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Giorgia Marisi,1 Emanuela Scarpi,2 Alessandro Passardi,3 Oriana Nanni,2 Flavia Pagan,2 Martina Valgiusti,3 Andrea Casadei Gardini,3 Luca Maria Neri,4 Giovanni Luca Frassineti,3 Dino Amadori,3 Paola Ulivi1 1Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy; 2Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy; 3Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy; 4Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara 44100, Italy Purpose: Bevacizumab (B) plus chemotherapy (CT) is a common choice for first-line treatment of metastatic colorectal cancer. Molecular predictors of B efficacy have still not been identified. We analyzed the role of 22 angiogenesis-associated proteins in patient outcome.Patients and methods: Serum samples collected at baseline and at the first clinical evaluation were available for 58 patients enrolled in the randomized multicenter ITACa trial and who received CT+ B. Serum protein levels were determined using multiplex ELISA.Results: Patients with baseline ≥145 pg/mL IL-8 showed shorter median progression-free survival and overall survival (OS) than those with lower levels (6.5 vs 6. 12.6 months; HR 7.39, P

Andrea Casadei Gardini,1,* Emanuela Scarpi,2,* Elena Orlandi,3 Davide Tassinari,4 Silvana Leo,5 Ilaria Bernardini,6 Fabio Gelsomino,7 Stefano Tamberi,8 Silvia Ruscelli,1 Roberto Vespignani,9 Sonia Ronconi,10 Giovanni Luca Frassineti,1 Dino Amadori,1 Alessandro Passardi1 1Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy; 2Unit of Biostatistics and Clinical Trials, IRST IRCCS, Meldola, Italy; 3Medical Oncology Department, Piacenza Hospital, Piacenza, Italy; 4Department of Oncology, City Hospital, Rimini, Italy; 5Medical Oncology Unit, Vito Fazzi Hospital, Lecce, Italy; 6Medical Oncology Unit, Ramazzini Hospital, Carpi, Italy; 7Department of Oncology and Hematology, Division of Oncology, University Hospital Modena, Italy; 8Oncolgy Unit, Degli Infermi Hospital, Faenza, Italy; 9IT Service, IRST IRCCS, Meldola, Italy; 10Hematology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy *These authors contributed equally to this work Background: The aim of this study was to investigate the role of pre-treatment aspartate aminotransferase-lynphocyte ratio (ALRI) as a predictor of prognosis and treatment efficacy in patients with metastatic colorectal cancer (mCRC) enrolled in the prospective multicenter randomized ITACa (Italian Trial in Advanced Colorectal Cancer) trial to receive first-line chemotherapy (CT) + bevacizumab (B) or CT alone. Patients and methods: Patients randomly received CT+B or CT alone as first-line therapy. CT consisted of either FOLFOX4 or FOLFIRI at the clinician’s discretion. Results: Out of the 284 patients enrolled, increased ALRI levels were associated with shorter PFS and OS (p

Federica Recine, Alberto Bongiovanni, Nada Riva, Valentina Fausti, Alessandro De Vita, Laura Mercatali, Chiara Liverani, Giacomo Miserocchi, Dino Amadori, Toni Ibrahim Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy Abstract: Soft tissue sarcomas (STS) represent a variety of tumors of mesenchymal origin, accounting for about 1% of all adult cancers. This group of tumors comprises over 60 different histotypes with different biology showing different sensitivity to therapeutic agents. For decades, the standard first-line systemic treatment of metastatic STS has comprised anthracycline based-chemotherapy. Second-line therapy options include agents such as ifosfamide, gemcitabine, and pazopanib, but the optimal sequential therapy for the management of metastatic disease has yet to be defined. Trabectedin is one of the new molecules approved for patients in progression after first-line chemotherapy with anthracyclines or for those unfit for these agents. The compound is characterized by multiple potential mechanisms of action combining cytotoxic, targeted, and immunological effects. This article takes an in-depth look at the role of trabectedin in the management of metastatic STS, including L-sarcoma and non-L-sarcoma. Keywords: soft tissue sarcoma, histotypes, chemotherapy, L-sarcomas, non-L-sarcomas

Alessandro De Vita,1 Laura Mercatali,1 Federica Recine,1 Federica Pieri,2 Nada Riva,1 Alberto Bongiovanni,1 Chiara Liverani,1 Chiara Spadazzi,1 Giacomo Miserocchi,1 Dino Amadori,1 Toni Ibrahim1 1Osteoncology and Rare Tumors Center, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, FC, 2Pathology Unit, Morgagni-Pierantoni Hospital, Forlì, Italy Abstract: Sarcomas are a heterogeneous group of mesenchymal tumors arising from soft tissue or bone, with an uncertain etiology and difficult classification. Soft tissue sarcomas (STSs) account for around 1% of all adult cancers. Till date, more than 50 histologic subtypes have been identified. Adipocyte sarcoma or liposarcoma (LPS) is one of the most common STS subtypes, accounting for 15% of all sarcomas, with an incidence of 24% of all extremity STSs and 45% of all retroperitoneal STSs. The new World Health Organization classification system has divided LPS into four different subgroups: atypical lipomatous tumor/well-differentiated LPS, dedifferentiated LPS, myxoid LPS, and pleomorphic LPS. These lesions can develop at any location and exhibit different aggressive potentials reflecting their morphologic diversity and clinical behavior. Patients affected by LPS should be managed in specialized multidisciplinary cancer centers. Whereas surgical resection is the mainstay of treatment for localized disease, the benefits of adjuvant and neoadjuvant chemotherapy are still unclear. Systemic treatment, particularly chemotherapy, is still limited in metastatic disease. Despite the efforts toward a better understanding of the biology of LPS, the outcome of advanced and metastatic patients remains poor. The advent of targeted therapies may lead to an improvement of treatment options and clinical outcomes. A larger patient enrollment into translational and clinical studies will help increase the knowledge of the biological behavior of LPSs, test new drugs, and introduce new methodological studies, that is, on treatment response. Keywords: liposarcomas, adipocytic sarcomas, classification, management

Alberto Bongiovanni,1 Nada Riva,1 Marianna Ricci,1 Chiara Liverani,1 Federico La Manna,1 Alessandro De Vita,1 Flavia Foca,2 Laura Mercatali,1 Stefano Severi,3 Dino Amadori,4 Toni Ibrahim1 1Osteoncology and Rare Tumors Center, 2Unit of Biostatistics and Clinical Trials, 3Nuclear Medicine Unit, 4Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, FC, Italy Background and aim: To investigate the efficacy of platinum-based chemotherapy in patients with metastatic gastroenteropancreatic neuroendocrine carcinoma (mGEP-NEC) and define predictive and prognostic factors. Methods: Twenty mGEP-NEC patients were treated with cisplatin or carboplatin/etoposide between April 2010 and October 2014. Both large-cell and small-cell histologies were included. Cisplatin 25 mg/m2 was administered on days 1–3 followed by etoposide 100 mg/m2 on days 1–3 every 21 days. Carboplatin 300 mg/m2 was administered on day 1 followed by etoposide 100 mg/m2 on days 1–3. Results: Of the 19 evaluable patients, 13 obtained a partial response, four showed stable disease, and two progressed. Median overall survival (mOS) was 13.5 months and median progression-free survival (mPFS) was 10.9 months. Gallium-68 positron emission tomography/computerizsed tomography-positive patients had a higher, albeit not significantly, OS than those with negative results (75% vs 34.3% at 18 months; P=0.06). mPFS was 19.3 and 6.3 months (P55%, respectively. mOS was 8.1 months in the latter group but was not reached in the Ki67 ≤55% group (P-value =0.039). Patients with a lower body mass index (BMI) had a better prognosis in terms of both OS and PFS. Patients with BMI ≥25 had a mOS of 11.7 months (P=0.0293) and a mPFS of 6.2 months (P=0.0057). Conclusion: Platinum-based chemotherapy showed good efficacy in mGEP-NEC patients. Those with Ki67 ≤55%, positive Gallium-68 positron emission tomography/computerized tomography and BMI

Alberto Bongiovanni,1 Nada Riva,1 Sebastiano Calpona,1 Marianna Ricci,1 Erica Gunelli,1 Chiara Liverani,1 Federico La Manna,1 Alessandro De Vita,1 Manuela Monti,1 Stefano Severi,2 Federica Pieri,3 Elena Amadori,1 Riccardo Galassi,1 Davide Cavaliere,4 Alberto Zaccaroni,5 Andreas Tartaglia,6 Veronica Lunedei,7 Andrea Gardini,8 Laura Mercatali,1 Dino Amadori,1 Toni Ibrahim11Osteoncology and Rare Tumors Center, 2Nuclear Medicine Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, 3Pathology Unit, 4Unit of Oncological Surgery and Advanced Therapies, 5Endocrine Surgery Unit, 6Endocrinology Unit, 7Gastroenterology and Digestive Endoscopy Unit, 8Department of General Surgery, Morgagni-Pierantoni Hospital, Forlì, ItalyBackground: We present a retrospective analysis of metronomic capecitabine in metastatic gastroenteropancreatic neuroendrocrine tumors (GEP-NETs). A review of the literature is also presented.Methods: From January 2007 to December 2013, ten patients with metastatic GEP-NETs (four pancreatic and six ileal) who progressed after treatment with somatostatin analogs and other cytotoxic agents received oral capecitabine 1,500 mg/day continuously. The median patient age was 68 (range 29–82) years. The median treatment duration was 8 months.Results: Five (50%) patients achieved a partial radiographic response, four (40%) showed stable disease, and one (10%) progressed. Median overall survival was 56 months. Three of the four pancreatic patients achieved a partial radiographic response that lasted for a median of 15.5 months; overall survival and progression-free survival in this subgroup was 58 and 6 months, respectively.Conclusion: Data in the literature show that capecitabine has only occasionally been used as a single agent, with increased toxicity. Only one study using single-agent capecitabine reported a progression-free survival of 9.9 months and overall survival of 36.5 months, without an objective response or major toxicity. In our experience, metronomic capecitabine was well tolerated, although minor side effects may have been underestimated due to the retrospective nature of our study. This regimen also seems to be feasible in elderly people. Although high response rates and prolonged response duration indicate the potential efficacy of this treatment, our results should be interpreted cautiously because of the small number of patients involved. Capecitabine was most effective in the pancreatic subgroup, which would seem to be more sensitive to chemotherapy.Keywords: capecitabine, gastroenteropancreatic neuroendocrine tumors, metronomic chemotherapy