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1. Oral Antibiotics Alone versus Oral Antibiotics Combined with Mechanical Bowel Preparation for Elective Colorectal Surgery: A Propensity Score-Matching Re-Analysis of the iCral 2 and 3 Prospective Cohorts

Author: Marco Catarci, Stefano Guadagni, Francesco Masedu, Massimo Sartelli, Leonardo Antonio Montemurro, Gian Luca Baiocchi, Giovanni Domenico Tebala, Felice Borghi, Pierluigi Marini, Marco Scatizzi, and the Italian ColoRectal Anastomotic Leakage (iCral) Study Group
Subjects: colorectal surgery, mechanical bowel preparation, oral antibiotics, anastomotic leakage, surgical site infections, morbidity, Therapeutics. Pharmacology, RM1-950
Abstract: The evidence regarding the role of oral antibiotics alone (oA) or combined with mechanical bowel preparation (MoABP) for elective colorectal surgery remains controversial. A prospective database of 8359 colorectal resections gathered over a 32-month period from 78 Italian surgical units (the iCral 2 and 3 studies), reporting patient-, disease-, and procedure-related variables together with 60-day adverse events, was re-analyzed to identify a subgroup of 1013 cases (12.1%) that received either oA or MoABP. This dataset was analyzed using a 1:1 propensity score-matching model including 20 covariates. Two well-balanced groups of 243 patients each were obtained: group A (oA) and group B (MoABP). The primary endpoints were anastomotic leakage (AL) and surgical site infection (SSI) rates. Group A vs. group B showed a significantly higher AL risk [14 (5.8%) vs. 6 (2.5%) events; OR: 3.77; 95%CI: 1.22–11.67; p = 0.021], while no significant difference was recorded between the two groups regarding SSIs. These results strongly support the use of MoABP for elective colorectal resections.
Published: 2024
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2. A Study of Alternative TrkA Splicing Identifies TrkAIII as a Novel Potentially Targetable Participant in PitNET Progression

Author: Maddalena Sbaffone, Marie-Lise Jaffrain-Rea, Lucia Cappabianca, Francesca Carbonara, Francesca Gianno, Tiziana Feola, Marianna Ruggieri, Veronica Zelli, Rita Maccarone, Stefano Guadagni, Marco Clementi, Antonietta Arcella, Vincenzo Esposito, Giulia Carozza, Ilaria Martelli, Antonietta Rosella Farina, and Andrew Reay Mackay
Subjects: PitNETs, alternative splicing, TrkAIII splice variant, HIF2α, splice factors SF3B1, U2AF and SRSF2, hotspot SF3B1 mutation, Biology (General), QH301-705.5
Abstract: Pituitary neuroendocrine tumors (PitNETs) are generally benign but comprise an aggressive, invasive, therapy-resistant, metastatic subset, underpinning a need for novel therapeutic targets. PitNETs exhibit low mutation rates but are associated with conditions linked to alternative splicing, an alternative oncogene pathway activation mechanism. PitNETs express the neurotrophin receptor TrkA, which exhibits oncogenic alternative TrkAIII splicing in other neuroendocrine tumors. We, therefore, assessed whether TrkAIII splicing represents a potential oncogenic participant in PitNETs. TrkAIII splicing was RT-PCR assessed in 53 PitNETs and TrkA isoform(s) expression and activation were assessed by confocal immunofluorescence. TrkAIII splicing was also compared to HIF1α, HIF2α, SF3B1, SRSF2, U2AF1, and JCPyV large T antigen mRNA expression, Xbp1 splicing, and SF3B1 mutation. TrkAIII splicing was detected in all invasive and most non-invasive PitNETs and was significantly elevated in invasive cases. In PitNET lineages, TrkAIII splicing was significantly elevated in invasive PIT1 PitNETs and high in invasive and non-invasive SF1 and TPIT lineages. Immunoreactivity consistent with TrkAIII activation characterized PitNET expressing TrkAIII mRNA, and invasive Pit1 PitNETs exhibited elevated HIF2α expression. TrkAIII splicing did not associate with SF3B1 mutations, altered SF3B1, SRSF2, and U2AF1 or JCPyV large T antigen expression, or Xbp1 splicing. Therefore, TrkAIII splicing is common in PitNETs, is elevated in invasive, especially PIT1 tumors, can result in intracellular TrkAIII activation, and may involve hypoxia. The data support a role for TrkAIII splicing in PitNET pathogenesis and progression and identify TrkAIII as a novel potential target in refractory PitNETs.
Published: 2024
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3. Circulating tumour cell gene expression and chemosensitivity analyses: predictive accuracy for response to multidisciplinary treatment of patients with unresectable refractory recurrent rectal cancer or unresectable refractory colorectal cancer liver metastases

Author: Stefano Guadagni, Francesco Masedu, Giammaria Fiorentini, Donatella Sarti, Caterina Fiorentini, Veronica Guadagni, Panagiotis Apostolou, Ioannis Papasotiriou, Panagiotis Parsonidis, Marco Valenti, Enrico Ricevuto, Gemma Bruera, Antonietta R. Farina, Andrew R. Mackay, and Marco Clementi
Subjects: Predictive accuracy, Precision oncotherapy, Liquid biopsies, Circulating tumor cells, Chemosensitivity tests, Tumor gene expressions analyses, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Patients with unresectable recurrent rectal cancer (RRC) or colorectal cancer (CRC) with liver metastases, refractory to at least two lines of traditional systemic therapy, may receive third line intraarterial chemotherapy (IC) and targeted therapy (TT) using drugs selected by chemosensitivity and tumor gene expression analyses of liquid biopsy-derived circulating tumor cells (CTCs). Methods In this retrospective study, 36 patients with refractory unresectable RRC or refractory unresectable CRC liver metastases were submitted for IC and TT with agents selected by precision oncotherapy chemosensitivity assays performed on liquid biopsy-derived CTCs, transiently cultured in vitro, and by tumor gene expression in the same CTC population, as a ratio to tumor gene expression in peripheral mononuclear blood cells (PMBCs) from the same individual. The endpoint was to evaluate the predictive accuracy of a specific liquid biopsy precision oncotherapy CTC purification and in vitro culture methodology for a positive RECIST 1.1 response to the therapy selected. Results Our analyses resulted in evaluations of 94.12% (95% CI 0.71–0.99) for sensitivity, 5.26% (95% CI 0.01–0.26) for specificity, a predictive value of 47.06% (95% CI 0.29–0.65) for a positive response, a predictive value of 50% (95% CI 0.01–0.98) for a negative response, with an overall calculated predictive accuracy of 47.22% (95% CI 0.30–0.64). Conclusions This is the first reported estimation of predictive accuracy derived from combining chemosensitivity and tumor gene expression analyses on liquid biopsy-derived CTCs, transiently cultured in vitro which, despite limitations, represents a baseline and benchmark which we envisage will be improve upon by methodological and technological advances and future clinical trials.
Published: 2022
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4. Patient-Reported Outcomes and Return to Intended Oncologic Therapy After Colorectal Enhanced Recovery Pathway

Author: The Italian ColoRectal Anastomotic Leakage (iCral3) study group, Marco Catarci, MD, FACS, Giacomo Ruffo, MD, Massimo Giuseppe Viola, MD, Ferdinando Ficari, MD, Paolo Delrio, MD, Felice Pirozzi, MD, Felice Borghi, MD, Raffaele De Luca, MD, Alberto Patriti, MD, Gianluca Garulli, MD, Walter Siquini, MD, Stefano D’Ugo, MD, PhD, FEBS, FACS, Stefano Scabini, MD, Marco Caricato, MD, FACS, Giusto Pignata, MD, Andrea Liverani, MD, Roberto Campagnacci, MD, Pierluigi Marini, MD, Ugo Elmore, MD, Francesco Corcione, MD, Roberto Santoro, MD, Massimo Carlini, MD, FACS, Antonio Giuliani, MD, Mario Sorrentino, MD, Giovanni Ferrari, MD, Gianandrea Baldazzi, MD, Alberto Di Leo, MD, Augusto Verzelli, MD, Giuseppe Sica, MD, Stefano Rausei, MD, Davide Cavaliere, MD, Gian Luca Baiocchi, MD, FACS, Marco Milone, MD, Giovanni Ciaccio, MD, Giovanni Domenico Tebala, MD, FACS, FRCS, Marco Scatizzi, MD, Luigi Boni, MD, FACS, Stefano Mancini, MD, Mario Guerrieri, MD, Roberto Persiani, MD, Andrea Lucchi, MD, FACS, Dario Parini, MD, Antonino Spinelli, MD, Michele Genna, MD, Vincenzo Bottino, MD, Andrea Coratti, MD, Dario Scala, MD, Andrea Muratore, MD, Maurizio Pavanello, MD, Umberto Rivolta, MD, Micaela Piccoli, MD, FACS, Carlo Talarico, MD, Alessandro Carrara, MD, Stefano Guadagni, MD, Mauro Totis, MD, Franco Roviello, MD, Alessandro Anastasi, MD, Gianluca Guercioni, MD, Giuseppe Maria Ettorre, MD, Mauro Montuori, MD, Pierpaolo Mariani, MD, Nicolò de Manzini, MD, Annibale Donini, MD, Mariano Fortunato Armellino, MD, Lucio Taglietti, MD, Gabriele Anania, MD, Mariantonietta Di Cosmo, MD, Carlo Vittorio Feo, MD, Paolo Millo, MD, Corrado Pedrazzani, MD, Silvio Guerriero, MD, Andrea Costanzi, MD, Nereo Vettoretto, MD, Federico Marchesi, MD, Massimo Basti, MD, Graziano Longo, MD, Moreno Cicetti, MD, Paolo Ciano, MD, Michele Benedetti, MD, Leonardo Antonio Montemurro, MD, Maria Sole Mattei, MD, Elena Belloni, MD, Elisa Bertocchi, MD, Gaia Masini, MD, Amedeo Altamura, MD, Francesco Rubichi, MD, Francesco Giudici, MD, Fabio Cianchi, MD, Gabriele Baldini, MD, Ugo Pace, MD, Andrea Fares Bucci, MD, Antonio Sciuto, MD, Desirée Cianflocca, MD, Marco Migliore, MD, Michele Simone, MD, Marcella Lodovica Ricci, MD, Francesco Monari, MD, Alessandro Cardinali, MD, Massimo Sartelli, MD, Marcello Spampinato, MD, PhD, FEBS (HPB), Alessandra Aprile, MD, Domenico Soriero, MD, Gabriella Teresa Capolupo, MD, FACS, Jacopo Andreuccetti, MD, Ilaria Canfora, MD, Andrea Scarinci, MD, Angela Maurizi, MD, Grazia Maria Attinà, MD, Giulia Maggi, MD, Umberto Bracale, MD, Roberto Peltrini, MD, Pietro Amodio, MD, Domenico Spoletini, MD, PhD, FACS, Rosa Marcellinaro, MD, Giovanni Del Vecchio, MD, Massimo Stefanoni, MD, Carmelo Magistro, MD, Diletta Cassini, MD, Lorenzo Crepaz, MD, Andrea Budassi, MD, Bruno Sensi, MD, Silvia Tenconi, MD, Leonardo Solaini, MD, Giorgio Ercolani, MD, Sarah Molfino, MD, Giovanni Domenico De Palma, MD, Paolo Locurto, MD, Antonio Di Cintio, MD, Lorenzo Pandolfini, MD, Alessandro Falsetto, MD, Elisa Cassinotti, MD, Andrea Sagnotta, MD, PhD, Monica Ortenzi, MD, Alberto Biondi, MD, Giacomo Martorelli, MD, Maurizio De Luca, MD, Francesco Carrano, MD, Annalisa Maroli, PhD, Francesca Fior, MD, Antonio Ferronetti, MD, Giuseppe Giuliani, MD, Roberto Benigni, MD, Graziella Marino, MD, Patrizia Marsanic, MD, Nicoletta Sveva Pipitone Federico, MD, Carlo Di Marco, MD, Camillo Leonardo Bertoglio, MD, PhD, Francesca Pecchini, MD, Vincenzo Greco, MD, Michele Motter, MD, Giuseppe Tirone, MD, Marco Clementi, MD, Nicolò Tamini, MD, Riccardo Piagnerelli, MD, Giuseppe Canonico, MD, Simone Cicconi, MD, Marco Colasanti, MD, Enrico Pinotti, MD, Roberta Carminati, MD, Edoardo Osenda, MD, Luigina Graziosi, MD, Ciro De Martino, MD, Giovanna Ioia, MD, Arianna Birindelli, MD, Matteo Chiozza, MD, Daniele Zigiotto, MD, Fioralba Pindozzi, MD, Manuela Grivon, MD, Cristian Conti, MD, Lorenzo Organetti, MD, Michela Monteleone, MD, Emanuele Botteri, MD, Giorgio Dalmonte, MD, Diletta Frazzini, MD, Simone Santoni, MD, Gabriele La Gioia, MD, and Diana Giannarelli, MS, PhD
Subjects: Surgery, RD1-811
Abstract: Objective:. To evaluate the influence of enhanced recovery pathway (ERP) on patient-reported outcome measures (PROMs) and return to intended oncologic therapy (RIOT) after colorectal surgery. Background:. ERP improves early outcomes after colorectal surgery; however, little is known about its influence on PROMs and on RIOT. Methods:. Prospective multicenter enrollment of patients who underwent colorectal resection with anastomosis was performed, recording variables related to patient-, institution-, procedure-level data, adherence to the ERP, and outcomes. The primary endpoints were PROMs (administered before surgery, at discharge, and 6 to 8 weeks after surgery) and RIOT after surgery for malignancy, defined as the intended oncologic treatment according to national guidelines and disease stage, administered within 8 weeks from the index operation, evaluated through multivariate regression models. Results:. The study included 4529 patients, analyzed for PROMs, 1467 of which were analyzed for RIOT. Compared to their baseline preoperative values, all PROMs showed significant worsening at discharge and improvement at late evaluation. PROMs values at discharge and 6 to 8 weeks after surgery, adjusted through a generalized mixed regression model according to preoperative status and other variables, showed no association with ERP adherence rates. RIOT rates (overall 54.5%) were independently lower by aged > 69 years, ASA Class III, open surgery, and presence of major morbidity; conversely, they were independently higher after surgery performed in an institutional ERP center and by ERP adherence rates > median (69.2%). Conclusions:. Adherence to the ERP had no effect on PROMs, whereas it independently influenced RIOT rates after surgery for colorectal cancer.
Published: 2023
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5. Hypoxia-induced alternative splicing: the 11th Hallmark of Cancer

Author: Antonietta Rosella Farina, Lucia Cappabianca, Michela Sebastiano, Veronica Zelli, Stefano Guadagni, and Andrew Reay Mackay
Subjects: Hypoxia, Alternative splicing, Cancer hallmarks, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Hypoxia-induced alternative splicing is a potent driving force in tumour pathogenesis and progression. In this review, we update currents concepts of hypoxia-induced alternative splicing and how it influences tumour biology. Following brief descriptions of tumour-associated hypoxia and the pre-mRNA splicing process, we review the many ways hypoxia regulates alternative splicing and how hypoxia-induced alternative splicing impacts each individual hallmark of cancer. Hypoxia-induced alternative splicing integrates chemical and cellular tumour microenvironments, underpins continuous adaptation of the tumour cellular microenvironment responsible for metastatic progression and plays clear roles in oncogene activation and autonomous tumour growth, tumor suppressor inactivation, tumour cell immortalization, angiogenesis, tumour cell evasion of programmed cell death and the anti-tumour immune response, a tumour-promoting inflammatory response, adaptive metabolic re-programming, epithelial to mesenchymal transition, invasion and genetic instability, all of which combine to promote metastatic disease. The impressive number of hypoxia-induced alternative spliced protein isoforms that characterize tumour progression, classifies hypoxia-induced alternative splicing as the 11th hallmark of cancer, and offers a fertile source of potential diagnostic/prognostic markers and therapeutic targets.
Published: 2020
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6. Circulating tumour cell liquid biopsy in selecting therapy for recurrent cutaneous melanoma with locoregional pelvic metastases: a pilot study

Author: Stefano Guadagni, Giammaria Fiorentini, Ioannis Papasotiriou, Panagiotis Apostolou, Francesco Masedu, Donatella Sarti, Antonietta Rossella Farina, Andrew Reay Mackay, and Marco Clementi
Subjects: Liquid biopsies, Circulating tumour cells, Precision oncotherapy, Recurrent melanoma, Hypoxic pelvic perfusion, Melphalan, Medicine, Biology (General), QH301-705.5, Science (General), Q1-390
Abstract: Abstract Objectives Circulating tumour cells (CTCs) from liquid biopsies provide an exceptional opportunity to obtain real-time tumour information and are under current investigation in several cancers, including cutaneous melanoma, but face significant drawbacks in terms of non-standardised methodology, low viable cell numbers and accuracy of CTC identification. In this pilot study, we report that chemosensitivity assays using liquid biopsy-derived metastatic melanoma (MM) CTCs, from 7 patients with stage IIIC, BRAF wild-type metastatic melanomas, localized exclusively to the pelvic region, un-eligible for immunotherapy and treated with melphalan hypoxic pelvic perfusion (HPP), is both feasible and useful in predicting response to therapy. Viable MM CTCs (> 5 cells/ml for all 7 blood samples), enriched by transient culture, were characterised in flow cytometry-based Annexin V-PE assays for chemosensitivity to several drugs. Results Using melphalan as a standard, chemosensitivity cut-off values of > 60% cell death, were predictive of patient RECIST 1.1 response to melphalan HPP therapy, associated with calculated 100% sensitivity, 66.67% specificity, 33.33% positive predictive, 100% negative predictive, and 71.43% accuracy values. We propose that the methodology in this study is both feasible and has potential value in predicting response to therapy, setting the stage for a larger study. Trial registration Clinical Trials.gov Identifier NCT01920516; date of trial registration: August 6, 2013
Published: 2020
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7. Transarterial chemoembolization alone or followed by bevacizumab for treatment of colorectal liver metastases

Author: Giammaria Fiorentini, Donatella Sarti, Michele Nardella, Riccardo Inchingolo, Massimiliano Nestola, Alberto Rebonato, Caterina Fiorentini, Camillo Aliberti, Roberto Nani, and Stefano Guadagni
Subjects: angiogenesis, bevacizumab, colorectal carcinoma, DC beads radiopaque, irinotecan, liver metastases, Diseases of the digestive system. Gastroenterology, RC799-869, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Aims: Bevacizumab (B) in association with systemic chemotherapy is commonly used for the treatment of colorectal cancer liver metastases. The aim of this study was to monitor tumor response, overall survival (OS) and progression-free survival (PFS) of patients with colorectal cancer liver metastases treated with transarterial chemoembolization (TACE) + B compared with TACE alone and to correlate the results with KRAS mutational status. Patients & methods: This was an observational multicentric case–control study (NCT03732235) on the efficacy and safety of B administered after TACE. Results: The disease control rate was significantly higher for the TACE + B than the TACE alone group (p
Published: 2022
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8. Blood Transfusions and Adverse Events after Colorectal Surgery: A Propensity-Score-Matched Analysis of a Hen–Egg Issue

Author: Marco Catarci, Stefano Guadagni, Francesco Masedu, Leonardo Antonio Montemurro, Paolo Ciano, Michele Benedetti, Paolo Delrio, Gianluca Garulli, Felice Pirozzi, and Marco Scatizzi
Subjects: blood transfusion, colorectal surgery, transfusion hazards, anastomotic leakage, morbidity, mortality, Medicine (General), R5-920
Abstract: Blood transfusions are considered a risk factor for adverse outcomes after colorectal surgery. However, it is still unclear if they are the cause (the hen) or the consequence (the egg) of adverse events. A prospective database of 4529 colorectal resections gathered over a 12-month period in 76 Italian surgical units (the iCral3 study), reporting patient-, disease-, and procedure-related variables, together with 60-day adverse events, was retrospectively analyzed identifying a subgroup of 304 cases (6.7%) that received intra- and/or postoperative blood transfusions (IPBTs). The endpoints considered were overall and major morbidity (OM and MM, respectively), anastomotic leakage (AL), and mortality (M) rates. After the exclusion of 336 patients who underwent neo-adjuvant treatments, 4193 (92.6%) cases were analyzed through a 1:1 propensity score matching model including 22 covariates. Two well-balanced groups of 275 patients each were obtained: group A, presence of IPBT, and group B, absence of IPBT. Group A vs. group B showed a significantly higher risk of overall morbidity (154 (56%) vs. 84 (31%) events; OR 3.07; 95%CI 2.13–4.43; p = 0.001), major morbidity (59 (21%) vs. 13 (4.7%) events; OR 6.06; 95%CI 3.17–11.6; p = 0.001), and anastomotic leakage (31 (11.3%) vs. 8 (2.9%) events; OR 4.72; 95%CI 2.09–10.66; p = 0.0002). No significant difference was recorded between the two groups concerning the risk of mortality. The original subpopulation of 304 patients that received IPBT was further analyzed considering three variables: appropriateness of BT according to liberal transfusion thresholds, BT following any hemorrhagic and/or major adverse event, and major adverse event following BT without any previous hemorrhagic adverse event. Inappropriate BT was administered in more than a quarter of cases, without any significant influence on any endpoint. The majority of BT was administered after a hemorrhagic or a major adverse event, with significantly higher rates of MM and AL. Finally, a major adverse event followed BT in a minority (4.3%) of cases, with significantly higher MM, AL, and M rates. In conclusion, although the majority of IPBT was administered with the consequence of hemorrhage and/or major adverse events (the egg), after adjustment accounting for 22 covariates, IPBT still resulted in a definite source of a higher risk of major morbidity and anastomotic leakage rates after colorectal surgery (the hen), calling urgent attention to the implementation of patient blood management programs.
Published: 2023
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9. The Alternative TrkAIII Splice Variant, a Targetable Oncogenic Participant in Human Cutaneous Malignant Melanoma

Author: Lucia Cappabianca, Veronica Zelli, Cristina Pellegrini, Michela Sebastiano, Rita Maccarone, Marco Clementi, Alessandro Chiominto, Pierdomenico Ruggeri, Ludovica Cardelli, Marianna Ruggieri, Maddalena Sbaffone, Maria-Concetta Fargnoli, Stefano Guadagni, Antonietta R. Farina, and Andrew R. Mackay
Subjects: cutaneous malignant melanoma, TrkA, alternative TrkA splicing, TrkAIII, reductive stress, unfolded protein response, Cytology, QH573-671
Abstract: Post-therapeutic relapse, poor survival rates and increasing incidence justify the search for novel therapeutic targets and strategies in cutaneous malignant melanoma (CMM). Within this context, a potential oncogenic role for TrkA in CMM is suggested by reports of NTRK1 amplification, enhanced TrkA expression and intracellular TrkA activation associated with poor prognosis. TrkA, however, exhibits tumour-suppressing properties in melanoma cell lines and has recently been reported not to be associated with CMM progression. To better understand these contradictions, we present the first analysis of potential oncogenic alternative TrkA mRNA splicing, associated with TrkA immunoreactivity, in CMMs, and compare the behaviour of fully spliced TrkA and the alternative TrkAIII splice variant in BRAF(V600E)-mutated A375 melanoma cells. Alternative TrkA splicing in CMMs was associated with unfolded protein response (UPR) activation. Of the several alternative TrkA mRNA splice variants detected, TrkAIII was the only variant with an open reading frame and, therefore, oncogenic potential. TrkAIII expression was more frequent in metastatic CMMs, predominated over fully spliced TrkA mRNA expression in ≈50% and was invariably linked to intracellular phosphorylated TrkA immunoreactivity. Phosphorylated TrkA species resembling TrkAIII were also detected in metastatic CMM extracts. In A375 cells, reductive stress induced UPR activation and promoted TrkAIII expression and, in transient transfectants, promoted TrkAIII and Akt phosphorylation, enhancing resistance to reductive stress-induced death, which was prevented by lestaurtinib and entrectinib. In contrast, fully spliced TrkA was dysfunctional in A375 cells. The data identify fully spliced TrkA dysfunction as a novel mechanism for reducing melanoma suppression, support a causal relationship between reductive stress, UPR activation, alternative TrkAIII splicing and TrkAIII activation and characterise a targetable oncogenic pro-survival role for TrkAIII in CMM.
Published: 2023
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10. A pilot study of alternative TrkAIII splicing in Merkel cell carcinoma: a potential oncogenic mechanism and novel therapeutic target

Author: Lucia Cappabianca, Stefano Guadagni, Rita Maccarone, Michela Sebastiano, Alessandro Chiominto, Antonietta Rosella Farina, and Andrew Reay Mackay
Subjects: Merkel cell carcinoma, Merkel cell polyomavirus, MCPyV large T-antigen, Alternative TrkAIII splicing, Oncogenic activation mechanism, Therapeutic target, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Merkel cell carcinomas (MCCs) are rare, aggressive, therapeutically-challenging skin tumours that are increasing in incidence and have poor survival rates. The majority are caused by genomic Merkel cell polyomavirus (MCPyV) integration and MCPyV T-antigen expression. Recently, a potential oncogenic role for the tropomyosin-related tyrosine kinase A receptor (TrkA) has been proposed in MCC. Alternative TrkAIII splicing is a TrkA oncogenic activation mechanism that can be promoted by SV40 large T-antigen, an analogue of MCPyV large T-antigen. In this pilot study, therefore, we have evaluated TrkAIII splicing as a novel potential oncogenic mechanism and therapeutic target in MCPyV positive MCC. Methods Formalin-fixed paraffin-embedded MCC tissues, consisting of 10 stage IV, 1 stage IIIB, 1 stage IIB, 4 stage IIA and 2 stage I tumours, from patients diagnosed and treated from September 2006 to March, 2019, at the University of L’Aquila, L’Aquila, Italy, were compared to 3 primary basal cell carcinomas (BCCs), 3 primary squamous cell carcinomas (SCCs) and 2 normal skin samples by RT-PCR for MCPyV large T-antigen, small T-antigen, VP-1 expression and alternative TrkAIII splicing and by indirect IF for evidence of intracellular TrkA isoform expression and activation. Results 9 of 10 Recurrent stage IV MCCs were from patients (P.1–3) treated with surgery plus loco-regional Melphalan chemotherapy and remaining MMCs, including 1 stage IV tumour, were from patients treated with surgery alone (P. 4–11). All MCPyV positive MCCs exhibiting MCPyV large T-antigen expression (17 of 18MCCs, 90%) exhibited alternative TrkAIII mRNA splicing (100%), which was exclusive in a significant number and predominant (> 50%) in all stage IV MCCs and the majority of stage 1-III MCCs. MCCs with higher TrkAIII to 18S rRNA expression ratios also exhibited strong or intermediate immunoreactivity to anti-TrkA antibodies, consistent with cytoplasmic TrkAIII expression and activation. In contrast, the MCPyV negative MCC, BCCs, SCCs and normal skin tissues all exhibited exclusive fully-spliced TrkA mRNA expression, associated with variable immunoreactivity for non-phosphorylated but not phosphorylated TrkA. Conclusions MCPyV positive MCCs but not MCPyV negative MCC, BCCs and SCCs exhibit predominant alternative TrkAIII splicing, with evidence of intracellular TrkAIII activation. This establishes a new potential MCC subset, unveils a novel potential MCPyV oncogenic mechanism and identifies TrkAIII as a novel potential therapeutic target in MCPyV positive MCC.
Published: 2019
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11. Laparoscopic treatment of obstructed internal supravesical hernia: A cases series and rewiev of the literature

Author: Marco, Clementi, Luigi, Bonanni, Federico, Sista, Vincenzo, Vicentini, Andrea, Salvatorelli, Marino, Di Furia, Ilaria, Puccica, and Stefano, Guadagni
Published: 2018
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12. Re: Response to Recommendation of Regional Hyperthermia in the Treatment of Breast Cancer

Author: Giammaria Fiorentini MD, Donatella Sarti PhD, Cosmo Damiano Gadaleta MD, Marco Ballerini MD, Caterina Fiorentini MD, Tommaso Carfagno MD, Girolamo Ranieri MD, and Stefano Guadagni MD
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published: 2021
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13. A Narrative Review of Regional Hyperthermia: Updates From 2010 to 2019

Author: Giammaria Fiorentini MD, Donatella Sarti PhD, Cosmo Damiano Gadaleta MD, Marco Ballerini MD, Caterina Fiorentini MD, Tommaso Garfagno MD, Girolamo Ranieri MD, and Stefano Guadagni MD
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: The role of hyperthermia (HT) in cancer therapy and palliative care has been discussed for years in the literature. There are plenty of articles that show good feasibility of HT and its efficacy in terms of tumor response and survival improvements. Nevertheless, HT has never gained enough interest among oncologists to become a standard therapy in clinical practice. The main advantage of HT is the enhancement of chemotherapy (CHT), radiotherapy (RT), chemoradiotherapy (CRT), and immunotherapy benefits. This effect has been confirmed in several types of tumors: esophageal, gastrointestinal, pancreas, breast, cervix, head and neck, and bladder cancers, and soft tissue sarcoma. HT effects include oxygenation and perfusion changes, DNA repair inhibition and immune system activation as a consequence of new antigen exposure. The literature shows a wide variety of randomized, nonrandomized, and observational studies and both prospective and retrospective data to confirm the advantage of HT association to CHT and RT. There are still many ongoing trials on this subject. This article summarizes the available literature on HT in order to update the current knowledge on HT use in association with RT and/or CHT from 2010 up to 2019.
Published: 2020
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14. Relevance of Pharmacogenomics and Multidisciplinary Management in a Young-Elderly Patient With KRAS Mutant Colorectal Cancer Treated With First-Line Aflibercept-Containing Chemotherapy

Author: Gemma Bruera, Antonio D'Andrilli, Maurizio Simmaco, Stefano Guadagni, Erino Angelo Rendina, and Enrico Ricevuto
Subjects: aflibercept/chemotherapy, case report, young-elderly unfit MCRC, multidisciplinary management, pharmacogenomic analyses, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Introduction: Intensive oncological treatment integrated with resection of metastases raised the clinical outcome of metastatic colorectal cancer (MCRC). In clinical practice, complex evaluation of clinical (age, performance status, comorbidities), and biological (tumoral genotype, pharmacogenomic) parameters addresses tailored, personalized multidisciplinary treatment strategies. Patients with MCRC unsuitable for first-line intensive medical treatments are prevalent and showed worse clinical outcome. After progression to oxaliplatin-based chemotherapy, aflibercept/FOLFIRI significantly improved clinical outcome, even if no survival benefit was reported in adjuvant fast relapsers by aflibercept addition. The case reported a young-elderly (yE) patient with KRAS mutant colorectal cancer rapidly progressing to adjuvant chemotherapy, unfit owing to comorbidities, with multiple pharmacogenomic alterations, who gained long-term survival in clinical practice by multidisciplinary treatment strategy consisting of first-line and re-introduction of aflibercept-containing chemotherapy and two-stage lung metastasectomies.Case presentation: A 71-years-old yE patient, unfit for intensive oncological treatments owing to Cumulative Illness Rating Scale (CIRS) stage secondary, affected by KRAS c.35 G>T mutant colorectal cancer, rapidly progressing with lung metastases after adjuvant XelOx chemotherapy, reached long-term survival 66 months with no evidence of disease after first-line and re-introduction of tailored, modulated aflibercept (4 mg/kg) d1,15-irinotecan (120 mg/m2) d1,15-5-fluorouracil (750 mg/m2/day) dd1–4, 15–18; and secondary radical bilateral two-stage lung metastasectomies. Safety profile was characterized by limiting toxicity syndrome at multiple sites (LTS-ms), requiring 5-fluorouracil discontinuation and aflibercept reduction (2 mg/kg), because of G2 hand-foot syndrome (HFS) for >2 weeks, and G3 hypertension. Pharmacogenomic analyses revealed multiple alterations of fluoropyrimidine and irinotecan metabolism: severe deficiency of fluorouracil degradation rate (FUDR), single nucleotide polymorphisms of UGT1A1*28 variable number of tandem repeats (VNTR) 7R/7R homozygote, ABCB1 c.C3435T, c.C1236T, MTHFR c.C667T homozygote, DPYD c.A166G, TSER 28bp VNTR 2R/3R heterozygote.Conclusions: In clinical practice, a complex management evaluating clinical parameters and RAS/BRAF genotype characterizing an individual patient with MCRC, particularly elderly and/or unfit owing to comorbidities, is required to properly address tailored, multidisciplinary medical and surgical treatment strategies, integrated with careful monitoring of superimposing toxicity syndromes, also related to pharmacogenomic alterations, to gain optimal activity, and long-term efficacy.
Published: 2020
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15. Updates of colorectal cancer liver metastases therapy: review on DEBIRI

Author: Giammaria Fiorentini, Donatella Sarti, Roberto Nani, Camillo Aliberti, Caterina Fiorentini, and Stefano Guadagni
Subjects: colorectal cancer, CRC-LM, DEBIRI, liver metastases, liver resection, Diseases of the digestive system. Gastroenterology, RC799-869, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Colorectal cancer is a worldwide public health issue, presenting an advanced stage at diagnosis in more than 20% of patients. Liver metastases are the most common metastatic sites and are not indicated for resection in 80% of cases. Unresectable colorectal cancer liver metastases that are refractory to systemic chemotherapy may benefit from transarterial chembolization with irinotecan-loaded beads (DEBIRI). Several studies show the safety and efficacy of DEBIRI for the treatment of colorectal cancer liver metastases. The development of transarterial chembolization and the introduction of new embolics have contributed to better outcomes of DEBIRI. This article reviews the current literature on DEBIRI reporting its use, efficacy in terms of tumor response and survival and side effects.
Published: 2020
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16. Surgical versus percutaneous isolated pelvic perfusion (IPP) for advanced melanoma: comparison in terms of melphalan pharmacokinetic pelvic bio-availability

Author: Stefano Guadagni, Giancarlo Palumbo, Giammaria Fiorentini, Marco Clementi, Luca Marsili, Aldo Victor Giordano, Francesco Masedu, and Marco Valenti
Subjects: Melphalan, Isolated pelvic perfusion, Melanoma, Medicine, Biology (General), QH301-705.5, Science (General), Q1-390
Abstract: Abstract Background Isolated pelvic perfusion (IPP) can be used to treat unresectable melanoma metastases of the pelvis. IPP can be performed either by surgical or percutaneous approaches, using different balloon catheters. The aim of this study was to examine whether the surgical and percutaneous approaches were comparable with respect to tumor drug exposure in the pelvis. Methods A pharmacokinetic study was performed in 5 melanoma patients treated with surgical IPP and five with percutaneous IPP. Both groups received melphalan at the dose of 30 mg/m2. Melphalan pharmacokinetic analyses were performed and the main parameter used to evaluate pelvic tumor drug-exposure was the ratio of areas under the melphalan plasma concentration curves in the pelvis and the systemic compartment, during the perfusion time (AUC0 to 20). Non-parametric Mann–Whitney tests were employed for statistical comparisons. Results The median and interquartile range (IQR) values of the ratios between melphalan AUC0 to 20 in pelvic and systemic compartments were 7.9 (IQR 7.2 to 9.9) and 5 (IQR 4 to 7.9) for surgical and percutaneous IPPs, respectively (p = 0.209). Conclusions Tumor exposure to drug using these two methods did not statistically differ and both methods, therefore, can be adopted interchangeably, utilizing a perfusion blood flow rate of approximately 120 ml/min. The small sample size is a limitation of this study but our preliminary results can be used to calculate the effect size of a larger trial. Trial Registration Clinical Trials.gov Identifier NCT01920516; date of trial registration: August 6, 2013
Published: 2017
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17. Modulated Electro-Hyperthermia as Palliative Treatment for Pancreatic Cancer: A Retrospective Observational Study on 106 Patients

Author: Giammaria Fiorentini MD, Donatella Sarti PhD, Virginia Casadei MD, Carlo Milandri MD, Patrizia Dentico MD, Andrea Mambrini MD, Roberto Nani MD, Caterina Fiorentini MD, and Stefano Guadagni MD
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Background: Pancreatic adenocarcinoma has a poor prognosis, resulting in a
Published: 2019
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18. Modulated Electrohyperthermia in Integrative Cancer Treatment for Relapsed Malignant Glioblastoma and Astrocytoma: Retrospective Multicenter Controlled Study

Author: Giammaria Fiorentini MD, Donatella Sarti PhD, Carlo Milandri MD, Patrizia Dentico MD, Andrea Mambrini MD, Caterina Fiorentini MD, Gianmaria Mattioli MD, Virginia Casadei MD, and Stefano Guadagni MD
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Background: There are interesting studies on glioma therapy with modulated electrohyperthermia (mEHT), which combines heat therapy with an electric field. Clinical researchers not only found the mEHT method feasible for palliation but also reported evidence of therapeutic response. Purpose: To study the efficacy and safety of mEHT for the treatment of relapsed malignant glioma and astrocytoma versus best supportive care (BSC). Methods: We collected data retrospectively on 149 patients affected by malignant glioma and astrocytoma. Inclusion criteria were informed consent signed; >18 years old; histological diagnosis of malignant glioma or astrocytoma; relapsed after surgery, adjuvant temozolomide-based chemotherapy, and radiotherapy; and indication for treatment with mEHT in palliative setting. mEHT was performed with capacitive coupling technique keeping the skin surface at 26°C and the tumor temperature at 40°C to 42.5°C for > 90% of treatment duration (20-60 minutes). The applied power was 40 to 150 W using a step-up heating protocol. Results from patients treated with mEHT were compared with those treated with BSC. Results: A total of 149 consecutive patients were enrolled in the study, 111 (74%) had glioblastoma multiforme (GBM), and 38 (26%) had astrocytoma (AST). mEHT was performed for 28 (25%) of GBM and 24 (63%) of AST patients. Tumor response at the 3-month follow-up was observed in 29% and 48% of GBM and AST patients after mEHT, and in 4% and 10% of GBM and AST patients after BSC, respectively. The survival rate at first and second year in the mEHT group was 77.3% and 40.9% for AST, and 61% and 29% for GBM, respectively. The 5-year overall survival of AST was 83% after mEHT versus 25% after BSC and 3.5% after mEHT versus 1.2% after BSC for GBM. The median overall survival of mEHT was 14 months (range 2-108 months) for GBM and 16.5 months (range 3-156 months) for the AST group. We observed 4 long-term survivors in the AST and 2 in the GBM group. Two of the long survivors in AST and 1 in GBM group were treated by mEHT. Conclusions: mEHT in integrative therapy may have a promising role in the treatment and palliation of relapsed GBM and AST.
Published: 2019
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19. A Prospective Study of Intraarterial Infusion Chemotherapy in Advanced Wild-Type BRAF Melanoma Patients

Author: Francesco Masedu, Marco Clementi, Odysseas Zoras, Donatella Sarti, Konstantinos Lasithiotakis, Giammaria Fiorentini, Andrew R. Mackay, Antonietta R. Farina, and Stefano Guadagni
Subjects: Proto-Oncogene Proteins B-raf, Melphalan, medicine.medical_specialty, Skin Neoplasms, medicine.medical_treatment, Recurrent melanoma, BRAF wild-type, Hyperthermic isolated limb perfusion, medicine, Limb perfusion, Clinical endpoint, Humans, Infusions, Intra-Arterial, Stage IIIC, Prospective Studies, Prospective cohort study, Melanoma, Pelvis, Chemotherapy, business.industry, Hypoxic pelvic and limb perfusion, Extremities, medicine.disease, medicine.anatomical_structure, Locoregional metastases, Chemotherapy, Cancer, Regional Perfusion, Locoregional metastases, Hyperthermic isolated limb perfusion, Isolated limb infusion, Hypoxic pelvic and limb perfusion, Novel immunotherapies, Surgery, Radiology, Isolated limb infusion, business, medicine.drug
Abstract: Background Treatment strategies for advanced cutaneous melanoma (CM) patients, resistant or not treatable with novel target and immunotherapeutic drugs, remain a significant challenge, particularly for patients with unresectable stage IIIC/D disease localized to inferior limbs and pelvis, for whom specific outcomes are rarely considered. Materials and methods This is a prospective study of multidisciplinary treatments, including locoregional melphalan chemotherapy, in 62 BRAF wild-type CM patients with locoregional metastases in the inferior limbs and pelvis, including inguinal regions. Patients were either in progression following or ineligible for, or not treatable with novel immunotherapy. For exclusively inferior limb-localised disease, patients received locoregional melphalan chemotherapy performed by hyperthermic isolated limb perfusion (n = 19) or isolated limb infusion (n = 19), and for synchronous lesions localised to inferior limbs and pelvis, received hypoxic pelvic and limb perfusion (n = 24). Additional multidisciplinary therapy included local, locoregional and systemic treatments and the primary endpoint was tumour response. Results The objective response rate following first cycle of locoregional chemotherapy was 37.1% at 3 mo and median progression-free survival was 4-mo, with 12.9% procedure-related complications, 30.6% low-grade haematological toxicity and 11.3% severe limb toxic tissue reactions. Multivariate logistic regression showed that the odds of response were significantly higher for patients ≤ 75 y of age and for patients with locoregional metastases exclusively located in the inferior limbs. Conclusion In this subgroup of CM patients with BRAF wild-type status, locoregional metastases localized to inferior limbs and pelvis, in progression following or ineligible for immunotherapy, melphalan locoregional chemotherapy demonstrated a safe and effective profile. Trial Registration ClinicalTrials.gov Identifier NCT01920516; date of trial registration: August 6, 2013.
Published: 2021
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20. Modulated electro-hyperthermia in stage III and IV pancreatic cancer: Results of an observational study on 158 patients

Author: Carlo Milandri, Caterina Fiorentini, Donatella Sarti, Girolamo Ranieri, Giammaria Fiorentini, Stefano Guadagni, Andrea Mambrini, and Cosmo Damiano Gadaleta
Subjects: Hyperthermia, Oncology, medicine.medical_specialty, Modulated electro-hyperthermia, Locally advanced pancreatic cancer, Tumor response, Survival, genetic structures, business.industry, Observational Study, medicine.disease, eye diseases, Pancreatic cancer, Internal medicine, Medicine, Observational study, sense organs, Stage (cooking), business
Abstract: BACKGROUND An increasing number of studies report the beneficial effects of regional hyperthermia in association with chemotherapy (CHT) and radiotherapy for the treatment of pancreatic cancer; in particular, the use of modulated electro-hyperthermia (mEHT) results in increased survival and tumor response. AIM To compare outcomes of CHT alone or in association with mEHT for the treatment of stage III and IV pancreatic cancer. METHODS This was an observational retrospective study; data were collected for patients with stage III-IV pancreatic cancer that were treated with CHT alone or in combination with mEHT from 2003 to 2019. A total of 158 patients were included in the study out 270 patients screened in four Italian hospitals; 58 (37%) of these received CHT + mEHT and 100 (63%) CHT. CHT was mainly gemcitabine-based regimens in both groups. RESULTS Overall (19.5 mo vs 11.02 mo, P < 0.001) and progression-free (12 mo vs 3 mo, P < 0.001) survival were better for the CHT + mEHT group compared to the CHT group. The association of mEHT resulted also in an improvement of tumor response with disease control rate 95% vs 58% (P < 0.001) at 3 mo. Toxicity was comparable in the two study groups, and mEHT related adverse events were limited in 8 patients presenting G1-2 skin burns. CONCLUSION The addition of mEHT to systemic CHT improved overall and progression-free survival and local tumor control with comparable toxicity.
Published: 2021
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21. Short- and Long-Term, 11–22 Years, Results after Laparoscopic Nissen Fundoplication in Obese versus Nonobese Patients

Author: Mario Schietroma, Federica Piccione, Marco Clementi, Emanuela Marina Cecilia, Federico Sista, Beatrice Pessia, Francesco Carlei, Stefano Guadagni, and Gianfranco Amicucci
Subjects: Internal medicine, RC31-1245
Abstract: Background. Some studies suggest that obesity is associated with a poor outcome after Laparoscopic Nissen Fundoplication (LNF), whereas others have not replicated these findings. The effect of body mass index (BMI) on the short- and long-term results of LNF is investigated. Methods. Inclusion criteria were only patients who undergone a LNF with at least 11-year follow-up data available, patients with preoperative weight and height data available for calculation of BMI (Kg/m2), and patients with a BMI up to a maximum of 34.9. Results. 201 patients met the inclusion criteria: 43 (21.4%) had a normal BMI, 89 (44.2%) were overweight, and 69 (34.4%) were obese. The operation was significantly longer in obese patients; the use of drains and graft was less in the normal BMI group (p
Published: 2017
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22. Colostomy Reversal following Hartmann's Procedure: The Importance of Timing in Short- and Long-Term Complications: A Retrospective Multicentric Study

Author: Marco Clementi, Renato Pietroletti, Filippo Carletti, Federico Sista, Antonella Grasso, Fabiana Fiasca, Sonia Cappelli, Andrea Balla, Vinicio Rizza, Andrea Ciarrocchi, and Stefano Guadagni
Subjects: early and late complications, Hartmann’s Procedure, Hartmann’s Reversal, timing, General Medicine
Abstract: The restoration of bowel continuity following Hartmann’s Procedure (HP) has been reported hitherto with high morbidity and mortality rates. No clear guidelines exist about timing in Hartmann’s Reversal (HR), the literature data being conflicting. We have sought to investigate the effect of the interval time between HP and HR in short- and long-term HR outcomes through a retrospective study based on consecutive patients undergoing HR between 2009 and 2017 in two regional hospitals in Italy. Demographic characteristics, comorbidities, intra- and post-operative data, as well as early complications, were recorded. Long-term data were collected on the surgical site occurrences of Incisional Ventral Hernia (IVH). One hundred and five patients were recruited for the study. Late HR, female gender, and long operating time were related to the highest incidence of peri-operative complications. Patients who developed IVH had undergone HR at significantly shorter times and had a higher Body Mass Index (BMI). The timing of HR seems to be an important variable linked to the onset of early and late post-operative complications. The patients submitted to early HR show a significantly lower complication rate but, at the same time, a higher rate of IVH incidence after restorative surgery. These data, in our opinion, reflect the need for planning, where possible, an early restoration of bowel continuity after HP.
Published: 2022

23. Circulating tumour cell liquid biopsy in selecting therapy for recurrent cutaneous melanoma with locoregional pelvic metastases: a pilot study

Author: Francesco Masedu, Giammaria Fiorentini, Marco Clementi, Antonietta Rossella Farina, Andrew R. Mackay, Panagiotis Apostolou, Donatella Sarti, Stefano Guadagni, and Ioannis Papasotiriou
Subjects: Melphalan, Oncology, Adult, Pelvic loco-regional metastases, medicine.medical_specialty, Skin Neoplasms, medicine.medical_treatment, Cell, Recurrent melanoma, Circulating tumour cells, Hypoxic pelvic perfusion, Liquid biopsies, Precision oncotherapy, lcsh:Medicine, Pilot Projects, General Biochemistry, Genetics and Molecular Biology, Flow cytometry, Internal medicine, medicine, Humans, Stage IIIC, Stage (cooking), Liquid biopsy, lcsh:Science (General), Melanoma, lcsh:QH301-705.5, Aged, Neoplasm Staging, Pelvic Neoplasms, Aged, 80 and over, medicine.diagnostic_test, business.industry, lcsh:R, Liquid Biopsy, General Medicine, Immunotherapy, Middle Aged, Neoplastic Cells, Circulating, Research Note, medicine.anatomical_structure, lcsh:Biology (General), Cutaneous melanoma, Neoplasm Recurrence, Local, business, medicine.drug, lcsh:Q1-390
Abstract: Objectives Circulating tumour cells (CTCs) from liquid biopsies provide an exceptional opportunity to obtain real-time tumour information and are under current investigation in several cancers, including cutaneous melanoma, but face significant drawbacks in terms of non-standardised methodology, low viable cell numbers and accuracy of CTC identification. In this pilot study, we report that chemosensitivity assays using liquid biopsy-derived metastatic melanoma (MM) CTCs, from 7 patients with stage IIIC, BRAF wild-type metastatic melanomas, localized exclusively to the pelvic region, un-eligible for immunotherapy and treated with melphalan hypoxic pelvic perfusion (HPP), is both feasible and useful in predicting response to therapy. Viable MM CTCs (> 5 cells/ml for all 7 blood samples), enriched by transient culture, were characterised in flow cytometry-based Annexin V-PE assays for chemosensitivity to several drugs. Results Using melphalan as a standard, chemosensitivity cut-off values of > 60% cell death, were predictive of patient RECIST 1.1 response to melphalan HPP therapy, associated with calculated 100% sensitivity, 66.67% specificity, 33.33% positive predictive, 100% negative predictive, and 71.43% accuracy values. We propose that the methodology in this study is both feasible and has potential value in predicting response to therapy, setting the stage for a larger study. Trial registration Clinical Trials.gov Identifier NCT01920516; date of trial registration: August 6, 2013
Published: 2020
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24. Real-life multidisciplinary treatment for unresectable colorectal cancer liver metastases including hepatic artery infusion with chemo-filtration and liquid biopsy precision oncotherapy: observational cohort study

Author: Gemma Bruera, Ioannis Papasotiriou, Giammaria Fiorentini, Donatella Sarti, Enrico Ricevuto, Andrew R. Mackay, Francesco Masedu, Paola Palumbo, Marco Clementi, Marco Valenti, Stefano Guadagni, Panagiotis Apostolou, and Aldo Victor Giordano
Subjects: Male, Melphalan, Oncology, Cancer Research, medicine.medical_specialty, Chemo-filtration, Original Article – Clinical Oncology, Antineoplastic Agents, Liquid biopsies, Cohort Studies, Colorectal cancer, Hepatic artery infusion, Liver metastases, Precision oncotherapy, Third-line therapy, chemistry.chemical_compound, Hepatic Artery, Internal medicine, medicine, Humans, Infusions, Intra-Arterial, Precision Medicine, Liquid biopsy, Adverse effect, Aged, Performance status, business.industry, Liver Neoplasms, Liquid Biopsy, General Medicine, Middle Aged, Neoplastic Cells, Circulating, Progression-Free Survival, Carboplatin, Oxaliplatin, Irinotecan, chemistry, Quality of Life, Female, Colorectal Neoplasms, business, Raltitrexed, medicine.drug
Abstract: Background Hepatic artery infusion (HAI) and drug selection by liquid biopsy precision oncotherapy are under investigation for the multidisciplinary treatment of unresectable colorectal liver metastases (CRCLM) in progression after systemic therapy. Here, we compare the safety and efficacy of third-line HAI followed by target therapy with drug regimes selected by liquid biopsy precision oncotherapy to third-line systemic therapy with drug regimes selected partly by tissue biopsy precision oncotherapy, in a retrospective real-life study of 106 unresectable CRCLM patients. Methods Drug regimens for HAI/target therapy were selected by assessing the sensitivity of purified circulating tumor cell (CTCs) to 5-fluorouracil, carboplatin, cisplatin, oxaliplatin, irinotecan, doxorubicin, mitomycin, raltitrexed, and melphalan in-vitro and by real-time qRT-PCR gene expression assays, and for the Systemic therapy cohort were selected by age, comorbidity, performance status, and absence of RAS mutations. Therapeutic responses, adverse events, and quality of life were evaluated by RECIST 1.1, CTCAE 4.03, and ECOG criteria, respectively, and chemo-filtration performed following HAI to reduce systemic toxic effects. Results HAI/target therapy with drugs selected by liquid biopsy precision oncotherapy (44 patients), resulted in 2.27% CRs, 38.63% PRs, 56.81% SD,s and 2.27% PDs; ECOG 2 to 1 improvement, but no infusion-related technical or vascular complications, or deaths. Systemic therapy (62 patients) resulted in 1.6% CRs, 17.74% PRs, 37.09% SDs, and 45.16% PDs; more grade 1–2 adverse events and 4.84% ECOG 1 to 2 worsening. The median 5 month PFS in the HAI/target therapy cohort was significantly longer than 3 months in the systemic cohort (P Conclusions HAI plus chemo-filtration followed by target therapy, with drug regimens selected by liquid biopsy precision oncotherapy, is a safe and efficacious alternative therapeutic strategy for unresectable CRCLM in progression after two lines of systemic therapy and should be considered for a multicentre prospective phase III study, to fully confirm this potential.
Published: 2020
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25. Chemoembolization Alone or Associated With Bevacizumab for Therapy of Colorectal Cancer Metastases: Preliminary Results of a Randomized Study

Author: Donatella Sarti, Alberto Rebonato, Stefano Guadagni, Giammaria Fiorentini, Riccardo Inchingolo, Massimiliano Nestola, and Michele Nardella
Subjects: Male, Cancer Research, medicine.medical_specialty, Bevacizumab, Colorectal cancer, Kaplan-Meier Estimate, Irinotecan, Tumor response, Gastroenterology, General Biochemistry, Genetics and Molecular Biology, law.invention, Liver metastases, 03 medical and health sciences, Antineoplastic Agents, Immunological, 0302 clinical medicine, Randomized controlled trial, colorectal carcinoma, law, Internal medicine, medicine, Humans, In patient, Prospective Studies, Chemoembolization, Therapeutic, Adverse effect, chemoembolization, Complete response, Aged, Pharmacology, TACE, tumor response, business.industry, Liver Neoplasms, Middle Aged, medicine.disease, anti-angiogenesis, bevacizumab, irinotecan, Treatment Outcome, 030220 oncology & carcinogenesis, Female, Topoisomerase I Inhibitors, Colorectal Neoplasms, business, Research Article, medicine.drug
Abstract: Aim to assess efficacy and safety of chemoembolization alone (TACE) and followed by bevacizumab (TACE-B) in patients with colorectal liver metastases (CRC-LM) (NCT03732235). Patients and methods The study included 30 consecutive patients with CRC-LM. They were informed about the types of treatment available: TACE with irinotecan loaded into polythylene glycol embolics alone or followed by bevacizumab therapy. Each patient underwent self-randomization and 17 chose TACE, whereas 13 chose TACE-B. Results Tumor response at 3 months was complete response in one (6%) and four (31%) patients, and partial response in two (13%) and six (46%) patients, after TACE and TACE-B, respectively. No complications were observed during TACE. Most TACE-related adverse events were correlated with post-embolic syndrome. Conclusion The preliminary results of the study showed that the TACE-B is feasible and tolerable. This study will be continued in order accrue a larger number of patients and longer follow-up.
Published: 2020
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26. Successful laparoscopic trans-peritoneal repair of an incisional inguinal hernia, resulting from deep lymph node dissection for melanoma: A case report

Author: Federico Sista, Marco Clementi, M. Di Furia, Andrew R. Mackay, and Stefano Guadagni
Subjects: medicine.medical_specialty, Deep groin lymph-node dissection, Incisional inguinal/groin hernia, Laparoscopic trans-peritoneal repair, Melanoma, Article, law.invention, 03 medical and health sciences, 0302 clinical medicine, Port (medical), law, medicine, Lymph node, business.industry, medicine.disease, digestive system diseases, Surgery, stomatognathic diseases, Inguinal hernia, Dissection, surgical procedures, operative, medicine.anatomical_structure, Cyanoacrylate, 030220 oncology & carcinogenesis, Conjoint tendon, Deep cervical lymph nodes, 030211 gastroenterology & hepatology, business
Abstract: Highlights • Groin incisional hernia may result like late complication of deep pelvic dissection. • When this type of inguinal ventral hernia develops, the surgeon is facing some problems different to the common ventral hernia repair. • Most of these difficulties may be overcome using laparoscopic approach. • We present a case of successful laparoscopic repair of a giant ventral hernia developed like late complication of deep pelvic dissection for melanoma. • To our knowledge, no other laparoscopic repair of this type of ventral hernia has been previously reported., Introduction Deep pelvic lymph node dissection for cancer may result in incisional inguinal hernias. We present a case report of successful laparoscopic trans-peritoneal repair of a large ventral inguinal hernia that developed following ileo-inguinal lymph node dissection (CLND) for melanoma. Case presentation A successful 3 port laparoscopic trans-peritoneal procedure was performed on a 56-year-old female for the repair of a left inguinal hernia, developed 13 months following CLND for melanoma. The large oval 18 × 14 cm inguinal defect, with superior margins bordering the conjoint tendon and inferior margins bordering the ileo-psoas muscle, femoral vessels and nerve, was not closed in order to avoid excessive tension and was repaired by fixing a 25 × 20 cm intra-peritoneal mesh to abdominal borders at superior and lateral margins with permanent fasteners and at the inferior margin by a cyanoacrylate-glued overlap to protect femoral vessels and nerves from damage. No hernia recurrence was observed 8 months following this procedure. Discussion Incisional inguinal hernias, following CLND, are rare but present a challenge to surgeons due to the difficulty in identifying both anatomical plains and safe sites for stable repair. Conclusions We report a laparoscopic trans-peritoneal approach for the safe, reproducible and efficacious repair of incisional inguinal hernias that result from CLND. In our opinion prevention of hernia recurrence can be achieved by a intraperitoneal large mesh fixed at superior and lateral margin borders with permanent fasteners and using cyanoacrylate glue to overlap inferior margin borders in order to prevent vessels and/or nerve injury.
Published: 2020
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27. Surgical site infections in patients undergoing breast oncological surgery during the lockdown: An unexpected lesson from the COVID-19 pandemic

Author: Sonia, Cappelli, Diletta, Corallino, Marco, Clementi, Stefano, Guadagni, Fabio, Pelle, Ilaria, Puccica, Maddalena, Barba, Patrizia, Vici, Isabella, Sperduti, Maurizio, Costantini, and Claudio, Botti
Subjects: Breast cancer, Additional treatment, Serous discharge, Erythema, Purulent exudate, Center for Disease Control and Prevention (CDC), Covid-19 pandemic, Isolation of bacteria, Separation of deep tissues, Stay (ASEPSIS), Surgical site infections
Abstract: The present study aims to evaluate how the measures to contain the SARS-CoV-2 spreading affected the surgical site infections (SSIs) rate in patients who underwent nondeferrable breast cancer surgery (BCS).This study is a retrospective analysis of prospectively collected data from a consecutive series of patients underwent nondeferrable BCS in a regional Italian Covid-free hub during two different period: March to April 2020 (pandemic cohort [PC]) and March till April 2019 (control cohort [CC]). SSIs were defined according to the criteria established by the Center for disease control and prevention (CDC) and additional treatment, serous discharge, erythema, purulent exudate, separation of deep tissues, isolation of bacteria, and stay (ASEPSIS) scoring systems.One hundred ninety-nine patients were included in the present study: 100 and 99 patients who underwent nondeferrable BCS from March to April 2020 (PC) and from March to April 2019 (CC), respectively. The overall SSIs rate in this series was 9.1% according to CDC criteria and 6.5% according to ASEPSIS criteria. The SSIs incidence decreased during the pandemic period. Moreover, the SSIs rate according to ASEPSIS criteria was statistically lower in the PC than in the CC. We observed significant evidence of higher SSIs, both in terms of CDC and ASEPSIS score, in patients having undergone breast reconstruction compared with patients not undergoing immediate reconstruction.The restrictive measures issued during the lockdown period seemed to lower the SSIs rates in patients undergoing nondeferrable BCS.
Published: 2022

28. Immune response and locoregional treatments for peritoneal carcinomatosis

Author: Caterina Fiorentini, Donatella Sarti, Stefano Guadagni, and Giammaria Fiorentini
Subjects: Hyperthermic intra peritoneal chemotherapy, Antibody-dependent cellular cytotoxicity, Cytoreductive surgery, Immunogenic cell death, Peritoneal carcinomatosis, Pressurized intraperitoneal aerosol chemotherapy, Combined Modality Therapy, Humans, Immunity, Hyperthermia, Induced, Peritoneal Neoplasms, Induced, Hyperthermia
Published: 2022
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29. Transarterial chemoembolization alone or followed by bevacizumab for treatment of colorectal liver metastases

Author: Donatella Sarti, Alberto Rebonato, Stefano Guadagni, Camillo Aliberti, Riccardo Inchingolo, Caterina Fiorentini, Giammaria Fiorentini, Roberto Nani, Massimiliano Nestola, and Michele Nardella
Subjects: medicine.medical_specialty, Bevacizumab, Angiogenesis, Colorectal cancer, polyethylene glycol microspheres, angiogenesis, bevacizumab, colorectal carcinoma, DC beads radiopaque, irinotecan, liver metastases, transarterial chemoembolization, Tumor response, medicine.disease_cause, Gastroenterology, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Mutational status, Hepatology, business.industry, Cancer, medicine.disease, Irinotecan, Oncology, 030220 oncology & carcinogenesis, KRAS, business, medicine.drug, Research Article
Abstract: Aims: Bevacizumab (B) in association with systemic chemotherapy is commonly used for the treatment of colorectal cancer liver metastases. The aim of this study was to monitor tumor response, overall survival (OS) and progression-free survival (PFS) of patients with colorectal cancer liver metastases treated with transarterial chemoembolization (TACE) + B compared with TACE alone and to correlate the results with KRAS mutational status. Patients & methods: This was an observational multicentric case–control study (NCT03732235) on the efficacy and safety of B administered after TACE. Results: The disease control rate was significantly higher for the TACE + B than the TACE alone group (p
Published: 2021

30. Precision oncotherapy based on liquid biopsies in multidisciplinary treatment of unresectable recurrent rectal cancer: a retrospective cohort study

Author: Marco Catarci, Marco Clementi, Gemma Bruera, Michele De Simone, Francesco Masedu, Stefano Guadagni, Donatella Sarti, Giammaria Fiorentini, Odisseas Zoras, Enrico Ricevuto, Andrew R. Mackay, Panagiotis Apostolou, and Ioannis Papasotiriou
Subjects: Male, Oncology, Cancer Research, medicine.medical_specialty, Colorectal cancer, medicine.medical_treatment, Original Article – Clinical Oncology, Systemic therapy, law.invention, Cohort Studies, Liquid biopsy, Perfusion, Precision oncotherapy, Rectal cancer, Recurrence, Randomized controlled trial, law, Internal medicine, Humans, Medicine, Precision Medicine, Adverse effect, Neoadjuvant therapy, Aged, Retrospective Studies, Chemotherapy, Rectal Neoplasms, business.industry, Retrospective cohort study, Chemoradiotherapy, Adjuvant, General Medicine, Middle Aged, medicine.disease, Neoadjuvant Therapy, Disease Progression, Female, Neoplasm Recurrence, Local, business
Abstract: Background Third line innovative systemic treatments and loco-regional chemotherapy by hypoxic pelvic perfusion (HPP) have both been proposed for the treatment of unresectable not responsive recurrent rectal cancer (URRC). In the present study, we have compared the safety and efficacy of HPP/target therapy, using drug regimens selected by liquid biopsy precision oncotherapy, to third-line systemic therapy based on tissue specimens precision oncotherapy. Methods HPP/target therapy regimens were selected based on precision oncotherapy, including assays for chemosensitivity and viability, and qRT-PCR for tumor-related gene expression. In the control group, systemic third-line and further lines of therapy were defined according to clinical and biological parameters. Results From 2007 to 2019, 62 URRC patients were enrolled, comprised of 43 patients in the HPP/target-therapy group and 19 patients in the systemic therapy control group. No HPP related complications were reported and the most common adverse events were skin and bone marrow toxicity. In the HPP/target-therapy group, the ORR was 41.8% whereas in the systemic therapy control group was 15.8%. DCR of the HPP/target-therapy group was significantly improved over the systemic therapy group (P = 0.001), associated with a PFS of 8 vs 4 months (P = 0.009), and OS of 20 vs 8 months (P = 0.046). Conclusions The present data indicate that in URCC patients, the integration of HPP/target-therapy and precision oncotherapy based upon liquid biopsy is as effective and efficacious as third-line treatment in local disease control and, therefore, deserves to be further assessed and compared to conventional systemic treatments in future prospective randomized trials.
Published: 2019
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31. Combined approach with negative pressure wound therapy and biological mesh for treatment of enterocutaneous fistula after synthetic mesh repair of incisional hernia. A case report

Author: Marino, Di Furia, Andrea, Della Penna, Ilaria, Puccica, Derna, Stifini, Andrea, Salvatorelli, Federico, Sista, Stefano, Guadagni, and Marco, Clementi
Subjects: Bioprosthesis, Male, Reoperation, Prosthesis-Related Infections, Middle Aged, Surgical Mesh, Combined Modality Therapy, Hernia, Ventral, Intestinal Fistula, Humans, Incisional Hernia, Device Removal, Herniorrhaphy, Negative-Pressure Wound Therapy, Retrospective Studies
Abstract: Enterocutaneous fistula is a rare but severe complication of prosthetic incisional hernia repair. Management requires re-exploration with intestinal repair/resection and mesh removal. Repair of the parietal defect in this contaminated field is challenging.A 58-years male patient presented to our department one year after synthetic mesh repair of large incisional hernia with mesh infection and enterocutaneous fistula. The diagnosis was confirmed by ultrasound guided drainage and CT scans with oral contrast. A multiple-step surgical approach has been adopted: first, the mesh was removed, intestinal resection performed and posterior fascial closure obtained by bilateral transversus abdominis release (TAR) and supra-fascial NPWT (negative pressure wound therapy) was positioned and maintained for one week; second, a definitive repair was obtained by a biological prothesis fixed to posterior fascia and covered by anterior fascia closure. Then, new NPWT was positioned and maintained for 6 days on the skin closure. At 18-months follow-up, the patient showed no clinical or radiological signs of recurrence or reinfection.Surgical strategies to face enterocutaneous fistula after prosthesis ventral hernia repair are not standardized. After bowel fistula treatment and mesh removal, the challenge of abdominal wall closure stay unsolved because of the high rate of complication and failure of a new prosthetic repair. A case-by-case management plan, often with the use of a multi-step strategy, may be an option.This is a single recovery multiple-step strategy combined approach using NPWT and biological prothesis to manage a case of mesh infection by an enterocutaneous fistula. This unique approach has revealed safe and effective for the treatment of parietal defect in infected field resulting from a mesh removing procedure.Biological prosthesis, Bowel mesh erosion, Enterocutaneous fistula, Negative Pressure Wound Therapy, Open incisional hernia repair.La fistola enterocutanea è una complicanza rara ma assai temuta legata all’utilizzo di reti per la plastica del laparocele. Non essendoci ancora una tecnica standardizzata, abbiamo descritto un caso clinico di rilevanza: maschio, 58 anni, a distanza di 1 anno dall’essere stato sottoposto a plastica per un voluminoso laparocele con utilizzo di rete sintetica, mostrava segni e sintomi clinici di infezione della protesi con presenza di una fistola enterocutanea. La diagnosi veniva confermata da ecografia, col drenaggio dell’ascesso e TC con mdc per os. Data la complessità del caso, abbiamo adottato una strategia multi-step: in primo luogo, rimozione della protesi, resezione intestinale e chiusura della fascia posteriore dei muscoli retti con associata TAR (transversus abdominis release) e posizionamento di dispositivo NPWT soprafasciale per 1 settimana; successivamente, chiusura definitiva con protesi biologica fissata tra la fascia posteriore ed anteriore dei muscoli retti, ancora con NPWT a protezione della cute per ulteriore 6 giorni. Il decorso postoperatorio è stato privo di eventi avversi e il paziente, ad un follow-up clinico-radiologico di 18 mesi, non presenta segni di recidiva o reinfezione. Questo approccio multi-step si è rivelato sicuro ed efficace nel nostro caso, e data la mancanza di standardizzazione per una patologia poco frequente, rappresenta una concreta possibilità terapeutica.
Published: 2021

32. Re: Response to Recommendation of Regional Hyperthermia in the Treatment of Breast Cancer

Author: Stefano Guadagni, Tommaso Carfagno, Caterina Fiorentini, Marco Ballerini, Girolamo Ranieri, Donatella Sarti, Cosmo Damiano Gadaleta, and Giammaria Fiorentini
Subjects: Hyperthermia, Oncology, Regional hyperthermia, medicine.medical_specialty, business.industry, Breast Neoplasms, Hyperthermia, Induced, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, lcsh:RC254-282, Combined Modality Therapy, Hyperthermia induced, Text mining, Breast cancer, Complementary and alternative medicine, Internal medicine, medicine, Humans, Letter to the Editor, Integrative Cancer Therapies, Female, business
Published: 2021

33. Hypoxia-induced alternative splicing: the 11th Hallmark of Cancer

Author: Lucia Cappabianca, Veronica Zelli, Michela Sebastiano, Antonietta R. Farina, Stefano Guadagni, and Andrew R. Mackay
Subjects: 0301 basic medicine, Cancer Research, Programmed cell death, Epithelial-Mesenchymal Transition, Angiogenesis, Cancer hallmarks, Cell, Review, Biology, lcsh:RC254-282, law.invention, 03 medical and health sciences, 0302 clinical medicine, Immune system, law, Neoplasms, medicine, Humans, Epithelial–mesenchymal transition, Hypoxia, Alternative splicing, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, RNA splicing, Disease Progression, Cancer research, Suppressor
Abstract: Hypoxia-induced alternative splicing is a potent driving force in tumour pathogenesis and progression. In this review, we update currents concepts of hypoxia-induced alternative splicing and how it influences tumour biology. Following brief descriptions of tumour-associated hypoxia and the pre-mRNA splicing process, we review the many ways hypoxia regulates alternative splicing and how hypoxia-induced alternative splicing impacts each individual hallmark of cancer. Hypoxia-induced alternative splicing integrates chemical and cellular tumour microenvironments, underpins continuous adaptation of the tumour cellular microenvironment responsible for metastatic progression and plays clear roles in oncogene activation and autonomous tumour growth, tumor suppressor inactivation, tumour cell immortalization, angiogenesis, tumour cell evasion of programmed cell death and the anti-tumour immune response, a tumour-promoting inflammatory response, adaptive metabolic re-programming, epithelial to mesenchymal transition, invasion and genetic instability, all of which combine to promote metastatic disease. The impressive number of hypoxia-induced alternative spliced protein isoforms that characterize tumour progression, classifies hypoxia-induced alternative splicing as the 11th hallmark of cancer, and offers a fertile source of potential diagnostic/prognostic markers and therapeutic targets.
Published: 2020
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34. Updates of colorectal cancer liver metastases therapy: review on DEBIRI

Author: Camillo Aliberti, Stefano Guadagni, Caterina Fiorentini, Giammaria Fiorentini, Roberto Nani, and Donatella Sarti
Subjects: Oncology, medicine.medical_specialty, Hepatology, business.industry, Colorectal cancer, Systemic chemotherapy, DEBIRI, Advanced stage, colorectal cancer, Review, medicine.disease, Tumor response, CRC-LM, Resection, Refractory, liver metastases, liver resection, Internal medicine, Medicine, business
Abstract: Colorectal cancer is a worldwide public health issue, presenting an advanced stage at diagnosis in more than 20% of patients. Liver metastases are the most common metastatic sites and are not indicated for resection in 80% of cases. Unresectable colorectal cancer liver metastases that are refractory to systemic chemotherapy may benefit from transarterial chembolization with irinotecan-loaded beads (DEBIRI). Several studies show the safety and efficacy of DEBIRI for the treatment of colorectal cancer liver metastases. The development of transarterial chembolization and the introduction of new embolics have contributed to better outcomes of DEBIRI. This article reviews the current literature on DEBIRI reporting its use, efficacy in terms of tumor response and survival and side effects.
Published: 2020

35. A Pilot Study of the Predictive Potential of Chemosensitivity and Gene Expression Assays Using Circulating Tumour Cells from Patients with Recurrent Ovarian Cancer

Author: Donatella Sarti, Giovanni Scambia, Giammaria Fiorentini, Marcello Deraco, Marco Clementi, Francesco Masedu, Shigeki Kusamura, Antonietta Rossella Farina, Giuseppe Vizzielli, Karl R. Aigner, Giuseppe Zavattieri, Andrew R. Mackay, Ioannis Papasotiriou, Stefano Guadagni, and Panagiotis Apostolou
Subjects: 0301 basic medicine, endocrine system diseases, Gene Expression, Pilot Projects, Carcinoma, Ovarian Epithelial, lcsh:Chemistry, liquid biopsies, 0302 clinical medicine, Annexin, recurrent ovarian cancer, Gene expression, Medicine, Stage (cooking), lcsh:QH301-705.5, Spectroscopy, Ovarian Neoplasms, medicine.diagnostic_test, General Medicine, Middle Aged, Neoplastic Cells, Circulating, female genital diseases and pregnancy complications, Computer Science Applications, Reverse transcription polymerase chain reaction, 030220 oncology & carcinogenesis, Female, circulating tumour cells, hypoxic isolated abdominal perfusion, precision oncotherapy, Adult, Programmed cell death, Antineoplastic Agents, Article, Catalysis, Flow cytometry, Inorganic Chemistry, 03 medical and health sciences, Humans, Stage IIIC, Physical and Theoretical Chemistry, Molecular Biology, Aged, business.industry, Gene Expression Profiling, Organic Chemistry, Liquid Biopsy, Gene expression profiling, 030104 developmental biology, lcsh:Biology (General), lcsh:QD1-999, Cancer research, Neoplasm Recurrence, Local, business
Abstract: Circulating tumour cells (CTCs) from liquid biopsies are under current investigation in several cancers, including epithelial ovarian cancer (EOC) but face significant drawbacks in terms of non-standardised methodology, low viable cell numbers and accuracy of CTC identification. In this pilot study, we report that chemosensitivity assays using liquid biopsy-derived metastatic EOC CTCs, from 10 patients, nine with stage IIIC and one with stage IV disease, in progression after systemic chemotherapy, submitted for hypoxic isolated abdominal perfusion (HAP), are both feasible and useful in predicting response to therapy. Viable metastatic EOC CTCs (&gt, 5 cells/mL for all 10 blood samples), enriched by transient culture and identified by reverse transcription polymerase chain reaction (RT-PCR) and indirect immunofluorescence (IF), were subjected to flow cytometry-based Annexin V-PE assays for chemosensitivity to several chemotherapeutic agents and by RT-PCR for tumour gene expression profiling. Using a cut-off value of &gt, 80% cell death, CTC chemosensitivity tests were predictive of patient RECIST 1.1 responses to HAP therapy associated with 100% sensitivity, 50% specificity, 33% positive predictive, 100% negative predictive and 60% accuracy values. We propose that the methodology employed in this study is feasible and has the potential to predict response to therapy, setting the stage for a larger study.
Published: 2020

36. High Resected Gastric Volume and poorly controlled DM2 in laparoscopic sleeve gastrectomy

Author: Sergio Carandina, Federico Sista, Marco Clementi, Stefano Guadagni, and Valentina Abruzzese
Subjects: medicine.medical_specialty, Sleeve gastrectomy, medicine.medical_treatment, 030209 endocrinology & metabolism, Gastroenterology, Group B, 03 medical and health sciences, chemistry.chemical_compound, Diabetes mellitus type 2, 0302 clinical medicine, Internal medicine, Volume resected, medicine, Obesity, Original Research, Bariatric surgery, Laparoscopic sleeve gastrectomy, Hb1Ac, C-peptide, business.industry, Significant difference, Type 2 Diabetes Mellitus, General Medicine, medicine.disease, chemistry, 030211 gastroenterology & hepatology, Surgery, business, Body mass index
Abstract: Background Our aim is to evaluate the effects of High Resected Gastric Volume(HRGV) on poorly Type 2 Diabetes Mellitus(DM2) after Laparoscopic Sleeve Gastrectomy(LSG). Methods 256 patients were divided into two groups according to the RGV: < 1500 mL(Group A: 131 pts) and > 1500 mL(Group B: 147 pts). % excess body mass index loss (%EBMIL), Fasting Blood Glucose (FBG), HbA1c, C peptide were assessed before surgery and at the 3rd day, 6th,12th,24th,36th month after LSG. Results A significant difference in %EBMIL between the two groups at 24 and 36 months was found. RGV was not significantly associated with DM2 in the multivariate logistic regression. FBG levels showed no differences between the two groups. A significant decrease of Hb1Ac at 6 and 12 months was found in group B. The C-peptide level showed a significant reduction at 6 and 12 months in group B. Conclusion The HRGV may play a role in the regulation of the glucose metabolism in the first year after LSG without influence in poorly DM2 control. Further studies are needed to confirm these findings., Highlights • The study showed that the High Resected Gastric Volume (HRGV) play a role in the regulation of the glucose metabolism in the first year after LSG without influence in poorly DM2 control.
Published: 2018
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37. Chemoembolization in Conjunction with Bevacizumab: Preliminary Results

Author: Donatella Sarti, Camillo Aliberti, Alessandro Felicioli, Stefano Guadagni, Giammaria Fiorentini, Riccardo Carandina, and Luca Mulazzani
Subjects: Male, Oncology, medicine.medical_specialty, Bevacizumab, Colorectal cancer, Angiogenesis Inhibitors, Irinotecan, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Text mining, Nuclear Medicine and Imaging, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Radiology, Nuclear Medicine and imaging, Prospective Studies, Chemoembolization, Therapeutic, Aged, business.industry, Liver Neoplasms, Radiology, Nuclear Medicine and Imaging, Cardiology and Cardiovascular Medicine, Middle Aged, medicine.disease, Disease control, Angiogenesis inhibitor, Treatment Outcome, Italy, 030220 oncology & carcinogenesis, Quality of Life, Administration, Intravenous, Camptothecin, Female, Colorectal Neoplasms, Tomography, X-Ray Computed, Radiology, business, Preliminary Data, medicine.drug
Abstract: Transarterial chemoembolization is an effective, minimally invasive therapy that is widely used for treatment of unresectable colorectal cancer liver metastases (CRC-LM). However, chemoembolization induces a hypoxic microenvironment, which increases neoangiogenesis and may promote early progression. For this reason, transarterial chemoembolization efficacy may be improved by combining it with an angiogenesis inhibitor, such as bevacizumab. This report shows that transarterial chemoembolization with irinotecan-loaded polyethylene glycol embolics and bevacizumab therapy was effective and well tolerated by 6 patients with CRC-LM, resulting in a disease control rate of 83% and an overall improvement in quality of life.
Published: 2018
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38. Advantage of laparoscopic resection for pelvic Schwannoma: Case report and review of the literature

Author: Federico Sista, Marco Clementi, Vincenzo Vicentini, Alessandro Chiominto, Andrea Della Penna, Marino Di Furia, Stefano Guadagni, and Andrea Salvatorelli
Subjects: tumor, medicine.medical_specialty, Schwannoma, Article, Benign tumor, Anatomical space, 03 medical and health sciences, 0302 clinical medicine, Pneumoperitoneum, Pelvic disease, otorhinolaryngologic diseases, medicine, Robotic surgery, Laparoscopy, medicine.diagnostic_test, business.industry, fungi, food and beverages, medicine.disease, Dissection, 030220 oncology & carcinogenesis, 030211 gastroenterology & hepatology, Surgery, Radiology, Presentation (obstetrics), Retroperitoneum, business
Abstract: Highlights • Retroperitoneal schwannomas are usually asymptomatic, rare neoplasms. • Diagnosis can only be achieved with surgical removal of mass. • Laparoscopy is the most useful therapeutic approach., Introduction Single pelvic schwannomas are rare tumor arising from the retrorectal, lateral or obturatory space. Laparoscopic approach to schwannoma located in lateral pelvic space has been previously described only in one case report. We present a case of a successful laparoscopic resection of pelvic schwannoma emphasizing the advantages of such a minimal invasive approach. Presentation of case A 54-years-old, obese, male patient was admitted to our hospital referring dysuria and strangury. Abdominal CT scan showed a lateral pelvic well-circumscribed mass with smooth regular margins. A CT-guided fine needle biopsy resulted non-diagnostic. An elective laparoscopic resection was performed. The patient had a short, uneventful post-operative course. Pathological examination revealed a benign schwannoma. Discussion Using PubMed database, we reviewed the English language international literature using the MeSH terms “laparoscopic,” “minimally invasive” and “schwannoma”. We identified quite 20 previous cases of pelvic schwannomas removed by laparoscopy or robotic surgery. We found out that a preoperative diagnosis of these rare neoplasms is difficult to be obtained; in most cases, laparoscopic approach was successfully performed. Conclusion Despite it could not be proven yet, due to the rarity of this tumor, we agree with literature that laparoscopic removal of pelvic benign tumor may offer several advantages. The direct high-definition vision deeply into this narrow anatomical space, especially in obese patients, provides a detailed view that makes easier to isolate and spear the anatomical structures surrounding the tumor. Furthermore, the pneumoperitoneum may create the right plane of dissection, minimizing the risk of tumor rupture and bleeding.
Published: 2018
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39. MGMT methylation correlates with melphalan pelvic perfusion survival in stage III melanoma patients: a pilot study

Author: Alessandro Chiominto, Marco Valenti, Giancarlo Palumbo, Marcello Deraco, Giammaria Fiorentini, Francesco Masedu, Cristina Pellegrini, Stefano Guadagni, Marco Clementi, and Giovanni de Manzoni
Subjects: Male, 0301 basic medicine, Melphalan, Oncology, Cancer Research, Pathology, medicine.medical_treatment, Pilot Projects, pelvis, 0302 clinical medicine, Stage (cooking), Promoter Regions, Genetic, DNA Modification Methylases, Pelvic Neoplasms, Melanoma, Methylation, Middle Aged, Prognosis, 030220 oncology & carcinogenesis, DNA methylation, Female, MGMT, medicine.drug, medicine.medical_specialty, Dermatology, perfusion, 03 medical and health sciences, Internal medicine, melanoma, medicine, Humans, Antineoplastic Agents, Alkylating, neoplasms, Survival analysis, Neoplasm Staging, Retrospective Studies, Chemotherapy, ORIGINAL ARTICLES: Translational research, business.industry, Tumor Suppressor Proteins, Cancer, DNA Methylation, medicine.disease, Survival Analysis, DNA Repair Enzymes, 030104 developmental biology, Chemotherapy, Cancer, Regional Perfusion, methylation, business
Abstract: Approximately 25% of melanoma patients with locoregional metastases are nonresponsive to new molecular target therapy and immunotherapy. When metastases are located in the pelvis, melphalan hypoxic perfusion can be an optional treatment. Because methylation of MGMT promoter increases the efficacy of alkylating agents, studies on melanoma outcome of patients treated with melphalan regional chemotherapy should consider this epigenetic change. This study aims to evaluate whether the survival of stage III melanoma patients treated with melphalan regional chemotherapy may be correlated with MGMT methylation status. The metastatic tissues of 27 stage III melanoma patients with locoregional metastases located in the pelvis subjected to melphalan hypoxic pelvic perfusion were examined. The methylation status of the MGMT promoter was investigated by MS-MLPA probes analysis and the presence of the BRAF V600E mutation was analyzed by CAST-PCR. The median survival times were estimated using the Kaplan–Meier curves and were stratified according to the clinicopathological characteristics of patients and lesions. The overall median survival time was 17 months. The 1-year, 3-year, and 5-year survival rates were 66.7, 18.5, and 7.4%, respectively. Disease stage, burden, and percentage of MGMT methylation significantly affected survival. We estimated an MGMT promoter methylation cut-off of at least 14%, which was significantly associated with a longer survival after melphalan regional chemotherapy. Our data suggest that MGMT promoter methylation could be an important factor in determining which melanoma patients should receive melphalan regional chemotherapy, but its prognostic significance in the routine clinical setting needs to be clarified in a larger study.
Published: 2017
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40. Transarterial chemoembolization with DC Bead LUMI™ radiopaque beads for primary liver cancer treatment: preliminary experience

Author: Donatella Sarti, Riccardo Carandina, Umberto Cillo, Stefano Guadagni, Gaetano Ramondo, Giammaria Fiorentini, Enrico Pizzirani, and Camillo Aliberti
Subjects: Male, Cancer Research, medicine.medical_specialty, Carcinoma, Hepatocellular, arterially directed embolic therapy, Contrast Media, Computed tomography, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, Humans, Medicine, Distribution (pharmacology), Tissue Distribution, Prospective Studies, Chemoembolization, Therapeutic, Adverse effect, DC Bead LUMI radiopaque beads, TACE, chemoembolization, hepatocellular carcinoma, Aged, Neoplasm Staging, Aged, 80 and over, medicine.diagnostic_test, business.industry, Liver Neoplasms, General Medicine, Middle Aged, medicine.disease, Combined Modality Therapy, Microspheres, Tumor Burden, Treatment Outcome, Oncology, Doxorubicin, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Retreatment, Vomiting, Female, Radiology, medicine.symptom, Tomography, X-Ray Computed, business, Primary liver cancer
Abstract: Aim: Primary objectives of the study were to assess the safety of transarterial chemoembolization (TACE) using DC Bead LUMI™ for the treatment of hepatocellular carcinoma and beads distribution after TACE. Patients/methods: This was a prospective observational cohort study. The study included 44 hepatocellular carcinoma patients who were treated with TACE using DC Bead LUMI. Beads distribution was monitored 1 h after TACE by CT scan. Results: TACE had no intraprocedural complications. Observed side effects were of mild intensity and included pain in 5 (11%), fever in 4 (9%) and vomiting in 2 (5%) patients. Most patients (89%) reported no adverse event. Non-target distribution was observed in only two cases (5%). Conclusion: DC Bead LUMI allowed assessing in real time their distribution. This could prevent non-target infusion and reduce toxicity.
Published: 2017
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41. Pancreatic enzyme supplementation after gastrectomy for gastric cancer: a randomized controlled trial

Author: Francesco Masedu, Giovanni Battista Grassi, Manuele Berlanda, Stefano Guadagni, and Marco Catarci
Subjects: Male, Cancer Research, medicine.medical_specialty, Normal diet, medicine.medical_treatment, Stomach neoplasms, Exocrine pancreatic insufficiency, Nutritional Status, Adenocarcinoma, Gastroenterology, law.invention, 03 medical and health sciences, 0302 clinical medicine, Gastrointestinal Agents, Randomized controlled trial, Quality of life, Gastrectomy, law, Internal medicine, Multicenter trial, medicine, Humans, Aged, Gastrointestinal agent, Pancrelipase, business.industry, Oncology, General Medicine, Middle Aged, medicine.disease, 030220 oncology & carcinogenesis, Original Article, Female, 030211 gastroenterology & hepatology, business, Body mass index
Abstract: Background Gastrectomy for gastric cancer is a significant cause of secondary exocrine pancreatic insufficiency. Pancreatic enzyme replacement therapy may influence nutritional status and quality of life after gastrectomy, but the pertinent clinical research to date remains controversial. A randomized controlled trial to test this hypothesis was carried out. Methods After gastrectomy, 43 patients with gastric cancer were randomly assigned to a normal diet (Normal-d; n = 21) or to a pancreatic enzyme supplementation diet (PES-d; n = 22) and were followed up during a 12-month period, assessing nutritional status and quality of life through body mass index (BMI), instant nutritional assessment (INA) class status, serum pre-albumin (SPA) values, and GastroiIntestinal Quality of Life Index (GIQLI). Results BMI was not significantly influenced by the type of diet; INA class status was significantly improved in the PES-d arm, particularly during the first 3 months after gastrectomy; SPA levels increased in both arms at 6 months after gastrectomy, reaching significantly higher values in the PES-d arm at 12 months. GIQLI was not significantly influenced by the type of diet throughout the follow-up period; however, this index significantly improved in the PES-d arm between the first and third month after gastrectomy. Conclusions PES-d improves nutritional status and quality of life after gastrectomy for gastric cancer, particularly within 3 months from the operation. A larger, multicenter trial is necessary to address the potential influence of several confounding variables such as disease stage and adjuvant treatments.
Published: 2017
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42. Hepatic intra-arterial and systemic chemotherapy followed by maintenance therapy for the treatment of cholangiocarcinoma

Author: Donatella Sarti, Giammaria Fiorentini, Andrea Mambrini, Gian Maria Mattioli, Maurizio Cantore, Luca Mulazzani, and Stefano Guadagni
Subjects: Oncology, medicine.medical_specialty, Anemia, Nausea, intra-arterial chemotherapy, Capecitabine, 03 medical and health sciences, 0302 clinical medicine, Maintenance therapy, biliary tract cancer, Internal medicine, medicine, Adverse effect, cholangiocarcinoma, tumor response, Hepatology, business.industry, Retrospective cohort study, medicine.disease, Gemcitabine, 030220 oncology & carcinogenesis, Vomiting, 030211 gastroenterology & hepatology, medicine.symptom, business, Research Article, medicine.drug
Abstract: Aim: The aim is to report clinical outcomes of hepatic intra-arterial (IACHT) and systemic chemotherapy (SCHT), followed by gemcitabine-based maintenance therapy (maintenance), for the treatment of relapsed or unresectable cholangiocarcinoma. Patients & methods: In this retrospective observational study, 145 cholangiocarcinoma patients were treated with Epirubicin-Cisplatin as IACHT associated with Capecitabine or 5-fluorouracil as SCHT. Maintenance was performed with gemcitabine-based schedule. Toxicity was assessed with NCI-CTCAE and tumor response with RECIST 1.1. Results: Tumor response was complete in 1%, partial in 20%, stable disease in 48% and progression in 31% of patients (3 months after therapy). The most frequent adverse events were: anemia (24%), nausea and vomiting (33%), alopecia (60%). Conclusion: Cholangiocarcinoma patients may benefit from IAHCT-SCHT. Maintenance may prolong clinical benefits. ClinicalTrials.gov registry Identifier: NCT01920503.
Published: 2017
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43. Septic Complications after Resection for Middle or Low Rectal Cancer: Role of Gut Barrier Function and Inflammatory Serum Markers

Author: Marco Clementi, Stefano Guadagni, Mario Schietroma, Sara Colozzi, Gianfranco Amicucci, Beatrice Pessia, and Francesco Carlei
Subjects: Male, Colorectal cancer, Interleukin-1beta, 030230 surgery, Gastroenterology, Postoperative Complications, 0302 clinical medicine, Gut barrier function, Medicine, Mannitol, Postoperative Period, Prospective Studies, Intestinal Mucosa, Prospective cohort study, Inflammatory serum markers, Pancreatic elastase, Aged, 80 and over, Extraperitoneal rectal cancer, Rectal surgery, Surgery, Pancreatic Elastase, biology, Elastase, Middle Aged, Lactulose, C-Reactive Protein, 030220 oncology & carcinogenesis, Preoperative Period, Female, Adult, medicine.medical_specialty, Permeability, Sepsis, 03 medical and health sciences, Internal medicine, Humans, Aged, Intestinal permeability, Interleukin-6, Rectal Neoplasms, business.industry, C-reactive protein, Cancer, medicine.disease, Endotoxemia, Endotoxins, biology.protein, business, Biomarkers
Abstract: Background: The focus of this study was to understand the relationship between the failure of gut barrier function, inflammatory markers and septic complications after resection for extraperitoneal rectal cancer. Methods: One hundred seven patients were enrolled into this prospective observational study and underwent open colorectal resection for extraperitoneal cancer. All patients underwent an assessment of intestinal permeability (L/M ratio), endotoxemia, interleukin-1β (IL-1β), interleukin-6 (IL-6), C-reactive protein (CRP) and elastase levels before surgery and on postoperative days 1, 3, and 7. Results: Septic complications developed in 23.3% of patients. There were no significant differences in preoperative L/M ratio, endotoxine, CRP, interleukin-1 (IL-1), IL-6, and elastase levels between septic and non-septic groups. All patients showed a significant increase in intestinal permeability, endotoxemia, IL-1, IL-6, CRP, and elastase on the first postoperative day. At postoperative day 7, the septic group continued to demonstrate an increase in intestinal permeability, endotoxemia and elastase and significant difference was observed between the 2 groups (p < 0.05), whereas there was no significant difference in IL-1, IL-6, and CRP levels. Conclusion: The pattern of change in the postoperative period of intestinal permeability, systemic endotoxemia and elastase concentration is significantly higher in patients in whom sepsis develops, while the concentration of IL-1β, IL-6, and CRP does not permit to distinguish infection from inflammation.
Published: 2017
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44. Immune response activation following hyperthermic intraperitoneal chemotherapy for peritoneal metastases: A pilot study

Author: Giammaria Fiorentini, Donatella Sarti, Stefano Guadagni, Francesco Masedu, Francesco Guerra, Emilio Eugeni, Alberto Patriti, and Andrew R. Mackay
Subjects: 0301 basic medicine, Lymphocyte, CD3, Regulatory T lymphocytes, Observational Study, Pharmacology, 03 medical and health sciences, 0302 clinical medicine, Immune system, medicine, Cytotoxic T cell, Pseudomyxoma peritonei, Immune response, Hyperthermic intraperitoneal chemotherapy, Peritoneal metastases, Colorectal cancer, biology, business.industry, T lymphocyte, Acquired immune system, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, biology.protein, business, CD8
Abstract: Background Hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal metastases (PM) is considered to be feasible, safe and to improve survival. Aim To investigate whether an immune response is activated following HIPEC for PM. Methods Six patients were enrolled in this study. Peripheral blood samples were obtained from each patient prior to (day 0) and post-procedure (day 30), and used to evaluate the number of CD3+ total, CD3+/CD4+ T-Helper, CD3+/CD8+ cytotoxic T, CD3+/CD56+ natural killer and CD19+ B lymphocyte numbers, and CD4+: CD8+ T lymphocyte ratios. Results The total numbers of CD3+, CD3+/CD4+ T-Helper, CD3+/CD8+ cytotoxic T, CD3+/CD56+ natural killer and CD19+ B lymphocytes, and CD4+: CD8+ lymphocyte ratios were increased in all but one patient 30 d following the cytoreductive surgery-HIPEC procedure, and these increases were significant (P ≤ 0.05) for CD3+/CD4+ T Helper and CD3+/CD8+ cytotoxic T lymphocyte numbers. Conclusion This report provides the first evidence that HIPEC exhibits immunomodulating activity in PM patients, resulting in generalized activation of the adaptive immune response. Moreover, the majority of lymphocyte populations increased following HIPEC and continued to be elevated several weeks following the procedure, consistent with a potential authentic immunomodulating effect rather than a normal inflammatory response, to be fully characterised in future studies.
Published: 2019

45. Multidisciplinary palliative treatment including isolated thoracic perfusion for progressive malignant pleural mesothelioma: a retrospective observational study

Author: Stefano, Guadagni, Francesco, Masedu, Odisseas, Zoras, Giuseppe, Zavattieri, Kornelia, Aigner, Veronica, Guadagni, Lucio, Fumi, and Marco, Clementi
Subjects: Male, Mesothelioma, Lung Neoplasms, Pleural Neoplasms, Mesothelioma, Malignant, Palliative Care, Humans, Female, Middle Aged, Survival Analysis, Retrospective Studies
Abstract: To investigate the relative importance of isolated thoracic perfusion (ITP) in the multidisciplinary palliative treatment of progressive malignant pleural mesothelioma (MPM) patients.Fifty-two MPM patients with progressive disease after systemic chemotherapy with cisplatin and pemetrexed were submitted to 112 ITP using mitomycin C (25 mg/m2) and cisplatin (70 mg/m2) between 2000 and 2017. Isolation of the chest was achieved by insertion of stop-flow balloon catheters via femoral or iliac access. Primary endpoints were adverse events, tumor response rate, progression-free survival (PFS) and overall survival (OS) from initial ITP.Median interval-time from MPM diagnosis was 9 months. There were no perfusion-related postoperative deaths. The main procedure-related complication was persistent leakage of lymphatic fluid from the incision in less than 10% of ITP. No severe perfusion-related toxicity was reported, with grade 3 haematological toxicity and platinum-induced neurotoxicity in less than 8% of the patients. Following initial ITP, overall tumor response rate was 25%, median PFS was 7 months (IQR 5-10.5), and median OS was 16 months (IQR 12.5-21). After the last ITP, 14 patients received further therapies, including targeted therapy with cetuximab or bevacizumab. Non-epithelioid histology, stage III, and ECOG performance status 3 pre-ITP were prognostic factors with a significant influence on OS. Median OS, calculated from the diagnosis of MPM, was 26.5 months (IQR 22.5-28).ITP is safe, tolerable, and useful but its inclusion in the multidisciplinary palliative treatment of progressive MPM patients should be investigated in a larger multicentre controlled study.
Published: 2019

46. Hypoxic pelvic perfusion with cisplatin and mitomycin C in multidisciplinary palliative treatment of patients with unresectable recurrent rectal cancer: a retrospective study

Author: Marcello Deraco, Paola Palumbo, Gemma Bruera, Francesco Masedu, Caterina Fiorentini, Shigeki Kusamura, Giammaria Fiorentini, Stefano Guadagni, Donatella Sarti, Sabine Gailhofer, Marco Clementi, and Enrico Ricevuto
Subjects: Male, medicine.medical_specialty, Mitomycin, medicine.medical_treatment, Cetuximab, Antineoplastic Agents, Rectal neoplasms, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, medicine, Humans, Local neoplasms recurrence, Epidermal growth factor receptor, Survival rate, Aged, Retrospective Studies, Patient Care Team, Cisplatin, biology, business.industry, Palliative Care, Mitomycin C, Retrospective cohort study, Middle Aged, Oxygen, Perfusion, Radiation therapy, Chemotherapy, Cancer, Regional Perfusion, 030220 oncology & carcinogenesis, biology.protein, Female, 030211 gastroenterology & hepatology, Surgery, Neoplasm Recurrence, Local, business, medicine.drug
Abstract: BACKGROUND Patients with unresectable recurrent rectal cancer that progresses after systemic chemotherapy and radiotherapy may be candidates for palliation with hypoxic pelvic perfusion (HPP). The aim of this observational retrospective study was to evaluate if a multimodality treatment including HPP and targeted-therapy may be useful to prolong clinical responses and survival of these patients. METHODS Thirty-seven patients with unresectable recurrent rectal cancer in progression after standard treatments underwent repeated HPP with mitomycin C (25 mg/m2) and cisplatin (70 mg/m2). Twenty patients, exhibiting epidermal growth factor receptor (EGFR) overexpression, also received cetuximab targeted-therapy, following the ultimate HPP treatment. RESULTS Following initial HPP treatment, median progression-free survival was 7 months (range: 5-19 months), median time-to-death or termination of follow-up was 13 months (range: 9-18 months), one-year survival-rate was 59.45%, two-year survival rate was 10.81%, and three-year survival rate was 2.7%. Survival was significantly influenced by cetuximab targeted-therapy post-HPP and the presence of additional metastatic sites (P
Published: 2019
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47. Modulated Electrohyperthermia in Integrative Cancer Treatment for Relapsed Malignant Glioblastoma and Astrocytoma: Retrospective Multicenter Controlled Study

Author: Virginia Casadei, Carlo Milandri, Donatella Sarti, P. Dentico, Stefano Guadagni, Caterina Fiorentini, Giammaria Fiorentini, Andrea Mambrini, and Gianmaria Mattioli
Subjects: Adult, Male, Oncology, medicine.medical_specialty, medicine.medical_treatment, Astrocytoma, Tumor response, lcsh:RC254-282, survival, 03 medical and health sciences, 0302 clinical medicine, Glioma, Internal medicine, Temozolomide, medicine, Humans, relapsed malignant glioma, Antineoplastic Agents, Alkylating, Aged, Retrospective Studies, Aged, 80 and over, tumor response, modulated electrohyperthermia, Brain Neoplasms, urogenital system, business.industry, Hyperthermia, Induced, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, Combined Modality Therapy, Heat therapy, nervous system diseases, 030205 complementary & alternative medicine, Cancer treatment, Survival Rate, Complementary and alternative medicine, 030220 oncology & carcinogenesis, Female, Neoplasm Recurrence, Local, Glioblastoma, business, Research Article
Abstract: Background: There are interesting studies on glioma therapy with modulated electrohyperthermia (mEHT), which combines heat therapy with an electric field. Clinical researchers not only found the mEHT method feasible for palliation but also reported evidence of therapeutic response. Purpose: To study the efficacy and safety of mEHT for the treatment of relapsed malignant glioma and astrocytoma versus best supportive care (BSC). Methods: We collected data retrospectively on 149 patients affected by malignant glioma and astrocytoma. Inclusion criteria were informed consent signed; >18 years old; histological diagnosis of malignant glioma or astrocytoma; relapsed after surgery, adjuvant temozolomide-based chemotherapy, and radiotherapy; and indication for treatment with mEHT in palliative setting. mEHT was performed with capacitive coupling technique keeping the skin surface at 26°C and the tumor temperature at 40°C to 42.5°C for > 90% of treatment duration (20-60 minutes). The applied power was 40 to 150 W using a step-up heating protocol. Results from patients treated with mEHT were compared with those treated with BSC. Results: A total of 149 consecutive patients were enrolled in the study, 111 (74%) had glioblastoma multiforme (GBM), and 38 (26%) had astrocytoma (AST). mEHT was performed for 28 (25%) of GBM and 24 (63%) of AST patients. Tumor response at the 3-month follow-up was observed in 29% and 48% of GBM and AST patients after mEHT, and in 4% and 10% of GBM and AST patients after BSC, respectively. The survival rate at first and second year in the mEHT group was 77.3% and 40.9% for AST, and 61% and 29% for GBM, respectively. The 5-year overall survival of AST was 83% after mEHT versus 25% after BSC and 3.5% after mEHT versus 1.2% after BSC for GBM. The median overall survival of mEHT was 14 months (range 2-108 months) for GBM and 16.5 months (range 3-156 months) for the AST group. We observed 4 long-term survivors in the AST and 2 in the GBM group. Two of the long survivors in AST and 1 in GBM group were treated by mEHT. Conclusions: mEHT in integrative therapy may have a promising role in the treatment and palliation of relapsed GBM and AST.
Published: 2019

48. A pilot study of alternative TrkAIII splicing in Merkel cell carcinoma: a potential oncogenic mechanism and novel therapeutic target

Author: Alessandro Chiominto, Andrew R. Mackay, Rita Maccarone, Lucia Cappabianca, Michela Sebastiano, Antonietta R. Farina, and Stefano Guadagni
Subjects: Adult, Male, Cancer Research, Therapeutic target, Cell, Merkel cell polyomavirus, Pilot Projects, Biology, lcsh:RC254-282, Merkel cell carcinoma, Oncogenic activation mechanism, medicine, Alternative TrkAIII splicing, Humans, Receptor, trkA, MCPyV large T-antigen, Receptor, Aged, Aged, 80 and over, Research, Middle Aged, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, biology.organism_classification, medicine.disease, Carcinoma, Merkel Cell, medicine.anatomical_structure, Oncology, Apoptosis, RNA splicing, Cancer research, Female, Merkel cell, Tyrosine kinase
Abstract: Background Merkel cell carcinomas (MCCs) are rare, aggressive, therapeutically-challenging skin tumours that are increasing in incidence and have poor survival rates. The majority are caused by genomic Merkel cell polyomavirus (MCPyV) integration and MCPyV T-antigen expression. Recently, a potential oncogenic role for the tropomyosin-related tyrosine kinase A receptor (TrkA) has been proposed in MCC. Alternative TrkAIII splicing is a TrkA oncogenic activation mechanism that can be promoted by SV40 large T-antigen, an analogue of MCPyV large T-antigen. In this pilot study, therefore, we have evaluated TrkAIII splicing as a novel potential oncogenic mechanism and therapeutic target in MCPyV positive MCC. Methods Formalin-fixed paraffin-embedded MCC tissues, consisting of 10 stage IV, 1 stage IIIB, 1 stage IIB, 4 stage IIA and 2 stage I tumours, from patients diagnosed and treated from September 2006 to March, 2019, at the University of L’Aquila, L’Aquila, Italy, were compared to 3 primary basal cell carcinomas (BCCs), 3 primary squamous cell carcinomas (SCCs) and 2 normal skin samples by RT-PCR for MCPyV large T-antigen, small T-antigen, VP-1 expression and alternative TrkAIII splicing and by indirect IF for evidence of intracellular TrkA isoform expression and activation. Results 9 of 10 Recurrent stage IV MCCs were from patients (P.1–3) treated with surgery plus loco-regional Melphalan chemotherapy and remaining MMCs, including 1 stage IV tumour, were from patients treated with surgery alone (P. 4–11). All MCPyV positive MCCs exhibiting MCPyV large T-antigen expression (17 of 18MCCs, 90%) exhibited alternative TrkAIII mRNA splicing (100%), which was exclusive in a significant number and predominant (> 50%) in all stage IV MCCs and the majority of stage 1-III MCCs. MCCs with higher TrkAIII to 18S rRNA expression ratios also exhibited strong or intermediate immunoreactivity to anti-TrkA antibodies, consistent with cytoplasmic TrkAIII expression and activation. In contrast, the MCPyV negative MCC, BCCs, SCCs and normal skin tissues all exhibited exclusive fully-spliced TrkA mRNA expression, associated with variable immunoreactivity for non-phosphorylated but not phosphorylated TrkA. Conclusions MCPyV positive MCCs but not MCPyV negative MCC, BCCs and SCCs exhibit predominant alternative TrkAIII splicing, with evidence of intracellular TrkAIII activation. This establishes a new potential MCC subset, unveils a novel potential MCPyV oncogenic mechanism and identifies TrkAIII as a novel potential therapeutic target in MCPyV positive MCC.
Published: 2019

49. Isolated thoracic perfusion in lung metastases from breast cancer: a retrospective observational study

Author: Enrico Ricevuto, Francesco Masedu, Marcello Deraco, Giammaria Fiorentini, Odisseas Zoras, Stefano Guadagni, Marco Clementi, and Karl R. Aigner
Subjects: Adult, Male, Oncology, medicine.medical_specialty, Lung Neoplasms, Mitomycin, Breast Neoplasms, Triple-negative status, Breast Neoplasms, Male, Isolated thoracic perfusion, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Breast cancer, hemic and lymphatic diseases, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, Humans, Medicine, Retrospective Studies, Lung, business.industry, Palliative Care, Retrospective cohort study, medicine.disease, Metastatic breast cancer, Surgery, Treatment Outcome, medicine.anatomical_structure, Tolerability, Chemotherapy, Cancer, Regional Perfusion, 030220 oncology & carcinogenesis, Concomitant, Cohort, Female, 030211 gastroenterology & hepatology, Cisplatin, business, Lung metastases, Perfusion
Abstract: The median overall survival of metastatic breast cancer (MBC) patients is still approximately 2 years. This is even lower in triple-negative breast cancer (TNBC) patients with concomitant lung metastases. These patients are often not suitable for surgery and not responsive to systemic chemotherapy. Isolated thoracic perfusion (ITP) followed by chemofiltration has been used for palliation in selected specialised centres. A retrospective observational study evaluating 162 MBC patients who underwent 407 ITP procedures was performed. The primary objective was the evaluation of the feasibility, safety, tolerability and efficacy of ITP in the complete cohort of 162 patients with LM from breast cancer. The secondary objective of the study was the evaluation of responses and median survivals in 43 TNBC patients with LM. In the 162 patients, ITP appeared safe and well tolerated with MST from LM diagnosis to death or last contact of 19.5 months. In the subgroup of patients treated with systemic chemotherapy followed by ITP at progression, the MST from LM diagnosis to death or last contact was 29 months. In the subgroup of TNBC patients treated with systemic chemotherapy followed by ITP at progression, the MST from LM diagnosis to death or last contact was 19 months (ITP overall response rate was 65.52%). ITP followed by chemofiltration could be adopted in the sequential palliation treatments of BC patients with LM in progression after systemic chemotherapy, especially with TNBC. The present data allow interesting considerations about tolerability and responses, but do not allow robust conclusions about survival.
Published: 2019

50. Palliation with a multimodality treatment including hypoxic pelvic perfusion for unresectable recurrent rectal cancer: outcomes based on a retrospective study

Author: Francesco Masedu, Marco Clementi, Caterina Fiorentini, Stefano Guadagni, Maria Bencivenga, and Shigeki Kusamura
Subjects: Male, medicine.medical_treatment, Cetuximab, Gastroenterology, 0302 clinical medicine, Antineoplastic Agents, Immunological, Antibiotics, Mitomycin C, Epidermal growth factor receptor, Recurrent Rectal Cancer, Cancer, Antibiotics, Antineoplastic, biology, Palliative Care, Middle Aged, Antineoplastic, Combined Modality Therapy, Survival Rate, Immunological, Local, 030220 oncology & carcinogenesis, Cohort, Disease Progression, 030211 gastroenterology & hepatology, Unresectable recurrent rectal cancer, Female, medicine.drug, medicine.medical_specialty, Mitomycin, Antineoplastic Agents, Pelvic Pain, Pelvis, 03 medical and health sciences, Hypoxic pelvic perfusion, Aged, Humans, Neoplasm Recurrence, Local, Rectal Neoplasms, Retrospective Studies, Chemotherapy, Cancer, Regional Perfusion, Internal medicine, medicine, Chemotherapy, business.industry, Regional Perfusion, Retrospective cohort study, Surgery, Radiation therapy, Neoplasm Recurrence, Cancer cell, biology.protein, business
Abstract: Patients with unresectable recurrent rectal cancer that progresses after systemic chemotherapy and radiotherapy are candidates for palliation with hypoxic pelvic perfusion (HPP). The aim of this observational retrospective study was to evaluate if a multimodality treatment including HPP and targeted-therapy may be useful to prolong clinical responses and survival of these patients. From a cohort of 77 patients with unresectable recurrent rectal cancer in progression after standard treatments and submitted to HPP, 21 patients underwent repeat HPP using mitomycin C (MMC) at the dose of 25 mg/m2. After the last HPP, 7 patients received a targeted-therapy with cetuximab according to overexpression of epidermal growth factor receptor in recurrence cancer cells. The median overall survival of these 21 patients from the diagnosis of unresectable recurrent rectal cancer was 23 months (iqr 18–24). After the first HPP, the median survival of the 21 patients until death or end of follow-up was 10 months (iqr 9–13). The 1-year and 2-year survival rates were 71.4%, and 4.8%, respectively. From the first HPP, age > 60 years, a recurrence shrinkage of at least 30% (partial response), and the addition of a post-HPP targeted-therapy with cetuximab significantly affected survival (P
Published: 2018

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