raffaele; De Carlis, Luciano; de Wilde, Roeland F.; Del Chiaro, Marco; Di Benedetto, Fabrizio; Di Sebastiano, Pierluigi; Dokmak, Safi; Hogg, Melissa; Egorov, Vyacheslav I.; Ercolani, Giorgio; Ettorre, Giuseppe Maria; Falconi, Massimo; Ferrari, Giovanni; Ferrero, Alessandro; Filauro, Marco; Giardino, Alessandro; Grazi, Gian Luca; Gruttadauria, Salvatore; Izbicki, Jakob R.; Jovine, Elio; Katz, Matthew; Keck, Tobias; Khatkov, Igor; Kiguchi, Gozo; Kooby, David; Lang, Hauke; Lombardo, Carlo; Malleo, Giuseppe; Massani, Marco; Mazzaferro, Vincenzo; Memeo, Riccardo; Miao, Yi; Mishima, Kohei; Molino, Carlo; Nagakawa, Yuichi; Nakamura, Masafumi; Nardo, Bruno; Panaro, Fabrizio; Pasquali, Claudio; Perrone, Vittorio; Rangelova, Elena; Liu, Rong; Romagnoli, Renato; Romito, Raffaele; Rosso, Edoardo; Schulick, Richard; Siriwardena, Ajith; Spampinato, Marcello Giuseppe; Strobel, Oliver; Testini, Mario; Troisi, Roberto Ivan; Uzunoglo, Faik G.; Valente, Roberto; Veneroni, Luigi; Zerbi, Alessandro; Vicente, Emilio; Vistoli, Fabio; Vivarelli, Marco; Wakabayashi, Go; Zanus, Giacomo; Zureikat, Amer; Zyromski, Nicholas J.; Coppola, Roberto; D'Andrea, Vito; Davide, José; Dervenis, Christos; Frigerio, Isabella; Konlon, Kevin C.; Michelassi, Fabrizio; Montorsi, Marco; Nealon, William; Portolani, Nazario; Sousa Silva, Donzília; Bozzi, Giuseppe; Ferrari, Viviana; Trivella, Maria G.; Cameron, John; Clavien, Pierre-Alain; Asbun, Horacio J.; REDISCOVER Multidisciplinary Advisory Board; Surgery, School of Medicine
    Objective: The REDISCOVER consensus conference aimed at developing and validating guidelines on the perioperative care of patients with borderline-resectable (BR-) and locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC). Background: Coupled with improvements in chemotherapy and radiation, the contemporary approach to pancreatic surgery supports the resection of BR-PDAC and, to a lesser extent, LA-PDAC. Guidelines outlining the selection and perioperative care for these patients are lacking. Methods: The Scottish Intercollegiate Guidelines Network (SIGN) methodology was used to develop the REDISCOVER guidelines and create recommendations. The Delphi approach was used to reach a consensus (agreement ≥80%) among experts. Recommendations were approved after a debate and vote among international experts in pancreatic surgery and pancreatic cancer management. A Validation Committee used the AGREE II-GRS tool to assess the methodological quality of the guidelines. Moreover, an independent multidisciplinary advisory group revised the statements to ensure adherence to nonsurgical guidelines. Results: Overall, 34 recommendations were created targeting centralization, training, staging, patient selection for surgery, possibility of surgery in uncommon scenarios, timing of surgery, avoidance of vascular reconstruction, details of vascular resection/reconstruction, arterial divestment, frozen section histology of perivascular tissue, extent of lymphadenectomy, anticoagulation prophylaxis, and role of minimally invasive surgery. The level of evidence was however low for 29 of 34 clinical questions. Participants agreed that the most conducive means to promptly advance our understanding in this field is to establish an international registry addressing this patient population ( https://rediscover.unipi.it/ ). Conclusions: The REDISCOVER guidelines provide clinical recommendations pertaining to pancreatectomy with vascular resection for patients with BR-PDAC and LA-PDAC, and serve as the basis of a new international registry for this patient population.
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    Role of Adjuvant Multimodality Therapy After Curative-Intent Resection of Ampullary Carcinoma
    (American Medical Association, 2019-08) Ecker, Brett L.; Vollmer, Charles M., Jr.; Behrman, Stephen W.; Allegrini, Valentina; Aversa, John; Ball, Chad G.; Barrows, Courtney E.; Berger, Adam C.; Cagigas, Martha N.; Christein, John D.; Dixon, Elijah; Fisher, William E.; Freedman-Weiss, Mollie; Guzman-Pruneda, Francisco; Hollis, Robert H.; House, Michael G.; Kent, Tara S.; Kowalsky, Stacy J.; Malleo, Giuseppe; Salem, Ronald R.; Salvia, Roberto; Schmidt, Carl R.; Seykora, Thomas F.; Zheng, Richard; Zureikat, Amer H.; Dickson, Paxton V.; Surgery, School of Medicine
    Importance: Ampullary adenocarcinoma is a rare malignant neoplasm that arises within the duodenal ampullary complex. The role of adjuvant therapy (AT) in the treatment of ampullary adenocarcinoma has not been clearly defined. Objective: To determine if long-term survival after curative-intent resection of ampullary adenocarcinoma may be improved by selection of patients for AT directed by histologic subtype. Design, setting, and participants: This multinational, retrospective cohort study was conducted at 12 institutions from April 1, 2000, to July 31, 2017, among 357 patients with resected, nonmetastatic ampullary adenocarcinoma receiving surgery alone or AT. Cox proportional hazards regression was used to identify covariates associated with overall survival. The surgery alone and AT cohorts were matched 1:1 by propensity scores based on the likelihood of receiving AT or by survival hazard from Cox modeling. Overall survival was compared with Kaplan-Meier estimates. Exposures: Adjuvant chemotherapy (fluorouracil- or gemcitabine-based) with or without radiotherapy. Main outcomes and measures: Overall survival. Results: A total of 357 patients (156 women and 201 men; median age, 65.8 years [interquartile range, 58-74 years]) underwent curative-intent resection of ampullary adenocarcinoma. Patients with intestinal subtype had a longer median overall survival compared with those with pancreatobiliary subtype (77 vs 54 months; P = .05). Histologic subtype was not associated with AT administration (intestinal, 52.9% [101 of 191]; and pancreatobiliary, 59.5% [78 of 131]; P = .24). Patients with pancreatobiliary histologic subtype most commonly received gemcitabine-based regimens (71.0% [22 of 31]) or combinations of gemcitabine and fluorouracil (12.9% [4 of 31]), whereas treatment of those with intestinal histologic subtype was more varied (fluorouracil, 50.0% [17 of 34]; gemcitabine, 44.1% [15 of 34]; P = .01). In the propensity score-matched cohort, AT was not associated with a survival benefit for either histologic subtype (intestinal: hazard ratio, 1.21; 95% CI, 0.67-2.16; P = .53; pancreatobiliary: hazard ratio, 1.35; 95% CI, 0.66-2.76; P = .41). Conclusions and relevance: Adjuvant therapy was more frequently used in patients with poor prognostic factors but was not associated with demonstrable improvements in survival, regardless of tumor histologic subtype. The value of a multimodality regimen remains poorly defined.