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De Cesare M.,Molecular Pharmacology Unit | Sfondrini L.,University of Milan | Pennati M.,Molecular Pharmacology Unit | De Marco C.,Biomarker Unit | And 5 more authors.
Journal of Translational Medicine | Year: 2016

Background: Diffuse malignant peritoneal mesothelioma (DMPM) is a rare and locally aggressive disease. DMPM prognosis is dismal, mainly due to the lack of effective treatment options and the development of new therapeutic strategies is urgently needed. In this context, novel immunotherapy approaches can be explored in an attempt to improve DMPM patients' survival. Methods: We tested the efficacy of CpG-oligodeoxynucleotides (CpG-ODN), synthetic DNA sequences recognized by Toll-like receptor 9 and able to induce innate/adaptive immune response, in two DMPM orthotopic xenografts (MesoII and STO), which properly recapitulate the dissemination pattern of the disease in the peritoneal cavity. Severe combined immunodeficiency mice carrying DMPM xenografts were treated at different stages of tumor development with i.p. delivered CpG-ODN1826 for 4 weeks. CpG-ODN1826-induced modulation in the composition of peritoneal immune infiltrate was assessed by flow cytometry. Results: When administered to early-stage tumors (i.e., 4 days after i.p. DMPM cell injection in mice), the agent exhibited impressive efficacy against MesoII by completely inhibiting tumor take and ascites development (no evidence of tumor masses and ascites in 6/6 mice at necropsy), and also impaired STO tumor take and growth (4/6 tumor-free mice; i.p. tumor masses reduced by 94 % in the 2 remaining mice, P = 0.00005). Interestingly, when tested against late-stage STO tumors (i.e., 11 days after i.p. DMPM cell injection in mice), CpG-ODN1826 was still able to reduce the growth of i.p. tumor masses by 66 % (P = 0.0009). Peritoneal washings of tumor-bearing mice revealed a strong increase of macrophage infiltration together with a decrease in the presence of B-1 cells and a reduced IgM concentration after CpG-ODN1826 treatment. Conclusions: Our results indicate that locally administered CpG-ODN1826 is able to markedly affect the growth of both early- and late-stage DMPM orthotopic xenografts in the absence of severe side effects, and suggest a possible clinical role for the agent in the therapy of DMPM. © 2016 De Cesare et al. Source


The aim of this study was to evaluate the effects of perioperative systemic chemotherapy (CT) on short-term surgical and long-term oncologic results in diffuse malignant peritoneal mesothelioma (DMPM) patients treated with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). We retrospectively analyzed data obtained from an institutional prospective database at NCI of Milan. The study group comprised 116 DMPM patients treated with CRS + HIPEC from August 1995 to October 2011. A total of 60 cases underwent preoperative CT (PRECT), 30 underwent postoperative CT (POSTCT), and 26 did not undergo any CT (NOCT). Also, 55 cases used the perioperative combination of platinum and pemetrexed. We tested whether covariates related to clinical, histologic, PRECT, and surgical treatment were correlated with completeness of cytoreduction (CC), postoperative G3-5 morbidity, and progression-free survival and overall survival (OS). Univariate and multivariate analyses were performed. Factors independently associated with CC were ECOG performance status (PF) of 0, and PCI <20. Factors independently associated with postoperative G3-5 morbidity were ECOG >1, bowel anastomosis, and number of peritonectomy procedures. Preoperative platelet count >400 × 103/mm(3), histological subtype (biphasic and sarcomatoid vs epithelial), CC, and G3-5 morbidity were independent prognostic factors. PRECT was not associated with CC or G3-5 morbidity. There was no significant difference in terms of survival between the PRECT, POSTCT, and NOCT groups. The CC, G3-5, and OS were not influenced by aspects related to perioperative CT. The present data warrants confirmation reconducting the comparative analysis in a larger multi-institutional series preferably using matching control techniques. Source


Kusamura S.,Peritoneal Surface Malignancy Program | Torres Mesa P.A.,Peritoneal Surface Malignancy Program | Torres Mesa P.A.,Surface Oncology | Cabras A.,Fondazione Istituto Nazionale Dei Tumori di Milan | And 2 more authors.
Annals of Surgical Oncology | Year: 2016

Background: We conducted a prognostic analysis of preoperative parameters and Ki-67 determination to develop selection criteria for cytoreductive surgery (CRS) and HIPEC in patients with diffuse malignant peritoneal mesothelioma (DMPM). Methods: DMPM patients treated with CRS and HIPEC at NCI of Milan participated in this study. Multivariate analysis was conducted using Cox proportional hazard model and conditional inference tree method to select independent predictors of overall survival (OS) from the followings pre-cytoreduction parameters: age, sex, ECOG performance status, Charlson comorbidity index, previous systemic chemotherapy, CA-125, histological subtype (epithelioid vs. biphasic/sarcomatoid), Ki-67 (determined with immunohistochemistry), and peritoneal cancer index (PCI). Results: A total of 117 patients (male/female: 67/50) with median age of 60.5 (range 22–75) years were included. Eighty-three patients had ECOG performance status = 0, median Charlson comorbidity index was 4 (range 2–9), and 102 cases had epithelioid subtype. Median Ki-67 was 5 % (range 1–60). Ninety-four (80.3 %) cases were optimally cytoreduced. The Cox analysis identified Ki-67, PCI, and histological subtype as independent prognosticators of OS. Conditional inference tree method identified three prognostic subsets: (I) Ki-67 ≤ 9 %; (II) Ki-67 > 9 % and PCI ≤ 17; and (III) Ki-67 > 9 % and PCI > 17. The median OS for subsets I, II, and III were, 86.6, 63.2, and 10.3 months, respectively. Conclusions: Ki-67 is a powerful prognosticator that allows, along with PCI, and histological subtype, a good prediction of OS in patients with DMPM. Patients with Ki-67 > 9 % and PCI > 17 are unlikely to benefit from the procedure and should be considered for other treatment protocols. © 2015, Society of Surgical Oncology. Source


Melero J.T.,Peritoneal Surface Malignancy Program | Ortega F.G.,University of Granada | Gonzalez A.M.,Peritoneal Surface Malignancy Program | Carmona-Saez P.,University of Granada | And 5 more authors.
Surgery (United States) | Year: 2016

Purpose Complete cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has changed the therapeutic landscape, improving overall survival in patients with peritoneal carcinomatosis with a colonic origin. The main limitation of this aggressive locoregional procedure, however, is extra-abdominal or distant spread. The objective of this study was to identify the prognostic value of circulating tumor cells (CTCs) in patients with peritoneal carcinomatosis of colonic origin undergoing CRS + HIPEC. Patients and methods Fourteen patients diagnosed with peritoneal carcinomatosis from colon cancer and suitable for potentially curative treatment with CRS + HIPEC were included in this study. CTCs were isolated from the peripheral blood by immunomagnetic techniques by the use of a multi-cytokeratin-specific antibody and detected via immunocytochemical methods. The phenotypic characterization of EGFR on CTCs was analyzed by immunofluorescence. Results At baseline, 50% of the patients were positive for CTCs, with a mean value of 5.5 CTCs per 10 mL of peripheral blood. After surgery, 28.57% of the patients presented CTCs, with a mean value of 6.75 CTCs per 10 mL. A positive correlation was found between the presence of CTC-negative, epidermal growth factor receptor-positive at baseline and the patients who had symptoms of intestinal obstruction (21.4%). In addition, the presence of CTCs identified patients with distant dissemination and was also significantly correlated with progression-free survival (P =.0024). Conclusion The detection and characterization of CTCs are good prognostic and predictive markers in patients with peritoneal carcinomatosis resulting from colon cancer. These analyses could be used as a new tool to identify subpopulations of patients who could benefit from CRS + HIPEC treatment. © 2016 Elsevier Inc. Source


Kusamura S.,Peritoneal Surface Malignancy Program | Hutanu I.,Grigore T. Popa University of Medicine and Pharmacy | Baratti D.,Peritoneal Surface Malignancy Program | Deraco M.,Peritoneal Surface Malignancy Program
Journal of Surgical Oncology | Year: 2013

Background Incomplete cytoreduction (IC) is one of the main prognostic factor in pseudomyxoma peritonei (PMP). We evaluated the ability of preoperative Ca125, CEA, and Ca19-9 to predict IC and prognosis in PMP. Methods One hundred fifty-six cases elected candidate to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy from 1996 to 2011 were included in the study. We assessed the: (1) optimal cut-off values for circulating Tumor markers (CTM) in predicting IC (residual disease >2.5 mm) using receiver-operating characteristics (ROC); (2) discriminant power of CTM and risk prediction models for IC by calculating the area under ROC curve (AUC-ROC); (3) prognostic factors using Cox proportional-hazard model. Results Optimal cut-offs were 125 U/ml for Ca125, 18 ng/ml for CEA, and 89 U/ml for Ca19-9. The AUCs-ROC were 0.76, 0.68, and 0.69 for Ca125, CEA, and Ca19-9, respectively. The addition of CTM to risk prediction model that considered preoperative clinicopathological factors increased marginally the AUC-ROC (0.80-0.84). Ca125 > 125 U/ml, Ca19-9 > 89 U/ml independently affected overall survival. Conclusions Preoperative CTMs were reasonable but not perfect discriminators of IC. Moreover, Ca125 and Ca19-9, using new cut-off values, were proven to be new strong prognostic factors that overcome the value of disease extension and histological subtype. Copyright © 2013 Wiley Periodicals, Inc. Source

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